AU763115B2

AU763115B2 - N,N-disubstituted amides that inhibit the binding of integrins to their receptors

Info

Publication number: AU763115B2
Application number: AU66601/00A
Authority: AU
Inventors: Ronald J. Biediger; Vanessa O. Grabbe; Jamal M. Kassir; Timothy P Kogan; Shuqun Lin; Robert V. Market; Bore G. Raju; Ian L Scott
Original assignee: Texas Biotechnology Corp
Current assignee: Encysive Pharmaceuticals Inc
Priority date: 1998-04-16
Filing date: 2000-10-18
Publication date: 2003-07-10
Anticipated expiration: 2019-04-15
Also published as: AU6660100A

Description

N,N-Disubstituted Amides that Inhibit the Binding of Integrins to their Receptors Field of the Invention This invention is directed generally to the inhibition of the binding of a4p1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds that inhibit this binding; to pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of disease states in which a41 is involved.

Background of the Invention When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream. However, when a tissue is infected or becomes damaged, the white blood cells recognize the invaded or damaged tissue, bind to the wall of the capillary and migrate through the capillary into the affected tissue. These events are mediated by a family of proteins called cell adhesion molecules.

There are three main types of white blood cells: granulocytes, monocytes and lymphocytes.

The integrin a431 (also called VLA-4 for very late antigen-4) is a heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognize and bind VCAM-1 and fibronectin, proteins associated with the endothelial cells that line the interior wall of capillaries.

Following infection or damage of tissue surrounding a capillary, endothelial cells express a series of adhesion molecules, including VCAM-1, that are critical for binding the white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1 or fibronectin, the white blood cells 25 initially bind to certain adhesion molecules to slow their flow and allow the cells to "roll" along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood vessel wall via the a411 integrin. There is evidence that such interactions are also involved in transmigration of these white blood cells into the damaged tissue, as well as the initial rolling event itself.

30 Although white blood cell migration to the site of injury helps fight infection and destroy foreign material, in many instances this migration can become uncontrolled, with white blood cells flooding to the scene, causing widespread tissue damage. Compounds capable of blocking this process, therefore, may be beneficial as therapeutic agents. Thus, it would be useful to develop inhibitors that would prevent the binding of white blood cells to VCAM-1 and fibronectin.

35 Some of the diseases that might be treated by the inhibition of a4pi binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, sickle cell disease and type I diabetes. In addition to being found on some white blood cells and some reticulocytes, 4131 is also found on various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving a411 may be involved in the metastasis of certain cancers.

Inhibitors of a411 binding may, therefore, also be useful in the treatment of some forms of cancer.

LibC/526783speci 2 The isolation and purification of a peptide which inhibits the binding of a43 1 to a protein is disclosed in US 5,510,332. Peptides which inhibit binding are disclosed in WO 95/15973, EP 0 341 916, EP 0 422 938 Al, US 5,192,746 and WO 96/06108. Novel compounds which are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966, WO 98/04247 and WO 98/04913.

It is therefore an object of the invention to provide novel compounds which are inhibitors of a43 1 binding, and pharmaceutical compositions including such novel compounds.

The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.

The present invention further relates to a process of inhibiting the binding of a 4 1 integrin to VCAM-1 comprising exposure of a cell expressing a41 integrin to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention. The VCAM-1 may be on the surface of a vascular endothelial cell, an antigen presenting cell, or other cell type. The a4 1 may be on a white blood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; or any other cell that naturally expresses a4 3 1 The invention also relates to a method for treating disease states mediated by a431 binding which comprises administration of an effective amount of a compound of the present invention, either alone or in formulation, to an afflicted patient.

Brief Summary of the Invention According to a first embodiment of the invention there is provided a compound of Formula I as follows: 1 R M

R

3

R

4 j

M

R2 K A) L

N

R2 A E T R

J

Formula I wherein A is -NR6; E is -NR 7 30 each J is T is selected from the group consisting of and -(CH 2 wherein b is an •integer of from 0 to 3; s and t are each 1; [I:\DayLib\LBH]02470.doc: UG 3 L is selected from the group consisting of -NR 9 and -(CH 2 wherein n is an integer of 0 or 1; M is X is -CO 2

B;

B, R, R, R 4

R

5 R R 7

R

9

R

1 0 and R 11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkoxy, cycloalkylalkyl, alkylamino, haloalkyl, alkylaryl, arylalkyl, heterocyclyl, heterocyclylalkyl and alkylheterocyclyl groups; wherein B, R 2

R

3

R

4

R

5

R

6

R

7

R

9

R'

1 and R 1 are unsubstituted or substituted with at least one electron donating or electron to withdrawing group; and wherein R' and R 2 taken together may form a ring; R 3 and R 4 taken together may form a ring; R 5 and R 9 taken together may form a ring; and R io and R" taken together may form a ring; and pharmaceutically acceptable salts thereof.

More specifically, compounds of the invention may be described by Formula II: R s R 3

R

4

RR

10 R2 N N R O R 6

R

7 Formula II, wherein X, s, t and R' to R 7

R

10 and R" are as defined in the first embodiment of the invention.

According to a second embodiment of the invention there is provided a compound of Formula III: H 0 l)s aO e x OH

R

2 N N R

O

Formula III wherein s is zero or one; R' and R 2 are each independently selected from the group consisting of alkyl, 2thienyl, methoxyphenyl and phenyl;

R

5 is selected from the group consisting of 1,3-benzodioxol-5-yl, dimethoxyphenyl, 2,3-dihydro-l-benzofuran-5-yl, fluorophenyl, and methoxyphenyl; and pharmaceutically acceptable salts thereof.

[l:\DayLib\LIBH]02470.doc: JG 4 According to a third embodiment of the invention there is provided a compound selected from the group consisting of: (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1S)-1 -[methyl(2-thienylmethyl)amino]carbonylpentyl)amino]carbonylamino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1S)-1 -[methyl(3-methoxybenzyl)amino]carbonylpentyl)amino]carbonyl amino) propanoic acid, (3S)-3-(3,5-dimethoxyphenyl)-3-( 1- [bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl} amino)propanoic acid, (3S)-3-(2,3-dihydro-1 -benzofuran-5-yl)-3-( [bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl} amino)propanoic acid, (3S)-3-(4-fluorophenyl)-3-( 1- [bis(2-thienylmethyl)amino]carbonyl} pentyl)amino]carbonyl} amino) propanoic acid, (3S)-3-(4-methoxyphenyl)-3-( [bis(2-thienylmethyl)amino]carbonyl} pentyl)amino]carbonyl} amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-( [butyl(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl} amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((((1 S)-1 -((bis(2-thienylmethyl)amino)carbonyl)pentyl)amino)carbonyl)amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-( ([(1,3-thiazol-2-ylmethyl)(2-thienylmethyl)amino]carbonyl} pentyl)amino]carbonyl} amino)propanoic acid; and pharmaceutically acceptable salts thereof.

Accordingly, in a fourth embodiment the invention provides a pharmaceutical 25 composition comprising a compound of any one of the first to third embodiments of the invention in a pharmaceutically acceptable carrier.

The invention also relates to a method for treating disease states mediated by c4P 1 binding which comprises administration of an effective amount of a compound of the present invention, either alone or in formulation, to an afflicted patient.

Thus, according to a fifth embodiment of the invention there is provided a method for selectively inhibiting a4PI integrin binding in a mammal comprising administering to said mammal a therapeutic amount of a compound of any one of the first to third embodiments of the invention or of a composition of the fourth embodiment of the invention.

35 According to a sixth embodiment of the invention there is provided a compound according to any one of the first to third embodiments of the invention or a composition [I:\DayLib\LIBH]02470.doc:tG according to the fourth embodiment of the invention when used for selectively inhibiting a 4 J3 1 integrin binding.

According to a seventh embodiment of the invention there is provided the use of a compound according any one of the first to third embodiments of the invention for the manufacture of a medicament for selectively inhibiting a43 1 integrin binding.

For Formula 11, presently preferred compounds may have RI as methyl, 2thienylmethyl, 5-methylfuranylmethyl, or butyl; R 2as 2-thienylmethyl, 3-methoxybenzyl, N-(cyclopropylmethyl) amninobenzyl, benzyl, or 5-methylfuranylmethyl; and R 5 as 1,3- 4-methylphenyl, 3-trifluoromethylphenyl, 3 ,5-dimethoxyphenyl, 2,3dihydro-l1-benzofuran-5-yl, phenyl, 4-flurophenyl, 4-methoxyphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4,5-trimethoxyphenyl or 3-chlorophenyl.

Moreover, for structures I and II above, R' and R 2 taken together may form a ring, and said ring is of the structure (R4 )Z wherein Y, at each occurrence is independently selected from the group consisting of -C(R' 5 -N(R'1 6

-SO

2 N(R 1 7 -C(0)N(R' 8

-NR'

9 and -N1R 2 0 S0 2 R1 4 R 15 R 1 6 R1 7 R1 8

R

19 and R 20 at each occurrence are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, -CF 3 nitro, amino, cyano, -N(C 1

-C

3 alkyl)-C(0)(CI-C 3 alkyl), -CI-C 3 alkylamino, see*.:alkenylamino, alkynylamino, di(CI-C 3 alkyl)wmino,-C(0)0-(C-C 3 alkyl), -C(0)NI{- 3 alkyl), -CH=NOH, -P0 3

H

2 -0P0 3

H

2 -C(0)N(CI-C 3 alkyl) 2 haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamnate, aryloxyalkyl, carboxyl and -C(0)NI{(benzyl); wherein R' 4

R'

5 R R' 7

R

18 R9 and R2 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; y is an integer of two to eight; z is an integer of zero to sixteen; and r an integer of zero to two.

30 The ring may be 4-(2-thienylmethyl)piperazino, 4-(3-thienylmethyl)piperazino, 4- :(2-methoxyphenyl)piperazino, 4-(2-thienylcarbonyl)piperazino, 4-(2-thienylsulfonyl) piperazino, 4-phenyl-4-cyano-piperidino or 4-((benzyloxy)carbonyl)piperazino.

[I:\DayLib\LIBHj02470.doc:UG Presently preferred compounds are (3S)-3 ,3-benzodioxol-5 1- [methyl(2-thienylmethyl)amino]carbonylpentyl)amnino]carbonylamino) propanoic acid, (3S)-3 ,3-benzodioxol-5-yl)-3 S)-l1-[methyl(3-methoxybenzyl)amino]carbonylpentyl)amino]carbonylamnino) propanoic acid, (3 ,5 -dimethoxyphenyl)-3-( S)- 1 [bis(2-thienylmethyl)amnino]carbonyl }pentyl)amino]carbonyl} amino) propanoic acid, (3 S)-3-(2,3-dihydro-l1-benzofuran-5-yl)-3 {[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl} amino) propanoic acid, (3 S)-3-(4-fluorophenyl)-3- 1- [bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl} amino) propanoic acid, (3 S)-3-(4-methoxyphenyl)-3 1- {[bis(2-thienylmethyl)amnino]carbonyllpentyl)amnino]carbonyl} amino) propanoic acid, (3 1,3-benzodioxol-5-yl)- 3 1- {[butyl(2-thienylmethyl)amino]carbonyl} pentyl)amino]carbonyl }amnino) propanoic acid, (3 1,3 -benzodioxol-5-yl)-3-((((( 1S)- 1-((bis(2-thienylmethyl) amino)carbonyl)pentyl)amino)carbonyl) amino) propanoic acid, (3 1,3 -benzodioxol- 5-yl)-3 1- ,3-thiazol-2-ylmethyl)(2-thienylmethyl)amino]carbonyl} pentyl)amino] carbonyl I amino) propanoic acid, (3 S)-3 1- {[bis(2-thienylmethyl) amino] carbonyl)} pentyl)amino]carbonyl I amino)-4-morpholino-4-oxobutanoic acid, (3R)- 3 ,3-benzodioxol-5-yl)-3-( 1- {[bis(2-thienylmethyl)amino]carbonyl} pentyl)amino] carbonyl) amino)-2,2-dimethylpropanoic acid, (3 S)-3 -benzodioxol-5-yl)-3- 1S)-l1-[(diallylamino)carbonyl]pentyl} amino)carbonyl]amino} propanoic acid, (3 S)- 1,3-benzodioxol-5-yl)-3- 1-Ij(diisobutylamino)carbonyl]pentyl} amino)carbonyl]amnino propanoic acid, (3 1,3-benzodioxol-5-yl)-3-( 1- {[bis(3methoxybenzyl)amnino]carbonyl }pentyl)amino]carbonyl} amino) propanoic acid, (3 S)-3- (1 ,3-benzodioxol-5 S)-l1-((bis(2-thienylmethyl)amino)carbonyl)pentyl)amino)carbonyl) (methyl)amino)propanoic acid, (3 1- {[bis(2-thienylmethyl)amino] carbonyl Ipentyl)amino] carbonyl} amino)-3 -(2-thienyl) propanoic acid, (3S)-3- 1- {[bis(2-thienylmethyl)amino] carbonyl} pentyl)amino]carbonyl} amino)-3-(3methoxyphenyl) propanoic acid, (3 S)-3 ,3-benzodioxol-5 1- thienylsulfonyl)piperazino]carbonyl} pentyl)amino]carbonyl} amino) propanoic acid, and pharmaceutically acceptable salts thereof.

Derivatives of Formulae 1, 11 and III include esters, carbamnates, aminals, amides, and optical isomers.

Also disclosed herein is a process of inhibiting the binding Of a 4 fPI integrin to :VCAM-1 comprising exposure of a cell expressing a40 1 integrin to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention. The VCAM-1I may be on the surface of a vascular endothelial cell, an antigen [I:\Day~ib\L1BH102470.doc:UG presenting cell, or other cell type. The a 4 1 may be on a white blood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; or any other cell that naturally expresses a4P1- Detailed Description of the Invention Definition of Terms The term "alkyl" as used herein alone or in combination refers to Ci-C 1 2 straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tertbutyl among others.

The term "alkenyl", alone or in combination, refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.

The term "alkynyl", alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

The term "lower" modifying "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to a Cl-C 6 unit for a particular functionality. For example lower alkyl means CI-C 6 alkyl.

The term "cycloalkyl" as used herein alone or in combination refers to a substituted or unsubstituted aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among others. Cycloalkyl groups can be unsubstituted or substituted with one, 25 two or three substituents independently selected [I:\DayLib\LBH]02470.doc:UG from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. This term is meant to encompass cycloalkenyl and cycloalkynyl groups. "Cycloalkyl" includes cis or trans forms.

Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.

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

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a lower alkyl radical, including, but not limited to cyclohexyl methyl.

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

The term "haloalkyl" as used herein refers to a lower alkyl radical, to which is appended at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl among others.

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

The term "alkenoxy", alone or in combination, refers to a radical of formula alkenyl-0-, provided that the radical is not an enol ether, wherein the term "alkenyl" is as defined above. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z- 3-methyl-2-propenoxy and the like.

The term "alkynoxy", alone or in combination, refers to a radical of formula alkynyl-0-, 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.

The term "carboxyl" as used herein refers to -CO 2

H.

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

The term "carboxaldehyde" as used herein refers to -C(O)R wherein R is hydrogen.

The term "carboxamide" as used herein refers to -C(O)NR 2 wherein R is hydrogen, alkyl or any other suitable substituent.

30 The term "alkoxyalkoxy" as used herein refers to RbO-RcO- wherein Rb is lower alkyl as defined above and Rc is alkylene wherein alkylene is wherein n' is an integer from 1 to 6.

Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, and tbutoxymethoxy among others.

The term "alkylamino" as used herein refers to RdNH- wherein Rd is a lower alkyl group, for 35 example, ethylamino, butylamino, among others.

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

The term "alkynylamino", alone or in combination, refers to a radical of formula alkynyl-NH- or (alkynyl)2N- wherein the term "alkynyl" is as defined above, provided that the radical is not an amine.

An example of such alkynylamino radicals is the propargyl amino radical.

LibC/526783speci The term "dialkylamino" as used herein refers to ReRfN- wherein Re and Rf are independently selected from lower alkyl, for example diethylamino, and methyl propylamino, among others.

The term "amino" as used herein refers to H 2

N-.

The term "alkoxycarbonyl" as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl among others.

The term "aryl" or "aromatic" as used herein alone or in combination refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1Hindazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[1,5-c]triazinyl and the like. "Arylalkyl" and "alkylaryl" employ the term "alkyl" as defined above. Rings may be multiply substituted.

The term "aralkyl", alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.

The term "aralkenyl", alone or in combination, refers to an aryl substituted alkenyl radical, wherein the terms "aryl" and "alkenyl" are as defined above.

The term "arylamino", alone or in combination, refers to a radical of formula aryl-NH-, wherein 25 "aryl" is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino(anilido), naphthlamino, and 4- pyridylamino and the like.

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 30 term "aryl" is as defined above. An example of a thioaryl radical is the thiophenyl radical.

The term "aroyl", 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 term "heterocyclyl", alone or in combination, refers to a non-aromatic 3- to 10- membered ring containing at least one endocyclic N, O, or S atom. The heterocycle may be optionally aryl-fused.

The heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.

The term "alkylheterocyclyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a heterocyclyl group.

LibC/526783speci The term "heterocyclylalkyl" as used herein refers to a heterocyclyl group as previously defined appended to the parent molecular moiety through an alkyl group.

The term "aminal" as used herein refers to a hemi-acetal of the structure RCH(NH2)(OH).

The terms "electron-withdrawing" or "electron-donating" refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, incorporated herein by reference.

Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, and aryl lower alkanoyl among others. Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.

The most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio and alkyldithio.

Use of the above terms is meant to encompass substituted and unsubstituted moieties.

Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, 25 alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of or Rings may be substituted multiple times.

30 The term "mammals" includes humans and other animals.

The term "heteroatom" as used herein encompasses nitrogen, sulfur and oxygen.

The term "alpha" as used herein indicates the position immediately adjacent to the position described.

For example, R 1 and R 2 in Formulas I, II and Ill above may independently be, but are not limited to, phenyl, isobutyl, n-butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-benzothiophen-2-yl, allyl, isobutyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, 4-((2-toluidinocarbonyl) amino)benzyl, 2-pyridinylethyl, 2-(1H-indol-3-yl)ethyl, 1Hbenzimidazol-2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-hydroxyphenethyl, 4aminobenzyl, phenylsulfonylmethyl, isopropyl or 2-oxo-1-pyrrolidinyl.

Some of the substituents which may be linked to form a first, second, third or fourth ring as described above. Examples of such rings include 4-(2-thienylmethyl)piperazino, 4-(3thienylmethyl)piperazino, 4-(2-methoxyphenyl)piperazino, 4-(2-thienylcarbonyl)piperazino, 4-(2- LibC/526783speci thienylsulfonyl)piperazino, 4-((benzyloxy) carbonyl)piperazino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-piperidinyl, and 4-tetrahydropyranyl, pyrrolidino, 1-piperidino, 4-methyl-i -piperazino, 4aceto-1-piperazino, or 4-morpholino among others. Rings so formed may be substituted by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyloxy, alkoxyalkoxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of or Rings may be substituted multiple times.

The R 5 substituent for Formulas 1, II and Ill above may be, but is not limited to, 1,3-benzodioxol- 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2,6-dimethylphenyl, allyloxyphenyl, 3-bromo-4methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl, methysulfanyl, phenylsulfanyl, phenethylsulfanyl, 4-bromo-2-thienyl, 3-methyl-2-thienyl, or 4,5-dihydro-1,3-oxazol-2yl. These substituents may be further substituted with groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyloxy, alkoxyalkoxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylhete'rocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of or Rings may be substituted multiple times.

Abbreviations 25 Abbreviations which have been used in the schemes and the examples which follow are: BOC for t-butyloxycarbonyl; EtOAc for ethyl acetate; DMF for dimethylformamide; THF for tetrahydrofuran; Tos for p-toluenesulfonyl; DCC for dicyclohexylcarbodiimide; HOBT for 1-hydroxybenzotriazole; TFAA for trifluoroacetic anhydride;nmM for N-methyl morpholine; DIPEA for diisopropylethylamine; DCM for methylene dichloride; LHMDS for lithium hexamethyl disilazide; NaHMDS for sodium hexamethyl disilazide; CDI for 1,1'-carbonyldiimidazole and TBS for TRIS-buffered saline.

The compounds and processes of the persent invention will be better understood in connection with the following sythetic schemes which illustrate the methods by which the compounds of the invention may be prepared.

An example of a procedure that may be used to synthesize compounds of the formulae shown 35 above is presented in Scheme 1.

LibC/526783speci 0 /l S NH 2

+H

NaCNBH 3 MeOH AcOH

S-"

N' I BOC-L-Lys(CBZ)-OH I DCC, DMF 4HCBZ 0 0

O

2 Nd 2 Y 4 EtN

TI

4

F

NBC-2N

HCI

~ffNHBOCdioxane 0 2 3

NHCBZ

0 H H O Mee 00 HO0

TIF

NHCBZ

0 NN NqNO H H 6 Scheme I A second synthetic example is shown in Scheme 2.

IMDS, THF, -78 TC to Rt thiophene carboxaldehyde 0 TC to RT, 18 hrs TFA, MeOH 0QIC S111 7 i. NaHMDS, EtOAc, Et 2

O

-78 TC, then sulfinimine in Et 2 0, 5 hrs

C

S

Sees

S.

C. S *ec~.

0* S C

S

*4S@ eeC.

C

6CSC 0 10 OEt N j

H

0 KCEt 8 /5 0 I/N" OEt 0o H H S H2N 9 LiOH-H 2 0,

THF/H

2 0/MeOH a) CDI, CH 2

CI

2

IS

N<KH

100 Scheme 2 '09.44A third synthetic example is shown in Scheme 3 below.

LibC/526783speci

CO

2 Me 1. Isobutylchloroformate CO 2 Me f THF, 0C BOCHN COOH 2. CH 2

N

2 BOCHNf N 2 0 48% HBr Ether

CO

2 Me BOCHN f Br 0 14

H

2

N

CO

2 Me BOCHNf-\ CO Me HCI

H

2 N

S

*HCI 16Nz THF, DIP EA, rt N N NaGOH 0 H H COONa S N 0-NS N N 'fN e\ N~ 18 19 Scheme 3 Another synthetic example is found in Scheme 4 below.

0 HOOC COOR 0 H

NH

2 S N N COH DCC e\ Scheme 4 Another synthetic example is found in Scheme 5 below.

a) LHMDS o z CHO0

K

0 I HN4

COR'

R=CI

21: R 0tBu a) BuLi -45 "C b) 23, -45 OC to 0 OC c) Chromatography 10: W H _]PhOCOCI 23: R' COOPh

N

S\0 H Li0H*H 2 0,

THF/H

2 0 Scheme Still another synthetic example is found in Scheme 6 below, LibC/526783speci COOtBu COOtBu SBo 2 0 a) KHMDS

H

2 N "N J BocHN b)CH -I 0 0 26 27 COOtBuCOOH BHC O> H C N

NO

29 28 /S N a) COCl 2 DIPEA COOH b)29 NN N 1 'N XINH" N U, O Scheme 6 A detailed description of the preparation of representative compounds of the present invention is set forth in the Examples.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically 10 acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, ptoluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized 20 with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such LibC/526783speci as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminium salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of ooooo 35 the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well .ooooi S•within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.001 to about 5mg/kg/day. If desired, the LibC/526783speci effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent. The present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, or the like.

The compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary sternt (a tubular device composed of a fine wire mesh), or via a biodegragable polymer. The compounds may also be complexed to ligands, such as antibodies, for targeted delivery.

Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for 25 reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters .such as ethyl oleate, and suitable mixtures thereof.

These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and 30 dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminium monostearate and gelatin.

35 Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

LibC/526783speci In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled.

Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a bacterialretaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal ooooo 35 tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more oooo• of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, LibC/526783speci ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances.

Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

The term "pharmaceutically acceptable prodrugs" as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, 25 irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S.

30 Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.

The present invention contemplates both synthetic compounds of formulas I, II and III of the present invention, as well as compounds formed by in vivo conversion to compounds of the present invention.

Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are or depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by attachment of a LibC/526783speci 17 mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallisation or chromatography and liberation of the optically pure product from the auxiliary or direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention. In another aspect, the present invention contemplates a process of inhibiting the binding of ca41 integrin to VCAM-1. A process of the present invention can be used either in vitro or in vivo. In accordance with a process of the present invention, a cell expressing a4p 1 integrin is exposed to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention.

A cell expressing a 4 0 1 integrin can be a naturally occurring white blood cell, mast cell or other cell type that naturally expresses a40 1 on the cell surface, or a cell transfected with an expression vector that contains a polynucleotide genomic DNA or cDNA) that encodes a 4 l 1 integrin. In an especially preferred embodiment, a43 1 integrin is present on the surface of a white blood cell such as a monocyte, a lymphocyte or a granulocyte an eosinophil or a basophil).

A cell that expresses VCAM-1 can be a naturally occurring cell an endothelial cell) or a cell transfected with an expression vector containing a polynucleotide that encodes VCAM-1. Methods for producing transfected cells that express VCAM-1 are well known in the art.

Where VCAM-1 exists on the surface of cell, the expression of that VCAM-1 is 25 preferably induced by inflammatory cytokines such as tumour necrosis factor-a, interleukin-4 and interleukin-1 Where the cells expressing a 4 0 1 integrin and VCAM-1 are in a living organism, a compound of the present invention is administered in an effective amount to the living organism. Preferably, the compound is in a pharmaceutical composition of this invention.

A process of the present invention is especially useful in treating diseases associated with uncontrolled migration of white blood cells to damaged tissue. Such diseases include, but are not limited to, asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, :lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia, and brain cancer. Administration is preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or oral delivery.

35 intravascular, subcutaneous, intranasal, transdermal or oral delivery.

[L\DayLib\LIBH]02470.doc: UG 17a Also disclosed herein is a process of selectively inhibiting the binding of a4P 1 integrin to a protein comprising exposing the integrin to the protein in the presence of an effective inhibiting amount of a compound of the present invention. In a preferred embodiment, the a43 1 integrin is expressed on the surface of a cell, either naturally occurring or a cell transformed to express a401 integrin.

The protein to which the a4 3 integrin binds can be expressed either on a cell surface or be part of the extracellular matrix. Especially preferred proteins are fibronectin or invasin.

The ability of compounds of the present invention to inhibit binding is described in detail hereinafter in the Examples. These Examples are presented to describe preferred embodiments and utilities of the invention and are not meant to limit the invention unless otherwise stated in the claims appended hereto.

[I:\DayLib\LIBH]02470.doc: UG Example 1 Synthesis of (9S,13S)-13-(1,3-benzodioxol-5-yl)-9-{[benzyl(2-thienylmethyl) amino]carbonyl}-3,11-dioxo-1phenyl-2-oxa-4,10,12-triazapentadecan-15-oic acid Step One: Thiophene 2-methylamine (1.36mL, 13.26mmol) was dissolved in methanol To this solution was added benzaldehyde (1.34mL, 13.26mmol), sodium cyanoborohydride (832mg, 13.26mmol) and 2 drops of acetic acid. The reaction was stirred at room temperature for 24h. The mixture was concentrated under reduced pressure and then taken up in ethyl acetate (500mL). The organic layer was washed with water (200mL), saturated NaHCO3 (200mL) and brine (200mL). The organic solution was dried over MgSO4 and then concentrated under reduced pressure. The residue was flushed through silica gel with ethyl acetate:hexane which yielded 1 (1.305g, 48%).

Step Two: Compound 1 (50mg, 0.246mmol) and N -t-BOC-N -Cbz-L-lysine (94mg, 0.246mmol) were dissolved in DMF (3mL), 1,3-dicyclohexylcarbodiimide (61mg, 0.295mmol) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (100mL), and the solution washed with water (2 x 100mL), dried over MgSO4, and concentrated under reduced pressure. The residue was flushed through silica gel with ethyl acetate:hexane which yielded 2 (127mg, 91%).

Step Three: Compound 2 (120mg, 0.212mmol) was dissolved 2N HCI in dioxane (4mL) and stirred at room temperature for 3h. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150mL) and washed with saturated NaHCO3 (150mL). The organic layer was dried over MgSO4, and concentrated under reduced pressure to yield 3 92%).

Step Four: Compound 3 (85mg, 0.18mmol) and 4 (71mg, 0.18mmol) were dissolved in a mixture of THF (2mL) and CH 2

CI

2 (2mL). Triethylamine (0.03ml, 0.18mmol) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with ethyl acetate 25 (100mL), the solution was washed with 0.5N aqueous NaOH (5 x 25mL) and dried over MgSO4.

Concentration under reduced pressure gave 5 (119mg, 92%).

Step Five: Compound 5 (110mg, 0.154mmol) was dissolved in a mixture of methanol (2mL), water (2mL), and THF (1mL). Lithium hydroxide (13mg, 0.31mmol) was added and the reaction mixture was heated at 50 C overnight. After cooling, the reaction mixture was diluted with ethyl acetate (100mL), washed with 0.5N aqueous HCI (50mL), dried over MgSO4, and concentrated under reduced pressure. Purification by reversed-phase HPLC (C18, water:acetonitrile plus 0.1% TFA, gradient 20-60% acetonitrile over 30 minutes, detection at 254nm) yielded 6 (10mg, 1

HNMR

(400 MHz, methanol-d4): 6 7.25-7.35 10 6.7-7.0 6 5.9 2 5.0-5.1 4 4.4- 4.7 4 2.9-3.0 2 2.6-2.8 2 1.1-1.6 6 H).

35 Example 2 Synthesis of 3-({[((1S)-1-{[benzyl(2-thienylmethyl)amino]carbonyl}pentyl)amino]carbonyl}amino)-3-(4butoxyphenyl) propanoic acid (12).

Step One: (1S, 2R, 5S)-(+)-Menthyl (R)-p-toluenesulfinate (0.59g, 2.0mmol) was dissolved in THF (5mL) and chilled to -78°C under nitrogen. The mixture was treated with lithium N, Nbis(trimethylsilyl)amide (3.0mL, 1.0M in THF) via dropwise addition. Upon completion, the cold bath was removed and the mixture was stirred at room temperature for 5h. The solution was chilled to 0 C and thiophene-2-carboxaldehyde (0.37mL, 4.0mmol) was added, via syringe followed immediately LibC/526783speci 19 with powdered cesium fluoride (0.61g, 4.0mmol). The resulting suspension was stirred at room temperature for 18h. The reaction was quenched with saturated, aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine and dried over Na2SO4. The organic solution was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 14:1 hexanes:ethyl acetate) to give compound 7 (0.30g, 67%).

Step Two: Sodium N, N-bis(trimethylsilyl)amide (1.4mL, 1.0M in THF) was chilled to -78 0 C and treated dropwise with ethyl acetate (0.14mL, 1.4mmol). After 15 minutes, diethyl ether (4.2mL) was added slowly down the side of the flask followed by a solution of compound 7 in diethyl ether (3.6mL).

The mixture was maintained at -780C for 5h, then quenched with saturated, aqueous ammonium chloride and warmed to room temperature. The mixture was extracted with ethyl acetate (three times). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient elution 6:1 to 3:1 to 2:1 hexanes:ethyl acetate) to give compound 8 (0.259g, 80% yield at 78% conversion).

Step Three: Compound 8 (0.259g, 0.827mmol) dissolved in dry methanol (3.3mL) was chilled to 0°C and trifluoroacetic acid (0.127mL, 1.65mmol) was added dropwise. The mixture was stirred for at 0°C, then concentrated under reduced pressure. The residue was partitioned between diethyl ether and 2N HCI. The aqueous layer was poured into dichloromethane and saturated aqueous sodium bicarbonate and washed with dichloromethane The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Compound 9 (0.119g, 72%) was recovered as a clear oil and was used without further purification.

Step Four: Compound 9 (0.119g, 0.598mmol) dissolved in dichloromethane was treated with 1,1'-carbonyldiimidazole (0.097g, 0.60mmol). After stirring 30 minutes at room temperature, compound 10 (0.19g- 0.60mmol) was added and the solution was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with 2N H HCI, water, saturated sodium bicarbonate solution, and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient elution 3:1 to 2:1 hexanes:ethyl acetate) to give compound 11 (0.26g, 79%).

30 Step Five: Compound 11 (0.26g, 0.48mmol) was dissolved in 3:1 THF:water (1.9mL) and methanol (0.5mL). Lithium hydroxide monohydrate (0.030g, 0.72mmol) was added as a solid at room temperature. After 4h, the mixture was diluted with water and extracted with diethyl ether. The ether layer was discarded, and the aqueous layer was acidified with excess 2N HCI. The acidic aqueous layer was extracted with ethyl acetate (2x) and combined. The organic layer was washed with water 35 and brine and dried over Na2SO4. The organic solution was filtered and concentrated under reduced pressure to give compound 12 (0.23g, 1 HNMR (400 MHz, DMSO-d 6 6 12.25 (br. S, 1H), 7.47 (dd, J 1.1, 5.1 Hz, 1H), 7.42 (dd, J 1.1, 5.1 Hz, 1H), 7.35 (dd, J 1.4, 5.1 Hz, 1H), 7.07 J 3.3 Hz, 1H), 7.00 2H), 6.93 (m 3H), 6.65 J= 8.8 Hz, 1H), 6.43 J 8.8 Hz, 1H), 5.29 (dd, J 7.1, 15.4 Hz, 1H), 4.92 J 16.5 Hz, 1H), 6.68 3H), 4.56 J 15.0 Hz, 1H), 2.75 J 7.0 Hz, 2H), 1.46 2H), 1.18 4H), 0.78 J 7.0 Hz, 3H).

LibC/526783speci Example 3 Synthesis of (3S)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]-carbonyl}amino)-3-(2methyl-1,3-thiazol-4-yl)propanoic acid, sodium salt (19).

Step One: To a solution of N-t-Boc-aspartic acid -methyl ester (6.0g, 24.2mmol) in dry THF (30mL) was added triethylamine (5.2mL, 36.4mmol). The reaction mixture was cooled to 0°C, treated with isobutylchloroformate (3.6g, 26.2mmol), and then stirred at 0°C for 1h. The ice-cold solution was filtered and then treated with a solution of diazomethane (100mmol) in ether (75mL). After stirring at low temperature for 1h, nitrogen gas was bubbled into the reaction to remove the excess diazomethane. Concentration gave 13 which was used without further purification.

Step Two: Diazoketone 13 (4g, 14.7mmol) was dissolved in ether (20mL). The reaction mixture was cooled to -300C, and then treated with 48% HBr in H20 (5mL). When a persistent yellow color formed the mixture was diluted with EtOAc and washed with water. The organic solution was dried over MgSO4 and concentrated. Purification by chromatography (silica gel, 3:1 hexanes:EtOAc) gave 14 (3.5g, 74%).

Step Three: To a solution of 14 (1g, 3.0mmol) in dry THF (7mL) was added triethylamine (0.45g, 4.5mmol) and thioacetamide (0.23g, 3.3mmol). The reaction mixture was stirred at 50°C for minutes and then concentrated under reduced pressure. Purification of the crude product by chromatography (silica, 35% EtOAc in hexanes) gave 15 (0.92g, Step Four: Compound 15 (800mg, 2.5mmol) was dissolved in dioxane (3mL) and 4.0M HCI in dioxane (3mL) was added. The reaction mixture was stirred at room temperature for 1h, and then concentrated under reduced pressure. This gave 16 (580mg, which was used without further purification.

Step Five: Compound 16 (300mg, 1.40mmol) was suspended in dry THF (5mL) and then diisopropylethylamine (0.40mL, 2.8mmol) was added. The reaction mixture was treated with carbamate 17 (700mg, 1.6mmol), and the reaction was stirred at room temperature for 3h. The reaction mixture was diluted with ethyl acetate, extracted with 5% solution of NaOH, and then the organic layer was dried over MgSO4. Concentration and purification by chromatography (silica gel, 1:1 Hexane:EtOAc) gave 18 (175mg, Step Six: Compound 18 (100mg, 0.18mmol) was dissolved in THF (2mL), and then a solution of 30 NaOH 7.0mg, 0.18mmol) in water (1mL) was added. The reaction mixture was stirred at 45°C for 2h. The crude reaction was lyophilized to give 19 as a yellow solid. 'HNMR (400 MHz, MeOH-d 4 6 0.85 3H), 1.42 4H), 1.48 2H), 2.65 3H), 2.80 1H), 3.05 1H), 3.65 3H), 4.95 *in 1H), 5.30 1H), 5.63(m, 1H), 5.85 1H), 6.90 1H), 7.25 4H), 7.30 2H).

Example 4 35 Synthesis of -[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino]-5-oxo-3-phenylpentanoic acid To a solution of 10 (0.30g, 1.0mmol) and 3-phenylglutamic acid (214mg, 1.1mmol) in dry DMF (8mL), DCC (225mg, 1.2mmol) was added and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was partitioned between EtOAc and 5% HCI. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification by chromatography (silica gel, 2% MeOH in EtOAc) gave 20 (80mg, 1 HNMR (400 MHz, MeOH-d4): 6 0.89 3 0.95 LibC/526783speci 21 4 1.30 2 2.85 1 2.95 2 3.83 1 4.6-4.8 4 5.00 1 H), 6.95 4 7.22 5 H).

Example Synthesis of (3R)-3-(1,3-benzodioxol-5-yl)-3-({[((1S)-1-{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino] carbonyl}amino)-2,2-dimethylpropanoic acid Step One: To a solution of isobutyryl chloride (47g, 0.44mol) in CH 2

CI

2 (75mL) and tert-butanol at 0°C, pyridine (39.3mL, 486mmol) was added slowly by syringe. The mixture was allowed to warm to room temperature, stirred overnight, diluted with CH 2

CI

2 (400mL) and washed with H 2 0, HCI (2N, two times), H 2 0 (two times) and saturated NaHCO 3 The organic phase was dried over MgSO4 and filtered. The filtrate was then concentrated under reduced pressure without heat. The resulting oil was simply distilled, collecting the fraction boiling at 128-129°C to give tert-butyl isobutyrate, 21 (35.9g, 56%).

Step Two: To a solution of piperonal (751mg, 5.0mmol) in THF (5.0mL) cooled to 0°C under a dry nitrogen atmosphere, lithium bistrimethylsilylamide (5.0mL of a 1.OM solution in THF, was added by syringe. The resulting mixture was stirred at 0°C for 15 minutes and then was allowed to warm to room temperature. This solution of the TMS-aldimine was used directly as described below.

Step Three: To a solution of diisopropylamine (0.84mL, 6.0mmol) in THF (10mL) cooled to -78"C under a dry nitrogen atmosphere, butyllithium (3.75mL of a 1.6M solution in hexanes, was added by syringe. The mixture was stirred at -78°C for 15 minutes, then a solution of 21 (721mg, in THF (10mL) was added by cannula dropwise along the side of the flask over the course of 20 minutes along with a THF (1mL) rinse. The mixture was stirred at -780C for 15 minutes, then the TMS-aldimine solution prepared in step two was added dropwise by cannula along the side of the flask over the course of 15 minutes along with a THF (ImL) rinse. The resulting mixture was allowed to gradually warm to room temperature over the course of 24h, then was quenched with HCI 2N) followed immediately by the addition of ethyl acetate. The mixture was washed with H 2 0 (two times), saturated NaHCO3 and brine and the organic phase was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography, eluting with 3:2 hexanes:ethyl acetate increasing to 1:1 hexanes:ethyl acetate and 30 finally 1:3 hexanes:ethyl acetate to yield -lactam 22 (226mg, 21%) as a white solid.

Step Four: To a solution of amine 10 (770mg, 2.39mmol) in CH2C12 (12mL) cooled to 0°C under a dry nitrogen atmosphere, triethylamine (0.50mL, 3.6mmol) and phenyl chloroformate (0.37mL, 3.0mmol) were added by syringe. The resulting mixture was stirred at 0°C for 1h, then was diluted with 7:3 hexanes:ethyl acetate and washed with H 2 0 (twice) and brine. The organic phase was dried 35 over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate to yield carbamate 23 (907mg, 86%) as a colorless oil.

u*n.d. Step Five: To a solution of p-lactam 22 (117mg, 0.53mmol) in THF (5.3mL) cooled to under a dry nitrogen atmosphere, butyllithium (0.33mL of a 1.6M solution in hexanes, 0.53mmol) was added by syringe. The resulting mixture was stirred for 15 minutes at -45 0 C then was added rapidly to a solution of carbamate 23 (293mg, 0.66mmol) in THF (1.3mL) cooled to -45oC under a dry nitrogen atmosphere by cannula along with a THF (1mL) rinse. The resulting mixture was allowed to LibC/526783speci 22 warm to 0°C over the course of 1h, then was quenched with a solution of glacial acetic acid (0.5mL) in

H

2 0 (5mL) and immediately diluted with a 1:1 mixture of hexanes:ethyl acetate and H 2 0. The organic phase was washed with H 2 0 (twice), saturated NaHCO3, H 2 0 and brine. The organic phase was dried over MgSO4 and filtered. Then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate increasing to 3:1 hexanes:ethyl acetate and finally 13:7 hexanes:ethyl acetate to yield -lactam 24 (most polar diastereomer, 106mg, 35%) as a colorless oil.

Step Six: To a solution of -lactam 24 (73mg, 0.13mmol) in THF (1.5mL) at room temperature, a solution of lithium hydroxide (27mg, 0.65mmol) in H 2 0 (0.75mL) was added. The mixture was stirred at room temperature for 24h, then was acidified with HCI and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 25 (78mg, 100%) as a light yellow powder. 1 HNMR (400 MHz,

CD

3

SOCD

3 :5 0.73 J 6.8 Hz, 3H), 1.01 3H), 1.02 3H), 1.05-1.53 6H), 4.63 4H), 4.86 J 10.2 Hz, 1H), 4.94 J 16.9 Hz, 1H), 5.96 1H), 5.97 1H), 6.52 J 8.1 Hz, 1H), 6.66 (dd, J 8.1, 1.5 Hz, 1H), 6.71 J 8.0 Hz, 1H), 6.73 J 1.5 Hz, 1H), 6.81 J 8.0 Hz, 1H), 6.95 (dd, J 5.1, 3.3 Hz, 1H), 7.01 2H), 7.05 J 2.9 Hz, 1H), 7.43 1H), 7.47 1H).

Example 6 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-[{[((1 S)1 -{[bis(2-thienylmethyl)amino]carbonyl}pentyl)amino] carbonyl}(methyl)amino] propanoic acid Step One: To a solution of 26 (513mg, 1.93mmol) in CH 2 CI2 (4mL) at room temperature under a dry nitrogen atmosphere, triethylamine (0.32mL, 2.3mmol) and di-tert-butyl dicarbonate (443mg, 2.03mmol) were added. The resulting mixture was stirred at room temperature overnight, then was diluted with a 7:3 mixture of hexanes:ethyl acetate and washed with HCI H 2 0, saturated NaHCO 3 and brine. The organic phase was dried over MgSO4 and filtered. Next, the filtrate was concentrated under reduced pressure to give the N-tert-butoxycarbonyl-p-aminoester 27 (743mg) as a pale yellow oil. This material contained 4-5% of di-tert-butyl dicarbonate but was used without purification.

Step Two: To a solution of 27 (370mg, 1.01mmol) in THF (10mL) at room temperature under a dry nitrogen atmosphere, potassium bis(trimethylsilyl)amide (4.04mL of a 0.50M solution in toluene, 30 2.02mmol) was added by syringe. The resulting mixture was stirred at room temperature for minutes, then iodomethane (0.25mL, 4.04mmol) was added rapidly by syringe. The mixture was stirred at room temperature for 30 minutes, quenched with HCI (2N) and immediately diluted with 3:2 hexanes:ethyl acetate. The organic phase was washed with H20, saturated NaHCO3 and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was 35 purified by silica gel chromatography, eluting with 17:3 hexanes:ethyl acetate to yield N-methyl-N-tertbutoxycarbonyl- -aminoester 28 (238mg, 62%, [87% based on consumed 27]) as a colorless oil along with N-tert-butoxycarbonyl- -aminoester 27 (106mg, 29%).

Step Three: To a flask containing 28 (405mg, 1.07mmol) sealed with a rubber septum at room temperature under a dry nitrogen atmosphere, HCI (5.3mL, 4.0M in dioxane, 21mmol) was added by syringe. The nitrogen needle was removed and the mixture in the sealed flask was stirred overnight.

The resulting suspension was diluted with diethyl ether, the excess HCI was removed under a stream LibC/526783speci of nitrogen. The mixture was then concentrated under reduced pressure and the residue was taken up in H 2 0 (40mL) and lyophilized to give 29 (251mg, 95%) as a tan solid.

Step Four: To a solution of 10 (110mg, 0.34mmol) in 1,2-dichloroethane (1mL) at room temperature under a dry nitrogen atmosphere, N, N-diisopropylethylamine (0.13mL, 0.75mmol) and phosgene (0.18mL of a 1.9M solution in toluene, 0.34mmol) were added by syringe. The mixture was stirred for 30 minutes, then added to a solution of 29 (88mg, 0.34mmol) in 1,2-dichloroethane (1mL) and N,N-diisopropylethylamine (0.066mL, 0.38mmol) by cannula. The resulting mixture was heated to overnight, then was cooled to room temperature, diluted with ethyl acetate and washed with HCI (2N, twice) and brine. The organic phase was dried over MgSO4 and filtered. Next, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 19:1 chloroform:methanol increasing to 9:1 chloroform:methanol to yield 30 (129mg, 66%).

1 HNMR (400 MHz, CD 3

SOCD

3 :5 0.80 3H), 1.20 4H), 1.59 2H), 2.60 (dd, J 15.4, 7.3 Hz, 1H), 2.82 1H), 4.57-4.75 4H), 5.61 J 7.3 Hz, 1H), 5.98 1H), 5.99 1H), 6.72 (dd, J 8.1, 1.5 Hz, 1H), 6.80 J 1.5 Hz, 1H), 6.83 J 8.1 Hz, 1H), 6.95 (dd, J 5.1, 3.3 Hz, 1H), 7.02 2H), 7.10 J 3.3 Hz, 1H), 7.42 1H), 7.48 1H).

Example 7 Compound 36, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1S)-1-[methyl(2-thienylmethyl)amino]carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, was synthesized as follows.

0 OH 0 HH i> 036 The structures of the compounds identified by number in this Example are found in Scheme 1 above.

Step 1: Methyl(2-thienylmethyl)amine (1.27g, 10mmol) and t-BOC-L-norleucine (2.31g, 10mmol) were dissolved in DMF (10mL). EDC (2.35g, 12mmol) and HOBT (1.62g, 12mmol) was 25 added and the reaction sealed and allowed to stand at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100mL), washed (2X 100mL) with water, dried over MgSO4, and concentrated under reduced pressure. The residual materials were further purified by silica gel chromatography using ethyl acetate:hexane to yielded 3.09g of Compound 32.

Step 2: Compound 32 (1.7g, 5.0mmol) was dissolved in 2N HCI in dioxane (10mL) and then the reaction mixture was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure and the residual materials dissolved in ethyl acetate (150mL). This solution was washed with saturated NaHCO3 (50mL), dried over MgSO4 and concentrated under reduced •pressure to yielded 1.30g of Compound 33.

Step 3: Compound 33 (0.52g, 2mmol) and Compound 34 (0.8g, 2mmol) were combined with S 35 THF (4mL) and CH 2

CI

2 (4mL). Triethylamine (2mmol) was added and the reaction was then sealed and allowed to stand at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100mL) and washed (5X 20mL) with 0.5N NaOH. The organic solution was dried over MgSO4 and concentrated under reduced pressure to yield 0.65g of Compound LibC/526783speci Step 4: Compound 35 (0.2mmol) was combined with methanol (2mL), water (2mL), THF (2mL) and lithium hydroxide (0.4mmol) and this mixture was heated to 50 oC overnight. Upon cooling, the reaction mixture was combined with ethyl acetate (100mL) and 0.5N HCI (50mL). The organic layer was separated, dried over MgSO4, and then condensed under reduced pressure to yield Compound 36. 1 HNMR (d 4 -MeOH) 6 0.85 3H), 1.30 4H), 1.65 1.75 2.55 3.05 4.15 (dd,lh J 10 Hz), 4.90 (dd,1H J 10 Hz), 5.0 5.85 6.80 6.90 7.15 7.20 and 7.45 mp 71-730C.

Example 8 Compound 37, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(3-thienylmethyl)amino]carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(3-thienylmethyl)amine for methyl,(2-thienyl methyl)amine in Step 1.

s 0 OH SCJ- _N

NA-.

0 o 37 Example 9 Compound 38, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1 S)-1-[methyl(2-furylmethyl)amino]carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(2-furylmethyl)amine for methyl,(2-thienylmethyl)amine in Step 1.

0 OH 0 N N N.

oH H o 38 20 Example Compound 39, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(3-methoxybenzyl)amino] carbonylpentyl)amino]carbonylamino)propanoic acid, of the structure shown below, was synthesized .by the procedure of Example 7 by substituting methyl,(3-methoxybenzyl)amine for methyl,(2thienylmethyl)amine in Step 1. 1 HNMR, CDCI 3 6: 0.85 3H), 1.2 2H), 1.4 2H), 1.55 2H), 2.80 2H), 3.05 3H), 3.75 3H), 4.35 1H, J 12Hz), 4.85 1H, J =12 Hz), 4.85 1H), 5.20 1H), 5.80 2H), 6.75-6.90 5H), 7.2 1H), and 7.35 1H).

SOH

'O N N N O O 0H H o 39 Example 11 Compound 40, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(3-cyanobenzyl)amino]carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(3-cyanobenzyl)amine for methyl,(2thienylmethyl)amine in Step 1.

LibC/526783speci v d4 0 Example 12 Compound 41, ,3-benzodioxol-5-y)-3-([((l1S)-1 -[methyl(1 ,3-thiazol-2-ylmethyl)amino] carbonylpentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(1 ,3-thiazol-2-ylmethyl)amine for methyl,(2-thienylmethyl)amine in Step 1.

17-N 0 OH H H

>O

Example 13 Compound 42, ,3-benzodioxol-5-y)-3-([((1 S)-1 -[methyl(benzyl)amino]carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting methyl,benzylamine for methyl,(2-thienylmethyl)amine in Step 1; mp 60-64'C.

$0 OH qI ~-42 Example 14 Compound 43, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(4-cyanobenzyl)amino]carbony pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the :procedure of Example 7 by substituting methyl,(4-cyanobenzyl)amine for methyl,(2thienylmethyl)amine in Step 1.

*NC

0 OH N0 N N 0 'H H 0 43 20 Example Compound 44, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(1 ,3-oxazol-2-ylmethyl)amino] carbonylpentyi)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(1,3-oxazol-2-ylmethyl)amine for methyl,(2-thienylmethyl)amine in Step 1.

0 N 1 0 OH '0 k N N k N N 0 O 44 LibC/526783speci Example 16 Compound 45, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(2-methoxybenzyl)amino] carbonylpentyl)amino]carbonylamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting methyl,(2-methoxybenzyl)amine for methyl,(2thienylmethyl)amine in Step 1; mp 81-830C.

0 OH o H H 0 0 Example 17 Compound 46, ,3-benzodioxol-5-y)-3-([((1 S)-1 -[methyl(l1-naphthyl)amino] carbon yl pen tyl) am ino]carbonylami no) pro panoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting methyl,(1-naphthylmethyl)amine for methyl,(2thienylmethyl)amine in Step 1; mp 117-120'C.

I I 0 OH 0 q 4> Example 18 Compound 47, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(2-chlorobenzyl)aminolcarbony pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(2-chlorobenzyl)amine may be methyl,(2thienylmethyl)amine in Step 1.

0 OH N N' fl, N~N.k 0 ci o H H 047 20 Example 19 Compound 48, ,3-benzodioxol-5-y)-3-([((1 S)-1 -[methyl(4-dimethylaminobenzyl)amino carbon yl pentyl)am ino]carbonylam in o)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(4-dimethylaminobenzyl)amine for ~;*methyl,(2-thienylmethyl)amine in Step 1.

0 OH N. N 0~ ~~11fl 0 048 S* 25 Example Compound 49, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl,[4-(N-(cyclopropylmethyl) amino) benzyl] ami no]carbon yl pentyl)ami no]carbon yl amino) propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting methyl,((4cyclopropylmethylbenzyl) amino)amine for methyl,(2-thienylmethyl)amine in Step 1, mp 180-1 83'C.

LibC/526783speci W O 49 Example 21 Compound 50, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(cyanomethyl)aminolcarbony pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting methyl,(cyanomethyl)amine for methyl,(2-thienylmethyl)amine in Step 1; mp 79-81 OC.

I 0 OH or HH 0 ~O Example 22 Compound 51, (3S)-3-(4-methylphenyl)-3-([((l1 -[methyl(2-chlorobenzyl)amino] carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(2-chlorobenzyl)amine for methyl,(2thienylmethyl)amine in Step 1 and by substituting Compound 52 for Compound 4 in Step 3.

O02N 0 OH O 2 0 OBt N N~Kt N kN0) Hi H f I H f~ ci 0 51 Example 23 Compound 53, 3-(3S)-3-(3-trifluoromethylphenyl)-3-([((1 S)-1 -[methyl(2-methylbenzyl)amino] carbonylpentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(2-methylbenzyl)amine for methyl,(2-thienylmethyl)amine in Step 1 and by substituting Compound A for Compound 4 in Step 3.

(:000 0 lov 0 OH 0N0 OEt N N -0 10 N N H H IH .00CF 3 53 CF 3

A

Example 24 Compound 54, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(cyanoethyl)amino]carbony pentyl) am ino]ca rbonyl amino) pro panoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(2-cyanoethyl)amine for methyl,(2-thienylmethyl)amine in Step 1.

0 OH NC--_N lk N

NO

0 54 LibC/526783speci Example Compound 55, 3-(2,3-dihydro-1 -benzofuran-5-yl)-3-([((1 S)-1 -[methyl(2-thienylmethyl)amino] carbonylpentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting Compound 56 for Compound 4 in Step 3.

S0 2

N

OH 0 OEt S- N N N N' ON o 0 55 H 56 Example 26 Compound 57, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1 S)-1 -[methyl(4-fluorobenzyl)amino]carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, may be synthesized by the procedure of Example 7 by substituting methyl,(4-fluorobenzyl)amine for methyl,(2thienylmethyl)amine in Step 1.

F o i0 F N N OH NN 'NoN 0 o 57 Example 27 Compound 58, (3S)-3-(4-trifluoromethylphenyl)-3-([((1 S)-1 -[methyl,benzylamino]carbonylpentyl) amino]carbonylamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting methyl,benzylamine for methyl,(2-thienylmethyl)amine in Step 1 and by substituting Compound 59 for Compound 4 in Step 3; mp 85-90 0

C.

0 0 0 OH 0 2 N 0 OEt <N I N N ON S H H CF3 58 H CF 3 59 Example 28 .Compound 60, (3S)-3-(4-methylphenyl)-3-([((1 S)-1 -[methyl,benzylamino]carbonylpentyl)amino] carbonylamino) propanoic acid, of the structure shown below, was synthesized by the procedure of Example 1 by substituting methyl,benzylamine for methyl,(2-thienylmethyl)amine in Step 1 and by substituting Compound 61 for Compound 4 in Step 3; mp 118-122 0

C.

$0 0 0 OH 0 2 N OEt 'N <)ON N o 60 61 Example 29 Compound 62, (3S)-3-(4-methylphenyl)-3-({[((1 S)-1 -{[bis(2-thienylmethyl)amino] carbonyl}pentyl)amino] carbonyl}amino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting compound 52 for compound 4 in Step 3; mp 60-65'C.

LibC/526783speci Example Compound 63, (3S)-3-(3-trifluoromethylphenyl)-3-([((1 S)-1 -{[bis(2-thienylmethyl)aminoj carbon yllpentyl) amino]carbonyl~am ino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting compound A for compound 4 in Step 3; mp 50-54 0

C.

Example 31 Compound 64, (3S)-3-(3,5-dimethoxyphenyl)-3-([((1 S)-i -{[bis(2-thienylmethyl)amino] carbonyl} pen tyl)am ino]carbon yl~am ino) propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 59-63'C.

Example 32 Compound 65, (3S)-3-(2,3-dihydro-1 -benzofuran-5-yl)-3-([((1 5)-i -{[bis(2-thienylmethyl)amino] carbonyllpentyl)amino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting compound 56 for compound 4 in Step 3.

ni 0 <T T

OH

0 H H 0 06 Example 33 Compound 66, (3S)-3-phenyl-3-([((1 S)-i1 is(2-th ie nyl meth yl) am ino] carbon yllpe ntyl)a min o] carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 50-56*C.

0 S 0. OH S N N N )H H I~6 LibC/526783speci Example 34 Compound 67, (3S)-3-(4-fl uo rophe nyl)-3-( 1 -{[bis(2-th ien yl meth yl) am ino] carbon yilpe ntyl) amino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 65-680C.

s 0 OH 0 H F 67 Example Compound 68, (3S)-3-(4-methoxyphenyl)-3-([((1 S)-1 -{[bis(2-thienylmethyl)amino] carbonyll pentyl)amino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 58-6 1 0

C.

$0 0 OH 0 0" 68 Example 36 Compound 69, (3S)-3-(4-chlorophenyl)-3-([((1 S)-1 -{[bis(2-thienylmethyl)amino] carbonyl) pentyl)amino]carbonyl~amino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 58-61'C.

NI 0 0 0l: cl 069 Example 37 Compound 70, (3S)-3-(2,4-dichlorophenyl)-3-([((1 S)-1 -{[bis(2-thienylmethyl)amino] carbonyl} pentyl)amino]carbonyl~amino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 58-61 *C 200 OH 07 Example 38 Compound 71, (3S)-3-(3,4-dichlorophenyl)-3-([((l1S)-1 -{[bis(2-thienylmethyl)amino] carbonyl} pentyl)amino]carbonyl~amino)propanoic acid, of the structure shown below, was synthesized by the .9...:procedure of Example 7; mp 53-560 C.

LibC/526783speci Ci 71 Example 39 Compound 72, (3S)-3-(3,4,5-trimethoxyphenyl)-3-([((1 S)-1 -{[bis(2-thienylmethyl)amino] carbon yl~pentyl)am ino]carbonyl~amino) propan oic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 54-60*C.

$0 N I N= 0

OH

0 H H q O11 72 Example Compound 73, (3S)-3-(3-ch lorophenyl)-3-( 1 -{[bis(2-th ienylmethyl) amino] carbonyl} pentyl)amino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 59-63*C.

0$ 0

OH

s N N ai 73 Example 41 Compound 74, ,3-benzodioxol-5-yl)-3-({[((l1S)-1 carbonyllpentyl)aminolcarbonyl~amino)propanoic acid, of the structure shown below, was synthesized 15 by the procedure of Example 7; 'HNMR (MeOH-d4) 6: 0.8-0.9 (in, 3H), 1.2-1.35 (in, 5H), 1.5-1.65 (mn, 1 2.15-2.25 6H), 4.6-4.8 (mn, 2H), 4.3-4.4 1 4.5 2H), 4.75-4.85 1 5.15 (mn, 1 H), 5.89 2H), 5.9-5.95 (in, 2H), 6.08-6.15 (in, 2H), and 6.7-6.85 (mn, 3H).

0- 0 OH N 9 0 <N N 0

H

0O 74 Example 42 Compound 75, 1,3-benzodioxol-5-yl)-3-([(-1 -{[bis(2-thienylmethyl)ainino] carbonyl} cyclopropyl)amino]carbonyl~amino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; inp 180-183*C.

S~l 0 O75 LibC/526783speci Example 43 Compound 76, ,3-benzodioxol-5-y)-3-({[((1 S)-1 -{[butyl(2-thienylmethyl)amino] carbon yl~pentyl) am ino]carbonyllam ino) propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7 by substituting methyl,(4-fluorobenzyl)amine for methyl,(2thienylmethyl)amine in Step 1.

0 O7 Example 44 Compound 77, 1,3-benzodioxol-5-yl)-3-([((1 S)-1 -{[4-(3-cyanobenzyl) piperazino] carbon yllpentyl) am ino]carbon yl~am ino) pro panoic acid, of the structure shown below, was synthesized by the procedure of Example 7.

S $0 OH N it N 0 cN 0 H I O7 Example Compound 78, ,3-benzodioxol-5-yl)-3-([((1 S)-i -{[4-(4-benzyloxy-3-methoxybenzyl) piperazino]carbonyllpentyl)amino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7.

01~ N 0 0

OH

O~c 011 0 H I -78 Example 46 Compound 79, ,3-benzodioxol-5-yl)-3-({[((1 S)-1 -{[4-phenyl-4-cyano piperidino] carbon yllpen tyl) am ino]carbonyllam ino) propa noic acid, of the structure shown below, was synthesized by the procedure of Example 7.

*0 OH9 Nc N O *0 qO 79 *woo Example 47 Compound 80, ,3-benzodioxol-5-yl)-3-({[(( 1 S)-i1 -{[4-phenyl-4-hyd roxypi pe rid ino] carbonyllpentyl)amino]carbonyl~amino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7.

9 9 HO) 0 OH N I 11 0 >~o8 LibC/526783speci Example 48 Compound 81, ,3-benzodioxol-5-y)-3-([((1 S)-1 -{[4-phenyl-4-acetyl piperidino] carbon yllpentyl) ami no]carbonyllam in o)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7.

oK 0 0 OH 0 ,08 1 Example 49 Compound 82, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -{[4-(2-methoxyphenyl)piperidino] carbon yllpentyl)amino]carbonyllam ino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 87-95 0

C.

0 OH 0 82 Example Compound 83, ,3-benzodioxol-5-yl)-3-([(( 1 S)-1 -f{[bis(2-thienylmethyl)amino] carbonyl}- 3-bu ten yl)am ino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7; mp 64-67 0

C.

0 .0 OH N N

O

HH I 083 Example 51 Compound 84, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -f{[bis(2-th ie nyl methyl) amino] carbonyl}- 3-pyridinylmethyl)amino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7.

N0 0 OH S~ 0 0 O 84 ***~.Example 52 Compound 85, ,3-benzod ioxol-5-yl)-3-( 1 -f{[bis(2-eth oxyeth yl) am ino] carbon y}2thienylmethyl)amino]carbonyllamino)propanoic acid, of the structure shown below, was synthesized by the procedure of Example 7.

x 0 0 OH 0 HH I 0u LibC/526783speci 34 Example 53 Compound 86, ,3-benzodioxol-5-yl)-3-({[((l1S)-1 -{[bis(2-thienylmethyl)amino] carbonyl} pentyl)amino]carbonyl~amino)propanoic acid 1-{[(ethyloxy)carbonyl]oxy~ethyl ester, of the structure shown below, was synthesized by the procedure of Example 7.

N o 0I 86 Example 54 Compound 87, ,3-benzodioxol-5-yl)-3-({[((l1S)-1 -{[bis(2-thienylmethyl)amino] carbonyl} pentyl)amino]carbonyllamino)propanoic acid 1-{[(cyclohexyloxy)carbonyl]oxylethy ester, of the structure shown below, was synthesized by the procedure of Example 7.

N 0

N

0 0~ 87 Example Compound 88, (4S,8S, 12S)-8-(1 ,3-benzodioxol-5-yl)-4-butyl-1 2-(1 -methylethyl)-3,6, 1 -trioxo-1 (2-thienyl)-2-(2-thienylmethyl)-2,5,7,1 1 -tetraazatridecan-1 3-oic acid ethyl ester of the structure shown below, was synthesized by the procedure of Example 7.

0 ,sj0 N CO 2 Et

H

Ir N 0 00 88 Example 56 Compound 89, (4S,8S, 12S)-8-(1 ,3-benzodioxol-5-yl)-4-butyl-1 2-(1 -methylethyl)-3,6, 1 -trioxo-1 (2-thienyl)-2-(2-thienylmethyl)-2,5,7, 11 -tetraazatridecan- 13-oic acid, of the structure shown below, was synthesized by the procedure of Example 7.

N C0 2

H

HHH

0~ 89 Example 57 Compound 90, (6S, 1 OS)-6-(1 ,3-benzodioxol-5-yl)-1 O-butyl-2,2,4,8-tetraoxo-N ,N-bis(2-thieny methyl)-2lambda-6-thia-3,7,9-triazaundecan-1 1 -amide, of the structure shown below, was synthesized by the procedure of Example 7.

0

SP

S3 0 NS S N N H 0 0 o90 LibC/526783speci Example 58 Compound 91, ,3-benzodioxol-5-yl)-2-(4,5-dihydro-1 ,3-oxazol-2-yl)ethyl]amino carbonyl)amino]-N,N-bis(2-thienylmethyl)hexanamide, of the structure shown below, was synthesized by the procedure of Example 7.

SS0 0 0 0O91 Example 59 Compound 92, ,3-benzodioxol-5-yl)-3-({[((1 S)-1 -{[bis(2-thienylmethyl) amino] carbonyl) pentyl)amino]carbonyllamino)2,2-difluoropropanoic acid, of the structure shown below, was synthesized by the procedure of Example 7.

O 0F- OH 0(r 1~ 0o >92 The procedures described above may also be utilized to synthesize the following compounds: (9S, 13S)-1 3-(1 ,3-benzodioxol-5-yl)-9-{[benzyl(2-thienylmethyl)amino] carbonyl}-3, 11 -dioxo-1 -phenyl- 2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, 1,3-benzodioxol-5-yl)-3-({[(( 1 S)-1 -{[benzyl(2thienylmethyl)amino]carbonyllpentyl)amino] carbonyl~amino) propanoic acid, ,3-benzodioxol- 5-yl)-3-{[(2-[benzyl(2-thienylmethyl)amino]-2-oxoethyllamino)carbonyl]amino~propanoic acid, 3- S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyllpentyl)amino]carbonyllamino)-3-( 1 -naphthyl) propanoic acid, S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyl} pentyl)amino]carbonyllamino)-3carbonyl)pentyl)amino)carbonyl)amino) propanoic acid, 1 -{[benzyl(2-thienylmethyl) amino] carbon yllpentyl) ami no]carbonyllam in o)-3-(4-isobu toxyphe nyl) propan oic acid, -{[benzyl(2thienylrnethyl)amino]carbonyl~pentyl)amino]carbonyl~amino)-3-(2,6-dimethylpheny1) propanoic acid, 3- .*[4-(allyloxy)phenyl]-3-([((1 S)-1 -{[benzyl(2-thienylmethyl)aminolcarbonyllpentyl)amino] carbonyl} ***amino) propanoic acid, 3-[4-(benzyloxy)phenyl]-3-([((1 S)-1 -{[benzyl(2-thienylmethyl)amino] carbonyl~pentyl)amino]carbonyl~amino) propanoic acid, ,3-benzodioxol-5-yl)-3-[({(1 1- 25 ibenzyl amino) carbonyl]pentyllamino) carbon yl]am inolpro panoic acid, thienylmethyl)amino] carbonyl~pentyl)amino]carbonyl~amino)-3-(3-bromo-4-methoxyphenyl) propanoic acid, S)-1 -{[benzyl(2-thienylmethyl)amino] carbonyl} pentyl)amino]carbonyllamino)-3-(2- *naphthyl) propanoic acid, S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyllpentyl)amino] *:.*:carbonyl~amino)-3-(4-butoxyphenyl) propanoic acid, S)-1 -{[bis(2-thienylmethyl)amino] carbonyl~pentyl) amino]carbonyl~amino)-3-(2-thienyl)propanoic acid, S)-1 -{[bis(2-thienylmethyl) amino]carbonyllpentyl)amino] carbonyl} amino)-3-(3-thienyl)propanoic acid, 3-(1 -benzofuran-2-yl)-3- S)-1 -{[bis(2-thienylmethyl)amino] carbon yl~pentyl) am ino]carbo nyllam ino) propan oic acid, (3S)-3- (1 ,3-benzodioxol-5-yl)-3-([((1 S)-1 -{[bis(2-thienylmethyl)aminojcarbonyl~penty)oxy]carbonyl~amino) propanoic acid, ,3-benzodioxol-5-yl)-3-({[((1 S)-1 -{[bis(3-pyridinylmethyl)amino]carbonyl) pentyl)amino]carbonyllamino)propanoic acid, ,3-benzodioxol-5-yl)-3-([(( 1 S)-1 -{[bis(2thienylmethyl)amino]carbonyl}-3-morpholino-3-oxopropyl)amino] carbonyl~amino)propanoic acid, (3S)- LibC/526783speci 36 3-(1 ,3-benzodioxol-5-y)-3-[({(1 S)-1 -benzyl-2-[bis(2-thienylmethyl)amino]-2-oxoethyllamino)carbonyl] amino) propanoic acid, 1,3-benzodioxol-5-yl)-3-{[((1 R)-1 -[(benzylthio)methyl]-2-[bis(2thienylmethyl)amino]-2-oxoethyllamino) carbonyl]aminolpropanoic acid, S)-1 -[(benzyioxy)methyl]-2-[bis(2-thienylmethyl)amino]-2-oxoethyl~amino)carbonyl]amino propanoic acid, 1,3-benzodioxol-5-y)-3-[({(1 R)-2-[bis(2-thienylmethyl)amino-1 [(ethylthio)methyl]-2-oxoethyllamino)carbonyl] amino) propanoic acid, ,3-benzodioxol-5-yI)-3- S)-1 -{[[(3-methyl-1 -benzothiophen-2-yl)methyl](2-thienylmethyl)amino]carbony1} pentyl)amino] carbonyl~amino)propanoic acid, ,3-benzodioxol-5-yl)-3-({[(( 1 S)-1 -{[(3-pyridinylmethyl)(2thienylmethyl)amino]carbonyllpentyl)aminolcarbonyl} amino)propanoic acid, ethyl ,3benzodioxol-5-y)-3-({[((1 S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino]carbonyllamino) propanoate, S)-1 -{[bis(2-thienylmethyl)amino] carbonyl~pentyl) amino] carbonyl) methyl-2-thienyl)propanoic acid, S)-1 -{[bis(2-thienylmethyl)aminojcarbonyl~pentyl) amino] carbon yljam ino)-3-(2-meth yl- 1 3-th iazol-4-yl) propa noic acid, ,3-benzodioxol-5-yl)-3-({[((l1S)- 1 ,3-thiazol-2-ylmethyl)(2-thienylmethyl)amino] carbonyl) pentyi)amino]carbonyl} amino)propanoic acid, ,3-benzodioxol-5-y)-3-[((1 S)-2-[bis(2-thienylmethyl)amino]-1 -methyl-2-oxoethyl} amino)carbonyl]amino} propanoic acid, ,3-benzodioxol-5-y)-3-{[({2-[bis(2-thieny methyl)amino]-2-oxoethyllamino)carbonyl]aminolpropanoic acid, ,3-benzodioxol-5-yI)-3- S)-1 -{[bis(2-thienylmethyl)aminojcarbonyl}-3-methylbutyl)amino carbon yl~a m ino) propanoic acid, ,3-benzodioxo-5-y)-3-([((1 S)-1 -{[bis(2-thienylmethyl)amino]carbonyl}-2-methylpropyl)amino] carbonyllamino) propanoic acid, S)-1 ,3-benzodioxol-5-yI)-2-carboxyethyl]amino} carbonyl)amino]-5-[bis(2-thienylmethyl)amino]-5-oxopentanoic acid, methyl S)-1 -{[bis(2-thienyl methyl)amino]carbonyllpentyl)amino]carbonyl~amino)-3-(3-thienyl)propanoate, 1,3-benzo dioxol-5-yI)-3-({[((1 S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino]carbonyllamino)-2,2- :dimethyl propanoic acid, S)-1 -f{[bis(2-thienylmethyl)amino]carbonyllpenty)amino] carbon yljam ino)-4-morphol ino-4-oxobutanoic acid, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -{[bis(2thienylmethyl) amino]carbonyllpentyl)amino]carbonyllamino)-2,2-dimethylpropanoic acid, 1,3benzodioxol-5-y)-3-[({(1 S)-1 -[(diallylamino)carbonyl]pentyllamino)carbonyl]amino} propanoic acid ,3-benzodioxol-5-y)-3-[({(1 S)-1 -[(diisobutylamino)carbonyllpentyl~amino)carbonyl]amino} propanoic acid, (9S, 1 3S)-1 3-(1 ,3-benzodioxot-5-yl)-9-{[bis(2-thienylmethyl)aminolcarbonyl}-3, 11dioxo-1 -phenyl-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, ,3-benzodioxol-5-y)-3-[[((1 S)-1 {[bis(2-thienylmethyl)amino]carbonyllpentyl) amino]carbonyl}(isopropyl)amino]propanoic acid, (3S)-3- (1 ,3-benzodioxol-5-y)-3-([((1 S)-1 -{[bis(3-methoxybenzyl)aminolcarbonylpentyl)amino]carbonyl} amino) propanoic acid, S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino]-5-oxo-3- *phenylpentanoic acid, 1,3-benzodioxol-5-yl)-3-[[((1 S)-1 -{[bis(2-thienylmethyl)amino] carbon yllpentyl) amino]carbonyl}(meth yl) amino] propanoic acid, S)-1 -{[bis(2-thienylmethy) amino]carbonyllpentyl)amino]carbonyllamino)-3-(4-bromo-2-thienyl)propanoic acid, S)-1 {[bis(2-thienylmethyl)amino] carbonyllpentyl)aminolcarbonyl~amino)-3-(3-methyl-2-thienyl)propanoic acid, ,3-benzodioxol-5-y)-3-[({(1 S)-1 -[(dimethylamino)carbonyl]pentyllamino)carbonyl] amino) propanoic acid, S)-1 -{[bis(2-thienylmethyl)amino] carbonyllpentyl) amino] carbonyllamino)-3-[2-(3-thienylmethyl)-1 ,3-thiazol-4-yI]propanoic acid, ,3-benzodioxol-5-yI)-3- S)-1 -[(dipropylamino)carbonyl] pentyl} amino)carbonyl]aminolpropanoic acid, 1,3benzod 1 1 ipropyl am ino)carbonyll pen tyl~am in o)carbon yl]am inolpro pan oic acid, LibC/526783speci S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl~amino)-3-(2-thieny) propanoic acid, (8S, 12S)-1 2-(1 ,3-benzodioxol-5-yl)-8-butyl-6-(2-ethoxyethyl)-7, 1 -dioxo-3-oxa-6,9, 11triazatetradecan-1 4-aic acid, S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino] carbonyllam in ihyd ro-1, ,3-oxazol-2-yl) pro panoic acid, ,3-benzodioxol-5-yl)-3-({[( 1- {[bis (cyclopropylmethyl)amino]carbonyl} pentyl)aminojcarbonyllamino)propanoic acid, 3-(1 ,3benzodioxol-5-yl)-5-[((1 5)-i -{[bis(2-thienylmethyl)aminolcarbonyl} pentyl)amino]-5-oxopentanoic acid, S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyllamino)-3-(3-methoxy phenyi) propanoic acid, (1 OS, 1 4)-i 4-(1 ,3-benzodioxol-5-yl)-1 O-[bis(2-thienylmethyl)amino]carbonyl}- 2,2-dimethyl-4, 12-dioxo-3-oxa-5, 11,1 3-triazahexadecan-1 6-oic acid, S)-5-amino-1 -{[bis(2thienyl methyl)amino]carbonyl~pentyl)amino]carbonyl~amino)-3-(1 ,3-benzodioxol-5-yI)propanoic acid, ,3-benzodioxol-5-yl)-3-({[((1 S)-i -{[4-(2-thienylmethyl)piperazino]carbonyllpentyl)amino] carbonyllamino) propanoic acid, S)-i -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino] acid, ,3-benzodioxol-5-y)-3-({[((1 S)-i -{[4-(3-thienylmethyl) piperazinolcarbonyllpentyl)aminolcarbonyl} amino) propanoic acid, ,3-benzodioxol-5-yl)-3- S)-i -{[4-(2-methoxyphenyl)piperazino]carbonyllpentyl)amino]carbonyllamino) propanoic acid, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -{[4-(2-thienylcarbonyl)piperazino]carbonyllpentyl)amino carbonyl~amino) propanoic acid, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -{[4-(2-thienylsulfonyl) piperazino] carbonyllpentyl)amino]carbonyllamino)propanoic acid, ,3-benzodioxol-5-yl)-3- S)-1 -({4-[(benzyloxy)carbonyl]piperazino~carbonyl)pentyl]amino~carbonyl)amino] propanoic acid, ethyl ,3-benzodioxol-5-yI)-3-((((i 5)-i -{(bis(2-thienylmethyl) amino)carbonyl~pentyl)amino) carbonyllamino) propanoate, methyl 5)-i -{(bis(2-thienylmethyl)amino) carbonyl~pentyl)amino) carbon yl~am ino)-3-(3-th ien yl) propanoate and pharmaceutically acceptable salts thereof.

Example The ability of compounds of the present invention to inhibit binding is described in detail hereinafter in the Examples by a procedure in which a 26-amino acid peptide containing the 051 sequence of fibronectin with an N-terminal Cys was coupled to maleimide activated ovalbumin.

Ovalbumin and CS1 conjugated ovalbumnin were coated onto 96-well polystyrene plates at 5W/mL in TBS (50mM Tris, pH7.5; 150mM NaCI) at 40C for 16h. The plates were washed three times with TBS and blocked with TBS containing 3% BSA at room temperature for 4h. Blocked plates were washed three times in binding buffer (185; 1 MM MgCI2; 1 mM CaCI2; 1 mM MnCI2) prior to assay. Ramos cells fluorescently labeled with calcein AMC-3099 were resuspended in binding buffer (107 cells/mI) and diluted 1:2 with same buffer with or without compound. The cells were added immediately to the wells x 105 cells/well) and incubated for 30 minutes at 3700. Following three washes with binding buffer, adherent cells were lysed and quantitated using a fluorometer.

35 The results are shown in Tables 1 and 2. IC50 is defined as the dose required to give inhibition. The lower the lCso value and the greater the percentage of inhibition, the more efficient the compound is at prevention of cell adhesion. A stands for inhibition in Table 1, and the percent inhibition indicates the inhibition of cell adhesion when compound is included in the assay at a concentration of 100pMv.

Table 1 Cornpound IC50 A (9S,1 3S)-i3-(i ,3-benzodioxol-5-yl)-9-{[benzyl(2-thienylmethyl)amino] 0.000 100 carbony}-3,1 ii-dioxo-1 -phenyl-2-oxa-4, 10,1 2-triazapentadecan-i 5-oic acid, 6 8 LibC/526783speci Compound 1050 %A 1,3-benzodioxol-5-y)-3-([((1 1 -{[benzyi(2-thienyimethyl)ami no] 0.007 100 carbonyllpentyl)amino]carbonyl~amino)propanoic acid____ 1,3-benzodioxol-5-yI)-3-{[({2-[benzyl(2-thienylmethyl)amino]-2-oxoethyl~amino)carbon 0.9 100 yI]aminolpropanoic acid S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyllpentyl)amino]carbonyl~amino)-3-( 1 -naph 2 100 thyl)propanoic acid S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyl~pentyI)amino]carbonyl 0.075 100 amino)-3-(2-thienyl)propanoic acid 1,3-benzodioxol-5-y)-3-((((( 1 S)-1 0.000 100 thienylmethyl)amino)carbonyl)pentyl)amino)carbonyl)amino)propanoic acid 4 S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl 0.2 100 amino)-3-(4-isobutoxyphenyl)propanoic acid S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl 2 100 amino)-3-(2,6-dimethylphenyl)propanoic acid 3-[4-(allyloxy)phenyl]-3-({[((1 S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyI} 0.3 100 pentyl)aminolcarbonyllamino)propanoic acid 3-[4-(benzyloxy)phenyl]-3-({[(( 1 S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyl~pentyl)amino]ca 2 99 rbonyllamino)propanoic acid____ 1,3-benzodioxol-5-y)-3-[({( 1 S)-l1-[(dibenzylamino)carbony]pentyl} 0.2 100 amino)carbonyl]aminolpropanoic acid S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl 0.2 99 amino)-3-(3-bromo-4-methoxyphenyl)propanoic acid S)-1 -{[benzyl(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl 2 100 amino)-3-(2-naphthyl)propanoic acid S)-1 -{[benzyl(2-thienylmethyl)aminolcarbonyl~pentyl)amino]carbonyI} 2 100 amino)-3-(4-butoxyphenyl)propanoic acid, 12 S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl 0.017 100 amino)-3-(2-thienyl)propanoic acid S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl 0.02 100 amino)-3-(3-thienyl)propanoic acid 3-(l1-benzofuran-2-y)-3-({[((1 S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyI)amino]carbony 2 100 )amino) propanoic acid 1,3-benzodioxol-5-y)-3-([((1 S)-1 -{[bis(2-thienylmethyi)amino] 2 100 carbonyllpentyl)oxylcarbonyllamino)propanoic acid 1,3-benzodioxol-5-y)-3-({[((1 S)-1 -{[bis(3-pyddinylmethyl)amino] 0.3 100 carbonyllpentl) amino]carbon yIlamino)propanoic acid ,3-benzodioxol-5-y)-3-({[(( 1 S)-1 -{[bis(2-thienylmethyl)amino] 0.08 100 carbonyl}-3-mompholino-3-oxopropyl)aminolcarbonyllamino)propanoic acid ,3-benzodioxol-5-y)-3-{[({( 1 S)-1 -benzyl-2-[bis(2-thienylmethyl)amino]-2-oxoethyllam 0.000 100 ino)carbonyllaminolpropanoic acid ,3-benzodioxol-5-yl)-3-{[({( 1 R)-1 -[(benzylthio)methyl]-2-[bis(2-thienylmethyl)amino]-2 0.001 100 -oxoethyllamino)carbonyl]amino~pro panoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-1 -[(benzyloxy)methyl]-2-[bis(2-thienylmethyl)amino]-2 0.006 100 -oxoethyllamino)carbonyllaminolpropanoic acid ,3-benzodioxol-5-y)-3-{(((1 R)-2-[bis(2-thienylmethyl)amino]-1 -[(ethylthio)methyl]-2-o 0.03 100 xoethyllamino)carbonyl]amino~propanoic acid ,3-benzodioxol-5-y)-3-({[((1 S)-1 -{[[(3-methyl-1 -benzothiophen-2-yI) 0.5 100 methyl](2-thienylmethyl)amino]carbonyllpentyl)aminolcarbonyl~amino)propanoic acid ,3-benzodioxol-5-y)-3-({[(( 1 S)-l1-{[(3-pyridinylmethyl)(2-thieny 0.003 100 methyl)amino]carbonyllpentyl)amino]carbonyllamino)propanoic acid____ S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino]carbonyl) 0.04 100 amino)-3-(5-methyl-2-thienyl)propanoic acid S)-1 -{[bis(2-thienylmethyl)amino]carbonyilpentyl)amino]carbonyllamino)-3-(2-met 0.2 100 hyl-1 ,3-thiazol-4-yl)propanoic acid, 19 LibC/526783speci Compound IC 5 0

%A

,3-benzodioxol-5-y)-3-({[((1 S)-1 1,3-thiazol-2-ylmethy)(2-thieny 0.015 100 methyl)amino]carbonyllpentyi)amino]carbonyllamino)propanoic acid___ ,3-benzodioxol-5-y)-3-{[({(1 S)-2-[bis(2-thienylmethyl)amino]-1 0.4 100 methyl-2-oxoethyIlamino)carbon yI]amino~propanoic acid ,3-benzodioxol-5-y)-3-{[({2-[bis(2-thienylmethyi)amino]-2-oxoethyl 0.7 100 amino)carbonyl]aminolpropanoic acid ,3-benzodioxol-5-y)-3-({[((l S)-1 -{[bis(2-thienylmethyl)amino] 0.003 100 carbonyl}-3-methylbutyl)aminolcarbonyllamino)propanoic acid 1,3-benzodioxol-5-y)-3-({[((1 S)-1 -{[bis(2-thienyimethyl)amino] 0.07 100 carbonyl}-2-methylpropyi)amino]carbonyl~amino)propanoic acid S)-1 ,3-benzodioxol-5-yI)-2-carboxyethyl]amino~carbonyl)amino]-5-[bis(2-thienyI 0.2 100 acid ,3-benzodioxol-5-y)-3-({[((1 S)-1 -{[bis(2-thienylmethyl)amino] nd 0 carbonyllpenty)amino]carbonyllamino)-2,2-dimethylpropanoic acid S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl~amino)-4-morph 0.8 100 olino-4-oxobutanoic acid ,3-benzodioxol-5-y)-3-({[(( 1 S)-1 -{[bis(2-thienylmethyl)amino] 40 79 carbonyl~pentyl)aminolcarbonyl~amino)-2,2-d imethyipropanoic acid, 1,3-benzodioxol-5-y)-3-[({( 1 S)-1 -[(diallylamino)carbonyl]pentyl} 0.09 100 amino)carbonyl]aminolpropanoic acid 1,3-benzodioxol-5-yl)-3-{[({( 1 S)-1 -[(diisobutylamino)carbonyl]pentyl} 0.75 100 amino)carbonyl]amino~propanoic acid (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-yI)-9-{[bis(2-thienylmethyl)aminolcarbony-3, 1 -dioxo-1 -phe 0.000 100 nyl-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid 4 ,3-benzodioxol-5-y)-3-[{[((1 S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino]c nd 46 arbonyl}(isopropyl)aminolpropanoic acid ,3-benzodioxol-5-y)-3-({[(( 1 S)-1 -{[bis(3-methoxybenzyl)amino] 0.01 100 carbonyllpentyl)aminolcarbonyllamino)propanoic acid -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]-5-oxo-3-phenylpentanoic acid, 0.3 100 ,3-benzodioxol-5-y)-3-[{[((1 S)-1 -{[bis(2-thienylmethyl)amino] 1.5 100 carbonyllpentyl)amino]carbonyl}(methyl)aminolpropanoic acid, S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbony} 0.25 100 amino)-3-(4-bromo-2-thienyl)propanoic acid S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl) 0.06 100 amino)-3-(3-methyl-2-thienyl)propanoic acid ,3-benzodioxol-5-y)-3-{[({( 1 S)-1 -[(dimethylamino)carbonyl]pentyl) 0.7 100 amino)carbonyl]amino~propanoic acid 1 S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino]carbonyllamino)-3-[2-(3-t 0.2 100 hienylmethyl)-1 ,3-thiazol-4-yI]propanoic acid 1,3-benzodioxol-5-y)-3-{[({(1 S)-1 -[(dipropylamino)carbonyllpentyl} 0.7 100 amino)carbonyllaminolpropanoic acid S)-1 -{[bis(2-thienylmethyl)amino]carbonyllpenty)amino]carbonyllamino)-3-(2-thie 0.004 100 nyi)propanoic acid (8S, 12S)-1 2-(1 ,3-benzodioxol-5-yi)-8-butyl-6-(2-ethoxyethyl)-7, 10-dioxo-3-oxa-6,9, 1-triazate 0.3 100 tradecan-14-oic acid S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyl~amino)-3-(4, 5-di 3 nd hydro-1 ,3-oxazol-2-yl)propanoic acid ,3-benzodioxol-5-y)-3-({[(1 -{[bis(cyclopropylmethyl)amino]carbonyl} 0.6 100 pentyl)amino]carbonyllamino)propanoic acid 1,3-benzodioxol-5-yl)-5-[((1 S)-1 -{[bis(2-thienylmethyl)amino]carbonyl} 0.3 100 acid a.

a a a.

a a S)-1 -{[bis(2-thienylmethyl)amino]carbonyl~pentyl)amino]carbonyllamino)-3-(3-met hoxyphenyl)propanoic acid 0.035 LibC/526783speci Compound IC50 %A (1 OS, 1 4S)-i 4-(1 ,3-benzodioxol-5-y)-1 0-{[bis(2-thienylmethyl)amino]carbonyl2,2-dimethyl-4, 0.3 100 1 2-dioxo-3-oxa-5, 11,1 3-triazahexadecan-1 6-aic acid (3S)-3-({[((lS)-5-amino-l-{[bis(2-thienylmethyl)amino]carbonyl~pentyl)aminoI 0.1 100 carbonyllamino)-3-(1 ,3-benzodioxoi-5-yI)propanoic acid (3S)-3-(1,3-benzodioxol-5-y)-3-([((1 S)-l-{[4-(2-thienylmethyl)piperazino] 0.05 100 carbonyllpentyl)amino]carbonyllamino)propanoic acid 5)-i -{[bis(2-thienylmethyl)amino]carbonyllpentyl)amino]carbonyl amino)-5-hexenoic 0.125 100 acid (3S)-3-(1,3-benzodioxol-5-yl)-3-([(( 1 S)-l-{[4-(3-thienylmethyl)piperazino] 0.7 100 carbonyl~pentyl)aminolcarbonyllamino)propanoic acid ,3-benzodioxol-5-yl)-3-([((1 S)-1 -{[4-(2-methoxyphenyl)piperazino] 0.7 100 carbonyllpentyl)aminolcarbonyllamino)propanoic acid ,3-benzodioxol-5-y)-3-([((1 5)-i -{[4-(2-thienylcarbonyl)piperazino] 1.5 100 carbonyl~pentyl)amino]carbonyllamino)propanoic acid ,3-benzodioxol-5-yl)-3-([((1 5)-i -{[4-(2-thienylsulfonyl)piperazino] 2 100 carbonyllpentyl)amino]carbonyllamino)propanoic acid ,3-benzodioxol-5-y)-3-[([(1 S)-i -({4-[(benzyloxy)carbonyi]piperazino~carbonyl)penty 1 100 ]amino)carbonyl)aminolpropanoic acid nd not determined Table 2 Compound IC 5 0 (nM) Compound IC 5 0 (nM) Compound IC50 (nM) Compound IC 5 0 (nM) Number Number Number Number 36 8 63 15 73 20 83 39 9 64 8 74 35 84 42 40 65 1 75 >1000 85 200 140 66 25 76 5 86 200 46 900 67 7 77 200 87 1800 49 35 68 4 78 400 88 >1000 50 >1000 69 40 79 30 89 >1000 59 100 70 30 80 600 90 4000 60 71 30 81 200 91 >1000 62 10 72 20 82 200 92 >100 All references cited are hereby incorporated by reference.

The present invention is illustrated by way of the foregoing description and examples. The foregoing description is intended as a non-limiting illustration, since many variations will become apparent to those skilled in the art in view thereof. It is intended that all such variations within the scope and spirit of the appended claims be embraced thereby.

Changes can be made in the composition, operation and arrangement of the method of the present invention described herein without departing from the concept and scope of the invention as defined in the following claims: a.

LibC/526783speci

Claims

1. A compound of the structure R R 3 R 4 J M R t2 A E TL R J Formula I wherein A is -NR 6 E is -NR 7 each J is T is selected from the group consisting of and -(CH 2 wherein b is an integer of from 0 to 3; s and t are each 1; L is selected from the group consisting of-0-, -NR 9 and -(CH 2 wherein n is an integer of 0 or 1; M is -C(Rio)(R X is -CO 2 B; B, R 2 R 3 R 4 R 5 R 6 R 7 R 9 R 1 o and R" are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, hydroxyalkyl, alkoxy, alkoxyalkoxy, cycloalkylalkyl, alkylamino, haloalkyl, alkylaryl, arylalkyl, heterocyclyl, 20 heterocyclylalkyl and alkylheterocyclyl groups; wherein B, R 2 R 3 R 4 R 5 R 6 R 7 R 9 R 1 and R' 1 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; and wherein R and R2 taken together may form a ring; R3 and R 4 taken together may wherein R and R taken together may form a ring; R and R taken together may form a ring; R 5 and R 9 taken together may form a ring; and R' 1 and R" taken together may form a ring; and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 of the structure R X R S R3 R R S 30 Formula II 0*660: 30 Formula II, [I:\DayLib\LIBH]02470.doc:UG 42 wherein X, s, t and R' to R 7 R 10 and are as defined in claim 1.

3. A compound of claim 2 wherein R' is selected from the group consisting of methyl, 2-thienylmethyl, methylfuranylmethyl, and butyl; R2 is selected from the group consisting of 2-thienylmethyl, 3-methoxybenzyl, N- (cyclopropylmethyl)aminobenzyl, benzyl, and 5-methylfuranylmethyl; and R 5 is selected from the group consisting of 1,3-benzodioxol-5-yl, 4-methylphenyl, 3-trifluoromethylphenyl, 3,5-dimethoxyphenyl, 2,3-dihydro-1-benzofuran-5-yl, phenyl, 4- flurophenyl, 4-methoxyphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 1o 3,4,5-trimethoxyphenyl and 3-chlorophenyl.

4. A compound of any one of claims 1 to 3 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, aminals and amides thereof.

A compound of the structure 0 2 '0 OH R 2 O O R2N N Rs 15H H O Formula III wherein s is zero or one; R' and R 2 are each independently selected from the group consisting of alkyl, 2- thienyl, methoxyphenyl and phenyl; R5 is selected from the group consisting of 1,3-benzodioxol-5-yl, dimethoxyphenyl, 2,3-dihydro- 1 -benzofuran-5-yl, fluorophenyl, and methoxyphenyl; and pharmaceutically acceptable salts thereof.

6. A compound of claim 5 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, aminals and amides thereof.

7. A compound selected from the group consisting of: (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1S)- -[methyl(2-thienylmethyl)amino]- carbonylpentyl)amino]carbonylamino)propanoic acid, ,3-benzodioxol-5-yl)-3-([((1S)-1 -[methyl(3-methoxybenzyl)amino]- carbonylpentyl)amino]carbonyl amino) propanoic acid, 30 (3S)-3-(3,5-dimethoxyphenyl)-3 1- [bis(2-thienylmethyl)amino]- carbonyl pentyl)amino]carbonyl} amino)propanoic acid, S [I:\DayLib\LIBH]02470.doc:UG (3 -dihydro- 1 -benzofuran-5 1- I [bis(2-thienylmethyl)amino] carbonyllpentyl)amino]carbonyl} amino)propanoic acid, (3 S)-3 -(4-fluorophenyl)-3 1 [bis(2-thienylmethyl)amino]carbonyl} pentyl)amnino]carbonyl} amino) propanoic acid, (3 S)-3-(4-methoxyphenyl)-3 1 [bis(2-thienylmethyl)amino]carbonyl} pentyl)amnino]carbonyl} amino)propanoic acid, (3 1,3 -benzodioxol-5-yl)-3-( 1-I{ [butyl(2-thienylmethyl)amino]- carbonyllpentyl)amino]carbonyl} amino)propanoic acid, (3 S)-3 -benzodioxol-5-yl)-3 1-((bis(2-thienylmethyl)amino)carbonyl)- pentyl)amino)carbonyl)amino)propanoic acid, 1,3-benzodioxol-5-yl)-3-( 1- ,3-thiazol-2-ylmethyl)(2-thienyl- methyl)amino]carbonyl} pentyl)amino]carbonyl} amino)propanoic acid; and pharmaceutically acceptable salts thereof.

8. A compound of claim 7 further comprising derivatives of said compound selected from the group consisting of esters, carbamnates, amninals and amides thereof.

9. A compound of claim 2 wherein R' and R 2 taken together form a ring, wherein said ring is of the structure (R wherein Y, at each occurrence is independently selected from the group consisting of -C(R' 5 )r -N(R 6 -SO 2 N(R 1 7 -C(0)N(R 18>_ _NR' 9 and -NR 20 S0 2 R 14, R 15, R 16, R 17, R 18, R9 and R2 at each occurrence are independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, ***.alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, -CF 3 nitro, amino, cyano, -N(C 1 -C 3 alkyl)-C(0)(C 1 -C 3 alkyl), -C 1 -C 3 alkylamino, alkenylamino, alkynylamino, di(CI-C 3 alkyl)amino,-C(O)0-(C 1 -C 3 alkyl), -C(O)NH-(C 1 -C 3 alkyl), -CH=NOH, -P0 3 11 2 -0P0 3 H 2 -C(0)N(C 1 -C 3 alkyl) 2 haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, hioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, .30 aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamnate, aryloxyalkyl, carboxyl and -C(0)NH(benzyl); *wherein R1 4 R1 5 R 16 R 1 7 ,R 18 ,R 19 and R 20 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; L\DayLib\LIBH]02470.doc:ULG y is an integer of two to eight; z is an integer of zero to sixteen; and r is an integer of zero to two.

A compound of claim 9, wherein said ring is selected from the group consisting of 4-(2-thienylmethyl)piperazino, 4-(3 -thienylmethyl)piperazino, 4-(2- methoxyphenyl)piperazino, 4-(2-thienylcarbonyl)piperazino, 4-(2-thienylsulfonyl)- piperazino, 4-phenyl-4-cyano-piperidino and 4-((benzyloxy)carbonyl)piperazino.

11. A compound of claim 9 or 10 further comprising derivatives of said compound selected from the group consisting of esters, carbamnates, aminals and amides thereof.

12. A compound of claim 1 selected from the group consisting of: S)-3 1- {[bis(2-thienylmethyl)amino]carbonyl} pentyl)amnino] carbonyl} amino)-4-morpholino-4-oxobutanoic acid, 1,3-benzodioxol-5-yl)-3 1- [bis(2-thienylmethyl)amino]- carbonyl} pentyl)amino]carbonyl} amino)-2,2-dimethylpropanoic acid, (3S)-3 -benzodioxol-5 -yl)-3 15)- 1-[(diallylamino)carbonyl]pentyl} amino)- carbonyl] amino) propanoic acid, 1,3 -benzodioxol-5-yl)-3 15)- 1-[(diisobutylamino)carbonyl]pentyl amino)carbonyl] amino}I propanoic acid, (3S)-3 ,3-benzodioxol-5-yl)-3 1- {[bis(3-methoxybenzyl)amino] carbonyl} pentyl) amino] carbonyl}I amnino)propanoic acid, 1,3-benzodioxol-5-yl)-3 -(((((15)-l1-((bis(2-thienylmethyl)amino)carbonyl)- pentyl)amino)carbonyl)(methyl)amino) propanoic acid, 25 1- {[bis(2-thienylmethyl)amino]carbonyl} pentyl)amnino]- 25 carbonyllamino)-3-(2-thienyl)propanoic acid, 1 [bis(2-thienylmethyl) amino] carbonyl}I pentyl)amino]- carbonyl} amino)-3 -(3-methoxyphenyl)propanoic acid, (3S)-3 ,3-benzodioxol-5-yl)-3 1- {[4-(2-thienylsulfonyl)piperazino] carbonyl}I pentyl) amino] carbonyl}I amino)propanoic acid, 30 and pharmaceutically acceptable salts thereof.

An N,N-disubstituted amide that inhibits the binding of integrins to their ~'*receptors, said amide being substantially as hereinbefore described with reference to any one of the examples. [I:\DayLib\LIBH]02470.doc:UG

14. A process for preparing an N,N-disubstituted amide that inhibits the binding of integrins to their receptors, said process being substantially as hereinbefore described with reference to any one of the examples.

A pharmaceutical composition comprising a compound of any one of claims 1 to 13 in a pharmaceutically acceptable carrier.

16. A method for selectively inhibiting a 4 f 1 integrin binding in a mammal comprising administering to said mammal a therapeutic amount of a compound of any one of claims 1 to 13 or of a composition of claim

17. A compound according to any one of claims 1 to 13 or a composition according to claim 15 when used in selectively inhibiting a 4 0 1 integrin binding.

18. The use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for selectively inhibiting a40 1 integrin binding. Dated 16 May, 2003 Texas Biotechnology Corporation Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 S* 6 S So o S0 0 [I:\DayLib\LIBH]02470.doc: JG