AU766538B2 - Cell adhesion inhibitors - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT a. a Name of Applicant: Address for Service: Invention Title: Biogen Inc.

CULLEN CO., Patent Trade Mark Attorneys, 239 George Street, Brisbane, Qld. 4000, Australia.

CELL ADHESION INHIBITORS The following statement is a full description of this invention, including the best method of performing it known to us: la CELL ADHESION INHIBITORS TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds that are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. This invention also relates to pharmaceutical formulations comprising these compounds and methods of using them for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. The compounds and pharmaceutical compositions of this invention can be used as therapeutic or prophylactic agents. They are particularly well-suited for treatment of many inflammatory and autoimmune diseases.

BACKGROUND OF THE INVENTION Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localize within the extra-cellular matrix.

As such, cell adhesion constitutes one of the fundamental mechanisms underlying numerous biological phenomena. For example, cell adhesion is responsible 2 for the adhesion of hemoatopoietic cells to endothelial cells and the subsequent migration of those hemopoietic cells out of blood vessels and to the site of injury.

As such, cell adhesion plays a role in pathologies such as inflammation and immune reactions in mammals.

Investigations into the molecular basis for cell adhesion have revealed that various cell-surface macromolecules collectively known as cell adhesion molecules or receptors mediate cell-cell and cellmatrix interactions. For example, proteins of the superfamily called "integrins" are the key mediators in adhesive interactions between hematopoietic cells and Stheir microenvironment Hemler, "VLA Proteins in the Integrin Family: Structures, Functions, and Their 15 Role on Leukocytes.", Ann. Rev. Immunol., 8, p. 365 (1990)). Integrins are non-covalent heterodimeric complexes consisting of two subunits called a and i.

There are at least 12 different a subunits (al-a6, a-L, a-M, a-X, a-IIB, a-V and a-E) and at least 9 different S (1-89) subunits. Based on the type of its a and 9 subunit components, each integrin molecule is categorized into a subfamily.

a491 integrin, also known as very late antigen-4 CD49d/CD29, is a leukocyte cell surface receptor that participates in a wide variety of both cell-cell and cell-matrix adhesive interactions Hemler, Ann. Rev. Immunol., 8, p. 365 (1990)).

It serves as a receptor for the cytokine-inducible endothelial cell surface protein, vascular cell adhesion molecule-i as well as to the extracellular matrix protein fibronectin (Ruegg et al., J. Cell Biol., 177, p. 179 (1991); Wayner et al., J. Cell Biol., 105, p. 1873 (1987); Kramer et al., J. Biol. Chem., 264, p. 4684 (1989); Gehlsen et al. Science, 24, p. 1228 (1988)). Anti-VLA4 3 monoclonal antibodies ("mAb's"Y have been shown to inhibit VLA4-dependent adhesive interactions both in vitro and in vivo (Ferguson et al. Proc. Natl. Acad.

Sci., 88, p. 8072 (1991); Ferguson et al., J. Immunol., 150, p. 1172 (1993)). Results of in vivo experiments suggest that this inhibition of VLA-4-dependent cell adhesion may prevent or inhibit several inflammatory and autoimmune pathologies L. Lobb et al., "The Pathophysiologic Role of a-4 Integrins In Vivo", j.

Clin. Invest., 94, pp. 1722-28 (1994)).

In order to identify the minimum active amino acid sequence necessary to bind VLA-4, Komoriya et al.

S.:i ("The Minimal Essential Sequence for a Major Cell Type- Specific Adhesion Site (CS1) Within the Alternatively 15 Spliced Type III Connecting Segment Domain of Fibronectin Is Leucine-Aspartic Acid-Valine", j. Biol Chem., 266 pp. 15075-79 (1991)) synthesized a variety of overlapping peptides based on the amino acid -sequence of the CS-1 region (the VLA-4 binding domain) 20 of a particular species of fibronectin. They identified an 8-amino acid peptide, Glu-Ile-Leu-Asp- Val-Pro-Ser-Thr [SEQ ID NO: 11, as well as two smaller overlapping pentapeptides, Glu-Ile-Leu-Asp-Val [SEQ ID NO: 2] and Leu-Asp-Val-Pro-Ser [SEQ ID NO: that possessed inhibitory activity against FN-dependent cell adhesion. These results suggested the tripeptide Leu- Asp-Val as a minimum sequence for cell-adhesion activity. It was later shown that Leu-Asp-Val binds only to lymphocytes that express an actived form of VLA-4, thus bringing into question the utility of such a peptide in vivo Wayner et al., "Activation- Dependent Recognition by Hematopoietic Cells of the LDV Sequence in the V Region of Fibronectin", J. Cell.

Biol., 116(2), pp. 489-497 (1992)). However, certain larger peptides containing the LDV sequence were 4 subsequently shown to be active in Yviv A. Ferguson et al., "Two Integrin Binding Peptides Abrogate T-cell- Mediated Immune Responses In Vivo," Proc. Natl. Acad.

Sci. USA, 88, pp. 8072-76 (1991); and S.M. Wahl et al., "Synthetic Fibronectin Peptides Suppress Arthritis in Rats by Interrupting Leukocyte Adhesion and Recruitment," J. Clin. Invest., 94, pp. 655-62 (1994)].

A cyclic pentapeptide, Arg-Cs-Asp-TPro-Cs (wherein TPro denotes 4-thioproline), which can inhibit both VLA-4 and VLA-5 adhesion to FN has also been described M. Nowlin et al. "A Novel Cyclic Pentapeptide Inhibits a491 and a591 Integrin-mediated Cell Adhesion", J. Biol. Chem., 268(27), pp. 20352-59 15 (1993); and PCT publication PCT/US91/04862). This peptide was based on the tripeptide sequence Arg-Gly- Asp from FN which had been known as a common motif in ~the recognition site for several extracellular-matrix proteins.

Despite these advances, there remains a need for small, specific inhibitors of VLA-4-dependent cell adhesion. Ideally, such inhibitors would be semipeptidic or non-peptidic so that they may be orally administered. Such compounds would provide useful 25 agents for treatment, prevention or suppression of various pathologies mediated by cell adhesion and VLA-4 binding.

SUMMARY OF THE INVENTION The present invention solves this problem by providing novel non-peptidic compounds that specifically inhibit the binding of ligands to VLA-4.

These compounds are useful for inhibition, prevention and suppression of VLA-4-mediated cell adhesion and pathologies associated with that adhesion, such as inflammation and immune reactions. The compounds of 5 this invention may be used alone or in combination with other therapeutic or prophylactic agents to inhibit, prevent or suppress cell adhesion. This invention also provides pharmaceutical formulations containing these VLA-4-mediated cell adhesion inhibitors and methods of using the compounds and compositions of the invention for inhibition of cell adhesion.

According to one embodiment of this invention, these novel compounds, compositions and methods are advantageously used to treat inflammatory and immune diseases. The present invention also provides methods for preparing the compounds of this invention and intermediates useful in those methods.

DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the term "alkyl", alone or in combination, refers to a straight-chain or branchedchain alkyl radical containing from 1 to 10, preferably from 1 to 6 and more preferably from 1 to 4, carbon 20 atoms. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, decyl and the like.

The term "alkenyl", alone or in combination, refers to a straight-chain or branched-chain alkenyl radical containing from 2 to 10, preferably from 2 to 6 and more preferably from 2 to 4, carbon atoms.

Examples of such radicals include, but are not l mited to, ethenyl, E- and Z-propenyl, isopropenyl, E- And Zbutenyl, E- and Z-isobutenyl, E- and Z-pentenyl, decenyl and the like.

The term "alkynyl", alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing from 2 to 10, preferably from 2 to 6 6 and more preferably from 2 to 4, carbon atoms.

Examples of such radicals include, but are not limited to, ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

The term "cycloalkyl", alone or in combination, refers to a cyclic alkyl radical containing from 3 to 8, preferably from 3 to 6, carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "cycloal.cenyl", alone or in combination, refers to a cyclic carbocycle containing from 4 to 8, preferably 5 or 6, carbon atoms and one or more double bonds. Examples of such cycloalkenyl 15 radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl and the like.

The term "aryl" refers to a carbocyclic aromatic group selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,?23-oxadiazolyl, 1,2,3triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5trithianyl, indolizinyl, indolyl, isoindolyl, 3Hindolyl, indolinyl, benzo[b]furanyl, 2,3dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

-7- "Aryl" groups, 'as defined in this application may independently contain one to four substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy, Ar'substituted alkyl, Ar'-substituted alkenyl or alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted alkoxy, Ar'-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or a'kynylamino, Ar'-substituted alkylamino, Ar'substituted alkenylamino or alkynylamino, Ar'substituted carbonyloxy, alkylcarbonyloxy, aliphatic or aromatic acyl, Ar'-substituted acyl, Ar'-substituted 15 alkylcarbonyloxy, Ar'-substituted carbonylamino, Ar'substituted amino, Ar'-substituted oxy, Ar'-substituted carbonyl, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, alkoxy-carbonylamino, Ar'- -substituted alkoxycarbonyl-amino, Ar'-oxycarbonylamino, alkylsulfonylamino, mono- or bis-(Ar'-sulfonyl)amino, Ar'-substituted alkyl-sulfonylamino, morpholinocarbonylamino, thiomorpholinocarbonylamino, N-alkyl guanidino, N-Ar' guanidino, N-N-(Ar',alkyl) guanidino, N,N-(Ar',Ar')guanidino, N,N-dialkyl guanidino, N,N,N-trialkyl guanidino, N-alkyl urea, N,N-dialkyl urea, N-Ar' urea, N,N-(Ar',alkyl) urea and N,N-(Ar') 2 urea; acylcarbonylamino; Ar'-substituted aryl; aromatic acyl-substituted aromatic or aliphatic acyl; Ar'-substituted heterocyclyl; Ar'-substituted cycloalkyl or cycloalkenyl; heterocyclylalkoxy;

N,N-

hydroxyl)urea;Ar'-substituted cycloalkyl and cycloalkenyl; Ar'-substituted biaryl; Ar'-substituted aminocarbonylamino; Ar'-mercapto-substituted alkyl; Ar' -amino-substituted aryl; Ar'-oxysubstituted alkyl; Ar'-substituted aminocycloalkyl and cycloalkenyl; 8aralkylaminosulfonyl; aralkoxyalkyl; N-Ar' -Substituted thiourea; N-aralkoxyurea; N-hydroxylurea;

N-

alkenylurea; N,N- (alkyl, hydroxyl) urea; heterocyclyl; thioaryloxy-substituted aryl; N,N- (aryl,alkyl)hydrazino; Ar' -substituted sulfonylheterocyclyl; aralkyl-substituted heterocyclyl; cycloalkyl and cycloakenyl-substituted heterocyclyl; cycloalkyl-fused aryl; aryloxy-substjtuted alkyl; heterocyclylamino; Ar' -substituted arylaminosulfonyl; thicaryl-substituted thioxy; and Ar' -substituted a2.kenoyl; aliphatic or aromatic acylaminocarbonyl; aliphatic or aromatic acyl-substituted alkenyl; Ar'substituted aminocarbonyloxy; Ar' ,Ar' -disubstituted l aihai or aromatic acyl-substituted acyl; substituted alkylimino; Ar' -substituted heterocyclyl; Ar' ,Ar' -disubstituted acylamino; Ar' -substituted .0.0.cycloalkenonylamino; heterocyclylalkoxy; N, N- Ar', hydroxylurea; N, N'-Ar' ,hydroxylurea; heterocyclylcarbonylamino; Ar' -substituted aminocarbonylheterocyclyl; Ar' -substituted aminocarbonyl; Ar'-substituted carbonylamino; Ar'substituted aminosulfonylamino; Ar' -substituted mercaptoalkyl; Ar'-amino substituted biaryl; aralkylaminoalkoxy; alkyl- and aryloxy-substituted alkoxy; heterocyclylcarbonyl; Ar' -substituted sulfonylalkyl; Ar' -amino carbocyclyl; aralkylsulfonyl; aryl-substituted alkenyl; heterocyclylalkylamino; heterocyclylalkylaminocarbonyl; Ar' -substitutedsulfonylaminoalkyl; Ar' -substituted cycloalkyl; thioaryloxyalkyl; thioaryloxymercapto; cycloalkylcarbonylalkyl; cycloalkyl-substituted amino; Ar' -substituted arylamino; aryloxycarbonylalkyl; phosphorodiamidyl acid or ester; aryloxydimethylsiloxy; 9 1,3-indandionylcarbonylalkyl;-1,3-indandionylcarbonyl; oxamidyl; heterocyclylalkylidenyl; formamidinyl; benzalizinyl; benzalhydrazino; arylsulfonylurea; benzilylamino; 2-carboxyalkyl-1-(1,3-benzodioxol- 5-yl)-amino-N-leucinylalkylamidylarylurea); Ar'carbamoyloxy and alkyl- and aryloxy-substituted urea; wherein is a carbocyclic or heterocyclic aryl group as defined above having one to three substituents selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino or *fe alkynylamino, alkylcarbonyloxy, aliphatic or aromatic acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkyl urea.

The term "alkoxy", alone or in combination, 99*9 refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable 20 alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

O. The term "alkenoxy", alone or in combination, .refers to a radical of formula alkenyl-O-, wherein the term "alkenyl" is as defined above provided that the radical is not an enol ether. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy and the like.

The term "alkynyloxy", alone or in combination, refers to a radical of formula alkynyl-O-, wherein the term "alkynyl" is as defined above provided that the radical is not an ynol ether. Examples of suitable alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.

10 The term "thioalkoxyO refers to a thioether radical of formula alkyl-S-, wherein alkyl is as defined above.

The term "alkylamino", alone or in combination, refers to a mono- or di-alkyl-substituted amino radical a radical of formula alkyl-NH- or (alkyl) 2 wherein the term "alkyl" is as defined above. Examples of suitable alkylamino radicals include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, t-butylamino, N,N-diethylamino and the like.

S" The term "alkenylamino", alone or in combination, refers to a radical of formula alkenyl-NHor (alkenyl) 2 wherein the term "alkenyl" is as 15 defined above, provided that the radical is not an enamine. An example of such alkenylamino radicals is the allylamino radical.

s The term "alkynylamino", alone or in combination, refers to a radical of formula alkynyl-NHor (alkynyl) 2 wherein the term "alkynyl" is as defined above, provided that the radical is not an ynamine. An example of such alkynylamino radicals is the propargyl amino radical.

The term "aryloxy", alone or in combination, refers to a radical of formula aryl-O-, wherein aryl is as defined above. Examples of aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, pyridyloxy and the like.

The term "arylamino", alone or in combination, refers to a radical of formula aryl-NH-, wherein aryl is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino (anilido), naphthylamino, 3- and 4-pyridylamino and the like.

11 The term "biaryl", alone or in combination, refers to a radical of formula aryl-aryl-, wherein the term "aryl" is as defined above.

The term "thioaryl", alone or in combination, refers to a radical of formula aryl-S-, wherein the term "aryl" is as defined above. An example of a thioaryl radical is the thiophenyl radical.

The term "aryl-fused cycloalkyl", alone or in combination, refers to a cycloalkyl radical which shares two adjacent atoms with an aryl radical, wherein the terms "cycloalkyl" and "aryl" are as defined above.

An example of an aryl-fused cycloalkyl radical is the benzofused cyclobutyl radical.

The term "aliphatic acyl", alone or in 15 combination, refers to radicals of formula alkyl-CO-, alkenyl-CO- and alkynyl-CO- derived from an alkane-, alkene- or alkyncarboxylic acid, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as defined above.

Examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl, methylpropiolyl and the like.

The term "aromatic acyl", alone or in combination, refers to a radical of formula aryl-CO-, wherein the term "aryl" is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.

The terms "morpholinocarbonyl" and "thiomorpholinocarbonyl", alone or in combination with other terms, refer to an N-carbonylated morpholino and an N-carbonylated thiomorpholino radical, respectively.

The term "alkylcarbonylamino", alone or in combination, refers to a radical of formula alkyl-CONH, wherein the term "alkyl" is as defined above.

I

12 The term "alkoxycarbonylamino", alone or in combination, refers to a radical of formula alkyl-OCONH-, wherein the term "alkyl" is as defined above.

The term "alkylsulfonylamino", alone or in combination, refers to a radical of formula alkyl-SO 2

NH-

,wherein the term "alkyl" is as defined above.

The term "arylsulfonylamino", alone or in combination, refers to a radical of formula aryl-SO 2

NH-,

wherein the term "aryl" is as defined above.

The term "N-alkylurea", alone or in combination, refers to a radical of formula alkyl-NH-CO-NH-, wherein the term "alkyl" is as defined above.

15 The term "N-arylurea", alone or in combination, refers to a radical of formula aryl-NH-CO- NH-, wherein the term "aryl" is as defined above.

The term "halogen" means fluorine, chlorine, -bromine and iodine.

20 The term "heterocycle" (and corresponding "heterocyclyl" radical form) unless otherwise defined herein, refers to a stable 3-7 membered monocyclic heterocyclic ring or 8-11 membered bicyclic heterocyclic ring which is unsaturated, and which may be optionally benzofused. Each heterocycle consists of one or more carbon atoms and from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, the terms "nitrogen and sulfur heteroatoms" include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. In addition, any ring nitrogen may be optionally substituted with a substituent R 4 as defined herein for compounds of formula I. A heterocycle may be attached at any endocyclic carbon or heteroatom which results in the creation of a stable 13 structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. Heterocycles may be optionally oxosubstituted at 1-3 ring positions and may optionally be independently substituted with 1-4 substituents selected from the group of "aryl" substituents described above.

The term "leaving group" generally refers to groups readily displaceable by a nucleophile, such as an amine, and alcohol or a thiol nucleophile. Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N-hydroxybenzotriazole, halogen (halides), triflates, tosylates, mesylates, alkoxy, thioalkoxy and the like.

The terms "activated derivative of a suitably protected a-amino acid" and "activated substitutedphenylacetic acid derivative" refer to the corresponding acyl halides acid fluoride, acid -chloride and acid bromide), corresponding activated 20 esters nitrophenyl ester, the ester of 1hydroxybenzotriazole, HOBT, or the ester of hydroxysuccinimide, HOSu), and other conventional derivatives within the skill of the art.

In view of the above definitions, other chemical terms used throughout this application can be easily understood by those of skill in the art. Terms may be used alone or in any combination thereof. The preferred and more preferred chain lengths of the radicals apply to all such combinations.

This invention provides compounds which are capable of inhibiting VLA-4-mediated cell adhesion by inhibiting the binding of ligands to that receptor.

These compounds are represented by formula 14 72 (n H4 and pharmaceutically acceptable derivatives thereof; wherein: X is selected from the group consisting of -C0 2 11,- P0- 3 H, -S0 2

R

5

-SO

3 H, -0P0- 3 H, -C0 2

R

4 and wherein R5 is selected f rom the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, and aryl-substituted alkenyl or alkynyl; Y is selected from the group consisting of -Co-,

-SO

2 and -P0 2 R, is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl (iaralkylil), :15 aryl-substituted alkenyl or alkynyl, cycloalkylsubstituted alkyl, cycloalkenyl -substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl-substituted alkoxy ("aralkoxy"l), aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, N-alkylurea-substituted alkyl, N-arylurea-substituted alkyl, alkylcarbonylamino-substituted alkyl, aminocarbonyl-substituted alkyl, heterocyclyl, heterocyclyl -substituted alkyl, heterocyclylsubstituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl and heterocyclylalkyl; 15

R

2 is selected from the gloup consisting of hydrogen, aryl, alkyl, alkenyl or alkynyl, cycloalkyl, cycloalkenyl, aryl-substituted alkyl and wherein R 2 and

R

3 may be taken together with the atoms to which they are attached, to form a heterocycle;

R

3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxysubstituted alkyl, alkoxy-substituted alkyl, aralkoxysubstituted alkyl, amino-substituted alkyl, (arylsubstituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, acylamino- 15 substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulfonylamino-substituted alkyl, morpholinoalkyl, thiomorpholino-alkyl, morpholino carbonylsubstituted alkyl, thiomorpholinocarbonyl-substituted alkyl, [N-(alkyl, alkenyl or alkynyl)- or N,N-[dialkyl, 20 dialkenyl, dialkynyl or (alkyl,alkenyl)-amino]carbonylsubstituted alkyl, carboxyl-substituted alkyl, dialkylamino-substituted acylaminoalkyl and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, valine, threonine, serine, aspartic acid, beta-cyanoalanine, and allothreonine,wherein

R

2 and R 3 may be taken together with the atoms to which they are attached, to form a heterocycle;

R

4 is selected from the group consisting of aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, hydrogen, heterocyclyl, 16 heterocyclylcarbonyl, aminocarbonyl, amido, mono- or dialkylaminocarbonyl, mono- or diarylaminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or diacylaminocarbonyl, aromatic or aliphatic acyl, alkyl optionally substituted by substituents selected from the group consisting of amino, hydroxy, mercapto, monoor dialkylamino, mono- or diarylamino, alkylarylamino, diarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy and heterocyclyl; and n is 0, 1 or 2.

A "pharmaceutically acceptable derivative" denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention.

15 The invention also includes any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention a prodrug). The invention also .includes metabolites or residues of a compound of this 20 invention characterized by the ability to inhibit, prevent or suppress cell adhesion and cell adhesionmediated pathologies.

In another preferred embodiment of this invention, R, is selected from the group consisting of benzyloxy, cyanomethyl, cyclohexylmethyl, methyl, nhexyl, N-phenylamino, phenyl, phenylcarbonyl, phenylmethyl, t-butoxy, t-butylamino, 1-indanyl, l-naphthylmethyl, 1-phenylcyclopropyl, 2-(4-hydroxylphenyl)ethyl, 2-(benzyloxycarbonylamino)-phenylmethyl, 2-(bis(phenyl-sulfonyl)amino)-phenylmethyl, 2- phenylurea)phenyl-methyl, 2-aminophenylmethyl, 2benzamidophenylmethyl, 2-bromo-4-hydroxy-5methoxyphenylmethyl, 2-hydroxyphenyl-methyl, 2naphthylmethyl, 2-phenylethyl, 2-pyridylmethyl, 2quinolinyl., 2-[4-(N'-phenylurea)phenyl] -ethyl, 3- 17- (benzyloxycarbonylamino) -phenyimethyl, 3- phenylurea) -phenylmethyl, 3- -phenylurea) propyl, 3- (phenylsulfon-amido) -phenylmethyl, 3 -acetamidophenyl.methyl, 3 -amino-phenylmethyl, 3 -benzamidophenylmethyl, 3-hydroxy-4- -phenylurea) -phenylmethyl, 3hydroxyphenylmethyl, 3-indolyl, 3-methyoxy-4- phenylurea) -phenylmethyl, 3-methoxy-4- methyiphenyl) urea) -phenylmethyl, 3-methyl-4- phenylurea) -phenylmethyl, 3 -nitrophenylmethyl, 3phenyipropyl, 3 -pyridylmethyl, 4- (2 -aminobenzamido) phenylmethyl, 4- (benzamido) phenylmethyl, 4- (benzyloxycarbonylamino) -phenylmethyl, 4- (morpholinocarbonyl amino) -phenylmethyl, 4- -(2-chiorophenyl) urea) phenylmethyl, 4- -(2-chiorophenyl) urea) -3methoxyphenylmethyl, 4- (2-ethyiphenyl) urea)phenylmethyl, 4- -(2-isopropyiphenyl) urea) phenylmethyl, 4- (N (2-methoxyphenyl) urea) phenylmethyl, 4- (2-methyl-3-pyridyl)urea) -phenyl-methyl, 4- -(2-nitrophenyl)urea) -phenylmethyl, 4- pyridyl) urea) -phenylmethyl, 4- (2-t-butylphenyl) urea) -phenylmethyl, 4- -(2-thiazolyl)urea) -phenylmethyl, 4- -(3-chiorophenyl) urea) -phenylmethyl, 4- -(3-methoxyphenyl)urea) -phenylmethyl, 4- ~pyridyl) -urea) -phenylmethyl, 4- -(4-pyridyl) urea) phenylmethyl, 4- -(3-methyiphenyl) urea) -phenylmethyl, 4- -(2-methyiphenyl) -urea) -phenylmethyl, 4- benzylurea) phenylmethyl, 4- -cyclohexylurea) phenylmethyl, 4- -ethylurea) -phenylmethyl, 4- isopropylurea) -phenylmethyl, 4- -methylurea) phenylmethyl, 4- -p-toluylurea)-phenyl-methyl, 4- (Nphenylurea) phenyl, 4- -phenylurea) phenyl-amino, 4- -phenylurea) phenylmethyl, 4- -t-butylurea) phenylmethyl, 4- (phenylaminocarbonylamino-methyl) phenyl, 4- (phenylsulfonamido) -phenylmethyl, 4- (tbutoxycarbonylamino) -phenylmethyl, 4-acetamido- 18 phenylmethyl, 4 -aminopherrylamino, 4 -amino-phenylmethyl, 4-benzamidophenylmethyl, 4-chlorophenylmethyl, 4hydroxy-3 -nitrophenylmethyl, 4 -hydroxyphenylmethyl, 4methoxyphenylmethyl, 4 -nitrophenylamino, 4nitrophenylmethyl, 4 -phenacetamidophenylmethyl, 4phenyiphenylmethyl, 4 -pyridylmethyl, 4 -trifluoromethylphenylmethy., 4- -methylurea) benzamido] phenylmethyl, 4- (2-methyiphenyl) urea) phenylmethyl, 4- -phenyl-N' '-methylguanidino)phenyl..methyl, 5- -phenylurea)pentyl, 5- -t-butylurea) -pentyl, 2, 2-dimethyipropyl, 2, 2-diphenylmethyl, 2,3 benzocyclobutyl, 3,4 -dihydroxyphenylmethyl, dimethoxy-4-hydroxy-phenylmethyl, 4- (1-indolecarboxylamino) -phenylmethyl, 6-methoxy-5- -(2-methylphenyl)urea) -2-pyridylmethyl, 4- 3-benzoxazol-2ylamino) -phenylmethyl and 4- 3 -imdazol-2-ylamino) phenylmethyl, 3 -carboxy- 1-phenyipropyl; 3 -hydroxy-4 methyiphenyl) ureaphenylmethyl; 3 -hydroxy-4 chiorophenyl) ureaphenylmethyl; 6- (phenylurea) heptyl, 4phenylurea)butyl; 2-thienylmethyl; 4- (2,6dimethylphenylurea)phenylmethyl; 4- (2hydroxyphenylurea) phenylmethyl; 3 -butoxy-4 methyiphenyl) ureaphenylmethyl; 3 -butoxy-4 (phenylurea)phenylmethyl; 4- (N-2pyrazinylurea)phenylmethyl; 2-phenylethynyl; phenylurea-2-pyridylmethyl; 5- (2-methylphenylurea) -2pyridylmethyl; 4- (3 -methyl-2 -pyridylurea) phenylmethyl; 3-nitro-4- (phenylurea) phenylmethyl; 3-acylamino-4 (phenylurea) phenylmethyl; 4- N-phenyl, methylurea)phenylmethyl; 4-(3hydroxyphenylurea) phenylmethyl; 4- (2acetylaminophenylurea)phenylmethyl; 4- (2propionylaminophenylurea)phenylmethyl; 4- (3-benzyloxy- 2-pyridylurea)phenylmethyl; 4- (3-methyl-2pyridylurea)phenylmethyl; 4- 19- (indolylcarbonylamino)phe-nylmethyl; 2- (4- (phenylurea) phenyl) oxiranyl; 4- -phenyl, methylurea)phenylmethyl; 4- (2dimethylaminophenylurea) phenylmethyl; 4- (2benzimidazolylamino)phenylmethyl; 4- (2benzoxazolylamino)phenylmethyl; 4- (2benzthiazolylamino) phenylmethyl; 4- (tetrahydroquinolinylcarbonylamino) phenylmethyl; 1,3 dimethyl (phenylurea) butyl; hydroxyethylthiomethyl; 4- (phenylurea)phenylethenyl; 3-amino-4- :(phenylurea)phenylmethyl; 4-(4hydroxyphenylurea)phenylmethyl; 4- (2aminophenylurea) phenylmethyl; 4- ~methylurea) phenylurea) phenyl; 4- (2 -hydroxyphenylurea) 3-methoxyphenylmethyl; 4-(2methylsulfonylmethylphenylurea)phenylmethyl; 4- (2methylphenylurea) tetrahydro-2-pyrimidonylmethyl; 3methoxy-4- (phenylurea) -2-pyridylmethyl; 4- (2trifluoromethylphenylurea)phenylmethyl; 4- (3-methyl-2pyridylurea)phenylmethyl; 4- (2,4 (1H,3H) quinazolinedionyl) phenylmethyl; 4 -thioureaphenylmethyl; 4- (phenylthiourea)phenylmethyl; 4- (pyrrolidinylcarbonylamino) phenylmethyl; 4- (2benzoxazolinonylcarbonylamino) phenylmethyl; 4- (benzyloxyurea)phenylmethyl; 4- (thiazolidinylcarbonylamino) phenylmethyl; 4benzoylureaphenylmethyl; hydroxylureaphenylmethyl; N' ety, hydroxylureaphenylmethyl; 4- allylurea)phenylmethyl; 4- (3pyrrolidinylcarbonylamino) phenylmethyl; 4- (1pyrrolylcarbonylamino) phenylmethyl; 4- (2pyrrolylcarbonylamino) phenylmethyl; 4- (propylurea) phenylmethyl; 4- (methoxyurea) phenylmethyl; 4- (dimethylurea)phenylmethyl; 4- (2quinazolinylamino) phenylmethyl; 4- (2- 20 furanoylamino) phenylmethyl; 4-(2 -hydroxy- 6methylphenylurea)phenylmethyl; 4- (2pyridylcarbonylamino) phenylmethyl; 4- (3 -hydroxy..2methylphenylurea) phenylmethyl; 4- (2fluorophenylurea)phenylmethyl; 4- (3fluorophenylurea) phenylmethyl; 4- (4fluorophenylurea) phenylmethyl; 4- (2quinolinylcarbonylamino) phenylmethyl; 4- (isoquinolinylcarbonylamino) phenylmethyl; 4- (2,3 dirnethylphenylurea) phenylmethyl; 4- dimethylphenylurea) phenylmethyl; 4- (2-methyl-4 fluorophenylurea) phenylmethyl; 4- (2-nethyl-3fluorophenylurea) phenylmethyl; 3 -carboxy-3 phenyipropyl; 4- (5-hydroxy-2 methylphenylurea) phenylmethyl; 4- (4 -hydroxy-2 methylphenylurea)phenylmethyl; 4- (2,4difluorophenylurea) phenylmethyl; 3dibenzofuranylcarbonyl; 4- (phenoxycarbonylamino) phenylmethyl; 3 -phenylureapropyl; 4- (phenylaminocarbonyloxy) phenylmethyl; 4cinnamoylphenylmethyl; dibenzofuranylmethyl; 4- (2methyiphenylaminocarbonyloxy) phenylmethyl; methylphenylurea) phenylamino; 4- (3indolylcarbonylamino) phenylmethyl; 4- (phenylaminocarbonyl) phenylmethyl; 4phenylalkynylphenylmethyl; 4- (3pyrrolylcarbonylamino) phenylmethyl; 5 -nitrobenzofuran- 2-yl; 5- (2-methylphenylurea) benzofuran-2-yl; 3-carboxy- 3-phenyipropyl; 2- (3-pyridyl) -thiazol-4-yl; 2- (4pyridyl)-thiazol-4-yl; 2-oxo- and 4-oxo-4,5,6,7tetrahydrobenzo[b] furan-3-yl; 3-methoxy-4- (phenylcarbarnoyloxy) phenylmethyl; 5-amino-benzofuran-2yl; benzilylaminophenylmethyl and 4- EN-2-carboxyethyl- 1- (1,3-benzodioxolyl-5-yl)amino-Nleucinylacetamidylphenylureal phenyirnethyl.

21 Most preferably7 R, is selected from the group consisting of 4-hydroxyphenylmethyl, 3-methoxy-4-(N' phenylurea) -phenylmethyl, 4- -phenylurea) -phenylmethyl, 4- -(2-methyiphenyl) urea)phenylmethyl, 4- 2-pyridyl) -urea) -phenylmethyl, 3-methoxy-4- methylphenyl)urea)phenylmethyl, 6-methoxy-5- methylphenyl)urea) -2-pyridylmethyl, 4- -3-methyl-2pyridylurea)phenylmethyl, 3-methoxy-4- -3-methyl-2pyridylurea)phenylmethyl, and 3-methoxy-4- -2pyridylurea) phenylmethyl.

.:In an alternate preferred embodiment, R, is an aryl -substituted

C

1

-C

4 alkyl group. More preferably, R, is a (N-Ar'-urea)-para-substituted arylalkyl group, and most preferably, a (N-Ar'-urea)-para-substituted phenylmethyl group.

According to another preferred embodiment,

R

2 is selected from the group consisting of hydrogen, methyl or phenacetyl. Most preferably, R 2 is hydrogen.

According to another preferred embodiment,

R

3 5...20 is selected from the group consisting of 2-(methylsulfonyl) -ethyl, 3- (hyrdoxypropylthio) -methyl, 4- (methylsulfonylamino) -butyl, 4 -acetylaminobutyl, aminomethyl, benzyl, butyl, hydroxymethyl, isobutyl, methyl, methylthiomethyl, phenylmethyl, propyl, 4- (benzyloxycarbonylamino) -butyl, N, N- (methyipropargyl) amino, 2- (methylthio) -ethyl, 2- (morpholino-N-carbonyl) ethyl, 2- (N-morpholino) -ethyl, 2- (N,N-dimethylamino) ethyl, 4 -amino-butyl, 4 -benzyloxyphenylmethyl, 2benzylthiomethyl, t-butoxycarbonylaminomethyl, secbutyl, 't-butyl, N,N-dimethylaminocarbonylmethyl, 1,1ethano, 4-hydroxyphenylmethyl, 1-hydroxyethyl, 1methoxyethyl, 4 -methoxyphenylmethyl, benzyloxy-methyl, *The amino acid side chain derived from 1-aminocyclopropylcarboxylic acid.

22 benzylthio-methyl, carbonylmethyl, 2 -methylsulfinyl ethyl, morpholino-N-carbonylmethyl, thiomorpholino.Ncarbonylmethyl, 2 -phenylethyl, asparagine side-chain, proline side-chain, 2-thiazolyl-methyl, 4- (phenylurea) butyl; 4- (methylurea) butyl; morpholinocarbonylmethylthiomethyl; morpholinoethylthiomethyl; 3 -pyridylmethyl; 4methylsulfonylaminobutyl; hydroxymethylthiomethyl; 2methyl sulfonylethyl, 4 -propionylaminobutyl; 4ethoxycarbonylaminobutyl; methoxycarbonylaminobutyl; :ca:bomethoxymethylthiomethyl; 4 -t-butylureabutyl; carboxyrnethyithiomethyl; dimethylamidomethylthiomethyl; acetylaminopropyl; 3 -methylureapropyl; 4biotinoylaminobutyl; 2 -thienylmethyl; 3 -pyridylmethyl; 4 -trif luoroacetylaminobutyl; dimethylaminomethylthiomethyl; dimethylaminoethylthiomethyl; 4- (dimethylaminoacetylamino)buty. or in comibinat ion with

R

2 forms a proline, azetidine or pipecolinic ring.

*20 Most preferably, R 3 is selected from the group consisting of isobutyl, 2-(methylthio)-ethyl, 3- (hydroxypropylthio) -methyl, 2- (methylsulfonyl) -ethyl, 4-acetylamino-butyl, 4- (methylsulfonylamino) -butyl, and 4- (ethoxycarbonylamino) butyl.

According to yet an-ther embodiment,

R

4 is selected from the group consisting of 4-carbomethoxyphenyl, 4 -carboxyphenyl, 4- fluorophenyl, 4 -methoxyphenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3, 4-difluorophenyl, 3,4 dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphen-yl, 4methoxyphenyl, 2-nitrophenyl, 3-pyridyl, 4phenoxyphenyl; 4 -ethoxyphenyl; 4 -nitrophenyl; 4acetylaminophenyl; 4 -methylureaphenyl; 2-f luorophenyl; naphthyl; 3-f luorophenyl; 3-nitrophenyl; hydrogen; 2nitrophenyl; 4-cyanophenyl; 3-methoxyphenyl; 4- 23 methylsulfonylamino; 3-cyanophenyl; 4 -propionylamino; 4 -aminophenyl; 3 -aminophenyl; 4- trifluoromethoxyphenyl.

4-methyiphenyl; 4-amino-3-nitrophenyl; 4-hydroxy-3methoxyphenyl; 4 -hexyloxyphenyl; 4 -methyithiophenyl; 3furanyl; 4 -dimethylaminophenyl; 3 -hydroxy-4 nitrophenyl; n-pentyl; carboxymethyl; 2 -carboxyethyl; ethynyl; 2-thienyl; 2-propenyl; 2-propynyl; methyl; and propyl. More preferably, R 4 is selected from the group consisting 4-methoxyphenyl, 3, 4-dimethoxyphenyl, 4fluorophenyl, 4 -carboxyphenyl, 4- carbomethoxyphenyl, .:phanylethyl, phenylmethyl, illyl, ethynyl, and 3,4a*methylenedioxyphenyl.

In another preferred embodiment Y is Co, CH 2 S0 2 Most preferably, Y is CO.

According to another preferred embodiment, X in formula is COOH.

According to yet another preferred embodiment, n is 1.

Examples of some preferred compounds of this *20 invention wherein X is a carboxyl group and n is 1 are provided in Table 1.

Table 1.

R2R ~1

M

1 R 2 R 3 24 1002 cyanomethyl H -isobutyl phenyl Co 1003 cyclohexylmethyl H isobutyl phenyl co 1004 2-pyridylmethyl H isobutyl phenyl Co 1005 3-pyridylmethyl H isobutyl phenyl CO 1006 4-hydroxyphenylmethyl H isobutyl 1 ,3-benzo- CO 1007 4-pyridylmethyl H isobutyl phenyl CO 1008 phenyl H isobutyl phenyl CO :1009 4-phenylphenylmethyl H isobutyl phenyl CO :1010 4-chlorophenylmethyl H isobutyl phenyl CO 0%010 1011 4.-trifluoromethylphenylmethyl H isobutyl phenyl

CO

1013 phenylmethyl H isobutyl phenyl SO 2 1014 3-indolyl H isobutyl phanyl CO 1015 4-benzamidophenylmethyl H isobutyl phenyl CO 1016 4-aminophenylmethyl H isobutyl phenyl CO 1017 1 -phenylcyclopropyt H isobutyl phenyl CO 1 0 3-acetamidophenylmethyl H isobutyl phenyl CO .:1020 3-benzamidophenylmethyl H isobutyl phenyl CO 1021 1 -naphthylmethyl H isobutyl phenyl CO 1022 2-naphthylmethyl H isobutyl phenyl CO 1023 4-phenacetamidophenylmethyl H isobutyl phenyl CO 1024 2-aminophenylmethyl H isobutyl phenyl CO 1025 2-(bis(phenylsulfonyl)amino)- H isobutyl phenyl CO phenylmethyl 1026 2-benzamidophenylmethyl H isobutyl phenyl CO0 1027 2-(benzyloxycarbonylamino).: H isobutyl phenyl. CO phenylmethyl 1028 4-(2-aminobenzamido)- H isobutyl phenyl Co.

phenylmethyl 25 1029 4-12-(N-methylurea)-banzamido phenylmethyl 1030 3-aminophenylmethyl 1031 3-lbenzyloxycarbonylamino)phenylmethyl 1032 3-Iphenylsulfonamido)phenylmethyl 1036 phenylmethyl 1037 4-(N'-phenylurea)phenylmethyl 1038 phenylmethyl 1039 phenytmethyl 1040 phenylmethyl 1041 t-butoxy 1042 t-buyoxy 1043 t-butoxy 1044 t-butoxy 1045 phenylmethyl 15 1046 phenylmethyl 1047 phenylmethyl 1048 phenylmethyl 1049 B phenylmethyl H isobutyl H isobutyl H isobutyl H isobutyl H isabutyl H 2-thiazolylmethyl H propyl H butyl H sec-butyl H hydroxymethyl H phenylmethyl H 1, 1 -thano methyl isobutyl H hydroxymethyl H phenylmethyl H proline side-chain H 1, 1-ethano' H asparagine side-chain H isobutyl Phenyl Phonyl phenyl phenyl 1.3-be nzophenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl 1 .3-benzophenyl phenyl phenyl phenyl Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co .Co Co Co Cb 1050 4-(N'-phenylurea)phenylmethylI 1051 1052 1053 1054 4-(N -phenylurea)phenyl 2-[4-(N'-phenylurea)phenylJethyl 4-(N'-phenylurea)phenylmethyl 3-(N'-phenylurea)phenylmethyl isobutyl isobutyt isobutyl isobutyl methyl

H

26 *e 9 .9

S.

0* @9

S

9 S. 9 S 9* S *5*9 a

S

*9G* 9. 9

*S

S

9@90 1055 1056 1057 1058 1060 1063 1064 1065 1066 10 1067 1068 1069 1070 1072 1073 1074 1075 1076 1077 4-(N'-phenylurea)phenylmethyl methyl isobutyl 3-methoxy-4-(N'-phenylurea)- H isobutyl phenylmethyl 3-hydroxy-4-(N'-phenylurea)- H isobutyl phenylmethyl 3-methyl-4-(N'-phenylurea)- H isobutyl phenylmethyl 4-(N'-phenylurea)phenylmethyt H isobutyl 4-(N'-phenylurea)phenylmethyl H isobutyl 4-(N'-methylurea)phenylmet-.y H isobutyl 4-(N'-isopropylurea)- H isobutyl phenytmethyl 4-(N -phenylurea)phenylmethyl H isobutyl 4-(N'-p-toluylurea)- H isobutyl phenylmethyl 4-(N'-cyclohexylurea)- H isobutyl phenylmethyl 4-(N'-phenylurea)phenylmethyl H isobutyl 4-hydroxyphenylmethyl H isobutyl 4-(N'-phenylurea)phenylmethyl H isobutyl 4-(benzyloxycarbonylamino)- H isobutyl phenylmethyl 4-(phenylsulfonamido) H isobutyl phenyl-methyl 4-(benzamido)phenylmethyl H isobutyl 4-(N '-t-butylurea)phenylmethyl H isobutyl 4-(N'-ethylurea)phenylmethyl H isobutyl 1 .3-be nzo- 1 .3-be nzo- 1.3-be nzo- 1.3-be nzophenyl benzyl 1 .3-benzo- 1 .3-benzo- 1 .3-benzo- 1.3-be nzo- 1 .3-benzo- 2-methoxy phenyl 2-methoxy phenyl 3-methoxy phenyl 1 ,3-benzo- 1 .3-benzodioxol 1.3-be nzo- 1 ,3-benzo- 1 ,3-benzo- Co Co co Co Co Co Co Co Co

CO

Co

CO

Co Co Co Co cb Co Co 27 1078 4-(N -(3-methoxyphenyl)urea)-- H phenylmethyl 1079 4 -(N.-(2-methoxyphenyl~urea)-

H

phenylmethyl 1080 4 -(N'-(3-pyridyl)urea)-

H

phenylmethyl I UO 1082

S

0O

S*

OS OS S 0

S

0 .5

SO

S.

S.

S. S 045* *0@S

S

0@*e .50

S

0@OS *550 5 *055 1083 1084 1085 1086 10 1087 1088 pnenyimetnyl H 3-phenyipropyl

H

methyl

H

2-(4-hydroxyphenyl)ethyl

H

benzyloxy

H

N-phenylamino

H

2-(4-hydroxyphenyl)ethyl methyl 4-(N'-phenylurea)phenylmethyl

H

*isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl 1 .3-benzo- 1 .3-benzo- 1 ,3-benzo.

dioxol-S-yl phenyl phenyl phenyl phenyl phenyl phenyl phenyl 4-methoxy phenyl 4-methoxy phenyl 1 .3-benzo-

CO

Co Co co Co co Co Co Co Co Co Co co 1089 4-(N-phenylurea)phenylmethyl

H

1090 4-tN -phenylurea)phenylmethyl

H

2-(methylthio)ethyl isobutyl 55 0 @0

OS

00.a

S

6005 15 1091 1092 1093 1094 4-hydroxyphenylmethyl 4-methoxyphenylmethyl 4-nitrophenylmethyl n-hexyl 1096 2-hydroxyphenylmethyl 1097 3-hydroxyphenylmethyl 1098 3,4-dihydroxyphenylmethyl 1099 2,2-diphenylethyl 1100 2-bromo-4-hydroxy-5methoxyphenyimethyl 1101 4-(benzyloxycarbonylamin)phenylmethyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl phenyl phenyl phenyl phenyl phenyl phenyl phenylphenyl phenyl H isobutyl H iobuylphenyl Co.

28 S. S 1102 1103 1104 1105 1106 1107 1108 1109 1110 10 1111 1112 1113 1114 1115 15 1116 1117 1119 1120 1122 1123 1124 2-(N'-phenylurea~phenylmethy* 4-aminaphenylmethyl 4-(Phenylsulfonamido)phenylmethyl 4-(banzamido~phenylmethyl 5-(N '-phenylurea)pentyl 5-(N'-t-butylurea)pentyl 4-nitrophenylamino 4-amino phe nylamino 4-(N '-phenylurea)phenylamino 3,5-dimethoxy-4-hydroxyphenylmethyl 4-hydroxy-3-nitrophenylmethyl 3-nitrophenylmethyl phenylmethyl phenylmethyl

H

H

H

H

H

H

H

H

H

H

H

H

methyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl Phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl 4-chioro phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl phenyl Co Co Co Co Co Co Co Co Co Co Co Co Co Co .Co Co co Co phenylmethyl phenylmethyl phenylmethyl phenylmethyl phenylmethyl phenylmethyl phenylmethyl H 1 -hydroxy-ethyl H 1 -methoxy-ethyl H methyl methyl methyl H 4-methoxyphenylmethyl H 2-phenylethyl H 4-benzyloxyphenylmethyl H 4-hydroxyphenylmethyl H benzyloxymethyl 1125 phenylmethyl 1126 phenylmethyl 29 1127 phenylmethyl H benzylthiomethyl Phenyl 1128 4-(N'-phenylurea)phenylmethyl

H

1129 4 -(N'-phenylurea)phenylmethyl

H

isobutyl benzyl 1130 1131 1132 4-(N -phenylurea)phenylmethyl 4-(N'-phenylurea)phenylmethyl 4-IN -phenylurea)phenylmhethyl 1133 4-(N'-phenylurea)pheniylmethyl 1134 4-(N'-phenylurea)phenylmethyl 1135 4-(N'-phenylurea)phenylmethyl 10 1136 4-(N.-phenylurea)phenylrnethyl 1137 phenylmethyl H benzyl H sec-butyl H 4-(benzyloxycarbonylamino)butyl H sec-butyl H t-butoxycarbonylaminomethyl H 2-(methylthio)ethyl H 2-benzylthiomethyl H isobutyl 1,3-benzo- 1 ,3-benzophenyl phenyl phenyl 1 .3-benzophenyl phenyl phenyl 2-nitro phenyl phenyl phenyl phenyl phenyl phenyl benzyl pheny[ phenyl 3-rnethoxy phenyl co Co co Co co co Co co 1138 1139 1140 1141 4-f N -phenylurea)phenylmethyl 4-(N -phenylurea)phenylmethyl phenylcarbonyl phenylcarbonyl

H

H

H

phenacyl

H

H

H

H

amninomethyl 4-amino-butyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl 1142 2,3-benzocyclobutyl 1143 4-hydroxyphenylmethyl 1144 4-hydroxyphenylmethyl 1145 4-It-butoxycarbonylamino)phenylmethyl 1146 4-hydroxyphenylmethyl H isobutyl 30 1147 1148 1149 1150 1152 1153 1154 1155 1156 10 1157 1158 4-acetamidophenylmethyl 4-hydroxyphenylmethyl 2-quinolinyl 2-phenylethyl 2,2-dimethyipropyl benzytoxy t-butylamino phenylmethyl methyl phenylmethyl phenylmethyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl t-butyl t-butyl isobutyl isobutyl

S

1159 phenylmethyl 1160 phenylmethyl 1162 1163 benzyloxy 4-(N '-phenylurea Iphenylmethyl 1164 phenylmethyl 1168 4-(N'-(m-toluyl)urea)phenylmethyl 1169 4-(N'-benzylurea)phenylmethyl 1170 4-(N'-phenylurea)phenylmethyl 1173 4-hydroxyphenylmethyl 1174 4-hydroxyphenylmethyl 1175 phenylmethyl H isobutyl H isobutyl H isobutyl H 2-(methylthio)ethyl H 2-(methylthio)ethyl H isobutyl H isobutyl H morpholino-Ncarbonylmethyl H isobutyl H 2-(methylthio)ethyl H 2-(methylthio)ethyl phenyl 3-pyridyl phenyl phenyl phenyl 3-pynidyl phenyl phenyl phenyl benzyl 1 .3-benzo- 2-methoxy phenyl 3-methoxy phenyl methyl 1 ,3-benzo- 1 ,3-benzo- 1 ,3-banzo- 1 ,3-benzo- 1 ,3-banzo- 4-methoxy phenyl 4-methoxy phenyl 4-methoxy phenyl Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co 31 a. 1176 1177 1178 1179 1180 1181 1182 1185 1186 -1187 1188 1189 1190 1191 1192 1193 1194 1195 phenylmethyl 4-(N -(o-toluyl)urea)phenylmethyl 4-(N '-(2-thiazolyl)urea)phenylmethyl 4-(N '-(3-chlorophenyl)urea)phenylmethyl 4-(N'-(4-pyridyl ~urea)phenylmethyl 4-(N'-(2-chlorophenyl)urea)phenylmethyl 4-tN -phenylurea)phenylmethyl 3-f N -phenylurea)propyl 1 -phenylcyclopropyl 1 -indanyl 4-(N'-(o-toluyilurea)phenylmethyl 4-(N'-phenylurea)phenylmethyl 4-(N -(2-methoxyphenyl)urea)phenylmethyl 4-(N -phenylurea )phenylmethyl 4-(N'-(2-pyridyl)urea)phenylmethyl 4-(N'-phenylurea)phenylmethyl

H

H

H

H

H

H

H

H

H

H

H

H

H

methyl

H

H

4-(N'-phenylurea~phenylmethyr H 4-(N'-phenylurea)phenylmethyl H -thiomorpholino-Ncarbonylmethyl N,N-tmethylprop argy~amino carbonyl-methyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl 2-(N-morpholino)ethyl isobutyl isobutyl isobutyl isobutyl 1 .3-benzo- 1 .3-benzo- 4-methoxy phenyl 1 .3-benzo- 4-methoxy phenyl 1 ,3-benzo- 1.3-be nzo- 1 ,3-benzoisobutylaminocarbonyl phenyl 1 .3-benzophenyl 4-methoxy phenyl 1 ,3-benzo- 4-methoxy phenyl 4-methoxy phenyl 4-methoxy phenyl 3 .4-difluorophenyl Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co Co 32 1196 4-(N'-phenylurea)phenylmethyl'

H

-isobutyl 1197 4-(N'-(o-toluyl)urea)- H isobutyl phenylmothyl 1198 4 -(morpholinocarbonylamino)- H isobutyl phenylmethyl 1199 4-(N'-phenylurea)phenylmethyl H 2-methylsulfinylethyl 1200 4-(N'-(2-ethylpheny)urea)- H isobutyl phenylmethyl 1 201 4 -(N'-(2-nitrophenyl)urea)- F- isobutyl phenylmethyl 1206 4 -(N'-(2-isopropylphanyl)urea)- H isobutyl phenylmethyl 1207 4-(N'-(2-isopropylphenyl)urea)- H isobutyl phenylmethyl 1208 4-(N'-(2-othylphenyl)urea)- H isobutyl phenylmethyl 1209 4-(N'-(2-t-butylphenyl)urea)- H isobutyl phenylmethyl 3 .4-dimeth OXY-phenyl phenyl 1 .3-benzo- 4-methoxy phenyl 1 ,3-benzo- 1 ,3-benzo- 1 ,3-benzo- 4-methoxy phenyl 4-methoxy phenyl 1 ,3-benzo- 1 ,3-benzo- 3,4-dimethoxy phenyl Co Co Co Co Co Co Co Co Co Co 1210 4-(N'-(o-toluyl)urea)phenylmethyl 1212 4-(N'-(o-toluyl)urea)phenylmethyl H isobutyl H isobutyl 1214 4-(N'-phenylurea)phenylmethyl 1215 4-(N'-phenylurea)phenylmethyl 1216 4-(N'-phenylurea)phenylmethyl H N,N-dimethyl aminocarbonylmethyl H 2-(N,N-dimethylamino)-ethyl H 2-(morpholino-Ncarbonyl)-ethyl H 4-(benzyloxycarbonylamino)butyl H isobutyl 1 ,3-benzo- 1 ,3-benzo- 1 ,3-benzo- 1217 4-(N'-(o-toluyl)urea)phenylmethyl 1218 4-(N'-(2-pyridyl)urea)phenylmethyl 3 .4-dimethoxy phenyl 3,4-dimethoxy CO.

phenyl 33 1219 4-(N'-(3-pyridyl)urea)phenylmethyl 1220 4-(N'-(2-methyl-3-pyridyl) urea)-phenylmethyl 1221 3-methoxy-4-(N-(o-toluyl)urea)phenylmethyl 1222 4-(N'-(2-chlorophenyl)urea)- 3-methoxyphenylmethyl H isobutyl H isobutyl H isobutyl H isobutyl 3 4 -dimethoxy

CO

phenyl 4 -methoxy phenyl 1 .3-be nzo- 1 .3-benzo- 1 .3-be nzo- 1223 4 -(phenylaminocarbonylaminomethyl)-phenyl 1224 4-(N'-(o-toluyl)urea)phenylmethyl 1225 4-(N'-fo-toluyl)urea)phenylmethyl 1227 4-(N'-(o-toluyl)urea)phenylmethyl 1238 4-(N'-(o-toluylurea)phenylmethyl 1245 4-(N'-(o-toluyl)urea)phenylmethyl 1246 4-(N'-(o-toluyl)urea)phenylmethyl 1248 4-(N'-(o-toluyl)urea)phenylmethyl 1270 4-(N'-(o-toluyl)urea)phenylmethyl 1272 4-(N'-(2-methylphenyl) urea) phenylmethyl 1282 4-(N'-(o-toluyl)urea)-pyrid-5yilmethyl 1294 4-(N'-(o-toluyl)urea)phenylmethyl H isobutyl F. 2-(mothylthio)ethyl H 4-(benzyloxycarbonylamino)butyl H methyithiomnethyl H 2-(methylthio)ethyl 3,4-dimethoxy CO phenyl 1 .3-be nzo- 1 ,3-benzo- 4-methoxy phenyl H 2-(methyl-sulfonyl)- 1 .3-be nzoethyl H 3-(hyrdoxypropythio)-methyl 1 .3-be nzo- H isobutyl 4-fluorophenyl CO H 4-acetylaminobutyl H 4-(methoxy carbonyl amino) butyl H isobutyl 1 .3-benzo- 1 ,3-benzo- 1 .3-benzo- H 4-(methylsulfonyl- 1 ,3-benzoamino)-butyl 1311 4-(N'-(3-methyl-2-pyridyl) urea) phenylmethyl H 4-(methgxy carboniyl amino) butyl 3,4-dimethoxy CO phenyl 34

C.

1319 4-f indolylcarbonyl aminolphenylmethyl 1321 4-(N'-(o-toluyl)urea)phenylmethyl 1327 4-01-indolecarboxylamino)phenylmethyl 1336 6-methoxy-5-(N'-(o-toluyl) urea)-2-pyridylmethyl 1345 4-(N'-(o-toluyl)urea)phenylmethyt 1 Z147 4-(N'-2-pyridyl) urea)phenylmethyl 1358 4-(N'-phenylthiourea) phenylmethyl 1360 4-(N'-(o-toluyl)urea)phenylmethyl 1361 4-(N'-(o-toluyl)urea)phenylmethyl 1380 4-(N'-phenyl-N"-methylguanidino)-phenylmethyl 1382 4-(N'-(o-toluyl)urea)phenylmethyl 1388 4-(phenylurea) phenylmethyl 1390 4-cl ,3-imidazol-2-ylamino)phenylmethyl 1393 4-f N'-(2-pyridyl) urea) phenylmethyl 1396 4-(1 ,3-benzoxazol-2-ylamino)phenytlmethyl 1400 4-(N'-(2-methylphenyl)urea)phenylmethyl -H -isabutyt H isobutyl H isobutyl H isobutyl H dimethylamino ethylthiomethyl H 2-(methylthio)ethyl H isobutyl H isobutyl H methyithio ethyl H isobutyl H 4-(methylsulfonylamino)-butyl H isobutyl H isobutyl H 2-(methylthio)ethyl H isobutyl 1 ,3-benzo- 1 ,3-benzo- 1 .3-benzo- 1,3-benzo-

CO

4-

CO

carboxyphenyl 3,4-dimethoxy- Co phenyl a 1 ,3-benzo- 2,3-dihydro-

VI

4-carbomethoxy phenyl 1 ,3-benzo- 4-carbomethoxy-phenyl 4-carbomethoxy-phenyl 1 ,3-benzo- 1 ,3-benzo- 1 ,3-benzophenylethyl H isobutyl 1429 4 -(N'-(3-mothyl-2-pyridyl) urea) phenylmethyl H 2-(methylthio)ethyl 1 ,3-benzo- 1444 4-f 2-benzoxa zolinonyl carbonylaminolphenylmethyl 1474 4-(2-pyrrolylcarbonylamino) phenylmethyl 1475 4-f N'-allylurea)phenylmethyl 1490 4-f N'-(2-methylphenyl) urea)phenylmethyl 1515 4-(N'-f2-methylphenyl) urea)phenylmethyl 1325 4-f N'-f 2-fluorophenyl) urea)phenylmethyl 1526 4-f 4-fluorophenylurea) phenylmethyl 1536 4-(N'-f2-methylphenyl) urea)phenylmethyl 1594 4-f N'-2-methylpenylurea)phenylmethyl 1648 4-f 2-indoylycarbonylamino) phenylmethyl 1655 4-f 3-indolylcarbonylamino) phenylmethyl 1721 4-fW-(2-methylphenyl) urea)phenylmethyl 1725 3-methoxy-4-(N'-phenyl urea) phenylmethyl 1726 3-methoxy-4-(N'-phenyl urea) phenylmethyl 1727 3-mothoxy-4-(N'-phenyl urea) phenylmethyl 1728 3-methoxy-4-(N'-2-pyridyl urea) phenylmethyl 1729 3-mothoxy-4-(N'-3-methyl-2pyridyl) urea phenylmethyl 1730 3-methoxy-4-(N'-3-methyl-2pyridyl) urea phenylmethyl

-H

H

H

H

h

H

H

H

H

H

H

H

H

H

H

H

H

-isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl isobutyl 2-f methyithio)ethyl isobutyl 2-f methyithio)ethyl isobutyl isobutyl 2-f methylthio)ethyl 1,3-benzo-

CO

1,3-benzo- Co 1,3-benzo- CO ethynyl

CO

allyl co 3,4-diemthoxy- CO phenyl 3,4-dimethoxy CO phenyl methyl Co H co H co 1,3-benzo- CO morpholino- CO methyl 1,3-benzo- CO 3.4-dimethoxy- CO phenyl 3,4-dimethoxy- CO phenyl 3,4-dimethoxy- CO phenyl 3,4-dimethoxy- CO phenyl 3,4-dimethoxy- CO phenyl 36 1731 3-methoxy-4-(N'-3-methyl-2- H 2-(methylthio)- 1 3 -benzo- CO pyridyl) urea phenylmethyl ethyl 1732 4-(N'-(3-methyl-2-pyidyl) H 2-(methylthio)- 3.4-dimethoxy. CO urea) phenylmethyl ethyl phenyl The more preferred compounds of formula (I) are: BIO-1006, BIO-1056, BIO-1089, BIO-1179, BIO-1194, B10-1221, BIO-1224, BIO-1238, B10-1245, B10-1246, 1248, BIO-1270, BIO-1282, BIO-1294, BIO-1321, BIO-1336 BIO-1382 and BIO-1400. Even more preferred compounds are BIO-1218, BIO-1272, BIO-1311, BIO-1319, BIO-1345, BIO-1347, BIO-1358, BIO-1361, BIO 1388, BIO-1390, BIO- 1393, BIO-1396, BIO-1429, BIO-1444, BIO-1474, BIO-1475, BIO-1490, BIO-1515, BIO-1525, BIO-1526, BIO-1536, BIO- 1594, BIO-1648, BIO-1655, BIO-1721, BIO-1725, BIO-1726, BIO-1727, BIO-1728, BIO-1729, BIO-1730, BIO-1731, and BIO-1732. Most preferred are BIO-1218, BIO-1272, BIO- 1311, BIO-1347, BIO-1393, BIO-1429, BIO-i51S, BIO-1725, BIO-1726, BIO-1727, BIO-1728, BIO-1729, BIO-1730, BIO- 1731, and BIO-1732.

Compounds of this invention may be synthesized using any conventional technique.

Preferably, these compounds are chemically synthesized from readily available starting materials, such as a~amino acids. Modular and convergent methods for the synthesis of these compounds are also preferred. In a convergent approach, for example, large sections of the final product are brought together in the last stages of the synthesis, rather than by incremental addition of small pieces to a growing molecular chain.

According to one embodiment, compounds of the present invention may be synthesized in the following manner. A protected chiral amine is added to an a,8~- 37 unsaturated ester to produce a-protected P-amino acid ester. Upon suitable deprotection, the p-amino acid ester is coupled to an appropriate activated ester moiety. The coupled product, if suitably functionalized, may be further reacted with yet another activated ester moiety. This material can be further manipulated to give the desired compounds of the invention. At each step of the above sequence, the ester can be hydrolyzed to the corresponding acid to 10 give another compound of the invention.

Alternatively, the activated ester moieties mentioned above can be attached together first, then the resulting compound can be attached to the P-amino acid ester portion. At this point the final manipulations and/or necessary deprotection steps can be performed.

Alternatively, under suitable conditions, the desired functionalities can be incorporated (protected -or unprotected) in one of the activated ester moieties.

20 That piece is then coupled with a P-amino acid ester or a moiety consisting of a P-amino ester previously coupled to an activated ester. The resulting product can then be subjected to any deprotection steps, if necessary, to give compounds of the invention.

Alternatively, the chiral g-amino acid esters used in the synthesis of the compounds of this invention may be synthesized by well-known techniques, such as those described in United States patent 5,344,957, the disclosure of which is herein incorporated by references.

The compounds of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given 38 biological system blood; lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

As used throughout this application, the term "patient" refers to mammals, including humans. And the term "cell" refers to mammalian cells, including human cells.

10 Once synthesized, the activities and VLA-4 specificities of the compounds according to this invention may be determined using in vitro and in vivo assays.

For example, the cell adhesion inhibitory activity of these compounds may be measured by determining the concentration of inhibitor required to block the binding of VLA-4-expressing cells to fibronectin- or CS1-coated plates. In this assay -microtiter wells are coated with either fibronectin 20 (containing the CS-1 sequence) or CS-1. If CS-1 is used, it must be conjugated to a carrier protein, such as bovine serum albumin, in order to bind to the wells.

Once the wells are coated, varying concentrations of the test compound are then added together with appropriately labelled, VLA-4-expressing cells.

Alternatively, the test compound may be added first and allowed to incubate with the coated wells prior to the addition of the cells. The cells are allowed to incubate in the wells for at least 30 minutes.

Following incubation, the wells are emptied and-washed.

Inhibition of binding is measured by quantitating the fluorescence or radioactivity bound to the plate for each of the various concentrations of test compound, as well as for controls containing no test compound.

39 VLA-4-expressing cells that may be utilized in this assay include Ramos cells, Jurkat cells, A375 melanoma cells, as well as human peripheral blood lymophocytes (PBLs). The cells used in this assay may be fluorescently or radioactively labelled.

A direct binding assay may also be employed to quantitate the inhibitory activity of the compounds of this invention. In this assay, a VCAM-IgG fusion protein containing the first two immunoglobin domains 10 of VCAM (D1D2) attached above the hinge region of an IgG1 molecule ("VCAM 2D-IgG"), is conjugated to a marker enzyme, such as alkaline phosphatase The synthesis of this VCAM-IgG fusion is described in PCT publication WO 90/13300, the disclosure of which is herein incorporated by reference. The conjugation of that fusion to a marker enzyme is achieved by crosslinking methods well-known in the art.

The VCAM-IgG enzyme conjugate is then placed in the wells of a muti-well filtration plate, such as 20 that contained in the Millipore Multiscreen Assay System (Millipore Corp., Bedford, MA). Varying concentrations of the test inhibitory compound are then added to the wells followed by addition of VLA-4expressing cells. The cells, compound and VCAM-IgG enzyme conjugate are mixed together and allowed to incubate at room temperature.

Following incubation, the wells are vacuum drained, leaving behind the cells and any bound VCAM.

Quantitation of bound VCAM is determined by adding an appropriate colorimetric substrate for the enzyme conjugated to VCAM-IgG and determining the amount of reaction product. Decreased reaction product indicates increased cell adhesion inhibitory activity.

In order to assess the VLA-4 inhibitory specificity of the compounds of this invention, assays 40 for other major groups of- integrins, 92 and 93, as well as other 61 integrins, such as VLA-5, VLA-6 and a497 are performed. These assays may be similar to the adhesion inhibition and direct binding assays described above, substituting the appropriate integrin-expressing cell and corresponding ligand. For example, polymorphonuclear cells (PMNs) express 92 integrins on their surface and bind to ICAM. 83 integrins are involved in platelet aggregation and inhibition may be 1 0 measured in a standard platelet aggregation assay.

VLA-5 binds specifically to Arg-Gly-Asp sequences, while VLA-6 binds to laminin. a4S7 is a recently discovered homologue of VLA-4, which also binds fibronectin and VCAM. Specificity with respect to a467 is determined in a binding assay that utilizes the above-described VCAM-IgG-enzyme marker conjugate and a cell line that expresses a4i7, but not VLA-4, such as RPMI-8866 cells.

Once VLA-4-specific inhibitors are 20 identified, they may be further characterized in in Y1OQ assays. One such assay tests the inhibition of contact hypersensitivity in an animal, such as described by P.L. Chisholm et al., "Monoclonal Antibodies to the Integrin a-4 Subunit Inhibit the Murine Contact Hypersensitivity Response", Eur. J.

Immunol., 23, pp. 682-688 (1993) and in "Current Protocols in Immunology", J. E. Coligan, et al., Eds., John Wiley Sons, New York, 1, pp. 4.2.1-4.2.5 (1991), the disclosures of which is herein incorporated by reference. In this assay, the skin of the animal is sensitized by exposure to an irritant, such as dinitrofluorobenzene, followed by light physical irritation, such as scratching the skin lightly with a sharp edge. Following a recovery period, the animals are re-sensitized following the same procedure.

41 Several days after sensitization, one ear of the animal is exposed to the chemical irritant, while the other ear is treated with a non-irritant control solution.

Shortly after treating the ears, the animals are given various doses of the VLA-4 inhibitor by subcutaneous injection. In vivo inhibition of cell adhesionassociated inflammation is assessed by measuring the ear swelling response of the animal in the treated versus untreated ear. Swellling is measured using 10 calipers or other suitable instrument to measure ear t.ickness. In this manner, one may identify those inhibitors of this invention which are best suited for inhibiting inflammation.

Another in vivo assay that may be employed to test the inhibitors of this invention is the sheep S. asthma assay. This assay is performed essentially as described in W. M. Abraham et al., "a-Integrins Mediate Antigeninduced Late Bronchial Responses and Prolonged -Airway Hyperresponsiveness in Sheep," J. Clin. Invest., 20 93, pp. 776-87 (1994), the disclosure of which is herein incorporated by reference. This assay measures inhibition of Ascaris antigen-induced late phase airway responses and airway hyperresponsiveness in asthmatic sheep.

The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids and bases.

Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, 42 maleate, methanesulfonate-, 2 -naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and 10 salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides.and -others. Water or oil-soluble or dispersible products 20 are thereby obtained.

The compounds of the present invention may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions of this invention comprise any of the compounds of the present invention, or pharmaceutically acceptable salts thereof, together with any pharmaceutically acceptable carrier. The term "carrier" as used herein includes acceptable adjuvants and vehicles. Pharmaceutically 43 acceptable carriers that Tnay be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, 15 polyethylene glycol and wool fat.

According to this invention, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile -injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable Spreparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or 44 castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Hely or similar alcohol.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.

In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch.

Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for 15 oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration.

These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositionsof this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

45 Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical 15 compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not -limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared 46 as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the e *activity of the specific compound employed, the age, body weight, general health, sex, diet, time of 5 administration, rate of excretion, drug combination, 15 and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which -the ingredient is co-administered.

The dosage and dose rate of the compounds of this invention effective to prevent, suppress or inhibit cell adhesion will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature pe of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day of the active ingredient compound are useful.

According to another embodiment compositions containing a compound of this invention may also comprise an additional agent selected from the group consisting of corticosteroids, bronchodilators, 47 antiasthmatics (mast cell stabilizers), antiinflammatories, antirheumatics, immunosuppressants, antimetabolites, immunonodulators, antipsoriatics and antidiabetics. Specific compounds within each of these classes may be selected from any of those listed under the appropriate group headings in "Comprehensive Medicinal Chemistry," Pergamon Press, Oxford, England, pp. 970-986 (1990), the disclosure of which is herein incorporated by reference. Also included within this group are compounds such as theophylline, sulfasalazine and aminosalicylates (antiinflammatories); cyclosporin, FK-506, and rapamycin (immunosuppressants); Scyclophosphamide and methotrexate (antimetabolites); and interferons (immunomodulators).

15 According to other embodiments, the invention provides methods for preventing, inhibiting or suppressing cell adhesion-associated inflammation and ~cell adhesion-associated immune or autoimmune *responses. VLA4-associated cell adhesion plays a central role in a variety of inflammation, immune and autoimmune diseases. Thus, inhibition of cell adhesion by the compounds of this invention may be utilized in methods of treating or preventing inflammatory, immune and autoimmune diseases. Preferaby the diseases to be treated with the methods of this invention are selected from asthma, arthritis, psoriasis, transplantation rejection, multiple sclerosis, diabetes and inflammatory bowel disease.

These methods may employ the compounds of this invention in a monotherapy or in combination with an anti-inflammatory or immunosuppressive agent. Such combination therapies include administration of the agents in a single dosage form or in multiple dosage forms administered at the same time or at different times.

48 In order that this invention may be more fully understood, the following examples are set forth.

These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

Procedure A Synthesis of Cinnamate Esters Method A: To a cinnamic acid or substituted cinnamic acid (1.0 mmol) in CH 2 Cl (10 ml) was added (COC1) 2 mmol) slowly. The reaction mixture was stirred at r.t.

for 4 h and the solvent was removed in vacuo to afford the acid chloride. Methanol or t-butyl alcohol (5 ml) was added to quantitatively provide the methyl or tbutyl ester after removal of the solvents.

Method B: To an appropriate aldehyde (1.0 mmol) in THF (10 ml) was added t-butoxycarbonyl methylene .triphenylphosphorane (1.0 mmol, Aldrich) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with petroleum 20 ether (10 ml) and was filtered through a pad of celite.

The filtrate was collected and concentrated in vacuo to afford the desired product.

C

E-1: CO2tBu Method A; Yield: 95%; (CDC1 3 '300 MHz, ppm): 7,57 (d, 1H, J 16 Hz), 7.47 2 7.34 3H), 6.35 (d, 1H, J 16 Hz), 1.52 9H); E-2: c02~tBu 49 Method B; Yield: 90%; (CDCl 3 300 MHz, ppm) 7.48 (df 1H) 7.28-7.18 (mn, 5H) 5.69 2H) 3.44 2H) 1.42 9H); E-3:

I

~J.C2M S Method A; Yield: 94%; (CDC1 3 300 MHz, ppm) 95 (d, 1H, J 16 Hz) 7.49 1H) 7.42 1H) 6.94 (dd, 21) 6.51 2H) J= 16 Hz) 3.86 3H) 3.76 (s, 3H) E-4: 2 tBu Method A; Yield: 92%; (CDC1 3 300 MHz, ppm) :7.52 (d, 1H, J 15.9 Hz), 7.28 7.09 1H), 7.02 (br, s, 1H), 6.89 1H), 6.34 1H, J =15.9 Hz) 3.82 3H), 1.54 9 H); Method MetodA: Yield: 98%; (CDC1 3 300 MHz, ppm) :7.64 (d, 1H, J 16 Hz), 7.29 1H), 7.10 1H), 7.06 (br, s, 1H), 6.94 1H, J 16 Hz), 3.82 3H), 3.80 (s, 3H); E-6: SC0 2 tBu Method B; Yield: 88%; (CDC1 3 300 MHz, ppm) :8.62 (br,s, 1H), 8.51 (in, 1H), 7.72 1H), 7.48 1H1, J 50 15. 9 Hz) 7.22 (in, 1H)-6. 36 d, 1H, J 15 .9 Hz) 1.49 9H); E-7: Method B; Yield: 90%; (CDCl 3 300 MHz, ppm) 8.60 (br, s, 1H), 7.66 1H), 7.55 1H, J =15.9 Hz), 7.36 1H), 7.21 (mn, 1H), 6.78 1H, J =15.9 Hz), 1.52 9 H); E-8:

CO

2 tBu Method A; Yield: 91%; (CDC1 3 300 MHz, ppm) 7.52 (d, 1H, J 15.9 Hz), 7.44 1H, J 8.0 Hz), 6.85 (d, 1H1, J 8.0 Hz), 6.21 1H1, J 15.9 Hz), 3.81 (s, 3H1), 1. 52 9H); E-9: Method A; Yield: 90%; (CDC1 3 300 MHz, ppm) :7.61 (d, 1H, J 16 Hz), 7.42 2H, J 7.9Hz), 6.86 1H1, J 7.9 Hz), 6.28 1H, J 16 Hz), 3.78 3H1), 3.74 3H);

C

2 MG e Method B; Yield: 91%; (CDC1 3 300 MHz, ppm) :7.56 (d, 1H1, J 16 Hz), 7.46 2H), 7.02 2H), 6.26 (d, 211, J 16 Hz) 1.-54 911); E-11: -51 m*O y.4CfftBu Method A; Yield: 89t; (CDCl 3 300 MHz, ppm) :7.47 d, 1H, J 15.9 Hz), 7.01 1H, J 8.3 Hz), 6.98 (br, s, 1H), 6.78 1H, J 8.3 Hz), 3.84 6H), 1.48 9H); E-12: M6oO ),oC 2

MO

moo Method A; Yield: 91%; (CDCl 3 300 MHz, ppm) :7.61 (d, 1H, J 15.9 Hz, 7.07 1H, J =8.3 Hz), 7.02 (br, s, :10 1H), 6.83 1H, J 8.3 Hz), 6.28 1H, J 15.9 Hz), 3.88 3H), 3.76 3H); .**Method A; Yield: 92%; (CDCl 3 300 MHz, ppm) :7.46 (d, 1H, J 16.1 Hz), 6.99 1H), 6.97 1H), 6.76 (d, 1H), 6.18 1H, J 16.1 Hz), 5.96 2H), 1.50 (s, E-14: Method A; Yield: 88k; (CDC1 3 300 MHz, ppm) :7.55 (d, 1H, J 15.9 Hz), 6.98 -6.75 (in, 2H), 6.22 1H, J 15.9 Hz), 5.96 2H), 3.75 3H1); O C 2tsu 52 Method B; Yield: 89%; (CDCI 3 300 MHz, ppm): 7.45 (d, 1H, J 15.8Hz), 6.99 1H), 6.98 1H), 6.80 (d, 1H), 6.18 1H, J 15.8 Hz), 4.21 (br,s, 4H), 1.49 s, 9H); E-16: PCO2tBu Method B; Yield: 88%.

E-17: CO2tBu Mo2C 10 Method B; Yield: 93%; 1 HNMR(CDC1) 6 8.00 (2H, d, J= 5.5Hz), 7.53 (2H, d, J=5.5Hz), 7.58 (1H,d,J=10,7Hz), 6.42(1H,d,J=10.7Hz), 3.90(3H, 1.51(9H, s).

-Procedure B Synthesis of 9-Amino Acids 15 A 2 L round bottom flask, equipped with a magnetic stir bar, was charged with 1000 mL of MeOH and the flask tared with its contents. Anhydrous HC1 11 g, 0.29 mol) was bubbled in from a cylinder. To this solution was added a cinnamic acid (0.29 mol) neat in one portion. The resulting mixture was heated at reflux until the reaction was judged complete by TLC analysis. The reaction was cooled to RT, then refrigerated overnight. The crystalline product was collected by suction filtration on a medium frit and the cake washed with cold MeOH. The solid was dried onthe filter to give a white or nearly white product.

Precursor to 8-3: Yield: 94%; TLC (3:1 hexane/EtOAc; UV): Rf 0.48; mp 134-1360 C; 'H NMR (CDC1 3 300 MHz): 7.58 1H, J 15.9 Hz), 7.00-6.97 3H), 53 6.79 1H, J 7.9 Hz), 6.24 Id, 1H, J 15.9 Hz), 5.98 2H), 3.77 3H); MS (FAB): 206.

Precursor to 9-5: Yield: 84%; TLC (3:1 hexane/EtOAc; UV) Rf 0.48; mp 89-91" C; H NMR (CDC13, 300 MHz): 7.63 1H, J 15.9 Hz), 7.46 2H, J 8.7 Hz), 6.89 2H, J 8.7 Hz), 6.29 1H, J 15.9 Hz), 3.82 3H), 3.77 3H); MS (FAB): 192.

Michael addition of benzyl-1-phenylethylamine to methyl 4-methoxy-cinnamate A 1 L 3-neck round bottom flask, equipped with a stopper, thermometer, and 250 mL addition funnel with an Ar inlet was charged with (R)-(+)-N-benzyl-lphenylethylamine hydrochloride (0.132 mol, 32.6 g, 1.1 15 eq based on cinnamate) and the apparatus flushed with Ar 30 min. The salt was suspended in dry THF (200 mL) and the mixture cooled to an internal temperature of .700 C with a dry ice/acetone bath. To the suspension was added n-BuLi (2.5 M in hexanes, 0.257 mol, 103 mL, 20 1.95 eq based on amine hydrochloride) from the addition funnel at such a rate that the internal temperature did not exceed -65° C. The addition required 90 min.

After completing the addition, the reaction was stirred at. -70° C for 1 hr. A solution of methyl 4methoxycinnamate (0.120 mol, 23 g, 1 eq) in THF (125 mL) was added from the addition funnel over 90 min at such a rate that the internal temperature did not exceed -65" C. After completing the addition, the reaction was stirred at -700 C 2 hrs. TLC analysis indicated complete reaction. The reaction was quenched cold by the addition of 5% citric acid (250 mL) and stirred overnight at RT. In a 2 L separatory funnel, the layers were separated and the organic washed with citric acid (1 x 125 mL). The combined aqueous were extracted with EtOAc (1 x 200 mL). The combined 54 organics were then washed-with-5% NaHCO3 (1 x 150 mL) and brine (1 x 150 mL) and dried (MgSO 4 Filtration and evaporation to constant weight provided crude product (50.04 g, 103% of theory) as a viscous oil which solidified on standing. Pure material was obtained by triturating and stirring crude product with heptane (1.5-2 mL/g, 75-100 mL total volume) at RT overnight. The solids were collected by suction filtration on a medium frit and the cake washed by flooding with cold heptane (2 x 50 mL). The solids were dried on the filter to give pure product (28.93 g, 60% yield) as a white powder. TLC (4:1 hexane/EtOAc): Rf 0.50 (12, UV); mp 87-88° C; 1H NMR (CDC13, 300 MHz): 1.20 3H, J 6.9 Hz), 2.51 (dd, 1H, J 9.4, 15 14.8 Hz), 2.66 (dd, 1H, J 5.7, 14.8 Hz), 3.45 (s, 3H), 3.67 (ABq, 2H, J 14.7 Hz), 3.79 3H), 3.98 1H, J 6.8 Hz), 4.37 (dd, 1H, J 5.7, 9.3 Hz), 6.86 2H, J 8.6 Hz), 7.16-7.33 10 7.40 (d, 2H, J =7.3 Hz); MS (FAB): 404 20 Hydrogenolysis of benzvl groups The above adduct (0.071 mol, 28 g) was suspended in MeOH (300 mL) and treated with formic acid 0.179 mol, 8.25 g, 6.8 mL, 2.5 eq) neat in one portion with stirring. To this suspension was added Degussa type E101 NE/W 10% Pd/C (50% wet, 0.00179 mol, 3.81 g, 0.025 eq) in one portion. The resulting mixture was heated at reflux for 1-2 hr until judged complete by TLC analysis. The mixture was cooled to RT, then filtered on a pad of Celite, washing the flask and pad with MeOH (150 mL). The combined filtrates were evaporated to give crude product (15.42 g, 102% of theory) as an oil. The crude product was dissolved in i-PrOH (250 mL) and heated to a gentle reflux. D- 55 tartaric acid (0.071 mol,-10.76 g, 1 eq) was added as a solid in one portion. Heating was continued for min, during which time the salt precipitated as a fine white solid. The mixture was cooled to RT, then refrigerated overnight. The crystalline salt was collected by suction filtration on a medium frit, washing with cold i-PrOH (50-75 mL), and dried on the filter to give product (23 g, The above salt was converted to the free base by dissolving in a minimum volume of H 2 0 (125 mL) and treating the solution with solid NaHCO 3 until the aqueous was saturated. This was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (1 x 100 mL) and dried (MgSO 4 Filtration and evaporation provided pure 15 product (11.75 g, 78%) as a nearly colorless oil which solidified on cooling.

TLC (9:1 CHC13/MeOH): Rf 0.30 (I2, UV); HPLC (reverse phase; MeCN/H 2 0/TFA gradient): 96% pure, Rt 17.9 min; -H NMR (CDC13, 300 MHz): 1.87 (br s, 2H), 2.62 2H, J 6.9 Hz), 3.64 3H), 3.76 3H), 4.35 1H, J 6.9 Hz), 6.84 2H, J 8.6 Hz), 7.25 2H, J 8.6 Hz) MS (FAB) 210.

S-1: COgtBu

*S

H

2

N

H NMR: (CDC13, 300MHz, ppm) 7.41-7.28 5H), 4.18 (q, 2H), 2.65 2H), 2.12 (br, 2H), 1.16 3H).

9-2: COtBu

H

2 N

O

56 'H NMR (CDC1 3 3 00MHz, ppmT 6.8:t Cd, 1H, J 1.-6 Hz) 6.72 1H, J 7.9 Hz) 6.66 1H, J 7.9 Hz) 5.85 2H), 4.22 (1H, dd, J 7.5 Hz and 7.3 Hz), 2.47 (2H, dd, J 7.5Hz and 5.6 Hz), 2.21(s, 2H), 1.35 (9Hl, a).

:9-3:

H

2

N>

lH NMR (CDC1 3 300MHz, ppm) 6.82 1H, J 1. 6 Hz), 6.76 1H, J 7.9 Hz), 6.73 1H, J 7.9 Hz), 5.89 2H), 4.29 C1H, dd, J =6.9 Hz and 6.8 Hz), 3.63 (3H, 2.57 Cd, 2H, J =6.9Hz), 1.75 2H); !ili:H2N lH NMR (CDC1 3 30014Hz, ppm) 67-.78(, (in, .0t 2 d1, 2H 6. Hz), 3.75 3.7, .52 3H), 3.6 (s 6.Hz (b 2HJ68H), 1.42 eQ.. 2H); 9-6:M 57

H

2

N(~

lH NMR (CDC1 3 300MHz, ppm) 7.24 J 8.4 Hz) 6.82 2H, J =8.4 Hz) 4.26 Ct, IH, 6 .8 Hz) 3.66 (s, 3H) 2.47 2H, J 6.6 Hz) 1.41 Cs, 9H); 0-7:

H

2

N-J

lNMR (CDC1 3 300MHz, ppm) 7.21( dd, 1H, J 8.2 Hz and 8.1Hz 6.95-6. 93 Cm, 2H) 6.78 1H, 6 .8 Hz) 4.34 1,J 6.7 Hz), 3.79 Cs, 3H), 2.54 Cd, 2H, J =6.9 Hz) 1. 74 Cs, 2H) 1. 40 9H); C0 2 tBu 2

N

I1 NMR CCDC1 3 300 MHz, ppm): 7.34-7.08 Cm, 2H1), 6.82- 6.68 Cm, 2H), 4.45 Cm, 1H1), 3.65 Cs, 3H), 3.49 Cs, 3H), 2.58 Cd, 2H), 1.68 Cbr s, 2H).

H

2 N G 58 'H NMR (CDC1 3 300MHz, ppm) 7.28-7.25 (in, 2H), 7.01 (df, lH), 4.31(t, 1H), 2.50 2H), 2.01 (br, 2H), 1.41 (s, 9H);

H

2

N

'H NMR (CDC1 3 300MHz, ppm) 6.84 1H) 6.79-6. 76 (in, 1H), 4.24-4.19 (in, 1H), 4.19~ 4H), 2.50 2H), 1. 63 (br, 2H) 1. 41 9H);

CO

2 tBu

H

2 N 'H NMR (CDC1 3 300MHz, ppm) 3.34-3.05 (mn, 1H), 2.65- 2.58 (mn, 2H), 1.65 2H);

CO

2 tBu 0S09 H 2

N

'H NMR (CDC1 3 300MHz, ppm) 7.34-7.28 (mn, 3H), 7.26- 7.15 (mn, 3H), 3.42-3.15 (mn, 1H), 2.71 (dd, 1H, -J Hz and 13.3 Hz), 2.54 (dd, 1H, J 8.1 Hz and 13.3 Hz),* 2.36 (dd, 1H, J =4.2 Hz and 15.7 Hz), 2.20 (dd, J 8.6 and 15.7 Hz) 1.42 9H).

To prepare :9-13 amino acid 59 COztBu IM TMSC1 in CH 2 Cl 2 (33 ml, 33 mmol) was added to a mixture of (R)-a-methylbenzylamine (3.4 g, 28 mmol) and Et 3 N (4 g, 40 mmol) in THF (10 ml) was added and the mixture was allowed to stir for 1 h at room temperature. After the solid was removed by filtration, the solution war concentrated to afford a liquid. This silylamine (2.4 g, 12.5 mmol) was dissolved in THF (35 ml) and was cooled to -78 To 10 this cooled solution was added n-BuLi (7.8 ml of 1.6 M solution in hexanes, 12.5 mmol) slowly. After stirring for 0.5 h at the temperature, to the reaction mixture was added a solution of t-butyl trans-3-(3-

*S*

pyridyl)acrylate (2.56 g, 12.4 mmol) in THF (10 ml).

15 The stirring was continued for another 1/2 h and the mixture was quenched with sat. NH 4 C1 (20 ml) and was allowed to warm up to room temperature and extracted with ether. The combined ether layers were dried

(K

2

CO

3 and concentrated to afford an oil. This oil 20 (500 mg) was dissolved in ethanol (1.5 ml), t-butanol (15 ml), ammonium formate (1.5 g) and 10% Pd/C (1.2 g) were added. The resulting mixture was heated to reflux for 3 h followed by acid and base workup to afford the desired amine 6-13 (300 mg). FAB-MS 223.

0-14: H2 CO 2 Me 60 'HNMR (CDC1 3 6 7.97(2H, a, 7.41(2H, d, J=5.4Hz), 4.40(1H, t, J=4.5Hz), 3.88(3H,s), 2.55(2H, d, 1.71(2H, br), 1.39 (9H, s).

General Procedure for synthesis of M-1. M-2 and M-3 To a solution of the commercially available amino acid (1.5 mmoles) in CH 2 Cl 2 (4 ml) and MeOH (1 ml) cooled to 0°C, was added thionyl chloride (0.125 ml, 1.65 mmol). The reaction was warmed to 40 oC for 2 h, 10 ar.d concentrated to dryness in vacuo to afford the desired amino ester HCl salt.

M-1: 0* Co 2 HCfH 2

N

89% yield; 'HNMR (DMSO-d 6 300 MHz, ppm): 9.00-8.75 (3H, 15 bm), 7.71 (2H, d, J 7.3 Hz), 7.58 (2H, d, J 7.3 Hz) 4.71 (1 H, bs), 3.64 (3 3.40-3.06 (2H, m); M-2: o o

HCMH

2

N

yield as a tan solid. 'HNR (CDC13' 300 MHz; ppm): 7.55-7.05 (6 H, bm), 3.66 (3H, 3.65-3.45 (2H, bm), 3.10-2.77 (5H, bm), 2.17-1.95 (2H, bm); M-3: 61 HCrH 2

N

0 2

N

84% yield as a pale tan solid; 1 HNMR (CDC1 3 300 MHz, ppm): 8.1-7.8 (4H, bm), 7.65-7.45 (3H, bm), 5.45 (1H, br), 3.80-3.30 (2H, bm), 3.55 (3H, s).

Procedure C Synthesis of Coupled Amino Acids To a solution of ethyl 3-amino-3-phenyl-lpropanoate (or other 9-amino acid ester prepared by Procedure B) (0.50g, 5.25 mmol) in CH 2 C12 (5 ml) was 0 added BocLeuOSu (1.5g, 4.67 mmol) (CbzLeuOSu is used for the Cbz protected analog) with cooling and Et 3 N drops). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH 2 Cl 2 and washed with 5% citric acid (5mlX2), 5% NaHCO 3 15 (5ml) and sat. NaC1 (5ml). The organic layer was dried (Na 2

SO

4 and concentrated to afford 1.26 g as a white solid.

Procedure D Synthesis of Deprotected Amino Acids To a stirred solution of the product of Procedure C (a Boc-Leu-S-amino acid ester) (41.5 mg, 0.102 mmol) at 0-5°C. in 2 mL of CH 2 C1 2 was added 4 mL of TFA. The mixture was allowed to come to room temperature with continued stirring for 1 hour. The reaction was concentrated in vacuo, redissolved in

CH

2 C1 2 concentrated two more times and placed under high vacuum to remove final traces of TFA. HPLC showed complete conversion to two new peaks of shorter retention time. The residue can taken up in DMF and 62 TEA added with stirring until basic to litmus in preparation for further reaction.

A Cbz group is removed using the following method: The product from Procedure C (where t-butyl 3 -amino-3-phenyl-l-propanoate and CbzLeuOSu were used) (110 mg, 0.23 mmol) in MeOH with a catalytic amount of palladium on charcoal was stirred overnight under hydrogen at 40 psi. The reaction was filtered through Celite® and concentrated in vacuo yielding the free base Leu BOC S-amino acid (87 mg, quantitative) as a clear oil. 1H NMR: (CDC13, 300 MHz, ppm), 7.30 m, S 5H), 5.33 (dd, 1H, J=6, 8.82 Hz), 4.00 1H) 2.77 (dd 1H J=9, 15 Hz), 2.90 (dd, 1H, J=6, 15 Hz), 1.69 (m, 2H), 1.45 1H), 1.29 9H), 0.90 6H, J=6 Hz).

EXAMPLE 1 Synthesis of BIO-1002 A. A stirred solution of cyanoacetic acid (13 mg, 0.15 mmol), EDC (30 mg, 0.16 mmol), and HOBt 0 (30 mg, 0.20 mmol) in DMF (0.5 mL) was treated with a 20 solution of the amine prepared in Procedure D (52 mg, 0.105 mmol) and diisopropylethylamine (0.30 mL, 1.7 mmol) in DMF (1.0 mL) at room temperature. After the solution was stirred for over 18 h, the reaction was partitioned in ethyl acetate (15 mL) and 60 sat.

NaHCO 3 (10 mL). The organic phase was washed with sat. aq. NaHCO 3 (2 X 10 mL), H20 (5 mL), 5% citric acid (3 X 10 mL), H20 (5 mL), and sat. aq. NaC1 (10 mL). The organic phase was dried (MgSO 4 and concentrated in vacuo to afford BI01002-OEt (27 mg, 69%) as a foam: 1 H NMR (CDC1 3 300 MHz, ppm) 7.58 1H), 7.45 1H), 7.40-7.20 5H), 5.28 1H), 4.46 1H), 4.05 (m, 2H), 3.23 2H), 2.79 2H), 1.78-1.53 3H), 1.23 3H), 0.90 6H).

0 63- B. A stirred sdluticn of B101002-OEt (27 mg, 0.072 mmol) in methanol (3 mL) was treated with aq.

LiOH (1.0 M, 0.25 mL, 0.25 mmol) at room temperature for 22 h. The reaction was acidified with trifluoroacetic acid then concentrated inY~= The crude products were purified by HPLC to give BIO-1002A mg, 10k) and BIO-1002B (4.4 mg, 18k) as white solids: BIO1002A: 'H NMR (CDCl 3 300 MHz, ppm) 8.08 1H) 7.87 1H), 7.30-7.16 (in, 5H), 5.25 (mn, 1H), 4.37 (in, 1H), 3.36 2H), 2.75 (in, 1.70-1.45 (in, 3H), 0.90 (in, 6H); HPLC (Gradient 16.7 min; MS, m/z 346 BIO1002B: 1H NMR (CDCl 3 300 MHz, ppm) 8.00-7.70 (in, 2H), 7.40-7.20 (in, 5H), 5.28 (in, 1H), 4.39 (in, 1H), 3.45 2H), 2.78 (in, 2H), 1.65-1.40 (in, 3H), 0.90 (in, 6H); HPLC (Gradient 20.6 min; MS, m/z 346.

EXAMLEa2 Synthesis of RTO-1003 A. The procedure as described Example 1A was performed utilizing cyclohexylacetic acid (22 mg, 0.15 mmcl), EDC (30 mg, 0.16 minol), and HOBt (30 mng, 0.20 minol), amine from Procedure D (52 mng, 0.105 minol) and diisopropylethylamine (0.30 inL, 1.7 inmol) in DMF rnL) to afford B101003-OEt (32 mg, as a foam: 1H NMR (CDCl 3 300 MHz, ppm) 7.42-7.18 (in, 6H) 6.08 (in, 1H), 5.36 (in, 1H), 4.50 (in, 1H), 4.05 (in, 2H), 2.81 (mn, 2H), 2.11-0.80 (in, B. The procedure as described in Example lB was performned utilizing B101003-OEt (32 ing, 0.074 mmol) and aq. LiOH (1.0 M, 0.25 mL, 0.25 minol) in MeOH rnL) to give BIO-1003A (3.5 ing, 11t) and BIO-1003B (5.3 ing, 18t) as white solids: BIO-1003A: 'H NNR (CDCl,, 300 MHz, ppm) 7.35-7.16 (in, 5.23 (in, 1H), 4.38 (in, 1H), 2.28 2H), 2.03 (in, 64 2H), 1.75-0.80 (in, 22H); -HPLC -(Gradient 34.1 min and 35.3 min 1) MS, mhz 403.

BIO-1003B: 1H1 NMR (CDCl 3 300 MHz, ppm) 7.35-7.16 (in, SH) 5.23 (mn, 1H) 4.38 (mn, 1H), 2.28 (mn, 2H) 2.03 (mn, 2H), 1.75-0.80 (in, 22H); HPLC (Gradient 34.1 min and 35.3 min MS, mhz 403.

EXAMLE

Synthegisq of RTO-1014 A. Methyl 3-aiino-3-phenyl-1-propanoate was :10 coupled with BocLeuOSu by the method described in Procedure C. This material was subjected to the conditions used in Procedure D1 to give the desired TFA-ainine salt.

B. The procedure as described in Example 1A was performed utilizing indole-3-carboxylic acid (19 mng, 0.12 inmol), EDC (26 ing, 0.14 inmol), HOBt (26 mg, 0.17 minol), amine from Example 3A (44 ing, 0.11 minol) and di isopropyl ethyl amine (0.10 mL, 0.56 iniol) in CH 2 Cl 2 inL) to afford BI01014-e (25 mng, 52ks) as a foam.

C. The same procedure as described in Example lB was performed utilizing B101014-OMe (25 ing, 0.057 inmol) and aq. LJ.OH (1.0 0.115 mL, 0.115 iniol) in MeOH (5 inL) to give BIO-1014A (5.1 ing, 21k) and BIO- 1014B (4.7 ing, 20%) as white solids: BIO-1014A: 1 NNR (CDCl 3 300 MHz, ppm) 8.52 1H), 8.13 1H), 8.10 1H), 7.81 1H), 7.46-7.03 (in, 9H), 5.20 (in, 1H), 4.58 (in, 1H), 2.69 (in, 2H), 1.75- 1.45 (mn, 3H), 0.90 (in, 6H); HPLC (Gradient 28.1 min; MS, mn/z 422.

BIO-1014B: 'H NMR (CDCl 3 300 MHz, ppm) 8.55 1H) 8.18 1H), 8.13 1H), 7.79 1H), 7.46-7.03 (mn, 9H), 5.20 (mn, 1H), 4.58 (in, 1H), 2.70 (mn, 2H), 1.55- 1.40 (mn, 3H1), 0.90 (mn, 6H); HPLC (Gradient 29.5 min; MS, m/z 422.

EXMPLE

Synthesis of RTO-1017 A. The procedure as. des -cribed in Example 1A was performed utilizing 1-phenyl-1:-cyclopropanecarboxylic acid (21 mg, 0.13 mmol), EDC (26 mg, 0.14 mmol), HOBL (26 mg, 0.17 mmol), amine from Example 3A (44 mg, 0.11 inmol) and diisopropylethylamine (0.10 mL, 0.56 mmol) in CH 2 Cl 2 (5.0 m.L) to afford B101017-OMe (39 mg, 68k) as a foam.

B. The procedure as described in Example 1B was performed utilizing B101017-OMe (39 mg, 0.089 mmol) and aq. LiCH (1.0 M, 0-.27 mL, 0.27 mmol) in MeOW (2 m.L) to give BIO-1017A (10.3 mg, 27V~) and BIO-1017B (12.2 mg, 32%) as white solids: BIO-1017A: 1H NMR (CD 3

SOCD

3 300 MHz, ppm) 8.46 1H) 7.40-7.20 (in, 10H), 6.30 lW), 5.09 (in, 1H), 4.33 (mn, 1H), 2.62 (in, 2H), 1.50-1.20 (in, 5H), 0.98 (in, 2H), 0.82 (mn, 6H); HPLC (Gradient 33.9 min; MS, mhz 423.

BIQ-1017B: 'H NMR (CD 3 SOCD3, 300 MHz, ppm) 8.55 1H), 7.48-7.15 (in, 10H), 6.30 1H), 5.08 (in, 1H), 4.35 1W), 2.63 (in, 2H), 1.48-1.15 (in, 5H), 1.10-0.88 (in, 2H), 0.85-0.64 (mn, 6H); HPLC (Gradient 33.9 min and .:34.5 min MS, m/z 423.

Synthesis of RTO-1022 A. The procedure as described in Example 1A was performed utilizing 2-naphthylacetic acid (20 mng, 0.11 iniol), EDC (25 mg, 0.13 mmol), HOBt (25 mg, 0.16 iniol), amine from Example 3A (42 mng, 0.10 inmol) and diisopropylethylamine (0.10 rnL, 0.56 inmol) in DMF mL) to afford B101022-OMe (36 mng, as a foam.

B. The procedure as described in Example lB was performed utilizing B101022-OMe (36 mng, 0.078 inmol) and aq. LiOH (1.0 M, 0.50 mL, 0.50 inmol) in MeOW (3 mL) 66to give BIO-1022A (1.7 mg, and BIO-1022B (6.8 mng, 19%) as white solids: BIO-1022A: 1H NNR (CDCl 3 300 MHz, ppm) 7.90-7.17 (in, 12H), 5.30 1H1), 4.45 (in, 1H), 2.79 (in, 2H), 1.68- 1.33 (in, 3H), 0.87 6H); HPLC (Gradient 25.7 min; MS, m/z 447.

BIO-1022B: 'H NMR (CDCl 3 300 MHz, ppm) 7.90-7.17 (in, 12H), 5.35 1H), 4.49 (mn, 1H), 2.79 2H), 1.58- 1.33 (in, 3H1), 0.82 (in, 6H); HPLC (Gradient 25.7 min and 26.4 min MS, mhz 447.

XAMTLR.

Synthesig of RTO-1Q29 A. t-Butyl 3 -amino-3-phenyl-1-propanoate was :::.coupled with BocLeuOSu using the method described in Procedure C. This material was subjected to the conditions of Procedure D2 to give the desired amine salt.

B. The procedure as described in Example 1A was performed utilizing 4-(2-aminobenzanido)phenylacetic acid (18 mg, 0.067 mmcl), EDC (13 mg, 0.067 inmol), and HOBt (13 ing, 0.085 mmol), amine from Example 6A (18 mg, 0.054 iniol) and diisopropylethylanine (0.048 mL, 0.27 inmol) in DMF inL) to afford NH 2 -BI01029-OtBu (32 mg, 100%) as an oil: 'H NMR (CDCl 3 300 MHz, ppm) 7.65-7.43 (mn, 4H) 7.40- 7.10 (in, 9H), 6.72 (in, 2H1), 6.49 1H), 5.28 (in, 1H), 4.45 3.52 2H), 2.68 (in, 2H), 2.00 (bs, 2H),1.65-1.15 (in, 13H), 0.85 (mn, 6H).

C. A solution of NH 2 -B101029-OtBu (16 mg, 0.027 mmol) in trifluoroacetic acid (1 inL) was--stirred at room temperature for 45 min and then concentrated.

The crude product was purified by HPLC to afford NH 2 BI01029 ing, 26%) as a white solid: MS, zn/z 531.

D. A solution of N11 2 -B101029 (3.4 ing, 0.0064.

minol), methyl isocyanate (3 drops), and diisopropyl- 67 ethylamine (1 drop) in CH 2 I12 (0.30 mL) was stirred at room temperature for 18 h and then concentrated in acu. The crude product was purified by HPLC to afford BIO-1029 (2.6 mg, 69%) as a white solid: 'H NMR

(CD

3

SOCD

3 300 MHz, ppm) consistent with structure;

HPLC

(Gradient 28.2 min; MS, m/z 588.

EXAMPLE 7 Synthesis of BIO-1032 A. The procedure as described in Example 1A 10 was performed utilizing 3-arino-phenylacetic acid (29 mg, 0.19 mmol), EDC (44 mg, 0.23 mmol), and HOBt (44 m g, 0.29 mmol), amine from Example 6A (49 mg, 0.15 .mmol) and diisopropylethylamine (0.17 mL, 0.95 mmol) in DMF (1.0 mL) to afford NH 2 -BI01032-OtBu (22 mg, 31%) as a foam after flash chromatography (SiO 2 60% ethyl acetate-hexane): IH NMR (CDC13, 300 MHz, ppm) 7.45-7.05 7H), 6.75-6.50 3H), 5.97 1H), 5.30 1H), 4.46 1H), 3.50 2H), 2.71 2H), 1.70-1.39 (m, 3H), 1.33 9H), 0.84 6H).

20 B. A mixture of NH 2 -BI01032-OtBu (7.0 mg, 0.015 mmol), phenylsulfonyl chloride (1.7 AL, 0.014 mmol), and diisopropylethylamine (5.4 AL, 0.030 mmol) in CH 2 C12 was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue diluted with ethyl acetate. The organic solution was washed with 60% sat. aq. NaHCO 3 (2 H 2 0, citric acid (3 H 2 0, and sat. aq. NaC1, dried (MgSO 4 and concentrated. The residue (9 mg) was stirred in trifluoroacetic acid (1 mL) at room temperature for 30 min before concentrating in vacuo.

The resulting crude product was purified by HPLC to afford BIO-1032 (3.9 mg, 47%) as a white solid: 'H NMR

(CD

3

SOCD

3 300 MHz, ppm) 8.52 1H), 8.17 1H), 7.75 2H), 7.61-7.45 3H), 7.35-6.85 9H), 68 5.13 1H), 4.28 3.40 2H), 2.65 (bs, 2H), 1.50-1.12 3H), 0.79 3H), 0.71 3H) HPLC (Gradient 18.7 min; MS, m/z 552.

EXAMPLE.

Synthesis of BIO-1093 A. To a stirred solution of the Bocprotected amine product of Procedure C (41.5 mg, 0.102 mmol) at 0-5 0 C. in 2 mL of CH 2 C1 2 was added 4 mL of TFA.

The mixture was allowed to come to room temperature 1 0 with continued stirring for 1 hour. The reaction was concentrated in vacuo, redissolved in CH 2 C1 2 concentrated two more times and placed under high vacuum to remove final traces of TFA. HPLC showed complete conversion to two new peaks of shorter retention time.

B. The material from Example 8A was redissolved in 0.75 mL DMF, cooled to 0-5 and DIEA was added until the mixture was basic to litmus and the ice bath was removed. This material combined with 4- 20 nitrophenyl acetic acid (16.5 mg, 0.091 mmol), HOBt (20.4 mg, 0.151 mmol) and EDC (19.4mg, 0.101 mmol) under conditions described in Example 1A to yield BIO 1093-OEt (21.4 mg, 50%) as a clear oil.

C. A solution of BIO 1093-OEt (21.4 mg, 0.053 mmol) in 1 ml of MeOH was stirred overnight at room temperature with 1N LiOH (130 Al, 0.13 mmol). The mixture was acidified (red to litmus) with TFA and concentrated in vacuo. Pure isomers were resolved via preparative HPLC followed by lyophilization. Repeated dissolution in 50/50 MeOH/CH 2 Cl 2 and in vacuo concentration followed by 24 hours under high vacuum provided BIO-1093 (3 mg, 13%) of each isomer as white amorphous solids: Isomer A: 1H NMR: (CDC13, 300 MHz, ppm) 8.09 (d 2H J=8.2 Hz), 7.38 2H, J= 8.21 Hz), 7.15 5H), 5.21 1H), 4.32 1H), 3.28 1H), -69 2.67 (mn, 2H), 1.40 3HI, 0.75 (dd, 6H J=6-9, 7.6 Hz) FAB: 442 464 Na) +Mw 441.43. HPLC: Gradient 1 single peak >99% 19.5 min. Tic: MeOH/CH 2 Cl 2 Rf=0.25, EtOAc plus 196 HOAc Rf=0.35.

Isomer B: 1H NMR: (CDCl 3 300 MHz, ppm), 8.0 2H, J=9.7 Hz), 7.56 1H J=8.0 Hz), 7.73 d, 2H J=9.7 Hz), 7.07 5H), 5.15 1H, J=5.5 Hz), 4.29 (mn, 1H), 3.45 2H), 2.65 (mn, 2H), 1.45 (in, 3H1), 0.78 (dd, 6H, J=6.9, 4.8 Hz) FAB: 442 464 (M+Na) MW 441.43.

HPLC: Single peak >99t, 19.3 min. Tic: 10% MeOH/CH 2 C1 2 Rf 0.29, EtOAc plus 1% HOAc Rf 0.55.

EXAMPTLE2 S9=hesis of ETO-1099 A. The amine from Example 3A (50.0 ing, 0.127 inmol) was subjected to the conditions described in Example 8B using diphenylacetic acid (25.6 mg, 0.121 mmol), HOBt (26 mng, 0.19 inmol), and EDC (27 mg, 0.14 inmol) in DMF to afford BIO 1099-OMe (49.2 mg, 83k) as a clear viscous oil.

20 B. B101099-OMe (49 mg, 0.1 inmol) was saponified and purified as described in Example 8C to provide BIO-1099A (7 mng, 15%) and BIO-1099B (5 ing, ilks) as white amorphous solids. Isomer A: 'H NMR: (CDCl 3 300 MHz, ppm), 7.95 1H1 8Hz), 7.19 (mn, 15H), 6.95 1H 8Hz), 5.25 1H1, 4.84 1H1), 4.41 (mn, 1H), 2.70 (dd, 2H, J= 2.5, 1.3 Hz), 1.41 (in, 3H), 0.79 (dd, 6H, (J=6Hz) FAB: 474, (M+Na) +496 MW 472.54 HPLC: 1 peak; 100% pure; 30.074 min. Tic: MeOH/CH 2 Cl 2 Rf =0.33; 50/50 EtOAc/Hex, 1% HOAc Rf--=O.

4 Isomer B 'H NMR: (CDCl 3 300 MHz, ppm) 7.72 1H, 8Hz), 7.22 (mn, 15H), 5.31 1H, 1.2Hz), 6.70 1H 8Hz), 4.93 1H), 4.60 (in, 1H1), 2.68 1H), 2.65 (in, 2H 1.35 (mn, 3H1), 0.61 (dd, 6H, J=2.5, 1.3 Hz).

FAB 473 495 MW 472.54 HPLC: 1 Peak; 70 100%; 30.38 min. Tic: 10% MeOH/CH, 2

C

2 R, =0.33, 50/50 EtOAc/Hex plus 1% HOAc Rf 0.38.

EXAMPLE Synthesis of BIO-1100 A. The amine salt described in Example 6A (prepared from 40.5 mg, 0.093 mmol of Boc protected material) was taken up in 1.0 mL of DMF and TEA was added with stirring until basic to litmus.

B. The method described in Example 1A was 10 performed using 2 -bromo-5-methoxy-4-hydroxy phenyl acetic acid (23.1 mg, 0.089 mmol), HOBt (18.9 mg, 0.14 mmol), EDC (19.6 mg, 0.10 mmol) in 1.0 ml DMF and free amine prepared in Example 10A to give a white solid (49 mg, quantitative). An aliquot was purified by preparative reverse phase HPLC (gradient 2), lyophilized and dried by repeatedly dissolving in 50/50 MeOH/CH 2 Cl 2 and concentrated under reduced pressure to yield BIO-1100 (1.8 mg) as an amorphous white solid. 1

H

NMR:' (CDCl 3 300 MHz, ppm), 7.25 5H), 7.05 1H), 20 6.30 1H), 5.28 1H), 3.81 3H), 3.59 2H), 2.77 2H), 1.45 3H), 0.82 (dd, 6H J=2.5, 1.2).

S..FAB: 521, 523; 543, 545; MW 521.44 HPLC: Major peak at 29.1 min; >97% purity. Tic: 10%MeOH/CH 2 Cl 2 Rf= 0.16; 50/50 EtOAc/Hex plus 1% HOAc Rf =0.28 EXAMPLE 11 Synthesis of BIO-1106 A. To a solution of 6-aminohexanoic acid g, 7.6 mmol) in dioxane 6 ml) and water (6 ml) containing TEA (1.7 ml, 11.25 mmol) was added BOC-ON (2.1g, 8.4 mmol, Aldrich). After stirring for 3h at room temperature, the reaction was diluted with water ml) and washed twice with ethyl acetate (10 ml).

The aqueous was then acidified to PH 1-2 with 1N HC1 and the aqueous layer extracted five times with ethyl 71 acetate, dried over Na 2

SO

4 -and concentrated to afford 1106-1 (842 mg, IHNMR (CDC1 3 300 MHz, ppm): 4.61 (1H, bs), 3.15-2.95 (4H, bm), 2.55-2.23 (4 H, 1.65- 1.50 (4 1.46 (9 1.45-1.30 (2 H, m).

B. t-Butyl 3 -amino-3-phenyl-l-propanoate was coupled with CbzLeuOSu as described in Procedure C.

This material was subjected to the conditions of Procedure D2 to give the desired free amine.

C. N-Boc 6-aminohexanoic acid (prepared in 10 Example 11A) (17.3 mg, 0.075 mmol), HOBt (15.2 mg, 0.11 mmol) and EDC (17.3 mg, 0.09 mmol) were stirred in 0.5 ml of DMF at room temperature for 1.5 hours. The f. ree amine from Example 11B (25 mg, 0.075mmol) in ml of DMF was added to the stirred solution of activated ester along with two drops of TEA so that the reaction was basic to litmus. After several hours the reaction was determined to be incomplete by HPLC.

Small portions of N-Boc-6-aminohexanoic acid, HOBt, and -EDC were then added to drive the reaction to 20 completion. Purification, as detailed in Example 8C, provided BIO 1106 Boc t-butyl ester (26 mg, 63%) as a clear viscous oil. 1 H NMR: (CDC13 300 MHz, ppm), 7.40 1H, 8Hz), 7.32 -7.25 5H), 6.30 1H, J=8Hz), 5.30 1H, J=7 Hz), 4.49 1H) 3.09 (bs, 2H), 2.79 (dd, 1H, J=8, 15 Hz), 2.69 (dd, 1H, J=7, 15 Hz), 2.20 2H J=8 Hz), 1.69-1.39 9H), 1.42 9H), 1.29 9H), 0.88 6H). HPLC: 1 peak, 100% purity at 28.3 min.

Both t-butyl protecting groups of BIO 1106 Boc t-butyl ester were removed as described in Example The resulting residue was stirred in 0.5 ml of DMF, made basic to litmus by the addition of two drops of TEA, followed by phenyl isocyanate (13.6 mg, 0.3 mmol) and stirred overnight. The reaction mixture was purified as detailed in Example 10B resulting in BIO- 72 1106 (3.5 mg, 29k) as a beige amorphous solid. 'H NMR: (CDCl 3 300 MHz, ppm) 7.97 1H, 8 Hz) 7.22 (in, 11H), 6.91 1H J=8 Hz) 5. 30 (in, 1H) 4. 33 (in, 1H) 3.12 (mn, 6H), 2.63 (in, 2H), 2.13 2H, J=6 Hz), 1.41 (bin, 9H), 0.80 (mn, 6H) FAB: 511, (M+Na) "533; MW 510.59. HPLC: 1 peak; 100k at 19.4 min. Tic: 2 C1 2 Rf 0.32, 10%MeOH/EtOAc plus lI-HOAc Rf =0.31.

flXAML Ia 10 Sytei of RTO--1142 -1-Benzocyclobutene carboxylic acid (16.3 ing, 0.11 inmol), HOBt (22.4 ing, 0.165 mmcl), and EDC (23.7 mg, 0.121 minol) were stirred in 0.5 ml DMF at *room temperature for 45 minutes to give the activated ester. The product of Example 10A (15.3 mg, 0.055 mmcl) was added to the activated ester and the mixture stirred for two hours. Filtration and preparative

HPLC

purification, as described in Example 10B, yielded BIO- 1142 isomer A 4.4 mng, 70%) and BIO-1142 isomer B (4.9 mg, 22t) as white amorphous solids.

BIO-1142 isomer A: 'H NNR: (CDCl 3 300 MHz,ppm) 7.79 1H J=8 Hz), 7.31- 7.05 (in, 9H), 6.81 1H J=8 Hz) 5.24 (in, 1H) 4.36 (in, 1H) 4.15 (in, 1H) 3.00- 3.50 (bin, 11H) 2.70 (in, 2H) 1.43 (in, 3H) 0.70 (in, 6H). FAB: 409 431; MW 408.46. HPL C: Major peak at 20.2 min; >99%k purity. Tic: MeOH/CH 2 Cl 2 Rf =0.46, EtOAc plus 1% HOAc Rf =0.53.

BIO-1142 isomer B: 'H NNR: (CDCl 3 3 00 MHz, ppm) 7. 92 1H, J=8 Hz) 7.31-7.05 (in, 9H) 6.91 1H,--J=8z), 5.25 (mn, 1H) 4.38 (in, 1H) 4.14 (in, 1H) 3.28 (in, 2H), 2.72 (in, 2H), 1.42 (mn, 3H), 0.77 (in, 6H). FAB: 409 431; MW 408.46. HPLC: Major peak at 20.62 min; >96t purity. Tic :10V MeOH/C11 2 C1 2 Rf =0.52; EtOAc plus 1% HOAc Rf 54.

73 EXAMPLE I-A Synthenig of RT0-1189 (±)-1-indancarboxylic acid (6.2 iag, 0.038 mmol), HOBt (7.7 mg, 0.057 mmol), and EDC (8.0 'mg, 0.042 mmol) were stirred in 0.5 ml DMF at room temperature for two hours. The free amine prepared in Example 11B was treated with TFA and this material mg, 0.038 mmol) was then added and the mixture stirred overnight. Filtration and preparative HPLC purification as described in Example lOB yielded BIO- 0: 1189 isomer A (less than 1mg) and isomer B (2 mg, 12V) as white amorphous solids.

BIO118 ismerA: IH NMR: (CDCl 3 300 M4Hz, ppm), 7.3- 7.1 12H), 5.32 (in, 1H), 4.48 (in, 1H), 3.91 Ct, 1H J=6.6Hz), 3.1-2.7 (in, 3H), 2.5-2.2 CM, 1H), 1.6-1.4 (mn, 3H) 0. 85 (mn, 6H).

FAB: 423 445; MW 422.5.

HPLC: Major peak 21.2 min.; >97t purity.

Tic: 5t MeOH/CH 2 Cl 2 Rf =0.19; EtOAc plus 1% HOAc Rf 73.

BIO-1189 isomer B: 1HNMR: (CDCl 3 300 MHz, ppm) 7.7 (d, 1H, J=8 Hz), 7.45-7.1 (in, 9H), 6.65 1H, J= 8Hz), 5.33 (mn, 1H), 4.48 (in, 1H), 3.90 1H, J=6.6Hz), 3.1-2.8 Cm, 3H), 2.45-2.3 2H), 1.48 Cm, 3H), 0.80 Cm, 6H).

FAB: (M4+ 423 (M4 445; MW 422.5.

HPLC: Major peak 21.5 min; 94k purity.

Tic: 5k MeOH/CH 2 Cl 2 Rf 12, EtOAc plus 1% NOAc Rf =0.60.

RXAMPL 14 Synthesis of STO-1006 A. Amine I9-3 was coupled with BocLeuOSu according to Procedure C (product recrystallized from diethyl ether) and deprotected according to Procedure D to give the desired TFA-ainine salt.

74 'H-NMR (300 MHz, CDC1 3 for BOC- amine: 0. 90 (in, 6H) 1.42 1.55-1.75 (mn, 3H), 2.8 (mn, 2H), 3.61 (s, 3H) 4.05 (mn, 1H) 4.83 mn, 1H) 5.26 (mn, 1H) 5.92 2H), 6.68-6.78 (in, 3H), 7.06 1 H).

1H-NMR (300 MHz, CDC1 3 for TFA-amine: 0. 83 3H) 0.87 3H), 1.50 (in, 1H), 1.63 bt, 2H), 2.73-2.92 (mn, 2H), 3.63 3H), 4.27 (bs, 1H), 5.26 (mn, 1w), 5.95 2H), 6.66-6.78 (mn, 3H), 7.58 (bs, 3H), 8.02 1 H).

B. A solution of amine-TFA salt of Example :14A (24 mng) in CH 2 C1 2 was added to 4 -hydroxyphenylacetic acid succinimidyl ester (14 ing, 1.1 eq) and stirred at room temperature for about 2 hours. The reaction mixture was washed with 5 citric acid sat. aq.

NaHCQ 3 (2X) and brine (1X) dried (Na 2

SO

4 I filtered and concentrated to give 28 mng of crude BIO-1006 methyl ester. 'H-NMR: (300 MHz, CDCl3) 0.82 (6 H) 1.35-1.58 (3 2.62-2.82 (2 3.48 (2 3.57 (3 4.41 (1 5.70 (1 5.89 (2 6.08 (1 6.65-6.75 H) 7.04 (2 H) 7.22 (1 H) C. Crude BIO-1006 methyl ester in MeOH was added to 1 N LiOH and stirred at room temperature for about 1 hour. The reaction mixture was neutralized by trifluoroacetic acid and purified by HPLC. The clean fraction was collected and dried to give BIO-1006.

'H-NMR (300 MHz, CDCl 3 0.73 J=6 Hz, 3H) 0. 80 (d, J=6 Hz, 3H), 1.35 (bt, 2 1.45 (mn, 1H), 2.40 (in, 2H), 3.22-3.38 (mn, 2H), 4.23 (bq, iN), 5.02 (in, 1H), 5.93 2H), 6.65 J=8 Hz, 2H), 6.68-6.80 (in, 2H), 6.83 IN), 7.03 J= Hz, 2H), 8.11 (bd, iNW.

Mass Spec. M/z 457 EXAMLE 1 Synthe~in of RIO-1050 75 A. To a suspension- of 4-amino phenylacetic acid (9 g, 60 mmol) and N-(benzyloxycarbonyloxy)succinimide (15 g, 60 mmol) in CH 2 C1 2 was added enough triethylamine to form a homogeneous solution. The mixture was stirred at room temperature for 30 min and then CH 2 C1 2 was removed by rotavapor. The resulting residue was dissolved in water and acidified with HC1. The solid thus formed was filtered and washed with 5% HC1, water, and diethyl ether to give 12 g of Cbz-aminophenylacetic acid as a brownish pcwder. 'H-NMR (300 MHz, DME3-d6): 3.48 2H), 5.13 2H), 7.14 2H), 7.29-7.45 7H), 9.73 1

H).

B. The method of Example 1A was performed 15 using Cbz-aminophenylacetic acid from Example 15A (342 mg, 1.2 mmol) in DMF, HOBT (275 mg, 1.8 mmol), EDC (276 mg, 1.44 mmol), and a solution of free amine prepared in Example 14A (432 mg, 0.94 mmol) in DMF to give the .coupled product which was used without further 20 purification.

C. The product of Example 15B was subjected to hydrogenation

(H

2 50 psi, 10 Pd/C, MeOH/H 2 0, "overnight). The reaction mixture was filtered through a pad of Celite®, and concentrated to give 0.4 g (90 of free amine as a brown powder. 'H-NMR (300 MHz, CDC1 3 for 0.82 6H), 1.30-1.62 3H), 2.62-2.82 (m, 2H), 3.45 2H), 3.57 3H), 4.37 1H), 5.18 (m, 1H), 5.91 2H), 6.65-6.80 5H), 7.02 2 H).

D. To a solution of free amine from Example 15C (22 mg) in CH 2 C1 2 was added phenylisocyanate mg, eq) with one drop of triethylamine. The solution was then stirred at room temperature for 2 hours.

After diluting with ethyl acetate (15 mL), the mixture was washed with 5% citric acid sat. aq. NaHC03 (2X) and brine (1X) dried (Na 2

SO

4 filtered and 76 concentrated to give the erude-phenylureamethyl ester.

E. The crude phenylureamethyl ester was dissolved in MeOH and 1 N LiOH was added at 0°C and mixture was stirred at room temperature for 2 h. After neutralization with trifluoroacetic acid, the reaction mixture was purified by HPLC. The pure fraction was collected and dried to give BIO-1050. 'H-NMR: (300 MHz, DMSO-D6): 0.76 3H), 0.80 3H), 1.30-1.50 (m, 3H), 2.52-2.72 2H), 3.28-3.50 comp, 2H), 4.30 (m, 1H), 5.06 1H), 5.97 2H), 6.70 1H), 6.79- 6,87 2H), 6.95 1H), 7.13 2H), 7.25 2H), 7.85 2H), 7.43 2H), 8.12 1H), 8.40 1H), 8.60 1H), 8.66 1H). Mass Spec: M/z 575.

EXAMPLE 16 Synthesis of BIO-1068 The procedure of Example 15D was followed S* .utilizing cyclohexylisocyanate for phenylisocyanate.

The resulting product was hydrolyzed as described in Example 15E and the pure fraction from HPLC 20 purification was collected and dried to give BIO-1068.

'H-NMR (300 MHz, DMSO-d6): 0.73 J 6 Hz, 3H), 0.80 J 6 Hz, 3H), 1.05-1.85 13H), 2.50-2.75 (m, 2H), 3.23-3.50 3H), 4.28 (bq, 1H), 5.05 (bq, 1H), 5.95 (bs, 2H), 6.02 J 8 Hz, 1H), 6.72 (bd, 1H), 6.71 J 8 Hz, 1H), 6.84 (bs, 1H), 7.08 J 8 Hz, 2H), 7.25 J 8 Hz, 2H), 8.07 J 8 Hz, 1H), 8.20 1H), 8.40 J 8 Hz, 1H).

Mass Spec. M/z 581.

EXAMPLE 17 Synthesis of BIO-1079 The procedure of Example 15D was followed utilizing 2-methoxyphenylisocyanate for phenylisocyanate. The resulting product was hydrolyzed 77 as described in Example 15E and the pure fraction from HPLC purification was collected and dried to give Bio- 1079. 'H-NMR (300 MHz, DMSO-d6): 0.75 3H), 0.80 (d, 3H), 1.30 -1.50 3H), 2.50-2.72 2H), 3.30-3.45 2H), 3.85 3H), 4.28 1H), 5.06 1H), 5.96 (bs, 2H), 6.69-7.02 8H), 7.13 2H), 7.34 (d, 2H), 8.05-8.15 3H), 8.42 (bd, 1H), 8.87 1H), 9.13 1H). Mass Spec. M/z 605.

EXAMPLE 18 i 10 Synthesis of BIO-1082 A. Triethylamine was added to a solution of the TFA-amine salt prepared in Procedure D (43 mg) in

CH

2 Cl1 at 0°C until pH reached 9.0 was reached, followed by the addition of 4-phenylbutyryl chloride (26 mg).

After stirring at room temperature for 2 h, the reaction mixture was diluted with ethyl acetate (20 mL) and then washed with 5% citric acid sat. aq.

NaHCO 3 (2X) and brine dried (Na 2 filtered and concentrated to give the desired product as an ethyl 20 ester.

B. The crude ethyl ester was dissolved in MeOH, 1 N LiOH was added at 0°C and the mixture was stirred at room temperature for 2 h. After neutralization with trifluoroacetic acid, the reaction mixture was purified by HPLC. Two diastereomers were separated and the pure fractions were collected and dried to give Bio-1082-A and Bio-1082-B.

Bio-1082-B 'H-NMR (300 MHz, DMSO-d6): 0.79 3H), 0.83 3H), 1.29-1.37 2H), 1.47 1H), 1.70-1-,83 (m, 2H), 2.08-2.17 2H), 2.48-2.58 2H), 2.67 (bt, 2H), 4,31 1H), 5.03 1H), 7.12-7.32 7.90 1H), 8.45 1 Mass. Spec. M/z 425.

78 EXAMPLE-19 Synthesis of BIO-1148 A. Amine 6-13 was coupled with BocLeuOSu using the method described in procedure C. This material was subjected to the conditions of Procedure D1 to give the desired amine salt 1148-1.

B. To a solution of 4 -hydroxyphenylacetic acid (3.0 g, 20 mmol) in DMF was added HOBT (3.7 g, 24 mmol) followed by EDC (4.2 g, 22 mmol) and the mixture was stirred at room temperature for 30 min. Nhydroxysuccinimide (2.3 g, 20 mmol) was added and stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate (150 ml) extracted with 5% citric acid saturated NaHCO 3 15 (2X) and brine (IX) and was dried over anhydrous Na 2

SO

4 Following removal of the solvent in vacuo the product was dissolved in CH 2 Cl 2 and precipitated with hexanes to afford 4-hydroxyphenylacetic acid succinimidyl ester (3.9 g, 'H NMR (300 MHz, DMSO-d6): 2.79 4 H), 20 3.93 2 6.72 J 8.5 Hz, 2 7.12 J Hz, 2 9.41 1 H).

C. Amine salt 1148-1 was hydrolysed under MeOH/aqueous LiOH conditions to give an acid. A solution of this acid, triethylamine, and 4hydroxyphenylacetic acid-OSu (prepared in Example 19B) in CH 2 Cl 2 was stirred at room temperature for 1 h. The reaction mixture was purified by HPLC and the pure fraction was collected and dried to give Bio-1148 as a mixture of two diastereomers. 'H-NMR (300 MHz, DMSO-d6): 0.70-0.90 6H), 1.29-1.63 3H), 2.73-2.85. (m, 2H), 3.17-3.40 2H), 4.15-4.30 1H), 5.12-5.28 1H), 6.58-6.68 2H), 6.94-7.06 2H), 7.54- 7.67 1H), 7.93-8.16 2H), 8.53-8.75 3 H).

Mass. Spec. M/z 414.

79 EXAMPLE Synthesis of BIO-1168 The procedure that was used in Example was followed utilizing 3-methylphenylisocyanate for phenylisocyanate. The resulting product was hydrolyzed as described in Example 15E and the pure fraction from HPLC purification was collected and dried to give Bio- 1168. 'H-NMR (300 MHz, DMSO-d6): 0.76 3H), 0.82 (d, 3H), 1.30-1.52 3H), 2.28 3H), 2.54-2.70 (m, 2H), 3.35-3.48 2H), 4.28 1H), 5.07 1H), 5.96 2H), 6.68-6,86 4H), 7.10-7.25 4H), 7.30 1H), 7.35 2H), 8.11 1H), 8.44 1H), 8.63 1H), 8.67 1 Mass Spec. M/z 589.

EXAMPLE 21 Synthesis of BIO-1179 The procedure that was used in Example was followed utilizing 2-methylphenylisocyanate for phenylisocyanate. The resulting product was hydrolyzed as described in Example 15E and the pure fraction from HPLC purification was collected and dried to give Bio- 1179. 'H-NMR (300 MHz, DMSO-d6): 0.75 3H), 0.80 (d, 3H), 1.27-1.51 3H), 2.23 3H), 2.62 2H), 3.40 2H), 4.28 1H), 5.06 1H), 5.98 (bs, 2H), 6.71 (bd, 1H), 6.80 1H), 6.83 (bs, 1H), 6.92 (bt, 1H), 7.05-7.20 4H), 7.38 2H), 7.82 (d, 1H), 7.87 1H) 8.10 1H), 8.42 1H), 8.93 (s, 1 Mass Spec. M/z 589.

EXAMPLE 22 Synthesis of BIO-1195 A. Amine 9-9 was coupled with BocLeuOSu according to Procedure C to give the desired product.

'H-NMR (300 MHz, CDC1 3 0.90 6H), 1.32 9H), 1.42 9H), 1.58-1.90 3H), 2.61-2.80 2H), 80 4.08 1H), 4.89 (bd, 1H), 5,37 (bq, 1H), 6.95-7.15 3H), 7.45 (bd, 1 H).

B. The product of Example 22A was treated with TFA as described in Procedure D to give the corresponding TFA-amine salt 1195-2.

C. A mixture of 4-amino-phenylacetic acid (10.0 g, 66.1 mmol) and 98% phenyl isocyanate (8.27 g, 68.0 mmol) in ethyl acetate (100 mL) was stirred at RT for 1 h then refluxed for 1.5 h. The mixture was allowed to cool to RT and the product was filtered, washed with ethyl acetate, methanol, and then ether affording phenylureaphenylacetic acid 1195-3 (17.5 g, 98%) as a white powder. 'HNMR (DMSO-d 6 300 MHz, ppm): 8.72-8.64 2H), 7.44 2H), 7.36 2H), 7.28 (d, 15 2H), 7.16 2H), 6.96 1H), 3.52 2H). FAB-MS 272.

D. A solution of phenylureaphenylacetic acid 1195-3, HOBT, and EDC in DMF was stirred at room temperature for 30 min and then the free amine prepared 20 from the product of Example 22B and TEA treatment was added. After stirring at room temperature overnight, the reaction mixture was purified by HPLC and the pure fraction was collected and dried to give Bio-1195.

'H-NMR (300 MHz, DMSO-d6): 0.71 3H), 0.78 3H), 1.25-1.46 3H), 2.56-2.72 2H), 3.26-3.41 (m, 2H), 4.21 (bq, 1H), 5.07 (bq, 1H), 6.90 (bt, 1H), 7.02- 7.14 3H), 7.17-7.42 8H), 8.10 1H), 8.47 (d, 1H), 8.58 1H), 8.63 1 Mass Spec. M/z 567.

EXAMPLE 23 Synthesis of BIO-1198 A. To a solution of phosgene in CH 2 C1, at 0 C was added a solution of morpholine and triethylamine in

CH

2 C1 2 dropwise. The reaction was then stirred at room temperature for 30 min and concentrated in vacuo to 81 give a white solid. This-crude product was dissolved in CH 2 C1 2 and 4-aminophenylacetic acid t-butyl ester was added. The mixture was stirred at room temperature overnight, diluted with ethyl acetate (20 mL), washed with 5% citric acid sat. aq NaHCO 3 (2X) and brine dried (Na 2

SO

4 filtered and concentrated to give morpholineurea t-butyl ester 1198-1.

'H-NMR (300 MHz, CDC1 3 for t-butyl ester 1.40 (s, 9H), 3.38-3.46 4H), 3.60-3.70 6H), 6.67 (s, 1H), 7.13 2H), 7.27 2 H).

B. The morpholineurea t-butyl ester 1198-1 was dissolved in CH 2 C1 2 and trifluoroacetic acid was added. The solution was stirred at room temperature 1 for 3 h. and concentrated to give 26 mg of the corresponding carboxylic acid 1198-2.

C. The method described in Example 1A was "'performed using carboxylic acid 1198-2 (26 mg) dissolved in DMF, HOBT, EDC, and the amine prepared in -Example 14A to give 27 mg of crude methyl ester 1198-3.

20 D. A solution of crude methyl ester 1198-3 was treated as described in Example 14C to give Bio- 1198. 1 H-NMR (300 MHz, DMSO-d6) for BIO 1198: 0.75 (d, 3H), 0.82 3H), 1.27-1.50 3H), 2.53-2.70 (m, 2H), 3.28-3.45 6H), 3.55-3.60 4H), 4.27 (m, 1H), 5.07 (bq, 1H), 5.96 (bs, 2H), 6.72 (bd, 1H), 6.82 1H), 6.85 (bs, 1H), 7.09 2H), 7.35 2H), 8.08 1H), 8.42 1H), 8.47 1 Mass Spec.

M/z 569 EXAMPLE 24 Synthesis of Bio-1190 A. Amine 6-5 was coupled with BocLeuOSu as described in Procedure C. This material was subjected to the conditions of Procedure D1 to give the desired amine salt.

82 B. The protocol described in Example 1A was performed using 2 -methylphenylureaphenylacetic acid (135 mg, 0.47 mmol) in DMF (2.5 ml), HOBt (135 mg, 0.88 mmol), EDC (0.71 mmol) and the amine salt from Example 29A (200 mg, 0.46 mmol) (treated with Et 3 N until pH was reached) to give 1190-1 235 mg, 89 as a white solid.

C. To a stirred solution of 1190-1 (20 mg, 0.034 mmol) in MeOH (3 mL) was added aqueous LiOH (3 mL of 2N). After stirring at room temperature overnight, the reaction mixture was cooled to 0 OC and acidified by adding TFA until pH 3-4 (pH paper). The desired product was isolated and purified by LC (Vydac C18 column; gradient 8) to give 10 mg (0.017 mmol; 50%) of 15 BIO-1190 as a white solid. 'H NMR (DMSO-d 6 300 MHz, ppm) 8.95 1 H, NH), 8.39 1 H, J 9 Hz, NH), 8.11 1 H, J 9 Hz, NH), 7.88 1 H, NH), 7.83 1 H, J 8 Hz, Ar), 7.36 2 H, J 8.4 Hz, Ar), .7.2-7.1 (comp, 6 H, Ar), 6.92 1 H, Ar), 6.83 2 20 H, J 9 Hz, Ar), 5.08 1 4.28 1 3.70 3 H, OMe), 3.39 1 H, J 8 Hz), 3.31 1 H, J 7 Hz), 2.63 1 2.23 3 H, Me), 1.50-1.25 (comp, 3 0.81 3 H, J 6 Hz), 0.75 3 H, J 6 Hz) FABMS, m/z 575 (C 32

H

38

N

4 0 6 of M'1 requires 575).

EXAMPLE Synthesis of Bio-1197 A. Amine 8-1 (0.884 g, 4.0 mmol) was coupled with BocLeuOSu (1.32 g, 4.0 mmol) as described in Procedure C. This material was subjected to theconditions of Procedure D1 to give the desired amine salt (1.42 g, 85 as a white solid.

'H NMR (CDC13, 300MHz, ppm): 7.31-7.22 5H), 7.14 1H), 5.37 -5.30 1H), 4.84 1H), 4.10 (m, 83 1H), 2.85-2.66 (in, 2H), 1:.72-1:58 (in, 2H), 1.51-1.49 1.48 9H), 1.29 9H), 0.91 (in, 9H).

B. The procedure of Example 1A was performed using 2 -methylphenylureaphenylacetic acid (34 mg, 0.12 inmol), HOBT (20 mng, 0.14 mmol), EDC (26 mg, 0.134 mmol) and the amine salt of Example 25A (30 mg, 0.079 mmol) in the presence of Et 3 N to give 15 mg (0.028 rnmol; of Bio-1197 as a white foam: FABMS, m/z 545 (C 31

H

36

N

4 0 5 Of M*1 requires 545).

10

EUP,

Synthesis of RIO-12n1 A. The procedure of Example 15D was ;performed using the free amine from Example 15C (40 mg, 0.086 mmol) and 2-nitrophenyl isocyanate (28 mng, 0.172 inmol) to give 50 mng of 1201-1 as a light yellow *oil. 1H NMR (DMSO-d 6 300 MHz, ppm) 8.55 1 H, NH), 8.50 1 H, NH), 8.15 1 H, NH), 8.05 1 H, NH), 7.6-6.7 (11 H, Ar), 5.85 (bs, 2 5.25 (in, 1 H), 4.6 (in, 1 3.8-3.55 (comp), 3.5 3 H, OMe), 2.75 (mn, 2 1.7-1.4 (comp, 3 0.85 (in, 6 H).

B. The procedure of Example 24C was C :performed using 1201-1 (50 mg, 0.079 minol) to give 17 mg (0.027 inmol; 35%) of BIO-1201 as a light yellow solid. FABMS, m/z 620 (C 3 1

H

3 5N 5 0 9 of M+1 requires 620) EXAMPLE .27 Syntheis of Bin-1217 A. Amine 13-4 (30 ing, 0.1 inmol) was coupled with Na-t-Boc-Ne-CBZ-L-Lysine-N-Hydroxysuccinimide ing, 0.1 mmiol) as described in Example 25A to give 60 mg of 1217-1 as a white foam. 1H NMvR (CDC1 3 300 MHz, ppm) 7.35-7.25 (comp, 5 H, Ar), 6.8-6.7 (comp, 3 H, Ar), 5.3-5.1 (comp, 2 4.95 (in, 1 4.05 (mn, 1H), 3.8 3 H, OMe), 3.78 3 H, OMe), 3.1 (in, 2 H), 84 2.7 (in, 2 1.9-1.4 (comp), 1.35 9 H, But), 1.3 9 H, But) B. Compound 1217-1 (60 mg, 0.09 mmiol) in

CH

2 C1 2 (5 mL) was deprotected with trifluoroacetic acid (0.5 inL) as described in Procedure. D1 to give 56 mg (100 of 1217-2 as a white foam.

'H NMR (CDC1 3 300 M4Hz, ppm) 8.75 7.35-7.15 (comp, Ar), 6.85-6.65 (comp, Ar), 5.4 5.2-4.9 (bs, Bn), 4.15 3.75 3.15-2.6 (comp), 1.8 (m),1.4-1.0 (comp).

C. The procedure of Example 1A was performed using 2-methyiphenylureaphenylacetic acid 40 mg, 0.14 iniol), HOBT (23 ing,0.167), EDC (30 mng, 0.158 minol) and amine 1217-2 (5 g .9 no)was added in the presence of Et 3 N to give 21 mg (30 ~)of BIO-1217 as a white foam. 'H NMR (DMSO-d 6 300 MHz, ppm) 9.05 (mn, 1H, NHl), 8.4 (in, 1 H, NH), 8.1 (mn, 1 H, NH), 8.0 (mn, 1 H, NH), 7.4-6.7 (comp, Ar), 5.1 (mn, 1 5.0 (bs, 2 H), -4.2 (in,-1 3.7 (bs, 6 H, OMe), 2.9-2.6 (comp), 2.2 S..20 3 H, Me) 1. 6-1. 1 (comp); FABMS, in/z 754 (C 4 jH 4 7

N

5 0 9 of M+1 requires 754).

Examle 28 Synthesis of RTO-122 A. Amine 13-3 (90 mng, 0.4 mmiol) coupled with Na-t-Boc-Ne-CBz-L-Lysine-N-Hydroxysuccininide (193 mng, 0.4 iniol) as described in Example 25A to give 220 mg (94k) of 1225-1 as a white foam. 1H NMR (CDC1 3 300 MHz, ppm) 7.4-7.25 (5 H, Ar), 7.1 (in, 1 H, NH), 6.8- 6.65 (3 H, Ar), 5.9 2 5.25 (mn, 1 5._15 (mn, NH), 5.05 2 4.85 (in, 1 4.0 (in, 1 3.6 3 H, OMe), 3.15 (in, 2 2.80 (mn, 2 1.90-1.20 (6 1.4 9 H).

85 B. The BOC protecting-group of 1225-1 (170mg, 0.29 mmol) was removed as described in Procedure D1 to give 100 mg of free amine 1225-2 as a white foam.

IH NMR (CDC1 3 300 MHz, ppm) 8.07 1 H, J 9 Hz), 7.4-7.2 (comp, 5 6.80-6.65 (comp, 3 5.90 2 5.25 1 5.05 2 4.98 (bs, 1 3.58 3 H, OMe), 3.32 1 3.16 2 2.27 2 1.90-1.70 (comp, 3 1.6-1.25 (comp, 5 H).

C. The procedure of Example 1A was performed using 2 -methylphenylureaphenylacetic acid (44 mg, 0.155 mmol), HOBT (36 mg, 0.264 mmol), EDC (47 mg, 0.248 mmol) and free amine 1225-2 (50 mg, 0.103 mmol) to give 46 mg of BIO-1225-3 as a white foam. 1H NMR '.:(DMSO-d 6 300 MHz, ppm) 6 9.0-6.7 (21 H, Ar NH),5.96 15 2 5.1 2 4.98 2 4.2 1 H), 3.50 3 H, OMe), 3.48-3.4 (comp, 2 2.88 2 2.71 2 2.24 3H, Me),1.6-1.0 (comp, 6 H) FABMS, m/z 752 (C 41

H

45 NsO, of M'1 requires 752).

D. BIO-1225-3 (25 mg, 0.033 mmol) was treated as described in Example 24C to give 15 mg of BIOe 1225 as a white solid. FABMS, m/z 738 (C 40

H

43 NsO, of M*1 requires 738).

EXAMPLE 29 Synthesis of BIO-1036 A. The method described in Procedure C was followed using methyl 3 -amino-5-indanyl-1-propanoate (ester M-l, preparation described in Procedure B) mg, 0.33 mmol) to give 1036-1 as a yellow foam (96 mg, 0.22 mmol, 67%) which was used without further purification in the next step. 'HNMR (CDC1 3 6 7.15 6.95 5.30 4.95 4.15 3.55 2.90-2.80 2.05 1.70 1.35 (9H), 0.85 (6H).

86 B. Compound 1036-1 (98 mg, 0.22 mmol) was treated as described in Procedure D to produce the corresponding amine salt. The method described in Example 1A was performed using phenylacetic acid and the resulting amine salt (in the presence of TEA) to give 1036-2 as a yellowish solid (75 mg, 0.17 mmol, which was used without further purification in the next step. 'HNMR(CDC 3 6 7.35-6.8 6.25 (1H), 5.25 4.45 (1H) 3.6 (1.5H) 3.5 2.80-2.60 2.00 1.70-1.30 0.85 (6H).

C. Using the general procedure above a small portion.of compound 1036-2 was hydrolyzed as described in Example 1B, purified by HPLC and the clean fractions collected to afford Bio-1036A mg) m/z= 437 (98% 15 pure by HPLC) along with Bio-1036B mg) m/z =437 (98% pure by HPLC) as white solids.

Bio-1036A: 'H NMR (300MHz, DMSO-d 6 6 8.45 (1H, d, J= 7.3Hz), 8.21 (1H, d, J= 7.3Hz), 7.37-7.05 (8H, 5.20 (1H, 4.37 (1H, 3.57-3.43 (2H, 2.86 (4H, m), 2.69 (2H, 2.03 (2H, 1.60 (1H, 1.49 (2H, m), 0.91 (3H, d, J= 6.3Hz), 0.84 (3H, d, J= 6.3Hz).

Bio-1036B: H NMR (300 MHz, DMSO-d 6 6 8.45 (1H, d.

9: J= 8.4 Hz), 8.22 (1H, d, J= 8.4 Hz), 7.40-7.00 (8H, m), 5.18 (1H, 4.35 (1H, 3.55 (2H, 2.85 (4H, m), 2.57 (2H, m) 2.05 (2H, 1.55 (1H, 1.40 (2H, m), 0.90 (3H, d, J= 6.3 Hz), 0.75 (3H, d, J= 6.3 Hz).

EXAMPLE Synthesis of BIO-1137 A. The method described in Procedure C-was followed using methyl 3-amino-3-(2-nitrophenyl)-1propanoate (ester M-3, preparation described in Procedure B) (58 mg, 0.22 mmol) to afford 1137-1 (106 mg, 0.22 mmol, 100%) as a thick pale yellow oil.

87 'HNMR(CDC1 3 6 7.95 7.85-7.35 5.85 (1H), 4.95 4.15 3.55 3.50 2.90 1.70-1.60 1.45 0.90 (6H).

B. Compound 1137-1 (106 mg, 0.22 mmol) was treated as described in Example 29B to afford 1137-2 (69 mg, 0.16 mmol, 73%) as a yellow semi-solid.

'HNMR(CDC1) 6 7.90-7.15 (10H), 6.35 6.20 5.75 4.45 3.55 3.50 2.85 1.70-1.30 0.70 (6H).

C. A small portion of compound 1137-1 was hydrolyzed as described in Example 1B, purified by HPLC and the clean fractions isolated to afford Bio-1037A mg) m/z= 442 (97% pure by HPLC) and Bio-1037B 2mg) m/z= 442 (100% pure by HPLC).

EXAMPLE 31 Synthesis of BIO-1043 A. The commercially available N-BOC-1aminocyclopropane carboxylic acid (80 mg, 0.4 mmol) in DMF (3 mL) was activated at room temperature using BOP 20 (221 mg, 0.5 mmol). After 15 minutes the methyl 3amino-3-phenyl-l-propanoate HC1 salt (86 mg, 0.4mmol) (neutralized with excess Hunig's base (0.15 mL, 0.8 mmol)) was added in DMF (1 mL). After stirring overnight at room temperature the reaction was diluted with ethyl acetate (10 mL), washed with 60% sat.

bicarbonate (2X10 mL), 5% citric acid (2X5 mL) and brine (10 mL), dried over sodium sulfate and concentrated to afford 1043-1 as a white foam (143 mg, 0.4 mmol, 100%). 'H NMR (CDC13) 6 7.6 (1H) 7.2 5.4-5.3 3.55 2.85-2.70 1.55 1.40 0.9 (2H).

B. A small portion of compound 1043-1 was hydrolysed as described in Example 1B and purified by HPLC. Collection of the pure fractions afforded Bio- 88 1043 mng) m/z= 349 (100% pure by HPLC) as a white solid which was submitted for bioassay.

'H NMR (300 MHz, DMSO-d 6 6 8.55-8.05 (2H, bin), 7.15(5H, ma), 5.40 (2H, bin), 3.0-2.65 (2H, in), 1.45 (9H, s) 1.43-1.10 (2H1, in), 0.97 (1H, bin), 0.85 (1H, bin).

EXAMLE U Synthesis of BIO-1119 A. The method described in Procedure C was followed using methyl 3-ainino-3- (4-chiorophenyl) -1propanoate HCl salt (ester M-i, preparation described in procedure B) (68 mng, 0.27 inmol) to afford 1115-1 (94 mng, 0.22 iniol, 821) as a white foam.

1HN (CDCl 3 6 7.35 7.25-7.10 5.35 (1H), 4.95 4.05 3.60 (1.511), 3.55 2.80- 2.65 (211), 1.65 1.40 (1011), 0.80 (611).

B. Compound 1115-1 (68 mg, 0.27 inmol) was .treated as described in Example 29B to afford crude 1115-2 (67 ing, 0.15 minol, 68%) as a pale yellow solid.

'HNMR: 6 7.50 7.40-7.00 6.20 5.25 4.45 3.60 3.55 2.7-2.55 1.65-1.40 0.80 (6H).

C. A small portion of crude 1115-1 was 9 hydrolysed, purified by LC and the pure fractions collected to afford Bio-1115A mg) in/z= 431 (100k pure by HPLC) along with Bio-111SB in/z= 431 (100t pure by HPLC) as white solids.

Bio-1115A: 1H NMR (300MHz, DMSO-d 6 6 8.46 (11, d, J= 8.2Hz), 8.27 (1H1, d, J= 8.2Hz), 7.46-7.18 (9H, in), 5-20- (1H, in), 4.35 (1H,m) 3.60-3.45 (2H, mn), 2.71 (21, d, J= 7.3 Hz), 1.63 (11, mn), 1.48 (2H, mn), 0.91 (311, d, J=" 6.4 Hz), 0.84 (31, d, J= 6.4 Hz).

Bio-111SB: 'H NNR (300MHz, DMSO-d 6 6 8.60 (1H, d, J= 8 Hz), 8.26 (1H1, d, J= 8Hz), 7.45-7.15 (9H, mn), 5.18 (1H1, 4.35 (1H, mn), 3.50 (211, mn), 2.70 (211, mn), 89 1.50(1H, 1.42 (2H, 0.85 (3H, d, J= 6.3 Hz), 0.75 (3H, d, J= 6.3 Hz).

EXAMPLE 33 Synthesis of BIO-1129 A. To a solution of 4 -(phenylurea)phenylacetic acid (540 mg, 2.0 mmol; prepared in Example 22C) in DMF mL) was added EDC (460 mg., 2.4 mmol). After storing at room temperature for 15 min, phenylalanine t-butyl ester HC1 salt (515 mg, 2.0 mmol) which was 10 neutralized with excess Hun.g's base (0.7 mL, 4.0 mmol) was added in DMF (3 mL). After stirring overnight the reaction was diluted with ethyl acetate (20 mL) and washed with 60% sat. bicarbonate (2X10 mL), citric acid (2X10 mL), brine (2X10 mL), dried over sodium sulfate and concentrated to afford crude 1129-1 (662 mg, 1.40 mmol, 70%) as a thick pale yellow oil.

I* 'HNMR (CDC1 3 5 7.45-6.90 (16H), 6.45 4.70 (1H), .3.4 3.15-2.90 1.35 (9H).

B. To crude product 1129-1 (662 mg, 1.40 mmol) 20 was added methylene chloride (5 mL) followed by TFA (1 mL). After stirring overnight the reaction was 9 :concentrated to dryness and dried on a vacuum pump. A small portion (21 mg, 0.05 mmol) was dissolved in DMF (ImL) and HOBt (11 mg, 0.07 mmol) was added followed by EDC (14 mg, 0.06 mmol). After stirring for 15 min at room temperature amine 0-3 (13 mg, 0.05 mmol) was added in DMF (0.5 mL). After stirring overnight the reaction was diluted with ethyl acetate (20 mL), washed with sat. bicarbonate (2x10 mL), citric acid (10 mL),-brine (10 mL) dried over sodium sulfate and concentrated to afford crude 1129-2 (26 mg, 0.04 mmol, 80%) as a light tan solid. 'HNMR (CDC1 3 6 8.4 7.4-6.5 (19H), 5.95 5.7 5.25 4.70 3.65-3.50 3.10-2.65 (4H).

90 C. A small aliquot of-crude 1129-2 was hydrolysed as described in Example 1B and purified by HPLC to afford: Bio-1129A mg) m/z= 609 (80:20 ds) (100ks pure by HPLC); and Bio-1129B (-2mg) m/z= 609 (9:91 ds) (100% pure by HPLC) as white solids.

Bio-1129A: 'H NMR (300MHz, DMSO-d 6 6 8.18 (1H, s), 8.14 (1H, 8.50 (1H, bd), 8.23 (1H, bd), 7.50 (2H, d, J= 8.1Hz), 7.40-7.10 O9H, in), 7.08-6.72 (6H, in), 6.04 (2H, 5.15 (1H, in), 4.07 (1H, in), 3.38 (2H, mn, 3.05-2.70 (2H, mn), 2.62 (2H, s).

SEXAMLE 3 0*Synthesis of RTO-11-41 5e**15 A. The method of Example 1A was performed using phenylureaphenyl acetic acid (prepared in Example 22C) and isoleucine methyl ester HCl salt (362 mg, .inmol) (treated with TEA) to afford crude 1131-1 (344 mg, 1.0 minol, 51k) as a clear thick oil.

20 'HM CDl) 7.7 7.35-6.95 (1ON), 6.60 (1H) 4.55 3.65 3.45 1.90 1.45-1.20 (3H1), 0.85 B. To a solution of crude 1131-1 (344 mng, 0.95 mmol) in methanol (5 inL) was added 2N LiOH (2 inL).

After stirring overnight the methanol was removed, H 2 0 added and the pH adjusted to pH=1-2. The aqueous layer was extracted with ethyl acetate M520 inL) dried over sodium sulfate and concentrated to give 1131-2 (365mg, 0.95 iniol, 100k) as a tan solid. 'H NMR (CDCl 3 6 8. 70 (2H) 8. 30 (1H) 7.6 0 20 (8H); 7.00 (1H1), 4.25 3.55 1.90 (1H1), 1.55 (1H), 1.30 (2H1), 0.85 (SN).

C. Prepared from 1131-2 (27 mg, 0.07 inmol) and amine 5-3 (11 mg, 0.07 iniol) as described in Example 1A 91 to afford crude 1131-3 (314 mg,- as a pale brownish solid. 'H NMR (CDCl 3 6 8.3 (2H) 7.45-6.65 (16H) 5.45 4.45-4.30 3.55 3.2-2.90 (2H), 2.00-0.70 (9H).

D. A small aliquot of crude 1131-3 was hydrolysed as described in Example lB and purified by HPLC to afford Bio-1131A mg)m/z= 531 (100:Ods) (100tpure by HPLC)and Bio-1131B mg) m/z= 531 (0:lO0ds) (100k pure by HPLC)as white solids.

Bio-1131A: 'H NMR (300MHz, DMSO-d 6 6 8.69 (iH, s) 8.63 (1H, s) 8.50 (1H, d, J= 7.50 (2H, d, J= 7.8Hz) 7.44-7.22 (8H, mn), 7.19 (2H, d, J= 8.4Hz) 7. 00 9:001H, in), 5.27 (1H, in), 4.36 (1H, mn), 3.52 (2H, in), 3.00 0~ (2H, bin), 2. 71 (2H, d, J= 7. 3 1. 70 (1H, bin), 1. 44 000. 15 1.26 (1H, in), 1.22-1.00 (3H, in), 0.95-0.78 (5H, in).

0000 0 0 8.68 (lH, 8.60 (1H, d, J= 8 Hz), 8.15 (1H, d, J= 8 0 Hz), 7.50 (2H, d, J= 7.9 Hz), 7.42 (2H, d, JT= 8.4 Hz), -7.37-7.23 (5H, in), 7.20 (2H, d, J= 8.4 Hz), 7.00 (1H, 0 se 020 in), 5.35 (iN, in), 4.23 (iH, mn), 3.50 (2H, in), 3.05 (2H, 806:bin), 2.71 (2H, in), 1.72 (1H, bin), 1.20 O3H, in), 0.72- 0.60 (5H, in).

0000 0 6000 EXAMPLE I S Synthesis of RTO-1136 A. The method described in Example IA was performed utilizing commercially available N-BOC-Sbenzyl-cysteine (25 mng, 0.08 iniol) and methyl 3-amino- 3-phenyl-1-propanoate (17 ing, 0.09 iniol) to afford crude protected amine 1136-1 (42mg, 0.08 iniol, IMO).

'H NNR (CDCl 3 6 7.35 (10H), 5.40-5.20 4.20 3.65 3.55 3.54 3.25-2.65 1.45-1.30 (9H).

92 B. The protected-amine 1136-1 was treated as described in Procedure D to give the TFA-amine salt 1136-2.

C. The method described in Example 22D was performed utilizing free amine 1136-2 (42 mg, 0.08 mmol) (TEA treatment) to afford crude 1136-3 which was used in the hydrolysis step without further purification.

D. A small aliquot of crude 1136-3 was hydrolysed as described in Example 1B and purified by HLC to afford Bio-1136 mg 611 (100% pure by HPLC) as a white solid. 'H NMR (300MHz, DMSO-d 6 9.05 (2H, bm), 8.90 (1H, br), 8.37(1H, br), 7.50 (1H, d, J=7.7 Hz), 7.45 (1H, d, J= 8.3 Hz), 7.4-7.2 (9H, m), 15 7.00 1H m) 5.25 (1H, br), 4.65 (1H, br), 3.5-3.2 (4H, 2.70 (2H, bm).

EXAMPLE 36 Synthesis of BIO-1176 A. To a solution of commercially available N- 20 BOC-aspartic acid a-benzyl ester (500 mg, 1.55 mmol) in DMF (5 mL) was added HOBt (283 mg, 2.10 mmol) followed by EDC (343 mg, 1.80 mmol). After stirring for minutes at room temperature thiomorpholine (500 mg, 1.54 mmol) was added followed by Hunig's base (0.7 mL, 92 mmol) and the reaction mixture stirred at room temperature overnight. The reaction was worked up by diluting with ethyl acetate (25mL) and washing with sat. bicarbonate (5 mL) 5% citric acid (5 mL) and brine (5 mL). The organics were separated, dried over sodium sulfate and concentrated to give ester 1176-1 asa thick orange oil (421 mg, 1.03 mmol, H NMR (CDC1 3 6 7.13 (5H, 5.69 (1H, bd, J= 9.4 Hz) 5.03 (1H, d, J= 12.6 Hz), 4.42 (1H, 3.61 (1H, 3.60- 93 3.40 (4H, 2.96 (1H, bm), 2:58 (1H, bm), 2.35 (4H, m) 1.22 (9H, s) B. Ester 1176-1 (100 mg, 0.25 mmol) was treated as described in Example 1B to afford acid 1176- 2 (76 mg, 0.24 mmol, 96%) as a clear thick oil.

'H NMR (CDC1 3 6 7.39-7.28 (5H, 7.15-6.70 (1H, br), 5.70 (1H, bs, J= 6.3Hz), 4.55 (1H, br), 4.40-3.40 (4H, m) 3.15 (1H, 2.80-2.52 (5H, 1.43 (9H, s).

C. The method of Example 1A was performed using acid 1176-2 (32 mg, 0.10 mmol), in DMF, HOBT, EDC, and amine 0-3 to afford 1176-3 (36 mg, 0.07 mmol, as a thick pale yellow oil. 'H NMR (CDC1 3 6 7.71 (1H, br), 6.61 (3H, m) 6.00 (0.5H, br), 5.90 (1H, 5.77 (0.5H, br), 5.21 (1H, 4.51 (1H, bm), 3.90- 15 3.40 (4H, 3.39 (3H, 3.12-3.00 (1H, 2.85- 2.65 (3H, 2.63-2.45 (4H, 1.43 (4.5H, 1.43 *4 H s(4 .5H s).

D. The protected amine 1176-3 (36 mg, 0.07 -mmol) was treated as described in Procedure D to give 20 TFA-amine salt 1176-4 (51 mg, 0.07 mmol, 100%) as a pale yellow solid.

E. The method described in Example 22D was performed utilizing free amine 1176-4 (42 mg, 0.08 mmol) (after TEA treatment) to afford crude 1176-5 which was used in the hydrolysis step without further purification. 'H NMR (CDC1 3 6 7.95-6.9 (13H, m), 6.61 (3H, 5.85 (2H, s) 5.23 (1H, 4.88 (1H, m), 3.89-3.60 (4H, 3.55 (3H, 3.43 (2H, br), 3.11- 2.96 (2H, 2.71 (2H, 2.46 (4H, m).

F. Crude 1176-5 was hydrolyzed as described in Example 1B and injection of a small aliquot into the HPLC afforded Bio-1176 (~4mg) m/z= 662 pure by HPLC) as a white solid. 'HNMR: (DMSO-d 6 6 8.69 (2H, d, J= 9.8Hz), 8.33 (1H, d, J= 8.0 Hz), 8.26 (1H, d, J= 8.0Hz), 7.61 (2H, d, J= 8.0Hz), 7.43 (2H, d, J= 94 7.34 (2H, mn), 7.21 (2H, d- J= B.0OHz) 7. 10-6. 95 (4H, in), 6.11(2H, 5.13(1H, in), 4.68(1H, mn), 3.71(4H1, br), 3.56-3.18 (2H, in), 2.73-2.46 (8H, in).

FXAMTLR 1 Synthesig of RIo-1177 A. The procedure described in Example 36A was carried out using methyipropargylamine in place of thiomorpholine to afford crude 1177-1 (374 mng, 0.99 inmol, 66%) as a white foam. 111 NMR (CDC1 3 6 7.20 :10 5.25 (1H1), 5.10 4.45 4.15-3.8 (2H), 3.15-2.65 2.2-2.15 (111), 1.30 (9H).

Crude 1177-1 was treated as described in .:Example 1B to afford acid 1177-2 (76 mg, 0.26 mmol, 96%) as a clear oil. *H NMR (CDCl 3 6 5.35 (1H), 4.55(1H), 4.35-3.8(2H), 3.30-2.65(11), 2.4-2.25(11), 1. 45 (9H).

C. The method of Example 1A was performed .using acid 1177-2 (76 mg, 0.26 minol), in DMF, HOBT, EDC, and amine 03-3 to afford crude 1177-3 (78 mng, 0.15 rnmol) as a white foam. 'H NMR (CDCl 3 6 7.70 (1H) 7.35 6.65 5.80 (111) 5.30-5.00 (2H), 4.60(1H), 4.45-3.80 3.60 3.30-2.70 (511), 2.30 (111), 1.45 1.40 (4.5H1).

D. The protected amine 1177-3 (78 mng, 0.15 inmol) was treated as described in Procedure D t o afford TFA-amine salt 1177-4.

The method described in Example 22D was performed utilizing free amine 1177-4 to afford 1177-5- (52 mng, 0.08 mmol, 771k) as a tan solid. "H NMR.- -(CDCl 3 6 7. 5 9 (1411), 6. 65 (311), 5. 85 (211) 5.2 5 00 (211), 4.85 (1H1), 4.25-3.70 (211), -3-.60 (311), 3.55 (211), 3.30-2.65 (511), 2.22 (1M).

95 F. A small portion of-1177-5 was hydrolyzed as described in Example lB to afford Bio-1177 mg) m/z= 628 (100% pure by HPLC) as a white solid.

'H NMR: (DMSO-d 6 6 8.64 (2H, bd), 8.27 (2H, bm), 7.55- 7.13 (7H, 7.11-6.75 (3H, m) 6.15 (2H, 5.12 (1H, bm), 4.65 (1H, bm), 4.25 (2H, bm), 3.25 (2H, 3.05 (2H, br) 2.88 (1H, bm), 2.62 (2H, m).

EXAMPLE 3 8 Synthesis of BIO-1214 10 A. The procedure described in Example 36A was carried out on the N-BOC-aspartic acid a-benzyl ester (1.60 g, 4.9 mmol) using dimethylamine in place of thiomorpholine to afford ester 1214-1 (1.43 g, 4.1 mmol, 83%) as a thick colorless oil.

'H NMR (CDC1 3 6 7.32 (5H, 5.85 (1H, br), 5.15 (2H, m) 4.55 (1H, br), 3.12 (1H, 2.94 (3H, 2.88 (3H, 2.73 (1H, 1.40 (9H, s).

B. Ester 1214-1 (124 mg, 0.33 mmol) was dissolved in ethyl acetate (2 mL) and 10% Pd/C (~50 mg) 20 was added and the mixture was hydrogenated under pressure (40 psi) for 2h. The reaction was filtered through Celite® and concentrated to afford acid 1214-2 mg, 0.33 mmol, 100%), as a colorless oil. !H NMR: (CDC1 3 6 5.81 (1H, bm), 4.48 (1H, bs), 3.15 (1H, m), 3.00 (3H, 2.93 (3H, 2.59 (1H, 1.39 (9H, s).

C. The method of Example 1A was performed using acid 1214-2 (28 mg, 0.10 mmol) and amine 0-3 (17 mg, 0.80 mmol) to afford protected amine 1214-3 (55 mg, 0.10 mmol, 100%) as a white foam. 'H NMR: (CDC1 3 6 7.77 (1H, bd), 6.71 (3H, 6.11 (1H, bd), 5.91 (2H, s) 5.25 (1H, 4.51 (1H, br), 3.60 (3H, 3.12 (1H, 2.94 (3H, 2.90 (3H, 2.88-2.68 (2H, 2.48 (1H, 1.43 (9H, s).

96 D. The protected-amine 1214-3 (55 mg, 0.10 mmol) was treated as described in Procedure D to afford TFA-amine salt 1214-4.

E. The method described in Example 22D was performed utilizing free amine 1214-4 to afford 1214-5 (31mg, 0.05mmol, 50%) as a tan solid. 'H NMR (CDC1 3 6 7.45-6.90 (13H, 6.61 (3H, 5.85 (2H, 5.24 (1H, 4.82 (1H, 3.55 (3H, 3.47 (2H, m), 3.08-2.94 (1H, 2.92 (3H, 2.84 (3H, 2.77- 2.50 (2H, 2.45 (1H, m).

F. A small portion of 1214-5 was hydrolyzed as described in Example 1B to afford BIO-1214 mg) m/z= 604 (100% purity by HPLC) as a white solid.

EXAMPLE 39 15 Synthesis of BIO-1215 A. To a solution of amide 1214-1 (prepared in Example 38A) (671 mg, 1.9 mmol) in dry tetrahydrofuran mL) cooled to 0 "C was added 1 N BH 3 /THF solution (4.1 mL, 3.8 mmol) dropwise. After stirring the 20 reaction mixture for 2 h at room temperature the reaction was quenched with methanol (2 mL) and concentrated to dryness. Methanol (5 mL) was added and removed three times to remove all (MeO) 3 B formed.

Drying under high vacuum afforded amine 1215-1 (623 mg, 1.7 mmol, 90%) as a thick colorless oil. 'H NMR (CDC1 3 6 7.38 (5H, 5.48 (1H, bm), 2.65-2.35 (8H, 1.95 (2H, 1.42 (9H, s).

B. Amine 1215-1 (124 mg, 0.34 mmol) was subjected to catalytic hydrogenation using methanol/ethyl acetate/acetic acid as solvent and Pd/C (-50 mg). After 2 h the reaction mixture was filtered and concentrated to give acid 1215-2 (90 mg, 0.33 mmol, 97%) as a thick colorless oil.

97 1H NMR (CDCl 3 6 5.91 br); 3.95 (1H, br), 3.54 (Jjj bin), 2.71-2.42 (8H, in), 2.15 (2H, br), 1.33 (9Hj, s).

C. The method of Example lA was performed using acid 1215-2 (55 mg, 0.12 inmol) and the amine 03-3 (22 mng, 0.10 minol) to afford protected amine 1215-3 (44 mg, 0.09 minol, 90t) as a white foam. 1H NMR(CDCl 3 6.75 (3H, in), 6.51 (1H, bd), 5.91 (2H, 5.30 (1H, in), 4.37-4.12 (2H, in), 3.61 (3H, 2.90-2.65 (2H, in), 2.55-2.00 (10H1, in), 1.42 (9H, s).

D. The protected amine 1215-3 (44 mg, 0.09 rmol) was treated as descriled in Procedure D to afford TFA-amine salt 1215-4.

E. The method described in Example 22D was performed utilizing free amine 1215-4 to afford 1215-5 (38 mg, 0.06 inmol, 70%) as a white solid.

1H NMR (CDCl 3 6 7.41-6.90 (13H1, 6.71 (3H, mn), 5.91 (2H1, 5.29 (111, in), 4.21 (1H1, in), 3.61 (3H1, 3.45 (2H, in), 2.90-2.70 (2H, in), 2.40-1.95 (10H, in).

F. A small portion of 1214-5 was hydrolyzed as described in Example lB to afford BIO-1215 mng) in/z= (100t pure by HPLC) as a white solid.

EXAMPLP, 4 Synthegig of RTO-1227 A. The method as described in Example 1B was performed using commercially available BOC-S-methylcysteine (28 mg, 0.12 iniol) and amine 13-3 (21 mg, 0.10 mmol) to afford protected amine 1227-1 (32 mg, 0.07 minol, 70%) as a white foam.

'H NM (CDCl 3 6 7.38 (1H1, bd) 6.81-6.67 (311,_m), 5.90 (2H, 5.40 (1H, bd), 5.37 (1H, in), 4.20 (1H, in), 3.59 (3H, 2.95-2.68 (411, in), 2.10 (3H, 1.43 (9H, s).

98 B. The protected-amine 1227-1 (32 mg, 0.07 mmol) was treated as described in Procedure D to afford TFA-amine salt 1227-2.

C. The method described in Example 22D was performed utilizing free amine 1227-2 and the 2methylphenylureaphenylacetic acid (28 mg. 0.10 mmol) to afford crude ester 1227-3 (29 mg, 0.047 mmol, 67%) as a light tan solid. 'H NMR (CDCl 3 6 7.62 (1H, bd), 7.4-6.9 (12H, 6.80 (3H, m) 5.90 (2H, s) 5.15 (1H, 4.45 (1H, 3.63-3.45 (5H, 3.15-2.61 (4H, m), 2.21 (3H, 2.10 (3H, s).

D. A small aliquot of crude ester 1227-3 was hydrolyzed as described in Example 1B to afford BIO- 1227 mg) m/z= 593 pure by HPLC) as a white 15 solid. 'H NMR (DMSO-d): 6 9.01 (1H, 8.67 (1H, d, J= 7.9Hz), 8.31 (1H, d, J= 8.3Hz), 7.97 (1H, 7.90 (1H, d, J= 8 Hz), 7.44 (2H,d, J= 8.3Hz) 7.23 (4H, m), 6.99 (2H, 6.85 (2H, 6.03 (2H, 5.16 (1H, m), -4.54 (1H, 3.39 (2H, 2.81-2.58 (4H, m) 2.30 (3H, 2.05 (3H, s).

EXAMPLE 41 Synthesis of BIO-1149 A. To a solution of the product from Procedure C (272mg, 0.67 mmol) in CH 2 C12 (2.5ml) was added TFA (2.5ml) slowly and the mixture was stirred at room temperature for 1 h. The solvents were removed to give an oil. This oil was dissolved in CH 2 Cl 2 (2.5ml). To this solution was added Et 3 N to pH 9 and then succinimidyl 2-quinolinecarboxylic acid (170mg, 0.63mmol). The mixture was stirred at room temperature for 1 h followed by usual workup citric acid, NaHC03 and sat. NaCi) to afford ester 1149-1 (200mg, 76%) as a white solid.

99 B. Acid 1149-1 (200mg; 0.43mmol) was dissolved in methanol (1.5 ml) and to the solution was added 1M aqueous LiOH (0.5 ml). The mixture was stirred at room temperature for 3 h and neutralized with 5% citric acid to pH 3 and was extracted with EtOAc (3 x 5ml). The combined extracts were dried (Na 2

SO

4 and concentrated to afford 155 mg crude 1149. A small amount of the crude product (30 mg) was purified by HPLC to give BIO-1149, and the diastereomers were separated.

HPLC: Room temperature; A: 36 min; B:38 min.

FAB-MS 434. 'H NMR: (CDC1 3 300MHz, ppm) 8.72 (m, 1H), 8.30-7.98 3H), 7.82-7.64 2H), 7.60-7.51 1H), 7.30-7.09 SH), 5.46-5.38 1H), 4.86- 4.72 1H), 2.92-2.74 2H), 1.

8 8-1.61(m, 3H), 15 0.96-0.83 6H).

EXAMPLE 42 Synthesis of BIO-1152 A. To a solution of the product of Procedure D2 (33 mg, 0.1 mmol) in CH 2 C12 (0.5 ml) was added 2,2- 20 dimethylbutyric acid chloride (14 mg, 0.1 mmol) and Et 3

N

The mixture was stirred at room temperature for 16 h. The usual workup NaHCO 3 5% citric acid and sat. NaCI) afforded 1152-2 (37 mg, 76%) as a white solid. 'H NMR: (CDC1 3 300MHz, ppm) 7.32-7.19 6.08 1H), 5.36-5.27 1H), 4.53-4.44 1H), 2.86-2.61 2H), 2.05 2H), 1.26 9H), 1.01 (s, 9H), 0.99-0.84 9H).

B. Ester 1152-2 was dissolved in CH 2 C1 2 ml) and TFA (2.5 ml) and stirred at room temperature for 3 h to afford an oil. The purification of the oil.

by HPLC to give a pure BIO-1152. 'H NMR: (CDC1 3 300MHz, ppm) 8.29 1H), 7.44 1H), 7.34 -7.18 (m, 5.44-5.32 1H), 4.78-4.69 1H), 3.21-3.14 100 2H), 2.98-2.77 (dd, 2H), 1.-59-1.38 3H), 0.96 9H), 0.84 3H), 0.73 3H).

EXAMPLE 43 Synthesis of BIO-1089 A. To a solution of amine 0-6 (2.2g, 8.76 mmol) in CH 2 C1 2 (25 ml) was added N-BOC-methionine succinimidyl ester (2.77g, 8.0 mmol) and Et 3 N (5 drops) and the mixture was stirred at room temperature for h. The mixture was washed with 5% citric acid (2 x 10 10ml), 5% NaHCO 3 (2 x 10ml) and sat. NaCI (15ml), dried (Na 2

SO

4 and concentrated to give 1089-1 (3.2 g, 83%) as white solid. 1H NMR: (CDC1 3 300MHz, ppm) 7.27 (d, 2H), 6.81 2H), 5.31-5.20 2H), 4.38-4.28 (m, 1H), 3.72 3H), 2.82-2.64 2H), 2.12 3H), 1.44 9H), 1.30 9H).

B. To a solution of 1089-1 (3.2 g, 6.64 mmol) in EtOAc (15 ml) was added a 1M HC1-EtOAc solution .ml) and the mixture was stirred at room temperature for 4.5h. The reaction mixture was quenched with H 2 0 20 ml) and the aqueous layer was collected. It was neutralized with solid NaHCO 3 to pH 8 and was extracted *with EtOAc (2 x 45 ml). The combined organic extracts were washed with sat. NaCl (20 ml), dried (Na 2

SO

4 and concentrated to afford 1089-2 (1.7 g, 67%) as an oil.

'H NMR: (CDC1 3 300MHz, ppm) 7.98 1H), 7.19 2H, J 8.3 Hz), 6.81 2H, J= 8.3 Hz), 5.32-5.18 (m, 1H), 3.74 3H), 3.48-3.44 1H), 2.82-2.62 (m, 2H), 2.53 2H), 2.18-2.06 1H), 2.04 3H), 1.8-1.66 1.31 9H).

C. The method of Example 22D was performed using 1089-2 (1.7 g, 4.45 mmol) to afford 1089-3 (2.3 g, 81.6%) as a solid. This material was used in the next step without further purification.

101 'H NMR: (DMSO-d 6 300MHz, .ppm) -8.60 2H), 8.41 (d, 1H), 8.24 1H), 7.44 2H), 7.31( d. 2H), 7.26 (t, 2H), 7.13 2H), 6.91 1H), 6.79 2H), 5.10- 5.01 1H), 4.36 -4.33 1H), 3.68 3H), 3.29 2H), 2.61-2.58 2H), 1.89 3H), 1.26 9H).

D. Compound 1089-3 2.3 g, 3.63mmol) was dissolved in 4N HCl-dioxane (8ml) and the solution was stirred at room temperature for 16 h. After the dioxane was removed, ether (15 ml) was added and mixture was stirred for 10 min. The precipitate was collected and was recrystallized from methanol to give pure BIO-1089 as a pale brown solid. FAB-MS 579.

'H NMR: (DMSO-d 6 300MHz, ppm) 8.76 2H), 8.52 (d, 1H), 7.54 2H), 7.46 2H), 7.36 1H), 7.34- 15 7.26 4H), 7.04 1H), 6.95 2H), 5.22-5.20 (m, 1H), 4.46-4.35 1H), 3.81 3H), 3.50, 2H), 3.20 2H), 2.79-2.73 2H), 2.35 2H), 2.03 (s, 3H), 1.87-1.80 2H).

EXAMPLE 44 20 Synthesis of BIO-1090 A. The method described in Procedure C was followed using amine B- 10 (28 mg, 1.0 mmol) to afford 1090-1 (38 mg, 84%) as a white solid. 'H NMR: (CDC1 3 300MHz, ppm) 7.08 1H), 6.82 1H), 6.74-6.70 (m, 2H), 5.24-5.15 1H), 4.98-4.93 1H), 4.16-4.13 4H), 2.74-2.53 2H), 1.62-1.42 3H), 1.44 (s, 9H), 1.40 9H), 0.89 6H).

B. The white solid of 1090-1 (38 mg, 0.77 mmol) was treated as described in Procedure D1 to-give 1090-2 as an oil. This compound was used in next step without further purification. 'H NMR: (CDC1 3 300MHz, ppm) 7.24-7.15 2H), 6.84-6.61 3H), 5.81-5.78 1H), 4.23 4H), 4.19-4.08 1H), 2.88-2.62( m, 2H), 1.70-1.46 3H), 0.90-0.81 6H).

102 C. The method of-Example 22D was performed using amine 1090-2 to afford crude 1090 (27 mg, 59%).

The purification of crude product by HPLC gave pure BIO-1090 as a white solid. FAB-MS 603.

EXAMPLE. Synthesis of BIO-1194 A. To a well-stirred cold solution of methyl p-aminophenylacetate (9.8 g, 59.4 mmol) in CH 2 Cl 2 (200 ml) and Et 3 N (25 ml, 18 g, 178.2 mmol) was added COC1 2 1 0 (96 ml of 1.9M solution in toluene) through an additional funnel for 1 h. The reaction mixture was stirred at OC for another 1 h. The reaction mixture was concentrated and ether: pet ether (125ml) was added. The solid was filtered and the filtrate was collected. Removal of the solvents gave crude 1194-1 as a brown liquid. The purification of crude product by distillation (118-120C/10mm) gave pure 1194-1 g, 75%) as a colorless liquid.

1H NMR: (CDC13, 300MHz, ppm) 7.20 J 8.4 Hz), 7.02 20 J 8.4 Hz), 3.69 3H), 3.48 2H).

B. To a solution of 1194-1 (5.73 g, 30.0 mmol) in CH 2 C1 2 (60ml) was added 2-aminopyridine (2.82 g, o. mmol) in portions. The mixture was stirred at room *too temperature for 0.5 h then 35 0 C for 0.5 h. The resulting mixture was diluted with pet ether (60 ml) and a white solid was formed. Filtration of the solid gave pure 1194-2 (8.35g, 98%) as a white solid.

'H NMR: (CDC13, 300 MHz, ppm): 8.20 2H), 7.62-7.51 3H), 7.33 2H), 7.01 2H), 6.89-6.85 1H), 3.70 3H), 3.59 2H).

C. Compound 1194-2 5.7 g, 20.0 mmol) was dissolved in methanol (20 ml) and to this was added IN NaOH (40 ml). The mixture was heated until a clear solution was formed and was stirred at room temperature 103for 16 h, followed by a carefut neutralization with IN HC1 to pH 7 then with acetic acid to pH 3. The white solid thus formed was filtered and washed with methanol ml) and ether (2 x 30m1) to give 1194-3 (4.7 g, 87V) as a white powder. 'H1 NMR: (DMSO-D 6 300MHz, ppm) 10.62 (br, s, 1H), 9.53 (br, s, 111), 8.39 1H1), 7.82 1H) 7. 6 3-7. 55 (in, 1H1), 7.3 3- 7. 27 2H1), 7. 14 7. 08 (mn, 1H) 3. 62 3H).- D. Standard Procedure C was followed to prepare 1194-4 by coupling amine 03-6 (2.65 g, 10.56 iniol) with BocLeuOSu (3.28 g, 10 inmol) in CH 2 C1 2 (25ml) and Et 3 N (5 drops) then followed by deprotection S (TFA/CH 2 Cl 2 to afford 1194;.4 (4.5 g, 83.69k) in two S. steps 1194-4-Boc: 1H NMR: (CDCl,, 300MHz, ppm) 7.18 2H) 6.36 2H1), 5.13 -5.10 (in, 1H), 4.12-4.01 (mn, 1H1), 3.72 3H), 2.79-2.60 (in, 2H), 1.62-1.40 1.38 9H), 1.26 911), 0.85-0.80 (mn, 6H).

-1194-4: 1H NNR: (CDCl 3 300MHz, ppm) 7.10 2H1), 6.78 2H1), 5.43-5.27 (in, 1H), 4.21-4.06 (in, 1H1), 3.71 (s, 3H), 2.95-2.76 (in, 1H1), 2.75-2.56 (mn, 1H1), 1.62-1.32 (in, 6H).

E. The method of Example 1A was followed using acid 1194-3 (1.36 g, 5.0 minol) and amine 1194-4 to afford crude BIO-1194 (2.1 g, 78%) as a white solid.

The pure product (purity >97.5k) was obtained by crystallization from methanol. 1H NNR: (CDCl 3 300MHz, ppm) 8.03-7.97(mn, 2H), 7.59 (in, 111), 7.51 2H), 7.18-7.07 (in, 4H), 6.27 2H), 5.24 (mn, 1H1), 4.39- 4.36 (in, 1H), 3.61 3H), 3.43 211), 2.69-2.66 (in, 2H), 1.54-1.33 (in, 2H), 0.86-0.75 (in, 6H).

EZAMTLF 4 Synthesis of ETO-1180 104 A. The method described in Example 45A was followed using t-butyl p-aminophenylacetate to give 1180-1 in 94% yield. FAB-MS=234. H NMR: (CDC13, 300 MHZ, ppm) 7.18 2H, J 8.2 Hz), 6.98 2H, 8.2 Hz), 3.49 3H), 1.45 9H).

B. To a solution of isocyanate 1180-1 (233 mg, mmol) in CH 2 C1 2 (5 ml) was added 2 -aminothiazole (100 mg, 1.0 mmol) and the mixture was heated until a clear solution was formed and was stirred at room temperature for 1 h. Removal of the solvents gave 1180-2 (335 mg) as a brown-yellow solid. This solid was dissolved in CH 2 C1 2 (2.5 ml), and to this was added C: "TFA (2.5 ml). The mixture was stirred at room temperature for 1.5 h and was concentrated to afford 15 1180-3 (300 mg) as a yellow solid. FAB-MS 278.

C. To a solution of 1180-3 (28 mg, 0.1 mmol) in DMF (0.25ml) was added EDC (60 mg, 0.31 mmol) and DMAP (55 mg). The mixture was stirred at room .temperature for 10 min. and to this was added amine-TFA salt P-3 (23 mg, 0.051 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. The usual workup citric acid, 5% NaHCO 3 sat. NaC1) drying (Na 2

SO

4 and concentration gave crude 1180-4 (22 mg, FAB-MS 596.

25 D. The crude 1180-4 was hydrolyzed as described in Example 1B to give crude Bio-1180.

Purification of the crude product by HPLC afforded pure BI01180. HPLC: Room temperature; 26.3 min. >99% purity. FAB-MS 582. 'H NMR: (DMSO-D 6 300MHz, ppm) 9.00 (br, s, 1H), 8.52 2H, J 8.3 Hz), 8.24 (d, 2H, J 8.3 Hz), 7.50-7.47 3H), 7.28 2H, J Hz), 7.20 (1H, d, J 3.5 Hz), 6.95-6.81 3H), 6.08 1H, J 5.19-5.16 1H), 4.4-4.2 (m, 1H), 3.51 (dd, J 14.1 Hz and 23.8 Hz), 2.76-2.65 (m, 105 2H), 1.57-1.50 .50-1-.44 2H), 0.92 2H, J 6.3 Hz), 0.86 J 6.3 Hz).

EXAMPLE 47 Synthesis of BIO-1199 To a solution of BIO-1089 (15 mg) in DMSO ml), H 2 0 (2ml) was added Oxone® (20 mg) and the mixture was stirred at room temperature. The HPLC trace showed that Bio-1089 (Room temperature 20 min) was disappearing and a new peak (retention time 16.9 min) was forming. After stirrinq at room temperature for 16 h, the starting Bio-1089 was almost totally consumed. Bio-1199 (Room temperature 16.9 min) was *isolated by HPLC and was >99% pure. FAB-MS 595.

EXAMPLE 48 15 Synthesis of BIO-1207 A. Procedure C was carried out using amine S* (220 mg, 1.053 mmol), this product was then subjected to the conditions descibed in Procedure D1 to afford 1207-1 (383 mg, 88% for two steps).

20 B. The method of Example 1A was followed using p-Cbz-aminophenylacetic acid (260 mg, 0.91 mmol) and amine 1207-1 (375 mg, 0.86 mmol) (treated with Et 3

N)

afford 1207-2 (415 mg, 82%) as a pale brown solid.

C. Compound 1207-2 '390 mg, 0.66 mmol) was deprotected as described in Procedure D2 to afford 1207-3 (140 mg, 47%) as a pale brown solid.

D. To a solution of 2-isopropylaniline (135 mg, 1.0 mmol) in CH 2 C1 2 (2 ml) and Et 3 N (0.5 ml) was added COC1 2 (1.6 ml of 1.9 M solution in toluene, mmol) solution at 0°C slowly and the resulting mixture was stirred at room temperature for 1 h and diluted with ether (15 ml). Removal of the solid thus formed and the solvents gave 1207-4 (165 mg) as a brown 106 liquid. 'H NMR: (CDC13, 300MHz,-ppm) 7.87-7.64 4H), 3.83-3.74 1H), 1.81 6H).

E. To a solution of 1207-4 (12 mg, 0.074 mmol) in DMF (0.12 ml) was added 1 drop of Et 3 N and 1207-3 (28 mg, 0.062 mmol). The resulting mixture was stirred for 1 h (FAB-MS 617) and was added to methanol (2 ml) and 2M LiOH (0.25 ml). This mixture was stirred at room temperature for 16 h and was subjected to HPLC. The pure fractions were collected and concentrated to afford BIO-1207 as a white solid. FAB-MS 603. HPLC: Rnom temperature 31.2 min; >98.5% purity.

EXAMPLE 49 Synthesis of BIO-1210 The procedure described in Example 22D was 15 followed using 2 -methylphenylureaphenylacetic acid and the free amine of the TFA-amine salt prepared in Example 44B (65 mg). The resulting product was *'.subjected to HPLC. The pure fractions were collected and concentrated to afford BIO-1210 as a white solid.

20 FAB-MS 603. HPLC: Room temperature 28.6 min, 99% purity.

EXAMPLE Synthesis of BIO-1224 A. Procedure C was performed using amine 0-4 (48 mg, 0.2 mmol) to afford 1224-1 (82 mg, 91%) as a white solid. 1 H NMR: (CDC13, 300MHz, ppm) 7.49-7.39 6.73-6.62 3H), 5.35-5.28 1H), 5.19-5.06 1H), 4.16-4.08 1H), 3.74 3H), 3.69 ts, 3H), 2.72-2.51 2H), 2.40-2.36 2H), 1.98-1.75 (m, 2H), 1.90 3H), 1.28 9H), 1.19 9H).

B. Compound 1224-1 (60 mg, 0.13 mmol) was dissolved in CH 2 Cl 2 (1.5 ml) and TFA (1.5 ml). The mixture was stirred room temperature for 5 h and the 107 solvents were removed to give 1224-2 as a TFA salt.

This compound was used in the next step without purification.

'H NMR: (CDC1 3 300MHz, ppm) 7.92 (br, 1H), 6.82-6.78 3H), 5.44-5.26 1H), 4.40-4.28 1H), 3.84- 3.72 6H), 2.92-2.70 4H), 2.60-2.25 2H), 1.92 3H).

C. The method described in Example 22D was followed using 2-methylphenylureaphenylacetic acid (37 mg, 0.13 mmol) and amine 1224-2 (60 mg, 0.13 mmol).

The resulting product was subjected to HPLC. The pure fractions were collected and dried to afford BIO-1224 (22 mg, 22%) as a white solid. FAB-MS 623. HPLC: Room temperature= 23.8 min, >99% purity. 'H NMR: 15 (CDC13, 300MHz, ppm) 7.38 1H), 6.98 2H), 6.74 2H), 6.72 2H), 6.51 1H), 6.43-6.40 1H), 6.35-6.31 1H), 4.84-4.76 1H), 4.04-3.97 (m, 1H), 3.39 6H), 3.33 2H), 2.36-2.18 2H), 1.91-1.75 2H), 1.72 3H), 1.19-0.99 2H), 0.46-0.37 6H).

EXAMPLE 51 Synthesis of Compound BIO-1056 A. A mixture of 3-methoxy-4-nitrobenzoic acid (2.01 g, 10.2 mmol) and thionyl chloride (2.3 mL, 31.5 mmol) was stirred at 80-90 0 C for 1.5 h. The reaction was concentrated and the residue diluted with ether.

The organic solution was washed with sat. aq. NaHC03 (2

H

2 O, then sat. aq. NaC1, dried (MgSO 4 and concentrated to afford 3-methoxy-4-nitrobenzoyl chloride (1.92 g, 87%) as a white solid: 1 H NMR (CDC1 3 300 MHz, ppm) 7.95-7.70 3H), 4.06 3H).

B. To a cold solution of TMSCHN 2 (2 M in hexane, 1.5 mL, 3.0 mmol) and triethylamine (420 gL, mmol) was added a solution of 3-methoxy-4- 108 nitrobenzoyl chloride (0.52 g, -2.4 mmol) in acetonitrile (8.5 mL). -The reaction was stirred at 0 C for 24 h and then concentrated. The residue was slurried with sat. aq. NaHCO 3 and the mixture extracted with ether The combined ether washes were washed with water, then sat. aq. NaCI, dried (MgSO 4 and concentrated to afford &-diazo-3-methoxy-4-nitroacetophenone (0.53 g, 100%) as a yellow foam: H NMR (CDC13, 300 MHz, ppm) 7.88 Hz, 1H), 7.61 1H), 7.27 10 Hz, 1H), 5.97 (s, 1H), 4.02 3H).

To a refluxing solution of &-diazo-3methoxy-4-nitroacetophenone (7.95 g, 35.9 mmol) in tBuOH (100 mL) was added a filtered solution of silver 15 benzoate (2.50 g, 10.9 mmol) in triethylamine (15 mL) dropwise over 1 h. After refluxing for 45 min, decolorizing carbon was added and the hot mixture filtered thru a pad of Celite. The filtrate was -concentrated and the residue diluted with ethyl acetate. The organic solution was washed with 5% aq.

NaHCO3 (2 H 2 0, 5% aq. citric acid, H20, then sat.

aq. NaC1, dried (MgSO 4 and concentrated to afford tbutyl 3-methoxy-4-nitrophenylacetate (8.92 g, 93%) as a brown oil: 1H NMR (CDC1 3 300 MHz, ppm) 7.83 8.3 25 Hz, 1H), 7.03 1H), 6.93 8.3 Hz, 1H), 3.97 (s, 3H), 3.58 2H), 1.45 9H).

D. A mixture of t-butyl 3-methoxy-4nitrophenylacetate (0.144 g, 0.539 mmol) and 10% Pd on carbon (0.155 g) in ethyl acetate (8 mL) and methanol-- (2 mL) was stirred under H 2 (40-60 psi) for 2 The mixture was filtered through Celite and the filtrate concentrated to afford t-butyl 4-amino-3methoxyphenylacetate (0.123 g, 96%) as a light yellow oil: 1H NMR (CDC1 3 300 MHz, ppm) 6.70 3H), 4.04 (bs, 2H), 3.84 3H), 3.42 2H), 1.43 9H).

109 E. To a solutiorrof t--Butyl 4-amino-3methoxyphenylacetate (0.123 g, 0.52 mmol) in methylene chloride (2.0 mL) was added phenyl isocyanate (60 PL, 0.55 mmol). The reaction was stirred for 45 min then concentrated to afford t-butyl 3-methoxy-4phenylureidophenylacetate (0.190 g, 100%) as a pale yellow foam: 'H NMR (CDC1 3 300 MHz, ppm) 8.00 (d,ll Hz, 1H) 7.65-6.94 7H), 6.80 9.0 Hz, 1H), 6.74 1H), 3.68 3H), 3.45 2H), 1.44 9H).

F. A solution of t-butyl 3-methoxy-4phenylureidophenylacetate (0.108 g, 0.303 mmol) in trifluoroacetic acid (5.0 mL) was stirred for 30 min.

The reaction was concentrated and the residue coevaporated with methylene chloride (2X) then ether to 15 afford 3 -methoxy-4-phenylureidophenylacetic acid (0.090 g, 99%) as a white foam: 1H NMR (CD 3

SOCD

3 300 MHz, ppm) 9.28 8.18 1H), 8.02 7.5 Hz, 1H), 7.58-7.15 5H), 6.91 (bin, 2H), 6.77 7.5 Hz, 1H), S3.85 3H), 3.49 2H).

G. A solution of 3-methoxy-4phenylureidophenylacetic acid (0.33 g, 0.88 mmol), Leu-S-2, prepared utilizing procedures C and D, (0.27 g, 0.90 mmol), BOP 0.39 g, 0.90 mmol) and DIPEA (0.77 mL, 4.4 mmol) in DMF (5 mL) was stirred for 18 h. The 25 reaction was diluted with ethyl acetate and washed with sat. aq. NaHCO 3

H

2 0, 5% aq. citric acid (3X),

H

2 0, then sat. aq. NaC1, dried (MgSO 4 and concentrated to afford crude product (0.49 The crude product was purified by flash chromatography (silica gel, 1:4 hexane-ethyl acetate) to give BI01056 t-butyl ester (0.35 g, 60%) as a white foam: 'H NMR (CDC13, 300 MHz, ppm) 8.00 (d,8.1 Hz, 1H), 7.55-7.20 8H), 7.05 (m, 1H), 6.70 5H), 5.89 2H), 5.18 1H), 4.50 (s, 1H), 3.63 3H), 3.47 2H), 2.67 2H), 1.68- 1.40 (bm, 3H), 1.33 9H).

110- To a cold (000) soltition of BI01056 t-buty-l ester (0.35 g, 0.53 mmol) in methylene chloride tnL) was added trifluoroacetic acid (5.0 rnL). The reaction was allowed to warmi to RT and stirred for 1 h then concentrated to afford crude BI01056 (0.315 g).

The crude product was purified by HPLC in two port ions to give BI01056 (0.16 g, 50%) as a white solid: 'H NMR

(CD

3

SOCD

3 300 MHz, ppm) 9.25 1H), 8.43 8.2 Hz, 1H), 8.15 (in, 2H), 8.01 8.2 Hz, 1H), 7.50-6.55 (mn, 10H), 5.97 2H), 5.08 (in, lH), 4.31 (mn, 1H), 3.85 3H), 3.41 (mn, 2H), 2.64 (mn, 2H), 1.55-1.22 (bin, 3H), 0.80 (in, 6H); HPLC (Gradient 35.2 min, (Gradient 19.4 min; MS, m/z 605.

EXAMPLE JU Synthesis of Compound RTO-1221 A. To a solution of t-butyl 4-amino-3methoxyphenylacetate (0.024 g, 0.10 rnmol) in methylene chloride (2.0 inL) was added o-tolyl isocyanate (15 AiL, 0.12 iniol). The reaction was stirred for 2 h then concentrated to afford t-Butyl 3-methoxy-4-otolylureidophenylacetate (0.036 g, 97k) as a tan foam: 1H NMR (CDCl 3 300 MHz, ppm) 8. 05 7.9 Hz, 1H) 7.55 7.9 Hz, lH), 7.45-7.05 (mn, 5H), 6.78 (mn, 2H), 3.73 3H), 3.48 2H), 2.23 3H), 1.44 9H).

B. A solution of t-butyl 3-methoxy-4-otolylureidophenylacetate (0.016 g, 0.043 minol) in trifluoroacetic acid (1.0 inL) was stirred for 1 h. The reaction was concentrated and the residue coevaporatedwith inethylene chloride (2X) then ether to afford 3iethoxy-4-o-tolylureidophenylacetic acid (0.0135 g, 100k) as a white residue.

C. The procedure described in Example 51G was performed using 3 -iethoxy-4-o-tolylureidophenylacetic acid (0.0135 g, 0.043 inmol) and amine salt prepared 111 from 6-3 utilizing procedures C and D (0.0185 g, 0.041 mmol)to afford BI01221 methyl ester (0.016 g, 60%) as a white foam: 'H NMR (CDC13, 300 MHz, ppm) 8.10 1H), 7.61 1H), 7.45-7.00 7H), 6.85-6.65 5.93 2H), 5.20 1H), 4.37 1H), 3.85 3H), 3.61 3H), 3.52 2H), 2.75 2H), 2.30 (s, 3H),1.65-1.10 (bm, 3H), 0.86 6H).

D. BI01221 methyl ester (0.016 g, 0.025 mmol) was hydrolyzed using the method described in Example 1B to give BIO-1221 (0.0087 g, 56%) as a white powder: 'H NMR (CDC1 3 300 MHz, ppm) '.93 1H), 7.70 1H), 7.49 1H), 7.37-6.92 6H), 6.78-6.55 5H) 5.81 2H), 5.09 1H), 4.27 1H), 3.73 3H), 3.40 2H), 2.58 2H), 2.19 3H), 1.48-1.25 (bm, 15 3H), 0.76 6H); HPLC (Gradient 35.2 min; MS, m/z 619.

EXAMPLE 53 Synthesis of Compound BIO-1238 A. The procedure described in Example 43A was performed using amine -5 to give 1238-1. Yield:92%.

1 HNMR (CDC1 3 300MHz, ppm): 7.19 2 H, J 8.6 Hz), 6.82 2 H, J 8.6 Hz), 5.36-5.28 2 4.25- -4.22 1 3.72 3H), 3.56 3H), 2.72-2.66 2H), 2.49-2.41 2 2.1 3 1.92-1.78 1H), 1.48 9 The Boc group was removed by TFA /CH 2 Cl 2 to afford TFA salt 1238-1. 1 HNMR (CDC1 3 300MHz, ppm): 7.12 2 H, J 8.5 Hz), 6.74 2 H, J 8.5 Hz), 5.32 1 4.38 1 3.68 3 3.51 3 2.77-2.69 2 2.55-2.38- 1 2.36-2.31 1 2.16-2.02 2 1.91 3

H).

B. The procedure described in Example 1A was performed using 2-methylphenylureaphenylacetic acid mg, 0.7 mmol) and TFA salt 1238-1 (30 mg, 0.7 mmol) to 112 give 1238-2 35 mg, 83 10Fas awhite solid. III (DMSO-d 6 300MHz, ppm): 7.91 lH), 7.52 2 H, J 8.5 Hz), 7.35-7.30 (in, 4 7.02 1 6.80 (d, 2 H, J 8.5 Hz), 5.79-5.68 (mn, 1 4.40-4.28 (in, 1 3.71 3 3.63 3 3.35-3.38 (mn, 2 H), 2.49 (br, s, 2 2.00 (s 3 H).

C. A solution of 1238-2 (20 mg, 0.033 minol) in MeOH (3 inL) and aqueous LiOH (3 m.L of 2N) was stirred at room temperature overnight, the reaction mixture was cooled to 0 0 C and acidified by adding TFA until pH 3 4 (pH paper). The desired product was isolated and purified by LC (Vydac C18 column; gradient 8) to give 12 mng (0.017 minol; 61%) of BIO-1238 as a white solid: FAB3-MS =595.

Synthesis of Compound RTO-1249 A. 1245-1 was prepared from commercially available N-BQC-methionine sulfone (562mg, 2.Ominol) and amine f9-3 (470mg, 2.l10miol) using the method described in Example 1A to afford crude 1245-1 (962mg, 1.90 iniol, 95t) as a white foam which was used without further purification. 'HNMR(CDCl 3 5 7.31 (1H, d, J=8.3Hz), S6.77-6.7(3W, in), 5.91(2H, 5.04(1H, d, J=7.6Hz), 5.27(1W, in), 4.30(1W, br), 3.61(3H, 3.15(1W, in), 2.93(1H, in), 2.89(3H, 2,85(2H, in), 2.22(2H, in), 1.42(9H, s).

B. Compound 1245-1 (962mg, 1.9Omnol) was treated with 4N HC1/dioxane as the reagent.

Concentration affords the hydrochloride salt 1245-2 as a white solid (800mg, 1.89mg, 1.89mnol, 99U) which was used without further purification. 'HNMR(CDCl 3 8.75(1H,br)., 8.20(2W, br), 6.91-6.55(3H,n), 5.90(2H, bs), 5.42(1W, br), 4.55(1W, br) 3.60(3H, 3.45- 3.0(2W, bin), 2.90 (3H, 2.85-2.40(4H, bin).

113 C. The procedure-desciibed in Example 22D was performed using compound 1245-2 (800mg, l.89mmol) and o-methyiphenylureaphenyl acetic acid (543mg, l.89mmo1) to afford crude 1245-3 (1.15g, 1.76mmol, as a white solid which used without further purification.

'HNMR(DMSO=d 6 6 7.95(1H,s), 7.89(1H,d,J=7.9Hz), 7.43(2H, D, J=7.9Hz), 7.20(4H, in), 7.00-6.78(4H, in), 6.03(2H,s), 5.18(1H, in), 4.40(1H, in), 3.58(3H, a), 3.49(3H, 3.39(2H, br), 2.90-2.49 (211, mn), 2.29(31, 2.00(2H, mn).

D. Compound 1245-? (1.1 g, 1.7 iniol) was hydrolyzed as described in Example lB to afford crude BIO-1245 (490mg, 0.77niol, 45tc) as a white solid pure by HPLC. A small amount (-150mg) was purified by prep HPLC to afford pure BIO-1245(Blmg, 54t recovery) as a white solid m/z=639(100t pure by HPLC).

'HNMR(DMSO-d 6 6 8.60(0.5H, bs), 8.57(1H, d, J=8.lHz), 8.37(1H, d, J=8.lHz), 8.18(1H, 8.05(0.5H, s), 7.89(1H, d, J=8.OHz), 7.43(2H, d, J=8.04z), 7.21(41, mn), 6.97-6.81(4H1, in), 6.03(2H, S.13(lH,m), 4.43(lH, mn), 3.80(111, br), 3.49(3H, 2.93(2H, in), 2.45(2H1, mn), 2.30(3H, 2.01(2H, in).

EVXAM2.E Synthesisq of PTO-1246 A. To a suspension of L-cysteine 12.4mmol) in methanol (BuiL) was added excess sodium methoxide (2.0g, 37.2inmol) followed by a catalytic amount of sodium iodide VlO00ing). After stirring at room temperature for 30 min. 1-broino-2-propanofl7(1.7g, 12.4inmol) was added and the reaction was stirred overnight. The reaction mixture was then neutralized to pH- 7 diluted with water (2OmL) and concentrated to remove the methanol. The solution was then diluted with dioxane (2OinL) and triethylamine (7.OinL, 114 was added followed by BOCON (3:1g, 12.4mmol) and the reaction was stirred at room temperature for 3h. The reaction was worked up by diluting with water (2OmL) and extracting with ethyl acetate (3X25rnL). The organic extracts were discarded and the aqueous solution acidified to pH=l with 1N HCl. The aqueous was extracted with ethyl acetate (4x3OmL), dried over sodium sulfate and concentrated to afford 1246-1 (2.87g, 1O.4mmol, 83%, 2 steps) as a thick pale yellow syrup. 'HNMR(CDCl 3 6 5.60-5.50(1H, br), 4.60-4.SO(lH, br), 4.44(2H,, t, J=6.3Hz), 3.02(2H, bin), 32.65(2H,br) 2.03 1.45(9H, S).

B. The procedure of Example 1A was performed using 1246-1 (33mg, 0.llmmol) and amine 19-3 (22mg, 0.10mmol) to afford 1246-2 (39mg, 0.O8mmol, 80k) as a pale yellow foam which was used without purification in the next step. 'HNMR (CDCl 3 6 6.80-6.60(3H,m), 5.91(2H,s), S.50(lH,bm), 4.35(lH,bm), 3.71, (211,bt), -3.61(3H, 3.15-2.65(6H,m), 1.85(2H,m), 1.46(9H, s).

C. Compound 1246-2 (39mg, 0.O8mmol) was treated with TFA to give the corresponding amine-TFA .salt of 1246-2 which was subjected to the conditions described in Example 54C to give a white solid which was directly hydrolysed as described in Example lB to the free acid. A small aliquot was purified by HPLC.

The clean fractions were collected to afford BIO- 1246(-3mg) M/Z=637(100k pure by HPLC) as a white solid.

'HNMR (DMSO -d 6 6 .9.0 1 (1Hs) 8 -6 6 (H,d,J=5.3Hz), 8.30(1H,d,J=5.5Hz), 7.94(1H,s), 7.88(lH,d,J=5.3Hz), 7.42(2H,d,J=5.SHz), 7.20-7.15(4H,m), 7.00-6.94(2H,n), 6.88-6.79(2H,m), 6.02(2H,s), 5.12(1H,m), 4.48(1H,m), 3.65(2H,in), 2.90-2.45(6H,m), 2.28(3H,s), 1.65(2H,rn).

FXAMPTF S Synthesis of RT-1248 115 A. A mixture of 4-fluorobenzaldehyde (2.48 g; mmol), malonic acid (2.5 g, 24 mmol) and ammonium acetate (2.16 g; 28 mmol) in ethanol (100 mL) was refluxed under argon overnight. After cooling to room temperature, the solid precipitate was collected by filtration and washed with ethanol 3 x 30 mL) and dried under vacuum to give 1.0 g of white solid, which was used without further purification.

*To a suspension of the white solid (1.0 g, 9.4 mmol) in methanol was added SOC1 2 (6.01 mmol; 5.2 mL of 2 M in CH 2 C1 2 The resultant solution was stirred at room temperature overnight. After removal of excess solvent, the residue was dissolved in EtOAc, basified with sat. NaHCO 3 and dried with Na 2

SO

4 The organic 15 solution was concentrated under reduced pressure to give 900 mg of amine 1248-1 as a light yellow oil: 'H NMR (CDC13, 300 MHz, ppm) 7.28 2 H, Ar), 6.96 2 H, Ar), 4.46 J 6.8, 1 3.62 3 OMe), 2.58 J 6.8 Hz, 2 1.69 2 H, NH); TLC, 10%MeOH/CH 2 C12, Rf B. Amine 1248-1 (300 mg, 1.52 mmol) was coupled with Na-t-Boc-Ne-leu-N-hydroxysuccinimide (300 mg, 1.52 mmol) using the method described in Procedure C. The resulting adduct was deprotected with 25 trifluoroacetic acid and, then basified with Et 3 N as described in Procedure D1 to give the amine 1248-2 in 84%: H NMR (CDC1 3 300 MHz, ppm) 8.20 J 7.1 Hz, 1 7.24 2 H, Ar), 6.97 2 H, Ar), 5.33 1 3.58 3 H, OMe), 3.38 1 2.82 2 H), 1.66 2 1.30 1 1.22 2 0.91 6 TLC, 10%MeOH/CH 2 Cl 2 Rf 0.47 and 0.38.

C. 2-Methylphenylureaphenylacetic acid (77 mg, 0.27 mmol) was coupled with amine 1248-2 (70 mg, 0.23 mmol) using the method described in Example 22D to give 1248-3 in 61% yield. 'H NMR (DMSO-d 6 300 MHz, ppm) 6 116 9.15 J 5.9 Hz, 1 8.53 J 7.5 Hz, 1 8.17 J 8.2 Hz, 1H), 8.0 1 7.84 J Hz, 2 7.35 4 7.13 6 6.92 J 8.2 Hz, 1 5.20 1 4.30 1 3.52 (s, two peaks, 3 H, OMe), 3.45-3.24 2 2.75 2 2.24(s, 3 H, Me), 1.57-1.33 3 0.82 6 HPLC (gradient 21.2 min and 21.5 min (1:24); FABMS, m/z 577 (C 33

H

37

N

4 0sF of M'+1 requires 577).

D. A solution of 1248-3 (22 mg, 0.038 mmol) in DMSO (1 mL) and MeOH (2 mL) was hydrolyzed with aqueous LiOH as described in Example lB. The product was purified on a Vydac reverse-phase C18 column (22 mm x 25 cm) using a linear gradient of 15 CH 3

CN/H

2 0 (0.1 TFA) to 40 CH 3

CN/H

2 0 (0.1 TFA) with a flow rate of 15 10 mL/min to give BIO-1248 in 29% isolated yield. 'H NMR (DMSO-d 6 300 MHz, ppm) 6 8.93 (s,l 8.46 J 8.3 Hz, 1 8.25 J 8.2 Hz,l 7.87 1 7.82 J 8.0 Hz, 1 7.33 5 7.12 5 H), -6.93 1 5.15 1 4.28 1 3.35 2 2.65 J 7.2 Hz, 2 2.22 3 H, Me), 1.55 1 1.43 2 0.83 6 HPLC (gradient i 1) 18.7 min and 19.3 min FABMS, m/z 563 (Cz 3

H

35

N

4 0 5 F of M'+1 requires 563).

EXAMPLE 57 Synthesis of BIO-1270 A. Amine 6-3 (500 mg, 2.24 mmol) was coupled with Na-Cbz-Ne-t-Boc-L-Lys-N-hydroxysuccinimide (1.0 g, 2.1 mmol) using Procedure C to give the coupled adduct- 1270-1 (1.1 g, This adduct was deprotected with trifluoroacetic acid and was basified with Et 3 N as previously described in Procedure D to give 1270-2 in 54% yield. 1H NMR (CDC13, 300 MHz, ppm) 6 7.31 6 H), 6.72 3 5.90 2 5.58 J 9 Hz, 1 H), 5.26 1 5.07 2 4.15 1 3.58 3 117 H, OMe) 2. 77 (in, 2 H) f. 61 (ii, 2 H) 1. 79 (in, 1 H), 1. 59 (in, 1 H) 1. 41-1.30 (in, 6 H) TLC, 10%MeOH/Cm 2 Cl 2 Rf= 0. 11.

B. To a Btirred solution of 1270-2 (15.5mg, 0.O32mmiol) and pyridine (10.1mg, 0.128mno1) in CH 2 Cl 2 at rt is added acetyl chloride (7.5mg, 0.O96mmiol).

After stirring for 3 hours the reaction is concentrated and reverse phase chromatography provided 1270-3 (16.3mg, 95k) as a white foam. 'HNMR(CDC1 3 300MHz, ppm) 7.32(S, 5H), 6.70(m, 3H) 5.91(s, 2H), 5.82(mn, 1H), 5.55(m, 111), 5.25 (in, 1H), 5.09(s, 1H), 4.13(mn, 1H), 1.9-1.76(n, 1H) 1.70-1.58 (mn, 1H),1.52-1.42(n, 2H), 1.36-1.22(m, 2H).

C. Procedure D2 was performed using 1270-3 (reaction progress was followed by HPLC) to give compound 1270-4 (14.1mg, quantitative yield) as a clear oil which was used as the crude material.

D. The procedure of Example 54C was performed using 1270-4 14.1mg, 0.O36niol) Purification was carried out via preperative HPLC and provided Bio 1270- *OMe (9.1mg, 38t) as a white solid. IHNMR (DMSOD 6 300MHz, ppm), 8.13(d, 1H1 J=10.35), 8.03(s, 1H1), 7.93(d, 1H J=10.35), 7.83(mn, 1H), 7.49(d, 2H J=10.35), 7.28(mn, 511), 7.10-6.81(m. 511), 6.08(s, 2H1), 5.20(dd, 111 J=9.66, 17.25), 4.33(dd, 1H J=8.97, 15.18), 3.63(s, 3H), 2H), 3.1-2.95(m, 2H1), 2.85-2.74(mn, 2H), 2.33(s, 3H), 1.86(s, 3H), 1.72-1.49(mn, 2H), 1.5-1.32(mn, 3H), 1.31- 1.09(m, 2H).

E. To Bio 1270-OMe (9.1mg, 0.016) in imnI of DMSODE, (NMR sample) was added 20 ul of 2N LiOH(O04iniol) and the reaction was stirred at rt.

overnight. The reaction was acidified (red to litmus) with 3 drops of TFA and purified by preparative HPLC This afforded BIO-1270 (6.2mg, 60t) as a white solid.

118

'HNMR(DMSO

6 300MHz, ppm)-, 8.5td, 12H J=10.35), 8.19(d, 1H J=10.35), 7.99(s, 1H), 7.93(d, 1H1 J=10.35), 7.82 (in, 1H1), 7.45(d, 211 J=10.35). 7.28(m, 4H), 7.05(m, 1H1), 6.98-6.89 (mn, 211) 6.86(m, 1H), 6.09(S, 2H), 5.66(dd, 1H J=8.28, 16.56) 4.32(dd, 1H J=7.59, 13,8), 3.27 2H), 2.98 (mn, 2H) 2.75(m, 2H), 2.33 3H1), 1.87(s, 3H), 1.69-1.48 (in, 211), 1.46-1.32(m, 3H), 1.28-1.12 (mn, 2H); MS, m/z 646; HPLC (Gradient 1) 19.73 min. 100t.

Gradient 3 15k B -65t B 50 min.

Gradient 1 20t B -70% B 50 min.

EXAMPT.E S SSynthesis of RTO-1282 A. A solution of ethyl 3-pyridylacetate (1.65 9.90 inmol) in 32% peracetic acid (10 inL) was stirred at 80-90*C for 2 h. The reaction was concentrated and the residue coevaporated with methanol (2X) then iethylene chloride to afford ethyl 3-pyridylacetate N- -oxide (1.80 g, 100%) as a white solid: 1'H NMR (CDC 3 300 MHz, ppm) 8.38 111), 8.22 1H1), 7.39 111), 4.20 2H1), 3.62 2H1), 1.26 3H1).

*Vdo:B. A solution of salicylanide (4.14 g, 30.2 mmiol) and conc. sulfuric acid (3 drops) in acetone mL) was refluxed for 5 h. The reaction was *concentrated and the residue taken up in ethyl acetate.

The organic solution was washed with 1 N NaOH 1 N HCl (2X) H 2 01 then sat. aq. NaCl, dried (MgSO 4 and concentrated to afford 2, 2-diinethyl-4-keto-1, 3benzoxazine (2.50 g, 47t) as a white solid: 'H NIIR (CDCl 3 300 MHz, ppm) 7. 92 11) 7.60 (bs, JRi), 7.47 (mn, 1H), 7.06 (in, 1H), 6.92 1H), 1.65 611).

C. A solution of 2,2-dimethyl-4-keto-1,3benzoxazine. (1.77 g, 10.0 inmol) and PC1 5 (2.09 g, 10.0 inmol) in PoC1 3 (3.0 inL) was stirred at RT for 1 h then at 50-60 0 C for 2 h. The reaction was concentrated and 119 the product distilled (90-95°C/2-3 mm Hg) to afford 4chloro-2,2-dimethyl-3H-1,3-benzoxazine. (0.496 g, as a clear oil: 1H NMR (CDC13, 300 MHz, ppm) 7.58 (d, 1H), 7.48 1H), 6.97 1H), 6.94 1H), 1.63 (s, 6H).

D. A mixture of 4-chloro-2,2-dimethyl-3H-1,3benzoxazine (0.145 g, 0.741 mmol) and ethyl 3pyridylacetate N-oxide (0.270 g, 1.49 mmol) in methylene chloride (5.0 mL) was refluxed for 20 h. The reaction was concentrated and the residue taken up in ethyl acetate. The organic mixture was washed with sat. aq. NaHCO 3 H20, sat. aq. NaC1, dried (MgSO,), and concentrated to afford an oily residue (0.148 g).

The crude oily residue (0.148 g) in cone. HC1 15 (10 mL) was refluxed for 18 h. The reaction was concentrated and the residue partitioned in H 2 0 and methylene chloride. The aqueous solution was washed 0with methylene chloride (2X) and then concentrated to 0 *00 -afford a white solid (0.105 g).

A solution of the white solid (0.105 g) in methanol (5.0 mL) was treated with thionyl chloride S* (0.5 mL, 7 mmol) dropwise over 30 min. The reaction was stirred for 2 h then concentrated. The residue was S" taken up in 5% aq. NH40H and extracted with methylene 25 chloride The organic extracts were dried (MgSO 4 and concentrated to afford methyl 5-(2aminopyridyl)acetate (0.012 g, 10% for three steps) as a white solid: 1H NMR (CDCl 3 300 MHz, ppm) 7.93 (s, 1H), 7.40 1H), 6.50 1H), 4.52 (bs, 2H), 3.70 3H), 3.49 2H); MS, m/z 167.

E. To a solution of methyl 5-(2aminopyridyl)acetate (0.012 g, 0.072 mmol) in methylene chloride (1.0 mL) was added o-tolyl isocyanate (10 AL, 0.081 mmol). The reaction was stirred for 1 h then 120 concentrated to afford a white-residue (0.020 g) containing methyl 5-(2-o-tolylureido)pyridylacetate.

F. A solution of crude methyl 5-(2-otolylureido)pyridylacetate (0.020 g) in methanol mL) was treated with 2 M LiOH (100 AL, 0.20 mmol). The reaction was stirred for 18 h then concentrated. The crude product was purified by HPLC to afford 5-(2-otolylureido)pyridylacetic acid (0.013 g, 65%) as a white powder: 1H NMR (CDC1 3 300 MHz, ppm) 8.10 (s, 1H), 7.87 (bd, 1H), 7.75 (bd, 1H), 7.21 (mn, 1H), 7.08 1H), 3.62 2H), 2.38 3H); MS, m/z 286.

G. The procedure described in Example 1A was performed using 5-(2-o-tolylureido)pyridylacetic acid (0.013 g, 0.045 mmol) and the amine prepared in Example 15 14A (0.022 g, 0.049 mmol) to afford BI01282 methyl ester (0.020 g, H NMR (CDC13, 300 MHz, ppm) 8.18-7.73 4H), 7.55 1H), 7.35-6.65 5.93 1H), 5.28 1H), 4.45 1H), 3.69-3.45 (m, 2.81 (bm, 2H), 2.20 3H), 1.54 (bm, 3H), 0.92 20 6H).

H. To a mixture of BI01282 methyl ester (0.020 g, 0.033 mmol) in methanol (02.0 mL) was added 2.0 M LiOH (200 L, 0.40 mmol). The reaction was stirred for 20 h then concentrated. The residue (containing a mixture of BI01282 and starting ester) was dissolved in DMF (0.5 mL) and methanol (0.5 mL) then stirred for an additional 28 h. The reaction was acidified with trifluoroacetic acid and concentrated. The crude product was purified by HPLC to give BIO-1282 (0.0056g, 24%) as a white powder: 'H NMR (CDC1 3 300 MHz, ppm) 8.44 8.1 Hz, 1H), 8.26 8.3 Hz, 1H), 8.15 (s, 1H), 8.04 8.0 Hz, 1H), 7.66 8.7 Hz, 1H), 7.32- 7.13 3H), 7.05- 6.94 1H), 6.85- 6.65 3H), 5.96 2H), 5.06 1H), 4.29 1H), 3.45 2H), 121 2.63 2H), 2.31 3H) 1.57-1.20 3H), 0.78 (m, 6H); HPLC (Gradient 27.0 min; MS, m/z 590.

EXAMPLE 59 Synthesis of BIO-1294 A. To a stirred solution of the amine prepared in Example 57A (102 mg, 0.21 mmol) in CH 2 Cl 2 (20) was added CH 3 SOCl (48 mg, 32 AL, 0.42 mmol) and Et 3 N iL). The resulting mixture was stirred at RT for 18 h.

The reaction mixture was diluted with CH 2 C12 (40 mL), washed with 5% citric acid (20 mL), H 2 0 (10 mL), Sat.

NaHCO3 (20 mL) Sat. NaC1 (20 mL) and dried with Na 2

SO

4 The organic solution was concentrated under reduced pressure to give 110 mg of 1294-1 as a white solid: 1 H NMR (CDC1 3 300 MHz, ppm) 6 7.30 6 H), 6.74 3 5.90 2 5.70 1 5.25 1 5.07 3 4.16 1 3.58 3 H, OMe), 3.02 2 2.88 3 2.75 2 1.76 1 1.60 1 1.50 2 1.32 2 TLC, 2 C1 2 Rf 0.67.

20 B. To a solution of compound 1294-1 (110 mg,0.195 mmol) was dissolved in methanol (10 ml) was added acetic acid (0.2 ml) and Pd(OH) 2 (110 mg). The resulting mixture was hydrogenated (H 2 50 psi) at RT for 48 h. After standard work-up, 1294-2 (35 mg, 42%) was obtained as colorless oil: 'H NMR (CDC13, 300 MHz, ppm) 6 8.06 1 6.75 3 5.92 2 H), 5.25 1 5.02 1 3.61 3 3.35 1 3.10 2 2.94 3 2.80 2 1.87- 1.30 8 HPLC (gradient 8) 12 min.

C. 2-Methylphenylureaphenylacetic acid (35 mg, 0.12 mmol) was coupled with the amine 1294-2 (35 mg, 0.08 mmol) as described in Example 1A to give compound 1294-3 in 88%. 'H NMR (CDC1 3 300 MHz, ppm) 6 8.50 (m,1 8.30 1 8.16 (m,1 7.82 1 7.40 122 2 7.22-7.05 7.00-6.70 5 5.98 2 5.11 1 4.22 1 3.52 3 H), 3.36 2 2.91-2.62 7 2.25 3 1.60- 1.05 6 HPLC (gradient 8) 31 min; FABMS, m/z 696

(C

34

H

41

N

s OgS of M++1 requires 696).

D. A solution of compound 1294-3 (50 mg, 0.07 mmol) in MeOH (3 mL) was hydrolyzed with aqueous LiOH as previously described. The product was purified on a Vydac reverse-phase C18 column (22 mm x 25 cm) using a linear gradient of 15 CH 3

CN/H

2 0 (0.1 TFA) to 40

CH

3

CN/H

2 0 (0.1 TFA) with a flow rate of 10 mL/min to give BIO-1294 in 41% isolated yield. *H NMR (CDC1 3 300 MHz, ppm) 6 8.95 (m,1 8.42 J 8.2 Hz, 1 H), i 8.08 J 8.1 Hz, 1 7.88 1 7.83 J 15 8.0 Hz, 2 7.36 J 8.2 Hz, 2 7.15 4 H), 7.10-6.71 5 5.97 2 5.04 1 4.22 1 3.41-3.25 2 2.83-2.80 6 2.23 3 1.70-1.04 6 HPLC (gradient 8) 27 min; -FABMS, m/z 682 (C 33

H

39 Ns0 9 S of M'+1 requires 682).

EXAMPLE Synthesis of BIO-1321 A. A mixture of methyl 4-formylbenzoate (3.48 g; 20 mmol), malonic acid (2.5 g, 24 mmol) and ammonium acetate (2.16 g; 28 mmol) in ethanol (100 mL) was refluxed under argon overnight. After cooling to room temperature, the solid precipitate was collected by filtration and washed with ethanol 3 x 30 mL). The white solid was dried under vacuum overnight to give 2.8 g of 1321-1.

B. To a suspension of compound 1321-1 (1.0 g, 4.48 mmol) in methanol (50 mL) was added SOC1 2 (5.4 mmol; 2.7 mL of 2 M in CH 2 C1 2 The resultant solution was stirred at room temperature overnight. After removal of excess solvent, the residue was dissolved in EtOAc, 123 basified with sat. NaHCO 3 and aried with Na 2

SO

4 The organic solution was concentrated under reduced pressure to give 780 mg of the amine 1321-2 as a light yellow oil: 1 H NMR (CDC1 3 300 MHz, ppm) 7.99 2 H, Ar), 7.56 J 8.1 Hz 1 H, Ar), 7.42 J 8.0 Hz 1 H, Ar), 4.46 J 6.7, 1 3.85 3 H, OMe), 3.65 3 H, OMe), 2.65 J 6.8 Hz, 2H), 1.88 2 H, NH).

C. The amine 1321-2 (500 mg, 1.11 mmol) was coupled with Na-t-Boc-Ne-Leucine-N-Hydroxysuccinimide (380 mg, 1.0 mmol) as described in Procedure C to give material which was deprotected with trifluoroacetic acid and, then basified with Et 3 N as described in Procedure D1 to give amine 1321-3 in 70% yield: 1 H NMR (CDC13, 300 MHz, 15 ppm) 8.32 J 9.1 Hz 1 8.20 J 8.3 Hz, 2 7.34 2 H, Ar), 5.40 1 3.86 3 H, OMe), 3.58 3 H, OMe), 3.41 1 2.85 2 H), 1.67 2 1.53 2 1.30 1 0.90 6 H) 20 D. 2-Methylphenylureaphenylacetic acid 54 mg, i 0.19 mmol) was coupled with amine 1321-3 (70 mg, 0.23 mmol) using the method described in Example 22D to give the 1321-4 in 87% yield: 'H NMR (DMSO-d 6 300 MHz, ppm) 6 8.62 1 8.18 J 8.1 Hz, 1 8.10 1H), 7.94-7.82 4 7.48 -7.34 4 7.17-7.13 4 6.91 J 7.3 Hz, 1 5.24 1 4.30 1 3.53 two peaks, 3 H, OMe), 3.39-3.34 2 H); 3.05 2 2.24(s, 3 H, Me), 1.60-1.36 3 H), 0.83 6 HPLC (gradient 8) 40 min FABMS, m/z 617 (C 33

H

40

N

4 0 7 of M'+1 requires 617).

E. A solution of 1321-4 (70 mg, .0.11 mmol) in DMSO (1 mL) and MeOH (2 mL) was hydrolyzed with aqueous LiOH as described in Example IB. The product was purified on a Vydac reverse-phase C18 column (22 mm x cm) using a linear gradient of 15 CH 3 CN/HzO (0.1 TFA) 124 to 40 CH 3

CN/H

2 0 (0.1 TFA) with a flow rate of mL/min to give BIO-1321 (22 mg, 34% isolated yield): 'H NMR (DMSO-d 6 300 MHz, ppm) 6 8.95 J 4.6 Hz, 1 H), 8.57 1 8.13 J 8.3 Hz, 1 7.88-7.81 (m, 4 7.44 -7.32 4 7.17-7.10 4 6.92 (t, J 7.4 Hz, 1 5.20 1 4.31 1 3.46- 3.27 2 2.70 2 2.22(s, 3 H, Me), 1.59- 1.32 3 0.81 6 HPLC (gradient 8) 27.8 min and 28.1 min FABMS, m/z 589 (C 31

H

36

N

4 0 7 of M'+1 requires 589)" EXAMPLE 61 Synthesis of Compound 1336 A. A slurry of 2,6-dichloro-3-nitropyridine 9.9 g, 47 mmol) and K 2 C03 powder (6.5 g, 47 mmol) 15 in methanol (100 mL) was stirred for a week at RT. The reaction was filtered and concentrated. The residue was partitioned in ethyl acetate and 60% sat. aq. NaHCO The organic solution was washed with 60% sat. aq. NaHC03

H

2 0, then sat. aq. NaC1, dried (MgSO 4 and concentrated to afford 2-chloro-6-methoxy-5nitropyridine and 2-chloro-6-methoxy-3-nitropyridine (8.9 g, 100%) as a light yellow solid: 'H NMR (CDC1 3 300 MHz, ppm) 8.31 8.3 Hz, 1H), 8.28 8.9 Hz, 1H), 7.10 8.3 Hz, 1H), 6.82 8.9 Hz, 1H), 4.15 3H), 4.06 3H).

B. A mixture of 2-chloro-6-methoxy-5nitropyridine and 2-chloro-6-methoxy-3-nitropyridine (8.9 g, 47 mmol), t-butyl methyl malonate (10 mL, mmol), and NaH 3.1 g, 120 mmol) in THF (250 mL) was stirred at RT for 24 h. The reaction was concentrated and the residue treated with trifluoroacetic acid (200 mL) for 2 h. The reaction was concentrated and the product separated by flash chromatography (silica gel, 95:5 hexane-ethyl acetate) 125 to afford methyl 6-(2-methoxy-3-nitro)pyridylacetate (3.3 g, 62%) as a yellow oil: H NMR (CDC1 3 300 MHz, ppm) 8.27 8.0 Hz, 1H), 7.04 8.0 Hz, 1H), 4.09 3H), 3.85 2H), 3.75 3H).

C. A mixture of methyl 6-(2-methoxy-3nitro)pyridylacetate (0.047 g, 0.21 mmol) and 10% Pd on carbon (0.063 g) in ethyl acetate (2 mL) and ethanol (1 mL) was stirred under H 2 (40-50 psi) for 6 h. The mixture was filtered thru Celite and the filtrate concentrated to afford methyl 6-(3-amino-2methoxy)pyridylacetate (0.041 g, 100%) as a light yellow oil: 1H NMR (CDC13, 300 MHz, ppm) 6.82 7.6 Hz, 1H), 6.65 7.6 Hz, 1H), 3.94 3H), 3.70 3H), 3.65 2H).

5 D. To a solution of methyl 6-(3-amino-2methoxy)pyridylacetate (0.078 g, 0.33 mmol) and triethylamine (50 mL, 0.36 mmol) in methylene chloride mL) was added o-tolyl isocyanate (41 AL, 0.36 -mmol). The reaction was stirred for 4 h then concentrated. The crude product was purified by flash chromatography (silica gel, 3:2 hexane-ethyl acetate) to afford the Methyl 6-(2-methoxy-3-otolylureido)pyridylacetate (0.060 g, 55%) as a white powder: 'H NMR (CDC13, 300 MHz, ppm) 8.33 7.9 Hz, 1H), 7.51 7.8 Hz, 1H), 7.41 1H), 7.17 2H), 7.08 2H), 6.77 7.9 Hz, 1H), 3.81 3H), 3.71 3H), 3.67 2H), 2.20 3H).

E. A solution of methyl 6-(2-methoxy-3-otolylureido)pyridylacetate (0.023 g, 0.070 mmol) in methanol (1.0 mL) was treated with 2 M LiOH (90 ~iL, 0.18 mmol). The reaction was stirred for 18 h, diluted with

H

2 0 (5.0 mL) and washed with ether The aqueous solution was then acidified with 5% aq. citric acid.

The product was filtered and washed with H 2 0 then ether to give 6-( 2 -Methoxy-3-o-tolylureido)pyridylacetic acid 126 (0.014 g, 64k) as a white-solid: 'H NMR (CD 3 OD, 300 MHz, ppm) 8.50-8.25 (in, 3H), 7.60 (bd, 1H), 7.28-7.00 (mn, 3H), 4.01 3H), 3.69 2H), 2.30 3H); MS, m/z 316.

F. Procedure C was performed using amine 19-2.

The resulting product was subjected to the conditions described in Procedure D1 to provide TFA-amine salt 1336 -1.

G. The procedure described in Example 1A was performed using 6-(2-methoxy-3-otclylureido)pyridylacetic acid (0.014 g, 0.044 inmol) and amine-TFA salt 1336-1 (0.017 g, 0.045 minol) to afford BI01336 t-butyl ester (0.024 g, 79t) as a white foam: 'H NMR (CDCl 3 300 MHz, ppm) 8.40 7.9 Hz, 1H) 7.63 (d, 8.3 Hz, 1H), 7.50 7.9 Hz, 1H), 7.43-7.06 (in, 6H), 6.80-6.67 (in, 4H), 5.92 2H), 5.19 (mn, 1H), 4.47 (in, 1H), 3.91 3H), 3.61 3H), 2.65 (in, 2H), 2.31.(s, 3H) 1.58 (in, 3H) 1.31 9H).

H. To a solution of BI01336 t-butyl ester (0.024 g, 0.035 mmcl) in methylene chloride (3.0 inL) was added trifluoroacetic acid (3.0 mL) The reaction was stirred for 2 h then concentrated. The crude product was *puirified by HPLC to afford BIO-1336 (0.011 g, 50k) as a.

.*white powder: 'H NNR (CD 3

SOCD

3 300 MHz, ppm) 8.73 (s, 1H), 8.52 1H), 8'.47 8.3 Hz, 1H), 8.31 7.9 Hz, 1H), 8.11 8.3 Hz, 1H), 7.81 7.9 Hz, 1H), 7.21-7.09 (in, 2H), 7.00-6.70 (mn, SH), 5.98 2H), 5.08 (in, 1H), 4.36 (in, 1H), 3.97 3H), 3.52 (mn, 2H), 2.64 (in, 2H), 2.25 3H), 1.55-1.25 (mn, 3H), 0.81 (in, 6H); HPLC (Gradient 20.0 min; MS, rn/z 620.

EXAMPL 62 Synthesis of RTO-1182 A. To methyl 6-amino-2 -N-BOC-aminohexanoate hydrochloride salt (200mg, 0.6Oinmol) in CH 2 C1 2 (5m1) and 127 TEA (basic to litmus) is-addea methanesulfonyl chloride (76.2mg, 0.67mmol) dropwise over 2 min. at rt.

Following 1 hour of stirring the reaction is diluted with CH 2 Cl 2 (10m1) partitioned 3 times with 5k citric acid (3X.5m1), water (iximi), brine (lxlml), and dried over MgSO 4 The organic phase was concentrated in vacuo to yield 1382-1 (230 mg, 100t) as a clear oil.

'HNMR(CDC1 3 300 M4Hz, ppm) 7.26 5H), 5.58(d, 1H, 5.02 4.27 (in, 1H), 3.64 3H), 3.02 (in, 2H), 2.78 3M) 1.85-1.20 (in, 6H). HPLC (Gradient 3) :24.26 min. 98t MS, mz 373.

B. To 1382-1 (225mg, O.6Ommol) in l0ml MeQH at rt with stirring is added 2N LiOH (0.91in1, 1.Bmmol) :dropwise over 2 min. Stirring is continued overnight.

The reaction mixture is acidified with TFA (red to litmus) and concentrated in vacuo. The clear crude gum was taken up in EtOAc (20m1) and worked up as described in Example 62A yielding 1382-2 (122 mng, 57t) as a clear gum. 'HNMR(CDC1 3 300Mz, ppm), 7.33(s, 4H), 5.54(d, 1H J=7.89), 4.39(mn, 1H), 3.47(S, 3H), 3.09 (in, 2H), 1.92- 1.28(mn, 6H). NPLC (Gradient 19.23 min. MS, mz 359.

The procedure described in Example 1A was performed using 1382-2 (48mg, O.l3mmol) and amine f9-14 (25mg, 0.O9inmol) to give 1382-3 (51 mng, 62U) 1 HNMR (CDC1 3 3 00MHz, ppm) 7. 97 2H J=7. 38) 7. 3 7H), 5-51(mn, 1H), 5.35 (dd, 1H J=5.77, 13.50), 5.09(s, 2H), 4.75(m, 1H), 4.14(mn, 1N), 3.88(s, 3H),-3.62(s, 3H), 3.09(n, 2H), 2.73(mn, 2H), 1.92-1.77(mn, 1H), i.70-1.55(ri, 1H), 1.55-1.49(m, 2H), 1.49-1.15(m, 13H).

D. The CBZ protecting group of compound 1382-3 was removed under catalytic hydrogenation conditions as described in-Procedure D2 to give (13.2 ing, 35t) of product 1382-4. 1 HNNR(CDCl 3 300MHz, ppm). 8.23-8.12(mn, 2H), 8.02-7.82(mn, 2H), 7.49-7.38(m, 2H), 5.50-5.31 (in, 128 1W), 3.86(s, 3H), 3.57(s,73H),3.20-2.65(m, 4H), 1.897 172(m, 1H), 1.50-1.10(m, 14H).

E. The procedure described in Example 49 was performed using 1382-4 (15.5mg, O.O5mmol)to give Bio 1382 t-butyl ester (22.6 mg, 111k) as a white solid.

'HNMR(CDC1 3 300MHz, ppm).- 8.02(d, 1H 7.87(d, 2H 7.59(d, 1H 7.29-7.19(m, 5H), 7.11- 7.02(m, 4H), 6.92(t, 1H J=7.19), 5.25-5.16(m, 1H), 4.20- 4.30(m, 1H), 3.8(s, 3H), 3.39 2W), 2 86 2 .73(m, 2.68-2.58(m, 2H), 2.17(s, 3H), 1.65-1.18(m, 15H). MS, mz 752.

Bio 1382 t-butyl ester (27.6mg, O.O27mmol) is stirred in CW 2 Cl 2 (imi) at 5 0 C. TFA (1.Oml) is added :in one portion; the ice bath is removed and stirring is continued for 2 hours. The reaction mixture is concentrated in vacuo and subjected to preparative WPLC purification to provide BIO-1382 (14mg, 75k) as a white solid. 'HNMR(DMSOD 6 ,1 300MHz, ppm) 8.71(d, 1W J=7.82)., 8.21(d, 1W J=8.01), 8.04-7.91 (in, 3H), 7 .59-7.44(m, 3H), 7.32-7.20(m, 3H), 7.0l-6.98(m.2W), 5.3,0(dd, 1W J=7.50, 14.93) 4.35(m, 1W), 3.93(s, 3W), 3.84-3.62(m, 2W), 3.09- 3.45(m, 2W), 2.99-2.78(m, 6H), 2.32(s, 3H) 1.75-1.15(m, 6H) WPLC (Gradient 3) 27.8 min. (95t) MS, mz 696.

EXAMTLF 6- Synthesis of RIO-1400 A. To 4-phenyl-1-butene (3.47 g, 3.94 mL, 26 mmol) at RT was added chiorosulfonyl isocynate (3.54 g, 2.17 mL, 25 mmol) under argon. The resulting mixture was stirred overnight. The reaction mixture was added dropwise to a rapidly stirring solution of NaHCO 3 (5 g), NaWSO 3 (1.5 g) and W 2 0/CH 2 Cl 2 (15 mL/10 mL) at 0 0

C.

After 1 h,-the solution was concentrated under reduced pressure and the residue was extracted with EtOAc (2 x mL). After separation, the organic layer was washed 129 with sat. NaCl (30 mL), dried with Na 2

SO

4 and concentrated under reduced pressure to give 600 mg of the beta lactam 1400-1 as a light yellow oil: 1H NMR (CDC1 3 300 MHz, ppm) 6 7.30-7.13 5 H, Ar), 6.45 1H, NH), 3.0 (ddd, J 14.8, 4.7, 1.7 Hz, 1 2.64 J 7.6 Hz, 2 2.52 J 14.8 Hz, 1H), 1.92 2 TLC, Rf 0.27.

B. A solution of the beta lactam 1400-1 (500 mg, 2.86 mmol), MeOH (25 mL), and HC1 (1 mL of 33%) was stirred at RT for 18 h. The reaction mixture was diluted with EtOAc (100 mL and basified with Et 3 N until pH 9-10 (pH paper). The resulting solution was washed with H 2 0 (10 mL), Sat. NaHCO 3 (30 mL), Sat. NaCI (30 mL) Sdried with Na 2

SO

4 and concentrated under reduced pressure to give 270 mg of amine 1400-2 as a yellow oil: 'H NMR (CDC13, 300 MHz, ppm) 6 7.28-7.15 5 H, Ar), 3.66 3 H, OMe), 2.66 2 2.48 (dd, J 15.7, SHz, 1 2.29 (dd, J =15.7, 8.8 Hz, 1 1.70 2 1.54 2 H, NH); TLC, 10%MeOH/CH 2 Cl 2 Rf 0.35; 20 FABMS, m/z 207 (C12H,,NO 2 of M'+1 requires 207).

C. Free amine 1400-2 (100 mg, 0.55 mmol)) was coupled with Na-t-Boc-Ne-leu-N-hydroxysuccinimide (163 mg, 1.52 mmol) as described in Procedure C to give material which was deprotected with trifluoroacetic acid (0.5 mL) and then basified with Et 3 N as described in Procedure D1 to give the amine 1400-3 in 95% yield: 'H NMR (CDC13, 300 MHz, ppm) 6 9.02 J 9.0 Hz, 1 H), 7.27-7.14 5 H, Ar), 4.26 1 3.64 two peaks, 3 H, OMe), 3.44 1 2.79 2 2.62 (t, J 7.8 Hz, 1 2.54 J 4.9 Hz, 1 1.87 2 1.68 2 1.36 1 0.92 6 TLC, 2 Cl 2 Rf 0.47 and 0.18; HPLC (gradient 1) 12.2 min and 13.6 min FABMS, m/z 321 (C,1H 2 6

N

2 0 3 of M'+1 requires 321).

130 D. 2-Methylphenyl-ureaphenylacetic acid 64 mg, 0.24 mmol) was coupled with free amine 1400-3 (64 mg, 0.20 mmol) as described in Example 49 to give compound 1400-4 in 60%: 1H NMR (DMSO-d 6 300 MHz, ppm) 6 9.50 (d, J 6.8 Hz, 1 8.26-8.17 2 7.97 J 6.1 Hz, 1H), 7.84 J 8.0 Hz, 1 7.38 4 7.27- 7.09 9 6.91 J 7.3 Hz, 1 4.26 1 H), 4.03 1 3.52 two peaks, 3 H, OMe), 3.38 2 2.57-2.40 4 2.25 3 1.70-1.41 0.86 6 FABMS, m/z 587 (C 34

H

42

N

4 0 of M'+1 requires 587).

E. Compound 1400-4 (70 mg, 0.119 mmol) in DMSO (1 mL) and MeOH (2 mL) was hydrolyzed with aqueous LiOH as described in Example lB. The product was purified on 15 a Vydac reverse-phase C18 column (22 mm x 25 cm) using a linear gradient of 20 CH 3

CN/H

2 0 (0.1 TFA) to 50

CH

3

CN/H

2 0 (0.1 TFA) with a flow rate of 10 mL/min to give the BIO-1400 in 22% isolated yield: 'H NMR (DMSO-d 6 300 MHz, ppm) 6 8.93 1 8.14 1 7.91-7.81 3 7.34 2 7.27-7.09 9 6.92 J 7.4 Hz, 1 4.27 1 4.00 1 3.43 J 14.2 Hz, 1 3.36 J 14.2 Hz, 1 2.60-2.30 4 2.22 3 1.68-1.55 3 1.45 J 6.9 Hz, 2 0.86 6 HPLC (gradient 1) 20 min and 20.5 min FABMS, m/z 573 (C 33 Ho 40

N

4 0 of M*+1 requires 573).

Conditions for analytical HPLC: Gradient 1: a linear gradient of 20 CH 3

CN/H

2 0 (0.1 TFA) to 70 CH 3

CN/H

2 0 (0.1 TFA).

Gradient 8: a linear gradient of 15 CH 3

CN/H

2 0 (0.1 TFA) to 40 CH 3

CN/H

2 0 (0.1 TFA).

EXAMPLE 64 Synthesis of BIO 1051 131 A. 4-Aminobenzoic aci'd (420 mg, 3.1 mmol) in

CH

2 Cl 2 was treated with phenyl isocyanate (340 il, 3.1 mmol) at RT. The reaction was stirred for minutes and then concentrated. The residue was washed with IN HC1 then excess ether to afford the product (98 mg, 12%) as a white powder. 1H NMR: (CDC1 3 300 MHz, ppm), 9.08 1H), 8.80 1H), 7.90 2H), 7.58 2H), 7.45 2H), 7.30 2H), 7.00 1H).

FAB:257 MW 256.26.

B. A solution of the amine from Example 6A mg, 0.045 mmol) and the product from Example 64A (12 mg, *0.047 mmol) in DMF was treated with DIPEA (40 Al, 0.22 mmol) and BOP (20 mg, 0.045) at RT. After the reaction was stirred overnight it was worked up as in Example 1A 15 to afford BIO-1051-OtBu (18 mg, 69%)'as a foam.

C. BIO-1051-OtBu (19 mg, 0.031 mmol) was treated with TFA (2 mL) at RT for 30 min and then concentrated. The crude product was purified by HPLC to -afford BIO-1051 (6.3 mg, 39%) as a white powder: HPLC_ 20 (gradient A) 19.2 min, FAB: 517 MW 516.3.

9 9 EXAMPLE Synthesis of BIO-1110 A. The amine from Example 6A (49 mg, 0.15 mmol) in CH 2 C12 was treated with TFA (10 mL) at RT. The reaction was stirred for 3 hours and concentrated. The residue was dissolved in DMF and-neutralized with triethylamine at RT. This was followed by addition of 4-nitrophenylphenylisocyanate (26.5 mg, 0.16 mmol) and stirred 1 hr. at RT. Purification by HPLC result-ed in 62 mg of a beige solid. 1 HNMR (CDC13, 300 MHz, ppm): 8.05 2H), 7.25 5H), 5.35 1H), 4.34 1H), 2.22 2H), 1.59 3H), 0.84 6H). FAB: 442.9 MW 442.41. HPLC: (Gradient A) 21.05 min.

132 B. The product of Examiple 65A (55 mg, 0.12 mmol) was reduced with 10% Pd/C in MeOH while stirring under 40 psi hydrogen gas. The reaction mixture was filtered through Celite 545 and concentrated to yield 49 mg of a beige solid. lHNMR (CDC13, 300 MHz, ppm): 7.19 5H), 7.03 2H), 6.94 2H), 5.27 1H), 4.23 2H), 2.72 2H), 1.52 3H), 0.78 6H). FAB: 413.3 MW 412.45. HPLC: (Gradient A) 11.93 min.

C. The product of Example 65B (5 mg, 0.012 mmol) in DMF and triethylamine was treated with phenylisocyanate (1.4 mg, 0.12 mmol). After stirring overnight, the material was purified by HPLC. IHNMR (CDC13, 300 MHz, ppm): 7.55 2H), 7.36 12H), 7.04 1(m, 1H), 6.34 1H), 5.36 1H), 4.41 1H), 2.78 15 2H),'1.39 3H), 0.91 6H). FAB: 532 (M+H) MW 531.36. HPLC: (Gradient A) 20.31 min.

EXAMPLE 66 Synthesis of BIO-1527 20 A. To a solution of amine 0-3 (1 equiv.) In

CH

2 C1 2 was added BOC-Pro-OSu (1 equiv.) and then stirring at rt overnight. The resulting mixture was diluted with ethylacetate and then washed with 5% citric acid (2X), sat. aq NaHCO3 (2X) and brine dried (Na 2

SO

4 filtered and concentrated to give crude product as a white foam. The above crude product was dissolved in

CH

2 C1 2 and TFA was added at 0°C. Mixture was stirred at room temperature for 1 hour and concentrated to give the amine as a TFA salt.

B. To a solution of 2methylphenylureaphenylacetic acid in DMF was added HOBT equiv.) and EDC (1.2 equiv.) followed by free amine from Example 66A and then stirred at room temperature overnight. The resulting mixture was diluted with 133 ethylacetate and then washed with 5% citric acid (2X), sat. aq NaHCO 3 (2X) and brine dried (Na 2

SO

4 filtered and concentrated to give methyl ester. The resulting methyl ester was dissolved in methanol and then treated with IN LiOH (aqueous solution). The final product (carboxylic acid) was purified by HPLC. The pure fraction from HPLC purification was collected and dried to give Bio-1527.

Mass Spect: 573 (M 595 (M Na).

S: 10 EXAMPLE 67 Inhibition of VLA4-Dependent Adhesion to BSA-CS1 This assay was used to assess the potency of VLA4-directed inhibitory compounds of this invention.

1. Conjugation of CS1 to BSA 15 We dissolved BSA-SMCC (Pierce Chemical, Rockford, IL; Catalog 77115) in H 2 0 at a concentration of 10 mg/mL. [SEQ ID NO:4]:Cys-Tyr-Asp-Glu-Leu-Pro-Gln- Leu-Val-Thr-Leu-Pro-His-Pro-Asn-Leu-His-Gly-Pro-Glu-Ile- Leu-Asp-Val-Pro-Ser-Thr ("Cys-Tyr-CS1 peptide"), which we synthesized by conventional solid phase chemistry and purified by HPLC, was dissolved in 10mM HEPES pH 5, mM NaCl and 0.1 mM EDTA also at a concentration of mg/mL. We then mixed 500 AL of BSA-SMCC, 250 AL of Cys- Tyr-CS1 peptide and 75 AL of 1 mM HEPES pH 7.5 and allowed the conjugation reaction to proceed for minutes. We stopped the reaction by adding 1 AL of beta-mercaptoethanol. Samples were analyzed for-crosslinking by SDS-PAGE. This reaction produced multiple molecules of the Cys-Tyr-CS1 peptide conjugate to each BSA molecule.

2. Preparation of Plates for Adhesion Assay 134 We coated the well of a Linbro titertek polystyrene 96-well flat bottom plate (Flow Laboratories, Maclean, VA; catalog #76-231-05) with 100 AL of the above-described BSA-CS1 solution diluted to 1 Ag/mL in 0.05 M NaHCO 3 (15mM NaHCO 3 35mM Na 2

CO

3 pH 9.2.

Some wells were not coated with CS1 in order to assess non-specific cell binding (NSB). The plate was then incubated overnight at 4"C.

Following this incubation, the contents of the wells were removed by inverting and blotting the plate.

All of the wells were then locked with 100 ~L of 1% BSA in PBS, 0.02% NaN 3 for a minimum of one hour at room temperature.

15 3. Preparation of Fluorescently Labelled Ramos Cells Ramos cells are grown, maintained and labelled in RPMI 1640 culture medium containing 1% BSA. Just o o prior to running the assay, we added 2',7'-bis-(2- (and carboxyfluorescein 20 acetoxymethyl ester ("BCECF-AM"; Molecular Probes Inc., Eugene, Oregon; catalog #B-1150) to a final concnetration of 2MM to a culture of Ramos cells (4 x 106 cells/mL). We incubated the cells for 20 minutes at 37 0

C.

Following labelling, the cells were washed twice in assay buffer (24 mM TRIS, 137 mM NaCl, :2.7 mM KC1, pH 7.4, containing 0.1% BSA and 2mM glucose) to remove any cations originating from the culture medium. The cells were then resuspended in assay buffer to 4 x 10 6 cells/mL and 2mM MnCl 2 was added to upregulate VLA4 on the surface of the cells.

4. Running the Assay Immediately prior to running the assay, we removed the BSA blocking solution from the 96-well 135 plates and washed the wells with 100 AL of assay buffer.

We then added to each well 25 AL of test compound at 2x the final concentration and 25 AL of the labelled Ramos cells. Final concentrations were selected across a range of anticipated IC50s, usually between 0.01 nM AM. Each concentration of compound was tested in triplicate. The compound and cells are allowed to incubate for 30 minutes at room temperature.

We then emptied the contents of the plate and washed the wells 4 times with assay buffer. Using a light microscope, we examined the the NSB wells. If more than a few cells are bound to those wells, we washed the plate once more to remove the excess nonspecifically bound cells.

Binding of the Ramos cells to the CS1 peptidecoated wells was measured by adding 100 AL of assay buffer to each well and quantitating fluorescence in a Millipore Cytofluor 2300 System platereader set at 485 -nm excitation and 530 nm emission. Binding was expressed as an IC50 the concentration of inhibitor at which 50% of control binding occurs. Percent binding is calculated by the formula: (FTB FNs) (FI FNS)]/[(FTB FNs) x 100 binding, where FTB is total fluorescence bound to CS1-containing wells without added inhibitor; FNS is fluorescence bound in wells lacking CS1; and F, is fluorescence bound in wells containing an inhibitor of this invention.

Other compounds according to this invention were similarly assayed. The IC50 for each of these compounds is indicated in the table below: BIO IC, BIO ICso BIO IC BIO IC 1002 nd 1064 B 1122 C 1185 A 1003 nd 1065 B 1123 C 1186 B 136 810 c I #C 8101 lCo 6#0 IC5 810 i1 1004 C 1066 nd 1124 nd 1187 c 1005 C 1067 B 1125 nd 1188 C 1006 B 1068 B 1126 C 1189 C 1007 C 1069 A 1127 B 1190 A 1008 C 1070 B 1128 B 1191 B 1009 C 1072 A 1129 B 1192 A 1010 B 1073 B 1130 B 1193 B 1011 C 1074 B 1131 8 1194 A 1113 nd 1075 B 1132 B 1195 A 1014 C 1076 B 1133 B 1196 A 1015 B 1077 B 1134 B 1197 A 1016 C 1078 B 1135 A 1198 C 1017 C 1079 A 1136 B 1199 8 1018 C 1080 B 1137 nd 1200 B 1020 C 1081 B 1138 B 1201 B 1021 B 1082 C 1139 B 1206 A 1022 C 1083 nd 1140- nd 1207 C 1023 B 1084 nd 1141 nd 1208 B .1024 C 1085 C 1142 nd 1209 C 1025 nd 1086 8 1143 C 1210 A 1026 C 1-087 C 1144 B 1212 A 1027 C 1088 A 1145 B 1214 B 1028 B 1089 A 1146 B 1215 C 1029 C 1090 A 1147 B 1216 B 1030 C 1091 B 1148 C 1217 A 1031 C 1092 C 1149 C 1218 B 1032 C 1093 C 1150 C 1219 B 1036 B 1094 C 1152 nd 1220 B 1037 B 1096 C 1153 C 1221 A 1038 C 1097 B 1154 nd, 1222 A 1039 B 1098 C 15rd 1223 n 137

S

8101 ICM, 6101 lC'O 81t IC BI0O Ic., 1040 B 1099 C 1156 rid 1224 A 1041 nd 1100 B 1157 C 1225 nd- 1042 rid 1101 C 1158 8 1227 nd 1043 rid 1102 rid 1159 C 1238 A 1044 rid 1103 C 1180 B 1245 A 1045 rid 1104 B 1162 rid 1248 A 1046 C 1105 B 1163 B 1248 A 1047 rid 1106 C 1164 B 1270 A 1048 rid 1107 C 1168 B 1282 A 1049 rid 1108 C 1169 a 1294 A

B

1050 A 1109 C 1170 B 1321 1 A 1051 rid 1110 B 1173 B 1327 a 1052 B 1111 C 1174 B 1336 A 1053 1 B 1112 C 1175 B 1360 A 1054 B 1113 C 1176 B 1380 8 1055 A 1114 C 1177 B 1382 A 1056 A 11 15 B 1178 B 1390B 1057 rid 1116 rid 1179 A 1396 B 1058 rid 1117 C 1180 B 1400 A 1060 B 1119 rid 1181 B 1272 A 1063 B 1120 rid 1182 B 1311 B 1319 B 1345 A 1347 A 1358 B 1361 A 1388 A 1393 A 1429 B 1444 B 1474 B 1475 B 1490 A 1515 A 1525 B 1526- B 1536 A 1594 B 1648 B 1655 B 1721 B 1725 rid 1726 rid 1727 rid 1728 rid 1729 rid 1730 rid 1731 nd 1732 n Table abbreviations: A 50 riM: B -O ri M 10 uM; C >l10 M; rid riot determined. All comPounds tested in this table demonstrated an IC50 1 mM 138 EXAMPLE 68 Direct Binding Of VLA4-Presenting Cells To VCAM-IgG We next examined the ability of the compounds of this invention to inhibit VCAM/VLA4 binding, utilizing a VCAM-IgG-alkaline phosphatase conjugate. To carry out this assay, we used the Millipore Multiscreen Assay System (Millipore Corp., Bedford, MA) to wash the cells efficiently.

1. Preparation of VCAM-IgG-AP conjiuates 10 The construction of VCAM 2D-IgG expression vectors, transfection of CHO cells with those constructs and purification of the resulting expression product is described in PCT publication WO 90/13300, the disclosure of which is herein incorporated by reference.

1.2 ml of purified VCAM 2D-IgG (5 mg/ml in 10 mM HEPES, pH 7.5) was reacted with 44 1l of Traut's reagent (2-iminothiolane, 20 mg/ml in water; Pierce Chemical, Rockford, IL.) at room temperature for 30 minutes. The sample was desalted on a 15 ml Sephadex G-25 column 20 equilibrated with 100 mM NaC1, 10 mM MES, pH 5.0. One ml fractions were collected and absorbance at 280 nm was determined. The two peak fractions were pooled.

One ml of calf intestinal alkaline phosphatase (19 mg/ml; Pierce Chemical, Rockford, IL) was reacted with 100 pl of sulfo-SMCC (30 mg/ml in water) and 100 Al 1 M HEPES, pH 7.5 for 35 minutes at room temperature.

The reaction mix was desalted on a 12 ml Sephadex column equilibrated with 150 mM NaC1, 10 mM HEPES, pH One ml fractions were collected and absorbance at 280 nm was determined. The two peak fractions were pooled and stored on ice.

The alkaline phosphatase-SMCC and VCAM 2D-IgGiminothilane adducts were cross-linked at a molar ratio of 2:lin Tris-HCL, pH 7.5 by incubation at room 139 temperature for 30 minutes. Extent of cross-linking was determined by SDS-PAGE. The cross-linked products were stabilized by the addition of 2 mM MgCl 2 and 0.25 nM ZnC12 and stored at 4 0

C.

2. Binding Assay We first blocked a 96-well filtration plate for by adding 275 pL of PBS containing 0.1% Tween 20 and 2% BSA ("blocking buffer") to each well and incubating for 1 hour at room temperature. The plate was then placed onto a vacuum manifold and the blocking buffer was drained through the bottom of the filtration wells into a waste collection tray. Then we washed the wells three times with 200-250 /L of Tris-buffered saline, containing 0.1% BSA, 2 mM glucose and 1 mM HEPES, pH ("assay buffer") to wash out any remaining blocking buffer. We then drained the plates and blotted them on paper towels to remove buffer on the underside of the plate.

We then prepared a stock solution of VCAM-IgG-AP (4 Ag/mL in assay buffer) and filtered it thorugh a 0.2 low protein binding syringe filter (Gelman Sciences, Ann Arbor, MI 4454). This solution was then diluted 1:10 in assay buffer and 25 IL was added to every well of the washed plate.

We diluted the cell adhesion inhibitor being tested to 2x final concentration in assay buffer and added 25 AL of each dilution to triplicate wells in the plate. Final concentrations used ranged from 0.01 nM AM. Control wells for total binding and non-specific binding recieved 25 pL of assay buffer, instead of inhibitor. Total binding wells contained cells and VCAM-IgG-AP in assay buffer. Non-specific binding wells contained only VCAM-IgG-AP in assay buffer.

Jurkat cells were washed once in assay buffer to remove growth medium and resuspended at 8 x 10 6 /mL in 140 assay buffer containing 2 -mM MnCI 2 We added 50 Al of Jurkat cells to every well, except the non-specific binding wells, which received 50 AL of assay buffer to maintain a final assay volume of 100 AL per well. We gently mixed the contents of the wells by tapping the sides of the plate. The plate was then allowed to incubate undisturbed for 60 minutes at room temperature.

At the end of the 60 minute incubation, we placed the plate on the vacuum manifold to drain the wells. We carefully added 100 pL of assay buffer containing ImM MnCl 2 (wash buffer) to each well so as not to disturb the cells on the bottom. The wash buffer was removed by vacuum and the plate was washed again with 150 AL of wash buffer. After draining the wash buffer 15 again, the underside of the plate was blotted on paper towels.

Next, we prepared a 10 mg/mL solution of 4nitrophenylphosphate in 0.1 M glycine, 1 mM ZnCl 2 pH -10.5 (substrate buffer) and added 100 pL immediately added to each well. The plate was incubated for minutes at room temperature to allow the colorimetric reaction to proceed. We stopped the reaction by adding 100 ML of 3 N NaOH to each well.

The contents of the 96-well filtration plate was then transferred directly into a 96-well flat bottom plate using the vacuum manifold. The plate was read at a wavelength of 405 nm to determine the amount of VCAM conjugate bound to the cells. Percent binding is calcualted by the formula: [(ATB ANs) (AI ANs)]/[(ATB ANS) x 100 binding, where ATB is the absorbance at 405 nm of CS1-containing wells without added inhibitor; ANs is the absorbance at 405 nm in wells lacking CS1; and A, is absorbance at 405 nm in wells containing an inhibitor of this invention We assayed other compounds of this 141 invention in the same assay. The IC50 values are comparable to those derived from the CS1 binding assay described in the previous example, although certain compounds demonstrated up to 10-fold greater binding in this assay than in the previous assay.

EXAMPLE 69 Inhibition Of Mouse Contact Hypersensitivity We anesthetized 20-g female Balb/c mice (Jackson Laboratories, Bar Harbor, ME) with sodium pentobarbital (90 mg/kg, A 3 cm 2 patch of abdominal skin was tnen exposed by closely shaving the fur. The skin was then scrubbed with 70% ethanol, followed by application of 25 (L of 0.5% DNFB in 4:1 v/v acetone:olive oil onto the bare abdominal skin. We then lightly scratched the skin with the applying pipet tip to encourage mild inflammation. Twenty four hours after the initial sensitization we again sensitized the mouse with 25 pL of 0.5% DNFB at same abdominal skin location, again followed by light scratching with the pipet tip. The 20 second sensitization was performed while restraining the unanesthetized mouse.

On Day 5 (120 hours after the initial sensitization), we anesthetized the mice with 90:10 mg/kg ketamine:xylazine, i.p. and applied a sub-irritant dose of 10 AL of 0.2% DNFB to the dorsal surface of the left ear. The right ear received a similar application of the 4:1 v/v acetone:olive oil vehicle.

Four hours after challenging the immune response, we administered various concentrations of the inhibitors of this invention to the mice in 100 gL sodium phosphate buffer, pH 8.8, and 3% v/v DMSO by subcutaneous injection. Less soluble inhibitors occasionally required up to 30% DMSO addition the highest concentrations tested. Groups of 8 mice were 142 used for each treatment tested". Positive (PS2 antimouse VLA-4 antibody, 8 mg/kg, and negative control (phosphate-buffered physiological saline, PBS, 100 AL DMSO in PBS, 100 LL groups were routinely tested for comparison as part of the assay of test compounds.

Twenty four hours after challenge mice were again anesthetized with ketamine:xylazine and the ear thickness of both ears measured with an engineer's micrometer to an accuracy of 10 4 inches. The ear swelling response for each louse was the difference S. between its control- and DNFB-challenged ear thickness.

S* Typical uninhibited ear swelling responses were 65-75 x 10-' in. Inhibition of the ear swelling response was 15 judged by comparison of treated groups with their negative control group. Percent inhibition was calculated as: o (mean negative control group (mean test group ear ear swelling) swellin) 1 100 mean negative control group ear swelling Statistical significance of the difference among treatment groups was evaluated using one-way analysis of "variance followed by computation of the Tukey-Kramer Honestly Significant Difference (JMP, SAS Institute) using p<0.05.

The inhibitors of this invention cause a statistically significant reduction in the ear swelling response of DNFB-treated mice as compared to uninhibited control animals.

EXAMPLE Inhibition Of Ascaris Antigen-Induced Late Phase Airway Sensitivity In Allergic Sheen Sheep which had previously been shown to develop both early and late bronchial responses to Ascaris suum 143 antigen were used in this-stud. The protocol used for the experiment was that described in W. M. Abraham et al., J. Clin. Invest., 93, pp. 776-87 (1994), except that the VLA-4 inhibitors of this invention were administered to the animals was dissolved in 3-4 ml of aqueous ethanol and delivered by aerosol spray.

The results showed that all of the VLA-4 inhibitors of this invention inhibited the airway responses associated with administration of Ascaris suum antigen.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our o basic construction can be altered to provide other compounds and methods which utilize the compounds of 15 this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the claims appended hereto rather than the specific embodiments which have been presented hereinbefore by way of example.

o o 144 SEQUENCE LISTING GENERAL INFORMATION:

APPLICANT:

NAME: BIOGEN, INC. (All states except US) STREET: 14 Cambridge Center CITY: Cambridge STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 02142 TELEPHONE: (617)679-2817 TELEFAX: (617)679-2838 NAME: LIN, Ko-Chung (US only) STREET: 253 Lincoln Street CITY: Lexington STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 02173 NAME: ADAMS, Steven P (US only) STREET: 12 Berkeley Lane CITY: Andover STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 01810 NAME: CASTRO, Alfredo C (US only) STREET: 31 Glenwood Avenue CITY: Woburn STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 01801 e.

NAME: ZIMMERMAN, Craig N (US only) STREET: 134 Highland Avenue #6 CITY: Somerville STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 02143 NAME: CUERVO, Julio H (US only) STREET: 16 Elmer Street #303 CITY: Cambridge STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 02138 NAME: LEE, Wen-Cherng (US only) STREET: 192 Spring Street CITY: Lexington STATE: Massachusetts 145 COUNTRY: United -States"of America POSTAL CODE (ZIP): 02173 NAME: HAMMOND, Charles E (US only) STREET: 4 Chester Avenue CITY: Burlington STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 01803 NAME: LIAO, Yu-Sheng (US only) STREET: 4401 Starns Hill Road CITY: Waltham STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 02154 NAME: SINGH, Juswinder (US only) S(B) STREET: 485 Charles Street CITY: Malden o STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP): 021489 (ii) TITLE OF INVENTION: CELL ADHESION INHIBITORS *see (iii) NUMBER OF SEQUENCES: 4 (iv) CORRESPONDENCE ADDRESS: ADDRESSEE: Fish Neave STREET: 1251 Avenue of the Americas CITY: New York STATE: New York COUNTRY: United States of America ZIP: 10020 COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk COMPUTER: IBM PC compatible OPERATING SYSTEM: PC-DOS/MS-DOS SOFTWARE: PatentIn Release Version #1.30 (vii) PRIOR APPLICATION DATA: APPLICATION NUMBER: US 08/376,372 FILING DATE: 23-JAN-1995 INFORMATION FOR SEQ ID NO:1: SEQUENCE CHARACTERISTICS: LENGTH: 8 amino acids TYPE: amino acid STRANDEDNESS: single 146 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: Glu Ile Leu Asp Val Pro Ser Thr 1 INFORMATION FOR SEQ ID NO:2: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear too (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Glu Ile Leu Asp Val :1 INFORMATION FOR SEQ ID NO:3: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Leu Asp Val Pro Ser 1 INFORMATION FOR SEQ ID NO:4: 147 Wi SEQUENCE CHARACTERISTICS: LENGTH: 27 amino acids TYPE: amino acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Cys Tyr Asp Glu Leu Pro Gin Leu Val Thr Leu Pro His Pro Asn Leu 1 5 10 1 *His Giy Pro Giu Ile Leu Asp Val Pro Ser Thr

Claims (9)

1. A cell adhesion inhibitory compound of formula x R2 0 RNf R Y N R4 H K3 and pharmaceutically acceptable derivatives of wherein: X is selected from the group consisting of -CO 2 H, -P0O 3 H, -S0 2 R 5 -OPO- 3 H, -SO 3 H, and -C0 2 R 4 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, and aryl-substituted alkenyl or alkynyl; Y is selected from the group consisting of-CO-, -SO 2 and -P0 2 R 1 is selected from the group consisting of cyanoalkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, substituted aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, 15 aryloxy, N-alkylurea-substituted alkyl, N-arylurea-substituted alkyl, aminocarbonyl-substituted alkyl, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclylfused aryl and heterocyclylalkyl; provided that R' is not t- butoxy, benzyloxy, or arylalkyl in which the aryl is substituted with alkyl, halo, or hydroxy; R 2 is selected from the group consisting of hydrogen, aryl, alkyl, alkenyl alkynyl, cycloalkyl, cycloalkenyl, phenylacyl and aryl-substituted alkyl; R 3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy- substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted 0025 alkyl, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, 0 S acylamino-substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulfonylamino- .:oeo: substituted alkyl, morpholino-alkyl, thiomorpholino-alkyl, morpholino carbonyl-substituted alkyl, thiomorpholinocarbonyl-substituted alkyl, N-(alkyl, alkenyl or alkynyl)aminocarbonyl- 149 substituted alkyl, N,N-(dialkyl, dialkenyl, dialkynyl)aminocarbonyl-substituted alkyl, N,N- (alkyl, alkenyl)aminocarbonyl-substituted alkyl, carboxyl-substituted alkyl, dialkylamino- substituted acylaminoalkyl and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, valine, threonine, serine, aspartic acid, beta-cyanoalanine, and allothreonine; or R 2 and R 3 may be taken together with the atoms to which they are attached, to form a heterocycle; R 4 is selected from the group consisting of aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl aryl-substituted alkyl, hydrogen, heterocyclyl, heterocyclylcarbonyl, aminocarbonyl, amido, mono- or dialkylaminocarbonyl, mono- or diarylaminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or diacylaminocarbonyl, aromatic or aliphatic acyl, and alkyl optionally substituted by substituents selected from the group consisting of amino, carboxy, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, diarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy or heterocyclyl; and nisO, 1 or2; further provided that when R 1 is N-alkylurea-substituted alkyl or N-arylurea-substituted alkyl, and when Y is CO, R3 is not 3-indolylmethyl.

2. The cell adhesion inhibitory compound according to claim 1, x R2 0 RN1 Y N R4 H R3 S wherein: X is selected from the group consisting of-CO 2 H, -PO- 3 H, -S0 2 R 5 -SO 3 H and -OPO 25 3 H; i wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, S cycloalkenyl, aryl, aryl-substituted alkyl, and aryl-substituted alkenyl or alkynyl; Y is selected from the group consisting of-CO, -SO 2 and -P0 2 R 1 is selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, substituted aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl-substituted alkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, N-alkylurea-substituted alkyl, N-arylurea-substituted alkyl, and aminocarbonyl-substituted alkyl; provided that R' is not t-butoxy, benzyloxy, or arylalkyl in which aryl is substituted with only alkyl, halo, or hydroxy; R 2 is selected from the group consisting of hydrogen, aryl, alkyl, alkenyl or alkynyl, cycloalkyl, cycloalkenyl, and aryl-substituted alkyl; R 3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy- substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl (hydroxy-substituted alkylthio) substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulfonylamion~substituted alkyl, morpholino-alkyl, thiomorpholino-alkyl, morpholino carbonyl-substituted alkyl, thiomorpholinocarbonyl-substituted alkyl, N-(alkyl, alkenyl or alkynyl)aminocarbonyl-substituted alkyl, N,N-(dialkyl, dialkenyl, dialkynyl)aminocarbonyl- substituted alkyl, N,N-(alkyl, alkenyl)aminocarbonyl-substituted alkyl, carboxyl-substituted alkyl, and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo-isoleucine, tertleucine, norleucine, phenylalanine, tyrosine, tryptophan, proline, alanine, ornithine, histidine, glutamine, valine, threonine, serine, aspartic acid, beta- cyanoalanine, and allothreonine; R 4 is selected from the group consisting of aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alynyl and aryl-substituted alkyl; and n is O, 1 or 2. The cell adhesion inhibitory compound according to claim 1 or 2, wherein R 1 is a (N-Ar'-urea)-para-substituted arylalkyl group.

7. The cell adhesion inhibitory compound according to claim 1 or 2, wherein R, is selected from the group consisting of cyanomethyl, cyclohexylmethyl, phenyl, phenylcarbonyl, t-butylamnino, 1 -indanyl, 1 -phenylcyclopropyl, 2-(benzyloxycarbonylamino)phenylmethyl, 2- (bis(phenylsulfonyl)amino)-phenylmethyl, 2-(N'-phenylurea)phenylmethyl, 2- aminophenylmethyl, 2-benzamidophenylmethyl, 2-bromo-4-hydroxy-5 -methoxyphenylmethyl, 2-quinolinyl, 2- [4-(N'-phenylurea)phenyl] -ethyl, 3 -(benzyloxycarbonylamnino)-phenylmethyl, 2- (N'-phenyl-urea)phenylmethyl, 3-(N'-phenylurea)propyl, 3 -(phenylsulfonamido)-phenylmethyl, 3-acetamidophenyl-methyl, 3 -aminophenylmethyl, 3-benzamidophenylmethyl, 3 -hydroxy-4- (N'-phenylurea)-phenylmethyl, 3-indolyl, 3 -methoxy-4-(N'-phenylurea)-phenylmethyl, 3- methoxy-4(N'-(2-methylphenyl)-urea)-phenylmethyl, 3-methyl-4-(N'-phenylurea)- phenylmethyl, 3-nitrophenylmethyl, 4-(benzamido)phenyl-methyl, 4- (benzyloxycarbonylamino)-phenylmethyl, 4-(morpholinocarbonyl-amino)-phenylmethyl, (2-chlorophenyl)urea)-3 -methoxyphenylmethyl, 4-(N t -(2-ethylphenyl)urea)phenylmethyl, 4-N'- (2-methoxyphenyl)urea)-phenyl-methyl, 4-(N'-(2-methyl-3 -pyridyl)urea)-phenylmethyl, (2-nitrophenyl)urea)-phenylmethyl, 4-(N'-(2-pyridyl-urea)-phenylmethyl, butylphenyl)-urea)-phenylmethyl, 4-(N'-(2-thiazolyl)urea)-phenyl-methyl, chlorophenyl)urea)-phenylmethyl, 4-(N'-(3-methoxyphenyl)urea)-phenylmethyl, pyridyl)urea)phenylmethyl, 4-(N'-(4-pyridyl)urea)-phenylmethyl, 4-(N'-(3-methylphenyl)urea)- phenylmethyl, 4-(N'-(2-methylphenyl)urea)-phenylmethyl, 4-(N'-benzylurea)phenylmethyl, 4- :020 (N'-cyclohexylurea)-phenylmethyl, 4-(N'-ethylurea)phenylmethyl, 4-(N'-isopropylurea)- phenylmethyl, 4-(N'-methylurea)-phenylmethyl, 4-(N'-p-toluylurea)phenylmethyl, phenylurea)phenyl, 4-(N'-phenylurea)phenylamino, 4-(N'-phenylurea)phenyl-methyl, butylurea)-phenylmethyl, 4-(phenylamninocarbonylamino-methyl)-phenyl, 4- (phenylsulfonamido)phenylmethyl, 4-(t-butoxycarbonyl-amino)-phenylmethyl, 4- acetamidophenylmethyl, 4-amninophenylamino, 4-amino-phenylmethyl, 4- benzamnidophenylmethyl, 4-hydroxy-3-nitrophenylmethyl, 4-methoxyphenylmethyl, 4- nitrophenylamino, 4-nitrophenylmethyl, 4-phenacetamidophenylmethyl, 4- phenylphenylmethyl, 4-trifluoro-methylphenylmethyl, 4-12-(N'-methylurea)-benzamido] .00.0phenylmethyl, 4-(N'-(2-methylphenyl)urea)-phenylmethyl, 4(N'-phenyl-N"-methylguanidino)- phenylmethyl, 5-(N'-phenylurea)pentyl, 5 -(N'-t-butylurea)pentyl, 2,2-diphenylmethyl, 2,3 benzocyclobutyl, 3,5 -dimethoxy-4-hydroxy-phenylmethyl, 1-indolecarboxylamino)- phenylmethyl, 6-methoxy-5 -(N'-(2-methylphenyl)urea)-2-pyridylmethyl, 1,3-benzoxazol-2- ylamino)-phenylmethyl, 1,3-imidazol-2-ylamino)phenylmethyl, 3 -carboxy-l1-phenylpropyl, 152 3-hydroxy-4-(2-methylphenyl)ureaphenylmethyl, 3 -hydroxy-4-(2- chlorophenyl)ureaphenylmethyl, 6-(phenylurea)heptyl, 4-phenylurea)butyl, 2-thienylmethyl, 4- (2,6-dimethylphenylurea)phenylmethyl, 4-(2-hydroxyphenylurea)phenylmethyl, 3 -butoxy-4(2- methylphenyl)ureaphenylmethyl, 3-butoxy-4-(2-methylphenyl)ureaphenylmethyl, 3 -butoxy-4- (2-methylphenyl)ureaphenylmethyl, 3-butoxy-4-(phenylurea)phenylmethyl, 4-(N-2- pyrazinylurea)phenylmethyl, 2-phenylethynyl, 5 -phenylurea-2-pyridylmethyl, 5 methylphenylurea)-2-pyridylmethyl, 4-(3-methyl-2-pyridylurea)phenylmethyl, 3-nitro-4- (phenylurea)phenylmethyl, 3 -acylamino-4-(phenylurea)phenylmethyl, 4-(N,N-phenyl, methylurea)phenylmethyl, 4-(3-hydroxyphenylurea)phenylmethyl, 4-(2- acetylaminophenylurea)phenylmethyl, 4-(2-propionylaminophenylurea)phenylmethyl, 4-(3 benzyloxy-2-pyridylurea)phenylmethyl, 4-(3-methyl-2-pyridylurea)phenylmethyl, 4- (indolylcarbonylamino)phenylmethyl, 2-(4-(phenylurea)phenyl)oxiranyl, 4-(N,N'-phenyl, methylurea)phenylmethyl, 4-(2-dimethylamninophenylurea)phenylmethyl, 4-(2- benzimidazolylamino)phenylmethyl, 4-(2-benzoxazolylamino)phenylmethyl, 4-(2- benzthiazolylamino)phenylmethyl, 4-(tetrahydroquinolinylcarbonylamino)phenylmethyl, 1,3- dimethyl-3 -(phenylurea)butyl, hydroxyethylthiomethyl, 4-(phenylurea)phenylethenyl, 3-amino- 4-(phenylurea)phenylmethyl, 4-(4-hydroxyphenylurea)phenylmethyl, 4-(2- amninophenylurea)phenylmethyl, 4-((2-methylurea)phenylurea)phenyl, 4-(2- hydroxyphenylurea)-3 -methoxyphenylmethyl, 4-(2- methylsulfonylmethylphenylurea)phenylmethyl, 4-(2-methylphenylurea)tetrahydro-2- pyrimidonylmethyl, 3 -methoxy-4-(phenylurea)-2-pyridylmethyl, 4-(2- trifluoromethylphenylurea)phenylmethyl, 4-(3-methyl-2-pyridylurea)phenylmethyl, 4-(2, 4(1 H,3H)-quinazolinedionyl)phenylmethyl, 4-thioureaphenylmethyl, 4- (phenylthiourea)phenylmethyl, 4-(pyrrolidinylcarbonylamino)phenylmethyl, 4-(2- benzoxazolinonylcarbonylamino)phenylmethyl, 4-(benzyloxyurea)phenylmethyl, 4- (thiazolidinylcarbonylamino)phenylmethyl, 4-benzoylureaphenylmethyl, hydroxylureaphenylmethyl, N',N'-methyl, hydroxylureaphenylmethyl, allylurea)phenylmethyl, 4-(3 -pyrrolidinylcarbonylamino)phenylmethyl, 1- pyrrolylcarbonylamino)phenylmethyl, 4-(2-pyrrolylcarbonylamino)phenylmethyl, 4- o30 (propylurea)phenylmethyl, 4-(methoxyurea)phenylmethyl, 4-(dimethylurea)phenylmethyl, 4-(2- quinazolinylamino)phenylmethyl, 4-(2-pyridylcarbonylamino)phenylmethyl, 4-(3 -hydroxy-2- methylphenylurea)phenylmethyl, 4-(2-fluorophenylurea)phenylmethyl, 4-(3- fluorophenylurea)phenylmethyl, 4-(4-fluorophenylurea)phenylmethyl, 4-(2- quinolinylcarbonylamino)phenylmethyl, 4-(isoquinolinylcarbonylamino)phenylmethyl, 4-(2,3- dimethylphenylurea)phenylmethyl, 4-(2,5-dimethylphenylurea)phenylmethyl, 4-(2-methyl-4- fluorophenylurea)phenylmethyl, 4-(-2-methyl-3 -fluorophenylurea)phenylmethyl, 3-carboxy-3 phenyipropyl, 4-(5-hydroxy-2-methylphenylurea)phenylmethyl, 4-(4-hydroxy-2- methylphenylurea)phenylmethyl, 4-(2,4-difluorophenylurea)phenylmethyl, 3- dibenzofuranylcarbonyl, 4-(phenoxycarbonylamino)phenylmethyl, 3-phenylureapropyl, 4- (phenylaminocarbonyloxy)phenylmethyl, 4-cinnamoylphenylmethyl, dibenzofuranylmethyl, 4- (2-methylphenylaminocarbonyloxy)phenylmethyl, (methylphenylurea)phenylamino, 4-(3 indolylcarbonylamino)phenylmethyl, 4-(phenylaminocarbonyl)phenylmethyl, 4- phenylalkynyiphenylmethyl, 4-(3 -pyrrolylcarbonylamino)phenylmethyl, 5-nitrobenzofuran-2- yl, 5 -(2-methylphenylurea)benzofuran-2-yl, 3 -carboxy-3 -phenyipropyl, 2-(3-pyridyl)-thiazol-4- yl, 2-(4-pyridyl)-thiazol-4-yl, 2-oxo- and 4-oxo-4,5 ,6,7-tetrahydrobenzo[b]fuiran-3 -yl, 3- methoxy-4-(phenylcarbonoyloxy)phenylmethyl, 5 -amino-benzofuran-2-yl, benzilylaminophenylmethyl, and 4-[N-2-carboxyethyl-l1-(1,3 -benzodioxolyl-5 -yl)amino-N- leucinylacetamidylphenylurea]phenylmethyl.

8. The cell adhesion inhibitory compound according to claim 1 or 2, wherein R, is selected from the group consisting of cyanomethyl, cyclohexylmethyl, phenyl, phenylcarbonyl, t-butylamino, 1 -indanyl, 1 -phenylcyclopropyl, 2-(benzyloxycarbonylamino)phenylmethyl, 2- :20 (bis(phenylsulfonyl)amino)-phenylmethyl, 2-(N'-phenylurea)phenylmethyl, 2- aminophenylmethyl, 2-benzamidophenylmethyl, 2-bromo-4-hydroxy-5-methoxyphenylmethyl, :2-quinolinyl, 2-[4-(N'-phenylurea)phenyl] -ethyl, 3 -(benzyloxycarbonylamino)-phenylmethyl, 3- (N'-phenyl-urea)phenylmethyl, 3-(N'-phenylurea)propyl, 3-(phenylsulfonamido)-phenylmethyl, 3-acetamidophenyl-methyl, 3-aminophenylmethyl, 3-benzamidophenylmethyl, 3 -hydroxy-4- (N'-phenylurea)-phenylmethyl, 3-indolyl, 3-methoxy-4-(N'-phenylurea)-phenylmethyl, 3- methoxy-4-(N'-(2-methylphenyl)-urea)-phenylmethyl, 3 -methyl-4-(N t -phenylurea)- phenylmethyl, 3-nitrophenylmethyl, 4-(2-aminobenzamido)-phenylmethyl, 4- (benzamidio)phenyl-methyl, 4-(benzyloxycarbonylamino)-phenylmethyl, 4- (morpholinocarbonyl-amino)-phenylmethyl, 4-(N'-(2-chlorophenyl)urea)-phenylmethyl, (2-ethylphenyl)urea)phenylmethyl, 4-(N'-(2-isopropylphenyl)urea)-phenylmethyl, methoxyphenyl)urea)-phenyl-methyl, 4-(N'-(2-methyl-3-pyridyl)urea)-phenylmethyl, 5 nitrophenyl)urea)-phenylmethyl, 4-(N'-(2-pyridyl)urea)phenylmethyl, 4-(N'-(2-t-butylphenyl)- urea)-phenylmethyl, 4-(N'-(2-t-butylphenyl)-urea-phenylmethyl, 4-(N'-(2-thiazolyl)urea)- phenyl-methyl, -methylphenyl)urea)-phenylmethyl, 4-(N'-(2-methylphenyl)urea)- phenylmethyl, 4-(N'-benzylurea)phenylmethyl, 4-(N'-cyclohexylurea)-phenylmethyl, ethylurea)phenylmethyl, 4-(N'-isopropylurea)-phenylmethyl, 4-(N'-methylurea)-phenylmethyl, 4-(N'-p-toluylurea)phenylmethyl, 4-(N'-phenylurea)phenyl, 4-(phenylaminocarbonylamino- methyl)-phenyl, 4-(phenylsulfonamido)phenylmethyl, 4-(t-butoxycarbonyl-amino)- phenylmethyl, 4-acetamidophenylmethyl, 4-aminophenylamino, 4-amino-phenylmethyl, 4- benzamidophenylmethyl, 4-hydroxy-3 -nitrophenylmethyl, 4-methoxyphenylmethyl, 4- nitrophenylamnino, 4-nitrophenylmethyl, 4-phenacetamidophenylmethyl, 4- phenyiphenylmnethyl, 4-trifluoro-methyiphenylmethyl, 4-[2-(N'-methylurea)-benzamido] phenylmethyl, 4-(N'-(2-methylphenyl)urea)-phenylmethyl, 4(N'-phenyl-N"-methylguanidino)- phenylmethyl, 5-(N'-phenylurea)pentyl, 5-(N'-t-butylurea)pentyl, 2,2-diphenylmethyl, 2,3- benzocyclobutyl, 3,5 -dimethoxy-4-hydroxy-phenylmethyl, 1-indolecarboxylamnino)- phenylmethyl, 6-methoxy-5 -(N'-(2-methylphenyl)urea)-2-pyridylmethyl, 1,3-benzoxazol-2- ylamino)-phenylmethyl, and 1,3-imidazol-2-ylamino)-phenylmethyl.

9. The cell adhesion inhibitory compound according to claim 1 or 2, wherein R, is selected from the group consisting of 3 -methoxy-4-(N'-phenylurea)-phenylmethyl, phenylurea)-phenylmethyl, 4-(N'-(2-methylphenyl)urea)-phenylmethyl, 4-(N t -(2-pyridyl)-urea)- phenylmethyl, 3 -methoxy-4-(N t -(2-methylphenyl)urea)-phenylmethyl, 6-methoxy-5 020 methylphenyl)urea)-2-pyridylmethyl, -methyl-2-pyridylurea)phenylmethyl, 3 -methoxy- -methyl-2-pyridylurea)phenylmethyl, and 3-methoxy-4-(N'-2-pyridylurea)- phenylmethyl. The cell adhesion inhibitory compound according to claim 9, wherein R, is selected from the group consisting of 3-methoxy-4-(N'-phenylurea)-phenylmethyl, phenylurea)-phenylmethyl, 4-(N'-(2-methylphenyl)urea)-phenylmethyl, 4-(N'-(2-pyridyl)urea)- phenylmethyl, 3 -methoxy-4-(N'-(2-methylphenyl)urea)-phenylmethyl, and 6-methoxy-5 methylphenyl)urea)-2-pyridylmethyl. 30 11. The cell adhesion inhibitory compound according to claim 1 or 2, wherein Y is 99999,

14. The cell adhesion inhibitory compound according to claim 1 or 2, wherein R 3 is selected from the group consisting of 2-(methylsulfonyl)-ethyl, 3 -(hydroxy-propylthio)-methyl, 4-(methylsulfonylamino)-butyl, 4-acetylaminobutyl, aminomethyl, benzyl, butyl, hydroxymethyl, isobutyl, methyl, methyithiomethyl, phenylmethyl, propyl, 4- (benzyloxycarbonylamino)-butyl, N,N-(methylpropargyl)amino, 2-(methylthio)-ethyl, 2- (morpholino-N-carbonyl)ethyl, 2-(N-morpholino)- ethyl, 2-(N,N-dimethylamino)ethyl, 4- amino-butyl, 4-benzyloxyphenylmethyl, 2-benzylthiomethyl, t-butoxy-carbonylaminomethyl, sec-butyl, t-butyl, N,N-dimethyl-aminocarbonylmethyl, 1, 1 -ethano, 4-hydroxyphenylmethyl, 1 hydroxyethyl, 1 -methoxyethyl, 4-methoxyphenylmethyl, benzyloxymethyl, benzylthiomethyl, carbonylmethyl, 2-methylsulfinylethyl, morpholino-N-carbonylmethyl, thiomorpholino-N- carbonyl-methyl, 2-phenylethyl, asparagine side-chain, proline side-chain and 2- thiazolylemthyl, 4-(phenylurea)butyl, 4-(methylurea)butyl, morpholinocarbonylmethylthiomthyl, morpholinoethylthiomethyl, 3 -pyridylmethyl, 4- methylsulfonylaminobutyl, hydroxymethylthiomnethyl, 2-methylsulfonylethyl, 4- propionylaminobutyl, 4-ethoxycarbonylamninobutyl, methoxycarbonylaminobutyl, carbomethoxymethylthiomethyl, 4-t-butylureabutyl, carboxymethyithiomethyl, dimethylamidomethyithiomethyl, acetylamninopropyl, 3 -methylureapropyl, 4- biotinoylaminobutyl, 2-thienylmethyl, 3 -pyridylmethyl, 4-trifluoroacetylamninobutyl, dimethylaminomethyithiomethyl, dimethylaminoethylthiomethy, and 4- (dimethylaminoacetylamino)butyl; or in combination with R 2 forms a proline, azetidine or pipecolinic ring. The cell adhesion inhibitory compound according to claim 14, wherein R 3 is selected from the group consisting of isobutyl, 2-(methylthio)-ethyl, 3-(hydroxypropylthio)- methyl, 2-(methylsulfonyl)-ethyl, 4-acetylamino-butyl, 4-(methylsulfonylamino)-butyl, and 4- (ethoxycarbonylamnino)butyl.

17. The cell adhesion inhibitory compound according to claim 16, wherein R 3 is selected from the group consisting of isobutyl, 2-(methylthio)-ethyl, 3-(hydroxypropylthio)- >30 methyl, 2-(methylsulfonyl)-ethyl, 4-acetylamino-butyl, and 4-(methylsulfonylamino)-butyl.

518. The cell adhesion inhibitory compound according to claim 1 or 2, wherein R 4 is selected from the group consisting of 4-carbomethoxy-phenyl, 4-carboxyphenyl, 4- 156 fluorophenyl, 4-methoxy-phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4- chiorophenyl, 3 ,4-difluorophenyl, 3 ,4-dimethoxyphenyl, 2-methoxyphenyl, 3 -methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3 -pyridyl, 4-phenoxyphenyl, 4-ethoxyphenyl, 4-nitrophenyl, 4-acetylaminophenyl, 4-methylureaphenyl, 2-fluorophenyl, naphthyl, 3 -fluorophenyl, 3- nitrophenyl, hydrogen, 2-nitrophenyl, 4-cyanophenyl, 3 -methoxyphenyl, 4- methylsulfonylaminophenyl, 3-cyanophenyl, 4-propionylaminophenyl, 4-aminophenyl, 3- aminophenyl, 4-trifluoromethoxyphenyl, 4-methyiphenyl, 4-amino-3-nitrophenyl, 4-hydroxy-3 methoxyphenyl, 4-hexyloxyphenyl, 4-methyithiophenyl, 3 -furanyl, 4-dimethylaminophenyl, 3- hydroxy-4-nitrophenyl, n-pentyl, carboxymethyl, 2-carboxyethyl, ethynyl, 2-thienyl, 2- propenyl, 2-propynyl, methyl, and propyl. 19. The cell adhesion inhibitory compound according to claim 18, wherein R 4 is selected from the group consisting of 4-carbomethoxy-phenyl, 4-carboxyphenyl, 4- fluorophenyl, 4-methoxy-phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4- chlorophenyl, 3,4-difluorophenyl, 3,4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. 22. The cell adhesion inhibitory compound according to claim 1 or 2, wherein Y is CO- or -SO 2 6 020 23. The cell adhesion inhibitory compound according to claim 22, wherein Y is- The cell adhesion inhibitory compound selected from the group consisting of: P-Alanine, [(phenylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl] -L-leucyl-3 V.060 benzodioxol-5-yl)-, 0 0 1-Alanine, [4-[[(phenylamino)carbonyl] amino]phenyl]acetyl]-L-methionyl-3-(4 0 00 methoxyphenyl)-, 3 0 P-Alanine, [4-[[(2-ethylphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3 00... 0 benzodioxol-5-yl)-, j3-Alanine, N- [[4-[[(2-pyridylamino)carbonyl] amino]phenyl] acetyl]-L-leucyl-3 methoxyphenyl)-, f3-Alanine, [4-[[(2-pyridylamino)carbonyl] amino]phenyl] acetyl]-L-leucyl-3-(3 ,4- dimethoxyphenyl)-, P-Alanine, [4-[[(2-methylphenylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl]-L- leucyl-3-(1 ,3-benzodioxol-5-yl)-, f-Alanine, [4-[[(2-methylphenylamino)carbonyl] amino]phenyl]acetyl]-L-methionyl-3 1-Alanine, [4-[[(2-methylphenylamino)carbonyl] amino]phenyl]acetyl]-L-methionyl-3 methoxyphenyl)-, 1-Alanine, N- [[(2-methylphenylamino)carbonyl] amino] phenyl] acetyl] -L- methioninesulfonyl-3-( 1,3 -benzodioxol-5 1-Alanine, [4-[[(2-methylphenylamino)carbonyl] amino]phenyl]acetyl]-L-( 1 hydroxypropyl)cysteinyl-3-( 1,3-benzodioxol-5-yl)-, 1-Alanine, [[(2-methylphenylamino)carbonyl] amino]phenyl]acetyl]-L-leucinyl-3-(4- fluorophenyl)-, 1-Alanine, N6-acetyl-N2-[ [4-[[(2-methylphenyl)amino] carbonyl] amino]phenyl] acetyl]-L-lysyl- 3-(1 ,3-benzodioxol-5-yl)-, P-Alanine, [4-[[(2-methylphenylamino)carbonyl] amino] (3-pyridyl)] acetyl] -L-leucinyl-3 (1,3-benzodioxol-5-yl)-, j3-Alanine, N6-(methanesulfonyl)-N2-[ methylphenyl)amino] carbonyl] amino] phenyl] acetyl] -L-lysyl-3 1,3 -benzodioxol-5 f-Alanine, [4-[[(5-methyl-2-pyridinylamino)carbonyl] amino]phenyl]acetyl] -L-leucyl-3 carboxyphenyl)-, P-Alanine, [[(2-methylphenylamino)carbonyl] amino] (3 -methoxy-2-pyridyl)] acetyl] -L- leucinyl-3-(1 ,3-benzodioxol-5-yl)-, 1-Alanine, N6-(methanesulfonyl)-N2- methylphenyl)amino]carbonyl] amino]phenyl] acetyl] -L-lysyl-3 -(4-carbomethoxyphenyl)-, and j3-Alanine, [(2-methylphenylamino)carbonyl] amino]phenyl] acetyl] -L-methionyl-3 (1-phenethyl)-, 26. The cell adhesion inhibitory compound selected from the group consisting of: P-Alanine, N-[[4-[[(2-pyridylamino)carbonylllamino]phenyll acetyl] -L-leucyl-2-(3 ,4 dimethoxyphenyl)-, f-Alanine, N6-(methoxycarbonyl)-N2-[[4-[ [(2 methylphenyl)amino] carbonyl] amino]phenyl] acetyl] -L-lysyl-3-( 1,3 -benzodioxol-5 j3-Alanine, N-[[4-[I(5-methyl-2-pyridinylamino)carbonyl]amino]phenyl] acetyl]-L-leucyl-3 (3 ,4-dimethoxyphenyl)-, 1-Alanine, -dihydroindole)carbonyl] amino]phenyl] acetyl]-L-leucyl-3-( 1,3- benzodioxol P-Alanine, N2-[ [(2-methylphenyl)amino] carbonyl] amino]phenyl] acetyl] dimethylaminoethyl)-(cysteinyl)] -3 ,3-benzodioxol-5-yl)-, 1-Alanine, [4-[[(2-pyridinylamino)carbonyl]amino]phenyl] acetyl]-L-methionyl-3 dimethoxyphenyl)-, P-Alanine, [[(phenylamino)thiocarbonyl] amino]phenyl] acetyl] -L-leucyl-3 P-Alanine, [4-[[(2-methylphenylamnino)carbonyl] amino]phenyl]acetyl] -L-methionyl-3 carbomethoxyphenyl)-, f-Alanine, [4-[[(phenylamnino)carbony1] amino]phenyl]acetyl] -L-methionyl-3 -(4 carbomethoxyphenyl)-, P~~-Alanine, 1,3-benzimidazolecarbonyl] amino]phenyl] acetyl] -L-leucy]-3 20 benzodioxol-5-yl)-, -Aanine, N- [[4-[[(2-pyridinylamino)carbonyl] amino]phenyl] acetyl] -L-methionyl-3-( 1,3 f-Alanine, -benzoxazolecarbonyl] amino]phenyl] acetyl]-L-leucyl-3-( 1,3 benzodioxol P-Alanine, -methyl-2-pyridinylamino)carbonyl]amino]phenyl] acetyl] -L-methionyl-3 (1,3-benzodioxol-5-yl)-, P-Alanine, [[(2-acetoxyphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3 benzodioxol-5-yl)-, j3-Alanine, N- [[4-[[(2-pyrolocarbonyl] amino]phenyl] acetyl] -L-leucyl-3 -benzodioxol-5 -yl)- (S- 1-Alanine, N- [(allylcarbonly] amino] phenyl] acetyl] -L-leucyl-3 1,3 -benzodioxol-5 P-Alanine, N-[[4-[[(2-methylphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3 (ethynyl)-, f3-Alanine, [4[[(2-methylphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3-(allyl)-, P-Alanine, N-[[4-[[(2-fluorolphenylamino)carbonyl] amino]phenyl]acetyl]-L-leucyl-3-(3 ,4- dimethoxyphenyl)-, f3-Alanine, [[(4-fluorolphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3 dimethoxyphenyl)-, 1-Alanine, [4-[[(2-methylphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3 -(methyl)- P-Alanine, N- [(2-methylphenylamino)carbonyl] amino] phenyl] acetyl[ -L-leucyl-3 P-Alanine, 1H-indol-2-yl-carbonylamnino]phenyl] acetyl]-L-leucyl-3 ,3-benzodioxol- j3-Alanine, N- [1H-indol-3 -yl-carbonylamino]phenyl] acetyl]-L-leucyl-3 ,3-benzodioxol- 1-Alanine, N-[[4-[[(2-methylphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3-(4- methylmorpholinyl)-, P-Alanine, [4-[[(phenylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl] -L-methionyl-3 two: (1,3 benzodioxol-5-yl)-, 1-Alanine, [(phenylamino)carbonyl] amino] (3-methoxyphenyl)] acetyl] -L-leucyl-3 dimethoxyphenyl)-, P3-Alanine, N- [[(phenylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl] -L-methionyl-3 (3,4-dimethoxyphenyl)-, f3-Alanine, [4-[[(2-pyridinylamnino)carbonyl] amino] (3-methoxyphenyl)] acetyl] -L- methionyl-3-(3,4-dimethoxyphenyl)-, :twos* -Alanine, N- (5 -methyl-2-pyridinylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl] -L- leucyl-3-(3 ,4-dimethoxyphenyl)-, *00 w o P-Alanine, N-[[4-[[(5-methyl-2-pyridinylamino)carbonyl] [amino] (3-methoxyphenyl)] acetyl] -L- 0*0 methionyl-3-(3,4dmtoyhnl f-Alanine, -methyl-2-pyridinylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl] -L- methionyl-3-(1 ,3-benzodioxol-5-y)-, and 160 f3-Alanine, -methyl-2-pyridinylamino)carbonyl]amino]phenyl] acetyl] -L-methionyl-3- (3 ,4-dimethoxyphenyl)-, 27. The cell adhesion inhibitory compound selected from the group consisting of: P-Alanine,N- [[4-[[(2-pyridylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3 -(3,4 dimethoxyphenyl)-, P-Aanine,N6-(methoxycarbonyl)-N2-[ methylphenyl)amino] carbonyl] amino] carbonyl] amino]phenyl] acetyl] -L-lysyl-3 1-Alanine, [4-[[(5-methyl-2-pyridinylamino)carbonyl] amino]phenyl] acetyl]-L-leucyl-3 (3,4-dimethoxyphenyl)-, P-Alanine, [(2-pyridinylamino)carbonyl] amino]phenyl] acetyl]-L-methionyl-3-(3 ,4- dimethoxyphenyl)-, 1-Alanine, [(2-pyridinylamino)carbonyl] amino]phenyl]acetyl]-L-methionyl-3 benzodioxol-5-yl)-, 1-Alanine, [4-[[(5-methyl-2-pyridinylamino)carbonyl] amino]phenyl] acetyl] -L-methionyl-3 (1 ,3-benzodioxol-5-y)-, P-Alanine, [[(2-methylphenylamino)carbonyl] amino]phenyl] acetyl] -L-leucyl-3-(allyl)-, -ln, N-[4[phnamncaonlamn](-ehypey)act]-Lehonl 1-Alanine, N- [(phenylamino)carbonyl] amino] (3-methoxyphenyl)] acetyl] -L-leciyl-3-,4 (1,3-benzodioxol-5-yl)-, dimethoxypheny1)-, j3-Alanine, N- [[4-[[(phenylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl] -L-methionyl-3 (3,4-dimethoxyphenyl)-, P-Alanine, N- [4-[[(2-pyridinylamino)carbonyl] amino] (3-methoxyphenyl)] acetyl]-L- methionyl-3-(3,4-dimethoxyphenyl)-, f3-Alanine, N- -methyl-2-pyridinylamino)carbonyl] amino] (3 -mehtoxyphenyl)] acetyl] -L- leucyl-3-(3 ,4-dimethoxyphenyl)-, P-Alanine, N- [4-[[(5-methyl-2-pyridinylamino)carbonyl] amino] (3 -methoxyphenyl)] acetyl] -L- methionyl-3-(3,4-dimethoxyphenyl)-, P-Alanine, N- -methyl-2-pyridinylamino)carbonyl] amino](3 -methoxyphenyl)] acetyl] -L- methionyl-3-(1,3-benzodioxol-5-y)-, and P-Alanine, -methyl-2-pyridinylamino)carbonyl] amino]phenyl] acetyl] -L-methionyl-3 (3,4-dimethoxyphenyl)-, 30. The cell adhesion inhibitory compound of claim 1 or claim 2, wherein R 1 is selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, substituted aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkenyl- substituted alkyl, alkylamino, alkenylamino, alkynylamino, aryl-substituted alkylamino, aryl- substituted alkenylamino or alkynylamino, N-alkylurea-substituted alkyl, N-arylurea- substituted alkyl, and aminocarbonyl-substituted alkyl. 31. The cell adhesion inhibitory compound of claim 1, wherein Y is CO, R 1 is (N- Ar'-urea)-para-substituted aralkyl group; R 2 is H; R 3 is selected from the group consisting of isobutyl, 2-(methylthio)-ethyl, 3 -(hydroxypropylthio)-methyl, 2-(methylsulfonyl)-ethyl, 4- acetylamino-butyl, 4-(methylsulfonylamino)-butyl, and 4-(ethoxycarbonylamino)butyl; and R 4 is selected from the group consisting of 4 carbomethoxy-phenyl, 4-carboxyphenyl, 4- fluorophenyl, 4-methoxy-phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4- chlorophenyl, 3, 4-difluorophenyl, 3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. 32. The cell adhesion inhibitory compound of claim 1, wherein Y is SO 2 R 2 is H; R 3 is selected from the group consisting of isobutyl, 2-(methylthio)ethyl, 3- (hydroxypropylthio)methyl, 2-(methylsulfonyl) ethyl, 4-acetylaminobutyl, 4- (methylsulfonylamino)butyl, and 4-(ethoxycarbonylamino)butyl; and R 4 is selected from the group consisting of 4 carbomethoxyphenyl, 4-carboxyphenyl, 4-fluorophenyl, 4-methoxy- phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3, 4- difluorophenyl, 3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, I' 2-nitrophenyl, and 3-pyridyl. 30 33. The cell adhesion inhibitory compound of claim 1, wherein R2 is selected from the group consisting of aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aryl- substituted alkyl. 162 34. The cell adhesion inhibitory compound of claim 1, wherein R 2 and R 3 together with the atoms to which they are attached, form a heterocycle. The cell adhesion inhibitory compound of claim 34, wherein R 2 and R 3 together with the atoms to which they are attached, form a 4-6 membered monocyclic heterocyclic ring or a 8-11 membered bicyclic heterocyclic ring. 36. The cell adhesion inhibitory compound of claim 35, wherein the bicyclic heterocyclic ring contains a 4-6 membered monocyclic heterocyclic ring and a cycloalkyl or an aryl. 37. The cell adhesion inhibitory compound of claim 34, wherein the heterocycle is optionally substituted with hydroxyl, amino, alkyl, Ar'-substituted carbonylamino, Ar'- substituted amino, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, heterocyclylamino, benzofused-heterocyclylcarbonylamino, Ar', Ar'-disubstituted acylamino, heterocyclylcarbonylamino, heterocyclylalkylamino, cycloalkyl-substituted amino, or Ar'- substituted arylamino. 38. The cell adhesion inhibitory compound of claim 1, wherein Y is CO, R 1 is (N- Ar'-urea)-para-substituted aralkyl group; R 2 and R 3 together with the atoms to which they are attached, form a heterocycle; and R 4 is selected from the group consisting of 4- carbomethoxyphenyl, 4-carboxyphenyl, 4-fluorophenyl, 4-methoxy-phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3, 4-difluorophenyl, 3, 4-dimethoxyphenyl, S2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. e 39. The cell adhesion inhibitory compound of claim 38, wherein R 2 and R 3 together with the atoms to which they are attached, form a 4-6 membered monocyclic heterocyclic ring or a 8-11 membered bicyclic heterocyclic ring; the monocyclic or bicyclic heterocyclic ring being optionally substituted with hydroxyl, amino, alkyl, Ar'-substituted carbonylamino, Ar'- substituted amino, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, heterocyclylamino, benzofused-heterocyclylcarbonylamino, Ar', Ar'-disubstituted acylamino, heterocyclylcarbonylamino, heterocyclylalkylamino, cycloalkyl-substituted amino, or Ar'- substituted arylamino. 163 The cell adhesion inhibitory compound of claim 1, wherein Y is SO 2 R 2 and R 3 together with the atoms to which they are attached, form a heterocycle; and R4 is selected from the group consisting of 4 carbomethoxyphenyl, 4-carboxyphenyl, 4-fluorophenyl, 4- methoxyphenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3, 4- difluorophenyl, 3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. 41. The cell adhesion inhibitory compound of claim 40, wherein R 2 and R 3 together with the atoms to which they are attached, form a 4-6 membered monocyclic heterocyclic ring or a 8-11 membered bicyclic heterocyclic ring; the monocyclic or bicyclic heterocyclic ring being optionally substituted with hydroxyl, amino, alkyl, Ar'-substituted carbonylamino, Ar'- substituted amino, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, heterocyclylamino, benzofused-heterocyclylcarbonylamino, Ar', Ar'-disubstituted acylamino, heterocyclylcarbonylamino, heterocyclylalkylamino, cycloalkyl-substituted amino, or Ar'- substituted arylamino. 42. A cell adhesion inhibitory compound of formula x SR2 Y N H H R3 and pharmaceutically acceptable derivatives of wherein: 25 X is selected from the group consisting of-CO 2 H; Y is selected from the group consisting of-CO- and -SO 2 R, is selected from the group consisting of cyanomethyl., cyclohexymethyl, phenyiphenylmethyl, trifluoromethyiphenylmethyl, benzamidophenylmethyl, aminophenylmethyl, phenylcyclopropyl, acetamidophenylmethyl, phenacetamidophenylmethyl, (bis(phenylsulfonyl)amino)phenylmethyl, benzamnidophenylmethyl, (benzyloxycarbonylamnino)phenylmethyl, (aminobenzamido)phenylmethyl, methylurea)benzamido)phenylmethyl, (phenylsulfonamnido)phenylmethyl, phenylurea)phenylmethyl, (N'-phenylurea)phenyl, (N'-phenylurea)phenylethyl, methoxy-(N'- phenylurea)phenylmethyl, hydroxyl-(N'-phenylurea)phenylmethyl, methylurea)phenylmethyl, (N'-propylurea)phenylmethyl, (N'-toluylurea)phenylmethyl, cyclohexylurea)phenylmethyl, (N'-butylurea)phenylmethyl, (N'-ethylurea)phenylmethyl, N'- ((methoxyphenyl)urea)phenylmethyl, N'-((pyridyl)urea)phenylmethyl, methoxyphenylmethyl, nitrophenylmethyl, diphenylethyl, bromohydroxymethoxyphenylmethyl, (phenylurea)pentyl, (butylurea)pentyl, nitrophenylamino, dimethoxy-hydroxyl-phenylmethyl, hydroxy-nitro- phenylmethyl, benzocyclobutyl, (butoxycarbonylamino)phenylmethyl, quinolinyl, butylamino, N'-(benzylurea)phenylmethyl, N'-(thiazolylurea)phenylmethyl, N'- ((chlorophenyl)urea)phenylmethyl, phenylureapropyl, indanyl, (morpholinocarbonylamino)phenylmethyl, N'-((nitrophenyl)urea)phenylmethyl, N'- ((methylpyridyl)urea)phenylmethyl, methoxy-(N'-(toluylurea))phenylmethyl, methoxy-(N'- (chlorophenylurea))phenylmethyl, phenylaminocarbonyl-amninomethyiphenyl, N'- ((methylphenyl)urea)phenylmethyl, N'-(toluylurea)pyridylmethyl, (indolylcarbonylamino)phenylmethyl, methoxy-(N'-(toluylurea))pyridylmethyl, phenylthiourea)phenylmethyl, (N'-phenyl-N"-methyl-guanidino)phenylmethyl, (imidazolylamino)phenylamino, (benzoxazolylamnino)phenylmethyl, (benzoxazolinoylcarbonylamino)phenylmethyl, (pyrrolylcarbonylamnino)phenylmethyl, allylurea)phenylmethyl, (N'-fluorophenylurea)phenylmethyl, and methoxy-((N'- methylpyridyl)urea)phenylmethyl; R 2 is hydrogen or methyl; V. C R 3 is selected from the group consisting of butyl, thiazolylmethyl, propyl, hydroxymethyl, phenylmethyl, ethano, proline side chain, asparagine side chain, (methylthio)ethyl, hydroxyethyl, methoxyethyl, methyl, methoxyphenylmethyl, phenylethyl, benzyloxyphenylmethyl, hydroxyphenylmethyl, benzyloxymethyl, benzylthiomethyl, (benzyloxycarbonylamnino)butyl, butoxycarbonylaminomethyl., aminomethyl, aminobutyl, morpholino-N-carbonylmethyl, N,N-(methylpropargyl)aminocarbonylmethyl, (N- morpholino)ethyl, methylsulfinylethyl, N,N-dimethylaminocarbonylmethyl, (N,N- dimethylamino)ethyl, morpholino-N-carbonylethyl, (benzyloxycarbonylamino)butyl, methyithiomethyl, methylsulfonylethyl, (hydroxypropylthio)methyl, acetylaminobutyl, (methoxycarbonylamino)butyl, (methylsulfonylamino)butyl, and dimethylaminoethyithiomethyl; R 4 is selected from the group consisting of phenyl, benzodioxolyl, benzyl, methoxyphenyl, chiorophenyl, nitrophenyl, pyridyl, methyl, butylaminocarbonyl, difluorophenyl, dimethoxyphenyl, fluorophenyl, carboxyphenyl, dihydrobenzofuryl, carbomethoxyphenyl, phenylethyl, ethynyl, allyl, hydrogen, and morpholinomethyl; and n is 0, 1 or 2; provided that when R, is N-alkylurea-substituted alkyl or N-arylurea-substituted alkyl, and when Y is CO, R 3 is not an unsubstituted 3-indolylmethyl. 43. The cell adhesion inhibitory compound of claim 42, wherein R, is selected from the group consisting of phenylphenylmethyl, trifluoromethylphenylmethyl, benzamidophenylmethyl, aminophenylmethyl, acetamidophenylmethyl, phenacetamidophenylmethyl, (bis(phenylsulfonyl)amino)phenylmethyl, benzamidophenylmethyl, (benzyloxycarbonylamino)phenylmethyl, (aminobenzamido)phenylmethyl, ((N'-methylurea)benzamido)phenylmethyl, (phenylsulfonamnido)phenylmethyl, (N'-phenylurea)phenylmethyl, (N'-phenylurea)phenylethyl, methoxy-(N'-phenylurea)phenylmethyl, hydroxyl-(N'-phenylurea)phenylmethyl, methylurea)phenylmethyl, (N'-propylurea)phenylmethyl, (N'-toluylurea)phenylmethyl, cyclohexylurea)phenylmethyl, (N'-butylurea)phenylmethyl, (N'-ethylurea)phenylmethyl, N'- ((methoxyphenyl)urea)phenylmethyl, N'-((pyridyl)urea)phenylmethyl, methoxyphenylmethyl, nitrophenylmethyl, diphenylethyl, bromohydroxymethoxyphenylmethyl, dimethoxy-hydroxyl- phenylmethyl, hydroxy-nitro-phenylmethyl, (butoxycarbonylamino)phenylmethyl, N'- (benzylurea)phenylmethyl, N'-(thiazolylurea)phenylmethyl, N'- ((chlorophenyl)urea)phenylmethyl, (morpholinocarbonylamino)phenylmethyl, N'- ((nitrophenyl)urea)phenylmethyl, N'-((methylpyridyl)urea)phenylmethyl, methoxy-(N'- (toluylurea))phenylmethyl, methoxy-(N'-(chlorophenylurea))phenylmethyl, phenylaminocarbonyl-aminomethyiphenyl, N'-((methylphenyl)urea)phenylmethyl, (indolylcarbonylamino)phenylmethyl, (N'-phenylthiourea)phenylmethyl, (N'-phenyl-N"- methyl-guanidino)phenylmethyl, (benzoxazolylamino)phenylmethyl, (benzoxazolinoylcarbonylamino)phenylmethyl, (pyrrolylcarbonylamino)phenylmethyl, allylurea)phenylmethyl, (N'-fluorophenylurea)phenylmethyl, and methoxy-((N'- methylpyridyl)urea)phenylmethyl. 44. The cell adhesion inhibitory compound of claim 42, wherein R, is selected from the group consisting of ((N'-methylurea)benzamido)phenylmethyl, phenylurea)phenylmethyl, (N'-phenylurea)phenylethyl, methoxy-(N'-phenylurea)phenylmethyl, hydroxyl-(N'-phenylurea)phenylmethyl, (N'-methylurea)phenylmethyl, propylurea)phenylmethyl, (N'-toluylurea)phenylmethyl, (N'-cyclohexylurea)phenylmethyl, butylurea)phenylmethyl, (N'-ethylurea)phenylmethyl, N'-((methoxyphenyl)urea)phenylmethyl, N'-((pyridyl)urea)phenylmethyl, N'-(benzylurea)phenylmethyl, N'-(thiazolylurea)phenylmethyl, N'-((chlorophenyl)urea)phenylmethyl, (N'-((nitrophenyl)urea)phenylmethyl, N'- ((methylpyridyl)urea)phenylmethyl, methoxy-(N'-(toluylurea))phenylmethyl, methoxy-(N'- (chlorophenylurea))phenylmethyl, N'-((methylphenyl)urea)phenylmethyl, phenylthiourea)phenylmethyl, (N'-allylurea)phenylmethyl, (N'.-fluorophenylurea)phenylmethyl, and methoxy-((N'-methylpyridyl)urea)phenylmethyl. Th celahso niioycmon f li 2 hri 2i yrgn

2545. The cell adhesion inhibitory compound of claim 42, wherein R3 is hyroen (methylsulfonyl)-ethyl, 3 -(hydroxy-propylthio)-methyl, 4-(methylsulfonylamino)-, 4- acetylamninobutyl, butyl, aminomethyl, methyl, butyl, isobutyl, sec-butyl, t-butyl, hydroxymnethyl, methylthiomethyl, phenylmethyl, propyl, 4-(benzyloxycarbonylamino)butyl, 2- (methylthio)ethyl, 2-(N,N-dimethylamino)ethyl, 4-amninobutyl, 4-benzyloxyphenylmethyl, 2- 230 benzylthiomethyl, t-butoxy-carbonylamninomethyl, N,N-dimethylamninocarbonylmethyl, 1, 1 ethano, 4-hydroxyphenylmethyl, 1 -hydroxyethyl, I -methoxyethyl, 4-methoxyphenylmethyl, a: benzyloxymethyl, benzylthiomethyl, carbonylmethyl, 2-methylsulfinylethyl, morpholino-N- carbonylmethyl, thiomorpholino-N-carbonyl-methyl, 2-phenylethyl, asparagine side-chain, 2- 167 thiazolylmethyl, 4-(phenylurea)butyl, 4-(methylurea) butyl, morpholinocarbonylmethyithiomethyl, morpholinoethyithiomethyl, 3-pyridylmethyl, 4- methylsulfonylaminobutyl, hydroxymethyithiomethyl, 2-methylsulfonylethyl, 4- propionylaminobutyl, 4-ethoxycarbonylaminobutyl, methoxycarbonylaminobutyl, carbomethoxymethyithiomethyl, diethylamidomethyithiomethyl, acetylaminopropyl, 3- methylureapropyl, 4-biotinoylaminobutyl, 2-thienylmethyl, 3 -pyridylmethyl, 4- trifluorocetylaminobutyl, dimethylaminomethyithiomethyl, dimethylaminoethyithiomethyl, 4- (dimethylaminoacetylamino) butyl, or in combination with R 2 forms a proline side chain. 47. The cell adhesion inhibitory compound of claim 46, wherein R 2 and R 3 together with the atoms to which they are attached, form a proline side chain. 48. The cell adhesion inhibitory compound of claim 42, wherein R 4 is 4- carbomethoxyphenyl, 4-carboxyphenyl, 4-fluorophenyl, benzyl, methyl, phenyl, phenylethyl, 4- chlorophenyl, 3, 4-difluorophenyl, 3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-pyridyl, 4-nitrophenyl, 2-fluorophenyl, 3-fluorophenyl, 3- nitrophenyl, hydrogen, or ethynyl. 49. The cell adhesion inhibitory compound of claim 42, wherein n is 1 or 2. 50. The cell adhesion inhibitory compound of claim 49, wherein n is 1. 51. The cell adhesion inhibitory compound of claim 42, wherein Y is -CO-. 52. The cell adhesion inhibitory compound of claim 42, wherein R 2 is H; R 3 is 2- (methylsulfonyl)-ethyl, 3-(hydroxy-propylthio)-methyl, 4-(methylsulfonylamino)-, 4- acetylaminobutyl, butyl, aminomethyl, methyl, butyl, isobutyl, sec-butyl, t-butyl, hydroxymethyl, methylthiomethyl, phenylmethyl, propyl, 4-(benzyloxycarbonylamino)butyl, 2- (methylthio)ethyl, 2-(N,N-dimethylamino)ethyl, 4-aminobutyl, 4-benzyloxyphenylmethyl, 2- benzylthiomethyl, t-butoxy-carbonylaminomethyl, N,N-dimethylaminocarbonylmethyl, 1, 1 ethano, 4-hydroxyphenylmethyl, 1 -hydroxyethyl, 1 -methoxyethyl, 4-methoxyphenylmethyl, benzyloxymethyl, benzylthiomethyl, carbonylmethyl, 2-methylsulfinylethyl, morpholino-N- carbonylmethyl, thiomorpholino-N-carbonyl-methyl, 2-phenylethyl, asparagine side-chain, 2- thiazolylmethyl, 4-(phenylurea)butyl, 4-(methylurea) butyl, morpholinocarbonylmethyithiomethyl, morpholinoethyithiomethyl, 3 -pyridylmethyl, 4- methylsulfonylaminobutyl, hydroxymethyithiomethyl, 2-methylsulfonylethyl, 4- propionylaminobutyl, 4-ethoxycarbonylaminobutyl, methoxycarbonylaminobutyl, carbomethoxymethyithiomethyl, diethylamidomethyithiomethyl, acetylamninopropyl, 3- methylureapropyl, 4-biotinoylaminobutyl, 2-thienylmethyl, 3-pyridylmethyl, 4- trifluorocetylamninobutyl, dimethylaminomethyithiomethyl, dimethylaminoethylthiomethyl, 4- (dimethylamninoacetylamino) butyl, or in combination with R 2 forms a proline side chain; and R 4 is 4-carbomethoxyphenyl, 4-carboxyphenyl, 4-fluorophenyl, benzyl, methyl, phenyl, phenylethyl, 4-chiorophenyl, 3, 4-difluorophenyl, 3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-pyridyl, 4-nitrophenyl, 2-fluorophenyl, 3- fluorophenyl, 3-nitrophenyl, hydrogen, or ethynyl. 53. The cell adhesion inhibitory compound of claim 52, wherein R, is methylurea)benzamido)phenylmethyl, (N'-phenylurea)phenylmethyl, phenylurea)phenylethyl, methoxy-(N'-phenylurea)phenylmethyl, hydroxyl-(N'- phenylurea)phenylmethyl, (N'-methylurea)phenylmethyl, (N'-propylurea)phenylmethyl, toluylurea)phenylmethyl, (N'-cyclohexylurea)phenylmethyl, (N'-butylurea)phenylmethyl, ethylurea)phdnylmethyl, N'-((methoxyphenyl)urea)phenylmethyl, N'- ((pyridyl)urea)phenylmethyl, N'-(benzylurea)phenylmethyl, N'-(thiazolylurea)phenylmethyl, 0* N'-((chlorophenyl)urea)phenylmethyl, (N'-((nitrophenyl)urea)phenylmethyl, N'- ((methylpyridyl)urea)phenylmethyl, methoxy-(N'-(toluylurea))phenylmethyl, methoxy-(N'- (chlorophenylurea))phenylmethyl, N'-((methylphenyl)urea)phenylmethyl, phenylthiourea)phenylmethyl, (N'-allylurea)phenylmethyl, (N'-fluorophenylurea)phenylmethyl, or methoxy-((N'-methylpyridyl)urea)phenylmethyl. 54. A pharmaceutical composition for use in prevention, inhibition, or suppression of cell adhesion comprising a compound of any one of claims 42 to 53 and a pharmaceutically acceptable carrier. Use of a compound of any one of claims 42 to 53 and an agent selected form the group consisting of corticosteroids, bronchodilators, anti-asthmatics, anti-inflammatonies, anti- rheumatics, immunosuppressants, anti-metabolites, immunomodulators, anti-psoriatics, and 169 anti-diabetics for the preparation of a pharmaceutical composition for preventing, inhibiting, or suppressing cell adhesion in a mammal. 56. Use of a compound of any one of claims 42 to 53 for the preparation of a pharmaceutical composition for preventing, inhibiting, or suppressing cell adhesion in a mammal. 57. A cell adhesion inhibitory compound of formula x R 2 o I n Y N (I) H R3 and pharmaceutically acceptable derivatives of wherein: X is selected from the group consisting of-CO 2 H, -PO 3 H, -S0 2 R 5 -SO 3 H, -OPO 3 H, and -C0 2 R 4 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, aryl-substituted alkenyl, and aryl-substituted alkynyl; Y is -CO-; R 1 is selected from the group consisting of aryl or substituted aralkyl, provided that the aryl in substituted aralkyl is not substituted with only alkyl, halo, or hydroxy; R 2 is selected from the group consisting of hydrogen, aryl, alkyl alkenyl or alkynyl, cycloalkyl, cycloalkenyl, and aryl-substituted alkyl and, wherein R 2 and R 3 may be taken together with the atoms to which they are attached, to form a heterocycle; atoms to which they are attached, to form a heterocycle; 170 R 3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)- substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino- substituted alkyl, arylsulfonylamino-substituted alkyl, morpholino-alkyl, thiomorpholino-alkyl, morpholino carbonyl-substituted alkyl, thiomorpholinocarbonyl-substituted alkyl, N-(alkyl, alkenyl or alkynyl)aminocarbonyl-substituted alkyl, N,N-(dialkyl, dialkenyl, dialkynyl)aminocarbonyl-substituted alkyl, N,N-(alkyl, alkenyl)aminocarbonyl-substituted alkyl, carboxyl-substituted alkyl, dialkylamino-substituted acylaminoalkyl and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo- isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, trytophan, proline, alanine, omithine, histidine, glutamine, valine, threonine, serine, beta-cyanoalanine, and allothreonine; and wherein R 2 and R 3 may be taken together with the atoms to which they are attached, to form a heterocycle; R 4 is selected from the group consisting of aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, hydrogen, heterocyclyl, heterocyclylcarbonyl, amido, mono- or dialkylaminocarbonyl, mono- or diaryl aminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or diacylaminocarbonyl, aromatic acyl, alkyl optionally substituted by substituents selected from the group consisting of amino, carboxy, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, diarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy and heterocyclyl; and n is O, 1 or 2. 58. The cell adhesion inhibitory compound of claim 57, wherein X is -CO 2 H. 59. The cell adhesion inhibitory compound of claim 57, wherein R 1 is aryl. 000... The cell adhesion inhibitory compound of claim 57, wherein R, is (N-Ar'-urea)- para-substituted aralkyl group. 61. The cell adhesion inhibitory compound of claim 60, wherein R, is (N-Mr'-urea)- para-substituted phenylmethyl group. 62. The cell adhesion inhibitory compound of claim 57, wherein R 2 is hydrogen, methyl, or phenacyl. 63. The cell adhesion inhibitory compound of claim 57, wherein R 3 is selected from the group consisting of 2-(methylsulfonyl)-ethyl, 3 -(hydroxy-propylthio)-methyl, 4- (methylsulfonylamino)-butyl, 4-acetylaminobutyl, aminomethyl, benzyl, butyl, hydroxymethyl, isobutyl, methyl, methylthiomethyl, phenylmethyl, propyl, 4-(benzyloxycarbonylamino)-butyl, N, N- (methylpropargyl) amino, 2-(methylthio)-ethyl, N-dimethylamino)ethyl, 4-amino- butyl, 4-benzyloxyphenylmethyl, 2-benzylthiomethyl, t-butoxy-carbonylaminomethyl, scc- butyl, t-butyl, N, N-dimethyl-aminocarbonylmethyl, 1,1 -ethano, 4-hydroxyphenylmethyl, 1- hydroxyethyl, 1 -methoxyethyl, 4-methoxyphenylmethyl, benzyloxymethyl, benzylthiomethyl, carbonylmethyl, 2-methylsulfinylethyl, morpholino-N-carbonylmethyl, thiomorpholino-N- carbonyl-methyl, 2-phenylethyl, asparagine side-chain, proline side-chain and 2- thiazolylmethyl, 4-(phenylurea)butyl, 4-(methylurea)butyl, *.:morpholinocarbonylmethylthiomethyl, morpholinoethyithiomethyl, 3-pyridylmethyl, 4- methylsulfonylamninobutyl, hydroxymethylthiomethyl, 2-methylsulfonylethyl, 4- ~propionylaminobutyl, 4-ethoxycarbonylaminobutyl, methoxycarbonylaminobutyl, diethylamidomethylthiomethyl, acetylaminopropyl, 3- methylureapropyl, 4-biotinoylaminobutyl, 2-thienylmethyl, 3-pyridylmethyl, 4- trifluorocetylaminobutyl, dimethylaminomethylthiomethyl, dimethylaminoethylthiomethyl, and 4-(dimethylaminoacetylamino)butyl; or R 3 in combination with R 2 forms a proline, azetidine, or pipecolinic ring. 64. The cell adhesion inhibitory compound of claim 57, wherein R 2 and R 3 together with the atoms to which they are attached, form a heterocycle. 172 The cell adhesion inhibitory compound of claim 64, wherein R 2 and R 3 together with the atoms to which they are attached, form a 4-6 membered monocyclic heterocyclic ring or a 8-11 membered bicyclic heterocyclic ring. 66. The cell adhesion inhibitory compound of claim 65, wherein the bicyclic heterocyclic ring is formed of a 4-6 membered monocyclic heterocyclic ring fused with a cycloalkyl or an aryl. 67. The cell adhesion inhibitory compound of claim 57, wherein the heterocycle is optionally substituted with hydroxyl, amino, alkyl, Ar'-substituted carbonylamino, Ar'- substituted amino, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, heterocyclylamino, benzofused-heterocyclylcarbonylamino, Ar',Ar'-disubstituted acylamino, heterocyclylcarbonylamino, heterocyclylalkylamino, cycloalkyl-substituted amino, or Ar'- substituted arylamino. 68. The cell adhesion inhibitory compound of claim 57, wherein R 4 is selected from the group consisting of 4-carbomethoxy-phenyl, 4-carboxyphenyl, 4-fluorophenyl, 4-methoxy- phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3, 4- difluorophenyl, 3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-pyridyl, 4-phenoxyphenyl, 4-ethoxyphenyl, 4-nitrophenyl, 4- acetylaminophenyl, 4-methylureaphenyl, 2-fluorophenyl, naphthyl, 3-fluorophenyl, 3- Snitrophenyl, hydrogen, 2-nitrophenyl, 4-cyanophenyl, 3-methoxyphenyl, 4- S. methylsulfonylaminophenyl, 3-cyanophenyl, 4-propionylaminophenyl, 4-aminophenyl, 3- aminopheyl, 4-trifluoromethoxyphenyl, 4-methlphenyl, 4-amino-3-nitrophenyl, 4-hydroxy-3- methoxyphenyl, 4-hexyloxyphenyl, 4-methylthiophenyl, 3-furanyl, 4-dimethylaminophenyl, 3- hydroxy-4-nitrophenyl, n-pentyl, carboxymethyl, 2-carboxyethyl, ethynyl, 2-thienyl, 2- propenyl, 2-propynyl, methyl, and propyl. *69. The cell adhesion inhibitory compound of claim 57, wherein n is or 2. 30 70. The cell adhesion inhibitory compound of claim 6957, wherein n is 1 or 2. 30 70. The cell adhesion inhibitory compound of claim 69, wherein n is 1. so: 71. The cell adhesion inhibitory compound of claim 57, wherein R 2 is H; R 3 is selected from the group consisting of isobutyl, 2-(methylthio)ethyl, 3- (hydroxypropylthio)methyl, 2-(methylsulfonyl)ethyl, 4-acetylaminobutyl, 4- (methylsulfonylamino)butyl, and 4-(ethoxycarbonylamino)butyl; and R 4 is selected from is selected from the group consisting of 4 carbomethoxyphenyl, 4-carboxyphenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3, 4-difluorophenyl, 3, 4- dimethoxyphenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. 72. The cell adhesion inhibitory compound of claim 71, wherein R 1 is substituted aralkyl. 73. The cell adhesion inhibitory compound of claim 72, wherein R 1 is (N- Ar'-urea)-para-substituted phenylmethyl group. 74. The cell adhesion inhibitory compound of claim 57, wherein R 1 is (N-Ar'-urea)- para-substituted aralkyl group; R 2 and R 3 together with the atoms to which they are attached, form a heterocycle; and R4 is selected from is selected from the group consisting of 4 carbomethoxyphenyl, 4-carboxyphenyl, 4-fluorophenyl, 4-methoxy-phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3, 4-difluorophenyl, 3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. The cell adhesion inhibitory compound of claim 74, wherein R 2 and R 3 together with the atoms to which they are attached, form a 4-6 membered monocyclic 20 heterocyclic ring or a 8-11 membered bicyclic heterocyclic ring; the monocyclic or bicyclic heterocyclic ring being optionally substituted with hydroxyl, amino, alkyl, Ar'- substituted carbonylamino, Ar'-substituted amino, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, heterocyclylamino, benzofused-heterocyclylcarbonylamino, Ar',Ar'-disubstituted acylamino, heterocyclylcarbonylamino, heterocyclylalkylamino, cycloalkyl-substituted amino, or Ar'-substituted arylamino. 76. A pharmaceutical composition for use in prevention, inhibition, or suppression of cell adhesion comprising a compound of any one of claims 57 to 75 and a pharmaceutically acceptable carrier. 77. Use of a compound of any one of claims 57 to 75 and an agent selected form the group consisting of corticosteroids, bronchodilators, anti-asthmatics, anti-inflammatories, anti- rheumatics, immunosuppressants, anti-metabolites, immunomodulators, anti-psoriatics, and anti-diabetics for the preparation of a pharmaceutical composition for preventing, inhibiting, or suppressing cell adhesion in a mammal. 78. A cell adhesion inhibitory compound of formula x 0 (n N R Y N H R3 and pharmaceutically acceptable derivatives of wherein: X is selected from the group consisting of-CO 2 H, -PO 3 H, -S0 2 R 5 -SO 3 H, -OPO- 3 H, and -CO 2 R 4 wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, and aryl-substituted alkenyl or alkynyl; Y is -SO 2 R 1 is selected from the group consisting of alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, substituted aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl- substituted alkyl, cycloalkenyl-substituted alkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aralkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl- substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, N-alkylurea- substituted alkyl, N-arylurea-substituted alkyl, aminocarbonyl-substituted alkyl, heterocyclyl, heterocyclyl-substituted alkyl, heterocycly-substituted amino, carboxylalkyl substituted aralkyl, oxocarbocyclyl-fused aryl and heterocyclylalkyl; with the proviso that R 1 cannot be t-butoxy, benzyloxy, or aralkyl substituted with alkyl, halo, or hydroxy; 175 R 2 is selected from the group consisting of hydrogen, aryl, alkylalkenyl, alkylalkynyl, cycloalkyl, cycloalkenyl, and aryl-substituted alkyl; R 3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)- substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino- substituted alkyl, arylsulfonylamino-substituted alkyl, morpholino-alkyl, thiomorpholino-alkyl, morpholino carbonyl-substituted alkyl, thiomorpholinocarbonyl-substituted alkyl, N-(alkyl, alkenyl or alkynyl)aminocarbonyl-substituted alkyl, N,N-(dialkyl, dialkenyl, dialkynyl)aminocarbonyl-substituted alkyl, N,N-(alkyl, alkenyl)aminocarbonyl-substituted alkyl, carboxyl-substituted alkyl, dialkylamino-substituted acylaminoalkyl and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, allo- isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, trytophan, proline, alanine, ornithine, histidine, glutamine, valine, threonine, serine, beta-cyanoalanine, and allothreonine; or R 2 and R 3 together with the atoms to which they are attached, form a heterocycle; R 4 is selected from the group consisting of aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, hydrogen, heterocyclyl, heterocyclylcarbonyl, amido, mono- or dialkylaminocarbonyl, mono- or diarylaminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or diacylaminocarbonyl, aromatic acyl, alkyl optionally substituted by substituents selected from the group consisting of amino, carboxy, hydroxy, mercapto, mono- or dialkylamino, mono- or diarylamino, alkylarylamino, diarylamino, mono- or diacylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thioalkenoxy, thioalkynoxy, thioaryloxy and heterocyclyl; and n is 0, 1 or 2. 79. The cell adhesion inhibitory compound of claim 78, wherein X is -CO 2 H. 176 The cell adhesion inhibitory compound of claim 78, wherein R 1 is aryl or aralkyl. 81. The cell adhesion inhibitory compound of claim 78, wherein R 1 is (N-Ar'-urea)- para-substituted aralkyl group. 82. The cell adhesion inhibitory compound of claim 81, wherein R 1 is (N-Ar'-urea)- para-substituted phenylmethyl group. 83. The cell adhesion inhibitory compound of claim 78, wherein R 2 is hydrogen, methyl, or phenacyl. 84. The cell adhesion inhibitory compound of claim 78, wherein R 3 is selected from the group consisting of 2-(methylsulfonyl)-ethyl, 3 -(hydroxy-propylthio)-methyl, 4- (methylsulfonylamino)-butyl, 4-acetylaminobutyl, aminomethyl, benzyl, butyl, hydroxymethyl, isobutyl, methyl, methylthiomethyl, phenylmethyl, propyl, 4-(benzyloxycarbonylamino)-butyl, N,N-(methylpropargyl)-amino, 2-(methylthio)-ethyl, 2-(N,N-dimethylamino)-ethyl, 4-amino- butyl, 4-benzyloxyphenylmethyl, 2-benzylthiomethyl, t-butoxy-carbonylaminomethyl, sec- butyl, t-butyl, N,N-dimethyl-aminocarbonylmethyl, 1,1-ethano, 4-hydroxyphenylmethyl, 1- hydroxyethyl, 1-methoxyethyl, 4-methoxyphenylmethyl, benzyloxymethyl, benzylthiomethyl, carbonylmethyl, 2-methylsulfinylethyl, morpholino-N-carbonylmethyl, thiomorpholino-N- carbonyl-methyl, 2-phenylethyl, asparagine side-chain, proline side-chain, 2-thiazolylmethyl, 4- (phenylurea)-butyl, 4-(methylurea)-butyl, morpholinocarbonylmethylthiomethyl, morpholinoethylthiomethyl, 3-pyridylmethyl, 4-methylsulfonylaminobutyl, hydroxymethylthiomethyl, 2-metfylsulfonylethyl, 4-propionyl aminobutyl, 4- ethoxycarbonylaminobutyl, methoxycarbonylaminobutyl, carbomethoxymethylthiomethyl, diethylamidomethylthiomethyl, acetylaminopropyl, 3-methylureapropyl, 4- biotinoylaminobutyl, 2-thienylmethyl, 3-pyridylmethyl, 4-trifluorocetylaminobutyl, dimethylaminomethylthiomethyl, dimethylaminoethylthiomethyl, and 4- (dimethylaminoacetylamino)-butyl; or R 3 in combination with R 2 forms a proline, azetidine, or pipecolinic ring. 177 The cell adhesion inhibitory compound of claim 78, wherein R 2 and R 3 together with the atoms to which they are attached, form a heterocycle. 86. The cell adhesion inhibitory compound of claim 85, wherein R 2 and R 3 together with the atoms to which they are attached, form a 4-6 membered monocyclic heterocyclic ring or a 8-11 membered bicyclic heterocyclic ring. 87. The cell adhesion inhibitory compound of claim 86, wherein the bicyclic heterocyclic ring is formed of a 4-6 membered monocyclic heterocyclic ring fused with a cycloalkyl or an aryl. 88. The cell adhesion inhibitory compound of claim 85, wherein the heterocycle is optionally substituted with hydroxyl, amino, alkyl, Ar'-substituted carbonylamino, Ar'- substituted amino, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, heterocyclylamino, benzofused-heterocyclylcarbonylamino, Ar',Ar'-disubstituted acylamino, heterocyclylcarbonylamino, heterocyclylalkylamino, cycloalkyl-substituted amino, or Ar'- substituted arylamino. 89. The cell adhesion inhibitory compound of claim 78, wherein R 4 is selected from the group consisting of4-carbomethoxy-phenyl, 4-carboxyphenyl, 4-fluorophenyl, 4-methoxy- phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3,4-difluorophenyl, S3, 4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, 3-pyridyl, 4-phenoxyphenyl, 4-ethoxyphenyl, 4-nitrophenyl, 4-acetylaminophenyl, 4- methylureaphenyl, 2-fluorophenyl, naphthyl, 3-fluorophenyl, 3-nitrophenyl, hydrogen, 2- 25 nitrophenyl, 4-cyanophenyl, 3-methoxyphenyl, 4-methylusulfonylaminophenyl, 3-cyanophenyl, 4-propionylaminophenyl, 4-aminophenyl, 3-aminophenyl, 4-trifluoromethoxyphenyl, 4- methlphenyl, 4-amino-3-nitrophenyl, 4-hydroxy-3-methoxyphenyl, 4-hexyloxyphenyl, 4- methylthiophenyl, 3-furanyl, 4-dimethylaminophenyl, 3-hydroxy-4-nitrophenyl, n-pentyl, carboxymethyl, 2-carboxyethyl, ethynyl, 2-thienyl, 2-propenyl, 2-propynyl, methyl, and propyl. The cell adhesion inhibitory compound of claim 78, wherein n is 1 or 2. 91. The cell adhesion inhibitory compound of claim 90, wherein n is 1. 92. The cell adhesion inhibitory compound of claim 78, wherein R 2 is H; R 3 is selected from the group consisting of isobutyl, 2-(methylthio)-ethyl, 3-(hydroxypropylthio)- methyl, 2-(methylsulfonyl)-ethyl, 4-acetylamino-butyl, 4-(methylsulfonylamino)-butyl, and 4- (ethoxycarbonylamino)butyl; and R 4 is selected from is selected from the group consisting of 4 carbomethoxy-phenyl, 4-carboxyphenyl, 4-fluorophenyl, 4-methoxy-phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4-chlorophenyl, 3,4-difluorophenyl, 3,4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. 93. The cell adhesion inhibitory compound of claim 92, wherein R 1 is aryl or substituted aralkyl. 94. The cell adhesion inhibitory compound of claim 78, wherein R 1 is (N-Ar'-urea)- para-substituted phenylmethyl group. The cell adhesion inhibitory compound of claim 78, wherein R 2 and R 3 together with the atoms to which they are attached, form a heterocycle; and R 4 is selected from is selected from the group consisting of 4 carbomethoxy-phenyl, 4-carboxyphenyl, 4- fluorophenyl, 4-methoxy-phenyl, benzyl, methyl, phenyl, phenylmethyl, phenylethyl, 4- chlorophenyl, 3,4-difluorophenyl, 3,4-dimethoxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-nitrophenyl, and 3-pyridyl. 96. The cell adhesion inhibitory compound of claim 95, wherein R 2 and R3, together with the atoms to which they are attached, form a 4-6 membered monocyclic heterocyclic ring 25 or a 8-11 membered bicyclic heterocyclic ring; the monocyclic or bicyclic heterocyclic ring being optionally substituted with hydroxyl, amino, alkyl, Ar'-substituted carbonylamino, Ar'- substituted amino, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, heterocyclylamino, benzofused-heterocyclylcarbonylamino, Ar',Ar'-disubstituted acylamino, heterocyclylcarbonylamino, heterocyclylalkylamino, cycloalkyl-substituted amino, or Ar'- S* 30. substituted arylamino. 97. A pharmaceutical composition comprising a compound of any one of claims 78 Sto 96 and a pharmaceutically acceptable carrier. 179 98. Use of a compound of any one of claims 78 to 96 or claims 82 to 100 and an agent selected form the group consisting of corticosteroids, bronchodilators, anti-asthmatics, anti-inflammatories, anti-rheumatics, immunosuppressants, anti-metabolites, immunomodulators, anti-psoriatics, and anti-diabetics for the preparation of a pharmaceutical composition for preventing, inhibiting, or suppressing cell adhesion in a mammal. 99. A cell adhesion inhibitory compound selected from a compound of the formula R2 0 N Y NN H R3 and pharmaceutically acceptable derivatives of wherein: X is selected from the group consisting of-CO 2 H; **20 20 25 Y is selected from the group consisting of-CO-; RI is indolyl, phenylcyclopropyl, (N'-phenylurea)phenyl, 2,3-benzocyclobutyl, quinolinyl, or indanyl, each of which optionally substituted by cyclohexyl, naphthyl, or phenyl optionally substituted by hydroxyl, nitro, halo, (N'-methylurea)phenylacylamino, phenylsulfonamido, N'- phenylurea, C1- 6 alkoxy, N'-cyclohexylurea, N'-(methylphenyl)urea, N'-thiazolylurea, N'-(CI-6 alkylphenyl)urea, N'-pyridylurea, morpholinylcarbonylamino, or (N'-nitrophenyl)urea; R 2 is hydrogen; R 3 is C -6 alkyl, benzyl, thiomorpholino-N-carbonylmethyl, or N,N-(methylpropargyl)- aminocarboxyl each of which optionally substituted by C 1 6 alkylthio, benzylthio, 180 methylsulfonyl, methylsulfinyl, C 1 6 alkylamino, benzyloxycarbonylamino, hydroxyl, C 1 6 alkylthio, C 1 6 alkylacylamino, or C 1 alkylsulfonylamino; R 4 is phenyl, 1,3-benzodioxol-5-yl, or benzyl each of which optionally substituted by C 1 6 alkoxy, halo, nitro, carbonyl, or C 1 6 alkoxycarbonyl; and n isO0, 1 or 2. DATED this eleventh day of August 2003 BIOGEN, INC. By their Patent Attorneys CULLEN CO.