AU8678698A - Compounds which inhibit leukocyte adhesion mediated by vla-4 - Google Patents

Description

WO 99/06433 PCT/US98/15952 -1 5 COMPOUNDS WHICH INHIBIT LEUKOCYTE ADHESION MEDIATED BY VLA-4 CROSS-REFERENCE TO RELATED APPLICATIONS 10 This application claims the benfit of U.S. Provisional Application No. 60/ , , which was converted pursuant to 37 C.F.R. §1.53(c)(2)(i) from U.S. Patent Application No. 08/904,416, filed July 31, 1997, the disclosure of which is incorporated by reference in its entirety. 15 BACKGROUND OF THE INVENTION Field of the Invention 20 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 25 application as superscript numbers: Hemler and Takada, European Patent Application Publication No. 330,506, published August 30, 1989 30 2 Elices, et al., Cell, 60:577-584 (1990) Springer, Nature, 346:425-434 (1990) 4 Osborn, Cell, 62:3-6 (1990) 35 S Vedder, et al., Surgery, 106:509 (1989) 6 Pretolani, et al., J. Exp. Med., 180:795 (1994) WO 99/06433 PCT/US98/15952 -2 Abraham, et al., J. Clin. Invest., 93:776 (1994) 8 Mulligan, et al., J. Immunology, 150:2407 (1993) 5 9 Cybulsky, et al., Science, 251:788 (1991) o10 Li, et al., Arterioscler. Thromb., 13:197 (1993) 11 Sasseville, et al., Am. J. Path., 144:27 (1994) 10 12 Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993) 13 Burkly, et al., Diabetes, 43:529 (1994) 15 14 Baron, et al., J. Clin. Invest., 93:1700 (1994) 15 Hamann, et al., J. Immunology, 152:3238 (1994) 16 Yednock, et al., Nature, 356:63 (1992) 20 17 Baron, et al., J. Exp. Med., 177:57 (1993) 18 van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991) 25 19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993) 20 Elices, et al., J. Clin. Invest., 93:405 (1994) 21 Postigo, et al., J. Clin. Invest., 89:1445 (1991) 30 22 Paul, et al., Transpl. Proceed., 25:813 (1993) 23 Okarhara, et al., Can. Res., 54:3233 (1994) 35 24 Paavonen, et al., Int. J. Can., 58:298 (1994) 25 Schadendorf, et al., J. Path., 170:429 (1993) 26 Bao, et al., Diff., 52:239 (1993) 40 27 Lauri, et al., British J. Cancer, 68:862 (1993) 28 Kawaguchi, et al., Japanese J. Cancer Res., 83:1304 (1992) WO 99/06433 PCT/US98/15952 -3 29 Kogan, et al., U.S. Patent No. 5,510,332, issued April 23, 1996 30 International Patent Appl. Publication No. WO 96/01644 5 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. 10 State of the Art VLA-4 (also referred to as a 4 1 integrin and CD49d/CD29), first identified by Hemler and Takadal is a member of the P1 integrin family of cell surface receptors, each of which comprises two subunits, an a chain and a P chain. VLA-4 contains an a4 chain and a P1 chain. There are at least nine P1 integrins, all sharing the same P1 15 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 20 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 25 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 30 leukocytes migrate across the blood vessel wall to enter the injured site and release WO 99/06433 PCT/US98/15952 -4 chemical mediators to combat infection. For reviews of adhesion receptors of the immune system, see, for example, Springer 3 and Osborn 4 . Inflammatory brain disorders, such as experimental autoimmune 5 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 10 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 15 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 6-8 , Alzheimer's disease, atherosclerosis 9 -10, AIDS dementia", diabetes 12

-

" 14 (including acute juvenile onset diabetis), inflammatory bowel 1510-17 disease 5 (including ulcerative colitis and Crohn's disease), multiple sclerosis' , 20 rheumatoid arthritis 8- 21 , tissue transplantation 2 2 , tumor metastasis 23- 28 , 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. 25 In view of the above, assays for determining the VLA-4 level 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

',

3 0 . The 30 present invention addresses these and other needs.

WO 99/06433 PCT/US98/15952 -5 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 5 example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC0 of about 15 uM or less (as measured using the procesure shown in Example 46 below) which compounds are defined by formula I below: 10 R 3 O R'-S0 2 -N(R)-C-Q-CH-C-OH I I I H R 5 15 where R' is selected from the group consisting of alkyl, substituted alkyl, aryl, 20 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, and substituted heteroaryl, 25 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 hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 2 and R 3 together with 30 the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form an unsaturated heterocyclic group or a unsaturated substituted heterocyclic group; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, WO 99/06433 PCT/US98/15952 -6 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;

R

5 is -CH 2 X where X is selected from the group consisting of hydrogen, 5 hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, 10 substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the further provisos that: A. R 5 is not -(CH 2 )x-Ar-R 5 ' where R 5 ' is -O-Z-NRR 8 ' or -O-Z-R 1 2 wherein

R

8 and R 8 ' are independently selected from the group consisting of hydrogen, alkyl, 15 substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic, and R 8 and R 8 ' can be joined to form a heterocycle or a substituted heterocycle, R1 2 is selected from the group consisting of heterocycles and substituted heterocycles, and Z is selected from the group consisting of -C(O)- and -SO 2 -, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, 20 x is an integer of from 1 to 4; B. R 5 is not -(CH 2 )x-Ar-R 5 ' where R 5 ' is -NR1 2 C(Z')NRSR"' or -NR1 2 C(Z)R13 wherein Z' is selected from the group consisting of oxygen, sulfur and

NR

12 , R1 2 is selected from the group consisting of hydrogen, alkyl and aryl, R and R 8 ' are independently selected from the group consisting of hydrogen, alkyl, substituted 25 alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z' is oxygen, at least one of R 8 and R 8 ' is sustituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, or substituted heterocyclic or

R

8 and R 8 ' can be joined to form a saturated heterocycle other than morpholino or 30 thiomorpholino, a saturated substituted heterocycle or a saturated/unsaturated WO 99/06433 PCT/US98/15952 -7 heterocycle having an amino group substituted with an alkoxycarbonyl substituent, and further provided that when Z' is sulfur, at least one of R s and R 8 ' is a group other than aryl, substituted aryl, heteroaryl or substituted heteroaryl, and RI 3 is selected from the group consisting of substituted heterocycles and saturated heterocycles other than 5 morpholino and thiomorpholino, substituted heterocycles, Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer of from 1 to 4; C. R 5 is not -ALK-X' where ALK is an alkyl group of from 1 to 10 carbon atoms attached via a methylene group (-CH 2 -) to the carbon atom to which it is 10 attached; X' is selected from the group consisting of substituted alkylcarbonylamino, substituted alkenylcarbonylamino, substituted alkynylcarbonylamino, heterocyclylcarbonylamino, substituted heterocyclylcarbonylamino, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, 15 substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic, substituted saturated heterocyclic, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted heterocycloxy, substituted thioalkyl, substituted 20 thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, guanidino, amidino, alkylamidino, thioamidino, halogen, cyano, nitro, -OS(O) 2 -alkyl, OS(O) 2 -substituted alkyl, -OS(O) 2 -cycloalkyl, -OS(O) 2 -substituted cycloalkyl, -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, -NRS(O) 2 -alkyl, 25 NRS(O) 2 -substituted alkyl, -NRS(O) 2 -cycloalkyl, -NRS(O) 2 -substituted cycloalkyl, 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-cycloalkyl, -NRS(O) 2

-NR

substituted cycloalkyl, -NRS(O) 2 -NR-aryl, -NRS(O) 2 -NR-substituted aryl, -NRS(O) 2 30 NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, - WO 99/06433 PCT/US98/15952 -8

NRS(O)

2 -NR-substituted heterocyclic where R is hydrogen or alkyl, -S(O) 2 -alkyl, S(O) 2 -substituted alkyl, -S(O) 2 -aryl, -S(O) 2 -substituted aryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 -heterocyclic, -S(O) 2 -substituted heterocyclic, mono- and di-(substituted alkyl)amino, N,N-(alkyl, substituted 5 alkyl)amino, N,N-(aryl, substituted alkyl)amino, N,N-(substituted aryl, substituted alkyl)amino, N,N-(heteroaryl, substituted alkyl)amino, N,N-(substituted heteroaryl, substituted alkyl)amino, N,N-(heterocyclic, substituted alkyl)amino, N,N-N,N (substituted heterocyclic, substituted alkyl)amino, mono- and di-(heterocyclic)amino, mono- and di-(substituted heterocyclic)amino, N,N-(alkyl, heterocyclic)amino, N,N 10 (alkyl, substituted heterocyclic)amino, N,N-(aryl, heterocyclic)amino, N,N-(substituted aryl, heterocyclic)amino, N,N-(aryl, substituted heterocyclic)amino, N,N-(substituted aryl, substituted heterocyclic)amino, N,N-(heteroaryl, heterocyclic)amino, N,N (heteroaryl, substituted heterocyclic)amino, N,N-(substituted heteroaryl, heterocyclic)amino, and N,N-(substituted heteroaryl, substituted heterocyclic)amino; 15 D. R 5 is not -(CH 2 )x-Ar-R" where R 5 " is a substituent selected from the group consisting of: (a) 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, 20 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 25 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, heteraryloxy, substituted heteroaryloxy, 30 heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, WO 99/06433 PCT/US98/15952 -9 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, -OSO 2 -NRR, -NRS(O) 2 -alkyl, NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 5 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, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono 10 and di-arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted 15 heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl groups substituted with -SO2-alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO2 substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO2 20 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; (b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR 23 where R 23 is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, (c) aryl and heteroaryl; 25 (d) -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 or substituted heterocyclic and with the further proviso that when R' is 30 substituted alkyl at least one of the substituents on the substituted alkyl moiety is WO 99/06433 PCT/US98/15952 -10 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, 5 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, 10 thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, 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 15 heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -OSO 2 -NRR, 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, 20 -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2

-NR

substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-(substituted aryl)amino, mono- and di-heteroarylamino, mono- and di-(substituted heteroaryl)amino, mono- and di heterocyclic amino, mono- and di-(substituted heterocyclic) amino, unsymmetric di 25 substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like), and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -SO2-substituted alkyl, -SO 2 30 alkenyl, -SO2-substituted alkenyl, -SO 2 -cycloalkyl, -SO2-substituted cycloalkyl, -S02- WO 99/06433 PCT/US98/15952 -11 aryl, -SO2-substituted aryl, -SO 2 -heteroaryl, -S0 2 -substituted heteroaryl, -SO 2 heterocyclic, -SO 2 -substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; (e) -alkoxy-NR"R" wherein each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted 5 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, 10 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, 15 guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, 20 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(0)2 heterocyclic, -OS(0) 2 -substituted heterocyclic, -OS0 2 -NRR, -NRS(O) 2 -alkyl, NRS(O) 2 -substituted alkyl, -NRS(0) 2 -aryl, -NRS(0) 2 -substituted aryl, -NRS(0) 2 heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS(0) 2 25 substituted heterocyclic, -NRS(0) 2 -NR-alkyl, -NRS(0) 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(0) 2 -NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono and di-arylamino, mono- and di-(substituted arylamino), mono- and di-heteroarylamino, 30 mono- and di-(substituted heteroaryl)amino, mono- and di-heterocyclic amino, mono- WO 99/06433 PCT/US98/15952 -12 and di-(substituted heterocyclic) amino, and unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic; substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional 5 blocking groups (such as Boc, Cbz, formyl, and the like), and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -S0 2 -aryl, -SO 2 substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -S0 2 -heterocyclic, -SO 2 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; 10 (f) 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, 15 alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; (g) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy-substituted saturated heterocyclic; (h) -O-heterocyclic and -O-substituted heterocyclic; (i) tetrazolyl; 20 (j) -NR-SO 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, 25 alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; (1) substituted alkoxy with the proviso that the substitution on the alkyl moiety of 30 said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclyl, WO 99/06433 PCT/US98/15952 -13 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, 5 alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; (m) amidine and amidine substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; (n) -C(O)NR"R' where each R"' is independently selected from the group 10 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 R'" is unsaturated heterocyclic, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, 15 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 R' is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, 20 substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic; (o) -NR 22

C(O)-R"

8 where R 1 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 2 is alkyl, 25 substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; (p) -SO 2 -aryl, -SO 2 -substituted aryl, -S0 2 -heteroaryl, -SO 2 -substituted heteroaryl or -SO 2 -alkyl; (q) -NR'C(O)NR"R 9 wherein R' is selected from the group consisting of alkyl, 30 substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, WO 99/06433 PCT/US98/15952 -14 substituted heteroaryl, heterocyclic and substituted heterocyclic and each R1 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: 5 (r) -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 RI 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and 10 substituted heterocyclic; (s) -aminocarbonyl-(N-formylheterocylcyl); and (t) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, and E. When R 3 is other than H, R 5 is not -(CH 2 )x-Ar-R" where R 5 " is substituted alkenyl or substituted alkynyl with the proviso that at least one of the 15 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 20 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, 25 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, 30 cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, WO 99/06433 PCT/US98/15952 -15 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, -OSO 2 -NRR, -NRS(O) 2 -alkyl, 5 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 10 heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono and di-arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, 15 substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO2 20 substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO2 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; and pharmaceutically acceptable salts thereof and still further with the following provisos excluding the following compounds A. when R 1 and R 2 are joined together with the SO 2 and nitrogen atom to which 25 they are attached respectively to form a benzoisothiazolone heterocyclic ring, R is hydrogen, and Q is -C(O)NH-, then R 5 is not benzyl; and B. when R 1 is p-methylphenyl, R 2 is methyl, R 3 is hydrogen, Q is

-C(O)NCH

3 -, then R 5 is not benzyl.

WO 99/06433 PCT/US98/15952 -16 In another embodiment, the compounds of this invention can also be provided as prodrugs which convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid in the compound of formula I is modified into a group which, in vivo, will convert to the 5 carboxylic acid (including salts thereof). In a particularly preferred embodiment, such prodrugs are represented by compounds of formula IA:

R

3 O II 10 R'-SO 2

-N(R

2

)-C-Q-CH-C-R

6 IA I I H R 15 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; 20 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; 25 R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R form an unsaturated heterocyclic group or a unsaturated substituted heterocyclic group; 30 Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; WO 99/06433 PCT/US98/15952 -17

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-3-3-yl, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, -NH(CH 2 )pCOOY where p is an 5 integer of from 1 to 8 and Y is as defined above, -OCH2NR 9 Ro where R 9 is selected from the group consisting of -C(O)-aryl and -C(O)-substituted aryl and R l 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 10 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;

R

5 is -CH 2 X where X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, 15 carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, 20 heterocyclic and substituted heterocyclic with the further provisos that: A. R 5 is not -(CH 2 )x-Ar-R 5 ' where R 5 ' is selected from the group consisting of -O-Z-NRR 8 ' and -O-Z-R 12 wherein R 8 and R 8 ' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted 25 cycloalkyl, heterocyclic, substituted heterocyclic, and where R 8 and R 8 ' are joined to form a heterocycle or a substituted heterocycle, R 1 2 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO 2 -, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, 30 x is an integer of from 1 to 4; WO 99/06433 PCT/US98/15952 -18 B. R 5 is not -(CH2)x-Ar-R 5 ' where R 5 ' is selected from the group consisting of -NR 12 C(Z')NRR"' and -NR'12C(Z')R 1 3 wherein Z' is selected from the group consisting of oxygen, sulfur and NR 12 , R 12 is selected from the group consisting of hydrogen, alkyl and aryl, R 8 and R 8 ' are independently selected from the group 5 consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z' is oxygen, at least one of R and R 8 ' is sustituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, substituted heterocyclic or R 8 and R 8 ' can be joined to form a 10 saturated heterocycle other than morpholino or thiomorpholino, a saturated substituted heterocycle or a saturated/unsaturated heterocycle having an amino group substituted with an alkoxycarbonyl substituent, and further provided that when Z' is sulfur, at least one of R 8 and R 8 ' is a group other than aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R' 3 is selected from the group consisting of substituted heterocycles and 15 saturated heterocycle other than morpholino and thiomorpholino, Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer of from 1 to 4; C. R 5 is not -ALK-X' where ALK is an alkyl group of from 1 to 10 carbon atoms attached via a methylene group (-CH 2 -) to the carbon atom to which it is 20 attached; X' is selected from the group consisting of substituted alkylcarbonylamino, substituted alkenylcarbonylamino, substituted alkynylcarbonylamino, heterocyclylcarbonylamino, substituted heterocyclylcarbonylamino, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, 25 substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic, substituted saturated heterocyclic, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted heterocycloxy, substituted thioalkyl, substituted 30 thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, WO 99/06433 PCT/US98/15952 -19 guanidino, amidino, alkylamidino, thioamidino, halogen, cyano, nitro, -OS(O) 2 -alkyl, OS(O) 2 -substituted alkyl, -OS(O) 2 -cycloalkyl, -OS(O) 2 -substituted cycloalkyl, -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, 5 -OSO 2 -NRR, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -cycloalkyl,

-NRS(O)

2 -substituted cycloalkyl, -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-cycloalkyl, -NRS(O) 2 -NR-substituted cycloalkyl, -NRS(O) 2 -NR-aryl, 10 -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, -S(O) 2 -alkyl, -S(O) 2 -substituted alkyl, -S(O) 2 -aryl, -S(O) 2 substituted aryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 heterocyclic, -S(O) 2 -substituted heterocyclic, mono- and di-(substituted alkyl)amino, 15 N,N-(alkyl, substituted alkyl)amino, N,N-(aryl, substituted alkyl)amino, N,N (substituted aryl, substituted alkyl)amino, N,N-(heteroaryl, substituted alkyl)amino, N,N-(substituted heteroaryl, substituted alkyl)amino, N,N-(heterocyclic, substituted alkyl)amino, N,N-N,N-(substituted heterocyclic, substituted alkyl)amino, mono- and di (heterocyclic)amino, mono- and di-(substituted heterocyclic)amino, N,N-(alkyl, 20 heterocyclic)amino, N,N-(alkyl, substituted heterocyclic)amino, N,N-(aryl, heterocyclic)amino, N,N-(substituted aryl, heterocyclic)amino, N,N-(aryl, substituted heterocyclic)amino, N,N-(substituted aryl, substituted heterocyclic)amino, N,N (heteroaryl, heterocyclic)amino, N,N-(heteroaryl, substituted heterocyclic)amino, N,N (substituted heteroaryl, heterocyclic)amino, and N,N-(substituted heteroaryl, substituted 25 heterocyclic)amino; and D. R 5 is not -(CH 2 )x-Ar-R 5 " where R 5 " is a substituent selected from the group consisting of: (a) substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of 30 alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, WO 99/06433 PCT/US98/15952 -20 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, 5 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, 10 cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, 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, -NRS(O) 2 -alkyl, 15 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 20 heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono and di-arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, 25 substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl groups substituted with -SO2-alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -SO 2 substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -S0 2 -aryl, -SO 2

-

WO 99/06433 PCT/US98/15952 -21 substituted aryl, -SO 2 -heteroaryl, -SO2-substituted heteroaryl, -S0 2 -heterocyclic, -S02 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; (b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR 23 where R 23 is alkyl, substituted alkyl, 5 cycloalkyl, aryl, heteroaryl or heterocyclic, (c) aryl and heteroaryl; (d) -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 10 proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic or 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, 15 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, 20 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, heteraryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, 25 oxycarbonylamino, oxythiocarbonylamino, -OS(0) 2 -alkyl, -OS(0) 2 -substituted alkyl, OS(0) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, -OS(0) 2 -substituted heteroaryl, -OS(0) 2 -heterocyclic, -OS(0) 2 -substituted heterocyclic, -OSO 2 -NRR, 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(O) 2 -heterocyclic, 30 -NRS(0) 2 -substituted heterocyclic, -NRS(0) 2 -NR-alkyl, -NRS(0) 2 -NR-substituted alkyl, WO 99/06433 PCT/US98/15952 -22

-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, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-(substituted aryl)amino, mono- and 5 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups 10 blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -SO2-substituted alkyl, -S02 alkenyl, -SO2-substituted alkenyl, -S0 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO2 aryl, -SO 2 -substituted aryl, -S0 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO2 heterocyclic, -SO2-substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; 15 (e) -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 20 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, 25 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, 30 cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, WO 99/06433 PCT/US98/15952 -23 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, -OSO 2 -NRR, -NRS(O) 2 -alkyl, 5 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 10 heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono and di-arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, 15 substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -SO2-substituted alkyl, -S0 2 -alkenyl, -SO 2 substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO2 20 substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO2 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; (f) 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 25 dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; (g) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy-substituted saturated 30 heterocyclic; WO 99/06433 PCT/US98/15952 -24 (h) -O-heterocyclic and -O-substituted heterocyclic; (i) tetrazolyl; (j) -NR-SO 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 5 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; 10 (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; (1) substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl/heteroaryl substituted with 15 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; (m) amidine and amidine substituted with from 1 to 3 substituents independently 20 selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; (n) -C(0)NR"'R"' where each R"' is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, 25 heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one R"' is unsaturated heterocyclic, 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, 30 alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, WO 99/06433 PCT/US98/15952 -25 N-alkyl or N,N-dialkylurea, then the other R"' is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic; 5 (o) -NR 2 2

C(O)-R

18 where R' 18 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 22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; 10 (p) -S0 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl or -SO 2 -alkyl; (q) -NR'C(O)NR1 9

R

19 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 RI 9 is 15 independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic: (r) -NR'C(O)OR 19 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, 20 substituted heteroaryl, heterocyclic and substituted heterocyclic and R 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (s) -aminocarbonyl-(N-formnylheterocylcyl); and 25 - (t) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, E. When R 3 is other than H, R 5 is not -(CH 2 )x-Ar-R" where R 5 " is 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 30 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic WO 99/06433 PCT/US98/15952 -26 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, 5 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, 10 guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, 15 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, -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 20 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, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono and di-arylamino, mono- and di-(substituted aryl)amino, mono- and di-heteroarylamino, 25 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional 30 blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl WO 99/06433 PCT/US98/15952 -27 groups substituted with -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -S0 2 -aryl, -SO2 substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -S0 2 -heterocyclic, -SO 2 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; 5 and pharmaceutically acceptable salts thereof with the following provisos A. when R' is o-carboxymethylphenyl, R 2 is hydrogen, R 3 is hydrogen or methyl, R 5 is benzyl and Q is -C(O)NH-, then R 6 is not -O-benzyl; B. when R' and R 2 are joined to form a benzoisothiazolone heterocyclic ring, R 3 10 is hydrogen or methyl, R 5 is benzyl and Q is -C(O)NH-, then R 6 is not -O-benzyl; C. when R' is p-methylphenyl, R 2 is hydrogen, R 5 is benzyl or p-hydroxybenzyl, R 3 is -(CH 2 )sC(O)O-t-butyl where s is 1 or 2, Q is -C(0)NH-, then R 6 is not -O-t-butyl; D. when R 1 is p-methylphenyl, R 2 is methyl, R 5 is benzyl, R 3 is 15 -CH(W) 2 , Q is -C(O)NH-, then R 6 is not -O-benzyl; E. when R 1 is p-methylphenyl, R 2 is methyl, R 5 is methyl, R 3 is -hydroxymethyl, Q is -C(O)NH-, then R 6 is not -O-methyl; and F. when R' is p-methylphenyl, R 2 is methyl, R 3 is methyl or t-butyl, R 5 is p hydroxybenzyl, Q is -C(0)NH-, then R 6 is not -O-t-butyl. 20 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 heteroaryl. Even more preferably R' is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4 25 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(0)NH )phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di (trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1 30 N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4- WO 99/06433 PCT/US98/15952 -28 bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4-[CH 3 SC(=NH)]phenyl, 5 chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl 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' 5 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 -. 10 In one embodiment, R 1 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. 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 the group consisting of nitrogen, oxygen and sulfur which ring is optionally fused to 15 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 the group consisting of nitrogen, oxygen and sulfur. Specifically preferred R'/R 2 joined groups include, by way of example, benzisothiazolonyl (saccharin-2-yl). 20 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, t-butyl, -CH 2 0-benzyl and hydroxymethyl. 25 Q is preferably -C(O)NH- or -C(S)NH-.

R

5 is preferably selected from the group consisting of all possible isomers arising by substitution with the following groups: benzyl, (N-benzylimidazol-4 30 yl)methyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 4-[2- WO 99/06433 PCT/US98/15952 -29 (pyridin-2-yl)ethynyl]benzyl, 4-[2-(3-hydroxyphenyl)ethynyl]benzyl, 4-iodobenzyl, 4 cyanobenzyl, 4-(2-bromobenzamido)benzyl, 4-(pyridin-4-yl-C(O)NH-)benzyl, and 4 hydroxybenzyl. 5 In the compounds of formula IA, R 6 is preferably 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo pentoxy, 2-a-iso-propyl-4-p-methylcyclohexoxy, 2-p-isopropyl-4-p methylcyclohexoxy, -NH 2 , benzyloxy, -NHCH 2 COOH, -NHCH 2

CH

2 COOH, -NH adamantyl, -NHCH 2

CH

2

COOCH

2

CH

3 , -NHSO 2 -p-CH 3 -0, -NHOR 8 where R 8 is 10 hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), -O-cholest-5-en-3-P-yl, OCH 2

-OC(O)C(CH

3

)

3 , -O(CH 2 )zNHC(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, -NR"C(O)-R' where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or

-CH

2

C(O)OCH

2

CH

3 . 15 Preferred compounds within the scope of formula I and IA above include by way of example: N-(toluene-4-sulfonyl)-(2S-indolin-2-carbonyl)-L-phenylalanine 20 N-(toluene-4-sulfonyl)-(2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl-L phenylalanine N-(toluene-4-sulfonyl)glycyl-L-phenylalanine 25 N-(toluene-4-sulfonyl)sarcosyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-alanyl-L-phenylalanine 30 N-(2-methoxycarbonylbenzenesulfonyl)glycyl-L-phenylalanine N-(2-methoxycarbonylbenzenesulfonyl)-L-alanyl-L-phenylalanine N-(saccharin-2-yl)-L-alanyl-L-phenylalanine 35 N-(toluene-4-sulfonyl)-D,L-phenylglycyl-L-phenylalanine WO 99/06433 PCT/US98/15952 -30 N-(toluene-4-sulfonyl)-N-methyl-L-phenylalanyl-D,L-phenylalanine N-(toluene-4-sulfonyl)-L-diphenylalanyl-L-phenylalanine 5 N-(toluene-4-sulfonyl)-N-methyl-L-diphenylalanyl-L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-L-(N-benzyl)histidine N-(toluene-4-sulfonyl)sarcosyl-D,L-P-(3-pyridyl)alanine 10 N-(toluene-4-sulfonyl)sarcosyl-D,L-P-(4-pyridyl)alanine N-(toluene-4-sulfonyl)sarcosyl-L-P-(2-pyridyl)alanine 15 N-(toluene-4-sulfonyl)-D,L-phenylsarcosyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-aspartyl-L-phenylalanine N-(toluene-4-sulfonyl)-(2S-1,2,3,4-tetrahydroisoquinolin-3-carbonyl)-L 20 phenylalanine benzyl ester N-(toluene-4-sulfonyl)-(2S-indolin-2-carbonyl)-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-L-alanyl-L-phenylalanine benzyl ester 25 N-(toluene-4-sulfonyl)sarcosyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-D,L-phenylglycyl-L-phenylalanine ethyl ester 30 N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)seryl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)seryl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-diphenylalanyl-L-phenylalanine benzyl ester 35 N-(toluene-4-sulfonyl)-N-phenylglycyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-D,L-phenylglycyl-L-phenylalanine ethyl ester 40 N-(toluene-4-sulfonyl)sarcosyl-L-(N-benzyl)histidine methyl ester N-(toluene-4-sulfonyl)-N-methyl-L-seryl-L-(N-benzyl)histidine methyl ester N-(toluene-4-sulfonyl)-D,L-phenylglycyl-L-phenylalanine benzyl ester WO 99/06433 PCT/US98/15952 -31 N-(toluene-4-sulfonyl)-N-methyl-D,L-phenylglycyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-N-benzylglycyl-L-phenylalanine methyl ester 5 N-(toluene-4-sulfonyl)-N-benzylglycyl-L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-[2-(pyridin-2-yl)ethynyl]-D,L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-[2-(3-hydroxyphenyl)ethynyl]-D,L-phenylala 10 nine N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(iodo)phenylalanine N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycyl-L-phenylalanine methyl ester 15 N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-L-seryl-L-(N-benzyl)histidine methyl ester 20 N-(toluene-4-sulfonyl)-N-(2-phenylethyl)glycyl-L-(N-benzyl)histidine methyl ester N-(toluene-4-sulfonyl)-N-(2-phenylethyl)glycyl-L-phenylalanine 25 N-(toluene-4-sulfonyl)sarcosyl-D,L-4-cyanophenylalanine N-(toluene-4-sulfonyl)-L-tert-butylglycyl-L-phenylalanine N-(saccharin-2-yl)-D,L-alaninyl-L-4-(isonicotinamido)phenylalanine methyl 30 ester 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 35 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. 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 40 or IA above under conditions wherein said compound binds to VLA-4.

WO 99/06433 PCT/US98/15952 -32 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 5 pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of formula I or IA above with the exception that IW and R 5 are derived from L-amino acids or other similarly configured starting materials. Alternatively, racemic mixtures can be used. 10 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, 15 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 20 inflammatory disease in a patient mediated by VLA-4 which methods comprise administering to the patient the pharmaceutical compositions described above. Preferred compounds of formula I and IA above include those set forth in Table I below: WO 99/06433 PCT/US98/1 5952 -33 lz -- r - I I -u- I ~ IiIe-ln~~ WO 99/06433 PCTIUS98/1 5952 -34 II 000~~ 0 0 I I I I I I I I Io U U U Urn I I II I II I u- , o 140 e -~ - ~ -~ I u u I~f WO 99/06433 PCTIUS98/15952 -35 0 u I I I WO 99/06433 PCTIUS98/1 5952 -36 II U Cl Cl Cl ClU Cl U U U o o I I I I Cl Cl I ClCl U U U UU I I

I

U 0 '*0 III ~ t~ '0 4 4 444 I I I U U U UU WO 99/66433 PCTIUS98/1 5952 -37 u u 9 9 9 CA Qn WO 99/06433 PCTIUS98/1 5952 -38 III *e-n u I 0 6 6 6 6 6 6 u u WO 99/06433 PCT/US98/1 5952 -39 Z, 0 E C)N i -e I~ ~ u s~~ z u WO 99/06433 PCTIUS98/15952 -40 II UY f WO 99/06433 PCT/US98/15952 -41 DETAILED DESCRIPTION OF THE INVENTION As above, this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by 5 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 10 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 15 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino,thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, 20 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, 25 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 WO 99/06433 PCT/US98/15952 -42 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 5 heterocyclic, -OS(O) 2 -substituted heterocyclic, -OSO 2 -NRR, -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

10 substituted aryl, -NRS(O) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-(substituted aryl)amino, mono- and di-heteroarylamino, mono- and di-(substituted 15 heteroaryl)amino, mono- and di-heterocyclic amino, mono- and di (substituted heterocyclic) amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having 20 amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl groups substituted with SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, 25 -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic or -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, 30 sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

WO 99/06433 PCT/US98/15952 -43 "Substituted alkoxy" refers to the group "substituted alkyl-O-". "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted 5 alkynyl-C(O)- cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O), heterocyclic-C(O)-, and substituted heterocyclic-C(O)- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, 10 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, 15 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, 20 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 25 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 30 substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, WO 99/06433 PCT/US98/15952 -44 substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. 5 "Acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted 10 heterocyclic-C(O)O- 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. 15 "Alkenyl" refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. "Substituted alkenyl" refers to alkenyl groups having from 1 to 5 20 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, 25 hydroxyl, cyano, 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, 30 thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, WO 99/06433 PCT/US98/15952 -45 thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, 5 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, -OSO 2 NRR, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, 10 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

15 substituted heterocyclic, mono- and di-alkylamino, mono- and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di (substituted aryl)amino, 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 20 having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkenyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkenyl/substituted alkenyl groups substituted 25 with -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -S0 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO2 heterocyclic, -SO 2 -substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl. 30 WO 99/06433 PCT/US98/15952 -46 "Alkynyl" refers to alkynyl group preferably having from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. 5 "Substituted alkynyl" refers to alkynyl groups having from 1 to 5 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, 10 aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, 15 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, 20 substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 -substituted alkyl, -OS(0)2 aryl, -OS(0) 2 -substituted aryl, -OS(0) 2 -heteroaryl, -OS(O) 2 -substituted heteroaryl, -OS(0) 2 -heterocyclic, -OS(0) 2 -substituted heterocyclic, -OSO2 25 NRR, -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 heterocyclic, -NRS(0) 2 -NR-alkyl, -NRS(O) 2

-NR

substituted alkyl, -NRS(0) 2 -NR-aryl, -NRS(0) 2 -NR-substituted aryl, WO 99/06433 PCT/US98/15952 -47

-NRS(O)

2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(O) 2 NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic, mono- and di alkylamino, mono- and di-(substituted alkyl)amino, mono- and di arylamino, mono- and di-(substituted aryl)amino, mono- and di 5 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, 10 substituted alkynyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkynyl/substituted alkynyl groups substituted with -SO 2 -alkyl, -SO 2 substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -S0 2 -cycloalkyl, SO 2 -substituted cycloalkyl, -S0 2 -aryl, -SO 2 -substituted aryl, -S02 15 heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl. "Amidino" refers to the group H 2 NC(=NH)- and the term "alkylamidino" refers to compounds having 1 to 3 alkyl groups (e.g., 20 alkylHNC(= NH)-). "Thioamidino" refers to the group RSC(=NH)- where R is hydrogen or alkyl. 25 "Aminoacyl" refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(0)substituted cycloalkyl, -NRC(O)alkenyl, -NRC(0)substituted alkenyl, -NRC(0)alkynyl, -NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl, -NRC(O)heteroaryl, -NRC(O)substituted 30 heteroaryl, -NRC(0)heterocyclic, and -NRC(O)substituted heterocyclic WO 99/06433 PCT/US98/15952 -48 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. 5 "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)O cycloalkyl, -NRC(O)O-substituted cycloalkyl, -NRC(O)O-aryl, -NRC(O)O 10 substituted aryl, -NRC(O)O-heteroaryl, -NRC(O)O-substituted heteroaryl, -NRC(O)O-heterocyclic, and -NRC(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, 15 heterocyclic and substituted heterocyclic are as defined herein. "Oxycarbonylamino" refers to the groups -OC(O)NH 2 , -OC(O)NRR, -OC(O)NR-alkyl, -OC(O)NR-substituted alkyl, -OC(O)NR alkenyl, -OC(O)NR-substituted alkenyl, -OC(O)NR-alkynyl, -OC(O)NR 20 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 25 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. 30 "Oxythiocarbonylamino" refers to the groups -OC(S)NH 2

,

WO 99/06433 PCT/US98/15952 -49 -OC(S)NRR, -OC(S)NR-alkyl, -OC(S)NR-substituted alkyl, -OC(S)NR alkenyl, -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 5 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 10 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Aminocarbonylamino" refers to the groups -NRC(O)NRR, -NRC(O)NR-alkyl, -NRC(O)NR-substituted alkyl, -NRC(O)NR-alkenyl, 15 -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, and -NRC(O)NR-substituted 20 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, 25 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, 30 -NRC(S)NR-alkyl, -NRC(S)NR-substituted alkyl, -NRC(S)NR-alkenyl, WO 99/06433 PCT/US98/15952 -50 -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)NR heteroaryl, and -NRC(S)NR-substituted heteroaryl, -NRC(S)NR 5 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, 10 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. 15 "Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H) one-7yl, and the like). Preferred aryls include phenyl and naphthyl. 20 Substituted aryl refers to aryl 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, 25 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, 30 carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl- WO 99/06433 PCT/US98/15952 -51 substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, 5 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, 10 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 15 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, -OSO 2 -NRR, -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, 20 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, mono- and di-alkylamino, mono- and di-(substituted 25 alkyl)amino, mono- and di-arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, 30 substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, WO 99/06433 PCT/US98/15952 -52 heterocyclic, substituted heterocyclic, amino groups on the substituted aryl blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) or -SO 2 NRR, where R is hydrogen or alkyl. 5 "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. 10 "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, 15 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 20 heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, 25 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, substituted heterocyclic, cycloalkoxy, substituted WO 99/06433 PCT/US98/15952 -53 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 5 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, -OSO 2 -NRR, -NRS(O) 2 -alkyl, -NRS(O) 2 10 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 15 NR-heterocyclic, -NRS(O) 2 -NR-substituted heterocyclic, mono- and di alkylamino, mono- and di-(substituted alkyl)amino, mono- and di arylamino, mono- and di-(substituted aryl)amino, mono- and di heteroarylamino, mono- and di-(substituted heteroaryl)amino, mono- and di-heterocyclic amino, mono- and di-(substituted heterocyclic) amino, 20 unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) or -SO 2 NRR, where R is 25 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 30 from this definition are multi-ring alkyl groups such as adamantanyl, etc.

WO 99/06433 PCT/US98/15952 -54 "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 5 cycloalkyl and cycloalkenyl groups, preferably of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (= O), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, 10 aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, 15 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, 20 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 25 substituted heterocyclic, -OSO 2 -NRR, -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 heterocyclic, -NRS(0) 2 -NR-alkyl, -NRS(0) 2

-NR

substituted alkyl, -NRS(0) 2 -NR-aryl, -NRS(0) 2 -NR-substituted aryl, WO 99/06433 PCT/US98/15952 -55 -NRS(0) 2 -NR-heteroaryl, -NRS(O) 2 -NR-substituted heteroaryl, -NRS(0) 2 NR-heterocyclic, -NRS(0) 2 -NR-substituted heterocyclic, mono- and di alkylamino, mono- and di-(substituted alkyl)amino, mono- and di arylamino, mono- and di-(substituted aryl)amino, mono- and di 5 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, 10 substituted alkynyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkynyl/substituted alkynyl groups substituted with -SO 2 -alkyl, -SO 2 substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 15 heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl. "Cycloalkoxy" refers to -O-cycloalkyl groups. 20 "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, 25 -NRC(=NR)NR-alkenyl, -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 30 heterocyclic where each R is independently hydrogen and alkyl as well as WO 99/06433 PCT/US98/15952 -56 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 5 heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Guanidinosulfone" refers to the groups -NRC(=NR)NRSO 2 -alkyl,

-NRC(=NR)NRSO

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

-NRC(=NR)NRSO

2 -substituted alkenyl, -NRC(=NR)NRSO 2 -alkynyl, 10 -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

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

-NRC(=NR)NRSO

2 -heterocyclic, and -NRC(=NR)NRSO 2 -substituted 15 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. 20 "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 25 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl. 30 WO 99/06433 PCT/US98/15952 -57 "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, 5 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, 10 carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, 15 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, 20 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(0)2 substituted aryl, -S(0) 2 -heteroaryl, -S(O) 2 -substituted heteroaryl, -S(0)2 heterocyclic, -S(0) 2 -substituted heterocyclic, -OS(0) 2 -alkyl, -OS(0) 2 25 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, -OS0 2 -NRR, -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, 30 NRS(0) 2 -substituted heterocyclic, -NRS(0) 2 -NR-alkyl, -NRS(0) 2

-NR-

WO 99/06433 PCT/US98/15952 -58 substituted alkyl, -NRS(0) 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, mono- and di alkylamino, mono- and di-(substituted alkyl)amino, mono- and di 5 arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, 10 heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, amino groups on the substituted aryl blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like), and -SONRR, where R is hydrogen or alkyl. 15 "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 20 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of 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 25 condensed rings lacking unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like). "Unsaturated heterocyclic" refers to non-aromatic heterocycles of 30 single or multiple condensed rings having unsaturation in any ring (e.g., WO 99/06433 PCT/US98/15952 -59 carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like). "Substituted heterocyclic" refers to heterocycle groups which are 5 substituted with from 1 to 3 substituents selected from the group consisting of oxo (=0O), thioxo (=S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, 10 aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, 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, 15 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, 20 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, -OSO 2 -NRR, -NRS(0) 2 -alkyl, -NRS(0) 2 25 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 heterocyclic, -NRS(0) 2 -NR-alkyl, -NRS(0) 2

-NR

substituted alkyl, -NRS(0) 2 -NR-aryl, -NRS(0) 2 -NR-substituted aryl, -NRS(0) 2 -NR-heteroaryl, -NRS(0) 2 -NR-substituted heteroaryl, -NRS(0) 2 30 NR-heterocyclic, -NRS(0) 2 -NR-substituted heterocyclic, mono- and WO 99/06433 PCT/US98/15952 -60 alkylamino, mono- and di-(substituted alkyl)amino, mono- and di arylamino, mono- and di-(substituted aryl)amino, mono- and di heteroarylamino, mono- and di-(substituted heteroaryl)amino, mono- and di-heterocyclic amino, mono- and di-(substituted heterocyclic) amino, 5 unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkynyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and 10 alkynyl/substituted alkynyl groups substituted with -SO 2 -alkyl, -SO 2 substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO2 heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl. 15 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, quinolizine, isoquinoline, quinoline, phthalazine, 20 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, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, 25 thiazolidine, thiophene, benzo[b]thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. "Saturated substituted heterocyclic" refers to substituted heterocycles of single or multiple condensed rings lacking unsaturation in WO 99/06433 PCT/US98/15952 -61 any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like). "Unsaturated substituted heterocyclic" refers to non-aromatic 5 substituted heterocycles of single or multiple condensed rings having unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like). "Heterocyclyloxy" refers to the group -O-heterocyclic and 10 "substituted heterocyclyloxy" refers to the group -O-substituted heterocyclic. "Thiol" refers to the group -SH. 15 "Thioalkyl" refers to the groups -S-alkyl. "Substituted thioalkyl" refers to the group -S-substituted alkyl. "Thiocycloalkyl" refers to the groups -S-cycloalkyl. 20 "Substituted thiocycloalkyl" refers to the group -S-substituted cycloalkyl. "Thioaryl" refers to the group -S-aryl and "substituted thioaryl" 25 refers to the group -S-substituted aryl. "Thioheteroaryl" refers to the group -S-heteroaryl and "substituted thioheteroaryl" refers to the group -S-substituted heteroaryl.

WO 99/06433 PCT/US98/15952 -62 "Thioheterocyclic" refers to the group -S-heterocyclic and "substituted thioheterocyclic" refers to the group -S-substituted heterocyclic. 5 "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of Formula I or IA 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 10 compound contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. Compound Preparation 15 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 (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be 20 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. Additionally, as will be apparent to those skilled in the art, 25 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.

WO 99/06433 PCT/US98/15952 -63 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 5 one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., 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 10 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. 15 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 20

R

2 -NH-C-COOH II H 25 wherein R 2 and R 3 are as defined above, with a sulfonyl chloride of formula III:

R'-SO

2 -Cl III WO 99/06433 PCT/US98/15952 -64 wherein R' is as defined above, to provide an N-sulfonyl amino acid of formula IV:

R

3 5 |

R'-SO

2

-N(R

2 )-C-COOH IV I H 10 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 15 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 40oC 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 20 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 25 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 30 compounds by conventional synthetic procedures. Examples of suitable amino acids for use in this reaction include, but are not limited to, glycine, WO 99/06433 PCT/US98/15952 -65 2-tert-butylglycine, D,L-phenylglycine, L-alanine, a-methylalanine, N methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D,L phenylsarcosine, L-aspartic acid P-tert-butyl ester, L-glutamic acid y-tert butyl ester, L-(O-benzyl)serine, 1-aminocyclopropanecarboxylic acid, 1 5 aminocyclobutanecarboxylic 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 10 hydrolysis of the ester group to the carboxylic acid using conventional reagents and conditions, i.e., treatment with an alkali metal hydroxide in an inert diluent such as methanol/water, then provides the N-sulfonyl amino acid IV. 15 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, i.e., from compounds of the formula R'-SO 3 H where R' is as defined 20 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 0OC to about 80'C for about 1 to about 25 48 hours to afford the sulfonyl chloride. Alternatively, the sulfonyl chlorides of formula III can be prepared from the corresponding thiol compound, i.e., from compounds of the formula R'-SH where R 1 is as defined above, by treating the thiol with chlorine (Cl 2 ) and water under conventional reaction conditions. 30 WO 99/06433 PCT/US98/15952 -66 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, 1 naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p 5 toluenesulfonyl chloride, a-toluenesulfonyl chloride, 4 acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4 tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2 carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4 dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 10 3,4-dimethoxybenzenesulfonyl chloride, 3,5 ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2 methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl 15 chloride, 4-trifluoromethylbenzenesulfonyl chloride, 4 trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5 chloro-2-thiophenesulfonyl chloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonyl chloride, 2-methyl-4-thiazolesulfonyl chloride, 20 1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonyl chloride, 5-chloro-1,3-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 25 the N-sulfonyl amino acids of formula IV. The intermediate N-sulfonyl amino acids of formula IV, wherein R 3 is hydrogen, can also be prepared by reacting a sulfonamide of formula V: 30 R'-S0 2

-NH-R

2

V

WO 99/06433 PCT/US98/15952 -67 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 5 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 from about 24oC to about 37oC for about 0.5 to about 4 hours. This reaction is further described in Zuckermann et al., J. Am. 10 Chem. Soc., 1992, 114, 10646-10647. Preferred carboxylic acid derivatives for use in this reaction are a-chloro 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 15 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: 20 O II

R

7

-NH-CH-C-R

6 VI 1 25 R 5 wherein RS-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 30 hexafluorophosphonate) and the like. Suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide (DCC), 1-(3- WO 99/06433 PCT/US98/15952 -68 dimethylaminopropyl)-3-ethylcarbodiimide (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, well-known coupling promoters, such 5 as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, may be used to facilitate the coupling reaction. This coupling reaction is typically conducted by contacting the N sulfonylamino acid IV with about 1 to about 2 equivalents of the coupling 10 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,N dimethylformamide and the like. Generally, this reaction is conducted at a temperature ranging from about 0OC to about 37'C for about 12 to about 15 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 20 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 25 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 O'C to about 80oC for about 1 to about 48 hours. A catalyst, such as N,N-dimethylformamide, may also be used in 30 this reaction.

WO 99/06433 PCT/US98/15952 -69 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 -70oC to about 40 0 C for about 1 to about 5 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 10 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. 15 Alternatively, the compounds of formula I can be prepared by first forming a diamino acid derivative of formula VII:

R

3

R

7 O 20 R 2 -NH-C-C(0)N-CH-C-R 6 VII I I H R 5 wherein R 2

,R

3

,R

5-7 are as defined above. The diamino acid derivatives of 25 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 30 described above to provide a compound of formula I.

WO 99/06433 PCT/US98/15952 -70 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 5 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 one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing 10 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. 15 Examples of amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-alanine methyl ester, L-isoleucine methyl ester, L-leucine methyl ester, L-valine methyl ester, P-tert-butyl-L-aspartic acid methyl ester, L-asparagine tert-butyl ester, E-Boc-L-lysine methyl ester, e-Cbz-L-lysine methyl ester, y-tert 20 butyl-L-glutamic acid methyl ester, L-glutamine tert-butyl ester, L-(N methyl)histidine methyl ester, L-(N-benzyl)histidine methyl ester, L methionine methyl ester, L-(O-benzyl)serine methyl ester, L-tryptophan methyl ester, L-phenylalanine methyl ester, L-phenylalanine isopropyl ester, L-phenylalanine benzyl ester, L-phenylalaninamide, N-methyl-L 25 phenylalanine benzyl ester, 3-carboxy-D,L-phenylalanine methyl ester, 4 carboxy-D,L-phenylalanine methyl ester, L-4-chlorophenylalanine methyl ester, L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester, L-4 iodophenylalanine methyl ester, L-3,4-methylenedioxyphenylalanine methyl ester, L-3,4-ethylenedioxyphenylalanine methyl ester, L-4 30 nitrophenylalanine methyl ester, L-tyrosine methyl ester, D,L- WO 99/06433 PCT/US98/15952 -71 homophenylalanine methyl ester, L-(O-methyl)tyrosine methyl ester, L-(O tert-butyl)tyrosine methyl ester, L-(O-benzyl)tyrosine methyl ester, L-3,5 diiodotyrosine methyl ester, L-3-iodotyrosine methyl ester, P-(1-naphthyl) L-alanine methyl ester, P-(2-naphthyl)-L-alanine methyl ester, P-(2 5 thienyl)-L-alanine methyl ester, P-cyclohexyl-L-alanine methyl ester, 3-(2 pyridyl)-L-alanine methyl ester, P-(3-pyridyl)-L-alanine methyl ester, 3-(4 pyridyl)-L-alanine methyl ester, P-(2-thiazolyl)-D,L-alanine methyl ester, P-(1,2,4-triazol-3-yl)-D,L-alanine methyl ester, and the like. If desired, of course, other esters or amides of the above-described compounds may also 10 be employed. For ease of synthesis, the compounds of formula I are typically prepared as an ester, i.e., where R 6 is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolysed using 15 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 0oC to 20 about 24oC 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 25 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 30 groups present on any of the substituents of the compounds of formula I WO 99/06433 PCT/US98/15952 -72 can be 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 5 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 20oC 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 Rs substituent can be prepared, for example, by using a 4 10 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 15 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 20oC to about 500C for about 2 to about 24 hours in an acidic diluent, such as a mixture of 20 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)-L-alanine derivatives in the above-described coupling reactions. 25 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. 30 Compounds having a primary amino group on the R substituent may be WO 99/06433 PCT/US98/15952 -73 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. 5 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 5 is a (4-aminophenyl)methyl group, can be readily N-acylated using conventional acylating reagents and conditions to provide 10 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 yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the 15 like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and the like, at a temperature ranging from about 0 0 C to about 37 0 C for about 4 to about 24 hours. Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxy benzotriazole and the like, is used to facilitate the acylation reaction. 20 Examples of carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert butyloxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-butyloxycarbonylisonipecotic acid, N methylisonipecotic acid, N-tert-butyloxycarbonylnipecotic acid, N-tert 25 butyloxycarbonyl-L-tetrahydroisoquinoline-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 30 acyl halide or a carboxylic acid anhydride to form the corresponding WO 99/06433 PCT/US98/15952 -74 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 5 about -70 0 C to about 40oC 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 base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary 10 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. 15 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, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoro methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, 20 picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N,N-dimethylcarbamyl 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. 25 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 30 this reaction include, but are not limited to, methanesulfonyl chloride, WO 99/06433 PCT/US98/15952 -75 chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides, such as dimethylsulfamoyl chloride, can be used to provide sulfamides (e.g., > N-SO 2 -N <). 5 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 10 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 toluene and the like, at a temperature ranging from about 24oC 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 15 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 20 isocyanate, 3-methoxyphenyl 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. 25 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 30 the amino compound with at least one equivalent, preferably about 1.1 to WO 99/06433 PCT/US98/15952 -76 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 5 from about 0OC to about 50oC for about 1 to about 72 hours. Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4-chlorobenzaldehyde, valeraldehyde and the like. In a similar manner, when a compound of formula I or an 10 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 be prepared using an amino acid derivative of 15 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 20 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 25 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 60oC to about 150'C for about 24 to about 72 hours. Preferably, a WO 99/06433 PCT/US98/15952 -77 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 5 suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl a bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,N ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,N dibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propyl chloride, 3-(N 10 benzyl-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-4 phenylpiperidine)ethyl chloride, N-tert-butyloxycarbonyl-3 piperidinemethyl tosylate, and the like. 15 Alternatively, a hydroxyl group present on a substituent of a compound of formula I or an intermediate thereof can be O-alkylating using the Mitsunobu reaction. In this reaction, an alcohol, such as 3-(N,N dimethylamino)-1-propanol and the like, is reacted with about 1.0 to about 20 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 -10oC to about 5oC for about 0.25 to about 1 hour. About 1.0 to about 1.3 equivalents of a hydroxy compound, such as N-tert-butyltyrosine methyl ester, is then added 25 and the reaction mixture is stirred at a temperature of about 00OC 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 30 to provide a diaryl ether. Generally, this reaction is conducted by forming WO 99/06433 PCT/US98/15952 -78 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 -25oC to about 10 0 C. The salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a 5 temperature ranging from about 10oC 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. 10 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 15 chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about -25 0 C to about 0OC 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 20 a primary or secondary amine provides the carbamate. Examples of amines suitable for using in this reaction include, but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like. 25 Alternatively, in another method for preparing carbamates, a hydroxy-containing 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 C to about 70'C for about 2 to about 72 hours. Typically, this reaction is conducted in the 30 presence of a suitable base to scavenge the acid generated during the WO 99/06433 PCT/US98/15952 -79 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 5 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 10 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 of 4 hydroxy-L-proline can be converted into the corresponding 4-amino, 4-thio or 4-fluoro-L-proline derivatives via nucleophilic displacement of the 15 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 20 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 p-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperature of from about O'C to about 70oC for about 1 to about 48 hours. The resulting tosylate can then be readily 25 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,N-dimethylformamide and water, at a temperature ranging from about 0OC to about 37 0 C for about 1 to about 12 hours to provide the corresponding azido compound. The azido group can then be reduced by, WO 99/06433 PCT/US98/15952 -80 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 5 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 0OC to about 37 0 C for about 1 to about 12 hours 10 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 0 C to about 37oC for about 12 to about 24 hours affords the corresponding fluoro compound. 15 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 20 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 24oC to about 30oC until reaction completion. This reaction is further described, for 25 example, in Rieke, J. Org. Chem. 1991, 56, 1445. In some cases, the compounds of formula I or IA 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 30 II employed in the above reactions is derived from L-thiazolidine-4- WO 99/06433 PCT/US98/15952 -81 carboxylic acid, L-(5,5-dimethyl)thiazolidine-4-carboxylic acid, L thiamorpholine-3-carboxylic acid and the like. When present, such sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and 5 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 10 in an inert diluent, such as dichloromethane, at a temperature ranging from about -50 0 C to about 75 0 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 15 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. 20 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 25 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 N-alkylation 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 30 as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and WO 99/06433 PCT/US98/15952 -82 the like, at a temperature ranging from about 25oC to about 700C 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. 5 Additionally, the sulfonamides of formula I or IV wherein R 2 is hydrogen and RI 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 10 (2-methoxycarbonylphenylsulfonyl)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 0OC to about 30oC for about 2 to about 48 hours to afford the cyclized 1,2-benzisothiazol-3-one derivative. 15 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., 20 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 25 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 WO 99/06433 PCT/US98/15952 -83 manner well known in the pharmaceutical art and comprise at least one active compound. This invention also includes pharmaceutical compositions which 5 contain, as the active ingredient, one or more of the compounds of formula I and 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 10 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 15 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 20 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 25 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, 30 polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The WO 99/06433 PCT/US98/15952 -84 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 propylhydroxy benzoates; sweetening agents; and flavoring agents. The compositions of 5 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. The compositions are preferably formulated in a unit dosage form, 10 each dosage containing from about 5 to about 100 mg, more usually about 10 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 produce the desired therapeutic effect, in 15 association with a suitable pharmaceutical excipient. The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually 20 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. 25 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 30 preformulation compositions as homogeneous, it is meant that the active WO 99/06433 PCT/US98/15952 -85 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 5 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 10 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 an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in 15 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. 20 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 25 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 30 contain suitable pharmaceutically acceptable excipients as described supra.

WO 99/06433 PCT/US98/15952 -86 Preferably the compositions are administered by the oral or nasal 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 5 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. 10 The following formulation examples illustrate the pharmaceutical compositions of the present invention. Formulation Example 1 Hard gelatin capsules containing the following ingredients are 15 prepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 20 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities. 25 Formulation Example 2 A tablet formula is prepared using the ingredients below: Quantity Ingredient (mg/tablet) 30 Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 WO 99/06433 PCT/US98/15952 -87 The components are blended and compressed to form tablets, each weighing 240 mg. Formulation Example 3 5 A dry powder inhaler formulation is prepared containing the following components: Ingredient Weight % Active Ingredient 5 10 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance. 15 Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity 20 Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 25 (as 10% solution in water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg 30 Total 120 mg The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinyl pyrrolidone is mixed with the resultant powders, which are then passed 35 through a 16 mesh U.S. sieve. The granules so produced are dried at 50' to 60 0 C and passed through a 16 mesh U.S. sieve. The sodium WO 99/06433 PCT/US98/15952 -88 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. 5 Formulation Example 5 Capsules, each containing 40 mg of medicament are made as follows: Quantity 10 Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg 15 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 20 gelatin capsules in 150 mg quantities. Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as 25 follows: Ingredient Amount Active Ingredient 25 mg 30 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 WO 99/06433 PCT/US98/15952 -89 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 5 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows: Ingredient Amount 10 Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g 15 Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water to 5.0 ml 20 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 25 produce the required volume.

WO 99/06433 PCT/US98/15952 -90 Formulation Example 8 Quantity Ingredient (mg/capsule) 5 Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg 10 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. 15 Formulation Example 9 An intravenous formulation may be prepared as follows: Ingredient Quantity 20 Active Ingredient 250.0 mg Isotonic saline 1000 ml Formulation Example 10 25 A topical formulation may be prepared as follows: Ingredient Ouantity Active Ingredient 1-10 g Emulsifying Wax 30 g 30 Liquid Paraffin 20 g White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid paraffin and 35 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.

WO 99/06433 PCT/US98/15952 -91 Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. 5 The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. e.g., 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. 10 Direct techniques can be used 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. 15 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 20 formulating the compositions to provide for drug latentiation by the conversion of hydrophilic 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. 25 Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

WO 99/06433 PCT/US98/15952 -92 Utilit y The compounds of this invention can be employed to bind VLA-4 (cA 1 integrin) in biological samples and, accordingly have utility in, for example, assaying such samples for VLA-4. In such assays, the 5 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 competitive binding assay to measure for the presence of VLA-4 in the sample. Other suitable assays 10 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. 15 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, 20 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. 25 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 30 express VLA-4 such as T cells, B cells, monocytes, eosinophils, and WO 99/06433 PCT/US98/15952 -93 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 5 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 (e.g., IgG) so that binding to 10 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 brain endothelial cells, the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This 15 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 20 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, 1251, 35 S, 1 4 C, or 32p labelled compounds and the like. Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, 25 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.

WO 99/06433 PCT/US98/15952 -94 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. 5 Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications. For instance, inclusion of one or more 10 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. 15 Pharmacokinet., 1990, 15(2):83-93). 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 20 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, and the like. 25 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 (e.g., gamma-emitting radioisotopes such as technetium-99 or indium-111), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, 30 bioluminescent compounds, and the like. Those of ordinary skill in the art WO 99/06433 PCT/US98/15952 -95 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. 5 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 10 invention can be used to assay for potential inhibitors of VLA-4/VCAM-1 interactions. For in vivo diagnostic imaging to identify, e.g., sites of inflammation, radioisotopes are typically used in accordance with well known techniques. 15 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. 20 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 are well known. In general, any conventional method for visualizing diagnostic images can be used. 25 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 WO 99/06433 PCT/US98/15952 -96 whether a particular therapeutic regimen aimed at ameliorating the disease is effective. The pharmaceutical compositions of the present invention can be used 5 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, e.g., transplantation rejection (e.g., allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset 10 diabetes), retinitis, cancer metastases, rheumatoid arthritis, acute leukocyte-mediated lung injury (e.g., 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 15 embodiments the pharmaceutical compositions are used to treat inflammatory brain disorders, such as multiple sclerosis (MS), viral meningitis and encephalitis. Inflammatory bowel disease is a collective term for two similar 20 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 25 be involved, although the disease most commonly affects the terminal ileum and/or colon. 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. 30 WO 99/06433 PCT/US98/15952 -97 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, 5 eosinophilic and neutrophilic chemotactic factors, leukotrines, prostaglandin and platelet activating factor. Release of these factors recruits basophils, eosinophils and neutrophils, which cause inflammatory injury. 10 Atherosclerosis is a disease of arteries (e.g., 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. 15 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 20 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 e.g., Paul, Immunology (3d ed., Raven Press, 1993). 25 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, 30 heart, lung, pancreas and bone marrow. Perhaps the principal outstanding WO 99/06433 PCT/US98/15952 -98 problem is the lack of satisfactory agents for inducing immunotolerance in the recipient to the transplanted allograft or organ. When allogenetic cells or organs are transplanted into a host (i.e., the donor and donee are different individuals from the same species), the host immune system is 5 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 10 responses in the donee thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. See, e.g., 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); 15 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 e.g., Schlegel et al., J. Immunol. 155, 3856-3865 (1995). 20 GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogenetic 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 25 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 30 the host.

WO 99/06433 PCT/US98/15952 -99 A further use of the compounds of this invention is inhibiting tumor metastasis. Several tumor cells have been reported to express VLA-4 and compounds 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. 5 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 10 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 15 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 20 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 25 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, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is 30 incorporated herein by reference.

WO 99/06433 PCT/US98/15952 -100 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 5 administered to a patient already suffering 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 10 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 15 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 20 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. 25 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 30 range of about 20 ,g to about 500 ,g per kilogram body weight, preferably WO 99/06433 PCT/US98/15952 -101 about 100 pg to about 300 4g per kilogram body weight. Suitable dosage ranges for intranasal administration are generally 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. 5 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 this invention. Unless otherwise stated, all temperatures are in degrees Celsius. 10 EXAMPLES In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. 15 aq or aq. = aqueous AcOH = acetic acid bd = broad doublet bm = broad multiplet bs = broad singlet 20 Bn = benzyl Boc = N-tert-butoxylcarbonyl Boc 2 0 = di-tert-butyl dicarbonate BOP = benzotriazol-1-yloxy tris(dimethylamino)phosphonium 25 hexafluorophosphate Cbz = carbobenzyloxy CHC1 3 = chloroform

CH

2 C1 2 = dichloromethane (COC1) 2 = oxalyl chloride 30 d = doublet dd = doublet of doublets dt = doublet of triplets DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCC = 1,3-dicyclohexylcarbodiimide 35 DMAP = 4-N,N-dimethylaminopyridine DME = ethylene glycol dimethyl ether DMF = N,N-dimethylformamide WO 99/06433 PCT/US98/15952 -102 DMSO = dimethylsulfoxide EDC = 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride Et 3 N = triethylamine 5 Et 2 0 = diethyl ether EtOAc = ethyl acetate EtOH = ethanol eq or eq. = equivalent Fmoc = N-(9-fluorenylmethoxycarbonyl) 10 FmocONSu = N-(9-fluorenylmethoxycarbonyl) succinimide g = grams h = hour

H

2 0 = water 15 HBr = hydrobromic acid HCI = hydrochloric acid HOBT = 1-hydroxybenzotriazole hydrate hr = hour

K

2 C0 3 = potassium carbonate 20 L = liter m = multiplet MeOH = methanol mg = milligram MgSO 4 = magnesium sulfate 25 mL = milliliter mm = millimeter mM = millimolar mmol = millimol mp = melting point 30 N = normal NaCl = sodium chloride Na 2

CO

3 = sodium carbonate NaHCO 3 = sodium bicarbonate NaOEt = sodium ethoxide 35 NaOH = sodium hydroxide

NH

4 Cl = ammonium chloride NMM = N-methylmorpholine Phe = L-phenylalanine Pro = L-proline 40 psi = pounds per square inch PtO 2 = platinum oxide q = quartet quint. = quintet rt = room temperature WO 99/06433 PCT/US98/15952 -103 s = singlet sat = saturated t = triplet t-BuOH = tert-butanol 5 TFA = trifluoroacetic acid THF = tetrahydrofuran TLC or tic = thin layer chromatography Ts = tosyl TsCl = tosyl chloride 10 TsOH = tosylate L = microliter In the examples below, all temperatures are in degrees Celcius (unless 15 otherwise indicated). The following Methods were used to prepare the compounds set forth below as indicated. Method 1 N-Tosylation Procedure 20 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 25 Amino acid methyl esters were prepared using the method of Brenner and Huber Helv. Chim. Acta 1953, 36, 1109. Method 3 BOP Coupling Procedure 30 The desired dipeptide ester was prepared by the reaction of a suitable N-protected amino acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate [BOP] (2.0 equivalent), triethylamine (1.1 equivalent), and DMF. The reaction WO 99/06433 PCT/US98/15952 -104 mixture was stirred at room temperature overnight. The crude product is purified flash chromatography to afford the dipeptide ester. Method 4 5 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. 10 Method 5 Hydrolysis Procedure I To a chilled (0OC) THF/H 2 0 solution (2:1, 5 - 10 mL) of the appropriate ester was added LiOH (or NaOH) (0.95 equivalents). The 15 temperature was maintained at 0oC 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 20 Ester Hydrolysis Procedure II To a chilled (0OC) THF/H 2 0 solution (2:1, 5 - 10 mL) of the appropriate ester was added LiOH (1.1 equivalents). The temperature was maintained at 0 0 C and the reaction was complete in 1-3 hours. The reaction mixture was concentrated and the residue was taken up into O120 25 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 4 , filtered and concentrated to yield the desired acid.

WO 99/06433 PCT/US98/15952 -105 Method 7 Ester Hydrolysis Procedure III The appropriate ester was dissolved in dioxane/H 2 0 (1:1) and 0.9 equivalents of 0.5 N NaOH was added. The reaction was stirred for 3-16 5 hours and then 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 10 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 15 temperature and was stirred for 48 hr. The reaction solution was transferred to a 250 mL separatory funnel with methylene chloride (100 mL) and extracted with 1N HCI (50 mL x 3), brine (50 mL), and water (100 mL). The organic phase was dried (MgSO 4 ) and the solvent concentrated to yield the desired product. 20 Method 9 Reductive Amination Procedure Reductive amination of Tos-Pro-p-NH 2 -Phe with the appropriate aldehyde was conducted using acetic acid, sodium triacetoxyborohydride, 25 methylene chloride and the combined mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography.

WO 99/06433 PCT/US98/15952 -106 Method 10 BOC Removal Procedure Anhydrous hydrochloride (HC1) gas was bubbled through a methanolic solution of the appropriate Boc-amino acid ester at 0oC for 15 minutes and 5 the reaction mixture was stirred for three hours. The solution was concentrated to a syrup and dissolved in Et 2 0 and reconcentrated. This procedure was repeated and the resulting solid was placed under high vacuum overnight. 10 Method 11 Tert-Butyl Ester Hydrolysis Procedure I The tert-butyl ester was dissolved in CH 2 C1 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 H 2 0 and lyophilized to yield the 15 desired acid. Method 12 EDC Coupling Procedure I To a CH 2 C1 2 solution (5-20 mL) of N-(toluene-4-sulfonyl)-L-proline (1 20 equivalent), the appropriate amino acid ester hydrochloride (1 equivalent), N-methylmorpholine (1.1-2.2 equivalents) and 1-hydroxybenzotriazole (2 equivalents) were mixed, placed in an ice bath and 1-(3 dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalents) added. The reaction was allowed to rise to room temperature and stirred overnight. 25 The reaction mixture was poured into H 2 0 and the organic phase was washed with sat. NaHCO 3 , brine, dried (MgSO 4 or Na 2

SO

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

WO 99/06433 PCT/US98/15952 -107 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 5 equivalent), Et 3 N (1.1 equivalents) and 1-hydroxybenzotriazole (2 equivalents) were mixed, placed in an ice bath 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 H20 and the 10 organic phase washed with 0.2 N citric acid, H 2 0, sat. NaHCO 3 , and brine, then dried (MgSO 4 or Na 2

SO

4 ), filtered and concentrated. The crude product was purified by column chromatography or preparative TLC. Method 14 15 Sulfonylation Procedure II The appropriate sulfonyl chloride was dissolved in CH 2 C1 2 and placed in an ice bath. L-Pro-L-Phe-OMe *HC1 (1 equivalent) and EtN (1.1 equivalent) was added and the reaction allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The 20 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 4 or Na 2

SO

4 ), filtered and concentrated. The crude product was purified by column chromatography or preparative TLC. 25 Method 15 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 C1 2 was added Et 3 N (5 equivalents) followed by the appropriate 30 sulfonyl chloride (1.1 equivalent). The reaction was allowed to warm to WO 99/06433 PCT/US98/15952 -108 room temperature and stirred overnite 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 5 was washed with brine, dried (MgSO 4 or Na 2

SO

4 ), filtered and concentrated. The crude methyl ester was purified by preparative TLC. The corresponding acid was prepared using the procedure described in Method 7. 10 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 40 psi H 2 . After 8 - 16 hours, the reaction mixture was 15 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 (5 10 mL), to which was added 0.5 N NaOH (1.05 equivalents). After stirring for 1- 3 hours, the reaction mixture was concentrated and the residue was redissolved in H20 and washed with EtOAc. The aqueous 20 phase was made acidic with 0.2 N HCI and the product was extracted with EtOAc. The combined organic phase was washed with brine (1 x 5 mL), dried (MgSO 4 or Na 2 SO4), filtered and concentrated to yield the acid as approximately a 1:1 mixture of diastereomers. 25 Method 17 Tert-Butyl Ester Hydrolysis Procedure II The tert-butyl ester was dissolved in CH 2 C1 2 (5 mL) and treated with TFA (5 mL). The reaction was complete in 1-3 hours at which time the reaction mixture was concentrated and the residue dissolved in H20 and WO 99/06433 PCT/US98/15952 -109 concentrated. The residue was redissolved in H20 and lyophilized to yield the desired product. Example 1 5 Synthesis of N-(Toluene-4-sulfonyl) (2S-indolin-2-carbonyl)-L-phenylalanine N-(Toluene-4-sulfonyl)-2S-indoline-2-carboxylic acid (331.2 mg, 1.04 mmol) was dissolved in dry DMF (5 mL) with 4-methyl morpholine (3.5 10 eq, 400 ML), BOP (1.1 eq, 506 mg), and phenylalanine benzyl ester (1.0 eq, 444 mg). The dipeptide was isolated as an oil. The benzyl ester was dissolved in EtOH:H 2 0 (1:1) [2.5 mL] containing a catalytic amount of 10% Pd on C and hydrogenated under 50 psi H 2 . Upon filtration over celite, and evaporation of the solvents under reduced pressure the title 15 material was isolated as a solid, mp = 167-170'C. NMR data was as follows: 1H NMR (300 MHz, CDCl 3 ): 6 = 7.64 (d, 1H, J = 8.50 Hz), 7.43 (d, 2H, J = 8.25 Hz), 7.23 (m, 2H), 7.12-7.00 (m, 6H), 6.86 (m, 2H), 4.82 (m, 1H), 4.60 (m, 1H), 3.12 (m, 3H), 2.62 (m, 1H), 2.32 (s, 3H). 20 13C NMR (75 MHz, CD 3 OD): 6 = 174.37, 173.24, 146.90, 142.92, 138.09, 136.61, 133.74, 131.49, 130.92, 129.90, 129.49, 129.13, 128.22, 127.37, 126.78, 119.34, 65.28, 55.44, 38.74, 34.15, 22.03. Mass Spectroscopy: (FAB) 465 (M+H). 25 Example 2 Synthesis of N-(Toluene-4-sulfonyl)-(2S-1,2,3,4 tetrahydroisoquinoline-3-carbonyl-L-phenylalanine Following the experimental procedure described for the synthesis of 30 Example 1 (20), affords the title compound as a white solid, mp = 74 78 0

C.

WO 99/06433 PCT/US98/15952 -110 NMR data was as follows: 'H NMR (300 MHz, CDC13): 6 = 7.61 (mn, 3H), 7.24-6.85 (min, 10 H), 4.65 (min, 1H), 4.55 (min, 1H), 4.22 (d, 1H, J = 10.5 Hz), 4.05 (d, 1H, J = 10.5 Hz), 3.18-2.92 (min, 4H), 2.34 (s, 3H). 5 1 3 C NMR (75 MHz, CD30D): 6 = 174.62, 173.36, 146.96, 138.63, 136.89, 134.17, 131.34, 131.03, 130.12, 129.62, 129.25, 128.87, 128.23, 127.74, 57.59, 56.83, 47.14, 38.75, 31.72, 32.00. Mass Spectroscopy: (FAB) 479 (M+H). 10 Example 3 Synthesis of N-(Toluene-4-sulfonyl)glycyl-L-phenylalanine N-(Toluene-4-sulfonyl)glycine (547 mg, 2.40 mmol) was slurried in

CH

2 Cl 2 (7 mL) and cooled in an ice bath. Oxalyl chloride (0.30 mL) was 15 added, followed by one drop of DMF. The mixture was warmed to room temperature and stirred for 1 hr. The volatiles were removed in vacuo and the acid chloride dissolved in CH 2 C1 2 (8 mL) and cooled in an ice bath. Phenylalanine benzyl ester toluensulfonate (919 mg, 2.1 mmol) was added, followed by triethylamine (0.75 mL). The mixture was allowed to slowly 20 warm to room temperature and stirred for 19 hr. The mixture was diluted with CH 2 C1 2 (40 mL) and washed with 1N HCI (2 x 10 mL), 1M NaHCO (15 mL), brine (10 mL), dried (MgSO 4 ), filtered and evaporated in vacuo. The residue was purified by silica gel flash chromatography (3:2 Hexane/EtOAc) to give the dipeptide benzyl ester (0.51g, 50%). The 25 - benzyl ester was dissolved in THF (20 mL) and 10% Pd/C (60 mg) was added. The mixture was hydrogenated at 15 psi 1H12 for 1.5 hr. The mixture was filtered through a pad of diatomaceous earth and evaporated in vacuo to give a residue which was recrystallized from MeOH/CHC 3 to give the title compound as a white solid (304 mg, 76%), mp = 157-161 0 C. 30 NMR data was as follows: WO 99/06433 PCT/US98/15952 -111 1 H NMR (CDC13): 6 = 12.8 (bs, 1H), 8.13 (d, 1H, J = 8.0 Hz), 7.86 (d, 1H, J = 6.1 Hz), 7.65 (d, 2 H, J = 8.2 Hz), 7.35 (d, 2H, J = 8.2 Hz), 7.29-7.17 (5H), 4.49 (min, 1H), 3.01 (dd, 1H, J = 5.0, 13.7 Hz), 3.57 (inm, 3H), 2.85 (dd, 1H, J = 8.5, 13.7 Hz), 2.37 (s, 3H). 5 1 3 C NMR (CDCl 3 ): 8 = 172.9, 167.7, 143.0, 137.7, 137.6, 129.9, 129.5, 128.6, 127.0, 53.7, 45.3, 37.2, 21.4. Mass Spectroscopy: FAB m/e 377 (M+H). Example 4 10 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl-L-phenylalanine The product from Example 21 (180) (0.62 mmoles) was added to ethanol (40 mL) and 5% Pd-C (10%) and shaken under 35 psi hydrogen for 16 hours. The reaction mixture was filtered through celite and 15 concentrated. The crude product was crystallized from EtOAc/Hexane to afford the title compound as a white solid (190 mg, 78.5%), mp = 128 130 0 C. NMR data was as follows: 1H NMR (CDC1 3 , 300 MHz): 6 = 7.65 (d, 2H, J = 8.18 Hz); 7.26 20 (min, 7H); 4.84 (min, 1H); 3.73 (q, 1H, J = 7.02); 3.58 (d, 1H, J = 4.28 Hz); 3.20 (min, 2H); 2.55 (s, 3H); 2.43 (s, 3H). 13 C NMR (CDCl 3 , 300 MHz): 5 = 175.23, 168.75, 144.90, 136.50, 133.53, 130.57, 129.89, 129.34, 128.17, 127.75, 54.39, 53.84, 37.82, 37.18, 22.15. 25 - Mass Spectroscopy: (+FAB) 391 (M+H), 413 (M+Na).

WO 99/06433 PCT/US98/15952 -112 Example 5 Synthesis of N-(Toluene-4-sulfonyl)-L alanyl-L-phenylalanine 5 The title compound was prepared according to the procedure described in Example 4 (41). The crude product was crystallized from EtO/Hexane to yield a white solid, mp = 105 -108oC. NMR data was as follows: 'H NMR (CDCl 3 , 300 MHz): 8 = 7.72 (d, 2H, J = 8.06 Hz); 7.26 10 (m, 6H), 7.09 (d, 2H, 7.63 Hz); 6.84 (d, 1H, J = 7.69 Hz); 5.46 (d, 1H, J = 7.70 Hz); 4.71 (m, 1H); 3.77 (m, 2H); 3.09 (m, 2H); 2.41 (s, 3H); 1.14 (d, 3H, J = 7.14 Hz). 13C NMR (CDCl 3 , 300 MHz): 6 = 174.60, 172.17, 144.69, 136.79, 136.19, 130.47, 129.93, 129.26, 129.20, 127.80, 127.72, 53.94, 53.05, 15 37.74, 22.17, 19.71. Mass Spectroscopy: (+FAB) 391 (M+H), 413 (M+Na). Example 6 Synthesis of 20 N-(2-Methoxycarbonylbenzenesulfonyl) glycyl-L-phenylalanine The title compound was prepared according to the procedure described for Example 4 (41), yielding a white solid, mp = 140-143 0 C. NMR data was as follows: 25 'H NMR (CD 3 OD, 300 MHz): 6 = 7.75 (m, 2H); 7.50 (m, 2H); 7.02 (m, 5H); 4.32 (m, 1H); 3.74 (s, 3H); 3.44 (d, 2H, J = 7.57 Hz); 2.91 (m, 1H); 2.72 (m, 1H). 13C NMR (CD 3 OD, 300 MHz): 8 = 170.66, 169.90, 140.00, 138.73, 134.49, 133.15, 131.96, 131.05, 130.95, 130.92, 130.01, 129.96, 128.35, 30 55.79, 54.29, 46.98, 38.08, 31.23. Mass Spectroscopy: (+FAB) 421 (M+H), 443 (M+Na).

WO 99/06433 PCT/US98/15952 -113 Example 7 Synthesis of N-(2-Methoxycarbonylbenzenesulfonyl) L-alanyl-L-phenylalanine 5 The title compound was prepared according to the procedure described in Example 4 (41), yielding a glassy semi-solid. NMR data was as follows: 1H NMR (CDC13, 300 MHz): 8 = 8.02 (d, 1H, J = 7.14 Hz); 7.84 (d, 1H, J = 7.15 Hz); 7.62 (min, 2H); 7.20 (min, 6H); 6.50 (d, 1H, J = 6.59 10 Hz); 4.71 (min, 1H); 3.98 (s, 3H); 3.87 (min, 1H); 3.10 (min, 2H); 1.14 (d, 3H, J = 7.14 Hz). 13C NMR (CDCl 3 , 300 MHz): 6 = 175.08, 172.26, 168.58, 138.99, 136.47, 133.47, 132.58, 131.63, 130.78, 130.51, 129.95, 129.15, 127.65, 54.12, 54.01, 53.68, 37.93, 19.23. 15 Mass Spectroscopy: (+FAB) 435 (M+H). Preparative Example A Synthesis of N-(Saccharin-2-yl) 20 glycyl-L-phenylalanine To L-prolyl-L-phenylalanine benzyl ester (4.64 mmoles) in THF (15 mL) was added triethylamine (4.70 mmoles) and the reaction proceeded for 30 minutes at room temperature. The reaction mixture was chilled to 0OC and methyl 2-(chlorosulfonyl) benzoate (4.64 mmoles) was added and the 25 reaction proceeded for 4 hours at room temperature. The reaction was extracted with EtOAc (3 x 50 mL) and water (50 mL), and the combined organic layers were successively washed with sat. NaHCO 3 (50 mL) and sat NaCl (2 x 50 mL), dried over MgSO 4 , filtered and rotovaped to yield a colorless oil (2.30 g, 90%). The crude product was purified by silica gel 30 chromatography (50% EtOAc/Hexane, Rf = 0.47) to yield N-(2 Methoxycarbonylphenylsulfonyl)-L-prolyl-L-phenylalanine benzyl ester as WO 99/06433 PCT/US98/15952 -114 a colorless oil (1.49 g, 58%). Sodium hydride (1.47 mmoles, washed free of mineral oil) in THF (10 mL) was chilled to 0OC, and a solution of N-(2-methoxycarbonyl 5 phenyl)sulfonyl-L-glycine-L-phenylalanine benzyl ester in THF (5 mL) was added dropwise. The reaction was stirred at 0oC for one hour and then at room temperature for two hours. The reaction mixture was extracted with EtOAc (3 x 100 mL) and 0.2 N HCI (50 mL), the combined EtOAc layers were washed successively with 0.2 N HCI (50 mL), satd. NaHCOQ (50 10 mL), and satd. NaCl (2 x 50 mL). The organic layer was dried over MgSO 4 , filtered and concentrated to yield a colorless oil (0.63 g, 91%). The crude product was filtered by silica gel chromatography (50% EtOAc/Hexanes, Rf = 0.42) to afford N-(benzisothiazolone)-L-glycyl-L phenylalanine benzyl ester as a colorless oil (0.25 g, 36%) which was then 15 hydrogenated with 10% Pd on C in THF and the mixture was shaken under 50 psi H 2 . The mixture was filtered through celite and evaporated to provide the title compound as a white solid (42 mg, 52%), mp = 201-204'C. NMR data was as follows: 20 1H NMR (CD 3 OD, 300 MHz): 6 = 7.80 (min, 4H); 7.01 (mn, 5H); 4.43 (t, 1H, J = 5.43 Hz); 4.17 (d, 2H, J = 5.43); 2.99 (min, 1H); 2.82 (inm, 1H). 13 C NMR (CD 3 OD, 300 MHz): 8 = 167.94, 160.99, 139.70, 138.87, 137.10, 136.46, 131.11, 129.89, 129.01, 128.21, 126.77, 122.87, 56.57, 25 41.57, 39.04. Mass Spectroscopy: (+FAB) 398 (M+H), 411 (M+Na). 30 WO 99/06433 PCT/US98/15952 -115 Example 8 Synthesis of N-(Saccharin-2-yl)-L alanyl-L-phenylalanine 5 The title compond was prepared using the procedures described for the preparation of Preparative Example A (48), yielding a white solid, mp = 190-193 0 C. NMR data was as follows: 1H NMR (CDCl 3 , 300 MHz): 6 = 7.86 & 6.95 (min, 9H); 4.66(bs, 2H); 10 3.18 (m,1H); 2.97 (min, 1H); 1.69 (d, 3H, J = 6.59). 13C NMR (CDC1 3 , 300 MHz): 6 = 176.31, 169.18, 158.14, 138.01, 136.68, 135.86, 129.77, 128.81, 127.27, 127.21, 126.13, 121.68, 112.01, 66.48, 54.99, 51.80, 37.53, 14.65. Mass Spectroscopy: (+FAB) 403 (M +H), 425 (M +Na). 15 Example 9 Synthesis of N-(Toluene-4-sulfonyl) D,L-phenylglycyl-L-phenylalanine 20 N-(Toluene-4-sulfonyl)phenylglycine was prepared from phenylglycine using the procedure described in Method 1. N-(Toluene-4-sulfonyl)phenylglycine-OH and L-Phe-OBnHCl were treated with BOP and NMM in DMF, to give after aqueous workup and 25 flash chromatography, N-(Toluene-4-sulfonyl)phenylglycine-L-Phe-OBn. This product was treated with 10% Pd on C in THF, and the mixture was shaken under 50 psi 1H2. The mixture was filtered through Celite, and evaporated to give the title compound as a solid, mp = 150-152°C. NMR data was as follows: 30 1H NMR (DMSO-d 6 , 300 MHz): 6 = 2.30 (s, 3H), 2.70-2.95 (inm, 2H), 4.13-4.30 (min, 1H), 5.03-5.20 (min, 1H), 6.88-7.34 (min, 12H), 7.55 (inm, 2H), 8.38-8.67 (min, 2H).

WO 99/06433 PCT/US98/15952 -116 13C NMR (DMSO-d 6 , 75 MHz): 6 = 21.3, 37.3, 53.7, 59.6, 126.7, 126.8, 126.87, 126.92, 127.4, 127.6, 128.2, 128.26, 128.35, 128.6, 129.4, 129.5, 137.2, 137.9, 138.8, 142.5, 169.0, 172.8. Mass Spectroscopy: (FAB+) 453 (M+H). 5 Example 10 Synthesis of N-(Toluene-4-sulfonyl)-N-methyl-L phenylalanyl-D,L-phenylalanine 10 N-Methyl-L-phenylalanine (500 mg, 2.79 mmol) was dissolved in 1N NaOH (6 mL). Dioxane (9 mL)) was added, followed by p-toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was vigorously stirred for 1 hr. The volatiles were removed in vacuo and the residue was dissolved in 15 water (30 mL) and washed with Et 2 O (2 x 30 mL) before making acidic with 1N HC1. The mixture was extracted with CHC1 3 (3 x 30 mL) and the extracts were evaporated in vacuo to give N-(toluene-4-sulfonyl)-N methylphenylalanine as a solid (424 mg, 45%). N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L 20 phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analyis indicated a mixture of diastereomers. NMR data was as follows: 25 'H NMR (CDCl 3 ): 8 = 9.15 (bs, 1H), 7.38-6.89 (14H), 4.82 (m, 1H), 4.70 (m, 1H), 3.31-2.95 (3H), 2.81 (s, 1/2 X 3H), 2.55 (s, 1/2 X 3H), 2.50 (m, 1H), 2.37 (s, 1/2 X 3H), 2.35 (s, 1/2 X 3H). 13C NMR (CDCl 3 ): 8 = 175.3, 169.6, 169.5, 143.5, 143.4, 137.0, 136.9, 135.6, 135.5, 135.3, 135.2, 129.8, 129.7, 129.6, 129.3, 129.2, 30 129.1, 129.0, 128.7, 128.6, 128.5, 128.4, 127.2, 127.1, 127.0, 126.6, WO 99/06433 PCT/US98/15952 -117 126.4, 124.8, 61.2, 61.0, 53.5, 53.4, 37.4, 37.1, 33.9, 33.5, 29.9, 29.6, 21.4. Mass Spectroscopy: FAB m/e 481 (M +H). 5 Example 11 Synthesis of N-(Toluene-4-sulfonyl)-L diphenylalanyl-L-phenylalanine 10 Boc-L-Diphenylalanine was coupled to L-phenylalanine benzyl ester using the procedure described in Method 3. The Boc group was removed by treatment with TFA and anisole, and the mixture was evaporated. The residue was dissolved in Et 2 0 and washed with sat. NaHCO 3 and sat. NaC1. The Et 2 0 layers were dried with MgSO 4 , filtered, and evaporated to 15 give the deprotected dipeptide. The resulting ester of the title compound was tosylated using the procedure described in Method 1. The title compound was prepared using the procedure described in Method 7 as a solid, mp = 228-230 0 C. NMR data was as follows: 20 'H NMR (CD 3 OD, 300 MHz): 6 = 2.11 (s, 3H), 2.37-2.46 (min, 2H), 3.78 (min, 1H), 3.99 (d, 1H, J = 10.8 Hz), 4.49 (d, 1H, J = 10.8 Hz), 6.86-7.04 (min, 17H), 7.36 (d, 2H, J = 8.3 Hz). 13C NMR (CD 3 OD, 75 MHz): 6 = 22.0, 39.8, 56.1, 56.3, 61.6, 128.09, 128.14, 128.4, 128.7, 128.8, 129.8, 129.9, 130.0, 130.1, 130.3, 25 131.07, 131.11, 138.7, 140.0, 142.2, 142.4, 144.9, 172.3, 174.5. Mass Spectroscopy: (FAB+) 549 (M + Li).

WO 99/06433 PCT/US98/15952 -118 Example 12 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl L-(N-benzyl)histidine 5 N-(Toluene-4-sulfonyl)sarcosine was prepared from sarcosine using the procedure described in Method 1. Coupling was conducted using the procedure described in Method 3. The title compound, prepared by hydrolysis of the ester using the procedure described in Method 7, was 10 obtained as a solid, mp = >200'C (dec.). NMR data was as follows: 'H NMR (D 2 0,300 MHz): 6 = 2.17 (s, 3H), 2.28 (s, 3H), 2.71-3.05 (min, 2H), 3.31-3.48 (dd, 2H), 4.34 (min, 1H), 6.74 (s, 1H), 6.97-7.16 (inm, 7H), 7.37 (d, 2H, J = 8.0 Hz), 7.44 (s, 1H). 15 " 3 C NMR (D 2 0, 75 MHz): 6 = 27.7, 37.2, 43.0, 57.3, 59.8, 61.7, 124.7, 134.3, 134.6, 134.9, 135.8, 137.0, 138.9, 143.7, 144.2, 144.3, 152.0, 176.0, 184.6. Mass Spectroscopy: (FAB+) 493 (M+H). 20 Example 13 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl-D,L P-(3-pyridyl)alanine 25 Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100 mL) containing diethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolyl chloride hydrochloride (5.00 g, 30.5 mmol) were added. The mixture was heated to reflux for 6 hr, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture 30 was taken up into saturated aqueous NaHCO 3 (100 mL) and extracted with EtOAc (3 x 100 mL). The solvent was removed and the residue purified WO 99/06433 PCT/US98/15952 -119 by silica gel flash chromatography (95:5 CH 2 Cl 2 /MeOH) to give diethyl 2 (3-pyridylmethyl)-2-acetamidomalonate (2.84 g, 30%). Diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate was dissolved in 6N 5 HCI (30 mL) and heated to reflux for 19 hr whereupon it was cooled to room temperature and the HCI solution was removed by evaporation in vacuo. The intermediate amino acid dihydrochloride salt was taken up into MeOH (30 mL) saturated with HCI gas and stirred for 3.5 hr. The MeOH/HCl was removed by evaporation in vacuo to give P-(3 10 pyridyl)alanine methyl ester dihydrochloride (2.235 g, 100%). N-(Toluene-4-sulfonyl)sarcosine was coupled to 3-(3-pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-p-(3-pyridyl)alanine (166 mg, 17%). 15 The title compound was prepared via hydrolysis of the methyl ester using 1N aqueous NaOH in dioxane/water (129 mg, 100%). NMR data was as follows: 1H NMR (DMSO-d 6 ): 8 = 8.30 (m, 2H), 7.66 (d, 2H, J = 8.0 Hz), 7.63 (m, 1H), 7.51 (m, 1H), 7.42 (d, 2H, J = 7.9 Hz), 7.20 (m, 1H), 4.07 20 (m, 1H), 3.56 (s, 2H), 3.11 (dd, 1H, J = 4.8, 13.2 Hz), 2,96 (dd, 1H, J = 5.5, 13.4 Hz), 2.52 (s, 3H), 2.40 (s, 3H). 13C NMR (DMSO-d 6 ): 8 = 172.7, 166.0, 150.8, 147.3, 143.8, 137.3, 134.8, 134.0, 130.2, 127.7, 123.3, 55.3, 53.2, 36.2, 34.9, 21.4. Mass Spectroscopy: FAB m/e 392 (M+H). 25 WO 99/06433 PCT/US98/15952 -120 Example 14 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl D,L-P-(4-pyridyl)alanine 5 The title compound was prepared as described in Example 13 (107) except 4-picolylchloride hydrochloride is used in place of 3-picolylchloride hydrochloride. NMR data was as follows: 10 'H NMR (CD 3 OD): 6 = 8.39 (d, 2H, J = 5.3 Hz),7.68 (d, 2H, J = 8.2 Hz), 7.41 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 5.8 Hz), 4.58 (m, 1H), 3.70 (d, 1H, J = 16.6 Hz), 3.54 (d, 1H, J = 16.5 Hz), 3.30 (dd, 1H, J = 4.9, 13.7 Hz), 3.07 (dd, 2H, J = 7.6, 13.7 Hz), 2.66 (s, 3H), 2.43 (s, 3H). 15 13C NMR (CD 3 OD): 8 = 176.0, 270.2, 150.8, 150.1, 146.1, 135.7, 131.5, 129.3, 127.4, 56.4, 54.8, 39.1, 37.6, 22.1. Mass Spectroscopy: FAB m/e 392 (M+H). Example 15 20 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl-L P-(2-pyridyl)alanine N-(Toluene-4-sulfonyl)sarcosine was coupled to L-P-(2-pyridyl)alanine 25 methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-p-(2-pyridyl)alanine methyl ester. The title compound was prepared via hydrolysis of the methyl ester using 1N aqueous NaOH in dioxane/water. NMR data was as follows: 30 'H NMR (DMSO-d 6 ): 8 = 8.38 (m. 1H),7.72 (d, 1H, J = 7.4 Hz), 7.65 (d, 2H, J = 8.2 Hz), 7.59 (m, 1H), 7.41 (d, 2H, J = 8.2 Hz), 7.21 (d, 1H, J = 7.8 Hz), 7.12 (m 1H), 4.23 (m, 1H), 3.50 (m, 2H), 3.23 (dd, WO 99/06433 PCT/US98/15952 -121 1H, J = 4.8, 13.4 Hz), 3.01 (dd, 2H, J = 7.1, 13.4 Hz), 2.53 (s, 3H), 2.40 (s, 3H). 13C NMR (DMSO-d,): 8 = 173.4, 165.7, 159.7, 148.9, 243.8, 136.1, 134.0, 130.2, 127.7, 124.0, 121.4, 54.7, 53.3, 36.1, 21.4. 5 Mass Spectroscopy: FAB m/e 414 (M+Na). Example 16 Synthesis of N-(Toluene-4-sulfonyl) 10 D,L-phenylsarcosyl-L-phenylalanine N-(Toluene-4-sulfonyl)phenylsarcosine was prepared from phenylsarcosine using the procedure described in Method 1. The title compound was prepared using the procedure described for Example 9 (65) 15 as a solid, mp = 78-82oC. NMR data was as follows: 'H NMR (CDC1 3 , 300 MHz): 5 = 2.41 (s, 3H), 2.48 (s, 3H), 2.97 3.34 (m, 2H), 4.89 (m, 1H), 5.63 (s, 1H), 6.77-6.92 (m, 3H), 7.13-7.35 (m, 10H), 7.66 (d, 2H, J = 7.5 Hz). 20 13C NMR (CDCl 3 , 75 MHz): 8 = 22.2, 32.3, 38.0, 53.9, 64.4, 127.8, 128.1, 129.1, 129.4, 129.88, 129.95, 130.0, 130.3, 133.9, 136.2, 136.4, 144.4, 169.8, 175.2. Mass Spectroscopy: (FAB+) 467 (M + H). 25 Preparative Example B Synthesis of N-(Toluene-4-sulfonyl)sarcosyl N-methyl-L-phenylalanine 30 N-(Toluene-4-sulfonyl)sarcosine was coupled to N-methyl-L phenylalanine methyl ester using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-N-methylphenylalanine methyl ester.

WO 99/06433 PCT/US98/15952 -122 The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water. Proton and carbon NMR analysis indicated a mixture of amide bond rotomers in about a 65:35 ratio. NMR data was as follows: 5 1H NMR (CDC13): 6 = 7.59 (d, 0.65 x 2H, J = 7.4 Hz), 7.54 (d, 0.35 x 2H, J = 7.3 Hz), 7.34-7.18 (7H), 5.25 (m, 0.65H), 5.09 (m, 0.35H), 3.93 (d, 0.65H, J = 14.6 Hz), 3.58 (d, 0.65H, J = 14.6 H), 3.41 (m, 1H), 3.10 (m, 1H), 2.97 (s, 0.65 x 3H), 2.92 (s, 0.35 x 3H), 2.41 (s, 3H), 2.39 (s, 0.65 x 3H), 2.38 (s, 0.35 x 3H). 10 13C NMR (CDC1 3 ): 8 = 173.3, 168.1, 167.8, 143.9, 143.8, 136.9, 136.8, 133.3, 129.7, 129.1, 128.8, 128.7, 128.6, 127.5, 127.0, 126.8, 59.0, 52.8, 52.7, 35.0, 34.7, 34.2, 33.0, 30.1, 21.5. Mass Spectroscopy: FAB m/e 405 (M +H). 15 Example 17 Synthesis of N-(Toluene-4-sulfonyl)-L-aspartyl-L-phenylalanine Cbz-4-(1,1-dimethylethyl)aspartic acid was coupled with phenylalanine 20 t-butyl ester using the procedure described in Method 3. The Cbz group was removed using the procedure described in Method 4. The resulting ester was tosylated using the procedure described in Method 1. The title compound was prepared using the procedure outlined in Method 11. NMR data was as follows: 25 'H NMR (CD 3 OD, 300 MHz): 8 = 2.18 (s, 3H), 2.18-2.39 (m, 2H), 2.68-2.89 (m, 2H), 3.97 (t, 1H, J = 5.2 Hz), 4.22 (t, 1H, J = 4.9 Hz), 6.97-7.12 (m, 7H), 7.45 (d, 2H, J = 8.2 Hz). 13C NMR (CD 3 OD), 75 MHz): 6 = 22.1, 38.6, 38.9, 55.1, 55.9, 128.5, 128.8, 130.1, 130.9, 131.0, 131.3, 138.3, 138.6, 139.4, 145.5, 30 172.6. Mass Spectroscopy: (FAB+) 435 (M+H).

WO 99/06433 PCT/US98/15952 -123 Example 18 Synthesis of N-(Toluene-4-sulfonyl)-(2S-1,2,3,4-tetrahydroisoquinolin 5 3-carbonyl)-L-phenylalanine Benzyl Ester N-(toluene-4-sulfonyl)-(2S-1,2,3,4-tetrahydroquinolin-3-carbonyl) (1 eq) was dissolved in DMF, with Et3N (2.0 eq), BOP (1.1 eq), and L-phenylalanine benzyl esterHC1 salt (1.1 eq). The benzyl ester was 10 isolated as an oil. NMR data was as follows: 'H NMR (300 MHz, CDCl 3 ): 6 = 7.62 (d, 2H, J = 8.16 Hz), 7.33 (m, 5H), 7.23-7.08 (m, 8H), 6.70 (d, 2H, J = 8.16 Hz), 5.10 (q, 2H, J = 11.50 Hz), 4.72 (m, 1H), 4.52 (m, 1H), 4.18 (m, 2H), 3.07 (m, 2H), 2.85 15 (m, 2H), 2.52 (m, 1H), 2.34 (s, 3H). Example 19 Synthesis of N-(Toluene-4-sulfonyl)-(2S-indolin-2-carbonyl) 20 L-phenylalanine Benzyl Ester The procedure used for the preparation of Example 18 (173) was utilized. The title compound was isolated as an oil. NMR data was as follows: 25 'H NMR (300 MHz, CDCl 3 ): 6 = 7.66 (d, 1H, J = 7.98 Hz), 7.42 6.92 (m, 16H), 6.66 (d, 2H, J = 8.50 Hz), 5.17 (q, 2H, J = 10.08 Hz), 4.83 (m, 1H), 4,58 (m, 1H), 3.07 (m, 3H), 2.62 (m, 1H), 2.32 (s, 3H).

WO 99/06433 PCT/US98/15952 -124 Example 20 Synthesis of N-(Toluene-4-sulfonyl)-L-alanyl L-phenylalanine Benzyl Ester 5 To N-(toluene-4-sulfonyl)-L-alanine (2.0 mmoles) in DMF (10 mL) was added BOP (2.1 mmoles) and N-methylmorpholine (4.0 mmoles) and the reaction stirred at room temperature for 45 minutes. L-Phenylalanine benzyl ester (2.0 mmoles) was added and the reaction stirred for 16 hours 10 at room temperature. The reaction mixture was extracted with water (100 mL) and diethyl ether (3 x 50 mL) The combined organic layers were successively washed with 0.2 N HCI (2 x 50 mL), sat. NaHCO 3 (50 mL), and sat. NaCl (50 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated to yield a colorless oil (387 mg, 40%). The crude product 15 was purified by silica gel chromatography (50% EtOAc /Hexane, Rf = 0.61). The title compound was crystalized from CHCl 3 /Hexane to yield a white solid, mp = 109-110 0 C. NMR data was as follows: 'H NMR (CDCl 3 , 300 MHz): 8 = 7.75 (d, 2H, J = 8.24 Hz); 7.26 20 (min, 13H); 5.88 (d, 1H, J = 7.69 Hz); 5.11 (q, 2H, J = 12.1 Hz); 4.76 (q, 1H, J = 7.69 Hz); 3.85 (min, 1H); 3.00 (d, 2H, J = 5.98 Hz); 2.37 (s, 3H); 1.19 (d, 3H, J = 7.09 Hz). 13 C NMR (CDCl 3 , 300 MHz): 8 = 171.83, 171.49, 144.30, 137.34, 136.12, 135.53, 130.36, 130.00, 129.90, 129.19, 129.12, 127.85, 127.71, 25 127.65, 67.92, 54.07, 52.94, 38.26, 22.13, 19.96. Mass Spectroscopy: (+FAB) 481 (M+H).

WO 99/06433 PCT/US98/15952 -125 Example 21 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl L-phenylalanine Benzyl Ester 5 The title compound was prepared according to Method 3, and the crude product was crystallized from Et 2 O/hexane to afford a white solid, mp = 80-82oC. NMR data was as follows: 10 1 H NMR (CDCl 3 , 300 MHz): 8 = 7.64 (d, 2H, J = 8.24 Hz); 7.26 (m, 13H); 5.16 (q, 2H, J = 12.1 Hz); 4.92 (d oft, 1H, J = 6.71 & 11.29 Hz); 3.7.70 (d, 1H, J = 16.48 Hz); 3.43 (d, 1H, J = 16.48 Hz); 3.15 (m, 2H); 2.56 (s, 3H); 2.44 (s, 3H). 13 C NMR (CDCl 3 , 300 MHz): 6 = 171.34, 167.88, 144.88, 135.97, 15 135.60, 133.61, 130.56, 129.85, 129.36, 129.22, 129.15, 128.16, 127.84, 67.93, 54.51, 53.51, 38.29, 37.15, 22.16. Mass Spectroscopy: (+FAB) 481 (M+H). Example 22 20 Synthesis of N-(Toluene-4-sulfonyl)-D,L-phenylglycyl-L phenylalanine Ethyl Ester N-(Toluene-4-sulfonyl)phenylglycine was prepared from phenylglycine 25 using the procedure described in Method 1. The title compound was prepared using the procedure described for Example 11 (86) as a solid, mp = 145-147oC. NMR data was as follows: 1H NMR (CDC1 3 , 300 MHz): 8 = 1.12-1.29 (m, 3H), 2.38 (s, 3H), 30 2.91-3.05 (m, 2H), 4.04-4.20 (m, 2H), 4.65-4.81 (m, 2H), 5.85-5.95 (m, 1H), 6.07-6.21 (m, 1H), 6.65 (m, 1H), 6.95 (m, 1H), 7.02-7.33 (m, 10H), 7.60 (m, 2H).

WO 99/06433 PCT/US98/15952 -126 13C NMR (CDC13, 75 MHz): 8 = (diastereomeric pairs separated by slashed line) 14.57/14.70, 22.09/22.10, 38.1, 53.7/54.2, 61.00/61.06, 62.26/62.34, 127.61/127.76, 127.81/127.88, 128.06/128.16, 129.06/129.16, 129.3, 129.6, 129.69/129.76, 130.06/130.08, 135.4, 5 136.01/136.55, 136.94/137.21, 144.03/144.13, 168.67/169.00, 171.07/171.22. Mass Spectroscopy: (FAB+) 481 (M+H). Example 23 10 Synthesis of N-(Toluene-4-sulfonyl)-N-methyl-L-(O-benzyl) seryl-L-phenylalanine Ethyl Ester L-(O-Benzyl)-serine methyl ester hydrochloride salt (6.28 g, 25.5 15 mmol) was dissolved in dichloromethane (50 mL) with tosyl chloride (1.1 eq, 5.36 g) and Et 3 N (2.2 eq, 7.48 mL). The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure. EtOAc was added as well as brine, and the organic layer dried over MgSO 4 . The desired N-(toluene-4-sulfonyl)-L-(O-benzyl)-serine 20 methyl ester was isolated as an oil, in 100% yield (10.04 g, 25.5 mmol). This was then taken up in dry acetone (50 mL) with iodomethane (1.1 eq, 1.88 mL) and K 2

CO

3 (1.1 eq, 4.10 g). The solution was refluxed overnight. The solvent was evaporated under reduced pressure. EtOAc was added and the organic layer was washed with brine. The organic layer 25 was dried over MgSO 4 . The solvent was evaporated under reduced pressure. The desired N-methyl derivative was isolated as a clear oil in 40% yield (4.16 g, 11 mmol). The ester was dissolved in a 1:1 solution of dioxane:H 2 0 with NaOH (1.1 eq, 50 mL). The desired compound was isolated as a solid. 30 WO 99/06433 PCT/US98/15952 -127 N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)serine (754 mg, 2.07 mmol) was dissolved in 30 mL of dry DMF with phenylalanine ethyl ester hydrochloride salt (1.1 eq, 525 mg), Et 3 N (2.2 eq, 636 mL) and BOP reagent (1.1 eq, 1.00 g). The reaction mixture was stirred at room 5 temperature for 12 hours. EtOAc was added. The organic layer was washed with NaHCO 3 saturated, 10% citric acid, and brine. 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; CHC1 3 /MeOH 9:1). The title ester was isolated as an oil in 10 60% yield (664 mg, 1.23 mmol) and as a mixture of diastereoisomers. NMR data was as follows: 'H NMR (300 MHz, CDCl 3 ): 6 = 7.69 (d, 2H, J = 8.22 Hz), 7.27 (min, 5H), 7.15 (min, 5H), 7.04 (min, 2H), 4.80 (min, 2H), 4.29 (min, 4H), 3.76 (min, 1H), 3.58 (min, 1H), 3.19 (min, 2H), 2.71 (s, 1.5 H), 2.57 (s, 1.5H), 15 2.35 (s, 3H), 1.27 (min, 3H). 13C NMR (75 MHz, CDC13): 6 = 171.50, 168.70, 143.98. 137.84, 136.44, 136.18, 129.93, 128.98, 128.45, 128.37, 128.25, 127.65, 73.75, 67.15, 66.99, 62.17, 60.35, 59.98, 53.93, 53.75, 38.34, 30.95, 22.15, 14.69. 20 Mass Spectroscopy: (FAB) 539 (M+H). Example 24 Synthesis of N-(Toluene-4-sulfonyl)-N-methyl-L 25 seryl-L-phenylalanine Ethyl Ester Example 23 (191) (664 mg, 1.23 mmol) was dissolved in MeOH (10 mL) with a catalytic amount of Pearlman's catalyst. The hydrogenation reaction was run for 2 hours at 5 psi. The solution was filtered over celite. 30 Upon evaporation of the solvent under reduced pressure, an oil was isolated as the title compound in quantitative yields.

WO 99/06433 PCT/US98/15952 -128 NMR data was as follows: 'H NMR (300 MHz, CDCl 3 ): 6 = 7.68 (m, 2H), 7.30 (m, 7H), 4.77 (m, 1H), 4.46 (m, 1H), 4.18 (m, 2H), 3.65 (m, 1H), 3.47 (m, 2H), 3.07 (m, 2H), 2.78 (s, 1.5H), 2.54 (s, 1.5H), 2.42 (s, 3H), 1.25 (m, 3H). 5 13C NMR (75 MHz, CDC13): 6 = 171.47, 170.31, 144.78, 136.42, 135.77, 130.67, 129.88, 129.33, 127.92, 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 (M+H). 10 Example 25 Synthesis of N-(Toluene-4-sulfonyl)-L-diphenylalanyl-L phenylalanine Benzyl Ester 15 Boc-L-diphenylalanine was coupled to L-phenylalanine benzyl ester using the procedure described in Method 3. The Boc group was removed using the procedure described in Example 11 (86). The resulting ester was tosylated using the procedure described in Method 1 yielding the title compound as a solid, mp = 79-84oC. 20 NMR data was as follows: 1H NMR (CDC1 3 , 300 MHz): 6 = 2.36 (s, 3H), 2.77 (m, 2H), 4.25 4.39 (m, 2H), 4.95 (d, 2H, J = 4.9 Hz), 5.19 (d, 1H, J = 8.0 Hz), 6.18 (d, 1H, J = 7.8 Hz), 6.92 (m, 2H), 7.08-7.38 (m, 20H), 7.55 (d, 2H, J = 8.4 Hz). 25 13C NMR (CDCl 3 , 75 MHz): 6 = 22.1, 38.8, 54.1, 54.7, 60.9, 67.7, 127.6, 127.70, 127.72, 128.0, 128.7, 129.10, 129.14, 129.3, 129.9, 130.2, 135.5, 136.0, 137.0, 139.4, 140.1, 144.2, 169.9, 170.8. Mass Spectroscopy: (FAB+) 633 (M+H).

WO 99/06433 PCT/US98/15952 -129 Example 26 Synthesis of N-(Toluene-4-sulfonyl)-N-methyl-D,L phenylglycyl-L-phenylalanine Ethyl Ester 5 N-(Toluene-4-sulfonyl)phenylglycine was esterified with thionyl chloride in methanol to give N-(toluene-4-sulfonyl)phenylglycine methyl ester. This was then taken up in dry acetone (50 mL) with iodomethane (1.1 eq, 1.88 mL) and K 2

CO

3 (1.1 eq, 4.10 g). The solution was refluxed 10 overnight. The solvent was evaporated under reduced pressure. EtOAc was added and the organic layer was washed with brine. The organic layer was dried over MgSO 4 . The solvent was evaporated under reduced pressure. The resulting ester was hydrolyzed using the procedure described in Method 6 to yield N-(Toluene-4-sulfonyl)-N-methyl 15 phenylglycine, which was coupled with L-phenylalanine ethyl ester using the procedure described in Method 3 to yield the title compound. NMR data was as follows: 'H NMR (CDC13, 300 MHz): 6 = 1.27 (t, 3H), 2.43 (s, 3H), 2.60 (s, 3H), 2.98-3.25 (m, 2H), 4.21 (q, 2H), 4.80-4.91 (m, 1H), 5.68 (s, 1H), 20 6.59 (br d, minor dia., 1H with 6.73) 6.73 (br d, major dia., 1H with 6.59), 6.92-7.02 (m, 2H), 7.11-7.43 (m, 10H), 7.69 (d, 2H). 13 C NMR (CDC13, 75 MHz): 6 = (Major diastereomer) 14.75, 22.16, 32.20, 38.38, 53.56, 62.21, 64.43, 127.79, 128.07, 129.07, 129.13, 129.27, 129.87, 129.92, 130.04, 134.18, 136.10, 136.32, 144.22, 169.08, 25 171.71; (Minor diastereomer) 14.68, 22.16, 32.12, 38.51, 53.97, 62.21, 64.22, 127.76, 128.16, 129.07, 129.13, 129.32, 129.87, 129.92, 130.26, 134.26, 136.10, 136.52, 144.26, 169.08, 171.71. Mass Spectroscopy: (FAB+) 495 (M+H).

WO 99/06433 PCT/US98/15952 -130 Example 27 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl-L (N-benzyl)histidine Methyl Ester 5 N-(Toluene-4-sulfonyl)sarcosine methyl ester was prepared from sarcosine methyl ester using the procedure described in Method 1. The title compound was prepared by coupling in DMF N-(toluene-4 sulfonyl)sarcosine with (N-benzyl)histidine methyl ester in the presence of 10 BOP and NMM, to give after aqueous workup and flash chromatography, the title compound. NMR data was as follows: 1H NMR (CDCl 3 , 300 MHz): 8 = 2.44 (s, 3H), 2.76 (s, 3H), 3.09 (m, 2H), 3.44 (d, 1H, J = 16.4 Hz), 3.68 (s, 3H), 3.83 (d, 1H, J = 16.5 Hz), 15 4.80 (m, 1H), 5.07 (s, 2H), 6.74 (s, 1H), 7.14 (d, 2H, J = 6.0 Hz), 7.33 (m, 5H), 7.50 (s, 1H), 7.68 (d, 2H, J = 8.3 Hz), 8.06 (br d, 1H, 8.1 Hz). 13C NMR (CDC1 3 , 75 MHz): 6 = 14.8, 22.1, 30.2, 37.1, 51.4, 52.6, 52.9, 54.4, 61.0, 117.8, 128.0, 128.2, 128.8, 129.6, 130.5, 134.0, 136.6, 137.8, 137.9, 144.6, 168.2, 172.1. 20 Mass Spectroscopy: (FAB+) 485 (M+H). Example 28 Synthesis of N-(Toluene-4-sulfonyl)-N-methyl-L-seryl-L 25 (N-benzyl)histidine Methyl Ester N-Methyl-N-(toluene-4-sulfonyl)-L-serine (420 mg, 1.53 mmol) was dissolved in dry DMF (20 mL) at ice bath temperature. L-(N benzyl)histidine methyl ester hydrochloride salt (1.1 eq, 500 mg) was 30 added as well as Et 3 N (2.2 eq, 471 mL), with HOBT (1.1 eq, 229 mg). After 15 mn, EDCI (1.1 eq, 502 mg) was added and the reaction mixture was stirred at room temperature overnight. EtOAc was added and the WO 99/06433 PCT/US98/15952 -131 organic layer washed with NaHCO 3 saturated, 10% citric acid and brine (3x50 mL). The organic layer was dried over MgSO 4 , and the solvent evaporated under reduced pressure. The crude material was eluted on column chromatography (silica gel), with EtOAc/hexanes 1:3, then with 5 CHC1 3 :MeOH 9:1. The title compound was isolated as an oil in 30% yield (230 mg, 0.447 mmol). NMR data was as follows: 'H NMR (300 MHz, CDC13): 5 = 7.91 (d, 1H, J = 7.50 Hz), 7.73 (d, 2H, J = 8.31 Hz), 7.46 (s, 1H), 7.32 (m, 5H), 7.15 (m, 2H), 6.69 (s, 10 1H), 5.04 (s, 2H), 4.74 (m, 1H), 4.46 (m, 1H), 3.71 (m, 2H), 3.66 (s, 3H), 3.06 (m, 2H), 2.80 (s, 3H), 2.40 (s, 3H). 13C NMR (75 MHz, CDC1 3 ): 8 = 171.98, 170.40, 144.41, 137.93, 136.54, 135.976, 130.41, 129.57, 128.88, 128.01, 117.74, 61.42, 61.15, 53.07, 51.46, 32.29, 30.09, 22.13 (lC missing). 15 Mass Spectroscopy: (FAB) 515 (M+H). Example 29 Synthesis of 20 N-(Toluene-4-sulfonyl)-D,L-phenylglycyl-L phenylalanine Benzyl Ester The title compound was prepared by coupling N-(toluene-4-sulfonyl) D,L-phenylglycine to L-phenylalanine benzyl ester using the procedure 25 described in Method 3 to provide a solid, mp = 148-150 0 C. NMR data was as follows: 'H NMR (CDC13, 300 MHz): 6 = 2.37 (s, 3H), 2.91-3.07 (m, 2H), 4.70-4.85 (m, 2H), 5.04 (dd, 2H), 5.94 (br d, 1H), 6.23 (br d, 1H), 6.84 (d, 2H), 7.00-7.40 (m, 15H), 7.60 (d, 2H).

WO 99/06433 PCT/US98/15952 -132 13C NMR (CDCl 3 , 75 MHz): 6 = 22.1, 38.1, 54.2, 61.1, 67.9, 127.7, 127.8, 127.9, 128.1, 128.2, 129.1, 129.4, 129.6, 129.7, 129.8, 130.0, 135.4, 135.8, 136.5, 137.2, 144.1, 169.1, 170.9. Mass Spectroscopy: (FAB+) 543 (M+H). 5 Example 30 Synthesis of N-(Toluene-4-sulfonyl)-N-methyl-D,L phenylglycyl-L-phenylalanine Benzyl Ester 10 The title compound was prepared following the procedure described in Example 26 (198) as a solid, mp = 46-49 0 C. NMR data was as follows: 1H NMR (CDCl 3 , 300 MHz): 8 = 2.41 (s, 3H), 2.54, (s, 3H), 2.96 15 3.22 (m, 2H), 4.90 (q, 1H, J = 3.0 Hz), 5.15 (dd, 2H), 5.65 (s, 1H), 6.51 (d, 1H, J = 6.9 Hz), 6.95 (d, 2H, J = 6.2 Hz), 7.04 (m, 2H), 7.15-7.40 (m, 13H), 7.67 (d, 2H, J = 8.2 Hz). 13C NMR (CDCl 3 , 75 MHz): 6 = 22.2, 32.1, 38.4, 53.9, 64.3, 68.0, 127.8, 128.1, 129.1, 129.2, 129.3, 129.4, 129.8, 129.9, 130.0, 130.1, 20 130.2, 134.2, 135.6, 136.2, 136.5, 144.2, 169.1, 171.4. Mass Spectroscopy: (FAB+) 557 (M+H). Example 31 Synthesis of 25 N-(Toluene-4-sulfonyl)-N-(2-thienylethyl) glycyl-L-phenylalanine Methyl Ester N-(Toluene-4-sulfonyl)-2-thienylethylamine was prepared using the procedure described in Method 1. This compound was reacted with t-butyl 30 bromoacetate yielding N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycine t butyl ester (following the method of Zuckermann, Kerr, Kent, and Moos J. Am. Chem. Soc. 1992, 114, 10646-10647). The ester was hydrolyzed WO 99/06433 PCT/US98/15952 -133 using the procedure described in Method 17. The title compound was prepared following the procedure described in Method 13. NMR data was as follows: 1H NMR (CDCl 3 , 300 MHz): 8 = 2.43 (s, 3H), 2.85 (m, 2H), 3.05 5 3.22 (m, 3H), 3.40 (m, 1H), 3.69 (dd, 2H), 3.73 (s, 3H), 4.83 (m, 1H), 6.73 (d, 1H, J = 2.3 Hz), 6.90 (t, 1H, J = 2.4 Hz), 6.98 (br d, 1H, J = 6.2 Hz), 7.13 (d, 1H, J = 3.2 Hz), 7.17-7.35 (m, 7H), 7.66 (d, 2H, J= 8.0 Hz). 10 Example 32 Synthesis of N-(Toluene-4-sulfonyl)-N-(2-thienylethyl) glycyl-L-phenylalanine 15 The title compound was prepared from the product of Example 31 (289) using the procedure described in Method 7 to provide a solid, mp = > 200 0 C. Example 33 20 Synthesis of N-(Toluene-4-sulfonyl)-N-(2-phenylethyl)glycyl-L (N-benzyl)histidine Methyl Ester The title compound was prepared according to procedures described in 25 Example 31 (289). NMR data was as follows: 1H NMR (CDC1 3 , 300 MHz): 6 = 2.41 (s, 3H), 2.82 (m, 2H), 3.02 3.30 (m, 3H), 3.46 (m, 1H), 3.67 (s, 3H), 3.75 (dd, 2H), 4.79 (m, 1H), 5.00 (s, 2H), 6.77 (s, 1H), 7.10-7.35 (m, 12H), 7.48 (s, 1H), 7.69 (d, 2H, 30 J = 7.3 Hz), 7.97 (br d, 1H, J = 6.9 Hz).

WO 99/06433 PCT/US98/15952 -134 13 C NMR (CDC13, 75 MHz): 8 = 22.1, 30.2, 35.3, 51.4, 52.6, 52.7, 52.9, 118.1, 127.2, 127.9, 128.0, 128.8, 129.2, 129.4, 129.5, 130.5, 135.7, 136.6, 137.6, 137.8, 138.5, 144.6, 168.9, 172.0. Mass Spectroscopy: (FAB+) 575 (M+H); 597 (M+Na). 5 Example 34 Synthesis of N-(Toluene-4-sulfonyl)-N (2-phenylethyl)glycyl-L-phenylalanine 10 The title compound was prepared according to procedures described in Examples 31 (289) and 32 (290). NMR data was as follows: 1H NMR (CDC1 3 , 300 MHz): 6 = 2.41 (s, 3H), 2.56 (m, 2H), 3.03 15 3.37 (m, 4H), 3.72 (dd, 2H), 4.84 (q, 1H, J = 3.4 Hz), 7.02 (d, 2H, J = 6.1 Hz), 7.12-7.34 (m, 10H), 7.63 (d, 2H, J = 8.3 Hz), 8.78 (br s, 1H). 13C NMR (CDC13, 75 MHz): 6 = 22.1, 35.1, 37.8, 52.6, 52.7, 53.8, 127.3, 127.9, 128.0, 129.2, 129.3, 129.4, 130.0, 130.6, 135.2, 136.0, 138.1, 144.9, 169.9, 175.0. 20 Mass Spectroscopy: (FAB+) 481 (M+H). Example 35 Synthesis of N-(Toluene-4-sulfonyl)sarcosyl 25 D,L-4-cyanophenylalanine 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 30 sulfonyl)sarcosyl-D,L-4-cyanophenylalanine methyl ester. The compond was prepared via hydrolysis of the methyl ester using 0.5 N NaOH in THF/water.

WO 99/06433 PCT/US98/15952 -135 NMR data was as follows: 1H NMR (CD 3 OD/CDCl 3 ): 85 = 7.69 (m, 3H), 7.41 (m, 3H), 4.79 (m, 1H), 3.77 (d, 1H, J = 16.7 Hz), 3.55 (d, 1H, J = 16.5 Hz), 3.32 (dd, 1H, J = 4.9, 14.0 Hz), 3.13 (dd, 1H, J = 8.8, 14.0 Hz), 2.67 (s, 3H), 5 2.45 (s, 3H). 1 3 C NMR (CD 3 OD/CDC1 3 ): 8 = 174.0, 170.6, 146.2, 144.9, 135.5, 134.0, 132.2, 131.6, 129.3, 120.4, 112.3, 54.8, 50.4, 39.0, 37.7, 22.4. Mass Spectroscopy: FAB m/e 416 (M+H). 10 Example 36 Synthesis of N-(Toluene-4-sulfonyl)-L-tert-butylglycyl L-phenylalanine 15 N-(Toluene-4-sulfonyl)-L-tert-butylglycine was prepared from L-tert butylglycine using the procedure described in Method 1. The title compound was prepared by coupling in DMF N-(toluene-4-sulfonyl)-Ltert-butylglycine with an L-phenylalanine ester in the presence of BOP and NMM. Conventional deesterification provided the title compound. 20 NMR data was as follows: 1H NMR (CDCl 3 ): 6 7.7 (d, 2H), 7.25 (m, 5H), 7.0 (m, 2H), 5.93 (d, 1H), 5.57 (d, 1H), 4.6 (m, 1H), 3.3 (d, 1H), 3.0-2.7 (d of d, 2H), 2.35 (s, 3H), 0.87 (s, 9H). 25 Example 37 Synthesis of N-(Saccharin-2-yl)-D,L-alaninyl L-4-(isonicotinamido)phenylalanine Methyl Ester 30 The title compound was prepared following the procedures described in Preparative Example A. N-(saccharin-2-yl)-D,L-alaninyl-L-p-amino phenylalanine methyl ester (1 eq) was dissolved in dichloromethane with WO 99/06433 PCT/US98/15952 -136 Et 3 N (1.1 eq) and reacted with isonicotinoyl chloride (1.1 eq, 860 mL) to provide the title compound. NMR data was as follows: 'H NMR (DMSO-d 6 ,400 MHz) (1:1 mixture of diastereomers): 6 = 5 10.43 (d, 1H); 8.80 (m, 2H); 8.45 and 8.25 (two m, 1H), 8.23 (m, 1H); 8.04 (m, 3H); 7.82 (m, 2H); 7.65 (m, 2H); 7.20 (m, 2H); 4.76 (m, 1H); 4.45 (m, 1H); 3.40 and 3.42 (two s, 3H); 3.00 (m, 2H), 1.65 and 1.70 (two s, 3H). 10 Other compounds prepared by the methods described above include those set forth in Table II below: WO 99/06433 PCT/US98/1 5952 -137 00 C 0 - q Sz I-- - CI. u 0 u C) I UU 1 In C P4 U u. 44 4 -E I I I U U U U U WO 99/06433 PCTIUS98/1 5952 -138 r.)) 0 C 0 E u -u U ~UU WO 99/06433 PCT/US98/15952 -139 Example 46 In vitro Assay For Determining Binding of Candidate Compounds to VLA-4 5 An in vitro assay was used to assess binding of candidate compounds to a 4 p 1 integrin. Compounds which bind in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays (e.g., competitive binding assays). This assay is sensitive to ICo values as low as about InM. 10 The activity of a43 1 integrin was measured by the interaction of soluble VCAM-1 with Jurkat cells (e.g., American Type Culture Collection Nos. TIB 152, TIB 153, and CRL 8163), a human T-cell line which expresses high levels of a43 1 integrin. VCAM-1 interacts with the cell surface in an 15 a 4 p 1 integrin-dependent fashion (Yednock, et al. J. Biol. Chem., 1995, 270:28740). Recombinant soluble VCAM-1 was expressed as a chimeric fusion protein containing the seven extracellular domains of VCAM-1 on the N 20 terminus 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 25 bovine serum, penicillin, streptomycin and glutamine as described by Yednock, supra. Jurkat cells were incubated with 1.5 mM MnC1 2 and 5 pg/mL 15/7 antibody for 30 minutes on ice. Mn +2 activates the receptor to enhance 30 ligand binding, and 15/7 is a monoclonal antibody that recognizes an activated/ligand occupied conformation of a4p1 integrin and locks the WO 99/06433 PCT/US98/15952 -140 molecule into this conformation thereby stabilizing the VCAM-1/a 4 p 1 integrin interaction. Yednock, et al., supra. Antibodies similar to the 15/7 antibody have been prepared by other investigators (Luque, et al, 1996, J. Biol. Chem. 271:11067) and may be used in this assay. 5 Cells were then incubated for 30 minutes at room temperature with candidate compounds, in various concentrations ranging from 66 pM to 0.01 tM using a standard 5-point serial dilution. 15 pL soluble recombinant VCAM-1 fusion protein was then added to Jurkat cells and 10 incubated for 30 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 15 and analyzed with a standard fluorescence activated cell sorter ("FACS") analysis as described in Yednock, et al., supra. Compounds having an IC 50 of less than about 15pM possess binding affinity to a43 1 . 20 When tested in this assay, each of the compounds in Examples 1-45 has an ICs 50 of 15 /tM or less. 25 Example 47 In vitro Saturation Assay For Determining Binding of Candidate Compounds to a 4 1 z 30 The following describes an in vitro assay to determine the plasma levels needed for a compound to be active in the Experimental Autoimmune WO 99/06433 PCT/US98/15952 -141 Encephalomyelitis ("EAE") model, described in the next example, or in other in vivo models. Log-growth Jurkat cells are washed and resuspended in normal animal 5 plasma containing 20 pg/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 10 ranging from 66 yM to 0.01 AM, 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 15 twice with phosphate-buffered saline ("PBS") containing 2% fetal bovine serum and 1mM 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 20 anti-mouse 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 4oC for 30 minutes. 25 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. Biol. Chem., 1995, 270:28740.

WO 99/06433 PCT/US98/15952 -142 The data is then graphed as fluorescence versus dose, e.g., 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. 5 This assay may also be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as the C9a 1 integrin, which is the integrin most closely related a 4 xl (Palmer et al, 1993, J. Cell Bio., 123:1289). Such binding is predictive of in vivo utility for inflammatory conditions mediated by 9p 1 integrin, including by way of 10 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 15 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 9 integrin (Yokosaki et al., 1994, J. Biol. Chem., 20 269:26691), in place of the Jurkat cells, to measure the binding of the ais integrin. As a control, SW 480 cells which express other a and P 1 subunits may be used. Accordingly, another aspect of this invention is directed to a method 25 for treating a disease in a mammalian patient, which disease is mediated by a 9 1 , 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 above. Effective daily dosing will depend upon the age, 30 weight, condition of the patient which factors can be readily ascertained by WO 99/06433 PCT/US98/15952 -143 the attending clinician. However, in a preferred embodiment, the compounds are administered from about 20 to 500 /g/kg per day. Using a conventional oral formulation, compounds of this invention would be active in this model. 5 Example 48 In vivo Evaluation The standard multiple sclerosis model, Experimental Autoimmune (or 10 Allergic) Encephalomyelitis ("EAE"), is 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 15 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 are homogenized in an equal volume of phosphate-buffered saline. An equal volume of 20 Freund's complete adjuvant (100 mg mycobacterium tuberculosis plus 10 ml Freund's incomplete adjuvant) is added to the homogenate. The mixture is emulsified by circulating it repeatedly through a 20 ml syringe with a peristaltic pump for about 20 minutes. 25 Female Lewis rats (2-3 months old, 170-220 g) or Hartley guinea pigs (20 day old, 180-200 g) are anesthetized with isoflurane and three injections of the emulsion, 0.1 ml each, are made in each flank. Motor impairment onset is seen in approximately 9 days.

WO 99/06433 PCT/US98/15952 -144 Candidate compound treatment begins on Day 8, just before onset of symptoms. Compounds are administered subcutaneously ("SC"), orally ("PO") or intraperitoneally ("IP"). Doses are given in a range of 10mg/kg to 200 mg/kg, bid, for five days, with typical dosing of 10 to 100 mg/kg 5 SC, 10 to 50 mg/kg PO, and 10 to 100 mg/kg IP. Antibody GG5/3 against a4p 1 integrin (Keszthelyi et al., Neurology, 1996, 47:1053-1059), which delays the onset of symptoms, is used as a positive control and is injected subcutaneously at 3 mg/kg on Day 8 and 10 11. Body weight and motor impairment are measured daily. Motor impairment is rated with the following clinical score: 15 0 no change 1 tail weakness or paralysis 2 hindlimb weakness 3 hindlimb paralysis 4 moribund or dead 20 A candidate compound is considered active if it delays the onset of symptoms, e.g., produces clinical scores no greater than 2 or slows body weight loss as compared to the control. 25 Example 49 Asthma Model Inflammatory conditions mediated by a 4 13 1 integrin include, for example, airway hyper-responsiveness and occlusion that occurs with chronic asthma. The following describes an asthma model which can be WO 99/06433 PCT/US98/15952 -145 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, 5 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, compounds 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 10 and/or block the late-phase airway response, e.g., have a protective effect against antigen-induced late responses and airway hyper-responsiveness ("AHR"), are considered to be active in this model. Allergic sheep which are shown to develop both early and late 15 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 20 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 25 Am 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 30 beginning of the inspiratory cycle of the respirator. Aerosols are delivered WO 99/06433 PCT/US98/15952 -146 at VT of 500 ml and a rate of 20 breaths/minute. A 0.5% sodium bicarbonate solution only is used as a control. To assess bronchial responsiveness, cumulative concentration-response 5 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 hours after antigen challenge. Bronchial biopsies can be preformed according to Abraham (1994). 10 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 15 A solution of the candidate compound in 0.5% sodium bicarbonate/saline (w/v) at a concentration of 30.0 mg/mL is prepared using the following procedure: A. Preparation of 0.5% Sodium Bicarbonate/Saline 20 Stock Solution: 100.0 mL Ingredient Gram / 100.0 mL Final Concentration Sodium Bicarbonate 0.5 g 0.5% Saline q.s. ad 100.0 mL q.s. ad 100% 25 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. 30 WO 99/06433 PCT/US98/15952 -147 B. Preparation of 30.0 mg/mL Candidate Compound: 10.0 mL Ingredient Gram / 10.0 mL Final Concentration Candidate Compound 0.300 g 30.0 mg/mL 0.5% Sodium Bicarbonate / q.s. ad 10.0 mL q.s ad 100% 5 Saline Stock Solution Procedure: 1. Add 0.300 g of the candidate compound into a 10.0 mL volumetric flask. 10 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. 15 Using a conventional oral formulation, compounds of this invention would be active in this model.

Claims (26)

1. A compound of formula I: 5 R O R' -SO 2 -N(R 2 )-C-Q-CH-C-OH I I H R 5 10 where R' is selected from the group consisting of alkyl, substituted alkyl, 15 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, 20 heteroaryl, substituted heteroaryl, and R' and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to RI can form a heterocyclic or a substituted heterocyclic group; R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, 25 substituted heteroaryl, heterocyclic, substituted heterocyclic, and where R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 form an unsaturated heterocyclic group or a unsaturated substituted heterocyclic group; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, 30 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; WO 99/06433 PCT/US98/15952 -149 X is selected from the group consisting of oxygen and sulfur; and R 5 is -CH 2 X where X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, 5 carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and 10 substituted heterocyclic, with the further provisos that: A. R 5 is not -(CH 2 )x-Ar-R 5 ' where R 5 ' is selected from the group consisting of -O-Z-NRSR 8 ' and -O-Z-R 1 2 wherein R 8 and R 8 ' are independently selected from the group consisting of hydrogen, alkyl, 15 substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 8 and R 8 ' are joined to form a heterocycle or a substituted heterocycle, R 1 2 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO 2 -, 20 Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; B. R 5 is not -(CH 2 )x-Ar-R 5 ' where R 5 ' is selected from the group consisting of -NR1 2 C(Z')NRSR 8 ' and -NR1 2 C(Z')R 13 wherein Z' is selected from the group consisting of oxygen, sulfur and NR 1 2 , R 12 is selected from 25 the group consisting of hydrogen, alkyl and aryl, R 8 and R 8 ' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z' is oxygen, at least one of R 8 and R 8 ' is sustituted 30 alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than WO 99/06433 PCT/US98/15952 -150 morpholino and thiomorpholino, substituted heterocyclic or R 8 and R 8 ' can be joined to form a saturated heterocycle other than morpholino or thiomorpholino, a saturated substituted heterocycle or a saturated/unsaturated heterocycle having an amino group substituted with 5 an alkoxycarbonyl substituent, and further provided that when Z' is sulfur, at least one of R 8 and R 8 ' is a group other than aryl, substituted aryl, heteroaryl or substituted heteroaryl, R 13 is selected from the group consisting of substituted heterocycles and saturated heterocycles other than morpholino and thiomorpholino, 10 Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer of from 1 to 4; C. R 5 is not -ALK-X' where ALK is an alkyl group of from 1 to 10 carbon atoms attached via a methylene group (-CH 2 -) to the carbon atom to which it is attached; X' is selected from the group consisting of 15 substituted alkylcarbonylamino, substituted alkenylcarbonylamino, substituted alkynylcarbonylamino, heterocyclylcarbonylamino, substituted heterocyclylcarbonylamino, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, 20 substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic, substituted saturated heterocyclic, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted 25 heterocycloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, guanidino, amidino, alkylamidino, thioamidino, halogen, cyano, nitro, -OS(O 2 -alkyl, -OS(O) 2 -substituted alkyl, -OS(O) 2 -cycloalkyl, -OS(O) 2 -substituted cycloalkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, WO 99/06433 PCT/US98/15952 -151 -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -OSO 2 -NRR, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -cycloalkyl, -NRS(O) 2 -substituted cycloalkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted 5 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 cycloalkyl, -NRS(O) 2 -NR-substituted cycloalkyl, -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 10 substituted heterocyclic where R is hydrogen or alkyl, -S(O) 2 -alkyl, -S(O) 2 substituted alkyl, -S(O) 2 -aryl, -S(O) 2 -substituted aryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 -heterocyclic, -S(O) 2 substituted heterocyclic, mono- and di-(substituted alkyl)amino, N,N (alkyl, substituted alkyl)amino, N,N-(aryl, substituted alkyl)amino, N,N 15 (substituted aryl, substituted alkyl)amino, N,N-(heteroaryl, substituted alkyl)amino, N,N-(substituted heteroaryl, substituted alkyl)amino, N,N (heterocyclic, substituted alkyl)amino, N,N-N,N-(substituted heterocyclic, substituted alkyl)amino, mono- and di-(heterocyclic)amino, mono- and di (substituted heterocyclic)amino, N,N-(alkyl, heterocyclic)amino, N,N 20 (alkyl, substituted heterocyclic)amino, N,N-(aryl, heterocyclic)amino, N,N-(substituted aryl, heterocyclic)amino, N,N-(aryl, substituted heterocyclic)amino, N,N-(substituted aryl, substituted heterocyclic)amino, N,N-(heteroaryl, heterocyclic)amino, N,N-(heteroaryl, substituted heterocyclic)amino, N,N-(substituted heteroaryl, heterocyclic)amino, and 25 N,N-(substituted heteroaryl, substituted heterocyclic)amino; D. R 5 is not -(CH 2 )x-Ar-R" where R 5" is a substituent selected from the group consisting of: (a) substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group 30 consisting of alkoxy, substituted alkoxy, acyl, acylamino, WO 99/06433 PCT/US98/15952 -152 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 5 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, 10 substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(O) 2 15 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, -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, 20 -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, mono- and di alkylamino, mono- and di-(substituted alkyl)amino, mono- and di 25 arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, 30 heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, WO 99/06433 PCT/US98/15952 -153 substituted alkyl groups having amino groups blocked by conventional blocking groups and alkyl/substituted alkyl groups substituted with -SO 2 alkyl, -S0 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO2 cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, 5 SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO2 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; (b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR 23 where R 2 3 is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, 10 (c) aryl and heteroaryl; (d) -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 15 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, 20 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 25 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 30 thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, WO 99/06433 PCT/US98/15952 -154 substituted cycloalkyoxy, heteraryloxy, 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 5 heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -OSO 2 NRR, -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, 10 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, mono- and di-alkylamino, mono- and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di (substituted aryl)amino, mono- and di-heteroarylamino, mono- and di 15 (substituted heteroaryl)amino, mono- and di-heterocyclic amino, mono- and di-(substituted heterocyclic) amino, and unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having 20 amino groups blocked by conventional blocking groups and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -S0 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -S0 2 -heteroaryl, SO 2 -substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic 25 or -SO 2 NRR, where R is hydrogen or alkyl; (e) -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 30 R" is substituted alkyl then at least one of the substituents on the substituted WO 99/06433 PCT/US98/15952 -155 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, 5 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, 10 guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, 15 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, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, 20 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 25 substituted heterocyclic, mono- and di-alkylamino, mono- and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di (substituted aryl)amino, 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 30 having different substituents selected from the group consisting of alkyl, WO 99/06433 PCT/US98/15952 -156 substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -SO 2 -substituted 5 alkyl, -SO 2 -alkenyl, -S0 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 heteroaryl, -SO2-substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; (f) substituted aryloxy and substituted heteroaryloxy with the proviso 10 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, 15 alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; (g) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy substituted saturated heterocyclic; (h) -O-heterocyclic and -O-substituted heterocyclic; 20 (i) tetrazolyl; (j) -NR-SO 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 25 - dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted 30 alkenylsulfonylamino and substituted alkynylsulfonylamino; WO 99/06433 PCT/US98/15952 -157 (1) 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, 5 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; 10 (m) amidine and amidine substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; (n) -C(O)NR"' R'' where each R' ' is independently selected from the 15 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 R' is unsaturated heterocyclic, aryl, heteroaryl or aryl/heteroaryl 20 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, 25 then the other R"' is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic and substituted heterocyclic; (o) -NR 22 C(O)-R 8 where R' 8 is selected from the group consisting of 30 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted WO 99/06433 PCT/US98/15952 -158 aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; 5 (p) -S0 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -S0 2 -substituted heteroaryl or -S0 2 -alkyl; (q) -NR'C(O)NR' 9 R 19 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted 10 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: (r) -NR'C(O)OR" 9 wherein R' is selected from the group consisting of 15 alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted 20 heterocyclic; (s) -aminocarbonyl-(N-formylheterocylcyl); and (t) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, and E. When R 3 is other than H, R 5 is not -(CH 2 )x-Ar-R" where R 5 " is 25 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 30 substituted with substituted alkyl then at least one of the substituents on the WO 99/06433 PCT/US98/15952 -159 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, 5 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, 10 guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, 15 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, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, 20 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 25 substituted heterocyclic, mono- and di-alkylamino, mono- and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di (substituted aryl)amino, 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 30 having different substituents selected from the group consisting of alkyl, WO 99/06433 PCT/US98/15952 -160 substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and alkyl/substituted alkyl groups substituted with 5 SO 2 -alkyl, -S0 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, SO 2 -cycloalkyl, -S0 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -S0 2 -heterocyclic, -S02 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; and pharmaceutically acceptable salts thereof 10 and still further with the following provisos excluding the following compounds A. when R' and R 2 are joined together with the SO 2 and nitrogen atom to which they are attached respectively to form a benzoisothiazolone heterocyclic ring, R 3 is hydrogen, and Q is -C(O)NH-, then R is not 15 benzyl; and B. when R' is p-methylphenyl, R 2 is methyl, R 3 is hydrogen, Q is -C(O)NCH 3 -, then R 5 is not benzyl.

2. A compound of formula IA: 20 R 3 O R 1 -S O z -N(R 2 )-C-Q-CH-C-R 6 IA 1 1 25 H 1 where R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, 30 substituted heterocylic, heteroaryl and substituted heteroaryl; R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted WO 99/06433 PCT/US98/15952 -161 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; 5 R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 form an unsaturated heterocyclic group or a unsaturated 10 substituted heterocyclic group; 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 15 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 1 I where R 9 is selected from the group consisting of -C(O)-aryl and -C(O)-substituted aryl and RI is selected from 20 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 25 hydrogen and alkyl; X is selected from the group consisting of oxygen and sulfur; R 5 is -CH 2 X where X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, 30 carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, WO 99/06433 PCT/US98/15952 -162 carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and 5 substituted heterocyclic, with the further provisos that: A. R 5 is not -(CH 2 )x-Ar-R 5 ' where R 5 ' is selected from the group consisting of -O-Z-NRR 8 ' and -O-Z-R 12 wherein R 8 and R 8 ' are independently selected from the group consisting of hydrogen, alkyl, 10 substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 8 and R 8 ' are joined to form a heterocycle or a substituted heterocycle, R 1 2 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO 2 -, 15 Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4; B. R 5 is not -(CH 2 )x-Ar-R 5 ' where R 5 ' is selected from the group consisting of -NR 1 2 C(Z')NRR 8 ' and -NR1 2 C(Z')R 3 wherein Z' is selected from the group consisting of oxygen, sulfur and NR' 2 , R1 2 is selected from 20 the group consisting of hydrogen, alkyl and aryl, R 8 and R 8 ' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z' is oxygen, at least one of R 8 and R 8 ' is sustituted 25 alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, substituted heterocyclic or R 8 and R 8 ' can be joined to form a saturated heterocycle other than morpholino or thiomorpholino, a saturated substituted heterocycle or a saturated/unsaturated heterocycle having an amino group substituted with 30 an alkoxycarbonyl substituent, and further provided that when Z' is sulfur, WO 99/06433 PCT/US98/15952 -163 at least one of R 8 and R 8 ' is a group other than aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R 1 3 is selected from the group consisting of substituted heterocycles and saturated heterocycles other than morpholino and thiomorpholino, 5 Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer of from 1 to 4; C. R 5 is not -ALK-X' where ALK is an alkyl group of from 1 to 10 carbon atoms attached via a methylene group (-CH 2 -) to the carbon atom to which it is attached; X' is selected from the group consisting of 10 substituted alkylcarbonylamino, substituted alkenylcarbonylamino, substituted alkynylcarbonylamino, heterocyclylcarbonylamino, substituted heterocyclylcarbonylamino, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, 15 substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic, substituted saturated heterocyclic, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted 20 heterocycloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, guanidino, amidino, alkylamidino, thioamidino, halogen, cyano, nitro, -OS(O) 2 -alkyl, -OS(O) 2 -substituted alkyl, -OS(O) 2 -cycloalkyl, -OS(O) 2 -substituted cycloalkyl, -OS(O) 2 -aryl, -OS(O) 2 -substituted aryl, -OS(O) 2 -heteroaryl, 25 -OS(O) 2 -substituted heteroaryl, -OS(O) 2 -heterocyclic, -OS(O),-substituted heterocyclic, -OSO 2 -NRR where R is hydrogen or alky, -NRS(O)-alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -cycloalkyl, -NRS(O) 2 -substituted cycloalkyl, -NRS(O) 2 -aryl, -NRS(O) 2 -substituted aryl, -NRS(O) 2 heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, 30 NRS(O) 2 -substituted heterocyclic, -NRS(O) 2 -NR-alkyl, -NRS(O) 2 -NR- WO 99/06433 PCT/US98/15952 -164 substituted alkyl, -NRS(O) 2 -NR-cycloalkyl, -NRS(O) 2 -NR-substituted cycloalkyl, -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 5 alkyl, -S(O) 2 -alkyl, -S(O) 2 -substituted alkyl, -S(O) 2 -aryl, -S(O) 2 -substituted aryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 -substituted heteroaryl, -S(O) 2 heterocyclic, -S(O) 2 -substituted heterocyclic, mono- and di-(substituted alkyl)amino, N,N-(alkyl, substituted alkyl)amino, N,N-(aryl, substituted alkyl)amino, N,N-(substituted aryl, substituted alkyl)amino, N,N 10 (heteroaryl, substituted alkyl)amino, N,N-(substituted heteroaryl, substituted alkyl)amino, N,N-(heterocyclic, substituted alkyl)amino, N,N N,N-(substituted heterocyclic, substituted alkyl)amino, mono- and di (heterocyclic)amino, mono- and di-(substituted heterocyclic)amino, N,N (alkyl, heterocyclic)amino, N,N-(alkyl, substituted heterocyclic)amino, 15 N,N-(aryl, heterocyclic)amino, N,N-(substituted aryl, heterocyclic)amino, N,N-(aryl, substituted heterocyclic)amino, N,N-(substituted aryl, substituted heterocyclic)amino, N,N-(heteroaryl, heterocyclic)amino, N,N (heteroaryl, substituted heterocyclic)amino, N,N-(substituted heteroaryl, heterocyclic)amino, and N,N-(substituted heteroaryl, substituted 20 heterocyclic)amino; D. R 5 is not -(CH2)x-Ar-R 5" where R 5 " is a substituent selected from the group consisting of: (a) substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group 25 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 30 cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl- WO 99/06433 PCT/US98/15952 -165 substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, 5 substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(O) 2 -alkyl, -OS(0) 2 10 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, -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, 15 -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, mono- and di alkylamino, mono- and di-(substituted alkyl)amino, mono- and di 20 arylamino, mono- and di-(substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, 25 heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and alkyl/substituted alkyl groups substituted with -SO 2 alkyl, -S0 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -S02 cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO2-substituted aryl, - WO 99/06433 PCT/US98/15952 -166 SO 2 -heteroaryl, -SO2-substituted heteroaryl, -S0 2 -heterocyclic, -SO2 substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; (b) alkoxyaryl substituted on the alkoxy moiety with a substituent selected from the group consisting of carboxyl and -COOR 23 where R 23 is 5 alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic, (c) aryl and heteroaryl; (d) -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 10 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, 15 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, 20 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, 25 thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkyoxy, heteraryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS(0) 2 -alkyl, -OS(0) 2 -substituted alkyl, -OS(0) 2 30 aryl, -OS(O) 2 -substituted aryl, -OS(0) 2 -heteroaryl, -OS(O) 2 -substituted WO 99/06433 PCT/US98/15952 -167 heteroaryl, -OS(O) 2 -heterocyclic, -OS(O) 2 -substituted heterocyclic, -OSO 2 NRR, -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, 5 -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, mono- and di-alkylamino, mono- and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di 10 (substituted aryl)amino, 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 the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 15 heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and alkyl/substituted alkyl groups substituted with -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -S0 2 -cycloalkyl, -SO2-substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -S02 20 heteroaryl, -SO2-substituted heteroaryl, -SO 2 -heterocyclic, -S0 2 -substituted heterocyclic or -SOzNRR, where R is hydrogen or alkyl; (e) -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, 25 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, 30 aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, WO 99/06433 PCT/US98/15952 -168 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 5 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, 10 substituted cycloalkyoxy, heteraryloxy, 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, -OSO 2 15 NRR, -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 20 substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR substituted heterocyclic, mono- and di-alkylamino, mono- and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di (substituted aryl)amino, mono- and di-heteroarylamino, mono- and di (substituted heteroaryl)amino, mono- and di-heterocyclic amino, mono- and 25 di-(substituted heterocyclic) amino, and unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and 30 alkyl/substituted alkyl groups substituted with -SO2-alkyl, -S0 2 -substituted WO 99/06433 PCT/US98/15952 -169 alkyl, -S0 2 -alkenyl, -SO2-substituted alkenyl, -SO 2 -cycloalkyl, -SO2 substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -S0 2 -heteroaryl, SO2-substituted heteroaryl, -SO 2 -heterocyclic, -SO 2 -substituted heterocyclic or -SO 2 NRR, where R is hydrogen or alkyl; 5 (f) 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, 10 alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea; (g) -alkoxy-saturated heterocyclic, -alkoxy-saturated substituted heterocyclic, -substituted alkoxy-heterocyclic and -substituted alkoxy substituted saturated heterocyclic; 15 (h) -O-heterocyclic and -O-substituted heterocyclic; (i) tetrazolyl; (j) -NR-SO 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, 20 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; 25 (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; (1) 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 30 and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, WO 99/06433 PCT/US98/15952 -170 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 5 N,N-dialkylurea; (m) amidine and amidine substituted with from 1 to 3 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; 10 (n) -C(O)NR'" R"' where each R"' 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 15 R"' is unsaturated heterocyclic, 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, 20 alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea, then the other R' " is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted-alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic and substituted heterocyclic; 25 (o) -NR 22 C(O)-R' 8 where R 18 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 22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, 30 heterocyclic or substituted heterocyclic; WO 99/06433 PCT/US98/15952 -171 (p) -S0 2 -aryl, -S0 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl or -SO 2 -alkyl; (q) -NR'C(O)NR1 9 R 1 9 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted 5 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 19 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: 10 (r) -NR'C(O)OR 19 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 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted 15 aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (s) -aminocarbonyl-(N-formylheterocylcyl); and (t) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, and 20 E. When R 3 is other than H, R 5 is not -(CH 2 )x-Ar-R" where R 5 " is 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, 25 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, 30 aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, WO 99/06433 PCT/US98/15952 -172 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, 5 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, 10 substituted cycloalkyoxy, heteraryloxy, 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, -OSO 2 15 NRR, -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 20 substituted heteroaryl, -NRS(O) 2 -NR-heterocyclic, -NRS(O) 2 -NR substituted heterocyclic, mono- and di-alkylamino, mono- and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di (substituted aryl)amino, mono- and di-heteroarylamino, mono- and di (substituted heteroaryl)amino, mono- and di-heterocyclic amino, mono- and 25 di-(substituted heterocyclic) amino, and unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, 30 formyl, and the like) and alkyl/substituted alkyl groups substituted with WO 99/06433 PCT/US98/15952 -173 -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 -cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -SO 2 -heterocyclic, -S02 substituted heterocyclic or -SOzNRR, where R is hydrogen or alkyl; 5 and pharmaceutically acceptable salts thereof, with the following provisos A. when R' is o-carboxymethylphenyl, R 2 is hydrogen, R 3 is hydrogen or methyl, R 5 is benzyl and Q is -C(0)NH-, then R 6 is not -O-benzyl; 10 B. when R' and R 2 are joined to form a benzoisothiazolone heterocyclic ring, R 3 is hydrogen or methyl, R 5 is benzyl and Q is -C(0)NH-, then R 6 is not -O-benzyl; C. when R' is p-methylphenyl, R is hydrogen, R 5 is benzyl or p-hydroxybenzyl, R 3 is -(CH 2 )sC(0)O-t-butyl where s is 1 or 2, Q is 15 -C(0)NH-, then R 6 is not -O-t-butyl; D. when R' is p-methylphenyl, R 2 is methyl, R 5 is benzyl, R 3 is -CH(Q) 2 , Q is -C(0)NH-, then R 6 is not -O-benzyl; E. when R 1 is p-methylphenyl, R 2 is methyl, R 5 is methyl, R 3 is -hydroxymethyl, Q is -C(0)NH-, then R 6 is not -O-methyl; and 20 F. when R' is p-methylphenyl, R 2 is methyl, R 3 is methyl or t-butyl, R 5 is p-hydroxybenzyl, Q is -C(0)NH-, then R 6 is not -O-t-butyl. 3. A compound according to Claims 1 or 2 wherein R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, 25 heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl.

4. A compound according to Claims 1 or 2 wherein R is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4 chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6 30 trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5- WO 99/06433 PCT/US98/15952 -174 dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4 dimethoxyphenyl, 4-(CH 3 C(O)NH-)phenyl, 4-trifluoromethoxyphenyl, 4 cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4 t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5 5 chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4-[CH 3 SC(=NH)]phenyl, 5 chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2 thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-[H 2 NC(S)]phenyl, 4 aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5 10 difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4-(3'-dimethylamino-n propoxy)-phenyl, and 1-methylpyrazol-4-yl.

5. A compound according to Claims 1 or 2 wherein R 2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, -(CH 2 ) 2 -2 15 thienyl, and -(CH 2 ) 2 - 4 .

6. A compound according to Claims 1 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. 20

7. A compound according to Claims 1 or 2 wherein R 3 is selected from the group consisting of methyl, phenyl, benzyl, diphenylmethyl, -CH 2 CH 2 -COOH, -CH 2 -COOH, 2-amidoethyl, iso-butyl, t-butyl, -CH 2 0 benzyl and hydroxymethyl. 25

8. A compound according to Claims 1 or 2 wherein R 2 and R 3 together with the nitrogen atom bound to R and the carbon atom bound to R 3 are joined to form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group. 30 WO 99/06433 PCT/US98/15952 -175

9. A compound according to Claims 1 or 2 wherein Q is -C(0)NH- or -C(S)NH-. 5

10. A compound according to Claims 1 or 2 wherein R is selected from the group consisting of benzyl, (N-benzylimidazol-4-yl)methyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 4-[2 (pyridin-2-yl)ethynyl]benzyl, 4-[2-(3-hydroxyphenyl)ethynyl]benzyl, 4 iodobenzyl, 4-cyanobenzyl, 4-(2-bromobenzamido)benzyl, 4-(pyridin-4-yl 10 C(0)NH-)benzyl, and 4-hydroxybenzyl.

11. A compound according to Claims 1 or 2 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 15 pentoxy, 2-a-iso-propyl-4-p-methylcyclohexoxy, 2-p-isopropyl-4-p methylcyclohexoxy, -NH 2 , benzyloxy, -NHCH 2 COOH, -NHCH 2 CH 2 COOH, -NH-adamantyl, -NHCH 2 CH 2 COOCH 2 CH 3 , -NHSO 2 p-CH 3 -4, -NHOR 8 where R 8 is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), -O-cholest-5-en-3-p-yl, -OCH 2 -OC(0)C(CH 3 ) 3 , 20 -O(CH2)zNHC(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, -NR"C(0)-R' where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH 2 C(0)OCH 2 CH 3 . 25

12. A compound selected from the group consisting of N-(toluene-4-sulfonyl)-(2S-indolin-2-carbonyl)-L-phenylalanine N-(toluene-4-sulfonyl)-(2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl L-phenylalanine 30 N-(toluene-4-sulfonyl)glycyl-L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-L-phenylalanine WO 99/06433 PCT/US98/1 5952 -176 N-(toluene-4-sulfonyl)-L-alanyl-L-phenylalanine N-(2-methoxycarbonylbenzenesulfonyl)glycyl-L-phenylalanine 5 N-(2-methoxycarbonylbenzenesulfonyl)-L-alanyl-L-phenylalanine N-(saccharin-2-yl)-L-alanyl-L-phenylalanine N-(toluene-4-sulfonyl)-D ,L-phenylglycyl-L-phenylalanine 10 N-(toluene-4-sulfonyl)-N-methyl-L-phenylalanyl-D ,L-phenylalanine N-(toluene-4-sulfonyl)-L-diphenylalanyl-L-phenylalanine 15 N-(toluene-4-sulfonyl)-N-methyl-L-diphenylalanyl-L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-L-(N-benzyl)histidine N-(toluene-4-sulfonyl)sarcosyl-D ,L-P-(3-pyridyl)alanine 20 N-(toluene-4-sulfonyl)sarcosyl-D ,L-P-(4-pyridyl)alanine N-(toluene-4-sulfonyl)sarcosyl-L-P-(2-pyridyl)alanine 25 N-(toluene-4-sulfonyl)-D ,L-phenylsarcosyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-aspartyl-L-phenylalanine N-(toluene-4-sulfonyl)-(2S- 1,2,3 ,4-tetrahydroisoquinolin-3-carbonyl) 30 L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-(2S-indolin-2-carbonyl)-L-phenylalanine benzyl ester 35 N-(toluene-4-sulfonyl)-L-alanyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)sarcosyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-D ,L-phenylglycyl-L-phenylalanine ethyl ester 40 N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)seryl-L-phenylalanine ethyl ester WO 99/06433 PCT/US98/15952 -177 N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)seryl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-diphenylalanyl-L-phenylalanine benzyl ester 5 N-(toluene-4-sulfonyl)-N-phenylglycyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-D,L-phenylglycyl-L-phenylalanine ethyl ester 10 N-(toluene-4-sulfonyl)sarcosyl-L-(N-benzyl)histidine methyl ester N-(toluene-4-sulfonyl)-N-methyl-L-seryl-L-(N-benzyl)histidine methyl ester 15 N-(toluene-4-sulfonyl)-D,L-phenylglycyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-N-methyl-D,L-phenylglycyl-L-phenylalanine benzyl ester 20 N-(toluene-4-sulfonyl)-N-benzylglycyl-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-N-benzylglycyl-L-phenylalanine 25 N-(toluene-4-sulfonyl)sarcosyl-4-[2-(pyridin-2-yl)ethynyl]-D,L phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-[2-(3-hydroxyphenyl)ethynyl]-D,L phenylalanine 30 N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(iodo)phenylalanine N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycyl-L-phenylalanine methyl ester 35 N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-L-seryl-L-(N-benzyl)histidine methyl ester 40 N-(toluene-4-sulfonyl)-N-(2-phenylethyl)glycyl-L-(N-benzyl)histidine methyl ester N-(toluene-4-sulfonyl)-N-(2-phenylethyl)glycyl-L-phenylalanine WO 99/06433 PCT/US98/15952 -178 N-(toluene-4-sulfonyl)sarcosyl-D,L-4-cyanophenylalanine N-(toluene-4-sulfonyl)-L-tert-butylglycyl-L-phenylalanine 5 N-(saccharin-2-yl)-D,L-alaninyl-L-4-(isonicotinamido)phenylalanine methyl ester and pharmaceutically acceptable salts thereof as well as any of the ester 10 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. 15

13. A method for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of Claims 1 or 2 under conditions wherein said compound binds to VLA-4.

14. The method of claim 13 wherein R' is selected from the group 20 consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl.

15. The method of claim 13 wherein R is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1 25 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, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t 30 butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5 chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4-[CH 3 SC(= NH)]phenyl, 5- WO 99/06433 PCT/US98/15952 -179 chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2 thiazolyl, 5-methyl-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 5 propoxy)-phenyl, and 1-methylpyrazol-4-yl.

16. The method of claim 13 wherein R 2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, -(CH 2 ) 2 -2-thienyl, and -(CH2)2- * 10

17. The method of 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. 15

18. The method of claim 13 wherein R 3 is selected from the group consisting of methyl, phenyl, benzyl, diphenylmethyl, -CH 2 CH 2 -COOH, -CH 2 -COOH, 2-amidoethyl, iso-butyl, t-butyl, -CH 2 0 benzyl and hydroxymethyl. 20

19. The method of claim 13 wherein R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 are joined to form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group. 25

20. The method of claim 13 wherein Q is -C(O)NH- or -C(S)NH-.

21. The method of claim 13 wherein R is selected from the group consisting of benzyl, (N-benzylimidazol-4-yl)methyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 4-[2-(pyridin-2 30 yl)ethynyl]benzyl, 4-[2-(3-hydroxyphenyl)ethynyl]benzyl, 4-iodobenzyl, 4- WO 99/06433 PCT/US98/15952 -180 cyanobenzyl, 4-(2-bromobenzamido)benzyl, 4-(pyridin-4-yl-C(O)NH )benzyl, and 4-hydroxybenzyl.

22. The method of claim 13 wherein R 6 is selected from the group 5 consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso propyl-4-p-methylcyclohexoxy, 2-p-isopropyl-4-p-methylcyclohexoxy, -NH 2 , benzyloxy, -NHCH 2 COOH, -NHCH 2 CH 2 COOH, -NH-adamantyl, -NHCH 2 CH 2 COOCH 2 CH 3 , -NHSO 2 -p-CH 3 -4, -NHOR 8 where R 8 is 10 hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), -O-cholest-5 en-3-p-yl, -OCH 2 -OC(O)C(CH3) 3 , -O(CHz)zNHC(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, -NR"C(O)-R' where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or 15 CH 2 C(O)OCH 2 CH 3 .

23. The method of claim 13 wherein the compound is selected from the group consisting of: N-(toluene-4-sulfonyl)-(2S-indolin-2-carbonyl)-L-phenylalanine 20 N-(toluene-4-sulfonyl)-(2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl L-phenylalanine N-(toluene-4-sulfonyl)glycyl-L-phenylalanine 25 N-(toluene-4-sulfonyl)sarcosyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-alanyl-L-phenylalanine 30 N-(2-methoxycarbonylbenzenesulfonyl)glycyl-L-phenylalanine N-(2-methoxycarbonylbenzenesulfonyl)-L-alanyl-L-phenylalanine N-(saccharin-2-yl)-L-alanyl-L-phenylalanine 35 WO 99/06433 PCT/US98/15952 -181 N-(toluene-4-sulfonyl)-D,L-phenylglycyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-L-phenylalanyl-D,L-phenylalanine 5 N-(toluene-4-sulfonyl)-L-diphenylalanyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-L-diphenylalanyl-L-phenylalanine N-(toluene-4-sulfonyl)sarcosyl-L-(N-benzyl)histidine 10 N-(toluene-4-sulfonyl)sarcosyl-D,L-P-(3-pyridyl)alanine N-(toluene-4-sulfonyl)sarcosyl-D,L-P-(4-pyridyl)alanine 15 N-(toluene-4-sulfonyl)sarcosyl-L-P-(2-pyridyl)alanine N-(toluene-4-sulfonyl)-D,L-phenylsarcosyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-aspartyl-L-phenylalanine 20 N-(toluene-4-sulfonyl)-(2S-1,2,3,4-tetrahydroisoquinolin-3-carbonyl) L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-(2S-indolin-2-carbonyl)-L-phenylalanine benzyl 25 ester N-(toluene-4-sulfonyl)-L-alanyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)sarcosyl-L-phenylalanine benzyl ester 30 N-(toluene-4-sulfonyl)-D,L-phenylglycyl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)seryl-L-phenylalanine ethyl ester 35 N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)seryl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-diphenylalanyl-L-phenylalanine benzyl ester 40 N-(toluene-4-sulfonyl)-N-phenylglycyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-D,L-phenylglycyl-L-phenylalanine ethyl ester WO 99/06433 PCT/US98/15952 -182 N-(toluene-4-sulfonyl)sarcosyl-L-(N-benzyl)histidine methyl ester N-(toluene-4-sulfonyl)-N-methyl-L-seryl-L-(N-benzyl)histidine methyl ester 5 N-(toluene-4-sulfonyl)-D,L-phenylglycyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-N-methyl-D,L-phenylglycyl-L-phenylalanine benzyl ester 10 N-(toluene-4-sulfonyl)-N-benzylglycyl-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-N-benzylglycyl-L-phenylalanine 15 N-(toluene-4-sulfonyl)sarcosyl-4-[2-(pyridin-2-yl)ethynyl]-D,L phenylalanine N-(toluene-4-sulfonyl)sarcosyl-4-[2-(3-hydroxyphenyl)ethynyl]-D,L phenylalanine 20 N-(toluene-4-sulfonyl)sarcosyl-D,L-4-(iodo)phenylalanine N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycyl-L-phenylalanine methyl ester 25 N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycyl-L-phenylalanine N-(toluene-4-sulfonyl)-N-methyl-L-seryl-L-(N-benzyl)histidine methyl ester 30 N-(toluene-4-sulfonyl)-N-(2-phenylethyl)glycyl-L-(N-benzyl)histidine methyl ester N-(toluene-4-sulfonyl)-N-(2-phenylethyl)glycyl-L-phenylalanine 35 N-(toluene-4-sulfonyl)sarcosyl-D,L-4-cyanophenylalanine N-(toluene-4-sulfonyl)-L-tert-butylglycyl-L-phenylalanine 40 N-(saccharin-2-yl)-D,L-alaninyl-L-4-(isonicotinamido)phenylalanine methyl ester and pharmaceutically acceptable salts thereof as well as any of the ester compounds recited above wherein one ester is replaced with another ester WO 99/06433 PCT/US98/15952 -183 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. 5

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of Claims 1 or 2.

25. A method for treating an inflammatory disease in a mammalian 10 patient which disease is mediated by VLA-4 which method comprises administering to said patient a therapeutically effective amount of the pharmaceutical composition of Claim 24.

26. The method according to Claim 25 wherein said inflammatory 15 condition 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 20 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.