AU756696B2 - Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4 - Google Patents

Description

WO 99/06431 PCT/US98/15313 SUBSTITUTED PHENYLALANINE TYPE COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4 Cross-Reference to Related Application This application claims the benefit of U.S. Provisional Application No.

which was converted pursuant to 37 C.F.R. from U.S. Patent Application No. 08/920,394, filed July 31, 1997.

Field of the Invention This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.

References The following publications, patents and patent applications are cited in this application as superscript numbers: Hemler and Takada, European Patent Application Publication No. 330,506, published August 30, 1989 2 Elices, et al., Cell, 60:577-584 (1990) Springer, Nature, 346:425-434 (1990) 4 Osborn, Cell, 62:3-6 (1990) Vedder, et al., Surgery, 106:509 (1989) 6 Pretolani, et al., J. Exp. Med., 180:795 (1994) Abraham, et al., J. Clin. Invest., 93: 7 7 6 (1994) 8 Mulligan, et al., J. Immunology, 15-0:2407 (1993) WO 99/06431 PCTIUS98/15313 9 Cybuisky, et al., Science, 25-1:788 (1991) to Li, et al., Arteriosicer. Thromb., 11: 197 (1993) 11 Sasseville, et al., Am. J1 Path., 1.44:27 (1994) 12 Yang, et al., Proc. Nat. Acad. Science (USA), 90: 10494 (1993) 13 Burkly, et al., Diabetes, 4U:529 (1994) 14 Baron, et J1 Clin. Invest., 93:1700 (1994) Hamann, et al., J1 Immunology, 152:3238 (1994) 16 Yednock, et al., Nature, 2.56:63 (1992) 17 Baron, et al., J Exp. Med., 111:57 (1993) 18van Dinther-Janssen, et al., J. Immunology, 1.47:4207 (1991) 19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993) Elices, et al., J Gun. Invest., 931405 (1994) 21 Postigo, et al., J Clin. Invest., .89:1445 (199 1) 22 Paul, et al., Transpi. Proceed., 2.5:813 (1993) 23 Okarhara, et at., Can. Res., 54:3233 (1994) 24 Paavonen, et al., Int. J Can., 5.8:298 (1994) Schadendorf, et at., J1 Path., 17fr429 (1993) 26 Bao, et al., Diff., 5.2:239 (1993) 27 Lauri, et al., British J Cancer, fia:862 (1993) 28 Kawaguchi, et al., Japanese J Cancer Res., U8: 1304 (1992) 29 Kogan, et at., U.S. Patent No. 5,510,332, issued April 23, 1996 International Patent Appl. Publication No. WO 96/01644 WO 99/06431 PCTIUS98/1 5313 3-- All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

State of the Art VLA-4 (also referred to as a4pl integrin and CD49d/CD29), first identified by Hemler and Takada', is a member of the p integrin family of cell surface receptors, each of which comprises two subunits, an a chain and a 3 chain. VLA-4 contains an a4 chain and a pi chain. There are at least nine Sl integrins, all sharing the same P1 chain and each having a distinct a chain.

These nine receptors all bind a different complement of the various cell matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities and each activity has been shown to be inhibited independently.

2 Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer 3 and Osbom 4 WO 99/06431 PCTIUS98/1 5313 4 Inflammatory brain disorders, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.

In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al.

5 Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma 8 Alzheimer's disease, atherosclerosis 9 0 AIDS dementia", diabetes 1 2 4 (including acute juvenile onset diabetis), inflammatory bowel disease 1 (including ulcerative colitis and Crohn's disease), multiple sclerosis 6 7 rheumatoid arthritis 8 2 tissue transplantation 22 tumor metastasis 2 32 8 meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocytemediated lung injury such as that which occurs in adult respiratory distress syndrome.

In view of the above, assays for determining the level VLA-4 in a biological sample containing VLA-4 would be useful, for example, to diagnosis VLA-4 mediated conditions. Additionally, despite these advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions 2 9 30 The present invention addresses these and other needs.

WO 99/06431 PCT/US98/15313 SUMMARY OF THE INVENTION This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and, in pharmaceutical compositions to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC 5 0 of about 15 or less (as measured by Example 136 below) which compounds are defined by formula I below:

R

3

O

I II R'-SO2-N(R 2

)-C-Q-CH-C-OH

I I H R where R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;

R

2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and where R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R' form a heterocyclic or a substituted heterocyclic group;

R

3 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group;

R

5 is -(CH 2 )x-Ar-R s where R 5 is selected from the group consisting substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group WO 99/06431 PCTIUS98/15313 consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, amninocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cyc loalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl,

-OS(O)

2 -substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl,

-NRS(O)

2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS(O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl,

-NRS(O)

2 -heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O) 2

-NR-

alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS (O) 2 -NR-aryl, -NRS(O) 2

-NR-

substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamnino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamnino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formnyl, and the like or alkyl/substituted WO 99/06431 PCT/IJS98/1 5313 7alkyl groups substituted with -S 2 O,-alkyl, -SO,-substituted alkyl, -SO 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -SO 2 -Substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -SO 2 heterocyclic, -SO,-substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; alkoxyaryl substituted on twe alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR where R is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, aryl and heteroaryl; -NR'R' wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxylcycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-OS(O)

2 -alkyl, -OS(0) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O),-heteroaryl, WO 99/06431 PCTIUS98/15313

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl,

-NRS(O)

2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl,

-NRS(O)

2 -heteroaryl,

-NRS(O)

2 -substituted heteroaryl,

-NRS(O)

2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl,

-NRS(O)

2 -NR-substituted alkyl, -NIRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-.heteroaryl,

-NRS(O)

2 -NR-substituted heteroaryl,

-NRS(O)

2 -NR-heterocyclic,

-NIRS(O)

2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroaryl amino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyllsubstituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -S0 2 -aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -S0 2 -heterocyclic, -SO-,-substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; -alkoxy-NR"R" wherein each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted WO 99/06431 WO 99/643 1PCT/US98/1 5313 alkyl, carboxyl-cycloalkyl, carboxyl- substituted cycloalky!, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl,

-OS(O)

2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl,

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS (O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -N7RS(O) 2 -heteroaryl,

-NRS(O)

2 -substituted heteroaryl,

-NRS(O)

2 heterocyclic,

-NRS(O)

2 -substituted heterocyclic,

-NRS(O)

2 -NR-alkyl,

-NRS(O)

2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl,

-NRS(O)

2 -NR-substituted heteroaryl,

-NRS(O)

2 -NR-heterocyclic,

-NRS(O)

2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)aniino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamnino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -SO2-substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S 0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 1 -heteroaryl, -S0 2 -substituted heteroaryl, _S02- WO 99/06431 PCT/US98/15313 heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents -on the substituted alkenyl/alkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amnidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl -substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosul fone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamnino, oxythiocarbonylamino,

-OS(O)

2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O)2-heteroaryl,

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl,

-NRS(O)

2 -Substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl,

-NRS(O)

2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS (O) 2 substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O)2-NR-substituted alkyl, -NRS (O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS (O) 2 -NR-substituted heteroaryl, WO 99/06431 PCT[S98/1 5313 11-- -NRS(0) 2 -NR-heterocyclic,

-NRS(O)

2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -SO2-alkyl, -S0 2 -substituted alkyl, -SO,-alkenyl, -SO,-substituted alkenyl, -S 2 O,-cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SO2-substituted heteroaryl, -SO,heterocyclic,

-SO

2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxysubstituted saturated heterocyclic; -O-heterocyclic and -O-substituted heterocyclic; tetrazolyl; -NR-S0 2 -substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, WO 99/06431 PCT/US98/15313 12 alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, .alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; (min) substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alko. y does not include alkoxy-NR"R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; amidine and amidine substituted with from 1 to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; where each is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea, then the other is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic;

-NR

12

C(O)-R

8 where R 8 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted WO 99/06431 PCTIUS98/1 5313 13heterocyclic, and R 1 2 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl or -SO2-alkyl;

-NR'C(O)NR'R

9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic:

-NR'C(O)OR

9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -aminocarbonyl-(N-formylheterocycyl); and -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; Q is -C(X)NR 7 wherein R 7 is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof In another embodiment, the compounds of this invention can also be provided as prodrugs which convert hydrolyze, metabolize, etc.) in vivo to a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid of the compound of formula I is modified WO 99/06431 PCTIUS98/1 5313 14 into a group which, in vivo, will convert to a carboxylic acid (including salts thereof). In a particularly preferred embodiment, such prodrugs are represented by compounds of formula IA:

R

3

O

R'-SO2-N(R 2

)-CH-Q-CH-C-R

6

IA

R

where R' is selected from the group consisting ofalkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;

R

2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R' can form a heterocyclic or a substituted heterocyclic group;

R

3 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group;

R

5 is -(CH 2 )x-Ar-R 5 where R 5 is selected from the group consisting substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted WO 99/06431 PCT/US98/15313 cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylieteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl -substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substi Luted thiohieterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-OS(O)

2 -alkyl,

-OS(O)

2 -substituted alkyl, -OS(O)2-aryl,

-OS(O)

2 -substituted aryl, -OS(O)2heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl,

-NRS(O)

2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl,

-NRS(O)

2 -heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O) 2

-NR-

alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2

-NR-

substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O)2-NR-heterocyclic,

-NRS(O)

2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formnyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S02-substituted alkyl, -SO.2-alkenyl, -SQ2-substituted alkenyl, -S0 2 -CYCloalkyl, -SQ2-substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SQ2-substituted heteroaryl, -SO 2 heterocyclic, -SQ2-substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; WO 99/06431 PCTIUS98/1 5313 16alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR where R is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, aryl and heteroaryl; -NR'R' wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxylcycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-OS(O)

2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl,

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -OS0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl,

-NRS(O)

2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O),-substituted aryl,

-NRS(O)

2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O),-NR-alkyl, WO 99/06431 PCTIUS98/1 5313 17--

-NRS(O)

2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl,

-NRS(O)

2 -NR-substituted heteroaryl,

-NRS(O)

2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -SO,-alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S 2 O,-heteroaryl, -S0 2 -substituted heteroaryl,

-SO-

heterocyclic, -S0 2 -substituted heterocyclic and -SO,NRR where R is hydrogen or alkyl; -alkoxy-NR"R" wherein each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalky, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted WO 99/06431 WO 9906431PCTIUS98/1 5313 -18thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-OS(O)

2 -alkyl, -05(0)2substituted alkyl, -OS(0) 2 -aryl, -OS(0) 2 -substituted aryl, -OS(0)2-heteroaryl, -OS(0) 2 -substituted heteroaryl, -OS(0) 2 -heterocyclic, -OS(0) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(0) 2 -alkyl, -NRS (0) 2 -substituted alkyl, -NRS(0)2-aryl, -NRS(0) 2 -substituted aryl, -NRS(0)2-heteroaryl, -NRS(0)2-substituted heteroaryl,. -NRS(0) 2 heterocyclic, -NRS(0) 2 -substituted heterocyci ic, -NRS (0) 2 -NR-alkyl, -NRS(0) 2 -NR-substituted alkyl, -NRS(0) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(0) 2 -NR-heteroaryl, -NRS(0) 2 -NR-substituted heteroaryl, -NRS(0) 2 -NR-heterocyclic, -NRS(0) 2 -NR-substituted heterocyclic- where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamnino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, form-yl, and the like or alkyl/substituted alkyl groups substituted with -S 0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO,aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SO -substituted heteroaryl, -SO 2 heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyl/alkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, WO 99/06431 PCTIUS98/15313 heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamnino, acyloxy, alkenyl, amino, amidino, alkyl amnidino, thioamidino, aminoacyl, aminocarbonyl amino, aminothiocarbonylamino, aminocarboziyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl -substituted alkyl, carboxyl-cycloalkyl, carboxyl -substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohieteroaryl, substituted thioheteroaryl, thiohieterocyclic, substituted thiohieterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-OS(O)

2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -Substituted aryl, -OS(O) 2 -heteroaryl,

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl,

-NRS(O)

2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O)2-substituted aryl,

-NRS(O)

2 -heteroaryl,

-NRS(O)

2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O)2-NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl,

-NRS(O)

2 -NR-substituted heteroaryl,

-NRS(O)

2 -NR-heterocyclic,

-NRS(O)

2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroaryl amino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, WO 99/06431 PCT/US98/15313 20 substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S 2 O,-alkyl, -S0 2 -substituted alkyl, -S 2 O,-alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -SO,-substituted cycloalkyl,

-SO,-

aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl,

-SO

2 heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxysubstituted saturated heterocyclic; -O-heterocyclic and -O-substituted heterocyclic; tetrazolyl; -NR-S0 2 -substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl WO 99/06431 PCTIS98/1 5313 21and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; amidine and amidine substituted with from 1 to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; where each is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea, then the other is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic;

-NR"

2 where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 12 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -S0 2 -aryl, -S0 2 -substituted aryl, -SO,-heteroaryl, -S0 2 -substituted heteroaryl or -S0 2 -alkyl; -NR'C(0)NR 9 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted WO 99/06431 PCT[US98/15313 22 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic:

-NR'C(O)OR

9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -aminocarbonyl-(N-formylheterocycyl); and -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4;

R

6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran- 3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O-(N-succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-p-yl, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, -NH(CH 2 )pCOOY where p is an integer of from 1 to 8 and Y is as defined above, -OCH 2

NR

9 R' where R 9 is selected from the group consisting of-C(O)aryl and -C(O)-substituted aryl and R'O is selected from the group consisting of hydrogen and -CH 2 COOR" where R" is alkyl, and -NHSOZ where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is -C(X)NR 7 wherein R 7 is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof with the proviso that when R' is p-CH 3

R

6 is methoxy, Q is WO 99/06431 PCT[US98/15313 23 and R 2 and R' are joined to formn a pyrrolidinyl group, then R' is not p-II-OCH 2

CH

2

N(C

2

H

5 2 ]-benzyl-, p-[-OCH 2

CH

2 N(isopropyl)2j-benzyl-, p-[-OCH 2

CH

2 1-pyrrolidinyl)-benzyl-, p-[-OCH 2

CH

2 1-(4-pyrimidinyl)piperazinyl]-benzyl-, p-[-OCH 2

CH

2 -N-morpholinyl)]-benzyl-, or p-[-OCH 2

CH

2

-N-

piperidinyl)]-benzyl-.

Preferably, in the compounds of formula I and IA above, R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted het-eroaryl.

Even more preferably R' is selected from the group consisting of 4methyiphenyl, methyl, benzyl, n-butyl, 4-chiorophenyl, 1 -naphthyl, 2naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethyiphenyl, 2- (methoxycarbonyl)phenyl, 2-carboxyphenyl, 3 ,5-dichlorophenyl, 4tri fluoromethyiphenyl, 3 ,4-dichlorophenyl, 3 ,4-dimethoxyphenyl, 4-

(CH

3 C(O)NI{-)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3 ,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4nitrophenyl, 2-thienyl, I -N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1 -N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4methylamidinophenyl, 4-[CH 3 S C(=N7H)]phenyl, 5-chloro-2-thienyl, dichloro-4-thienyl, 1 -N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl- 1,3,4thiadiazol-2-yl, 4-[H 2 NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2fluorophenyl, 3-fluorophenyl, 3 ,5-di fluorophenyl, pyridin-3 -yl, pyrimidin-2yl, 4-(3 -dimethylamino-n-propoxy)-phenyl, and 1 -methylpyrazol-4-yl.

Preferably, in the compounds of formula I and IA above, R 2 is hydrogen, methyl, phenyl, benzyl, -(CH 2 2 -2-thienyl, and -(CH 2 2 -4.

In one embodiment, R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R' are joined to formn a heterocyclic group or substituted heterocyclic group. Preferred heterocyclic and substituted heterocyclic groups include those having from 5 to 7 ring atoms having 2 to 3 heteroatoms in the ring selected from nitrogen, oxygen and sulfur which ring WO 99/06431 PCT/US98/15313 24is optionally fused to another ring such as a phenyl or cyclohexyl ring to provide for a fused ring heterocycle of from 10 to 14 ring atoms having 2 to 4 heteroatoms in the ring selected from nitrogen, oxygen and sulfur.

Specifically preferred joined groups include, by way of example, benzisothiazolonyl (saccharin-2-yl).

In one preferred embodiment, R 2 and R 3 together with the nitrogen atom bound to R 2 substituent and the carbon bound to the R' substituent form a heterocyclic group or a substituted heterocyclic group of 4 to 6 ring atoms having 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur which ring is optionally substituted with 1 to 2 substituents selected from fluoro, methyl, hydroxy, amino, phenyl, thiophenyl, thiobenzyl or can be fused to another ring such as a phenyl or cycloalkyl ring to provide for a fused ring heterocycle of from 10 to 14 ring atoms having 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur. Such heterocyclic rings include azetidinyl L-azetidinyl), thiazolidinyl L-thiazolidinyl), piperidinyl L-piperidinyl), piperizinyl L-piperizinyl), dihydroindolyl L-2,3-dihydroindol-2-yl), tetrahydroquinolinyl L-1,2,3,4-tetrahydroquinolin-2-yl), thiomorpholinyl L-thiomorpholin-3yl), pyrrolidinyl L-pyrrolidinyl), substituted pyrrolidinyl such as 4hydroxypyrrolidinyl 4-a-(or P-)hydroxy-L-pyrrolidinyl), 4fluoropyrrolidinyl 4-a-(or P-)fluoro-L-pyrrolidinyl), 3-phenylpyrrolidinyl 3-a-(or P-)phenyl-L-pyrrolidinyl), 3-thiophenylpyrrolidinyl 3-a-(or P-)thiophenyl-L-pyrrolidinyl), 4-aminopyrrolidinyl 4-a-(or P-)amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl 3-a-(or P-)methoxy-Lpyrrolidinyl), 4,4-di-methylpyrrolidinyl, substituted piperizinyl such as 4-N- Cbz-piperizinyl, substituted thiazolidinyl such as 5,5-dimethylthiazolindin-4yl, 1,1-dioxo-thiazolidinyl L-1,1-dioxo-thiazolidin-2-yl), substituted 1,1dioxo-thiazolidinyl such as L-1,1-dioxo-5,5-dimethylthiazolidin-2-yl, 1,1dioxothiomorpholinyl L-1,1-dioxo-thiomorpholin-3-yl) and the like.

WO 99/06431 WO 99/643 1PCT/US98/1 5313 25 Preferably, in the compounds of formula I and IA above, R 3 includes all of the isomers arising by substitution with methyl, phenyl, benzyl, diphenylmethyl, -CH 2

CH

2 -COOH, -CH 2 -COOH, 2-amidoethyl, iso-butyl, tbutyl, -CH 2 O-benzyl and hydroxymethyl. Additionally, in another preferred embodiment, R 3 and R 2 together with the nitrogen atom bound to R 2 can form a heterocyclic group or substituted heterocyclic group.

Q is preferably or

R

5 is preferably selected from all possible isomers arising by substitution with the following groups: 4-[NH- 2 CH.,C(O)NH-]benzyl, 4-[HOOCCH 2

CH

2 C(O)NI--]benzyl, 4-[-NHC(O)CH 2 NHBoc]benzyl, 4-[-NI-C(O)CH(CH3)NI-Boc]benzyl, 4-[-NHC(O)CH(CH 2 4)NiBoc]benzyl, 4- [-NIIC(O)CH 2 NHC(O)NI--3 methylphenyl]benzyl, 4-[-NHC(O)CH(NHBoc)(CH 2 4 NHCbz]benzyl, 4-[-NHC(O)CH 2 CH(C(O)0CH 2 4)-NHCbzlbenzyl, 4-4-benzyl, 4-[-NHC(O)CH(CH 2

CH

2

CH

2

CH

2

NH

2 )NHBoc]benzyl, 4-[H 2

NCH

2

CH

2

CH

2 C(O)NII-]benzyl, 4-(BocHNCH 2

CH

2

CH

2 C(O)NH-)benzyl, 4-[4 CH 2 0CH 2 (BocHN)CHC(O)NH-]benzyl, 4- [CH 3

NI-CH

2

CH

2

CH

2 C(O)N}I-]benzyl, 4-(N-methylpiperidin-4-oxy)-benzyl, 4-[CH 3 N(Boc)CH 2

CH

2

CH

2 C(O)N14-]benzyl, 4-[4 CH 2 0CH 2

(H

2 N)CHC(O)NH-]benzyl, 4-[HO(O)C(Cbz-NH)CHCH 2

CH

2 C(O)NH-]benzyl, 4-[4CH 2 0(O)C(Cbz-NH-)CHCH 2

CH

2 -C(O)NH-]benzyl, 4-[HO(O)C(NI{ 2

)CHCH

2

CH

2 -C(O)N-H-]benzyl, 4-[CH 3 (N-Boc)NCH 2 C(O)N}I-]benzyl, 4-IICH 3

NIICH

2 C(O)NH-]benzyl, 4- [(CH 3 2

NCH

2 C(O)NH-]benzyl, 4- [O-CH(COOH)&~enzyl, 4-[2-carboxylphenyl-] -benzyl, 4-[2-carboxylmethylphenyl-]-benzyl 4-[4CH 2 0C(O)NHCH 2

CH

2 NII-]benzyl, 4-N[-(S0 2 )CH3]-

CH

2

CH

2

CH

2

N(CH

3 2 ]benzyl, 4-t-butyl-O(O)CCH 2 -O-benzylNH~benzyl, 4-[N N-di(4-N,N-dimethylamino)benzyl)amino]benzyl, 4-(2-formyl- 1,2,3 ,4-tetrahydrolsoquinolin-3-yl-CH2NH)benzyl, WO 99/06431 PCT/US98/15313 26 4-[-OCH 2

CH

2 1 '-pyrimidinyl)-piperazinyl]-benzyl, 4-[-OCH 2

CH

2 1 '-piperidinyl)-benzyl, 4-[-OCH 2

CH

2 1'-Pyrrolidinyl)]benzyl, 4-[-OCH 2

CH

2

CH

2 1'-piperidinyl)]-benzyl, 4-[(CH3) 2

NCH

2

CH

2

CH

2 -O-]benzy1, 4-[(CH 3 2

NCH

2

CH

2 O-]-benzyl, 4-II-OCH 2

CH

2

CH

2 '-(4'-methylpiperazinyl))]-benzyl, 4-[-OCH 2

CH

2

C-

2 '-chlorophenyl)-piperazin- I -yI]-benzyl, 4+[OCH 2

CH

2 N(4 )CH,CH31-benzyl, 4-[-OCH 2 -(N-Boc)-piperidinyl]benzyl, 4-[-O-(3-(N-Boc)-piperidinyl]benzyl, 3-I-O-(N-methylpiperidin-4-yI]benzyl, 4-[-O-(N-methylpiperidin-4-yI]benzyl, 4-[di-iso-propylamino-CH 2 CH2O-] -benzyl, 4-[N-3-methylbutyl-N-tri fluoromethanesulfonyl)amino]benzy], 4-[-OCH 2

CH

2 -(N-morpholinyl)]-benzyl, 4-[-OCH 2 CH(NHBoc)CH~cyclohexyfl-benzyl, 4-[OCH 2

CH

2 -(N-piperidinyl]benizyl, 4

-[-OCH

2

CH

2

CH

2 -(4-rn-chlorophenyl)-piperazin- 1 -yl]-benzyl, 4-[-OCH 2

CH

2 -(N-homopiperidinyl)-benzyl, 4-[-OCH 2

CH

2 N(benizyl)2]-benlzyl, 3-[-OCH 2

CH

2

CH

2

N(CH

3 )j-benzyl, 4- [-OCH 2

CH

2

N(C

2

H

5 2 ]-benzyl, 4-[-OCFI 2

CH

2

CH

2

N(C

2

H

5 2 ]-benzyl, 4-[-OCH 2

CH

2

N(C

2 H)j1-benzyl, 4- [-OCH 2

CH

2

CH

2

N(CH

3 )benzyl]-benzyl, 4-[2-(2-azabicyclo[3 .2 .2]octan-2yl)ethyl-O-]benzyl, [cyclopentylacetylenyl]-benzyl, 4]-benzyl, 4--=C-CH 2

-O-S(O)

2 -4 '-CH 3 -4']-benzyl, C-CH 2

NHC(O)NH

2 ]-benzyl,

C-CH

2 -COOCH2,CH 3 )4 ]-benzyl, C-CH(NH 2 )-cyclohexyl] benzyl, 2 -O-phenyl]-benzyl, C-CH 2

OCH

3 ]-berizyl, 4--=C-CH 2 -C(O)0C 2

H

5 )phenyl]-benzyl, C-

CH

2

CH(C(O)OCH

3 2 ]-benzyl, C-CH 2 CH( NiC(O)CH 3

)C(O)OH]-

benzyl, NH-(4,5 -dihydro-4-oxo-5-phenyl-oxazol-2y1)]-benzyl, 4 -I-OCH2CH 2

CH

2 -(N-morpholino)]-benzy1, 4-[-OCH 2 COOH]-benzyl, 4-[-OCH 2 COO-t-butyl]-benzyl, 4-[-N(SO 2

CH

3

)(CH

2 3

-N(CH

3 2 -benzyl, 4-[-NH'S(O) 2 CF3]-benzyl, 4-[-C(=Nf)NE21-benzyl, 4-[-NHSO,-CH 2

CI]-

benzyl, 4-[OCH 2 C(O)NH-benzyl]-benzyl, 4-[-OCH 2 C(O)O-benzyl]-benzyl, 4-[-OCH 2 C(O)OH]-benzyl, 4-[-OCH 2

CH

2 -1I-(4-hydroxy-4-(3 -methoxypyrrol- 2 -yl)-piperazinyl]-benzyl, 4+[OCH 2 C(O)N1]-benzyl, 4-[-OCH 2 C(O)NHi-tbutyl]-benzyl, 4-[-OCH 2

CH

2 -1I-(4-hydroxy-4-phenyl)-piperidinyl] -benzyl, WO 99/06431 WO 9906431PCTL1S98/1 5313 27-- 2

-CH=CH

2 ]-benzyl, 4-[NH-SO2-CH 2

CH

2 CI] -benzyl, 4-benzylbenzyl, 4-[OCH 2 C(O)piperidin- I -yljbenzyl, 4-[-OCH 2

C(O)N(CH(CH

3 2 )j]benzyl, 4-amidinobenzyl, 4-acetamidobenzy], 4 -(N-methyl)acetamidobenzyl, 4 (-NIHC(O)CI-INHC(O)NH-fluorescin)benzyl, 4-(NHC(O)CH 2 CH(N}1 2 )COOH, (1 -to!I uenesul fontylim idizol-4-yl)-m ethyl-, [(I1-NN-dimethylaminosulfonyl)-imlizo I-4-yl]methyl-, 4-(N-toluenesulfonylamino)benzyl, and 4-[N-methyltri fluoroacetamido)phenyl.

In the compounds of formula IA, R 6 is preferably 2,4-dioxotetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, nec-pentoxy, 2 -o-iso-propyl-4-p-methylcyclohexoxy, 2 -p-isopropyl-4-f5-methylcyclohexoxy,

-NI-

2 benzyloxy, -NIHCH,COOH,

-NHCH

2

CH

2 COOH, -NI--adamantyl,

-NIICH

2

CH

2

COOCH

2

CH

3

-NHSO

2 -p-

CH

3 -41 -NI-bR 8 where R' is hydrogen, methyl, iso-propyl or benzyl, 0-(Nsuccinimidyl), -O-cholest-5-en-3-p-yl,

-OCH

2

-OC(O)C(CH

3 3

-O(CI-

2 ),NI-C(O)W where z is I or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-i ,4-dihydro-pyrid-3 yl, where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH 2

C(O)OCH

2

CH

3 Preferred compounds within the scope of formula I and IA above include by way of example: N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxyl.

carbonylglycyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl).L-prolyl.4-[(glycyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)L-proly..4-.[3-(carboxy)propionamido]-Lphenylalanine N-(toluene-4-sulfonyl)L-proly[44-(N-tert-butoxylcarbonylL.

alanyl)amino]-L-phenylalanine N-(toluene- 4 sulfony)iprolyl-4-[(N-tert-butoxylcarbonyl-D alanyl)amino]-L-phenylalanine WO 99/06431 PCTIUS98/15313 28-- N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert..butoxylcarbonyl-D phenylalanyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- (fluorescein)thiouriedo] acetamido }-L-phenylalanine N-(toluene-4-sulfonyl)-Lproly[44-(N-tert-butoxyl.

carbonylglycyl)amino]-L-phenylaianine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- methylphenyl)uriedo]acetamido -L-phenylalanine N-(toluene-4-sulfonyl)-L-proly[A4-(Na-tert-butoxylcarbonyl-NE.

carbobenzyloxy-L-lysyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-proyl-4[y(a-benzylINacarbobenzyioxy-L aspar-tyl)amino] -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl4[(Na-tert-butoxylcarbonylL.

lysyl)amino]-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyv.4-[y-(L-aspartyl)amino]-Lphenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-(4-aminobutyramido).L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-tert-butoxylcarbonylamino)butyramido]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-methylamino)butyramido]-L phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[4(Ntert-butoxylcarbonyl-N methylamino)butyramido]-L-phenylalanine N-(toluene-4-sulfonyl)Lproy4[(Obenzyl)>tseryl)amino]-Lphenylalanine N-(toluene-4-sulfonyl)Lprolyl-44&8(DLglutamyl)amino-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(Ntert-butoxylcarbonylsarcosyl)amino]-L-phenylalanine ,5 -dimethyl)thiaprolyl-4-[(N-tert-butoxylcarbonylsarcosyl)amino]-L-phenylalanine WO 99/06431 PCTIUS98/15313 29 N-(toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino] -L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-4[(sarcosyl)amino].L-phenylalanine N-(toluene- 4 -sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4.[(sarcosyl)amino]- L-phenylalanine N-(toluene-4-sulfonyl)-L-pro Iyl-4-[(NV,N-dimethylglycyl)amino]-Lphenylalanine N-(toluene-4-sulfonyl)L(,-dimethyl)thiaprolyi-4-(N,Ndimethylglycyl)amino] -L-phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-(a-carboxybenzyloxy)-L phenylalanine N-(toluene- 4 -sulfonyl)Lprolyl-4[2-(carboxy)phenyl-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4.[2-(methoxycarbony)phenyl..L phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-proly-4- carbobenzyloxyamino)ethyl] amino} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4 carbobenzyloxyamino)ethyl] amino)} -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-Lprolyl-L-4-.N- [3-(NNdimethylamino)propyl] [trifluoromethanesul fonyl] amino I -Lphenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-4 {N-[4-[(tertbutoxycarbonyl)methoxy]benzyl ]amiino -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-4. {NN-di [4-(NNdimethylamino)benzyl ]amino I -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-4 [(2-formyl- 1,2,3,4tetrahydroisoquinolin-3 -y1)methyl )amino)} -L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[3.(N,N-dimethylamino)propoxy] L-phenylalanine N-(toluene- 4 -sulfonyl)NmethylLserinyl-4[3.(N,,Vdimethylaminopropoxy]-L-phenylalanine methyl ester WO 99/06431 WO 9906431PCT/US98/15313 ,5-dimethyl)thiaprolyl-4-[2-(N,Ndimethylamino)ethoxy]-L-phenylalanine N-(toluene- 4 -sulfony)-L-proyl42(N~iVdimethylamino)ethoxy]-L phenylalanine N-(toluene-4-sulfonyl)-L-prolyl.4-[2..(Nethyl-N phenylamino)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sul fonyl)-L-prolyl-4-[2-(NA-diisopropylamino)ethoxy]- L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl4.3cyclohexyl2(N-tertbutoxycarbonylamino)propoxy-L-phenylalanine methyl ester N-(thiophene-2-sulfonyl)-L-prolyl..4-[3.(N,N-dimethylamino)propoxy]-L-phenylalani-ne -chlorothiophene-2 sul fonyl).t-pro ly-4- [3 (NNdi methyl amino)propoxy]-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[2-(N,N-diethylamino)ethoxy-Lphenylalanine N-(2,5-dichlorothiophene-3-sulfony)Lproly14-[3-(NIdimethylamino)propoxy]-L-phenylalanine I -methylpyrazole-4-sulfonyl)-L-proly[-4-[3-(NN-dimethylamino)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3(N,Ndiethylamino)propoxy]-L phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-3-[3-(N,NVdimethylamino)propoxy]- L-phenylalanine N-(thiazole-2-sulfonyl)-L-prolyl-4-[3.(N,N-dimethylamino)propoxy]- L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl4-[3(Nmethyl-N benzylamino)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl).Lprolyl-4[3(NN.diethylamino)propoxy]-Lphenylalanine N-(toluene-4-sulfonyl)Lprolyl-4-[3-(Nmethyl-N benzylamino)propoxy]-L-phenylalanine methyl ester WO 99/06431 WO 9906431PCT/US98/15313 31 1-methylimidazole-4-sulfonyl)-L-prolyl-4-[3-(N,Ndimethylamino)propoxy]-L-phenylalanine N-(2-methylthiadiazole-5-sulfonyl)-L-prolyl-4-[3-(N,Ndimethylam-ino)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-thiaprolyl-4-[3-(N,Ndimethylamino)propoxy]-L-phenylal anine N-(4-cyanobenzenesulfonyl)-L-(5 ,5-dimethyl)thiaprolyl-4-[3-(NNdimethylamino)propoxy] -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-(3,3-dimethyl)prolyl-4-[3-(N,Ndimethylamino)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-(5,5-dimethy1)thiaprolyl-4-[3-(N,Ndimethylamino)propoxy]j-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3 .2.2]octan-2yI)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-4-[3-(v,Ndimethylamino)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(2-azabicyclo[3 .2 .2]octan-2yl)ethoxy] -L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(cyclopentyl)ethynyl] D,L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4- 2-[4- (phenyl)phenyllethynyl} -D,L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4- [3-(toluene-4sulfonyloxy)prop- 1 -ynyl]-D,L-phenylalanine N-(toluene-4-sul fonyl)-D,L-phenylalanyl-4-[3-(ureido)prop- I -ynyl] D,L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3-(4ethoxycarbonylphenoxy)prop- I -ynyl]-D,L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4- I -aminocyclohex- I1yl)ethynyl] -D,L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(phenoxy)prop- 1 -ynyl]-D,Lphenylalanine WO 99/06431 PCT/US98/15313 32-- N-(toluene-4-sulfonyl)sarcosyj-4-[3-Qphenoxy)prop- I1-ynyl] -D,Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4[3.(methoxy)prop. 1 -ynyl]-D,Lphenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-[3-(methoxy)prop- I -ynyl]-D,Lphenylalanine N-(toluene- 4 -sufony)Lproyi4[3(4-ethoxycarbonylphenoxy)prop- 1 -ynyfl-D,L-phenylalaniine N-(toluene-4-sul fonyl)sarcosyl-4- 3 4 -ethoxycarbonylphenoxy)prop- 1 -ynyljj-D,L-phenylalanine N-(toluene-4-sulfonyI)-Lproy-4[4,4-di(methoxycarbony)but- 1ynyl] -D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl4[44di (methoxycarbonyl)but- 1 ynyl]-D,L-phenylalanine N-(toluene- 4 -sulfony1)-Lproly14-(4-acetamido.4carboxybut- 1 -ynyl)- D,L-phenylalanine N-(toluene- 4 -sulfonyl)sarcosyl4(4-acetamido-4carboxybut- I -ynyl)- D,L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4 {3-[(4,5-dihydro-4-oxo-5phenyloxazol-2-yl)amino]prop- I-ynyl -D,L-phenylalanine N-(toluene-4-sul fony])sarcosyl-4- f 3-[(4,5-dihydro-4-oxo-5 phenyloxazol-2-yI)aminolprop- 1 -ynyl I -D,L-phenylalanine N-(toluene-4-sulfonyl)-Lprolyl14-[2-(carboxy)phenoxy]-Lphenylalanine methyl ester N-(toluene-4-sul fonyl)-L-prolyl-4- f 2 -1 4 -(pyrimidin-2-yl)piperazin- I1yl]ethoxy} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4 13-(piperidin- 1 -yI)propoxy] -Lphenylalanine N-(toluene-4-sulfonyl)-Lprolyl-4 [2-(pyrroli din- I -yl)ethoxyl-Lphenylalanine N-(toluene-4-sulfonyl).L-prolyl-4-[3.(piperidin- I -yI)propoxy]-Lphenylalanine methyl ester WO 99/06431 WO 9906431PCTIUS98/1 5313 33 N-(toluene-4-sulfonyl)-L-prolyl-4- {3-[4-(3-chlorophenyl)piperazin- 1 yl]propoxy} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[( 1 -tert-butoxycarbonylpiperidin-3 yl)methoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(morpholin-4-yl)ethoxy]-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- -tert-butoxycarbonylpi1peri din-3 yl)methoxy]-L-phenylalanine N-(to luene-4-sul fonyl)-L-pro lyl [2-(pi peri din- I -yl)ethoxy]-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- f{3-[4-(3-chlorophenyl)piperazin- 1 yl]propoxy}-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan- 1 -yl)ethoxy]-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan- I -yI)ethoxy]-Lphenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin- 1 yl)propoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(pyrrolidin- I -yl)ethoxy]-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [3-(4-methylpiperazin- 1 yl)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(morpholin-4-yl)ethoxy]-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-1{2-[4-(3-methoxythien-2-yl)-4hydroxypiperidin- 1-yllethoxy)}-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-3-( 1 -methylpiperidin-4-oxy)-D,Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-( I -methylpiperidin-4-oxy)-D,Lphenylalanine N-(toluene-4-sulfonyl)-L-(s ,5 -dimethyl)thiaprolyl-4-( 1methylpiperidin-4-oxy)-L-phenylalanine ethyl ester WO 99/06431 PCTIUS98/15313 34- N-(toluene-4-sulfonyl)-L-(l 1, -dioxothiomorpholin-3-carbonyl)-4-( 1methylpiperidin-4-oxy)-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(, 1, -dioxothiomorpholin-3-carbonyl)-4-( 1methylpiperidin-4-oxy)-L-phenylalanine ,5-dimethyl)thi aprolyl-4-( I methylpiperidiri-4-oxy)-L-phenylalanine N-(a-toluenesulfonyl)-L-prolyl-4-( I -methylpiperidin-4-oxy)-Lphenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(tri fluoromethanesulfonyl)amino- L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(tri fluoromethanesulfonyl)amino.

L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyi-4-N-(chloromethanesulfonyl)amino-Lphenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsulfonyl)amino-Lphenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-(N-trifluoromethanesulfonyl-Nisobutyl)amino-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsulfonyl)amino-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-benzylaminocarbony)methoxy]- L-phenylalanine methyl ester N-(toluene- 4 -sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]

-L-

phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy]-Lphenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[(aminocarbonyl)methoxy]-Lphenylalanine WO 99/06431 PCTIUS98/15313 35 N-(toluene-4-sulfonyl)-L-prolyl-4-[(v-tertbutylaminocarbonyl)methoxy] -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(4-phenyI.4-hydroxypiperidin 1yl)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl4-(piperidin- 1 -ylcarbonyl)methoxy]- L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-(NAL diisopropylaminocarbonyl)methoxy-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)sarcosyl-D,L..4.(amidino)phenylalanine N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(aminocarbonyl)phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methylacetamido)-Lphenylalanine isopropyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methylacetamido)-Lphenylalanine, N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methyltrifluoroacetamido)-L phenylalanine methyl ester ,5 -dimethyl)thiaprolyl-4- Ndimethylamino)propoxy]-L-phenylalanine t-butyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-4-(N-methylpiperidinoxy)phenylalanine t-butyl ester ,5-dimethyl)thiapropy]-L-(4methylpiperidinoxy) phenylalanine t-butyl ester N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine t-butyl ester N-(toluene-4-sulfonyl)-L-prolyl-(4-phenyl)>L-phenylalanine and pharmaceutically acceptable salts thereof as well as any of the ester compounds recited above wherein one ester is replaced with another WO 99/06431 PCTIUS98/1 5313 36 ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tertbutyl ester.

This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of formula I or IA above under conditions wherein said compound binds to VLA-4.

Certain of the compounds of formula I and IA above are also useful in reducing VLA-4 mediated inflammation in vivo.

This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more the compounds of formula I or IA above with the exception that

R

3 and R 5 are derived from L-amino acids or other similarly configured starting materials. Alternatively, racemic mixtures can be used.

The pharmaceutical compositions may be used to treat VLA-4 mediated disease conditions. Such disease conditions include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetis), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.

Accordingly, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4 which methods comprise administering to the patient the pharmaceutical compositions described above.

WO 99/06431 PCT/US98/15313 37 Preferred compounds of formula I and IA above include those set forth in Table I below: R 3 0 S0 2 N(R 2

-C-Q-CH-C-R

6 I I H R In all cases Q is -C(O)NH- 3 R R Ip-CH 3

R

2 /R 3 Cyclic p-[NHC(O)CH 2 NHBocI-benzyl- -OH 3 carbon atoms (L-pyyrolidinyl) p-CH 3

R

2 /R 3 Cyclic p-[-NHC(O)CH 2

NH

2 I-benzyl- -OH 3 carbon atoms (L-pyrroldinyl) p-CH 3 R 2 /R 3 Cyclic p+[NHC(O)CH 2

CH

2 C(O)OH-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3 -40- R R3= Cyclic 4-[-NHC(O)CH*(CH 3 )NHBoc- -OH 3 carbon atoms benzyl- (L-pyrrolidinyl) (*corresponds to L PC3( R 2 /R1 cyclic 4-t-NHC(O)CH*(CH 3 )NHBoc- -OH 3 carbon atoms benzyl- (L-pyrrolidinyl) _________(*corresponds to D 0 0 00 0% 0% R1 R2 R 3

R-

6'

P-CH

3 -0- R/3= Cyclic 3 carbon atoms (L-pyrrolidinyl) 4-jj-NHC(O)CH *(CH 2 40)NHBocIbenzyl- I -C 4. 4 corresponds to D isomer)

[-NHC(O)CH

2 NHC(O)NH-fluorescinlbenzyI -oH

R

2 cyclic 3 carbon atoms (L-pyrrolidinyl) 4 p-CH 3 -0- R2/3= cyclic 3 carbon atoms (L-pyrrolidinyl) 4-[BocNHCH 2 C(O)NHI-berlzyl- I 4- I p-CH 3 -0- R2/3= Cyclic 3 carbon atoms (L-pyrroldinyl) p-[-NHC(O)CH 2 NHC(O)NH-mmethylphenyll -benzylp-[-NHC(O)CH(NHBoc)(CH 2 ),NHCbzkbenzyl- 4

-OCH

3

-OH

-OH

-OCH

3

-OH

p-CH 3 -0-

R

2

/R

3 Cyclic 3 carbon atoms (L-pyrrolidinyl) 1 4 p-CH 3 R 2

/R

3 Cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-NHC(O)CH 2 CH-NHCbzl-belzyl

C(O)OCH

2

A

1- I p-CH 3 R2/3= Cyclic 3 carbon atoms p-[-NHC(O)CH-NHBocI-belzyi

IHCIIC

2

H

rJ~roldn l I-H-

P-CH

3 -0& R 2

/R

3 Cyclic 3 carbon atoms (L-pyrrolidinyl) p-[NHC(O)CH 2

CH(NH

2

)COOH

-OH

I

R. R R 3 R- R p-H--R 2 cyclic p-(HNCH,1CH,1Cl,C(0)NH4)benzyl- -OFH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2 1R 3 Cyclic p-(Boc-HNCI-ICHCH1 2 C(O)NH)benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2

/R

3 Cyclic p-[CH 3

NHCH

2

CH

2 CH,-C(O)NH-Ibenzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3 40- R 2 cyclic p-[CH 3 (Boc)NCH 2

CH

2

CH

2

-OH

3 carbon atoms C(O)NH-]benzyl- (L-pyrrolidinyl) p-CH 3 -ck- R/3= Cyclic p-[4OCHOCH,(H 2 N)CHC(O)NH]benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2

/R

3 Cyclic p-[HO(O)C(Cbz-NH)CHCH 2

-OH

3 carbon atoms C(O)NH-lhenzyl- (L-pyrrolidinyl) p-CH 3

R

2 IR' cyclic p-[HO(O)C(H,N)CHCHCH 2

-OH

3 carbon atoms C(O)NHI-Ibcnzyl- (L-pyrrolidinyl)

P-CH

3 -40- R 2 cyclic p-ICH 3 (N-Boc)NCH 2 C(O)NH-Ibenzyl- -OH 3 carbon atoms (L-pyrrolidinyl)

'WI.

"0 0 0'~ 0" 0 R' R2 3

R

p-CH 3 cyclic p-f CH 3 (N-Boc)NCti 2 C(O)NH-belzyl- -OH

-CH,-S-C(CH

3 dimethyithiazolidin- 4 -yl)

P-CH

3

R

2 1R 3 Cyclic p-[CH 3 NHCHC(O)NH-JbelY

-OCHCH

3 3 carbon atoms (L-pyrrolidinyl) p-H--R 2 /R 3 Cyclic p-[CH 3

NHCH

2 C(O)NH-benflZY

-OH

3 carbon atoms (L-pyrrolidinyl) P-H--R2/3= Cyclic

PICH

3 NHCH2C(O)NH-benlZl

-OH

-CH-

2

-S-C(CH

3 2 owmethyithiazolidin- 4 p-CH 3 R/3= Cyclic p-I(CH3) 2

NCH

2 C(O)NH-Ibenzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) p-CH 3 -ck- R 2

/R

3 =Cyclic p4[(CH 3 2

NCH

2 C(O)NH-Ibenzyl-

-OH

-CH

2

-S-C(CH

3 2 dimethyithiazolidin- 4 -yl) p-CH 3

R

2

/R

3 Cyclic p+[O-CH(COOH)Ckl-benzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) 0 0% 0% '0 R R2 R3 R5 p-CH- 3

R

2 cyclic p-[o-carboxylplienylj-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CHA)-- R 2 1R' cyclic pjocarboxymthylphenyll-benlzyl- 0C -4 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2 1R' cyclic p-I4OCfl,OC(O)NHCH, 2

CH

2 NH-1-benzyI- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2

/R

3 Cyclic p-[OCH 2 0C(O)NHCH 2

CH

2 NHI-beflzy[ -OCH 3 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2 cyclic p-[-N(CH 2 3

-N(CH

3 h]i-benzyl- -OCH 3 3 carbon atomsI (L.-pyrrolidinyl) 2

CH

3 p-CH 3 R 2

/R

3 Cyclic p-[(Ieni-butyl-O(O)CCH,-O-benzyl)- -OCH 3 3 carbon atoms NH-lbenzyl- (L-pyrrolidinyl) p-CH 3

R

2 1R' cyclic p-j(NN-dii4-N,N- -OH 3 carbon atoms d imethylamino)benzyl)aminolbenzyI- (L-pyrrolidinyl) p-CH 3 -4k- R 2

/R

3 Cyclic p-(2-fornyl-1,2,3,4-tetrahydroisoquinolifl- 3

-OH

3 carbon atoms yl-CH 2 N H-)benzyl- (L-pyrrolidinyl) p-CH3-4.- R 2 cyclic 4-[(CH-I)2NC11 2 CHi,CH1,-O-I-O-Clf 2 -011 3 carbon atoms (L-pyrrolidinyl) p-H---CHj -C" 2 011 p-I(CH,) 2 NCi, 2

CI-

2 0-1-benzyl- -OCH 3 (L isomer) p-H -R 2 1R 3 5,5- p+tCH3) 2 NCHl 2 Cfl,OI-benzyl- -OH dimethyichiazolid in-4-yl

P-CH

3 R 2 cyclic p+[CH 3 2

NCH-

2 Ct1 2 0+Jbenzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH,-4P- R 2

/R

3 Cyclic p-j -OCH,CH,N(O)CH,CH 1 -h-enzyl- -OCH 3 3 carbon atorns (L-pyrrolidinyl)

P-CH

3 -R2/3 cycliC p-Ldi-iso-propylamino-CIlCH' 2 O- -benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3 -4P- R 2

/R

3 cyclic p-I-OCH,CH(NHBoc)CHi,cyclohexyll- -OCH, 3 carbon atoms benzyl (L-pyrrolidinyl) 2-thienyl- R 2 cyclic p-I-OCH 2 ,CHC11 2

N(C"

3 ),'1-benzyl- -OH4 3 carbon atoms (L-pyrrolidinyl) 5-chloro-2- -2R =Cyclic p-I-OCHCH,.CH 2

N(CH

3 2 1-benzyl- -OH thienyl- 3 carbon atoms (L-pyrrolidinyl)

C

0~~

R'-C

2

H

2 2 1 5 )Jbny R-2-R3

R

R6'

P-CH

3 -0-

R

2

/R

3 Cyclic 3 carbon atoms (L-pyrrolidinyl) p-[-OCIICliN(CH ,),I-ben-OH I I- 2, 5-dichloro- 4-thienyl

I

R 2 /R 3 =Cyclic 3 carbon atoms (L-pyrrolidinyl) P+IOCH~ 2 CH CHN(CH3 2 jhbenzyl- P- I-OC H 2 CH 2 C H 2 N(C H 32 1-benzy I-

-OH

pyrazolyl

P-CH

3 -0- R 2

/R

3 =Cyclic 3 carbon atoms (L-pyrrolidinyl) -t R 2

/R

3 Cyclic 3 carbon atoms (L-Dvrrolidinyl) P- [-OCH 2 C H 2 C H 2 N (C 2 H 2 1 belzyl 7-rOCH 3 I_ I- 4-

I

p-CH 3 -0- 2-thiazolyl p-CH 3 -0- R 2 /R 3 Cyclic 3 carbon atoms (L-pyrrolidiriyl)

R

2

/R

3 Cyclic 3 carbon atoms (L-pyrrolidinyl)

-I

m+fOCH 2

CH

2

CHI

2 N(CH,)2J-benzylp+jOc'H 2

CHCH

2

N(CH

3 2 1-benzyl- P-[-OCH4 2

CH

2

CH

2

N(CH

3 )benli-benzyl-

-OH

-OH

-OH

-0O1 3 carbon atoms j (L-pyrrolidinyl) p-CH 3 -40- R R3= Cyclic 3 carbon atoms (L-Dyrrolidinyl) P-[-OCH2CHICH2N(C2H5)21-benzyl- I

I

p-CH 3

R

2 /R 3 Cyclic p-[-OCHi,CH 2

CH

2

N(CH

3 )benzyl-belY- -OCH 3 3 carbon atoms (L-pyrrolidinyl) 1-N-methyl-4- R 2 /R 3 Cyclic p+[OCH 2

CHCH

2

N(CH

3 2 1-beflzyl- -OH imidazolyl 3 carbon atoms (L-pyrrolidinyl) 2-methyl-4- R 2 /R 3 Cyclic p-[-OCH 2

CH

2

CH-

2

N(CH

3 2 1-benzyl- -OH thiadiazolyl 3 carbon atoms (L-pyrrolidinyl)

P-CH

3 p-[-OCH 2

CHCH

2

N(CH

3 )2j-benzyl- -OH thiazol-4-yl p-NC-0- R2/3= Cyclic P-I(CH 3 2 NCH ,CH 2

CH

2 O1benzyl- -OCH 3

-CH

2

-S-C(CH

3 2 dimethyithiazolidin- 4 -yl) p-CH 3 40- R 2 /R 3 Cyclic p-[(CH 3 2

NCH

2

CH

2

CH

2 O1benzyI- -OH

-CH

2

CH

2

C(CH

3 )2r pC3-R 2 /R 3 =Cyclic p-[(CH 3 2

NCH

2

CH

2

CH

2 01benzyl- -OCH 2

CH

3

-CH

2

-S-C(CH

3 2 dimethythiazolidin- 0

P-H--R

2

/R

3 Cyclic p-1 2-(2-azabicyc lo(3 .2.2 2octan- -00 1 3 3 carbon atoms 2-yl)ethiyl-O-Ibenzyl- (L-pyrrolidinyl) p-CH 3

R

2 cyclic p-I(Cl- 3 ),NCHCHCll--1-belzyl-

-OH

-CH

2

CH,-S-CH-

(L-thiomorpholin- 3 -yl) p-H--R 2 1R 3 Cyclic p-[(CH 3 2

NCH

2

CH

2

CH

2 -O-1beflzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2 cyclic

P.I(CH

3 2

NCH

2

CH

2

CH

2 -O-lhelzyl- -OCH.

3 3 carbon atoms (L-pyrrolidinyl)

P-CH

3

R

2 1R 3 Cyclic p-[2-(2-azabicyclo[3.2.2loctal- -OH1 3 carbon atoms 2-Yl)ethyl-O-JhenzyI- (L-pyrrolidinyl) p-CH 3 -0i- p-(cyclopentyl-C =-C-)-benzyl-

-OH

(L isomer)

P-CH

3 H -CH,-O p+C[-C C-qp-1-belzyl- -OH7 isomer) p-CH 3 H -CH 2 -0 p-IC =C-CH 2

-O-S(O)

2 -p-Cll1 3 -PJ-benzyl- -OH (L isomer) p-CH 3 -0r

-CH

2

-(P

isomer) p+IC =-C-CH 2 NHC(O)NlH 2 1-benzyl-

-OH-

.1 J .1 '0 RI RJ RI p-CH 3 H -Cl1,-O p+[-C-C-CH,-O-p-COCI,C1-OI-benzyI- -O1il isomer) p-CH 3 H -0C1-0 p-j-C =-C-CI(N 2 )-cyclohexyJ-benzyl- -OH (L isomer) p-CH 3

R

2 /R 3 cyclic p+[C C-Cli-O-phenylj-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

-CH

3 11i p-I-C C-CH,-O-phenyl]-benzyl- -OH /R3= Cyclic p4- C-CH 2

-OCH

3 1-benzyI- -OH 3 carbon atoms (L-pyrrolidinyl) If P-I-C -=C-Cl 1 2 -OCI1 3 j -benzy I- -OH p-CH,-O- R 2 cyclic C-CH4 2 -O-p-(-C(O)0C 2 1f,)plliyl I- -OH- 3 carbon atoms beozyl- (L-pyrrolidinyl) p-CH 3 -Cl-i H p-I-C C-CH 2

-O-P-(-C(O)OC

2

H

5 )phenylI- -OH p-H--R 2

/R

3 Cyclic C-CH 2

CH(C(O)OCH

3 2 1-henzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

-CH

3 H P-I-C- C-CHCH(C(O)OCH) 2 I-benzyl- -OHp-CH 3 R R cyclic p+fC C-CH 2 CHC(O)OHI-benzyl--O 3 carbon atomsI (L-pyrrolidinyl) 3 0% 00 R' R' R 5 p-CH 3

-CH

3 Ifp-I(C' -CH 2 CIC(O)Oli]-benzyl- -OH N 1- C (O )C H 3 p-CH 3

R

2 /R 3 Cyclic p-IC -=C-CH 2 NI--(4,5-dihydro-4-oxo- -01- 3 carbon atoms 5-phenyl-oxazol-2-yl)Jbenzyl (1,-pyrrolidinyl) p-CH 3 -0b- -CH, p-IC =-C-CH 2 NH-(4,5-dihydro-4-oxo- -O1- ________________5-phenyl-oxazol-2-yIljbenzyl p-CH,-O- R 2 /R 3 Cyclic p-[-O-(o-carboxyphenyl)J-benzyl -OCH3 3 carbon atoms (L-pyrrolidinyl) p-CH 3 R 2 /R 3 Cyclic p-[-OCH 2

CH

2 0- 3 carbon atoms yiiiy)pprznl-eyl (L-pyrrolidinyl)pyidnl)ierzyj-nyp-CH 3 R R cyclic p-f -OCH-ICH-(l -piperidinyl)-henzyl- -OH7 3 carbor, atorns (L-pyrrolidinyl) p-CH 3 -40- cyclic P-[-OCH 2

CH

2 -(I-pyrrolidinyl)]-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) pC3A R 2 cyclic p-f-OCH 2 C11 2 CH2-(1-piperadinyl)]-benzyl-

-OCH

3 3 carbon atoms (L-pyrrolidinyl) p-H--R 2 cyclic p-[-OCH 2

CHCH

2

-OH

3 carbon atorns n-hoohnl-i'rznl-ez (L-pyrrolidinyl) Iiclrpey)pprznl-ezl R R 2 R R

P-H--R

2 cyclic p-I-OCHi,-3-(N-Boc)-piperidinyll-benizyl- -011 3 carbon atoms (I.-pyrrolidinyl) /R3= Cyclic p-[-OCHCH,-(N-morpholinyl)J-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) pC30R2/,= Cyclic P-[OCHi 2 CH,1-(N-piperidinyll-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2 cyclic p-[-OCH 2

CH

2

CH

2 0OCH 3 3 carbon atoms ,n-chlorophenyl)-piperazinyl]-benzyl- (L-pyrrolidinyl) cyclic p-[-OCIICH,-(N-homopiperidinyl)-benzyI -OH 3 carbon atoms (L-pyrrolidinyl) cyclic p-l-OCHCH 2 (N-homopiperidinyI)-benzyI -OCli 3 3 carbon atoms (L-pyrrolidinyl) p-CH- 3

R

2 cyclic p-I-OCHCH 2

CH

2 I-(4-methyl)- -OCH 3 3 carbon atoms piperazinylj-benzyl- (L-pyrrolidinyl) p-H--R 2 cyclic in-[-OCH 2

CH

2 I-pyrrolidinyl)]-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl)

ON

p-CLI 3 R' /R 3 cyclic p-I -OCCII,Cl 2 I, 1-(4-m-ethyl)--O 3 carbon atonis p iperazi nyl I-hcnzyl- (L-pyrrolidinyl) p-CH- 3 3=Cyclic

P-[-OCH

2 lCH 2 -(N-morpholino)j-benzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) p-CH 3 4- R 2

/R

3 Cyclic p+[OCH 2 CH2 I -(4-hydroxy-4-

-OCH

3 3 ([-prbon atonyl (3-methoxypyrrol-2-yl)-piperazinyll- (L-pyrolidnyl)benzylp-H--R 2 /R 3 Cyclic p-[-O-(3-(N-Boc)-piperidinyll-benzyl- 0HF 3 carbon atoms (L,-pyrrolidinyl) p-CH 3

R

2 /R3 Cyclic rn-[O-(N-methyl-piperidin-4-ylJ-benzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2 cyclic p-[-O-(N-methylpiperidin-4-yl)]-benzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2

/R

3 Cyclic p-[(1-methylpiperidin-4-yl)-O-Jbenzyl-

-OCHCH

3

-CH

2

-SC(CH

3 )r p-H--R 2 cyclic -methylpiperidin-4-yl)-O-]benzyl-

-OCHCH

3

-CHCH

2

SO,CH,-

1, 1dioxothiomorphol in-

ON

0

R

2 cyclic p-I(l-niethylpiperidin-4-yl)-O-Ibenzyl- -OCH,CH 3 -CHCli,-So,-C-lI,dioxoth lomorpholi n- 3 -yl) p-CH 3 -40- R 2 cyclic p-[Il-rncthylpiperidin-4-yl)-O-lbenzyl- -014 -CHCFI,-SorC1 '2 ,lId ioxothiomorphol in.

3 -yl)

P-CH-

3

R

2 /R 3 Cyclic -methylpiperidin-4-yl)-O-jhenzyl- -OHl

-CH

2

-S-C(CH

3 2 dimethylthiazolid in- 4 -yl)

O-HR

2 cyclic [p-I (1 -nethylpiperidin-4-yl)-O-Jbenzyl- -OCH 2

CH

3 3 carbon atoms (L-pyrrolidinyl) p-CH 3 -4i- R 2 1R 3 Cyclic p-[-NHSOCF 3 ]-benzyl- -OCH 3 3 carbon atoms (L-pyrrolidinyl) p-H1-R 2 cyclic p-[-NH-SO 2

CF

3 I-benzyl- -OH 3 carbon atoms (L-pyrrolidinyl) p-H--R 2

/R

3 Cyclic p-INHSO 2 -CHCIj-benzyl- -OCH 3 3 carbon atoms (L-pyrrolidinyl) RIR

R

3

IR

R

p-CH-0 R 2 cyclic p-I-NHSO-ClFI =CHI-benzyl-

-OCH

3 3 carbon atoms (L--pyrrolidinyl) p-CH 3

R

2 1R' cyclic p-[N-3-methylbutyl-N- 01C3 3 carbon atoms tilooehnsloy~mnlezl (L-pyrrol idinyl) tilooehnsloy~mnjez! p-CH- 3

R

2 /R 3 cyclic p-IN-vinylsulfonyl)aminojbenzyl-

-OH

3 carbon atomns (L-pyrrolidinyl) p-H--R 2 cyclic p-IOCH 2 C(O)Nf4-benzylp-benzyl-

-OCH

3 3 carbon atoins (L-pyrrolidinyl) pC3 R 2 cyclic p-1-OCHC(O)O-benzylj-benzyl-

-OCH,

3 carbon atoms (L,-pyrrolidinyl) p-CH 3 R 2 cyclic p-I-OCH2C(O)NH-benzylI-benzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) p-H--R 2 cyclic p-IOCfH 2 C(O)OHJ-benzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) p-CH 3 -0- cyclic 3 carbon atoms (L-pyrrolidinyl) P-[-OC-1C(O)NH 2 ]-benzyl-

-OCH

3 R1 2 IRj cyclic p-[-OCH 2

CCO)NUH

2 I-hcnzyl-

O

3 carhon atoms (L-pyrrolidinyl) p-CH 3 -cfr.2/R cyclic p-i -OClI 2 C(O)NH-t-butyll-benzyl- -oH 3 carbon atoms (L.-pyrrolidin yl) p-CH 3

R

2 /RI cyclic

,"-IOCH

2 lCHl 2 -(4-hydroxy-4-

-OH

3 carbon atoms phenyl)-piperidinyll- (L--pyrrolidinyl) beflzyl- P-CI1 3

R

2 1R' cyclic p-I (piperidini- 1-yl)C(O)CH 2 -O-Ibenzyl-

-OH

3 carbon atoms (L.-pyrrolidinyl)

P-CH

3 R 2 cyclic p-I (CHI)2CHI),NC(O)CH 2 -O-jbenzyI-

-OCH,

3 carbon atoms (L-pyrrolidinyl) p-CH 3 cyclic

P-[(CH

3 )2CH 2

NC(O)CH

2 -O-Jbenzyl-

-OH

3 carbon atoms (L-pyrrolidinyl) Cl13__O -ClH, H p-I-C( NH)NHJ-benzyl-

-OH

P-CH

3 -4i-

-CH

3 R R cyclic 3 carbon atoms (L-pyrrolidinyl) H jp+IC(O)NH 2 Jbnzl I -OH p-(N-methylacetamido)benzyl-

-OCIH(CH,),

P-"l- 3

R

2

/R

3 =Cyclic p-(N-rncthylacetamido)benzyl- -0H 3 carbon atoms (L-pyrrolidinyl) p-CH 3 R2-R cyclic p-(N-methylcrifluoroacetamido)benzyl- 0OCH, 3 carbon atoms (L-pyrrolidinyl) p-H--R 2 /R 3 Cyclic (1-toluenesulfonylirniidizol-4-yl)methyl-

-OCH

3 3 carbon atoms (L-pyrrolidinyl)

P-C'H

3 cyclic i N-dimetliylamninosulfonylj-imidizol-4-

-OCH

3 3 carbon atonms yl)inethyl- (L-pyrrolidinyl) p-CH 3

R

2 1R' cyclic p-(N-toluenesul fony lam ino)benzyl- -OCH, 3 carbon atoms (L-pyrrolidinyl) p-CH 3

R

2 cyclic p-(N-toluenesulfonylamino)benzyl-

-OH

3 carbon atoms (L-pyrrolidinyl)

P-CH

3

R

2 /R 3 Cyclic p(-Ndiehlrpx)brzl

O(H)

-CH

2

-S-C(CH

3 2 p(-,-intypooy-ezl

O(H)

dimethyithiazolidiin- 4 -yl) p-H -R 2 1R 3 Cyclic p-(N-methyliperidinoxy)-benzyl-

-OC(CH

3 3 3 carbon atoms (L-pyrrolidinyl) p-H--R 2 cyclic p-(N-inetliyiperidinoxy)-beftzyl-

-OC(CH

3 3 dimethylthiazolidin- 4 p-H--R 2

/R

3 Cyclic p-(O)-benyl- -OC(CH 3 3 3 carbon atoms (1-pyrrolidinyl) p-CH- 3 16- R 2

/R

3 cycliC p-(O)-benyl-

-OH

3 carbon atoms (L-pyrrolidinyl) WO 99/06431 PCT/US98/1 5313 56-- DETAILED DESCRIPTION OF THE INVENTION As above, this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.

However, prior to describing this invention in further detail, the following terms will first be defined.

Definitions As used herein, "alkyl" refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.

"Substituted alkyl" refers to an alkyl group, preferably of from 1 to carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, alkylthioamidinio, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-OS(O)

2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O),-heteroaryl,

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O)2-substituted heterocyclic, -OS0 2 -NRR where R is hydrogen or alkyl, WO 99/06431 PCT/US98/15313 57--

-NRS(O)

2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 substituted aryl, -NRS(O)2-heteroaryl, -NRS(O) 2 -substituted heteroaryl,

-NRS(O)

2 -heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2

-NR-

alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2

-NR-

substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono07and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0,-substituted alkyl, -SO-,-alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -S0 2 -aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -50-substituted heteroaryl, -S0 2 -heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl.

"Alkoxy" refers to the group "alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1 ,2-dimethylbutoxy, and the like.

"Substituted alkoxy" refers to the group "substituted alkyl-0-".

"Acyl" refers to the groups alkyl-C(0)-, substituted alkylalkenyl-C(0)-, substituted alkenyl-C(0)-, alkynyl-C(0)-, substituted alkynyl-C(0)- cycloalkyl-C(0)-, substituted cycloalkyl-C(0)-, aryl-C(0)-, substituted aryl-C(0)-, heteroaryl-C(O)-, substituted heteroaryl-C(0), heterocyclic-C(0)-, and substituted heterocyclic-C(0)- wherein alkyl, WO 99/06431 PCT/US98/15313 58 substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Acylamino" refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Thiocarbonylamino" refers to the group -C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkylalkenyl-C(O)O-, substituted alkenyl-C(0)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkylsubstituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)Owherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, WO 99/06431 PCT/US98/1 5313 59substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Alkenyl" refers to alkenyl group preferably having from 2 to carbon atoms and more preferably 2 to 6 carbon atoms and having at least I and preferably from 1-2 sites of alkenyl unsaturation.

"Substituted alkenyl" refers to alkenyl groups having from I to substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxylsubstituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O)2-alkyl, -OS(0)2substituted alkyl, -OS(0) 2 -aryl, -OS(0) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(0) 2 -substituted heteroaryl, -OS(O)-heterocyclic, -OS(0) 2 -substituted heterocyclic, -OS0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl,

-NRS(O)

2 -substituted alkyl, -NRS(0) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(0) 2 -heteroaryl, -NRS(0) 2 -substituted heteroaryl, -NRS(0) 2 heterocyclic, -NRS(0) 2 substituted heterocyclic, -NRS(O) 2 -NR-alkyl, WO 99/06431 PCT/US98/15313

-NRS(O)

2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl,

-NRS(O)

2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mone- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with -S0 2 -alkyl, -SO,-substituted alkyl, -SO,-2 alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -SO,-substituted cycloalkyl, -S0 2 -aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S 2 Oi-substituted heteroaryl, -S0 2 -heterocyclic, -S0 2 -substituted heterocyclic and -SO 2

NRR

where R is hydrogen or alkyl.

"Alkynyl" refers to alkynyl group preferably having from 2 to carbon atoms and more preferably 3 to 6 carbon atoms and having at least I and preferably from 1-2 sites of alkynyl unsaturation.

"Substituted alkynyl" refers to alkynyl groups having from 1 to substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxylsubstituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, WO 99/06431 WO 9906431PCTIUS98/1 5313 guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-OS(O)

2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl,

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O)2-substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS (O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O)2-substituted aryl,

-NRS(O)

2 -heteroaryl, -NRS(O)-,-substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl,

-NRS(O)

2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl,

-NRS(O)

2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amnino, mono- and di-arylamino, mono- and-di -substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroaryl amino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formnyl, and the like or alkynyl/substituted alkynyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -SO 2 alkenyl, -502-substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -S0 2 -aryl, -S0 2 -substituted aryl, -SO2-hteroaryl, -S0 2 -substituted heteroaryl, -S0 2 -heterocyclic, -S0 2 -substituted heterocyclic and -SO 2

NRR

where R is hydrogen or alkyl.

WO 99/06431 PCT/US98/15313 62 "Amidino" refers to the group H 2 NC- and the term "alkylamidino" Nil refers to compounds having I to 3 alkyl groups alky]H-NC-).

11

NE

"Thioamidino" refers to the group RSC- where R is hydrogen or 11 Nil alkyl.

"Aminoacyl" refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substi tuted cycloalkyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl, -NRC(O)alkynyl, -NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl, -NRC(O)heteroaryl, -NRC(O)substituted heteroaryl, -NRC(O)heterocyclic, and -NRC(O)substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminocarbonyloxy" refers to the groups -NRC(O)O-alkyl, -NRC(O)O- substituted alkyl, -NRC(O)O-alkenyl, -NRC(O)O-substituted alkenyl, -NRC(O)O-alkynyl, -NRC(O)O-substituted alkynyl, -NRC(O)Ocycloalkyl, -NRC(O)O-substituted cycloalkyl, -NRC(O)O-aryl, -NRC(O)Osubstituted aryl, -NRC(O)O-heteroaryl, -NRC(O)O-substituted heteroaryl, -NRC(O)O-heterocyclic, and -NkC(O)O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

WO 99/06431 PCTIUS98/1 5313 63 "Oxycarbonylamino" refers to the groups -OC(O)N1 2

-OC(O)NRR,

-OC(O)NR-alkyl, -OC(O)NR-substituted alkyl, -OC(O)NTR-alkenyl, -OC(O)NIR-substituted alkenyl, -OC(O)NR-alkynyl, -OC(O)NR-substituted alkynyl, -OC(O)NR-cycloalkyl, -OC(O)NR-.substituted cycloalkyl, -OC(O)NR-aryl, -OC(O)NR-substituted aryl, -OC(O)NR-heteroaryl, -OC(O)NR-substituted heteroaryl,- OC(O)NR-heterocyclic, and -OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkeny!, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Oxythiocarbonylamino" refers to the groups -OC(S)NH 2 -OC(S)NRR, -OC(S)NR-alkyl, -OC(S)NR-substituted alkyl, -OC(S)NRalkenyl, -OC(S)NR-substituted alkenyl, -OC(S)NR-alkynyl,

-OC(S)NR-

substituted alkynyl, -OC(S)NR-cycloalkyl, -OC(S)NR-substituted cycloalkyl, -OC(S)NR-aryl, -OC(S)NR-substituted aryl, -OC(S)NR-heteroaryl, -OC(S)NR-substituted heteroaryl, -OC(S)NR-heterocyclic, and -OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminocarbonylamino" refers to the groups -NRC(O)NRR, -N7RC(O)NR-alkyl, -NRC(O)NR-substituted alkyl, -NRC(O)NR-alkenyl, -NRC(O)NR-substituted alkenyl, -NRC(O)NR-alkynyl,

-NRC(O)NR-

substituted alkynyl, -NRC(O)NR-aryl, -NRC(O)NR-substituted aryl, -NRC(O)NR-cycloalkyl, -NRC(O)NR-substituted cycloalkyl,

-NRC(O)NR-

heteroaryl, and -NRC(O)NR-substituted heteroaryl, -NRC(O)NR-heterocyclic, WO 99/06431 PCT/US98/15313 64 and -NRC(O)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminothiocarbonylamino" refers to the groups -NRC(S)NRR, -NRC(S)NR-alkyl, -NRC(S)NR-substituted alkyl, -NRC(S)NR-alkenyl, -NRC(S)NR-substituted alkenyl, -NRC(S)NR-alkynyl,

-NRC(S)NR-

substituted alkynyl, -NRC(S)NR-aryl, -NRC(S)NR-substituted aryl, -NRC(S)NR-cycloalkyl, -NRC(S)NR-substituted cycloalkyl, -NRC(S)NRheteroaryl, and -NRC(S)NR-substituted heteroaryl, -NRC(S)NR-heterocyclic, and -NRC(S)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring phenyl) or multiple condensed rings naphthyl or anthryl) which condensed rings may or may not be aromatic 2 -benzoxazolinone, 2H-1, 4 -benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls include phenyl and naphthyl.

Substituted aryl refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, WO 99/06431 WO 9906431PCT/US98/1 5313 acylamino, thiocarbonyl amino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl -substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocycilic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl;, thioaryl, substituted thioaryl, thi oheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-S(O)

2 -alkyl, -S(O) 2 -substituted alkyl, -S(O) 2 -cycloalkyl, -S(O) 2 -substituted cycloalkyl,

-S(O)

2 -alkenyl, -S(O) 2 substituted alkenyl, -S(O) 2 -aryl, -S(O) 2 -substituted aryl, -S(O) 2 -heteroaryl,

-S(O)

2 -substituted heteroaryl, -S(O) 2 -heterocyclic, -S(O) 2 -substituted heterocyclic, -OS(O)2-alkyl,

-OS(O)

2 -substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where Ris hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 aryl, -NRS (O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS(O) 2 -substituted heterocyclic,

-NRS(O)

2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl,

-NRS(O)

2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl,

-NRS(O)

2

-NR-

substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, monoand di-(substituted alkyl)amino, mono- and di-arylamino, mono- and disubstituted arylamino, mono- and di-heteroarylamino, mono- and di- WO 99/06431 PCT/US98/15313 66 substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and disubstituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with

-SO

2 NRR where R is hydrogen or alkyl.

"Aryloxy" refers to the group aryl-O- which includes, by way of example, phenoxy, naphthoxy, and the like.

"Substituted aryloxy" refers to substituted aryl-O- groups.

"Aryloxyaryl" refers to the group -aryl-O-aryl.

"Substituted aryloxyaryl" refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxylsubstituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, WO 99/06431 WO 9906431PCTIUS98/15313 67substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S(O) 2 -alkyl, -S(O) 2 -substituted alkyl, -S(O) 2 -CYCloalkyl, _S (O) 2 substituted cycloalkyl, -S(O) 2 -alkenyl, -S(O) 2 substituted alkenyl, -S(O) 2 -aryl, -S(O),-substituted aryl, -S(O) 2 -heteroaryl,

-S(O)

2 -substituted heteroaryl, -S(O),-heterocyclic, -S(O) 2 -substituted heterocyclic, -OS(O) 2 -alkyl, -OS(O) 2 -substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O),-substituted alkyl, -NRS(O) 2 aryl, -NRS(O) 2 -substituted aryl, -NRS(O)-,-heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS (O) 2 -heterocyclic, -NRS(O)2-substituted heterocyclic,

-NRS(O)

2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NIRS(O) 2 -NR-aryl,

-NRS(O)

2 -NR--substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2

-NR-

substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, monoand di-(substituted alkyl)amino, mono- and di-arylamino, mono- and disubstituted arylamino, mono- and di-heteroarylamino, mono- and disubstituted heteroarylamino, mono- and di-heterocyclic amino, mono- and disubstituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with

-SO

2 NRR where R is hydrogen or alkyl.

"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.

WO 99/06431 WO 9906431PCT/US98/15313 68 "Cycloalkenyl" refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.

"Substituted cycloalkyl" and "substituted cycloalkenyl" refer to a cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbon atoms, having from 1 to 5 substituents selecked from the group consisting of oxo thioxo alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxylsubstituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl -substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0) 2 -alkyl, -OS(0) 2 substituted alkyl, -OS(0) 2 -aryl, -OS(0) 2 -substituted aryl, -OS(0) 2 -heteroaryl, -OS(0) 2 -substituted heteroaryl, -OS(0) 2 -heterocyclic, -OS(0) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(0) 2 -alkyl, -NRS(0) 2 -substituted alkyl, -NRS(0) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(0) 2 -heteroaryl, -NRS(0) 2 -substituted heteroaryl, -NRS(0) 2 heterocyclic, -NRS(0)2-substituted heterocyclic, -NRS(0) 2 -NR-alkyl, -NRS(0) 2 -NR- substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS (0) 2 -NR- substituted aryl, -NRS(0) 2 -NR-heteroaryl, -NRS(0) 2 -NR-substituted heteroaryl, -NRS(0) 2 -NR-heterocyclic, -NRS(0)2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted WO 99/06431 PCT/US98/15313 69alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with -SO,-alkyl, -SO,-substituted alkyl, -SO2 alkenyl, -S0 2 -substituted alkenyl, -SO,-cycloalkyl, -SO,-substituted cycloalkyl, -SO 2 -aryl, -SO,-substituted aryl, -SO,-heteroaryl, -SO,-substituted heteroaryl, -S0 2 -heterocyclic, -SO,-substituted heterocyclic and -SO,NRR where R is hydrogen or alkyl.

"Cycloalkoxy" refers to -O-cycloalkyl groups.

"Substituted cycloalkoxy" refers to -O-substituted cycloalkyl groups.

"Guanidino" refers to the groups -NRC(=NR)NRR, -NRC(=NR)NR-alkyl, -NRC(=NR)NR-substituted alkyl, -NRC(=NR)NRalkenyl, -NRC(=NR)NR-substituted alkenyl, -NRC(=NR)NR-alkynyl, -NRC(=NR)NR-substituted alkynyl, -NRC(=NR)NR-aryl, -NRC(=NR)NR-substituted aryl, -NRC(=NR)NR-cycloalkyl, -NRC(=NR)NR-heteroaryl, -NRC(=NR)NR-substituted heteroaryl, -NRC(=NR)NR-heterocyclic, and -NRC(=NR)NR-substituted heterocyclic where each R is independently hydrogen and alkyl as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Guanidinosulfone" refers to the groups -NRC(=NR)NRSO,-alkyl, WO 99/06431 PCT/US98/15313

-NRC(=NR)NRSO

2 -substituted alkyl, -NRC(=NR)NRSO 2 -alkenyl,

-NRC(=NR)NRSO

2 -substituted alkenyl, -NRC(=NR)NRSO 2 -alkynyl,

-NRC(=NR)NRSO

2 -substituted alkynyl, -NRC(=NR)NRSO 2 -aryl,

-NRC(=NR)NRSO

2 -substituted aryl, -NRC(=NR)NRSO 2 -cycloalkyl, -NRC(=NR)NRSO,-substituted cycloalkyl, -NRC(=NR)NRSO,-heteroaryl, and -NRC(=NR)NRSO 2 -substituted heteroaryl,

-NRC(=NR)NRSO

2 heterocyclic, and -NRC(=NR)NRSO 2 -substituted heterocyclic where each R is independently hydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.

"Heteroaryl" refers to an aromatic carbocyclic group of from 2 to carbon atoms and I to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring pyridyl or furyl) or multiple condensed rings indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl.

"Substituted heteroaryl" refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, WO 99/06431 WO 9906431PCTIUS98/1 5313 carboxyl-substituted aryl, carboxylieteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiohieteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thiohieterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino,

-S(O)

2 -alkyl, -S(O) 2 -substituted alkyl, -S(O)2cycloalkyl, -S(O)-,-substituted cycloalkyl, -S(O)2-alkenyl, -S(O) 2 -substituted alkenyl, -S(O)2-aryl, -S (O) 2 -substituted aryl, -S(O)2-heteroaryl,

-S(O)

2 substituted heteroaryl, -S(O) 2 -heterocyclic, -S(O) 2 -substituted heterocyclic,

-OS(O)

2 -alkyl, -OS(O) 2 -substituted alkyl, -OS(O)2-aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 aryl, -NRS (O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS(O) 2 -substituted heterocyclic,

-NRS(O)

2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl,

-NRS(O)

2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2

-NR-

substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, monoand di-(substituted alkyl)amino, mono- and di-arylamnino, mono- and disubstituted arylamino, mono- and di-heteroarylamino, mono- and disubstituted heteroarylamino, mono- and di-heterocyclic amino, mono- and disubstituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on -the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with

-SO

2 NRR where R is hydrogen or alkyl.

WO 99/06431 PCT/US98/15313 72 "Heteroaryloxy" refers to the group -O-heteroaryl and "substituted heteroaryloxy" refers to the group -O-substituted heteroaryl.

"Heterocycle" or "heterocyclic" refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be aryl or heteroaryl.

"Saturated heterocyclic" refers to heterocycles of single or multiple condensed rings lacking unsaturation in any ring carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).

"Unsaturated heterocyclic" refers to non-aromatic heterocycles of single or multiple condensed rings having unsaturation in any ring carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).

"Substituted heterocyclic" refers to heterocycle groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo thioxo alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxylsubstituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, WO 99/06431 PCTIUS98/15313 73substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocycljyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylaniino,

-OS(O)

2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl,

-OS(O)

2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl,

-NRS(O)

2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl,

-NRS(O)

2 -heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O)2-NR-alkyl, -NRS(O),-NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl,

-NRS(O)

2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetnic di-substituted amines having differenit substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -SO 2 alkenyl, -S0 2 -substituted alkenyl, _S0 2 -CYCloalkyl, -S0 2 -substituted cycloalkyl, -S0 2 -aryl, -S0,-substituted aryl, -SO 2 -hteroaryl, -S0 2 -substituted heteroaryl, -S0 2 -heterocyclic, -S0 2 -substituted heterocyclic and -SO 2

NRR

where R is hydrogen or alkyl.

Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, WO 99/06431 PCT/US98/15313 74 quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[bJthiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

"Saturated substituted heterocyclic" refers to substituted heterocycles of single or multiple condensed rings lacking unsaturation in any ring carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).

"Unsaturated substituted heterocyclic" refers to non-aromatic substituted heterocycles of single or multiple condensed rings having unsaturation in any ring carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).

"Heterocyclyloxy" refers to the group -O-heterocyclic and "substituted heterocyclyloxy" refers to the group -O-substituted heterocyclic.

"Substituted alkylcarbonylamino" refers to the group -NHC(0)substituted alkyl.

"Thiol" refers to the group -SH.

"Thioalkyl" refers to the group -S-alkyl.

"Substituted thioalkyl" refers to the group -S-substituted alkyl.

"Thiocycloalkyl" refers to the groups -S-cycloalkyl.

WO 99/06431 PCT/US98/15313 75 "Substituted thiocycloalkyl" refers to the group -S-substituted cycloalkyl.

"Thioaryl" refers to the group -S-aryl and "substituted thioaryl" refers t the group -S-substituted aryl.

"Thioheteroaryl" refers to the group -S-heteroaryl and "substituted thioheteroaryl" refers to the group -S-substituted heteroaryl.

"Thioheterocyclic" refers to the group -S-heterocyclic and "substituted thioheterocyclic" refers to the group -S-substituted heterocyclic.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Compound Preparation The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

WO 99/06431 PCT/US98/15313 76-- Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G.

M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

Furthermore, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

In a preferred method of synthesis, the compounds of formula I and IA wherein Q is -C(O)NR 7 are prepared by first coupling an amino acid of formula II:

R

3

R

2 -NH-CH-COOH

II

wherein R 2

R

3 and R 4 are as defined above, with a sulfonyl chloride of formula III: WO 99/06431 PCT/US98/15313 77-- R'-SO2-CI

II

wherein R' is as defined above, to provide an N-sulfonyl amino acid of formula IV:

R

3

R'-SO

2

-N(R

2 )-CH-COOH

IV

wherein R'-R 3 are as defined above.

This reaction is typically conducted by contacting the amino acid of formula II with at least one equivalent, preferably about 1.1 to about 2 equivalents, of sulfonyl chloride III in an inert diluent such as dichloromethane and the like. Generally, the reaction is conducted at a temperature ranging from about -70'C to about 40 0 C for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base. Upon completion of the reaction, the resulting N-sulfonyl amino acid IV is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.

The amino acids of formula II employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Examples of suitable amino acids for use in this reaction include, but are not limited to, L-proline, trans-4-hydroxyl-L-proline, cis-4-hydroxyl-L-proline, trans-3-phenyl-Lproline, cis-3-phenyl-L-proline, L-(2-methyl)proline, L-pipecolinic acid, L- WO 99/06431 PCT/US98/15313 78 azetidine-2-carboxylic acid, L-indoline-2-carboxylic acid, L-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L- (5,5-dimethyl)thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid, glycine, 2-tert-butylglycine, D,L-phenylglycine, L-alanine, c~methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D,Lphenylsarcosine, L-aspartic acid f-tert-butyl ester, L-glutamic acid y-tertbutyl ester, L-(O-benzyl)serine, 1-aminocyclopropanecarboxylic acid, 1aminocyclobutanecarboxylic acid, 1 -aminocyclopentanecarboxylic acid (cycloleucine) 1 -aminocyclohexanecarboxylic acid, L-serine and the like. If desired, the corresponding carboxylic acid esters of the amino acids of formula II, such as the methyl esters, ethyl esters and the like, can be employed in the above reaction with the sulfonyl chloride III. Subsequent hydrolysis of the ester group to the carboxylic acid using conventional reagents and conditions, treatment with an alkali metal hydroxide in an inert diluent such as methanol/water, then provides the N-sulfonyl amino acid IV.

Similarly, the sulfonyl chlorides of formula III employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Such compounds are typically prepared from the corresponding sulfonic acid, from compounds of the formula R'-S0 3 H where R' is as defined above, using phosphorous trichloride and phosphorous pentachloride. This reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorous trichloride and phosphorous pentachloride, either neat or in an inert solvent, such as dichloromethane, at temperature in the range of about 0°C to about 80°C for about 1 to about 48 hours to afford the sulfonyl chloride. Alternatively, the sulfonyl chlorides of formula III can be prepared from the corresponding thiol compound, from compounds of the formula R'-SH where R' is as defined above, by treating the thiol with chlorine (Cl 2 and water under conventional reaction conditions.

WO 99/06431 PCT/US98/15313 79-- Examples of sulfonyl chlorides suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1 -butanesulfonyl chloride, benzenesulfonyl chloride, 1naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, ptoluenesulfonyl chloride, a-toluenesulfonyl chloride, 4acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4dichlorobenzenesulfonyl chloride, 3 ,5-dichlorobenzenesulfonyl chloride, 3,4dimethoxybenzenesulfonyl chloride, 3,5 -ditri fluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesul fonyl chloride, 4methylamidobenzenesul fonyl chloride, 4-nitrobenzenesulfonyl chloride, 4thioamidobenzenesulfonyl chloride, 4-tri fluoromethylbenzenesul fonyl chloride, 4 -trifluoromethoxybenzenesulfonyl chloride, 2,4,6trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonyl chloride, dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonyl chloride, 2-methyl- 4-thiazolesulfonyl chloride, 1 -methyl-4-imidazolesulfonyl chloride, 1 -methyl- 4-pyrazolesulfonyl chloride, 5-chloro-1I,3-dimethyl-4-pyrazolesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride, and the like. If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used in place of the sulfonyl chloride in the above reaction to. form the N-sulfonyl amino acids of formula IV.

The intermediate N-sulfonyl amino acids of formula IV can also be prepared by reacting a sulfonamide of formula V: R'-S0 2 V WO 99/06431 PCT/US98/15313 wherein R' and R 2 are as defined above, with a carboxylic acid derivative of the formula L(R 3 )CHCOOR where L is a leaving group, such as chloro, bromo, iodo, mesylate, tosylate and the like, R 3 is as defined above and R is hydrogen or an alkyl group. This reaction is typically conducted by contacting the sulfonamide V with at least one equivalent, preferably 1.1 to 2 equivalents, of the carboxylic acid derivative in the presence of a suitable base, such as triethylamine, in an inert diluent, such as DMF, at a temperature ranging fromabout 24 0 C to about 37'C for about 0.5 to about 4 hours. This reaction is further described in Zuckermann et al., J. Am. Chem. Soc., 1992, 114, 10646- 10647. Preferred carboxylic acid derivatives for use in this reaction are achloro and a-bromocarboxylic acid esters such as tert-butyl bromoacetate, and the like. When an carboxylic acid ester is employed in this reaction, the ester group is subsequently hydrolyzed using conventional procedures to afford an N-sulfonyl amino acid of formula IV.

The compounds of formula I are then prepared by coupling the intermediate N-sulfonyl amino acid of formula IV with an amino acid derivative of formula VI: 0 Ii

R'-NH-CH-C-R

6

VI

R

wherein R'-R 7 are as defined above. This coupling reaction is typically conducted using well-known coupling reagents such as carbodiimides,

BOP

reagent (benzotriazol-1 -yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like. Suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide (DCC), 1-( 3 -dimethylaminopropyl)-3ethylcarbodiimide (EDC) and the like. If desired, polymer supported forms of carbodiimide coupling reagents may also be used including, for example, those described in Tetrahedron Letters, 34(48), 7685 (1993). Additionally, WO 99/06431 PCT/US98/15313 81 well-known coupling promoters, such as N-hydroxysuccinimide, 1hydroxybenzotriazole and the like, may be used to facilitate the coupling reaction.

This coupling reaction is typically conducted by contacting the Nsulfonylamino acid IV with about 1 to about 2 equivalents of the coupling reagent and at least one equivalent, preferably about 1 to about 1.2 equivalents, of amino acid derivative VI in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,Ndimethylformamide and the like. Generally, this reaction is conducted at a temperature ranging from about 0°C to about 37°C for about 12 to about 24 hours. Upon completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.

Alternatively, the N-sulfonyl amino acid IV can be converted into an acid halide and the acid halide coupled with amino acid derivative VI to provide compounds of formula I. The acid halide of VI can be prepared by contacting VI with an inorganic acid halide, such as thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, or preferably, with oxalyl chloride under conventional conditions. Generally, this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at temperature in the range of about 0°C to about 80 0 C for about 1 to about 48 hours. A catalyst, such as N,N-dimethylformamide, may also be used in this reaction.

The acid halide of N-sulfonyl amino acid IV is then contacted with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of amino acid derivative VI in an inert diluent, such as dichloromethane, at a temperature ranging from about -70°C to about 40°C for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base WO 99/06431 PCT/US98/15313 82to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like. Upon completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.

Alternatively, the compounds of formula I can be prepared by first forming a diamino acid derivative of formula VII:

R

3

R

7 0 I I II

R

2

-NH-CH-C(O)N-CH-C-R

6

VII

R

wherein R 2

R

3 and R 5

R

7 are as defined above. The diamino acid derivatives of formula VII can be readily prepared by coupling an amino acid of formula II with an amino acid derivative of formula VI using conventional amino acid coupling techniques and reagents, such carbodiimides, BOP reagent and the like, as described above. Diamino acid VII can then be sulfonated using a sulfonyl chloride of formula III and using the synthetic procedures described above to provide a compound of formula I.

The amino acid derivatives of formula VI employed in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. For example, amino acid derivatives of formula VI can be prepared by C-alkylating commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with an alkyl or substituted alkyl halide. This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least WO 99/06431 PCT/US98/15313 83 one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt.

Examples of amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-4-nitrophenylalanine methyl ester, L-tyrosine methyl ester, D,L-homo-4-nitrophenylalanine methyl ester, L-(O-benzyl)tyrosine methyl ester, L-3,5-diiodotyrosine methyl ester, L- 3-iodotyrosine methyl ester and the like. If desired, of course, other esters or amides of the above-described compounds may also be employed.

For ease of synthesis, the compounds of formula I are typically prepared as an ester, where R 6 is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolysed using conventional conditions and reagents to provide the corresponding carboxylic acid.

Typically, this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperature ranging about 0 C to about 24 0 C for about 1 to about 12 hours. Alternatively, benzyl esters may be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon. The resulting carboxylic acids may be coupled, if desired, to amines such as P-alanine ethyl ester, hydroxyamines such as hydroxylamine and N-hydroxysuccinimide, alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine and O-benzylhydroxylamine, and the like, using conventional coupling reagents and conditions as described above.

As will be apparent to those skilled in the art, other functional groups present on any of the substituents of the compounds of formula I can be WO 99/06431 PCT/US98/15313 84 readily modified or derivatized either before or after the above-described coupling reactions using well-known synthetic procedures. For example, a nitro group present on a substituent of a compound of formula I or an intermediate thereof may be readily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group. This reaction is typically conducted at a temperature of from about 20°C to about 50 0 C for about 6 to about 24 hours in an inert diluent, such as methanol. Compounds having a nitro group on the

R

5 substituent can be prepared, for example, by using a 4-nitrophenylalanine derivative and the like in the above-described coupling reactions.

Similarly, a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acidic diluent to provide the corresponding piperidinyl analogue. Generally, this reaction is conducted by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperature of about 20 0 C to about 50 C for about 2 to about 24 hours in an acidic diluent, such as a mixture of methanol and aqueous hydrochloric acid. Compounds having a pyridyl group can be readily prepared by using, for example, P-(2-pyridyl)-, P-(3-pyridyl)- or P-(4-pyridyl)-Lalanine derivatives in the above-described coupling reactions.

Additionally, when the R 5 substituent of a compound of formula I or an intermediate thereof contains a primary or secondary amino group, such amino groups can be further derivatized either before or after the above coupling reactions to provide, by way of example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like. Compounds having a primary amino group on the R 5 substituent may be prepared, for example, by reduction of the corresponding nitro compound as described above. Alternatively, such compounds can be prepared by using an amino acid derivative of formula VI derived from lysine, 4-aminophenylalanine and the like in the above-described coupling reactions.

WO 99/06431 PCT/US98/15313 85 By way of illustration, a compound of formula I or an intermediate thereof having a substituent containing a primary or secondary amino group, such as where R' is a (4-aminophenyl)methyl group, can be readily N-acylated using conventional acylating reagents and conditions to provide the corresponding amide. This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and the like, at a temperature ranging from about 0 C to about 37'C for about 4 to about 24 hours.

Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, is used to facilitate the acylation reaction.

Examples ofcarboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-Lphenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, Ntert-butyloxycarbonylnipecotic acid, N-tert-butyloxycarbonyl-Ltetrahydroisoquinoline-3-carboxylic acid, N-(toluene-4-sulfonyl)-L-proline and the like.

Alternatively, a compound of formula I or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide.

This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperature ranging from about of about -70'C to about 40 0 C for about 1 to about 24 hours. If desired, an acylation catalyst such as 4- (N,N-dimethylamino)pyridine may be used to promote the acylation reaction.

The acylation reaction is preferably conducted in the presence of a suitable WO 99/06431 PCT/US98/15313 86 base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like.

Examples of acyl halides and carboxylic acid anhydrides suitable for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N,Ndimethylcarbamyl chloride, N,N-diethylcarbamyl chloride and.the like, can also be used in this reaction to provide ureas. Similarly, dicarbonates, such as di-tert-butyl dicarbonate, may be employed to provide carbamates.

In a similar manner, a compound of formula I or an intermediate thereof containing a primary or secondary amino group may be N-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride.

Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides, such as dimethylsulfamoyl chloride, can be used to provide sulfamides >N-SO 2 Additionally, a primary and secondary amino group present on a substituent of a compound of formula I or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as WO 99/06431 PCT/US98/15313 87 toluene and the like, at a temperature ranging from about 24 C to about 37 C for about 12 to about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I) and the like.

Furthermore, when a compound of formula I or an intermediate thereof contains a primary or secondary amino group, the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature ranging from about 0°C to about 50°C for about 1 to about 72 hours. Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4chlorobenzaldehyde, valeraldehyde and the like.

In a similar manner, when a compound of formula I or an intermediate thereof has a substituent containing a hydroxyl group, the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions to provide, by way of example, ethers, carbamates and the like.

Compounds having a hydroxyl group on the R 5 substituent, for example, can WO 99/06431 PCT/US98/15313 88 be prepared using an amino acid derivative of formula VI derived from tyrosine and the like in the above-described reactions.

By way of example, a compound of formula I or an intermediate thereof having a substituent containing a hydroxyl group, such as where R 5 is a (4-hydroxyphenyl)methyl group, can be readily O-alkylated to form ethers.

This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group. This salt is generally not isolated, but is reacted in situ with at least one equivalent of an alkyl or substituted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether. Generally, this reaction is conducted at a temperature ranging from about 60°C to about 150°C for about 24 to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is employed in the reaction.

Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1 -bromoethylbenzene, ethyl abromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,Nethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,Ndibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propyl chloride, 3-(Nbenzyl-N-methylamino)propyl chloride, N-(2-chloroethyl)morpholine, 2- (hexamethyleneimino)ethyl chloride, 3-(N-methylpiperazine)propyl chloride, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine, 2-(4-hydroxy-4phenylpiperidine)ethyl chloride, N-tert-butyloxycarbonyl-3-piperidinemethyl tosylate, and the like.

Alternatively, a hydroxyl group present on a substituent of a compound of formula I or an intermediate thereof can be O-alkylating using the WO 99/06431 PCT/US98/15313 89-- Mitsunobu reaction. In this reaction, an alcohol, such as 3-(N,Ndimethylamino)-l-propanol and the like, is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about -10 0 C to about 5 0 C for about 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents of a hydroxy compound, such as Ntert-butyltyrosine methyl ester, is then added and the reaction mixture is stirred at a temperature of about 0°C to about 30°C for about 2 to about 48 hours to provide the O-alkylated product.

In a similar manner, a compound of formula I or an intermediate thereof containing a aryl hydroxy group can be reacted with an aryl iodide to provide a diaryl ether. Generally, this reaction is conducted by forming the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent such as xylenes at a temperature of about -25 C to about 10°C. The salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperature ranging from about 10 0 C to about 30°C for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. The reaction is then heated to about 70°C to about 150 0 C for about 2 to about 24 hours to provide the diaryl ether.

Additionally, a hydroxy-containing compound can also be readily derivatized to form a carbamate. In one method for preparing such carbamates, a hydroxy compound of formula I or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about -25 0 C to about 0 C for about 0.5 to about 2.0 hours.

Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine provides the carbamate. Examples of amines suitable for WO 99/06431 PCT/US98/15313 90 using in this reaction include, but are not limited to, piperazine, 1methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like.

Alternatively, in another method for preparing carbamates, a hydroxycontaining compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a temperature ranging from about 25 0 C to about 70 0 C for about 2 to about 72 hours. Typically, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Additionally, at least one equivalent (based on the hydroxy compound) of 4-(N,N-dimethylamino)pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.

Likewise, when a compound of formula I or an intermediate thereof contains a primary or secondary hydroxyl group, such hydroxyl groups can be readily converted into a leaving group and displaced to form, for example, amines, sulfides and fluorides. For example, derivatives of4-hydroxy-Lproline can be converted into the corresponding 4-amino, 4-thio or 4-fluoro-Lproline derivatives via nucleophilic displacement of the derivatized hydroxyl group. Generally, when a chiral compound is employed in these reactions, the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically inverted.

These reactions are typically conducted by first converting the hydroxyl group into a leaving group, such as a tosylate, by treatment of the hydroxy compound with at least one equivalent of a sulfonyl halide, such as ptoluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperature of from about 0 C to about 70°C for about 1 to WO 99/06431 PCT/US98/15313 91 about 48 hours. The resulting tosylate can then be readily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixture of N,Ndimethylformamide and water, at a temperature ranging from about 0°C to about 37 0 C for about 1 to about 12 hours to provide the corresponding azido compound. The azido group can then bc reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino

NH

2 compound.

Similarly, a tosylate group can be readily displaced by a thiol to form a sulfide. This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as 1, 8 -diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a temperature of from about 0°C to about 37°C for about 1 to about 12 hours to provide the sulfide. Additionally, treatment of a tosylate with morpholinosulfur trifluoride in an inert diluent, such as dichloromethane, at a temperature ranging from about 0°C to about 37°C for about 12 to about 24 hours affords the corresponding fluoro compound.

Furthermore, a compound of formula I or an intermediate thereof having a substituent containing an iodoaryl group, for example, when R 5 is a 4 -iodophenyl)methyl group, can be readily converted either before or after the above coupling reactions into a biaryl compound. Typically, this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2-(methoxycarbonyl)phenylzinc iodide, in the presence of a palladium catalyst, such as palladium tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about 24°C to about 30'C until reaction completion. This reaction is further described, for example, in Rieke, J. Org.

Chem. 1991, 56, 1445.

WO 99/06431 PCT/US98/15313 92 In some cases, the compounds of formula I or intermediates thereof may contain substituents having one or more sulfur atoms. Such sulfur atoms will be present, for example, when the amino acid of formula II employed in the above reactions is derived from L-thiazolidine-4-carboxylic acid, dimethyl)thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid and the like. When present, such sulfLr atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions. Suitable reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like. The oxidation reaction is typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperature ranging from about -50°C to about 75°C for about 1 to about 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. Such reactions are described further in March, "Advanced Organic Chemistry", 4th Ed., pp. 1201-1202, Wiley Publisher, 1992.

As described above, the compounds of formula I having an R 2 substituent other an hydrogen can be prepared using an N-substituted amino acid of formula II, such as sarcosine, N-methyl-L-phenylalanine and the like, in the above-described coupling reactions. Alternatively, such compounds can be prepared by N-alkylation of a sulfonamide of formula I or IV (where R 2 is hydrogen) using conventional synthetic procedures. Typically, this Nalkylation reaction is conducted by contacting the sulfonamide with at least one equivalent, preferably 1.1 to 2 equivalents, of an alkyl or substituted alkyl halide in the presence of a suitable base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, at a temperature WO 99/06431 PCT/US98/15313 93 ranging from about 25 0 C to about 70°C for about 2 to about 48 hours.

Examples of alkyl or substituted alkyl halides suitable for use in this reaction include, but are not limited to, methyl iodide, and the like.

Additionally, the sulfonamides of formula I or IV wherein R 2 is hydrogen and R' is a 2-alkoxycarbonylaryl group can be intramolecularly cyclized to form 1,2-benzisothiazol-3-one derivatives or analogues thereof.

This reaction is .typically conducted by treating a sulfonamide, such as N-(2methoxycarbonylphenylsulfonyl)glycine-L-phenylalanine benzyl ester, with about 1.0 to 1.5 equivalents of a suitable base, such as an alkali metal hydride, in a inert diluent, such as tetrahydrofuran, at a temperature ranging from about 0°C to about 30 0 C for about 2 to about 48 hours to afford the cyclized 1,2benzisothiazol-3-one derivative.

Lastly, the compounds of formula I where Q is -C(S)NR 7 are can prepared by using an amino thionoacid derivative in place of amino acid II in the above described synthetic procedures. Such amino thionoacid derivatives can be prepared by the procedures described in Shalaky, et al., J. Org. Chem., 61:9045-9048 (1996) and Brain, et al., J. Org. Chem., 62:3808-3809 (1997) and references cited therein.

Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of formula I and IA are usually administered in the form of pharmaceutical compositions.

These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.

These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I WO 99/06431 PCT/US98/15313 94and IA above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders; In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to-a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

WO 99/06431 PCT/US98/15313 95 The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to prodace the desireci therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound is effective over a wide dozage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can separated by enteric layer which serves to WO 99/06431 PCT/US98/1 5313 96 resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oralornasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

The following formulation examples illustrate the pharmaceutical compositions of the present invention.

Formulation Example 1 Hard gelatin capsules containing the following ingredients are prepared: WO 99/06431 PCT/US98/15313 97 Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0 Magnesium stearate The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.

Formulation Example 2 A tablet formula is prepared using the ingredients below: Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid The components are blended and compressed to form tablets, each weighing 240 mg.

Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components: Ingredient Weight Active Ingredient Lactose The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.

Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: WO 99/06431 PCT/US98/15313 98 Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a No. mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 500 to 60 0 C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch,, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

Formulation Example Capsules, each containing 40 mg of medicament are made as follows: Quantity Ingredient (mg/casule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, cellulose, starch, an magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.

Formulation Example 6 WO 99/06431 PCT/US98/15313 99 Suppositories, each containing 25 mg of active ingredient are made as follows: Ingredient Amount Active Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v.

Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.

The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

WO 99/06431 PCT/US98/15313 100-- Formulation Example 8 Quantity Ingredient (mg/rapsule) Active Ingredient 15.0 mg Starch 4 07.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.

Formulation Example 9 An intravenous formulation may be prepared as follows: Ingredient Quantity Active Ingredient 250.0 mg Isotonic saline 1000 ml Formulation Example A topical formulation may be prepared as follows: Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.

Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal WO 99/06431 PCT/US98/15313 101 patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

When it is desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 which is herein incorporated by reference.

Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion ofhydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.

Alternatively, the delivery ofhydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

Utility The compounds of this invention can be employed to bind VLA-4 (a 4 1 integrin) in biological samples and, accordingly have utility in, for example, assaying such samples for VLA-4. In such assays, the compounds can be bound to a solid support and the VLA-4 sample added thereto. The amount of VLA-4 in the sample can be determined by conventional methods such as use of a sandwich ELISA assay. Alternatively, labeled VLA-4 can be used in a WO 99/06431 PCT/US98/15313 102 competitive assay to measure for the presence of VLA-4 in the sample. Other suitable assays are well known in the art.

In addition, certain of the compounds of this invention inhibit, in vivo, adhesion of leukocytes to endothelial cells mediated by VLA-4 and, accordingly, can be used in the treatment of diseases mediated by VLA-4.

Such diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.

The biological activity of the compounds identified above may be assayed in a variety of systems. For example, a compound can be immobilized on a solid surface and adhesion of cells expressing VLA-4 can be measured. Using such formats, large numbers of compounds can be screened. Cells suitable for this assay include any leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils. A number of leukocyte cell lines can also be used, examples include Jurkat and U937.

The test compounds can also be tested for the ability to competitively inhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a labeled compound known to bind VLA-4 such as a compound of this invention or antibodies to VLA-4. In these assays, the VCAM-1 can be immobilized on a solid surface. VCAM-1 may also be expressed as a recombinant fusion protein having an Ig tail IgG) so that binding to VLA-4 may be detected in an immunoassay. Alternatively, VCAM-1 expressing cells, such as activated endothelial cells or VCAM-1 transfected fibroblasts can be used. For assays to measure the ability to block adhesion to WO 99/06431 PCT/US98/15313 103 brain endothelial cells, the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This application is incorporated herein by reference in its entirety.

Many assay formats employ labelled assay components. The labelling systems can be in a variety of forms. The label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art. A wide variety of labels may be used. The component may be labelled by any one of several methods. The most common method of detection is the use of autoradiography with 3 H, 25I, 1"S, 4 C, or 32 P labelled compounds or the like. Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair members for a labelled ligand. The choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.

Appropriate in vivo models for demonstrating efficacy in treating inflammatory responses include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models dependent upon a4 integrins.

Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties in vivo stability, bio-availability), or the ability to be detected in diagnostic applications. For instance, inclusion of one or more D-amino acids in the sulfonamides of this invention typically increases in vivo stability.

Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum.

A number of such protein stability assays have been described (see, e.g., Verhoef, et al., Eur. J. Drug Metab. Pharmacokinet., 1990, 15{2):83-93).

WO 99/06431 PCT/US98/15313 104-- For diagnostic purposes, a wide variety of labels may be linked to the compounds, which may provide, directly or indirectly, a detectable signal.

Thus, the compounds of the subject invention may be modified in a variety of ways for a variety of end purposes while still retaining biological activity. In addition, various reactive sites may be introduced at the terminus for linking to particles, solid substrates, macromolecules, or the like.

Labeled compounds can be used in a variety of in vivo or in vitro applications. A wide variety of labels may be employed, such as radionuclides gamma-emitting radioisotopes such as technetium-99 or indium- 1ll), fluorescers fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.. Those of ordinary skill in the art will know of other suitable labels for binding to the complexes, or will be able to ascertain such using routine experimentation. The binding of these labels is achieved using standard techniques common to those of ordinary skill in the art.

In vitro uses include diagnostic applications such as monitoring inflammatory responses by detecting the presence of leukocytes expressing VLA-4. The compounds of this invention can also be used for isolating or labeling such cells. In addition, as mentioned above, the compounds of the invention can be used to assay for potential inhibitors of VLA-4/VCAM-l interactions.

For in vivo diagnostic imaging to identify, sites of inflammation, radioisotopes are typically used in accordance with well known techniques.

The radioisotopes may be bound to the peptide either directly or indirectly using intermediate functional groups. For instance, chelating agents such as diethylenetriaminepentacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metallic ion radioisotopes.

WO 99/06431 PCT/US98/15313 105 The complexes can also be labeled with a paramagnetic isotope for purposes of in vivo diagnosis, as in magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which were well known. In general, any conventional method for visualizing diagnostic imaging can be used.

Usually gamma- and positron-emitting radioisotopes are used for camera imaging and paramagnetic isotopes are used for MRI. Thus, the compounds can be used to monitor the course of amelioration of an inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4 it is possible to determine whether a particular therapeutic regimen aimed at ameliorating the disease is effective.

The pharmaceutical compositions of the present invention can be used to block or inhibit cellular adhesion associated with a number of diseases and disorders. For instance, a number of inflammatory disorders are associated with integrins or leukocytes. Treatable disorders include, transplantation rejection allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), retinitis, cancer metastases, rheumatoid arthritis, acute leukocyte-mediated lung injury adult respiratory distress syndrome), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease (including Crohn's disease and ulcerative colitis).

In preferred embodiments the pharmaceutical compositions are used to treat inflammatory brain disorders, such as multiple sclerosis viral meningitis and encephalitis.

Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn's disease and ulcerative colitis. Crohn's disease is an idiopathic, chronic ulceroconstrictive inflammatory disease characterized by sharply delimited and typically transmural involvement of all layers of the bowel wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and/or colon.

WO 99/06431 PCT/US98/15313 106-- Ulcerative colitis is an inflammatory response limited largely to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in lesions of inflammatory bowel disease and may contribute to inflammatory injury.

Asthma is a disease characterized by increased responsiveness of the tracheobronchial tree to various stimuli potentiating paroxysmal constriction of the bronchial airways. The stimuli cause release of various mediators of inflammation from IgE-coated mast cells including histamine, eosinophilic and neutrophilic chemotactic factors, leukotrines, prostaglandin and platelet activating factor. Release of these factors recruits basophils, eosinophils and neutrophils, which cause inflammatory injury.

Atherosclerosis is a disease of arteries coronary, carotid, aorta and iliac). The basic lesion, the atheroma, consists of a raised focal plaque within the intima, having a core of lipid and a covering fibrous cap. Atheromas compromise arterial blood flow and weaken affected arteries. Myocardial and cerebral infarcts are a major consequence of this disease. Macrophages and leukocytes are recruited to atheromas and contribute to inflammatory injury.

Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily causes impairment and destruction of joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees. The arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints. See Paul, Immunology (3d ed., Raven Press, 1993).

Another indication for the compounds of this invention is in treatment of organ or graft rejection mediated by VLA-4. Over recent years there has been a considerable improvement in the efficiency of surgical techniques for transplanting tissues and organs such as skin, kidney, liver, heart, lung, WO 99/06431 PCT/US98/15313 107pancreas and bone marrow. Perhaps the principal outstanding problem is the lack of satisfactory agents for inducing immunotolerance in the recipient to the transplanted allograft or organ. When allogeneic cells or organs are transplanted into a host the donor and donee are different individuals from the same species), the host immune system is likely to mount an immune response to foreign antigens in the transplant (host-versus-graft disease) leading to destruction of the transplanted tissue. CD8 cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues. Compounds of this invention which bind to alpha-4 integrin are useful, inter alia, to block alloantigen-induced immune responses in the donee thereby preventing such cells from participating in the destruction of the transplanted tissue or organ.

See, Paul et al., Transplant International 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georcyznski et al., Transplant.

Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994).

A related use for compounds of this invention which bind to VLA-4 is in modulating the immune response involved in "graft versus host" disease (GVHD). See Schlegel et al., J. Immunol. 155, 3856-3865 (1995).

GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic recipient. In this situation, the donor's immunocompetent cells may attack tissues in the recipient. Tissues of the skin, gut epithelia and liver are frequent targets and may be destroyed during the course of GVHD. The disease presents an especially severe problem when immune tissue is being transplanted, such as in bone marrow transplantation; but less severe GVHD has also been reported in other cases as well, including heart and liver transplants. The therapeutic agents of the present invention are used, inter alia, to block activation of the donor T-cells thereby interfering with their ability to lyse target cells in the host.

A further use of the compounds of this invention is inhibiting tumor metastasis. Several tumor cells have been reported to express VLA-4 and WO 99/06431 PCT/US98/15313 108compounds which bind VLA-4 block adhesion of such cells to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J.

Cancer 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13, 47-52 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994).

A further use of the compounds of this invention is in treating multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States.

Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating sheath covering nerve fibers. In an animal model for multiple sclerosis, murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothelium, and thus prevent inflammation of the central nervous system and subsequent paralysis in the animals 6 Pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

In order to enhance serum half-life, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.

The amount administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a patient already WO 99/06431 PCT/US98/15313 109suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective dose." Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like.

The compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered.

The resulting.aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, the dose will typically be in the range of about ug to about 500 4g per kilogram body weight, preferably about 100 ug to about 300 /g per kilogram body weight. Suitable dosage ranges for intranasal administration are gencrally about 0.1 pg to 1 mg per kilogram body weight.

Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of WO 99/06431 WO 9906431PCT/US98/15313 this invention. Unless otherwise stated, all temperatures are in degrees Celsius.

EXAMPLES

In the examples below, the fo'lowing abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

aq or aq.

AcOR bd bm bs Bn Boc Boc 2

O

BOP

Cbz CHC1 3

CH

2 Cl 2 (COdl) 2 d dd dt

DBU

DCC

DMAP

DME

DMF

DMSO

EDC

Et 3

N

Et 2

O

EtOAc EtOH eq or eq.

Fmoc FmocONSu aqueous acetic acid broad doublet broad multiplet broad singlet benzyl N-tert-butoxylcarbonyl di-tert-butyl dicarbonate benzotriazol- I -yloxytris(dimethylamino)phosphonium hexafluorophosphate carbobenzyloxy chloroform dichloromethane oxalyl chloride doublet doublet of doublets doublet of triplets I,8-diazabicyclo[5 .4.O]undec-7-ene 1,3 -dicyclohexylcarbodiimide 4-NN-dimethylaminopyridine ethylene glycol dimethyl ether NN-dimethylformamide dimethylsulfoxide I-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride triethylamine diethyl ether ethyl acetate ethanol equivalent N-(9-fluorenylmethoxycarbonyl) N-(9-fluorenylmethoxycarbonyl)succinimide grams WO 99/06431 PCT/US98/15313 111 h

H

2 0 HBr

HCI

HOBT

hr

K

2

CO

3

L

m MeOH mg MgSO 4 mL mm mM mmol mp

N

NaCI Na 2

CO

3 NaHCO 3 NaOEt NaOH

NH

4 Cl

NMM-

Phe Pro psi PtO 2 q quint.

rt s sat t t-BuOH

TFA

THF

TLC or tic Ts TsCI TsOH .zL hour water hydrobromic acid hydrochloric acid 1-hydroxybenzotriazole hydrate hour potassium carbonate liter multiplet methanol milligram magnesium sulfate milliliter millimeter millimolar millimol melting point normal sodium chloride sodium carbonate sodium bicarbonate sodium ethoxide sodium hydroxide ammonium chloride N-methylmorpholine L-phenylalanine L-proline pounds per square inch platinum oxide quartet quintet room temperature singlet saturated triplet tert-butanol trifluoroacetic acid tetrahydrofuran thin layer chromatography tosyl tosyl chloride tosylate microliter WO 99/06431 PCT/US98/15313 112-- In the examples below, all temperatures are in degrees Celcius (unless otherwise indicated). The following Methods were used to prepare the compounds set forth below as indicated.

Method 1 N-Tosylation Procedure N-Tosylation of the appropriate amino acid was conducted via the method of Cupps, Boutin and Rapoport J. Org. Chem. 1985, 50, 3972.

Method 2 Methyl Ester Preparation Procedure Amino acid methyl esters were prepared using the method of Brenner and Huber Helv. Chim. Acta 1953, 36, 1109.

Method 3 BOP Coupling Procedure The desired dipeptide ester was prepared by the reaction of a suitable Nprotected amino acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate [BOP] equivalent), triethylamine (1.1 equivalent), and DMF. The reaction mixture was stirred at room temperature overnight. The crude product is purified flash chromatography to afford the dipeptide ester.

Method 4 Hydrogenation Procedure I Hydrogenation was performed using 10% palladium on carbon (10% by weight) in methanol at 30 psi overnight. The mixture was filtered through a pad of Celite and the filtrate concentrated to yield the desired amino compound.

WO 99/06431 PCT/US98/15313 113-- Method Hydrolysis Procedure I To a chilled THF/H 2 0 solution 5 10 mL) of the appropriate ester was added LiOH (or NaOH) (0.95 equivalents). The temperature was maintained at 0 C and the reaction was complete in 1-3 hours. The reaction mixture was extracted with ethyl acetate and the aqueous phase was lyophilized resulting in the desired carboxylate salt.

Method 6 Ester Hydrolysis Procedure II To a chilled THF/H 2 0 solution 5 10 mL) of the appropriate ester was added LiOH (1.1 equivalents). The temperature was maintained at 0 C and the reaction was complete in 1-3 hours. The reaction mixture was concentrated and the residue was taken up into H 2 0 and the pH adjusted to 2-3 with aqueous HC1. The product was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over MgSO,, filtered and concentrated to yield the desired acid.

Method 7 Ester Hydrolysis Procedure III The appropriate ester was dissolved in dioxane/H 2 0 and 0.9 equivalents of 0.5 N NaOH was added. The reaction was stirred for 3-16 hours and than concentrated. The resulting residue was dissolved in H20 and extracted with ethyl acetate. The aqueous phase was lyophilized to yield the desired carboxylate sodium salt.

Method 8 Sulfonylation Procedure I To the appropriately protected aminophenylalanine analog (11.2 mmol), dissolved in methylene chloride (25ml) and cooled to -78 0 C was added the desired sulfonyl chloride (12 mmol) followed by dropwise addition of pyridine (2 mL). The solution was allowed to warm to room temperature and was WO 99/06431 PCT/US98/15313 114stirred for 48 hr. The reaction solution was transferred to a 250 mL separatory funnel with methylene chloride (100 mL) and extracted with IN HCI (50 mL x brine (50 mL), and water (100 mL). The organic phase was dried (MgSO4) and the solvent concentrated to yield the desired product.

Method 9 Reductive Amination Procedure Reductive amination of Tos-Pro-p-NH2-Phe with the appropriate aldehyde was conducted using acetic acid, sodium triacetoxyborohydride, methylene chloride and the combined mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography.

Method BOC Removal Procedure Anhydrous hydrochloride (HCI) gas was bubbled through a methanolic solution of the appropriate Boc-amino acid ester at 0°C for 15 minutes and the reaction mixture was stirred for three hours. The solution was concentrated to a syrup and dissolved in Et20 and reconcentrated. This procedure was repeated and the resulting solid was placed under high vacuum overnight.

Method 11 Tert-Butyl Ester Hydrolysis Procedure I The tert-butyl ester was dissolved in CH 2 Cl 2 and treated with TFA. The reaction was complete in 1-3 hr at which time the reaction mixture was concentrated and the residue dissolved in H2, and lyophilized to yield the desired acid.

Method 12 EDC Coupling Procedure I To a CH 2 CI, solution (5-20 mL) of N-(toluene-4-sulfonyl)-L-proline (1 equivalent), the appropriate amino acid ester hydrochloride (1 equivalent), Nmethylmorpholine (1.1-2.2 equivalents) and 1-hydroxybenzotriazole (2 WO 99/06431 PCT/US98/15313 115equivalents) were mixed, placed in an ice bath and 1-(3dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalents) added. The reaction was allowed to rise to room temperature and stirred overnight. The reaction mixture was poured into H 2 0 and the organic phase was washed with sat. NaHC0 3 brine, dried (MgSO 4 or Na 2

SO

4 filtered and concentrated. The crude product was purified by column chromatography.

Method 13 EDC Coupling Procedure II To a DMF solution (5-20 mL) of the appropriate N-protected amino acid (1 equivalent), the appropriated amino acid ester hydrochloride (1 equivalent), Et 3 N (1.1 equivalents) and 1-hydroxybenzotriazole (2 equivalents) were mixed, placed in an ice batch and 1-( 3 -dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalents) added. The reaction was allowed to rise to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and H 2 0 and the organic phase washed with 0.2 N citric acid,

H

2 0, sat. NaHCO 3 brine, dried (MgSO, or Na 2

SO

4 filtered and concentrated.

The crude product was purified by column chromatography or preparative

TLC.

Method 14 Sulfonylation Procedure 11 The appropriate sulfonyl chloride was dissolved in CH 2

CI

2 and placed in an ice bath. L-Pro-L-Phe-OMe o HCI (1 equivalent) and Et 3 N (1.1 equivalent) was added and the reaction allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The reaction mixture was concentrated and the residue partitioned between EtOAc and H 2 0 and the organic phase washed with sat. NaHCO 3 brine, dried (MgSO, or Na 2

SO

4 filtered and concentrated. The crude product was purified by column chromatography or preparative TLC.

Method WO 99/06431 PCT/US98/15313 116-- Sulfonylation Procedure III To a solution of L-Pro-L-4-(3-dimethylaminopropyloxy)-Phe-OMe [prepared using the procedure described in Method 10] (1 equivalent) in

CH

2

CI

2 was added Et 3 N (5 equivalents) followed by the appropriate sulfonyl chloride (1.1 equivalent). The reaction was allowed to warm to room temperature and stirred ovemite under an atmosphere of nitrogen. The mixture was concentrated, dissolved in EtOAc, washed with sat. NaHCO 3 and 0.2 N citric acid. The aqueous phase was made basic with solid NaHCO 3 and the product extracted with EtOAc. The organic phase was washed with brine, dried (MgSO, or Na2SO4), filtered and concentrated. The crude methyl ester was purified by preparative TLC. The corresponding acid was prepared using the procedure described in Method 7.

Method 16 Hydrogenation Procedure II To a methanol (10 -15 mL) solution of the azlactone, was added NaOAc (1 equivalent) and 10% Pd/C. This mixture was placed on the hydrogenator at psi H 2 After 8 16 hours, the reaction mixture was filtered through a pad of Celite and the filtrate concentrated to yield the dehydrodipeptide methyl ester. The ester was dissolved in dioxane/H 2 0 10 mL), to which was added 0.5 N NaOH (1.05 equivalents). After stirring for 1- 3 hours, the reaction mix was concentrated and the residue was redissolved in H 2 0 and washed with EtOAc. The aqueous phase was made acidic with 0.2 N HCI and the product was extracted with EtOAc. The combined organic phase was washed with brine x 5 mL), dried (MgSO 4 or Na2S 4 filtered and concentrated to yield the acid as approximately a 1:1 mixture of diastereomers.

Method 17 Tert-Butyl Ester Hydrolysis Procedure II The tert-butyl ester was dissolved in CH 2

CI

2 (5 mL) and treated with TFA mL). The reaction was complete in 1-3 hours at which time the reaction mixture was concentrated and the residue dissolved in H,O and concentrated.

WO 99/06431 PCT/US98/15313 117-- The residue was redissolved in H 2 0 and lyophilized to yield the desired product.

Example 1 (2) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- I(N-tert-butoxylcarbonylglycyl)amino]-L-phenylalanine N-(Toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (2.00 g, 4.67 mmol) was dissolved 50 mL of dry DMF, with Boc-glycine (1.1 eq, 0.9 Et 3 N (2.2 eq, 1.43 mL), and BOP reagent (1.1 eq, 2.27g). The reaction mixture was stirred at room temperature for 12 hours. EtOAc (100 mL) was added. The organic layer was washed with NaHCO 3 saturated mL), 10% citric acid (20 mL), and brine (5x 50 mL). The organic layer was dried over MgSO 4 Upon evaporation of the solvents under reduced pressure, the crude material was eluted on column chromatography (silica gel;

CHCI

3 /MeOH The desired ester (1.90 g, 3.1 mmol) was isolated in 66% yield. The ester was then taken up in MeOH:H 2 0 (40 mL), with NaOH (1.1 eq, 176 mg), for 4 hours at room temperature. EtOAc was added as well as water. The aqueous layer was collected and acidified with IN HCI to pH and reextracted with EtOAc. The organic layer was dried over MgSO 4 Upon filtration and evaporation of the solvents under reduced pressure, the title compound was isolated in 73% yield, as an oil (1.33g, 2.26 mmol).

NMR data was as follows: 'H NMR (300 MHz, CDCl 3 6 8.65 (bs, 1H), 7.70 2H, J= 7.98 Hz), 7.50 1H, J= 7.14 Hz), 7.45 2H, J= 8.10 Hz), 7.32 2H, J= 7.80 Hz), 7.11 2H, J= 8.00 Hz), 5.75 (bs, 1H), 4.82 1H), 4.11 1H), 3.90 (bs, 2H), 3.38 1H), 3.21 3.10 3H), 2.41 3H), 1.99 1H), 1.55 (m, 3H), 1.43 9H).

"C NMR (75 MHz, CDCl 3 6 174.03, 172.19, 169.02, 157.28, 145.03, 137.17, 133.34, 132.58, 130.59, 128.44, 120.65, 81.16, 62.85, 54.05, 50.31, 37.34, 30.69, 28.87, 24.89, 22.14, 14.77.

Mass Spectroscopy: (FAB) 589 WO 99/06431 PCT/US98/15313 118-- Example 2 (7) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4f(glycyl)aminoj-L-phenylalanine The product from Example 1 (1.33 g, 2.26 mmol) was taken up in dry dichloromethane (20 mL) with trifluoroacetic acid (1.00 mL) and the reaction mixture was stirred at room temperature for 12 hours. The solvents were removed under reduced pressure. The crude material was left on a vacuum pump overnight, then dissolved in methanol and cooled to 0°C. Ethyl ether was added and the product was collected, as a trifluoroacetate salt, in yield (660 mg, 1.09 mmol).

NMR data was as follows: 'H NMR (300 MHz, CD30D): 6 7.51 2H, J= 8.25 Hz), 7.31 2H, J= 8.25 Hz), 7.19 2H, J= 7.92 Hz), 7.03 2H, J= 8.25 Hz), 4.43 (m, 1H), 3.87 1H), 3.63 2H), 3.13-2.82 4H), 2.21 3H), 1.56-1.26 (m, 4H).

3 C NMR (75 MHz, CD 3 OD): 6 174.39, 165.97, 146.34, 139.50, 135.38, 135.21, 131.28, 129.57, 121.47, 67.47, 63.86, 51.16, 42.72, 38.39, 32.20, 25.87, 22.09, 16.02.

Mass Spectroscopy: (FAB) 489 Example 3 (23) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 3 -(carboxy)propionamidol-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (455 mg, 1 mmol) was dissolved in DMF (10 mL) with Et 3 N (1.1 eq, 153 pL) and succinic anhydride (1.1 eq, 110 mg). The desired monoester was isolated in 53% yield (288 mg, 0.52 mmol) as a foam. The monoester (80 mg, 0.15 mmol) was then hydrolyzed in MeOH: H20 1:1 (5 mL) with NaOH (2.2 eq, mg) for 4 hours at room temperature. EtOAc was added as well as water. The aqueous layer was collected and acidified with IN HCI to pH 2.5, and reextracted with EtOAc. The organic layer was dried over MgSO 4 Upon WO 99/06431 PCT/US98/15313 119filtration and evaporation of the solvents under reduced pressure, the diacid was isolated as a foam.

NMR data was as follows: 'H NMR (300 MHz, CD30D): 6 7.51 2H, J= 8.31 Hz), 7.28 2H, J= 8.34 Hz), 7.19 2H, J= 8.10 Hz), 6.99 2H, J= 8.43 Hz), 4.48 (m, 1H), 3.91 1H), 3.17-2.83 4H), 2.43 4H), 2.21 3H), 1.44-1.29 (m, 4H).

3 C NMR (75 MHz, CD30D): 6 176.87, 174.68, 174.53, 173.30, 149.74, 146.31, 139.33, 135.50, 134.24, 131.61, 131.44, 129.53, 121.66, 80.05, 63.81, 55.37, 51.17, 38.25, 32.87, 32.24, 30.55, 25.89, 22.11.

Mass Spectroscopy: (FAB) 532 Example 4 (27) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- [(N-tert-butoxylcarbonyl-L-alanyl)aminoj-L-phenylalanine Following the experimental procedure described for Example 1 N- (toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g, 0.337 mmol) was taken into 5 mL of DMF, with Et 3 N (2.0 eq, 95 pL), Boc-Lalanine (1.1 eq, 70 mg), and BOP (1.1 eq, 163 mg). The desired methyl ester was isolated as an oil in 49% yield (102 mg, 0.16 mmol). The ester was then hydrolyzed with NaOH (1.1 eq, 8 mg) in a 1:1 MeOH:HO solution (4 mL).

The monoacid was isolated as an amorphous solid in quantitative yields.

NMR data was as follows: 'H NMR (300 MHz, CDCI 3 6 9.00 (broad s, 1H), 7.70 2H, J= 8.25 Hz), 7.45 2H, J= 8.37 Hz), 7.32 2H, J= 8.25 Hz), 7.09 2H, J= 8.25 Hz), 5.65 (bs, 1H), 4.82 1H), 4.35 (bs, 1H), 4.11 1H), 3.38-3.12 4H), 2.40 3H), 1.95 1H), 1.53 3H), 1.40 12H).

"C NMR (75 MHz, CDCI 3 6 174.71, 172.40, 172.09, 156.72, 144.98, 137.62, 133.43, 132.21, 130.58, 128.48, 120.47, 80.98, 62.87, 54.05, 51.10, 50.31, 37.23, 30.73, 28.88, 24.92, 22.16, 18.89.

Mass Spectroscopy: (FAB) 603 WO 99/06431 WO 9906431PCT/US98/15313 120-- Example 5 (28) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4i(N-tert-butoxylcarbonyl-D-alanyl)aminoj-L-phenylalanine Following the experimental procedure described for Example 1 N- (toluene-4-sulfonyl)-L-pro lyl-L-4-aminophenylalanine methyl ester 15 g, 0.33 7 mmol) was taken into 5 mL of DMF, with Et 3 N (2.0 eq, 95 tL), Boc-Dalanine (1.1I eq, 70 mg), and BOP (1.1I eq, 163 mg). The desired methyl ester was isolated as an oil in 33% yield (68 mg, 0. 11 mmol). The ester was then hydrolyzed with NaGH (I.1I eq, 5 mg) in a 1: 1 MeOH:H,O solution (4 mL).

The monoacid was isolated as a film in quantitative yields.

NMR data was as follows: 'H NMR (300 MHz, CDCI 3 8 8.90 (broad s, I 7.70 2H, J1 8.25 Hz), 7.45 2H, J= 8.37 Hz), 7.32 2H, J1= 8.25 Hz), 7.09 2H, J =8.25 Hz), 5.65 (bs, I1H), 4.82 (in, I1H), 4.3 5 (bs, I1H), 4.11 (in, ILH), 3.3 8-3.12 (mn, 4H), 2.40 3H), 1.95 (mn, IH), 1.53 (in, 3H), 1.40 12H).

3 C NMR (75 MHz, CDCL 3 6 174.71, 172.40, 172.09, 156.72, 144.98, 137.62, 133.43, 132.21, 130.58, 128.48, 120.47, 80.98, 62.87, 54.05, 51.10, 50.31, 37.23, 30.73, 28.88, 24.92, 22.16, 18.89.

Mass Spectroscopy: (FAB) 603 Example 6 (29) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- I(N-tert-butoxylcarbonyl-D-phenylaIanyl)amino-L-phenylalanine Following the experimental procedure described for Example 1 N- (toluene-4-sulfonyl)-L-prolyl-L-4-aininophenylalanine methyl ester 15 g, 0.337 nol) was taken into 5 mL of DMF, with Et 3 N (2.0 eq, 95 iL), Boc-Lphenylalanine 1 eq, 99 mg), and BOP (1.1I eq, 163 mg). The desired methyl ester was isolated as an oil in 16% yield (37 mg, 0.05 minol). The ester was then hydrolyzed with NaGH (I.1I eq, 3 mg) in a 1: 1 MeOH:H 2 0 solution (2 mL). The monoacid was isolated as an amorphous solid in quantitative yields.

NMR data was as follows: WO 99/06431 PCT/US98/15313 121 'H NMR (300 MHz, CDCl 3 8 8.56 (broad s, 1H), 7.73 2H, J 8.13 Hz), 7.43-7.22 10 7.09 2H, J 7.95 Hz), 5.78 1H), 4.87 (m, 1H), 4.65 1H), 4.11 1H), 3.44 IH), 3.29-3.01 4H), 2.43 (s, 3H), 2.08 1H), 1.60 3H), 1.33 9H).

3 C NMR (75 MHz, CDC13): 6 171.88, 171.44, 170.02, 156.56, 144. 96, 137.23, 136.83, 133.46, 132.78, 130.53, 130.33, 129.92, 129.36, 128.44, 127.64, 120.63, 81.16, 62.84, 53.96, 50.26, 38.91, 37.90, 30.35, 28.81, 24.96, 22.11.

Mass Spectroscopy: (FAB) 679 Example 7 (67) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- {2-[3-(fluorescein)thiouriedolacetamido}-L-phenylalanine The product of Example 2 was treated with NaHCO 3 and fluorescein isothiocyanate (isomer I obtained from Aldrich Chemical Company) in EtOH and H20. Acidification of the mixture and isolation of the resulting precipitate gave the title compound as an amorphous orange solid.

Mass Spectroscopy: (+FAB, 3-nitrobenzyl alcohol) 878 Example 8 (175) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- [(N-tert-butoxylcarbonylglycyl)aminol-L-phenylalanine Methyl Ester N-(Toluene-4-sulfonyl)-L-prolyl-L-(4-nitro)phenylalanine methyl ester (2.00 g, 4.48 mmol) was dissolved in MeOH (10 mL) with a catalytic amount of 10% Pd on C. The hydrogenation reaction was run at room temperature for 12 hours at 40 psi. Upon filtration of the reaction mixture over celite, the solvent was evaporated under reduced pressure yielding a pink foam in quantitative yields. The title compound was prepared therefrom and N-Boc glycine using the procedure described in Method 12.

NMR data was as follows: WO 99/06431 WO 9906431PCTIUS98/1 5313 -122-- 'H NMR (300 MHz, CDCI 3 85 7.72 2H, J 8.13 Hz), 7.45 2H, J =8.49 Hz), 7.35 2H, J 8.30 Hz), 7.10 2H, J 8.37 Hz), 5.40 (in, IH), 4.82 (in, ILH), 4.07 (in, I1H), 3.91 2H), 3.76 3 3.40 (in, I1H), 3.23 (mn, 1H), 3.05 (in, 2H), 2.43 3H), 2.43 (mn, 1H), 1.46 (in, 12H).

1 3 C NMR (75 MHz, CDCI 3 6 177.61, 171.97, 171.58, 168.52, 144.93, 137.25, 133.43, 132.55, 131.36, 130.54, 130.33, 128.39, 120.53, 80.50, 62.8 1, 54.00, 53.08, 50.25, 37.83, 30.42, 28.93, 28.87, 24.81, 22.14.

Mass Spectroscopy: (FAB) 603 Example 9 (306) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- {2-[3-(3-methylphenyl)uriedolacetamido}-L-phenylalanine The methyl ester was prepared by the reaction of N-(toluene-4-sulfonyl)- L-prolyl-L-(4-amino)phenylalanine with 2-(3-rn-tolyl-ureido)acetic acid (BOP, triethylamine, DMF, stir at room temperature overnight). The crude product was purified flash chromatography (silica, 9:1 EtOAc:hexane) to afford the methyl ester. The methyl ester was hydrolyzed using I M LiOH in THF. The title compound was isolated following acid/base work-up as a white solid.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): 8 12.8 (br s, I1H); 9.96 I 8.70 (s, I 8.04(d, I H, J 7.9Hz); 7.68 2H, J 8Hz); 7.48 2H, J 8.3Hz); 7.39 2H, J 8.3Hz); 7.21 IH); 7.16 3H, J 8.56Hz); 7.08 1H, J= 7.79Hz); 6.7 1H, J 7.68Hz); 6.38(t, IH, J 5.6Hz); 4.43 (in, 1H); 4.1 (dd, IlH, J 3.18, 8.23Hz); 3.89 2H, J 5.49Hz); 3.3 (in, I 3.05 (in, 2H); 2.92 (dd,IH, J 8.34, 13.63Hz); 2.38 (s,3H);2.22 1.38-1.62 (mn, 4H).

IR (KBr, cm-1): 3380, 2990, 1650, 1605, 1540, 1230, 1155, 660, 580, 545.

Mass Spectroscopy: in/e 644 (100 622 WO 99/06431 PCT/US98/15313 123 Example 10 (380) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- [y-(L-aspartyl)aminoj-L-phenylalanine Substitution ofBoc-L-aspartic benzyl ester for Boc-glycine and following the methods for preparation of Examples 1 and 2 gave the title compound as a white solid, mp 163-170 0

C.

NMR data was as follows: 'H NMR (DMSO-d 6 6 8.05 1H), 7.70 1H), 7.45 (dd, 4H), 7.18 2H), 4.40 1H), 4.10 1H), 2.40 3H), 1.60 6H) Mass Spectroscopy: (FAB) 547.

Example 11 (14) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- (a-carboxybenzyloxy)-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester (1.32 g, 2.95 mmol) was dissolved in dry DMF (50 mL) at room temperature. To this was added K 2

CO

3 (1.1 eq, 440 mg) and ethyl a-bromophenylacetate (1.1 eq, 750 mg). The reaction was stirred for 12 hours at room temperature. Ethyl acetate (100 mL) was added, and the organic layer washed several times with brine.

The organic layer was dried over MgSO 4 Upon filtration and evaporation of the solvents under reduced pressure, a residue was isolated which was then taken up in MeOH: H 2 0 1:1 (30 mL) with NaOH (1.1 eq, 427 mg). The desired diacid was isolated in 88% yield (754 mg, 1.33 mmol).

NMR data was as follows: 'H NMR (300 MHz, CD30D) 6 7.50 2H, J= 8.25 Hz), 7. 35 (d, 2H, J= 7.14 Hz), 7.15 5H), 6.95 2H, J= 8.13 Hz), 6.71 2H, J= 8.37 Hz), 5.48 1H), 4.51 1H), 3.87 1H), 3.10-2.79 4H), 2.15 (s, 3H), 1.45-1.01 4H).

3 C NMR (75 MHz, CDO3D): 6 174.71, 174.49, 173.98, 158.25, 146.39, 138.08, 135.37, 132.28, 131.74, 130.53, 130.36, 129.60, 129.00, 117.18, 79.95, 63.94, 55.31, 38.00, 32.23, 25.88, 22.32, 15.22.

WO 99/06431 WO 9906431PCT/US98/1 5313 124-- Mass Spectroscopy: (FAB) 567 Example 12 Synithesis of N-(Toluene-4-su lfonyl)-L-prolyl-4- 1 2 -(carboxy)phenvll-L-phenylalanine The product of Example 13 (178) was treated with NaOH in dioxane and water, to give after acidification, extraction, drying with MgSO,, filtration and evaporation the title compound as a clear oil.

NMR data was as follows: 'H NMR (CD 3 OD w/ CD 3 ONa, 300 MHz): 5 =7.75 J 8.2, 2H), 7.44-7.40 (in, 5H), 7.29-7.2 1 (in, 5H), 4.47 J 5.8, 1 4.03 (dd, J J 3.4, 1 3.37-3.25 (in, 2H), 3.17-3.06 (in, 2H), 1.89-1.80 (in, I1H), 1.64- 1.47 (mn, 3H).

1 3 C NMR (CD 3 OD w/ CD 3 ONa, 75 MHz): 8 179.1, 177.5, 173. 1, 145.8, 142.4, 141.3, 139.6, 137.8, 134.7, 131.0, 130.6, 130.5, 129.4, 129. 1, 128.7, 128.1, 127.6, 63.6, 57.0, 50.7, 38.7, 31.7, 25.2, 21.5.

Mass Spectroscopy: (+FAB, glycerol) 537 Example 13 (178) Synthesis of N-(Tolueo e-4-sulfonyl)-L-p rolyl-4- 1 2 -(methoxycarbonyl)phenyll-L-phenylalanine Benzyl Ester L-4-Iodophenylalanine [Phe(4-I)-OH] was treated with MeGH and HCI gas, to give after evaporation, HCI o Phe(4-I)-OMe. This product was treated with N-(toluene-4-sulfonyl)-L-Pro-OH, EDAC, HOBT, and Et 3 N in DMF, to give after aqueous workup, N-(toluene-4-sulfonyl)-L-Pro-L-Phe(441)OMe.

This product was treated in THF with Pd(PPh 3 4 and 2- (methoxycarbonyl)phenylzinc iodide, prepared by the method of Rieke (J.

Org. Chem. 1991, 56, 1445), to give after aqueous workup and flash chromatography, the title compound as a clear oil.

NMR data was as follows: WO 99/06431 WO 9906431PCTIUS98/1531 3 -125-- 'H NMR (CDC1 3 3 00 MHz): 8 7.81 J=7.7, I1H), 7.72 J=8.2, 2H), 7.54-7.49 (in, IH), 7.42-7.16 (in, 9H), 4.93-4.86 (in, 1H), 4.11-4.07 (mn, 1H), 3.80 3H), 3.64 3H), 3.42-3.28 (in, 2H), 3.15-3.08 (in, 2H), 2.43 3H), 2.09-2.04 (in, 1H), 1.58-1.45 (mn, 3H).

1 3 C NMR (CDCl 3 75 MHz): 6 171.3, 170.8, 169.1, 144.3, 141.9, 140. 1, 135.0, 132.9, 131.2, 130.8, 130.6, 129.9, 129.7, 129.0, 128.4, 127.8, 127.1, 62.2, 53.3, 52.5, 52.0, 49.7, 37.6, 29.7, 24.2, 21.5.

Mass Spectroscopy: (+FAB, 3-nitrobenzyl alcohol) 565 Example 14 Synthesis of N-(Tolu en e-4-su lfonyl)-L-prolyl-4-

{N-I

2 -(N-carbobenzyIoxyamino)ethyliamino}..L.phenylalanine Following the experimental procedure described for the synthesis of Example 3 the product from Example 15 (172) (32 mg, 0.05 1 inmol) was hydrolyzed in MeOH:H 2 0 1:1'(1 mL), with NaGH 1 eq, 3 ing). The title material was isolated in quantitative materials, as a foam.

NMR data was as follows: 'H NMR (300 MHz, CDCI 3 6 7.68 (mn, 2H), 7.30 (in, 5H), 7.20 (in, 2H), 4.77 (in, I 4.46 (in, I 4.18 (in, 2H), 3.65 (in, I1H), 3.47 (in, IlH), 3.12 (in, 2H), 2.78 1.5H), 2.54 1.5H), 2.42 3H), 1.26 (in, 3H).

1 3 C NMR (75 MHz, CDC1 3 6 171.47, 170.31, 144.78, 136.42, 135.77, 130.67, 129.88, 129.33, 127.80, 62.44, 60.99, 60.81, 54.00, 53.77, 38.32, 32.19, 31.96, 22.24, 14.76.

Mass Spectroscopy: (FAB) 449 Example 15 (172) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- IN- [2-(N-carb obe nzyloxya min o)etbyll amioI-L-pbhen ylalan ine Methyl Ester N-(Toluene- 4 -sulfonyl)Lproly-L-p-aiino-phenylalanine methyl ester (316 mg, 0.7 minol) was dissolved in a KOAc-HOAc solution in dry methanol WO 99/06431 PCT/US98/15313 126mL) [pH with NaCNBH 3 (10.0 eq, 446 mg), and carbobenzyloxyglycinal (1.1 eq). The reaction mixture was stirred at room temperature overnight and the solvents were evaporated under reduced pressure. EtOAc was added and the organic layer washed with brine, dried over MgSO 4 Upon filtration and evaporation of the solvents, the crude material was eluted on a preparative plate (Silica gel, EtOAc/hexanes The desired title compound was isolated, as a film in 5% yield (40 mg, 0.06 mmol).

NMR data was as follows: 'H NMR (300 MHz, CDCI 3 6 7.71 2H, J 6.90 Hz), 7.38 7.26 2H), 6.93 2H, J 7.20 Hz), 6.54 2H, J 7.50 Hz), 5.12 (m, 1H), 5.10 2H), 4.73 1H), 4.06 1H), 3.75 3H), 3.41 4H), 3.26 1H), 3.14 2H), 2.99 1H), 2.43 3H), 2.04 1H), 1.53 3H).

Mass Spectroscopy: (FAB) 623 Example 16 (368) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-L-4- {N-[3-(N,N-dimethylamino)propyll-N- [trifluoromethanesulfonyl]amino}-L-phenylalanine Methyl Ester N-(Toluene-4-sulfonyl)-L-prolyl-L-(4-amino)phenylalanine methyl ester was reacted with trifluoromethane sulfonyl anhydride in pyridine to produce the corresponding trifluoromethane sulfonamide. This compound was alkylated on the nitrogen of the trifluoromethane sulfonamide group under Mitsunobu conditions using 3-dimethylamino-l-propanol in THF. After solvent evaporation and aqueous wash the mixture was purified by filtration to yield the product as a solid, mp 45-55°C.

NMR data was as follows: 'H NMR (CDCI 3 400Mhz): 6 7.70 2H); 7.34 3H); 7.25 3H); 4.88 1H); 4.10 1H); 3.85 (brd s, 2H); 3.79 3H); 3.32 2H); 3.08 2H); 2.43 3H); 2.18 (brd s, 5H); 1.98 (brd s, 1H); 1.75-1.30 (brd m, 9H).

WO 99/06431 WO 9906431PCT/US98/15313 127-- JR (KBr, cm-i): 3400; 2970; 2800; 1750; 1675; 1525; 1450; 1400; 1350; 1225; 1200; 1165; 1150; 1100; 1075; 1000; 950; 825; 675; 600; 550.

Mass Spectroscopy: (+FAB) 663 603; 507; 438; 306; 191; 155; 91.

Example 17 (5 Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl.

L-4-{NN-di[4-(N,N-dimethylamino)benzyljamino..

L-phenvialanine The methyl ester was prepared- by-reductive amination of N-(toluene-4sulfonyl)-L-prolyl-L-4-aminobenzyl.Lphenylaianine with 4-NNdimethylaminobenzaldehyde (acetic acid, sodium triacetoxyborohydride, methylene chloride), stirred at room temperature overnight. The crude product was purified by flash chromatography to afford the methyl ester which was hydrolyzed in the manmer of Method 6 to provide the title compound.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): 8- 7.7 2H, J 8.34Hz); 7.54 1H, J =5.71 Hz); 7.40 1H, J 8.34Hz); 7.02 4H, J 8.78Hz); 6.75 2H, J 8.78Hz); 6.62 4H, J 8.78Hz); 6.48 2H, J 8.78Hz); 4.39 4H); 3.92 (dd, I H, J 2.85, 9.0Hz); 3.78 (in, I1H); 3.33 12H); 2.86 (mn, 4H); 2.39 3H); 1.62 (mn, I 1.30 (mn, I 1.09 (in, 2H).

JR (KBr, 3380, 1610, 1520, 1400, 1350, 1160, 800, 670.

MS FAB, inle 698 (2011M+H]Y).

Anal. Calc'd for C 39

H

46

N

5

O

5 Li 3H 2 0: C, 6 1,76; H, 6.91; N, 9.23. Found: C, 61.73; H, 6.91; N, 9.15.

Example 18 (138) Synthesis of N-(Toluene-4-sufonyl)-L.proyi..4 1 3 -(NN-dimetbylamino)propoxyI-L-phenylaanine Triphenyiphosphine (24.4 g, 92.9 minol) and 3 -diinethyl amino-1Ipropanol (8.72 g, 84.5 minol) were dissolved in THF (200 inL) and cooled in WO 99/06431 PCT/US98/15313 128 an ice bath. Diethyl azodicarboxylate (16.2 g, 14.6 mL, 92.9 mmol) was added dropwise via syringe over 5 minutes and stirred an additional minutes before addition of N-Boc-tyrosine methyl ester (24.95 g, 94.5 mmol) as a solution in 100 mL THF via cannula. The mixture was stirred for minutes at 0 C and 19 hr at room temperature. The mixture was concentrated on a rotary evaporator and taken up into Et20 (500 mL). The mixture was extracted with 0.2N HCI (3 x 350 mL) and the combined acidic extracts were made basic with solid NaHCO 3 This mixture was extracted with EtOAc (3 x 300 mL) and the combined extracts were dried (Na 2

SO

4 filtered and evaporated in vacuo to give N-Boc-L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester (26.5 g, 82 N-Boc-L- 4 -(3-N,N-dimethylaminopropyloxy)phenylalanine methyl ester (26.5 g, 69.5 mmol) was dissolved in MeOH (300 mL) and saturated with HCI gas. The mixture was stirred for 3 hr before removing the volatiles in vacuo to give L- 4 3 -N,N-dimethylaminopropyloxy)phenylalanine methyl ester dihydrochloride (23.6 g, N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-4-(3-N,Ndimethylaminopropyloxy)-phenylalanine methyl ester dihydrochloride using the procedure described in Method 13 to give N-(toluene-4-sulfonyl)-L-prolyl-

L-

4 3 -N,N-dimethylaminopropyloxy)phenylalanine methyl ester (16.3g, The title compound was prepared via hydrolysis of the methyl ester using 0.5 N NaOH in THF/water (14.71 g, 99%).

NMR data was as follows: 'H NMR (DMSO-d 6 6 7.75 2H, J= 8.2 Hz), 7.67 1H, J= 5.6 Hz), 7.42 2H, J= 8.2 Hz), 7.00 2H, J= 8.5 Hz), 6.71 2H, J= Hz), 3.98 2H), 3.90 2H, J= 6.5 Hz), 3.14-2.97 2.40 3H), 2.32 2H, J= 7.0 Hz), 2.13 6H), 1.83-1.75 1.45-1.36 (3H).

"C NMR (DMSO-d 6 6 173.5, 169.7, 157.2, 144.1,133.7, 130.9, 130.3, 128.1, 113.9, 65.9, 62.4, 56.0, 55.4, 49.4, 45.5, 36.1, 30.5, 27.3, 23.9, 21.4.

WO 99/06431 WO 9906431PCT/US98/15313 -129-- Mass Spectroscopy: FAB rn/c 562 (M+2Na-H).

Example 19 (282) Synthesis of N-(Toluene-4-sulfony)-N-methylLserinyl-4 1 3 -(N-dimethylaminopropoxyl-.Lphenylajanine Methyl Ester N-Methyl-N-(toluene-p-sulfonyl)-L-serine (655 mg, 2.4 mmol) was taken up in DMF (100 mL) with L- 4 -dim ethylam ino-propyloxy)p henylIal ani ne methyl ester hydrochloride salt [see Example 18 (138) for preparation] (1.0 g, 2.4 mmol), HOBT (1.1I eq, 356 mg), Et 3 N (3.2 eq, 1. 1 mL), and EDC (1.1I eq, 500 mg) following the procedure described in Method 13. The title compound was isolated in 70% yield (900 mg, 1 .7 mmol) as an oil.

NMR data was as follows: 'H NMR (300 MHz, CDCI 3 8 7.68 2H, J 8.40 Hz), 7.29 2H, J 8. 10 Hz), 7.08 I H, J 7.80 Hz), 7.04 2H, J 8.70 Hz), 6.82 2H, J 8.70 Hz), 4.71 (in, 1H), 4.43 (in, IH), 3.94 2H, J 6.60 Hz), 3.75 3H), 3.69 (in, I1H), 3.5 1 (in, I 3.14 (in, IlH), 2.91 (mn, I 2.5 9 3 2.45 (mn, 2H), 2.42 3H), 2.20 6H), 1.87 (in, 2H).

1 3 C NMR (75 MHz, CDC1 3 6 172.04, 170.15, 158.66, 144.56, 136.02, 130.72, 130.46, 128.19, 127.87, 115.31, 66.70, 60.86; 60.65, 56.87, 54.01, 53.08, 45.95, 37.39, 31.85, 27.91, 22.13.

Mass Spectroscopy: (FAB) 536 Example 20 (284) Synthesis of N-(Toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4 12-(NZ-dimethylamino)eth oxylj-L-p h eylalan in e Triphenylphosphine (1.1I eq) and 3 -dimethylamino-1I-propanol (I eq) were dissolved in THF and cooled in an ice bath. Diethyl azodicarboxylate (I eq) was added dropwise via syringe over 5 min and stirred an additional 10 min before addition of N-Boc-tyrosine methyl ester (1.02 eq) as a solution in 100 mL THF via cannula. The mixture was stirred for 30 min at 0 TC and 19 hr at room temperature. The mixture was concentrated on a rotary evaporator and WO 99/06431 PCT/US98/15313 130taken up into Et20 (500 mL). The mixture was extracted with 0.2N HCI (3 X 350 mL) and the combined acidic extracts were made basic with solid NaHCO 3 This mixture was extracted with EtOAc (3 X 300 mL) and the combined extracts were dried (Na 2

SO

4 filtered and evaporated in vacuo to give N-Boc-L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester.

N-Boc-L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester (26.5 g, 69.5 mmol) was dissolved in MeOH (300 mL) and saturated with HCI gas.

The mixture was stirred for 3 hr before removing the volatiles in vacuo to give

L-

4 3 -dimethylaminopropyloxy)phenylalanine methyl ester dihydrochloride (23.6 g, N-(Toluene-4-sulfonyl)-L-(5,5-dimethyl)-thiaproline was coupled to L-4-(3-dimethylaminopropyloxy)-phenylalanine methyl ester dihydrochloride using the procedure described in Method 13 to give N-(toluene-4-sulfonyl)-L- (5,5-dimethyl)-L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester (16.3g, The title compound was prepared via hydrolysis of the methyl ester using 0.5 N NaOH in THF/water to provide a solid, mp >200C (dec.).

NMR data was as follows: 'H NMR (CD30D, 300 MHz): 6 .85 3H), .94 3H), 1.78 2H), 2.23 3H), 2.28 6H), 2.57 2H), 2.83 2H), 3.71-3.74 2H), 4.22-4.27 2H), 4.41 1H, J 9.1 Hz), 6.58 2H, J 8.6 Hz), 6.98 (d, 2H, J 8.6 Hz), 7.20 2H, J 8.3 Hz), 7.54 2H, J 8.3 Hz).

"C NMR (CD 3 OD, 75 MHz): 6 22.2, 25.3, 27.8, 30.5, 39.4, 45.2, 51.9, 56.0,57.6,58.2,67.2,75.1, 115.8, 129.8, 131.6, 132.1, 132.5, 135.4, 146.7, 159.5, 170.9, 178.2.

Mass Spectroscopy: (FAB+) 586 Anal. HPLC: (Microsorb-MV C18 Rev. Phase, 4.6 x 150mm; Gradient 1:1 CH 3

CN/H

2 0 with 0.05% TFA; flow rate 1.0 ml/min; 1= 254 nm; sample vol.= 20 mL) Run 2.988 min retention time (100.0% purity) Run #2: 3.098 min retention time (100.0% purity).

WO 99/06431 WO 9906431PCTIUS98/1 5313 -131 Example 21 (287) Synthesis of N-(Toluene-4-su lfonyl)-L-prolyl-4- 1 2 -(NN-dimeth yiamin o)ethoxyl..L..ph enylalan in e The title compound was prepared as in Exannp., 20 (138), except that 2dimethylaminoethanol was used in plac t of 3-dimethylamino-1I-propanol.

NMR data was as follows: 'H NMR (DMSO-d 6 8 7.74 2 H, J 7.4 Hz), 7.6 7 I H, J 7.9 Hz), 7.42 2H, J 8.0 Hz), 7.01 2H, J 7.9 Hz), 6.71 2H, J =7.8 Hz), 3.95 (in, 4H), 3.14-2.98 2.57 2H, J 5.6 Hz), 2.40 3H), 2.18 6H), 1. 74 (in, I 1.40 (in, 3 H).

3 CNMR (DMSO-d 6 6 173.5, 169.7, 157.0, 144.1, 133.8, 131.0, 130.9, 130.3, 128.1, 113.9, 66.0, 62.4, 58.0, 55.4, 49.4, 45.9, 36.2, 30.5, 23.9, 21.4.

Mass Spectroscopy: FAB m/e 504 Example 22 (317) Synthesis of N-(Toluene-4-sulfonyl)-L..proly.4- 2 -(N-ethyl-N-ph enylamin o) eth oxyl.-L-.ph en la Ianin e Methyl Ester The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 2-(N-ethylN-phenyl)aminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7.

NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 6 1.08 (3H, t, J=8,8Hz); 1.39 in); 1.55 (3H, in); 2.19 (3H, 2.85-3.0 in); 3.12 (1IH, dd, J=6,10,6Hz); 3.41 (2H, q, J=6,8,6Hz); 3.6 (3H4, 3.62 (2H, t, J=5,5Hz); 4.01 (2H, t, 4.04 (1IH, t, J=8,8Hz); 4.43 (1IH, dd, J=7,6,7Hz); 6.5 5 (1IH, t, J=8,8Hz); 6.65 (2H, d, J=lIOHz); 6.8 (2H, d, J=10 Hz 7.1 (4H, in); 7.3 8 (2H, d, J=lIOHz); 7.64 (2H, d, J=10 Hz); 8.1 (1IH, d, J=10 Hz).

WO 99/06431 WO 9906431PCT/US98/1531 3 -132-- MS: +FAB, m/z 594 45 15 7 (100%).

Example 23 (32 1) Synthesis of N-(Toluene-4-sulfonyl)-L-proly.4- 12-(NN-diisop ropyla min o)etboxy] -L-ph enylalan ine The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 2-diisopropylaminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp 121-124'C.

NMR data was as follows: 'H NMR (DMSO-d6 400 Mh) 6=09 (12H, d, J=8Hz); 1.25-1.6 (3H, in); 1.78 (1 H, mn); 2.38 (3H, 2.7 (2H, t J=8,8Hz); 2.9 (2H, in); 3.0 (2H, q, J=5,5,5Hz); 3.1 (IH, dd, J=3,4,3Hz); 3.35 (1H, 3.78 (lH, t, J=7,7Hz); 3.8 (2H, t, J=5,5 Hz); 3.95 (1LH, d, J=1IOHz); 6.5 (1iH, d, J=I OHz); 6.65 (1iH; d, J=1IOHz); 6.8 5 (1lH, d, J=LIOHz); 6.9 (1 H, d, J=lIOHz); 7.4 (2H, d, J=lIOHz); 7.62 (1IH, mn); 7.75 (2H, d, J=I OHz).

MS: +FAB, m/z 560 70 154 (100).

Example 24 (333) Synthesis of N-(Thiophene-2-sulfonyl)-L-proly-4- I3-(NN-dimethylamino)propoxyI-L-phenylalanine The title compound was prepared using Method 15 and was isolated as a white, hygroscopic solid, mp =>200'C.

NMR data was as follows: 'H NMR (DMSO-d 6 300 MHz): 8 8.03 (br s, IH); 7.74 (in, 2H); 7.26 (br s, IH); 7.04 2H, J 7.0 Hz); 6.75 2H, J 6.0 Hz); 4.16 (in, 1H); 4.06 (in, I 3.85 (in, 2H); 3.33 (in, I 3.13 -3.00 (br m, 3H); 2.62 (in, 2H); 2.35 3H); 1.90 (in, 2H); 1.75 (in, lH); 1.90 1.50 (br m, 3H), WO 99/06431 WO 9906431PCT/US98/1 5313 -133 1 3 C NMR (DMSO-d 6 75 MHz): 8 173.4, 169.9, 157.3, 136.1, 134.3, 133.5, 130.8, 130.3, 128.7, 128.7, 114.1, 65.7, 62.5, 55.1, 54.9, 49.7, 43.9, 36.1, 30.6, 25.9, 24.1, 21.6.

Mass Spectroscopy: (PI-FAB) 532, Example 25 (334) Synthesis of N-(5-Cbiorothiophene-2-sulfonyl)-L-proly..4 13-(N-dimethylamino)propoxyj-L-ph enylalanine The title compound was prepared using Method 15 and was isolated as a white, hygroscopic solid, mp =>200'C.

NMR data was as follows: 'H NMR (DMSO-d6,300 Mz)8= 7.62 (in, 2H); 7.44 (in, 2H); 6.99 (in, 2H); 6.71(m, 4.05(m, I1H); 3.92(m, 3H); 3.26 (mn, 1H); 3.09 2.97 (br mn, 3H); 2.30(m, 2H); 2.13 6H); 1.82 (mn, 2H); 1.79 1.51 (br in, 4H).

3 C NMR (DMSO-d 6 75 MHz): 6 173.3, 169.3, 157.2, 137.3, 134.3, 132.5, 130.9, 130.9, 119.8, 113.9, 65.9, 62.8, 56.0, 55.5, 49.7, 45.5, 36.1, 30.6, 27.2, 24.0, 22.8.

Mass Spectroscopy: (PI-FAB) 588, Na) 4 Example 26 (336) Synthesis of N-(Toluene-4-sulfonvl)-L-prolyl-4- 12-(NNV-diethylamino)ethoxyj-L-phenylalanine The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 2-diethylaminoethyl chloride hydrochloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp 105-109'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 6 =1.0 (6H, t, J =8,8Hz); 1.25-1.45 (4H, in); 1.65 (2H, in); 2.18 (3H, 2.26 (2H, t, J 2,2Hz); 2.65 (4H, q, J 5,4,5Hz); 2.8-3.1 (4H, in); 3.84 (IH4, dd, J 5,4,514z); 3.9 (2H, t, J 3,3Hz); WO 99/06431 PCT/US98/15313 134-- 4.1 (1H, d, J 8Hz); 6.68 (2H, d, J 10Hz); 6.95 (2H, d, J 10Hz); 7.05 (2H, d, J 10Hz); 7.4 (2H, d, J 10Hz); 7.63 (1H, d, J 4Hz); 7.73 (2H, t, J 4,4Hz).

MS: +ESI, m/z 532.4 100 Example 27 (340) Synthesis of

N-(

2 ,5-Dichlorothiophene-3-sufonyl)-L-prolyl- 4 3 -(N,N-dimethylamino)propoxyl-L-phenylalanine The title compound was prepared using Method 15 and was isolated as a white, hygroscopic solid, mp >200 0

C.

NMR data was as follows: 'H NMR (DMSO-d 6 300 MHz): 6 7.77 1 H, J 6.6 Hz); 7.43 (s, 1H); 7.07 2H, J 7.4 Hz); 6.76 2H, J 7.4 Hz); 4.33 1H); 4.15 (m, 1H); 3.89 2H, J 6.1 Hz); 3.29 2H); 2.97 2H); 2.57(t, 2H, J 7.1 Hz); 2.31 6H); 1.85 4H); 1.65 2H).

"C NMR (DMSO-d 6 75 MHz): 6 173.4, 172.5, 170.0, 157.3, 134.2, 130.8, 130.5, 130.3, 127.7, 126.9, 114.1, 65.8, 61.9, 55.3, 54.9, 49.2, 44.2, 36.2, 30.9, 26.1, 24.3, 21.6.

Mass Spectroscopy: (PI-FAB) 600, Example 28 (341) Synthesis of N-(1-Methylpyrazole-4-sulfonyl)-L-prolyl-4- 1 3 -(N,N-dimethylamino)propoxy]-L-phenylalanine The N-methylpyrazole sulfonyl chloride was prepared by adding Nmethylpyrazole to chilled chlorosulfonic acid. The reaction mixture was allowed to warm to room temperature and the heated to 100 0 C overnight under a stream of N 2 The reaction mixture was then cooled to room temperature and chilled to 0°C. To this solution was added thionyl chloride eq.) and the reaction was stirred at room temperature for 30 min, then warmed to 70 oC for two hours. The reaction was cooled to room temperature and then chilled in an ice bath. Water and ice were slowly added to the WO 99/06431 WO 9906431PCTIUS98/1 5313 -135 reaction mixture to precipitate a white solid which was collected by filtration.

The desired sulfonyl chloride was washed with cold water and hexane. The title compound was prepared using Method 15 and was isolated as a white, hygroscopic solid, mp >200'C.

NMR data was as follows: 'H NMR(DMSO-d 6 3 00 MHz): 6 8.44 I 7.8 9 I1H); 7.66 (d, I H, J 5.6 Hz); 7.00 2H, J 8.5 Hz); 6.70 2H, J 8.6 Hz); 3.89 (in, 4 3.87 3H); 3.14 -2.98 (br m, 4H); 2.34 2H, J 7.2 Hz); 2.30 6H); 1.86 (in, 3H); 1.81 1.75 (br in, 3H).

3 C NMR(DMSO-d 6 75 MHz): 8 172.3, 169.8, 157.2, 138.9, 133.7, 130.9, 130.8, 117.4, 113.9, 65.9, 62.5, 55.9, 55.3, 49.5, 36.0, 30.6, 27.2, 23.9.

Mass Spectroscopy: (PI-FA-B) 530, Example 29 (346) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 1 3 -(NN-diethylanino)propoxyj-L-phenylalanine Methyl Ester The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 3-diethylaminopropyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.

NMR data was as follows: 'H NMR (DMSO-d6 400 Mhz) (6H, bs); 1.4-1.6 (4H, in); 1.85 (2H, in); 2.18 (3H, 2.5 (2H, bs); 2.5-2.8 (4H, bs); 2.9 (2H, in); 3.1 (IH, dd, J 8,10,8Hz); 3.35 (1 H, dd, J 8,4,8Hz); 3.6 (3H, 3.94 (2H, t, J 6,6Hz); 4.1 (1IH, in); 4.48 (1 H, dd, J 8,6,8Hz); 6.8 (2H, d, J 10OHz); 7.1 (2H, d, J 7.4 (2H, d, J 10OHz); 7.7 (2H, d, J 10OHz); 8.2 (1IH, d, J MS: +ESI, m/z 560.5 100 WO 99/06431 WO 9906431PCT/US98/1 5313 -136-- Example 30 (35 1) Synthesis of N-(Th iazole-2-sulfonyl)-L-prolyl.4t 3 -(NN-dimethylamino)propoxyJ-L-phenylaanine The sulfonyl chloride was prepared from the thiol as taught by Roblin and Clapp, JACS, 72, 4890, 1950. The title compound was prepared using Method and was isolated as a white, hygroscopic solid, mp >200'C.

NMR data was as follows: 'H NMR (DMSO-d 6 300 MHz): 6 8.24 I H, J 3.1 Hz); 8.15 (d, IlH, 3.1 Hz); 7.63 I1H, J 5.0 Hz); 6.98 2H; J 8.6 Hz); 6.70 2H, J 8.6 Hz); 4.24 (in, IH); 3.88 (in, 3H); 3.36 (in, 2H); 3.28 2.98 (mn, 2H); 2.31 2H, J 7.0 Hz); 2.12 6H); 1.83 1.79 (br m, 4H); 1.79 (in, IH); 1.45 (in, I H).

3 C NMR (DMSO-d 6 75 MHz): 85= 172.13, 168.9, 162.5, 157.2, 145.5, 131.0, 130.9, 127.5, 113.8, 65.9, 63.3, 56.1, 55.5, 50.1, 45.6, 38.8, 38.5, 35.9, 30.7, 27.3, 24.0.

Mass Spectroscopy: (P1-FAR) 555, Example 31 (353) Synthesis of N-(Toluene-4-sulfonvI).L-proliy.4.

1 3 -(N-methyl-N-benzvlamino)propoxyl..L-.phenylalanine The title compound was prepared from the product of Example 33 (356) using the procedure described in Method 7 as a solid, mp 87-90'C.

NMR data was as follows: 'H NMR. (DMSO-d 6 400 Mhz): 7.75 2H, J=lOHz); 7.65 IH, J =4Hz); 7.4 2H, J I10Hz); 7.18-7.3 (in, 5 6.96 2H, J I10Hz); 6.65 2H, J I10Hz); 3.97 I H, J 4Hz); 3.91 2H, J 4,4Hz); 3.8 I1H, J 2,2,2Hz); 3.42 2H); 2.95-3.1 4H); 2.42 2H, J 8,8Hz); 2.38 (s, 3H); 2.08 3H); 1.85 2H, 6,6Hz); 1.7 (in, 1H); 1.3 (bs, 4H).

WO 99/06431 WO 99/643 1PCTIUS98/1 5313 -137-- Example 32 (354) Synthesis of N-(Toluen e-4-su lfonyl)-L-prolyl-4- 1 3 -(NN-diethylamino)propoxy..L..ph enyla Ianin e The title compound was prepared from the product of Example 29 (346) using the procedure described in Method 7 as a solid, mp =76-82'6.

NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 6 1.0 (6H, t, J 8,8Hz); 1.38 (2H, in); 1.4-1.8 (4H4, in); 2.38 (3H, 2.45 (2H, t, J 7,7Hz); 2.6 (4H, q, J 6,5,6Hz); 2.95 (2H, in); 3.05 (1IH, dd, J 5,5,5Hz); 3.15 (1IH, dd, J 4,5,4Hz); 3.9 (2H, t, J 5,5Hz); 4.0 (1 H, t, J =6,6Hz); 4.1 (1iH, in); 6.7 (2H, d, J 10OHz); 6.95 (2H, d, J I 10Hz); 7.4 (2H, d, J I10Hz); 7.7 (1 H, d, J 4Hz); 7.75 (2H, d, J Example 33 (356) Synthesis of N-(Toluene-4-sulfonyl)-L-proly.4- 3 -(N-methyl-N-benzylami no)p ropoxyJ -L-phenyla Ian ine Methyl Ester The title compound was prepared via O-alkylation of N-(toluene-4sul fonyl)- L-pro lyl -L-tyro sine methyl ester with 3-(N-benzylNmethyl)aminopropyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide to provide a solid, mp 60-70'C.

Example 34 (372) Synthesis of N-(I -Methylimidazole-4-sulfonyl)-L-prolylI 4 3 -(NN-dimethylamino)propoxyl-L-phenylaianine The title compound was prepared using Method 15 and was isolated as a white, hygroscopic solid, mp >200'C.

NMR data was as follows: 'H NMR (DMSO-d 6 3 00 MHz): 6 7.8 6 I 7.8 2 I1H); 7.6 3 (d, I1H, J =5.6 Hz); 6.96 2H, J 8.2Hz); 6.97 2H, J 8.2 hz); 4.12 4.09 WO 99/06431 WO 99/643 1PCTIUS98/15313 -138-- (br m, 1H); 3.89 2H-, J 6.5 Hz); 3.70 3H); 3.13 (m 2H); 3.00 (in, 2H); 2.33 2H, 7.2Hz); 2.13 6H); 1.82-1.75 (mn, 3H), 1.60-1.40 (br m, 3H).

3 C NMR (DMSO-d 6 75 MHz): 8= 172.8, 169.9, 157.2, 140.7, 136.1, 130.9, 126.6, 113.9, 65.9, 62.9, 56.0, 55.3, 49.7, 45.5, 35.9, 33.9, 30.6, 27.3, 24.0, 21.9.

Mass Spectroscopy: (PI-FAB) 552, Example 35 (373) Synthesis of 4 3 -(N,N-dimethylamiuo)propoxyj..Lphenylalanine The sulfonyl chloride was prepared from the thiol as taught by Roblin and Clapp, JACS, 72, 4890, 1950. The title compound was prepared using Method 15 and was isolated the as a white, hygroscopic solid, mp >200'C.

NMR data was as follows: 'H NMR (DMSO-d 6 300 MHz): 8 7.66 I H, J =3.2 Hz); 7.02 (d, 2H, J 8.5 Hz); 6.72 2H, J 8.2 Hz); 4.28 1H; 5.8 Hz); 3.96-3.89 (br mn, 3H); 3.37-3.23 (br mn, 2H); 3.02 (in, 2.95 (in, 1K); 2.82 3H); 2.39 2H, J 7.0 Hz); 2.13 6H); 1.83 (mn, 3H); 1.80-1.40 (in, 3H).

3 C NMR (DMSO-d 6 75 MHz): 85 173.2, 170.9, 169.0, 165.9, 157.2, 130.9, 130.8, 113.9, 65.9, 63.1, 56.0, 55.6, 50.1, 45.4, 32.2, 30.9, 27.2, 24. 1, 22.3, 15.9.

Mass Spectroscopy: (PI-FAB) 548, Example 36 (393) Synthesis of N-(Toluene-4-sulfonyl)-L-thiaproly-4-

I

3 -(N,N-dimethylamino)propoxyI-L-phenylalanine The title compound was prepared as in Example 18 (138) except Lthiaproline is used in place of L-proline.

NMR data was as follows: 'H NMR (300 MHz, CD 3 OD): 5 7.57 2H, J =8.40 Hz), 7.20 2H-, J 8.10 Hz), 6.92 2H, J 8.40 Hz), 6.58 2H, J =8.40 Hz), 4.50 (dd, WO 99/06431 WO 9906431PCTIUS98/15313 -139-- I1H, J 4.20, 7.50 Hz), 4.45 I H, J 10.50 Hz), 4.17 (mn, I1H), 3.87 I1H, J -10.50 Hz), 3.76 2H, J 6.00 Hz), 3.10 (mn, 1H), 2.99 (mn, 2H), 2.80 (in, 1H), 2.55 (mn, 2H), 2.35 (in, 1H), 2.25 6H), 2.22 3H), 1.79 (mn, 2H).

3 C NMR (75 MHz, CD 3 OD): 8 177.75, 170.46, 159.43, 146.91, 135.93, 132.42, 131.73, 129.80, 115.75, 67.25, 57.90, 57.70, 52.92, 45.30, 38.33, 34.73, 27.94, 24.74, 22.16.

Mass Spectroscopy: (FAR) 546 Example 37 (472) Synthesis of N-(4-Cyanobenzenesulfonyl)-L-(5,5-dimethvl)thiaprolyl- 4-[3-(NN-dimetbylamino)propoxyJ-L-phenylalanine Methyl Ester The title compound was prepared following the procedure outlined for the preparation of Example 20 (284).

NMR data was as follows: 'H NMR (CDC1 3 8 7.98-7.95 2H), 7.83-7.80 2H), 7.06-7.03 (d, 2H), 6.80-6.77 2H), 4.80 (mn, IlH), 4.48 (mn, I1H), 3.95 (in, 3H), 3.73 3H), 3.02-(m, 2H), 2.45 2H), 2.26 6H), 1.94 (in, 2H), 1.21 3H), 1. 17 (s, 3H).

3 CNMR (CDC 3 6 179.9, 168.2, 158.8, 141.1, 133.7, 130.9, 128.1, 117.9, 115.2, 74.2, 66.7, 56.9, 55.3, 53.9, 53.0, 51.1, 46.0, 38.0, 29.9, 28.0, 24.4.

Example 38 (514) Synthesis of N-(Toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)- 4-13-(N,N-dimethylamino)propoxyl-L-phenylalanine acid was prepared by the method of Larsson and Carlson (Acta Chernica Scan. 1994,48a, 517-525). N-(Toluene-4acid using the procedure described in Method 1. The title compound was prepared following the procedure outlined for the preparation of Example 20 (284).

WO 99/06431 PCT/US98/15313 140-- NMR data was as follows: 'H NMR (CD 3 OD): 6 7.53-7.47 2H), 7.20-7.14 2H), 7.00-6.85 2H), 6.58-6.54 2H), 4.70-4.57 1H), 4.22-4.14 1H), 3.77-3.71 3H), 3.25-3.09 1H), 2.93-2.69 4H), 2.44 3H), 2.22 3H), 2.18 6H), 1.92 1H), 1.68 2H).

3C NMR (CD 3 OD): 6 177.9, 177.8, 169.6, 169.4, 159.6, 159.5, 146.3, 146.1, 138.9, 138.9, 132.8, 132.4, 131.8, 130.5, 129.8, 129.2, 126.9, 115.8, 115.7, 67.4, 58.1, 57.8, 57.1, 45.6, 44.9, 38.8, 37.9, 28.2, 28.2, 27.9, 26.6, 26.3, 24.7, 22.1.

Example 39 (169) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 2 -(carboxy)phenoxyl-L-phenylalanine Methyl Ester N-(Toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester (2.14 g, 5.16 mmol) was added to a suspension of sodium hydride (60% in oil, 1.1 eq, 228 mg) in xylenes (50 mL) at 0°C. The reaction mixture was stirred for minutes and cuprous bromideodimethyl sulfide complex (1.4 eq, 1.48 g) was added. The reaction mixture was stirred at 23°C for 0.5 hours. 2-Iodo sodium benzoate (1.5 eq, 8.06 mmol) was added and the reaction mixture was refluxed for 12 hours. EtOAc (100 mL) was added, and the organic layer washed with

NH

4 CI, 10% HCI, and brine, dried over MgSO 4 The crude material was eluted on column chromatography (silica gel), with CHCI 3 :MeOH 9:1, and the title compound was isolated as an oil.

NMR data was as follows: 'H NMR (300 MHz, CDCI 3 6 8.16 (broad d, 1H), 7.73 2H), 7.47 2H), 7.35 2H), 7.21 2H), 7.03 2H), 6.76 1H), 4.85 (m, 1H), 4.07 1H), 3.77 3H), 3.41 1H), 3.28 1H), 3.09 2H), 2.44 3H), 2.05 1H), 1.55 3H).

Mass Spectroscopy: (FAB) 567 WO 99/06431 WO 9906431PCT/US98/15313 141 Example 40 (309) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 2 4 -(pyrimidin-2-yl)piperazin-I -ylJ etboxy}-L-phenylalanine The methyl ester was prepared by Mitsunobu reaction of NV-(toluene-4sulfonyl)-L-prolyl-L-tyrosine methyl ester following the procedure described for the preparation of Example 20 (284). The title compound was prepared using the procedure described in Method 7 as a solid, mp =102-105 0

C.

NMR data was as follows: H NMR (DMSO-d 6 400 Mhz): 8 1.35 1.4 1.76 2.38 2.5 in); 2.66 (2H, t, J =8,8Hz); 2.9-3.1 3.68 (4H, t, J 5,5H-z); 3.8 (1lH, q, J 4,6,4Hz); 3.95 (1IH, dd, J 2,10,2Hz); 4.05 (2H, t, 6,6Hz); 6.6 (1 H, t, J 5,5 Hz); 6.7 (2H, d, J I10Hz); 6.96 (2H, d, J 10OHz); 7.4 (2H, d, J I10Hz); 7.65 (1 H, d, J 4Hz); 7.74 (2H, d, J 8.35 (2H, d,J Example 41 (3 Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 13-(piperidin-1 -yI)propoxyl-L-phenylalanine The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with I -(2-chloropropyl)piperidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp 122-125TC.

NMvR data was as follows: 'H NMR (DMSO-06, 400 Mh) 6=774 2H, J I10Hz); 7.65 1H, J =4Hz); 7.4 2H, J I10Hz); 6.96 2H, J I10Hz); 6.65 2H, J I 0Hz); 3.96 (dd, IlH, J 2,6,2Hz); 3.9 3H, J 7,7Hz); 2.95-3.1 (in, 4H); 2.46 (t, 1H, J 2,2Hz); 2.38 3H); 2.33 2H, J 8,8Hz); 2.24 (in, 2H); 1.78 (in, 3H); 1.45 4H, J=5,5Hz); 1.38 (mn, 4H).

WO 99/06431 WO 99/643 1PCT/US98/15313 142-- Example 42 (311) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- [2-(pyrrolidin-1 -yl)ethoxyj-L-phenylalanine The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 1-(2-chloroethyl)pyrrolidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp 127-130TC.

NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 6 7.73 2H-, J 10OHz); 7.65 IlH, J =4Hz); 7.4 2H, J =-10 Hz); 6.95 2H, J 10OHz); 6.65 2H, J =10 Hz); 3.95 3H, J 4,6Hz); 3.7 1H, J 2,4,2Hz); 2.95-3.1 (in, 4H); 2.72 2H, J 6,6Hz); 2.48 (mn, 3H); 2.38 3H); 1.74 (in, IH); 1.64 4H, J 4,4Hz); 1.42 (in, 1H); 1.37 3H).

Example 43 (316) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- {3-14-(3-chlorophenyl)piperazin-1 -yIJ propoxy}-l,-phenylalanine The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 1 -(3-chlorophenyl)-4-(3-chloropropyl)piperazine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp 1 I 6-8'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 8 7.74 2H, J I10Hz); 7.65 IlH, J =4Hz); 7.4 2H, J I10Hz); 7.2 1H, J 8,8Hz); 6.96 2H, J 6.9 IlH); 6.85 I H, J I10Hz); 6.75 IdH, J 10OHz); 6.7 2H, J 3.95 2H, J 8Hz); 3.92 1H, J 8,8Hz); 3.83 IH, J= 5,4,5Hz); 3.6 IdH, 5,5Hz); 3.15 4H, J 4,4Hz); 2.95-3.1 (in, 4H); 2.5 (in, 3H); 2.45 2H, J =8,8Hz); 2.38 3H); 1.84 2H, J 7,7Hz); 1.75 (in, 1 1.4 I H, J 8,10,8Hz); 1. 35 2H).

WO 99/06431 WO 9906431PCT/US98/15313 -143-- Example 44 (318) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- I(l-tert-butoxycarbonylpiperidin-3-ylomethoxy- L-phenylalanine Methyl Ester N-(Toluene-4-sulfonyl)-L-prolyl-O- -tert-butoxycarbonyl)-piperidin-3yl)methyl]-L-tyrosine methyl ester was prepared via O-alkylation of N- (toluene-4-sulfonyl)-L-prolyl.L-tyrosine methyl ester with N-Boc-3pipenidinemethyl tosylate in reiluxing 2-butanone in the presence of potassium carbonate and sodium iodide to provide a solid, mp 60-62 0

C.

The title compound was prepared from this product using the procedure described in Method 7 to provide a solid, mp 82-84'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): 5 12.77 (br s, IlH), 8.00 I H, J= 7.9Hz); 7.68 2H, J 8.3Hz); 7.39 2H, J 7.9Hz); 7.13 2H, J 8.6Hz); 6.81 2H, 8.6Hz); 4.42 (in, I 4. 10 (in, ILH), 3.78 (in, 3H); 3.07 (dd, I H, J 9.7, 4. 1Hz); 2.95 (dd, I1H, J= 19Hz, 5. 1Hz); 2.90 (dd, I1H, J =19Hz); 2.8 (mn, 2H); 1.80 (mn, 2H); 1.58 (in, 4H); 1.34 (br s 14H).

IR (KBr, 3400, 2900, 1745, 1700, 1525, 1450, 1350, 1250, 1160, 850, 800, 700, 650, 600.

Mass Spectroscopy: (FAB, mle 652 (75, 530.2 224 (100).

Example 45 (322) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 1 2 -(morpholin-4-yI)ethoxyl-L-phenylalanine The methyl ester was prepared by alkylation of N-(toluene-4-sulfonyl)-Lprolyl-L-tyro sine methyl ester with N-(2-chloroethyl)morpholine (cesium carbonate, DMF at 60 0 C under Argon for 72 his). The product was purified by flash column chromatography (silica, EtOAc) to afford the methyl ester as an off-white foam. The title compound was prepared using the procedure described in Method 6 as a solid, mp 99-10 1 0

C.

WO 99/06431 WO 9906431PCTIUS98/1 5313 144-- NMR data was as follows: NB contains traces Tos-Pro-Phe (NMR) 'H NMR (DMSO-d 6 400 MHz): 6 7.73 2H, J =8.6Hz); 7.62 (d, I H, J 5.5Hz); 7.40 2H, J 8.2Hz); 6.69 2H); 3.95 (in, 3H); 3.8 (in, LH); 3.55 (mn, 4H); 3.1 (in, 3H); 2.62 2H, J 4Hz); 2.4 (in, 4H); 2.38 (s, 3H); 1.7 (in, 2H); 1.4 (in, 3H).

JR (KBr, 3400, 2950, 2850, 1610, 1510, 1425, 1340, 1245, 1150, 1125, 825, 800, 675, 575, 525.

Mass Spectroscopy: (FAB, in/e 5 52 (100, Example 46 (325) Synthesis of' N-(Toluene-4-sulfonyl)-L-prolyl-4- 12-(piperidin- 1-yI)ethoxyl-L-phenylalanine The methyl ester was prepared by Mitsunobu reaction of N-(toluene-4sulfonyl)-L-prolyl-L-tyrosine methyl ester with piperidineethano I following the procedure described for the preparation of Example 20 (284). The title compound was prepared using the procedure described in Method 7 as a solid, mp =102-106'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): t5 7.73(d, 2H, J 8Hz); 7.60 I H, J 7.39 2H, J 8Hz); 6.96 2H, J 8.6Hz); 6.68 2H, J 8.6Hz); 3.96 (in, 3H); 3.84 (dd, 1 H J 5.2, 4.8Hz); 2.97-3. 10 (in, 4H); 2.56 2H, J 5.9Hz); 2.3 8 (hr s, 6H); 1. 72 (mn, I1H); 1. 34-1.48 (mn, I OH).

IR (KBr, 3400, 2900, 1660, 1610, 1510, 1450, 1350, 1150, 875, 675, 600, 550.

Mass Spectroscopy: (FAB, mle 542 (100, 196 155 WO 99/06431 WO 99/643 1PCTJUS98/1 5313 -145-- Example 47 (326) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 3 -[4-(3-chlorophenyl)piperazin-1 -ylJpropoxy}- L-phenylalanine Methyl Ester The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 1 -(2-chlorophenyl)-4-(3-chloropropyl)piperazine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.

NMR data was- as follows: 'H NMR (DMSO-d 6 400 Mhz): 6 8.2 IlH, J I10Hz); 7.6 8 2 H, J I 7.4 2H, J 10OHz); 7.19 I1H, J 8,8Hz); 7.13 2H, J= 6.9 I1H); 6.85 IlH, J I10Hz); 6.82 2H-, J I10Hz); 6.75 (d, 1 H, J 10OHz); 4.45 I H, J 8,5,8Hz); 4.08 I H, J 4,4Hz); 3.94 2H, J 5,5Hz); 3.3 3H); 3.12 (bs, 4H); 3.1 1H, J 8,8Hz); 2.96 (in, 2H); 2.47 (mn, 3H); 2.38 3H); 1.85 2H, J 6,6H1z); 1.57 (in, 3H); 1.4 (in, IH).

MS: El, in/z 682/684 18 209 Example 48 (327) Synthesis of N-(Toluene-4-su Ifonvl)-L-prolyl-4- [2-(azepan-I -yI)ethoxyl-L-phenvlalanine The title compound was prepared from the product of Example 49 (328) using the procedure described in Method 7 as a solid, mp: 105-107'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 5 7.75 2H, J 8,8Hz); 7.45 I1H, J 8Hz); 7.4 2H, J 8,8Hz); 7.05 I H, J 10OHz); 6.96 IlH, J 6.7 IH, J 10Hz); 4.1 lH, J 5,5Hz); 3.92 3H, J 8,8Hz); 3.82 (mn, 1H); 3.6 1H); 2.8 2H, J 6,6Hz); 2.66 4H, J 5Hz); 2.5 3H, J 1.76 IH, 7,7Hz); 1.65 (mn, 1H); 1.5 (bs, 6H); 1.43 2H, J 8,8Hz); 1.36 (mn, 2H); 1.28 1H); 1.15 lH).

WO 99/06431 WO 9906431PCTIUS98/15313 146-- Example 49 (328) Synthesis of N-(Toluene-4-su ifonyl)-L-prolyl-4- 12-(azepan-I -yl)ethoxyl-L-phenylaianine Methyl Ester The title compound was prepared via O-alkylation of N-(toluene-4sulfonyl)-L-prolyl-L-tyrosine methyl ester with 2-(hexamethylene-imino)ethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide to provide a solid, mp 60-65'C.

Example 50 (347) Synthesis of N-(Toluene-4-sulfonyI)-L-prolvI-4- 13-(4-methylpiperazin-1 -yl)propoxyj- L-phenylalanine Methyl Ester The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 3-(N-methylpiperazine)propyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.

NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 5 8.2 I H, J 10, 10Hz); 7.7 2H, J 12Hz); 7.4 2H, J 10OHz); 7.1 2H, J =10, 10Hz); 6.8 2H, J 4.44 IRH, J 4,6,6Hz); 4.1 (dd, IRH, J =14,8,8Hz); 3.93 2H, J= 6,6Hz); 3.6 3H); 3.08 1H, J 6,4,4Hz); 3.0 (dd, I H, J 12,4,4Hz); 2.9 (in, 2H); 2.38 3H); 2.2-2.35 (in, IGH); 2.12 3H); 1.8 2H, J 6,6Hz); 1.55 (mn, 3H); 1.41 (in, IH).

MS: +ESL, ml/z 587 ([MHI-4, 100%.

Example 51 (355) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- 13-(4-methylpiperazin-1 -yl)propoxyl-L-phenylanine The title compound was prepared from the product of Example 50 (347) using the procedure described in Method 7 as a solid, mp =80-83'C.

WO 99/06431 WO 9906431PCT/US98/1 5313 147-- NMR data was as follows: 'H NMR (DMSO-d 6 400 Mhz): 8 7.75 2H, J 10Hz); 7.63 ILH, J -4Hz); 7.4 2H, J 10OHz); 7.05 2H, J I10Hz); 6.95 2H, J 6.67 2H, J I10Hz); 4.1 ILH, J 8Hz); 3.94 I1H, J 8Hz); 3.9 2H, J =5,5Hz); 3.8 (bs, 11H); 3.08 (in, IR); 2.91 IH, J 10Hz); 2.85 (dd, 2H, J 6,18,6Hz); 2.38 3H); 2.15-2.35 Im, 8H); 2.14 3H); 1.78 2H, J= 6,8,6Hz); 1.7 (mn, 1H); 1.4 (mn, IH); 1.37 (in, 2H).

Example 52 (345) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyi- 4-N-(trifluoromethanesulfonyl)amino- L-phenylalanine Methyl Ester The title compound was produced by reaction of N-(toluene-4-sulfonyl)- L-prolyl-(4-amino)phenylalanine methyl ester with trifluoromethanesulfonic acid anhydride in pyridine to provide a solid, mnp 75-78*C.

Example 53 (370) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl- 4-N-(trifluoromethanesulfonyl)amino-L-phenylalanine The title compound was prepared from the product of Example 52 (345) using the procedure described in Method 6.

NMR data was as follows: 'H NMR (CDCI 3 400MHz): 8 8.08 I 7.7 2H); 7.56 I1H); 7.34 2H); 7.22 2H); 4.85 (mn, IR); 4.16 (in, 1H); 3.40 (mn, 3H); 3.09 (in, 2H); 2.44 3H); 1.86 (in, 1H); 1.50 (mn, 3H).

IR (KIBr, cm-i): 3390; 2950; 1750; 1650; 1525; 1425; 1375; 1340; 1200; 1150; 950; 825; 625; 590; 550.

Mass Spectroscopy: (-1ESI) 564 530; 462; 406; 362; 342; 335; 157.

WO 99/06431 WO 9906431PCTIUS98/15313 -148-- Example 54 (387) Synthesis of N-(Tolu ene-4-s ulfonyl)-L-prolyl-4- [(N-benzyla min ocarbony) methoxyj..Lph eny] alan ine Methyl Ester The title compound was prepared by alkylation of N-(toluene-4-sulfonyl).

L-prolyl-L-tyrosine methyl ester with N-benzyl-2-chloroacetamide (potasium carbonate, sodium iodide, refluxing butanone under Argon overnight). The product was purified by flash column chromatography (silica, 1: 1 hexane:EtOAc) to afford the methyl ester as a white solid, mp 57-59'C.

Example 55 (389) Synthesis of N-(Toluene-4-sulfonyl)-Lprolyl.4.

R~benzyloxycarbony)methoxy]-.L-.phenylalanine The title compound was prepared from the product of Example 4 (387) using the procedure described in Method 6 as a solid, mp =79-8 1 'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): d5= 12.2 (br s, 1H); 8.60 1H); 8.03 (d, IH, J 7.9Hz); 7.70 2H, J 6.6Hz); 7.39 2H, J 8.4Hz); 7.15 2H, J 8.6Hz); 6.87 2H, J 8.6Hz); 4.48 2H); 4.42 (in, IRH); 4.31 2H, J= 6.3Hz); 4.10 (in, IH); 3.0-3.2 (in, 2H); 2.8-2.9 (in, 2H); 2.38 3H); 1.2-1.6 (mn, 4H).

IR (K-Br, 3400, 2950, 1725, 1660, 1525, 1510, 1450, 1350, 1240, 1150, 1080, 670, 575, 550.

Mass Spectroscopy: (FAB, mle 602 (10, 580 131 (100).

Example 56 (390) Synthesis of N-(Toluene-4-sulfonyl)-L..proly..

4 -1(carboxy)methoxyl-.L-phenylalanine Alkylation of N-(toluene-4-sul fony1>-Lpro y[-L-tyro sine methyl ester with t-butyl bromoacetate (potasium carbonate, DMF, under Argon for 72 hrs) WO 99/06431 WO 99/643 1PCTIUS98/15313 -149gave N-(toluene-4-sulfonyl)-L-prolyl-L-O-QIert-butoxycarbonylmethyl)tyrosine methyl ester after purification by flash column chromatography (silica, 1: 1 hexane:EtOAc) to afford a white solid, mp, 55 0

C.

N-(Toluene-4-sulfonyl)-L-prolyl-L-O-Qtert-butoxycarbonylmethyl).

tyrosine was prepared from the N-(toluene-4-sulfonyl)-L-prolyl-L-O-Qertbutoxycarbonylmethyl)-tyrosine methyl ester using the procedure described in Method 6 as a solid, mp 69-70"C.

The title compound was prepared from Nl-(Toluene-4-sulfonyl)-L-prolyl- L-O-Qtert-butoxycarbonylmethyl)-tyrosine by reaction with formic acid.

Removal. of the formic acid and tituration with ether afforded the desired compound as a white solid, mp 70-73'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): 5 12.85 (br s, 2H); 8.01 1H, J= 7.9Hz); 7.69 2H, J =8.3Hz); 7.39 2H, J =8.3Hz); 7.13 2H, J 8.8Hz); 6.79 2H, J 8.6Hz); 4.6 2H); 4.42 (in, I 4. 10 (mn, IlH); 3.08 (mn, IH); 2.95 (mn, 2H); 2.38 3H); 1.5 (in, 4H).

IR (KBr, 3350, 2950, 1730, 1625, 1510, 1425, 1340, 1175, 1160, 1075, 825, 675, 575, 550.

Mass Spectroscopy: (FAB, inle 513 (100, 491 Example 57 (407) Synthesis of N-(Toluene-4-sulfonyl)-L-proly-4j(aminoc rbonyll-L-pbenylalanine Methyl Ester The title compound was prepared by alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 2-chloroacetamide (potasium carbonate, sodium iodide, refluxing butanone under Argon for 48 hr). The product was purified by flash column chromatography (silica, EtOAc, then 5% MeGH in EtOAc) to afford the title compound as a white solid, mp 60-64'C.

WO 99/06431 WO 9906431PCTIUS98/15313 Exam~ple 58 (408) Synthesis of N-(Toluene-4-su Ifonyl)-L-prolyl-4- I(aminocarbonyl)metboxyl-L-phenylalanine The title compound was prepared from the product of Example 57 (407) using the procedure described in Method 6 as a solid, mp 195-196'C.

NMR data was as follows: 'H NMR (DMSO-d6 400 Mz) J 2.2 (hr s, ILH); 8.02 IRH, J 8. 1Hz); 7.69 2H, J 8.3Hz); 7.47, (hr s, I 7.40 2H, J 7.9Hz); 7.3 (br s, I 7.14 2H, J 8.6Hz); 6.84 2H, .1 8.6Hz); 4.40 (in, IlH); 4.3 2H); 4.11 (dd, I1H); 3.09 (in, I1H); 2.91 (dd, I 2.39 3H); 1.45-1.55 (in, 3H); 1.40 (mn, I1H).

IR (K.Br, 3500, 3350, 3250, 2950, 1725, 1675, 1660, 1560, 15 1450, 1400, 1350, 1225, 1200, 1150, 1050, 825, 660, 575, 550.

Mass Spectroscopy: (FAB, in/e 488 (100, Example 59 (409) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- I(N-tert-bu tyla min ocarbonyl)methoxyl-L-phen ylalan ine The methyl ester was prepared by alkylation of N-(toluene-4-sulfonyl)-Lprolyl-L-tyrosine methyl ester with 2 -chloro-N-tert-butylacetamide (potasiumn carbonate, sodium iodide, reflux in butanone under Argon overnight). The product was purified by flash column chromatography (silica, 1: 1 hexane:EtOAc) to afford the methyl ester as a white solid. The title compound was prepared using the procedure described in Method 6 as a solid, mp 88- 89 0

C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): 6 12.2 (hr s, 1IH); 8.02 I H, J= 8Hz); 7.68 2H, J 8.3Hz); 7.39 3H, J 8Hz); 7.14 2H, J 8.8Hz); 6.82 (dd, 2H, J 2Hz); 4.4 (mn, I 4.32 2H); 4. 10 (dd, 1IH, J 2.9, 8Hz); 3.07 (in, I 3.0 (dd, IlH, J 18.7, 27.5Hz); 2.94 (dd, IlH, J =17.8, 26Hz), 2.39 3H); 1.5 (mn, 3H); 1.4 (in, 1.29 9H).

WO 99/06431 WO 9906431PCT/US98/1 5313 151 IR (K.Br, cm): 3400, 2950, 1745, 1675, 1525, 1450, 1350, 1225, 1160, 1075, 825, 675, 575, 540.

Mass Spectroscopy: (FAB, rn/c 544 (100, Example 60 (410) Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-4- [2-(4-phenyl-4-hydroxypiperidin-1 -yl)ethoxyj-L-phenylalanine Methyl Ester The methyl ester was prepared by alkylation of N-(toluene-4-sulfonyl)-Lpro lyl)-L-O-(2-chloroethyl)tyrosine methyl ester with 4-hydroxy-4-phenyl piperidine (potassium carbonate, sodium iodide, in refluxing butanone under Argon for 72 hr). The product was purified by flash column chromatography (silica, 5% methanol in chloroform) to afford the methyl ester as a white foam.

The title compound was prepared using the procedure described- in Method 6 as a solid, mp 122-123'C.

NMR data was as follows: 'H NMR (DMSO-d 6 400 MHz): i5= 7.72 (in, 2H); 7.61 I1H, J= 5.5Hz); 7.39 2H, J 7.2Hz); 7.28 (in, 2H); 7.17 (in, IH); 7.04 I H, J= 8.8Hz); 6.96 I H, J 8.6Hz); 6.71 (dd, 2H, J 2.4, 8.8Hz); 4.75 ILH); 4.1 (in, IH); 4.0 (in, 2H); 3.9 IH); 3.8 lH); 2.8-3.1 (in, 4H, overlapping signals); 2.7 (in, 4H, overlapping signals); 2.38 3H); 1.65 (in, 2H); 1.55 (in, 2H); 1.4 (in, 2H).

IR (K.Br, 3375, 2890, 1660, 1610, 1510, 1390, 1325, 1250, 1160, 1075, 1040, 700, 675, 575, 530.

Mass Spectroscopy: (FAB, rn/c 648 (100, 642 Example 61 (375) Synthesis of N-(Toluene-4-sulfonyl)sarcosyl- D,L-4-(amidino)phenylalanine WO 99/06431 PCT/US98/15313 152-- N-(Toluene-4-sulfonyl)sarcosyl-D,L-4-cyanophenylalanine methyl ester (see Example 61 (381) (167 mg, 0.388 mmol) was dissolved in pyridine (6 mL) and then H 2 S gas was bubbled in until saturated. The mixture was stirred for 19 hours then the volatiles were removed under a stream of N 2 The residue was taken up into EtOAc (50 mL) and washed with 5% aq KHSO 4 (2 X 25 mL). The organic solution was dried (Na 2

SO

4 filtered and evaporated in vacuo to give N-(toluene-4-sulfonyl)sarcosyl-D,L-4thiocarboxamidophenylal anine methyl ester. The thioamide was dissolved in acetone (10 mL). Iodomethane (1 mL) was added and the mixture was heated to reflux for lhr. The volatiles were removed in vacuo to give N-(toluene-4sulfonyl)sarcosyl-D,L-4-methylthioimidatephenylalanine methyl ester hydroiodide (256 mg, 100%). The thioimidate was dissolved in MeOH mL). Ammonium acetate (52 mg, 0.67 mmol) was added and the mixture was heated to reflux for 1.5 hr. The solvent was removed in vacuo and the residue was purified by preparative TLC (90:10:1 CH 2

CI

2 /MeOH/NH 4 OH) to give N- (toluene- 4 -sulfonyl)sarcosyl-D,L-4-amidinophenylalanine methyl ester mg, The title compound was prepared via hydrolysis of the methyl ester using 0.5 N NaOH in THF/water (66 mg, 87%).

NMR data was as follows: 'H NMR (DMSO-d 6 6 7.66 4H), 7.43 2H, J 7.7 Hz), 7.29 (d, 2H, J 8.0 Hz), 4.10 1H), 3.57 2H), 3.20-3.06 2H), 2.54 3H), 2.40 3H).

Mass Spectroscopy: FAB m/e 433 Example 62 (381) Synthesis of N-(Toluene-4-sulfonyl)sarcosyl- D,L-4-(aminocarbonyl)phenylalanine N-(Toluene-4-sulfonyl)sarcosine was coupled to 4-cyanophenylalanine methyl ester hydrochloride (prepared via the method of Wagner, Voight, and Vieweg Pharmazie 1984, 39, 226-230) to give N-(toluene-4-sulfonyl)sarcosyl- WO 99/06431 PCT/US98/15313 153-- D,L-4-cyanophenylalanine methyl ester. The compound was prepared via hydrolysis of the methyl ester using 0.5 N NaOH in THF/water.

N-(Toluene- 4 -sulfonyl)sarcosyl-D,L-4-cyanophenylalanine methyl ester (300 mg, 0.699 mmol) was slurried in EtOH (3mL). NaOH (ION, 98 tL) and

H

2 0 2 (475 5.51 mmol) were added. The mixture was heated to 50 °C for 16 hr whereupon a white precipitate deposited. The mixture was cooled to room temp and made acidic with HCI The mixture was diluted with water (20 mL) and extracted with chloroform (4 X 25 mL). The organic extracts were dried (Na 2

SO

4 filtered and recrystallized from methanol to give the compound as a white solid (135 mg, NMR data was as follows: 'H NMR (DMSO-d 6 6 8,31 (br d, 1H, J 3.6 Hz), 7.92 (br s, 1H), 7.72 2H, J 7.8 Hz), 7.62 2H, J 7.9 Hz), 7.40-7.21 4.47 1H), 3.59 2H), 3.15 1H), 2.94 1H), 2.53 3H), 2.39 3H).

"C NMR (DMSO-d 6 6 172.9, 168.0, 167.3, 143.7, 141.3, 134.2, 132.8, 130.1, 129.4, 127.8, 127.7, 53.4, 52.4, 36.7, 36.0, 21.3.

Mass Spectroscopy: FAB m/e 434 Other compounds prepared by the methods described above include those set forth in Table II below as Examples 63-135: WO 99/06431 WO 9906431PCT/US98/1 5313 154--

U~

R3 R6 Example No.

R-1 1 4 R 2

/R

3 cyclic p-ICII 3 ,NI IC1,IICIICI 2 -C(O)NII-Jhenzyl- -O1l 68 3 carbon atoms (L-pyrrolidinyl) P-Cll 3 'R cyclic p-I('llfloc)N1CIl,CI11- -01l 69 3 carbon atoms ('(O)NIl-Jbenzyl- (L-pyrrolidinyl) P-Cl 1 cyclic p-tl~o('11,(1(1 2 N)CHC(O)NIIbenzyl- -011 3 carbon atoms (1,-pyrrolidinyl) p-Cf 1

~-R

2 cyclic p-1llO(0)C(Chz-NHI)CIICI 2

CI

2 -ol71 3 carbon atoms (ONIIezl (L,-pyrrolidinyl) pRll 9 cyclic p?-jI l(O)C(l l2N)CtHCH 2 CII,- -Ol72 3 carbon atoms ((O)NI l-Jhenzyl- (1L-pyrrolidinyl) ThCl R/ cyclic py l( ll,(N-lBoc)N('ll 2 C(O)NII-Jhcnzyl- -()If7 3 carbon atoms (L-pyrrolidiflyl) p-ClIlt 0 RIR' cyclic dirnieliyithiazolidin- 4 -yl) i'-I~i I (N-floc)N(112C(O)NIIl-benzyI-

-()II

1~ 1 9 P-Clf34> cyclic 3 carbon atoms (1,-pyrrolidiflyl) p-i('11,Nll(*11,('(O)NII-lbettzyl- -Ut '1 II I- R' R 2 I3R R' Example No.

l1-1henzyl- -OHi 76 p-CH 3 -0- 3 carbon atoms (L.-pyrrolidinyl) p-ICIINIICHC(O)N 4 4 cyclic p-jCIlNliCHC(O)Nll-jbenzyl- -OH 77 p-CH 3 -40- -c S-C(c iI dimethylihliazol idin- 4-i) I i

-OH

p-CH,-O- RC/IC cyclic 3 carbon atoms (L.-pyrrolidinyl) p-I(CIldzN( I l 2 C(O)NII-lbeflzyl- -OH 1 79 4- p-CH,-O- -2R cyclic dimethylthiazolidin- 4 -yl) I I I CR =Iyci p-CH 3 -40- 3 carbon atoms (L-pyrrolidinyt) P-Cl1 3

R

2 1R' cyclic 3 carbon atoms (L-pyrrolidinyl) p-lIterl-hutyl-O())C(I I 2-O-benzyl)- Nil- jhcnzylp-(2-formfyl- 1 2.3 ,4-tctrahydroisoquiflolin- 3 yl.CII 2 ,NI-)benfl7p-[-OCHCHi(Nil Boc)CI1 2 cyclohexyl Ibenzyl

-OH

OCH

1 82- 81 IC/IC cyclic p-C11 3

-O-

3 carbon atoms (L-pyrrolidinyl) -OCH, 82

-I

JOR 711 ExamipleN r L 1 p-Cl4 3 -0p-CH ,-Or

R

2 cyclic 3 carbon atoms (L--pyrrolidinyl) cyclic ii-1-0('11,C lf,(:IIN(('113)21-benzyl- 1 p-i ~,'itI l,'ll( I ,Olenzy- -01l 83 84 I 4 1 R/'=cyclic dimethy Ithiazol id in- 4 -yl) cyclic 3 carbon atoms (L.-pyrrolidinyl)

R

2 cyclic 3 carbon atoms (1--pyrrolidinyl) p+[CI 13)2N( I 1 I,0jhcnzyl- -OCICIlI I- F 1 p-j 2-(2-azahicyclol 3 .2.2joctan- 2-yI)echyl-O-J hcnzyl- -0)Cl1 1 I I p-I (CI,2I 1),C 2 1 Ihcnzyl- -01[11 86 87 88 I t I- cyclic 3 carbon atonis (L-pyrrolidinyl) p-I (Cli ll jIbcnzyl- -0)Cl 1, 'R cyclic p-12-(2-azahicycloJ3.2.2locian- -OH 89 3 carbon atoms 2-yl)ethyl-0- ibcnzyl- (L-pyrrol idinyl) isomer) p-(cyclopentyl-C =-C-)-benzyl- I J "0 1 1 __I 1--xample No.

p-CH.

3

-O-

p-CH P-Cl 1 p-CiI,-k- J I I I 7 I If

R

2 cyclic 3 carbon atoms (L-pyrrolidinyl)

R

2 IR' cyclic 3 carbon atoms (L--pyrrolidinyl) -Cli, isomer) -Cll 2 -cO (L isomer) p-I -C C-Cl I~0-S(0) 2 -p-Cl I ~-kJ-benzyl- 0I. isome~r) I isomer) isomer) p-I-C =(i:-CI(Nl1 2 )-cyclohcxylI-henzyljp-I-('?=(-C1Ii 2 -O-phenylI-hcnzy)- j-0il 91 92 93 94 96 97 98 99 p-I-C= C-CI11 2 -O-phenyll-bcnzylp-1-C C-l ,-o(:lI,-benzyI- -()If If (-CIL-OCIIj-bcnzyl- f -Off I I I t p-I-C -C-l 2 [-O-p-(-C'(O)OC'lIi,)phenyl Ibcnzy I- -011 100 henzylfI R' R5 R6 Exaniple No.

T

P-C"

3 P- ll 3 ,-Or p-C1 3 k cyclic 3 carbon atoms (L-pyrrolidinyl) p-I-C 1 I-bCIIZYI- -011 102 1 03 104 r 4 1 9-

-CII,

R

2 cyclic 3 carbon atomis (1--pyrrolidinyl) p-1-C C-Cl 10 1 benzyl- I -oidl NllC~)CIl 1 4 4 T -011 IC C-l( I '()l-CnI 4 4

R

2 cyclic 3 carbon atoms (1L-pyrrolidinyl) p-l I 1 2 Nll-(4.5-dihydro-4-oxo- 5-phenyl-oxazol-2-yI)Ihcnzyl -Cl! II C-C lII-(,5-dhydo-4-xo-011 jhenzyl cyclic p-I-0C'11,C( I-piperadiniyl)I-bcnizyl--01l 3 carhon atoms ([-pyrrolidinyl) 106 107 109 110Ii p-CfI,-O- R 2 cyclic 3 carbon atoms (L-py rrol idiny I) i-I -OCI 12-( I-pyrrolidiinyl) I-hcnizyl- I I I P-CII,-(P- R 2 cyclic 3 carbon atoms (L-pyrrolidinyl) P-I -0(.712l('i2-( N-morpholino)I-henzyl- 4 T_ R 5 E x a m p le N o p-CH34- 7p-CHi 3 p-CtO R1 =cyclic 3 carbon atoms (I.-pyrrolidinyl) cyclic 3 carbon atoms (I.-pyrrohidinyl) R/l= cyclic 3 carbon atoms pyrrol idinyl) R/'=cyclic 3 carbon atoms (I.-pyrrolidinyl) p-I -OClCl -(4-hydroxy-4riiethoxypyrrol-2-yl)-piperazinyl Ihenzyl-

-OCH,

p-I-O-(3-(N-IBoc)-piperidinyll-henzyl- -01l ,ni-IO-( N-mcthilyl-piperidin-4-yII-bdnizyl- p-f N-incthylpiperidin-4-yl)I-hcnzyl- -01l

III

112 113 114 R2R' cyci R2IR' cyclic dioxothioMorpholin- 3-yl) -t t r p-I( I -methiylpiperidin-4-yl)-O- Jbenzyl- -0(7112(7111 115 116 L

T

I -ilcthiylpiperidin-4-yl)-O- jbenzyl- -071 1CI I I I 4 t cyclic -Cl l,C 1 2 ,-S0 2 -C1li 2 1dioxothiomnorpholin- 3 -yl) p-I (1 -nmthylpiperidin-4-yI)-O- Ibcnzyl- -0C-.l,cIII I C0 0

R

2 R6apl No.

R'1 11 -U118 P-C)13 0 cyclic

*CII,('H,-S

2

-C-

1 1 dioxothiomorpholin- 3 -yl) p-CH,-O- W/'=cyclic diincthylthiazolidin- 4 -yi) p-I( lincthylpiperidin-4yI)-O-Ibelzyl- J) I( I-..Intylpiperidiil-4-yI)-O Ibcnizylp1- methylpipcridifl-4-yl)O-IhenzYlp-I -Ni 1s0 2 -CI 1(II1-hcnzylp+INI ISO,-Cll =CI l 2 -hcfly- -011 119 _U11 I I I cyclic 3 carbon atoms (1 -pyrrolidinyl)

I

p-Cl 1 -4cyclic 3 carbon atoms ([.-pyrrolidinyl)

-OCI

2 CI I, 120 -O~ll 121 -O(I1 122 -ocIll 123 P-Ciyoi- R1/R' cyclic 3 carbon atoms (L.-pyrrolidinyl) p-CH,-O- 4p.~N~3~meIhyIbuLyIN cyclic 3 carhon atoms trifluoromethanesulfofnly)atninlbehl- 1 -oil p-C1I 3 -4A-

R

2 cyclic 3 carbon atoms (I pyrrolidinyl) p-IN-vinyisulfonyi)aminolbenzyl- -011

I

I- I R' RI R-1 R5 {6 Example No.

-OCH, 2 cyclic 3 carbon atoms (1L-pyrrolidinyl) p-I -OCi 2 C(O)O-henzyl 1-hdfzyl- I t -o

H

p-CH,-- R 2 cyclic 3 carbon atoms (1--pyrrolidinyl) p-!I(piperidin- I -yl)C(O)Cti 2 -O-lbelzylI- -0 4 1 -Ocill J 127 RV/R' cyclic 3 carbon atoms (1--pyrrolidinyl) ),N(C(O)CI jhcnzyl- 4 1 t

R

2 IR' =cyclic 3 carbon atoms ([.-pyrrolidinyl) P-j(C1 3 2 C1I 2 NC(O)Cii 2 -O-)henzyl- -OH 128 r -C R 2 cyclic 3 carbon atoms (I.-pyrrolidinyl) p-(N-methylacetamido)helzylr I -011 130 R 2 cyclic 3 carbon atoms (1--pyrrolidinyl) p-(N-mcihylacctamido)bcflzylr

R

2

R

3 Cyclic 3 carbon atoms (L-pyrrolidjnyl) p-(N-mcthyltri fluoroacctamido)bcnzyl- -OC 113 131 132 I I1_ p-CH 3 -0- R3=Cyclic 3 carbon atoms (L-pyrrolidinyl) (I -toluenesulfonylimidizol-4-yl)nmcthyl- -0(113 I R 6- Example No.

-0C11 1 133 cyclic 3 carhon atoms (1L-pyrrolidinyl) cyclic 3 carbon atoms (1.-pyrrolidinyl) I N-dinwithylailosulfollI-imiidizi)1- 4 yl )methylp -(N-toluensu I foflamlhilo)bcn.y

I

p N- ti utcnesu I fony lain i no )hcnzy I -011 134 135 p-CH 3 -0- R 2 cyclic 3 carbon atoms -yrI___yl WO 99/06431 WO 99/643 1PCTIUS98/15313 164-- Further to the above, the following additional compounds were prepared as Examples 136-140: Example 136 Synthesis of N-(Toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaproly..413- (N,N-d imethyla min o)p ropoxyj -L-ph enylalIan ine t-bytyl ester The title compound was prepared as in Example 20 except N-Boctyrosine t-butyl ester was used instead of N-Boc-tyrosine methyl ester.

MS: )ESI], [M+Hy- 620.

Example 137 Synthesis* of N-(Toluene-4-sulfonyl)-L-prolyl-L- 4 -(N-methylpiperidinoxy)phenylalanine) tert butyl ester The title compound was prepared by BOP coupling of Tos-Pro-OH with Tyr-O-1-methyl piperidine-t-butyl ester (prepared by Mitsunobu reaction).

The crude product was purified by flash chromatography (silica, 95:5 EtoAc:Et 3 N) to afford a white solid (0.615 g, MS ESI, m/z 586 (100 Anal. Calc'd for C 3 1 3

N

3 0 6 S: C, 63.57; H, 7.40; N, 7.17. Found: C, 63.11; H, 7.37; N, 6.96.

Example 138 Synthesis of N-(Toluene-4-sulfonyl)-L-(5,5-dimethyl)tliiaprolyl-L- (4-(N-methyl(piperidinoxy) phenylalanine t-butyl ester The title compound was prepared following the procedure described in Example 137 with substitution for the appropriate starting materials.

WO 99/06431 PCT/US98/15313 165-- Anal. Calc'd for C 3 2

H

45

N

3 0 6

S

2 .0.25 CHCI 2 C, 58.85; H, 7.02; N, 6.43.

Found: C, 58.75; H, 6.92; N, 6.48.

MS 632 Example 139 Synthesis ofN-(Toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine tert-butyl ester The title compound was prepared from the corresponding triflate (which was prepared from (N-(Toluene-4-sulfonyl)-L-prolyl-L-tyrosine tert-butyl ester as taught by Tilley and coworkers, J. Org. Chem., 55, 906, 1990). The dipeptide (505 mg, 0.8 mmol.), a catalytic amount of tetrakis(triphenylhosphine)palladium(0), potassium carbonate (201 mg, 1.5 phenylboronic acid (199 mg, 2.0 and 15 mL of toluene were refluxed for 10 hours-with stirring. Ethyl acetate was added and the organic layer was washed with water, IN NaOH, brine and dried over magnesium sulfate. Upon filtration, the solvent was evaporated under reduced pressure. The crude material was purified on a preparative plate (1:1 ethyl acetate:hexanes). The silica gel was washed several times with acetonitrile and ethyl acetate. The combined fractions were evaporated and the residue was dried under reduced pressure.

NMR data was as follows: 'H NMR (CDCI 3 300 MHz): 6 7.70 1H); 7.57 3.5H); 7.45 (m, 7.28 5H); 4.78 1H); 4.06 1H); 3.30 2H); 3.06 2H); 2.40 3H); 2.05 1H); 1.42 9H).

"C NMR (CDC1 3 6 171.02, 169.98, 144.4, 140.78, 139.82, 135.53, 132.82, 129.97, 129.9, 129.41, 128.78, 127.86, 127.04, 126.98, 82.65, 62.15, 53.74, 49.49, 37.43, 29.67, 27.78, 23.92, 21.37.

WO 99/06431 PCT/US98/15313 166 Example 140 Synthesis of N-(Toluene-4-sulfonyl)-L-prolyl-(4-phenyl)-L-phenylalanine The title compound was prepared from the product of Example 139 using the procedure described in Method 11.

NMR data was as follows: 'H NMR (CD30D, 300 MHz): 6 8.05 1H); 7.71 2H, J 8.24 Hz); 7.55 4H); 7.30 8H); 4.71 1H); 4.09 1H); 3.30 3.30); 3.15 3H); 2.37 3H); 1.78 1H); 1.62 4H).

1 3 C NMR (CD30D): 6 174.27, 145.88, 142.25, 141.23, 137.44, 135.12, 131.19, 131.15, 129.98, 129.09, 128.4, 128.17, 128.0, 63.25, 54.69, 50.52, 37.85, 3-1.52, 25.21, 21.43.

Example 141 In vitro Assay For Determining Binding of Candidate Compounds to VLA-4 An in vitro assay was used to assess binding of candidate compounds to c I integrin. Compounds which bind in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays competitive assays). This assay is sensitive to IC 5 s values as low as about InM.

The activity of ca,, integrin was measured by the interaction of soluble VCAM-1 with Jurkat cells American Type Culture Collection Nos. TIB 152, TIB 153, and CRL 8163), a human T-cell line which expresses high levels of a 4 integrin. VCAM-1 interacts with the cell surface in an a4p, integrin-dependent fashion (Yednock, et al. J. Bio. Chem., 1995, 270:28740).

Recombinant soluble VCAM-1 was expressed as a chimeric fusion protein containing the seven extracellular domains of VCAM-I on the N- WO 99/06431 PCT/US98/15313 167terminus and the human IgG, heavy chain constant region on the C-terminus.

The VCAM-1 fusion protein was made and purified by the manner described by Yednock, supra.

Jurkat cells were grown in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutamine as described by Yednock, supra.

Jurkat cells were incubated with 1.5 mM MnCI 2 and 5 4g/mL 15/7 antibody for 30 minutes on ice. Mn" 2 activates the receptor to enhance ligand binding, and 15/7 is a monoclonal antibody that recognizes an activated/ligand occupied conformation of a 4 integrin and locks the molecule into this conformation thereby stabilizing the VCAM-1/a, 4 integrin interaction.

Yednock, et al., supra. Antibodies similar to the 15/7 antibody have been prepared by other investigators (Luque, et al, 1996, J. Bio. Chem. 271:11067) and may be used in this assay.

Cells were then incubated for 30 minutes at room temperature with candidate compounds, in various concentrations ranging from 66 PM to 0.01 gM using a standard 5-point serial dilution. 15 uL soluble recombinant VCAM-1 fusion protein was then added to Jurkat cells and incubated for minutes on ice. (Yednock et al., supra.).

Cells were then washed two times and resuspended in PE-conjugated goat F(ab') 2 anti-mouse IgG Fc (Immunotech, Westbrook, ME) at 1:200 and incubated on ice, in the dark, for 30 minutes. Cells were washed twice and analyzed with a standard fluorescence activated cell sorter ("FACS") analysis as described in Yednock, et al., supra.

Compounds having an IC 5 0 of less than about 15juM possess binding affinity to ca 4 WO 99/06431 PCT/US98/15313 168 When tested in this assay, each of the compounds in Examples 1-135 has an IC 5 0 of 15 ,M or less.

Example 142 In vitro Saturation Assay For Determining Binding of Candidate Compounds to a4P, The following describes an itn vitro assay to determine the plasma levels needed for a compound to be active in the Experimental Autoimmune Encephalomyelitis model, described in the next example, or in other in vivo models.

Log-growth Jurkat cells are washed and resuspended in normal animal plasma containing 20 ig/ml of the 15/7 antibody (described in the above example).

The Jurkat cells are diluted two-fold into either normal plasma samples containing known candidate compound-amounts in various concentrations ranging from 66 pM to 0.01 iM, using a standard 12 point serial dilution for a standard curve, or into plasma samples obtained from the peripheral blood of candidate compound-treated animals.

Cells are then incubated for 30 minutes at room temperature, washed twice with phosphate-buffered saline containing 2% fetal bovine serum and ImM each of calcium chloride and magnesium chloride (assay medium) to remove unbound 15/7 antibody.

The cells are then exposed to phycoerythrin-conjugated goat F(ab') 2 antimouse IgG Fc (Immunotech, Westbrook, ME), which has been adsorbed for any non-specific cross-reactivity by co-incubation with 5% serum from the animal species being studied, at 1:200 and incubated in the dark at 4 0 C for minutes.

WO 99/06431 PCT/US98/15313 169-- Cells are washed twice with assay medium and resuspended in the same.

They are then analyzed with a standard fluorescence activated cell sorter ("FACS") analysis as described in Yednock et al. J. Bio. Chem., 1995, 270:28740.

The data is then graphed as fluorescence versus dose, in a normal dose-response fashion. The dose levels that result in the upper plateau of the curve represent the levels needed to obtain efficacy in an in vivo model.

This assay may also be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as the a,3, integrin, which is the integrin most closely related a,p, (Palmer et al, 1993, J. Cell Bio., 123:1289). Such binding is predictive of in vivo utility for inflammatory conditions mediated by axP 9 integrin, including by way of example, airway hyper-responsiveness and occlusion that occurs with chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular occlusion following angioplasty, fibrosis and glomerular scarring as a result of renal disease, aortic stenosis, hypertrophy of synovial membranes in rheumatoid arthritis, and inflammation and scarring that occur with the progression of ulcerative colitis and Crohn's disease.

Accordingly, the above-described assay may be performed with a human colon carcinoma cell line, SW 480 (ATTC #CCL228) transfected with cDNA encoding a, integrin (Yokosaki et al., 1994, J. Bio. Chem., 269:26691), in place of the Jurkat cells, to measure the binding of the a,p, integrin. As a control, SW 480 cells which express other a and P, subunits may be used.

Accordingly, another aspect of this invention is directed to a method for treating a disease in a mammalian patient, which disease is mediated by cp3I,, and which method comprises administering to said patient a therapeutically effective amount of a compound of this invention. Such compounds are preferably administered in a pharmaceutical composition described herein WO 99/06431 PCT/US98/15313 170above. Effective daily dosing will depend upon the age, weight, condition of the patient which factors can be readily ascertained by the attending clinician.

However, in a preferred embodiment, the compounds are administered from about 20 to 500 pg/kg per day.

Example 143 In vivo Evaluation The standard multiple sclerosis model, Experimental Autoimmune (or Allergic) Encephalomyelitis was used to determine the effect of candidate compounds to reduce motor impairment in rats or guinea pigs.

Reduction in motor impairment is based on blocking adhesion between leukocytes and the endothelium and correlates with anti-inflammatory activity in the candidate compound. This model has been previously described by Keszthelyi et al., Neurology, 1996, 47:1053-1059, and measures the delay of onset of disease.

Brains and spinal cords of adult Hartley guinea pigs were homogenized in an equal volume of phosphate-buffered saline. An equal volume of Freund's complete adjuvant (100 mg mycobacterium tuberculosis plus 10 ml Freund's incomplete adjuvant) was added to the homogenate. The mixture was emulsified by circulating it repeatedly through a 20 ml syringe with a peristaltic pump for about 20 minutes.

Female Lewis rats (2-3 months old, 170-220 g) or Hartley guinea pigs day old, 180-200 g) were anesthetized with isoflurane and three injections of the emulsion, 0.1 ml each, were made in each flank. Motor impairment onset is seen in approximately 9 days.

Candidate compound treatment began on Day 8, just before onset of symptoms. Compounds were administered subcutaneously orally or intraperitoneally Doses were given in a range of 10mg/kg to WO 99/06431 PCT/US98/15313 171 200 mg/kg, bid, for five days, with typical dosing of 10 to 100 mg/kg SC, to 50 mg/kg PO, and 10 to 100 mg/kg IP.

Antibody GG5/3 against aP, integrin (Keszthelyi et al., Neurology, 1996, 47:1053-1059), which delays the onset of symptoms, was used as a positive control and was injected subcutaneously at 3 mg/kg on Day 8 and 11.

Body weight and motor impairment were measured daily. Motor impairment was rated with the following clinical score: 0 no change 1 tail weakness or paralysis 2 hindlimb weakness 3 hindlimb paralysis 4 moribund or dead A candidate compound was considered active if it delayed the onset of symptoms, produced clinical scores no greater than 2 or slowed body weight loss as compared to the control.

When tested in this in vivo assay, the compounds of Examples 5, 12, 18 and 20 were active.

Example 144 Asthma Model Example Inflammatory conditions mediated by a 4 1 integrin include, for example, airway hyper-responsiveness and occlusion that occurs with chronic asthma.

The following describes an asthma model which can be used to study the in vivo effects of the compounds of this invention for use in treating asthma.

Following the procedures described by Abraham et al, J. Clin. Invest, 93:776-787 (1994) and Abraham et al, Am J. Respir Crit Care Med, 156:696- 703 (1997), both of which are incorporated by reference in their entirety, WO 99/06431 PCT/US98/15313 172compounds of this invention are formulated into an aerosol and administered to sheep which are hypersensitive to Ascaris suum antigen. Compounds which decrease the early antigen-induced bronchial response and/or block the latephase airway response, have a protective effect against antigen-induced late responses and airway hyper-responsiveness are considered to be active in this model.

Allergic sheep which are shown to develop both early and late bronchial responses to inhaled Ascaris suum antigen are used to study the airway effects of the candidate compounds. Following topical anesthesia of the nasal passages with 2% lidocaine, a balloon catheter is advanced through one nostril into the lower esophagus. The animals are then intubated with a cuffed endotracheal tube through the other nostril with a flexible fiberoptic bronchoscope as a guide.

Pleural pressure is estimated according to Abraham (1994). Aerosols (see formulation below) are generated using a disposable medical nebulizer that provides an aerosol with a mass median aerodynamic diameter of 3.2 gtm as determined with an Andersen cascade impactor. The nebulizer is connected to a dosimeter system consisting of a solenoid valve and a source of compressed air (20 psi). The output of the nebulizer is directed into a plastic T-piece, one end of which is connected to the inspiratory port of a piston respirator. The solenoid valve is activated for 1 second at the beginning of the inspiratory cycle of the respirator. Aerosols are delivered at V, of 500 ml and a rate of breaths/minute. A 0.5% sodium bicarbonate solution only is used as a control.

To assess bronchial responsiveness, cumulative concentration-response curves to carbachol can be generated according to Abraham (1994). Bronchial biopsies can be taken prior to and following the initiation of treatment and 24 WO 99/06431 PCT/US98/15313 173hours after antigen challenge. Bronchial biopsies can be preformed according to Abraham (1994).

An in vitro adhesion study of alveolar macrophages can be performed according to Abraham (1994), and a percentage of adherent cells is calculated.

Aerosol Formulation A solution of the candidate compound in 0.5% sodium bicarbonate/saline at a concentration of 30.0 mg/mL is prepared using the following procedure: A. Preparation of 0.5% Sodium Bicarbonate Saline Stock Solution: 100.0 mL Ingredient Gram 100.0 mL Final Concentration Sodium Bicarbonate 0.5 g Saline q.s. ad 100.0 mL q.s. ad 100% Procedure: 1. Add 0.5g sodium bicarbonate into a 100 mL volumetric flask.

2. Add approximately 90.0 mL saline and sonicate until dissolved.

3. Q.S. to 100.0 mL with saline and mix thoroughly.

B Preparation of 30 0 mg/mT. Candidate Comound: 10.0 ml, Ingredient Gram 10.0 mL Final Concentration Candidate Compound 0.300 g 30.0 mg/mL Sodium q.s. ad 10.0 mL q.s ad 100% Bicarbonate Saline Stock Solution WO 99/06431 PCT/US98/15313 174-- Procedure: 1. Add 0.300 g of the candidate compound into a 10.0 mL volumetric flask.

2. Add approximately 9.7 mL of 0.5% sodium bicarbonate saline stock solution.

3. Sonicate until the candidate compound is completely dissolved.

4. Q.S. to 10.0 mL with 0.5% sodium bicarbonate saline stock solution and mix thoroughly.

Using a conventional oral formulation, compounds of this invention would be active in this model.

Claims (34)

175-- WHAT IS CLAIMED IS: 1. A compound of formula I: R 3 O R'-SO2-N(R 2 )-CH-Q-CH-C-OH I R where R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and where R' and R 2 together with the nitrogen atom bound to R 2 and the SO, group bound to R' form a heterocyclic or a substituted heterocyclic group; R 3 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group; R 5 is -(CH,)x-Ar-R 5 where R s is selected from the group consisting substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted WO 99/06431 WO 9906431PCTIUS98/1 5313 -176-- cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl -substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thiohieterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O).,-alkyl, -OS(O) 2 -substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O)2-heterocyclic, -OS(O) 2 substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS (O) 2 -substituted heterocyclic, -NRS(O) 2 -NR- alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR- substituted aryl, -NRS (O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -SO-,-substituted alkyl, -SO.,-alkenyl, -SQ2-substituted alkenyl, -S0,-cycloalkyl, -SO, -substituted cycloalkyl, -S02- aryl, -SO,-substituted aryl, -SO-2-heteroaryl, -SO,-substituted heteroaryl, -S02- heterocyclic, -50,-substituted heterocyclic and -SONRR where R is hydrogen or alkyl; WO 99/06431 PCT/US98/15313

177-- alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR where R is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, aryl and heteroaryl; -NR'R' wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O),-substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -OS0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O),-substituted alkyl, -NRS(O) 2 -aryl, -NRS(O),-substituted aryl, -NRS(O),-heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O),-substituted heterocyclic, -NRS(O) 2 -NR-alkyl, WO 99/06431 PCT/US98/15313

178-- -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S 2 O,-cycloalkyl, -SO2-substituted cycloalkyl, -SO,2- aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -SO,2- heterocyclic, -SO2-substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; -alkoxy-NR"R" wherein each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted WO 99/06431 WO 9906431PCTIUS98/1 5313 -179-- thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O),-heterocyCliC, -OS(Q) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O),- heterocyclic, -NRS(O)2-substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS (O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- anid di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -SO 2 usiue alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -CYCloalkyl, -S0 2 -substituted cycloalkyl, -S02- aryl, -S0 2 -substituted aryl, -S0 2 ,-heteroaryl, -S0 2 -substituted heteroaryl, -SO,- heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; (f0 substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyl/alkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, WO 99/06431 WO 9906431PCTIUS98/1531 3

180-- heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, amninocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylbeterocyclic, carboxyl -substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O)2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O)2-aryl, -NRS(O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O).,-NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamnino, mono- and di-heteroarylamino, mono- and di-substituted h etero aryl amino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic a mino, and unsyn-metric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, WO 99/06431 PCT/US98/15313 181 substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S 2 O,-cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S 2 O,-substituted heteroaryl, -SO2 heterocyclic, -S0 2 -substituted heterocyclic and -SONRR where R is hydrogen or alkyl; substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy- substituted saturated heterocyclic; -0-heterocyclic and -O-substituted heterocyclic; tetrazolyl; -NR-S0 2 -substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; substituted alkoxy with'the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and Wo 99/06431 PCTJUS98/1 5313 -182- aryb'heteroaryl substituted with halogen, hydroxyl, ami no, nitro, trifluoromethyl, tr-ifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, I ,2-dioxyethylefle, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarboflylOxy, acyl, alkylcarbonylamiflo, alkoxycarbonylamiflo, alkylsulfolylaTino, N-alkyl or N,N-dialkylurea; amridine substituted with from 1 to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyriyl, ar-yl, heteroaryl and heterocyclic; where each is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, C substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted *heterocyclic with the proviso that when one is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, l,2-dioxyethylefle, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylainino, alkylcarbonyloxy, acyl, cC. alkylcarbonylamino, al koxycarbolylIaminlo, alkylsulfonylamino, N-alkyl or CC..N,N-dialkylurea, then the other is alkyl, substituted alkyl (other than :'20 unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, cc:::alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic; -NR 12 where R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R" 2 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heter ocyclic and substituted heterocyclic; -SO,-aryl, -SO,-substituted aryl, -SO,-heteroaryl, -SO,-substituted heteroaryl or -SO,-alkyl; 6b\L -NR'C(O)NR 9 R' wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted WO 99/06431 PCT/US98/15313

183-- cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic: -NR'C(O)OR 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -aminocarbonyl-(N-formylheterocycyl); and -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; Q is -C(X)NR 7 wherein R 7 is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof. 2. A compound of formula IA: R 3 O I II R'-SO2-N(R2)-CH-Q-CH-C-R 6 IA I R where R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; WO 99/06431 PCT/US98/15313

184-- R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R' and R 2 together with the nitrogen atom bound to R 2 and the SO, group bound to R' can form a heterocyclic or a substituted heterocyclic group; R 3 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group; Rs is -(CH 2 )x-Ar-R" where R 5 is selected from the group consisting substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O),-substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(0) 2 substituted heterocyclic, -OSO 2 -NRR where R is hydrogen or alkyl, WO 99/06431 PCT/US98/15313

185-- -NRS(O) 2 -alkyl, -NRS(O),-substituted alkyl, -NRS(O),-aryl, -NRS(O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR- alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR- substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -SO -substituted alkyl, -S0 2 -alkenyl, -S 2 O,-substituted alkenyl, -S0 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO,- aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S 2 O,-substituted heteroaryl, -SO,2- heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR where R is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, aryl and heteroaryl; -NR'R' wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, WO 99/06431 WO 9906431PCTIUS98/1531 3

186-- thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amnidino, thioamidino, aminoacyl, arninocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl- carboxyl-substituted cycloalkyl, carbdov,,laryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl -substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thio 1, thioalkyl, substituted thioalkyl, thi oaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino; oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O)2-NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted WO 99/06431 WO 99/643 1PCTIUS98/15313 -187-- alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -CYCloalkyl, -SQ2-substituted cycloalkyl, -S02- aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SQ2-substituted heteroaryl, -S02- heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; -alkoxy-NR"R" wherein each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonyl amino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted-arylr carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -05(0)2- substituted alkyl, -OS(O) 2 -aryl, -OS(0) 2 substituted aryl, -OS(0)2-heteroaryl, -OS(0) 2 -substituted heteroaryl, -OS(0) 2 -heterocyclic, -OS(0) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(0) 2 -alkyl, -NRS(0) 2 -substituted alkyl, -NRS(0) 2 -aryl, -NRS(0)2-substituted aryl, -NRS(O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS(0) 2 heterocyclic, -NRS(0) 2 -substituted heterocyclic, -NRS(0) 2 -NR-alkyl, WO 99/06431 PCT/US98/1 5313

188-- -NRS(O) 2 -NR-substituted alkyl, -NRS(O),-NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO,- aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -SO02 heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyl/alkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, WO 99/06431 WO 9906431PCTIUS98/15313 -189-- substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -05(0)2- substituted alkyl, -OS(0) 2 -aryl, -OS(0) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(0) 2 -substituted heteroaryl, -OS(0) 2 -heterocyclic, -OS(0) 2 -substituted heterocyclic, -0S0 2 -NP.R where R is hydrogen or alkyl, -NRS(0) 2 -alkyl, -NRS(0) 2 -substituted alkyl, -NRS(0) 2 -aryl, -NRS(0) 2 -substituted aryl, -NRS(0) 2 -heteroaryl, -NRS(0) 2 -substituted heteroaryl, -NRS(0) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(0) 2 -NR-aryl, -NRS(0) 2 -NR-substituted aryl, -NRS(0) 2 -NR-heteroaryl, -NRS (O) 2 -NR-substi tuted heteroaryl, -NRS(0) 2 -NR-heterocyclic, -NRS(0) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amnino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formnyl, and the like or alkyl/substituted alkyl groups substituted with -SO-,-alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -SQ2-substituted alkenyl, -S0,-cycloalkyl, -SO,-substituted cycloalkyl, -S02_ aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SO,-substituted heteroaryl, -SO 2 heterocyclic, -SO,-substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, WO 99/06431 PTU9/51 -190-- alkenyl, alkynyl, I ,2-dioxym ethylenle, I ,2-dioxyethylefle, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamiflo, alkoxycarbonylamilo, alkylsulfonylanhino, N-alkyl or N,N-dialkylurea; -alkoxy-saturated heterocyclic, -alkoxy-3a~urated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy- substituted saturated heterocyclic; -O-heterocyclhc and -0-substituted heterocyclic; tetrazolyl; -NR-SO,-substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylanfo is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, 1 ,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, 15 alkenylamino, alkynylamnino, alkylcarbonyloxy, acyl, alkylcarbonylamiflo, 1 alko xycarbonyl anfo, alkylsulfonylamilo, N-alkyl or N,N-dialkylurea; alkenylsulfonylamino, alkynylsulfonylanfo, substituted alkenyl sul fonyl anfo and substituted alkynylsul fonyl amino; (in) substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated a...:heterocyclyl, alkyloxy. aryloxy, heteroaryloxy, aryl, heteroaryl and aryllheteroaryl substituted with halogen, hydroxyl, amino, nitro, tiifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, I ,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino. alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylanfo, alkoxycarboflylamino, alkylsul fonylamino, N-alkyl or N,N-dialkylurea; amidine substituted with from I to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; -C(0)NR where each is independently selected from the group ,~J\IA 4 ,consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, WO 99/06431 PCT/US98/15313

191-- substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea, then the other is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic; -NR' 2 where R 8 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R' 2 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -SO2-aryl, -SO 2 -substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl or -SO2-alkyl; -NR'C(O)NR 9 R 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic: -NR'C(O)OR 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; WO 99/06431 WO 9906431PCT/US98/1 5313 -192-- -aminocarbonyl-(N-formylheterocycyl); and -alkyl-C(O)NIH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from I to 4; R 6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yI (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O-(N-succinimidyl), -N--adamantyl, -O-cholest-5 -en-3.f3-yl, -NI-iY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, -NI{(CH 2 )pCOOY where p is an integer of from 1 to 8 and Y is as defined above, -OCH2NR 9 R' 0 where R' is selected from the group consisting of aryl and -C(O)-substituted aryl and R 10 is selected from the group consisting of hydrogen and -CH 2 COOR" where R" 1 is alkyl, and -NHSO 2 Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is -C(X)NR 7 wherein R' is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof with the proviso that when R' is p-CH 3 R' is methoxy, Q is -C(O)NII-, and R 2 and R 3 are joined to form a pyrrolidinyl group, then R' is not p-[-OCH 2 CH 2 N(C 2 H 5 2 )-benzyl-, p-[-OCH 2 CH 2 N(isopropYl)2j-benzyl-, p- [-OCH 2 CH 2 I -pyrrolidinyl)-benzyl-, p-[-OCH 2 CH,- I -(4-pyrimidinyl)piper- azinyl]-benzyl-, p-[-OCH 2 CH 2 -N-morpholinyl)1-benzyl-, or p-[-OCH 2 CH 2 -N- piperidinyl)]-benzyl-. 3. A compound according to Claims I or 2 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. WO 99/06431 PCT/US98/15313

193-- 4. A compound according to Claim 3 wherein R' is selected from the group consisting of 4-methyiphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1 -naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2 4 ,6-trimethylphenyl, 2- (methoxycarbonyl)phenyl, 2-carboxyphenyl, 3, 5-dichlorophenyl, 4- trifluoromethylphenyl, 3 ,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (CH 3 C(O)NH-)phenyl, 4 -trifluoromethoxyphenyl, 4 -cyanophenyl, isopropyl, -di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4- nitrophenyl, 2-thienyl, l-N-methyl-3-methyl-5-chloropyraol-4-yl, phenethyl, I -N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4- methylamidinophenyl, 4-[CH 3 SC(=NH)]phenyl, 5-chloro-2-thienyl, dichloro-4-thienyl, I -N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl- 1,3,4- thiadiazol-2-yl, 4-IIH 2 NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2- fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2- yI, 4-(3 '-dimethylamino-n-propoxy)-phenyl, and 1 -methylpyrazol-4-yl. A compound according to Claims .1 or 2 wherein R' is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, -(CH 2 2 -2- thienyl, and -(CH 2 2 6. A compound according to Claims I or 2 wherein R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R' are joined to form a heterocyclic group or substituted heterocyclic group. 7. A compound according to Claims 1 or 2 wherein R 2 and R 3 together with the nitrogen atom bound to R 2 substituent and the carbon bound to the R 3 substituent form a heterocyclic group or a substituted heterocyclic group. 8. A compound according to Claims I or 2 wherein R' is selected from the group consisting of methyl, phenyl, benzyl, diphenylmethyl, -CH 2 CH 2 -COOH, -CH2-COOH, 2-amidoethyl, iso-butyl, t-butyl, -CH 2 O- benzyl and hydroxymethyl. WO 99/06431 PCTIUS98/15313

194-- 9. A compound according to Claims 1 or 2 wherein Q is -C(O)NH- or 10. A compound according to Claims I or 2 wherein R' is selected from the group consisting of: 2 CH 2 C(O)NH-]benzyl, 4- [HOOCCH 2 CH 2 C(O)NH-]benzyl, 4 -[-NHC(O)CH 2 NI-Bocjbenzy], 4-I-NHC(O)CH(CH 3 )NHBocjbenzyl, 4 +N{C(O)CH(CHA4)NI-Bocjbenzyl, 4-[-NHC(O)CH- 2 NHC(O)NH-3 methylphenyljbenzyl, 4 -[-NHC(O)CH(NHBoc)(CH 2 ),NH-Cbz]benzyl, 4 -[NHC(O)CH 2 CH(C(O)OCH2 >-NICbz]berzyl, 4-4benzyl, 4 -[NHC(O)CH(CH 2 CH,CH 2 CH 2 NH 2 )NHBoc]benzyl, 4 -[H 2 NCH 2 CH 2 CH 2 C(O)NH-]benzyl, 4-(BocHNCH 2 CH 2 CH 2 C(O)NH-)benzyl, 4 CH 2 OCH 2 (BocHN)CHC(O)NH..]benzyl, 4 -[CH 3 NIJCH 2 CH 2 CH 2 C(O)NH-lbenzyl, 4 -(N-methylpiperidin-4-oxy).benzyl, 4 -[CH 3 N(Boc)CH 2 CH 2 CH 2 C(O)NH-]benzyl, 4 CH 2 OCH 2 (H 2 N)CHC(O)NH-]benlzy], 4 -[HO(O)C(Cz-NA)CHCH 2 CH 2 C(O)NTJ-]benzyl, 4 CH2O(O)C(Cbz-NII)CHCH 2 CH 2 C(O)NH-]benzyl, 4 -[HO(O)C(NH 2 )CHCH 2 CH 2 .C(O)NH..]benzyl, 4 -[CH 3 (N-Boc)NCH 2 C(O)NH-]benzyl, 4-[CH 3 NHCH 2 C(O)Nl1i-]benzyl, 4-[(CH 3 2 NCH 2 C(O)NH-]benzyl, 4 +[--CH(COOH)f]benzyl, 4 -12-carboxylphenyl-]-benzyl, 4 2 -carboxylmethylphenyl-]benzyI 4 -[4CH 2 0C(O)NICH 2 CH 2 N1I-]benzyl, 4-N[-(S0 2 )CH 3 CH 2 CH 2 CH 2 N(CH- 3 2 ]benzyl, 4 -t-butyl-O(O)CCH 2 -O-benzylNH]benyl 4-N -i4N -iehlmiobny~mn~ezl 4-(2-formyl-1,,,-erIyriounoi- lCHN~ezl 4-[OCH 2 CH 2 -1 4 '-pyrimidiny)-piperazinyl]-benzyl, 4-[-OCH 2 CH 2 1'-piperidinyl)-benzyl, 4-[-OCH,CH 2 1 '-pyrrolidinyl)] benzyl, 4-[-OCH.,CH 2 1'-piperidinyl)]-benzyl, 4-[(CH 3 2 NCH 2 C-1CH 2 -O-]benzyl, 4 -[(CH 3 2 NCFJ 2 CH 2 O-I-benzyl, 4-[-OCH 2 CH 2 CH 2 I '-(4'-methylpiperazinyl))]-benzyl, 4-[-OCH 2 CH,CH 2 '-chlorophenyl)-piperazin- I -yl]-benzyl, WO 99/06431 WO 9906431PCTIUS98/1 5313 -195-- 4-[OCH 2 CH 2 N(4i)CH 2 CH3]-benzyl, 4-[-OCH 2 -3 '-(N-Boc)-piperidinyl]- benzyl, 4-[-O-(3-(N-Boc)-piperidinyl]benzyl, 3-[-O-(N-methylpiperidin-4-yl]benzyl, 4 -[-O-(N-methylpiperidin-4-yI]benzyl, 4-[di-iso-propylamino-CH 2 CH 2 O-]-benzyl, 4-[N-3 -methylbutyl-N-trifluoro- methanesulfonyl)amino]benzyl, 4-[-OCH 2 CH 2 -(N-morpholinyl)]-benzyl, 4-[-OCH 2 CH(NHBoc)CH 2 cyclohexyl]-benzyl, 4-[OCH 2 CH 2 -(N-piperidinyl]- benzyl, 4 -[-OCH 2 CH 2 CH 2 -(4-m-chlorophenyl).piperazin. I -yl]-benzyl, 4 -[-OCH 2 CH 2 -(N-homopiperidinyl)-benzyl, 4-I-OCHCH 2 N(benzyl)j-benzyl, 3 -[-OCH 2 CH 2 CH 2 N(CH 3 )j-benzyl, 4- [-OCH 2 CH2N(C 2 H)j-benzyl, 4-[-OCH 2 CH 2 CH 2 N(C 2 H 5 )j-benzyl, 4-[-OCH 2 CH 2 N(C 2 H)jI-benzyl, 4 -[-OCH 2 CH 2 CH 2 N(CH 3 )benzyl]-benzyl, 4-[2-(2-azabicyclo[3 .2.2]octan-2- yI)ethyl-O-]benzyl, [cyclopentylacetyienyljj-benzyl, 4-[CEC-4-4 ]-benzyI, =C-CH 2 -O-S(O) 2 -4 '-CH 3 -4 ]-benzyl, C-CH 2 NH-C(O)N}1 2 ]-benzyl, 4--=C-CH 2 '-COOCH 2 CH 3 )cfl-benzyl, C-CH(NH 2 )-cyclohexyl]- benzyl, C-CH 2 -O-phenyl]-benzyl, C-CH 2 OCH 3 ]-benzyl, C-CH 2 '-C(O)0C 2 H 5 )phenylj-benzyl, C- CH 2 CH(C(O)OCH 3 )2J-benzyl, C-CH 2 CH( NIC(O) CH 3 )C(O)OH]- benzyl, 4-[-C=-C-CH 2 NH-(4,5-dihydro-4-oxo-5-phenyl-oxazolI2yl)]-berizyl 4 -[-OCH 2 CH 2 CH 2 -(N-morpholino)]-benzyl, 4-II-OCHCOOH]-benzy1, 4-I-OCH 2 COO-t-butyl]-benzyl, 4-[-N(SOCH 3 )(CH 2 3 -N(CH 3 2 ]-benzyl, 4-[-NIIS(O) 2 CF 3 ]-benzyl, 4-[-C(=NI-)NHj,-benzyl, 4-II-NHSO 2 -CH 2 CI- benzyl, 4-[OCH 2 C(O)NH-benzyl]-benzyl, 4-[-OCH 2 C(O)O-benzyl]-benzyl, 4- [-OCH 2 C(O)OH]-benzyl, 4-[-OCH 2 CH 2 -1I-(4-hydroxy-4-(3-methoxypyrrol- 2 -yI)-piperazinyl]-benzyl, 4-I-OCH 2 C(O)NI-Ij-benzyl, 4-[-OCH 2 C(O)NI{-t- butyl]-benzyl, 4-II-OCH 2 CH,- I-(4-hydroxy-4-phenyl)-piperidinyl]-benzyl, 4-[-NHSO 2 -CH=CH 2 ]-benzyl, 4-[-NIISO,-CH 2 CH 2 C1]-benzyl, 4-benzyl- benzyl, 4 -[-OCH 2 C(O)Piperidin- I -yllbenzyl, 4-[-OCH 2 C(O)N(CH(CH 3 2 2 lbenzyl, 4-amidinobenzyl, 4-acetamidobenzyl, 4 -(N-methyl)acetamidobenzyl, 4(-NHC(O)CH 2 NHC(O)NI--fluorescin)benzyl, 4-(NHC(O)CHCH(NH 2 )COOH, (1 -toluenesulfonylimidizol-4-yI)-methyl-, N-dimethylaminosulfonyl)-imidizol-4-yI]methyl-, 4-(N-toluenesulfonyl- amino)benzyl, and 4-[N-methyltrifluoroacetamido)phenyl. WO 99/06431 WO 99/643 1PCT[US98/15313 -196-- 11. A compound according to Claim 2 wherein R 6 is selected from the group consisting of 2 ,4-dioxo-tetrahydrofuran-3 -yl (3 methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-aX-iso- propyl-4-p-methylcyclohexoxy, 2-p-isopropyl-4-p-methylcyclohexoxy, -NH 2 benlzyloxy, -N1-CH 2 COOH, -NHCH 2 CH 2 COOH, -NH--adamantyl, -NHCH 2 CH 2 COOCH 2 CH 3 -NHSO 2 -p-CH 3 -NHOR 8 where R 8 is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), -O-cholest-5-en-3-p-yl, -OCH2-OC(O)C(CH 3 3 -O(CH 2 ),NH-C(O)W where z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N- methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH 2 C(O)OCH 2 CH 3 12.. A compound selected from the group consisting of: N-tlee4sloy)L-rll4[Ntr-uoxlabn lclaio- L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(glycyl)amino] -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3 -(carboxy)propi onamido]-L-pheny- lalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylL- alanyl)amino] -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(NtertbutoxylcarbonyID- alanyl)amino] -L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[(N-tertbutoxylcarbonyl-D phenylalanyl)amino]-L-phenylalanine N-(toluene-4-sulfcenyl)-L-prolyl-4- (fluorescein)thiouriedo] acetamido -L-phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylglycyl)amino]- L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- 2- methylphenyl)uriedo~acetamido -L-phenylalanine WO 99/06431 WO 9906431PCT/US98/1 5313 -197-- N-(toluene- 4 -sulfonyl)-L-prolyl-4-[(Na-tert-butoxylcarbonyl-NE. carbobenzyloxy-L-Iysyl)amino]-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[y-(a-benzylN.carbobenzyloxy-L. aspartyl)amino]-L-phenylalanine methyl ester N-(toluene- 4 -sulfonyl)-L-prolyl-4-[(Nal-ert-utoxylcarbonyl.L lysyl)amino]-L-phenylalanine N-(toluene- 4 -sulfony)-L-prolyl-4[y(L-aspartyl)amino-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl4(4-aminobutyramido)-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl4[4(Ntert-butoxyl- carbonylamino)butyramido]-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl4[4-(N-methylamino)butyramido]-L phenylalanine N-(toluene- 4 -sulfonyl)-L-proly-4[4-(Ntert-butoxylcarbonyl-N methylamino)butyramido-L-phenylalanine N-(toluene- 4 -sulfony)L-proly4(Obenzy)Lseryl)amino]-L phenylalanine N-tlee4sloy)Lpoy--8-DLguay~mn]Lpeyaa nine N-(toluene-4-sul fonyl)-L-pro lyl-4- [(N-tert-butoxyl- carbonylsarcosyl)amino]-L-phenylalanine ,5-dimethyl)thiapro lyl-4-[(N-ter-t-butoxyl- carbonylsarcosyl)amino]-L-phenylalanine N-(to luene-4-sul fonyl)-L-prolyl-4- [(sarcosyl) amino] Lphenylal anine ethyl ester N-tlee4sloy)Lpoy--(acslaio--hnlinn N-(toluene-4-sulfonyl)-L-(5 ,5-dimethyl)thiaprolyl-4-[(sarcosyl)amino]-L phenylalanine N-(to Iuene- 4 -sul fonyl) Lpro Iy 14- [(NNdi methyl g Iycy1) amino]-L- phenylalanine ,5-dimethyl)thiaproly-4-[(N,N- dimethylglycyl)amino] -L-phenylalanine WO 99/06431 WO 99/643 1PCT/US98/I 5313 -198-- N-(toluene-4-sulfoy)Lpoy--(xcroyezlxy--hnlinn N-tlee4sloy)Lpoy--2(abx~hnl--hnllnn N-(toluene- 4 -sufony)Lprolyi-4-[2-(methoxycarbonyl)phenyl]-L phenylalanine methyl ester N-(toluene-4-sulfonyl)..L.prolyi-4 carbobenzyloxyamino)ethyljamino I -L-phenylalanine N-(toluene-4-sulfonyl-L-pro lyl-4- carbobenzyloxyamino)ethyl~lamino} -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)Lprolyl.L-4 {N-[3-(NN-dimethylamino)propyl]- N-[tri fluoromethanesulfonyl] amino I -L-phenylalanine methyl ester N-(toluene-4-sulfonyl-L-prolyl..L-4 {N-[4-[(tert- butoxycarbonyl)methoxylbenzyl] amino)} -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L.prolyl.L-4 {NN-di [4-(NN- dimethylamino)benzyl] amino)} -L-phenylalanine N-(toluene-4-sulfonyl)L-prolyl-L-4 {N-[(2-formyl- 1,2,3,4- tetrahydroisoquino lin- 3 yl)methyl]amino -L-phenylalanine N-tlee4sloy)Lpoy-4[-NNdmtyaiopooy-L- phenylalanine N-(toluene-4-sul fonyl)-N-methyl-L-serinyl4.[3(NNdimethylamino- propoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)L-(s ,-dimethyl)thiaprolyl-4[2.(N,pj dimethylamino)ethoxy]-L-phenylalanine N-tlee4sloy)Lpoy--2(Ndmtyaioehx]L phenylalanine N-(toluene-4-sulfoy)Lpoy -2(-tylNpeyaioehx]L phenylalanine methyl ester N-(toluene-4-sul fonyl)-L-prolyl-4-[2-(N,Ndiisopropylamino)ethoxy]-L phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-[3..cyclohexy12-(Atert. butoxycarbonylamino)propoxy-Lphenyalaninfe methyl ester N-(thiophene-2-sulfonyl>Lproly1.4.3(NNdimethylamino)propoxy]-L phenylalanine WO 99/06431 WO 9906431PCTIUS98/15313 -199-- N-(5-chlorothiophene-2-sulfonyl)-L-proly[4..43..(N,N-dimethylamino). propoxy]-L-phenylalanine N-(to luene-4-sul fonyl)-L-prolyl [2-(NNdi ethyl am ino)ethoxy] -L- phenylalanine N-(2,5-dichorothiophene3sufonyl)Lprolyi-4[3-(N}N- dimethylamino)propoxy]-L-phenylalanine 1 -methylpyrazoe4sulfony)iproyi-4[3-(NNdimethylamino)- propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4{3-(N,N-di ethylamino)propoxy]-L- phenylalanine methyl ester N-(tol uene-4-su fonyl)- Lproyl3 3(NNdi m ethyl ami1no)propoxy] -L- phenylalanine N-(thiazole- 2 -sufonyl)Lproyl4[3(NNdimethylamino)propoxy]-L phenylalanine N-(to luene-4-sulfonyl)-L-prolyl4[3(Nmethyl-N benzylamino)propoxy]Lpheny] alanine N-(toluene- 4 -sulfonyl>Lproly14-[3-(NNdiethylamino)propoxy].L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl14-.[3-(N-methyl-N- benzylamino)propoxy] -L-phenylalanine methyl ester l-m ethylimidazo Ie-4-sul fonyl)u Lpro Iy1 4-[3 -(NNdimethy Iamino)- propoxy]-L-phenylalanine -sulfonyl)-L-prolyl-4-[3 -(N,N-dimethylamino)- propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)Lthiaprolyl4[3-(N,N-dimethylamino)propoxy]- L-phenylalanine N-(4-cyanobenzenesulfonyl)-L-(s ,5 -dimethyl)thiaprolyl-4-[3 -(NN- dim ethylamino)propoxy] -L -pheny lalanin e methyl ester N-(toluene-4-sul fonyl) ,3 -dim ethyl)prolyl [3 -(NN- dimethylamino)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-(s ,5-dimethy)thiaproly-4-[3(N,T- dimethylamino)propoxy]-L-phenylalanine ethyl ester WO 99/06431 WO 99/643 1PCT/US98/15313

200-- N-(toluene-4-sulfonyl)-L-prolyl-4[2-(2-azabicyclo[3 .2 .2]octan-2- yl)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-4-[3-(N,N- dimethylamino)propoxy]-L-phenylalanine N-(toluene-4-sulfony)Lprolyi-4[2..(2-azabicyclo[3 .2.2]octan-2- yI)ethoxy]-L-phenylalanine N-(toluene- 4 sulfony)D,Lphenyaany4[2(cyclopenty)ethyylDL phenylalanine N-(toluene-4-sulfonyI)-D,L-phenylalanyl14 (phenyl)phenyl]ethynyl I -D,L-phenylalanine N-(toluene- 4 -sulfonyl)D,L-phenylalanyl-4-[3-(toluene-4 sulfonyloxy)prop- 1 -ynyl]-D,L-phenylalanine N-(toluene-4-sul fonyl)-D,L-phenylalanyl-4-[3 -(ureido)prop- I -ynyl] -D,L- phenylalanine- N-(toluene-4-sulfonyl>D,Lphenylalanyl-4-[3 ethoxycarbonylphenoxy)prop- I -ynyl]-D,L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylaiany..4-[2-( 1 -aminocyclohex- 1- yl)ethynyl]-D,L-phenylalanine N-(toluene-4-sulfony)LprolyI4-[3-(phenoxy)prop- 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4[3-(phenoxy)prop. 1 -ynyl]-D,L- phenylalanine N-(toluene-4sulfonyl)Lproyl4[3-(methoxy)prop- 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sul fonyl)sarcosyl-4-[3-(methoxy)prop- I -ynyfl-D,L- phenylalanine N-(toluene-4-sulfoiy1)-L-prolyl-4-[3 4 -ethoxycarbonylphenoxy)prop- I ynyl]-D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl4[3-(4ethoxycarbonylphenoxy)prop- I ynyl]-D,L-phenylalanine N-(toluene- 4 -sulfonyl-L-prolyl.4-[4,4-di(methoxycarbonyl)but- I -ynyl]- D,L-phenylalanine WO 99/06431 WO 9906431PCTIUS98/15313 201 N-(toluene-4-sulfonyl)sarcosyl-4- [4,4-di(methoxycarbonyl)but- Il-ynyl)- D,L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-(4-acetamido-4carboxybut- I-ynyl)- D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl4(4..acetamido-4carboxybut- I-ynyl)- D,L-phenylalanine N-(toluene-4-sulfonyl).u-proly-4- {3-[(4,5-dihydro-4-oxo-5- phenyloxazol-2-yl)aminojprop- 1 -ynyl -D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4 {3-[(4,5-dihydro-4-oxo-5-pheriyloxazol- 2-yl)amino]prop- 1 -ynyl -D,L-phenylalanine N-(toluene- 4 -sulfonyl)-LprolyI4-[2-carboxy)phenoxy-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4 2 4 -(pyrimidin-2-yI)piperazin- 1 yl]ethoxy} -L-phenylalanine N-(toluene-4-sulfonyl)-L-proly-4[3-(p iperidin- 1 -yl)propoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyI-4-[2(pyrrolidin- I -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyI-4-[3-(piperidin- I -yl)propoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- f 3-[4-(3-chlorophenyl)piperazin- 1 yI]propoxy} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[( 1 -tert-butoxycarbonylpiperidin-3- yl)methoxy]-L-phenylalanine methyl ester N-(toluene-4-sul fonyl)-L-prolyl-4- [2-(morpholin-4-y1)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[( 1 -tert-butoxycarbonylpiperidin-3- yl)methoxy]-L-phenylaianine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(piperidin- 1 -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- f 3-[4-(3-chlorophenyl)piperazin- 1 yI]propoxy} -L-phenylalanine methyl ester WO 99/0643 1 PCT/US98/15313 202 N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan- 1 -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan- I -yl)ethoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methy,!piperazin I1 -yl)propoxy]- L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-3 -[2-(pyrrolidin- 1 -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(4-methylpiperazin- 1 -yl)propoxy]- L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-3-[2-(morpholin-4yl)ethoxy].L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4 {2-[4-(3-methoxythien-2-yl)-4- hydroxypiperidin- 1-yl]ethoxy)}-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-3-(I -methylpiperidin-4-oxy)-D,L- phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-( I -methylpiperidin-4-oxy)-D,L- phenylalanine N-(toluene- 4 -sulfonyl)-L-(5,5-dimethyl)thiaprolyl-4-(.methylpiperidin- 4-oxy)-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(, 1, -dioxothiomorpholin-3-carbonyl)-4-( 1- methylpiperidin-4-oxy)-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(, 1, -dioxothiomorpholin-3-carbonyl)-4-( I methylpiperidin-4-oxy)-L-phenylalanine ,5-dimethyl)thiaprolyl-4-( I -methylpiperidin- 4-oxy)-L-phenylalanine N-(a-toluenesulfonyl)-L-prolyl-4-( 1 -methylpiperidin-4-oxy)-L- phenylalanine ethyl ester N-(toluene- 4 -sulfonyl)-L-prolyl-4-N-(trifluoromethanesul fonyl)amino-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-proly-4-N-(tri fluoromethanesulfonyl)amino-L- phenylalanine WO 99/06431 WO 99/643 1PCTIUS98/1 5313 203 N-(toluene-4-sulfonyl)-L-prolyl-4-N-(chloromethanesulfonyl)amino-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsul fonyl)amnino-L- phenylalanine methyl ester N-(toluene-4-sul fonyl)-L-prolyl-4-(N-tri fluoromethanesulfonyl-N- isobutyl)amino-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(vinylsul fonyl)amino-L- phenylalanine N-(toluene-4-sul fonyl)-L-pro lyI-4-[(N-benzylariinocarbony)methoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[(benzyloxycarbony)methoxy]-L phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(carboxy)methoxy] -L-phenylalanine N-(to luene-4-.sul fonyl)-L-prolyl-4-[(carboxy)methoxy] -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[(aminocarbonyl)methoxy-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butylaminocarbonyl)methoxy]- L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(4-phenyl-4-hydroxypiperidin- I1- yl)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- [(piperi din- I -ylcarbonyl)methoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- diisopropylaminocarbonyl)methoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[(N,N- dii sopropylaminocarbonyl)methoxy] -L-phenylalanine methyl ester N-(toluene-4-sul fonyl)sarcosyl-D,L-4-(amidino)phenylalanine N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(aminocarbonyl)phenylaanine WO 99/06431 WO 9906431PCT/US98/15313 204 N-(toluene- 4 -sulfonyl)-L-prolyl-4.{v..methyacetamido)Lphenylalanine isopropyl ester N-(toluene-4-sul fonyl)-L-prolyl-4-(N-methylacetamido)-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4.(N-methyltri fluoroacetamido)-L- phenylalanine methyl ester ,5-dimethyl)thiaproly-4-[3-(v,- dimethylamino)propoxy]-L-phenylalanine t-butyl ester N-(toluene- 4 -sulfonyl)-LprolylL-4yN-methylpiperidinoxy)- phenylalanine t-butyl ester N-(to Iuene-4-sul fony)L(5,5dim ethyl)thiapropylL(4- methylpiperidinoxy) phenylalanine t-butyl ester N-(toluene- 4 sulfonyl)Lprolyl-(4-phenyl-Lphenyalanine t-butyl ester N-tlee4sloy)Lpoyl(-hnl--hnllnn and pharmaceutically acceptable salts thereof as well as any of the ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester. 13. A method for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound: R 3 0 R'S2N,--C--HCR6 IA R where R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; WO 99/06431 PCT/US98/15313 205 R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R' can form a heterocyclic or a substituted heterocyclic group; R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group; R' is -(CH,)x-Ar-R 5 where is selected from the group consisting substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, amrninocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O),-substituted alkyl, -OS(O),-aryl, -OS(O) -substituted aryl, heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O)2-heterocyclic, -OS(0)2- substituted heterocyclic, -OSO,-NRR where R is hydrogen or alkyl, WO 99/06431 PCT/US98/15313 206 -NRS(O) 2 -alkyl, -NRS(O),-substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O),-substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR- alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR- substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O),-NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -SO,-substituted alkyl, -SO,-alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SO2-Substituted heteroaryl, -SO heterocyclic, -SO2-Substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR where R is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, aryl and heteroaryl; -NR'R' wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, WO 99/06431PCIS8153 PCT/US98/15313 207 thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, arninothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocycl ic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O)2-NR-substituted alkyl, -NRS (O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted WO 99/06431 WO 99/643 1PCTIUS98/1 5313 208 alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -Substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -S02- heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; -alkoxy-NR"R" wherein each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl amino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, ami nothi ocarbonyl amino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroa ryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -05(0)2- substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, WO 99/06431 PCT/US98/15313

209-- -NRS(O),-NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O),-NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -SO, 2 -substituted cycloalkyl, -S02- aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S 2 O,-substituted heteroaryl, -SO02 heterocyclic, -SO 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyl/alkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, WO 99/06431 WO 9906431PCT/US98/15313

210-- substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroa-yl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O)2-substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NRM-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetr-ic di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -al kenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0,-substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -S02- heterocyclic, -S0,-substituted heterocyclic and -SO.,NRR where R is hydrogen or alkyl; substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, WO 99/06431 PCT/US98/15313

211-- alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy- substituted saturated heterocyclic; -O-heterocyclic and -O-substituted heterocyclic; tetrazolyl; -NR-S0 2 -substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; (min) substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; amidine and amidine substituted with from 1 to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; where each is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, WO 99/06431 PCT/US98/15313

212-- substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea, then the other is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic; -NR' 2 C(O)-R 8 where R 8 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R' 2 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -SO 2 -aryl, -SO,-substituted aryl, -SO2-heteroaryl, -SO,-substituted heteroaryl or -SO,-alkyl; -NR'C(0)NR 9 R 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic: -NR'C(0)OR 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; WO 99/06431 PCT/US98/15313

213-- -aminocarbonyl-(N-formylheterocycyl); and -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; is selected from the group consisting of, hydroxy, 2,4-dioxo- tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O-(N-succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-p-yl, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, -NH(CH 2 )pCOOY where p is an integer of from 1 to 8 and Y is as defined above, -OCH,NR 9 R' 0 where R 9 is selected from the group consisting of-C(O)-aryl and -C(O)-substituted aryl and R' 0 is selected from the group consisting of hydrogen and -CH 2 COOR"'' where R" is alkyl, and -NHSO 2 Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is -C(X)NR 7 wherein R 7 is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof with the proviso that when R' is R 6 is methoxy, Q is and R 2 and R' are joined to form a pyrrolidinyl group, then R' is not p-[-OCH 2 CH 2 N(C 2 H)2]-benzyl-, p-[-OCHCH 2 N(isopropyl)2]-benzyl-, p- [-OCH 2 CH 2 -1 -pyrrolidinyl)-benzyl-, p-[-OCH 2 CH 2 -1 -(4-pyrimidinyl)piper- azinyl]-benzyl-, p-[-OCHCH-N-morpholinyl)]-benzyl-, or p-[-OCH 2 CH 2 -N- piperidinyl)]-benzyl- under conditions wherein said compound binds to VLA-4. 14. The method according to Claim 13 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. WO 99/0643 1PCUS/153 PCTIUS98/15313

214-- The method according to Claim 14 wherein R' is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chiorophenyl, 1 -naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2 4 ,6-trimethylphenyl, 2- (methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4- trifluoromethylphenyl, 3 ,4-dichlorophenyl, 3 4 -dimethoxyphenyl, 4- (CH 3 C(O)NI{-)phenyl, 4 -trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3 ,5-di-(tri fluoromethyl)phenyl, 4-it-butylphenyl, 4-t-butoxyphenyl, 4- nitrophenyl, 2-thienyl, I -N-methyl-3 -methyl-5-chloropyrazol4yl, phenethyl, I -N-methylimidazol-4-yi 4-bromophenyl, 4-amidinophenyl, 4- methylamidinophenyl, 4-[CH 3 SC(=NH)]phenyl, 5-chloro-2-thienyl, dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl- 1,3,4- thiadiazol-2-yl, 4-[H2NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2- fluorophenyl, 3-fluorophenyl, 3 ,5-di fluorophenyl, pyridin-3-yl, pyrimidin-2- yl, 4-(3 -dimethylamino-in-propoxy)-phenyl, and 1 -methylpyrazol-4-yl. 16. The method according to Claim 13 wherein R 2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, -(CH 2 2 -2-thienyl, and -(CH 2 2 17. The method according to Claim 13 wherein R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R' are joined to form a heterocyclic group or substituted heterocyclic group. 18. The method according to Claim 13 wherein R 2 and R' together with the nitrogen atom bound to R 2 substituent and the carbon bound to the R 3 substituent formn a heterocyclic group or a substituted heterocyclic group. 19. The method according to Claim 13 wherein R 3 is selected from the group consisting of methyl, phenyl, benzyl, diphenylmethyl, -CH 2 CH,-COOH, -CH 2 -COOH, 2-amidoethyl, iso-butyl, t-butyl, -CH 2 O- benzyl and hydroxymethyl. WO 99/06431 WO 9906431PCT/US98/1 5313

215-- The method according to Claim 13 wherein Q is or -C(S)NH-. 21. The method according to Claim 13 wherein R' is selected from the group consisting of.- 4-IINIJ 2 CH 2 C(O)NH--]benzyl, 4-[HOOCCH 2 CH 2 C(O)NH-]benzyl, 4 -[-NI4C(O)CH 2 NHBoc]benzyl, 4-[-NHC(O)CH(CH 3 )NHBocjbenzyl, 4 -[-NHC(O)CH(CH 2 4))NHBoc~benzyl, 4-[-NI-C(O)CH 2 NHC(O)NI.3 methylphenyl]benzyl, 4-[-NHC(O)CH(NHBoc)(CH 2 ),NHCbz]benzyl, 4 -[NHC(O)CH 2 CH(C(O)OCH 2 ()-NH-Cbzjbenzyl, 4-4-benzyl, 4-[NC(O)CH(CH 2 CHCH 2 CH 2 NH 2 )NHBocjbenzyl, 4 -[H 2 NCH 2 CH 2 CH 2 C(O)NI-jbenzy], 4-(BocHNCH 2 CH 2 CH 2 C(O)NH-)benzyl, 4 -[NCH 2 OCH 2 (BocHN)CHC(O)NHljbenzyl, 4 -[CH 3 NHCH 2 CH 2 CH 2 C(O)NI-]benzyl, 4 -(N-methylpiperidin-4-oxy)-benzyl, 4 -[CH 3 N(Boc)CH 2 CH 2 CH 2 C(O)N{.Jbe.zy1, 4 -[FCH 2 OCH 2 (H 2 N)CHC(O)NH-]benizyl, 4-IIHO(O)C(Cbz-NH)CHCH 2 CH 2 C(O)NIH-]benzyl, 4 -[4PCH 2 O(O)C(Cbz-NH)CHCH 2 CH 2 .C(O)NH-be.zyl, 4 -[HO(O)C(NH 2 )CHCH 2 CH 2 .C(O)NH-.]benzyl, 4 -[CH 3 (N-Boc)NCH 2 C(O)NH..]benzyl, 4-[CH 3 NHCH 2 C(O)NH-L]benzyl, 4 -[(CH 3 )2NCH 2 C(O)NH-]benzyl, 4 -[--CH(COOH)4 ]benzyl, 4 2 -carboxylphenyl-]-benzyl, 4 -[2-carboxylmethylphenyl-j -benzyl 4 -[4CH 2 0C(O)NICH 2 CH 2 NH-]benzyl, 4-N[-(S0 2 )CH 3 CH 2 CH 2 CH 2 N(CH 3 )]benzyl, 4 -t-butyl-O(O)CCH 2 -O-benzylNH]benzyl, 4 -[NN-di(4-N.N-dimethylamino)benzyl)amino]benzyl, 4-(2-formyl- 1,2,3 ,4-tetrahydroisoquinolin3ylCH 2 NH)benzyl, 4-[OCH 2 CH 2 -1 4 1 -pyrimidinyl)-piperazinyl]pbenzyI, 4-[-OCH 2 CH 2 I '-pipe-idinyl)-benzyl, 4-[-OCH 2 CH 2 1'-pyrrolidinyl)]- benzyl, 4-[-OCH 2 CH 2 CH 2 '-piperidinyl)]-benlzyl, 4-[(CH 3 2 NCH 2 CH 2 CH 2 -O-]benzyl, 4-[(CH 3 )2NCH 2 CH 2 O-]-benzyl, 4-II-OCH 2 CH 2 CH 2 '-(4'-methylpiperazinyl))]-benzyl, 4-[-OCH 2 CH 2 CH 2 '-chlorophenyl)-piperazin- I -yl]-benzyl, WO 99/06431 WO 9906431PCTIUS98/1 5313

216-- 4-[OCH 2 CH 2 N(4)CH 2 CH 3 ]-benzyl, 4-[-OCH 2 -3 '-(N-Boc)-piperidinyl]- benzyl, 4 -[-O-(3-(N-Boc)-piperidinyljbenzy], 3 -[-O-(N-methylpiperidin-4-yl]benzyl, 4 -[-O-(N-methylpiperidin-4-yljbenzyl, 4 -[di-iso-propylamino-CH2CH 2 O-].benzyl, 4-[N-3-methylbutyl-N-trifluoro- methanesulfonyl)amino]benzyl, 4-[-OCH 2 CH 2 -(N-morpholinyl)]-benzyl, 4-[-OCH 2 CH(NTIBoc)CH 2 cyclohexyl]-benzyl, 4-[OCH 2 CH 2 -(N-piperidinyl]- benzyl, 4 -[-OCH 2 CH 2 CH 2 -(4-rn-chlorophenyl)-piperazin- 1 -yl]-benzyl, 4- [-OCH 2 CH 2 -(N-homopiperi dinyl)-benzyl, 4-[OCH 2 CH 2 N(benzyl)2j-benzyl, 3-[OCH 2 CH 2 CH 2 N(CH 3 2 ]-benzyl, 4-[OCH 2 CH,N(C 2 H)]benzyl, 4-[-OCH 2 CH 2 CH 2 N(C 2 H)-benzyl, 4-[OCH2CH 2 N(C 2 H 5 2 ]-benzyl, 4 -[-OCH 2 CH 2 CHN(CH3)benzyl]-benzyl, 4-[2-(2-azabicyclo[3 .2.2]octan-2- yl)ethyl-O-]benzyl, [cyclopentylacetylenyl]-benzyl, 4-[C =C-4 -4 '4]-benzyl, 4--=C-CH 2 -O-S(O) 2 -4 '-CH 3 -4]-benzyl, 4- [C=C-CH 2 NIIC(O)NH 2 1J-benzyI, =C-CFI 2 '-COOCH 2 CH 3 ]-benzy1, 4+[C =_C-CH(NH 2 )-CYClohexyl]- benzyl, 4-[C =C-CH 2 -O-phenyl]-benzyl, C-CH 2 OCH 3 ]-benzyl, =C-CH 2 '-C(O)0C 2 H 5 )phenyl]-benzyl, 4- CH 2 CH(C(O)OCH 3 )2j-benzyl, =C-CH 2 CH( NHC(O)CH 3 )C(O)OH]- benzyl, 4-[-C=-C-CH 2 NH-(4,5-dihydro-4-oxo-5-pheny1..oxazo1.2y)-benzyl 4 -[-OCH 2 CH 2 CH 2 -(N-morpholino)]-benzyl, 4-[-OCH,COOH]-benzyl, 4 -[OCH 2 COO-t-butyl]-benzyl, 4-[-N(SO 2 CH 3 )(CH 2 3 -N(CH 3 )jbenzyl, 4-[NIIS(O) 2 CF 3 ]-benzyl, 4-[-C(=N)NE 2 ]-benzyl, 4-[-NHSO,-CH 2 CI- benzyl, 4 -[OCH 2 C(O)N}{-benzyl]-benzyl, 4-[OCH 2 C(O)O-benzyl]-benzyI, 4 -[OCH 2 C(O)OH]-benzyl, 4-[-OCH 2 CH 2 I-( 4 -hydroxy-4-(3-methoxypyrrol- 2 -yl)-piperazinyl] -berizyl, 4-[-GCH 2 C(O)NH2]-benzyl, 4-[OCH 2 C(O)NH-t- butylll-benzyl, 4-[-OCH 2 CH 2 1-( 4 -hydroxy-4-phenyl)-piperidiny]-benzyl, 4-[-NHSO,-CH-=CH2]-benzyl, 4-[-N}1S0 2 -CH 2 CH,CI]-benzyl, 4-benzyl- benzyl, 4-[-OCH,C(O)piperidin- 1-yI]benzyl, 4-[-OCH 2 C(O)N(CH(CH 3 2 )2]benzyl, 4-amidinobenzyl, 4-acetamidobenzyl, 4 -(N-methyl)acetamidobenzyl, 4 (-NHiC(O)CH 2 NHC(O)NHi-fluorescin)benzyl, 4-(NIIC(O)CH 2 CH(NI-1)COOH, (l--toluenesulfonylimidizol-4-yl)-methyl-, N-dimethyl aminosu fonyl)-imidizol4yl)m ethyl-, 4-(N-toluenesulfonyl- amino)benzyl, and 4-[N-methylri fluoroacetamnido)phenyl. WO 99/06431PCIS8153 PCTIUS98/15313

217-- 22. The method according to Claim 13 wherein R 6 is selected from the group consisting of 2 4 -dioxo-tetrahydrofiuran-3-yl (3 ,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso- propyl- 4 p-methylcyclohexoxy, 2 -jp-isopropyl-4-f 3 -methylcyclohexoxy, -N2 benzyloxy, -NHCH 2 COOH, -NHCH- 2 CH 2 CCOH, -NH-adamantyl, -NHCH 2 CH 2 COOCH 2 CH 3 -NI1S0 2 -p-CH 3 -4 -NHOR 8 where R' is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), -O-cholest-5-en-3-p-yI, -OCH 2 -OC(O)C(CH 3 3 -O(CH 2 ),N14C(O)W where z is I or 2 and W is selected from the group consisting of pyrid-3-yl, N- methylpyridyl, and N-methyl-1,4-dihydro-pyrid3yl, whereR' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH 2 C(O)OCH 2 CH 3 23. The method according to Claim 13 wherein said compound is selected from the group consisting of- N-tlee4sloy)Lpoy--(Ntr-uoycroygyy~mn] L-phenylalanine N-(toluene-4-sulfonyl)..L-prolyl-4[3 -(carboxy)propionamido] -L-pheny- lalanine N-tlee4sloy)Lpoy--(-etbtxlabnlL alanyl)amino] -L-phenylalanine N-tlee4sloy)Lpoy--(-etbtxlabnlD alanyl)amino]-L-phenyiaIanine N-(toluene-4-sulfonyl)-L.prolyl-4.[(N-tert-butoxylcarbonyl-D. phenylalany1)amino]-L.phenylatanine N-(toluene-4-sulfonyl).L-prolyl.4- (fluorescein)thiouriedojacetamido -L-phenylalanine N-(toluene-4-sulfonyly.-prolyl-4-[(N.tert-butoxycarbonylglycyl)amino]- L-phenylalanine methyl ester N-(toluene-4-sulfonyl-L-prolyl14 methylphenyl )uriedolacetamido -L-phenylalanine WO 99/06431 WO 99/643 1PCTIUS98/1 5313

218-- N-(toluene-4-sulfonyl)-L-prolyl-4-[(Na-tert-butoxylcarbonyl-NE. carbobenzyloxy-L-lysyl)amino]-L-phenylalanine N-tlee4sloy)Lpoy--y(-ezlN-abbnyoyL aspartyl)amino]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl4[(NatertbutoxylcarbonylL-. lysyl)amino]-L-phenylalanine N-(toluene-4-sulfony)-L-proy-4[y(Laspartyl)amino-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-(4..aminobutyramido).L-phenylaianine N-(toluene-4-sul fonyl)-L-prolyl-4-[4-(N-tert-butoxyl- carbonylamino)butyramido-L-phenylalanine N-(to luene- 4 -sulfonyl)-L-prolyi-4[4(N-methylamino)butyramidoyL- phenylalanine N-(toluene-4-sufony)Lproy44(NtertbutoxylcarbonyIN- methylamino)butyraiido]-L-phenylalanine AT(oun--ufnl--rll--(-ezl--ey~mn]L phenylalanine N-(toluene-4-sulfonyl)-L..prolyl-4.[&(D,L-glutamy1)amino]-L-phenylala- nine N-(toluene-4-sulfonyl)-L-prolyl4(Ntert-butoxyl- carbonylsarcosyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-(s ,5-dimethyl)thiaprolyl-4-[(N-tert-butoxyl- carbonylsarcosyl)amino]-L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyI4-(sarcosyl)amino-L-phenylalanine ethyl ester N-(toluene- 4 -sulfony1)-L-prolyl-4[(sarcosyl)amino]Lphenylalanine N-(toluene-4-sulfonyl)-L-( 5,5 -dimethyl)thiaprolyl-4-[(sarcosyl)amino]-L. phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[(N,Ndimethylglycyl)amino-L- phenylalanine ,5-dimethyi)thiaprolyl-4-[(N,N- dimethylglycyl)amino]-L-phenylalanine WO 99/06431 WO 9906431PCTIUS98/1 5313

219-- N-(toluene- 4 -sulfonyl)-L-proly14-(a.carboxybenzyloxyy..L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[2..(carboxy)phenylpL-phenylalanine N-(toluene- 4 -sulfonyI)-Lproyl4[2-(methoxycarbonyl)phenyl]-L phenylalanine methyl ester N-(toluene-4-sulfonyI)-L-prolyl-4- carbobenzyloxyamino)ethyl]amino }-L-phenylalanine N-(toluene-4-sulfonyl)-LprolyI4- carbobenzyloxyamino)ethyl]amino)}-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-LprolylL-4-{N- [3-(N,N-dimethylamino)propylj- N-[tri fl uoromethanesul fonyl] amino I -L-pheny lal anine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-4-. N-[4-[Qtert- butoxycarbonyl)methoxy]benzyl] amino)} -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-Lproly-L-4 {ANdi [4-(NN- dimethylamino)benzyl] amino) -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl.L-4 f{N-[(2-formyl- 1,2,3,4- tetrahydroi soquinolin-3 -yI)methyl] amino I -L-phenylalanine N-(toluene-4-sulfonyl)..D-prolyl..4..3(NN.dimethylamino)propoxy]-L phenylalanine N-tlee4sloy) -ehlLsnnl4[3-(N,N-dimethylamino- propoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-(s ,5-dimethyl)thiaprolyl-4-[2-(N,N- dimethylamino)ethoxy] -L-phenylalanine N-(toluene- 4 -sulfony)Lprolyl4[2(NN-dimethylamino)ethoxy]-L phenylalanine N-(toluene-4-sul fonyl)- L-prol yl-4- ethyl -N-phenylamino) ethoxy-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)Lprolyl.4-[ 2 -(N,N-diisopropylamino)ethoxy-L. phenylalanine N-(toluene-4-sulfonyl)-L-proly-4- [3-cyclohexyl-2-(N-tert- butoxycarbonylamino)propoxy] -L-phenylalanine methyl ester N-(thiophene-2-sulfonyl)-L-prolyl.4-.[3-(N,N-dimethylamino)propoxy]-L- phenylalanine WO 99/06431 WO 9906431PCTIUS98/15313 220 -chlorothiophene-2-sulfonyl)-L-prolyl-4-[3 -(N,N-dimethylamino)- propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [2-(N,N-diethylamino)ethoxy]-L- phenylalanine N-(2,5-dichlorothiophene-3-sulfonyl)yL-prolyl..4[3 dimethylamino)propoxy] -L-phenylalanine I -methylpyrazole-4-sulfonyl)-L-prolyl-4-[3-(NN-dimethylamino)- propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [3-(N,N-diethylamino)propoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-3 -[3-(N,N-dimethylamino)propoxy]-L- phenylalanine N-(thiazole-2-sulfonyl)-L-prolyl-4-[3.(N,N-dimethylamino)propoxy] -L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3..(N-methyl.N- benzylamino)propoxy]-L-phenylalanine N-(toluene- 4 -sulfony)Lprolyl4[3-(NNdiethylamino)propoxy]-L phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-[3-(N-methyl-N- benzylamino)propoxy]-L-phenylalanine methyl ester 1 -methylimidazole-4-sulfonyl)-L-prolyl-4-[3 -(N,N-dimethylamino)- propoxy]-L-phenylalanine fonyl)-L-prolyl-4- [3 -(N,N-dimethylamino)- propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-thiaprolyl-4-[3 -(N,N-dimethylamino)propoxy]- L-phenylalanine N-(4-cyanobenzenesulfonyl)-L-(5 ,5-dimethyl)thiaprolyl-4-[3-(NN- dimethylamino)propoxy]-L-phenylalanine methyl ester N-(toluene-4-sulIfonyl)- L-(3,3 -dim ethyl)prolyl4-[ 3 -NNp dimethylamino)propoxy]-L-phenylalanine ,5-dimethyl)thiaprolyl-4-[3-(N,N- dimethylamino)propoxy] -L-phenylalanine ethyl ester WO 99/06431 WO 9906431PCTIUS98/1 5313 221 N-(toluene-4-sufonyl)-Lproy4[2(2-aabicyclo[3 .2.2]octan-2- yl)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-(thiamorpholin.3 -carbonyl)-4-73-(N,N- dimethylamino)propoxy-L-phenylalanine N-(toluene-4-sufonyl)-L-proy4[2(2.zb zyclo[3 .2.2]octan-2- yl)ethoxy]-L-phenylaianine N-(toluene-4-sul fonyI)-D,L-phenylalanyl-4-[2-(cyclopentyI)ethyny phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4 [4- (phenyl)phenyl]ethynyl -D,L-phenylalanine N-(toluene-4-sulfonylyD,L-phenylalany14-[3-(toluele-4. sulfonyloxy)prop- 1 -ynyl]-D,L-phenylalanine N-(toluene- 4 -sulfonyl)-D,L-phenylalanyl-4[3.(ureido)prop- I -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)..D,L-phenylalanyl-4-[3-(4- ethoxycarbonylphenoxy)prop- 1 -ynyl]-D,L-phenylalanine N-(toluene-4sufonyl)D,L-phenylaany14[2.( I -aminocyclohex- I1- yl)ethynyl]-D,L-phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-[3-(phenoxy)prop. 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)sarcosyl4[3-(phenoxy)prop- 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)-L-proly14-[3-(methoxy)prop- 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)sarcosyl4[3-(methoxy)prop- 1 -ynyl]-D,L- phenylalanine, N-(toluene- 4 -sulfony1)-L-proyI4-[3.(4-ethoxycarbonylphenoxy)prop 1- ynyl]-D,L-phenylalanine N-(toluene-4-sul fonyl)sarcosyl-4-[3 4 -ethoxycarbonylphenoxy)prop 1- ynyl] -D,L-phenylalanine N-(toluene- 4 -sulfonyl)Lproly14-[4,4di(methoxycarbonyl)but- I-ynyl]- D,L-phenylalanine WO 99/06431 WO 9906431PCT/US98/1 5313 222 N-(toluene-4-sulfonyl)sarcosyl-4- [4,4-di(methoxycarbonyl)but- Il-ynyl]- D,L-phenylalanine N-(toluene-4-sulfony)-L-prolyl-4-(4-acetamido4carboxybut- I-ynyl)- D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-(4-acetarnido-4carboxybut- I-ynyl)- D,L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- f 3-[(4,5-dihydro-4-oxo-5- phenyloxazol-2-yl)amino]prop- Il-ynyl} -D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4- 5-dihydro-4-oxo-5-phenyloxazol- 2-yI)amino]prop- 1 -ynyl -D,L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4[2-(carboxy)phenoxy-L-phenylaianine methyl ester N-(toluene-4-sulfonyl)-L-proly-4- 2 -[4-(pyrimidin-2-yl)piperazin- 1- yllethoxy) -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3.(piperidin. 1 -yI)propoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4[2-(pyrrolidin- I -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-proly4[3-(iperidin- 1 -yl)propoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- 3 -[4-(3-chlorophenyl)piperazin- 1 yI]propoxy} -L-phenylalanine N-(toluene-4-sul fonyl)-L-pro lyl-4- -tert-butoxycarbonylpiperidin-3 yl)methoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfony)-L-proly4[2(morpholin4yl)ethoxy-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[( 1 -tert-butoxycarbonylpiperidin-3- yl)methoxy]-L-phenylalanine N-(toluene-4-sulfonyl)Lproly-4[2-(piperidin-I -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- {3-[4-(3-chlorophenyl)piperazin- I yljpropoxy}I -L-phenylalanine methyl ester WO 99/06431 WO 9906431PCTIUS98/15313 223 N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan- I -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan- I -yl)ethoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyL-4-[3(4-.methylpiperazin- I -yI)propoxy]- L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl.3-[2..(pyrrolidin. I -yI)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [3-(4-methylpiperazin- I -yl)propoxy]- L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-3 -[2-(morpholin-4-yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-proly..4- -methoxythien-2-yl)-4- hydroxypiperidin- I -yI]ethoxy} -L-phenylalanine- methyl ester N-(toluene-4-sulfonyl)-L-prolyl-3 -methylpiperidin-4-oxy)-D,L- phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-( I -methylpiperidin-4-oxy)-D,L- phenylalanine ,5-dimethyl)thiaprolyl-4-( I -methylpiperidin- 4-oxy)-L-phenylalanine ethyl ester N-(toluene-4-sul fonyl)-L-(, 1, -dioxothiomorpholin-3 -carbonyl)-4-( 1- methylpiperidin-4-oxy)-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(l 1, -dioxothiomorpholin-3-carbonyl)-4-( 1- methylpiperidin-4-oxy)-L-phenylalanine ,5 -dimethyl)thiaprolyl-4-( I -methylpiperidin- 4-oxy)-L-phenylalanine N-(ca-toluenesulfonyl)-L-prolyl-4-( I -methylpiperidin-4-oxy)-L- phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(tr-i fluoromethanesulfonyl)amino-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-N-(tri fluoromethanesulfonyl)amino-L phenylalanine WO 99/06431 WO 9906431PCTIUS98/1 5313 224 N-(toluene- 4 -sulfonyl)Lproly[-4N..(chloromethanesulfonyl)amino-L phenylalanine methyl ester N-(toluene-4-sulfonyl)-Lprolyi-4-N(vinyisulfonyl)amino-L phenylalanine methyl ester N-(to luene-4-sulfonyl)-L-prolyl-4-(N-tifluoromethanesulfonyl-N- isobutyl)amino-L-phenylalanine methyl ester N.-(toluene-4-sulfonyl)-L-pro IyI-4-N-(vinylsulfonyl)amino-L- phenylalanine N-(toluene-4-sulfonyl)-Lprolyl-4-[(N-benzylaminocarbony)methoxy]-L phenylalanine methyl ester N-(toluene- 4 sulfonylyLprolyi-4..(benzyloxycarbofly)rnethoxy]-L phenylalanine methyl ester N-(toluene 4 sulfonylLprolyl4-[(benzyloxycarbony)methoxy]-L phenylalanine N-(toluene- 4 -sulfony).Lprolyl..4-[(carboxy)methoxy]-L-phenyalaninfe N-(toluene-4-sulfonyl).L-prolyl-4-.[(carboxy)methoxy]-L-phenylalanine methyl ester N-(toluene- 4 -sulfonyl)..L.prolyl-4-[(aminocarbonyl)methoxy] -L- phenylalanine N-tlee4sloy)Lpoy--(Ntr-uyaioabn mtoy- L-phenylalanine N-(toluene-4-sulfonyl).L-prolyi-4. 2 4 -phenyl-4-hydroxypiperidin- 1- yl)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sul fonyl)-L-prolyl-4-[(piperidin-.I -ylcarbonyl)methoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-.[(N,N- diisopropylaminocarbonyl)methoxy]-Lphenylalanne methyl ester N-(toluene-4-sul fonyl)-L-prolyl-4-[(N,N- diisopropylaminocarbonyl)methoxy] -L-phenylalanine methyl ester N-(toluene- 4 -sufonyl)sarcosylD,L-4(amidino)phenylalaninfe N-(toluene- 4 -sulfonyl)sarcosyI.DL-4(aminocarbonyl)phenylalanfle WO 99/06431 WO 9906431PCT/US98/1 5313 225 N-tlee4sloy)Lpoy--Nmtyaeaio--hnllnn isopropyl ester N-(toluene- 4 -sulfonyl)-L-prolyl-4-(N.methylacetamido)Lphenylalanile N-(toluene-4-sulfonyl)-L-proly-4(N-methyltri fluoroacetamido)-L- phenylalanine methyl ester N-(to luene-4-sul fony)-L-(5,5-dim ctlhyl)thiaprolyl-4[3 N- dimethylamino)propoxy]-L-phenylalanine t-butyl ester N-(toluene- 4 -sulfonyl).Lproly[-L-4-7Vmethypiperdinoxy.. phenylalanine t-butyl ester N-(to luene-4-sufonyl)L(5-dim ethyl)thi apropyl L-(4- methylpiperidinoxy) phenylalanine t-butyl ester N-(toluene- 4 -sulfonyl)-L-prolyl..(4-phenyl).Lphenylalanine t-butyl ester N-(toluene-4-sul fonyl)-L-prolyl-(4-phenyl)-L-phenylalanine and pharmaceutically acceptable salts thereof as well as any of the ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester. 24. The method according to Claim 23 wherein said compound is: N-(toluene-4-sulfonyl)-L-prolyl-4- (N-tert-butoxylcarbonylglycyl) amino] L-phenylalanine. A pharmaceutical composition comprising a pharmnaceutically acceptable carrier and a therapeutically effective amount of one or more the compounds of the formula: WO 99/06431 PCT/US98/15313 226 R 3 O I II R'-SO 2 -N(R 2 )-CH-Q-CH-C-R 6 IA R where R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R' can form a heterocyclic or a substituted heterocyclic group; R' is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group; R 5 is -(CH 2 )x-Ar-R' where R 5 is selected from the group consisting substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, WO 99/06431 WO 9906431PCTIUS98/15313

227-- thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 -substituted alkyl, -OS(O) 2 -aryl, -OS (O) 2 -substituted aryl, -OS(O) 2 heteroaryl, -OS(O)2-substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS(O) 2 -substituted heterocycl ic, -NRS(O) 2 -NR- alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR- substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamnino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -SO,-substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryt, -S 0 2 -substituted heteroaryl, -SO 2 heterocyclic, SO--substituted heterocyclic and _SO 2 NRR where R is hydrogen or alkyl; alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR where R is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, WO 99/06431 WO 99/643 1PCT/1JS98/1 5313 228 aryl and heteroaryl; -NR'R' wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, ca rboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O)2-NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O).,-NR-substituted heteroaryl, WO 99/06431 PCT/US98/15313 229 -NRS(O),-NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SO,-substituted heteroaryl, -S02- heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; -alkoxy-NR"R" wherein each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, WO 99/06431 WO 9906431PCTIUS98/15313

230-- cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O)2-substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O),-substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O)2-NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylaniino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, _S2sbsiue heteroaryl, -S02- heterocyclic, -SO 2 sustituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyllalkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the WO 99/06431 WO 9906431PCTIUS98/15313 substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxyiheteroaryl, carboxyl-substituted heteroaryl, carboxyiheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteroayrloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonyl amino, -OS(O) 2 -alkyl, -OS(O) 2 substituted alkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -0S0 2 -NRR where R is hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O)2-substituted heteroaryl, -NRS(O) 2 heterocyclic, -NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional WO 99/06431 PCT/US98/15313

232-- blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -SO2-Substituted heteroaryl, -S02- heterocyclic, -S0 2 -substituted heterocyclic and -SO 2 NRR where R is hydrogen or alkyl; substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy- substituted saturated heterocyclic; -O-heterocyclic and -O-substituted heterocyclic; tetrazolyl; -NR-S0 2 -substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- WO 99/06431 PCT/US98/15313

233-- dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; amidine and amidine substituted with from I to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; where each is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea, then the other is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic; -NR 2 C(O)-R 8 where R 8 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 2 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -S0 2 -aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl or -S0 2 -alkyl; -NR'C(O)NR 9 R 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting WO 99/06431 PCT/US98/15313 234 of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic: -NR'C(O)OR 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; -aminocarbonyl-(N-formylheterocycyl); and -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; R 6 is selected from the group consisting of, hydroxy, 2,4-dioxo- tetrahydrofuran-3-yl (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O-(N-succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-P-yl, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, -NH(CH 2 )pCOOY where p is an integer of from 1 to 8 and Y is as defined above, -OCHNR 9 R' 0 where R 9 is selected from the group consisting of-C(O)-aryl and -C(O)-substituted aryl and R'O is selected from the group consisting of hydrogen and -CH 2 COOR" where R" is alkyl, and -NHSO 2 Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is -C(X)NR 7 wherein R 7 is selected from the group consisting of hydrogen and alkyl; and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof with the proviso that when R' is p-CH 3 R 6 is methoxy, Q is and R 2 and R 3 are joined to form a pyrrolidinyl group, then R 5 is not p-[-OCH2CHN(C 2 H)2]-benzyl-, p-[-OCHCH 2 N(isopropyl)2]-benzyl-, p- WO 99/06431 WO 9906431PCTIUS98/1 5313 235 [-OCH 2 CH 2 -1I-pyrrolidinyl)-benzyl-, p- [-OCH 2 CH 2 -1I-(4-pyrimidinyl)piper- azinyl]-benzyl-, p-[-OCH 2 CH 2 -N-moi-pholinyl)]-benzyl-, or p-[-OCH 2 CH 2 -N- piperidinyl)]-benzyl- under conditions wherein said compound binds to VLA-4. 26. The pharmaceutical composition according to Claim 13 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. 27. The pharmaceutical composition according to Claim 26 wherein R' is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n- butyl, 4-chiorophenyl, I -naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethyiphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, dichiorophenyl, 4-trifluoro methylphenyl, 3 ,4-dichlorophenyl, 3,4- dimethoxyphenyl, 4-(CH 3 C(O)NI--)phenyl, 4-trifluoromethoxyphenyl, 4- cyanophenyl, isopropyl, 3 ,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, butoxyphenyl, 4-nitrophenyl, 2-thienyl, I chloropyrazol-4-yl, phenethyl, I -N-methylimidazol-4-yl, 4-bromophenyl, 4- amidinophenyl, 4-methylamidinophenyl, 4-[CH 3 SC(=NI-)]phenyl, 5-chloro-2- thienyl, 2,5 -dichloro-4-thienyl, I -N-methyl-4-pyrazolyl, 2-thiazolyl, 1,3 ,4-thiadiazol-2-yl, 4-[H 2 NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2- fluorophenyl, 3 -fluorophenyl, 3 ,5-difluorophenyl, pyridin-3 -yl, pyrimidin-2- yl, 4-(3 '-dimethylamino-n-propoxy)-phenyl, and I -methylpyrazol-4-yl. 28. The pharmaceutical composition according to Claim 25 wherein R 2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, -(CH 2 2 -2-thienyl, and -(CH 2 2 29. The pharmaceutical composition according to Claim 25 wherein R' and R' together with the nitrogen atom bound to R 2 and the SO 2 group WO 99/06431 WO 9906431PCTIUS98/15313

236- bound to R' are joined to form a heterocyclic group or substituted heterocyclic group. The pharmaceutical composition according to Claim 25 wherein R 2 and R 3 together with the nitrogen atom bound to W( substituent and the carbon bound to the R 3 substituent form a heterocyclic group or a substituted heterocyclic group. 31. The pharmaceutical composition according to Claim 25 wherein R 3 is selected from the group consisting of methyl, phenyl, benzyl, diphenylmethyl, -CH 2 CH 2 -COOH, -C2 OOH, 2-amidoethyl, iso-butyl, t- butyl, -CH 2 O-benzyl and hydroxymethyl. 32. The pharmaceutical composition according to Claim 25 wherein Q is -C(O)NH- or -C(S)NH-. 33. The pharmaceutical composition according to Claim 25 wherein R 5 is selected from the group consisting of: 4-[NH 2 CH 2 C(O)NI--]benzyl, 4-[HOOCCH 2 CH 2 C(O)NH-]benzyl, 4-[-NI-C(O)CH 2 NHBoc]benzyl, 4-[-NHC(O)CH(CH 3 )NI-Boc]benzyl, 4-[NHC(O)CH(CH 2 4iNHBoc]benzyl, 4-[-N1IC(O)CH 2 NIIC(O)NH-3 methylphenyl]benzyl, 4-[-NHC(O)CH(NIlBoc)(CH 2 ),NHCbz]benzyl, 4-[-NI{C(O)CH 2 CH(C(O)0CH 2 4 )-NHCbz]benzyl, 4-4-benzyl, 4-[-NI{C(O)CH(CH 2 CH 2 CH 2 CH,NI{ 2 )NI{Boc]benzyl, 4-[H 2 NCH 2 CH 2 CH 2 C(O)NII-]benzyl, 4-(BocRNCH 2 CH 2 CH 2 C(O)NE--)benzyl, 4-[4CH 2 0CH 2 (BocHN)CHC(O)NH-]benzyl, 4-[CH 3 NHCH 2 CH 2 CH 2 C(O)NH-]benzyl, 4-(N-methylpiperidin-4-oxy)-benzyl, 4-[CH 3 N(Boc)CH 2 CH 2 CH 2 C(O)NII-]benzyl, CH 2 OCH 2 (H 2 N)CHC(O)NH-]benzyl, 4-[HO(O)C(Cbz-NH)CHCH 2 CH 2 C(O)NH-]benzyl, 4-[4CH 2 0(O)C(Cbz-NH)CHCH 2 CH 2 -C(O)NI{-]benzyl, 4-IIHO(O)C(NH 2 )CHCH-,CH 2 -C(O)NH-]benzyl, 4-[CH 3 (N-Boc)NCH 2 C(O)N14-]benzyl, 4-[CH 3 NH-CH 2 C(O)NI{-]benzyl, WO 99/06431 WO 9906431PCTIUS98/15313

237-- 4-[(CH 3 2 NCH 2 C(O)NH-]benzyl, 4-[--CH(COOH)4l]benzyl, 4-[2-carboxylphenyl-]-benzyl, 4-[2-carboxylmethylphenyl-]-benzyl 4-[4 CH 2 OC(O)NHCH 2 CH 2 NH-]benzy1, 4-N[-(S0 2 )CH3]- CH 2 CH 2 CH 2 N(CH 3 2 ]benzyl, 4.-t-butyl-O(O)CCH 2 -O-benzylNli]benzyl, 4-[NN-di(4-N.N-dimethylamino)benzyl)aminojbenzyl, 4-(2-formyl- 1,2,3 ,4-tetrahydroisoquino in-3-yI-CH 2 NI-)benzyl, 4-[-OCH 2 CH 2 1 '-pyrimidinyl)-piperazinyl]-benzyl, 4-[-OCH 2 CH 2 I -piperidinyl)-benzyl, 4-[-OCH- 2 CH 2 1 -pyrrolidinyl)]- benzyl, 4-[-OCH 2 CH 2 CH 2 -piperidinyl)]-benzyl, 4-[(CH 3 2 NCH 2 CH 2 CH 2 -O-]benzyl, 4-[(CH 3 2 NCH 2 CH 2 O-]-benzyl, 4-[-OCH 2 CH 2 CH 2 '-methylpiperazinyl))]-benzyl, 4-[-OCH 2 CH 2 CH 2 '-chlorophenyl)-piperazin- 1 -yl]-benzyl, 4+[OCH 2 CH 2 N(4 )CH 2 CH 3 ]-benzyl, 4-[-OCH 2 -3'-(N-Boc)-piperidinyl]- benzyl, 4-II-O-(3-(N-Boc)-piperidinyl]benzyl, 3-[-O-(N-methylpiperidin-4-yl]benzyl, 4-[-O-(N-methylpiperidin-4-yl]benzyl, 4-[di-iso-propylamino-CH 2 CH 2 -benzyl, 4- [N-3-methylbutyl-N-tri fluoro- methanesulfonyl)amino]benzyl, 4-[-OCH 2 CH 2 -(N-morpholinyl)]-benzyl, 4-[-OCII 2 CH(NHBoc)CH 2 cyclohexyl]-benzyl, 4-[OCH 2 CH 2 -(N-piperidinyl]- benzyl, 4-[-OCH 2 CLI 2 CH 2 -(4-m-chlorophenyl)-piperazin- l-yl] -benzyl, 4-[-OCH 2 CH 2 -(N-homopiperidinyl)-benzyl, 4- [-OCH 2 CH 2 N(benzy))2j-benzyI, 3-[-OCH 2 CH 2 CH 2 N(CH 3 )j-benzyl, 4-[-OCH 2 CH 2 N(C 2 H 5 2 ]-benzyl, 4- [-OCH 2 CH 2 CH 2 N(C 2 H)j-benzyl, 4-[-OCH 2 CH 2 N(C 2 H 5 2 ]-benzyl, 4-[-OCH 2 CH 2 CH 2 N(CH 3 )benzyl]-benzyl, 4-[2-(2-azabicyclo[3 .2.2]octan-2- yl)ethyl-O-]benzyl, [cyclopentylacetylenyl]-benzyl, '4]-benzyl, C-CH 2 -O-S(O) 2 -4 '-CH 3 -4]l-benzyl, C-CH 2 NHC(O)NE2]-benzyl, 4--=C-CH 2 '-COOCH 2 CH 3 ]-benzy1, C-CH(NH 2 )-Cyclohexyl]- beuzyl, 4-[-C-C-CH 2 -O-phenyl]-benzy1, 44[-C= C-CH 2 OCH3]-benzyl, 4--=C-CH 2 -C(O)0C 2 H 5 )phenyl]-benzyl, C- CH 2 CH(C(O)OCH 3 )jI-benzyl, C-CH 2 CH( NHC(O)CH 3 )C(O)OH]- benzyl, C-CH 2 NH--(4,5-dihiydro-4-oxo-5-phenyl-oxazol-2y1)]-benzyl, 4 [-OCH 2 CH 2 CH 2 -(N-morpholino)3-benzyl, 4-[-OCH 2 COOH]-benzyl, 4-fI-OCH 2 COO-t-butyl]-benzyl, 4- [-N(SO 2 CH 3 )(CH 2 3 -N(CH 3 )1-benzyl, WO 99/06431 WO 99/643 1PCT/US98/1 5313

238-- 4-[NIIS(O) 2 CF 3 ]-benzyl, 4-[-C(=NH)N}1 2 ]-benzyl, 4-[-NHSO 2 -CH 2 C1]- benzyl, 4-[-OCH 2 C(O)NH-benzyl]-benzyl, 4-[-OCH 2 C(O)O-benzyl]-benzyl, 4-[-OCH 2 C(O)OH]-benzyl, 4-[-OCH 2 CH 2 1-(4-hydroxy-4-(3-methoxypyrrol- 2-yl)-piperazinyl]-benzyl, 4-[-OCH 2 C(O)NH 2 I-benzyl, 4-[-OCH 2 C(O)NH-t- butyl]-benzyl, 4-[-OCH 2 CH 2 -1I-(4-hydroxy-4-phenyl)-piperidinyl]-benizyl, 4-I-NHSO 2 -CH=CH2]-benzyl, 4-[-NHSO 2 -CH 2 CH 2 C1]-benzyl, 4-benzyl- benzyl, 4-[-OCH 2 C(O)piperidin- 1 -yl]benzyl, 4-[-OCH 2 C(O)N(CI-(CH 3 2 )]benzyl, 4-amidinobenzyl, 4-acetamidobenzyl, 4-(N-methyl)acetamidobenzyl, 4(-NIIC(O)CH 2 N-HC(O)NH--fluorescin)benzyl, 4-(NHC(O)CH 2 CH(NH 2 )COOH, (1 -toluenesulfonylimidizol-4-yl)-methyl-, -NN-dimethylaminosulfonyl)-imidizol-4-yl]methyl-, 4-(N-toluenesulfonyl- amino)benzyl, and 4- [N-methyltri fluoroacetamido)phenyl. 34. The pharmaceutical composition according to Claim 25 wherein R 6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-ca-iso-propyl-4-p-methylcyclohexoxy, 2-p-isopropyl-4-P- methylcyclohexoxy, -NH 2 benzyloxy, -NI--CH 2 COOH, -NHCH 2 CH 2 COOH, -NH-adamantyl, -NHCH 2 CH 2 COOCH 2 CH 3 -NHSO 2 -P-CH 3 -NHOR 8 where R' is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), -en-3-p-yl, -OCH 2 -OC(O)C(CH 3 3 -O(CH 2 ),,NHC(O)W where z is I or 2 and W is selected from the group consisting of pyrid-3-yl, N- methylpyridyl, and N-methyl-I ,4-dihydro-pyrid-3-yl, -NR where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH2C(O)OCH 2 CH 3 The pharmaceutical composition according to Claim 25 wherein said compound is selected from the group consisting of. N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonylglycyI)amino]- L-phenylalanine N-(toluene-4-sul fonyl)-L-pro lyl [(glycyl) amino] -L-phenylal anine WO 99/06431 WO 9906431PCTIUS98/1 5313

239-- N-(toluerie-4-sulfonyl)-L-prolyl-4-[3 -(carboxy)propionamido]-L-phenyl- alanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-L- alanyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylcarbonyl-D- alanyl)amino] -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxylearbonyl-D- phenylalanyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- (fluorescein)thiouriedo]acetamido -L-phenylalanine N-(toluene-4-sulfonyl)-L-pro Iyl-4-[(N-tert-butoxylcarbonylglycyl)amino]- L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- methylphenyl)uriedo]acetamido -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(Na-tert-butoxylcarbonyl-NE- carbobenzyloxy-L-iysyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[y-(a-benzyl-Na-carbobenzyloxy-L- aspartyl)amino]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[(Na-tert-butoxylcarbonyl-L- lysyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[y -(L-aspartyl)amino] -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-(4-aminobutyramido)-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-tert-butoxyl- carbonylamino)butyramido]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-methylamino)butyramido]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[4-(N-tert-butoxylcarbonyl-N- methylamino)butyramido] -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(O-benzyl)-L-seryl)amino]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[5-(D,L-glutamyl)amino]-L-phenylala- nine WO 99/06431 WO 9906431PCTIUS98/15313 240 N-(toluene-4-sulfonyl)-L-prolyl-4-[(N-tert-butoxyl- carbonylsarcosyl)amino]-L-phenylalanine ,5-dimethyl)thiaprolyl-4- [(N-tert-butoxyl- carbonylsarcosyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[(sarcosyl)amino]-L-phenylaanine ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- [(sarcosyl)amino]-L-phenylalanine ,5-dimethyl)thiaprolyl-4-[(sarcosyl)amino]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [(NN-dimethylglycyl)amino]-L- phenylalanine ,5-dimethyl)thiaprolyl-4-[(N,N- dimethylglycyl)amino]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-(a-carboxybenzyloxy)-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(carboxy)phenyl]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(methoxycarbonyl)phenyl]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- carbobenzyloxyamino)ethyl] amino I -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- carbobenzyloxyamino)ethyl] amino I -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-4- {N-[3-(NN-dimethylamino)propyl]- N-[trifluoromethanesul fonyl] amino)} -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-4- [4-[(tert- butoxycarbonyl)methoxylbenzyl] amino I -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-4- {NN-di[4-(NN- dimethylamino)benzyll amino)} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-4- [(2-formyl- 1,2,3,4- tetrahydroisoquinolin-3-yl)methyl] amino)} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy-L- phenylalanine WO 99/06431 WO 9906431PCTIUS98/15313 241 N-(toluene-4-sulfonyl)-N-methyl-L-serinyl-4-[3-(N,NV-dimethylarnino- propoxy]-L-phenylalanine methyl ester ,5-dimetliyl)thiaprolyl-4-[2-(N,N- dimethylamino)ethoxy]-L-phenylalanine NV-(toluene-4-sulfonyl)-L-prolyl-4-[2-(NN-dimethylamino)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N-ethyl-N-phenylamino)ethoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(N,N-diisopropylamino)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3 -cyclohexyl-2 -(N-tera- butoxycarbonylamino)propoxy]-L-phenylalanine methyl ester N-(thiophene-2-sulfonyl)-L-prolyl-4-[3-(N,N-dimethylamino)propoxy]-L- phenylalanine N-(5-chlorothiophene-2 -sul fonyl)-L-prolyl-4- [3 -(NN-dimethyl amino)- propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(NN-diethylamino)ethoxy]-L- phenylalanine N-(2,5-dichlorothiophene-3-sulfonyl)-L-proly-4- dimethylamino)propoxy]-L-phenylalanine 1 -methylpyrazo le-4- sul fonyl)-L-pro lyl-4- [3 -(N,N-di methyl amino)- propoxy]-L-phenylalanine N-(toluene-4-sul fonyl) -L-prolyl-4- [3 -(NN-di ethyl amino)propoxy] -L- phenylalanine methyl ester N-(toluene-4-sul fonyl)-L-prolyl-3 3-(N,N-dimethylamino)propoxy] -L- phenylalanine N-(thiazole-2-sul fonyl)-L-prolyl-4- [3-(NN-dimethylamino)propoxy]-L- phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-[3-(N-methyl-N- benzylamino)propoxy] -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [3 -(N,N-diethylamino)propoxy]-L- phenylalanine WO 99/06431 WO 9906431PCT[US98/15313 242 N-(toluene-4-sulfonyl)-L-prolyl-4-[3 -(N-methyl-N- benzylamino)propoxy]-L-phenylalanine methyl ester 1 -methylimidazole-4-sulfonyl)-L-prolyl-4-[3-(NN-dimethylamino)- propoxy]-L-phenylalanine N-(2-methylthiadiazole-5-sulfonyl)-L-prolyl-4-[3 -(N,N-dimethylamino)- propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-thiaprolyl-4-[3 -(NN-dimethylamino)propoxy]- L-phenylalanine ,5-dimethyl)thiaprolyl-4- dimethylamino)propoxy] -L-phenylalanine methyl ester N-(toluene:-4-sulfonyl)-L-(3 ,3-dimethyl)prolyl-4-[3-(N,N- dimethylamino)propoxy] -L-phenylalanine ,5-dimethyl)thiaprolyl-4-[3 dimethylamino)propoxy]-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- [2-(2-azabicyclo[3 .2.2]octan-2- yl)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-4-[3 -(NN- dimethylamino)propoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [2-(2-azabicyclo[3 .2.2 ]octan-2- yl)ethoxy]-L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-(cyclopentyl)ethynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4- 2-[4- (phenyl)phenyl] ethynyl -D,L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3 -(toluene-4- sulfonyloxy)prop- I -ynyl]-D,L-phenylaianine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[3 -(ureido)prop- I -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)-D ,L-phenylalanyl-4- ethoxycarbonylphenoxy)prop- I -ynyl]-D,L-phenylalanine N-(toluene-4-sulfonyl)-D,L-phenylalanyl-4-[2-( I -aminocyclohex- I yI)ethynyl]-D,L-phenylalanine WO 99/06431 WO 99/643 1PCTIUS98/15313 243 N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(phenoxy)prop- 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-[3-(phenoxy)prop. 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyI-4-[3-.(methoxy)prop. 1 -ynyl]-D,L- phenylalanine N-(toluene-4-sul fonyl)sarcosyl-4-[13 -(methoxy)prop- I -ynyl J-D,L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- [3-(4-ethoxycarbonylphenoxy)prop- I1- ynyl]-D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl[.3-(4-ethoxycarbonylphenoxy)prop 1- ynyl]-D,L-phenylalanine N-(toluene-4-sul fonyl)-L-prolyl-4-[4,4-di(methoxycarbonyl)but- I-ynyl]- D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-[4,4-di(methoxycarbonyl)but- I-ynyl]- D,L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-(4.acetamido-4carboxybut- I-ynyl)- D,L-phenylalanine N-(toluene- 4 -sulfonyI)sarcosyl-4-(4-acetamido-4carboxybut- I-ynyl)- D,L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- f 3-[(4,5-dihydro-4-oxo-5- phenyloxazo 1-2 -yl)amino] prop- 1 -ynyl) -D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4- 5-dihydro-4-oxo-5-phenyloxazol- 2-yl)amino]prop- Il-ynyl -D,L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4-[2-(carboxy)phenoxy-L-phenylaanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- 2 -14-(pyrimidin-2-yl)piperazin-1- yl]ethoxy} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[3-(piperidin I -yl)propoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(pyrroI din- 1 -yI)ethoxy]-L- phenylalanine WO 99/06431 WO 99/643 1PCT/US98/15313

244-- N-(to luene-4-sul fonyl)-L-prolyl-4- 3-(piperi din- I -yl)propoxy]-L- phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4- 3-[4-(3-chlorophenyl)piperazin- 1 yllpropoxy} -L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[( 1 -tert-butoxycarbonylpiperidin-3 yl)methoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[2(morpholin4yl)ethoxy-L- phenylalanine N-(toluene-4-sul fonyl)-L-pro lyl-4- -tert-butoxycarbonylpiperidin-3- yl)methoxy]-L-phenylaianine N-(to Iuene-4-su Lfonyl)-L-pro Iyl [2-(piperi din- 1 -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-pro lyl-4- (3 -[4-(3-chlorophenyl)piperazin- 1 yl]propoxy} -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan-1 -yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-[2-(azepan- 1 -yl)ethoxy]-L- phenylalanine methyl ester N-tlee4sloy)Lpoll4[-4mtypprzn I -yl)propoxy]- L-phenylalanine methyl ester N-(to luene-4-sulfonyl)- L-pro lylI- 3 [2 -(pyrroli din- I -yl)ethoxy]-L- phenylalanine N-tlee4sloy)Lpoll4[-4mtypprzn I -yl)propoxy]- L-phenylalanine N-(toluene-4-sulfonyl)>L-prolyl.3 -[2-(morpholin-4-yl)ethoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4- {2-[4-(3-methoxythien-2-yl)-4- hydroxypipenidin- I -yl]ethoxy -L-phenylalanine methyl ester N-(toluene-4-sulfonyl)Lproly-3 -methylpiperidin-4-oxy)-D,L- phenylalanine N-(toluene-4-sulfonyl)iLprolyl-4-( I -methylpiperidin-4-oxy)-D,L- phenylalanine WO 99/06431 WO 99/643 1PCTIUS98/15313 245 N-(toluene-4-sulfonyl)L(5,5-dimethyl)thiaproly1-4-(I -methylpiperidin- 4 -oxy)-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(, 1, -dioxothiomorpholin-3-carbonyl)4-( 1- methylpiperidin-4-oxy)-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(, 1, -dioxothiomorpholin-3-carbonyl)y4.( 1- methylpiperidin-4-oxy)-L..phenylalanine N-(toluene- 4 -sufonyl)L(5dimethyl)thiaprolyl4( 1 -methylpiperidin- 4 -oxy)-L-phenylalanine N-(a-toluenesulfonyl)-LprolyJ-4( 1 -methylpiperidin-4-oxy)-L- phenylalanine ethyl ester N-(toluene-4-sulfonyI)-LprolyI4-N.(ti fluoromethanesulfonyl)amino-L phenylalanine methyl ester N-(to Iuene-4-sulfonyl)-L-pro lyl-4-N-(tri fluoromethanesulIfonyl)amino-L- phenylalanine N-(toluene- 4 sufonyl-Lprolyl-4N(choromethalesujfonyl)amino-L- phenylalanine methyl ester N-(toluene- 4 -sulfonyl)L.prolyl4-N(vinylsulfony)amino.L- phenylalanine methyl ester N-(tol-uene-4-sulfonyl)Lprolyl4(N-tifluoromethanesul fonyl-N- isobutyl)amino-L-phenylalanine methyl ester N-(toluene-4-sulfonyl )-L-prolyl-4-N-(vinylsul fonyl)ami no- L- phenylalanine N-tlee4sloy)Lpoy--[Nbnyaioahn~ehx]L phenylalanine methyl ester N-tlee4sloy)Lpoy-4[bnyoyabn~ehx]L phenylalanine methyl ester N-tlee4sloy)Lpoy-4[bnyoyabn~ehx]L phenylalanine N-tlee4sloy)Lpoy--[croymtoy--hnllnn N-(toluene-4-sulfonyl)-L-prolyl-4.[(carboxy)methoxy]-L-phenylalanine methyl ester WO 99/06431 WO 9906431PCTIUS98/1 5313

246-- N-(toluene- 4 -sulfonyl)-Lpro I y1-4-(aminocarbonyl)methoxy] L- phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl-4[(N-ert.butylaminocabony)methoxy]- L-phenylalanine N-(toluene- 4 -sulfonyl)-L-prolyl4[2(4pheny-4-hydroxyiperidin 1- yl)ethoxy]-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-proy-4-[(piperidin- I -ylcarbonyl)methoxy]-L- phenylalanine N-(toluene-4-sulfonyl)-L-proly-4-[(N,N- diisopropylaminocarbonyl)methoxy-L-phenylaanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl.4-(N,Nv di isopropy lam inocarbonyl)methox y LphenyIl ai ne methyl ester 4 -sulfonyl)sarcosylD,L-4(amidino)phenylalanine N-(toluene- 4 -sulfonyl)sarcosy[.DL..4.(aminocarbonyl)phenylaianine N-(toluene-4-sul fonyl)-L-prolyl-4-(N-methylacetam ido)-L-phenylalanine isopropyl ester N-(toluene- 4 -sulfonyl)-L-proly1-4(Nmethylacetamido)-Lphenylalanine N-(toluene-4-sulfonyl)-L-prolyl-4-(N-methyltri fluoroacetamido)-L- phenylalanine methyl ester ,5-dimethyl)thiaprolyl-4-[3-(NN- dimethylamino)propoxy]-L-phenylalanine t-butyl ester N- (to luene-4- sulI fonyl)- L-prolIyl -L-4-(N-methy lpiperi dinoxy)- phenylalanine t-butyl ester N-(toluene-4-sul fonyl)-L-(5 ,5-dimethyl)thiapropyl-L-(4- methylpiperidinoxy) phenylalanine t-butyl ester N-(toluene-4-sul fonyl)-L-prolyl-(4-phenyl)-L-phenylalanine t-butyl ester N-(toluene-4-sul fonyl)-L-prolyl-(4-phenyl)-L-phenylalanine and pharmaceutically acceptable salts thereof as well as any of the ester compounds recited above wherein one ester is replaced with another ester WO 99/06431 PCT/US98/15313 247 selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester 36. A method for the treatment of an inflammatory disease in a patient mediated by VLA-4 which methods comprise administering to the patient the pharmaceutical composition of Claim 37. The method according to Claim 36 wherein said inflammatory disease is selected from the group consisting of asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetis), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.