MXPA00000678A - Sulfonylated dipeptide compounds which inhibit leukocyte adhesion mediated by vla-4 - Google Patents

Abstract

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Description

SULFONYLATED DIPEPTIDIC COMPOUNDS THAT INHIBIT THE ADHESION OF LEUKOCYTES MEDIATED BY VLA - 4.

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to compounds that inhibit the adhesion of leukocytes and in particular, the adhesion of leukocytes mediated by VLA-4.

References The following publications, patents and patent applications are cited in this application as super index numbers: Hemler and Takada, European Patent Application Publication Number. 330,506, published on August 30, 1989.

Elices, et al Cell, 60: 577-584 (1990) Springer, Nature, 346: 425-434 (1990) REF .: 32335 ^^ jgj - ^^ Osborn, Cell, 62_: 3-6 (1990) Vedder, et al., Surgery, 106: 509 (1989) Pretolani, et al., J. Exp. Med., 180: 795 (1994) Abraham, et al., J. Clin. Invest., 93: 776 (1994) 10 Mulligan, et al., J. Immunology, 150: 2407 (1993) Cybulsky, et al., Science, 251: 788 (1991) 10 Li, et al., Arteríoscler. Thromb., 13: 197 (1993) 11 Sasseville, et al. , Am. J. Path, 144: 27 (1994) 12 Yang, et al., Proc. Nat. Acad. Science (USA), 90: 10494 (1993) 13 Burkly, et al., Diabetes, 4X529 (1994) 14 Baron, et al., J. Clin. Invest. 93: 1700 (1994) Hamann et al. , J. Immunology, 152: 3231 (1994) 16 Yednock, et al., Nature, 356: 63 (1992 17 Baron, et al., J. Exp. Med., 177: 57 (1993) van Dinther-Janssen, et al., J. Imm nology, 147: 4207 (1991) 19 van Dinther-Janssen, et al., Anna ls Rheumatic Dis. , 52: 672 (1993) Ellees, et al. , J. Clin. Invest. 93: 405 (1994) 1 Postigo, et al. , J. Clin. Invest. 89: 1445 (1991) 2 Paul, et al. , Transpl. Proceed. , 25: 813 (1993) 23 Okarhara, et al Can. Res. , 54: 3233 (1994) 24 Paavonen, et al., Int. J. Can. Res., 58: 2 (1994) Schadendorf, et al., J. Path., 170: 429 (1993) 26 Bao, et al. , Diff. , 52: 239 (1993) 27 Lauri, et al. , British J. Cancer, 68: 862 (1993) 28 Kawaguchi, et al. , Japanese J. Cancer Res., 83: 1304 (1992) 29 Kogan, et al., U.S. Patent No. 5, 510,332, issued April 23, 1996 Publication of International Patent Application No. WO 96/01644 - * '^ "" ^^ F ^^ 1 * < ^^^^^ ¿^? E £ ^ ¡^ m ^^ & All prior publications, patents and patent applications are hereby incorporated by reference in their entirety, to the same degree, as if each publication, patent or individual patent application was specifically and individually indicated to be incorporated by reference in its entirety.

State of the Art VLA-4 (also referred to as a4β integrin and CD49d / CD29), was first identified by Hemler and Takada1 as being a member of the β1-integrin family of cell surface receptors, each of the which comprises two subunits, an alpha chain and a β chain. The VLA-4 contains an a4 and a ßl chain. There are at least nine ß1 -int egrinas, all that share the same chain ßl and each one that has a different chain. These nine receptors all bind to a different complement of the various molecules of the cell matrix, such as fibronectin, lammine, and collagen. The VLA-4, for example, joins the fibronect ina. VLA-4 binds to non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed in endothelial cells of the human umbilical vein, activated by cytokine, in culture. Epitopes other than VLA-4 are responsible for the binding activities of fibronectin and VCAM-1 and each activity has been shown to be independently inhibited.2 VLA-4 mediated cell adhesion and other surface receptors cellular, is associated with a number of inflammatory responses. At the site of a lesion or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive to leukocytes. The mechanisms of adhesion of leukocytes to endothelial cells comprise, in part, the recognition and binding of cell surface receptors in leukocytes to the corresponding molecules of the cell surface in endothelial cells. Once bound, the leukocytes migrate through the wall of the blood vessel to enter the injured site and release the chemical mediators to fight the infection. For reviews of adhesion receptors of the immune system, see, for example, Sppnger3 and Osborn Inflammatory disorders of the brain, such as encephalomyelitis is an experimental autoimmune disease (EAE), multiple sclerosis (MS) and meningitis, are examples of several disorders of the central nervous system in which the mechanism of endothelial adhesion / Leukocytes result in the destruction of otherwise healthy brain tissue. Large numbers of leukocytes migrate through the blood-brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause damage to the extensive tissue resulting in impaired conduction of the medium and paralysis. In other organ systems, tissue damage can occur via a mechanism of injury resulting in migration or activation of leukocytes. For example, it has been shown that the initial trauma after myocardial ischemia to cardiac tissue can be further complicated by the entry of leukocytes into the injured tissue, causing further trauma (Vedder et al.5). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma6-8, Alzheimer's disease, atherosclerosis 9-10 dementia per AIDS11, diabetes12 14 (including acute onset diabetes) inflammatory bowel disease 15 including ulcerative colitis and Crohn's disease), multiple sclerosis 16-17 rheumatoid arthritis 18- "21, tissue transplantation 22, tumor metastasis23" 28, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and leukocyte-mediated acute lung injury such as that which occurs in the respiratory distress syndrome in adults. In view of the foregoing, assays to determine the level of VLA-4 in a biological sample containing VLA-4 would be useful, for example, in the diagnosis of conditions mediated by VLA-4. Additionally, despite these advances in the understanding of leukocyte adhesion, the technique has only recently addressed the use of adhesion inhibitors in the treatment of inflammatory diseases of the brain and other inflammatory conditions29-30. The present invention addresses these and other needs.

BRIEF DESCRIPTION OF THE INVENTION This invention provides compounds that bind to VLA-4. These compounds can be used, for example, to assess the presence of VLA-4 in a sample and in pharmaceutical compositions, to inhibit cell adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have binding affinity to VLA-4 as expressed by IC50 of about 15 μM or less (as measured using the procedure shown in Example 203 below) compounds that are defined by Formula I below: R.}. O I (R'-SO, -N (R2VC-Q-CH-C-OH I I H R5 wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; R 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 R1 and R2 together with the other nitrogen bound to R2 and the group S02 bonded to R1 can form a heterocyclic or substituted heterocyclic ring; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and wherein R2 and R3 together with the hydrogen atom attached to R2 and the carbon atom attached to R3 can form a heterocyclic group saturated by a substituted, saturated heterocyclic group, with the proviso that when it is monosubstituted, the substituent in the group Substituted, saturated heterocyclic is not carboxyl; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl; x is an integer from 1 to 4; Q is -C (X) NR7, wherein R7 is selected from the group consisting of hydrogen and alkyl; X is selected from the group consisting of oxygen and sulfur; R5 is -CH2X, wherein X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, substituted alkylcarboxyl, carboxyl-cycloalkyl, substituted cycloalkyl-carboxyl , carboxylalkyl, substituted aryl-carboxyl, carboxyheteroaryloyl, substituted heteroarylcarboxyl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic; with the proviso that: A. R5 is not selected from the group consisting of - (CH2) n-aryl and - (CH2) n-het eroar ilo where n is an integer equal to 1 to 4 where R2 and R3 together with a nitrogen atom attached to R2 and the carbon atom attached to R3 form a saturated heterocyclic group or a substituted, saturated heterocyclic group; B. R5 is not - (CH2) X-Ar-R5 'wherein R5' is selected from the group consisting of -0-Z-NR8R8 'and -OZ-R12, where Ar is aryl, heteroaryl, aryl substituted or substituted heteroaryl, x is an integer of 1 to, R8 and R8 'are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, and wherein R8 and R8 'join to form a heterocycle or a substituted heterocycle, R12 is selected from the group consisting of heterocycles and substituted heterocycles, and Z is selected from the group consisting of -C (O) - and - SO2 -; C. R5 is not - (CH2) X-Ar-R5 ', where Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer from 1 to 4, R5' is selected from the group consisting of of -NR2 C (Z- *) NR8R8 'and -NR 4C (ZXR13 wherein Z' is selected from the group consisting of oxygen, sulfur and NR24, R24 is selected from hydrogen, alkyl and aryl, R8 and R8 'is independently selected from the group consisting of »» Ígft ^ Sáa £ S¡e »3a« «A» «, * ... of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl with the proviso that when Z 'is oxygen, at least one of R8 and R8' is substituted alkyl, cycloalkyl , substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, substituted heterocyclic or R8 and R8 'are joined to form a saturated heterocyclic other than morpholino or thiomorpholino, a substituted, saturated heterocycle or a saturated / unsaturated heterocycle having a substituted amino group with an alkoxycarbonyl substituent, and with the additional proviso that Z 'is sulfur, at least one of R8 and R8' is a different group of aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R13 is selected from the group consisting of substituted heterocycles and saturated heterocycles different from morpholino and thiomorpholino; D. R5 is not -ALK-X, wherein ALK is an alkyl group of 1 to 10 carbon atoms attached via a methylene group - (CH2-) the carbon atom to which it is attached; x is selected from the group that J ^? The present invention consists of substituted alkylcarbonylamino, substituted alkenyl carbonylamino, a substituted subcarbonyl, heterocyclic, 1-carbonyl, substituted heterocyclic, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted erocyclic acid, substituted cycloalkyl, substituted cycloalkyl, substituted heterocyclic, saturated, substituted heterocyclic, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, het substituted alkyloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonyl lamino, aminothioca rbonyl, guanidino, amidino, alkylamidino, thioamidino, halogen, cyano, nitro, -OS (O) 2 -alkyl, -OS (0) 2-substituted alkyl, -OS (O) 2-cycloalkyl, -OS (0) -substituted cycloalkyl, -OS (O) 2 -aryl, -OS (0) 2 -substituted aryl, -OS (O) 2- heteroaryl, -OS '(0) 2-substituted heteroaryl, -OS (O) 2-het erocyclic, OS (O) 2-substituted heterocyclic, -OS02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alqu? it, -NRS (0) 2-substituted alkyl, -NRS (0) 2-cycloalk? io, NRS (0) 2-substituted cycloalkyl, -NRS (0) 2-aryl, NRS (0) 2-substituted aryl, -NRS (0) 2-het eroar i lo, NRS (0) 2-substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR- alky substituted, -NRS (0) 2-NR-cycloalkyl, -NRS (0) 2-NR-substituted cycloalkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-ary lo Substituted, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2 -NR-he t -rocic, -NRS (0) 2-NR- substituted heterocyclic where R is hydrogen or alkyl, -S (0) 2 -alkyl, -S (0) 2 -substituted alkyl, -S (0) 2 -aryl, -S (0) 2 -substituted aryl, -S (0) 2-het eroari lo, -S (0) 2-heteroary i substituted, -S (0) 2-heterocyclic, -S (0) 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, substi- tuted alkyl) amino, N, N- (heteroaryl, alkyl) substi tuted) amino, N, N- (substituted heteroaryl, substi tuted alkyl) amino, N, N- (h Eterocyclic, substi- tuted alkyl) amino, N, N-N, N- (substituted heterocyclic, alkyl • Substained amino, mono- and di- (substituted heterocyclic) amino,, - (at least one, heterocyclic) amino, N, N- (alkyl, substituted heterocyclic) amino, N, N- (aryl, het erocyclic) amino, N, N- (substituted aryl, heterocyclic) amino, N, N- (aryl, heterocyclic substi tuted) amino, N, N- (substituted aryl, heterocyclic subst i tuido) amino, N, N- (heteroaryl, heterocyclic) amino, N, N- (heteroaryl, substi tuted heterocyclic) amino, N, N- (substituted heteroaryl, heterocyclic) amino, and N, N- (heteroaryl hetero) substituted, substituted heterocyclic) amino; and E. R5 is not - (CH2) X-Ar-R5 'where R5"is a substituent selected from the group consisting of: (a) alkylcarbonylamino substituted with the proviso that at least one of the substituents on the alkyl portion substituted is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkylamidoino, thioamidino, aminoacyl, aminocarbomlamino, aminotiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted alkylcarboxyl, carboxyl-cycloalkyl, substituted cycloalkyl-carboxy, carboxyl-laryl, substituted-aryl-carboxyl, carboxyl-heteroaryl, substituted 1-carboxyl, carboxylheterocyclic, substituted heterocyclic with carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, ti O-cycloalkyl, substituted-cycloalkyl, thioheteroaryl, thioheteroaryl, substituted sulphuric acid, substituted thiohcyl, substituted heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyl, oxy carbonylamino, oxitiocarboni lamino, -OS (0) 2-alkyl, -OS (O) -alkyl substituted, -OS (0) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2-heteroaryl lo, OS (O) 2-substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (O) 2-substituted erocyclic het, OS (0) 2 ~ NRR, -NRS (O) 2-alkyl, -NRS (O) 2-substituted alky, -NRS (O) 2-aryl, -NRS (O) 2-ary substituted, -NRS (0) 2-heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic, NRS (O) 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, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-het eroar i the substituted, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (alkyl) substi- tuted) amino, mono- and di-arylamino, mono- and di- (substi- tuted aryl) amino, mono- and di-heteroaryl, mono- and di- (het eroar i substi tuted) amino, mono- and di-het erocyclic-amino, mono- and di- (heterocyclic substi tuted) amino, non-asymmetric di-subs amines di-subsides having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like), and substituted alkyl / substituted alkyl groups with -S02-alkyl, -S02-substituted alkyl, -S0 -alkenyl, -S0 -substituted alkenyl, -S02-cycloalkyl, -S-substituted? -cycloalkyl, -S02-aryl-0S (0) -substituted aryl , S-2-het eroary, -S-2-substituted heteroaryl, -S02-heterocyclic, -S-2-substituted heterocyclic or S02NRR, wherein R is hydrogen or alkyl; (b) alkoxyaryl substituted on the alkoxy portion with a substituent selected from the group consisting of carboxyl and -COOR23, wherein R23 is 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 heterocyclic substituted with the condition that at least one of R 'is substituted alkyl, substituted cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the additional proviso that when R' is substituted alkyl at least one of the substituents in the substituted alkyl portion is selected from of the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbom lamino, acyloxy, alkenyl, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminotiocarbonylamino, aminocarboni loxi, aryloxy, substituted aryloxy, cyano, nitro, halogen , hydroxyl, carboxyl, carboxy lalky, carboxyl- Substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxyl-laryl, substituted-carboxyl-aryl, carboxy-heteroaryl, substituted-carboxyl-substituted, carboxy-lheterocyclic, carboxyl-substituted-heterocycle, cycloalkyl, substituted-cycloalkyl, guanidino , guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted-cycloalkyl, thioheteroaryl, substituted-thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclic het, oxycarbonyl lamino, oxy t -carbonylamino, -0S (0) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (O) 2 -aryl, -OS (O) 2 -aryl substituted, -OS (O) 2-het eroaryl, OS (O) 2 -substituted heteroaryl, -OS (0) 2-het erocyclic, -OS (O) 2-substituted erocyclic, OS (0) 2 ~ NRR, -OS (O) 2-alkyl, -NRS (O) 2-substituted alky, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O ) 2-heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic, NRS (O) 2 -substituted heterocyclic, -NRS (0) 2-NR- fegafea-sfa ^ s ^ g ^^ j ^^ Jfc? i-S? alkyl, -NRS (O) 2-NR-substituted alkyl, -NRS (0) 2- NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2- N4 -heteroaryl, - NRS (0) 2-NR-het eroar i the substituted, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR- heterocyclic, -NRS (0) ~ NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-ap-lamino, mono- and di- (substi tuted aryl) amino, mono- and di-heteroarylamino, mono- and di- (sub-substituted heteroaryl) amino, mono- and di-heterocyclic-amino, mono- and di- (substituted heterocyclic) amino, and di-subsided and asymmetric amines having different substituents, in wherein the substituents are selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Bo c, Cbz, formyl and the like), and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S0 -alkenne, -S02 -substituted alkenyl, -S02-cycloalkyl, -S02 - substituted cycloalkyl, -S02-aryl, -S0 -substituted aryl, -S0 -het eroar lio, -S02-het eroari lo substituted, -S02-heterocyclic, -S02-substituted erocyclic ester or -S02NRR, wherein 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 R "is substituted alkyl then at least one of the substituents on the substituted alkyl portion is selected from a group consisting of alkoxy, acyl, acylamino-thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbon-1-amino, aminot-iocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxy-1-aryl, substituted carboxyl-aryl, carboxyl-ether-yroyl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substi tuted thioaryl, thiocycloalkyl, substi tuted thio cycloalkyl, thioheteroaryl, substi tuted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclic hetero, oxycarbonylamino , oxitylcarbonylamino, -0S (0) 2 -alkyl, -OS (O) 2 -alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) - heteroarylo, OS (O) 2- substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (O) 2-substituted erocyclic, OS02-NRR, -NRS (O) 2 -alkyl, -NRS (O) 2-substituted alky, -NRS (O) 2-aryl, -NRS (O) 2-substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic, NRS (O) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (O) 2-NR-substituted alky, -NRS (0) 2-NR- aryl, -NRS (O) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl lo, -NRS (O) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- ( substi tuted alkyl) amino, mono- and di-arylamino, mono- and di- (substi tuted aryl) amino, mono- and di-heteroarylamino, mono- and di- (het eroari substi tuted) amino, mono - and di-het erocí clico-amino, mono- and di- (het erocílico substido) amino, di-substi tuted non-asymmetric amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl and the like), and substituted alkyl / alkyl groups, substituted with - S0 -alkyl, -S02-substituted alkyl, -S0 -alkenyl, -S02 -alkenyl substituted, -S02-c? -alkalkyl, -S02-cyclone or substituted alkyl, -SO? -aryl, -S02-substituted aryl, -S.sub.2 -het eroariol, -S? 2 -substituted heteroaryl, S02-heterocyclic, -S02-substituted erocyclic ester or -S0 NRR, where R it is hydrogen or alkyl. (f) substituted alkenyl, or alkynyl substituted with the proviso that at least one of them substituents on the alkenyl moiety thereof / alkynyl is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, cycloalkyl substituted, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted with the proviso that when substituted with substituted alkyl, then at least one of the substituents on the substituted alkyl portion is selected from the group consisting of alkoxy, substituted alkoxy, acyl , acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyanoNitro, halogen, hydroxyl, carboxyl, carboxyl-alkyl, carboxy-1-substituted alkyl, carboxyl-cycloalkyl, substituted 1-cycloalkyl carboxy, carboxylalkyl, substituted carboxyl-aryl, carboxy 1 -het-ero-aryl, substituted carboxyl-heteroaryl , substituted 1-het erocyclic carboxy, substituted carboxyl-heterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, t iohe t eroari lo, t ioheteroarilo substituted thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy substituted het eroar yloxy, heteroaryloxy substituted yloxy Parallel Synthesis, erocicliloxi substituted het, lamino oxicarbom, oxy t íocarbonilamino, -OS (0) 2-alkyl, -0S (0) 2_ substituted alkyl, -OS (0) 2-aryl, -OS (0) 2-substituted aryl, -OS (0) 2-heteroaryl, -0S (0) 2 -substituted heteroaryl, -OS (0) 2-het erocí clico, -OS (0) 2-substituted heterocyclic, -0S02-NRR, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2 -aryl, -NRS (0) 2-ar substituted i, NRS (0) 2-heteroaryl, -NRS (O) 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-ar i lo, -NRS (0) 2-NR -substituted alkyl, -NRS (0) 2-NR-heteroary lo, -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-arylamino, mono- and di- (substituted aryl) amino, mono- and di-het eroar ilamino , mono- and di- (substituted heteroaryl) amino, mono- and di-heterocyclic-amino, mono- and di- (substituted heterocyclic) amino, non-asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl , substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl and the like), and substituted alkyl / alkyl groups , substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alken? 1 or, -S02-a, which is substituted, -S02-cycloalkyl, -S02-cycloalkyl or substituted alkyl, -S02-aryl, -S02-substituted arylp, S02-heteroaryl, -S02 -substituted heteroaryl, -S02-heterocyclic , -S02-het substituted erocí cico or S02NRR, where R is hydrogen or alkyl. (g) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on aryloxy its titre / he troar i 1 oxy is different from halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, , 2-methoxyethane, 1,2-dioxyethyl, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, < s & Mtfe «-ána» «? »> ???????????????????????????????????????????????? (h) -alkoxy-saturated heterocyclic, substituted, saturated, substituted-alkoxy-substituted-alkoxy-het erocyclic and substituted-substituted-heterocyclic saturated, substituted alkoxy; (i) -O-heterocyclic and substituted O-heterocyclic; (j) tetrazolyl; (k) -NR-S02-substituted alkyl wherein R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl portion of the substituted alkylsulfonylamino is different from halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl , alkenyl, alkylo, 1,2-dioxymethyl, 1,2, -dioxyethyl, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N , N-dialkylurea; (1) alqueni lsul fom lamino, alkynylsulfoni lamino, substituted alkenyl sulphonylamino and substituted alkynylsulfonylamino; (m) alkoxy substituted with the proviso that the substitution in the alkyl portion of the alkoxy j ^ jaflM * ?? i? t¡rßk¿SÍBí ^? ^ t? substituted does not include alkoxy-NR '' R 'as defined above, unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl, or heteroaryl substituted heteroaryl, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethyl, 1,2-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkynylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbomamino, alkylsulfonylamino, N-alkyl or N, N -dialqui 1 -urea; (n) 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; (o) -C (O) NR '' 'R' 'X where each R' 1 'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that when an R '' 'is unsaturated heterocyclic, aryl, heteroaryl or aryl / heteroaryl substituted by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonixolo, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (different from unsaturated heterocyclic-substituted alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, alken substituted alkyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic; (p) -NR22C (0) -R18 wherein R18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; (q) -S02-aryl, -S02-substituted aryl, S02-heteroaryl, -S02-substituted heteroaryl, or S02-alkyl; (r) -NR 'C (0) NR19R19 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 R19 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; (s) -NR'C (0) 0R19 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 R19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (t) -aminocarbonyl- (N-formylheterocyclyl) and (u) -alkyl-C (0) H-het erocyclic and -alkyl-C (0) substituted NH-heterocyclyl, and pharmaceutically acceptable salts of the same; further with the following conditions which exclude the following compounds: A. when R1 is p-methylphenyl, R2 and R3 together with their pendant nitrogen and carbon atoms form a pyrrolidinyl ring and Q is -C (0) NH-, then R5 is not -CH2C00H or -CH2CH2COOH, and B. when R1 is p-methylphenyl, R2 and R3 together with their pendant nitrogen and carbon atoms forms a pyrene ring idini lo and Q is -C (0) NH-, then R5 is not 2, 4, 6-trimethebenzyl In another embodiment, the compounds of this invention can also be provided as prodrugs that are converted (eg, hydrolyzed, metabolized, etc.) in vivo to a compound of Formula I abIn a preferred example of this embodiment, the carboxylic acid of the compound of Formula I is modified in a group or that, it will be converted, in vivo, to the carboxylic acid (including the salts thereof). In a particularly preferred embodiment, these prodrugs are represented by the compounds of Formula IA: R 'O I l¡ R'-SO, -N < RXC-Q-CH-C-R6 IA H R; wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; R2 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, and R1 and R 'together with the nitrogen atom bonded to R2 and the group S02 bonded to R1 can form a heterocyclic or a substituted heterocyclic group; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aplo, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R2 and R3 together with the hydrogen atom attached to R2 and the carbon atom attached to R3 can form a heterocyclic group saturated by a substituted heterocyclic group, saturated with the proviso that when monosubstituted, the substituent on the substituted, saturated heterocyclic group is not carboxyl; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl; x is an integer from 1 to 4; R6 is selected from the group consisting of 2,4-dioxo-t-tetrahydrofuran-3-α, (3,4-enol), amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O- (N-) succinimidyl), -NH-adamant i lo, -O-choles t-5-en 3-ß-yl, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, -NH (CH2) pCOOY where p is an integer from 1 to 8 and Y is as defined ab -OCH2NR9R10 where R9 is selected from the group consisting of hydrogen and -CH2COOR11 where R11 is alkyl, and -NHSO2Z "where Z" is alkyl, substituted alkyl , cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; Q is -C (X) NR7-, wherein R7 is selected from the group consisting of hydrogen and alkyl; X is selected from the group consisting of oxygen and sulfur; R5 is -CH2X, wherein X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, substituted alkylcarboxy, carboxy-1-cycloalkyl, cycloalkyl- substituted carboxyl, carboxylaryl, substituted arylcarboxyl, carboxylheteroaryl, het eroar i 1 -carboxi substituted, carboxylheterocyclic, carboxylheterocyclic substituted, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic; With the condition that: A. R is not selected from the group consisting of - (CH2) n_aryl and - (CH2) n "het eroar i lo where n is an integer equal to 1 to 4 where R2 and R3 together with an atom of nitrogen bonded to R2 and the carbon atom attached to R3 form a saturated heterocyclic group or a substituted, saturated heterocyclic group: B. R5 is not - (CH2) X-Ar-R5 'wherein R5' is selected from group consisting of -OZ-NR8R8 'and -OZ-R12, wherein R8 and R8' is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and where R8 and R8 'are joined to form a heterocycle or a substituted heterocycle, R12 is selected from the group consisting of heterocycles and substituted heterocycles, and Z is selected from the group consisting of -C (O) - and - S02_; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is a n whole number from 1 to 4; C. R5 is not - (CH) X-Ar-R5 ', wherein R5' is selected from the group consisting of -NR24C (Z ') NR8R8' and -NR24C (Z ') R13 wherein Z' is selected from the group consisting of oxygen, sulfur and NR24, R24 is selected from hydrogen, alkyl and aryl, R8 and R8 'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl with the proviso that when Z 'is oxygen, at least one of R8 and R8' is substituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, substituted heterocyclic or R8 and R8 ' join to form a saturated heterocyclic other than morpholino or thiomorpholino, a substituted, saturated heterocycle or a saturated / unsaturated heterocycle having an amino group substituted with an alkoxycarbonyl substituent, and With the additional proviso that Z 'is sulfur, at least one of R8 and R8' is a different group of aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R13 is selected from the group consisting of substituted heterocycles and - ^ ¡¿? IßJfpí ^iária ^^ uá? M Saturated heterocycles different from morpholino and tnornor follo; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; D. R5 is not -ALK-X, wherein ALK is an alkyl group of 1 to 10 carbon atoms attached via a methylene group - (CH2-) the carbon atom to which it is attached; x is selected from the group consisting of substituted alkylcarbonylamino, alkenyl lamino carboni substituted alquinilcarbonilamino ituido subst lamino ilcarboni Parallel Synthesis, substituted heterocyclylcarbonylamino, acyl, acyloxy, aminocarbonyloxy, acylamino, lamino oxicarboni, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl, cycloalkyl, substituted cycloalkyl, substituted heterocyclic, saturated heterocyclic, substituted, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, het erocyclic yloxy, het erocicloxy ' "Í X AflII 2 ^,: ,, z > substituted thioalkyl substituted I thioalkenyl substituted I tioalquinilo substituted aminocarbonylamino, lamino aminotiocarboni, guanidino, amidino, alkylamidino, thioamidino, halogen, cyano, nitro, -OS (0) 2 -alqui lo, -0S (0) 2-substituted alkyl, -OS (0) 2-cycloalkyl, -0S (0) 2-substituted cycloalkyl, -OS (0) -ar i lo, -0S (0) 2 -aryl substituted, -OS (0) 2-yl eroar het, -0S (0) 2-substituted heteroaryl, -OS (0) 2-heterocí colic, -OS (0) 2-substituted heterocyclic -0S02-NRR where R is hydrogen or alkyl, -NRS (0) 2 -alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-cycloalkyl, -NRS (0) 2-substituted cycloalkyl, -NRS (0) 2-aryl, -NRS (0) 2-aryl substituted, -NRS (0) 2-het eroar i lo, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) 2-substituted erocyclic, -NRS (0) ) 2-NR-to the chyle, -NRS (0) 2-NR-to the substituted chyl, -NRS (0) 2-NR-cycloalkyl, -NRS (0) 2-NR-substituted cycloalkyl, -NRS (0) 2 -NR-ary lo, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-het eroar i the substituted, -NRS (0) 2 -NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic where R is hydrogen or alkyl, -S (0) 2 -alkyl, -S (0) 2 -substituted alkyl, -S (0) 2-ar i lo, -S (0) 2-substituted aryl, -S (O) 2-het eroar i lo, S (O) 2 -substituted heteroaryl, -S (O) 2-hetetracyclic, -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, substi tuted alkyl) amino, N, N- (heteroaryl, substituted alkyl) amino, N, N- (substituted heteroaryl, substituted alkyl) amino, N, N- (heterocyclic) , Substituted alkyl) amino, N, NN, N- (substituted heterocyclic, substi tuted alkyl) amino, mono- and di- (substituted heterocyclic) amino,, N- (alkyl, heterocyclic) ico) amino, N, N- (alkyl, substituted heterocyclic) amino, N, N- (aryl, het erocyclic) amino, N, N- (substituted aryl, heteroaryclic) amino, N, N- (aryl, substituted heterocyclic) amino, N, - (substituted aryl, substi tuted heterocyclic) amino, N, N- (heteroaryl, heterocyclic) amino, N, N- (het eroaryl, substituted heterocyclic) amino, N, N- (substituted het eroary, het erocyclic) amino, and N, N- (substituted heteroaryl, substituted heterocyclic) amino; and E. R5 is not - (CH2) X-Ar-R5 'where R5"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, amino, amidino, alkylamidino , thioamidino, aminoacyl, aminocarbonylamino, aminocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted alkylcarboxyl, carboxyl-cycloalkyl, substituted cycloalkyl-carboxyl, carboxyl-laryl, substituted-aryl-carboxyl, carboxyl-heteroaryl , substituted heteroaryl-carboxyl, carboxylheterocyclic, substituted carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidino sulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocyl, thioheteroaryl, thiolet eroar i the substituted, thioheterocyclic , substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, a & BM? agftá ¡, «? ¿¿¿jt? Zt * _ > -1-oxycarboni lamino, oxy-thiocarbonylamino, -0S (0) 2-alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-ar i lo, -OS (0) 2-substituted aryl, -OS (0) 2-heteroaryo, -OS (0) 2-substituted heteroaryl, -0S (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -0S (0) 2-NRR, -NRS (0) 2-alkyl, -NRS (0) 2 -alkyl substituted, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2-het eroaryl, -NRS ( 0) 2-substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-alky substituted , -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-ari substituted, -NRS (0) 2-NR-heteroaryl, -NRS (0) -NR-heteroary substituted, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-ar lamino, mono- and di- (aryl subtyped) amino, mono- and di-heteroarylamino, mono- and di- (heteroary substi- tuted) amino, mono- and di-heterocyclic-amino, mono- and di- (substituted heterocyclic) amino, non-asymmetric di-substi tuted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic . ^ p v-. ^. ? ~ _ -? sl "* ¿jLj ¡£ M. ^ S Z.éiXj * ^ M.! íilcs? -i? substituted substituted alkyl groups that have amino groups blocked by conventional blocking groups (such as Boc) , Cbz, formyl, and the like), and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-alkenyl substituted, -S02-cycloalkyl, -S02- substituted cycloalkyl, -S02-aryl-OS (0) 2-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, S02-het erocyclic, -S02-substituted erocyclic het or -S02NRR, wherein R is hydrogen or alkyl, (b) alkoxyaryl substituted on the alkoxy portion with a substituent selected from the group consisting of carboxyl and -COOR23, wherein R23 is 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, ar ilo, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the additional proviso that when R 'is substituted alkyl at least one of the substituents on the substituted alkyl portion is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonilamino, aminotiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxy-1-cycloalkyl, substituted carboxyl-cycloalkyl, carboxyl-laryl, substituted-carboxyl-aryl, carboxyl-ether-yroaryl, substituted-carboxyl-heteroaryl, carboxyl-heterocyclic, substituted-carboxyl-substituted-cycloalkyl, substituted-cycloalkyl, guanidino , guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioaryl, thioaryl, thiocycloalkyl, thiocycloalkyl, substituted, substituted, thioheterocyclic, thioheterocyclic, substi tuted, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy substituted, heteroaryloxy, substituted heteroaryloxy, het ero cycloalkoxy, substituted heteroxy loxy, oxycarbonylamino, oxy thiocarbonylamino, -0S (0) 2-alkyl, -OS (0) -substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, - OS (0) 2-het eroar i lo, -OS (0) 2-substituted heteroaryl, -0S (0) 2-heterocyclic, -OS (0) 2-substituted erocyclic, -0S02-NRR, - OS (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-alky substituted, -NRS (0) 2-NR-aryl, -NRS ( 0) 2-NR-aryl substituted, -NRS (0) 2-N4 -heteroaryl, -NRS (0) 2-NR-het eroar i the substituted, -NRS (0) 2-NR-heterocyclic, - NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-ar lamino, mono- and di- (aryl subtyped) amino, mono- and di-heteroarylammon, mono- and di- (het eroar i substi tuted) amino, mono- and di-heterocyclic-amino, mono- and di- di- (substituted heterocyclic) amino, and di-substi tuted and asymmetric amines having different substituents, selects from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc) , Cbz, formyl and the like), and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S0 -substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl , -S02-aryl, -S02-substituted aryl, -S02 ~ heteroaryl, -S02 -substituted heteroaryl, S02-heterocyclic, -S0 -het substituted erocyclic or -S02NRR, wherein 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 R "is substituted alkyl then at least one of the substituents on the substituted alkyl portion is selected from the group consisting of alkoxy, acyl, acylamino-thiocarbonylamino, acyloxy, alkenyl, amino, amidino , alkyl 1 -amidino, Jfc ^ aatift ^ fc ^ .. j ftSSAAEhar. *, .. thioamidino, aminoacyl, aminocarboni lamino, aminocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxy-1-cycloalkyl, substituted carboxyl-cycloalkyl, carboxy-1-ar i, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, substituted carboxylheterocyclic, substituted carboxyl-heterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, t-cycloalkyl, substituted t-cycloalkyl , thioheteroaryl, thioheteroaryl, thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclic, oxycarbonylamino, oxycarbonyl amino, -OS (0) 2- alkyl, -OS (O) 2 ~ alkyl substituted uido, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (0) 2 -heterocyclic, - OS (O) 2_het substituted erocyclic, -OS02-NRR, -NRS (O) 2-alkyl, -NRS (O) 2-substituted alky, -NRS (O) 2-aryl, -NRS (0) 2 -are substituted ilo, -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-aryl substituted, -NRS (0) 2- NR-heteroaryl, -NRS (0) -NR-het substituted eroaryl, -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- (aryl subtyped) amino, mono- and di-het eroar i lamino, mono- and di- (het) eroar ilo subs tu tiido) amino, mono- and di -het erocí clico-amino, mono- and di- (het erocí clico sub ti tuido) amino, amines d i-subst non-asymmetric substances having different substituents, selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by groups conventional blocking (such as Boc, Cbz, formyl and the like), and substituted alkyl / alkyl groups, substituted with -SO? -alkyl, -S0 -alkyl * J_ * - J Substituted alkyl, -S02-alkenyl, -S02 ~ a1 which is substituted, -S? 2-cycloalkyl, -S0 -cycloalkyl substituted, -S02-aryl, -S02-substituted aryl, -S02-het eroaryl, -S02-het eroar i the substituted, S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR, where R is hydrogen or alkyl. (f) substituted alkenyl, or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyl / alkenyl portion is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl , heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted 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, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl-alkyl, carboxy 1-substituted alky, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxy Substituted aryl, carboxyl-het eroaryl, substituted carboxyl-heteroaryl, substituted carboxyl-het, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl , cycloalkyl, substituted cycloalkyl, thioheteroaryl, thioether subrogate, thioheterocyclic, substi tuted thioheterocyclic, heterocyclic, substi tuted hetero cyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, het erocyclic, substituted heterocyclyloxy, oxycarboni lamino , oxitiocarbonylamino, -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-het erocyclic, -OS (O) 2-substituted heterocyclic, -OS02-NRR, -NRS (O) 2-alkyl, -NRS (0) 2-alky substituted, -NRS (0) 2-aryl, -NRS (O) 2-aryl sub Situitu, NRS (0) 2-heteroaryl, -NRS (O) 2-Substi tuted 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-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (lower alkyl) amino), mono- and di-arylamino, mono- and di- (substi- tuted aryl) amino, mono- and di-heteroarylamino, mono- and di- (heteroaryl substi- tuted) amino, mono- and di- Ethyl-amino, mono- and di- (substituted heterocyclic) amino, non-asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups Oketed by conventional blocking groups (such as Boc, Cbz, formyl and the like), and substituted alkyl / alkyl groups, substituted with -S-2-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl , -S-2-cycloalkyl, -S-2-cycloalkyl substituted, -S02-aryl, -S02-substituted aryl, Ut? ^ ÁSS ^^^ 4 ^? S? ^^ iiam¡t, ^ í -S02-heteroaryl, -S02-substituted heteroaryl, S02-het erocílic, -S02-substituted heterocyclic or -S02NRR, where R is hydrogen or alkyl. (g) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on substituted aryloxy / heteroaryloxy is different from halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethoxy; wood, 1,2-dioxyethyl, alkoxy, alkenoxy, alkynoxy, alkylamino, alkeni lamino, alkylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (h) -alkoxy-heterocyclic saturated, -alkoxy-substituted heterocyclic, saturated, -alkoxy substi tude-heterocyclic and -alkoxy substituted-heterocyclic saturated, substituted; (i) -O-heterocyclic and substituted O-heterocyclic; (j) tetrazolyl; k) -NR-SO? -alky substituted where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl portion of the substituted alkylsulfonylamino is different from halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethyl, 1, 2, -dioxyethyl, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenni lamino, -alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (1) alkenylsulfonylamino, alkynylsulphonylamino, alkenylsulfonylamino substituted and substituted alkynylsulphonylamino; (m) substituted alkoxy with the proviso that the substitution in the alkyl portion of the substituted alkoxy does not include alkoxy-NR '' R 'as defined above, unsaturated heterocyclic, alkyloxy, Aryloxy, heteroaryloxy, aryl, heteroaryl, or aryl / heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethyl, 1,2-dioxyethyl, alkoxy , alkenoxy, Alkyloxy, alkylamino, alkenylamino, alkynylamino, alkynylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl-1-urea; (n) amidine and amidine substituted with 1 to 3 substituents independently selected from ffi? ^ '£ S? l ~ rf?' 'n * fai (' ^ from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic; C (0) NRM IRM I, wherein each R '1' is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that when an R '' 'is unsaturated, aryl, heteroaryl or aryl / heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy , alkyl, alkenyl, alkynyl, 1,2-dioxymethyl, 1,2-dioxyethyl, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonixolo, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfo nilamino, N-alkyl or N, N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (different from unsaturated heterocyclyl-substituted alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic; (p) -NR22C (0) -R18 wherein R18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, cycloalkyl Substituted, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; (q) -S? 2 ~ aryl, -S? 2 ~ substituted aryl, -SO? -het eroaryl, -S0 -het substituted eroaryl, or -S02-alkyl; 15 (r) -NR 'C (0) NR19R19 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 R19 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; (s) -NR'C (0) OR19 wherein R 'is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted arflo, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and R19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (t) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (0) NH-substituted heterocyclyl; and pharmaceutically acceptable salts of the same; with the following additional condition: when R1 is p-methylphenyl, R2 and R3 together with their pendant nitrogen and carbon atoms form a pyrrolidinyl ring, R5 is p - [- 0CH2CH2- (4,5-dihydroimidizole-2-yl) , Q is -C (0) NH-, then R6 is not -O-methyl.

In the preferred compounds within the scope of the above formulas I and IA include by way of example, the following: N- (toluene-4-sulphonyl) -L-prolyl-4- (a-methylbenzyloxy) -phenylalanine N- (toluene-4'-sulfonyl) -L-prolyl-L-tyrosine N- (toluene-4-sulfonyl) -L-prol? L- -carboxi feni lalanin N- (toluene-4-fonyl) -L-prolyl-3- (carboxy) phenylalanine N- (toluene-sulfonyl) -L-prolyl-4- (2-carboxyphenoxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-O- (benzyl) -L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-4- (iodo) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (methoxy) -phenylalanine ^^ & fe ^ a ^ ......

N- (toluene-4-sulfonyl) -L-prolyl-4-n? Tro-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (O-tert-butyl) -L-tyros ina N- (toluene-4-sulfonyl) -L-prolyl-L- (3, 5-diiodo) -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (aminobenzoyl) -pheniramine N- (toluene-4-sulfonyl) -L-prolyl-L- (3-iodo-4-hydroxy) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-chloro) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-leucine N-toluene-sulphyl) -L-prolyl-L-alanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (acetamido phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-isoleucma N- (Toluene-4-sulfonyl) -L-prolyl-L-aspartic acid N- (Toluen-4 -sulonyl) -L-prolyl-L-lysine N- (toluene-4-sulfonyl) -L-prolyl-L-glutamic acid Methyl ester of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-dibenzylamino) -phenylalan N- (toluene-4-sulfonyl) -L-prolyl-L- (N-benzyl) -histidine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-dibenzylamino) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-methionine N- (toluene-4-sulfonyl) -L-prolyl-L-serine N- (toluene-4-sulfonyl) -L-prolyl-L- (5,5-dimethyl) thiaprolylL- (N-benzyl) histidma N- (toluene-4-sulfonyl) -L-prolyl-L- (1-methyl) histidine N- (toluene-4-sulfonyl) -L-prolyl-D- (N-benzyl) histidine N- (toluene-4-sulphyl) -L-glutamyl-L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L- (N -3-ethyl) histidine N- (toluene-4-sulfonyl) -L-prolyl-a-ammo-2,3-dihydro- (1,4-benzodioxm) -6-propanoic acid N- (Toluene-4-sulfonyl) -L-proly-a-ammo-1,2-benzodioxolo-5-propanoic acid N- (toluene-sulphyl) -L-prolyl-L-valma Methyl Ester N- (toluene-4 -sulonyl) -L-prol 11-L- (4-iodo) -phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prol i 1 -L-4 • (aminobenzoyl) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (chloro) phenylalanine Methyl ester N- (toluene-4-sulphonyl) -L-prol 11-L- (• amino) phenylalanine Methyl ester N- (toluene-4 -sulonyl) -L-prol 11 -L- (4 • acetamido) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (5, 5-dimetyl) thiaprolyl-L- (N-benzyl) -histidine N- (toluene-4-sulfonyl) -L-prolyl-4- (3-3'-tolylureide L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4 - [(2,3,3a7a-tet rahydro-lH-indol-2-carbonyl) -amino] -L-phenylalanine Methyl ester N- (toluene-4-sulphonyl) -L-prolyl-L- (4 • pentylamm) phenylalanine Methyl ester N- (toluene-sulfonyl) -L-prolyl-L-O- (2-dibenzylamino-yl) -tiroine N- (toluene-4-sulfonyl) -L-prolyl-L-0- [2- (dibenzylamino) ethyl] -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-pentylamino) phenylalanine Methyl ester N- (toluene-4 -sul foni 1) -L-prol 11 -L- 4 - (4-chlorobenzylamino) -phenylalanine Methyl ester N- (toluene-sulfonyl) -L-prolyl-L-4 - [3- (4-cyanophenyl) -ureido] -phenylalanine Methyl ester N- (toluene-sulphon-1) -L-prolyl-L-O- (tert-butoxycarbonylmethyl) tyrosine N- (toluene-4 -sily fonyl) -L-prolyl-L-O- (tert-butoxycarbonylmethyl) -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-4 - [(3S) -3, -dihydro-isoquiolin-3-yl-aminocarbonyl] -phenylalanine Methyl ester N- (toluene-4 -sul foni 1) -L-prol i 1-4 - [3- (3-methoxy-phenyl) -ureido] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- ([3- (3-methox? -phenyl) ureido] -L-phenylalanine 'is » N- (toluene-4-sulfonyl) -L-prolyl-L-O- (4,5-dihydro-lH-imidazol-2-ylmethyl) -thi rosi a N- (toluene-4-sulfonyl) -L-prol i 1-L- - (3-propyl-ureido) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-benzylamine) fem.

Methyl ester N- (toluene-4-sulfonyl) -L-prol i 1-L- (4 • benzylamino) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (4-chlorobenzylamine) -phenylalanine N- (toluene-4-sulfon? L) -L-prolyl-L- (4-chlorometansul foni lamino) - f eni la 1 aniña Methyl ester N- (toluene-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4- (aminobenzoyl) phenylalanine N- (toluene-4-sulfon? L) -L- (5, 5-d? Met? L) t? Aprol? L-L-4- (benz amido) phenylalanine MÜJM & gas & ^^^ w * < n a. Ethyl ester N- (toluene-4-fonyl) -L- (5, 5-dimet i 1) thiaprolyl-L-tyrosine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-4-yl) methylamino] phenylalanine Methyl ester N- (toluene-4 -sul foni 1) -L-prolyl-L- 4 • [(pyridin-4-yl) methylamino] phenylalanine Ethyl ester N- (t-oluen-4 -sulphyl) -L- (5, 5-d? Met il) • thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine Methyl ester N- (t-oluenesulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4- (pyridin-3-carboxamido) phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-3-ylmethyl) amino] phenylalanine Methyl ester N- (t oluen-4 -sul foni 1) -L- (5, 5 -dimethyl) -thiaprolyl-L-4-nitrophenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prol i l-L-4-n-t-riphenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-proli 1 -L-4 - (2-methoxybenzamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) -thiaprolyl-L- (-nitro) phenylalanine Ethyl ester N- (toluene-4-sulphonyl) -L-prolyl-L- 4 - (2-bromobenzamido) phenylalanine Ethyl ester N- (toluene-sulphonyl) -L- (5, 5-dimethyl) -thiamorphi 1-L-4-aminopheni lalanin Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4 acetamidophenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-methoxybenzamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L- (5, 5-d? Met il) • tiaprolil -L-4-acetamidopheniralaine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4-acetylamidophenylalanine Isopropyl Ester N- (toluene-4-sulfonyl) -L-proli 1-L- -acetamidophenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L- (5, 5-d? Met il) -L-4- (isonicotine gone) phenylalanine Ethyl ester- 4- (isonicotinamido) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prol i 1-L- (p-toluene-4-sulfonyl) histidine Ethyl ester N- (toluene-sulphon-1) -L- (5, 5-dimet i 1) -thiaprolyl-L-4- (nicotamido) phenylalanine Ethyl ester N- (toluene-4-sulphonyl) -L-prol i 1 -L- (0-methyl) tyrosine Ethyl ester N- (a-toluensul fonil) -L-prolyl-L- 4 (isonicotinamido) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-bromobenzamido) phenylalanine N- (a-toluensul fonil) -L-prol i 1-L- - (isonicotinamido) phenylalanine Ethyl ester N- (toluene-4 -sulonyl) -L- (1, 1- dioxo) t iamor folil-L-4 - (2-bromobenzamido) phenylalanine 10 N- (toluene-4-sulfonyl) -L- ( 1, 1-dioxo) tiamorfol? LL-4- (2-bromobenzamido) phenylalan N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -L-4- 15 (isonicotinamido) phenylalanine Ethyl ester N- (a-toluensul foni 1) -L-prol 11 -L- 4 - (2-bromobenzamido) phenylalanine Isopropyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) -thiaprolyl-L-tyrosine Ter-butyl ester N- (t-oluen-4-sulfonyl 1) -L- (5,5-dimethyl-yl) -thiaprol i 1-L-tyrosine 25 Ter-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-tyros ina Ethyl ester N- (toluene-4-sulfonyl) -L-proli 1 -L- - (2-trifluoromet-il-benzamido) phenylalanine Ethyl ester N- (toluene-4 -sul foni 1) -L-prol i 1 -L- 4 - (2-methylbenzamido) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-trifluoromethylbenzamido) phenylalanine Ter-butyl ester N- (- fluorobenzenesul foni 1) -L-t iaprol i 1-L-tyrosine Ter-butyl ester N- (4-fluorobenzenesul foni 1) -L- (5,5-dimethyl) -thiaprolyl-L-t iros ina N- (toluene-4-sulfonyl) -L-prolyl-4- (dimethylamino) -L-phenylalanine Ethyl ester N- (toluene-4-sulfonyl 1) -L-prolyl 1-4 - [(2-bromo) benzamido] -L-phenylalanine Methyl ester N- (toluene-4 -sulonyl) -L-proli 1-4 [(pyrazin-2-yl) C (O) NH] -L-phenylalanine Ethyl ester N- (toluene-4 -sulonyl) -L-prol i 1-4 (• nitrobenzoyl) -L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- (2-bromobenzamido) -L-phenylalanine T-butyl ester N- (toluene-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- (2-bromobenzamido-L-phenlalanine) T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 (l-H-2-oxo-3-methyltetrahydropyrimidin-l-yl) L- phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (l-H-2-oxo-3-methyltetrahydropyrimidin-1-yl) -L-phenylalanine T-butyl ester N- (toluene-4-sul foni 1) -L-prolyl-3 • chloro-4- (t-butoxy) -L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-3-chloro-4- (hydroxy) -L-phenylalanine T-butyl ester N- (t oluen-4 -sul foni 1) -L-prol i 1 -4 - (N, N-dimethylureido) -L-femlalanma T-butyl ester N- (-f luorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4-hydroxy) -L-phenylalanine Isopryl ester N- (4-f luorobenzenesulfonyl) -L- (5,5-dimethyl) t-aprolyl-3-chloro-4- (hydroxy) -L-femlalanine Isopropyl ester N- (4 -f luorobenzenesul foni 1) -L- (5, 5-d? Met? L) thiaprol? L-3-chloro-4- (hydroxy-L-phenylalanine) T-butyl ester N- (toluene-4 -sul foni 1) -L-prolyl-4 (2-methoxy phenyl) -L-phenylalanine N- (toluene-4-fonyl) -L-prol i 1-4- (2-methoxy phenyl) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl- [(5-N, -dimethyl-ureido) -pyridin-2-yl] -alanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N, N-dimethylsulfamyl) -L-phenylalanine "* -" * JÜE F &frai-SP¿% ?? * - * * - y- ^ i ^ tj * C ^ 3á ^ "L ^ ^ ^ j is x N- (toluene-4-sulfonyl) -L-prolyl-4- (N1, N1, N2-trimethyl sul family ) -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl- (1-t-butoxycarbonylmethyl-1-imide zol-4-yl) -L-alanine Methyl ester N- (toluene-4 -sul foni 1) -L-prol i 1 - [N, N-di eti laminocarbonylmethylimidazol-4-yl] -L-alanine Isopropyl Ester N- [4 - (dimethyl-ilium ureyl benzenesul fonyl] -L-prol i 1- -hydroxy-L-phenylalanine N- (toluene-4-sulphonyl) -L-prolyl- (5,5-dimethyl) thiaprolyl-3-chloro-4-hydroxy-L-phenylalanine isopropyl ester Isopropyl ester N- (toluene-4 -sul foni 1) -L-prolyl-3-chloro-4-hydroxy-L-phenylalanine Methyl ester N- (toluene-4 -sul foni 1) -L-prolyl-4 (carboxymethyl) -L-phenylalanine Methyl ester N- (toluene-4-sulphonyl) -L-prol i 1 - 4 - (2-metylbenzamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N, N-dimet and laminocarbonylmethyl) -L-phenylalanine Isopropyl Ester N- (1-met il imidazol-4-sulfonyl) -L-prolyl-4-hydroxy-L-phenylalanine Isopropyl Ester N- (toluene-4-sulphonyl) -L-prol i 1- 4 - (2,4,5-trioxo-3-phenyltetrahydroimidazol-1-yl) -L-phenylalanine Isopropyl ester N- (4-f luorobenzenesul f oni 1) -L- (5,5-dimethyl) thiaprolyl-3-fluoro-4-hydroxy-L-phenylalanine T-butyl ester N- (4-f luorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4-t-butoxy-L-phenylalanine T-butyl ester N-. { N- [(IS-2.10-camphorsultamil] acetyl.}. -L-tyrosine Isopropyl ester N-. { N- [I S) -2.10 'canforsultamil] acetyl} -3-chlorotyrosine T-butyl ester N- (4-f luorobenzenesul foni 1) -L-thiaprolyl-4-hydroxy-L-phenylalanine T-Butyl Ester N- (toluene-4 -sulonyl) -L-prolyl-4 - (N, -dimet-ylaminocarbonylmethyl) -L-phenylalanine T-butyl ester N- (t oluen- -sul foni 1) -L-prol i 1 - 4 - (hydroxy-L-phenylalanine Isopropyl Ester N- (t oluensulphyl) -L- (5,5-dimethyl) thiaprol il-4-hydroxy-L-phenylalanine T-butyl ester N- (toluene-4-sulphonyl) -L-prolyl 1-4-hydroxy-L-phenylalanine T-butyl ester N- (pyridin-3 -sul f oni 1) -L-prolyl-4 • hydroxy-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (methanesulfonamido) L-phenylalanine Benzyl ester N- (toluene-1-sulfonyl) -L-prolyl-4- (2,, 5 -tri oxo-3- (3-chlorophenyl) -tetrahydroimidazol-1-yl) -L-phenylalanine Ethyl ester N- (1 -met i limida zol- 4 -sul foni 1) -L- (5, 5-dimethyl) thiaprolyl-3-chloro-4-hydroxy-L-phenlalanine Ter-butyl ester N- (4-f luorobenzenesul foni 1) -L- (5,5-dimethyl) thiaprolyl-L-3-chloro-4-ter-butox y-phenylalanine Isopropyl ester N- [2- (N-2, 10-camphorsultamil) acetyl] -L-3-chloro-4-hydroxy-phenylalanine Preferably, in the compounds of Formula I and IA, above, R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl. Still more preferably, R1 is selected from the group consisting of 4-met i1 phenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylfenyl, 2- (me t-oxycarbonyl) phenyle, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4 - ( CH3C (O) NH-) phenyle, 4-trifluoromethoxyphenyl, 4-cyanophene, isopropyl, 3,5-di- (tri-foromethyl) phenyl, 4-1-but i 1-phenyl, 4-t-but oxi feni lo, 4-nitrophenyl, 2-thienyl, lN-methyl-3-met il-5-chloropyral zol-4-yl, phenytyl, 1-N-me ti 1 imide zol- 4 -i lo, - bromophenyl, 4-amidinophenyl, 4-methylaminidophenyl, 4 - [CH3SC (= NH)] phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-tienyl, lN-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-l, 3-4-thiadiazol-2-yl, 4- [H2NC (S)) phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorofeni lo, 3- f luorofeni 1 o, 3,5-dif luorofenil, pir idin- 3 -i lo, py imidin-2-ylo, 4- 0 (3'-dimet i lamino-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 -f. In one embodiment, R1 and R2 together with the nitrogen atom attached to R2 and the group S02 attached to R1 join to form a heterocyclic group or substituted heterocyclic group. Preferred substituted heterocyclic and heterocyclic groups include those having from 5 to 7 ring atoms and having from 2 to 3 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur, which ring is optionally fused to another ring such as a phenyl or cyclohexyl ring to provide a fused ring heterocycle of 10 to 14 ring atoms having from 2 to 4 ring heteroatoms from the group consisting of nitrogen, oxygen and sulfur. The specifically preferred R: / R2 linked groups include, by way of example, benzothiazolinyl (saccharin-2-yl). Preferably, the compounds of the Formula I and IA above, R3 includes all isomers that arise by substitution with methyl, phenyl, benzyl, di phenyl et i lo, -CH2CH2-C00H, -CH2-COOH, 2-amidoethyl, iso-butyl, t-butyl , -CH20-benzyl and hydroxymethyl. In another preferred embodiment, R2 and R3 together with the nitrogen atom attached to R2 and the carbon atom attached to R3 form a saturated heterocyclic group or a substituted heterocyclic group, saturated with the proviso that when it is monosubstituted, the substituent in the group substituted, saturated heterocyclic is not carboxyl. Q is preferably -C (0) NH- or -C (S) NH-. R5 is preferably selected from the group consisting of all possible isomers that arise by substitution with the following groups: p- [-OCH (CH3) f] -benzyl, 4-hydroxybenzyl, 2-carboxybenzyl, 3-carboxybenzyl 4-Carboxybenzyl, 4- (2-carboxy phenoxy) benzyl, 4- (benzyloxy) -benzyl, 4-iodobenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4- (tert-butoxy) benzyl, 3 , 5-d? Iodo-4-hydroxybenzyl, 4 - (benzamido) benzyl, benzyl, 4-hydroxy-3-iodobenzyl, 4-chlorobenzyl, isobutyl, methyl, 4- (acetamido) benzyl, n-butyl, carboxymethyl, 4-aminobutyl, 2-carboxymethyl, 4- (N, N- dibenzylamino) -benzyl, (N-benzyl imide zol-4-yl) -methyl, 2-1 iomet oxyethyl, hydroxymethyl, (N-methylimidazol-4-yl) methyl, 4- (isopropyl-C (O) NH- butyl, 4- (benzamido) butyl, 4 - (benzyl-C (O) NH-butyl, (-methylimide zol-5-yl) methyl, 4 - (pi idin-2 -il-C (0) NH-) butyl, 4- (6-methy1pyridin-3-y1C (O) NH-) butyl, 4- (3-methylthien-2-yl-C (O) NH-butyl, 4- ( pyrrol-2-yl-C (0) NH-butyl, 4- (furan-2-yl-C (O) NH-butyl, isopropyl, 4-aminobenzyl, 4- (4-phenylbutoxy) benzyl, 4 - ( 1-butyl indol-3-i 1 -C (O) NH-butyl, 4- (4-methanesulfonylphenyl-C (O) NH-butyl, 4- (4-acetylphenyl-C (O) NH-butyl) - (4-fluorophenyl-C (O) NH-) butyl, 4- [2- (pyridin-2-yl) ethynyl] benzyl, 4- [2- (3-hydroxyphenyl) ethynyl] benzyl, 4- [2- (p ridin-4-yl-C (O) NH-benzyl, 4 - (pyridin-3-i 1 -C (O) NH-) benzyl, 4 - (3- met il feni 1-NHC (O) NH-) benzyl, 4, (2,3-dihydroindol-2-yl-C (O) NH-) benzyl, 4- (N,? J- dipentylamino) benzyl, 4 - (N-pentylamino) benzyl, 4- [2- (N, N, -dibenzylamino) ethoxy] benzyl, 3-hydroxybenzyl, 4 - (Nn-but i 1-Nn-pentylamino) benzyl, 4 - (N-4-chlorophenylamino) benzyl, 4- (4-cyanophenyl-NHC (0) NH-) benzyl, 4- (carboxymethyl) benzyl, 4- (tert-butoxycarbonylmethoxy) benzyl, 4- (5-fluoroindole) 2-yl- 10 C (O) H-) benzyl, 4 - (1, 2, 3, 4 - 1 et rahidroisoquinol in- 3- il-C (O) NH-) benzyl, 4- (3-methoxy) feni 1-NHC (O) NH-) benzyl, 4 - [2 - (indol-3-yl) ethoxy] benzyl, 4- (4,5-dihydroimide zol-2-ylmethoxy) benzyl, 4- (n -propyl- NHC (O) NH-) benzyl, 4- (N-benzylamino) benzyl or 3-, 3-methoxybenzyl, 4- (pyridin-2 -yl-C (O) H-) benzyl, 4- (N-4-chlorobenzylamino) benzyl, 4- (2-chloromethylsulfonylamino) benzyl, 4- (N, N-dimethylamino) benzyl, 3-aminobenzyl, 4- (benzyl) benzyl, 2 -hydroxyethyl, 4 - nor robbery or, 4- 20 (phenyl-NHC (S) NH-) benzyl, - (pyridin-3-yl-NHC (S) NH- (benzyl, 4- (pyridin-4-ylmethylamino) benzyl, 4- [ fCH2OCH2 (Boc-HN) CHC (O) NH-] benzyl, 4- (pyridin-3-yl- C (O) NH-) butyl, 4- (pyridin- -i 1-C (O) NH-) butyl 4-pyridin-3-yl-C (O) NH-) benzyl, 4- (pyridin-4-yl- 25 C (O) NH-) benzyl, 4 - (Ntoluensulf onylpyrrolidin-2-yl- C (O) NH-) butyl, 4 (pyridin-butyl-C (0) NH-) butyl, 4- (2-Boc-1,2,3,4-tetrahydroisoquinolin-3-yl-NHCH2-) benzyl, 4- (2-Boc-1, 2, 3, 4-tetrahydroisoquinolin-3-yl-C (O) NH-) benzyl, 4- (pyridin-3-ylmethylamino) benzyl, 4- [fCH20 (0 ) C (CbzNH) CHCH2CH2C (0) NH-] benzyl, 4- (2-methoxybenzamido) benzyl, 4- (2-bromobenzamido) benzyl, 4- (pyrazin-2-yl-C (0) NH-) benzyl, (1-toluenesulfonylimidazol-4-yl) met i lo, [1- (N, N-dime ti laminosul fonyl) imide zol-4-i 1] met 11 o, 4- (trifluoromethyl) -benzyl, 4 - (3, 3-dimethyldureido) benzyl, 4- (methoxycarbonylamino) benzyl, 4- (1, 3, 3-trimethylolureido) benzyl, 4- (methoxycarbonyl-N-methylamino) benzyl, 4-cyanobenzyl, 4 - (? 2-form l-1, 2, 3, 4-tetrahidroisoquinolm-3-yl-C (0) NH-) benzyl, phenyl, (4 -aminoet i 1) benci l'or 4 - (1 - Boc-piper Idyn-4-yl-C (0) NH CH 2) benzyl, 4- (l-Boc-piperidm-4-yl-C (O) O-) benzyl, 4- (piperidin-4-yl-C (0) NHCH2) benzyl, 4- [(1-methylpiperidma-4-yl) -0-] benzyl, 4- (1, 2,3,4-tetrahydrate) oquinolin-2-yl-C (0) NH-) benzyl, α-methyl-4-ylbenzyl, 4- (trimethylacet amido) benzyl, 4- (2-methylpropionamido) benzyl, 4- (morpholin-4-yl-C (0 ) NH-) benzyl, 4- (3, 3-diethylurethane) benzyl, 4- (2-trifluoromethe lbenzamido) benzyl, 4- (2-meth i lbenzamido) benzyl, -hydroxy-3 -not robbed it, 3-hydroxy-4- (f-OC (O) NH-) benzyl, 4- (t -omorpholm- -il-C (0) NH-) benzyl, 4- (1, 1-di oxot iomorfol i non-4-yl-C (O) NH-benzyl, 3-nitro-4- (methoxycarbonylmethyl oxy) benzyl, (2-benzoxa zol inon-6-yl) methyl, (2H-1, 4 -benzoxazin- 3- (H) -one -7-yl) meth yl-4 - [N, N-diet laminosulfonil- (N-methyl) amino?] benzyl, 4 - [(2-meth ilpirrolidin- 1 - i 1) C (O) NH-] benzyl, (pyridin-4-yl) methyl, 4- (l-methylpiperidin-4-yl-C (0) NH-) benzyl, 4 [b? s (N, N -dimethylaminothiocarbonyl) amino] benzyl, 4 - (N, N-dimethylaninosulfonyl) -benzyl, 4- (imide zol id-2-one-1-yl) benzyl, 3,4- (ethylenedioxy) benzyl-, 3,4- (methylenedioxy) benzyl-1 and 4 - (3-formylimidazolid-2-one-li l) benzyl. In the compounds of Formula IA, R6 is preferentially 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-β-me t -ylcyclohexoxy, 2-isopropyl-β-met il-cyclohexoxy, -NH 2, benzyloxy, -NHCH 2 COOH, NHCH 2 CH 2 COOH. -NH-adamant i lo, NHCH2CH2COOCH2CH3, NHS02-p-CH3-f, -NHOR8 wherein R8 is hydrogen, methyl, iso-propyl, or benzyl, 0- (N-succinimidyl), -O-colest-5-en 3-ß-ilo, -C0H2. OC (O) C (CH3) 3, O (CH2) 2NHC (O) W wherein z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-meth i-pyridyl, and N-meth yl-1, 4 -dihydro-pyr idin- 3 -yl, -NR''C (0) -R 'where R' is aryl, heteroaryl or heterocyclic and R "is hydrogen or -CH2C (0) 0CH2CH3. This invention also provides methods for binding VLA-4 in a biological sample method comprising contacting the biological sample in a compound of Formula I or IA above under conditions wherein the compound binds to VLA-4. Certain compounds of Formula I and prior IA are also useful in reducing information mediated by VLA-4 in vivo. This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount and one or more of the compounds of the above Formula I and IA with the exception that R3 and R5 are derived from L-amino acids or other starting materials similarly configured Alternatively, racemic mixtures can be used. The pharmaceutical compositions can be used to treat conditions of diseases mediated by VLA-4. These disease conditions ^ HE ^^!? Ei I &. And include, by way of example, asthma, Alzheimer's disease, at eroscleros is, AIDS dementia, diabetes (including juvenile-onset diabetes acute), inflammatory bowel disease 5 (including ulcerative colitis and Crohn's disease, multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, attack and other brain traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute lung injury mediated by leukocytes, such as that which occurs in the respiratory pain syndrome in adults. Accordingly, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4, methods comprising administering to the patient the pharmaceutical compositions described above. The preferred compounds of Formula I and IA above include those set forth in Tables IA and IB below.

^ S ^^^ A ^ X ^^^^, R 'O R'-SOj-NíR'l-C-Q-CH-C-R * "H' R i, ' R 'R «Q = - pCU, f RZ / RX 3 atoms p [OCH (GH,)? benzyl- cyclic carbon OH (L-pyrrolidinyl) p Cll, f R2 / R3 = 3 atoms "-hydroxybenzyl- cyclic carbon OH (L-pyrrolidinyl) pCH, F- R2flX 3 carboxy-carbon atoms of cyclic carbon OH (L- pyrrolidinyl) pCl \, R2 / FX 3 p-carboxybenzyl-carbon cyclic atoms OH (L-pyrrolidinyl) ft-CHy R2 / RX 3 cyclic carbon atoms m carboxybenzyl- OH I (L-pyrrolidinyl) R 'R' R »R5 Q = -C (0) NR'- R7 /» CU, -f- R2 / R3 = 3 atoms p | (). { (carboxyphenyl) -benzyl-OH cyclic carbon 11 (L-pyrrolidinyl) p-CU F R2 / ^ 3 P-benzyloxybenzyl--OH atoms of cyclic carbon (L-pyrrolidinyl) p C.Uyf- R / R3 = 3 atoms vydobenzyl- -OH cyclic carbon (L-pyrrolidyl) p CH, tf R2 / R3 = 3 atoms-methoxybenzyl- -OH II cyclic carbon (L-pyrrolidinyl) oo p CH, F- R2 / ^ 3 p-nitrobenzyl atoms - -OH of cyclic carbon (L-pyrrolidinyl) p CH, f R / R3 = 3 P (i-butoxy) benzyl- -OH atoms of cyclic carbon (L-pyrrolidinyl) p C l, R2 / F ^ = 3 US atoms tl? Od (hydroxyphenyl) -CH, -OH cyclic carbon (L-pyrrolidyl) PC?, - R2 X 3 p atoms | NHC (O) f) benzyl- cyclic carbon OH (L-pyrrolidinyl) R 'R' R 'Q = -C (0) NR7- R7 P CH, -tf R2 / R = 3 atoms (4 hydroxy 3 iodofen? L) -CH, - cyclic carbon -OH H (L-pyrrolidiml) p CH, tf- R2! ^ 3 atoms p chlorobenzyl OH of cyclic carbon H (L-pyrrolidinyl) p CH, * R2 / R3 = 3 cyclic carbon atoms isobutyl- OH H (L-pyrrolidinyl) p CH, -tf R2 / R ^ = 3 cyclic carbon atoms methyl-OH II? (L-pyrrolidinyl) tp p CH, tf R2 / X 3 atoms 4 l NHC (0) CII,) cyclic carbon -OH II (L-pyrrolidiml) p C? Lyf R2 ^ 3 p-butyl-atoms of cyclic carbon OH H (L-pyrrolidinyl) pl F R2 / 3 = 3 H atoms, CCK) II OH of cyclic carbon (L-pyrrolidinyl) p CH, tf R2 ^ 3 atoms H. (CH,), OH of cyclic carbon H (L -pyrrolidiml) R 'Q = -C (0) NR'- R7 / ^ CH, tf R2 ^ 3 atoms CH.CH ^? OH OH cyclic carbon H (L-pyrrolidinyl) p-CU f- R2 / R3 = 3 atoms / > - | d¡bcn c lamino) benci I OCH, of cyclic carbon II (L-pyrrolidinyl) p-CU, -f 2 / R3 = 3 atoms l -N benci limidaz l 4- il-Cl lr cyclic carbon OH H (L-pyrrolidinyl) / CH, -tf- R2 / R3 = 3 atoms / > - (dil > enci lamino) benci I -OH co cyclic carbon H si (L-pyrrolidinyl) p CUy R2 ^ 3 atoms H.SCHjCH, cyclic carbon OH H (L-pyrrolidinyl) p- Uyf R2 ^ 3 atoms IKK H, OH of cyclic carbon (L-pyrrolidinyl) p Clly R2 ^ (L-5,5-I-N benzylimidazoM i l-CH, -OH dimethylthiazolidin-4-yl) cyclic -CH2S-C (CH3) 2 - 00 00 R 'R' R 'R' Q = -C (0) NR7- p Cll, tf R7 R2 / R = 3 atoms 6 mel ilpyrid 3 il C (0) NH < CH,), - of cyclic carbon -OH II (L-pyrrohdinil) P CHyf R2 / R ^ 3 atoms 3 n? Eliltiep-2 il C (0) NH (Cll,) 4- cyclic carbon OH (L-pyrrohdmil ) p CU, tf- R2 / R ^ = 3 atoms pirr? l 2 il C (()) NH (dimide carbon cyclic OH II (Lp? rrol? d? n? l) P CUyf- R2 R2 = 3 atoms itirán 2- il C (()) NII (CU,), - cyclic carbon OH II (L-pyrrolidinyl) P Cll, tf R2f ^ 3 cyclic carbon atoms -f'IKCHj, -OH co (L-pyrrolidyl) P - II, tf R2 / 2 = 3 atoms P yod? Ben ci I cyclic carbon OCH, H (L-pyrrolidyl) p-CUyf R2 / ^ 3 atoms P i NHC (O)) JH-? Cyclic carbon C 0 OCH, H (L-pyrrolidinyl) p CHyf- R2 ^ 3 atoms / > cyclic carbon chlorobenzyl OCH, (L-pyrrolidiml) OR v > R1 Q = -C (0) NR7- R7 pCH, R2 / R3 = 3 atoms p ^ l NHCH, - (p-chlorophenyl) l benci I- -OCH, cyclic carbon H (L-pyrroidinyl) p-CHyf - R2 / R3 = 3 atoms H NHC (0) NH- (pianophenol) l benz I-OCH, carbon cyclic H (L-pyrroidinyl) pCllyF 2 / X 3 atoms | NHC (0) NH (p <ianofenil) | benzyl I- -OH H cyclic carbon (L-pyrrolidinyl) pCH.tf R2R3 = 3 p- [0 (^ H, COOHl benz I-OCH, cyclic carbon H IO (L-pyrrolidinyl)? pCH, -tf - R2 ^ 3 atoms pf OCH, COO and butyl) benzyl- -OCH, of cyclic carbon H (L-pirtolinylin) p Cll, tf R2 / R ^ = 3 atoms l (X * H, COOí bnlill-liencil- (lll of cyclic carbon (L-pyrrolidinyl) CH, tf R / R3 = 3 atoms p l-NHC (O) 5-fluoroindol 2 yl) benz I-OH H cyclic carbon (L-pyrrolidinyl) p-CH.tf R2 / R3 = 3 atoms p | NHC (0) - (I.2,3.4 hydrocarbon OH cyclic carbon 11 isoquin? Lin-3-yl) benz I- (L-pyrrolidinyl) R 'R * Q = -C (0) NR7- R7 p [NHC (0) NH m-methoxyphenyl) benzyl-OCH, H p-CH, tf R2 / R3 = 3 cyclic carbon atoms (L-pntol? D? n? l) p- | -NHC (0) NH-fn methoxiferylj benzyl -OH H p-CHrf- R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) p ((XTIIjCH, indole 3 ill benzyl-OCH, 3 atoms II p CH, -tf- R2 / R2 = cyclic carbon (L-pyrrolidinyl) pl CII, -2- (4, 5-d? Hi dr?) Im? Dazol il | - OH H p CH.- tf- R2 ^ 3 cyclic carbon atoms benzyl- or (L-pyrro dinil) p | NIIC (0) NHCH ril, CH,] benzyl OH R2 / R3 = 3 atoms H p CH.tf of cyclic carbon (L-) pyrroidinyl) p- (benzylamino) benzyl- -OH II p-CH, -tf- R2 / R3 = 3 cyclic carbon atoms (L-pyrrolidinyl) R2 / R3 = 3 p-bencllapun atoms) benzyl OCH, HP CH, tf of cyclic carbon (L-pyrrolidyl) m-methox and benzyl OH p CH, tf R2 ^ 3 atoms 11 of cyclic carbon (L-pyrrolidinyl) R 'R »Q = C (0) NR7- R7 pCH, tf R2 / R2 = 3 p atoms | NHC (O) pyridin-2-yl] benzyl-cyclic carbon OH 11 (L-pyrrolidinyl) / 'Cll, tf R2 / R? = 3 atoms P | -NHCH, - (p-chlorophenyl) | benzyl - cyclic carbon OH H (L-pyrrolidinyl) pCH.tf- R2R3 = 3 atoms P (NHSOj-CHjCI) benzyl carbon cyclic OH II (L-pyrrolidinium) pCH, -tf- R2 /? = 3 p atoms ( CH,), N-benzyl-cyclic carbon OH H or (L-pyrrol? D? N? L) p-CH, tf R2 ^ (L-5.5- P ((fenll) C (0) NH Jbencil-CJCII , Cyclic H, dimethyltolityl) -CH2S-C (CH3) 2-pCH.tf R2 /? ^ = (L-5,5-p | (phenyl »C ((i) IMII | benzyl OH dimethylthiazol-4-yl) cyclic -CH2S-C (CH3) 2- vo C? R1 R 'Q = -C (0) NR7- R7 / > CH, - - R2 ^ 3 atoms MtfNHC (S) NH) benzyl - cyclic carbon -OCH, H (L-pyrro dinil) pCH, -tf- R2 ^ 3 p atoms (pyridin-3-yl-NHC (S) NH) benci |. of cyclic carbon -OCH, II (L-pyrrolidinyl) p-CH.-tf- R2 / R3 = 3 atoms / > < pyridin-4-yl-CHjNH-benzyl- of cyclic carbon OH 11 (L-pyrrolidinyl) pCH,? -R2 ^ 3 atoms PlpridH il CII, NH) benzyl- of cyclic carbon OCH, II (L-pyrrolidinyl) P Cllyf- R2 / R3 = 3 cyclic carbon atoms P ItfC H, OCH, (Boc HN) CHC (O) NH) benzyl-OCH, tf 11 (L-pyrro diml) p-CH, -tf- R2 ^ 3 atoms 4 ( pyridm-3 lC (0) NH) bu? il- of cyclic carbon OH H (L-pntol? d? n? l) / CH.tf R2 / R3 = 3 atoms 4 (? ipd? n-4 i I C CO) NH) bulyl- of cyclic carbon OH H (L-pyrrolidinyl) -CH, tf R2 / R3 = (L-4,4-pipipdm 3 i IC < 0) NH) benzyl dimethylpyrrolidinyl) cyclic OH-11 -CH2- CH2-C (CH3) 2- Q = -C (0) NR7- R7 p CH, tf- R2 / R3 = (L-4,4- p (pi? Id? N-4 il C (O) NH) benzyl- -OH dimethylpyrrolidinyl) H cyclic CH2-CH2-C (CH3) 2- / »- CH, -tf- R2 ^ (L-5,5-p (pyrid? N-3-yl-C (0) NH) benzyl--OCH, d? met? lt? azol? d? n-4- II l) cyclic -CH2S-C (CH3) 2- p Cll, f- R2 ^ 3 p atoms (pindin 3-yl NHC () NH) benzyl-OH carbon cyclic (L-pyrrolidinyl) pCHyf- R2 / R3 = 3 atoms 4 ((V toluene sulfonylpyrrolid 2-cyclic carbon OH il) C (0) NH Jbutyl-II vo 00 (Lp? rrol? d? n? l) P CH, tf R2R3 = 3 atoms 4 | (pi | iend? N-4 il) C (0) NH) bulyl- cyclic carbon OH H (L-pyrrolidiml) pCH.tf p (pyridin 3-yl C (0) NH) benzyl- R2 ^ (L-5,5-OH II d? Met? Lt? Azol? Dm-4-yl) cyclic -CH2S-C (CH3) 2- p-CH, tf R2 / R3 = 3 atoms p- (2-Boc-l, 2,3,4-tetrahydro-soqu? nol? n 3 il OH of cyclic carbon NHCH,) benzyl H (L-pyrrolidinyl) vo vo R7 R 'Q = -C (0) NR7- R7 p-CH, tf- R2f ¥ ^ = 3 atoms p J (2-bromophenyl) C (0) NH' benzyl carbon cyclic OCHjCH, 11 (L-pyrrolidinyl) p -CHr + - R2 / R? = 3 atoms p Kpipuin 2 il) C (0) NH | benzyl- -OCH, of cyclic carbon H (Lp? rrol? dm? l) rCHr-R2 ^ (L-5.5- p animo bencil -OCIIjCH, II d? met? lt? azol? d? n-4- íl) cyclic -CH2S-C (CH3) 2- R2 / R ^ = 3 atoms or p-CHyf- P Kpi razm 2- il) C (0) NH J benzyl cyclic carbon -OH or H (L-pyrrolidinyl) p-CUyf - R2ÍÍ ^ = 3 atoms p acetamirinbenzyl-OCIIjCH, of cyclic carbon II (L-pyrrolidinyl) p CHyf- R2 / R3 = 3 atoms p | (2 methoxyphenyl) C (()) NI IJ cyclic carbon benzyl -OH II ( L-pyrrolidinyl) p-CHyf- p acetamidobenzyl R2 ^ (L-5,5-OCH, CH, II d? Met? Lt? Azohd? N-4? L) cyclic -CH2S-C (CH3) 2- R 'Q = -C (0) NR7- R7 p ^ CH.tf p (pyridin-3-yl C (ü) NH) benzyl- R2 ^ (L-5,5- ^ CH, CH, H d? Met? lt? azole-4-yl) cyclic -CH2S-C (CH3) 2- / -CH, -tf- 2/3 = 3 atoms I (| N, N dimelilaminusuir? Nil] imidizo -OCH, of cyclic carbon Dmeiil 11 (L-pyrrolidinyl) pCH.tf- R2 ^ 3 p atoms (? / ./V-dimel ilammo) benzyl-OH of cyclic carbon H (L-pyrrolidyl) p Cll, tf- R2 / ^ 3 atoms p methoxy benzyl OCH, CH, H of cyclic carbon or (L-pyrrolidinyl) tfCH, R2 ^ 3 atoms / • (pipdu il C (0) NII) benzyl (X'HJCH, 11 cyclic carbon (Lp? Rtol? D? N? L) pC vf- R2 / 3 = 3 atoms p Cyclic carbon irifluoromelilbencil OH II (L-pyrro dinil) pCHyf- R2 / R3 = 3 atoms p | (2 brom phenyl) C (0) NI1"benzyl-OH H cyclic carbon (L-pyrrolidinyl) R 'R' j > -CII, - + - R2 / ^ 3 atoms p- | (CH,) lNC (0) NII-] benzyl - cyclic carbon (L-pyrrolidinyl) CH, R2 / R? = 3 atoms p | CH, OC ( 0) NH benzyl cyclic carbon (L-pyrrolidinyl) P CH, -f- R2 / R3 = 3 p atoms ((* H,), NC (0) N (CH1) Cyclic carbon benzene (L-ptrrohdinil) tf di, - R2 ^ 3 p atoms (pipd? n-4 il C (()) NH) benzyl carbon cyclic (L-pyrrohdinil) or? P CH, tf R2 ^ 3 atoms / > pi, O, (()) N (Clll)) cyclic carbon benzyl (L-pyrrolidinyl) P CH, tf R2R3 = 3 cyclic carbon cycbenzylbenzene atoms (L-pyrrolidiml) PÍ'M, tf | R2 / R3 = L-1,1-binomophenylK (O) NII) benzyl dioxothiomorpholin-3-yl) cyclic -CH2CH2-S02-CH2- OR R7 R 'R' Q = -C (0) NR7- R7 p-CH, tf- R2 / R3 = 3 p atoms (2 formyl-l, 2,3,4 tctrah id? O? Soquinol? N-3 OH of cyclic carbon 11 il C (0) NH) benzyl (L-pyrrolidinyl) p-CH, -tf- R2 / R3 = L-1,1- p- (I ^ .S ^ -teirahydrituisoxyiolin-il OCH, CH, II dioxothiomorpholin-C (O) NH) benzyl-3-yl) cyclic -CH2CB-S02-CH2- p ^ CH.-tf- R2 / R3 = 3 atoms -tf -OH H of cyclic carbon isomer-L (L -pyrrolidinyl) p CH, tf R2R3 = 3 atoms -tf or OH II of cyclic carbon isomer-D (L-pyrrolidinyl) p-CH.-tf R2 ^ 3 atoms p (a? nomciil) bencil OCH, II carbon cyclic (L-pyrrolidinyl) p-CH, ^ - R2 / R? = 3 p-atoms (l -Bot pipepdin 4 il) cyclic carbon OH II C (0) NII (| l, Ibencyl (L-pyrrolidyl) pCH. -tf R2R3 = 3 atoms p Kl-b? c-pipcpdm 4 il) OCH, 11 cyclic carbon C (0) NHCH, J-benzyl (L-pyrrolidinyl) R 'R7 Q = < T (OJNR7.R7 tf H2- R2 / R3 = 3 P atoms (1.2.3, -tetrahydroisoquinol? N-3-yl- cyclic carbon) OCH, CH, C (0) NH Jbenzyl-H (L-pyrrolidinyl) J > -CH, tf R2 / R3 = L-1,1- p (1, 2,3,4-tetrahydroquinolin-2-yl-dioxothiomorpholin--OH 11 3-yl) cyclic C (0) NH J-benzyl-CH2 «^ -SOrCH2- pCH.tf R2 ^ 3 atoms /» | (l Ikic pfe? D? N-4 il) C (0) (V) cyclic carbon benzyl OCH.CH, H (L-pyrrolidinyl) atoms or jt-CII, - + - R2 / ^ 3 P | (p? pend? n-4-yl) C (<)) NHCH,) benzyl if of cyclic carbon OH II (L-pyrrolidinyl) / ^ CH, tf R2 / R3 = 3 atoms pa inobencil -OH cyclic carbon H (L-pyrrolidyl) p CH, -tf 2 / R3 = 3 atoms p | (l mctilpipepdm 4 il) O cyclic carbon benzene • OCH, CH, H (L-pyrrolidinyl) tfCH, R2 / R3 = 3 P atoms (1,2,3,4-ielrahidroqu? Nol? N 2 OH cyclic carbon C (0) NH) benzyl II (L-pyrrohdinil) R7 R 'R' Q = -C (0) NR7- R7 n, -tf- p (pyridin-4-yl C (0) NH) benzyl- -OH R2R3 = L-1,1-H-dioxothiomorpholin-3-yl ) cyclic -CH2CF ^ -S02-CH2- p -hydroxybenzyl I / TH.-tf -OCIKCH,) - R2 / I ^ = (L-5,5-H dimethylthiazolidin-4-yl) cyclic -CH2S-C (CH3) 2- / TH.tf p hydroxybenzyl or R2 ^ (L-5,5- -OC (CH,), H-dimethylthiazolidin-4-yl) cyclic -CH 2 S-C (CH 3) 2 -methylbenzyl - /? - CH, tf R2R3 = 3 OH II atoms of cyclic carbon (L-pyrrolidinyl) | (CH0, CC () NH Jbenzyl p-CH, -tf R2 / R ^ = 3 p atoms (XH (CH, >, cyclic carbon (L- pyrrohdinil) p-CH, -tf- R2 / R3 = 3 atoms p | (CH,), CHC (()) NH J-benzyl CH (CH, >, cyclic carbon (L-pyrrolidinyl) o 00 R 'R' Rl R * Q = -C (0) NR7- R7 p CH, tf- P | (morpholyl? -4 il) C (0) NII Jbenzyl- R2 / R3 = L-1,1-OC ( CH,), cyclic H-dioxothiomorpholin-3-yl) pCH, R2R3 = 3 atoms P | (2 melIlfenl |) C (0) NH cyclic carbon Ibenzyl OCIIjCH, H (L-pyrrolidinyl) P CH, tf R2 / ¥ ^ 3 atoms p | (2-lnl) t? Orometilfepil) cyclic carbon -OH C (0) NII | benzyl II (L-pyrrolidmiI) P Cll, tf R / R3 = 3 atoms 4 liidinxj) niirnbenzyl < K H ,. of cyclic carbon II or vo (L-pyrrolidinyl) P Cll, tf R2 /? ^ = 3 atoms' l.idmxi 4 (tf (H (O) NII (cyclic carbon benzylated (XH.CII, 11 (L-pyrrolidinyl pCII.-tf- R2R3 = 3 atoms / - Kmorfol 4 j |) ((O) NII | en¡, cyclic carbon <H (CH, 1, (L-pyrrolidinyl) P CH, tf R2 / I ^ = 3 atoms Kiiomorfolm 4 il, ('(()) NH lbenzyl - carbon cyclic OH H,), H (L-pyrrolidinyl) ? ' R 'R' R4 Q = -C (0) NR7- R7 rCllyF R2 ^ 3 atoms p | (t? Omor? L? N ~ 4 il sul fon) -OC (CH,), 11 carbon cyclic C (0) ) NH Jbencil (Lp? Rrol? D? N? L) 2 / R3 = 3 atoms 3 ??? tro-4 (CH, (X (0) CH2 (»benzyl R l / -CH, -f OCH, CH, II cyclic carbon (L-pyrrolidyl) (2 bep7 atolmon 6 l) methyl CH, tf R2 / R ^ = 3 OH H atoms of cyclic carbon (L-pyrro dinil) p hi dioxybenzyl p-CU, f OC 'H,', II R2m? = | L-4-N- (Cbz) -piperizinyl] cyclic -CH2CH2- (Cbz) NH-CH2- R2 / R3 = 3 atoms (2 iK-nzoxazolinon t> g) methyl CH, tf (XlljCII, II cyclic carbon (L-pirrohdinil) R2 / R3 = 3 atoms (. '/' I 4 i iiioxa / m '(4 //) «m 7 il) mcli I pCll.tf OH II of cyclic carbon (L-pyrrolidyl) pCH, tf R2 / R ^ = 3 atoms p | (CII,), NS (()), N (CII,) | bencll (X '(CH,), cyclic carbon ( L-pyrrolidinyl) N > «Or R'-SO, -N (R1) -C-Q- Cll-C-R-1 H I R I. ' Ul K 'R' k '- C (0) NR' R 'Ptil.tf R2 / R3 = 3 atoms IN bencilnni izul 4 I (' II, cyclic carbon OH (L-pyrrolidinyl) P Cll, f R2 / R3 = 3 atoms / »|? L? Be ?? c¡l _ ??????? | cyclic carbon benzyl OH (L-pyrrolidinyl) P« i «? Tf R2 / R3 = 3 atoms (M.SCH ll, of cyclic carbon OH (L-pyrrohdinil) / Xyl.tf R / ^ 3 atoms INX II, OH of cyclic carbon (L-pyrrolidinyl) s> piii, * IN benzyl? m? U / ol 4? l (II , OH / '(II, tf R2 / R3 = 3 atoms IN ??? cl¡l ????? < | j / (il 4 .1 (II, OH of cyclic carbon (L-pirrohdiniI) /' (il .tf R2 / R = 3 atoms I Nbenzylisiiiiiil 4, 1 i II, OH of cyclic carbon (L-pyrrohdinil) / 'Cll, * (t 11,1,1 (Mili / > hydroxybenzyl (t HOIIUCI) or?? H 'R' k 'Q-4? (0) NR' R ' P CH, tf R ^ 3 atoms I N niclil ???? t? L? U > I 5 cyclic carbon dioxide OH (L-pyrrolidinyl) /. (II, tf R2 / R3 = 3 atoms 1.4 (clilcndi? ii) benzyl OH cyclic carbon (L-pyrrolidinyl) /. (II, tf R2 / R3 = 3 atoms 1.4 IncylitriilM (cyclic carbon OH II beetle (L-pyrrolidiml) / '(H.tf R2 / 3 = 3 atoms <11 (111,), of cyclic carbon OH II (L-pyrrolidinyl) il, tf R2 / RO 3 atoms p yialnbencil »H ||, of cyclic carbon (L -pyrrolidinyl) / 'CH, tf R2 / R = 3 atoms /' I NI I '«•) vlbenzyl IX II, cyclic carbon (L-pyrrolidinyl) /' (II, tf R2ñX 3 atoms / > chlorobenzyl (X II, cyclic carbon (L-pyrrolidinyl) R 'R' R 'R * 0 «C (0) NR' R '/ > CH, R2 ^ 3 atoms PI «XH, (H.NlbenciD.lbencil of cyclic carbon OH (L-pyrrolidinyl) 'H, tf R / R? = 3 atoms / • l <", «HlNII cyclic carbonylbenzene OH (L-pirrohdinil) / • (II, tf R2 / R? = 3 atoms /. | NI H II, (/. Chlorophenyl) | cyclic carbon benzyl (X II, (L-pyrrolidim!) /. < II, tf R / R * = 3 atoms / • I Nim? L) NII (I "l? Renn) | benc? Cyclic carbon • X II, (L-pyrrolidinyl) VO / »Cil, tf R2 / R ^ = 3 atoms,. | NIH (OiNII (/, ij ,,,, cyclic carbon phenylbenzyl OH (Lp? Rrol? D? N? L) M H.tf R2 / RO 3 atoms / 'Mx H,? IM),,. "I, I | benzyl cyclic carbon IM H, (L-pyrrolidinyl) M'H, tf R2fP? = 3 atoms p | (x ll,? Tx) i IMHIII cyclic carbon benzyl OH (L-pyrrolidinyl) / • < H , tf R2 / R3 = 3 atoms / l NIH (Ulll l Nil lyl ,,, of cyclic carbon iv-lhinpln, t iij bencil Olí (L-pyrrolidinil) R * Q- C (Ü) NR '/ »lil, * R2 / ^ 3 atoms R' p ((ll.jjN bencii of cyclic carbon OH (L-pyrrolidinyl) pcp.tf R2 ^ (L-5,5- pKphenyl) ((O) NII Ibhenyl-dimethylthiazolidyl-1X-yl, yl) cyclic -CH2S-C (CH3) 2- / »cu, f R2R7 = (L-5,5- /»! (phenyl) (( ) NII | benzyl OH d? Met? Lt? Azol? D? N-4-? L) cyclic -CH2S-C (CH3) 2- N> p (ll, tf R2 ^ (L-5,5- / "hydroxybenzyl <XH," ??, dimethylthiazolidinyl] -cyl) -CH2S-C (CH3) 2- / • cu, tf R-TR ^ (L-5.5- / 'hydroxybenzyl OH d? met? lt? azol? dm-4-yl) cyclic -CH2S-C (CH3) 2- / • (II, tf R2R5 = 3 p atoms (|> iitlni ii i li.Cyclic Carbon N -ibenzyl H (L-pyrrolidinyl) R 'Q- ClO) NR'- R' Mil, * R2 / 3 = 3 atoms / > Cyclic carbon (X il.CII, (L-pyrrolidinyl) P Ul, * - R2 ^ (L-5,5- P niiiiibenzyl dimet? lthiazolid? n-4- (p-methoxyphenyl K (O) NII) benzyl cyclic carbon Xil.UI, íl) cyclic -CH2S-C (CH3) 2- / 'CH, tf R2 / R3 = 3 atoms', ,, "" "phenyl i ((<)) NI | ibencil? X 11, ( 11, cyclic carbon (L-pyrrolidinyl) Mil, * R2 ^ 3 atoms / ?|(|il ?.m ?? 2 il) C (i)) NM Ibencyl IX II cyclic carbon (L-pyrrolidyl)? / • Cll, * / > Jiiiiu, encyl R-TR ^ (L-5,5- 1 11, (11, d? Methylthiazole? Din-4-yl) cyclic -CH ^ - CH ^ - / • CH, tf R ^ ^ 3 atoms p Oiruiiit Cyclic carbon benzyl? x 11, (11, (L-pyrrolidinyl) / 'CH, tf R2R3 = 3 atoms /' 11-methoxyphenyl) < |) NII Cyclic carbon benzyl OH (L-pyrrolidinyl) ) k 'Q- C (0) NR' R 'M "H, tf R2 ^ (L-55- / • (Pipdin) .K (0) NII) benzyl d? met? lt? aolol? d? n-4 - IXH.CII, íl) cyclic -CH2S-C (CH3) 2- / »(II, tf R2 ^ - 3 atoms methoxybenzyl cyclic carbon (Hll.CH, (L-pyrrolidyl) tf ip, R2ÍPX 3 atoms / • (| 'ip.l? "4,) < ((Cyclic carbon DNIDbenzyl <XH, <II, (L-pirro dinil) Ul / '(II, tf R2 / RX 3 atoms I / I phenyl K ((> MI! | Benc¡? Cyclic carbon OH (L-pyrrolidinyl) tf (II, R2fí ^ = 3 atoms / • (IHM.I.ii 4, 1 i () NIDbenzyl cyclic carbon OH (L-pyrrolidinyl) / '(II, * R2 / R3 = L-1,1- / • |?' B? .. H ". Phenyl) (, u, N |, | bend | (XH," II, dioxothiomorpholin-3-yl) cyclic -CH2CRj-S02-CH2- »' R * Q- C (0) NR'- R 'p P f R2 / R? = (L-5,5-II /> hydroxybenzyl - < X' (l "ll,), d? Met? Lt ? azole-4-yl) cyclic -CH2S-C (CH3) 2- to oo The additional compounds of formulas I and IA are set forth in the following Table IB. Completely throughout Table IB, the phrase "L-pyrrolidinyl" in the R2 position specifies that R2 / R3 = 3 cyclic carbon atoms, and the phrase "L-5, 5-dimethylthiazolidin-4-yl" in the position R2 specifies that R2 / R3 = "(L-5, 5-dimethylthiazolidin-4-yl)" -CH2 S-C (CH3) 2"cyclic T? III.? I H R 'O I I R' -SO.-N (K ") (- (,» (H-C-R "I t I I IC R * K "- ('(O) NR7 O p-CH, -? - L-pyrrolidinyl p- [nitrophenoxycarbonyloxy] -benzyl- -OH II L-5,5-dimethylthiazolidin p- [o-bromo benzamido] - P-? I .-? - -4-yl benzyl- -Oi-IJu II L-5,5-dimethylthiazolidin p- [o-bromo benzamido] - P-CH 3 -? - 4-yl benzyl- ( lt-Hu p- [lH-2-oxo-3-methyl P-CH 3 -? - L-pyrrolidinyl tetrahydropipmidin- 1 - -Ol-Bu II? l] benzyl- p- [1H-2-oxo-3 -methyl-CH, -f- L-pyrrolidinyl tetrahydropyrimidin- 1 - -OH II il] benzyl- ? or ? ? ro DETAILED DESCRIPTION OF THE INVENTION As before, this invention relates to compounds that inhibit the adhesion of leukocytes and in particular the leukocyte adhesion mediated by VLA-4. However, before describing this invention in further detail, the following terms will be defined first.

Definitions As used herein, "alkyl" refers to alkyl groups preferably having 1 to 10 carbon atoms, 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 1 to 10 carbon atoms, having 1 to 5 substituents selected from a group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonilamino, aminocarbonylamino, ammocarboni loxi, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxylar, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxy-1-cycloalkyl, carboxyl-substituted cycloalkyl, carboxyl-laryl, carboxyl-substituted aryl, carboxyl-heteroaryl, carboxyl-substituted heteroaryl, carboxy-heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thiolalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, thiocycloalkyl their substituted, thioheteroaryl, thio substituted eroar, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, het erocyl clyloxy, substituted heterocyclyloxy, oxycarbom lamino , oxy-iocarbonylamino, -OS (O) 2-alkylo, -OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS (0) 2-ary substituted, -OS (O) 2 -het eroar ilo, -OS (O) 2_het eroar ilo substituted, -OS (O) 2-het erocílic, -OS (0) 2-substituted heterocyclic, -OS (0) 2_NRR where R is hydrogen or alkyl, - NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (0) 2-het eroaryl, -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-het substituted eroary, NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR -substituted erocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di- -het eroar i lamino, mono- and di-heteroaryl substituted lamino, mono- and di-heterocyclic-amino, mono- and di-heteroaryl-substituted amino, non-symmetrical di-their amines having different substituents selected from from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like or alkyl / substituted alkyl groups uido, replaced with -S02- mz ^ ítiM ^^ z ££ m ^ ¡& amp; & alkyl, -S02-substituted alkylene, -S? 2-alkene, S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02 -substituted aryl, -S02-heteroaryl, -S? 2 heteroary substituted, -S? 2 ~ het erocí clico, -S? 2? Het erocíico substituted and -SO2NRR where R is hydrogen or alkyl. "Alkoxy" refers to the group "alkyl-O-" which includes, by way of example, methoxy, ethoxy, n -propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec -butoxy-n-pentoxy, n -hexoxi, 1, 2 -dimet i lbu t oxi, and imi lares. "Substituted alkoxy" refers to the group "alkyl-O-substituted". "Acyl" refers to the groups HC (O) -, alkyl-C (O) -, substituted alkyl-C (O) -, alkenyl- C (O) -, alkenyl their ti tuido-C (O) -, alkyne 1 -C (O) -, alkynyl its thiido-C (0) -, cycloalkyl-C (O) -, cycloalkyl its titido-C (O) -, aryl-C (O) -, aryl substituent-C (O) -, heteroaryl-C (O) -, 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, substituted heteroaryl, heterocyclic and Vfíti r * * 1 * 1 * t- * 'substituted heterocyclic are as defined herein. The "acylamino" refers to the group -C (0) NRR wherein each R is independently selected from a group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted ahenynyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein each R joins to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl substituted, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Thiocarboni lamino" refers to the group C (S) NRR where each R is independently selected from a 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 wherein each R joins to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Acyloxy" refers to the alkyl-C (0) 0- groupsAlkyl-C (O) O-, substituted alkenyl-C (O) O-, alkynyl-C (O) 0-, alkynyl their-tu-C (0) alkynyl; ) 0-, aryl-C (0) 0-, aryl substituted C (0) 0-, cycloalkyl-C (0) 0-, cycloalkyl substituted-C (0) 0-, heteroaryl-C (0) 0 - substituted heteroaryl-C (0) 0-, heterocyclic-C (0) 0-, and substituted heterocyclic-C (0) 0-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl substituted, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Alkenyl" refers to the alkenyl group having preferably 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably 1-2 sites of alkenyl unsaturation. "Substituted alkenyl" refers to alkenyl groups having from 1 to 5 substituents selected from a group consisting of acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alky1-amid, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarboni amino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxaryl, substituted aryloxaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyalkyl, alkyl substituted with carboxyl, carboxyl-cycloalkyl, cycloalkyl substituted with carboxyl, carboxylaryl , aryl substituted with carboxyl, carboxylheteroaryl, heteroaryl substituted with carboxyl, carboxylheterocyclic, heterocyclic substituted with carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thiolalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, thiocycloalkyl, substituted, t iohet eroar i lo, substituted thioheteroaryl, thioheterocyclic, t substituted ioheterocyclic, heteroaryl, substituted substituted, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (0) 2 -alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2-het eroar i lo, OS (0) 2 -substituted heteroaryl, -0S (0 ) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, 0S (0) -NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -her heteroary and the substituted, 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-ar i substituted, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-het erocí clico, -NRS (0) 2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-het eroarylamino, mono- and di-het eroar-substituted amino, mono- and di-het erocyclic co-amino, mono- and di -het erocyclic-amino substituted , unsymmetrical disubstituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc. Cbz, formyl and the like or substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S? 2 -alkeni lo, -SO? -a substituted-Phenyl, -S? 2-cycloalkyl, -S-2-substituted cycloalkyl, -S? 2-aryl, -S? 2 -substituted aryl, -S02-heteroaryl, -S02 -substituted heteroaryl, -S02-heterocyclic, -S02 -substituted heterocyclic, and SO2- NRR where R is hydrogen or alkyl. "Alkynyl" refers to the alkynyl group having preferably 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably 1-2 sites of alkynyl unsaturation. "Substituted alkynyl" refers to alkynyl groups having 1 to 5 substituents selected from a group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarboni lamino, aminothiocarboni lamino, aminocarboni loxi, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxylaryl, halogen, hydroxyl, cyanoNitro, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxyl, carboxyl-substituted, carboxyl-lheteroaryl, carboxyl-substituted 1-carboxyl, carboxy-lheterocyclic, carboxy-lhet substituted erocide, cycloalkyl, substituted cycloalkyl, quuaanniiddiinnoyl, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted cycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl lamino, oxy thiocarbonylamino, -OS (O) 2_ alkyl, -OS (0) 2 substituted alkyl, -OS (0) ) 2-aryl, -OS (O) 2-ar i substituted, -0S (0) 2 heteroaryl, -OS (O) 2-heteroary substituted, -O S (O) 2-heterocyclic, -0S (0) 2-substituted heterocyclic, -0S (0) 2_NRR, where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (O) 2 - substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2-ar i substituted, -NRS (O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2 -heterocyclic, NRS (O) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, - NRS (0) 2-NR-aryl substituted, -NRS (0) 2-NR-heteroaryl, -NRS (O) 2-NR-substituted heteroaryl, NRS (0) 2-NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-het eroar i lamino, mono- and di-het eroari lamino substituted, mono- and di-heterocyclic-amino, mono- and di-heterocyclic substituted amino-amines, non-symmetrical di-substituted amines they have different substituents selected from alq uilo, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or substituted alkynyl / alkynyl groups, substituted with S02-alkyl, -S-2-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, S02-substituted heteroaryl, -S? 2 ~ het erocyclic, S02-substituted heterocyclic, and -S02-NRR where R is hydrogen or alkyl. "Amidino" refers to group H, NC-NH "and the term" alkylamido "refers to compounds having from 1 to 3 alkyl groups (eg, alkylHC-) NH'Tioamidino" refers to the group RSC - NH where R is hydrogen or alkyl. "Acylamino" refers to the groups NRC (O) alkyl, -NRC (O) substituted alkyl, NRC (O) cycloalkyl, -NRC (O) substituted cycloalkyl, -NRC (O) alkenyl, -NRC (O) alkeni the replaced, and ^^^ L ^ i ^^^. *.

-NRC (O) alkynyl, -NRC (0) substituted alkynyl, -NRC (0) aryl, -NRC (0) substituted aryl, -NRC (0) heteroaryl, -NRC (0) het eroar yl substituted, -NRC ( 0) heterocyclic, and -NRC (0) 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, heteroaryl substituted, heterocyclic and substituted heterocyclic are as defined herein. "Aminocarbonyloxy" refers to the groups -NRC (0) O-alkyl, -NRC (0) 0-substituted alky, NRC (0) O-alkenyl, -NRC (0) 0-alkene substituted, -NRC ( 0) O-alkynyl, -NRC (0) 0-substituted alkyne, -NRC (0) 0-cycloalkyl, -NRC (0) O-substituted cycloalkyl, -NRC (0) 0-aryl, -NRC (0) 0-substituted aryl, -NRC (0) 0-het eroar i lo, -NRC (0) 0 -substituted heteroaryl, -NRC (0) O-heterocyclic and NRC (0) O-substituted heterocyclic where R is hydrogen or alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and The substituted heterocyclic are as defined herein. "Oxycarbonylamino" refers to the groups -OC (0) NH2, OC (0) NRR, -OC (0) NR-alkyl, -OC (0) NR-substituted alkyl, -OC (O) NR-alkeni lo, -0C (0) NR-substituted alkenyl, -OC (0) NR-alkynyl, -0C (0) NR-substituted alkynyl, -OC (0) NR-cycloalkyl, OC (0) NR-substituted cycloalkyl, -OC (0) NR-aryl, OC (0) R-substituted aryl, -OC (0) NR-heteroaryl, OC (0) NR-substituted heteroaryl, -0C (0) NR-heterocyclic and -OC (0) NR -substituted heterocyclic wherein R is hydrogen, alkyl or where each R joins to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl , substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Oxitiocarbonylamino" refers to groups -0C (S) NH2, -0C (S) NRR, -0C (S) NR-a, or -0C (S) NR-substituted alkyl, -0C (S) NR- alkenyl, -0C (S) NR-substituted alkenyl, -0C (S) NR-alkylo, -0C (S) NR-substituted alkynyl, -0C (S) NR-cycloalkyl, OC (S) R-cycloalkyl substituted , -OC (S) NR-a ri lo, OC (S) NR-substituted aryl, -OC (S) NR-heteroarylo, OC (S) NR-substituted heteroaryl, -OC (S) NR-heterocyclic, and -OC (S) substituted NR-heterocyclic wherein R is hydrogen alkyl, or where each R joins to form with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Aminocarbomlamino" refers to groups -NRC (0) NRR, -NRC (O) NR-alkylo, -NRC (O) NR-substituted alkyl, -NRC (O) NR-alkenyl, -NRC (O) R- substituted alkenyl, -NRC (O) R-alkylo, -NRC (O) substituted R-alkynyl, -NRC (O) NR-aryl, -NRC (O) R-ary substituted, -NRC (O) R- cycloalkyl, -NRC (0) NR-substituted cycloalkyl, -NRC (O) NR-heteroaryl, NRC (O) substituted R-heteroaryl, -NRC (0) NR-heterocyclic and -NRC (O) R-substituted heterocyclic, wherein each R is independently hydrogen alkyl, wherein each R joins to form together with the nitrogen a heterocyclic ring or ke & ** & - substituted heterocyclic M as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, cycloalkyl substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Amino-iocarbonylamino" refers to groups -NRC (S) NRR, -NRC (S) NR-alkyl, -NRC (S) NR-substituted alkyl, -NRC (S) NR-alkenyl, -NRC (S) NR- a substituted Ikenyl, -NRC (S) NR-alkylo, -NRC (S) NR-substituted alkyl, -NRC (S) NR-aryl, -NRC (S) NR-substituted aryl, -NRC (S) R- cycloalkyl, -NRC (S) NR-substituted cycloalkyl, -NRC (S) R-heteroarylo, and -NRC (S) NR-substituted heteroaryl, -NRC (S) NR-heterocyclic and -NRC (S) NR- substituted heterocyclic, wherein each R is independently hydrogen, alkyl or wherein each R joins to form together with the nitrogen atom a substituted heterocyclic or heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hete Rocyclic and substituted heterocyclic are as defined herein. "Aryl" or "Ar" refers to an aromatic, unsaturated carboxylic group of 6 to 14 carbon atoms that has a single ring (eg, phenyl) or multiple fused rings (eg, naphthyl or anthryl) fused rings that can be aromatic or not (for example, 2-benzoxa zol inona, 2H-1, 4-benzoxa zin-3 (4 H) -one- 7 -i lo and the like). Preferred aryls include phenyl and naphthyl. Substituted aryl refers to aryl groups that are substituted with from 1 to 3 substituents selected from a group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, alkenyl substituted, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, ammocarbonylamino, aminocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxy , carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylated ido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroar ilo, substituted thioheteroaryl, t-cycloalkyl, substituted t-cycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (0) 2 -alkyl, -S (O) 2 -substituted alkyl, -S (0) 2-cycloalkyl, -S (O) 2 -substituted cycloalkyl, -S (0) 2-alkenyl, -S (O) 2 -substituted alkenyl, -S (O) 2 -aryl, -S (0) 2 -substituted aryl, -S (0) 2 -heteroaryl, -S (0) 2 -heteroaryl substituted, -S (0) 2-heterocyclic, -S (0) 2-substituted heterocyclic, -OS (0) 2-alkyl, -0S (0) 2 substituted alkyl, -OS (0) 2-aryl, -OS (0) 2-substituted aryl, -0S (0) 2 heteroaryl, -OS (0) 2-het substituted eroaryl, -OS (0) 2-heterocyclic, -0S (0) 2-substituted heterocyclic, -0S (0) 2_NRR, where R is alkyl , -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2-substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) -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-NR-heterocyclic, NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- substituted arylamino, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic-amino, mono- and di-heterocyclic substituted-a, unsubstituted di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and amino groups that in the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, or substituted with -S02-NRR where R is hydrogen or alkyl. "Aryloxy" refers to the aryl-O- group, which includes, by way of example, phenoxy, naphthoxy, and imi res. "Substituted aryloxy" refers to aryl-O-substituted groups. "Aryloxyaryl" refers to the -aryl-O-aryl group. "Substituted aryloxyaryl" refers to substituted aryloxyaryl groups of 1 to 3 substituents on either or both aryl rings selected from a group consisting of hydroxy, acyl, acylamino, thiocarboni lamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy , alkenyl, substituted alkenyl alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarboni loxi, aminocarboni lamino, aminotiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, SßfaiM iMf- "" ^ -3MH * aa: substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, cycloalkyl carboxyl, substituted carboxyl-cycloalkyl, carboxy-laryl, substituted-carboxyl-aryl, carboxyl-heteroaryl , substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted cycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxitiocarbonylamino, -S (0) 2- alkyl , -S (0) 2 alq substituted uyl, -S (0) 2-cycloalkyl, -S (O) 2 -substituted cycloalkyl, -S (0) 2 alkenyl, -S (O) 2 -substituted alkenyl, -S (0) 2 -aryl, - S (0) 2-substituted aryl, -S (O) 2 -heteroaryl, -S (O) 2 -substituted heteroaryl, -S (O) 2 -heterocyclic, -S (O) 2 -substituted heterocyclic, -OS ( 0) 2-alkyl, OS (O) 2-substituted alkyl, -OS (O) 2-arylo, -0S (0) 2-substituted aryl, -OS (0) 2-heteroaryl, -0S (0) 2 - substituted heteroaryl, -OS (O) 2-heterocyclic, OS (0) 2-substituted heterocyclic, -0S02-NRR wherein R is hydrogen or alkyl, -NRS (0) 2-alkyl, NRS (0) 2-substituted alkyl, -NRS (0) 2-ary lo, NRS (0) 2-substituted aryl, -NRS (0) 2-het eroa ri lo, 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-ar i substituted, NRS (0) ) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, substituted mono- and di-arylamm, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-het erocyclic-amino, mono- and di-heterocyclic amino-substituted, non-symmetrical di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl and the like or substituted with -S02NRR where R is hydrogen or alkyl. "Cycloalkyl" refers to cyclic alkyl groups of 3 to 8 carbon atoms having an individual cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. Excluding these definitions are alkyl groups of various rings such as adamantyl, etc. "Cycloalkenyl" refers to cyclic alkenyl groups of 3 to 8 carbon atoms, having individual or multiple unsaturation, but which are not aromatic. "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to cycloalkyl and cycloalkenyl groups, preferably 3 to 8 carbon atoms, having 1 to 5 substituents selected from a group consisting of oxo (= 0), thioxo ( = S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminot iocarboni lamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl , halogen, hydroxy, cyano, nitro, carboxyl, carboxylalkyl, carboxy-1-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxy-laryl, substituted-carboxylaryl, carboxyl-heteroaryl, substituted-carboxyl-heteroaryl, carboxyl-heterocyclic, carboxyl- substituted cycloalkyl, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioaryl, Ituido, thiocycloalkyl, thiocycloalkyl substituted, tiohet eroari lo, thioheteroari substituted, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, heterocyclyloxy substituted, 0-oxycarbonylamino, oxy-thiocarbonylamino, -OS (0) 2-alkyl, -OS (O) 2-alky substituted, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS ( O) 2-het eroar i lo, OS (O) 2-substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (O) 2-substituted heterocyclic, 5 OS (0) 2-NRR where R is hydrogen or alkyl, -NRS (0) 2- alkyl, -NRS (0) 2-substituted alky, -NRS (0) 2- aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -heteroar i substituted, NRS (0) 2-heterocyclic, -NRS (0) 2 ~ heterocyclic substituted, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-alkyi substituted, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-ari substituted , -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR- substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic where R is Hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-t-eroarylamino, mono- and di -het eroar and substituted lamino, mono- and di-heterocyclic-amino, mono- and Di-heterocyclic its t-amino-aminos, unsymmetrical disubstituted amines, having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl heteroaryl, substituted heteroaryl, heterocyclic substituted, substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or substituted alkynyl / alkynyl groups, substituted with -S02 alkyl, -SO2 alkyl substituted, -S02- alkenyl, -S? 2-a lqueni lo jg ^^^^^ át ^? iÉ ^ dg gjg substituted, -S02-cycloalkyl, -S? 2 ~ c? substituted chloroalkyl, -S? 2 aryl, -S? 2 -substituted aryl, -S02-heteroaryl, -S0 -substituted heteroaryl -S02-heterocyclic, -S02-substituted heterocyclic, -S02-NRR where R is hydrogen or alkyl. "Cycloalkoxy" refers to -0-cycloalkyl groups. "Substituted cycloalkoxy" refers to cycloalkyl-O-substituted groups. "Guanidino" refers to groups NRC (= NR) NRR, -NRC (= NR) NR-alkyl, -NRC (= NR) NR-substituted alkyl, -NRC (= NR) NR-alqueni lo, NRC (= NR) NR-substituted alkenyl, -NRC (= NR) NR-alkynyl, -NRC (= NR) NR-substituted alkynyl, NRC (= NR) NR-aryl, -NRC (= NR) NR-ary substituted, NRC (= NR) NR-cycloalkyl, -NRC (= NR) NR-heteroaryl, -NRC (= NR) NR-hetero-substituted heterocycle, -NRC (= NR) NR-heterocyclic, and -NRC (= NR) NR-heterocy substituted alkyl, wherein each R is independently hydrogen and alkyl as well as wherein the amino groups are blocked by conventional blocking groups such as Boc, Cbz, formyl and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , substituted cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Guanidinosulfone" refers to groups NRC (= NR) NRS02-alkyl, -NRC (= NR) NRS02-a substituted lyqui, -NRC (= NR) NRS02-alkenyl, NRC (= NR) NRS02-substituted alkenyl, - NRC (= NR) NRS02-alkynyl, -NRC (= NR) NRS02-substituted alkynyl, NRC (= NR) NRS02-aryl, -NRC (= NR) RS02 -substituted aryl, -NRC (= NR) NRS02-cycloalkyl, NRC (= NR) NRS02-substituted cycloalkyl, NRC (= NR) NRS02-heteroaryl, and -NRC (= NR) NRS02-substituted heteroaryl, -NRC (= NR) NRSÜ2-het erocyclic and -NRC (= NR) NRS02 -het substituted hydroxy, where 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 they are as defined in the present. "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 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. These heteroaryl groups may have an individual ring (for example, pyridyl or furyl) or multiple fused rings (for example, indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, mdolyl and furyl. "Substituted heteroaryl" refers to heteroaryl groups that are substituted with 1 to 3 substituents selected from a group consisting of hydroxyacyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, alkenyl substituted alkynyl, substituted alkynyl, amidino, alkylamido, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminotiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyloxy, carboxylalkyl, substituted carboxyl-alkyl, ftfcfaAt &Agffifllfc *. carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, substituted 1-aryl carboxyl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxy lamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, t ioheteroaryl, substituted ioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy , substituted heterocyclyloxy, oxycarbonylamino, oxy thiocarbonylamino, -S (0) 2 -alkyl, -S (0) 2 substituted alkyl, -S (0) 2-cycloalkyl, -S (O) 2 -substituted cycloalkyl, -S (0 ) 2 alkenyl, -S (O) 2 -alkeni substituted, -S (0) 2 -aryl, -S (0) 2 -substituted aryl, -S (O) 2 -heteroaryl, -S (O) 2-substituted heteroaryl, -S (O) 2-heterocyclic, -S (O) 2 -substituted heterocyclic, -OS (O) 2 -alkyl, OS (O) 2 -substituted alkyl, - OS (O) 2-aryl, -OS (0) 2-substituted aryl, -OS (O) 2-het eroari lo, -OS (0) 2_ substituted heteroaryl, -OS (0) 2-het erocí ico, OS (0) 2-substituted heterocyclic, -0S (0) 2-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkylo, -NRS (0) 2-substituted alkyl, -NRS (0) 2 -ari lo, -NRS (0) 2-substituted aryl, -NRS (0) 2-heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2-heterocyclic, NRS (0) 2-heterocyclic substituted, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-alk? the substituted, -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 where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic-amino, mono- and di-heterocyclic substituted -amino, amines di-their non-symmetrical t-tides, having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups in the substituted aryl blocked by blocking groups conventional such as Boc, Cbz, formyl and the like or substituted with -S02NRR where R is hydrogen or alkyl. "Heteroaryloxy" refers to the group -0-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 fused rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring , wherein, in the fused ring systems, one or more of the rings may be aryl or heteroaryl. "Saturated heterocyclic" refers to single or multiple fused ring heterocycles 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 individual or multiple fused rings having unsaturation in any ring (eg, carbon-to-carbon unsaturation, carbon-to-nitrogen unsaturation, nitrogen-to-nitrogen unsaturation, and the like).

"Substituted heterocyclic" refers to heterocycle groups that are substituted with 1 to 3 substituents selected from a group consisting of oxo (= 0), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, z -carbonylamino, acyloxy, amino, amidino, alkylamide, thioamidino, aminoacyl, ammocarbonylamino, aminot iocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxy, cyano, nitro, carboryl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxy-laryl, substituted-carboxyl-aryl, carboxyl-heteroaryl, substituted carboxyl-heteroaryl, carboxyheterocyclic, substituted-carbo-heterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioapyl, substituted thioaryl, thiocycloalkyl X, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy -substituted, heteroaryloxy, ,. - ... r ,, ^ 'gaag! ^ G ^; fXlgfe substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonyl lamino, oxythiocarbonylamine, -OS (0) 2 -alkyl, -0S (0) 2- substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2 -heteroaryl, -OS (0) 2-het-substituted-aryl, -OS (0) 2-heterocyclic, -0S (0) 2-substituted heterocyclic, -0S (0) 2-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2- aryl, -NRS (0) 2-substituted aryl, -NRS (0) 2-heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2-heterocyclic, NRS (0) 2 -heterocyclic substituted , -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-ari substituted, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono - and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylammo, mono- and i-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic-amino, mono- and di-heterocyclic substituted amino-unsubstituted, di-substituted amines, which they have different substituents selected from alkyl, alkyl Substituted MS, aryl, substituted aryl heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or substituted alkynyl / alkynyl groups, substituted - S02-alkyl, -S02-substituted alkyl, -S0 -alkenyl, -S0 -substituted alkenyl, -S02-cycloalkyl, -S02-substituted c-chloro-alkyl, -S? 2 -aryl, -S02 -substituted aryl, -S02- heteroaryl, -S02-substituted heteroaryl -S02-heterocyclic, -S02-substituted heterocyclic, and S0 -NRR where R is hydrogen or alkyl. Examples of heterocycles and heteroaryls include, but are not limited to, acetidino, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalisin, naft 1 lpyridine, quinoxaline, quinozoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimidine, 1, 2, 3, 4 -et rahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazoline, thiophene, benzo [b] thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and s imilar. "Substituted saturated heterocycle" refers to substituted heterocycles of single or multiple fused rings that lack saturation in any ring (e.g., carbon-to-carbon unsaturation, carbon-to-nitrogen unsaturation, nitrogen-to-nitrogen unsaturation, and the like). "Unsaturated substituted heterocyclic" refers to substituted, non-aromatic heterocycles of single or multiple fused 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 -0-heterocyclic and "substituted heterocyclyloxy" refers to the heterocyclic-O-substituted group. "Tiol" refers to the group -SH. "Thioalkyl" refers to the -S-alkyl groups.

"Substituted thioalkyl" refers to the group at which 1-S -substituted. "Thiocycloalkyl" refers to the -S-cycloalkyl groups. "Substituted thiocycloalkyl" refers to the group -S-substituted cycloalkyl. "Thioaryl" refers to the group -S-aryl and "substituted thioaryl" refers to the group -S-substituted aryl. "Thioheteroaryl" refers to the group -S-heteroaryl and "substituted thioheteroaryl" refer to the group -S-substituted heteroaryl. "Thioheterocyclic" refers to the group -S-heterocyclic and "substituted thioheterocyclic" refer to the group -S-substituted heterocyclic. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of formula I, salts that are derived from a variety of organic and inorganic counter ions well known in the art include, by way of example, solely, sodium, potassium, calcium , magnesium, ammonium, tet racalkylammonium, and the like; and when the molecule contains a basic functionality, the salts of organic and inorganic acids, tíffp-tovA- ± * ^ *. such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Preparation of the compound 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 the typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless noted. else. The optimum reaction conditions may vary with the particular reagents or solvent used, but these conditions can be determined by one skilled in the art by routine optimization procedures. In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from being subjected to undesired reactions. The protective groups 5 suitable for various functional groups IffWttf É ^ as well as the proper conditions to protect and deprotect particular functional groups are well known in the art. For example, numerous protecting groups are described in T.W. Greene and G.M. Wuts, Pro tectin g Groups in Organ i c Syn th es i s, Second Edition, Wiley, New York, 1991, and references cited therein. Additionally, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, these compounds can be prepared or isolated as pure stereoisomers, that is, as enantiomers or diastereomers, or as mixtures enriched with stereoisomers. All stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of these compounds can be separated using, for example, chiral column chromatography, chiral resolution agents, and the like.

In a preferred method of synthesis, the compounds of formula I and IA wherein Q is -C (0) NR7- are prepared by first coupling an amino acid of formula II: R3 I RONH-C-COOH II I H where R2 and R3 are defined above, with a sulfonyl chloride of the formula III R'-S0, -C1 III wherein R1 is as defined above, to provide an N-sul fonyl-amino acid of formula IV: R * -SO: -N (R2) -C «COOH IV H wherein R1 and R3 are as defined. This reaction is typically carried out by reacting the amino acid of formula II with at least one preferred equivalent about 1.1 to about 2 equivalents, of sulfonyl chloride III in a diluent inert such as dichloromethane and the like. In general, the reaction is carried out at a temperature ranging from about -70 ° C to about 40 ° C for 1 hour to about 24 hours. Preferably, this reaction is carried out in the presence of a suitable base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethyl amine, JV- and ilmorpholine and the like. Alternatively, the reaction can be carried out under Schot t en-Baumann type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base. At the end of the reaction, the resultant amino acid IV is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtrations, and the like. The amino acids of formula II used in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthesis methods. Examples of amino acids suitable for use in this reaction include, but are not limited to, L-proline, t ra n s-A-hydroxyl-L-proline, cis-4 * hydroxyl-L-proline, tra n s- 3-phenyl-L-proline,? r? Sr-3-phenyl-L-proline, L- (2-methyl) proline, L-pipecolinic acid, L-ace tidine-2-carboxylic acid, L-? Ndoline-2-carboxylic acid, L-1 acid , 2, 3, 4 -tetrahydroisoquinoline-3-carboxylic acid, linozoline-4-carboxylic acid, L- (5, 5 -dimet il) thiazoline-4-carboxylic acid, lino-umid folina-3- acid carboxylic, glycine, 2, tert-butylglycine, D, L-phenylglycine, L-alanine, α-methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D, L-phenylsarcosine, β-ester L-aspartic acid, L-glutamic acid, L- (O-benzyl) serine, l-aminocyclopentanecarboxylic acid, l-aminocyclobutanecarboxylic acid, l-aspartic acid ester aminocyclopentanecarboxylic (cycloleucine), 1-aminocyclohexanecarboxylic acid, L-serine and the like. If desired, the corresponding esters of the carboxylic acid of the amino acids of the formula II, such as the methyl esters, ethyl esters and the like, can be used in the above reaction with the sulfonyl chloride III. Subsequent hydrolysis of the ester group to the carboxylic acid using conventional reagents and conditions, is to say, treatment with a metal or alkali hydroxide in an inert diluent such as methanol / water, then provides the N-s or l -ammo acid IV. Similarly, the sulfonyl chlorides of formula III used in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. These compounds are typically prepared from the corresponding sulfonic acid, i.e., from compounds of the formula R1-S03H wherein R1 is as defined above, using phosphorus trichloride and phosphorus pentachloride. This reaction is generally carried out by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorus trichloride and phosphorus pentachloride, either neat or in an inert solvent, such as dichloromethane, at a temperature in the range of about 0 ° C to about 80 ° C for about 1 to about 48 hours to give the sulfonyl chloride. Alternatively, the sulfonyl chlorides of the formula III can be prepared from the compound of The corresponding thiol, ie, of the compounds of the formula R1-SH where R1 is as defined above, by treating the thiol with the chloride (Cl2) and water under the reaction conditions conventional Examples of sulfonyl chloride suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesul fonyl chloride, benzenesulfonyl chloride, l-naphthalenesul fonyl chloride, chloride of 2-naphthalenesulfonyl, p-toluenesul fonyl chloride, a-toluenesulfonyl chloride, 4-acetamidobenzenesulfonyl chloride, 4-amidobenzenesul fonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, chloride of 2-carboxybenzenesulfonyl, 4-cyanobenzenesulonyl chloride, 3,4-di chlorobenzenesulonyl chloride, 3,5-chlorobenzenesulonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethoxybenzenesulfonyl chloride , 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulphonyl chloride, 4-n-t-robenosulphonyl chloride, 4-t-ioamidobe chloride ncenosul foni lo, 4-trifluoromethylbenzenesulfonyl chloride, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethyl-4-benzenesulfonyl chloride, 2-phenylethronyl chloride, 2-nitrophenol fonil chloride, 5-chlorochloride 2-t iofensul fonilo, chloride 2, 5-dichloro-4-thiophenesulfonyl, 2-thiazolesulfonyl chloride, 2-methyl-4-thiazolesulfonyl chloride, l-methyl-4-imidazolesulfonyl chloride, l-methyl-4-pyrazole sulphloyl chloride, 5-chloro-1,3-dimethyl-il-4-pyrazole sulphonyl chloride, 3-pyridinesulfonyl chloride, 2-pyrimidine sulfonyl chloride, and the like. If desired, sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride can be used in place of sulfonyl chloride in the reaction Above to form the N-s of the fonil-amino acids of formula IV. The intermediate W-sul foni -amino acids of the formula IV can also be prepared by reacting a sulfonamide of the formula V: i ^? ^^^. ^^^^^^^, ..

R'-SO, -NH-R2 wherein R1 and R2 are as defined above, with a carboxylic acid derivative of the formula L (R3) CHCOOR or where L is a leaving group, such as chlorine, bromine iodine, mesylate, tosylate and the like, R3 is as defined above and R is hydrogen or an alkyl group. This reaction is typically carried out by contacting the sulfonamide V with at least one equivalent, preferably 1.1 to 2 equivalents, of the carboxylic acid derivative in the presence of a suitable base, such as triethylamine, in an inert diluent, such as DMF, at a temperature ranging from about 24 ° C to about 37 ° C for about 0.5 to about 4 hours. This reaction is further described in Zuckermann et al., J. Am. Ch em. So c. , 1992, 114, 10646-10647. Preferred carboxylic acid derivatives for use in this reaction are esters of a-chloro and a-bromocarboxylic acid, such as tert-butyl bromoacetate and the like. When a carboxylic acid ester is employed in this reaction, the ester group is subsequently hydrolyzed using - ..? ft ^^ lhA. conventional to give a? Xsul foni 1 -aminoacid of formula IV. The compounds of the formula I and IA are then prepared by coupling the N-s or the intermediate fonnation of the formula IV with an amino acid derivative of the formula VI: R7-? H-CH-C-R6 VI R5 wherein R5-R7 are as defined above and, in addition, R6 may be hydroxyl. This coupling reaction is typically carried out using well known coupling reagents such as carbodiimides, BOP reagent (benzotriazol-1-yloxy -tris (dimethylammonium) phosphonium hexafluorophosphate) and the like. Suitable carbodiimides include, by way of example, dicycloxycarbodiimide (DCC), 1- (3-dimethyl-laminopropyl) -3-ylcarbodiimide (EDC) and the like. If desired, the polymer-supported forms of the carbodiimide coupling reagents can also be used, including, for example, those described in Te t ra h edron Le t t ers, 34 (48), 7685 (1993). Additionally, well-known coupling promoters, such as N-hydroxysuccinimide, 1-hydroxybenzotriazol and the like, can be used to facilitate the coupling reaction. This coupling reaction is typically carried out by contacting the N-s or f-amino acid IV with about 1 to about 2 equivalents of the coupling reagent and at least one equivalent, preferably from about 1 to about 1.2 equivalents, of the amino acid derivative VI in an inert diluent, such as dichloromethane, chloroform, acetonityl, tetrahydrofuran, N,? Z-dimethyl formamide and the like. In general, this reaction is carried out at a temperature ranging from about 0 ° C to about 37 ° C for about 12 to about 24 hours. At the end of the reaction, the compound of the formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like. Alternatively, the α-sulfonyl-amino acid IV can be converted to an acid halide and the acid halide is coupled to the amino acid derivative VI to provide the compounds of the formula I. The VI acid halide can be prepared by contacting VI with an inorganic acid halide such as thionyl chloride, phosphorus trichuride 5, phosphorus tribromide, or phosphorus pentachloride, or preferably, with oxalyl chloride or conventional conditions. In general, this reaction is carried out using about 1 to 5 molar equivalents of the The inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at a temperature in the range of about 0 ° C to about 80 ° C for about 1 hour. up to about 48 hours. A catalyst, such as N, N-dimethyl ilformamide may also be used in this reaction. The acid halide of the N-s u l f on i l-a inocid IV can then be contacted with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of the amino acid derivative VI in an inert diluent, such as dichloromethane, at a temperature ranging from about -70 ° C up to about 40 ° C for up to YJJ Hfft ^ approximately 1 to approximately 24 hours. Preferably, this reaction is carried out in the presence of a suitable base to remove the acid generated during a reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-meth ilmor folin, and the like. Alternatively, the reaction can be carried out under Schotten-Baumann type conditions using aqueous alkali, such as sodium hydroxide and the like. At the end of the reaction, the compound of the formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like. Alternatively, the compounds of the formula I can be prepared by first forming a diamino acid derivative of the formula VII: R7 O R-? H-C-C (0)? - CH-C-R6 VII j I H R5 where R2-R7 are as defined above. The diamino acid derivatives of formula VII can be easily prepared by coupling an amino acid in formula II with an amino acid derivative of formula VI using conventional, amino acid coupling techniques, and reagents, such as carbodiimides, BOP reagent and the like , as described previously. The diaminoacid VII can then be sulfonated using a sulfonyl chloride of the formula III and using the synthetic procedures described above to provide a compound of the formula I. The amino acid derivatives of the formula VI used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. For example, amino acid derivatives of formula VI can be prepared by the C-alkylation of commercially available diethylamide 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with a substituted alkyl or aikyl halide. This reaction was typically carried out by treating diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or alkyl halide substituted at reflux with ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated upon heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid typically as the hydrochloride salt. Examples of amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-alanine methyl ester, isoleucine methyl ester, leucine methyl ester, valine methyl ester, methyl ester of ß-tert-but-il-L-aspartic acid, tert-butyl ester of L-asparagine, methyl ester of e-Boc-L-1 isine, methyl ester of e-Cbz-L-lysine, methyl ester of acid ? -ter-butyl-L-glutamic acid, L-glutamine tert-butyl ester, L- (N-methyl) histidine methyl ester, L- (N-benzyl) histidine methyl ester, L-methionine methyl ester, methyl ester of L- (0-benzyl) serine, methyl ester of L-tritofan, methyl ester of L-phenylalanine, isopropyl ester of phenylalanine, benzyl ester of L-phenylalanine, L-phenylalaninamide, benzyl ester of N-methyl-L - phenylalanine, methyl ester of 3-carboxy-D, L- Phenylalanine, methyl ester of -carboxy-D, L-phenylalanine, methyl ester of L-4-chlorophenylamine, L-4- (3-demethylaminopropyloxy) phenylalanine, methyl ester of L-4-iodophenylalanine, methyl ester of L-3,4-methylenedioxyphenylalanine, methyl ester of L-3,4 - ethylenedioxyphenylalanine, methyl ester of L-4-nitrophenylalanine, methyl-L-irosine ester, methyl ester of D, L-homophenylalanine, methyl ester of L- (O-methyl) tyrosine, methyl ester of L- (0-tert-butyl) il) t iros ina, methyl ester of L- (0-benzyl) tyrosine, methyl ester of L-3,5-diiodotyrosine, methyl ester of L-3-iodotyrosine, methyl ester of β- (1 -naphthyl) -L -alanine, β- (2-naphthyl) -L-alanine methyl ester, β- (2-thienyl) -L-alanine methyl ester, methyl-β-cyclohexyl-L-alanine ester, β-methyl ester ( 2-pyridyl) -L-alanine, β- (3-pyridyl) -L-alanine methyl ester, β- (4-pyridyl) -L-alanine methyl ester, β- (2-tα-azolyl) methyl ester ) -D, L-alanine, ester met β- (1, 2, 4 -tria zol-3-yl) -D, L-alanine, and the like. If desired, other esters or amides of the above-described compounds may be employed in passing.

To facilitate synthesis, the compounds of the formula I are typically prepared as an ester, ie, wherein R6 is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolyzed, using conventional conditions and reagents to provide the corresponding carboxylic acid. Typically, this reaction is carried out 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, a temperature ranging from about 0 ° C to about 24 ° C for about 1 to about 12 hours. Alternatively, benzylic esters can be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon. The resulting carboxylic acids may be coupled, if desired, to the amines such as the β-alanine ethyl ester, hydroxyamines such as hydroxylamine and N-hydroxysuccinamide, alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamina and O-benzylhydroxylamino , and the like, using reagents ? flif, AIU * Jfa 'of conventional coupling and conditions as described above. As will be apparent to those skilled in the art, other functional groups present in any of the substituents of the compounds of the formula I can be easily modified or derivatized, either before or after the coupling reactions described above using either synthetic or known. For example, a nitro group present in a substituent of a compound of the formula I or an intermediate thereof can be easily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium in carbon to provide the corresponding amino group. This reaction is typically carried out at a temperature from about 20 ° C to about 50 ° C for about 6 to about 24 hours in an inert diluent, such as methanol. Compounds having a nitro group in substituent R3 can be prepared, for example, by using a 4-nit derivative rofeni lalanin and the like, in the coupling reactions described above.

Similarly, a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acid diluent to provide the corresponding piperidinyl analog. In general, this reaction is carried out by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperature of about 20 °. C to about 50 ° C for about 2 to about 24 hours in an acid diluent, such as a mixture of methanol and aqueous hydrochloric acid. Compounds having a pyridyl group can be easily prepared by using, for example, β- (2-pyridyl-, β- (3-pyridyl) - or β- (4-pyridyl) -L-alanine derivatives in the reactions In addition, when the R5 substituent of a compound of the formula I or an intermediate thereof contains a primary or secondary amino group, these amino groups can be further derivatized either before or after the reactions. of previous coupling for provide, by way of example, amides, sulfonamides, ureas, thioureas, carbonates, secondary or tertiary amines and the like. Compounds having a primary amino group in substituent R5 can be prepared, for example, by reduction of the corresponding nitro compound as described above. Alternatively, these compounds can be prepared by using an amino acid derivative of formula VI derived from lysine and the like, in the coupling reactions described above. By way of illustration, a compound of the formula I or an intermediate thereof having a substituent containing a primary or secondary amino group, such as where R 5 is a 4-aminobutyl group, can be readily cyclized using reagents from conventional acylation and conditions for providing the corresponding amide. This acylation reaction is typically carried out 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 ( hexafluorofos fonato of benzot ria zol-1-iloxi- Mtfe-J? ^, To ^ Afefe &-tri s (dimethylamino) fos fonio) and the like in an inert diluent, such as dichloromene, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethyl formamide and the like, at a varying temperature from about 0 ° C to about 37 ° C for about 4 to about 24 hours. Preferably, a promoter, such as N-hydroxy succinimide, 1-hydroxybenzotriazole and the like, is used to facilitate the acylation reaction. Examples of suitable carboxylic acids for use in this reaction include, but are not limited to N-t-butyloxycarbonylglisine, N-tert-butyloxycarbonyl-L-phenylalanine, N-t-butyloxycarbonyl benzyl ester - L-aspartic acid, benzoic acid, N-t-butyloxycarbonylisonipecotic acid, methylisonipecotic acid, N-tert-butyloxycarbonyl-norpecotic acid, N-t-butyloxycarbonyl-L-tetrahydroisoquinolma-3-carboxylic acid, N- (toluene-4 - sulfonyl) -L-proline and the like. Alternatively, a compound of the formula I or an intermediate thereof which contains a primary or secondary amino group can be N-a to c using an acyl halide or an , .Aj'ta £ 2¡ ^ iSSA. '. ^. carboxylic acid anhydride to form the corresponding amide. This reaction is typically carried out 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 which ranges from about -70 ° C to about 40 ° C for about 1 to about 24 hours. If desired, an acylation catalyst such as 4- (N, N-dimethylamino) pyridine can be used to promote the acylation reaction. The acylation reaction is preferably carried out in the presence of a suitable base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as t-riet-ylamine, diisopropylethylamine, N-me t-ilmorpholma, and the like. Alternatively, the reaction can be carried out under Schotten-Baumann type conditions using an aqueous alkali, such as sodium hydroxide and silanes. 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, 2-meth ilbenzoyl chloride, 2-trifluoromethyl-benzoyl chloride, isonicotyl chloride, m-cinnoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N, N-dimethylammonium chloride, N, N-di and ilcarbamyl chloride, and the like, can also be used in this reaction to provide ureas. Similarly, dicarbonates such as di-tert-butyl dicarbonate can be used to provide carbamates. In a similar manner, a compound of formula I or an intermediate compound thereof which contains a primary or secondary amino group can be ε-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethane anosul fonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides, such as dimethyl ilsul famoyl chloride, can be used to provide sulfonamides (eg, > N-S02 ~ N <). Additionally, a primary or secondary amino group present in a substituent of a compound of the formula I / IA or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively. This reaction is typically carried out with the contact of the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or otisocyanate in an inert diluent, such as toluene and the like, at a temperature ranging from about 24 ° C to about 37 ° C for about 12 to about 24 hours. The isocyanates and thiocyanates used in this reaction are commercially available and can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are easily 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, * a **** L * ^ & *** ¿¿¿»» ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, thioisocyanate of methyl, ethyl thiocyanate, 2-phenylethyl thiocyanate, 3-phenylpropyl thiocyanate, 3 (N, N-diethylamino) propyl thioisocyanate, phenylthioisocyanate, thioisocyanate of benzyl, 3-pyridyl thiocyanate, fluoroiscene isothiocyanate (isomer I) and similar. Additionally, when a compound of the formula I / IA or an intermediate thereof contains a primary or secondary amino group, the amino group can be alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically carried out by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures of the same and similar, at a temperature that varies m z ^^ z; ^ from about 0 ° C to about 50 ° C for about 1 to about 72 hours. Suitable aldehydes or ketones 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 the formula I / IA or an intermediate thereof has a substituent containing a hydroxyl group, the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions for provide, by way of example, ethers, carbamates and the like. Compounds having a hydroxyl group in, for example, substituent R3, for example, can be prepared using an amino acid derivative of formula VI derived from tyrosine and the like in the reactions described above. By way of example, a compound of formula I / IA or an intermediate thereof having a substituent containing a hydroxyl group, such as where R 3 is a (4-hydroxyphenyl) methyl group, can be easily O-alkylated to form ethers. This O-alkylation reaction is typically carried out by contacting the hydroxy compound with a suitable alkali metal 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 metal or alkaline earth salt of the hydroxyl group. This salt is generally not isolated, but m if t u is reacted with at least one equivalent of an alkyl halide or a substituted alkyl or sulfonate, such as an alkyl, bromide, iodide, mesylate or tosylate chloride, to give the ether. In general, this reaction is carried out at a temperature ranging from about 60 ° C to about 150 ° C for about 24 hours. up to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is used in the reaction. Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, W-tert-chloroacetamide, 1-bromoet-il-benzene, a-bromophenylacetate or ethyl, 2- (N-e t i l - N-phenylamino) et lio chloride, ^ ^ x ^^ x ^ M £ ^ g ^ Égg ^^ & ^^^ 2- (N, N-ethylamino) ethyl, 2- (N, N-diisopropylamino) ethyl chloride, 2- ( N, N-dibenzylamino) ethyl, 3- (N, N-ylamino) propyl chloride, 3- (N-benzyl-N-methylamino) propyl chloride, N- (2-chloroet i 1) mor fol ina , 2- (hexamet ileneimino) ethyl chloride, 3- (N-methylpiperazine) propyl chloride, 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine, 2- (4-hydroxy-4-phenylpiperidine) ethyl chloride, N-tert-butyloxycarbonyl tosylate 1-3-p? Per? Dmame linden, and the like. Alternatively, a hydroxyl group present in a substituent of the compound of the formula I or an intermediate thereof can be O-alkylated using the Mitsunobu reaction. In this reaction, an alcohol, such as 3- (N, N-dimethylamino) -1-propanol and the like, is reacted with from about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarbolate in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about -10 ° C to about 5 ° C for about 0.25 to about 1 hour. Approximately 1.0 to approximately 1.3 equivalents of a f-B ^ rffc ^. hydroxy compound, such as the N-tert-butyltyrosine methyl ester, then the reaction mixture is added and stirred at a temperature from about 0 ° C to about 30 ° C for about 2 to about 48 hours to provide the product O-rented. In a similar manner, a compound of the formula I or an intermediate thereof containing an aryl-hydroxy group can be reacted with an aryl iodide to provide a diaryl ether. In general, this reaction is carried out by forming the alkali metal salt of the hydroxyl group using a suitable base, such sodium hydride, in an inert diluent such as xylene at a temperature from about -25 ° C to about 10 ° C. . The salt is then reacted with from about 1.1 to about 1.5 equivalents of the dimethylsulfide-cuprous bromide complex at a temperature ranging from about 10 ° C to about 30 ° C for about 0.5 to about 2.0 hours, followed by about 1.1 up to about about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. The reaction It is then heated to about 70 ° C to about 150 ° C for about 2 to about 24 hours to provide the diaryl ether. Additionally, a hydroxy-containing compound can be easily derivatized to form a carbamate. A method for preparing these carbamates, a hydroxy compound of formula I or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about -25 ° C to about 0 ° C for about 0.5 to about 2.0 hours. Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine provides the carbamate. Examples of suitable amines for use in this reaction include, but are not limited to, piperazine, 1-methyl-piperazine, 1-acetyl-piperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like. 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 carried out in the presence of a suitable base to remove the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triet, laminate, diisopropylethylamine, N-methylmorpholine, and the like. Additionally, at least one equivalent (based on the hydroxy compound) of the 4- (N, N-dimethylamino) pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of carbamyl chloride suitable for use in this reaction include, by way of example, dimethyl chloride, diethylcarbamyl chloride, and the like.

Likewise, when a compound of the formula I or an intermediate thereof contains a primary or secondary hydroxyl group, these hydroxyl groups can easily be converted into a leaving group and are displaced to form, for example, amines, sulfides or chlorides. For example, the 4-hydroxy-L-proline derivatives can be converted into the corresponding 4-amino, 4-thio or 4 -f luoro-L-proline derivatives via Nucleophilic displacement of the derivatized hydroxyl group. In general, when a chiral compound is employed in these reactions the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically reversed. These reactions are typically carried out by first converting the hydroxyl group to 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 carried out at a temperature from about 0 ° C to about 70 ° C for about 1 to about 48 hours. The resulting tosylate can then be easily displaced with azide of sodium, 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 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the corresponding azido compound. The azido group can then be reduced, for example, by hydrogenation using a palladium on carbon catalyst to provide the amino compound (-NH2). Similarly, a tosylate group can be easily displaced by a thiol to form a sulfide. This reaction is typically carried out 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. .0] undec-7. -ene (DBU), in an inert diluent, such as N, N-d imetheyl formamide, at a temperature from about 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the sulfide. Additionally, the treatment of a tosylate with folin-a-trifluor trifluoride in an inert diluent, such as dichloromethane, at a temperature ranging from about 0 ° C to about 37 ° C for about 12 to about 24 hours gives the corresponding fluoro compound. Additionally, a compound of the formula I or IA or an intermediate thereof having a substituent containing an iodoaryl group, for example, when R3 is a (4-iodophenyl) methyl group, can be easily converted either before or after the above coupling reactions in a biaryl compound. Typically, this reaction is carried out by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2- (methoxycarbonyl) phenylzinc iodide, in the presence of a palladium catalyst, such as (triphenylphosphine) of palladium, in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about 24 ° C to about 30 ° C until the completion of the reaction. This reaction is further described, for example, in Rieke, J. Org. Ch em 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. These sulfur atoms will be present, for example, when the amino acid of formula II used in the above reactions is derived from L-iazolidin-4-carboxylic acid, L- (5, 5-dimet i 1) acid idol -carboxylic acid, iamorpholine-3-carboxylic acid, and the like. Even when present, these sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and conventional 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 was typically carried out by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent., such as dichloromethane at a temperature ranging from about -50 ° C to about 75 ° C for about 1 to about 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidation reagent such as hydrogen peroxide, MCPBA, potassium permanganate and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. These reactions are further described in March. "Adva n ced Orga n i c Ch emi s t ry", 4th Ed., Pp. 1201-1202, Wiley publisher, 1992. As described above, compounds of the formula I having a preferred substituent R 2 of a hydrogen can be prepared using an N-amino acid thereof of the formula II, such as sarcosine , N-me t il-L-phenylalanine and the like, in the coupling reactions described above. Alternatively, these compounds can be prepared with the N-alkylation of a sulfonamide of the formula I or IV (where R is hydrogen) using conventional synthetic methods. Typically, this N-alkylation reaction is carried out by contacting the sulfonamide with at least one equivalent, preferably 1.1 to 2 equivalents, of an alkyl or substituted alkyl halide in the presence of a suitable base, such as potassium carbonate. , an inert diluent, such as acetone 2-butanone and the like, at a temperature ranging from about 25 ° C to about 70 ° C for about 2 to about 48 hours. Examples of alkyl or substituted alkyl halides suitable for use in this reaction include, but are not limited to, methyl iodide, and the like. Additionally, the sulfonamides of formula I or IV wherein R 2 is hydrogen and R 1 is a 2-alkoxycarbonylaryl group can be cyclized intlecularly to form 1,2-benzyl zol-3-one derivatives or analogs thereof . This The reaction is typically carried out by treating a sulfonamide, such as the benzyl ester of N- (2-methoxycarbonyl phenylsul fonyl) gl? Cina-L-phenylalanine, with 1.0 to 1.5 equivalents of a suitable base, such as the hydride of alkali metal, in a thinner Inert, such as tetrahydrofuran, at a temperature ranging from about 0 ° C to about 30 ° C for about 2 to about 48 hours to give the cyclized derivative of 1,2-benzothotolol-3-a. , - ^ * > * @ *! < * i '' iisiA ^^^?? S &^ 2 ^^^^^^^^^^^^^ Finally, the compounds of the formula I where Q is -C (S) NR7 they can be prepared by using an amino-thio acid derivative in place of amino acid II in the synthetic procedures described above.These amino acid derivatives can be prepared by the procedures described in Shalaky, et al., J. Org. Ch em., 61: 9045-9048 (1996) and Brain, et al., J. Org. Chem. , 62: 3808-3809 (1997) and references cited therein.

Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of formula I and IA are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective both as injectable and oral compositions. These compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions containing, 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 attached with a carrier which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, a semi-solid or a liquid material, which acts as a carrier vehicle or medium for the active ingredient. In this way, the compositions may be in the form of tablets, pills, dragees, powders, lozenges, vials, seals, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments that they contain, for example, up to 10% by weight of the active compound, soft or hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. When preparing a formulation, it may be necessary to grind the active ingredient to * aJs &* * J provide the particle size or property before combining it with the other ingredients. If the active compound is substantially insoluble, it is ordinarily milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by the grind to provide a substantially uniform distribution in the formulation, for example near 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, albenates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose , water, syrup, and methylcellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil: wetting agents; emulsifying and dispersing agents; preservatives such as methyl- and propylhydroxybenzoate; sweetening agents and flavoring agents. The compositions of the invention can be formulated to provide rapid, 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 dose form each dose containing from about 5 to about 100 mg. most commonly about 10 to about 30 mg, of the active ingredient. The term "unit dose form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a Pharmaceutical excipient, suitable. The active compound is effective over a broad range of doses which is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound will actually be determined by a practitioner, in view of the pertinent circumstances, which include the condition being treated, the chosen route of administration, the actual compound administered, the weight and response age of the patient. patient ^^^^ g ^ | ggg ^ g | tó | s | individual, the severity of the patient's symptoms, and the like. To prepare the solid compositions such as tablets, the main active ingrnt is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogenous mixture of the present invention. When referring to these pre-formulation compositions as homogeneous, it is meant that the active ingrnt is dispersed uniformly throughout the composition, so that the composition can be sub-divided into equally effective unit dose forms such as tablets, dragees and capsules. This solid pre-formulation is then sub-divided in the form of unit doses of the type described above containing, for example, from 0.1 to about 500 mg. of the active ingrnt of the present invention. The tablets or lozenges of the present invention can be coated or otherwise compounded to provide a dosage form that gives the advantage of prolonged action. For example, the tablet or lozenge may comprise an internal dose and an external dose component, the latter of which * ^ ¿£ = 2jk is in the form of a wrap over the previous one. The two components can be separated by an enteric layer which serves to help resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay the release. A variety of materials can be used for these enteric layers or coatings, such as materials that include a number of polymeric acids and mixtures of polymeric acids with suitable materials such as sealant, cetyl alcohol and cellulose acetate. Liquid forms in which the new compositions of the present invention can be incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and emulsions flavored with le oils such as cottonseed oil, sesame oil , coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof or powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described above. Preferably, the compositions are administered by an oral or nasal breathing route for nasal or systemic effect. In pharmaceutically acceptable solvents, they can preferably be nebulized by the use of inert gases. The nebulized solutions can be breathed directly from the nebulizing device or the nebulizing device can be attached to face masks, or positive-pressure, intermittent breathing machines. The solution, suspension or powder compositions can be administered, preferably orally or nasally, from devices that distribute the formulation in an appropriate manner. The following formulation examples illustrate the pharmaceutical compositions of the present invention.

Formulation Example 1 Hard gelatin capsules containing the following ingrnts are prepared: Ingrnts Quantity (mg / capsule) Active ingrnt 30.0 Starch 305.0 Magnesium Stearate 5.0 The above ingrnts are mixed and filled into hard gelatin capsules in amounts of 340 mg.

Formulation Example 2 A tablet formula is prepared using the ingrnts below: Ingrnts Quantity (mg / tablet) Active Ingrnt 25.0 Cellulose microcris taima 200.0 Silicon dioxide 10.0 colloidal Stearic acid 5.0 The components are mixed and compressed to form tablets, each weighing 240 mg.

Figure imgf000018_0001 Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components: Ingredients in Weight Active Ingredient .5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a dry powder inhalation applicator.

Formulation Example 4 Tablets containing 30 mg are prepared as follows. of the active ingredient.

Ingredients Amount (mg / tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 Polyvinylpyrrolidone 4.0 mg (as a 10% solution in water) Carboxymethyl 4-starch sodium stearate magnesium 0.5 mg Talcum 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a No. 20 mesh American sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a North American 16 mesh screen. The granules produced in this manner are dried at 50 ° to 60 ° C and passed through a North American sieve. 16. Sodium carboxymethyl-starch, magnesium stearate, and talc, previously passed through a 30-mesh American sieve, are then added to the granules which, after mixing, are compressed in a tablet machine to produce tablets weighing 150 mg each Formulation Example 5 Capsules are made, each containing 40 mg of the medicament as follows: Ingredient Quantity (mg / capsule) Active ingredient 40.0 mg Starch 109.0 Magnesium stearate 1.0 Total 150.0 mg.

The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a No. 20 mesh American sieve and filled into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 Suppositories are made, each containing 25 mg of the active ingredient, as follows: Ingredient Quantity Active Ingredient 25 mg. Saturated glycerides of 2, 000 mg fatty acid a The active ingredient is passed through a North American 60 mesh screen and dispersed in the saturated fatty acid glycerides, previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold with a nominal capacity of 2.0 g. and left to cool.

Formulation Example 7 Suspensions are made, each containing 50 mg. of the medication per 5.0 ml dose as follows: ^^ tel-.? ^ ^ Z ^ .rtr? t .- ^, Ingredient Quantity Active Ingredient 50.0 mg. Xanthan gum 4.0 Sodium carboxymethyl cellulose 50.0 mg. (eleven%) . Microcrystalline cellulose (89%) Sucrose 1.75 gm Sodium benzoate 10.0 mg. Taste and color c.v Purified water at 5.0 ml.

The medicine, sucrose and xanthan gum are mixed, passed through a No. 10 mesh American sieve and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are diluted with some of the water and added with agitation. Then enough water is added to produce the required volume.

Formulation Example Ingredient Quantity ^ mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through a No. 20 mesh American sieve and filled into hard gelatine capsules in amounts of 560 mg.

Formulation Example 9 An intravenous formulation can be prepared as follows: Ingredient Quantity Active ingredient 250.0 mg. Isotonic saline solution 1000.0 ml - ^ t ^^^^ Z ^^ i ^ Formulation Example 10 A topical formulation can be prepared as follows: Ingredient Quantity Active Ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g Soft paraffin, white at 100 g The white soft parafma heats up to melt. The liquid paraffin and the emulsifying wax are incorporated and stirred until they dissolve. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled to solid. Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). These transdermal patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the distribution of Pharmaceutical agents are well known in the art, See, for example, U.S. Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference. These patches can be constructed for continuous dysfunction, or pulsatile or at the request of pharmaceutical agents. It may be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually comprise the placement of a drug delivery catheter via the ventricular system of the host to derive the blood barrier of the brain. This implantable distribution system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent No. 5,011,472 which is incorporated herein by reference. Indirect techniques, which are generally preferred, usually comprise the formulation of the compositions to provide drug latency by the conversion of hydrophilic drugs into lipid soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carboxyl, and primary amine groups present sulphate to return to the drug more lipid soluble and amenable to transportation across the blood brain barrier. Alternatively, the distribution of hydrophilic drugs can be improved by the intra-arterial infusion of hypertonic solutions that can open the brain barrier transiently.

Utility The compounds of this invention can be used to bind VLA-4 (αβ integrin) in biological samples and, therefore, have utility in, for example, assays and samples for VLA-4. In these assays, the compounds can be attached to a solid support and the VLA-4 sample bound thereto. The amount of VLA-4 can be determined by conventional methods such as by the use of an intercalation ELISA assay. Alternatively, the labeled VLA-4 can be used in a competitive assay to measure the presence of VLA-4 in the sample. Other suitable assays are well known in the art.

Further, certain compounds of this invention inhibit i n vi vo, leukocyte adhesion to endothelial cells mediated by VLA-4 and, therefore, can be used in the treatment of diseases mediated by VLA-4. Such diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, arterosclerosí s, AIDS dementia, diabetes (including juvenile onset diabetes acute), inflammatory disease interim (including ulcerative colitis and Crohn's disease) multiple sclerosis, arthritis rheumatoid, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, utopia dermatitis, psoriasis, myocardial ischemia and acute lung injury mediated by leukocytes such as that presented in syndrome respiratory pain in adults. The biological activity of the compounds identified above can be assessed in a variety of systems. For example, a compound can be immobilized on a solid phase and the adhesion of cells expressing VLA-4 can be measured. Using these formats, large numbers of compounds can be detected. Suitable cells for this assay include any of the known leukocytes that express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils. A number of leukocyte cell lines can also be used, examples include Jurkat and U937. Test compounds can also be tested for the ability to competitively inhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a labeled compound known to bind VLA-4 such as a compound of this invention or antibodies to VLA-4. In these assays, VCAM-1 can be mobilized on a solid surface. VCAM-1 can also be expressed as a recombinant fusion protein that has an Ig extremity, (for example IgG) so that binding to VLA-4 can be detected in an immunoassay. Alternatively, cells expressing VCAM-1, such as activated endothelial cells or fibroblasts transfected with VCAM-1 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 application is incorporated herein by reference in its entirety. Many test formats employ 5 labeled test components. The marking system can be in a variety of form. The tag or tag can be coupled directly or indirectly to the desired component of the assay according to the methods well known in the art. technique. A wide variety of brands or labels can be used. The component can be marked by any of several methods. The most common method of detection is the use of autoradiography with compounds labeled with 3H, 125I, 35S, 14C, or 32P or similar. Non-radioactive labels include ligands that bind to the antibodies of the labeled groups, fluorophores, chemiluminescent agents, enzymes and antibodies that can serve as binding pair members, specific for a ligand labeled. The choice of brand depends on the required sensitivity, ease of conjugation with the compound, stability requirements and available instrumentation. The models in vi vo appropriate for demonstrate the effectiveness in the treatment of Inflammatory responses include in EAE (experimental immunological encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models dependent on a4 integrins. Compounds having the desired biological activity can be modified as necessary to provide the desired properties such as improved pharmacological properties (e.g., stable stability, bioavailability) or the ability to be detected in diagnostic applications. For example, the inclusion of one or more D-ammo acids in the sulfonamides this invention typically increases the stability vi. Stability can be assessed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or plasma or human serum. A number of protein stability assays have been described (see, for example Verhoef, et al., Eur. J. Drug Metab, Pharmacokinet., 1990, 15 (2): 83-93). For diagnostic forecasts, a variety of labels can be linked to compounds that can provide, directly or indirectly, a detectable signal. In this manner, the compounds of the invention can be modified in a variety of ways for a variety of final purposes while biological activity remains. In addition, you can enter several reactive sites in the term for binding to particles, solid substrates, macromolecules, and the like. Marked compounds can be used in a variety of applications in vi ve or i n vi t ro. A variety of labels can be used such as radionuclides (eg, gamma-emitting radioisotopes such as technetium-99 or indium-111), fluorescers (eg fluorescein), enzymes, enzyme substrates, enzyme factors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like. Those skilled in the art will know other brands suitable for the binding of the complexes, will be able to assess using routine experimentation. The union of these marks is achieved using normal techniques common to those skilled in the art. Uses include diagnostic applications such as the monitoring of inflammatory responses by detecting the presence of leukocytes that express VLA-4. The compounds of this invention can also be used to isolate or label these cells. In addition, as mentioned above, the compounds of the invention can be used to assess potential inhibitors of VLA-4 / VCAM-1 interactions. For the formation of diagnostic images in vivo, to identify, for example sites of inflammation, radioisotopes are typically used according to well-known techniques. The radioisotopes can be linked to the peptide either directly or indirectly using intermediate functional groups. For example, chelating agents such as diethylaminopntaceutical acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metal ion radioisotopes. The complexes can also be labeled with a magnetic isotope for diagnostic purposes in vivo, as in the formation of magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which are well known. In general, any conventional method can be used to display the diagnostic image. Radioisotopes that emit gamma and positrons are usually used for camera imaging and paramagnetic isotopes are used for MRI. In this way, the compounds are used to monitor the improvement of an inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4, it is possible to determine if a particular therapeutic regimen is effective in improving the disease. The pharmaceutical compositions of the present invention can be used to block or inhibit cell adhesion associated with a number of diseases and disorders. For example, a number of inflammatory disorders are associated with integrins or leukocytes. The treatable disorders include, for example, transplant rejection (eg, allograft rejection) Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including juvenile onset diabetes, acute) retinitis, cancer metastasis, rheumatoid arthritis, lung injury Acute leukocyte-mediated acute (eg, respiratory distress syndrome in adults), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia and j - ** "» * «• - • • • • • • • • -" '- • iYf? «ftft? flr? ií? p? iit? Inflammatory bowel disease (including Crohn's disease and ulcerative colitis). In preferred embodiments, the pharmaceutical compositions are used to treat inflammatory disorders of the brain, such as multiple sclerosis (MS) viral meningitis and encephalitis. Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn's disease and colitis. ulcerative. Crohn's disease is an inflammatory, ulceroconstructive, chronic, idiopathic disease characterized by the acutely delimited and typically transmuscular compression of all the layers of the wall of the intestine by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus may be included, although the disease commonly affects the terminal ileum and / or colon. Ulcerative colitis is an inflammatory response severely limited to the mucosa and colonic sub-mucosa. Lymphocytes and macrophages are numerous in inflammatory bowel disease lesions and may contribute to inflammatory injury. tSií ^ ^ is Z U ^.

Asthma is a disease characterized by the increased sensitivity of the tracheobronchial tree to several stimuli that enhance the paroxysmal constriction of the bronchial airways. The stimuli cause release of several mediators of inflammation from IgE-coated stem cells including histamine, chemotactic factors, eosinophils and neutrophils, leukotrienes, prostaglandins and platelet activating factor. The release of these factors exacerbates the basophils, eosinophils and neutrophils, which cause inflammatory lesions. Atherosclerosis is a disease of the arteries (for example, coronary, carotid, aorta and iliac). The basic lesion, the atheroma, consists of a focal plate of relief within the intima, which has a lipid core and a fibrous layer of cover. Atheromas compromise arterial blood flow and weaken the affected arteries. Myocardial and cerebral infarcts are a consequence of this disease. Macrophages and leukocytes are recruited to atheromas and contribute to the inflammatory lesion.

Rheumatoid arthritis is an inflammatory, relapsing, chronic disease that mainly causes damage and destruction of the joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then includes the wrists, elbows, ankles and knees. Arthritis results from the interaction of synovial cells with leukocytes that infiltrate from the circulation in the synovial lining of the joints. See, for example, Paul, Imm unol ogy (3d ed., Raven Press, 1993). Another indication for the compounds of this invention is in the treatment of organ rejection or VLA-4 mediated grafting. During recent years there has been a considerable improvement in the effectiveness of surgical techniques to transplant tissues and organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow. Perhaps the main outstanding problem is the lack of satisfactory agents to induce immunotolerance in the recipient to the transplanted organ or graft. When allogenic cells or organs are transplanted into a host (ie, the donor and the grantee are different ißafe & ^ a - ~ * & - ~ individuals of the same species), the host's immune system is likely to mount an immune response to foreign antigens in the transplant (host disease versus graft) that leads the destruction of the transplanted tissue. CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues. The compounds of this invention that bind alpha-4 integrin are useful, inter alia, to block the immune responses induced by alloantigens in the donee, thus preventing these cells from participating in the destruction of the transplanted tissue or organ. See, for example, Paul et al., Transplant International 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georczynski et al., Transplant, Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994). A related use for the compounds of this invention that bind to VLA-4 is in relation to the immune response comprised in the "host graft" disease (GVHD). See, for example, Schlegel et al., J. Immunol. 155, 3856-3865 (1995), GVHD is a potentially fatal disease ^^^^^^^^^ ,, ^^., ^, ^. ,,,,, ^ ¡1 ^ which occurs when immunologically competent cells are transferred to an allogenic receptor. In this situation, the immunocompetent cells of the donor can attack tissues in the recipient. The tissues of the skin, epithelium of the intestine and liver are frequent targets that can be destroyed during the course of the GVDH. The disease presents a particularly severe problem when transplanting immune tissue, such as bone marrow transplantation; but less severe GDVA 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 the activation of donor T cells, thereby interfering with their ability to smooth the target cells in the host. A further use of the compounds of the present invention is the inhibition of tumor metastasis. Several tumor cells have been reported as expressing VLA-4 and compounds that bind to VLA-4 block the adhesion of these cells to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., In t J. Ca n cer 60, 867-71 (1995); Freedman et al., Le uk. Lymph oma 13, Gg ^^ l gií? Sgg Ssg &iraj to 47-52 (1994); Okahara et al., Cá n cer Res. 54, 3233-6 (1994). An additional use of the compounds of this invention is in the treatment of multiple sclerosis. Multiple sclerosis is an autoimmune, immunological, progressive disease that affects approximately 250,000 to 350,000 people estimated in the United States of America. 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 covering that covers the nerve fibers. In an animal model for multiple sclerosis, murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothelium, and thus prevent inflammation of the central nervous system and subsequent paralysis in animals. . The pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Formulations suitable for the use of the present invention are found in Remi n gt on 's Pha rma ce u t i ca l Sci in ces, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985). In order to improve the serum half-life, the compounds can be encapsulated, introduced into the liposome lumen, prepared as a colloid or other conventional techniques can be used that provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described, for example in Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028, each of which is incorporated herein by reference. The amount administered to the patient will vary depending on what is administered, the purpose of administration such as prophylaxis or therapy, the condition of the patient, the manner of administration, and the like. In therapeutic applications, the compositions are administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. An adequate amount to achieve this is defined by the "therapeutically effective dose". The amounts j ^^ 2g ^^^ j ^^ g! ^^^ jg ^^^ effective for this use will depend on the condition of the disease in question as well as the judgment of the attending physician depending on factors such as the severity of the inflammation, age, weight and general condition of the patient, and the like. The compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or they can be sterile filtered. The resulting aqueous solutions can be packaged for use as they are or freeze-dried, the lyophilized preparation which is combined with a sterile aqueous carrier before administration. The pH of the compound preparations will typically be between 3 and 11, more preferably Preferred from 5 to 9 and more preferably from 7 to 8. It will be understood that the use of certain carrier excipients or prior stabilizers will result in the formation of pharmaceutical salts. The therapeutic dose of the compounds of the present invention will therefore vary, according to, for example, the particular use for which the treatment is made, the manner of ~ - ^ ^ Bltotea ».jJAJt. ***** - administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. For example, for intravenous administration, the dose will typically be in the range of about 20 μg to about 500 μg per kilogram of body weight, preferably and about 100 μg to about 300 μg per kilogram of body weight. The dose ranges suitable for intranasal administration are generally from about 0.1 pg to 1 mg per kilogram of body weight. Effective doses can be explored from the dose response curves derived from the test systems of the animal model or in vi tro. The following synthetic and biological examples are offered to illustrate this invention and should not be considered in any way as limiting the scope of this invention. Unless stated otherwise, all temperatures are in degrees Celsius.

EXAMPLES In the following examples, the following abbreviations have the following meanings. If the abbreviation is not defined, it has a generally accepted meaning. ac or ac aqueous AcOH acetic acid bd broad double bm broad multiplet bs broad singlet Bn benzyl Boc N-tert-butoxycarbonyl Boc20 di-tert-butyl-dicarbonate BOP benzotriazole-1-yloxytris (dimethylamino) phosphonium- hexafluorophosphate Cbz carbobenzyloxy CHC13 chloroform CH2C12 dichloromethane (COCÍ) 2 oxalyl chloride d doublet d doublet doublet dt triplet doublet & amp; 6i & amp; amp; £ ^^ DBU 1.8 -diazabicyclo [5.4.0] undec-7-ene DCC 1,3- dicyclohexylcarbodiimide DMAP 4-N, N-dimethylaminopyridine DME ethylene glycol dimethyl ether DMF N, N-dimethylformamide DMSO dimethisulfoxide EDC l- (3-dimethylaminopropyl) -3-ethylcarbodiimide Et3N triethylamine Et20 diethyl ether EtOAc ethyl acetate EtOH ethanol ec ec equivalent Fmoc N- (9-fluorenylmethoxycarbonyl) FmocONSu N- (9- f-luorenylmethoxycarbonyl) -succinimide g grams h hour H20 water HBr bromic acid HCl hydrochloric acid HOBT 1-hydroxybenzotriazole hydrate hour K2C03 potassium carbonate L liter m multiplet MeOH methanol mg milligram mgS04 magnesium sulfate mL milliliter millimeter mM millimolar mmol millimole pf melting point N normal NaCl sodium chloride Na2C03 sodium carbonate NaHC03 sodium bicarbonate NaOEt sodium ethoxide NaOH sodium hydroxide NH4C1 ammonium chloride NMM N-methylmorpholine Phe L-phenylalanine Pro L-proline psi pounds per square inch Pt02 platinum oxide q quartet quintte ta ta room temperature s singlet e sat saturated t triplet t-BuOH tert-butanol TFA trifluoroacetic acid THF tetrahydrofuran TLC or tic thin layer chromatography Ts tosyl TsCl tosyl chloride TsOH tosylate μL microliter In the following examples, all temperatures are in degrees Celsius (unless otherwise indicated). The following methods were used to prepare the compounds subsequently exposed as indicated.

Method 1 N-tosylation procedure N-tosylation of the opriate amino acid was carried out via the method of Cupps, Boutin and Rapoport J. Org. Ch em. 1985, 50, 3972.

Method 2 Method of Preparation of Methyl Ester The methyl esters of amino acids were prepared using the method of Brenner and Huber Helv. Ch im. Ac t a 1953, 36, 1109.

Method 3 BOP Coupling Procedure The desired dipeptide ester was prepared by the reaction of a suitable N-protected amino acid (1 equivalent) with the opriate amino acid ester or the amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy-t-risfluoride hexafluorophosphate (dimet ilamino) phosphonium [BOP] (2.0 equivalent), triethylamine (1.1 equivalent), and DMF. The reaction mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography to give the dipeptide ester.

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

Method 5 Hydrolysis Procedure I To a cooled solution (0 ° C) of THF / H20 (2: 1.5-10 ml) of the opriate ester was added LiOH (or NaOH) (0.95 equivalent). The temperature was maintained at 0 ° C and the reaction was finished 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 Procedure II of Hydrolysis of the Ester To a cooled solution, (0 ° C) of THF / H20 (2: 1.5-10 mL) of the opriate ester was added LiOH (1.1 equivalent). The temperature was maintained at 0 ° C and the reaction was finished in 1-3 hours. The reaction mixture was concentrated and the residue was taken up in H20 and the pH was adjusted to 2-3 using HCl. The product is The mixture was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated to yield the desired acid.

Method 7 Procedure III of Hydrolysis of the Ester The opriate ester was dissolved in dioxane / H20 (1: 1) and 0.9 equivalents were added.

NaOH 0.5N. The reaction was stirred for 3-16 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. 25 • * 3 -.- f * ^ '^ * **, Method 8 Sulphonylation Procedure I To the opriately protected aminophenylalanine analogue (11.2 mmol), dissolved in methylene chloride (25 ml) and cooled to -78 ° C, desired sulfonyl chloride (12 mmol) was added followed by the dropwise addition of pyridine (2 mL). . The solution was allowed to warm to room temperature, stirred for 48 hours. The reaction solution was transferred to a 250 mL separatory funnel with methylene chloride (100 mL) and extracted with IN HCl (50 mL x 3), brine (50 mL) and water (100 mL). The organic phase was dried (MgSO 4) and the solvent was concentrated to obtain the desired product.

Method 9 Reductive Amination Procedure Reductive amination of Tos-Pro-p-NH2-Phe with the opriate aldehyde using acetic acid, sodium triacetoxyborohydride, methylene chloride and the combined mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography. ^ & ^ £ g ^^^^^ f? ^ rf ^^ Method 10 BOC Removal Procedure Anhydrous hydrochloride gas (HCl) was bubbled through a methanolic solution of the opriate Boc amino acid ester at 0 ° C for 15 minutes and the reaction mixture was stirred for three hours. The solution was concentrated to a syrup and dissolved in Et20 and reconcentrated. This procedure was repeated and the resulting solid was placed under high pressure overnight.

Method 11 Procedure I Hydrolysis of Ter-Butyl Ester The tert-butyl ester was dissolved in CH2C12 and treated with TFA. The reaction was finished in 1-3 hours at which time the reaction mixture was concentrated and the residue was concentrated in H20 and lyophilized to yield the desired acid.

Method 12 EDC Coupling Procedure I To a solution of CH2C12 (5-20 mL) of N- (toluene-4-sulfonyl) -L-proline (1 equivalent), the appropriate amino acid ester hydrochloride (1 equivalent), N-methylmorpholine (1.1-2.2) equivalent) and 1-hydroxybenzotriazole (2 equivalents) were mixed, placed in an ice bath and 1- (3-dimethylaminopropyl) -3-yl-carbodiimide (1.1 equivalent) was added. The reaction was allowed to rise to room temperature and stirred overnight. The reaction mixture was poured into H20 and the organic phase was washed with saturated NaHCO3, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. The crude product was purified by column chromatography.

Method 13 EDC Coupling Procedure II To a solution of DMF (5-20 mL) of the appropriate N-protected amino acid (1 equivalent), the appropriate amino acid ester hydrochloride (1 equivalent), Et3N (1.1 equivalent) and 1- "rntr * '- Mí *' -''-? t? - 'hydroxybenzotriazole (2 equivalents) were mixed, placed in an ice bath and 1 (3-dimethylaminopropyl) 3-ethyl carbodiimide (1.1 equivalent) was added. The reaction was allowed to rise to room temperature and stirred overnight.The reaction mixture was partitioned between EtOAc and H 0 and the organic phase was washed with 0.2 N citric acid, H20, saturated NaHCO3, brine, dried ( MgSO4 or Na2SO4), filtered and concentrated The crude product was purified by column chromatography or preparative TLC.

Method 14 Sulphonylation Procedure II The appropriate sulfonyl chloride was dissolved in CH 2 Cl 2 and placed in an ice bath. L-Pro-L-Phe-Ome or HCl (1 equivalent) and Et3N (1.1 equivalent) were added and the reaction was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was concentrated and the residue was partitioned between EtOAc and H20 and the organic phase was washed with saturated NaHCO3, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. The raw product is , h. <tb> Jf & amp; amp; aaa purified by column chromatography or preparative TLC.

Method 15 Sulphonylation 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 CH2C12 was added Et3N (5 equivalents) followed by the appropriate sulfonyl (1.1 equivalent). The reaction was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was concentrated, dissolved in EtOAc, washed with saturated NaHCO 3, and 0.2 N citric acid. The aqueous phase was made basic with solid NaHCO 3, and the product was extracted with EtOAc. The organic phase 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. ^. ^^^^^ ^^ sS ^^ Method 16 Hydrogenation Procedure II To a solution of methanol (10-15 mL) of azlactone, NaOAc (1 equivalent) and 10% Pd / C were added. This mixture was placed in a hydrogenator at 40 psi H2. After 8-16 hours, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to yield the methyl ester of dehydropeptide. The ester was dissolved in dioxane / H20 (5-10 mL), to which 0.5 N NaOH (1.05 equivalent) was added. After stirring for 1-3 hours, the reaction mixture was concentrated and the residue was dissolved in H20 and washed with EtOAc. The aqueous phase was made acidic with 0.2 N HCl 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 SO 4), filtered and concentrated to yield the acid as approximately a mixture of 1: 1 diastereomers.

Method 17 Procedure II Hydrolysis of Terbutyl Ester The tert-butyl ester was dissolved in CH2C12 (5 mL) and treated with TFA (5 mL). The reaction was finished in 1-3 hours, at which time the reaction mixture was concentrated and the residue was dissolved in H20 and concentrated. The residue was dissolved in H2O and lyophilized to yield the desired product.

Example 1 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4 - (a-methylbenzyloxy) -L-phenylalanine The N-L methyl ester (toluene-4-sulphonyl) -L-prolyl-L-tyrosine was dissolved (see Example 2 (3)) (785 mg, 1.89 mmol) in DMF (20 mL) at room temperature. To this was added f2C03 (1.1 ec, 281 mg) and 1-bromoet il-benzene (1.1 ec, 284 μL). The reaction was stirred for 12 hours at room temperature. Ethyl acetate (100 mL) was added, and the organic layer was washed several times with brine (5 x 50 mL). The organic layer was dried over MgSO4.

In the filtration and evaporation of the solvents under reduced pressure, an oil was isolated. The crude material was purified by silica gel elution (EtOAc / hexanes (1: 4)). The desired material was isolated in 32% yield (330 mg, 0.6 mmol). Methyl (330 mg, 0.6 mmol) was then converted to the corresponding acid in the NaOH treatment (1.1 eq, 27 mg), in MeOH: H20 (1: 1) (15 mL) for 24 hours at room temperature, EtOAc was added. also water The aqueous layer was collected and acidified with IN HCl to pH 2.5, and re-extracted with EtOAc The organic layer was dried over MgSO4 In the filtration and evaporation of the solvents under reduced pressure, a foam was isolated in quantitative yields The NMR data were as follows: NMR: H (300 MHz, CDC13): d = 7.71 (bd, 2H), 7.34 (m, 7H), 7.20 (m, ÍH), 7.01 (m, 2H ), 6.80 (d, 2H, J = 8.37 Hz), 5.27 (m, HH), 4.75 (m, HH), 4.04 (m, HH), 3.23-2.93 (m, 4H), 2.42 (s, 3H) , 1.85 (m, HH), 1.60 (d, 3H, J = 6.09 Hz), 1.36-1.26 (m, 3H). 13C NMR (75 MHz, CDC13): d = 174.74, 172.22, 157.53, 145.00, 143.77, 133.42, 130.76, 130.58, 129.14, 128.60, 128.48, 127.94, 126.15, 116.57, 76.39, 62.73, 53.90, 50.09, 37.09, 25.07, 24.52, 22.17. Mass spectroscopy: (FAB) 537 (M + H).

Example 2 Synthesis of N- (toluene-sulfonyl) -L-prolyl-L-t-irosine N-toluene-r-sul foni 1) -L-proline (1.56 g, 6.93 mmol) was dissolved in 50 mL of DMF, with this L-tyrosine methyl ester (1.1 eq, 1.76 g), Et3N (2.2 eq, 2.0 mL), and the BOP reagent (1.1 eq, 3.36 g). The ester was isolated in a 75% yield (2.14 g, 5.16 mmol). The ester (102 mg, 0.27 mmol) was taken in a 1: 1 mixture of MeOH: H20 (5 mL) with 1.1 eq of NaOH. The title acid was isolated in a quantitative yield as an oil. The NMR data were as follows: XH NMR (300 MHz, CD3OD): d = 7.46 (d, 2H, J = 8.25 Hz), 7.12 (d, 2H, J = 7.83 Hz), 6.77 (d, 2H, J = 8.35 Hz), 6.49 (d, 2H, J = 8.39 Hz), 4.46 (m, ÍH), 3.80 (m, ÍH), 3.11-2.70 (m, 4H), 2.19 (s, 3H), 1.66 (m , ÍH), 1.31 (m, 3H). 13 C NMR (75 MHz, CD3OD): d = 177.36, 176.12, 160.30, 149.12, 137.29, 134.79, 134.50, 132.22, 131.50, 119.63, 66.67, 57.90, 54.02, 41.06, 34.57, 28.54, 25.79. Mass spectroscopy: (FAB) 417 (M + H).

Example 3 Synthesis of N- (toluene-4-sulfonyl) -L-prolylcarboxyphenylalanine The diethyl 2-acetamidomalonate was treated with 4-cyanobenzyl bromide and NaOEt in EtOH, to give, after dilution with H20, the isolation of the resulting precipitate, diethyl 2-acetamido-2- (4-cyanobenzyl) malonate. This product was heated in HCl, and the mixture was evaporated to give 4-carboxy-D, L-phenylalanine hydrochloride [D, L-Phe (4-C02H) -OH-HCl. This product was treated with MeOH and HCl gas to give after evaporation, D, L-Phe (R-C02Me) -OmeHCl. This product was treated with N-toluene-4-sulfonyl) -L-Pro-OH, BOP, NMM in DMF, to give after aqueous treatment and flash chromatography, N- (toluene-4-sulfonyl) -L- Pro-D, L-Phe (-C02Me) -OMe. This product was treated with NaOH in dioxane and water, to give after acidification, extraction, drying with MgSO, filtration and evaporation of the title compound as a clear oil. The NMR data were as follows: NMR - H (CD3OD, 300 MHz): d = 7.86 (d, 2H, J = 8.2, IH), 7.83 (d, J = 8.2 IH), 7.74 (d, J = 8.3, ÍH), 7.41 (d, J = 8.2, 2 H), 7.31 (d, J = 8.2, ÍH), 7.21 (d, J = 8.1, ÍH), 4.53 (dd, J = 7.1, J = 4.7 , P.5 H), 4.46 (dd, J = 5.9, 0.5 H), 4.07-3.99 (m, ÍH), 3.58-3.45 (m, ÍH), 3.28-3.02 (m, 3H), 2.43 (s, 3H), 1.83-1.43 (m, 4H). 13 C NMR (CD3OD w / CD3ONa, 75 MHz): d = 179.12, 179.08, 177.5, 177.4, 173.1, 173.0, 145.83, 145.80, 139.6, 139.4, 137.8, 137.7, 134.77, 134.75, 131.0, 130.9, 130.5, 130.4, 129.44, 129.39, 129.1, 129.0, 63.61, 63.57, 57.0, 56.9, 50.74, 50.70, 38.7, 38.6, 31.71, 31.65, 25.2, 25.1, 2.50, 21.49. Mass spectroscopy: (+ FAB, nitrobenzyl alcohol-3) 461 (M + H).

Example 4 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-3- (carboxy) phenylalanine Substitution of 3-cyanobenzyl bromide with 4-cyanobenzyl bromide, and following the methods for the preparation of Example 3, gave the title compound as a clear oil. The NMR data were as follows: NMR: H (CD3OD, 300 MHz): d = 7.82 (s, 0.5 H), 7.77 (s, 0.5 H), 7.73 (d, J = 8.2, lh), 7.72 (d, J = 8.2, ÍH), 7.40 (d, J = 8.2, 2H), 7.37 -7.19 (m, 3H) 4.53 (dd, J = 7.5, J = 4.9, 0.5H), 4.46 (t, J = 5.9, 0.5H), 4.05 (dd, J = 8.2, J = 3.5, 0.5H), 3.99 (dd, J = 8.8, J = 3.4, 0.5 H), 3.48-3.42 (m, 0.5 H), 3.36-2.99 (m, 3.5H), 2.42 (s, 3H), 1.88-1.38 (m, 4H). 13 C NMR (CD30D w / CD3ONa, 75 MHz): d 179. 18, 179.16, 177.6, 177.5, 173.04, 172.97, 145.82, 145.81, 139.5, 139.4, 137.81, 137.78, 134.77, 134.75, 132.33, 132.31, 131.03, 130.96, 130.7, 130.6, 129.87, 129.85, 129.4, 129.34, 128.96, 128.4, 63.6, 63.5, 57.0, 56.8, 50.77, 50.76, 38.72, 38.68, 31.7, 31.6, 25.4, 25.1, 21.50, 21.48. Mass spectroscopy: (+ FAB, nitrobenzyl alcohol-3) 461 (M + H).

Example 5 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- (2-carboxyphenoxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine methyl ester (2.14 g, 5.16 mmol) was added to a suspension of sodium hydride, 60% in oil (1.1 eq, 228 mg) in xylenes (50 mL) at 0 ° C. The reaction mixture was stirred for 5 minutes and the cuprous bromide-dimethyl sulphide complex (1.4 eq, 1.48 g) was added. The reaction mixture was stirred at 23 ° C for 0.5 hours. To this was added sodium 2-iodobenzoate (1.5 eq, 8.06 mmol), and the reaction mixture was refluxed for 12 hours, EtOAc (100 mL) was added, the organic layer was washed with NH 4 Cl, 10% HCl , and brine, then dried over MgSO4. The crude material was eluted in column chromatography (silica gel), with CHCl3: MeOH (9: 1), and isolated with an oil. The acid was prepared by treatment with NOH (1.1 ec), in eOH: H2? (1: 1) for 4 hours at room temperature. The diacid was isolated as a foam. The NMR data were as follows: XH NMR (300 MHz, CDC13): d = 7.71 (m, 2H), 7.29 (m, 4H), 7.19 (m, 4H), 6.72 (m, HI), 4.84 (m , HH), 4.13 (m, HH), 3.39 (m, HH), 3.11 (m, 3H), 2.43 (s, 3H), 1.89 (m, HH), 1.48 (m, 3H). 13 C NMR (75 MHz, CDD13): d = 172.67, 157.84, 155. 89, 155.04, 145.17, 133.61, 133.19, 133.08, 131.69, 131.02, 130.64, 128.42, 127.87, 124.24, 120. 04, 119.61, 116.12, 62.81, 50.31, 37.28, 30.69, 24. 81, 22.15. Mass spectroscopy: (FAB) 553 (M + H).

Example 6 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-O- (benzyl) -L-tyrosine The N- (toluene-4-sulfonyl) -L-Pro-OH was treated with (COC) 2 and DMF in CH2CI2 to give, after evaporation, the N- (toluene-4-sulfonyl) -L-Pro- Cl. This product was treated with L-Tyr (Bn) -OH and NaOH in THF and H20, to give, after acidification, extraction, drying with MgSO 4, and evaporation, the title compound as a clear oil. The NMR data were as follows: 1 H NMR (DMSO-de, 300 MHz): d = 8.04 (d, J = 8. 2, ÍH), 7.70 (d, J = 8.1, 2H), 7.42-7.21 (m, 6H), 7. 15 (d, J = 8.5, 2H), 6.90 (d, J = 8.5, 2H), 5.04 (s, 2H), 4.49-4.42 (m, ÍH), 4.13-4.09 (m, ÍH), 3.33-3.27 (m, 2H), 3.10-2.89 (m, 3H) 2.38 (s, 3H), 1.60-1.35 (m, 4H). 13 C NMR (DMSO-de, 75 MHz): d = 172.63, 170.8, 157.0, 143.6, 137.2, 133.8, 130.3, 129.8, 129.4, 128.9, 128.4, 127.6, 125.3, 114.4, 69.1, 61.3, 53.4, 49.0, 35.8 , 30.4, 23.8, 21.0. Mass spectroscopy: (+ FAB, nitrobenzyl alcohol) 523 (M + H).

Example 7 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4 - (iodo) -L-phenylalanine Following the experimental procedure described for the synthesis of Example 8, he gave the title compound as a foam. The NMR data were as follows: NMR - * H (300 MHz, DMSO-d6): d = 8.30 (d, ÍH, J = 8.40 Hz), 7.87 (d, 2H, J = 8.50 Hz), 7.78 (d, 2H, J = 8.50 Hz), 7.55 (d, 2H, J = 8.30 Hz), 7.25 (d, 2H, J = 8.30 Hz), 4.63 (m, ÍH), 4.26 (m, ÍH), 3. 20 (m, 4H), 2.53 (s, 3H), 1.75 (m, 4H). Mass spectroscopy: (FAB) 543 (M + H).

Example 8 Synthesis of N- (toluene-sulphyl) -L-prolyl-L-4 - (methoxy) -phenylalanine Following the experimental procedure described for Example 1, N- (toluene-4-sulfonyl) -L-proline (861 mg, 3.2 mmol) was dissolved in 20 mL of DMF, with Et3N (2.0 eq, 981 μL), BOP (1.1 eq, 1.55 g), and the HCl salt of the methyl ester of O-methyl-L-10 tyrosine (ll ec). The methyl ester was isolated in a 25% element (370 mg, 0.80 mmol). It was then hydrolyzed in a 1: 1 solution of MeOH: H20 (5 mL), with NaOH (1.1 eq, 35 mg). The acid was isolated with a foam, in 60% yield (216 mg, 0.48 mmol).

The NMR data were as follows: NMR? H (300 MHz, CDC13): d = 7.72 (d, 2H, J = 7.80 Hz), 7.46 (d, ÍH, J = 6.30 Hz), 7.33 (d, 2H , J = 7.20 Hz), 7.26 (d, 2H, J = 7.80 Hz), 7.14 (d, 2H, J = 8.40 Hz), 5.65 (bs, 2H), 4.82 (m, ÍH), 4.10 (m, ÍH), 3.75 (s, 3H), 3.35-3.01 (m, 4H), 2.42 (s, 3H), 1.97 (m, ÍH), 1.48 (m, 3H). 13 C NMR (75 MHz, CDC13): d = 174.57, 172.25, 159.18, 145.07, 133.40, 130.97, 130.59, 128.66, 128.44, 114.53, 62.768, 55.84, 54.09, 50.20, 37.09, 30.48, 24.68, 22.15.

Mass spectroscopy: (FAB) 447 (M + H \ Example 9 Synthesis of N- (toluene-4-sulphonyl) -L-prolyl-4-nitro-L-phenylalanine N- (Toluene-sulfonyl) -L-proline (955 mg, 3.4 mmol) was dissolved in dry DMF (50 mL) with L- (4-nitro) -phenylalanine methyl ester (1.1 eq, 777 mg) , Et3N (2.2 eq, 1.04 mL), and the BOP reagent (1.1 eq, 1.65 g). The desired methyl ester was isolated in 40% yield (500 mg, 1.05 mmol). The ester was hydrolyzed in a 1: 1 solution of MeOH: H20 (10 L) with NaOH (1.1 eq, 42 mg). The title compound was isolated as an oil in 51% yield (246 mg, 0.53 mmol). The NMR data were as follows: XH NMR (300 MHz, CDC13): d = 8.10 (d, 2H, J = 8.79 Hz), 7.81 (d, ÍH, J = 8.25 Hz), 7.68 (d, 2H, J = 8.22 Hz), 7.42 (d, 2H, J = 8.79 Hz), 7.32 (d, 2H, J = 8.25 Hz), 4.93 (m, ÍH), 4.09 (m, ÍH), 3.44 (m, 2H), 3.24 (m, HH), 3.04 (m, HH), 2.38 (s, 3H), 1.83 (m, HH), 1.38 (m, 3H). 13 C NMR (75 MHz, CDC13): d = 174.25, 173.00, 147.87, 145.34, 145.06, 133.06, 131.13, 130.73, 128. 42, 124.18, 62.62, 53.29, 50.04, 37.48, 30.21, 24.35, 21.76. Mass spectroscopy: (FAB) 462 (M + H).

Example 10 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-1-4- (0-tert-butyl) -L-tyrosine Following the experimental procedure described for Example 8, the desired material was isolated as a solid, m.p. = desc > 80 ° C. The NMR data were as follows: 1 H NMR (300 MHz, CDC13): d = 7.66 (d, 2H, J = 8.40 Hz), 7.32 (d, 2H, J = 8.01 Hz), 7.09 (d, 2H, J = 8.37 Hz), 6.91 (d, 2H, J = 7.86 Hz), 4.75 (m, ÍH), 400 (m, ÍH), 3.25 (m, 2H), 3.05 (m, 2H), 2.40 (s, 3H), 1.95 (m, 4H), 1.27 (s, 9H). Mass spectroscopy: (FAB) 489 (M + H).

Example 11 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (3, 5-diiodo) ti ros ina Following the experimental procedure described for Example 8, but substituting the HCl salt of 3,5-d-iodo-L-thyrisine methyl ester for O-methyl-L-t-irosine provided the title compound as a foam. The NMR data were as follows: 1 H NMR (300 MHz, CDC13): d = 7.74 (d, 2H, J = 8.19 Hz), 7.51 (s, ÍH), 7.42 (m, ÍH), 7.36 (d, 2H , J = 8.22 Hz), 7.26 (s, HH), 4.75 (m, HH), 4.12 (m, HH), 3.55 (m, HH), 3.24 (m, 2H), 3.05 (m, HH), 2.44 (s, 3H), 1.62 (m, 4H). Mass spectroscopy: (FAB) 685 (M + H), 713 (M + Na).

Example 12 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4- (aminobenzoyl) -phenylalanine Following the experimental procedure described for Example 1, the title compound was isolated as an oil in quantitative yields. The NMR data were as follows: NMR "? (300 MHz, CD3OD): d = 7.70 (d, 2H, J = 8.50 Hz), 7.62 (d, 2H, J = 8.50 Hz), 7.44-7.17 (m, 5H), 7.20 (d, 2H, J = 8.25 Hz), 7.06 (d, 2H, J = 8.52 Hz), 4.47 (m, tH), 3.89 (m, ÍH), 3.18 (m, ÍH), 305- 2.83 (m, 3H), 2.20 (s, 3H), 1.60-1.39 (m, 4H), 13C NMR (75 MHz, CD3OD): d = 177.08, 171.91, 148.83, 141.80, 139.37, 138.10, 137.48, 136.92, 134.12, 132.72, 132.37, 131.69, 125.32, 66.34, 58.09, 53.70, 40.85, 34.78, 28.47, 24.61 Mass spectroscopy: (FAB) 537 (M + H).

Preparative Example A Synthesis of N- (toluene-4-sulfonyl) -D-prolyl-D-phenylalanine They were treated in Boc-D-Pro-OH and D-Phe-OBn • HCl with BOP and NMM in DMF, to give after the aqueous treatment and flash chromatography, Boc-D-Pro-D-Phe-OBn. This product was treated with TFA and anisole, and the mixture was evaporated. The residue was dissolved in Et20 and washed with saturated aqueous NaHCO3, and saturated aqueous NaCl. The Et20 layers were dried with MgSO4, filtered, and evaporated to give D-Pro-D-Phe-OBn. This product was treated with CH3S02C1 and Et3N in CH2C12, to give, after the aqueous treatment, flash chromatography, N- (CH3S03) -D-Pro-D-Phe-OBn. This product was treated with 10% Pd in C in THF, and the mixture was stirred under 50 psi of H2. The mixture was filtered through celite and evaporated to give the title compound as a solid, m.p. = 71-75 ° C. The NMR data were as follows: 1H-NMR (CDC13 300 MHz,): d = 1.24-1.54 (m, 3H) 1.95 (m, HH), 2.43 (s, 3H), 3.10 (m, 2H), 3.32 ( m, 2H), 4.09 (m, HH), 4.82 (m, HH), 7.10-7.40 (m, 7H), 7.69 (d, 2H, J = 8.0 Hz). 13 C NMR (CDC13, 75 MHz): d = 22.1, 25.8, 32.2, 38.8, 55.4, 63.8, 128.5, 129.5, 130.0, 131.1, 131.6, 135.5, 138.7, 146.3, 174.58, 174.63. Mass spectroscopy: (FAB +) 417 (M + H).

Example 13 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (3-iodo-hydroxy) -phenylalanine The title compound was prepared according to the procedure described for the described synthesis of Example 8. The corresponding material was isolated as a film. The NMR data were as follows: XH NMR (300 MHz, DMSO-d6): d = 7.72 (d, 2H, J = 8.50 Hz), 7.42 (s, ÍH), 7.43 (d, 2H, J = 8.50 Hz ), 7.08 (d, ÍH, J = 8.05 Hz), 6.75 (d, ÍH, J = 8.05 Hz), 4.81 (m, ÍH), 4.11 (m, ÍH), 3.45 (m, ÍH), 3.20 (m , 2H), 2.98 (m, ÍH), 6.62 (m, ÍH), 2.44 (s, 3H), 1.96 ((m, 2H).

Example 14 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-chloro) phenylalanine The title compound was prepared from Example 37 using the procedure described in Method 7, p.p. = > 200 ° C.

EXAMPLE 15 Synthesis of N- (t-oluen-4-sulfonyl) -L-prolyl-L-leucine The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L-leucine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via the hydrolysis of the methyl ester using LiOH in THF / water. The NMR data were as follows: 1H NMR (CDC13): d = 9.80 (bs, ÍH), 7.72 (d, 2H, J = 8.0 Hz), 7.47 (d, ÍH, J = 8.0 Hz), 7.32 (d , 2H, J = 8.0 Hz), 4.56 (m, HH), 4.16 (m, HH), 3.51 (m, HH), 3.17 (m, HH), 2.38 (s, 3H), 2.12 (m, HH) , 1.73-1.54 (6H), 0.91 (d, 3H, J = 6.0 Hz). 13C NMR (CDC13) A? 'B = 176.2, 172.5, 145.0, 133.4, 130.6, 128.4, 62.7, 51.7, 50.3, 41.4, 30.5, 25.5, 23.4, 22.4, 22.1. Mass spectroscopy: FAB m / e 383 (M + H).

Example 16 Synthesis of N- (toluene-sulfonyl) -L-prolyl-L-alanine The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L-alanine methyl ester hydrochloride using the procedure described in method 3. The resulting methyl ether was de-esterified via hydrolysis using LiOH in THF / water to provide the title compound as a solid, mp = 160.5-162.5 ° C. The NMR data were as follows: 1H-NMR (CDCl 3): d = 7.76 (d, 2H, J = 8.2 Hz), 7.52 (d, ÍH, J = 6.7 Hz), 7.37 (d, 2H, J = 8.0 Hz), 4.56 (p, 1H, J = 7.1 Hz), 4.14 (dd, ÍH, J = 2.6, 8.5 Hz), 3.56 (m, ÍH), 3.21 (dt, ÍH, J = 6.6 9.7 Hz), 2.45 (s, 3H), 2.21 (m, ÍH), 1.78 (m, ÍH), 1.62 (m, 2H) , 1.52 (d, 3H, J = 7.1 Hz). 13 C NMR (CDCl 3): d = 176.4, 172.3, 145.1, 133.3, 130.6, 128.5, 62..JiSFSO .4, 49.1, 30.5, 25.0, 22.2, 18.5. Mass spectroscopy: FAB m / e 341 (M + H).

Example 17 Synthesis of N- (toluene-sulfonyl) -L-prolyl-L-4 (acetamido) -phenylalanine The title compound was prepared from the product of Example 39 using the procedure described in Method 6. The NMR data were as follows: NMR "* H (300 MHz, CDC13): d = 7.50 (d, 2H, J = 8.25 Hz), 7.28 (d, 2H, J = 8.37 Hz), 7.17 (d, 2H, J = 8.20 Hz), 6.99 (d, 2H, J = 8.37 Hz), 4.50 (m, ÍH), 3.92 ( m, HH), 3.17 (m, HH), 3.04 (m, 2H), 2.81 m212.19 (s, 3H), 1.87 (s, 3H), 1.56 (m, HH), 1.40 (m, 3H). 13 C NMR (75 MHz, CD3OD): d = 174.61, 172.14, 146.30, 139.29, 135.47, 134.38, 131.64, 131.48, 129.54, 121.71, 63.82, 55.36, 51.20, 38.27, 32.26, 25.93, 24.50, 22.19 Mass spectroscopy : (FAB) 474 (M + H).

¡• ^ X ** ^ J * "*" "" "% 'Example 18 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-isoleucine The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L-isoleucine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via the hydrolysis of the methyl ester using LiOH in THF / water. The NMR data were as follows: XH NMR (CDC13): d = 7.72 (d, 2H, J = 8.3 Hz), 7.46 (d, ÍH, J = 7.5 Hz), 7.36 (d, 2H, J = 8.1 Hz ), 4.54 (dt, ÍH, J <0 5.4, 7.6 Hz), 4.16 (dd, ÍH, J = 2.6 8.7 Hz), 3.54 (m, ÍH), 3.21 (m, ÍH), 2.44 (s, 3H) ), 2.20 (m, ÍH), 1.97 (m, ÍH), 1.33-1.57 (H), 1.35 (m, 4H), 0.90 (d, 3H, J = 7.0 Hz). 13C NMR (CDC13): d = 176.2, 172.2, 145.1, 133.4, 130.6, 128.5, 62.8, 53.3, 50.4, 32.1, 30.4, 28.0, 25.1, 22.8, 22.2, 14.5. Mass spectroscopy: FAB m / e 383 (M + H).

Example 19 Synthesis of N- (toluene-sulfonyl) -L-prolyl-L-aspartic acid The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L-4- (1,1-dimethylethyl) -aspartic acid methyl ester hydrochloride using the procedure described in Method 3. The methyl ester hydrolyzed using LiOH in THF / water to provide a solid, mp 0 153-155 ° C. The title compound was prepared, via cleavage of the t-butyl ester using trifluoroacetic acid in CH2C12, as a solid, m.p. = 174-176 ° C. The NMR data were as follows: NMR? H (DMSO-d6): d = 8.27 (d, H, J = 8.0 Hz), 7.75 (d, 2H, J = 8.2 Hz), 7.44 (d, 2H, J = 8.2 Hz), 4.54 (m, ÍH), 4.16 (m, ÍH), 3.38 (m, ÍH), 3.13 (m, ÍH), 2.74 (dd, ÍH, J = 5.9, 16.7 Hz), 2.63 (dd) , ÍH, J = 6.3, 16.7 Hz), 2.41 (s, 3H), 1.75 (m, 2H), 1.51 (m, 2H). 13 C NMR (DMSO-d 6): d = 172.5, 172.2, 171.3, 144.0, 134.3, 130.2, 127.9, 61.7, 49.3, 36, .2, 30.9, 24.3, 21.4. Mass spectroscopy: FAB m / e 385 (M + H).

Example 20 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-lysine The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L-e-Cbz-lysine methyl ether hydrochloride using the procedure described in Method 3. The methyl ester was hydrolyzed using LiOH in THF / water. The title compound was prepared using the procedure described in Method 4 as a solid, m.p. = > 200 ° C.

Example 21 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-glutamic acid The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L-5- (1,1-dimethylethyl) -glutamic acid methyl ester hydrochloride using the procedure described in Method 3. The methyl ester hydrolyzed using LiOH in THF / water to provide a solid, mp = 164-166 ° C. The title compound was prepared, via cleavage of the t-butyl ester using trifluoroacetic acid in CH2C12 as a solid, m.p. = > 200 ° C.

Example 22 Synthesis of N- (toluene-4-sulphonyl) -L-prolyl-L- (4-dibenzylamino) -phenylalanine methyl ester The title compound was prepared using the procedure described in Method 9. The crude product was purified by flash chromatography (silica, EtOAc: hexane 1: 1) to give the methyl ester as a white solid, m.p. = 60-65 ° C.

Example 23 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (N-benzyl) -histidine The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L- (N-benzyl) -histidine methyl ester dihydrochloride using the procedure described in Method 3. The title compound was prepared via Hydrolysis of the methyl ester using LiOH in THF / water. The NMR data were as follows: XH NMR (DMSO-d6): d = 8.15 (2, 1H, J = 7.8 Hz), 7.72 (m, 3H), 7.42 (d, 2H, J = 8.0 Hz), 7.37 -721 (6H), 6.96 (s, ÍH), 5.11 (s, 2H), 4.42 (m, ÍH), 4.09 (m, ÍH), 3.29 (m, ÍH), 3.04 (m, ÍH), 2.90 ( m, 3H), 2.40 (s, 3H), 1.65-1.39 (4H). 13 C NMR (DMSO-de): d = 173.1, 171.0, 144.0, 138.0, 137.7, 137.1, 134.2, 130.2, 129.0, 128.9, 128.0, 127.9, 117.3, 61.8, 52.5, 49.9, 49.3, 30.7, 30.1, 24.1, 21.4. Mass spectroscopy: FAB m / e 497 (M + H).

Example 24 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-dibenzylamino) -phenylalanine The methyl ester was prepared using the procedure of Example 22. The crude product was purified by flash chromatography (silica, EtOAc: hexane 1: 1) to give the methyl ester as a white solid, m.p. = 60-65 ° C. The title compound was then prepared using the procedure described in Method 5. The NMR data were as follows: 1 H NMR (DMSO-d 6, 400 MHz): d = 7.72 (d, 2H, J = 8.34 Hz), 7.55 (d, ÍH, J = 5.71 Hz), 7.4 (d, 2H, J = 7.9 Hz); 7.24 (m, 4H); 7.18 (m, 6H), 6.76 (d, 2H, J = 8.56 Hz), 6.44 (d, 2H, J = 8.56 Hz); 4.58 &fe¡a¿a¡faaafe - '(d, 4H, J = 3.07 Hz), 3.89 (dd, ÍH, J = 2.74 8.89 Hz); 3.76 (m, 1H), 2.92 (m, 4H), 2.39 (s, 3H), 1.61 (m, ÍH), 1.05-1.34 (m, 3H). IR (KBr, cm "1) 3400, 1655, 1620, 1520, 1405, 1300, 1160. Mass spectroscopy: ((+) FAB, m / e (%)) 634 (20 [M + Li] +); 612 (100 [M + H] +).

Example 25 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-met ionin The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the methionine methyl ester using the procedure described in Method 3. The title compound was prepared via the hydrolysis of the methyl ester using LiOH in THF / water . The NMR data were as follows: 1 H NMR (CDC13): d = 9.05 (bs, ÍH), 7.76 (d, 2H, J = 8.2 Hz), 7.69 (d, ÍH, J = 7.7 Hz), 7.37 (d , 2H, J = 7.9 Hz), 4.68 (m, HH), 4.16 (m, HH), 3.57 (m, HH), 3.20 (m, HH), 2.59 (t, 2H, J = 7.4 H < z ), 2.45 (s, ÍH), 2.21 (m, 3H), 2.19 (s, 3H), 1.79 (m, ÍH), 1.63 (m, 2H). 13 C NMR (CDCl 3): d = 174.5, 172.0, 144.5, 132.6, 130.0, 127.9, 62.2, 51.9, 49.8, 30.8, 30.0, 29.9, 24.5, 21.6, 15.4. Mass spectroscopy: FAB m / e 401 (M + H).

Example 26 Synthesis of N- (toluene-4-sulphonyl) -L-prolyl-L-serine The title compound was prepared via the hydrogenolysis of the corresponding benzyl ester using 10% Pd / C in EtOH / HOAc (20: 1). The reaction mixture was filtered through celite and the filtrate was evaporated in vacuo to give a residue which was lyophilized from water to give the title compound as a white solid. The NMR data were as follows: XH NMR (CDCl 3): d = 7.97 (d, 1H, J = 7.1 Hz), 7.74 (d, 2H, J = 8.0 Hz <), 7.33 (d, 2H, J = 8.4 Hz), 4.62 (m, ÍH), 4.21-3.94 (2H), 3.60 (m, ÍH), 3.17 (m, ÍH), 2.41 (s, 3H), 2.07 (m, ÍH), 1.88-1.55 (3H). 13 C NMR (CDCl 3): d = 172.8, 144.4, 132.8, 130.0, 127.8, 62.3, 55.0, 49.8, 30.8, 30.2, 24.4, 21.5. & 0t £ i, ^ sz £.. «-« saf-ia Mass spectroscopy: FAB m / e 357 (M + H) Preparative Example B Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-D-aspartic acid The N-benzyloxycarbonyl-D-4- (1,1-dimethylethyl) -aspartic acid was converted to the methyl ester using the procedure described in Method 2. The methyl ester of D-4- (1,1-dimethylethyl) acid was prepared ) -aspartic from the product of the previous step using the procedure described in Method 4. The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the methyl ester of D-4- (1, 1) -dimethylethyl) -aspart resulting using the procedure in Method 3. The methyl ester was hydrolyzed using the procedure described in Method 6. The product was isolated as a white solid, mp. = 55 ° C. The title compound was then prepared using the procedure described in Method 11. The product was isolated as a white solid, m.p. 131-132 ° C. The NMR data were as follows: aÉ? üésiaiil ^ áteüi RMN *? (DMSO-de): d = 8.19 (d, ÍH, J = 8.0 Hz), 7.73 (d, 2H, J = 7.0 Hz), 7.43 (d, 2H, J = 8.0 Hz), 4.55, (m, ÍH ), 4.12, (m, HH), 3.40 (m, HH), 3.13 (m, HH), 2.60 (m, 2H), 2.41 (s, 3H), 1.76 (m, 2H), 1.55 (m, 2H) ). 13 C NMR (DMSO-d 6, 75 MHz): d = 172.5, 172.2, 171.3, 144.0, 134.2, 130.2, 127.9, 61.8, 49.4, 48.8, 36.2, 30.9, 24.2, 21.4. Mass spectroscopy: (PI-FAB) 385, (M + H).

Preparative Example C Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-D-glutamic The N-benzyloxycarbonyl-D-5- (1,1-d? -methyl) -glutamic acid was converted to the methyl ester using the procedure described in Method 2. The methyl ester of D-5- acid (1), 1-dimethylethyl) -glutamate was prepared from the product of the previous step using the procedure in Method 4. The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the methyl ester of D-5 acid - (1, 1-dimethylethyl) -glutamate resulting using the procedure in Method 3. The methyl ester was hydrolyzed using the procedure described in Method 6. The product was isolated as a white solid, mp = 50 ° C. The title compound was then prepared using the procedure described in Method 11. The product was isolated as a white solid, m.p. = 60 °. The NMR data were as follows: 1 H NMR (DMSO-de, 300 MHz): d = 8.12 (d, ÍH, J = 4.0 Hz); 7.73 (m, 2H), 7.43, (m, 2H), 4.25 (, ÍH), 4.05 (m, ÍH), 3.43 (m, ÍH), 3.15 (m, ÍH), 2.40 (s, 3H), w .45 (m, 2H), 2.02 (m, 2H), 1.90-1.40 (bm, 4H). 13 C NMR (75 MHz DMSO): d = 174.3, 173.3, 171.6, 144.0, 134.1, 130.3, 127.8, 61.9, 51.4, 49.5, 31.2, 30.3, 26, .3, 24.3, 21.4. Mass spectroscopy: (PI-FAB) 399 (M + H) X Example 27 Synthesis of N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) thiaprolyl-L- (N-benzyl) -histidine N- (Toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiazoline-4-carboxylic acid was prepared from L- (5,5-dimethyl) -thiazolidine-4-carboxylic acid , using the procedure described in Method 1. The title compound was then prepared using standard coupling procedures to provide a solid, mp. = > 200 ° C (dec.). The NMR data were as follows: XH NMR (D20, 300 MHz): d = 0.95 (s, 3H), 1.08 (s, 3H), 2.41 (s, 3H), 2.85-3.12 (m, 2H), 3.84 (s, ÍH), 4.32 (m, ÍH), 4.40 (s, 2H), 5.09 (s, 2H), 7.01 (s, ÍH), 7.24-7.43 (m, 7H), 7.60-7.71 (m, 3H ). 13 C NMR (D20, 75 MHz): d = 27.9, 30.2, 30.3, 35.6, 37.0, 57.7, 61.3, 61.7, 79.8, 124.9, 134.6, 135.06, 135.10, 135.8, 137.1, 138.9, 143.2, 143.4, 143.5, 152.6 , 176.7, 184.1. Mass spectroscopy: (FAB +) 565 (M + H).

Example 28 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (! • methyl) histidine The ester of the title compound was synthesized as described in Method 12. The ester was dissolved in dioxane / H20 (8 mL) to which s added solid NaOH (1 ec). After stirring overnight, the reaction mixture was concentrated. The residue was dissolved in H2O and loaded onto an ion exchange column (Dowex 50W-X8-100, H + form). After washing the column with H20, the compound was eluted with 5% 5% aqueous pyridine. The fractions containing the compound were mixed and concentrated and the residue was dissolved in H20 and lyophilized. The product was isolated as a white solid, m.p. = 135-137 ° C. The NMR data were as follows: 10 X H NMR (DMSO-de, 300 MHz): d = 8.16 (d, 2H, J = 8.0 Hz), 7.72 (d, 2H, J = 8.0 Hz), 7.54 (s, ÍH), 7.42 (d, 2H, J = 8.0 Hz); 6.91 (s, ÍH), 5.10 (bs, ÍH), 4.41 (m, ÍH), 4.11 (M, ÍH), 3.57 (s, 3H), 3.34 (m, ÍH), 3.10 (m, ÍH), 2.92 (m, 2H), 2.39 (s, 3H), 1.80-1.45 (bm, 4H). 13 C NMR (DMSO-de, 75 MHz): d = 73.0, 171.0, 143.9, 137.5, 136.9, 134.3, 130.2, 127.8, 118.6, 61.8, 52.5, 49.3, 33.3 30.8, 29.9, 24.2, 21.4 Mass spectroscopy: ( PI-FAB) 421 (M + H).

################## Synthesis of N- (toluene-4-sulfonyl) -L- ################################################## Synthesis of N- (toluene-4-sulfonyl) -L- prolyl-D- (N-benzyl) histidine A solution in CH2C12 of Boc-D- (N-benzyl) isthidine was cooled to -15 ° C (dry ice bath / CH3CN) alcohol was added diethylisopropylamine (1.5 ec), methanol (3.0 ec) and BOP (1.1 ec) to form the methyl ester. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was then poured into 0.1M HCl and the organic phase was washed with H20, saturated NaHCO3, brine dried (MgSO4), filtered and concentrated. The crude methyl ester was purified by flash chromatography. The Boc group was removed with TFA / CH2C12. The crude reaction mixture was taken up in CH 2 Cl 2 and washed with 5% Na 2 CO 3. The organic phase was washed with brine and dried (MgSO), filtered and concentrated to give the free amine. Coupling was performed using the procedure described in Method 12 and the ester was hydrolyzed using the procedure described in Method 7. The product was isolated as a white solid, m.p. = > 200 ° C. The NMR data were as follows: ^ tts¿ ts & i ^ sSM? X H NMR (DMSO-de, 300 MHz): d = 7.75-7.61 (ÍI, 3H), 7.51 (s, ÍH), 7.45-7.15 (bm, 7H), 5.05 (m, 2H), 4.05 (m, 2H) ), 3.30 (m, HH), 3.10 (m, HH), 2.95 (m, HH), 2.75 (m, HH), 2.38 (s, 3H), 1.67 (m, 2H), 1.35 (m, 2H) . 13 C NMR (75 MHz DMSO-d6): d = 17403, 169.6, 143.9, 139.3, 138.3, k 136.5, 134.1, 130.3, 128.9, 127.8, 127.7, 117.1, 62.4, 54.3, 49.8, 49.4, 31.8, 30.6, 24.2 , 21.4. Mass spectroscopy: (PI-FAB) 519 (M + H).

Example 30 Synthesis of N- (toluene-sulfonyl) -L-glutami-L-tyrosine The Cbz-L-5- (1,1-dimethylethyl) -glutamic acid was coupled with the t-butyl ester of L-tyrosine using the procedure described in Method 3. The Cbz group was removed using the procedure described in the 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 which gave a solid, p.f. = 173-175 ° C. The NMR data were as follows: 1 H-NMR (DMSO-300 MHz): d = 1.70-1.90, (m, 2H), 2.24-2.32 (m, 2H), 2.40 (s, 3H), 2.80-3.10 ( m, 2H), 3.51 (m, ÍH), 4.0-4.5 (CH-bury under a long peak H20), 6.87 (d, 2H, J = 8.4 Hz), 7.18 (d, 2H, J = 8.2 Hz), 7.44 (d, 2H, J = 8.2 Hz), 7.70 (d, 2H, J = 8.2 Hz), 8.34 (bs, ÍH). 13 C NMR (DMSO-d 6, 300 MHz d = 21.5, 28.5 31. 1, 36.7, 52.9, 54.8, 121.9, 128.5, 130.6, 131.1, 131.9, 138.0, 146.1, 147.9, 170.7, 173.0, 174.4. Mass spectroscopy: (FAB +) 465 (M + H).

Example 31 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (N-methyl) histidine The Boc-L- (3-methyl) histidine was dissolved in MeOH and cooled in an ice bath. Then HCl gas was bubbled through the reaction mixture for 15 minutes. After stirring overnight, the reaction mixture was concentrated to a bromine solid. The dihydrochloride was coupled to tos-Pro-OBn using the procedure described in Method 12 and hydrolyzed via Method 7. The product was isolated as a white solid, m.p. = > 200 ° C. The NMR data were as follows: XH NMR (DMSO-d6, 300 MHz): d = 7.74 (m, 3H), 7.45-7.35 (bm, 3H); 6.56 (s, ÍH), 4.10-3.93 (m, 2H), 3.51 (s, 3H), 3.22 (m, ÍH), 3.10 (m, 2H), 2.91 (m, ÍH), 2.38 (s, 3H) , 1.70 (m, ÍH), 1.45 (m, 3H). 13 C NMR (DMSO-d 6, 75 MHz): d = 173.3, 170.1, 144.1, 137.5, 133.0, 130.3, 128.8, 128.1, 127.5, 62.4, 53.6, 49.1, 31.2, 30.6, 26.2, 24.1, 21.4. Mass spectroscopy: (PI-FAB) 443, (M + H) X Example 32 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-a-amino-2,3-dihydro- (1,4-benzodioxin) -6-propanoic acid The title compound was prepared using the procedure described in Method 16 and isolated with a white solid. The NMR data were as follows: NMR ** H (CDC13, 300 MHz): d = 7.73 (m, 2H), 7.32 (m, 2H), 6.87-6.26 (m, 2H), 6.64 (m, ÍH) , 4.84 a? t * i. * j * ¡? t *? ** t¿ * iiß ?? **, (m, ÍH), 4.21 (m, 4H), 4.10 (m, ÍH), 3.55-3.40 (m , HH), 3.30-2.95 (m, 3H), 2.43 (m, 3H), 2.06 (m, HH), 1.64 (m, 3H). 13 C NMR (CDC 13.75 MHz): d = 175.0, 174.5 172. 4, 172.3, 145.0, 144.9, 144.2, 143.9, 143.4, 143.2, 133.5, 133.4, 130.6, 129.6, 129.1, 128.5, 123.2, 122.69, 118.9, 118.7, 118.1, 117.9, 64.9, 63.1, 62.8, 53.9, 53.8, 50.4, 50.2, 37.3, 37.2, 30.9, 30.5, 24.8, 24.7, 22.2. Mass spectroscopy: (PI-FAB) 475 (M + H) X Example 33 Synthesis of N- (toluene-4-sulfonyl) -L-prol i 1-a-amine-1,3-benzod? Oxol-5-propanoic The title compound was prepared using the procedure described in Method 16 and isolated as a white solid. The NMR data were as follows: 1 H-NMR (CDC13, 300 MHz): d = 7.71 (m, 2H), 7. 50-7.29 (bm, 3H), 7.81-760 (m, 3H), 5.90 (m, 2H), 4. 80 (m, ÍH), 4.15 (m, ÍH), 3.43 (m, ÍH), 3.30-3.00 (bm, 3H), 2.41 (s, 3H), 2.10 (m, ÍH), 1.70 (m, ÍH), 1.51 (m, 2H). ~. «- - ..- ^« - ^ - 13 C NMR (CDC 13.75 MHz): d = 174.9, 174.5, 172. 5, 172.3, 1478.5, 148.2, 147.4, 147.2, 145.0, 133.4, 133.2, 130.6, 130.2, 129.5, 128.5, 128.5, 123. 6, 123.1, 110.5, 1102, 109.2, 108.8, 101.5, 63.1, 62.7, 54.0, 53.7, 50.4, 50.2, 37.8, 37.6, 31.0, 30.4, 24.8, 22.1. Mass spectroscopy: (PI-FAB) 461 (M + H) \ Example 34 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-valine The N- (toluene-4-sulfonyl) -L-proline hydrate was coupled to the L-valine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF / water. The NMR data were as follows: NMR - H (CDC13): d = 8.20 (br s, ÍH), 7.76 (d, 2H, J = 8 Hz), 7.49 (d, ÍH, J = 8.3 Hz), 7.35 (d, 2H, J = 8.0 Hz), 450 (dd, ÍH, J = 4.8, 8.3 Hz), 4.19 (m, 3H), 3.54 (m, ÍH), 3.21 (m, ÍH), 2.44 (s, 3H), 2.31-2.18 (2H), 1.70-1.56 (3H), 1.00 (d, 3H, J = 6.9 Hz), 0.99 (d, 2H, J = 6.9 Hz). 13 C NMR (CDCl 3): d = 175.7, 172.3, 145.0, 133.5, 130.6, 128.5, 62.8, 58.1, 50.3, 31.6, 30.3, 25.1, 22.2, 19.7, 18.2. Mass spectroscopy: FAB m / e 369 (M + H).

Example 35 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-iodo) -phenylalanine methyl ester The procedure used for the preparation of Example 8 was used. The title compound was isolated as a white foam. The NMR data were as follows: NMR - * H (300 MHz, CDC13): d = 7.72 (d, 2H, J = 8.25 Hz), 7.64 (d, 2H, J = 8.25 Hz), 7.41 (d, 1H) , J = 8.20 Hz), 7.36 (d, 2H, J = 8.10 Hz), 7.00 (d, 2H, J = 8.25 Hz), 4.82 (m, ÍH), 4.08 (m, ÍH), 3.71 (s, 3H ), 3.35 (m, 2H), 3.10 (m, 2H), 2.44 (s, 3H), 2.01 (m, ÍH), 1.55 (m, 3H). Mass spectroscopy: (FAB) 557 (M + H). ^ j? & ^ jgj? g ^ Example 36 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4- (aminobenzoyl) phenylalanine methyl ester Following the described experimental section of Example 1, the N- (toluene-4-sulfonyl) -L-prolyl-Lp-amino-phenylalanine methyl ester (1.75 g, 3.93 mmol) in dichloromethane (25 mL) was dissolved with Et3N. (1.1 eq, 600 mL) and benzoyl chloride (1.1 eq, 860 mL). The title material was isolated as a solid, in a yield of 90% (1.95 g, 3.55 mmol), m.p. = 191-193 ° C. The NMR data were as follows: NMR - "" H (300 MHz, CDC13): d = 7.94 (s broad, ÍH), 7.67 (d, 2H, J = 8.31 Hz), 7.71 (d, 2H, J = 8.22 Hz), 7.60 (d, 2H, J = 8.37 Hz), 7.45 (m, 5H), 7.34 (d, 2H, J = 8.34 Hz), 7.16 (d, 2H, J = 8.25 Hz). 4.82 (m, ÍH), 4.40 (broad s, ÍH), 4.05 (m, ÍH), 3.77 (s, 3H), 3.40 (m, ÍH), 3.23 (m, ÍH), 3.09 (m, 2H), 2.42 (s, 3H), 2.02 (m, 1H0, 1.56 (m, 3H). 13C NMR (75 MHz, CDC13): d = 171.93, 171.46, 144.93, 137.98, 135.45, 133.49 , 132X8, 132.44, 130.55, 129.36, 128.43, 127.53, 120.80, 62.83, 54.02, 53.11, 50.29, 37.96, 30.31, 24.88, 22.16. tM ¿^ ^. ^ £ £ s ^ a Mass spectroscopy: (FAB) 550 (M + H) Example 37 Synthesis of the N- (toluene-4-sulfonyl) -L-prolyl-L- (4-chloro) phenylalanine methyl ester N- (toluene-4-sulfonyl) -L-proline (660 mg, 2.3 mmol) was added to 12 mL of DMF, at room temperature under N2. To this the hydrochloride was added of the methyl ester of L- (4-chloro) phenylalanine (1.1 eq, 493.3 mg), N-met il-morpholine (3.5 eq, 890 mL) and the BOP reagent (1.0 eq, 660 mg). The title compound was isolated as an oil of 31% yield (310 mg, 0.7 mmol). The NMR data were as follows: 1H-NMR (300 MHz, CDC13): d = 7.70 (broad, d, 2H), 7.35 (m, 2H), 7.25 (m, 2H), 7.11 (m, 2H), 4.82 (m, HH), 4.05 (m, HH), 3.78 (s, 3H), 3.35 (m, HH), 3.25 (m, HH), 3.05 (m, 2H), 2.45 (s, 3H), 1.52 (m, 3H). Mass spectroscopy: (FAB) 433 (M + H).

Example 38 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) phenylalanine methyl ester tttfÉÉi íÉlÉMttM ^ ÉBii ttiM? IttttÉ-.

The N- (toluene-4-sulfonyl) -L-prolyl-L- (4-nitro) phenylalanine methyl ester (2.00 g, 4.48 mmol) was dissolved in MeOH (10 mL) with a catalytic amount of 10% Pd in C. the hydrogenation reaction was run at room temperature for 12 hours at 40 psi. In the filtration of the reaction mixture over celite, the solvent was evaporated under reduced pressure yielding the title compound as a pink foam in quantitative yields. The NMR data were as follows:? NMR (300 MHz, CDC13): d = 7.68 (d, 2H, J = 8.25 Hz), 7.30 (d, 2H, J = 8.07 Hz), 6.88 (d, 2H, J = 8.25 Hz), 6.57 (d, 2H, J = 8.25 Hz), 4.74 (m, ÍH), 4.04 (broad m, 3H), 3.70 (s, 3H), 3.36 (m, ÍH), 3.11 (m , 2H), 2.92 (m, ÍH), 2.39 (s, 3H), 1.97 (m, ÍH), 1.48 (m, 3H). 13 C NMR (75 MHz, CDC13): d = 172.14, 171.31 145.97, 144.86, 133.61, 130.65, 130.51, 128.43, 126.23, 115.79, 111.35, 62.83, 54.16, 52.96, 50.21, 37.68, 30.34, 24.76, 22.16, 14.7. Mass spectroscopy: (FAB) 446 (M + H).

Example 39 Synthesis of N- (toluene-4-sulphonyl) -L-prolyl-L- (-acetamido) phenylalanine methyl ester The title compound was prepared following the experimental procedure described for Example 1 and was isolated as a foam in quantitative yields. The NMR data were as follows: 1H-NMR (300 MHz, CDC13): d = 7.70 (d, 2H, J = 8.10 Hz), 7.65 (m, 2H), 7.33 (d, 2H, J = 8.40 Hz), 7.08 (d, 2H, J = 8.40 Hz), 4.79 (m, ÍH), 4.05 (, ÍH), 3.75 (s, 3H), 3.37 (m, ÍH), 3.11 (m, 3H), 2.42 (s, 3H), 2.22 (s, 3H), 2.02 (m, ÍH), 1.48 (m, 3H). 13 C NMR (75 MHz, CDC13): d = 177.61, 171.92, 171.46, 169.07, 144.98, 137.69, 133.41, 132.25, 130.56, 130.32, 128.41, 120.40, 62.83, 54.00, 53.10, 50.28, 45.10, 37.89, 30.34, 25.13 , 24.84, 22.17. Mass spectroscopy: (FAB) 488 (M + H).

Example 40 Synthesis of the N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L- (N-benzyl) histidine methyl ester N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) thiazolidine-4-carboxylic acid was prepared from L- (5, 5, -dimethyl) thiazolidine-4-carboxylic acid using the procedure described in Method 1. The title compound was prepared using standard coupling procedures to provide a solid, mp. = 60-66 ° C. The NMR data were as follows: 1H-NMR (CDC13, 300 MHz): d = 1.73 (s, 3H), 1.30 (s, 3H), 2.43 (s, 3H), 3.09 (m, 2H), 3.67 (s, 3H), 3.92 (s, ÍH), 4.45 (d, ÍH, J = 10.2 Hz), 4.62 (s, d, ÍH, J = 10.1 Hz), 5.03 (s, 3H), 3.71 (s, ÍH), 7.13 (d, 2H, J = 7.7 Hz), 7.29-7.38 (m, 5H), 7.46 (s, ÍH) ), 7.76 (d, 2H, J = 8.1 Hz), 7.93 (d, ÍH, J = 7.4 Hz). 13 C NMR (CDC13, 75 MHz): d = 22.3, 24.9, 29.8, 30.3, 51.1, 51.5, 52.9, 53.0, 55.3, 74.0, 117.9, 128.0, 128.6, 128.9, 129.6, 130.5, 133.0, 136.5, 137.6, 137.9 , 145.0, 169.1, 171.9.

Mass spectroscopy: (PI-FAB) 557 (M + H) Example 41 5 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl- - (3-3'-tolylureido) -L-phenylalanine The methyl ester was prepared by the reaction of N- (toluene-4-sulfonyl) -L-prolyl-L-4- 10 aminophenylalanine with 3-tolyl isocyanate (triethylamine, toluene, reflux one hour). The resulting solid was removed by filtration and washed well with EtOAC / Hexane to give the methyl ester as a white solid. The methyl ester was hydrolyzed using 1M LiOH in THF. The title compound was isolated following the acid / base treatment as a white solid, m.p. = 135-140 ° C. The NMR data were as follows: XH NMR (DMSO-d6, 400 MHz): d = 12.79 (br s, ÍH), 8.55 (s, ÍH), 8.50 (s, ÍH), 8.02 (d, ÍH, J = 7.29 Hz), 7.69 (d, 2H, J = 8.3 Hz), 7.39 (d, 2H, J = 7.9 Hz), 7.33 (d, 2H, J = 8.56 Hz), 7.26 (s, ÍH), 7.18 (d, ÍH, J = 8.4 Hz); 7.12 (m, 3H), 6.75 (d, ÍH, J = 7.25 Hz), 4.43 (m, ÍH), 4.11 (dd, ÍH, J = 3, 8.1 Hz), 3.32 (m, ÍH), 3.1 (m, ÍH), 3.01 (dd, ÍH, J = . 05, 13.83 Hz), 2.91 (dd, ÍH, J = 8.45, 13.73 Hz); 2. 38 (s, 3H), 1.4-1.63 (m, 4H). IR (KBr, cm "1): 3340, 3290, 3090, 2980, 1730, 1650, 1600, 1550, 1495, 1350, 1290, 1210, 1160, 660. Mass spectroscopy: ((+) FAB, m / e (%)) 565 (M + H] +).

Example 42 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4 - [(2, 3, 3a, 7a-tetrahydro-lH-indole-2-carbonyl) -amino] - L-phenylalanine The N-Boc compound was prepared using the procedures described in Method 13 and Method 6. The title compound was then prepared using the procedure described in Method 10. The NMR data were as follows: XH NMR (DMSO) d6): d = 7.75 (d, 2H, J = 7.65 (m, 2H), 7.45 (d, 4H), 7.10 (m, 4H), 6.80 (d, 2H, J = 4.35 (m, ÍH), 4.10 (b, ÍH), 4.02 (m, ÍH), 3.10 (m, 4H), 2.40 (s, 3H), 1.70 (b, ÍH), 1.41 (m, 2H). Mass spectroscopy: (+) FAB ( M + H) ~ 579. ^^ í ^^ l ^ & ^ ^ ^ ^ ^ ^ ^ ^ ^ Example 43 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-phenylamino) phenylalanine methyl ester The methyl ester was prepared by reductive amination of N- (toluene-4-sulfonyl-L-prolyl-L- (4-amino) phenylalanine with valeraldehyde (acetic acid), sodium triacetoxyborohydride, methylene chloride, which was stirred at room temperature environment for 1 hour). The crude product was purified with flash chromatography (silica, EtOAc: hexane 1: 1) to give the methyl ester as a white solid, m.p. = > 160 ° C.

Example 44 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-O- (2-dibenzylamino-ethyl) tyrosine methyl ester The title compound was prepared via 0-alkylation of the N- (toluene-4-sulfonyl) -L-prolyl-L- (tyrosine) methyl ester with N- (2-chloroethyl-yl) dibenzylamine hydrochloride under reflux with 2-butanone in the presence of potassium carbonate and sodium iodide The obtained mixture was chromatographed on Si02 in 1% MeOH / CHCl3 (Rf = 0.75 using 10% MeOH / CHCl3). The NMR data were as follows: NMR? H (DMSO-de, 400 MHz ): d = 1.4-1.6 (4H, m), 2.38 (3H, s), 2.75 (2H, t, J = 7.7 Hz), 2.95 (2H, m), 3.1 (ÍH, dd, J = 6.10, 10.6 Hz), 3.33 (ÍH, dd), 3.6 (3H, s), 3.65 (4H, s), 4.0 (2H, t, J = 6.6 Hz), 4.1 (ÍH, t, J = 8.8 Hz), 4.5 ( ÍH, t, J = 8.8 Hz), 6.75 (2H, d, J = 10 Hz), 7.08 (2H, d, J = 10 Hz); 7.2-7.35 (10H, m); 7.4 (2H, d, J = 10 Hz), 7.68 (2H, d, J = 10 Hz), 8.1 (ÍH, d, J = 10 Hz). MS: + FAB, m / z 670 ([MH] +, 45%), 154 (100 Example 45 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-O- [2- (dibenzylamino) ethyl] tyrosine The methyl ester was prepared via the O-20 alkylation of the N- (toluene-4-sulfonyl) -L-prolyl-L-irosine methyl ester with N- (2-chloroethyl) dibenzylamine hydrochloride under reflux with 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7, and isolated in a solid, m.p. = 106-110 ° C. The NMR data were as follows: 1 H NMR (DMSO-de, 400 MHz): d = 1.2-1.45 (3H, m), 1.75 (1H, m); 2.38 (3H, s), 2.75 (2H, t, J = 6.6 Hz); 2.95 (2H, m), 3.1 (ÍH, dd, J 0 7.6, 7 Hz), 3.38 (ÍH, bs), 3.62 (4H, s); 3.85 (ΔI, dd, J <= 6.4, 6Hz), 3.95 ΔH, t, J = 4.4 Hz), 3.97 (2H, t, J = 8.8 Hz); 6.62 (2H, d, J = 10 HZ); 6.95 (2H, d, J = 10 Hz), 7.2-7.4 (10H, m); 7.41 (2H, d, J = 10Hz); 7.62 (ÍH, d, J = Hz); 7.75 (2H, d, J = 10Hz). MS: + FAB, m / z 656 ([MH] +, 15%), 154 (100 Example 46 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-pentylamino) phenylalanine The title compound was prepared from the product of Example 43 using the procedure described in Method 6. The NMR data were as follows: XH NMR (DMSO-de, 400 MHz): d = 7.73 (d, 2H, J = 8.1 Hz), 7.57 (d, ÍH, J = 5.7 Hz), 7.39 (d, 2H, J = 7.9 Hz), 6.76 (d, 2H, J = 8.3 Hz), 6.32 (d, 2H, i ^ Sri! t ^^ ii ^^^ ^ lto ^ l ^ i? ^^^^^ '^ * JA ^ -a "*; -Ox ^ aaüiiítíM J = 8.5 Hz), 5.14 (t, ÍH, J = 5.6 Hz), 3.94 (dd, ÍH, J = 2,007 Hz), 3.77 (m, ÍH), 3.18 (m, 2H), 2.90 (m, 4H), 2.38 (s, 3H), 1.73 (m, ÍH ), 1.41 (m, 5H), 1.29 (m, 4H), .85 (m, 3H), IR (KBr, cm "1): 3400, 2950, 2910, 2870, 1660, 1620, 1525, 1405, 1350 , 1155, 670, 600, 550.

Example 47 Synthesis of the N- (toluene-4-sulfonyl) -L-prolyl-L-4- (-chlorobenzylamino) phenylalanine methyl ester The title compound was prepared by reductive amination of the N- (toluene-sulfonyl) -L-prolyl-L- (4-amino) -phenylalanine methyl ester with 4-chlorobenzaldehyde (acetic acid, sodium triacetoxyborohydride, methylene chloride , was stirred at room temperature for 2.5 hours). The crude product was purified by flash chromatography (silica, EtOAc: hexane 1: 1) to give the title compound as a white solid.

Example 48 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4- [3- (4-cyanophenyl) ureido] -phenylalanine methyl ester The title compound was prepared by the reaction of the N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) -phenylalanine methyl ester with 4-cyanophenylisocyanate (triethylamine, toluene, reflux at 3.5 hours) . The crude product was purified by flash chromatography (silica, EtOAc: hexane 1: 1) to give the methyl ester as a white solid, m.p. = 204-206 ° C.

Example 49 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4- [3- (-cyanophenyl) -ureido] -phenylalanine The title compound was prepared from the product of Example 48 using the procedure described in Method 6 as a solid, m.p. = 163-165 ° C. The NMR data were as follows: X H NMR (DMSO-de, 400 MHz): d = 12.8 (br s, ÍH), 9.12 (s, ÍH), 8.78 (s, ÍH), 8.04 (d, ÍH, J = s- ^ »^ ii ß £ - ^ 8.1 Hz), 7.69 (m, 4H), 7.6 (d, 2H, J = 9 Hz), 7.39 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H , J = 8.5 Hz), 7.15 (d, 2H, J = 8.5 Hz), 7.12 (m, 3H), 4.43 (m, ÍH), 4.11 (dd, ÍH, J = 3.1, 8.2 Hz), 3.29 (m , HH), 3.06 (m, 2H), 2.92 (dd, HH, J = 8.4, 13.9 Hz); 2.38 (s, 3H), 1.38-1.63 (m, 4H). IR (KBr, cm "1): 3360, 2220, 1720, 1650, 1590, 1530, 1510, 1410, 1230, 1150, 1090, 830, 670, 595, 550. Mass spectroscopy: ((-) FAB, m / z (%)) 574 (40 [M + H] -).

Example 50 Synthesis of the N- (toluene-4-sulphonyl) -L-prolyl 1-L-O-tert-butoxycarbonylmethyl) tyrosine methyl ester The title compound was prepared by the reaction of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine with t-butyl bromoacetate (potassium carbonate, DMF, under argon for 72 hours). The product was purified by flash column chromatography (silica, hexane: EtOAc 1: 1) to give the methyl ester as a white solid, m.p. = 55 ° C.

Example 51 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-O- (tert-butoxycarbonylamino-yl) -tyrosine The title compound was prepared from the product of Example 50 using the procedure described in Method 6 and isolated as a solid, m.p. = 69-70 ° C. The NMR data were as follows: XH NMR (DMSO-de, 400 MHz): d = 12.2 (br s, ÍH), 8.00 (d, ÍH, J = 8.1 Hz), 7.67 (d, 2H, J = 8.2 Hz), 7.38 (d, 2H, J = 7.9 Hz), 7.11 (d, 2H, J = 8.6 Hz), 6.76 (d, 2H, J = 8.5 Hz), 4.5 (s, 2H), 4.4 (m, ÍH), 4.07 (, 1H), 2.8-3.1 (m, 4H), 2.37 (s, 3H), 1.5 (m, 4H), 1.38 (s, 9H). IR (KBr, cm "1): 3400, 2950, 1750, 1660, 1510, 1340, 1225, 1160, 1075, 660, 575, 525. Mass spectroscopy: (ESI, m / e (%)) 545 (M + H)).

Example 52 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4 - [(35 S) -3,4-dihydro-isoquinolin-3-yl-aminocarbonyl] -phenylalanine The methyl ester of N- (toluene-4-sulfonyl-L-prolyl-L- (4-amino) phenylalanine (20 mmol) was taken CH2C12 with HOBT, Boc-L-tet rahydro-isoquinoline-3-carboxylic acid ( 20 mmol), and DCC (24.3 mmol) The mixture was stirred overnight at room temperature, filtered and concentrated in vacuo, the resulting residue was partitioned between 10% acetic acid and EtOAc. H20, saturated NaHCO3, and H2O, dried over Na2SO4, and concentrated in vacuo to yield an amorphous solid.The resulting ester was converted to the acid using the procedure described in Method 6. The title compound was then prepared using the procedure described in Method 10 and isolated as a solid, mp = 145-150 ° C. The NMR data were as follows: XH NMR (DMSO-de): d = 8.12 (d, ÍH), 7.70 (d, 2H ), 7.55 (d, 2H), 7.40 (d, 2H), 7.25 (d, 6H), 4.45 (m, ÍH), 4.38 (d, ÍH), 4.28 (m, ÍH), 4.10 (d, ÍH) , 3.10 (m, 2H), 2.40 (s, 3H), 1.60 (m, 4H).

Mass spectroscopy: (FAB) (M + H) 591 (M + Na) "613.

Example 53 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (3-methoxy-phenyl) ureido] -L-phenylalanine methyl ester The title compound was prepared by the reaction of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) -phenylalanine methyl ester with 3-methoxy-phenylisocyanate (triethylamine, toluene, reflux one hour ). The resulting solid was removed by filtration and washed with EtOAc / hexane to give the methyl ester as a white solid, m.p. = 206-209 ° C.

Example 54 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-ureido] -L-phenylalanine The title compound was prepared from the product of Example 53, using the procedure described in Method 6. The NMR data were as follows: 1 H NMR (DMSO-d 6, 400 MHz): d = 12.80 (br s, 1 H), 8.6 (d, 2 H, J = 13.8), 8.03 (d, ÍH, J = 7.9 Hz), 7.69 (d, 2H , J = 8.1 Hz), 7.39 (d, 2H, J = 8.1 Hz), 7.33 (d, 2H, J = 8.56 Hz), 7.14 (m, ÍH), 6.9 (d, 2H), 1.53, 7.9 Hz) , 6.52 (dd, ÍH, J = 2.19, 8.12 Hz), 4.42 (m, ÍH), 4.11 (dd, ÍH, J = 2.96, 8.45 Hz), 3.7 (s, 3H), 3.35 (m, ÍH), 3.09 (m, ÍH), 3.01 (dd, ÍH, J = 4.83, 13.6 Hz), 2.91 (dd, ÍH, J = 8.34, 13.8 Hz), 2.48 (s, 3H), 1.41-1.63 (m, 4H) . IR (KBr, cm "1): 3390, 2940, 1655, 1595, 1545, 1500, 1450, 1345, 1320, 1210, 1160, 660, 580, 545. Mass spectroscopy: ((+) FAB, m / e (%)) 603 (30 [M + Na] +); 581 (10 [M + H] +).

Example 55 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-O- (4,5-dihydro-lH-imidazol-2-yl-methyl) -tyrosine The methyl ester was prepared by the reaction of the N- (toluene-4-sulfonyl) -L-prolyl) -L-O-cyanomethyl-t-ylsine methyl ester with ethylene-diamine (the reflux of methanol under argon overnight). The product was purified by flash column chromatography (silica, % methanol (5% methanol in chloroform) to give the methyl ester as a white foam. The title compound was prepared using the procedure described in Method 6 and isolated as a solid, m.p. = 147-149 ° C. The NMR data were as follows: XH NMR (DMSO-400 MHz): d = 7.74 (d, 2H, J = 8.4 Hz), 7.61 (d, ÍH, J = 5.7 Hz), 4.70 (d, 2H, J = 8.2 Hz), 6.97 (d, 2H, J = 8.6 Hz); 6.75 (m, 2H), 6.51 (br s, ÍH); 4.49 (s, 2H), 3.96 (dd, ÍH, J = 9.6 Hz), 3.04 (m, 4H), 2.39 (s, 3H), 1.70 (m, ÍH), 1.35 (m, 3H). IR (KBr, cm "1): 3400, 2900, 1650, 1610, 1510, 1400, 1315, 1245, 1150, 1075, 1040, 700, 600, 550. Mass spectroscopy: (ESI, m / e (%) ) 515 (M + H) +).

Example 56 Synthesis of N- (toluene-4 -sul foni 1) -L-prolyl-L- (3-propyl-ureido) -phenylalanine The methyl ester was prepared by the reaction of the N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) -phenylalanine methyl ester with ? Afaia? ltot > - 1-fti-rf r-X- i and propyl isocyanate (triethylamine, toluene, reflux 1.25 hours). The crude product was purified by flash chromatography (silica, EtOAc: hexane 1: 1) to give the methyl ester as a white foam. The title compound was prepared using the procedure described in Method 6. The NMR data were as follows: 1 H NMR (DMSO-de, 400 MHz): d = 12.78 (br, s 1H), 8.29 (s, ÍH) , 7.99 (d, 1H, J = 8.1 Hz), 6.68 0 (d, 2H, J = 8.1 Hz), 7.39 (d, 2H, J = 8.1 Hz), 7.26 (d, 2H, J = 8.5 Hz), 7.06 (d, 2H, J = 8.5 Hz), 6.04 (t, ÍH, J = 5.7 Hz), 4.39 (m, ÍH), 4.1 (dd, ÍH, J = 2.9, 8.2 Hz), 3.3 (m, ÍH ), 3.09 (m, ÍH), 2.99 (m, 3H), 2.87 (dd, ÍH, J = 8.34, 13.83 Hz), 2.38 (s, 5 3H), 1.49-1.64 (m, 3H), 1.40 (m , 3H), 0.84 (t, 3H, J = 7.46 Hz). IR (KBr, cm "1): 3590, 3350, 3220, 3050, 2960, 2930, 2860, 1750, 1660, 1630, 1590, 1560, 1540, 1345, 1320, 1160, 660, 590. Mass spectroscopy: ( (+) FAB m / e (%)) 539 (40, [M + Na] +); 517 (20 [M + H] +).

J? Fasia ^ • -s ^ - ^^ S ^^^ ^ tfg ,.

Example 57 Synthesis of N- (toluene-1-sulfonyl) -L-prolyl-L- (4-benzylamino) phenylalanine The title compound was prepared from the product of Example 58 using the procedure described in Method 6. The NMR data were as follows: 1H NMR (DMSO-de, 400 MHz): d = 7.72 (d, 2H, J = 8.3 Hz), 7.54 (d, ÍH, J = 5.49 Hz), 7.4 (d, 2H, J = 7.9 Hz), 7.27 (m, 4H), 717 (m, ÍH), 6.72 (d, 2H, J = 8.56 Hz), 6.34 (d, 2H, J = 8.56 Hz), 5.91 (t, ÍH, J = 6.15 Hz); 4.17 ((d, 2H, J = 6.15 Hz); 3.91 (dd, 1H, J = 2.74, 8.89 Hz), 3.75 (m, ÍH), 2.95 (m, 2H), 2.88 (m, 2H), 2.38 (s, 3H), 1.66 (m, ÍH), 1.18- 1.42 (m, 3H). IR (KBr, cm "1): 3400, 1655, 1620, 1525, 1410, 1340, 1160, 670. Analysis calculated for C28H3o 305S Li 1.5 H20; C, 60.64; H, 5.90; N, 7.57. Found: C, 60.60; H, 5.61; N, 7.45.

Example 58 Synthesis of the N- (toluene-4-sulphonyl) -L-prolyl-L- (4-benzylamino) phenylalanine methyl ester The title compound was prepared by reductive amination of the N- (toluene-4-sulfonyl-) L-prolyl-L-4-aminophenylalanine methyl ester with benzaldehyde, (acetic acid, sodium triacetoxyborohydride, methylene chloride, stirred at room temperature during the night). The crude product was purified by flash chromatography (silica, EtOAc: hexane 1: 1) to give the title compound as a white solid, m.p. = 53-56 ° C (0.501 g, 41%). The NMR data were as follows: 1 H-NMR (DMSO-de, 400 MHz): d = 8.09 (d, ÍH, J = 7.90 Hz), 7.68 (d, 2H, J = 8.34 Hz), 7.39 (d, 2H , J = 7.90 Hz), 7.28 (m, 4H), 717 (m, ÍH), 6.87 (d, 2H, J = 8.34 Hz), 6.46 (d, 2H, J = 8.56 Hz), 6.12 (t, ÍH , J = 6.15 Hz), 4.38 (m, HH), 4.20 (d, 2H, J = 5.71 Hz), 4.07 (m, HH), 3.58 (s, 3H), 3.27 (m, HH), 3.06 (m , ÍH), 2.82 (m, 2H), 2.39 (s, 3H), 1.53 (m, 3H), 1.36 (m, ÍH). IR (KBr, cm "1): 3400, 2950, 1745, 1675, 1610, 1525, 1450, 1350, 1210, 1100, 680, 595, 550.

^ Igj ^ igigiggg g MS ((+) FAB, m / e (%)) 536 (70 [M + H) +) Analysis calculated for C29H33N305S: C, 65.03 H, 6.21; N.7.84. Found: C, 64.57, H, 6.10; N. 7.58.

Example 59 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4 - (4-chlorobenzylamino) -phenylalanine The methyl ester was prepared by reductive amination of the N- (toluene-4-sulfonyl) -L-prolyl-L-4- (amino) -phenylalanine methyl ester with 4-chlorobenzaldehyde (acetic acid, sodium triacetoxyborohydride, methylene chloride , was stirred at room temperature for 2.5 hours). The crude product was purified by flash chromatography (silica EtOAc: Hexane 1: 1) to give the methyl ester as a white solid. The title compound was prepared using the procedure described in Method 6. The NMR data were as follows: NMR * H (DMSO-de, 400 MHz): d = 7.72 (d, 2H, J = 8.3 Hz); 7.53 (d, 1H, J = 5.7 Hz), 7.4 (d, 2H, J = 7.9 Hz), 7.3 (s, 4H), 6.62 (d, 2H, J = 8.3 Hz); 6.31 (d, 2H, J = 8.5 Hz), 6.0 (m, ÍH), 4.16 (d, 2H, J = 6.1 Hz), 3.92 (d, ÍH, J = 9, 2.85 Hz); 3.75 (m, HH), 2.91 (m, 4H), 2.38 (s, 3H), 1.65 (m, HH), 1.35 (m, HH), 1.18 (m, 2H). IR (KBr, cm "1): 3400,1620, 1525, 1410, 1340, 670. Mass spectroscopy: ((+) FAB, m / e (%)) 578 (95, [M + Na +); 562 ( 50, [M + Li] +); 556 (40 [M + H] +).

Example 60 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl) -L- (4-chlorometansul-phylamino) -phenylalanine The methyl ester of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) -phenylalanine (1.00 g, 2.2 mmol) was dissolved in methylene chloride (2.5 mL) and cooled to -78 ° C. With stirring, chlorometan-sulfonyl chloride (0.34 g, 2.2 mmol) was added followed by the dropwise addition of pyridine (182 mL), 2.2 mmol). The clear solution became yellow, then orange, finally red in the addition of cloromet chloride anil fonilo. The solution was allowed to warm to room temperature and was stirred 16 hours. The reaction solution was transferred to a 250 mL separatory funnel with CH2C12 (50 mL) l? &? i? í? s2a * So? s? & -s &; -; > and extracted with IN HCl (50 mL x 2), brine (50 mL x 2), and water (50 mL). The organic phase was dried (MgSO4) and the solvent was removed to give a red solvent which was flash chromatographed (Si02, CH2C12: CH3CN 3: 1) to yield a white solid. The title compound was prepared using the procedure described in Method 6 and isolated as a solid, m.p. = 163-170 ° C. The NMR data were as follows: XH NMR (DMSO-d6, 400 MHz): d = 8.08 (d, H, J = 7.7 Hz), 7.71 (dd, 4H, J = 14.7 Hz, 8.3 Hz), 7.51 ( d, ÍH, J = 59. Hz), 7.41-.39 (m, 4H), 6.84-6.82 (m, 2H), 6.78-7.72 (m, 4H), 6.68 (d, 2H, J = 7.5 Hz) , 4.40 (q, ÍH, J = 7.7 Hz), 4.18 (s, 3H), 4.19-4.08 (m, ÍH), 3.95-3.89 (m, 2H), 3.60 (s, 2H), 3.11-3.04 (m , 2H), 2.95-2.83 (m, 3H), 2.39 (s, 3H), 1.78-1.65 (m, ÍH), 1.61-1.56 (m, 3H), 1.42-1.37 (m, 4H). IR (KBr, cm "1): 3400, broad, 2960, 2850, 1749, 1650, 1510, 1450, 1400, 1350, 1300, 1260, 1160, 1100, 1000, 840, 800, 650, 600, 550. Spectroscopy of mass: (-) ESI: 542.1 (M - H), 483.8, 442.2, 341.6, 273.8, 202.1, 144.9. : ^^^ a Ha ^ ff * í: 1 Example 61 Synthesis of the N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -t? aprolyl-L-4- (aminobenzoyl) methyl ester phenylalanine The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: NMR -? (CDC13): d = 7.89-7.85 (m, 3H), 7.74 (d, 2H), 7.70-7.47 (m, 5H), 7.29 (d, 2H), 7.21 (d, 2H), 7.02 (d, HI) ), 4.89 (m, ÍH), 4.56 (d, ÍH), 4.37 (d, ÍH), 3.85 (s, ÍH), 3.75 (s, 3H), 3.12 (m, 2H), 2.44 (s, 3H) , 1.18 (s, 3H), 1.08 (s, 3H). 13 C NMR (CDCl 3): d = 171.8, 169.1, 166.3, 145.4, 137.6, 135.8, 133.3, 132.7, 132.5, 130.7, 130.6, 129.4, 128.7, 127.6, 120.7, 74.1, 55.2, 53.9, 53.1, 51.1, 38.4, 29.8, 24.6, 22.3. »*» «*« * «*» > '«' -« »- > Example 62 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-d? met il) -thiaprol? l-L-4- (benzamido) phenylalanine The title compound was prepared from the product of Example 61 using the procedure described in Method 7. The NMR data were as follows: 1H NMR (CDC13): d = 8.43 (s, ÍH), 7.84 (d, 2H ), 7.72 (d, 2H), 7.61 (d, 2H), 7.49-7.20 (m, 7H), 4. 93 (q, ÍH), 4.55 (d, ÍH), 4.37, (d, ÍH), 3.92 (s, ÍH), 3.15 (m, 2H), 2.42 (s, 3H), 1.19 (s, 3H), 1.08 (s, 3H). 13 C NMR (CDCl 3): d = 177.62, 174.35, 169.69, 145.53, 137.73, 135.51, 133.19, 132.44, 132.39, 130. 79, 130.63, 129.23, 128.63, 127.82, 121.1, 73. 94, 55.13, 53.97, 51.08 38.02, 29.79, 24.62, 22. 24 Example 63 Synthesis of N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosma ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: NMR - "- H (CDC13): d = 7.73 (d, 2H), 7.33 dd (7.08-7.04 ( m, 3H), 6.73 (d, 2H), 6.51 (s, ÍH), 4. 88 (e, 1H), 4.54 (d, 2H), 4.33 (d, 2H), 1.28 (t, 3H), 4.23 (q, 2H), 3.83 (s, ÍH), 3.14-2.93 (m, 2H), 2. 43 (s, 3H), 1.03 (s, 3H), 1.02 (s, 3H). 13 C NMR (CDCl 3): d = 171.56. 169.44, 155.87, 145.40, 133.16, 131.16, 130.59, 128.66, 127.97, 116.00, 74.01, 62.35, 55.11, 54.16, 51.04, 38.33, 29.79, 2.26, 22.24, 14.67.

Example 64 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -triaprolyl-L-tyrosine The title compound was prepared from the product of Example 63 using the procedure described in Method 7. - ^ a ^ ^ ^ ^ ZZ, i ^ ^ ^ ¿iu¡ ^., Z.-, The NMR data were as follows: XH NMR (CDCI3): d = 7.96 (d, ÍH), 7.49 (d, 2H), 7.17 (d, 2H), 6.91 (d, 2H), 6.49 (d, 2H), 4.40 (m, ÍH), 4.38-4.27 (dd, 2H), 3.83 (s, ÍH), 2.95-2.70 (m, 2H), 2.23 (s, 3H), 0.45 (s, 3H), 0.92 (s, 3H).

Example 65 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-4-yl) -methylaminogolfilanylaine The title compound was prepared from the product of Example 66 using the procedure described in Method 6. The NMR data were as follows: NMR - "- H (DMSO-de, 400 MHZ): d = 8.42 (d, 2H, J = 5.93 Hz), 7.72 (d, 2H, J = 8.34 Hz), 7.53 (d, ÍH, J = 5.71 Hz), 7.39 (d, 2H, J = 7.90 Hz), 7.28 (d, 2H, J = 59.93 Hz), 6.74 (d, 2H, J = 8.56 Hz), 6.31 (d, 2H, J = 8.34 Hz), 6.07 (t, ÍH, J = 6.26 Hz), 4.22 (d, 2H, J = 6.15 Hz), 3.91 (dd, ÍH, J = 2.85, 8.78 Hz), 3.77 (dd, ÍH, J = 5.38, 9.99 Hz), 2.95 (m, 2H), 2.38, (s, 3H), 1.66 (m , ÍH), 1.19-1.38 (m, 3H), IR (KBr, cm "1): 3400, 1650, 1520, 1420, 1340, 1155.

MS ((-) EIS, m / e (%)) 521 (100 [M-H] _) Analysis calculated for C2 H29H405S Li 2.5 H20 C, 56.47; H, 5.97; N, 9.76; Found: C. 56.32; H, 5.61; N, 9.64 Example 66 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-1-4 - [(pyridin-4-yl) methylamino] phenylamine methyl ester Substituting 4-pyridinecarboxaldehyde for benzaldehyde, and following the method for the preparation of Example 58, gave the title compound. The NMR data were as follows: NMR? H (DMSO-d6, 400 MHz): d = 8.43 (d, 2H, J = 6.15 Hz); 8.10 (d, ÍH, J = 7.90 Hz), 7.64 (d, 2H, J = 8.12 Hz), 7.39 (d, (2H, J = 7.90 Hz), 7.28 (d, 2H, J = 6.15 Hz), 4.38 (m, ÍH), 4.26 (d, 2H), J = 6.37 Hz), 4.06 (m, 1H), 3.58 (s, 3H), 3.28 (m, ÍH), 3.06 (m, ÍH), 2.84 (m , 2H), 2.39 (s, 3H), 1.51 (m, 3H), 1.34 (m, ÍH). IR (KBr, cm "1): 3400, 2930, 1745, 1675, 1615, 1600, 1520, 1345, 1160, 1090, 1000, 770, 720, 600, 550.

MS (+)) FAB, m / e (%)) 537 (75 [m + H] +).

Example 67 Synthesis of N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine methyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: XH NMR (CDC13): d = 9.01 (d, ÍH), (8.74 (m, ÍH), 8.23 (m, 2H), 7.73 (d, 2H), 7.59 (d, 2H), 7.43 (m, ÍH), 7.33 (d, 2H), 7.27 (m, ÍH), 7.20 (d, 2H), 15 4.84 (m, ÍH), 4.40-4.32 (dd, 2H), 3.86 (s, ÍH), 3.74 (s, 3H), 3.15-3.10 (m, 2H), 2.44 (s, 3H), 1.19 (s, 3H) ), 1.05 (s, 3H) 13C NMR (CDCl3): d = 171.8, 169.2, 164.3, 152.9, 148.5, 145.4, 137.25, 136.1, 133.3, 133.2, 20 131.3, 130.8, 130.6, 128.6, 124.3, 121.0, 74.1, 55.1, 54.1, 53.0, 51.1, 38.2, 29.8, 24.6, 22.2.

Example 68 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine The title compound was prepared from the product of Example 67 using the procedure described in Method 7. The NMR data were as follows: 1H NMR (CD3) 2SO): d = 9.10 (s, ÍH), 8.73 (d , ÍH), 8.33 (d, 1H), 7.78 (d, 2H), 7.73 (d, ÍH), 7.62 (d, 2H), 7.53 (m, -1H), 7.41 (d, 2H), 7.20 (d, 2H), 4. 51 (dd, 2H), 4.08-4.03 (m, 2H), 3.00 (m, 2H), 2.39 (s, 3H), 1.19 (s, 3H), 1.10 (s, 3H). 13 C NMR (CD3) 2SO): d = 173.1, 167.1 164.1, 152.3, 149.1, 144.3, 137.0, 135.8, 135.2, 134.2, 134.2, 131.1, 130.3, 130.2, 128.3, 123.8, 120.1, 73.0, 55.9, 54.9, 50.6, 37.5 , 29.9, 25.0, 21.4.

Example 69 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-3-ylmethyl) amino] phenylalanine Substituting 3-pyridinecarboxaldehyde for benzaldehyde, and following the method for ? ^ a ^ f? ^? ^^ idk? ff ^^? ^ Jí? JaL preparation of Example 58, gave the title compound. The NMR data were as follows: 1H-NMR (DMSO-de, 400 MHz): d = 8.51 (s, ÍH), 8.38 (m, ÍH), 7.72 (d, 2H, J = 8.13 Hz), 7.68 (m , ÍH), 7.54 (d, ÍH, J = 5.71 Hz), 7.40 (d, 2H, J = 7.90 Hz), 7.28 (m, ÍH), 6.75 (d, 2H, J = 8.56 Hz), 6.36 (d , 2H, J = 8.56 Hz), 5.98 (t, ÍH, J = 5.27, 9.88 Hz); 2.96 (m, 2H), 2.89 (m, 2H), 2.39 (s, 3H), 1.65 (m, ÍH), 1.16-1.43 (m, 3H). IR (KBr, cm "1): 3400, 1670, 1620, 1520, 1400, 1345, 1160, 675, 600. MS ((+) FAB, m / e (%)) 523 (25 [M + H] + ), 529 (100 [M + Li] O) Analysis calculated for C27H29N4Os5S Li 2.5 H20: C, 56.47; H, 5.97; N, 9.76 Found: C, 56.62, H, 57.57, N, 6.69.

Example 70 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl-thiaprolyl-L-4-nitrophenylalanine methyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: 1H-NMR (CDC13): d = 8.14 (d, 2H), 7.74 (d, 2H), 7.41 (d , 2H), 7.35 (d, 2H), 7.10 (d, ÍH), 4.94 (m, ÍH), 4.58 (d, ÍH), 4.33 (d, ÍH), 3.82 (s, ÍH), 3.76 (s, 3H), 3.25 (m, 2H), 2.44 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H). 13 C NMR (CDCl 3): d = 171.3, 169.3, 147.7, 145. 6, 144.6, 133.0, 131.0, 130.6, 128.6, 124.2, 74. 0, 54.9, 53.6, 53.3, 51.1, 38.7, 29.8, 24.5, 22.3.

Example 71 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4-nitrophenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: NMR -? (CDC13): d = 8.16 (d, 2H), 7.71 (d, 2H), 7.48 (d, ÍH), 4.40-7.31 (m, 4H), 4.87 (q, ÍH), 4. 24 (q, 2H), 4.07 (m, ÍH), 3.44-3.35 (m, 2H), 3.23- 3.05 (m, 2H), 2.44 (s, 3H), 2.04 (m, ÍH), 1.62-1.44 (m, 3H), 1.30 (t, 3H). 13 C NMR (CDCl 3): d = 171.5, 170.9, 147.6, 145.1, 144.7, 133.2, 130.9, 130.6, 128.4, 124.2, 62.7, 62.6, 53.7, 50.8, 38.4, 30.1, 25.0, 22.2, 14.7.

Example 72 Synthesis of N- (toluene-4-sulphonyl) ethyl ester L-prolyl-L-4- (2-methoxybenzamido) phenylalanine The title compound was prepared following the procedure outlined for the preparation of Example 36. £ ^ - flt ^ f ^^^^ J - ^^ > J ", - ..," ..... i The NMR data were as follows: XH NMR (CDCI3): d = 9.81 (s, ÍH), 8.27 (d, ÍH), 7.71 (d, 2H) , 7.60 (d, 2H, J = 7.49 (t, ÍH), 7.37-7.28 (m, 3H), 7.18-7.10 (m, 3H), 7.03 (d, ÍH), 4.82 (m, 2H), 4.22 ( q, 2H), 4.10-4.04 (m, 4H), 3.40 (m, ÍH), 3.30-3.02 (m, 3H), 2.42 (s, 3H), 2.03 (m, ÍH), 1.53 (m, 3H) 1.30 (t, 3H). 13 C NMR (CDCl 3): d = 171.4, 163.7, 157.8, 144.9, 137.9, 133.9, 133.6, 131.1, 132.4, 130.5, 128.5, 122.3, 120.9, 112.1, 62.9, 62.3, 56.8, 54.1, 50.3, 38.0, 30.5, 24.9, 22.2, 14.7.

Example 73 Synthesis of ethyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L- (4-nitro) phenylalanine The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: XH NMR (CDCl 3): d = 8.12 (d, 2H), 7.73 (d, 2H), 7.42 (d, 2H), 7.34 (d, 2H), 7.12 (d, ÍH), 4.92 (m, ÍH), 4.57 (d, ÍH), 4.33 (d, ÍH), 4.20 (q, 2H), 3. 83 (s, ÍH), 3.33-3.15 (m, 2H), 2.43 (s, 3H), 1.25 (t, 3H), 1.11 (s, 3H), 1.01 (s, 3H). 13 C NMR (CDCl 3): d = 170.8, 169.3, 147.6, 145. 5, 144.7, 133.0, 131.1, 130.6, 128.6, 124.2, 74. 0, 62.6, 54.9, 53.6, 51.0, 38.8, 29.8, 24.5, 22.2, 14.7.

Example 74 Synthesis of N- (toluene-4-sulfonyl) L-prolyl-L-4- (2-bromobenzamido) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: 1 Ti NMR (CDCl 3): d = 7.78 (s, ÍH), 7.70 (d, 2H), 7.65- 7.55 (m, 4H), 7.42-7.29 (m, 5H), 7.16 (d, 2H), 4.81 (m, ÍH), 4.23 (q, 2H), 4.06 (m, ÍH), 3.43- 3.00 (m, 4H), 2.43 (s, 3H), 2.08-1.99 (m, ÍH), 1.60 - 1.45 (m, 3H), 1.30 (t, 3H). 13 C NMR (CDCl 3): d = 171.5, 171.3, 166.1, 144.9, 138.3, 137.1, 134.1, 133.5, 133.3, 132.2, 130. 6, 130.5, 130.3, 128.5, 128.3, 120.6, 119.8, 62. 9, 62.3, 51.0, 50.3, 38.0, 30.4, 24.9, 22.2, 14. 7 aate8a &yyyy. & iai-i Example 75 Synthesis of ethyl ester of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -t i amor fi 1-L- -aminophenylalanine The title compound was prepared following the procedure outlined for the preparation of Example 38. The NMR data were as follows: 13 C NMR (CDC13): d = 7.74 (d, 2Hi 7.33 (d, 2H), 6.96 (m, 3H), 6.59 (d, 2H), 4.81 (m, ÍH), 4.53 (d, ÍH), 4.38 (d, ÍH), 4.19 (q, 2H), 3.85 (s, ÍH), 3. 61 (br s, 2H), 2.98 (m, 2H), 2.44 (s, 3H), 1.26 (t, 3H), 1.17 (s, 3H), 1.10 (s, 3H). 13 C NMR (CDC13): d = 171.5, 168.8, 125.9, 145.3, 133.4, 130.9, 130.5, 128.7, 126.3, 115.8, 74.1, 62.1, 55.3, 54.1, 38.2, 29.8, 24.6, 22.2, 14.7.

Example 76 Synthesis of the N- (toluene-4-sulphonyl) -L-prolyl-L-4-acetamidophenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 39.

The NMR data were as follows: NMR - "- H (CDCl 3): d = 7.69 (d, 2H), 7.52 (s, ÍH), 7.42 (d, 2H, J = 7.38-7.30 (m, 3H), 7.09 (d, 2H, J = 4.78 (m, ÍH), 4.21 (q, 2H), 4.04 (m, ÍH), 3.38 (m, ÍH), 3.25-2.97 (m, 3H), 2.43 (s, 3H ), 2.13 (s, 3H), 2.02 (m, ÍH), 1.58-1.44 (m, 3H), 1.28 (t, 3H), 13C NMR (CDCI3): d = 171.4, 169.0, 144.9, 137.6, 133.4, 132.4, 130.6, 130.4, 128.4, 120.4, 62.9, 62.3, 54.0, 50.3, 30.4, 25.2, 24.9, 22.2, 14.7.

Example 77 Synthesis of N- (toluene-sulfonyl) -L-prolyl-L- - (2-methoxybenzamido) phenylalanine The title compound was prepared from the product of Example 72 using the procedure described in Method 7. The NMR data were as follows: 13 C NMR (CD3OD): d = 7.82 (d, ÍH), 7.67 (d, ÍH), 7.51 (d, 2H), 7.41 (d, 2H), 7.31 (t, ÍH), 7.19 (d, 2H), 7.05 (d, 2H), 6.97 (d, ÍH), 6.89 (t, ÍH), 4. 49 (m, HH), 3.91 (m, HH), 3.78 (s, 3H), 3.23-2.83 (m, 3H), 2.21 (s, 3H), 1.68-1.28 (m, 4H).

Example 78 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl-thiaprolyl-L-4-acetamidophenylalanine ethyl ester) The title compound was prepared following the procedure outlined for the preparation of Example 39. The NMR data were as follows: X H NMR (CDC13): d = 7.73 (d, 2H), 7.50 (brs, ÍH), 7.42 ( d, 2H), 7.33 (d, 2H), 7.15 (d, 2H), 7.02 (d, ÍH), 4.84 (m, ÍH), 4.53 (d, ÍH), 4.35 (d, ÍH), 4.18 (q , 2H), 3.84 (s, ÍH), 3.08 (m, 2H), 2.43 (s, 3H), 2.15 (s, 3H), 1.25 (t, 3H), 1.13 (s, 3H), 1.06 (s, 3H). 13 C NMR (CDCl 3): d = 171.3, 169.1, 163.0, 145.4, 137.6, 133.3, 1 ° 32.4, 130.6, 128.7, 120.4, 112.0, 74.1, 62.3, 55.1, 54.0, 41.1, 38.4, 29.8, 25.2, 24.5, 22.2, 14.7. twenty emaM ^? ^ ^^ k > ^ Example 79 Synthesis of N- (toluene-4-sulfonyl) -L- (5, 5-d? Metyl-t-iaprolyl-L-4-acetamido phenylalanine The title compound was prepared from the product of Example 78 using the procedure described in Method 7. The NMR data were as follows: 13C NMR (CDC13): d = 8.19 (s, ÍH), 7.73 (d, 2H ), 7.40 (d, 2H), 7.32 (d, 2H), 7.23 (d, ÍH), 7.15 (d, 2H), 4.86 (m, ÍH), 4.55 (d, ÍH), 4.36 (d, ÍH) , 3.92 (s, ÍH), 3.10 (m, 2H), 2.42 (s, 3H), 2.10 (s, 3H), 1.19, (s, 3H), 1.07 (s, 3H).

Example 80 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4-acetamidophenylalanine isopropyl ester The title compound was prepared following the procedure outlined for the preparation of Example 39. The NMR data were as follows: 1H-NMR (CDCl 3): d = 7.70 (d, 2H), 7.42 (d, 2H), 7.33 (d , 2H), 7.10 (d, 2H), 5.11-5.03 (m, ÍH), 4.80-4.73 (m, ÍH), 4.06 (dd, ÍH), 3.41-3.36 (m, ÍH), 3.20 (dd, ÍH) ), 3.12-3.09 (m, ÍH), 3.02 (dd, ÍH), 2.44 (s, 3H), 2.15 (s, 3H), 2.05-2.01 (m, ÍH), 1.58-1.44 (m, 3H), 1.27 (d, 3H). 13 C NMR (CDC13): d = 170.7, 170.2, 168.3, 144.3, 136.9, 132.9, 131.9, 129.9, 129.9, 127.8, 119.7, 69.5, 62.3, 53.5, 49.7, 37.3, 29.8, 24.6, 24.2, 21.7, 21.7, 21.6.

Example 81 Synthesis of N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) -L-4- (isonicotinamido) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: NMR? H (CDCl 3): d = 8.75 (d, 2H), 8.27 (s, ÍH), 7.74- 7.68 (m, 4H), 7.59 (d, 2H), 7.33 (d, 2H, J = 7.22 (d, 2H, J = 7.08 (d, ÍH, J = 4.86 (m, ÍH), 4.54 (d, ÍH ), 4.34 (d, ÍH), 4.18 (q, 2H), 3.84 (s, ÍH), 3.18-3.03 (m, 2H), 2.43 (s, 3H), 1.26 (t, 3H), Io.26 ( t, 3H), 1.15 (s, 3H), 1.04 (s, 3H), 13C NMR (CDCI3): d = 171.1, 169.1, 164.3, 151.2, 145.4, 142.6, 137.0, 133.4, 133.2, 130.8, 130.6, 128.6 , 121.6, 121.0, 74.1, 62.4, 55.1, 54.0, 51.1, 38.4, 29.8, 24.6, 22.2, 14.7.

Example 82 Synthesis of ethyl N- (toluene-4-sulfonyl) -L-prolyl-L-4- (isonicotinamido) phenylalan The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: 1H NMR (CDC13): d = 8.76 (d, 2H), 8.34 (s, ÍH), 7.72 ( d, 2H), 7.68 (d, 2H), 7.59 (d, 2H), 7.40 (d, ÍH), 7.32 (d, 2H), 7.16 (d, 2H), 4.80 (m, ÍH), 5 4.21 (d, q, 2H), 4.04 (m, ÍH), 3.40 (m, ÍH), 3.28-3.02 (m, 3H), 2.43 (s, 3H), 2.03 (m, ÍH), 1.60-1.42 (m, 3H) , 1.29 (t, 3H). 13 C NMR (CDCl 3): d = 171.4, 171.3, 164.3, 151.2, 145.0, 142.6, 137.0, 133.5, 133.4, 130.6, 0 130.6, 128.4, 121.6, 121.0 62.9, 62.3, 54.1, 52.3, 38.0, 30.3, 24.9, 22.2, 14.7. «* - * - - ^ ffia ^ WffX- ^ XX1 ^ - ^^^ ¡g ^ ü Example 83 Synthesis of the N- (toluene-4-sulfonyl) -L-prolyl-L- (p-toluene-) methyl ester 4-sulfonyl) histidine The methyl ester of L-prolyl-L-histidine was treated with CH3S0 C1 and Et3N in CH2C12 to give the title compound. The NMR data were as follows: 1 H NMR (CDC13): d = 7.93 (s, ÍH), 7.81 (d, 2H), 7.77 (d, ÍH), 7.73 (d, 2H), 7.34 (d, 4H) , 7.09 (s, 1H), 4.82 (m, ÍH), 4.76-4.09 (dd, ÍH), 3.68 (s, 3H), 3.51-3.44 (m, ÍH), 3.18-3.08 (m, 3H), 2.45 (s, 3H), 2.41 (s, 3H), 2.10-2.05 (m, ÍH), 1.68-1.53 (m, 3H). 13 C NMR (CDCI3): d = 171.1, 171.0 146.2, 144.2, 140.0, 136.5, 134.8, 133.2, 130.4, 129.9, 127.8, 127.4, 114.8, 62.2, 52.5, 51.9, 49.5, 30.1, 29.9, 24.3, 21.7, 21.6 .

Example 84 Synthesis of N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4- (nicot inamido) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: X H NMR (CDC13): d = 9.06 (s, ÍH), 8.76 (d, ÍH), 8.22 ( d, ÍH), 8.14 (s, ÍH), 7.73 (d, 2H), 7.59 (d, 2H), 7.45 (t, ÍH), 7.33 (d, 2H), 7.23 (d, 2H), 7.18 (d , ÍH), 4.86 (m, ÍH), 4.52 (d, ÍH), 4.34 (d, ÍH), 4.20 (q, 2H), 3.06-2.20 (m, 2H), 2.43 (s, 3H), 1.27 (t, 3H), 1.20 (s, 3H), 1.08 (s, 3H),. 13 C NMR (CDCl 3): d = 1781.3, 169.1, 152.9, 148.4, 145.4, 137.1, 136.1, 133.4, 130.8, 130.6, 128.7, 124.3, 120.9, 74.1, 62.3, 55.1, 54.0, 51.1, 38.7, 29.8, 24.6, 22.3, 14.7. twenty iZüsf ^.

Example 85 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L- (O-methyl) tyrosine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: 1H-NMR (CDC13): d = 7.71 (d, 2H), 7.32 (m, 3H), 7.06 (d , 2H, J = 6.80 (d, 2H), 4.77 (m, ÍH), 4. 21 (q, ÍH), 4.18-4.06 (m, ÍH), 3.77 (s, 3H), 3.37- 3.34 (m, ÍH), 3.20-3.09 (m, 2H), 3.00 (dd, 3H), 2.43 (s, 3H), 1.55-1.46 (m, 3H), 1.28 (t, 3H). 13 C NMR (CDCl 3): d = 171.5, 171.3, 159.2, 144.9, 133.6, 130.9, 130.5, 128.7, 128.4, 114.4, 62.8, 62.2, 55.8, 54.1, 50.2, 37.7, 30.3, 24.8, 22.3, 14.7. Example 86 Synthesis of N- (α-toluenesulfonyl) -L-prolyl-L-4- (isonicotinamido) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: 1N-NMR (CDCl 3): d = 8.72 (d, 2H), 8.45 (s, ÍH), 7.69 (d, 2H), 7.55 (d, 2H), 7.45-7.30 (m, 5H), 7.13 (d, 2H) ), 6.99 (d, ÍH), 4.78 (m, ÍH), 4.28 (s, 2H), 4.18 (q, 2H), 4.02 (m, ÍH), 3.23-2.98 (m, 4H), 2.10-1.62 ( m, 4H), 1.27 (t, 3H). 13 C NMR (CDCl 3): d = 171.6, 174.5, 164.4, 151.1, 142.6, 137.1, 133.3, 131.4, 130.6, 129.5, 129.4, 129.0, 121.6, 121.1, 62.9, 62.4, 57.3, 53.9, 50.1, 37.9, 31.0, 25.5 , 14.7.

Example 87 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-bromobenzamido) phenylalanine The title compound was prepared from the product of Example 74 using the procedure described in Method 7. The NMR data were as follows: XH NMR (CDCl 3): d = 8.01 (brd, ÍH), 7.75-7.58 (m , 4H), 7.50-7.33 (m, 4H), 7.24 (d, 2H), 4.70 (m, ÍH), 3.50-3.00 (m, 5H), 2.43 (s, 3H), 1.85-1.48 (m, 4H ). 8BhtM &tt¿ ^ & < ^^ - rih ^ - ^ ML, ...- aa.

Example 88 Synthesis of N- (a-toluenesulfonyl) -L-prolyl-L-4 - (isonicotinamido) phenylalanine The title compound was prepared from the product of Example 86 using the procedure described in Method 7. The NMR data were as follows: 1H NMR (D20): d = 8.45 (d, 2H), 7.50 (d, 2H ), 7.26 (d, 2H), 7.18 (s, 5H), 7.05 (d, 2H), 4.29 (m, ÍH), 4.10 (m, 2H), 3.83 (m, ÍH), 3.20-2.97 (m, 3H), 2.76 (m, ÍH), 1.94 (m, ÍH), 1.70-1.43 (m, 3H).

Example 89 Synthesis of the N- (toluene-4-sulphonyl) -L- (1, 1-dioxo) t-morpholyl 1-L- (2-bromobenzamido)) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36 and the procedure described by Larsson et al., Ac ta Ch emi ca Sea n. , 1994, 48, 522. The NMR data were as follows: 1 H NMR (CDCl 3): d = 8.19 (d, ÍH), 7.70 (d, ÍH), 7.61-7.50 (m, 5H), 7.36-7.23 (m, 3H), 7.09- 7.094 (m, 2H), 6.84 (d, 1 / 2H), 6.74 (d, 1 / 2H), 5.10 (d, 1 / 2H), 4.97 (d, 1 / 2H), 4.81 (m, 1 / 2H), 4.66 (m, 1 / 2H), 4.14 (m, 3H), 3.87 (m, ÍH), 3.23-3.74 (m, 6H), 2.41 (s, 3H), 1.22 (t, 3H). 13 C NMR (CDCl 3) d = 170.9, 170.7, 166.0, 165.8, 165.1, 164.8, 145.76, 145.5, 137.9, 136.9, 136.7, 1351, 135.0, 135.0, 133.4, 132.0, 131.9, 131.5, 130.7, 130.6, 130.0, 130.1, 129.5, 129.4, 127.6, 127.4, 127.2, 120.7, 120.2, 61.8, 55.9, 55.8, 53.5, 53.3, 49.3, 49.2, 48.2, 48.6, 41.8, 41.7, 48.7 , 36.3, 21.5, 13.9.

Example 90 Synthesis of N- (toluene-4-sulfonyl) -L- (1, 1- dioxo) t-morpholyl-L-4 - (2-bromobenzamido) phenylalanine The title compound was prepared from the product of Example 89 using the procedure described in Method 7. The NMR data were as follows: 1 H NMR (CDCl 3): d = 8.12 (d, 0.5H), 7.97 ( d, 0.5H), 7.76-7.59 (m, 5.5H), 7.60-7.18 Ad7- CAT5.12 (m, HH), 4.64 (m, HH), 4.07 (m, HH), 3.62 (m, HH), 3.35 (m, 6H), 2.4 Os 32.32-2.14 (m, 3H). 13 C NMR (CD3OD): d = 174.1, 169.7, 169.6, 169.2, 169.1, 146.4, 146.2, 140.3, 140.3, 138.7, 138.6, 137.4, 137.2, 134.9, 134.6, 134.3, 132.5, 131. 6, 131.5, 131.2, 131.1, 130.09, 129.9, 128.9, 128. 7, 128.6, 122.1, 121.8, 120.6, 56.9, 56.8, 54.9, 54.5, 50.8, 50.3, 40.8, 10.4, 37.8, 37.4, 21.6.

Example 91 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl-L-4- (isonicotinamido) phenylalanine The title compound was prepared from the product of Example 81 using the procedure described in Method 7. The physical data were as follows: p.f. > 200 ° C; MS (FAB +) 583 (M + H).

Example 92 Synthesis of the N- (a-toluensul fonyl) -L-prolyl-L-4- (2-bromobenzamido) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: NMR - H (CDC13): d = 7.37 (s, ÍH), 7.68-7.30 10 (m, 11H), 7.16 (d, 2H), 6.93 (d, 2H), 4.83 (m, ÍH), 4.32 (s, 2H), 4.23 (q, 2H), 4.10 (m, ÍH), 3.27-3.03 (m , 5H), 2.10-1.62 (m, 4H), 1.29 (t, 3H). 13 C NMR (CDCl 3): d = 166.7, 161.2, 133.4, 132.2, 129.2, 128.1, 127.3, 126.4, 125.7, 125.4, 125.6, 124.5, 124.1, 123.4, 115.7, 114.9, 57.8, 57.3, 55.9, 52.4, 48.7, 45.1, 32.8, 26.0, 20.4, 9.6.

Example 93 Synthesis of N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine isopropyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: £ &? £ 3!? »_ £ sJL & NMR ** H (CDCl 3): d = 7.73 (d, 2H), 7.33 (d, 2H), 7.10 (br, IH), 7.08 (d, 2H), 6.75 (d, 2H, J = 5.06 (m, ÍH), 4.86 (m, ÍH), 4.54 (d, ÍH, J = 4.33 (d, ÍH, J = 3.84 (s, ÍH), 3.09-2.97 (m, 2H), 2.43 (s, 3H), 1.23 (dd, 6H), 1.05 (s, 3H), 1.02 (s, 3H), 13C NMR (CDCI3): d = 170.6, 169.0, 155. 3,144.9, 132.6, 130.6, 130.0, 128.1, 127.2, 115.4, 73.3, 69.6, 65.8, 54.4, 53.6, 50.3, 37.6, 29.0, 23.5, 21.5, 21.5.

Example 94 Synthesis of N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine tert-butyl ester The title compound was prepared by following the procedure outlined for the preparation of Example 36. The NMR data were as follows: XH NMR (CDCl 3): d = 7.75 (d, 2H), 7.34 (d, 2H), 7.11 (d , 2H), 7.07 (d, ÍH), 6.76 (d, 2H), 6, .6 2 (br s, ÍH), 4.79 (m, ÍH), 4.56 (d, ÍH), 4.35 (d, ÍH), 3.84 (s, ÍH), 3.07-2.96 (m, 2H), 2.45 (s, 3H), 1. 46 (s, 9H), 1.05 (s, 3H), 1.03 (s, 3H). 13 C NMR (CDCl 3): d = 170.1, 168.8, 155.3, 144.9, 132.6, 130.7, 130.0, 128.1, 127.6, 115.3, 82.7, 73.3, 54.5, 54.1, 50.4, 37 29.1 27 23.5, 21.5.

Example 95 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine tert-butyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: XH NMR (CDC13): d = 7.62 (d, 2H), 7.35 (d, ÍH), 7.25 (d , 2H), 6.96 (d, 2H), 6.71 (d, 2H), 4.65 (m, HH), 4.07 (m, HH), 3.30 (m, HH), 3.15-2.83 (m, 3H), 2.35 ( s, 3H), 1.84 (m, ÍH), 1.52-1.34 (m, 13H). 13 C NMR (CDCl 3): d = 171.5, 170.0, 155.8, 144.5, 132.8, 130.4, 130.0, 127.8, 127.1, 115.3, 82.5, 62.2, 54.1, 49.5, 37.0, 29.8, 27.7, 23.9, 21.3, 14.0.

Example 96 Synthesis of the N- (toluene-4-sulphonyl) -L-prolyl-L-4- (2-trifluoromethylbenzamido) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of the Example. The NMR data were as follows: lti NMR (CDC13): d = 7.81 (s, ÍH), 7.50-7.38 (m, 8H), 7.38 (d , 1H), 7.33 (d, 2H), 7.14 (d, 2H), 4.80 (m, ÍH), 4.22 (q, 2H), 4.03 (m, ÍH), 3.37 (m, ÍH), 3.30-3.20 ( m, HH), 3.14-2.98 (m, 2H), 2.43 (s, 3H), 1.95 (m, HH), 1.57-1.40 (m, 3H), 1.30 (t, 3H). 13 C NMR (CDCl 3): d = 171.2, 170.9, 165.8, 144.4, 136.6, 135.7, 132.9, 132.8, 132.2, 130.7, 130.2, 130.0, 130.0, 128.5, 127.9, 126.5, 120.2, 62.1, 61.7, 53.3, 49.6, 37.2, 29.7, 21.4, 13.9.

Example 97 Synthesis of N- (toluene-4-sulphonyl) -L-prolyl-L-4- (2-methylbenzamido) phenylalanine ethyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. "> Aa * a -" - A- * - * H The NMR data were as follows: NMR - "- H (CDCl 3): d = 7.72 (d, 2H), 7.58-7.43 (m, 4H), 7.40-7.20 (m, 7H), 7.15 (d, 2H), 4.82 (m, ÍH), 4.24 (q, 2H), 4.08 (m, ÍH), 3.43 (m, ÍH), 3.29-3.03 (m, 3H), 3.50 (s, 3H), 2.44 (s, 3H), 2.05 (m, ÍH), 1.55 (m, 3H), 1.31 (t, 3H), 13C NMR (CDCI3): d = 170.9, 170.9, 144.4, 137.0, 136.5, 133.0, 132.4, 131.3, 130.3, 130.1, 130.0, 127.9, 126.6, 125.9, 119.8, 62.2, 61.6, 53.4, 49.6, 37.3, 29.6, 24.2, 21.4, 19.7, 14.0.

Example 98 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-L-4 - (2-trifluoromethyl-benzamido) phenylalanine The title compound was prepared from the product of Example 96 using the procedure described in Method 7. The NMR data were as follows: 1 H NMR (CDCl 3): d = 8.28 (s, ÍH), 7.68-7.40 (m , 9H), 7.33 (d, 2H), 7.17 (d, 2H), 4.84 (m, ÍH), 4.05 (m, ÍH), 3.44-3.04 (m, 4H), 2.43 (s, 3H), 1.90 ( , ÍH), 1.49 (m, 3H).

Example 99 Synthesis of N- (4-fluorobenzensul fonyl) -L-thiaprolyl-L-tyrosyl tert-butyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: NMR - * H (CDC13): d = 7.87 (m, 2H), 7.23 (m, 3H), 7.03 (d, 2H), 6.73 (d, 2H), 6.29 (s, ÍH), 74.68 (m, ÍH), 4.56 (m, 2H), 4.10 (d, ÍH), 3.29-2.93 (m, 3H), 2.61 (m, ÍH), 1.49 '(s, 9H). 13 C NMR (CDCl 3): d = 169.9, 168.2, 155.4, 132.5, 130.9, 130.7, 127.3, 117.1, 116.8, 115.4, 82.9, 65.0, 54.1, 51.5, 36.8, 33.3, 27.9.

Example 100 Synthesis of the N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine tert-butyl ester The title compound was prepared following the procedure outlined for the preparation of Example 36. The NMR data were as follows: 1 H NMR (CDCl 3): d = 7.90 (m, 2H), 7.23 (m, 2H), 7.09 (d, 2H), 6.98 (d, ÍH), 6.76 (d, 2H), 4.77 (m, ÍH), 4.55 (d, ÍH, J = 4.37 (d, ÍH), 3.83 (s, ÍH), 3.01 (m, ÍH), 1.44 (s, 9H), 1.10 (s, 3H), 1.05 (s, 3H). 13 C NMR (CDCl 3): d = 170.1, 168.6, 155.3, 132.0, 131.0, 130.8, 127.7, 116.9, 116.6, 115.3, 82.8, 73.4, 54.6, 54.0, 50.4, 37.8, 29.1, 27.8, 23.5.

Example 203 Synthesis of N- (toluene-sulfonyl) -L-prolyl-L-4- (4-nitro-phenoxycarbonyloxy) phenylalanine ethyl ester Under a nitrogen atmosphere, Tos-Pro-Tyr ethyl ester was dissolved in CH2C12 at room temperature, the flask was cooled to 0 ° C and 4-nitrophenylchloroformate was added in one portion. Then, Et3N was slowly added dropwise, it was added at 0 ° C for 30 minutes and it was added at room temperature for 30 minutes. The reaction mixture was again cooled to 0 ° C and N, N-dimethylethanolamine was added dropwise. The ice bath was removed after 10 minutes and the reaction mixture was stirred at room temperature for 3 minutes. í.ife hours The reaction mixture was diluted with Et2? and washed with 10% K2CO3 until all the yellow color disappeared. Flash chromatography (Si02) eluting with 40% EtOAc / hex produced a white foam in 30% yield.

EXAMPLE 204 Synthesis of N- (toluene-4'-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- (2-bromobenzamido) -D-phenylalanine t-butyl ester The ter-butyl ester of (2R) -3- (4-amino-phenyl) -2- acid. { [4R) -5,5-dimethyl-3- (toluene-4-sulfonyl) -thiazolidine-4-carbonyl] -amino} -propionic start (230 mg), 2-bromobenzoic acid (100 mg), and 4-methylmorpholine (0.19 mL) were dissolved in DMF (5 mL) at 0 ° C in an ice bath. BOP (229 mg) was added to the solution. The ice bath was removed after 10 minutes. The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate (20 mL) was added. The mixture was washed with citric acid (5%, 20 mL, 2x) and saturated NaHCO 3 solution (20 mL, 2x), then washed with brine. The solution was dried with MgSO4. The solvent was evaporated in vacuo and the residue was purified using HPLC (inverted phase, 65-95 I CH3OH / water). The retention time was 13 minutes. The desired product was freeze-dried to give 181 mg of a white solid. p.f .: 92-93 ° C.

EXAMPLE 205 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- (2-bromobenzamido) -L-phenylalanine t-butyl ester The ter-butyl ester of the acid ( 2S) -3- (4-amino-phenyl) -2-. { [4R) -5,5-dimethyl-3- (toluene-4-sulphonyl) -thiazolidine-4-carbonyl] -amino} -propionic start (230 mg), 2-bromobenzoic acid (100 mg), and 4-methamorpholine (0.19 ml) were dissolved in DMF (5 ml) at 0 ° C in an ice bath. BOP (229 mg) was added to the solution. The ice bath was removed after 10 minutes. The reaction mixture was stirred at room temperature for 18 hours. HE added ethyl acetate (20 mL). The mixture was washed with citric acid (5%, 20 mL, 2x) and saturated NaHCO 3 solution (20 mL, 2x), then washed with brine. The solution was dried with MgSO4. The solvent was evaporated in vacuo and the residue was purified by HPLC (inverted phase, CH30H at 65.95 %/Water) . The retention time was 13.5 minutes. The desired product was freeze-dried to give 27 mg of the title compound as a white solid. p.f .: 92-93 ° C.

Example 207 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4 - (1-H, 2-oxo-3-methyltetrahydropyridim-din-l-yl) -L-phenylalanine The title compound was prepared by following the corresponding t-butyl ester using the procedure described in Method 11. The NMR data were as follows: XH NMR (CDC13): d = 7.73 (d, 2H), 7.58 (d , ÍH), 7.34 (d, 2H), 7.21 (d, 2H), 7.17 (d, 2H), 4.79 (q, ÍH), 4.15-4.11 (m, ÍH), 3.68-3.63 (m, 2H), 3.48-3.39 (m, 3H), 3.27 (dd, ÍH), 3.17 (dd, ÍH), 3.15-3.07 (m, ÍH), 2.99 (s, 3H), 2.43 (s, 3H), 2.16-2.08 ( m, 2H), 2.00-1.98 (m, ÍH). 13 C NMR (CDCl 3): d = 173.4, 172.2, 164.2, 156.4, 144.4, 142.5, 134.1, 133.0, 130.2, 130.0, 127.9, 126.2, 62. 1, 53.4, 49.5, 48.9, 47.9, 36.5, 35.9, 30.2, 24.2, 22.0, 21.4.

EXAMPLE 212 Synthesis of N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L-3-chloro-4-hydroxyphenin-alanine isopropyl ester The compound was prepared following the procedure described for the preparation of Example 36 employing N- (-f-luorobenzenesulfonyl) -L- (5,5-dimethyl, thiaproline (prepared according to Example 8 and 3-chloro isopropyl ester -L-tyrosine (prepared from commercially available 3-chloro-l, l-irosine and isopropyl alcohol in the presence of anhydrous HCl) MS: (-) ESI [M-H] "557. HPLC: 96.8% Example 214 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- (2-methoxyphenyl) -L-phenylalanine The title compound was prepared from the corresponding t-butyl ester using the procedure described in Method 11. The NMR data were as follows: ^^^ S ^^ J & ? NMR "H (CD3OD): d = 7.70 (m, 2H), 7.36 (m, 4H), 7.22 (m, 4H), 6.98 (m, 2H), 4.75 (m, 1H) ), 4.10 (m, ÍH), 3.71 (s, 3H), 3.29 (m, 2H), 3.11 (m, 2H), 2.39 (s, 3H), 1.75 (m, ÍH), 1.53 (m, 3H) . 13 C NMR (CD3OD): d = 174.4, 174.2, 158.1, 145.9, 138.9, 136.7, 135.1, 131.2, 130.8, 130.2, 129.9, 129.1, 122.0, 112.6, 63.3, 55.9, 54.6, 50.5, 37.9, 31.5, 25.2, 21.4.

Example 215 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4- (2-methoxyphenyl) -L-phenylalanine The title compound was prepared from the corresponding t-butyl ester using the procedure described in Method 11. The NMR data were as follows: 1H NMR (CDC1): d = 8.41 (d, ÍH), 8.21 (s, ÍH), 8.03 (d, ÍH), 7.98 (s, ÍH), 7.74 (d, 2H), 7.39 (d, ÍH), 7.33 (d, 2H), 4.72-4.68 (m, ÍH), 4.17-4.13 (m, ÍH), 3.54-3.34 (m, 3H), 3.20-3.12 (m, ÍH), 2.82 (s, 6H), 2.43 (s, 3H), 2.09-2.04 (m, ÍH), 1.79-1.59 (m, 3H). 13 C NMR (CDCl 3): d = 173.7, 171.8, 154.5, 147.2, 144.4, 137.8, 135.5, 133.2, 130.1, 127.9, £ 2 ^ ¡¿j2 ^^^^ ß 126.4, 6.2, 53.0, 49.5, 38.5, 36.0, 30.3, 24.4, 21.4.

Example 216 N- (toluene-4-sulfonyl) -Ltprolyl-4- (N, N-dimethylsulfamyl) -L-phenylalanine The title compound was prepared from the corresponding t-butyl ester using the procedure described in Method 11. The NMR data were as follows: NMR: H (CDC13): d = 7.71 (d, 2H), 7.58 (d , ÍH), 7.49 (bs, ÍH), 7.34 (d, 2H), 7.16 (d, 2H), 7.12 (d, 2H), 4.90-4.83 (m, ÍH), 4.13-4.09 (m, ÍH), 3.46- 3.40 (m, ÍH), 3.28 (dd, ÍH), 3.15-3.04 (m, 2H), 2.77 (s, 6H), 2.43 (s, 3H), 1.93-1.88 (m, ÍH), 1.54- 1.45 (m, 3H). 13 C NMR (CDCl 3): d = 173.7, 172.0, 144.7, 136.6, 132.6, 132.1, 130.4, 130.2, 127.9, 120.3, 62.2, 53.3, 49.7.38.0, 36.8, 29.9, 24.1, 21.4.

Example 217 Synthesis of N- (toluene-4-sulfonyl) -L-prol i 1 - (NI, Ni, N2 -trimet ilsulfamil) -L-phenylalanine The title compound was prepared from the corresponding t-butyl ester using the procedure described in Method 11. The NMR data were as follows: 1H-NMR (CDC13): d = 7.71 (d, 2H), 7.49 (d, ÍH), 7.35 (d, 4H), 7.24 (d, 2H), 4.89-4.82 (m, ÍH), 4. .10-4.07 (m, ÍH), 3.41-3.31 (m, 2H), 3.22 (s, 3H), 3. 16-3.06 (m, 2H), 2.76 (s, 6H), 2.44 (s, 3H), 1.98- 1.95 (m, ÍH), 1.55-1.38 (m, 3H). 13 C NMR (CDCl 3): d = 173.7, 171.8, 144.6, 141.7, 135.1, 132.7, 130.2, 103.1, 127.9, 126.6, 62.2, 53.2, 49.6, 39.4, 38.2, 36.7, 29.6, 24.1, 21.5.

EXAMPLE 220 Synthesis of N- [4- (3,3-dimethyl-ureido) -benzenesulfonyl] -L-prolyl- (4-hydroxy) -L-phenylalanine isopropyl ester The reaction vessel was flooded with N2, Pd / C was added to the flask and it was moistened with ^ aaess & amp; & s ^.

PrOH. Then, the nitro compound was added to the flask in iso-PrOH in a sphere filled with H20 attached to the flask. N2 was extracted, H2 was added, evacuated, and H2 was added again. The reaction was finished in 2 hours; it was diluted with iso-PrOH and filtered through celite and evaporated to dryness. Flash chromatography (Si02) by diluting with MeOH / CH2Cl2 yielded a white solid at 62% RF yield under separation.

EXAMPLE 225 Synthesis of N- (toluene-4-sulfonyl) -L-prolyl-4 - (N, N-dimethylaminocarbonylmethyl) -L-phenylalanine The title compound was prepared from the product of Example 233 using the procedure described in Method 11. The NMR data were as follows: XH NMR (CD3OD): d = 8.04 (d, ÍH), 7.70 (d, 2H ), 7.40 (d, 2H), 7.20 (m, 4H), 4.99 (bs, ÍH), 4.70 (m, ÍH), 4.10 (m, ÍH), 3.69 (s, 2H), 3.40 (m, ÍH), 3. 20 (m, ÍH), 3.04 (m, 2H), 3.01 (s, 3H), 2.92 (s, 3H), 2.41 (s, 3H), 1.80 (m, ÍH), 1.62 (m, 3H). 13 C NMR (CD3OD): d = 174.2, 174.1, 173.9, 145.8, 136.8, 135.0, 131.2, 131.0, 130.0, 129.1, 63.2, 54.7, 54.6, 50.5, 41.0, 38.3, 37.7, 35.9, 31.6, 25.2, 21.5. * Example 226 Synthesis of N- (1-methylimidazole-4-sulfonyl) -L-prolyl- (4-hydroxyl) -L-phenylalanine isopropyl ester The compound was prepared by coupling BOP of l-methylimidazole-4-sulfonyl-Pro with the Tyr-isopropyl ester. The crude product was purified by flash chromatography (silica, EtOAc: EtOH: Et3N 95: 3: 2) to give a white solid, m.p. = 159-162 ° C, (2.03 g, 65%) MSW ((+) ESI, m / z (%)) 465 (100 [M + H] +).

Example 227 Synthesis of N- (toluene-4'-sulfonyl) -L-prolyl-4- (2,4,5-trioxo-3-phenyltetrahydroimidazol-1-yl) -L-phenylalanine isopropyl ester The compound was prepared by the treatment of the isopropyl ester of N- (toluene-4-sulphonyl) -L-prolyl-4- [(phenyl-ureido) -tetrahydroimidazol-1-yl] -L-phenylalanine with oxalyl chloride in chloride HHg ^^ g methylene. The crude product was purified by flash chromatography (silica, Hex: EtOAc 3: 2) to give a white solid (0.490 g, 49%). MS ((+) ESI, m / z (%)) 647 (15 [M + H] +): 664 (100 [M + NH 4] +.

Example 229 N- (4-Fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-L-3-chloro-4-tert-butoxy-10-phenylalanine tert-butyl ester The compound was prepared according to the procedure described in Example 36. The requisite tert-butyl ester of 3-chloro-0-tert-but-yl-lysosin 15 was prepared from 3-chloro-l, l-irosine and iso-butylene in the presence of an equivalent of sulfuric acid was used without further purification. MS "(+) ESI [M + H]" 629 [M + NH 4] "646. twenty a ^ -sZ * J * ^ - * .. ^^^^^ m, ^. ^ J ^^^ Example 231 Isopropyl ester of N- [2 - (N-2, 10-camphorsultamil) acetyl] -L- 3-chloro-4-hydroxyphenylalanine The above compound was prepared by the following steps: Step 1: Preparation of N- (tert-butoxycarbonylmethyl) -canforsultam. Canforsultam (3 g, 14 mmol) in DMF (25 mol) was mixed with NaH (1.1 equivalent) for 15 minutes, then tert-butyl bromoacetate (2.5 ml) was added and the reaction mixture was stirred overnight. The solvent was evaporated to dryness and the residue was partitioned between aqueous citric acid and EtOAc. The organic layer was washed with aqueous, saturated NaHC03, and water, dried and evaporated to give the ester. (3.5 g).

Step 2: Preparation of N- (carboxymethyl) -canforsultam The ester (3.3 g) was converted to the acid according to Method 17.

MS (-) ESI [M - H] "272 Step 3: Preparation of the isopropyl ester of N- [2- (N-2, 10-canforsultamyl) acetyl-L-3-chloro-3-hydroxyphenylanine.

The title compound was prepared by the amide-binding formation according to the method similar to Example 52. MS: (+) ESI [M + H] +513. HPLC: 99.4% Example 236 Synthesis of N- (4-fluorobenzenesulfonyl) -L-prolyl-4-hydroxy-L-phenylalanine t-butyl ester The compound was prepared using the procedure described in Method 12. The crude product was purified by flash column chromatography (silica, hexane: EtOAc 1: 1) to give the title compound as a white foam (580 mg, 64%) . MS (+) ESI, [M + H] + @ m / z 479 (100%) [M + NH 4] + @ m / z 496.

Example 237 Isopropyl ester synthesis of N- (4-fluorobenzenesulfonyl) -L-proli 1-4-hydroxy-L-phenylalanine The compound was prepared using the procedure described in Method 12. The crude product was purified by flash column chromatography (silica, hexane: EtOAc 1: 1) (380 mg, 43 %). MS (+) ESI, [M + H] + @ m / z 479 ("100%) [M + NH4] + @ m / z 496.

Example 238 Synthesis of N- (l-methylimidazole-4-sulfonyl) -L-prolyl-4-hydroxy-L-phenylalanine tert-butyl ester The compound was prepared by coupling in BOP of 1-methylimide zol-4-sulphyl-Pro with Tyr-t-butyl ester. The crude product was purified by flash chromatography (silica, EtOAc: EtOH: Et3N 95: 3: 2) to give a white solid. (1.21 g, 66%). MS ((+) ESI, m / z (%)) 479 (100 [M + H) +).

BSB ^^^^ X? T? ¡? Example 239 Synthesis of N- (pyridine-3-sulfonyl) -L-proly1-4-hydroxy-L-phenylalanyl t-butyl ester The compound was prepared by coupling with BOP of 3-pyridinesulfonyl-Pro with Tyr-t-butyl ester. The crude product was purified by flash chromatography (silica, EtOAc: EtOH: Et3N 95: 3: 2) to give a pale orange foam. (0.930 g, 95%). MS ((+) ESI, m / z (%)) 476 (100 [M + H] +).

Example 240 Synthesis of N- (toluene-4-sulfonyl) -L-proli 1-4 - (methansul-fonamide) -L-phenylalanine The solution of the methyl ester of 3- (4-methanesulfonylamino-phenyl) -2-. { [1 - (toluene-4-sulfonyl) -pyrrolidine-2-carbonyl] -amino} -propionic (0.250 g, 0.477 mmol) in THF (1.0 mL) was added LiOH IN (955 mL, 0.955 mmol) and the clear solution was stirred at 25 ° C, under nitrogen, for 16 hours. The reaction solution was then eluted with additional water (50 mL) and washed with diethyl ether (25 mL). ^ a ^ a * k &, m ~ ¿¡¡^ mL). The aqueous layer was lyophilized to give a fluffy white solid (0.216 g, 87%). MS (-ESI): 508 [M -1] -.

Example 242 Synthesis of benzyl ester of N- (toluene-4-sulfonyl) -L-prolyl-4- (2, 4, 5-thioxo-3- (3-chlorophenyl) -tetrahydroimidazol-1-yl) L-phenylalanine The compound was prepared by the treatment of the N- (toluene-4-sulfonyl) -L-prolyl-4- [(3-chlorophenyl-ureido) -tetrahydroimidazol-1-yl] -L-phenylalanine isopropyl ester with oxaline chloride in Methylene chloride. The crude product was purified by flash chromatography (silica, Hex: EtOAc 3: 2) to give a white solid. (0.410 g, 50%). MS ((+) ESI, m / z (%) 746 (100 [M + H] +) (746/748 ICI) 20 Certain compounds exemplified above as well as other compounds that can be prepared by the methods described above include those experts in Table IA and IB above.

Example 244 In Vi Vi Test to determine the binding of the candidate compounds for VLA-4 An i n vi t ro assay was used to assess the binding of candidate compounds to cc β? integrin. The compounds that bind in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays (eg, competitive binding assays). This assay is sensitive to IC50 values as low as approximately InM. The activity of a4ß? integrin was measured by the interaction of soluble VCAM-1 with Jurkat cells (e.g., American Species Cultivation Collection Nos. TIB 152, TIB 153, and CRL 8163), a line of human T cells expressing high levels of H.H? integrin. VCAM-1 interacts with the cell surface in a manner dependent on a4β? integrin (Yednock, et al., J. Biol. Chem., 1995, 270: 28740). Soluble, recombinant VCAM-1 was expressed as a chimeric fusion protein containing seven extracellular domains of VCAM-1 in the N-terminus and the constant-chain constant region of human IgGi in the C-terminus. The VCAM-1 fusion protein was made and purified by the manner described by Yednock, supra. Jurkat cells were cultured in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutamine as described by Yednock, supra. Jurkat cells were incubated with 1.5 mM MnCl2 and 5 μg / mL of a 15/7 antibody for 30 minutes on ice. Mn + 2 activates the receptor to improve ligand binding, and 15/7 is a monoclonal antibody that recognizes a ligand-activated / activated conformation of a4β? integrin and ensures the molecule in this conformation, thus stabilizing the interaction of VCAM-l / a4ß? integrin. Yednock, et. al., upra. Antibodies similar to antibody 15/7 have been prepared by other investigators. (Luque et al., 1996, J. Biol. Chem, 271: 11067) and can be used in this assay. The cells were then incubated for 30 minutes at room temperature with the candidate compounds, in various concentrations ranging from 66 μM to 0.01 μM using a normal 5-dot serial dilution. The soluble recombinant VCAM-1 fusion protein, 15 μL, was then added to the Jurkat cells and incubated for 30 minutes on ice (Yednock et al., S upra). The cells were then washed twice and redispersed in Fc-anti-mouse IgG, goat F (ab ') 2, conjugated with PE (Immunotech, Westbrook, ME) at 1: 200 and incubated on ice, in the darkness, for 30 minutes. The cells were washed twice and analyzed with normal fluorescence activated cell sorter analysis ("FACS") as described in Yednock, et. al , upra. Compounds having an IC 50 of less than about 15 μM have binding affinity to a 4 β - When tested in this assay, each of the compounds in Examples 1-78 has IC 50 of 15 μM or less.

Example 245 In Vitro Saturation Test To Determine The Union Of The Candidate Compounds to a4J? .

The following describes an m vi tro assay to determine the plasma levels needed for a compound to be active in the experimental autoimmune encephalomyelitis model.

("EAE") described in the next example, or in other live models. Jurkat cells cultured with log were washed and redispersed in normal animal plasma containing 20 μg / ml of antibody 15/7 (described in the previous example). Jurkat cells were diluted twice in either normal plasma sample containing known amounts of the candidate compound in various concentrations ranging from 66 μM to 0.01 μM, using a standard 12-point serial dilution for a standard curve, or samples of plasma obtained from the peripheral blood of the animals treated with the candidate compound. Then, the cells are incubated for 30 minutes at room temperature, washed twice with phosphate-buffered saline ("PBS") containing 2% fetal bovine serum and 1 mM each of calcium chloride and magnesium chloride ( assay medium) to remove the unbound 15/7 antibody. The cells were then exposed to the anti-mouse IgG F, goat F (ab ') 2 conjugated with phycoerythrin (Immunotech, Westbrook, ME) which has been absorbed for any nonspecific cross-reactivity by co-incubation with serum 5. % from animal species being studied, to 1: 200 and incubated in the dark at 4 ° C for 30 minutes. The cells were washed twice with the test medium and redispersed therein. They were then analyzed with a normal fluorescence activated cell sorter ("FACS") analysis as described in Yednock et al., J. Biol. Chem., 1995, 270: 28740. The data were then plotted as fluorescence against dose, for example, in a normal dose response manner. The dose levels that result in the upper plateau of the curve represent the levels needed in an essence in a live model. This assay can also be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as 9β? integrin, which is the integrin most closely integrated to a9β? (Palmer et al, 1993, J. Cell Bio, 123, 1289). This binding is predictive of in vivo utility for inflammatory conditions mediated by otgßi integrin, including by way of example, hypersensitivity of airways and occlusion that occurs with chronic asthma, proliferation of smooth muscle cells in atherosclerosis , vascular occlusion after angioplasty, fibrosis and glomerular scarring as a result of kidney disease, aortic stenosis, hypertrophy of the smovial membranes in rheumatoid arthritis, and inflammation and scarring that occurs with the progress of ulcerative colitis in Crohn's disease . Accordingly, the assay described above can be performed with a human colon carcinoma cell line, SW 480 (ATTC # CCL228) transfected with cDNA encoding a9 integrin (Yokosaki et al., 1994, J. Biol. Chem,., 269: 26691), instead of Jurkat cells to measure the binding of a9β? integrin. As a control, SW 480 cells expressing other sub units a and ßi can be used. Using a conventional oral formulation, the compounds of this invention will be active in this model.

? ^ O - *? § & < %. -? ü ^ e .. * ^. Mjá ± jt & a + ^? Example 246 In Vi Vo Evaluation The normal multiple sclerosis model, experimental autoimmune (or allergic) encephalomyelitis ("EAE") is used to determine the effect of candidate compounds to reduce motor deterioration in rats or guinea pigs. The reduction in motor deterioration in blocking the adhesion between the leukocytes and the endothelium is related to the anti-inflammatory activity in the candidate compound. This model has been previously described by Keszthelyi et al., Neurology, 1996, 47: 1053-1059, and measures the delay of onset of the disease. The brains and spinal cords of the adult Hartley guinea pigs were homogenized in an equal volume of phosphate buffered saline. An equal volume of complete Freund's adjuvant (100 mg of my cobac t er i um t ubercu l s s plus 100 mL of Freund's complete adjuvant) was added to the homogenate. The mixture was emulsified by circulating it rapidly through a 20 ml syringe with a peristaltic pump for approximately 20 minutes.

Female Lewis rats (2-3 months of age, 170-220 g) or Hartley guinea pigs (20 days of age, 180-200 g) were anesthetized with isoflurane and three injections of the emulsion, 0.1 ml each, were made in each flask. The onset of motor deterioration is seen in approximately 9 days. Treatment with the candidate compounds started on day 8, just before the onset of symptoms. The compounds were administered subcutaneously ("SC"), orally ("PO") or intraperitoneally ("IP"). Doses were given in a range of 10 mg / kg to 200 mg / kg, bid, for five days, with the typical dose of 10 to 100 mg / kg SC, 10 to 50 mg / kg PO, and 10 to 100 mg / kg IP. The antibody GG5 / 3 against 4β? integrin (Keszthelyi et al., Neurology, 1996, 47: 1053-1059), which delays the onset of symptoms, is used as the positive control and injected subcutaneously at 3 mg / kg on day 8 and 11. They are measured daily body weight motor deterioration. The motor deterioration is classified with the following clinical score: o no c 10 1 debilid * »® or paralysis of the tail 2 weakness of the hind limbs paralysis of the dying or dead hind limbs A candidate compound is considered active if it delays the onset of symptoms, for example, it produces clinical scores no greater than 2 or slows down the loss of body weight compared to control. When tested in this in vivo assay, the compounds of Examples 10 and 27 were active.

Example 247 In vivo Evaluation - Asthma Inflammatory conditions mediated by a4β? integrin includes, for example, hypersensitivity of the airways and occlusion e ** ^ í s ^^ '- Sfe? É what happens with chronic asthma. The following describes an asthma model that can be used to study the in vivo effects of the compounds of this invention for the use of asthma treatment. Next, the procedures described by Abraham et al, J. Clin. Invest, 93: 776-787 (1994) and Abraham et al, Am J. Respir Crit Care Med, 156: 696-703 (1997), both of which are incorporated by reference in their entirety, The compounds of this invention are formulated in an aerosol and administered to sheep that are hypersensitive to the antigen As ca ri s s u um. Compounds that decrease the bronchial response induced by the early antigen and / or block the response of late phase airways, for example, have a protective effect against late responses induced by antigen and airway hypersensitivity ("AHR"), are considered to be active in this model. 20 Allergic sheep shown to develop both early and late bronchial responses upon inhaling the antigen As ca ri s s u um are used to study the effects on the airways of the candidate compounds. After anesthesia topical nasal passages of lidocaine at 2%, X? *? * Za ^ tui iá? ZM aMBH-Bfc »*» * ^ advanced a balloon catheter through a nostril into the lower esophagus, animals were then intubated with a widened endotrachial tube, through of the other nostril with a fiber optic bronchoscope, flexible as a guide. Pleural pressure was estimated, according to Abraham (1994). Aerosols were generated (see later formulation) using a disposable medical nebulizer that provides an aerosol with an average aerodynamic diameter of a mass of 3.2 μm as determined with an Andersen cascade impactor. The nebulizer is connected to a dosing system consisting of a solenoid valve and a compressed air source (20 psi). The outlet of the nebulizer is directed towards a plastic part T, one end of which is connected to the inspiration hole of a piston respirator. The solenoid valve is activated for one second at the beginning of the respirator inspiration cycle. The aerosols are distributed to Vt of 500 ml and a speed of 20 breaths / minute. It is also used as a control, a 0.5% sodium bicarbonate solution. & A ^ -a ^ »-.- ^ * - ^ - ^ ..

To assess the bronchial sensitivity, response curves to the cumulative concentration of carbachol can be generated according to Abraham (1994). Bronchial biopsies can be taken before and after the start of treatment and 24 hours after stimulation with the antigen. Bronchial biopsies can be performed according to Abraham (1994). A study of adhesion in vitro to alveolar macrophages can be performed according to Abraham (1994), and a percentage of adherent cells is calculated.

Aerosol Formulation A solution of the candidate compound in 0.5% sodium bicarbonate / saline (w / v) at a concentration of 30.0 mg / mL is prepared using the following procedure: A. Preparation of 0.5% sodium bicarbonate / saline. Concentrated solution: 100.0 mL.

Ingredient Grams / 100. O mL Final Concentration Bicarbonate 0.5 g 0.5% Sodium Saline Solution c.s. c.s.100.0 ml c.s.100% Process 1. Add 0.5 g of sodium bicarbonate in a 100 mL volumetric flask. 2. Additional approximately 90.0 mL of saline and try to consume it until it dissolves. 3. C.S. to 100.0 mL with saline and mix thoroughly.

B. Preparation of 30.0 mg / mL of candidate compound: 10.0 mL ..

Ingredient Grams / 10.0 mL Final Compound Concentration 0.300 g 30.0 mg / mL candidate Bicarbonate c.s. 10.0 ml c.s. 100% sodium 0.5% / concentrated saline solution Process 1. Add 0.300 g. of the candidate compound in a 10.0 mL volumetric flask. 2. Add 9.7 mL of 0.5% sodium bicarbonate / concentrated saline solution. 3. Treat with sound until the candidate compound dissolves completely. 4. C.S. at 10.0 mL with 0.5% sodium bicarbonate / concentrated saline solution, and mix thoroughly.

Using a conventional oral formulation, the compounds of this invention will be active in this model. It is noted that in relation to this date the best known method for the applicant to carry out the present invention is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property:

Claims (26)

1. A compound of the formula I R 3 O 1 R'-SO, -N (R 2) -CQ-CH-C-OH III 5 H R 1 characterized in that: R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, cycloalkyl Substituted, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Substituted cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R1 and R2 together with the other nitrogen attached to R2 and the group S02 attached to R1 can form A substituted heterocyclic or heterocyclic ring; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, aryl acsfe ^ - a & a: -f- ^ M- substituted, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and wherein R 2 and R 3 together with the hydrogen atom attached to R 2 and the carbon atom attached to R 3 can form a heterocyclic group saturated by a substituted heterocyclic group, saturated with the proviso that when monosubstituted, the substituent on the substituted, saturated heterocyclic group is not carboxyl; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl; x is an integer from 1 to 4; Q is -C (X) NR7, wherein R7 is selected from the group consisting of hydrogen and Alkyl; X is selected from the group consisting of oxygen and sulfur; R5 is -CH2X, wherein X is selected from the group consisting of hydrogen, Hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, substituted alkylcarboxyl, carboxyl-cycloalkyl, substituted cycloalkyl-carboxyl, carboxylaryl, substituted aryl-carboxyl, carboxylheteroaryl, 25 heteroaryl-substituted carboxyl, carboxylheterocyclic, substituted heterocyclic with carboxyl, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic; with the proviso that: A. R5 is not selected from the group consisting of - (CH2) n-aryl and - (CH2) n-heteroaryl wherein n is an integer equal to 1 to 4 wherein R2 and R3 together with a nitrogen atom attached to R2 and the carbon atom attached to R3 form a saturated heterocyclic group or a substituted, saturated heterocyclic group; B. R5 is not - (CH2) X-Ar-R5 wherein R5 is selected from the group consisting of -OZ- NR8R8 'and -OZ-R12, where Ar is aryl, heteroaryl, substituted aryl or heteroaryl substituted, x is an integer from 1 to 4, R8 and R8 'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, and wherein R8 and R8 'join to form a heterocycle or a substituted heterocycle, R12 is selected to | f | B ^ aa ^ - «rt« £ ^^. ^. jriMja ^ - ^ a ^ w = ^ if-. -Ba * AaaA ^ aa »faaMfc. from the group consisting of heterocycles and substituted heterocycles, and Z is selected from the group consisting of -C (0) - and -S02-; Ar is aryl, heteroanl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; C. R5 is not - (CH2) X-Ar-R5 ', wherein R5' is selected from the group consisting of NR24C (Z ') NR8R8' and -NR24C (Z ') R13 where Z' is selected from the group consisting of oxygen, sulfur and NR24, R24 is selected from hydrogen, alkyl and aryl, R8 and R8 'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl substituted cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl with the proviso that when Z 'is oxygen, at least one of R8 and R8' is substituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic different from morpholino and thiomorphol, substituted heterocyclic or R8 and R8 'are joined to form a saturated heterocyclic other than morpholino or thiomorpholino, a substituted, saturated heterocycle or a 38O heterocycle saturated / unsaturated having an amino group substituted with an alkoxycarbonyl substituent, and with the additional proviso that Z 'is sulfur, at least one of R8 and R8' is a different group of aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R13 is selected from the group consisting of substituted heterocycles and saturated heterocycles other than morpholino and thiomorpholino; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; D. R5 is not -ALK-X, wherein ALK is an alkyl group of 1 to 10 carbon atoms attached via a methylene group - (CH2-) the carbon atom to which it is 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, substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl, substituted cycloalkyl, substituted cycloalkyl, substituted heterocyclic, saturated, substituted heterocyclic, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted heterocyclyloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, guanidino, amidino, alkylamidoino, thioamidino, halogen, cyano, nitro, -OS (O) 2 -alkyl, -OS (0) 2- substituted alkyl, -OS (O) 2-cycloalkyl, -OS (0) 2-substituted cycloalkyl, -OS (O) 2-aryl, -OS (0) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (0) 2- substituted heteroaryl, -OS (O) 2-heterocyclic, OS (O) 2-substituted heterocyclic, -OSO2-NRR where R is hydrogen or alkyl, -NRS (O) 2-alkyl, -NRS (0) 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 (0) 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-cycloalkyl M ^^^ g ^^ gjljggig? ^ G ^^^^^^^^^^^^^ substituted, -NRS (0) 2-NR-aryl, -NRS (O) -NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR- substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic where R is 5 hydrogen or alkyl, -S (0) 2 -alkyl, -S (0) 2 -substituted alkyl, -S (0) 2 -arylo, -S (0) 2 -substituted aryl, -S (0) 2 -heteroaryl, -S (0) 2-substituted heteroaryl, -S (0) 2-heterocyclic, -S (0> 2-substituted heterocyclic, mono- and di- (substituted alkyl) amino, 10 N, N- (alkyl, alkyl substituted) amino, N, N- (aryl, substi tuted alkyl) amino, N, N- (substituted aryl, substituted alkyl) amino, N, N- (heteroaryl, substi tuted alkyl) amino, N, N- (substituted heteroaryl , substituted alkyl) amino, 15 N, N- (heterocyclic, substituted alkyl) amino, N, N- N, N- (substituted heterocyclic, substi tuted alkyl) amino, mono- and di- (substituted heterocyclic) amino, N, N- (alkyl, heter ocicyclic) amino, N, N- (alkyl, substituted heterocyclic) amino, N, N- (aryl, heterocyclic) amino, N, N- (substituted aryl, heterocyclic) amino, N, N- (aryl, heterocyclic subst ítuido) amino, N, N- (substituted aryl, substi tuted heterocyclic) amino, N, N- (heteroaryl, heterocyclic) amino, N, N- (heteroaryl, substituted heterocyclic) amino, N, N- (heteroaryl) substituted, heterocyclic) amino, and N, N- (substituted heteroaryl, substi tuted heterocyclic) amino; and E. R5 is not - (CH2) X-Ar-R5 'where R5"is a substituent selected from the group consisting of: (a) alkylcarbonylamino substituted with the proviso that at least one of the substituents in the substituted alkyl is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonylamino, aminotiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl , substituted alkylcarboxyl, carboxyl-cycloalkyl, substituted cycloalkylcarboxylic, carboxylaryl, substituted arylcarboxyl, carboxylheteroaryl, substituted heteroarylcarboxyl, carboxylheterocyclic, carboxylheterocyclic substituted, cycloalkyl, substituted cycloalkyl, guanidino, guanidino sulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxy carbonylamino, oxythiocarbonylamino, -0S (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, -0S (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, 0S (0) 2-NRR, -NRS (0) 2-alkyl, -NRS (0) 2-alkyl? substituted, -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 alky, -NRS (0) 2-NR-aryl, -NRS (0) 2- NR-ary substituted, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-heterocyclic substituted, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substi tuted aryl) amino, mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-heterocyclic-amino, mono- and di- (heterocyclic substi- tuted) amino, amines tlat "* ajg» .- and »_ J. -. ^^ j -" .. - .- non-asymmetric di-substu tutes having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like), and substituted alkyl / alkyl groups, 10 substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S? 2-cycloalkyl, -S? -2-substituted cycloalkyl, -S? 2 ~ aryl-OS (O) 2-substituted aryl, S02-heteroaryl, -S02-substituted heteroaryl, -S02- heterocyclic, -S02-substituted heterocyclic or S0 NRR, wherein R is hydrogen or alkyl; (b) alkoxyaryl substituted in the alkoxy portion with a substituent selected from the group consisting of carboxyl and -COOR23, wherein R23 is 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 25 of alkyl, substituted alkyl, aryl, aryl substituted, heteroaryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R 'is substituted alkyl, substituted cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the additional proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl portion is selected at Starting from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonylamino, aminotiocarbonylamino, aminocarbonyloxy, aryloxy, Substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted 1-aryl carboxy, carboxylheteroaryl, 20 substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioaryl 25 substituted, thiocycloalkyl, thiocycloalkyl substituted, thioheteroaryl, substituted thioheteroaryl, thioethocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (0) 2- alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2 -heteroaryl, 10 OS (0) 2 -substituted heteroaryl, -0S (0) 2- heterocyclic, -OS (0) 2-substituted heterocyclic, 0S (0) 2-NRR, -OS (0) 2-alkyl, -NRS (0) 2-alkyl? substituted, -NRS (0) 2-aryl, -NRS (0) 2-substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2- 15 substituted heteroaryl, -NRS (0) 2-het eroxy standard, 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- N4-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, twenty - . 20 -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR- heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (substituted subst amino), mono- and di-arylamino, mono- and di- (substi tuted aryl) amino, mono- and di-heteroarylamino, mono- and di- (het eroar ilo) substituted) amino, mono- and di-heterocyclic-amino, mono- and di- (heterocyclic substi tuted) amino, and di-substi tuted and asymmetric amines having different substituents, wherein the substituents are selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl and the like), and alkyl groups / substituted alkyl, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S0-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S? 2? Substituted heteroaryl, -S? 2? Heterocyclic, -S02-substituted heterocyclic or -S02NRR, wherein 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 R "is substituted alkyl then at least one of the substituents on the substituted alkyl portion is selected from the group consisting of 5-alkoxy, acyl, acylamino-thiocarbonylamino, acyloxy, alkenyl, amino, amidino , alkyl-amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxyl-aryl , substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, 15 carboxylheterocyclic, substituted carboxyl-substituted etocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, thiocycloalkyl Substi tude, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryloxy, Heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxitiocarbonylamino, -0S (0) 2 -alkyl, -OS (O) 2-substituted alkyl, -OS (O) 2-arylo, -OS (O) 2 -substituted aryl, -OS (O 2-heteroaryl, OS (O) 2 -substituted heteroaryl, -OS (0) 2 -heterocyclic, -OS (O) 2 -substituted heterocyclic, OS02-NRR, -NRS (O) 2-alkyl, -NRS (O) 2-substituted alky, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2- heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic, NRS (O) 2 -substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (O) 2-NR -substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (O) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (O) 2-NR-substituted heteroaryl , -NRS (0) 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- (substi- tuted aryl) amino, mono- and di-heteroarylamino, mono- and di- (heteroaryl substi- tuted) amino, mono- and di-heterocyclic-amino, mono- and di- (het eroxy) substituate) amino, non-asymmetric di-substuted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero occyclic and heterocyclic Gj ^^^ '& amp & & amp; & amp; amp; Bl ^^ ^ B ¡^^^^ agj ^ ^ Éfeáfc * '<; - ^^ * ^ & m substituted, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl and the like), and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, - S02-alkenyl, -S? 2-alkenyl substituted, -S02-cycloalkyl, -S? 2-substituted cycloalkyl, -S? 2-aryl, -S02-substituted aryl, S? 2-heteroaryl, -S02-heteroaryl substituted, -S02- 10 heterocyclic, -S0 -substituted heterocycle or SO2NRR, where R is hydrogen or alkyl. (f) substituted alkenyl, or substituted alkynyl with the proviso that at least one of the substituents on the alkenyl portion The substituted / alkynyl substituent is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted with the The condition is that when substituted with substituted alkyl, then at least one of the substituents on the substituted alkyl portion is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, 25-tiocarbonylamino, acyloxy, alkenyl, amino, a * Jw »ag ^, ^ - ~ - ^ .t ¿< * «Jd < < Ma «t¡Maa? ^^ * - ^ *. _ ~ AaSte 2sí # tt? U-amidino, alquil-amidino, thioamidino, aminoacilo, aminocarboni lamino, aminot i oca rboni lamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl-alkyl, carboxyl -substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxyl-heteroaryl, substituted carboxylheteroaryl, carboxyl-heterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiocycloalkyl, thioheteroaryl, substi tuted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxitiocarbonylamino, -OS (O) 2-alkyl, -O S (0) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (0) 2 -heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS ( O) 2-heterocyclic, OS (O) 2-substituted heterocyclic, -OS02-NRR, NRS (O) 2-alkyl, -NRS (O) 2-substituted alky, NRS (0) 2-aryl, -NRS (O) 2-substituted aryl, -NRS (0) 2-heteroaryl, -NRS (0) 2 -substituted heteroaryl, NRS (0) 2-heterocyclic, -NRS (0) 2-heterocyclic 5-substituted, -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-NR- heterocyclic, -NRS (0) 2-NR-heterocyclic Substituted, mono- and di-alkylamino, mono- and di- (substi- tuted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-t-eroarylamino, mono - and di- (substi tuted heteroaryl) amino, mono- and di-heterocyclic-amino, Mono- and di- (heterocyclic substi tuted) amino, non-asymmetric di-subsided amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heteroaryl Substituted, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, formyl and the like), and substituted alkyl / alkyl groups, 25 substituted with -S02-alkyl, -S02-alkyl substituted, -S02-alkenyl, -S0 -substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S? 2 -substituted aryl, S02-heteroaryl, -S? 2 -substituted heteroaryl, - S02- 5 heterocyclic, -S02-substituted heterocyclic or S02NRR, where R is hydrogen or alkyl. (g) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on substituted aryloxy / heteroaryloxy is different from halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethi log, 1,2-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (h) saturated-heterocyclic alkoxy, substituted-heterocyclic substituted, saturated, -substituted heterocyclic alkoxy, and substituted substituted-heterocyclic substituted alkoxy; (i) -O-heterocyclic and substituted O-heterocyclic; (j) tetrazolyl; (k) -NR-S02-substituted alkyl wherein R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl portion of the substituted alkylsulfonylamino is different from 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, -dialkylurea; (1) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; (m) substituted alkoxy with the proviso that the substitution in the alkyl portion of the substituted alkoxy does not include alkoxy-NR '' R 'as defined above, unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl, or substituted aryl / heteroaryl with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alchemyl amino, alkynylamino, alkynylcarbonyloxy, acyl, alkylcarbonylamino , alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl 1-urea; (n) 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; (o) -C (0) NR R where each R is 10 independently selects from the group consisting of hydrogen, alkyl, substituted alkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, heteroaryl Substituted, heterocyclic and substituted heterocyclic, with the proviso that when an 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-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonixolo, acyl, alkylcarbonylamino, alkoxycarbonylamino, Alkylsulfonylamino, N-alkyl or N, N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (different from unsaturated heterocyclic-substituted alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, substituted alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic; (p) -NR22C (0) -R18 wherein R18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, Substituted heterocyclic or heterocyclic; (q) -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, or -S02-alkyl; (r) -NR 'C (0) NR19R19 where R' is Is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocycle and each R19 is selected 25 independently from the group consisting ^^ ¡¡^^^^ ¡^^^^^ ^ ^^^^^ S ^^ g ^^ of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocyclic and substituted heterocyclic; (s) -NR'C (0) 0R19 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 R19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (t) -aminocarbonyl- (N-formylheterocyclyl); and (u) -alkyl-C (O) NH-het erocyclyl and -alkyl-C (O) NH-substituted heterocyclyl; and pharmaceutically acceptable salts thereof; and still further with the following conditions that exclude the following compounds: A. when R1 is p-methylphenyl, R2 and R3 together with their pendant nitrogen and carbon atoms ^^ S iii l? I¡¡m form a pyrrole ring idmilo and Q is -C (0) NH-, then R5 is not -CH2COOH or -CH2CH2COOH; and B. when R1 is p-methylphenyl, R2 and R3 together with their pendant nitrogen and carbon atoms form a pyrrolidyl ring and Q is -C (0) NH-, then R5 is not 2, 4, 6-trimethylbenzyl .

2. A compound of the formula: R5 OR I I! R'-SO: -N (R2) -C-Q-CH-C-R6 1A I! H R3 characterized in that: R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; R2 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 R1 and R2 together with the other nitrogen bound to R2 and the group S02 bonded to R1 can form a heterocyclic or substituted heterocyclic ring; R3 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 R2 and R3 together with the hydrogen atom attached to R2 and the carbon atom attached to R3 can form a heterocyclic group saturated by a substituted heterocyclic group, saturated with the proviso that when monosubstituted, the substituent on the substituted, saturated heterocyclic group is not carboxyl; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl; x is an integer from 1 to 4; R6 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-succmimidyl) , -NH-adamantyl, -O-cholest- 5-en 3-ß-il, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl and substituted aryl, -NH (CH2) PCOOY where p is a whole number from 1 to 8 and Y is as defined above, -OCH2NR9R10 where R9 is selected from the group consisting of hydrogen and -CH2COOR11 where R11 is alkyl, and NHS02Z "where Z" is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl , aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; Q is -C (X) NR7, wherein R7 is selected from the group consisting of hydrogen and alkyl; X is selected from the group consisting of oxygen and sulfur; R5 is -CH2X, wherein X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, substituted alkylcarboxyl, carboxyl-cycloalkyl, cycloalkyl-carboxyl substituted, carboxyl-laryl, substituted-aryl-carboxyl, carboxyl-heteroaryl, substituted-heteroaryl-carboxyl, carboxyl-heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic , substituted heterocyclic; with the proviso that: A. R5 is not selected from group 5 consisting of - (CH2) n_aryl and - (CH2) n-heteroaryl wherein n is an integer equal to 1 to 4 wherein R2 and R3 together with a nitrogen atom attached to R 2 and the carbon atom attached to R 3 form a saturated heterocyclic group or a substituted, saturated heterocyclic group; B. R5 is not - (CH2) X-Ar-R5 wherein R5 is selected from the group consisting of -OZ- NR8R8 'and -OZ-R12, where Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl , x is a 15 whole number from 1 to 4, R8 and R8 'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, and Where R8 and R8 'are joined to form a heterocycle or a substituted heterocycle, R12 is selected from the group consisting of heterocycles and substituted heterocycles, and Z is selected from the group consisting of -C (O) - and -SO2-; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; C. R5 is not - (CH2) X-Ar-R5 ', wherein R5' is selected from the group consisting of (Z ') 13 wherein Z' is selected from the group consisting of oxygen, sulfur and NR24, R24 is selected from hydrogen, alkyl and aryl, R8 and R8 'is selected 10 independently from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl 15 with the proviso that when Z 'is oxygen, at least one of R8 and R8' is substituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, substituted heterocyclic or R8 and R8 ' 20 join to form a saturated heterocyclic other than morpholino or thiomorpholino, a substituted, saturated heterocycle or a saturated / unsaturated heterocycle having an amino group substituted with an alkoxycarbonyl substituent, and 25 with the additional condition that Z 'is sulfur, aSatoa »- - ai Élagtaasaa & fcSSfe». except one of R and R is a different group of aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R13 is selected from the group consisting of substituted heterocycles and heterocycles saturated different from morpholino and thiomorpholino; Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; D. R5 is not -ALK-X, wherein ALK is an alkyl group of 1 to 10 carbon atoms attached via a methylene group - (CH2-) the carbon atom to which it is attached; x is selected from the group consisting of substituted alkylcarbonylamino, alkenylcarbonylamino substituted alquiñi read rboni lamino substituted heterocyclylcarbonylamino, heterocyclylcarbonylamino substituted, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, alkoxycarbonyl substituted aryloxycarbonyl, aryloxycarbonyl substituted cycloalkoxycarbonyl, cycloalkoxycarbonyl substituted, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclic haloxycarbonyl, substituted heterocyclic alkanoyl, cycloalkyl, LfrflS substituted cycloalkyl, substituted heterocyclic, substituted heterocyclic, substituted, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted heterocycloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonyl lamino, amy otiocarbonylamino, guanidino, amidino, alkylamidino, thioamidino , halogen, cyano, nitro, -OS (0) 2-alkyl, -0S (0) 2- 10 substituted alkyl, -OS (0) 2-cycloalkyl, -0S (0) 2-substituted cycloalkyl, -OS (0 ) 2-aryl, -0S (0) 2- substituted aryl, -OS (0) 2-heteroaryl, -0S (0) 2 -substituted heteroaryl, -OS (0) 2-het erocyclic, -OS (0) 2-substituted heterocyclic, -0S02-NRR where R 15 is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (0) 2- substituted alkyl, -NRS (0) 2-cycloalkyl, -NRS (0) 2-substituted cycloalkyl, -NRS (0) 2 -ar ilo, -NRS (0) 2-substituted aryl, -NRS (0) 2-het eroar lio, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2- heterocyclic, -NRS (0) 2-substituted cycloheterocycline, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-c-cloalkyl, -NRS (0) 2-NR-cycloalkyl substituted, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR- 25 heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, 'tí ^^^ Z ^^^^^ ^^ ^ f ^^ ff ^^ -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic where R is hydrogen or alkyl, -S (0) 2- alkyl, -S (O) 2 -substituted alkyl, -S (0) 2 -aryl, -S (0) 2 -substituted aryl, -S (0) 2 -heteroaryl, 5 -S (0) 2-substituted heteroaryl, -S (0) 2-heterocyclic, -S (0) 2-substituted heterocyclic, mono- and di- (substituted alkyl) amino, N, N- (alkyl, substituted alkyl) amino, N, N- (aryl, substituted alkyl) to ino, N, N- (substituted aryl, Substi tuted alkyl) amino, N, N- (heteroaryl, substi tuted alkyl) amino, N, N- (substituted heteroaryl, substi tuted alkyl) amino, N, N- (heterocyclic, substi tuted alkyl) amino, N, NN , N- (substituted heterocyclic, substi- tuted alkyl) amino, mono- and di- (substituted heterocyclic) amino, N, N- (alkyl, heterocyclic) amino, N, N- (alkyl, substituted heterocyclic) amino, N, N- (aryl, heterocyclic) amino, N, N- (substituted aryl, heterocyclic) amino, N, N- (aryl, heterocyclic substi tuted) amino, N, N- (aryl Substituted, substi tuted 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; Y aMB ^ -a ..,. », - * - ^ -» ^ f ^ -fia- & * ^ - E. R5 is not - (CH2) X-Ar-R5 'where R5"is a substituent selected from the group consisting of: (a) alkylcarbonylamino substituted with the proviso that at least one of the substituents in the substituted alkyl portion is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonylamino, aminotiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted alkylcarboxyl, carboxyl-cycloalkyl, substituted cycloalkyl-carboxyl, carboxyl-laryl, substituted-aryl-carboxyl, carboxyl-heteroaryl, substituted-heteroaryl-carboxyl, carboxyl-heterocyclic, carboxyl-substituted heterocyclic, cycloalkyl , substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, locicloalqui t it, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxitylcarbonylamino, -OS (0) 2-5 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 (O) 2-substituted heterocyclic, OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (O) 2 -alkyl 10-substituted, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic , NRS (O) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl, -NRS (0) 2- 15 NR-aryl, -NRS (O) Substituted 2-NR-aryl, -NRS (0) 2- NR-heteroaryl, -NRS (O) 2_NR-het substituted eroary, -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, 20 mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (heteroaryl substi tuted) amino, mono- and di-heterocyclic-amino, mono- and di- (heterocyclic substi tuted ) amino, non-asymmetric di-substituted amines that have different 25 substituents selected from the group that consists of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and 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 -S02-alkyl, -S? 2 ~ substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S? 2-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl- OS (O) 2-substituted aryl, S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S? 2? Substituted heterocyclic or S02NRR, wherein R is hydrogen or alkyl; (b) alkoxyaryl substituted on the alkoxy portion with a substituent selected from the group consisting of carboxyl and -COOR23, wherein R23 is 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, * ^ gg ^ ^. ^ j ^^^ ia ^^^^^^^^ a ^., 7. heterocyclic and substituted heterocyclic with the proviso that at least one of R 'is substituted alkyl, substituted cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the additional proviso that when R' is substituted alkyl at least one of the substituents on the alkyl portion substituted is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylmamino, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, uncle l, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, thioheterocyclic - ^^ - ~ - "" ^^ & ^ h ^^ fi ^ ,, ^^. ^ a ^^^^ fa ^^ substituted, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy , substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -0S (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, -0S (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, 0S02-NRR, -OS (0) 2-alkyl, -NRS ( 0) 2-alkyl? substituted, -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-N 4 -heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -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-heteroarylamino, mono- and di- (substi- tuted heteroaryl) amino, mono- and di-heterocyclic-amino, mono- and di- (heterocyclic substi- tuted) amino, and O ^^ jngsig di-substituted and asymmetric amines having different substituents, selects from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having groups amino blocked by conventional blocking groups (such as Boc, Cbz, formyl and the like), and alkyl / substituted alkyl groups, 10 substituted with -S02-alkyl, -SO? -substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S? 2-cycloalkyl, -S? 2-substituted cycloalkyl, -SO? -aryl, -S? 2-substituted aryl, S02-heteroaryl, -S02-substituted heteroaryl, -S02- heterocyclic, -S02-substituted heterocyclic or S02NRR, wherein 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 R "is substituted alkyl then at least one of the Substituents on the substituted alkyl portion are selects from the group consisting of alkoxy, acyl, acylamino-thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonilamino, aminot-iocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxyl-aryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulphone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryl, heteroaryloxy substituted, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (0) 2-alkyl, -OS (O) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl , -OS (O) 2-heteroary i lo, ^ (OS) 2-substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, 0S02-NRR, -NRS (0) 2-alkyl, -NRS (0) 2 -also-substituted, -NRS (0) 2-aryl, -NRS (0) 2-aryl 5 substituted, -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) -NR-substituted alk, -NRS (0) 2- NR- aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2- 10 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-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, non-asymmetric di-substi tuted amines having different substituents, selected from of the group that 20 consists of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having amino groups blocked by blocking groups 25 conventional (such as Boc, Cbz, formyl and similar), and substituted alkyl / alkyl groups, substituted with -S? 2 ~ alkyl, -S? 2 ~ substituted alkyl, -S02-alkenyl, -S02-alkene substituted, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S? 2 ~ aryl, -S02-substituted aryl, S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or SO2NRR, where R is hydrogen or alkyl. (f) substituted alkenyl, or alkynyl substituted with the proviso that at least one of them substituents on the substituted alkenyl / alkenyl portion is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted with the proviso that when substituted with substituted alkyl, then at least one of the substituents on the substituted alkyl portion is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino , tiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl-amidino, thioamidino, aminoacyl, aminocarbonilamino, aminotiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyl-alkyl, carboxyl-alkyl substituted, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-ary substituted, carboxyl-heteroaryl, substituted carboxylheteroaryl, carboxyl-heterocyclic, substituted carboxyl-heterocyclic, substituted 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 cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, -OS (0) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, OS (O) 2-substituted heterocyclic, -OS02-NRR, NRS (0) 2-alkyl, -NRS (O) 2 -substituted alkyl, NRS (0) 2 -aryl, -NRS (0) 2 -substituted aryl, -NRS (0 2-heteroaryl, -NRS (O) 2-heteroaryl replaced, Sítóíái ^ fiSáK & i: NRS (0) 2-heterocyclic, -NRS (O) 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, 5 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-arylamino, mono- and di- (substi- tuted aryl) amino, mono- and di- 10 heteroarylamino, mono- and di- (substi tuted heteroaryl) amino, mono- and di-heterocyclic-amino, mono- and di- (substituted heterocyclic) amino, non-asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl , substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, substituted alkyl groups having blocked amino groups by conventional blocking groups (such as Boc, Cbz, formyl and the like), and alkyl / alkyl groups substituted, substituted with -S02-alkyl, -S? 2 ~ substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl , ?????????????????????????????????????????????? substituted heterocyclic or S02NRR, where R is hydrogen or alkyl. (g) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on substituted aryloxy / heteroaryloxy is different from halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 2-10 dioxetic, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; 15 (h) -saturated heterocyclic alkoxy-substituted, -alkoxy-substituted heterocyclic, saturated, -alkoxy substituted-heterocyclic and -substituted substituted heterocyclic, substituted heterocyclic; (i) -O-heterocyclic and O-heterocyclic 20 replaced; (j) tetrazolyl; (k) -NR-S02-substituted alkyl wherein R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl portion of the 25 alkylsulfonylamino substituted is different from halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylene, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (1) alkenylsulfonylamino, alkynylsulfonymymino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino; (m) substituted alkoxy with the proviso that the substitution in the alkyl portion of the substituted alkoxy does not include alkoxy-NR '' R 'as defined above, unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl, or substituted aryl / heteroaryl with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkynylcarbonyloxy, acyl, alkylcarbonylamino , alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkyl urea; (n) amidine and amidine substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; 5 (o) -C (O) NR '' 'R' '', wherein each R * "is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that when an 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-full-dioxyethyl, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonixolo, acyl, Alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (different from unsaturated heterocyclyl-substituted alkyl), cycloalkyl, cycloalkyl 25 substituted, alkenyl, substituted alkenyl, G§¡fcy g j ^ alkynyl, substituted alkynyl, heterocyclic or substituted heterocyclic; (p) -NR22C (O) -R18 wherein R18 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, cycloalkyl Substituted, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; (q) -S02-aryl, -S02-substituted aryl, -S? 2-heteroaryl, -S-? 2-het eroar i the substituted, or -S02-alkyl; 15 (r) • NR 'C (O NR19R19 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 R19 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; (s) -NR'C (0) OR19 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 R19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (t) -aminocarbonyl- (N-formylhet erocyclic); and (u) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O) NH-substituted heterocyclyl; and pharmaceutically acceptable salts thereof; with the following additional condition: A) when R1 is p-methylphenyl, R2 and R3 together 20 with its pendant nitrogen and carbon atoms form a pyrrolidinyl ring and R5 is p - [- OCH2CH2- (4, 5-dihydroimidizole-2-yl), Q is -C (0) NH-, then R6 is not - O-methyl; B) when R1 is 1-methylimidazole, R2 / R3 together with L-pyrrolidinyl, and R5 is 4-hydroxybenzyl, then R6 is not isopropyl; C) when R1 is 1-met unlimited zol, R2 / R3 together with L-pyrrolidinyl, and R5 is 4-hydroxybenzyl, then R6 is not t-butyl; and D) when R1 is 4-trifluoromethoxybenzyl, R2 / R3 together with 5, 5-hydroxybenzyl, then R6 is not t-butyl;

3. A compound according to claim 1 or 2, characterized in that R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl.

4. A compound according to claim 1 or 2, characterized in that R1 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-trimethylphenyl, 2- (methoxycarbonyl) phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4 -tri fluorometylphenyl, 3,4- dichlorophenyl, 3,4-dimethoxy phenyl, 4- (CH 3 C (0) NH-) phenyl, 4-trifluoromethoxyphenyl, 4-cyano phenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-t-butylphenyl, 4- t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenyl-ethyl, 1-N-methylimidazol-4-yl, 4-bromo-phenyl, -amidinophenyl, 4-methylaminidophenyl, 4- [CH3SC (= NH)] phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-met il-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'-dimet and lamino-n-propoxy) -phenyl, and 1-methypyrazol-4-yl.

5. A compound according to claim 1 or 2, characterized in that R 2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, - (CH 2) 2-2-thienyl and - (CH 2) 2-f.

6. A compound according to claim 1 or 2, characterized in that R1 and R2 together with the nitrogen atom attached to R2 and ^ "^ • f -" - ÉZ-Ziá? the group S02 attached to R joins to form a heterocyclic group and substituted heterocyclic group.

7. A compound according to claim 1 or 2, characterized in that R3 includes all the high isomers by substitution with methyl, phenyl, benzyl, diphenylmet ilo, -CH2CH2-COOH, -CH2-COOH, 2-amidoethyl, iso-butyl, t -butyl, -CH20- benzyl and hydroxymethyl.

8. A compound according to claim 1 or 2, characterized in that R2 and R3 together with the nitrogen atom attached to R2 and the carbon atom attached to R3 form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when the monosubstituted group, the substituent, substituted heterocyclic group is not carboxyl.

9. A compound according to claim 1 or 2, characterized in that Q is -C (0) NH- or -C (S) NH-.

10. A compound according to claim 1 characterized in that R is .a ^ is selected from the group consisting of p - [- OCH (CH3) f] -benzyl, 4-hydroxybenzyl, 2-carboxybenzyl, 3-carboxybenzyl, 4-carboxymethyl, 4- (2-carboxyphenoxy) benzyl, 4- (benzyloxy) benzyl, 4-iodobenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4- (tert-butoxy) benzyl, 3, 5-diiodo-4 -hidroxibencilo, 4- (benzamido) benzyl, benzyl, 4- hydroxy-3- iodobenzyl, 4-chlorobenzyl, isobutyl, methyl, 4- (acetamido) benzyl, n-butyl, carboxymethyl, 4- aminobutyl, 2-carboxiet yl, 4- (N, N-dibenzylamino) - benzyl, (N -benzylimidazol- -il) -methyl, 2- thiomethoxyethyl, hydroxymethyl, (N-methylimidazol-4-yl) methyl, 4- (isopropyl-C (O) NH-) butyl, 4- (benzamido) butyl, - (benzyl-C (O) NH-butyl, (N-methylimidazol-5-yl) methyl, 4- (pyridin-2-yl-C (O) NH-) butyl, 4- (6-methylpyridin-3-) il-C (O) NH-) butyl, 4- (3-methylthien-2-yl-C (O) NH-butyl, 4- (pyrrol-2-yl-C (O) NH-butyl, 4- ( furan-2-yl-C (0) NH-butyl, isopropyl, 4-aminobenzyl, 4- (4- phenylbutoxy) benzyl, 4- (l-methylindol-3-yl-C (O) NH-butyl, 4- (4-methanesulfonylphenyl-C (O) NH-butyl, 4- (4-acetylphenyl-C (0) NH-butyl, 4- ( 4-fluorophenyl-C (O) NH-) butyl, 4- [2- (pyridin-2-yl) ethynyl] benzyl, 4- [2- (3-hydroxyphenyl) ethynyl] benzyl, 4- [2- (pyridine - 4-yl-C (O) NH-benzyl, 4 - • (pyridin-3-yl-C (O) NH- ) benzyl, 4- (3-methylphenyl-NHC (O) NH-) benzyl, 4, (2,3-dihydroindol-2-yl-C (0) NH-) benzyl, 4- (N, N-dipentylamino) benzyl, 4- (N-pentylamino) benzyl, 4- [2- (N, N, -dibenzylamino) ethoxy] benzyl, 3-hydroxybenzyl, 4- (Nn-butyl-Nn-pentylamino) benzyl, 4- (N-4-chlorophenyl amino) benzyl, 4- (4-cyanophenyl-NHC (0) NH-) benzyl, 4- (carboxymethoxy) benzyl, 4- (tert-butoxycarbonylmethoxy) benzyl, 4- (5-fluoroindol-2-yl-C (O) NH-) benzyl, 4- (1, 2, 3, -t and rahydroisoquinolin-3-yl-C (O) NH-) benzyl, 4- (3-methoxy phenyl-NHC (O) NH-) benzyl, - [2- (indol-3-yl) ethoxy] benzyl, 4- (4,5-dihydroimidazol-2-ylmethoxy) benzyl, 4- (n-propyl-NHC (O) NH-) benzyl, 4- (N-benzylamino) benzyl , 3-methoxybenzyl, 4- (pyridin-2-yl-C (O) NH-) benzyl, 4- (N-4-chlorobenzyl amino) benzyl, 4- (2-chloromethylsulfonylamino) benzyl, 4 - (N, N-dimethylamino) benzyl, 3-aminobenzyl, 4- (benzyl) benzyl, 2-hydroxyethyl, 4-nitrobenzyl, 4- (phenyl-NHC (S) NH-) benzyl, 4- (pyridin-3-yl- NHC (S) NH-) benzyl, 4- (pyridin-4-ylmethylamino) benzyl, 4- [fCH2OCH2 (Boc-HN) CHC (O) NH-] benzyl, 4- (pyridin-3-yl-C (O ) NH-) butyl, 4- (pyridin-4-yl-C (O) NH-) butyl, 4-pyridin-3-yl-C (O) NH-) benzyl, 4- (pyridin-4-yl-) C (O) NH-) benzyl, 4 - (Ntoluensulfonylpyrrolidin-2-yl- ^^ a &^^^^ mz? &, ^^^ C (0) NH-) butyl, 4 (pyridin-4-yl-C (O) NH-) butyl, 4- (2-Boc-1, 2, 3, 4-tetrahydroisoquinolin-3 -yl-NHCH2-) benzyl, 4- (2-Boc-1, 2,3,4-tetrahydroisoquinolin-3-yl-C (O) NH-) benzyl, 4- (pyridin-3-ylmethylamino) benzyl, 4- [fCH20 (0) C (CbzNH) CHCH2CH2C (O) NH-] benzyl, 4- (2-methoxybenzamido) benzyl, 4- (2-bromobenzamido) benzyl, 4- (pyrazin-2-yl-C (0 ) NH- (benzyl, (1-toluensulfonilimidazol-4-yl) meth yl, [1- 10 (N, N-dimethylaminosulfonyl) imidazol-4-yl] methyl, 4- (trifluoromethyl) -benzyl, 4- (3, 3- dimethylolureid) benzyl, 4- (methoxycarbonylamino) benzyl, 4- (1,3-, 3-trimethylolide) benzyl, 4- (raetoxycarbonyl-N-15-methylamino) benzyl, 4-cyanobenzyl, 4- (2- formyl- 1,2,3,4-tetrahydroisoquinolin-3-yl-C (0) NH-) benzyl, phenyl, (4-aminoethyl) benzyl, 4- (l-Boc-piperidin-4-yl-C (O ) NHCH 2 -) benzyl, 4- (1-Boc-piperidin-4-yl-C (O) O-) benzyl, 4- (piperidin-4-yl-C (0) NHCH 2) benzyl, 20 4- [(l-methylpiperidin-4-yl) -0-] benzyl, 4- (1, 2,3,4-tetrahydroquinolin-2-yl-C (0) NH-) benzyl, 'a-methybenzyl 4- (trimethylacetamido) benzyl, 4- (2-meth ipropionamido) benzyl, 4- (morpholinyl-C (O) NH- (benzyl, 4- (3, 3-diethyl-ureido) benzyl) 4- (2-25 trifluoromethylbenzamido) benzyl, 4- (2- methylbenzamido) benzyl, 4-hydroxy-3-nitrobenzyl, 3-hydroxy-4- (f-OC (O) NH-) benzyl, 4- (thiomorpholin-4-yl- C (0) NH-) benzyl, 4- (1, 1-d? Oxothiomorfol mo-4 -i 1- C (0) NH-benzyl, 3-nitro-4- (methoxycarbonylmethoxy) benzyl, (2-benzoxazolinon-6-yl) methyl, (2H-1, 4-benzoxazin-3- (4H) -one-7-yl) methyl-4, - [N, N-diethylaminosulfonyl- (N-methyl) amino] benzyl, 4- [(2-met ilpyrrolidin-1-yl) C (0) H-] benzyl, (pyridin-4-yl) methyl, 4- (l-10 methylpiperidin-4-yl-C (0) NH-) benzyl, 4 [bis (N, N-dimethylaminothiocarbonyl) amino] benzyl, 4- (N, N-dimethylaninosulfonyl) -benzyl, 4- (? midazolid-2-ona-l-yl) benzyl, 3,4- (ethylenedioxy) benzyl-, 3,4- (methylenedioxy) benzyl-1 and 4- (3-formylimidazolid-2-one-1-yl) benzyl.

11. A compound according to claim 2, characterized in that R6 is selected from the group consisting of 2,4-20 dioxo-tetrahydrofuran-3-yl, (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso-propyl-β-methylcyclohexoxy, 2β-isopropyl-4-β-met ilcyclohexoxy, -NH2, benzyloxy, -NHCH2C00H, -NHCH2CH2COOH. -NH- 25 adamantyl, NHCH2CH2COOCH2CH3, -NHS02-p-CH3-f, -NHOR8 wherein R8 is hydrogen, methyl, iso-propyl, or benzyl, 0- (N-succinimidyl), -0-cholest-5-en 3-ß-l, -C0H2.0C (0) C (CH3) 3, -0 (CH2) 2NHC (0) W wherein z is 1 or 2 and W is selected from the group consisting of 5-pyrid-3-yl, N-methylpyridyl, and N-met? -1.4- dihydro-pyridin-3-yl, -NR''C (0) -R 'where R' is aryl, heteroaryl or heterocyclic and R "is hydrogen or -CH2C (0) OCH2CH3.

12. A compound selected from the group consisting of: N- (toluene-4-sulfonyl) -L-prolyl-4- (a-met-il-benzyloxy) -phenylalanine 15 N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-4-carboxyphenylalanine 20 N- (toluene-4-sulfonyl) -L-prolyl-3- (carboxy) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (2-carboxyphenoxy) -L-phenylalanine -? «? ^ * at ^^, ^^ j ^ .líj? ie¿ ^^ i? l «u. ? & e? »^^« * ^ ~ «* ~~» *. »..., ...? ^^. 4 ^^^^^^ N- (toluene-4-sulfonyl) -L-prolyl-O- (benzyl) -L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-4- (iodo) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (methoxy) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-nr-tro-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (O-tert-butyl) -L-t-irosine N- (toluene-4-sulfonyl) -L-prolyl-L- (3, 5-diiodo) -tyrosine N- (toluene-4-fonyl) -L-prolyl-L-4- (aminobenzoyl) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (3-iodo-4-hydroxy) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-chloro) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-leucine N- (toluene-4-sulfonyl) -L-prolyl-L-alanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (acetamido) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-isoleucine N- (toluene-4-sulfonyl) -L-prolyl-L-aspartic acid N- (toluene-4-sulfonyl) -L-prolyl-L-lysine N- (toluene-4-sulfonyl) -L-prolyl-L-glutamic acid Methyl ester of N- (toluene-4-sulfonyl) -L-prolyl-L- (4-dibenzylamino) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (N-benzyl) -histidine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-dibenzylamino) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-methionine N- (toluene-4-sulfonyl) -L-prolyl-L-serine 5 N- (toluene-4-sulfonyl) -L-prolyl-L- (5, 5-dimethyl) thiaprolylL- (N-benzyl) histidine N- (toluene-4-sulfonyl) -L-prolyl-L- (1-met i 1) histidine 10 N- (toluene-4-sulfonyl) -L-prolyl-D- (N-benzyl) histidine N- (toluene-4-sulfonyl) -L-glutamyl-L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L- (N -3- 15 -methyl) histidine N- (Toluene-4-sulfonyl) -L-prolyl-a-amino-2, 3- dihydro- (1,4-benzodioxin) -6-propanoic acid 20 N- (Toluene-4-sulfonyl) -L-proly-a-amino-1, 2- benzodioxolo-5-propanoic acid N- (toluene-4-sulfonyl) -L-prolyl-L-valine flllfir * ÍfrT «- * - * - - ** • *" * "*" wteWh ^ * >, a ^ .. ^ t. ftt * ^^ - ^^^ - Methyl esters N- (toluene-4 - sulfonyl) -L-prol i 1-L- (4-iodo) -phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- (aminobenzoyl) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4 • chloro) phenylalanine 10 Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (- amino) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (- acetamido) phenylalanine 15 Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (5,5-dimethyl) thiaprolyl -L- (N-benzyl) -histidine N- (toluene-4-sulfonyl) -L-proli 1-4- (3-3 '-tolylureido) - 20 L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4 - [(2,3,3a7a-tetrahydro-lH-indole-2-carbonyl) -amino] -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4 • pentylamino) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-O- (2-dibenzylamino-ethyl) -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-O- [2- (dibenzylamino) ethyl] tyrosine N- (toiuen-4-sulfonyl) -L-prolyl-L- (4-pentylamino) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- (4-chlorobenzylamino) -phenylalanine Methyl ester N- (toluene-sulfonyl) -L-prolyl-L-4- [3- (4-cyanophenyl) -ureido] -phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-O- (tert-butoxycarbonylmethyl) tyrosine N- (toluene-4-sulfonyl) -L-prolyl-LO- (tert-butoxycarbonylmethyl) -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-4 - [(3S) -3, -dihydro -i sochiolin-3-yl-aminocarbonyl] -phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (3-methoxy-phenyl) -ureido] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- ([3- (3-methoxy-phenyl) ureido] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-O- (4,5-dihydro-lH-imide zol-2-yl-methyl) -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (3-propyl-ureido) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-benzylamino) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-proli 1-L- (4-benzylamino) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (4-chlorobenzylamino) -phenylalanine Í- ?? íS, a_? S ^^. , faith »'-jSggfe ^ -rt. N- (toluene-4-sulfonyl) -L-prolyl-L- (4-chloromethanesulphonylamino) -phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L- (5,5- 5 dimethyl) -thiaprolyl-L-4- (aminobenzoyl) phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimetyl) thiaprolyl-L-4- (benzamido) phenylalanine 10 N- (toluene-4-sulfonyl) -L- (5,5-d? Methyl) -thiaprolyl-L-tyrosine ethyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-t-irosine 15 N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridine-4 - il) methylamino] phenylalanine Methyl ester N- (toluene-sulphon-1) -L-prolyl-L-4-20 [(pyridin-4-yl) methylamino] phenylalanine N- (toluene-sulfonyl) -L- (5,5-d? Methyl) thiaprol? L-L-4- (pyridm-3-carboxamido) phenylalanine ethyl ester Methyl ester N- (toluene-4-sulfonyl) -L- (5,5'-dimethyl) -thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-3-yl-yl) amino] phenylalanine N-methyl ester (toluene-4-sulfonyl) -L- (5, 5-) dimethyl) -thiaprolyl-L-4-nitrophenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- • 15 nit rofenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-methoxybenzamido) phenylalanine 20 Ethyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) -thiaprolyl-L- (-nitro) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- - (2-bromobenzamido) phenylalanine ~ ^, x ^ r- ^ ~ * »** - * - ~ *** ~~? ~ - ~ ^,, • - ,; ^^^^^^^^^^ - ^^^^^^^ r ^^^^^^^ ethyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimet il) tiamorfi 1-L-4-aminophenylalanine Ethyl ester N- (toluene-4-sulphonyl) -L-prolyl-L-4 acetamidophenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-methoxybenzamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L- (5, 5-d? Met il) • tiaprolyl-L-4-acetamidophenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4-acetamidophenylalanine Isopropyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4-acetamidophenylalanine N- (toluene-4-sulphonyl) -L- (5, 5-d? Met il) ethyl ester • L-4- (isonicotinamido) phenylalanine Ethyl ester-4- (isonicotinamido) phenylalanine N-methyl ester (toluene-4-sulfonyl) -L-prolyl-L- (p-toluene-4-sulfonyl) histidine N- (toluene-4-sulfonyl) -L- (5, 5-d? Met) ethyl ester il) -thiaprolyl-L-4- (nicotamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (0-methyl) tyrosine Ethyl ester N- (a-toluenesulfonyl) -L-prolyl-L-4- (isonicotinamido) phenylalanine N- (toluene-4-fonyl) -L-prolyl-L-4- (2-bromobenzamido) phenylalanine N- (α-toluenesulfonyl) -L-prolyl-L-4- (isonicot inamido) phenylalanm Ethyl ester N- (toluene-4-sulfonyl) -L- (1,1-dioxo) t? Amorfolil-L-4- (2-bromobenzamido) phenylalanine N- (toluene-sulfonyl) -L- (1,1-dioxo) thiamorphol? L-L-4- (2-bromobenzamido) phenylalanine N- (toluene-4-sulfonyl) -L- (5, 5-d? Met? L) -L-4- (isonicotinamido) phenylalanine 35 * Ethyl ester N- (α-toluenesulfonyl) -L-prolyl-L-4 - (2-bromobenzamido) phenylalanine Isopropyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine Ter-butyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) -thiaprolyl-L-tyrosine Ter-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine Ethyl ester N- (toluene-sulphonyl) -L-prolyl-L-4- (2-t rifluoromet-ilbenzamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-methyl-isobenzamido) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-trifluoromethylbenzamido) phenylalanine Ter-butyl ester N- (4-fluorobenzenesulfonyl) -L-thiaprolyl-L-tyrosine Tert-butyl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine N- (toluene-4-fonyl) -L-proli 1-4- (dimethylamino) -L-5-phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [(2-bromo) benzamido] -L-phenylalanine 10 Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [(pyrazin-2-yl) C (O) NH] -L-phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 (4-nitrobenzoyl) -L-phenylalanine 15 T-butyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) ) thiaprolyl-4- (2-bromobenzamido) -L-phenylalanine 20 T-Butyl Ester N- (Toluene-4-Sulphonyl) -L- (5, 5-dimethyl) thiaprolyl-4- (2-bromobenzamido-L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (l-H-2-oxo-3-methyltetrahydropyrimidin-1-yl) L-25 phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (l-H-2-oxo-3-methyltetrahydropyrimid? N-l-yl) -L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-3 'chloro-4- (t-butoxy) -L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-3-chloro-4- (hydroxy) -L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 '(N, N-dimethylureido) -L-phenylalanine T-butyl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4-hydroxy) -L-phenylalanine Isopryl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4- (hydroxy) -L-phenylalanine Isopropyl ester N- (-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4- (hydroxy-L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 (2-methoxy phenyl) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (2-methoxyphenyl) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl- [(5-N, N-dimethyl-illideido) -pyridin-2-yl] -alanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N, N-dimet ilsulfami 1) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N1, N1, N2-trimethylsulfamyl) -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl- (1-t-butoxycarbonylmethylimidazol-4-yl) -L-alanine N-methyl ester (toluene-4-sulphonyl) -L-prolyl- [N, N-dimethylaminocarbonylmethylimidazol-4-yl] -L-alanine Isopropyl Ester N- [4 - (dimeth-il-urei lenyl) benzenesulfonyl] -L-prolyl-4-hydroxy-L-phenylalanine Isopropyl ester N- (toluene-4-sulfonyl) -L-prolyl- (5, 5-dimetyl) thiaprolyl-3-chloro-4-hydroxy-L-phenylalanine Isopropyl ester N- (toluene-4-sulfonyl) - L-prolyl-3-chloro-4-hydroxy-L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (carboxymethyl) -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 - (2-methylbenzamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N, N-dimethylaminocarbonylmethyl) -L-phenylalanine Isopropyl Ester N- (l-methylimidazol-4-sulfonyl) -L-prolyl-4-hydroxy-L-phenylalanine Isopropyl ester N- (toluene-4-sulphonyl) -L-prolyl-4 (2,4,5-trioxo-3-phenyltetrahydroimidazol-1-yl) -L-phenylalanine Isopropyl ether N- (4-fluorobenzenesulphyl) -L- (5,5-dimethyl) thiaprolyl-3-fluoro-4-hydroxy-L-phenylalanine T-butyl ester N- (4-fluorobenzenesulfonyl) -L- (5, 5- dimethyl) thiaprolyl-3-chloro-4-t-butoxy-L-phenylalanine T-butyl ester N-. { N- [(I S-2.10-camphorsultamil] acetyl.}.-L-tyrosine Isopropyl ester N-. { N- [IS) -2.10- camforsultamil] acetyl} -3-Chlorotyrosine T-butyl ester N- (4-fluorobenzenesulfonyl) -L-thiaprolyl-4-hydroxy-L-phenylalanine T-butyl ester N- (toluene-4 -sulonyl) -L-prolyl-4 - (N, N-dimethylaminocarbonylmethyl) -L-phenylalanine T-butyl ester N- (toluene-sulphyl) -L-prolyl-4 - (hydroxy-L-phenylalanine) Isopropyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) thiaprolyl-4-hydroxy-L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl- • hydroxy-L-phenylalanine T-butyl ester N- (pyridine-3-sulfonyl) -L-prolyl-hydroxy-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (methanesulfonamido) -L-phenylalanine Benzyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (2,4,5-trioxo-3- (3-chlorophenyl) -tetrahydroimidazol-1-yl) -L-phenylalanine Ethyl ester N- (1-methylimidazol-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4-hydroxy-L-phenylalanine Ter-butyl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-L-3-chloro-4-tert-butoxy-phenylalanine Isopropyl ester N- [2- (N-2, 10-camphorsultamil) acetyl] -L-3-chloro-4-hydroxyphenylalanine

13. A method for binding VLA-4 to a biological sample, the method is characterized in that it comprises contacting the biological sample with a compound according to claim 1 or 2 under conditions wherein the compound binds to VLA-4.

14. A pharmaceutical composition, 5 characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more compounds of formula 1 or 2.

15. A method for the treatment of inflammatory diseases in a mammalian patient, which is mediated by VLA-4, the method comprising administering to the patient a therapeutically effective amount of the composition 15 pharmaceutical of claim 14.

16. The method according to claim 15, characterized in that the inflammatory disease is selected from the 20 group consisting of asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease, sclerosis) 25 multiple, rheumatoid arthritis, tissue transplant, Tumor metastasis, meningitis, encephalitis, attack and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and leukocyte-mediated acute lung injury, such as that presented in the syndrome of respiratory pain in adults.

17. The method according to claim 14, characterized in that R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl.

18. The method according to claim 14, characterized in that R1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxy phenyl, phenyl, 2,4,6-trimethylphenyl, 2- (methoxycarbonyl) phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluorometylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (CH 3 C (O ) NH-) phenyl, 4-trifluoromethoxyphenyl, 4-nitrophenyl, isopropyl, 3,5-di- (tri fluoromethyl) phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, lN-methyl-3-methyl-5-chloropyrazol-4-yl, phenytyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylaminidophenyl, 4- [CH3SC (= NH) ] phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, lN-methyl-4-pyrazolyl, 2-thiazole, 5-methyl-1, 3-4-thiadiazole- 2-yl, 4 - [H 2 NC (S)) phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3, 5-difluorophenyl, pyridin-3-yl, 10-pyrimidin-2-yl, 4- (3'-dimethylamino-n-propoxy) -phenyl, and l-methylpyrazol-4-yl.

19. The method according to claim 14, characterized in that R2 is Is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, - (CH2) 2-2-thienyl, and - (CH2) 2-f.

20. The method of compliance with Claim 14, characterized in that R1 and R2 are joined together with the nitrogen atom attached to R2 and the group S02 linked to R1 is linked to form a heterocyclic group or a substituted heterocyclic group. 25

21. The method according to claim 14, characterized in that R3 includes all the high isomers by substitution with methyl, phenyl, benzyl, defenylmethyl, -CH2CH2-COOH, -CH2-COOH, 2-amidoethyl, iso-butyl, t-butyl, -CH20-benzyl and hydroxymethyl.

22. The method according to claim 14, characterized in that R2 and R3 together with the nitrogen atom binds to R2 and the carbon atom binds to R3 to form a saturated heterocyclic group, a saturated heterocyclic substituted group with the proviso that when the monosubstituted group, the substituent on the saturated substituted heterocyclic group is not carboxyl.

23. The method according to claim 14, characterized in that Q is -C (0) NH- or -C (S) NH-.

24. The method according to claim 14, characterized in that R5 is selected from the group consisting of p - [- OCH (CH3) f] -benzyl, 4-hydroxybenzyl, 2-carboxybenzyl, 3-carboxybenzyl, 4-carboxybenzyl , 4- (2-carboxyphenoxy) benzyl, 4- (benzyloxy) -benzyl, 4-iodobenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 4- (tert-butoxy) benzyl, 3,5-diiodo-4-hydroxybenzyl, 4- (benzamido) benzyl, benzyl, 4-hydroxy-3-iodobenzyl, 4-chlorobenzyl, isobutyl, methyl, 4- (acetamido) benzyl, n-butyl, carboxymethyl, 4-aminobutyl, 2-carboxyethyl, 4- (N, N-dibenzylamino) -benzyl, (N-benzylimidazol-4-yl) -methyl, 2-thiomethoxyethyl, hydroxymethyl, (N-methylimidazol-4-yl) methyl, 4- (isopropyl-C (0) NH-) butyl, 4- (benzamido) butyl, 4 - (benzyl-C (O ) NH-butyl, (N-methylimidazol-5-yl) methyl, 4- (pyridin-2-yl-C (0) NH-) butyl, 4- (6-methylpyridin-3-yl-C (0) NH) -) butyl, 4- (3-methyltien-2-yl-C (0) H-butyl, 4- (pyrrol-2-yl-C (0) NH-butyl, 4 - (furan-2-yl- C (0) NH-butyl, isopropyl, 4-aminobenzyl, 4- (4-phenylbutoxy) benzyl, 4- (1-methylindol-3-yl-C (0) NH-butyl, 4- (4-methanesulfonylphenyl-C (0) NH-butyl, 4- (4-acetylphenyl-C (0) NH-butyl, 4- (4-fluorophenyl-C (0) NH-) butyl, 4 - [2 - (pyridin-2-yl) Ethyl] benzyl, 4- [2- (3-hydroxyphenyl) et inyl] benzyl, 4- [2- (pyridin-4-yl-C (O) NH-benzyl, 4- (pyridin-3-yl-C (0) NH-) benzyl, 4- (3-methyphenyl-) NHC (0) NH-) benzyl, 4, (2,3-dihydroindol-2-yl-C (O) NH-) benzyl, 4- (N, N-dipentylamino) benzyl, 4- (N-pentylamino) ) benzyl, 4- j¡ & ^^ & [2- (N, N, -dibenzylamino) ethoxy] benzyl, 3- hydroxybenzyl, 4- (N-n-butyl-N-n-pentylamino) benzyl, 4- (N-4-chlorophenylamino) benzyl4- (4-cyanophenyl-NHC (0) NH-) benzyl, 4-5 (carboxymethoxy) benzyl, 4- (tert-butoxycarbonylmethoxy) benzyl, 4- (5-fluoroindol-2-yl-C (0) NH -) benzyl, 4- (1, 2, 3, 4-tetrahydroisoquinolin-3-yl-C (O) NH-) benzyl, 4- (3-methoxy phenyl-NHC (0) NH-) benzyl, 4- [ 2- (indol-3-yl) ethoxy] benzyl, 4- (4,5-10-dihydroimidazol-2-ylmethoxy) benzyl, 4- (n-propyl-NHC (0) NH-) benzyl, - (N-benzylamino ) benzyl, 3-methoxybenzyl, 4- (pyridin-2-yl-C (0) NH-) benzyl, 4- (N-4-chlorobenzylamino) benzyl, 4- (2-chloromethoxy sulphonylamino) benzyl, - (N, N-dimethylamino) benzyl, 3-aminobenzyl, 4- (benzyl) benzyl, 2-hydroxyethyl, -nit robencyl, 4- (phenyl-NHC (S) NH-) benzyl, 4- (pyridin- 3-yl-NHC (S) NH- (benzyl, 4- (pyridin- -lyl-methylamino) benzyl, 4- [fCH2OCH2 (Boc-HN) CHC (O) NH-] benzyl, 4- (pyridm-3-yl - 20 C (O) NH-) butyl, 4 - (pyridin- -il-C (0) NH-) butyl, 4-pyridin-3-yl-C (0) NH-) benzyl, 4- (pyrid) ? n-4-yl- C (O) NH-) benzyl, 4- (N-toluenesulfonylpyrrolid? n-2-yl- C (0) NH-) butyl, 4 (pyridin-4-yl-C (0) NH-) butyl, 4- (2-Boc-1, 2, 3, 4-tetrahydroisoquinolin-3-yl-NHCH2-25) benzyl, 4 - (2 -Boc-l, 2, 3, 4 -tetrahydroisoquinolin-3- il-C (O) H-) benzyl, 4- (pyridin-3-ylmethylamino) benzyl, 4- [fCH20 (0) C (CbzNH) CHCH2CH2C (O) NH-] benzyl, 4- (2-methoxybenzamido) benzyl, 4- (2-5-bromobenzamido) benzyl, 4 - (pyrazin-2-yl-C (0) H-) benzyl, (1-toluenesulfonylimidazol-4-yl) methyl, [1- (N, N- dimethylaminosulfonyl) imidazol-4-yl] methyl, 4- (trifluoromethyl) -benzyl, 4- (3, 3-dimethyldureido) benzyl, 4- (methoxycarbonylamino) benzyl, 4- (1, 3,3-trimethylureido) benzyl 4- (methoxycarbonyl-N-methylamino) benzyl, 4-cyanobenzyl, 4- (2-formyl- 1, 2, 3, 4-tetrahydroisoquinolin-3-yl-C (0) NH-) benzyl, phenyl ( 4-aminoethyl) benzyl, 4- (1-Boc-piperidin-15-yl-C (0) NHCH 2 -) benzyl, 4 - (1-Boc-piperid? N-4 -i-C (O) O- ) benzyl, 4- (piperidin-4-yl-C (0) NHCH2) benzyl, 4- [(1-methypiperidin-4-yl) -0-] benzyl, 4- (1, 2, 3, 4-) tetrahydroquinolin-2-yl-C (0) NH-) benzyl, α-methyl-4-ylbenzyl, 4- (trimethylacetamido) benzyl, 4- (2-methyl-methyl-1-propionamido) benzyl, 4- (mor-fol-4-yl) C (0) NH-) be ncilo, 4- (3, 3-diethyl-ureido) benzyl, 4- (2- t -dibluoromet-il-benzamido) -benzyl, 4- (2-methyl-ylbenzamido) -benzyl, 4-hydroxy-3-nitrobenzyl, 3- hydroxy-4- (f-0C (0) NH-) benzyl, 4- (tiorior fol? n-4 -yl- 25 C (O) NH-) benzyl, - (1,1-dioxot iomorpholino-4-yl-) C (O) NH-benzyl, 3-n-tro-4- (methoxycarbonylmethoxy) benzyl, (2-benzoxazol inon-6-yl) methyl, (2H-1,4-benzoxazin-3- (4H) -one -7-yl) methyl-4, - [N, N-diethylaminosulfonyl- (N-methyl) amino] benzyl, 4 - [(2-met ilpyrrolidin-1-yl) C (O) NH-] benzyl, (pyridin-4-yl) methyl, 4- (l-methylpiperidin-4-yl-C (0) NH-) benzyl, 4 [bis (N, N-dimethylaminotiocarbonyl) amino] benzyl, 4- (N, N - dimethylaninosulfonyl) -benzyl, 4- (imidazolid-2-one-1-yl) benzyl, 3,4- (ethylenedioxy) benzyl-, 3,4- (methylenedioxy) benzyl-1 and 4- (3-formylimidazolid-2) - ona-l-il) benzyl.

25. The method according to claim 14, characterized in that R6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl, (3,4-enol), methoxy, ethoxy, iso-propoxy, n -butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso-propyl-4-β-methylcyclohexoxy, 2β-isopropyl-4-β-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2COOH, -NHCH2CH2COOH. -NH- adamantyl, NHCH2CH2COOCH2CH3, -NHS02-p-CH3-f, -NHOR8 wherein R8 is hydrogen, methyl, iso-propyl, or benzyl, O- (N-succinimidyl), -O-colest-5-en-3 -ß-il, -COH2.OC (O) C (CH3) 3, -O (CH2) 2NHC (O) W wherein z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-met ilpyridyl, and N-methyl-1,4-dihydro-pyridin-3-yl, -NR''C (0) -R 'where R' is aryl, heteroaryl or heterocyclic R1 is hydrogen or -CH2C (0) OCH2CH3.

26. The method according to claim 14 wherein the compound is selected from the group consisting of: N- (toluene-4-sulfonyl) -L-prolyl-4- (a-methylbenzyloxy) -phenylalanine N- (toluene-4-fonil) -L-proll-L-t iros ina N- (toluene-4-sulfonyl) -L-prolyl-4-carboxyphenylalanine N- (toluene-4-sulfonyl) -L-prolyl-3- (carboxy) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (2-carboxyphenoxy) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-O- (benzyl) -L-tyrosine ^^ ¡^^^^^^^^^ gr ^ g ^ ^ ^ ^ N- (toluene-4-sulfonyl) -L-prolyl-4- (iodo) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (methoxy) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4-nitro-L-phenylalanine N- (toi en-4-sulfonyl) -L-prolyl-4- (0-tert-butyl) -L-t-irosine N- (toluene-4-sulfonyl) -L-prolyl-L- (3, 5-diiodo) -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (aminobenzoyl) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (3-iodo-4-hydroxyphenylalanine) N- (toluene-4-sulfonyl) -L-prolyl-L- (4-chloro) phenylalanine N- (toluene-4-sulphyl) -L-prol i 1-L-leucine | ^ .. '^ | g ^ - ^ gBgjai68afcB.ajafc ^. - a = ^ ^ * "^ ^^^^ N- (toluene-4-sulfonyl) -L-prolyl-L-alanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (acetamido) phenylalanine N- (toluene-4 -sulfonyl) -L-prolyl-L-isoleucine N- (toluene-4-sulfonyl) -L-prolyl-L-aspartic acid N- (toluene-4-sulfonyl) -L-prolyl-L-lysine N- (toluene-4-sulfonyl) -L-prolyl-L-glutamic acid Methyl ester of N- (toluene-4-sulfonyl) -L-prolyl-L- (-dibencylamino) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (N-benzyl) -histidine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-dibenzylamino) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-methionine N- (toluene-4-sulfonyl) -L-prolyl-L-serine N- (toluene-4-sulfonyl) -L-prolyl-L- (5,5-dimethyl) thiaprolylL- (N-benzyl) histidine N- (toluene-sulfonyl) -L-prolyl-L- (1-methyl) histidine N- (toluene-sulfonyl) -L-prolyl-D- (N-benzyl) histidine N- (toluene-4-sulfonyl) -L-glutamyl-L-tyrosma N- (toluene-4-sulfonyl) -L-prolyl-L- (N-3-met il) histidine N- (toluene-4-sulfonyl) -L-prolyl-a-amino-2,3-dihydro- (1, -benzodioxin) -6-propanoic acid N- (toluene-4-sulphonyl) -L-proly-a-am? No-1,2 'benzodioxolo-5-propanoic acid N- (toluene-4-sulfonyl) -L-prolyl-L-valine Methyl ester N- (toluene-4 -sulonyl) -L-proli 1-L- (4-iodo) -phenylalanine Methyl ester N- (toluene-sulfonyl) -L-prolyl-L-4 • (aminobenzoyl) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4 • chloro) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4-amino) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4-acetamido) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (5,5-dimethyl) thiaprolyl-L- (N-benzyl) -histidine N- (toiuen-4-sulfonyl) -L-prolyl-4- (3-3'-tolylureido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4 - [(2,3,3a7a-tetrahydro-lH-indole-2-carbonyl) -amino] -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4-pentylamino) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-LO- (2-dibenzylamino-ethyl) - tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-O- [2- (dibenzylamino) ethyl] -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-pentylamino) phenylalanine 10 Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4 - (4-chlorobenzylamino) -phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- [3- (4-cyanophenyl) -ureido] -phenylalanine 15 Methyl ester N- (toluene-4-sulfonyl) -L-prolyl- LO- (tert-butoxycarbonylmethyl) tyrosine N- (toluene-sulfonyl) -L-prolyl-L-O- (tert-butoxycarbonylmethyl) tyrosine N- (toluene-sulphyl) -L-prolyl-L-4- [(3S) -3, -dihydro-isoquiolin-3-yl-aminocarbonyl] -phenylalanine ^^^^^^^^ a ^^^^^ ^^ £ ^ É ^ £ ^^^^^^ mßßAM ^ É? ^ 3a ^ l¿iß & Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [3- (3-methoxy-phenyl) -ureido] -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- ([3- (3-methoxy-phenyl) ureido] -L-phenylalanine N- (toluene-sulfonyl) -L-prolyl-L-O- (4,5-dihydro-lH-imide zol -2 -i 1-methyl) -tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (3-propyl-ureido) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-benzylamino) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (4-benzylamino) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (4-chlorobenzylamino) -phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L- (4-chlorometansulfoni lamino) -phenollanine ? ^^ aS? ^? iE ^? ^ MSI ^, ^ Methyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4- (aminobenzoyl) phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-L-4- (benzamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-4-yl) methylamino] phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-4-yl) methylamino] phenylalanine Ethyl ester N- (toluene-4 -sul foni 1) -L- (5,5-d? Met il) -thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L- (5,5'-dimethyl) -thiaprolyl-L-4- (pyridine-3-carboxamido) phenylalanine 3Jfo ". '-i - ^^ - ^ jg ^^^ a ^^ aHiB ^. * ^ - N- (toluene-sulfonyl) -L- (5, 5-dimethyl) thiaprol? LL-4- ( pyridine-3-carboxamido) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- [(pyridin-3-ylmethyl) amino] phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-4-nitrophenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4-nitrophenylalanine Ethyl ester N- (toluene-4-sulphonyl) -L-prolyl-L-4 - (2-methoxybenzamido) femlalamine N- (toluene-4-sulfonyl) -L- (5,5-d? Methyl) -thiaprolyl-L- (4-nitro) phenylalanine ethyl ester Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4 - (2-bromobenzamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L- (5, 5-d? Met il) thiamorphyl-L-4-aminophen? Lalamine Ethyl ester N- (toluene-4-sulfonyl) -L-prol? LL -4 acetamidophenylalanine N- (toluene-4-sulphonyl) -L-prolyl-L-4- (2-5-methoxybenzamido) phenylalanine N- (toluene-4-sulfonyl) -L- (5,5-d? Methyl) -thiaprolyl-L-4-acetamidophenylalanine ethyl ester 10 N- (toluene-4-sulfonyl) -L- (5, 5-dimetyl) -thiaprolyl-L-4- acetamidophenylalanine Isopropyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4-acetamidophenylalanine 15 Ethyl ester N- (toluene-4-sulphonyl) -L- (5, 5-d? Met il) L-4 - (isonicotinamido) phenylalanine Ester etíl? Co-4- (isonicotinamido) phenylalanine 20 Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (p-toluene-sulfonyl) histidine Ethyl ester N- (toluene-4-fonyl) -L- (5, 5-d? Met il) 25 tiaprolyl-L-4- (nicotamido) phenylalanine g ^ f ^ s? l ^^^^^^^^^^^^^^^^ ^? ^ Jj? a íí? ^ ß? ßOBu ?? iK! »^^ Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L- (0-methyl) tyrosine Ethyl ester N- (α-toluenesulfonyl) -L-prolyl-L-4- (isonicotinamido) phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-L-4- (2-bromobenzamido) phenylalanine 10 N- (a-toluenesulfonyl) -L-prolyl-L-4- (isonicot inamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L- (1, 1- 15 dioxo) t iammorpholyl-L-4 - (2-bromobenzamido) phenylalanine N- (toluene-4-sulfonyl) -L- (1, 1-dioxo) tiamorphol-l- L- (2-bromobenzamido) phenylalanine 20 N- (toluene-4-sulfonyl) -L- (5, 5-dimetl) -L-4- (isonicotinamido) phenylalanine N- (a-toluensul fonyl) -L-prolyl-L-4 - (2 • bromobenzamido) phenylalanine ethyl ester * - * '' a * ^ »^, ^^^,« «.. ^" ^ riaji i ^ Isopropyl ester N- (toluene-4-sulfonyl) -L- (5, 5-dimethyl) -thiaprolyl- L-tyrosine Ter-butyl ester N- (toluene-4-sulfonyl) -L- (5, 5- 5 dimethyl) -thiaprolyl-L-tyrosine Ter-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-tyrosine 10 Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4 - (2-trifluoromethylbenzamido) phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-L-4 - (2-methyl-ilbenzamido) phenylalanine 15 N- (toluene-4-sulphonyl) -L-prolyl-L-4- (2 - trifluoromethyl lbenzamido) phenylalanine Ter-butyl ester N- (4-fluorobenzenesulfonyl) -L-20 thiaprolyl-L-tyrosine Ter-butyl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) -thiaprolyl-L-tyrosine N- (toluene-4-sulfonyl) -L-prolyl-4- (dimethylamino) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl- [(2-bromo) benzamido] -L-phenylalanine ethyl ester Methyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- [(pyrazin-2-yl) C (0) NH] -L-phenylalanine Ethyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 (4 • nitrobenzoyl) -L-phenylalanine T-butyl ester N- (toluene-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- (2-bromobenzamido) -L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-4- (2-bromobenzamido-L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-4- (l-H-2-oxo-3-methyltetrahydropyrimidin-l-yl) L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (l-H-2-oxo-3-methyltetrahydropyrimidin-1-yl) -L-phenylalanine X ^^ ^ j ^^ .- ^^^: A ^ A2f ^? T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-3-chloro-4- (t-butoxy) -L-phenylalanine 5 T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-3-chloro-4- (hydroxy) -L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 - (N, N-dimethexideid) -L-phenylalanine 10 T-butyl ester N- (-fluorobenzenesulfonyl) -L- (5, 5) - dimethyl) thiaprolyl-3-chloro-4-hydroxy) -L-phenylalanine Isopryl ester N- (4-fluorobenzenesulfonyl) -L- (5, 5- 15 dimethyl) thiaprolyl-3-chloro-4- (hydroxy) -L-phenylalanine Isopropyl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4- (hydroxy-L-phenylalanine) T-butyl ester N- (toluene-4-sulfonyl) -L- prolyl-4 - (2-methoxy phenyl) -L-phenylalanine N- (toluene-4-sulfonyl) -L-proli 1-4- (2-methoxy phenyl) -L-25 phenylalanine N- (toluene-4-sulfonyl) -L-prolyl- [(5-N, N-dimethyl-ureido) -pyridin-2-yl] -alanine N- (toluene-4-fonyl) -L-prolyl-4- (N, N-dimethylsulfamyl) -L-phenylalanine N- (toluene-4-fonyl) -L-prolyl-4- (N1, N1, N2-trimethylsulfamyl) -L-phenylalanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl- (l-t-butoxycarbonylmethylimidazol-4-yl) -L-alanine Methyl ester N- (toluene-4-sulfonyl) -L-prolyl- [N, N-dimethylaminocarbonylmethylimidazol-4-yl] -L-alanine Isopropyl Ester N- [4- (dimeth-il-ureilenyl) -benzenesulfonyl] -L-prolyl- -hydroxy-L-phenylalanine Isopropyl ester N- (toluene-sulfonyl) -L-prolyl- (5,5-dimethyl) thiaprolyl-3-chloro-4-hydroxy-L-phenylalanine Isopropyl ester N- (toluene-4-sulfonyl) -L-prolyl-3-chloro-4-hydroxy-L-phenylalanine Methyl ester N- (toluene-4 -sulonyl) -L-prolyl-4 (carboxymethyl) -L-phenylalanine N-methyl ester (toluene-4-sulfonyl) -L-prolyl-4 - (2-methyl-ylbenzamido) -L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (N, N-dimethyl-laminocarbonylmethyl) -L-phenylalanine Isopropyl ester N- (l-methylimidazol-4-sulfonyl) -L-prolyl-4-hydroxy-L-phenylalanine N- (toluene-4-sulphonyl) -L-prolyl-4 • (2, 4, 5-trioxo-3-phenyltetrahydro-imidazol-l-yl) -L-phenylalanine isopropyl ester Isopropyl ether N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-fluoro-4-hydroxy-L-phenylalanine T-butyl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-4-t-butoxy-L-phenylalanine T-butyl ester N-. { N- [(IS-2.10-camphorsultamil] acetyl.}. -L-tyrosine Isopropyl ester N-. { N- [IS) -2.10-camforsultamil] acetil} -3-Chlorotyrosine T-butyl ester N- (4-fluorobenzenesulfonyl) -L-thiaprolyl-4-hydroxy-L-phenylalanine T-Butyl Ester N- (toluene-4 -sulonyl) -L-prolyl-4 - (N, N-dimethyl-1-aminocarbonylmethyl) -L-phenylalanine T-butyl ester N- (toluene-4-sulphonyl) -L-prolyl-4 - (hydroxy-L-phenylalanine) Isopropyl ester N- (toluene-4-sulphonyl) -L- (5,5-dimethyl) thiaprolyl-4-hydroxy-L-phenylalanine T-butyl ester N- (toluene-4-sulfonyl) -L-prolyl-4-hydroxy-L-phenylalanine T-butyl ester N- (pyridin-3-sulphonyl) -L-prolyl-4-hydroxy-L-phenylalanine N- (toluene-4-sulfonyl) -L-prolyl-4- (methansul-fonmido) -L-phenylalanine Benzyl ester N- (toluene-4-sulfonyl) -L-prolyl-4 • (2,4,5-trioxo-3- (3-chlorophenyl) -tetrahydroimidazol-1-yl) -L-phenylalanine Ethyl ester N- (1-methylimidazole-4-sulfonyl) -L- (5,5-dimethyl) thiaprolyl-3-chloro-hydroxy-L-phenylalanine Ter-butyl ester N- (4-fluorobenzenesulfonyl) -L- (5,5-dimethyl) thiaprolyl-L-3-chloro-4-tert-butoxy-phenylalanine Isopropyl ester N- [2- (N-2, 10-camphorsultamil) acetyl] -L-3-chloro-4 'hydroxyphenylalanine ^ jtfj2