MXPA00000909A - 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

COMPOUNDS WHICH INHIBIT THE ADHESION OF LEUKOCYTES MEDIATED BY VLA-4 FIELD OF -INVENTION This invention relates to compounds that inhibit leukocyte adhesion and, in particular, adhesion of leukocyte mediated by VLA-4.

References The following publications, patents and patent applications are cited in this application with super index numbers: Hemler and Takada, European Patent Application Publication No. 330, 506, published on August 30, 1989 Elices, et al., Cell, 60: 577-584 (1990) 3 Springer, Na ture, 346: 423-434 (1990) Osborn, Cell, 62: 3-6 (1990) REF .: 32339 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^ Vedder, et al., Surgery, 106: 509 (1989) 6 Pretolani, et al., J. Exp. Med., 180: 795 (1994) 5 7 Abraham, et al., J. Clin. Invest., 93: 776 (1994) 8 Mulligan, et al., J. Immunology, 150: 2407 10 (1993) 9 Cybulsky, et al., Science, 251: 788 (1991) Li, et al., Arterioscler. Thromb., 13: 197 15 (1993) 11 Sasseville, et al., Am. J. Path., 144: 27 (1994) ? 2 Yang, et al Proc. Nat. Acad. Science (USA), 90: 10494 (1993) 13 Burkly, et al., Diabetes, 43: 529 (1994; Baron, et al., J. Clin. Invest., 93: 1700 (1994) Hamann, et al., J. Immunology, 152: 3238 (1994) 16 Yednock, et al., Nature, 356: 63 (1992; Baron, et al., J. Exp. Med., 177: 57 (1993) 10 18 van Dmther-Janssen, et al., J. Immunology, 147: 4207 (1991). 19 van Dinther-Janssen, et al., Annals, Rheumatic Dis. , 52: 672 (1993) Elices, et al., J. Clin. Invest., 93: 405 (1994) 21 Postigo, et al., J. Clin. Invest., 89: 1445 (1991) 22 Paul, et al., Transpl. Proceed. , 25: 813 (1993) 25 23 Okarhara, et al., Can. Res., 5_4: 3233 (1994) 2 Paavonen, et al., Int. J. Can., 58: 29 (1994) Schadendorf, et al., J. Path., 170: 42 '(1993) 26 Bao, et al., Diff., 52: 239 (1993; 2 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 International Patent Appl. Publication No, WO 96/01644 All previous publications, patents and patent applications have been incorporated in it for full reference to the same points as ^^ r ^^^^^ uijÁ. '^ M. if each individual publication, patent or patent publication was specifically and individually indicated to be incorporated for its reference in its entirety.

BACKGROUND OF THE INVENTION VLA-4 (also assigned as integrin a4β and CD49d / CD29), first identified by Hemler and Takada1, is an element of the ßl integrin family of cell surface receptors, each of which comprises two subunits, a chain a and a string ß. The VLA-4 contains an a4 chain and a ßl chain. There are at least nine ßl mtegrinas, all carry or carry the same ßl chain and each has a different chain. All of these nine receptors bind to a different complement of the various cellular matrix molecules, such as fibronectin, laminin, and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed in endothelial cells in cultured human cytokine-activated umbilical vein. Distinct epitopes of VLA-4 are responsible for the binding activities of fibronectin and VCAM-1 and each activity has been shown to be independently inhibited.2 Intracellular adhesion mediated by VLA-4 and other cell surface receptors are associated with 5 number of inflammatory responses. At the site of an injury or other inflammatory stimuli, the molecules express activated vascular endothelial cells that are adhesive to leukocytes. The mechanisms of adhesion of leukocyte to endothelial cells comprise, in part, the recognition and binding of cell surface receptors in leukocytes to the corresponding cell surface molecules in endothelial cells. Once bound, leukocytes migrate through the blood vessel wall to enter the site of the injury or injury and release the chemical mediator to fight the infection. For review of adhesion receptors of the immune system, see, for example, Springer3 and Osborn4. Inflammatory disorders of the brain, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium / leukocyte adhesion mechanism results in destruction by another part of healthy brain tissue. Big numbers of leukocytes migrate through the blood-brain barrier (BBB) in subjects with these inflammatory diseases. Leukocytes reveal toxic mediators that cause dilated or expanded tissue injury resulting in impaired nerve transmission and paralysis.

In other organ systems, tissue injury also occurs via an adhesion mechanism that results in an emigration or activation of leukocytes. For example, this has shown that the initial trauma after myocardial ischemia to the heart tissue can be further complicated by the entrance of the leukocyte to the damaged tissue causing still further trauma (Vedder et al.5). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma "8, Alzheimer's disease, atherosclerosis9" 10, AIDS, dementia11, diabetes12"14 (including early juvenile diabetes), inflammatory bowel disease15 (including ulcerative colitis and Crohn's disease), multiple sclerosis16"17, rheumatoid arthritis18" 21, tissue transplantation22, tumor metastasis23"28, meningitis, encephalitis, attacks or strokes, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in the respiratory distress syndrome in an adult.

In view of the foregoing, assays for determining the level of VLA-4 in a biological sample containing VLA-4 could be useful, for example, for diagnosing conditions mediated by VLA-4. Additionally, underestimating these advances in the understanding of leukocyte adhesion, the technique has only recently been directed to 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 fifteen This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, for assay in the presence of VLA-4 in a sample and, in pharmaceutical compositions, to inhibit cell adhesion mediated by VLA-4, for example, by binding VCAM-1 to VLA. -. The compounds of this invention have a binding affinity for VLA-4 as expressed by an IC50 of about 15 μM or less (as measured * aS * ^^ using the procedure shown in Example 46 below) said compounds are defined by the following formula I: OR II R'-SO, -N (R2) -C-Q-CH-C-OH! I H R where 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, and substituted heteroaryl, and R1 and R2 together with the nitrogen bound 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 aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R2 and R3 together with the nitrogen atom attached to R2 and the carbon atom attached to R3 can form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group; 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; and X is selected from the group consisting of oxygen and sulfur; R5 is -CH2X where X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxy, carboxyl, carboxyalkyl, carboxyalkyl substituted I, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, substituted carboxyl-aryl, ^ '^^ ^ v ^ fci? ^^^^^^^^^^^^^^ A ^^^^ ^^^^ tó carboxylheteroaryl, I carboxylheteroaryl substituted carboxilheterociclico, carboxilheterociclico substituted cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the additional proviso that: A. R5 is not - (CH2) X-Ar-R5 'wherein R5' is -OZ-NR8R8 'or -OZ-R12 where R8 and R8' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and R8 and R8 'together may 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 (0) - and -S02-, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; ^ ^? ^:? ^^^ ^ ^^^ B. R5 is not - (CH2) X-Ar-R5 where R5 is -NR12C (Z ') NR8R8' or -NR12C (Z) R13 where Z 'is selected from the group consisting of oxygen, sulfur and NR12, R12 is selected from the group consisting of hydrogen, alkyl and aryl, R8 and R8 'are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and heteroaryl always replaced when Z 'is oxygen, at least one of R8 and R8' is alkyl substituted, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, or substituted heterocyclic or R8 and R8 'may be together to form a saturated heterocycle other than morpholino or thiomorpholino, a heterocycle substituted saturated or a saturated / unsaturated heterocycle having an amino group substituted with an alkoxycarbonyl substituent, and in addition s provided that when V 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 saturated heterocycles and substituted heterocycles other than morpholino and thiomorpholino, substituted heterocycles, Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer from 1 to 4; C. R5 is not -ALQ-X 'wherein ALQ is an alkyl group of 1 to 10 carbon atoms attached via a methylene group (-CH2) to 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, heteroaryloxycarbonyl substituted heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl I, cycloalkyl, substituted cycloalkyl, saturated heterocyclic, substituted saturated heterocyclic, substituted alkoxy, alkenoxy substituted alkynoxy substituted heterocyclyloxy, substituted heterocycloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, guanidino, amidino, alkylamidino, thioamidino, halogen, cyano, nitro, -OS (0) 2 -alkyl, -OS (0) 2 -substituted alkyl, -OS ( 0) 2-cycloalkyl, -0S (0) 2-substituted cycloalkyl, OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2 -heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -0S02-NRR, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS ( 0) 2-cycloalkyl, -NRS (0) 2-substituted cycloalkyl, -NRS (0) 2-aryl, -NRS (O) 2 -substituted aryl, -. 10 -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 (O) 2-NR-cycloalkyl, -NRS (O) 2-NR-substituted cycloalkyl, -NRS (O) 2-NR-aryl, -NRS (O 2-NR-aryl Substituted, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR- substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -NRS (O) 2-NR-heterocyclic substituted where R is hydrogen or alkyl, -S (0) 2-alkyl, -S (0) 2-substituted alkyl, -S (0) 2-aryl, -S (0) 2 -substituted aryl, twenty - . 20 -S (0) 2-substituted heteroaryl, -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) amino, N, N- (substituted alkyl, alkyl substituted) amino, N, N- (heteroaryl, alkyl , TW ^ MJ ^ M ^ fflfe ^^ Aii & ^ fc - ^^ substituted) amino, N, N- (substituted heteroaryl, substituted alkyl) amino, N, N- (heterocyclic, substituted alkyl) amino, N, NN , N- (substituted heterocyclic, substituted alkyl) amino, mono- and di- (heterocyclic) amino, mono- and di- (substituted heterocyclic) amino, N, N- (alkyl, heterocyclic) amino, N, N- (alkyl) , substituted heterocyclic) amino, N, N- (aryl, heterocyclic) amino, N, N- (substituted aryl, heterocyclic) amino, N, N- (aryl, substituted heterocyclic) amino, N, N-substituted aryl, substituted heterocyclic ) amino, N, N- (heteroaryl, heterocyclic) amino, N, N- (heteroaryl, substituted heterocyclic) amino, N, N- (substituted heteroaryl, heterocyclic) amino, and N, N- (substituted heteroaryl, substituted heterocyclic) Not me; D. R5 is not - (CH2) x-Ar-R5"wherein 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, amidino alkyl, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyalkyl substituted I, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, 5 substituted carboxylaryl, I carboxylheteroaryl , carboxyl- substituted heteroaryl, carboxilheterociclico, carboxilheterociclico substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfona, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioaryl substituted, thiocycloalkyl, substituted thiocycloalkyl I, thioheteroaryl, substituted thioheteroaryl I, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy substituted heteroaryloxy, substituted heterocyclyloxy, heterocyclyloxy substituted oxicarbonilammo, oxitiocarbonilamino, -OS (0) 2_alquilo, -OS (O) 2-substituted alkyl, -OS (0) 2-aryl, -OS (0) 2-substituted aryl, -OS (0) 2-heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2-heterocyclic Substituted, -0S02-NRR, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0 ) 2-heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2- NR-alkyl substituted, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-aryl ^^^? A substituted alkali, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, - NRS (0) 2-NR-substituted heterocyclic, mono- and dialkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino , mono- and di- (heteroaryl substituted) amino, mono- and di-amino heterocyclic, mono- and di- (heterocyclic substituted) amino, and asymmetric disubstituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by blocking groups conventional (such as Boc, Cbz, Formyl, and the like) and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, - S02-substituted cycloalkyl, -S? 2-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -SO? -heterocyclic, -S? 2-substituted heterocyclic or -SO2NRR, wherein R is hydrogen or alkyl; (B) alkoxyaryl substituted on the alkoxy portion by a substituent selected from the group consisting of carboxyl and -COOR 23 where 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 proviso that at least one of R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic or 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, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl , carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, What is it? substituted aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, substituted carboxylheterocyclic, substituted carboxyl-heterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, thioheterocyclic substituted, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy substituted, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy substituted, oxycarbonylamino, oxitiocarbonilamino, -OS (O) 2-alkyl, -OS (0) 2-substituted alkyl, -OS (O ) 2-aryl, -OS (O) 2-substituted aryl, -OS (O) 2-heteroaryl, -OS (O) 2-substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2- substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (O) 2-ary so, -NRS (O) 2-substituted aryl, -NRS (0) 2-heteroaryl, -NRS (0) 2-substituted heteroaryl, -NRS (O) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (O ) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono - and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di- heterocyclic amino, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by group conventional blocking (such as Boc, Cbz, Formyl, and the like) and substituted alkyl / alkyl groups, substituted with -S0-alkyl, -S02-substituted alkyl, -S? 2-alkenyl, -S? 2 -substituted alkenyl , -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-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 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, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-alkyl substituted, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroappe, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, or xitiocarbonylamino, -OS (O) 2_alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2 -aryl, -OS (0) -substituted aryl, -OS (0) 2-heteroaryl, -OS ( 0) 2-substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (O) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2 - substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2-5 substituted heteroaryl, -NRS (O) 2- heterocyclic, -NRS (0) 2- substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2- NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) ) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR- substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -. 10-NRS (O) 2-NR-substituted heterocyclic, mono- and dialkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono and di- -heteroarylamino, mono- and di- (heteroaryl substituted) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and disubstituted asymmetric amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and substituted alkyl / alkyl groups, substituted with -S0-alkyl, -S02-substituted alkyl , -. 25 -S02-alkenyl, -S02-substituted alkenyl, -S02- cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02 -substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S0NRR, wherein R is hydrogen or I rent; (f) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy / heteroaryloxy is any of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1, 2-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, - alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (g) saturated-heterocyclic alkoxy, saturated substituted-heterocyclic substituted heterocyclic, substituted-alkoxy-heterocyclic and substituted substituted-heterocyclic saturated substituted; (h) -O-heterocyclic and -O-heterocyclic substituted; (i) tetrazolyl; Jaey & Jasfeafcjfefe ^ (j) -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 any of halogen, hydroxyl, amino, nitro , trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N , N-dialkylurea; (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (1) substituted alkoxy with the proviso that the substitution in the alkyl portion of said substituted alkoxy does not include alkoxy-NR "R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl / heteroaryl substituted with halogen, hydroxyl , amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylammo, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N -alkyl or N, N-dialkylurea; (m) amidine and amidine substituted with from 1 to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; (n) -C (0) NR "'R'" wherein each R "'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that when 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-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkylamine, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N , N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (any unsubstituted heterocyclic substituted alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic or substituted heterocyclic; (o) -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; (p) -S0-aryl, -S02-substituted aryl, -S02-heteroaryl, -S-2-substituted heteroaryl or -S02-alkyl; (q) -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; (r) -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; (s) -aminocarbonyl- (N-formylheterocyclyl); Y (t) -alkyl-C (O) H-heterocyclyl and -alkyl-C (O) NH-substituted heterocyclyl, and E. When R3 is different from H, R5 is not - (CH2) X- Ar-R5 wherein R5 is substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the alkenyl / alkynyl portion is ^^ sS ei ^ t ^ k, selects from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with the substituted alkyl at least one of the substituents on the 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, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, g uanidino, 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 (0) 2 -alkyl, -OS (0) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (0) 2 -substituted aryl, -OS (0) 2- heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (O) 2 -substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2 -alkyl, - NRS (0) 2-substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) -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- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono and di- -heteroarylamino, mono- and di- (heteroaryl substituted) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric di-substituted amines having different substituents selected from the group consisting of of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, 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 -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02- cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02 -substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR, wherein R it is hydrogen or alkyl; and pharmaceutically acceptable salts thereof and still additionally with the following conditions that exclude the following compounds A. when R1 and R2 are bonded together with S02 and the nitrogen atom to which they are attached respectively form a heterocyclic benzoisothiazolone ring, R3 is hydrogen, and Q is -C (0) NH-, then R5 is not benzyl; Y B. when R1 is p-methylphenyl, R2 is methyl, R3 is hydrogen, Q is -C (0) NCH3-, then R5 is not benzyl. ^^^^^^^^^^^^^^^^^^^? ^^^^^^^^^^^^^ j ^^; j =? In another embodiment, the compounds of this invention can also be provided as prodrugs such as the convert (eg, hydrolyzes, metabolizes, etc.). ) in vivo in a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid of the compound of the formula I was modified into a group which, in vivo, was converted to the carboxylic acid (including salts thereof). In a particularly preferred embodiment, such prodrugs are represented by compounds of the formula IA: R3 O I I R'-SO ^ NG ^ -C-Q-CH-C-R * 1A I I H R5 where 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, and substituted heteroaryl, and R1 and R2 together with the nitrogen bound 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 aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and wherein R2 and R3 together with the nitrogen atom attached to R2 and the carbon atom attached to R3 can form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group; Ar is aryl, heteropole, 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-succinimidyl), -NH-adamantyl, -O-cholest-5-en-3-yl, -NHOY wherein Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, -NH (CH2) pCOOY wherein p is a whole number from 1 to 8 and Y is as defined above, -OCH2NR9R10 wherein R9 is selected from the group consisting of -C (0) -aryl and -C (0) -substituted aryl and R10 is selected from the group which consists of hydrogen and -CH2COORn wherein R11 is alkyl, and -NHS02Z "wherein Z" is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is -C (X) NR7- wherein R7 is selected from the group consisting of hydrogen and alkyl; and 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, substituted cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic , with the additional condition that: A. R5 is not - (CH2) X-Ar-R5 'wherein R5' is selected from the group consisting of -0-Z-NR8R8 'or -OZ-R12 wherein R8 and R8' are independently selected from From the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, and wherein R8 and R8 'are linked to form a heterocycle or a substituted heterocycle, R12 is selected from the group consisting of 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 an integer from 1 to 4; B. R? 5"no_ e_s_ _- (wherein R" is selected from the group consisting of -NR12C (Z ') NR8R8' and -NR12C (Z) R13 where Z 'is selected from the group that consists of oxygen, sulfur and NR12, R12 is selected from the group consisting of hydrogen, alkyl and aryl, R8 and R8 'are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, aryl substituted, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided 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, or substituted heterocyclic or R8 and R8 'may be together to form a saturated heterocycle different from morpholino or thiomorpholino, a saturated substituted heterocycle or a saturated / unsaturated heterocycle having an amino group substituted with a substituted alkoxycarbonyl, and further provided that when 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 saturated heterocycles and substituted heterocycles different from morpholino and thiomorpholino, ^^ éj &^^ U ^ ^^ í tS ^ 'U ^ - Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer from 1 to 4; C. R5 is not -? ALQ-X 'wherein ALQ is an alkyl group of 1 to 10 carbon atoms attached via a methylene group (-CH2) to 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, cycloalkyl, substituted cycloalkyl, saturated heterocyclic, substituted heterocyclic substituted, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted heterocycloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, guanidino, amidino , alkylamine, thioamidino, halogen, cyano, nitro, -OS (0) 2-alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-cycloalkyl, -0S (0) 2-substituted cycloalkyl, OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2 -heteroaryl, -OS (0 ) 2-substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -0S02-NRR, -NRS (0) 2-alkyl, -NRS (O) 2-substituted alkyl, - NRS (O) 2-cycloalkyl, -NRS (O) 2 -substituted cycloalkyl, -NRS (O) 2 -aryl, -NRS (O) 2 -substituted aryl, -NRS (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 (O) 2-NR-cycloalkyl, -NRS (O) 2-NR-substituted cycloalkyl, -NRS (O) 2-NR-aryl, -NRS (O) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic wherein R is hydrogen or alkyl, -S (0) 2_alkyl, -S (O) 2 -substituted alkyl, -S (O) 2 -aryl, -S (0) 2 -substituted aryl, -S (0) 2 -substituted heteroaryl, -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) amino, N, N- (substituted aryl, substituted alkyl) amino, N, N- (heteroaryl, substituted alkyl) amino, N, N- (substituted heteroaryl, substituted alkyl) amino, N, N- (heterocyclic, substituted alkyl) amino, N, NN, N- (substituted heterocyclic, substituted alkyl) amino, mono- and di- 5 (heterocyclic) amino, mono- and di- (substituted heterocyclic) amino, N , N- (alkyl, heterocyclic) amino, N, N- (alkyl, substituted heterocyclic) amino, N, N- (aryl, heterocyclic) amino or, N, N- (substituted aryl, heterocyclic) amino, N, N- (aryl, substituted heterocyclic) amino, N, N-substituted aryl, substituted heterocyclic) amino, N, N- (heteroaryl, heterocyclic) amino, N, N- (heteroaryl, substituted heterocyclic) amino, N, N- (substituted heteroaryl, heterocyclic) amino, and N, N- (substituted heteroaryl, substituted heterocyclic) amino; D. R5 is not - (CH2) x-Ar-R5"wherein 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 substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amid , thioamidino, aminoacyl, aminocarbonylamine, aminothiocarbonylamino, ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^ A ^^^^^^ M ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted catrboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, 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 (O) 2 -substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2 -substituted heterocyclic, -OS02- NRR, -NRS (O) 2-alkyl, -NRS (O) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, - NRS (O) 2-substituted heteroaryl, -NRS (O) 2-heterocyclic, -NRS (O) 2 -substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl , -NRS (O) 2-NR-aryl, -NRS (O) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS ( O) 2-NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and dialkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (aryl) substituted) amino, mono and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different selected substituents to from the a group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and alkyl / substituted alkyl groups, substituted with -S? 2 ~ alkyl, -S? 2 -substituted alkyl, -S? 2 ~ alkenyl, -S? 2 -substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, - S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S-2-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -SO2NRR, wherein R is hydrogen or alkyl; (B) alkoxyaryl substituted on the alkoxy portion by a substituent selected from the group consisting of carboxyl and -COOR 23 where 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, cycloalkyl, substituted cycloalkyl, heterocyclic or 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, thiocarbonylamino, acyloxy, alkenyl, amino, amid, alkylamidino, thioamid, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl , carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, ca rboxylaryl, "Substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, thiocycloalkyl substituted, 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 (O) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2- heterocyclic, -OS (O) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2- substituted alkyl, -NRS (O) 2-aryl, - NRS (O) 2-substituted aryl, -NRS (0) 2-heteroaryl lo, -NRS (0) 2- substituted heteroaryl, -NRS (O) 2 -heterocyclic, -NRS (0) 2- substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2- NR-alkyl substituted, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR- substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by groups conventional blocking (such as Boc, Cbz, Formyl, and the like) and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S0-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl , -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S? 2 -substituted heteroaryl, -S? 2 -heterocyclic, -S02-substituted heterocyclic or -SO2NRR, wherein R it 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 4 alkyl substituted 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, 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, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, heterocyclic substituted, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (O) 2 -aryl, - OS (O) 2-substituted aryl, -OS (O) -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS ( O) 2-alkyl, -NRS (0) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O ) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR -heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and dialkylamino, 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-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different substituents selected from the group consisting of of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl , -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR, wherein R is hydrogen or alkyl; (f) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy / heteroaryloxy is any of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, -dialkylurea; (g) saturated-heterocyclic alkoxy, saturated substituted-heterocyclic-substituted heterocyclic, substituted-heterocyclic-alkoxy, and substituted substituted-heterocyclic substituted-saturated; (h) -O-heterocyclic and -O-heterocyclic substituted; (i) tetrazolyl; (j) -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 any of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy , alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (1) substituted alkoxy with the proviso that the substitution in the alkyl portion of said substituted alkoxy does not include alkoxy-NR "R", unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl / heteroaryl substituted by halogen, hydroxyl , amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N -alkyl or N, N-dialkylurea; (m) amidine and amidine substituted with from 1 to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; (n) -C (0) NR "'R"' wherein each R "'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that when 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-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N , N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (any unsubstituted heterocyclic substituted alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, alkenyl or substituted, substituted alkynyl, alkynyl and heterocyclic or substituted heterocyclic; (o) -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; (p) -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl or -S02-alkyl; (q) -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; 5 (r) -NR'C (0) OR19 wherein R 'is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, heteroaryl Substituted, heterocyclic and substituted heterocyclic and R19 is selected from that consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic replaced; (s) -aminocarbonyl- (N-formylheterocyclyl); Y (t) -alkyl-C (O) H -heterocyclyl and -alkyl- 20 C (O) NH-substituted heterocyclyl, and E. When R3 is different from H, R5 is not - (CH2) X- Ar-R5"wherein R5" is substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents in the alkenyl / alkynyl portion are selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with the substituted alkyl at least one of the substituents on the 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 , cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl , substituted cycloalkyl, guanidino, g uanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, heteroaryloxy • > -. Substituted ~, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (0) 2 -alkyl, -OS (0) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (0) 2 -substituted aryl , -OS (O) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2 -substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2- substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2- substituted heteroaryl, -NRS (O) 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 (O) 2_NR-substituted heterocyclic, mono- and dialkylamino, 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-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by groups conventional blocking (such as Boc, Cbz, Formyl, and the like) and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02- cycloalkyl , -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR, wherein R is hydrogen or alkyl; And pharmaceutically acceptable salts thereof with the following conditions A. When R1 is o-carboxymethylphenyl, R2 is hydrogen or methyl, R5 is benzyl and Q is -C (0) NH-, then R6 is not -O-benzyl; B. when R1 and R2 are together to form a heterocyclic benzoisothiazolone ring, R3 is hydrogen or methyl, R5 and benzyl and Q is -C (0) NH-, then R6 is not -O-benzyl; C. when R1 is p-methylphenyl, R2 is hydrogen, R5 is benzyl or p-hydroxybenzyl, R3 is - (CH2) SC (O) O-t- ? Aatga ^? Étife¿taSaS «^» ^ j. & Aaij > butyl where s is 1 or 2, Q is -C (0) NH-, then R is not -O-t-butyl; D. when R1 is p-methylphenyl, R2 is methyl, R5 is benzyl, R3 is -CH (f) 2, Q is -C (0) NH-, then R6 is not -O-benzyl; E. when R1 is p-methylphenyl, R2 is methyl, R5 is methyl, R3 is -hydroxymethyl, Q is -C (0) NH-, then R6 is not -O-methyl; Y F. when R1 is p-methylphenyl, R2 is methyl, R3 is methyl or t-butyl, R5 is p-hydroxybenzyl, Q is -C (0) NH-, then R6 is not -O-t-butyl.

Preferably, in the compounds of formula I and IA above, R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl. Even more preferably R1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4- '^? ¡Jgi ^^^^^ 2 ^ £? ¿£ ítíá ^^^^^^^^^^^^ chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2, 4, 6-trimethylphenyl, 2- (methoxycarbonyl) phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (CH 3 C (O) NH-) phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-t-butylphenyl, 4-butoxyphenyl, 4-nitrophenyl, 2-thienyl, lN-methyl-3-methyl-5- chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- [CH3SC (= NH)] phenyl, 5-chloro-2-thienyl, 2, 5-dichloro-4-thienyl, lN-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-l, 3,4-thiadiazol-2-yl, 4- [H2NC (S)] phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4- (3'-dimethylamino-n-propoxy) -phenyl, and l-met? lpirazol-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 are linked to form a heterocyclic group or substituted heterocyclic group. Heterocyclic and heterocyclic groups A? - fc. Í.

Preferred substituted include those having a ring of 5 to 7 atoms having 2 to 3 heteroatoms in the ring selected from nitrogen, oxygen and sulfur; said ring is optionally fused to another ring such as a phenyl or cyclohexyl ring to provide a ring heterocycle fused from a ring of 10 to 14 atoms having 2 to 4 heteroatoms in the ring selected from nitrogen, oxygen and sulfur. Particularly preferred R1 / R2 groups include, by way of example, benzisothiazolonyl (saccharin-2-yl).

Preferably, in the compounds of formula I and IA above, R3 includes all isomers arising by substitution with methyl, phenyl, benzyl, diphenylmethyl, -CH2CH2-COOH, -CH2-COOH, 2-amidoethyl, isobutyl, t -butyl, -CH0-benzyl and hydroxymethyl.

Q is preferably -C (0) NH- or -C (S) NH-.

R is preferably selected from all possible isomers arising by substitution with the following groups: benzyl, (N-benzylimidazol-4-yl) methyl, (pyridin-2-yl) methyl, (pyridin-3-yl) ) methyl, (pyridin-4-yl) methyl, 4-7 [2- (pyridin-2-yl) ethynyl] benzyl, 4- [2- (3-hydroxyphenyl) ethynyl] benzyl, 4-iodobenzyl, 4-cyanobenzyl, 4- (2-bromobenzamido) benzyl, 4- (pyrid? n-4-yl-C (0) NH-) benzyl, and 4-hydroxybenzyl.

In the compounds of the formula IA, R6 is preferably 2-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy,. neo-pentoxy, 2-a-iso-propyl-4-β-methylcyclohexoxi, 2-ß-isopropyl-4-β-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2C00H, -NHCH2CH2COOH, -NH-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-yl, -0CH2-0C (0) C (CH3) 3, -0 (CH2) ZNHC ( 0) W wherein z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methι-1,4-dihydro-pyrid-3-yl, -NR "C (0) -R 'wherein R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH2C (0) OCH2CH3.

Preferred compounds within the scope of the above formulas I and IA include by way of example: N- (toluene-4-sulfonyl) - (2S-indolin-2-carbonyl) -L-phenylalanine N- (toluene-4 -sily fonyl) -2S-1, 2, 3, 4-tetrahydroquinoline-3-carbonyl-L-phenylalanine N- (toluene-4-sulfonyl) glycyl-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-L-phenylalanine 10 N- (toluene-4-sulfonyl) -L-alanyl-L-phenylalanine N- (2-methoxycarbonylbenzenesulfonyl) glycyl-L-phenylalanine 15 N- (2-methoxycarbonylbenzenesulfonyl) L-alanyl-L-phenylalanine N- (saccharin-2-yl) -L-alanyl-L-phenylalanine 20 N- (toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-met i 1 -L-f eni la lani 1-D, L-25 f enylalanine N- (toluene-4-sulfonyl) -L-diphenylalanyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-diphenylalanyl-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-L- (N-benzyl) histidine N- (toIuen-4-sulfonyl) sarcosi1-D, L-ß- (3-pyridyl) alanine N- (toluene-4-sulfonyl) sarcosi1-D, L-β- (4-pyridyl) alanine N- (toluene-4-sulfonyl) sarcosyl-L-β- (2-pyridyl) alanine N- (toluene-4-sulfonyl) -D, L-phenylsarcosyl-1-L-phenylalanine N- (toluene-4-sulfonyl) -L-aspartyl-L-phenylalanine Benzyl ester of N- (toluene-4-sulfonyl) - (2S- 1,2,3,4-tetrahydroisoquinoline-3-carbonyl) - L- phenylalanine Benzyl ester of N- (toluene-4-sulfonyl) - (2S-indolin-2-carbonyl) -L-phenylalanine N- (toluene-4-sulfonyl) -L-alanyl-L-phenylalanine benzyl ester Benzyl ester of N- (toluene-4-sulfonyl) sarcosi1-L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -N-methyl-L- (O-benzyl) seryl-L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -N-methyl-L- (O-benzyl) seryl-L-phenylalanine ethyl ester Benzyl ester of N- (toluene-4-sulfonyl) -L- diphenylalani1-L-phenylalanine N- (toluene-4-sulfonyl) -N-phenylglycyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-D, L-phenylglycyl-L-phenylalanine ethyl ester Methyl ester of N- (toluene-4-sulfonyl) sarcosyl-L- (N-benzyl) histidine ? - (Toluene-4-sulfonyl) -N-methyl-L-seryl-L- (N-benzyl) histidine methyl ester Benzyl ester of? - (toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine Β-benzyl ester (toluene-4-sulfonyl) -N-methyl-D, L-phenylglycyl-L-phenylalanine Methyl ester of? - (toluene-4-sulfonyl) -N-benzylglici1-L-phenylalanine ? - (toluene-4-sulfon? l) -N-benzylglycyl-L-phenylalanine N- (toluene-4-sulfon? l) sarcosyl-4- [2- (pyridin-2-yl) ethynyl] -D, L -phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [2- (3-hydroxyphenyl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosi1-D, L-4- (iodo) phenylalanine N- (toluene-4-sulfonyl) -N- (2-thienylethyl) glycyl-L-phenylalanine methyl ester N- (toluene-4-sulfonyl) -N- (2-thienylethyl) glycyl-L-phenylalanine Methyl ester of? - (toluene-4-sulfonyl) -N-methyl-L-seryl-L- (N-benzyl) histidine ? - (Toluene-4-sulfonyl) -N- (2-phenylethyl) glycyl-L- (N-benzyl) histidine methyl ester ? - (toluene-4-sulfonyl) -N- (2-phenylethyl) glycyl-L-phenylalanine ^^^^^ i ^^ j ^ ¡£ i! ^^^ ¿¡j¿ ^^^ i ^^ & ^^ N- (toluene-4-sulfonyl) sarcosyl-D, L-4-cyanophenylalanine N- (toluene-4-sulfonyl) -L-tert-butylglycyl-L-phenylalanine Methyl ester of N- (saccharin-2-yl) -D, L-alaninyl-L-4 - (isonicotinamido) phenylalanine and pharmaceutically acceptable salts thereof as well as any of the ester compounds mentioned above wherein one ester is substituted with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, ester n-butyl, isobutyl ester, sec-butyl ester and tert-butyl ester.

This invention also provides methods for binding VLA-4 to a biological sample, in which the method comprises contacting the biological sample with a compound of formula I or IA above under conditions wherein said compound binds to VLA- Four. Certain compounds of formula I and IA above are also useful in reducing inflammation in vivo mediated by VLA-4.

This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of formula I or IA above with the exception that R3 and R5 are derived from L-amino acids or other starting materials or initials of similar configuration. Alternatively, racemic mixtures may be used. The pharmaceutical compositions can also be used to treat disease conditions mediated by VLA-4. Such disease conditions include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including early juvenile diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, attacks or strokes, and other brain traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as occurs in the respiratory distress syndrome in an adult. Accordingly, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4 said methods comprising administering to the patient the pharmaceutical compositions described above. Preferred compounds of formula I and IA above include those indicated below in the following Table I: «S H In n ) O cp (_p (Ti CD NJ NJ or (-i c_p o NJ NJ one or Ul Cn DETAILED DESCRIPTION OF THE INVENTION As above, this invention relates to compounds that inhibit leukocyte adhesion and, in particular, adhesion of leukocyte mediated by VLA-4. However, to describe this invention previously in additional detail, the following terms were first defined.

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

"Substituted alkyl" refers to an alkyl group, preferably 1 to 10 carbon atoms, having 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidoino, thioamidino, alkylthioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, ¡¡¡¡¡¡¡¡! aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, 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, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, -OS (0) 2 -al substituted ilo, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2 -heterocyclic, -OS (O) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS ( O) 2-substituted aryl, -NRS (O) 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-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 dialkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (aryl) substituted) amino, mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, disubstituted asymmetric amines having different substituents selected from of the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and substituted alkyl / alkyl groups, substituted with -S? 2-alkyl, -S0-substituted alkyl, -S? 2-alkenyl, -S02-substituted alkenyl, -S02- cycloalkyl, -S? 2- substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR wherein R is hydrogen or alkyl.

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

"Alkoxy substituted" refers to the group "alkyl-O-substituted".

"Acyl" refers to the groups HC (O) -, alkyl-C (O) -, alkyl-C (O) -substituted, alkenyl-C (O) -, alkenyl-C (O) -substituted, alkynyl- C (O) -, C (O) -substituted alkynyl, C (O) - cycloalkyl, C (O) -substituted cycloalkyl, aryl-C (O) -, aryl-C (O) -substituted, heteroaryl -C (O) -, heteroaryl-C (O) -substituted, heterocyclic-C (O) -, and heterocyclic-C (O) -substituted 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.

"Acylamino" refers to the group -C (0) NRR wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl , substituted cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein each R is linked to form, together with the nitrogen atom, a substituted heterocyclic or heterocyclic ring 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.

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

"Acyloxy" refers to the groups alkyl-C (0) 0-, alkyl-C (O) -substituted, alkenyl-C (O) O-, alkenyl-C (O) O-substituted, alkynyl-C (O ) O-, (0) -substituted (C) 0 alkynyl, aryl-C (0) 0-, aryl-C (0) 0 -substituted, cycloalkyl-C (O) O-, cycloalkyl-C (O) O- substituted, heteroaryl-C (O) O-, heteroaryl-C (O) O-substituted, heterocyclic-C (O) O-, and heterocyclic-C (O) O-substituted wherein alkyl, substituted alkyl, alkenyl, alkenyl substituted, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Alkenyl" refers to the alkenyl group which preferably has from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and has at least 1 and preferably 1-2 sites of alkenyl unsaturation.

- "* - * - * '? A ^ ^ Í1ffffflí ilíl" lMlll ^ faÉJl ¥ ^ Ml ^ -MÍ-Í- * "Substituted alkenyl" refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, alkylthioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen , hydroxyl, cyano, nitro, 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, thiol, thioalkyl, thioalkyl substituted, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino , -OS (0) 2-alkyl, ts & amp; SS? & amp; amp; amp; & amp; S & amp; SMtea > * ß? li Z £ & ": -OS (0) 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) -alkyl, -NRS (0) 2-substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (O) 2 -substituted heteroaryl, -NRS (0) 2 -heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl , -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and dialkylamino, 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- -aminocyclic amino, mono and di- (substituted heterocyclic) amino, disubstituted asymmetric amines that have different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkenyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and substituted alkenyl / alkenyl groups, substituted with -S? 2 ~ 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, -S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR, wherein R is hydrogen or alkyl.

"Alkynyl" refers to the alkynyl group which preferably has from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and has at least 1 and preferably 1-2 sites of alkynyl unsaturation.

"Substituted alkynyl" refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidoino, thioamidino, alkylthioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxyl -substituted aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thiohetero Icyl, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, Substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, -OS (0) 2-substituted alkyl, -OS (O) 2-aryl -OS (O) 2-aryl Substituted, -OS (O) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2- substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS ( O) 2-heteroaryl Substituted, -NRS (O) 2-heterocyclic, -NRS (0) -substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2- NR-substituted alkyl, -NRS (O) 2 -NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR- substituted heteroaryl, -NRS (O) -NR-heterocyclic, -. 25 -NRS (O) 2-NR-substituted heterocyclic, mono- and di- alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di- heterocyclic amino, mono and di- (substituted heterocyclic) amino, disubstituted asymmetric amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, groups substituted alkynyls having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and substituted alkynyl / alkynyl groups, substituted with -S? 2-alkyl, -S02-substituted alkyl, -S? 2 -alkenyl, -S? -sub.2 -substituted alkenyl, -S02-cycloalkyl, -S02-cycloalkyl, -S? 2 -aryl, -S0 -substituted aryl, -S0-heteroaryl, -S02 -substituted heteroaryl, -S02 -heterocyclic, -S02-substituted heterocyclic or -SO2NRR wherein R is hydrogen or alkyl. "amidino" refers to the group H2NC (= NH) - and the term "alkylamidoino" refers to compounds having 1 to 3 alkyl groups (eg, alkyl HNC (= NH) -).

"Thioamidino" refers to the group RSC (= NH) - wherein R is hydrogen or alkyl.

"Aminoacyl" refers to the groups -NRC (O) -5 alkyl, -NRC (0) -substituted alkyl, -NRC (O) -cycloalkyl, -NRC (0) -substituted cycloalkyl, -NRC (0) -alkenyl , -NRC (0) -substituted alkenyl, -NRC (0) -alkynyl, -NRC (0) -substituted alkynyl, -NRC (0) -aryl, -NRC (0) -substituted aryl, -. 10 -. -NRC (0) -heteroaryl, -NRC (0) -substituted heteroaryl, -NRC (0) -heterocyclic, and -NRC (0) -substituted heterocyclic wherein R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminocarbonyloxy" refers to the groups -NRC (0) 0 -alkyl, -NRC (0) -substituted alkyl, -NRC (0) 0 -alkenyl, -NRC (0) -O-substituted alkenyl, -NRC ( 0) 0-alkynyl, -NRC (0) O-substituted alkynyl, -NRC (0) 0-cycloalkyl, -NRC (0) O-substituted cycloalkyl, -NRC (0) 0 -aryl, -NRC (0) 0 -substituted aryl, -NRC (0) 0- 25 heteroaryl, -NRC (0) O-substituted heteroaryl, -NRC (0) 0- heterocyclic, and -NRC (0) substituted O-hetrocyclic wherein R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heterocyclic, heterocyclic and substituted heterocyclic are as defined herein.

"Oxicarbonylamino" refers to groups -0C (0) NH2, -0C (0) NRR, -OC (0) NR-alkyl, -OC (0) NR-substituted alkyl, -OC (O) NR-alkenyl, -OC (0) NR- substituted alkenyl, -0C (O) NR-alkynyl, -OC (0) NR-substituted alkynyl, -OC (O) NR-cycloalkyl, -OC (0) NR-substituted cycloalkyl, -OC (O) NR-aryl, -OC (0) NR-substituted aryl, fifteen - . 15-OC (O) NR-heteroaryl, -OC (0) NR-substituted heteroaryl, -OC (0) NR-heterocyclic, -OC (0) NR-substituted heterocyclic wherein R is hydrogen, alkyl or wherein each R is ligated to form, together with the nitrogen atom a heterocyclic or heterocyclic ring substituted where Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as define here. aaa ^ fcáá "Oxitiocarbonylamino" refers to the groups -OC (S) NH 2, -OC (S) NRR, -OC (S) R-alkyl, -OC (S) NR-substituted alkyl, -OC (S) NR -alkenyl, -OC (S) NR-substituted alkenyl, -OC (S) NR-alkynyl, -OC (S) NR-substituted alkynyl, -OC (S) NR-cycloalkyl, -OC (S) NR-substituted cycloalkyl, -OC (S) NR-aryl, -OC (S) R-substituted aryl, -OC (S) NR-heteroaryl, -OC (S) NR-substituted heteroaryl, -OC (S) NR-heterocyclic, and - NR-substituted heterocyclic OC (S) wherein R is hydrogen, alkyl or wherein each R is linked to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminocarbonylamino" refers to the groups -NRC (O) NRR, -NRC (O) NR-alkyl, -NRC (O) NR-substituted alkyl, -NRC (O) NR-alkenyl, -NRC (O) NR- substituted alkenyl, -NRC (O) NR-alkynyl, -NRC (O) NR-substituted alkynyl, -NRC (O) NR-aryl, -NRC (O) NR-substituted aryl, -NRC (O) NR-cycloalkyl, -NRC (O) NR-substituted cycloalkyl, -NRC (0) NR-heteroaryl, -NRC (O) NR-heteroaryl Ü JUÜJBSattBS ». ^^^^ ^^^^^^ gÉg ^^^^^^^^^ r ^^^^^^^^^^^^^ substituted, -NRC (0) NR-heterocyclic, -NRC (0) substituted NR-hetrocyclic wherein each R is independently hydrogen, alkyl or wherein each R is linked to form together with the nitrogen atom a substituted heterocyclic or heterocyclic ring as well as one of the amino groups is blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminothiocarbonylamino" refers to groups -NRC (S) NRR, -NRC (S) NR-alkyl, -NRC (S) NR-substituted alkyl, -NRC (S) NR-alkenyl, -NRC (S) NR-substituted alkenyl, -NRC (S) NR-alkynyl, -NRC (S) NR-substituted alkynyl, -NRC (S) NR-aryl, -NRC (S) NR-substituted aryl, -NRC (S) NR-c? Cloalkyl, -NRC (S) R -substituted cycloalkyl, -NRC (S) NR-heteroaryl, -NRC (S) NR-substituted heteroaryl, -NRC (S) NR-heterocyclic, -NRC (S) NR-substituted hetrocyclic wherein each R is independently hydrogen, alkyl or wherein each R is linked to form together with the nitrogen atom a substituted heterocyclic or heterocyclic ring as well as one of the amino groups is blocked by conventional blocking groups (such as Boc, Cbz, formyl, and the like) and in where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as define here.

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

"Substituted aryl" refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl , you oheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (0) 2-alkyl, -S (0) 2-substituted alkyl, -S (0) 2-cycloalkyl, -S (0) 2-substituted cycloalkyl, -S (0) 2- alkenyl, -S (0) 2-substituted alkenyl, -S (0) 2 -aryl, -S (0) 2 -substituted aryl, -S (O) 2 -heteroaryl, -S (O) 2 -substituted heteroaryl, -S (0) 2- heterocyclic, -S (0) 2-substituted heterocyclic, -0S (0) 2- alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS ( 0) 2-substituted aryl, -OS (0) 2-heteroaryl, -0S (0) 2- 5 substituted heteroaryl, -OS (0) 2-heterocyclic, -0S (0) 2- substituted heterocyclic, -0S02-NRR , -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2- substituted aryl, -NRS (0) 2-heteroaryl, -NRS (0) 2- substituted heteroaryl, -NRS (0) 2-heterocyclic, 10 -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-het erocyclic, -NRS (0) 2-NR-substituted heterocyclic, 15 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-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, 20 asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, amino groups on the substituent aryl blocked by conventional blocking groups (such as ^^^^^^^ ^^^^^^^ ^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ iagS ^^ s ^^^^^ ^^^^^^^^^^^^^^^^^ a ^^ Boc, Cbz, Formilo, and similar) or -S02NRR, in where R is hydrogen or alkyl.

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

"Substituted aryloxy" refers to the aryl-O- substituent groups.

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

"Substituted aryloxyaryl" refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl substituted thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (O) 2 -alkyl, -S (O) 2 -substituted alkyl, -S (0) 2-cycloalkyl, -S (O) 2 -substituted cycloalkyl, -S (O) 2-alkenyl, -S (O) 2 -substituted alkenyl, -S (O) 2 -aryl, -S (0) -substituted aryl, -S (0) 2 -heteroaryl, -S (O) 2-substituted heteroaryl, -S (0) 2-heterocyclic, -S (O) -heterocyclic substituted, -OS (0) 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 (O) 2 -heterocyclic, -0S (0) 2 -heterocyclic substituted, -OS02 -NRR, -NRS (O) 2-alkyl, -NRS (0) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS (0) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (0) 2-substituted heteroaryl, -NRS (O) 2-heterocyclic, -NRS (O) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (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- (substituted aryl) amino, mono- and di-heteroarylamino, mono and di- (substituted heteroaryl) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and amino groups in the substituent aryl blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) or -SO2NRR, wherein R is hydrogen or alkyl.

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

"Cycloalkenyl" refers to cyclic alkenyl groups of 3 to 8 carbon atoms having multiple or single unsaturation but which are not aromatic.

"Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups, preferably from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (= 0), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl , cyano, nitro, carboxyl, carboxylalkyl, 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, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl gone, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O ) 2-alkyl, -OS (0) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2- substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (O) 2 -substituted heteroaryl, -NRS (O) 2 -heterocyclic, -NRS ( 0) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR- substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR-heteroaryl subst n-NR (O) -NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and dialkylamino, 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-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, disubstituted asymmetric amines having different substituents selected from starting from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkynyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) ) and substituted alkynyl / alkynyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S0-substituted cycloalkyl, -S02-aryl, -S02 -substituted aryl, -S02-heteroaryl, -S? 2-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S0NRR, wherein R is hydrogen or alkyl.

"Cycloalkoxy" refers to -0-cycloalkyl groups.

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

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

"Guanidinosulfone" refers to the groups -NRC (= NR) NRS02-alkyl, -NRC (= NR) NRS02-substituted alkyl, -NRC (= NR) NRS02-alkenyl, -NRC (= NR) NRS02-substituted alkenyl, -NRC (= NR) NRS02-alkynyl, -NRC (= NR) NRS02-substituted alkynyl, -NRC (= NR) NRS02-aryl, -NRC (= NR) NRS02-substituted aryl, -NRC (= NR) NRS02- ^^ a &^; ^ i ^ = -? ^ »AM» «M- ^ ¿^!« JA¿Aji ^^ cycloalkyl, -NRC (= NR) NRS02-substituted cycloalkyl, -NRC (= NR) NRS02-heteroaryl , -NRC (= NR) NRS02-substituted heteroaryl, -NRC (= NR) NRS02-heterocyclic, and -NRC (= NR) NRS02-substituted heterocyclic wherein each R is independently hydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

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

"Heteroaryl" refers to an aromatic carbocyclic group of 2 to 10 carbon atoms and 1 to 4 heteroatoms within the ring selected from group consisting of oxygen, nitrogen and sulfur. Such heteroaryl groups may have a single ring (eg, pyridyl or furyl) or multiple fused rings (eg, indolizinyl or benzothienyl). Preferred heteroaryls include, pyridyl, pyrrolyl, indolyl and furyl. g ^^ ^^^^^^ í ^^^^^^^^^^^^^^^^^^^^^^^^^^ gJj ^^^ - ^ g ^^^^^^^ ^^^^^^ "Substituted heteroaryl" refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy substituted alkoxy, alkenyl, substituted alkenyl, alkyloxy, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamido, anus, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, heterocyclic substituted, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (0) 2 -alkyl, -S (0) 2-substituted alkyl, -S (0) 2-cycloalkyl, - S (0) 2-substituted cycloalkyl, -S (0) 2-alkenyl, -S (0) 2 -substituted alkenyl, -S (0) 2 -aryl, -S (0) 2 -substituted aryl, -S ( 0) 2-heteroaryl, -S (0) 2 -substituted heteroaryl, -S (0) 2- heterocyclic, -S (0) 2-substituted heterocyclic, -0S (0) 2 -alkyl, -OS (0) 2 -substituted alkyl, -OS (0) -aryl, -. 10 -OS (0) 2-substituted aryl, -OS (0) 2-heteroaryl, -0S (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -0S (0) 2- substituted heterocyclic, - 0S02-NRR, -NRS (0) 2-alkyl, -NRS (0) 2 -substituted alkyl, -NRS (0) 2 -aryl, -NRS (0) 2- substituted aryl, -NRS (0) 2-heteroaryl , -NRS (0) 2- 15 substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR -substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2- 20 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- di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-amino Heterocyclic, mono and di- (substituted heterocyclic) amino, amines di-substituted asymmetric having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and amino groups on the aryl substituent blocked by groups conventional blocking (such as Boc , Cbz, Formyl, and the like), and -S02NRR, wherein R is hydrogen or alkyl.

"Heteroaryloxy" refers to the group -O-heteroaryl and "substituted heteroaryloxy" refers to the -O-substituted heteroaryl group.

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

"Saturated heterocyclic" refers to single ring or multiple ring heterocyclics 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 heterocyclic simple or multiple condensed rings having unsaturation in any that ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen unsaturation 10 to nitrogen, and the like).

"Substituted heterocyclic" refers to heterocyclo groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (= 0), thioxo (= S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, 20 substituted aryloxy, aryloxyaryl, I aryloxy substituted, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl- substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, Sg ^ ^ | ^^^^^^ ^^^^^^^^^^^^^^^^^^^^ A carboxilheterociclico, carboxilheterociclico substituted cycloalkyl, substituted guanidino, guanidinosulfona, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, -OS (0) 2 -substituted alkyl, -OS (O) 2 -aryl, -OS (O) -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2-substituted heteroaryl, -OS (O) -heterocyclic, -OS (O) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0 ) 2-substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (O) 2 -heteroaryl substituted gone, -NRS (O) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2 -NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR-heterocyclic , -NRS (O) 2_NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and ^^^^ ^^^^^ ^ ^^^^^^^ di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-heterocyclic amino, mono- and di- (substituted heterocyclic) amino, di- amines substituted five asymmetric having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , heterocyclic, substituted heterocyclic, alkynyl groups Substituents having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and substituted alkynyl / alkynyl groups, substituted with -S02-alkyl, -S? 2 -substituted alkyl, -S02-alkenyl , -S02-substituted alkenyl, -S02- 15 cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S0-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S? 2-heterocyclic, -S Substituted 2-heterocyclic or -S02NRR, wherein R is hydrogen or alkyl.

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

"Saturated substituted heterocyclic" refers to single or multiple ring substituted heterocyclics lacking unsaturation 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 non-aromatic substituted heterocyclics 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 -O-heterocyclic and "substituted heterocyclyloxy" refers to the -O-substituted heterocyclic group.

"Tiol" refers to the group -SH.

"Thioalkyl" refers to the S-alkyl group.

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

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

"Substituted thiocycloalkyl" refers to the group -S-substituted cycloalkyl.

"Tioaplo" 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" refers to the group -S-substituted heteroaryl.

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

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

Preparation of Compounds The compounds of this invention can be prepared from initially available starting materials using the following general methods and procedures. It can be appreciated that where typical or preferred process conditions (ie, reaction temperatures, mole portion of reactants, solvents, pressures, etc.) are given, other process conditions may also be used, unless they are established from another way. The optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as manifested by those skilled in the art, conventional protection groups may be necessary to prevent certain functional groups from experiencing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for the particular protection and deprotection of functional groups are well known in the art. For example, numerous protection groups are described in T.W. Greene and G. M. Wuts, Protecting Gruposin Organi c Synthesis, Second Edition, Wiley, New York, 1991, and references cited here. In addition, the compounds of this invention typically can contain one or more chiral centers. According to, if desired, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or diastereomers, or as mixtures of enriched stereoisomers. Such 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 such compounds can be prepared using, for example, chiral column chromatography, chiral solvent reagents and the like. In a preferred synthesis method, the compounds of formula I and IA wherein Q is -C (0) NR7- are prepared in principle by coupling an amino acid of formula II: R3 R'-NH-C-COOH p I H wherein R and R are as defined above, with a sulfonyl chloride of formula III: R ^ SO? -Cl III wherein R1 is as defined above, to provide an amino acid of N-sulfonyl of formula IV: R3 I R'-SO ^ -NCR ^ -C-COOH IV I H wherein R1-R3 are as defined above.

This reaction is typically conducted by contacting the amino acid of formula II with at least one equivalent, preferably about 1.1 up to about 2 equivalents, of sulfonyl chloride III in an inert diluent such as dichloromethane and the like. Generally, the reaction is conducted at a temperature ranging from about -70 ° C to about 40 ° C for about 1 to about approximately 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to recover the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-25 methylmorphol and the like. Alternatively, the reaction ^ ¡^^^^^ < ^ -! ^ & te -. »^ S ^» ^ < á > ^ a ^ J & ^^^ »J. __ - ^ - ^ t »* ^. ^^^^^^^^ ^ -y-? a ^^^^^^^ ifa ^ S ^^. ^, can be conducted under Schotten-Baumann type conditions using aqueous alkali, such as sodium hydroxide and the like , as the base. At the completion of the reaction, the resulting N-sulfonyl amino acid IV is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. The amino acids of formula II used in the above reaction are both known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. Examples of amino acids suitable for use in this reaction include, but are not limited to, glycine, 2-tert-butylglycine, D, L-phenylglycine, L-alanine, α-methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D, L-phenylsarcosine, ß-erc-butyl ester of L-aspartic acid, β-erc-butyl ester of L-glutamic acid, L- (O- benzyl) serine, 1-ammocyclopropanecarboxylic acid, aminocyclobutanecarboxylic acid, 1- 20 aminocyclopentanecarboxylic acid (cycloleucine) 1-aminocyclohexanecarboxylic acid, L-serine and the like. If desired, the esters of the corresponding carboxylic acid of the amino acids of formula II, such as the methyl ester, ethyl ester and the like, can be used in the above reaction with the sulfonyl chloride III. The x &káe * subsequent hydrolysis of the ester group to the carboxylic acid using conventional reagents and conditions, i.e., treatment with an alkali metal hydroxide in an inert diluent such as methanol / water, provides the amino acid of N-sulfonyl IV. Similarly, the sulfonyl chlorides of formula III used in the above reaction are both known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. Such compounds can typically be prepared from the corresponding sulfonic acid, i.e., from compounds of formula R1-S03H wherein R1 is as defined above, using phosphorus trichloride and phosphorus pentachloride. This reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorus trichloride and phosphorus pentachloride, both pure or unmixed in an inert solvent, such as dichloromethane, at a temperature ranging from about 0 ° C. to about 80 ° C for about 1 to about 48 hours to provide the sulfonyl chloride. Alternatively, the sulfonyl chlorides of the formula II can be prepared from the corresponding thiol compound, ie, from the compounds of the formula R1-SH wherein R1 is as defined above, treating the thiol with chlorine (Cl2) and water under conventional reaction conditions. Examples of sulfonyl chlorides suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1-naphthalene sulfonyl chloride, naphthalenesulfonyl, p-toluenesulfonyl chloride, a-toluenesulfonyl chloride, 4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4-tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2-carboxybenzenesulfonyl chloride, cyanobenzenesulfonyl, 3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride, methoxycarbonylbenzenesulfonyl, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl chloride, 4-trifluoromethylbenzenesulfide chloride onyl, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chlorophylphosphonyl chloride, 2, 5-d-chloro-4- chloride 5-thiophenesulfonyl, 2-thiazolesulfonyl chloride, 2-methyl-4-thiazolesulfonyl chloride, l-methyl-4-imidazolesulfonyl chloride, l-methyl-4-pyrazolesulfonyl chloride, 5-chloro-l, 3-dimethyl chloride -4-pyrazolesulfonyl, 3-pyridinesulfonyl chloride, 2-pyrimidine sulfonyl chloride, and similar. If desired, a sulfonyl fluoride, sulfonyl bromide or anhydrous sulfonic acid can be used in place of the sulfonyl chloride in the above reaction to form the N-sulfonyl amino acids of formula IV. The amino acid intermediates of N-sulfonyl Formula IV can also be prepared by reaction of a sulfonamide of formula V: R1-S02-NH-R2 V 20 wherein R1 and R2 are as defined above, with a carboxylic acid derived from the formula L (R3) CHCOOR wherein L is a residual group, such as chlorine, 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 conducted by contacting the sulfonamide V with at least one equivalent, preferably 1.1 to 2 equivalents, of the carboxylic acid derivative in the presence of a suitable base, such as triethylamine, in an inert diluent, such as DMF, at a temperature that varies from approximately 24 ° C to approximately 37 ° C for approximately 0.5 to 4 hours. This reaction is further described in Zuckermann et al., J. Am. Chem. Soc, 1992, 114, 10646-10647. Preferred carboxylic acid derivatives for use in this reaction are α-chloro and a-bromocarboxylic acid esters such as tert-butyl bromoacetate, and the like. When an ester of the carboxylic acid is employed in this reaction, the ester group is subsequently hydrolyzed using conventional procedures to provide an N-sulfonyl amino acid of formula IV. The compounds of the formula I are prepared by coupling the intermediate N-sulfonyl amino acid of the formula IV with an amino acid derived from the formula VI: O I R7-NH-CH-C-R6 VI R5 wherein R5-R7 are as defined above. The coupling reaction is typically conducted using well known coupling reagents such as carbodiimides, BOP reagents (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate) and the like. Suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide (for its acronym in English DCC), 1- (3-dimethylaminopropyl) -3-atilcarbodiimide (for its acronym in English EDC) and the like. If desired, the carbodiimide supported polymeric forms of the coupling reagents can also be used including, for example, those described in Tetrahedron Letters, 34 (48), 7685 (1993). Additionally, well-known coupling promoters, such as N-hydroxysuccinamide, 1-hydroxybenzotriazole and the like, can be used to facilitate the coupling reaction. This coupling reaction is typically conducted by contacting the N-sulfonylamino IV acid with about 1 to about 2 equivalents of the coupling reagent and at least one equivalent, preferably about 1 to about 1.2 equivalents, of the amino acid derivative VI in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylforfamide and the like. Generally, this reaction is conducted at a temperature ranging from about 0 ° C to about 37 ° C for about 12 to 24 hours. At the completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. Alternatively, the N-sulfonyl amino acid IV can be converted to an acid halide and the acid halide is coupled to the derivatives of amino acid VI to provide the compounds of formula I. The acid halide of VI can be prepared by contacting VI with a inorganic acid halide, such as thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or preferably, with oxalyl chloride under conventional conditions. Generally, this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, both pure or unmixed in an inert solvent, such as dichloromethane or carbon tetrachloride, at a temperature ranging from about 0 ° C to about 80 ° C for about 1 to about 48 hours. A catalyst, such as N, N-dimethylformamide, can also be used in this reaction.

The acid halide of the N-sulfonyl amino acid IV is contacted with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of amino acid derivative VI in an inert diluent, such as dichloromethane, at a temperature ranging from about -70 °. C to about 40 ° C for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to recover the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann type conditions using aqueous alkali, such as sodium hydroxide and the like. At the completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. Alternatively, the compounds of the formula I can be prepared initially by forming a diamino acid derivative of the formula VII: .. a ^. -Yfiriffpj iif ^^ R3 R 'O I I. R2-NH-C-C (0) N-CH-C-R6 vp I I H R5 wherein R2, R3 and R5"7 are as defined above The diamino acid derivatives of formula VII can be prepared initially by coupling an amino acid of formula II with an amino acid derivative of formula VI using amino acid with coupling techniques and conventional reagents, such as carbodiimides, BOP reagent and the like, as described above. The diamino acid VII can be sulfonated using a sulfonyl chloride of formula III and using the procedures Synthetics described above to provide a compound of formula I. The amino acid derivatives of formula VI employed in the above reactions are both known compounds or compounds that can be prepared Starting from compounds known by conventional synthetic methods. For example, amino acid derivatives of formula VI can be prepared by the commercially available C-alkylation diethyl acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with a Alkyl or substituted alkyl halide. This reaction is it typically involves treating diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or alkyl halide refluxed with ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in refluxing hydrochloric acid 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, methyl ester of L-4-nitrofrenylalanine, methyl ester of L-alanine, methyl ester of L-isoleucine, methyl ester of L -leucine, L-valine methyl ester, ß-tert-butyl-L aspartic acid methyl ester, L-asparagine tert-butyl ester, e-Boc-L-lysine methyl ester, e-Cbz-methyl ester L-lysine, α-tert-butyl-L-glutamic acid methyl ester, L-glutamine tert-butyl ester, L- (N-methyl) histidine methyl ester, L- (N-benzyl) histidine methyl ester , methyl ester of L-methionine, methyl ester of L- (O-benzyl) serine, methyl ester of L-tryptophan, methyl ester of L-phenylalanine, isopropyl ester of L-phenylalanine, benzyl ester of L-phenylalanine, L- phenylalanine, benzyl ester of N-methyl-L-phenylalanine, methyl ester of 3-carboxy-D, L-phenylalanine, methyl ester of 4 -carboxy-D, L-phenylalanine, methyl ester of L-4-chlorophenylalanine, methyl ester of L-4- (3-dimethylaminopropyloxy) 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 ester of L-tyrosine, methyl ester of D, L-homophenylalanine, methyl ester of L- (0-methyl) tyrosine, ester Methyl ester of L- (O-tert-butyl) tyrosine, L- (O-benzyl) tyrosine methyl ester, L-3 methyl ester, 5-diiodotyrosine, L-3-iodothyrosine methyl ester, β-methyl ester (1-naphthyl) -L-alan a, β- (2-naphthyl) -L-alanine methyl ester, β- (2-thienyl) -L-alanine methyl ester, β-cyclohexyl methyl ester L-alanine, β- (2-pyridyl) -L-alanine methyl ester, β- (3-pyridyl) -L-alanine methyl ester, β- (4-pyridyl) -L-alanine methyl ester, ester ß- (2-thiazolyl) -D, L-alanine methyl ester, β- (l, 2,4-tr? azol-3-yl) -D, L-alanine methyl ester, and the like. If desired, other esters or amides of the compounds described above may also be used in passing.

For ease of synthesis, the compounds of the formula can typically be prepared as an ester, that is, wherein R6 is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolyzed using reagents and conventional conditions to provide the corresponding carboxylic acid. Typically, this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperature which varies from about 0 ° C to about 2 ° C for about 12 hours. Alternatively, the benzyl esters can be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon. The resulting carboxylic acids can be coupled, if desired, to amines such as β-alanine ethyl ester, alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine and O-benzylhydroxylamine, and the like, using coupling reagents and conventional conditions as described previously. As manifested by those skilled in the art, other functional groups present in any of the substituents of the compounds of the formula I can in principle be modified or derivated both before or after after the coupling reactions described above using well-known synthetic procedures. For example, a nitro group present in a substituent of a compound of formula I or an intermediate thereof can be initially reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group. The reaction is typically conducted at a temperature of 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 the substituent R5 can be prepared, for example, using a 4-nitrophenylalanine derivative and the like in the coupling reactions described above. Similarly, a pyridyl group can be hydrogenated in the presence of a palladium catalyst, such as palladium oxide, in an acidic diluent to provide the corresponding piperidinyl analog. Generally, this reaction is conducted by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperature of about 20 ° C to about 50 °. C for about 2 to about 24 hours in an acidic diluent, such as a mixture of methanol and aqueous hydrochloric acid. Compounds having a pyridyl group can be initially prepared using, for example, β- (2-pyridyl) -, β- (3-pyridyl) - or β- (4-pyridyl) -L-alanine derivatives in the reactions of coupling described above. Additionally, when the R5 substituent of a compound of formula I or an intermediate thereof contains a primary or secondary amino group, such as amino groups, it may additionally be derived both before or after the coupling reactions to provide, via example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like. Compounds having a primary amino group in the substituent R5 can be prepared, by way of example, by reduction of the corresponding nitro compound as described above. Alternatively, such compounds can be prepared using an amino acid derivative of formula VI derived from lysine, 4-aminophenylalanine and the like in the coupling reactions described above. By way of illustration, a compound of the formula I or an intermediate of this has a substituent that contains a primary or secondary amino group, such as where R5 is a (4-aminophenyl) methyl group, initially N-acylated using reagents and acylation conditions to provide the corresponding amide. The acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as carbodiimide, BOP reagent (benzotriazol-1-yloxy). tris (dimethylamino) phosphorus hexafluorophosphate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide and the like, at a temperature ranging from about 0 ° C to about 37 ° C approximately 4 to approximately 24 hours. Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, is used to facilitate the acylation reaction. Examples of carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, acid benzoic acid, N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert-butyloxycarbonyl-norpecotic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N- (toluene-4-sulfonyl) -L-proline and Similar. Alternatively, a compound of the formula I or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide. This reaction typically is conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperature which varies 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-dimethylammo) pyridine can be used to promote the acylation reaction. The acylation reaction is conducted preferably in the presence of a suitable base to recover the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the The reaction can be conducted under Schotten- type conditions.

Baumann using aqueous alkali, such as sodium hydroxide and the like. Examples of acyl halides and carboxylic acid anhydrides suitable for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoromethylbenzoyl chloride, isonicotinoyl chloride, Nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like. Carbamyl chlorides, such as N, N-dimethylcarbamyl chloride, N, N-diethylcarbamyl chloride, and the like, can also be used in this reaction to provide ureas. From 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 thereof containing an amino group Primary or secondary can be N-sulfonated to form a sulfonamide using sulfonyl halide or a sulfonic acid anhydride. Sulphonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, Chloromethanesulfonyl chloride, p-chloride toluenesulfonyl, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides, such as di-ethylsulfamoyl chloride, can be used to provide sulphonamides (eg, > N-S02-N <). Additionally, a primary or secondary amino group present in a substituent of a compound of formula I or an intermediate thereof can be reacted with an isocyanate or thioisocyanate to give a urea or thiourea, respectively. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperature ranging from about 24 ° C. about 37 ° C for about 12 to about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic methods. For example, isocyanates and thioisocyanates are prepared initially by reaction of the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanate suitable for use in this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, thioisocyanate methyl, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3- (N, N-diethylamino) propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer) I) and similar. In addition, when a compound of formula I or an intermediate thereof contains a primary or secondary amino group, the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically conducted by cotacting 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 reagent reagent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature ranging from about 0 ° C to about 50 ° C for about 1 to about 72 hours. Suitable aldehydes and ketones for use in this reaction include, by way of example, benzalheido, 4-chlorobenzaldehyde, valeraldehyde and the like.

In a similar manner, when a compound of formula I or an intermediate of this has a substituent containing a hydroxyl group, the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions to provide, by means of of the example, ethers, carbamates and the like. Compounds having a hydroxyl group in substituent R5, 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 the formula I or an intermediate of this having a substituent containing a hydroxyl group, such as where R 5 is a (4-hydroxyphenyl) methyl group, can be initially O-alkylated to form ethers . This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the salt of alkali or alkaline earth metal of the hydroxyl group. This salt in general gg ^^^ ^ | É | ká ^^^ fe? j does not isolate, but if it reacts with at least one equivalent of an alkyl halide or sulfonate of alkyl or substituted alkyl, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to provide the ether. Generally, this reaction is conducted at a temperature ranging from about 60 ° C to about 150 ° C for about 24 to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is used in the reaction.

Examples of alkyl or substituted alkyl halides and sulfonates suitable for use in this Reactions include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl a-bromophenylacetate, 2- (N-ethyl-N-phenylamino) ethyl chloride, chloride 2- (N, N-ethylamino) ethyl, 2- (N, N-diisopropylamino) ethyl chloride, 2- (N, N-dibenzylamino) ethyl chloride, 3- (N, N-ethylamino) propyl chloride, 3- (N-benzyl-N-methylamino) ethyl chloride, N- (2-chloroethyl) morpholine , 2- (hexamethyleneimino) ethyl chloride, 3- (N-methylpiperazin) propyl chloride, 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine, 2- (4-hydroxy-4-) chloride phenylpiperid a) ethyl, N-tert-butyloxycarbonyl-3-piperidinmethyl tosylate, and the like.

Alternatively, a hydroxyl group present or a substituent of a 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, reacts with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about -10 ° C to about 5 ° C for about 0.25 to about 1 hour. Approximately 1.0 to about 1.3 equivalents of a hydroxy compound, such as N-tert-butyl methyl ester, is then added and the reaction mixture is stirred at a temperature from about 0 ° C to about 30 ° C for about 2 to about about 48 hours to provide the 0-alkylated product.

In a similar manner, a compound of the formula I or an intermediate thereof containing a hydroxyaryl group can react with an aryl iodide to provide a diaryl ether. Generally, this reaction is conducted by forming the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent such as xylenes at a temperature of about -25 ° C to about 10 ° C. This salt is then treated with about 1.0 to about 1.5 equivalents of a cuprous bromide dimethyl sulfide 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 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. This reaction 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 also be initially derived to form a carbamate. In a method for the preparation of such carbamates, a hydroxy compound of formula I or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents. of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about -25 ° C to about 0 ° C for about 0.5 to about 2.0 hours. The treatment of the resulting carbonate with an excess, preferably from 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-methylpiperazine, 1-acetylpiperazine, morpholm, thiomorpholine, pyrrolidine, piperidine and similar.

Alternatively, in another method for the preparation of carbamates, a hydroxy-containing compound is contacted with about 1.0 up 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 leads in the presence of a suitable base to pick up iiii ii iiiiii "A '' r ~ A? iT¡'ii rPr i" "rf '' '2 l-Tf? tt WifTríí'itrilM Airti" "' ^ the acid generated during the reaction. Suitable examples include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like Additionally, at least one equivalent (based on the hydroxy compound) of 4- (N, N-dimethylamino) pyridine is preferably added to the reaction mixture to facilitate the reaction Examples of carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.

Likewise, when a compound of the formula I or an intermediate thereof contains a primary or secondary hydroxyl group, such as hydroxyl groups it can be initially converted into a residual group and displaced to form, for example, amines, sulfides and fluorides. For example, 4-hydroxy-L-proline derivatives can be converted to the corresponding 4-amino, 4-thio or 4-fluoro-L-proline derivatives via nucleophilic displacement of the derivatized hydroxyl group. Generally, when a chiral compound is used in these reactions, the stereochemistry of the carbon atom linked to the hydroxyl group derivative is typically inverted.

These reactions are typically conducted in principle by converting the hydroxyl group to a residual 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 priridine . This reaction is generally conducted at a temperature from about 0 ° C to about 70 ° C for about 1 to about 48 hours. The resulting tosylate then may be initially displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixture of N, N-dimethylformamide and water, at a varying temperature. 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 by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino compound (-NH2).

Similarly, a tosylate group can be initially displaced by a thiol to form a sulfide. This reaction is typically conducted by putting in contact the tosylate with at least one equivalent of a "8 ^? Te" .tfcj thiol, such as thiophenol, in the presence of a suitable base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), in an inert diluent, such as N, N-dimethylformamide, at a temperature from about 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the sulfide. Additionally, treatment of a tosylate with morpholinesulfur 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 to provide the corresponding fluoro compound .

In addition, a compound of the formula I or an intermediate of this having a substituent containing an iodoaryl group, for example, when R 5 is a (4-iodophenyl) methyl group, can be initially converted either before or after the reactions of previous coupling in a biaryl compound. Typically, this reaction is conducted by treatment of 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 tetra (triphenylphosphine) of palladium, in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about 24 ° C to about 30 ° C to complete the reaction. This reaction is further described, for example, in Rieke, J. Org. Chem. 1991, 5 56, 1445.

In some cases, the compounds of formula I or intermediates thereof may contain substituents having one or more sulfur atoms. Such atoms of Sulfur can occur, for example, when the amino acid of formula II used in the above reactions is derived from L-thiazolidine-4-carboxylic acid, L- (5,5-dimethyl) thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid and similar. When present, such sulfur atoms can be oxidized both before or after the coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions. Suitable reagents for the oxidation of A sulfide compound to a sulfoxide includes, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like. The oxidation reaction is typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidation 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 oxidation reagent. Such reactions are further described in March, "Advanced Organic Chemistry," 4th Ed., P. 1201-1202, Wiley Publisher, 1992.

As described above, compounds of the formula I having a substituent R 2 other than a hydrogen can be prepared using an N-substituted amino acid of formula II, such as sarcosine, N-methyl-L-phenylalanine and the like, in the reactions of coupling described above. Alternatively, such compounds can be prepared by N-alkylation of a sulfonamide of formula I or IV (wherein R2 is hydrogen) using conventional synthetic methods. Typically, this N-alkylation reaction is conducted by contacting the sulfonamide with at least one equivalent, preferably 1.1 to 2 equivalents, of an alkyl or substituted alkyl halide in the presence of a suitable base, such as potassium carbonate, in 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 intramolecularly to form 1,2-benzisothiazol-3-one derivatives or analogs thereof. This reaction is typically conducted by treatment of a sulfonamide, such as N- (2-methoxycarbonylphenylsulfonyl) glycine-L-phenylalanine benzyl ester, with about 1.0 to 1.5 equivalents of a suitable base, such as an alkali metal hydride, in a inert diluent, such as tetrahydrofuran, at a temperature from about 0 ° C to about 30 ° C for about 2 up to - ^ g ^ - ^ - ^ - Jb KA ^ - ^ a ^ g, approximately 48 hours to provide the cyclized 1, 2-benzisothiazol-3-one derivative.

Finally, the compounds of the formula I wherein Q is -C (S) NR7- can be prepared using an amino thionoacid derivative instead of an amino acid II in the synthetic procedures described above. Such amino thioacid derivatives can be prepared by the procedures described in Shalaky, et al., J. Org. Chem. , 61: 9045-9048 (1996) and Brain et al., J. Org. Chem. , 62.3808-3809 (1997) and the references cited here.

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

This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I and IA previously associated with pharmaceutically acceptable carriers. In the manufacture of the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which 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, semi-solid, or liquid material, such as act as a carrier, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, tablets, pouches, capsules, elixirs, suspensions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and powders sterile packed.

In the preparation of a formulation, it is necessary to grind the active compound to provide the appropriate particle size for combination with the other ingredients. If the active compound is Substantially insoluble, it is ordinarily ground 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 milling 5 to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginados, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; soaking agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated to provide rapidity, maintain or delay the release of the active ingredient after administration to the patient by methods known in the art. 25 The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a pharmaceutically acceptable excipient.

The active compound is effective over a broad dosage range, and is generally administered in a pharmaceutically effective amount. It is understood, however, that the amount of the compound currently administered is determined by a physician, in view of the relevant circumstances, which include the condition to be treated, the chosen route of administration, the current compound administered, the age, weight, and individual response of the patient, the severity of the patients' symptoms, and the like.

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

The pills or pills of the present invention may be coated or otherwise combined to provide a dosage form that provides the long-acting advantage. For example, the tablet or pill may comprise an internal dosage component and an external dosage, the latter being in the form of an envelope on top of the previous one. The two components can be separated by enteric layers which serve to resist disintegration in the stomach and allow the internal component to pass intact to the duodenum or delay its release. A variety of materials can be used for such enteric or coated layers, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as lacquer, cetyl alcohol, and cellulose acetate.

Liquid forms in which the new compositions of the present invention may be incorporated by oral or injection administration, include aqueous solutions of suitable flavored syrups, aqueous or oil suspensions, and flavoring emulsions with edible oils such as cottonseed oil. , sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the respiratory route ^^ Zá¡ «^ ~ * ~ ^, ^ ^^. A. ^. ^ Ia ^ ^ oral or nasal for local or systemic effect. The compositions in pharmaceutically acceptable solvents can preferably be atomized by the use of inert gases. The atomized solutions can be aspirated directly from the atomizing device or the atomizing device can be added to a mask to cover the face, or a positive intermittent pressure vacuum machine. The solution, suspension, or powder compositions can be administered, preferably orally or nasally, from devices which 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 ingredients are prepared: Ingredient Quantity (mg / capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in amounts of 340 mg.

Formulation Example 2 A formula for tablets is prepared using the following ingredients: Ingredient Quantity (mg / tablet) Active ingredient 25.0 Microcrystalline cellulose 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are mixed and compressed to form tablets, each weighing 240 mg.

Z ^ Ss ^^ t &UjeU Formulation Example 3 A dry powder formulation for inhalation is prepared, containing the following components: Ingredient by weight Active ingredient 5 Lactose 95 10 The active mixture is mixed with the lactose and the mixture is added to a dry powder for its application by inhalation.

Formulation Example 4 Tablets are prepared, each containing 30 mg of the active ingredient, as follows: 20 Ingredient Amount (mg / tablet) Active ingredient 30.0 mg 25 Starch 5.0 mg ^^^^ ^^^^^ ^ ^) > ^^ '^ - ^ - 3-wa¡ Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (with 10% solution in water) 4.0 mg Sodium carboxylmethyl starch 4.5 mg Magnesium stearate 0.5 mg Talcum 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a U.S. sieve. No. 20 mesh and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. from mesh No. 16. The granules produced are dried at 50 ° to 60 ° C and passed through a U.S. 16 mesh. Sodium carboxymethyl starch, magnesium stearate, and talc, are previously passed through a U.S. No. 30 mesh, then they are added to The granules which, after being mixed, are compressed in a tablet machine to produce each tablet each weighing 150 mg.

Formulation Example 5 25 Capsules are made, each containing 40 mg of medication, as follows: Ingredient Quantity (mg / capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg The active ingredient, cellulose, starch, and magnesium stearate are mixed, passed through a U.S. No. 20 mesh, and filled into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 Suppositories are prepared, each containing 25 mg of the active ingredient, as follows: Ingredient Quantity Active ingredient 25.0 Saturated fatty acid glycerides at 2,000.0 The active ingredient is passed through a U.S. No. 60 mesh and suspended in the saturated fatty acid glycerides previously melted using the minimum heat required. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. 10 Formulation Example 7 Suspensions are made, each containing 50 mg 15 mg per 5.0 ml dose, as follows: Ingredient Amount Active ingredient 50.0 mg 20 Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg 25 Taste and color q.v.

Hüfl ^ g ^ j ízt? M £ í! S & a ^ aa | a g a ^^ ggg Purified water 5. O ml The medicine, sucrose and xanthan gum are mixed, passed through a U.S. No. 10 mesh, and then mixed with a pre-processed solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavoring, and coloring are diluted with a little water and added with agitation. Then enough water is added to produce the required volume.

Formulation Example 8 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, magnesium stearate are mixed, passed through a U.S. sieve. No. 20 mesh, and filled into hard gelatine capsules in amounts of 560 mg.

Formulation Example 9 An intravenous formulation can be prepared as follows: Ingredient Amount Active ingredient 250.0 mg Isotonic saline 1000 ml Formulation Example 10 A topical formulation can be prepared as follows: Ingredient Amount Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g Soft white paraffin at 100 g The soft white paraffin is heated until melted. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirred continuously until dispersed. The mixture is then cooled until solidified.

Another preferred formulation employed in the methods of the present invention employ transdermal delivery devices ("patches"). Such 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 patches for the release of pharmaceutical agents is well known in the art. See, for example, U.S. Patent 5,023,252, issued June 11, 1991, incorporated herein by reference. Such patches can be constructed by pharmaceutical agents, continuous, pulsative, or in a required release.

Direct techniques can be used when it is convenient or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve the use of a drug delivery probe within the host ventricular system to bypass the blood barrier of the brain. In such an implantable delivery system used for the transport of biological factors to specify anatomical regions of the body is described in U.S. Patent 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 numbing by the conversion of hydrophilic drugs into the soluble lipid drugs. Numbing is generally carried out by blocking the hydroxy, carbonyl, sulfate, and primary amine groups present in the drug to produce the most lipid soluble and docile drug for transport through the blood carrier to the brain. Alternatively, the release of hydrophilic drugs can be increased by intra-arterial infusion of hypertonic solutions which can transiently open the blood barrier of the brain. * - ^^^^? ^^^^^^^^ s ^^^. ^ s ^^ jk2j. ^ ff ^ s ^ & ^ Utility The compounds of this invention can be used to bind VLA-4 (integrin a4ßx) in biological samples and, consequently, have utility in, for example, testing such samples for VLA-4. In such assays, the compounds can be bound to a solid support and the VLA-4 sample added thereto. The amount of VLA-4 in the sample can be determined by conventional methods such as the use of an ELISA sandwich assay. Alternatively, classified VLA-4 can be used in competitive assays by measurement for the presence of VLA-4 in the sample. Other suitable assays are well known in the art. fifteen In addition, certain compounds of this invention inhibit, in vivo, the adhesion of leukocytes to endothelial cells mediated by VLA-4 and, consequently, can be used in the treatment of diseases mediated by VLA-4. Such diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including early juvenile diabetes), disease inflammatory bowel (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, seizures or strokes, and other brain traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in the respiratory distress syndrome in an adult.

The biological activity of the compounds identified above can be tested in a variety of systems. For example, a compound can be immobilized on a solid surface and the cell adhesion expressed by VLA-4 can be measured. Using such formats, you can sift or select large numbers of compounds. Suitable cells for these assays include any leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils. It can also be used, a number of leukocyte cell lines, examples include Jurkat and U937.

The test compounds can also be tested for their ability to competitively inhibit the link between VLA-4 and VCAM-1, or between VLA-4 and a compound t &iBtt¿eaaAAJi¿. ^ -S * e ta? A »Aittadá8 - * - i? > *? 3 ^ & »Sa '" ai * 1 ^ labeling known to bind to VLA-4 such as a compound of this invention or antibodies to VLA-4 In this assay, VCAM-1 can be immobilized in a solid surface The VCAM-1 can also be expressed as a recombinant fusion protein having an Ig extremity (eg, IgG) so that the binding to VLA-4 can be detected in an immunoassay. l expresses cells, such as activated endothelial cells, or transfected fibroblasts VCAM-1 can be used In tests to measure the ability to block adhesion in brain endothelial cells, the assays described in the Application Publication are particularly preferred. of International Patent No. WO 91/05038, this application is incorporated herein by reference in its entirety.

Any test format used labels the test components. Labeled systems can be in a variety of forms. The labels may be coupled directly or indirectly to the desired test compound in accordance with methods well known in the art. An extensive variety of labeling can be used. The component can be labeled by any one of the particular methods. The most common method of detection is the use of autoradiography with labeled 3H, 125I, 35S, 1C, or 32P or similar. Non-radioactive labeling includes ligands which bind to labeled antibodies, fluorophores, chemical fluorescence agents, enzymes and antibodies which can serve as even binding elements specific for a labeled ligand. The choice of label depends on the sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.

Appropriate models in vivo to demonstrate efficacy in the treatment of inflammatory reactions include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models that depend 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., in vivo stability, bioavailability), or the ability to be detected in diagnostic applications. For example, the inclusion of one or more D-amino acids in the sulfonamides of this invention typically increases the ^^^^? ^ ¿^ ¿^ Stability in vivo. The stability can be tested in a variety of ways such as measuring the life span of the proteins during incubation with peptidases or human plasma or serum. A number of such assays for protein stability have been described (see, for example, Verhoef, et al., Eur. J. Drug Metab, Pharmacokinet., 1990, 15 (2): 83-93).

For diagnostic purposes, a wide variety of labels can be linked to the compounds, which can provide, directly or indirectly, a detectable signal. Thus, the compounds of the subject of the invention can be modified in a variety of ways for a variety of final purposes while still retaining the biological activity. In addition, several reactive sites can be introduced at the end to bind to particles, solid substrates, macromolecules, and the like.

The labeled compounds can be used in a variety of applications in vivo or in vi tro. A wide variety of labels may be employed, such as, radionuclides (e.g., gamma emitting radioisotopes such as technetium-99 or indium-111), fluorescers (e.g., fluorescein), enzymes, enzyme substrate, enzyme cofactors, enzyme inhibitors, chemical phosphorescence compounds, bioluminescent compounds, and the like. Those of ordinary skill in the art are well aware of other labels suitable for binding to the complexes, or would be capable of ascertaining such, using routine experimentation. The linkage of these labels is carried out using standard techniques common to those of ordinary skill in the art.

Uses in vi tro include diagnostic applications such as monitored inflammatory responses for the detection of the presence of leukocytes expressing VLA-4. The compounds of this invention can also be used to isolate or label such cells. In addition, as mentioned above, the compounds of the invention can be used for the assay of potential inhibitors of VLA-4 / VCAM-1 interactions.

To identify in vivo diagnostic images, for example, sites of inflammation, radioisotopes are typically used in accordance with well-known techniques. The radioisotopes can be linked to the peptide either directly or indirectly using intermediate functional groups. For example, », ^ ¡^? ^? i. ! - «^ ñ 1 Chelating agents such as diethylenetriaminpentaacetic acid (DPTA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metal ion radioisotopes.

The complexes can also be classified with a paramagnetic isotope to determine in vivo diagnoses, such as magnetic resonance imaging (MRI) or electronic spin resonance (ESR), which are well known. In general, any conventional method for displaying diagnostic images can be used. Usually the emission of gamma- and positron-radioisotopes are used for imaging cameras and paramagnetic isotopes are used for MRI. Thus, the compounds can be used to verify the course of improvement or alleviation of an inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4 it is possible to determine whether a particular therapeutic regimen aimed at improving the disease is effective.

The pharmaceutical compositions of the present invention can be used to block or inhibit the 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, rejection or repudiation of transplantation (for example, rejection or repudiation of allograft), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including early juvenile diabetes), retinitis, metastasis of cancer, rheumatoid arthritis, acute leukocyte-mediated lung injury 10 (eg, respiratory distress syndrome in an adult), asthma, nephritis, acute and chronic inflammation, atopic dermatitis, psoriasis, myocardial ischemia and inflammatory bowel disease (including Crohn's disease and ulcerative colitis 15). In preferred embodiments, the pharmaceutical compositions are used to treat inflammatory disorders of the brain, such as multiple sclerosis (MS), viral meningitis and encephalitis. 20 Inflammatory bowel disease is a collective term for two similar diseases referred to as Cohn's disease and ulcerative colitis. Crohn's disease is of unknown cause (idiopathic), 25 the chronic ulceroconstrictive inflammatory disease is «Tusa» Ujgi | g §g jg | ¡gj ^^ ^? ^^^^^ S? characterized by sharply and typically delimiting the transmural involvement of all layers of the intestinal wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, can be complicated, although the disease most commonly affects the ileum and / or colon. Ulcerative colitis is an inflammatory response largely limited to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in inflammatory bowel disease lesions and may contribute to the inflammatory lesion.

Asthma is a disease characterized by increased sensitivity of the tracheobronchial tree to various contraction stimuli to increase the paroxysmal power of the bronchial respiratory tract. The stimulus causes the release of several mediators of inflammation from mast cells coated with IgE including histamine, eosinophilic chemotactic factors and neutrophils, leukotrienes, prostaglandin activating factor and platelet. The release of these basophilic recruited factors, eosinophils and neutrophils, cause inflammatory lesions. ^^^^^ u ^ i ^ ^^^^ i ^ & í & ñ Atherosclerosis is a disease of arteries (eg, coronary, carotid, aorta, and iliac). The basic lesion, the atheroma, consists of a focal plate projecting into the intima, which has a lipid core and a fibrous layer covering. Atheromas include flows of affected blood arteries and weakened arteries. Myocardial and cerebral infarcts are a major consequence of these diseases. Macrophages and leukocytes are recruited by atheromas and contribute to the inflammatory injury or wound.

Rheumatoid arthritis is chronic, relapsing into an inflammatory disease that primarily causes deterioration and destruction of the joints. Arthritis rheumatoid usually affects the small joints of the hands and feet first, but when it can, it encompasses 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, Immunology (3d ed., Raven Press, 1993).

Another indication for the compounds of this invention is an organ or graft rejection treatment mediated by VLA-4. In recent years there has been a • considerable improvement in the efficiency of surface techniques for the transplantation of tissues and organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow. Perhaps the main problem distinguished, is the lack of satisfactory agents for the induction of immunotolerance in the recipient to the transplanted allograft or organ. When the allogeneic cells or organs are transplanted into a host (ie, the donor and the donee are different individuals of the same species), the host immune system is likely to increase an immune response to foreign antigens in the transplant (host disease) against graft) leading to the destruction of the transplanted tissue. CD8 + cells, CD4 cells and monocytes are all included in the rejection of tissue transplantation. The compounds of this invention which bind to alpha-4 integrin are useful, inter alia, to block alloantigen immune responses, induced in the donor thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. . See, for example, Paul et al., International Transplant 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georcyznski et al., Transplan t. Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994).

A related use for compounds of this invention, which bind to VLA-4 is a modulation of the immune response that includes a "graft versus host" disease ( GVHD). See for example, Schlegel et al., J. Immunol. 155, 3856-3865 (1995). GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic container. In this situation, the cells of immunocompetent donors can attack tissues in the container. The tissues of the skin, epithelial intestine and liver are frequent targets and can be destroyed during the course of GVHD. The disease presents a particularly severe problem when the immune tissue is being transplanted, such as a bone marrow transplant; but less severe, GVHD has also been reported in other cases as good, including heart and liver transplants. The therapeutic agents of the present invention are used, inter alia, to block the activation of the T cells of the donor in such a way that they interfere with their ability to cause lysis of the target cells in the host.

An additional use of the compounds of this invention is the inhibition of tumor metastasis.

Various tumor cells have been reported by ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ g ^^^^^^^^^^^ ^^^^^^^^^ express VLA-4 and compounds which bind to VLA-4 by blocking such cells in endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13, 47-52 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994).

An additional use of the compounds of this invention is in the treatment of multiple sclerosis. Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the envelope insulator that surrounds 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 subsequently paralysis in animals16.

The pharmaceutical compositions of the invention are suitable for use in a variety of systems. drug release. Formulations suitable for use in the present invention are found in Remmgton's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985). To increase the average life of the serum, the compounds can be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques can be used which provide a average life of the broad serum, in the compounds. A variety of methods are available for preparing liposomes, as described in, for example, Szoka, et al., US Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference. reference.

The amount administered to the patient will vary depending on what is administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, the compositions are administered to a patient who already suffers from a disease in an amount sufficient to cure or at least diminish the symptoms of the disease and its complications. An adequate amount to effect this it is defined as "therapeutically effective dose". The effective amounts for this use will depend on the conditions of the disease to be treated as well as the criteria of the attending physician, 5 depending on factors such as the severity of the inflammation, the age, weight and general condition of the patient, and Similar.

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 filtered in sterile form.

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

The therapeutic dose of the compounds of the present invention will vary according to, for example, the ^^^^^^^^^^^^^^^^^^^^^^^^^^^^, particular use for which the treatment is done, the manner of administration of the compound , the health and condition of the patient, and the criteria 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 about 100 μg to about 300 μg per kilogram of body weight. The proper dose ranges for intranasal administration are generally from about 0.1 pg to 1 mg per kilogram of body weight. Effective doses can be extrapolated from dose response curves derived from animal model or in vitro test systems. The following synthetic and biological examples are presented to illustrate this invention and are not constructed 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 25 abbreviations have the following meanings. If the abbreviation is not defined, in general, its meaning has been accepted. ac. or ac. aqueous AcOH acetic acid bd broad double bm broad multiplet bs extensive singlet Bn benzyl Boc n-tert-butoxycarbonyl Boc20 di-tert-butyl dicarbonate BOP benzotriazole-1-α-loxytris (dimethylamino) phosphorus hexafluorophosphate Cbz carbobenzyloxy CHC13 chloroform CH2C12 dichloromethane (C0C1) 2 Oxalyl chloride d doublet dd doublet dt double triplet DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene DCC 1,3-dicyclohexyl carbodiimide DMAP 4-N, N-dimethylamine Pyridine DME ethylene glycol dimethyl ether DMF N, N-dimethylformamide DMSO dimethisulfoxide EDC l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et3N triethylamine Et20 diethyl ether EtOAc ethyl acetate EtOH ethanol eq. or eq, equivalent Fmoc N- (9-fluorenylmethoxy carbonyl) FmocONSu N- (9-fluorenylmethoxycarbonyl) succinamide g grams h hour H20 water HBr hydrobromic acid HCl hydrochloric acid HOBT hydrate 1-h? drox? -benzotriazole hour K2C03 carbonate potassium L liter m multiplet MeOH methanol mg milligram MgSO4 magnesium sulfate 10 mL milliliter mm millimeter mM millimolar mmol millimole pf melting point 15 N normal NaCl sodium chloride Na2C03 sodium carbonate NaHC03 sodium bicarbonate NaOEt sodium ethoxide 20 NaOH hydroxide sodium NH4C1 ammonium chloride NMM N-methylmorpholine Phe L-phenylalanine Pro L-proline 25 psi pound square inch Pt02 platinum oxide Quint quartet quintet ta room temperature simplet sat saturated t triplet t-BuOH tert-butanol 10 TFA trifluoroacetic THF tetrahydrofuran TLC or tic thin layer chromatography T tosyl 15 CITs tosyl chloride TsOH tosylate μL microliter In the later examples, all the temperatures are in degrees Celsius (unless otherwise indicated). The following Methods were used to prepare the compounds described below as indicated. 1 Mét "odo 1 N-Tosylation procedure N-Tosylation of the appropriate amino acid is conducted via the method of Cupps, Boutin and Rapoport J. Org. Chem. 1985, 50, 3972.

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

Method 3 BOP Coupling Procedure The desired dipeptide ester was prepared by the reaction of a suitable N-protected amino acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate [BOP] (2.0 equivalents), trethylamine (1.1 equivalent), and DMF. The reaction mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography to provide the dipeptide ester.

Method 4 Hydrogenation Procedure I The hydrogenation was carried out 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 yield the desired ammo compound.

Method 5 Hydrolysis Procedure I To a solution (2: 1.5-10 mL) of THF / H20 cooled to (0 ° C) of the appropriate ester was added LiOH (or NaOH) (0.95 equivalents). The temperature was maintained at 0 ° C and the reaction was complete in 1-3 hours. The reaction mixture was extracted with ethyl acetate and the aqueous phase was lyophilized resulting in the desired carboxylate salt.

Method 6 Ester Hydrolysis Procedure II To a solution (2: 1.5-10 mL) of THF / H20 cooled to (0 ° C) of the appropriate ester was added LiOH (1.1 equivalents). The temperature was maintained at 0 ° C and the reaction was complete in 1-3 hours. The reaction mixture was concentrated and the residue was taken up in H20 and the pH was adjusted to 2-3 with aqueous HCl. The product 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 ! . '- # Ie «J - J Procedure III of rH * ester hydrolysis The appropriate ester was dissolved in dioxane / H20 (1: 1) and 0.9 equivalent of 0.5 N NaOH was added.

The reaction was stirred for 3-16 hours and concentrated. The resulting residue was dissolved in H2O and extracted with ethyl acetate. The aqueous phase was lyophilized to yield the desired sodium carboxylate salt.

Method 8 Sulfonylation Procedure I To the appropriately protected amidoenylalan analogue (11.2 mmol), dissolved in methylene chloride (25 ml) and cooled to -78 ° C was added the desired sulfonyl chloride (12 mmol) followed by the dropwise addition of pindine (2). mL). The solution was allowed warmed to room temperature and stirred for 48 h. 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 (MgSO4) and the solvent was concentrated to produce the desired product.

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

Method 10 BOC Removal Procedure The anhydrous Hydrochloride gas (HCl) was bubbled through a methanolic solution of the 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 re-concentrated. This procedure was repeated and the resulting solid was placed at high vacuum overnight.

Sfe, Method 11 Procedure I for Hydrolysis of Tere-Butyl Ester The tert-butyl ester was dissolved in CH2C12 and treated with TFA. The reaction was complete in 1-3 hr at this time the reaction mixture was concentrated and the residue was dissolved in H20 and lyophilized to yield the desired acid.

Method 12 EDC Coupling Procedure To a solution of CH2C12 (5-20 mL) of N- (toluene-4-sulfonyl) -L-proline (1 equivalent), the amino acid ester hydrochloride (1 equivalent), N-methylmorpholine (1.1-2.2) were mixed. equivalents) and 1-hydroxybenzotriazole (2 equivalents) were placed in an ice bath and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.1 equivalents) was added. The reaction was allowed to reach room temperature and stirred overnight. The reaction mixture was poured into H20 and the organic phase was washed with sat. NaHC0, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. The crude product was purified by column chromatography.

Method 13 EDC Coupling Procedure To a solution of DMF (5-20 ml) of the appropriately N-protected amino acid (1 equivalent), the appropriate amioacid ester hydrochloride (1 equivalent), Et3N (1.1 equivalent) and 1-hydroxybenzotriazole (2 equivalents) were mixed, were placed in an ice bath and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.1 equivalents) was added. The reaction was allowed to reach room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and H0 and the organic phase was washed with 0.2 N citric acid, H20, sat. NaHC03, 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 CH2C12 and placed in an ice bath. L-pro-L-Phe-Ome or HCl (1 equivalent) and Et3N (1.1 equivalents) 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 The organic phase was washed with sat. NaHCO 3, brine, dried (MgSO 4 or Na 2 SO 4), filtered and concentrated. The crude product was purified by column chromatography 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 CH2C1 was added Et3N (5 equivalents) followed by the chloride of appropriate sulfonyl (1.1 equivalents). 25 The reaction was allowed to warm up to the rBMflf-f "* -On room temperature and stirred overnight under a nitrogen atmosphere, the mixture was concentrated, dissolved in EtOAc, washed with sat.NaHCO3 and 0.2 N citric acid.The aqueous phase was basified with NaHCO3. The product was extracted with EtOAc The organic phase was washed with brine, dried (MgSO 4 or NaSO 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.

Method 16 Hydrogenation Procedure II To a methanol solution (10-15 mL) of the azlactone was added NaOAc (1 equivalent) and 10% Pd / C. this mixture was placed in the 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 dehydropeptide. The ester was dissolved in dioxane / H20 (5-10 mL), to which 0.5 N NaOH (1.05 equivalents) was added. After stirring for 1-3 hours, the mixed reaction was concentrated and the residue was redissolved in H20 and washed with EtOAc. The aqueous phase was basified 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 with approximately 1: 1 mixture of diastereomers.

Method 17 Procedure II of Hydrolysis of Tere-Butyl Ester The tert-butyl ester was dissolved in CH2Cl2 (5 mL) and treated with TFA (5 mL) the reaction was complete in 1-3 hours at which time the reaction mixture was concentrated and the residue was dissolved in H20 and the concentrated.

The residue was redissolved in H0 and lyophilized to produce the desired product.

Example 1 Synthesis of N- (Toluen-4-sulfonyl) - (2S-indolin-2-carbonyl) - L-phenylalanine < JußUIMaáaáiBM8l £ ésS% gsfc N- (Toluen-4-sulfonyl) -2S-indoline-2-carboxylic acid (331.2 mg, 1.04 mmol) was dissolved in dry DMF (5 mL) with 4-methyl morpholine (3.5 eq 400 μL), BOP (1.1 eq 506 mg), and phenylalanine benzyl ester (1.0 eq 444 mg). The dipeptide was isolated as an oil. The benzyl ester was dissolved in EtOH: H20 (1: 1) [2.5 mL] containing a catalytic amount of 10% Pd on C and hydrogenated under 50 psi H2. During filtration on celite, and the evaporation of the solvents under reduced pressure, the title material was isolated as a solid, m.p. = 167-170 ° C. The NMR data are as follows: 1 H NMR (300 MHz, CDC 13): d = 7.64 (d, 1 H, J = 8.50 Hz), 7.43 (d, 2 H, J = 8.25 Hz), 7.23 (m, 2 H), 7.12-7.00 (m, 6H), 6.86 (m, 2H), 4.82 (m, 1H), 4.60 (m, 1H), 3.12 (m, 3H), 2.62 (m, 1H), 2.32 (s, 3H) . 13 C NMR (75 MHz, CD3OD): d = 174.37, 173.24, 146.90, 142.92, 138.09, 136.61, 133.49, 130.92, 129.90, 129.49, 129.13, 128.22, 127.37, 126.78, 119.34, 65.28, 55.44, 38.74, 34.15, 22.03 . Mass spectroscopy: (FAB) 465 (M + H).

Example 2 Synthesis of N- (Toluene-4-sulfonyl) - (2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl-L-phenylalanine Following the experimental procedure described for the synthesis of Example 1 (20), the title compound is produced as a white solid, mp = 41-78 ° C. The NMR data are as follows:? H NMR (300 MHz, CDC13): d = 7.61 (m, 3H), 7.24-6.85 (m, 10H), 4.65 (m, 1H), 4.55 (m, 1H), 4.22 (d, 1H, J = 10.5 Hz), 4.05 (d, 1H, J = 10.5 Hz), 3.18-2.92 (m, 4H), 2.34 (s, 3H). 13 C NMR (75 MHz, CD3OD): d = 174.62, 173.36, 146.96, 138.63, 136.89, 134.17, 131.34, 131.03, 130.12, 129.62, 129.25, 128.87, 128.23, 127.74, 57.59, 56.83, 47.14, 38.75, 31.72, 32.00 . Mass spectroscopy: (FAB) 479 (M + H).

Example 3 Synthesis of N- (Toluen-4-sulfonyl) glycyl-L-phenylalanine The N- (Toluen-4-sulfonyl) glycine (547 mg, 2.40 mmol) was converted to a slurry in CH2C12 (7 mL) and cooled in an ice bath. Oxalyl chloride (0.30) < & aaßAaiBaíU &? ta ?? ÍM? UßSl¿ mL) was added, followed by a drop of DMF. The mixture was warmed to room temperature and stirred for 1 hr. The volatiles were removed in vacuo and the acid chloride was dissolved in CH2C12 (8 mL) and cooled in an ice bath. Phenylalanine benzyl ester toluene sulfonate (919 mg, 2.1 mmol) was added, followed by triethylamine (0.75 mL). The mixture was allowed to slowly warm to room temperature and was stirred for 19 hr. The mixture was diluted with CH2Cl2 (40 mL) and washed with IN HCl (2 x 10 mL), 1M NaHCO 3 (15 mL), brine (10 mL), dried (MgSO 4), filtered and evaporated in vacuo. The residue was purified by flash chromatography of silica gel (3: 2 Hexane / EtOAc) to give the dipeptide benzyl ester (0.51 g 50%). The benzyl ester is dissolved in THF (20 mL) and 10% Pd / C (60 mg) was added. The mixture was hydrogenated at 15 psi of H2 per 1.5 hr. The mixture was filtered through a pad of diatomaceous earth and evaporated in vacuo to give a residue which was recrystallized from MeOH / CHCl3 to give the composed of the title as a white solid (304 mg, 76%), mp = 157-161 ° C. The NMR data are as follows: X H NMR (CDCl 3): d = 12.8 (bs, 1 H), 8.13 (d, 1 H, J = 8.0 Hz), 7.86 (d, 1 H, J = 6.1 Hz), 7.65 (d , 2H, J = 8.2 Hz), 7.29-7.17 (5H), 4.49 (m, 1H), 3.01 (dd, 1H, J = . 0, 13.7 Hz), 3.57 (m, 3H), 2.85 (dd, 1H, J = 8.5, 13.7 Hz), 2.37 (s, 3H). 13C NMR (CDC13): d = "l72.9, 167.7, 143.0, 137.7, 137.6, 129.9, 129.5, 128.6, 127.0, 53.7, 45.3, 37.2, 21.4 Mass spectroscopy: (FAB) m / e 377 (M + H) Example 4 Synthesis of N- (Toluen-4-sulfonyl) sarcosyl-L-phenylalanine The product of Example 21 (180) (0.62 mmol) was added to ethanol (40 mL) and 5% Pd-C (10%) and shaken under 35 psi of hydrogen for 16 hours. The reaction mixture was filtered through celite and concentrated. The crude product was crystallized from EtOAc / Hexane to yield the title compound as a white solid (190 mg, 78.5%), mp = 128-130 ° C. The NMR data are as follows: X H NMR (CDCl 3, 300 MHz): d = 7.65 (d, 2 H, J = 8.18 Hz); 7.26 (m, 7H); 4.84 (m, 1H); 3.73 (q, 1H, J = 7.02); 3.58 (d, 1H, J = 4.28 Hz); 3.20 (m, 2H); 2.55 (s, 3H); 2.43 (s, 3H). ^ '^^ - t ^^^ feHr 13C NMR (CDCI3, 300 MHz): d = 175.23, 168.75, 144.90, 136.50, 133.53, 130.57, 129.89, 129.34, 128.17, 127.75, 54.39, 53.84, 37.82, 37.18, 22.15 . Mass spectroscopy: (+ FAB) 391 (M + H), 413 (M + Na).

Example 5 Synthesis of N- (Toluen-4-sulfonyl) -L-alanyl-L-phenylalanine The title compound was prepared according to the procedure described in Example 4 (41). The crude product was crystallized from Et20 / Hexane to give a white solid, mp = 105-108 ° C. The NMR data are as follows: X H NMR (CDCl 3, 300 MHz): d = 7.72 (d, 2 H, J = 8. 06 Hz); 7.26 (m, 6H), 7.09 (d, 2H, 7.63 Hz); 6.84 (d, 1H, J = 7.69 Hz); 5.46 (d, 1H, J = 7.70 Hz); 4.71 (m, 1H); 3.77 (m, 2H); 3.09 (m, 2H); 2.41 (s, 3H); 1.14 (d, 3H, J = 7. 14 Hz). 13 C NMR (CDCl 3, 300 MHz): d = 174.60, 172.17, 144.69, 136.79, 136.19, 130.47, 129.93, 129.26, 129.20, 127.80, 127.72, 53.94, 53.05, 37.74, 22.17, 19.71. tsawr * ^ s ^ - go ¿üSar Mass spectroscopy: (+ FAB) 391 (M + H) 413 (M + Na) Example 6 Synthesis of N- (2-Methoxycarbonylbenzenesul nyl) -glycyl-L-phenylalanine The title compound was prepared according to the procedure described for Example 4 (41), yielding a white solid, m.p. = 140-143 ° C. The NMR data are as follows: X H NMR (CD30D, 300 MHz): d = 7.75 (m, 2H); 7.50 (m, 2H); 7.02 (m, 5H); 4.32 (m, 1H); 3.74 (s, 3H); 3.44 (d, 2H, J = 7.57 Hz); 2.91 (m, 1H); 2.72 (m, 1H). 13 C NMR (CD3OD, 300 MHz): d = 170.66, 169.90, 140.00, 138.73, 134.49, 133.15, 131.96, 131.05, 130.95, 130.92, 130.01, 129.96, 128.35, 55.79, 54.29, 46.98, 38.08, 31.23. Mass spectroscopy: (+ FAB) 421 (M + H), 443 (M + Na). Example 7 ^^^^^^^^^^^^^^^^^^^^^^^^^ JV- (2-Methoxycarbonylbenzenesulfonyl) -L-alanyl-L-phenylalanine synthesis The title compound was prepared according to the procedure described in Example 4 (41), yielding a crystalline semi-solid. The NMR data were as follows: XH NMR (CDC13, 300 MHz): d = 8.02 (d, 1H, J = 7.14 Hz); 7.84 (d, 1H, J = 7.15 Hz); 7.62 (m, 2H); 7.20 (m, 6H); 6.50 (d, 1H, J = 6.59 Hz); 4.71 (m, 1H); 3.98 (s, 3H); 3.87 (m, 1H); 3.10 (m, 2H); 1.14 (d, 3H, J = 7.14 Hz). 13 C NMR (CDC13, 300 MHz): d = 175.08, 172.26, 168.58, 138.99, 136.47, 133.47, 132.58, 131.63, 130.78, 130.51, 129.95, 129.15, 127.65, 54.12, 54.01, 53.68, 37.93, 19.23. Mass spectroscopy: (+ FAB) 435 (M + H).

Preparatory Example A Synthesis of N- (Sacarin-2-yl) glycyl-L-phenylalanine To the benzyl ester of L-phenylalanine (4.64 mmoles) in THF (15 mL) was added triethylamine (4.70 mmoles) and the reaction proceeded for 30 minutes at room temperature. The reaction mixture was cooled to 0 ° C and methyl 2- (chlorosulfonyl) benzoate (4.64 mmole) was added and the reaction proceeded for 4 hours at room temperature. The reaction was extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed successively with sat. NaHCO 3. (50 mL) and sat. NaCl. (2 x 50 mL), dried over MgSO4, filtered and rotoevaporated to give a colorless oil (2.30 g, 90%). The crude product was purified by silica gel chromatography (50% EtOAc / Hexane, Rf = 0.47) to yield N- (2-Methoxycarbonylphenylsulfonyl) -L-prolyl-L-phenylalanine benzyl ester as a colorless oil (1.49 g). , 58%). Sodium hydride (1.47 mmol, washed free of mineral oil) in THF (10 mL) was cooled to 0 ° C, and a solution of benzyl ester of N- (2-methoxycarbonyl-phenyl) sulfonyl-L-glycine- L-phenylalanine in THF (5 mL) was added dropwise. The reaction was stirred at 0 ° C for one hour and then at room temperature for two hours. The reaction mixture was extracted with EtOAc (3 x 100 mL) and 0.2 N HCl (50 mL), the combined EtOAc layers were washed successively with 0.2 N HCl (50 mL), sat. NaHCO 3. (50 mL), and sat. NaCl. (2 x 50 mL). The organic layer was dried over MgSO4, filtered and concentrated to give a colorless oil (0.63 g, 91%). The crude product was filtered by silica gel chromatography (50% EtOAc / Hexanes, Rf = 0.42) to give N- (benzisothiazolon) -L-glycyl-L-phenylalanine benzyl ester as a colorless oil (0.25 g, 36%). %) which was then hydrogenated with 10% Pd on C in THF and the mixture was shaken under 50 psi of H2. The mixture was filtered through celite and evaporated to give the title compound as a white solid (42 mg, 52%), mp = 201-204 ° C. The NMR data were as follows: XH NMR (CD3OD, 300 MHz): d = 7.80 (m, 4H); 7.01 (m, 5H); 4.43 (t, 1H, J = 5.43 Hz); 4.17 (d, 2H, J = 5.43); 2.99 (m, 1H); 2.82 (m, 1H). 13 C NMR (CD3OD, 300 MHz): d = 167.94, 160.99, 139.70, 138.87, 137.10, 136.46, 131.11, 129.89, 129.01, 128.21, 126.77, 122.87, 56.57, 41.57, 39.04. Mass spectroscopy: (+ FAB) 398 (M + H), 411 (M + Na).

Example 8 Synthesis of N- (Sacarin-2-yl) -L-alanyl-L-phenylalanine The title compound was prepared using the procedures described for the preparation of Preparative Example A (48), yielding a white solid, mp = 190-193 ° C. The NMR data are as follows: X H NMR (CDCl 3, 300 MHz): d = 7.86 & 6.95 (m, 9H); 5 4.66 (bs, 2H); 3.18 (m, 1H); 2.97 (m, 1H); 1.69 (d, 3H, J = 6.59). 13 C NMR (CDCl 3, 300 MHz): d = 176.31, 169.18, 158.14, 138.01, 136.68, 135.86, 129.77, * 128.81, 127.27, 127.21, 126.13, 121.68, 112.01, 66.48, 54.99, 51.80, 10 37.53, 14.65. Mass spectroscopy: (+ FAB) 403 (M + H), 425 (M + Na).

Example 9 Synthesis of N- (Toluen-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine N- (Toluene-4-sulfonyl) phenylglycine was prepared from phenylglycine using the procedure described in Method 1. N- (Toluene-4-sulfonyl) phenylglycine-OH and L-Phe-OBn-HCl were treated with BOP and NMM in DMF, to give after the aqueous preparation and flash chromatography, N- a ^ É | ^^^^^^ j «| ^ ^^^ g (Toluen-4-sulfonyl) phenylglycine-L-Phe-Obn. This product was treated with 10% Pd on 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, mp = 150-152 ° C. The NMR data were as follows: XH NMR (DMSO-d6, 300 MHz): d = 2.30 (s, 3H), 2.70-2.95 (m, 2H), 4.13-4.30 (m, 1H), 5.03-5.20 ( m, 1H), 6.88-7.34 (m, 12H), 7.55 (m, 2H), 8.38-8.67 (m, 2H). 13C NMR (DMSO-de, 75 MHz): d = 21.3, 37.3, 53.7, 59.6, 126.7, 126.8, 126.87, 126.92, 127.4, 127.6, 128.2, 128.26, 128.35, 128.6, 129.4, 129.5, 137.2, 137.9, 138.8 , 142.5, 169.0, 172.8. Mass spectroscopy: (FAB +) 453 (M + H).

Example 10 Synthesis of N- (Toluen-4-sulfonyl) -N-methyl-L-phenylalanyl- D, L-phenylalanine The N-methyl-L-phenylalanine (500 mg, 2.79 mmol) was dissolved in IN NaOH (6 mL). Dioxane (9 mL) was added, followed by p-toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was stirred vigorously for 1 hr.

The volatiles were removed in vacuo and the residue was dissolved in water (30 mL) and washed with Et20 (2 x 30 mL) before making acid with IN HCl. The mixture was extracted with CHC13 (3 x 30 mL) and the extracts were evaporated m vacuo to give N- (toluene-4-sulfonyl) -N-methylphenylalanine as a solid (424 mg, 45%). The N- (Toluen-4-sulfonyl) -N-methylphenylalanine was bound to L-phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analysis indicates a mixture of diastereomers. The NMR data were as follows:? H NMR (CDCI3): d = 9.15 (bs, 1H), 7.38-6.89 (14H), 4.82 (m, 1H), 4.70 (m, 1H), 3.31-2.95 (3H) ), 2.81 (s, 1/2 X 3H), 2.55 (s, 1/2 X 3H), 2.50 (m, 1H), 2.37 (s, 1/2 X 3H), 2.35 (s, 1/2 X) 3H). 13 C NMR (CDCl 3): d = 175.3, 169.6, 169.5, 143.5, 143. 4, 137.0, 136.9, 135.6, 135.5, 135.3, 135.2, 129. 129.7, 129.6, 129.3, 129.2, 129.1, 129.0, 128.7, 128.6, 128. 5, 128.4, 127.2, 127.1, 127.0, 126.6, 126.4, 124. 61.2, 61.0, 53.5, 53.4, 37.4, 37.1, 33.9, 33.5, 29.9, 9.6, 21.4. Mass spectroscopy: FAB m / e 481 (M + H).

Example 11 Synthesis of N- (Toluene-4-sulfonyl) -L-diphenylalanyl-L-phenylalanine 5 Boc-L-diphenylalanine was bound to benzyl ester of L-phenylalanine using the procedure described in Method 3. The Boc group was removed by treatment with TFA and anisole, and the mixture was evaporated. The residue was dissolved in Et20 and washed with sat. NaHCO3. and NaCl sat. The Et20 layers were dried with MgSO4, filtered, and evaporated to give the deprotected dipeptide. The resulting ester of the title compound was treated with tosyl using the procedure described in Method 1. The title compound was prepared using the procedure described in Method 7 as a solid, mp = 228-230 ° C. The NMR data were as follows: 1 H NMR (CD 3 OD, 300 MHz): d = 2.11 (s, 3 H), 2.37-2.46 (m, 2 H), 3.78 (m, 1 H), 3.99 (d, 1 H, J = 10.8 Hz), 4.49 (d , 1H, J = 10.8 Hz), 6.86-7.04 (m, 17H), 7.36 (d, 2H, J = 8.3 Hz). 13 C NMR (CD3OD, 75 MHz): d = 22.0, 39.8, 56.1, 56.3, 61.6, 128.09, 128.14, 128.4, 128.7, 128.8, 129.8, & S & amp; mc? - ¡1 129. 9, 130.0, 130.1, 130.3, 131.07, 131.11, 138.7, 140.0, 142.2, 142.4, 144.9, 172.3, 174.5. Mass spectroscopy: (FAB +) 549 (M + Li).

Example 12 Synthesis of N- (Toluen-4-sulfonyl) sarcosyl-L- (N-benzyl) histidine N- (Toluene-4-sulfonyl) sarcosine was prepared from sarcosine using the procedure described in Method 1. The coupling was conducted using the procedure described in Method 3. The title compound, prepared by hydrolysis of the ester using the procedure described in Method 7, was obtained as a solid, pf = > 200 ° C (dec.). The NMR data were as follows: XH NMR (CD30D, 300 MHz): d = 2.17 (2, 3H), 2.28 (s, 3H), 2.71-3.05 (m, 2H), 3.31-3.48 (dd, 2H) , 4.34 (m, 1H), 6.74 (s, 1H), 6.97-7.16 (m, 7H), 7.37 (d, 2H, J = 8.0 Hz), 7.44 (s, 1H). 13 C NMR (D20, 75 MHz): d = 27.7, 37.2, 43.0, 57.3, 59.8, 61.7, 124.7, 134.3, 134.6, 134.9, 135.8, 137.0, 138.9, 143.7, 144.2, 144.3, 152.0, 176.0, 184.6.

J:? S¡iiíí ii M¡ É ^ Mass Spectroscopy: (FAB +) 493 (M + H) Example 13 Synthesis of N- (Toluen-4-sulfonyl) sarcosyl-D, L-ß- (3-pyridyl) alanine The sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100 mL) containing diethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolyl chloride hydrochloride (5.00 g, 30.5 mmol) was added. The mixture was heated to reflux for 6 hours, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up in saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3 x 100 mL). The solvent was removed and the residue was purified by flash chromatography on silica gel (95: 5 CH2Cl2 / MeOH) to give diethyl 2- (3-pyridylmethyl) -2-acetamidomalonate (2.84 g, 30%). The diethyl 2- (3-pyridylmethyl) -2-acetamidomalonate was dissolved in 6N HCl (30 mL) and heated to reflux for 19 hr after which it was cooled to room temperature and the HCl solution was removed by evaporation in. empty. The dihydrochloride salt of mf & The intermediate amino acid was recovered in MeOH (30 mL) saturated with HCl gas and stirred for 3.5 hr. The MeOH / HCl was removed by evaporation in vacuo to give β- (3-pyridyl) alanine methyl ester dihydrochloride (2.235 g, 100%). N- (Toluen-4-sulfonyl) sarcosine was attached to 3- (3-pyridyl) alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N- (toluene-4-sulfonyl) sarcosyl-β- (3-pyridyl) alanine (166 mg, 17%). The title compound was prepared via hydrolysis of the methyl ester using IN aqueous NaOH in dioxane / water (129 mg, 100%). The NMR data were as follows: XH NMR (DMSO-d6): d = 8.30 (m, 2H), 7.66 (d, 2H, J = 8.0 Hz), 7.63 (m, 1H), 7.51 (m, 1H) , 7.42 (d, 2H, J = 7.9 Hz), 7.20 (m, 1H), 4.07 (m, 1H), 3.56 (s, 2H), 3.11 (dd, 1H, J = 4.8, 13.2 Hz), 2.96 ( dd, 1H, J = 5.5, 13.4 Hz), 2.52 (s, 3H), 2.40 (s, 3H). 13 C NMR (DMSO-d 6): d = 172.7, 166.0, 150.8, 147.3, 143.8, 137.3, 134.8, 134.0, 130.2, 127.7, 123.3, 55.3, 53.2, 36.2, 34.9, 21.4. Mass spectroscopy: FAB m / e 392 (M + H).

Example 14 -Q 2 Synthesis of N- (Toluene-sulfonyl) sarcosyl-D, L-β- (4-pyridyl) alanine The title compound was prepared as described in Example 13 (107) except that 4-picolyl chloride hydrochloride was used in place of 3-picolyl chloride hydrochloride. The NMR data were as follows: XH NMR (CD3OD): d = 8.39 (d, 2H, J = 5.3 Hz), 7.68 (d, 2H, J = 8.2 Hz), 7.41 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 5.8 Hz), 4.58 (m, 1H), 3.70 (d, 1H, J = 16.6 Hz), 3.54 (d, 1H, J = 16.5 Hz), 3.30 (dd, 1H, J = 4.9, 13.7 Hz), 3.07 (dd, 2H, J = 7.6, 13.7 Hz), 2.66 (s, 3H), 2.43 (s, 3H). 15 13 C NMR (CD 3 OD): d = 176.0, 270.2, 150.8, 150.1, 146.1, 135.7, 131.5, 129.3, 127.4, 56.4, 54.8, 39.1, 37.6, 22.1. Mass spectroscopy: FAB m / e 392 (M + H).

Example 15 Synthesis of N- (Toluen-4-sulfonyl) sarcosyl-L-β- (2-pyridyl) alanine 25 The N- (Toluen-4-sulfonyl) sarcosine was bound to L-β- (2-pyridyl) alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N- methyl ester ( toluene-4-sulfonyl) sarcosyl-β- (2-pyridyl) alanine. The title compound was prepared via hydrolysis of the methyl ester using IN aqueous NaOH in dioxane / water. The NMR data were as follows: X H NMR (DMSO-d 6): d = 8.38 (m, 1 H), 7.72 (d, 1 H, 10 J = 7.4 Hz), 7.65 (d, 2 H, J = 8.2 Hz), 7.59 (m, 1H), 7.41 (d, 2H, J = 8.2 Hz), 7.21 (d, 1H, J = 7.8 Hz), 7.12 (m, 1H), 4.23 (m, 1H), 3.50 (, 2H) , 3.23 (dd, 1H, J = 4.8, 13.4 Hz), 3.01 (dd, 2H, J = 7.1, 13.4 Hz), 2.53 (s, 3H), 2.40 (s, 3H). 15 13 C NMR (DMSO-d 6): d = 173.4, 165.7, 159.7, 148.9, 243.8, 136.1, 134.0, 130.2, 127.7, 124.0, 121.4, 54.7, 53.3, 36.1, 21.4. Mass spectroscopy: FAB m / e 414 (M + Na).

Example 16 Synthesis of N- (Toluene-4-sulfonyl) -D, L-phenylsarcosyl-L-phenylalanine ^ *.

Sulfi-N-sulfonyl) phenylsarcosine was prepared from phenylsarcosine using the procedure described in Method 1. The title compound was prepared using the procedure described for Example 9 (65) as a solid, mp = 78-82 ° C. The NMR data were as follows: XH NMR (CDC13, 300 MHz): d = 2.41 (s, 3H), 2.48 (s, 3H), 2.97-3.34 (m, 2H), 4.89 (m, 1H), 5.63 (s, 1H), 6.77-6.92 (m, 3H), 7.13-7.35 (m, 10H), 7.66 (d, 2H, J = 7.5 Hz). 13 C NMR (CDCl 3, 75 MHz): d = 22.2, 32.3, 38.0, 53.9, 64.4, 127.8, 128.1, 129.1, 129.4, 129.88, 129.95, 130.0, 130.3, 133.9, 136.2, 136.4, 144.4, 169.8, 175.2. Mass spectroscopy: (FAB +) 467 (M + H).

Preparative Example B Synthesis of N- (Toluene-4-sulfonyl) sarcosyl-N-methyl-L-phenylalanine N- (Toluen-4-sulfonyl) sarcosine was coupled to the methyl ester of N-methyl-L-phenylalanine using the procedure described in Method 3 to give N- (toluene-4-sulfonyl) sarcosyl-N- methyl ester methylphenylalanine. The title compound was prepared via ^ &A »¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡iisS? á ^ & amp; s ^^^^ i hydrolysis of the methyl ester using LiOH in THF / water. Proton and carbon NMR analysis indicates a mixture of amide bond rotomers in approximately a ratio of 65:35. The NMR data were as follows: XH NMR (CDC13): d = 7.59 (d, 0.65 x 2H, J = 7.4 Hz), 7.54 (d, 0.35 x 2H, J = 7.3 Hz), 7.34-7.18 (7H) , 5.25 (m, 0.65H), 5.09 (m, 0.35H), 3.93 (d, 0.65H, J = 14.6 Hz), 3.58 (d, 0.65H, J = 14.6 H), 3.41 (m, 1H), 3.10 (m, 1H), 2.97 (s, 0.65 x 3H), 2.92 (s, 0.35 x 3H), 2.41 (s, 3H), 2.39 (s, 0.65 x 3H), 2.38 (s, 0.35 x 3H). 13 C NMR (CDCl 3): d = 173.3, 168.1, 167.8, 143.9, 143.8, 136.9, 136.8, 133.3, 129.7, 129.1, 128.8, 128.7, 128.6, 127.5, 127.0, 126.8, 59.0, 52.8, 52.7, 35.0, 34.7, 34.2, 33.0, 30.1, 21.5. Mass spectroscopy: FAB m / e 405 (M + H).

Example 17 Synthesis of N- (Toluen-4-sulfonyl) -L-aspartyl-L-phenylalanine Cbz-4- (1,1-d-methylethyl) aspartic acid was coupled with t-butyl phenylalanine ester using the ** g & $ 3KAjáa & procedure described in Method 3. The Cbz group was removed using the procedure described in Method 4. The resulting ester was treated with tosyl using the procedure described in Method 1. The title compound was prepared using the procedure outlined in the Method 11. The NMR data were as follows: XH NMR (CD3OD, 300 MHz): d = 2.18 (s, 3H), 2.18-2.39 (m, 2H), 2.68-2.89 (m, 2H), 3.97 (t, 1H, J = 5.2 Hz), 4.22 (t, 1H, J = 4.9 Hz), 6.97-7.12 (m, 7H), 7.45 (d, 2H, J = 8.2 Hz). 13C NMR (CD3OD), 75 MHz): d = 22.1, 38.6, 38.9, 55.1, 55.9, 128.5, 128.8, 130.1, 130.9, 131.0, 131.3, 138.3, 138.6, 139.4, 145.5, 172.6. Mass spectroscopy: (FAB +) 435 (M + H).

Example 18 Synthesis of Benzyl Ester of N- (Toluene-4-sulfonyl) - (2S- 1,2,3,4-tetrahydroisoquinoline-3-carbonyl) -L-phenylalanine N- (Toluen-4-sulfonyl) - (2S-1,2,3,4-tetrahydroquinoline-3-carbonyl) (1 eq.) Was dissolved in DMF, with Et 2 N (2.0 eq), BOP (1.1 eq.) ), and salt of L-phenylalanine benzyl ester HCl. The benzyl ester was isolated as an oil. The NMR data were as follows: XH NMR (300 MHz, CDC13): d = 7.62 (d, 2H, J = 8. 16 Hz), 7.33 (m, 5H), 7.23-7.08 (m, 8H), 6.70 (d, 2H, J = 8.16 Hz), 5.10 (q, 2H, J = 11.50 Hz), 4.72 (, 1H), 4. 52 (m, 1H), 4.18 (m, 2H), 3.07 (m, 2H), 2.85 (m, 2H), 2.52 (m, 1H), 2.34 (s, 3H).

Example 19 Synthesis of Benzyl Ester of N- (Toluen-4-sulfonyl) - (2S- indolin-2-carbonyl) -L-phenylalanine The procedure used for the preparation of Example 18 (173) was used. The title compound was isolated as an oil. The NMR data were as follows: XH NMR (300 MHz, CDC13): d = 7.66 (d, 1H, J = 7. 98 Hz), 7.42-6.92 (m, 16H), 6.66 (d, 2H, J = 8.50 Hz), 5.17 (q, 2H, J = 10.08 Hz), 4.83 (m, 1H), 4.58 (m, 1H) , 3.07 (m, 3H), 2.62 (m, 1H), 2.32 (s, 3H). - & .. - fá ^ ^^ á ^ ^? ^^^ I ^^^^ Ss ^ ^^ B ^^^^ A Example 20 Synthesis of Benzyl Ester of N- (Toluen-4-sulfonyl) -L-alanyl-L-phenylalanine 5 A N- (Toluen-4-sulfonyl) -L-alanine (2.0 mmol) in DMF (10 mL) was added BOP (2.1 mmole) and N-methylmorpholine (4.0 mmole) and the reaction was stirred at room temperature for 45 minutes. The benzyl ester of L-Phenylalanine (2.0 mmol) was added and the reaction was stirred for 16 hours at room temperature. The reaction mixture was extracted with water (100 mL) and diethyl ether (3 x 50 mL). The combined organic layers were washed successively with 0.2 N HCl (2 x 50 mL), sat. NaHCO 3. (fifty L), and NaCl sat. (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give a colorless oil (387 mg, 40%). The crude product was purified by chromatography on silica gel (50% EtOAc / Hexane, Rf = 0.61). The title compound crystallized to from CHCl3 / Hexane to give a white solid, mp = 109-110 ° C. The NMR data were as follows:? H NMR (CDC13, 300 MHz): d = 7.75 (d, 2H, J = 8.24 Hz); 7.26 (m, 13H); 5.88 (d, 1H, J = 7.69 Hz); 5.11 (q, 2H, J = 12.1 Hz); 4.76 (q, 1H, J = 7.69 Hz); 3.85 (m, 1 HOUR); 3.00 (d, 2H, J = 5.98 Hz); 2.37 (s, 3H); 1.19 (d, 3H, J = 7.09 Hz). 13C NMR (CDC13, 300 MHz): d = 171.83, 171.49, 144.30, 137.34, 136.12, 135.53, 130.36, 130.00, 129.90, 129.19, 129.12, 127.85, 127.71, 127.65, 67.92, 54.07, 52.94, 38.26, 22.13, 19.96 . Mass spectroscopy: (+ FAB) 481 (M + H).

Example 21 Synthesis of Benzyl Ester of N- (Toluen-4-sulfonyl) sarcosyl-L-phenylalanine The title compound was prepared according to Method 3, and the crude product was crystallized from Et20 / hexane to give a white solid, mp = 80-82 ° C. The NMR data were as follows: X H NMR (CDCl 3, 300 MHz): d = 7.64 (d, 2 H, J = 8. 24 Hz); 7.26 (m, 13H); 5.16 (q, 2H, J = 12.1 Hz); 4.92 (d of t, 1H, J = 6.71 and 11.29 Hz); 3.7.70 (d, 1H, J • = 16.48 Hz); 3.43 (d, 1H, J = 16.48 Hz); 3.15 (m, 2H); 2.56 (s, 3H); 2.44 (s, 3H). ^ .... mA ^ u * 13C NMR (CDCI3, 300 MHz): d = 171.34, 167.88, 144.88, 135.97, 135.60, 133.61, 130.56, 129.85, 129.36 129.22, 129.15, 128.16, 127.84, 67.93, 54.51, 53.51 , 38.29, 37.15, 22.16. Mass spectroscopy: (+ FAB) 481 (M + H).

Example 22 Synthesis of N- (Toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine Ethyl Ester N- (Toluene-4-sulfonyl) phenylglycine was prepared from phenylglycine using the procedure described in Method 1. The title compound was prepared using the procedure described for Example 11 (86) as a solid, mp = 145- 147 ° C. The NMR data were as follows:? H NMR (CDCI3, 300 MHz): d = 1.12-1.29 (m, 3H), 2.38 (s, 3H), 2.91-3.05 (ra, 2H), 4.04-4.20 (m , 2H), 4.65-4.81 (m, 2H), 5.85-5.95 (m, 1H), 6.07-6.21 (m, 1H), 6.65 (m, 1H), 6.95 (m, 1H), 7.02-7.33 (m , 10H), 7.60 (m, 2H). 13 C NMR (CDCl 3, 75 MHz): d = (diastereomeric pairs separated by diagonal line) 14.57 / 14.70, 22.09 / 22.10, 38.1, 53.7 / 54.2, 61.00 / 61.06, 62.26 / 62.34, 127.61 / 127.76, 127.81 / 127.88, 128.06 /128.16, 129.06 / 129.16, 129.3, 129.6, 129.69 / 129.76, 130.06 / 130.08, 135.4, 136.01 / 136.55, 136.94 / 137.21, 144.03 / 144.13, 168.67 / 169.00, 171.07 / 171.22. 5 Mass spectroscopy: (FAB +) 481 (M + H).

Example 23 Synthesis of N- (Toluene-4-sulfonyl) -N-methyl-L- (O-benzyl) -seryl-L-phenylalanine Ethyl Ester The salt of L- (0-benzyl) -serine methyl ester hydrochloride (6.28 g, 25.5 mmol) was dissolved in Dichloromethane (50 mL) with tosyl chloride (1.1 eq 5.36 g) and Et2N (2.2 eq, 7.48 mL). The reaction mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure. EtOAc was added as well as brine, and the organic layer was dried over MgSO4.

The desired N- (Toluene-4-sulfonyl) -L- (O-benzyl) -serine methyl ester was isolated as an oil, in 100% yield (10.04 g, 25.5 mmol). This was recovered in dry acetone (50 mL) with iodomethane (1.1 eq., 1.88 mL) and K2C03 (1.1 eq 4.10 g). The solution was refluxed all night. The solvent evaporated under pressure g ^ jj |||| j ^^^^ á ^^ riMg ^ fe ^ j3 ^^^ r, - -.-. f ^^^ Ml ^ M ^ iAfclA ^^ ffi ^ ferT ^^ lfflM! É ^ reduced. EtOAc was added and the organic layer was washed with brine. The organic layer was dried over MgSO4. The solvent was evaporated under reduced pressure. The desired N-methyl derivative was isolated as a clear oil in 40% yield (4.16 g, 11 mmol). The ester was dissolved in a 1: 1 solution of dioxane: H20 with NaOH (1.1 eq., 50 mL). The desired compound was isolated as a solid. The N- (Toluen-4-sulfonyl) -N-methyl-L- (0-benzyl) serine (754 mg, 2.07 mmol) was dissolved in 30 mL of dry DMF with phenylalanine ethyl ester hydrochloride salt (1.1 eq, 525 mg), Et2N (2.2 eq, 636 mL) and BOP reagent (1.1 eq, 100 g). The reaction mixture was stirred at room temperature for 12 hours. EtOAc was added. The organic layer was washed with saturated NaHC 3, 10% citric acid, and brine. The organic layer was dried over MgSO4. During the evaporation of the solvents under reduced pressure, the crude material was eluted on a column chromatography (Silica Gel; CHCl 3 / MeOH 9: 1) The title ester was isolated as an oil in 60% strength. yield (664 mg, 1.23 mmol) and as a mixture of diastereomers. The NMR data were as follows: H NMR (300 MHz, CDC13): d = 7.69 (d, 2H, J = 8.22 Hz), 7.27 (m, 5H), 7.15 (m, 5H), 7.04 (m, 2H) ), 4.80 (m, 2H), 4.29 (m, 4H), 3.76 (m, 1H), 3.58 (m, 1H), 3.19 (m, 2H), 2.71 (s, 1.5 H), 2.57 (s, 1.5H), 2.35 (s, 3H), 1.27 (m, 3H). 13C NMR (75 MHz, CDC13): d = 171.50, 168.70, 143.98, 137.84, 136.44, 136.18, 129.93, 128.98, 128.45, 128.37, 128.25, 127.65, 73.75, 67.15, 66.99, 62.17, 60.35, 59.98, 53.93, 53.75 , 38.34, 30.95, 22.15, 14.69. Mass spectroscopy: (FAB) 539 (M + H).

Example 24 Synthesis of Ethyl Ester of N- (Toluen-4-sulfonyl) -N-methyl-L-seryl-L-phenylalanine Example 23 (191) (664 mg, 1.23 mmol) was dissolved in MeOH (10 mL) with a catalytic amount of Pearlman's catalyst. The hydrogenation reaction was carried out for 2 hours at 5 psi. The solution was filtered over celite. During evaporation of the solvent under pressure When reduced, an oil was isolated as the title compound in quantitative yields. The NMR data were as follows. X H NMR (300 MHz, CDC13): d = 7.68 (m, 2H), 7.30 (m, 7H), 4.77 (m, 1H), 4.46 (m, 1H), 4.18 (m, 2H), 3.65 (m, 1H), 3.47 (m, 2H), 3.07 (m, 2H), 2.78 (s, 1.5H), 2.54 (s, 1.5H), 2.42 (s, 3H), 1.25 (m, 3H). 13C NMR (75 MHz, CDC13): d = 171.47, 170.31, 144.78, 136.42, 135.77, 130.67, 129.88, 129.33, 127.92, 127.80, 62.44, 60.99, 60.81, 54.00, 53.77, 38.32, 32.19, 31.96, 22.24, 14.76 . Mass spectroscopy: (FAB) 449 (M + H).

Example 25 Synthesis of Benzyl Ester of N- (Toluen-4-sulfonyl) -L- diphenylalanyl-L-phenylalanine Boc-L-diphenylalanine was coupled to benzyl ester of L-phenylalanine using the procedure described in Method 3. The Boc group was removed using the procedure described in Example 11 (86). The resulting ester was tosylated using the procedure described in Method 1 yielding the title compound as a solid, mp = 79-84 ° C. The NMR data were as follows: X H NMR (CDCl 3, 300 MHz): d = 2.36 (s, 3 H), 2.77 (m, 2 H), 4.25-4.39 (m, 2 H), 4.95 (d, 2 H, J = 4.9 Hz), 5.19 ^^ =, ^, ^^^^^ ... ... Aa ^^^ (d, 1H, J = 8.0 Hz), 6.18 (d, 1H, J = 7.8 Hz), 6.92 (m, 2H) , 7.08-7.38 (m, 20H), 7.55 (d, 2H, J = 8.4 Hz). 13C NMR (CDC13, 75 MHz): d = 22.1, 38.8, 54.1, 54.7, 60.9, 67.7, 127.6, 127.70, 127.72, 128.0, 128.7, 129.10, 129.14, 129.3, 129.9, 130.2, 135.5, 136.0, 137.0, 139.4 , 140.1, 144.2, 169.9, 170.8. Mass spectroscopy: (FAB +) 633 (M + H).

Example 26 Synthesis of Ethyl Ester of N- (Toluen-4-sulfonyl) -limethyl-D, L-phenylglycyl-L-phenylalanine The N- (Toluene-4-sulfonyl) phenylglycine was esterified with thionyl chloride in methanol to give N- (toluene-4-sulfonyl) phenylglycine methyl ester. This was recovered in dry acetone (50 mL) with iodomethane (1.1 eq, 1.88 mL) and K2CO3 (1.1 eq, 4.10 g). The solution is refluxed overnight. The solvent was evaporated under reduced pressure. EtOAc was added and the organic layer was washed with brine. The organic layer was dried over MgSO4. "The solvent was evaporated under reduced pressure.The resulting ester was hydrolyzed using the procedure described in Method 6 to give N- (Toluen-4-sulfonyl) -N-methyl- j? i ji gag ^^ j ^^^? gjg »g? igg ^ i ^ g? ^^ g ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ with L-phenylalanine ethyl ester using the procedure described in Method 3 to give the title compound. The NMR data were as follows: XH NMR (CDC13, 300 MHz): d = 1.27 (t, 3H), 2.43 (s, 3H), 2.60 (s, 3H), 2.98-3.25 (m, 2H), 4.21 (q, 2H), 4.80-4.91 (m, 1H), 5.68 (s, 1H), 6.59 (br d, lower day, 1H with 6.73) 6.73 (br d, higher day, 1H with 6.59), 6.92 -7.02 (m, 2H), 7.11-7.43 (m, 10H), 7.69 (d, 2H). 13 C NMR (CDCl 3, 75 MHz): d = (Main diastereomer) 14.75, 22.16, 32.20, 38.38, 53.56, 61.21, 64.43, 127.79, 128.07, 129.07, 129.13, 129.27, 129.87, 129.92, 130.04, 134.18, 136.10, 136.32. , 144.22, 169.08, 171.71; (minor diastereomer) 14.68, 22.16, 32.12, 38.51, 53.97, 62.21, 64.22, 127.76, 128.16, 129.07, 129.13, 129.32, 129.87, 129.92, 130.26, 134.26, 136.10, 136.52, 144.26, 169.08, 171.71. Mass spectroscopy: (FAB +) 495 (M + H).

Example 27 Synthesis of N- (Toluene-4-sulfonyl) sarcosyl-L- (N-benzyl) histidine Methyl Ester N- (Toluene-4-sulfonyl) sarcosine methyl ester was prepared from sarcosine methyl ester using the procedure described in Method 1. The title compound was prepared by linking or linking in DMF N- (toluene-4-sulfonyl) sarcosm with (N-benzyl) histidine methyl ester in the presence of BOP and NMM, to give after aqueous stimulation and flash chromatography, the title compound. The NMR data were as follows: XH NMR (CDC13, 300 MHz): d = 2.44 (s, 3H), 2.76 (s, 3H), 3.09 (m, 2H), 3.44 (d, 1H, J = 16.4 Hz), 3.68 (s, 3H), 3.83 (d, 1H, J = 16.5 Hz), 4.80 (m, 1H) , 5.07 (s, 2H), 6.74 (s, 1H), 7.14 (d, 2H, J = 6.0 Hz), 7.33 (m, 5H), 7.50 (s, 1H), 7.68 (d, 2H, J = 8.3) Hz), 8.06 (br d, 1H, 8.1 Hz). 13 C NMR (CDCl 3, 75 MHz): d = 14.8, 22.1, 30.2, 37.1, 51.4, 52.6, 52.9, 54.4, 61.0, 117.8, 128.0, 128.2, 128.8, 129.6, 130.5, 134.0, 136.6, 137.8, 137.9, 144.6 168.2, 172.1. Mass spectroscopy: (FAB +) 485 (M + H).

Example 28 Synthesis of Methyl Ester of N- (Toluene-4-sulfonyl) -N-methyl-L-seryl-L- (N-benzyl) histidine The N-Methyl-N- (toluene-4-sulfonyl) -L-serine (420 mg, 1.53 mmol) was dissolved in dry DMF (20 mL) at bath temperature with ice. Salt of L- (N-benzyl) histidine methyl ester hydrochloride (1.1 eq, 500 mg) as well as Et3N (2.2 eq, 471 mL) was added with HOBT (1.1 eq, 229 mg). After 15 min, EDCl (1.1 eq, 502 mg) was added and the reaction mixture was stirred at room temperature overnight. EtOAc was added and the organic layer was washed with saturated NaHCO3, 10% citric acid and brine (3x50 mL). The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure. The crude material was eluted on column chromatography (silica gel), with EtOAc / hexanes 1: 3, then with CHCl3: MeOH 9: 1. The title compound was isolated as an oil in 30% yield (230 mg, 0.447 mmol). The NMR data were as follows: 1 H NMR (300 MHz, CDC13): d = 7.91 (d, 1H, J = 7. 50 Hz), 7.73 (d, 2H, J = 8.31 Hz), 7.46 (s, 1H), 7.32 (m, 5H), 7.15 (m, 2H), 6.69 (s, 1H), 5.04 (s, 2H) , 4.74 (m, 1H), 4.46 (m, 1H), 3.71 (m, 2H), 3.66 (s, 3H), 3.06 (m, 2H), 2.80 (s, 3H), 2.40 (s, 3H). 13C NMR (75 MHz, CDC13): d = 171.98, 170.40, 144.41, 137.93, 136.54, 135.976, 130.41, 129.57, 128.88, 128.01, 117.74, 61.42, 61.15, 53.07, 51.46, 32.29, 30.09, 22.13 (loss of 1C ). Mass spectroscopy: (FAB) 515 (M + H).

Example 29 N- (Toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine Benzyl Ester Synthesis The title compound was prepared by coupling N- (toluene-4-sulfonyl) -D, L-phenylglycine to 15 L-phenylalanine benzyl ester using the procedure described in Method 3 to provide a solid, mp = 148-150 ° C . The NMR data were as follows:? H NMR (CDCI3, 300 MHz): d = 2.37 (s, 3H), 2.91- 3.07 (m, 2H), 4.70-4.85 (m, 2H), 5.04 (dd, 2H) ), 5.94 (br 20 d, 1 H), 6.23 (br d, 1 H), 6.84 (d, 2 H), 7.00-7.40 (m, 15 H), 7.60 (d, 2 H). 13 C NMR (CDCl 3, 75 MHz): d = 22.1, 38.1, 54.2, 61.1, 67.9, 127.7, 127.8, 127.9, 128.1, 128.2, 129.1, 129.4, 129.6, 129.7, 129.8, 130.0, 135.4, 135.8, 136.5, 25 137.2, 144.1, 169.1, 170.9.

Mass spectroscopy: (FAB +) 543 (M + H) Example 30 5 Synthesis of Benzyl Ester of N- (Toluene-4-sulfonyl) -N-methyl-D, L-phenylglycyl-L-phenylalanine The title compound was prepared following the procedure described in Example 26 (198) as a solid, mp = 46-49 ° C. The NMR data were as follows: 1 H NMR (CDC 13, 300 MHz): d = 2.41 (s, 3 H), 2.54 (s, 3 H), 2.96-3.22 (m, 2 H), 4.90 (q, 1 H, J = 3.0 Hz), 5.15 (dd, 2H), 5.65 (s, 1H), 6.51 (d, 1H, J = 6.9 Hz), 6.95 (d, 2H, J = 6.2 Hz), 7.04 (m, 2H), 7.15-7.40 (m , 13H), 7.67 (d, 2H, J = 8.2 Hz). 13 C NMR (CDCl 3, 75 MHz): d = 22.2, 32.1, 38.4, 53.9, 64.3, 68.0, 127.8, 128.1, 129.1, 129.2, 129.3, 20 129.4, 129.8, 129.9, 130.0, 130.1, 130.2, 134.2, 135.6, 136.2, 136.5, 144.2, 169.1, 171.4. Mass spectroscopy: (FAB +) 557 (M + H).

Example 31 1 Synthesis of Methyl Ester of N- (Toluen-4-sulfonyl) -N- (2-thienylethyl) -glycyl-L-phenylalanine N- (Toluene-4-sulfonyl) -2-thienylethylamine was prepared using the procedure described in Method 1. This compound was reacted with t-butyl bromoacetate yielding t-butyl ester of N- (toluene-4-sulfonyl) -N- (2-thienylethyl) glycine (following the method of Zuckermann, Kerr, Kent, and Moos J. Am. Chem. Soc. 1992, 114, 10646-10647). The ester was hydrolyzed using the procedure described in Method 17. The title compound was prepared following the procedure described in Method 13. The NMR data were as follows: X H NMR (CDC 13, 300 MHz): d = 2.43 (s) , 3H), 2.85 (m, 2H), 3.05-3.22 (m, 3H), 3.40 (m, 1H), 3.69 (dd, 2H), 3.73 (s, 3H), 4.83 (m, 1H), 6.73 (d, 1H, J = 2.3 Hz), 6.90 (t, 1H, J = 2.4 Hz), 6.98 (br d, 1H, J = 6.2 Hz), 7.13 (d, 1H, J = 3.2 Hz), 7.17-7.35 (m, 7H) , 7.66 (d, 2H, J = 8.0 Hz).

Example 32 22 Synthesis of N- (Toluen-4-sulfonyl) -N- (2-thienylethyl) -glycyl-L-phenylalanine The title compound was prepared from the product of Example 31 (289) using the procedure described in Method 7 to provide a solid, pf = > 200 ° C.

Example 33 Synthesis of Methyl Ester of N- (Toluen-4-sulfonyl) -N- (2-phenylethyl) glycyl-L- (N-benzyl) histidine The title compound was prepared according to the procedures described in Example 31 (289). The NMR data were as follows:? H NMR (CDC13, 300 MHz): d = 2.41 (s, 3H), 2.82 (m, 2H), 3.02-3.30 (m, 3H), 3.46 (m, 1H), 3.67 (s, 3H), 3. 75 (dd, 2H), 4.79 (m, 1H), 5.00 (s, 2H), 6.77 (s, 1H), 7. 10-7.35 (m, 12H), 7.48 (s, 1H), 7.69 (d, 2H, J = 7.3 Hz), 7.97 (br d, 1H, J = 6.9 Hz). 13 C NMR (CDCl 3, 75 MHz): d = 22.1, 30.2, 35.3, 51.4, 52.6, 52.7, 52.9, 118.1, 127.2, 127.9, 128.0, 128.8, ^ ^ ^ ^ ^ ^ ^ ^, 129.2, 129.4, 129.5, 130.5, 135.7, 136.6, 137.8, 138.5, 144.6, 168.9, 172.0. Mass spectroscopy: (FAB +) 575 (M + H); 597 (M + Na +).

Example 34 Synthesis of N- (Toluen-4-sulfonyl) -N- (2-phenylethyl) glycyl-L-10 phenylalanine The title compound was prepared according to the procedures described in Examples 31 (289) and 32 (290). The NMR data were as follows: XH NMR (CDC13, 300 MHz): d = 2.41 (s, 3H), 2.56 (m, 2H), 3.03-3.37 (m, 4H), 3.72 (dd, 2H), 4.84 (q, 1H, J = 3.4 Hz), 7.02 (d, 2H, J = 6.1 Hz), 7.12-7.34 (m, 10H), 7.63 (d, 2H, J = 8.3 Hz), 8.78 (br s, 1 HOUR) . 20 13 C NMR (CDC 13, 75 MHz): d = 22.1, 35.1, 37.8, 52.6, 52.7, 53.8, 127.3, 127.9, 128.0, 129.2, 129.3, 129.4, 130.0, 130.6, 135.2, 136.0, 138.1, 144.9, 169.9, 175.0. Mass spectroscopy: (FAB +) 481 (M + H). 25 ^ S & ^^ ^^^^^^^^^^^^^^^^^^^^^^^^^ Synthesis of N- (Toluen-4-sulfonyl) sarcosil-D, L-4-cyanophenylalanine N- (Toluen-4-sulfonyl) sarcosine was bound to 4-cyanophenylalanine methyl ester hydrochloride (prepared by the method of Wagner, Voight, and Vieweg Pharmazie 1984, 39, 226-230) to give N- methyl ester. (toluene-4-sulfonyl) sarcosyl-D, L-4-c-anophenylalanine. The compound was prepared via hydrolysis of the methyl ester using 0.5 N NaOH in THF / water. The NMR data were as follows:? H NMR (CD3OD / CDCI3): d = 7.69 (m, 3H), 7.41 (m, 3H), 4.79 (m, 1H), 3.77 (d, 1H, J = 16.7 Hz ), 3.55 (d, 1H, J = 16.5 Hz), 3.32 (dd, 1H, J = 4.9, 14.0 Hz), 3.13 (dd, 1H, J = 8.8, 14.0 Hz), 2.67 (s, 3H), 2.45 (s, 3H). 13 C NMR (CD3OD / CDCl 3): d = 174.0, 170.6, 146.2, 144.9, 135.5, 134.0, 132.2, 131.6, 129.3, 120.4, 112.3, 54.8, 50.4, 39.0, 37.7, 22.4. Mass spectroscopy: FAB m / e 416 (M + H).

Example 36 Synthesis of N- (Toluene-4-sulfonyl) -L-tert-butylglycyl-L-phenylalanine N- (Toluene-4-sulfonyl) -L-tert-butylglycine was prepared from L-tert-butylglycine using the procedure described in Method 1. The title compound was prepared by coupling in DMF N- (toluene-4-). sulfonyl-L-tert-butylglycine with an L-phenylalanine ester in the presence of BOP and NMM Conventional deesterification provides the title compound.The NMR data were as follows: XH NMR (CDC13): d = 7.7 (d , 2H), 7.25 (m, 5H), 7.0 (m, 2H), 5.93 (d, 1H), 5.57 (d, 1H), 4.6 (m, 1H), 3.3 (d, 1H), 3.0-2.7 ( d of d, 2H), 2.35 (s, 3H), 0.87 (s, 9H).

Example 37 Synthesis of Methyl Ester of N- (Sacarin-2-yl) -D, L-alaninyl-L-4- (isonicotinamido) phenylalanine The title compound was prepared following the procedures described in Preparative Example A. The methyl ester of N- (saccharin-2-yl) -D, L-alaninyl-Lp-amino-phenylalanine (1 eq) was dissolved in dichloromethane with Et 3 N (1.1 eq) and reacted with isonicotinoyl chloride (1.1 eq, 860 mL) to provide the title compound. The NMR data were as follows: X H NMR (DMSO-de, 400 MHz) (mixture of diastereomers 1: 1): d = 10.43 (d, 1H); 8.80 (m, 2H); 8.45 and 8.25 (two m, 1H), 8.23 (m, 1H); 8.04 (m, 3H); 7.82 (m, 2H); 7.65 (m, 2H); 7.20 (m, 2H); 4.76 (m, 1H); 4.45 (m, 1H); 3.40 and 3.42 (two s, 3H); 3.00 (m, 2H), 1.65 and 1.70 (two s, 3H). Other compounds prepared by the methods described above include those described in Table II below: f ¥ ** NJ J in o tp NJ Example 46 In Vitro Assay for the Determination of the Linkage of the Candidate Compounds to VLA-4 An in vi tro assay was used for the binding assays of the a4β? Integrin candidate compounds. The compounds which are linked in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays (eg, competitive assays). This assay is sensitive to IC50 values as low as approximately 1 nM. The activity of integrin aß? was measured by the interaction of soluble VCAM-l with Jurkat cells (for example, from American Type Culture Collection Nos. TIB 152, TIB 153, and CRL 8163), a human T cell line which expresses high levels of a4β integrin? . VCAM-1 interacts with the cell surface in a form dependent on integrin a4β? (Yednock, et al., J. Biol. Chem., 1995, 270: 28740) Recombinant soluble VCAM-1 is expressed as a chimeric fusion protein containing the seven extracellular domains of VCAM-1 in the N-terminus and the region IgGi heavy chain constant in the C-term. The VCAM-1 fusion protein is made and purified in the manner described by Yednock, supra. Jurkat cells were grown in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutamine as described by Yednock, supra.

Cells were incubated with 1.5 mM MnCl2 and 5 μg / mL 15/7 antibody for 30 minutes on ice. Mn + 2 activates the receptor to increase the ligand binding, and 15/7 is a monoclonal body that recognizes an activated activated / ligand confirmation of the a4β integrin? and binds the molecule in this confirmation with it, stabilizes the interaction VCAM-1 / integrin a4ß ?. Yednock, et al., Supra. 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 candidate compounds, in various concentrations ranging from 66 μM to 0.01 μM, using standard serial dot 5 dilution. 15 μL of soluble recombinant VCAM-1 fusion protein were then added to the Jurkat cells and incubated for 30 minutes on ice. (Yednock, et al., Supra).

The cells were then washed twice and resuspended in F (ab ') 2 anti-mouse IgG Fc goat conjugate PE (Ipvmunotech, Westbrook, ME) at 1: 200 and incubated on ice, in the dark, for 30 minutes. The cells were washed twice and analyzed with a standard fluorescent activated cell distributor assay ("FACS") as described in Yednock, et al., Supra. Compounds having an IC50 of less than about 15 μM have binding affinity to a4β ?. When tested in this assay, each of the compounds in Examples 1-135 has an IC 50 of 15 μM or less.

Example 47 In Vitro Saturation Assay for the Determination of the Link of the Candidate Compounds to a4β? The following describes an in vi tro assay to determine the plasma levels necessary for a compound to be activated in the Experimental Autoimmune Encephalomyelitis ("EAE") model, described in the following example, or in other in vivo models. 25 ^ g ^^^^^^^^^^^^^^^^^^^^^ M ^ __ ^ __.._. > , ^ ^ ^ ^, ^ k ^ ^^ s ^ ^ ¡& ^^ S2?, ^ ¿, é? ss? ^ s ^^ &^ Jurkat cells that grew to Logarithm, washed and resuspended in the normal animal plasma containing 20 μg / ml of antibody 15/7 (described in the previous example). Jurkat cells were diluted in two parts within any of the normal plasma samples containing known quantities of the candidate compound at various concentrations ranging from 66 μM to 0.01 μM, using a standard 12-dot serial dilution for a standard curve, or in the plasma samples obtained from the peripheral blood of the animals treated with the candidate compound. The cells were then incubated for 30 minutes at room temperature, washed twice with buffered phosphate saline ("PBS") containing 2% fetal bovine serum and 1 mM each of calcium chloride and magnesium chloride (medium test) to remove the unbound 15/7 antibody. Cells were then exposed to goat anti-mouse F (ab ') 2 conjugated goat IgG Fc (Immunotech, Westbrook, ME), which have been absorbed by any nonspecific cross-reactivity, by co-incubation with 5% serum from animal species that are studied, at 1: 200 and incubated in the dark at 4 ° C for 30 minutes. 2 The cells were washed twice with the assay medium and resuspended therein. They were then analyzed with a standard fluorescent activated cell distribution ("FACS") analysis, as described in Yednock et al. J. Biol. Chem., 1995, 270: 28740. The data is then plotted as dose against fluorescence, for example, in a form of response to the normal dose. The dose levels that result in the top plate of the curve represent the levels necessary to obtain efficacy in the in vivo model. This assay can also be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as the 4β integrin, which is the integrin most closely related to a4ß? (Palmer et al, 1993, J. Cell. Bio., 123: 1289). Such a binding site is predicted from in vivo utility for inflammatory conditions mediated by the α4β integrin, including by way of example, hypersensitivity and occlusion that occurs with chronic asthma, cell proliferation of smooth muscle in atherosclerosis, vascular occlusion, after angioplasty, fibrosis and glomerular scarring as a result of renal disease, aortic stenosis, hypertrophy of synovial membranes in arthritis rehumatoid, and inflammation and scarring that occurs with 2 4 the progress of ulcerative colitis and Crohn's disease. Accordingly, the assay described above can be performed with a human colon carcinoma cell line, SW 480 (ATTC # CCL228), transfected with cDNAs encoding the integrin (Xg (Yokosaki et al., 1994, J. Bio. Chem., 269: 26691), in place of the Jurkat cells, to measure the binding of the mtegrin ocgßi.As a control, the SW 480 cells which express other subunits a and ßi can be used.As a consequence, another aspect of the invention is directed to a method for the treatment of a disease in a mammalian patient, wherein the condition is mediated agßi, and in which the method comprises administering to said patient a therapeutically effective amount in a pharmaceutical composition described herein, The effective daily dosage will depend on the age, weight, and condition of the patient, in which the factors can be easily ascertained by the specialist's attention. efferred, the compounds are administered at about 20 to 500 μg / kg per day. Using a conventional oral formulation, the compounds of this invention could be active in this model.

Example 48 In vivo evaluation The model of Experimental Autoimmune (or Allergic) Encephalomyelitis ("EAE"), of standard multiple sclerosis, was used to determine the effect of candidate compounds to reduce motor deterioration in rats or guinea pigs. The reduction in motor deterioration is based on the adhesion of the block between the leukocytes and the endothelium, and correlates with the anti-inflammatory activity in the candidate compound. This model has been previously described by Keszthelyi et al., Neurology, 1996, 47: 1043-1049, and the delay in onset or attack of the disease. The brain and spinal cord of Hartley guinea pigs were homogenized in an equal volume of buffered phosphate salt. An equal volume of complete Freund's adjuvant (100 mg of mycobacterium um) was added to the homogenate. tuberculosis plus, 10 ml of Freund's incomplete adjuvant). The mixture was emulsified by circulation repeatedly through a syringe with a peristaltic pump for approximately 20 minutes. Female Lewis rats were anesthetized (2-3 months of age, 170-220 g) or Hartley guinea pigs (20 days old, 180-200 g), with isoflurane and three injections of the emulsion, 0.1 ml each, were made in each side. The onset or attack of motor deterioration was observed in approximately 9 days. The treatment of the candidate compound began on day 8, just before the onset or attack of the symptoms. The compounds were administered subcutaneously ("SC"), orally ("PO") or intraperitoneally ("IP").

Doses were given in the range of 10 mg / kg to 200 mg / kg, ordered for five days, with typical dosages of 10 to 100 mg / kg SC, 10 to 50 mg / kg PO, and to 100 mg / kg IP. The GG5 / 3 antibody against the integrin a4β? (Keszthelyi et al., Neurology, 1996, 47: 1053-1059), which delays the onset of symptoms, was used as a positive control and injected subcutaneously at 3 mg / kg on day 8 and 11. It was measured daily motor deterioration by body weight. The motor deterioration was provided with the following chemical record: 0 no change 1 weakening or paralysis of the tail 2 weakening of the hind limb 3 paralysis of the hind limb 4 dying or dead A candidate compound was considered active if the onset of symptoms was delayed, for example, clinical records produced no greater than 2 or slow loss of body weight compared to the control.

Example 49 Example of Asthmatic Model Inflammatory conditions mediated by the a4β integrin include, for example, the hyper-sensitivity and occlusion of the airways that occurs with chronic asthma. The following describes asthmatic models, which can be used to study the in vivo effect of the compounds of this invention for use in the treatment of asthma. After 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 herein by reference in their entirety, the compounds of this invention were formulated in aerosol and administered to sheep, which are hypersensitive to the antigen Ascaris suum. Compounds that decrease the early bronchial response induced by the antigen, and / or block the response of the respiratory tract in the last stage, for example, have a protective effect against the late response induced by the antigen and hypersensitivity of the respiratory tract (" AHR "), are considered to be active in this model. Allergic sheep that are shown to develop both early and late bronchial responses by inhaling the antigen Ascaris suum, are used to study the effects on the respiratory tract of the candidate compounds. After topical anesthesia of the nasal passage with 2% lidocaine, a round catheter is pushed through a nasal orifice in the lower esophagus. The animals are then intubated with an endotracheal tube that spins through the other nostril with a flexible fiber optic bronchoscope as a guide. Pleural pressure is estimated in accordance with Abraham (1994). The aerosols (see the following formulation) are generated using a disposable medical nebulizer that provides an aerosol with a diameter of 3.2 μm as determined with an Andersen cascade effector. The nebulizer is connected to the dosimeter system consisting of a solenoid valve and a compressed air source (20 psi). The outlet of the nebulizer is directed to a plastic part T, one end of which is connected to the port of a piston respirator. The second valve is activated for 1 second at the beginning of the inspiratory cycle of the respirator. The aerosols are released at Vt of 500 ml and at a rate of 20 exhalations / minute. A 0.5% sodium bicarbonate solution is used as a control. 10 In order to assess the bronchial sensitivity, the cumulative concentration response curves to carbachol can be generated according to Abraham (1994). Bronchial biopsies can be taken before and after the start of treatment and 24 hours after of the antigen change. Bronchial biopsies can be preformed according to Abraham (1994). Adhesion studies in alveolar macrophage can be performed, according to Abraham (1994), and a percentage of adherent cells is calculated. 20 Aerosol Formulation Prepared using the following procedure, a solution of the candidate compound in bicarbonate of sodium at 0.5% / saline (w / v) at a concentration of 30.0 ^^ feigi ^^^^^^^^^^^ g ^ tój mg / Ml.

A. Preparation of 0.5% sodium bicarbonate / Stock solution saline: 100.0 mL Process: 1. Add 0.5 g of sodium bicarbonate in a 100 mL volumetric flask. 2. Add approximately 90.0 mL of saline and sonicate until dissolved. 3. Sufficient quantity up to 100.0 mL with saline and mix it evenly.

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

Process : 1. Add 0.300 g of the candidate compound in a 10.0 mL volumetric flask. 2. Add approximately 9.7 mL of 0.5% sodium bicarbonate / saline stock solution. 3. Add sonicate until the candidate compound is completely dissolved. 4. Sufficient amount up to 10.0 mL with 0.5% sodium bicarbonate / stock saline and mix it evenly.

Using a conventional oral formulation, the compounds of this invention could be active in this model.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned 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. h ****? at **

Claims (26)

1. A compound of the formula I R'-SO, -N (R2) -C-Q-CH-C-OH H RJ characterized because 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 nitrogen atom bound 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 aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and wherein R2 and R3 together with the nitrogen atom attached to R2 and the carbon atom attached to R3 form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group; 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; and R5 is -CH2X wherein X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl , carboxylaryl, carboxylaryl substituted, carboxylheteroaryl, I carboxylheteroaryl substituted carboxilheterociclico, carboxilheterociclico substituted cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, aryloxyaryl substituted, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted, with the additional proviso that: A. R5 is not - (CH2) X-Ar-R5 'where R5' is -0-Z-NR8R8 'or -OZ-R12 where RB and R8' are selected from independently from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic, and R8 and R8 'together een forming 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 an integer from 1 to 4; B. R = is not - (CH2) X-Ar-R5 wherein R "is selected from the group consisting of -NR12C (Z ') NR8R8' and -NR12C (Z) R13 wherein Z 'is selected from the group consisting of oxygen, sulfur and NR12, R12 is selected from the group consisting of hydrogen, alkyl and aryl, R8 and R8 'are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, atfifc ^ fcAjaaá a1? rf jfa .. heterocyclic, substituted heterocyclic, heteroaryl and heteroaryl always replaced when Z 'is oxygen, at least one of R8 and R8' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic five different saturated morpholino and thiomorpholino, or substituted heterocyclic or R8 and R8 'can be together to form a saturated heterocycle different from morpholino or thiomorpholino, a saturated substituted heterocycle or a saturated / unsaturated heterocycle having an amino group Substituted with an alkoxycarbonyl substituent, and further provided that when Z 'is sulfur, at least one of R8 and R8' is a different group of aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R13 is selected from the group consisting of of saturated heterocycles And substituted heterocycles different from morpholino and thiomorpholino, substituted heterocycles, Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer from 1 to 4; C. R5 is not -ALQ-X 'wherein ALQ is an alkyl group of 1 to 10 carbon atoms attached via a methylene group (-CH2) to the carbon atom to which it is attached; X 'is selected from the group consisting of substituted alkylcarbonylamino, alkenylcarbonylamino 25 substituted, substituted alkynylcarbonylamino, heterocyclylcarbonylamino, substituted heterocyclic alkyl, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, heterocyclyloxycarbonyl, substituted heterocyclyloxycarbonyl, cycloalkyl, substituted cycloalkyl, Saturated heterocyclic, substituted heterocyclic substituted, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted heterocycloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonylamino, 15 aminothiocarbonylamino, guanidino, amidino, alkylamidino, 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 (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -heteroaryl 20 substituted, -OS (O) 2-heterocyclic, -OS (O) 2 -substituted heterocyclic, -OS02-NRR, -NRS (O) 2 -alkyl, -NRS (O) 2 -substituted alkyl, -NRS (O ) 2-cycloalkyl, -NRS (O) 2 -substituted cycloalkyl, -NRS (O) 2 -aryl, -NRS (O) -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (O) 2 -heteroaryl replaced, 25 -. 25 -NRS (O) 2-heterocyclic, -NRS (O) 2-substituted heterocyclic, Á3. "* .. -NRS (0) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl, -NRS (O) 2-NR-cycloalkyl, -NRS (O) 2-NR-substituted cycloalkyl, -NRS (0) ) 2-NR-aryl, -NRS (O) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR -heterocyclic, -NRS (O) 2-NR-substituted heterocyclic wherein R is hydrogen or alkyl, -S (O) 2 -alkyl, -S (0) 2 -substituted alkyl, -S (0) 2 -aryl, -S (0) 2-substituted aryl, -S (0) 2 -substituted heteroaryl, -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) amino, N, N- (substituted aryl, substituted alkyl) amino, N, N - (heteroaryl, substituted alkyl) amino, N, N- (substituted heteroaryl, substituted alkyl) amino, N, N- (heterocyclic, substituted alkyl) amino, N, NN, N- (substituted heterocyclic, substituted alkyl) amino, mono - and di- (heterocyclic) amino, m ono- 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, substituted heterocyclic) amino, N, N-substituted aryl, substituted heterocyclic) amino, N, N- (heteroaryl, heterocyclic) amino, N, N- (heteroaryl, heterocyclic) substituted) amino, N, N- (substituted heteroaryl, heterocyclic) amino, and N, N- (substituted heteroaryl, substituted heterocyclic) amino; D. R5 is not - (CH2) x-Ar-R5"wherein 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, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol , thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, .-% e .. * g ^^^ Ut 0 substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, heterocyclyloxy substituted, oxycarbonylamino, oxitiocarbonilamino, -OS (O) 2-alkyl, -OS (0) 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, -OS02-NRR, -NRS (0) 2-alkyl, -NRS (O) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, -NRS (O) 2-substituted heteroaryl, -NRS (0) 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 (O) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2- NR-heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and dialkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (heteroaryl substituted) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, alkyl groups FíiS «ía¿a £« S * 1 substituted which have amino groups blocked by conventional blocking groups and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S? 2-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, - S? 2-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR, wherein R is hydrogen or alkyl; (B) alkoxyaryl substituted on the alkoxy portion by a substituent selected from the group consisting of carboxyl and -COOR 23 where 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, 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, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkylamidino, thioamidino, aminoacyl, 5 aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl or, carboxylaryl, 10 carboxyl- substituted aryl, carboxylheteroaryl, I carboxylheteroaryl substituted carboxilheterociclico., Carboxilheterociclico substituted, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfona, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioaryl 15 substituted, thiocycloalkyl, substituted thiocycloalkyl I, thioheteroaryl, substituted thioheteroaryl I, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy substituted heteroaryloxy, Substituted, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (O) 2 -aryl, -OS (O) 2 -substituted aryl, -OS (O) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2-heterocyclic 25 substituted, -OS (0) 2-NRR, -NRS (O) -alkyl, -NRS (0) 2" ## STR3 ## substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, - NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR- aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and di-alkylammo, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di- heteroarylamino, mono- and di- (heteroaryl substituted) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and disubstituted asymmetric amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, alkyl groups their Bitumens having amino groups blocked by conventional blocking groups and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S? 2-cycloalkyl, - S02-substituted cycloalkyl, -S02-aryl, -S? 2 -substituted aryl, -S? 2 -heteroaryl, -S02 -substituted heteroaryl, -S? 2-heterocyclic, -S02- substituted heterocyclic or -S02NRR, wherein R it 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, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy alkenyl, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, carboxyl-heterocyclic substituted alkyl, 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 (0) 2-alkyl, -OS (0) 2- substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2 -heteroaryl, -OS (0) 2 -heteroaryl substituted, -OS (0) 2 -heterocyclic, -OS (0) 2-substituted heterocyclic, -0S (0) 2-NRR, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS ( 0) 2-substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) -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-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 dialqui lamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (heteroaryl substituted) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and substituted alkyl / alkyl groups, substituted with -S? 2-alkyl, -S ? 2-substituted alkyl, -S02-alkenyl, -S? 2 -substituted alkenyl, -S? 2-cycloalkyl, -S? 2 -substituted cycloalkyl, -S02-aryl, -S02 -substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic or -S02NRR, wherein R is hydrogen or alkyl; (f) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy / heteroaryloxy is any of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-d? oxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (g) saturated alkoxy-saturated heterocyclic, saturated substituted-heterocyclic-substituted heterocycle, substituted-alkoxy-heterocyclic and substituted substituted-heterocyclic saturated substituted; (h) -O-heterocyclic and -O-heterocyclic substituted; 5 (i) tetrazolyl; (j) -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 any of Halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, Alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, substituted 20 (1) alkoxy with the proviso that the substitution in the alkyl portion of said substituted alkoxy does not include alkoxy-NR "R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl / heteroaryl substituted with halogen, 25 hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (m) amidine and amidine substituted with from 1 to 3 substituents independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; (n) -C (0) NR'i 'i' rR r > wherein each R 'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that when 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-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, tHiiiilfilíiT j ^ - ^ --- - - - ^^^^ - alkylsulfonylamino, N-alkyl or N, N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (any unsubstituted heterocyclic substituted alkyl) cycloalkyl , substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic or substituted heterocyclic; (o) -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 R 22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or Substituted heterocyclic; (p) -S02-aryl, -S? 2 ~ substituted aryl, -S02- heteroaryl, -S02 -substituted heteroaryl or -S02-alkyl; (q) -NR'C (0) NR19R19 wherein R 'is selected from the group consisting of alkyl, alkyl Substituted, aryl, substituted aryl, substituted cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R19 is independently selected from the group consisting of hydrogen, alkyl, alkyl 25 substituted, cycloalkyl, substituted cycloalkyl, ? ' M aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (r) -NR 'C (O) 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; (s) -aminocarbonyl- (N-formylheterocyclyl); and (t) -alkyl-C (O) NH-heterocyclyl and -alkyl-C (O) H -substituted heterocyclyl, and E. When R3 is different from H, R5 is not ~ (CH2) X-Ar-R5" wherein R5"is substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the alkenyl / alkynyl portion is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl , heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with the substituted alkyl at least one of the substituents on the 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, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl substituted 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 (O) 2 -heteroaryl substituted, -OS (O) 2-heterocyclic, -OS (O) 2-substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2- substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2 -heterocyclic, -NRS (0) 2_ substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2- NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic , mono- and dialkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di-heteroarylamino, mono- and di- (heteroaryl substituted) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, heteroaryl substituted, heterocyclic, 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, -S0-substituted alkyl, -S0-alkenyl, -S02-alkenyl substituted, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S0-aryl, -S0-substituted aryl, -S? 2-heteroaryl, -S02 -substituted heteroaryl, -S02-heterocyclic, -S0-substituted heterocyclic or -S02NRR , wherein R is hydrogen or alkyl; and pharmaceutically acceptable salts thereof and still further with the following conditions which exclude the following compounds A. when R1 and R2 are attached together with the S02 and the nitrogen atom to which they are attached respectively form a heterocyclic ring of benzoisothiazolone, R3 is hydrogen, and Q is -C (0) NH-, then R5 is not benzyl; and B. when R1 is p-methylphenyl, R2 is methyl, R3 is hydrogen, Q is -C (0) NCH3-, then R5 is not benzyl.

2. A compound of formula IA: characterized because 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, and substituted heteroaryl, and R1 and R2 together with the atom of nitrogen bonded to R2 and the SO2 group attached 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 aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and wherein R2 and R3 together with the nitrogen atom attached to R2 and the carbon atom attached to R3 can form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group; 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, cycloalkoxy 25 substituted, -O- (N-succinimidyl), -NH-adamantyl, -0- 'f A "i' ^? s cholest-5-en-3-ß-ilo, -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 above, -OCH2NR9R10 wherein R9 is selected from the group consisting of -C (0) -aryl and -C (0) -substituted aryl and R10 is selected from from the group consisting of hydrogen and -CH2COORn wherein R11 is alkyl, and -NHS02Z "wherein Z" is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy,E-SsiJítf = ^ S = 'ií': ^ 'substituted aryl, substituted aryloxy, substituted aryloxyphoxy, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the additional proviso that: A. R5 is not - (CH2 ) X-Ar-R5 'wherein R5' is selected from the group consisting of -0-Z-NR8R8 'or -OZ-R12 wherein 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 'are linked 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 an integer from 1 to 4; B. Rb is not - (CH2) X-Ar-R wherein R- is selected from the group consisting of -NR12C (Z ') NR8R8' and -NR12C (Z) R13 wherein Z 'is selected from of the group consisting of oxygen, sulfur and NR12, R12 is selected from the group consisting of hydrogen, alkyl and aryl, R8 and R8 'are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z 'is oxygen, at least one of R8 and R8' is substituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, or substituted heterocyclic or R8 and R8 'may be together to form a saturated heterocycle different from morpholino or thiomorpholino, a saturated substituted heterocycle or a saturated / unsaturated heterocycle having an amino group substituted with a substituent alkoxycarbonyl, and furthermore provided that when 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 saturated heterocycles and substituted heterocycles different from morpholino and thiomorpholino, Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer from 1 to 4; C. R5 is not -'ALQ-X 'wherein ALQ is an alkyl group of 1 to 10 carbon atoms attached via a methylene group (-CH2) to 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, cycloalkyl, substituted cycloalkyl, saturated heterocyclic, substituted heterocyclic substituted, substituted alkoxy, substituted alkenoxy, substituted alkynoxy, heterocyclyloxy, substituted heterocycloxy, substituted thioalkyl, substituted thioalkenyl, substituted thioalkynyl, aminocarbonylamino, aminothiocarbonylamino, guanidino, amidino , alkylamine, 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 (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2-substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2-substituted heterocyclic, -OS02-NRR wherein R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (O) 2-substituted alkyl, -NRS (0) 2-cycloalkyl, -NRS (0) 2-substituted cycloalkyl, -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-cycloalkyl, -NRS (0) 2-NR-substituted cycloalkyl, -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, -S (0) 2-alkyl, -S (0) 2 -alkyl substituted, -S (0) 2-aryl, -S (0) 2 -substituted aryl, -S (0) 2 -substituted heteroaryl, -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) amino, N, N- ( substituted aryl, substituted alkyl) amino, N, N- (heteroaryl, substituted alkyl) amino, N, N- (substituted heteroaryl, substituted alkyl) amino, N, - (heterocyclic, substituted alkyl) amino, N, NN, N- (substituted heterocyclic, substituted alkyl) amin or, mono- and di- (heterocyclic) amino, mono- and di- (substituted heterocyclic) amino, N, - (alkyl, heterocyclic) amino, N, N- (alkyl, substituted heterocyclic) amino, N, N- ( aryl, heterocyclic) amino, N, N- (substituted aryl, heterocyclic) amino, N, N- (aryl, substituted heterocyclic) amino, N, N-substituted aryl, substituted heterocyclic) amino, N, N- (heteroparyl, heterocyclic) amino, 5 N, N- (heteroaryl, substituted heterocyclic) amino, N, N- (substituted heteroaryl, heterocyclic) amino, and N, N- (substituted heteroaryl, substituted heterocyclic) amino; D. R5 is not - (CH2) x-Ar-R5"wherein 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, Alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, ammocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, 20 substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, 25 thioalkyl, substituted thioalkyl, thioaryl, thioaryl "A *, ^^^ u¿ && Substituted thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (0) 2-alkyl, -OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS (0) 2 -substituted aryl, -OS (0) 2-heteroaryl, -OS (0) 2-heteroaryl substituted, -OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -0S02-NRR, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0 ) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2 -heterocyclic, -NRS (0) 2- substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, - NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR -heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylammo, mono- and di- (substituted aryl) amino , mono- and di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric di-substituted amines having different substituents selected from of the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and substituted alkyl / alkyl groups, substituted with -S02- alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S? 2 -substituted aryl, -S? 2 -heteroaryl, -S02-substituted heteroaryl, -S0 -heterocyclic, -S02-heterocyclic or substituted or -S02NRR, wherein R is hydrogen or alkyl; (B) alkoxyaryl substituted on the alkoxy portion by a substituent selected from the group consisting of carboxyl and -COOR 23 where 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 proviso that at least one of R 'is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic or 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, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl , carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocycle, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heterocyclic, substituted heterocyclic, cycloalkoxy , substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (O) 2 -aryl, -OS (O ) 2-substituted aryl, -OS (O) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2 -substituted heterocyclic, -OS (0) 2 -NRR, -NRS (O) 2-alkyl, -NRS (0) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS (O) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2-substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS ( 0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (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 dialkylamino, 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-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and substituted alkyl / alkyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S? 2-alkenyl, -S02-alkenyl substi embedded image, -S02-cycloalkyl, -S-2-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-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 alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl amino, amidino, alkylamidino, thioamid, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, carboxyl-heterocyclic ico replaced, '? ^^ i 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 (0) 2-heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2-substituted heterocyclic, -0S (0) 2-NRR, -NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (0) 2 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS ( 0) 2-substituted heteroaryl, -NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, - NRS (0) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2 -NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, mono- and dialkylamino, 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-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different substituents selected from the group which consists of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups and substituted alkyl / alkyl groups, substituted with -S0-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl do, -S02- aryl, -S? 2 -substituted aryl, -S02-heteroaryl, -S02- substituted heteroaryl, -S02-heterocyclic, -S02- substituted heterocyclic or -S02NRR, wherein R is hydrogen or alkyl; (f) substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy / heteroaryloxy is any of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1, 2-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (g) saturated-heterocyclic alkoxy, saturated substituted-heterocyclic-substituted heterocyclic, substituted-heterocyclic-alkoxy, and substituted substituted-heterocyclic substituted-saturated; (h) -O-heterocyclic and -O-heterocyclic substituted; (i) tetrazolyl; (j) -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 any of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy , alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (k) alkenylsulfonylamino, alkynylsulfonylamino, substituted alkenylsulfonylamino and substituted alkynylsulfonylamino, (1) substituted alkoxy with the proviso that the substitution in the alkyl portion of said substituted alkoxy does not include alkoxy-NR "R", unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy , aryl, heteroaryl and aryl / heteroaryl substituted by halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, aliphatic-, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylurea; (m) amidine and amidine substituted with from 1 to 3 substituents selected independently from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; (n) -C (0) NR "'R"' wherein each R '"is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl , substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the proviso that when 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-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N , N-dialkylurea, then the other R '' 'is alkyl, substituted alkyl (any unsubstituted heterocyclic substituted alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, alkeni substituted, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic; (o) -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, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; (p) -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl or -S02-alkyl; (q) -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 Jwfcreterocyclic 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; (r) -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 that consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (s) -aminocarbonyl- (N-formylheterocyclyl); and (t) -alkyl-C (O) NH-heterocyclyl and -alkyl-Cι) NH-substituted heterocyclyl, and E. When R 3 is different from H, R 5 is not - (CH 2) X- Ar-R 5 wherein R 5"is substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the alkenyl / alkynyl portion is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted, heterocyclic, and substituted heterocyclic heteroaryl with the proviso that when substituted with the substituted alkyl at least one of the substituents on the 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, cyano, nitro, halogen, hydroxyl, carboxyl, carboxyalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, 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 (O) 2 -substituted heteroaryl, -OS (O) 2 -heterocyclic, -OS (O) 2 -substituted heterocyclic, -OS (0) 2-NRR, -NRS (O) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2 -substituted aryl , -NRS (0) 2-heteroaryl, -NRS (0) 2-heteroaryl the substituted, -NRS (O) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, -NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR- heterocyclic, -NRS (O) 2-NR-substituted heterocyclic, mono- and dialkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- (substituted aryl) amino, mono- and di- di-heteroarylamino, mono- and di- (substituted heteroaryl) amino, mono- and di-amino heterocyclic, mono- and di- (substituted heterocyclic) amino, and asymmetric disubstituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, substituted alkyl groups having amino groups blocked by conventional blocking groups (such as Boc, Cbz, Formyl, and the like) and alkyl / substituted alkyl, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02- cycloalkyl, -S02-substituted cycloalkyl, -S0-aryl, -S02-aryl substituted, -S02-heteroaryl, -S02-substituted heteroaryl, -S0-heterocyclic, -S02-substituted heterocyclic or -SO2NRR, wherein R is hydrogen or alkyl; and pharmaceutically acceptable salts thereof with the following conditions A. When R 1 is o-carboxymethylphenyl, R 2 is hydrogen or methyl, R 5 is benzyl and Q is -C (0) NH-, then R 6 is not -O-benzyl; B. when R1 and R2 are together to form a heterocyclic benzoisothiazolone ring, R3 is hydrogen or methyl, R5 and benzyl and Q is -C (0) NH-, then R6 is not -O-benzyl; C. when R1 is p-methylphenyl, R2 is hydrogen, R5 is benzyl or p-hydroxybenzyl, R3 is - (CH2) SC (O) Ot-butyl where s is 1 or 2, Q is -C (0) NH -, then R6 is not -Ot-butyl; D. when R1 is p-methylphenyl, R2 is methyl, R5 is benzyl, R3 is -CH (f) 2, Q is -C (0) NH-, then R6 is not -O-benzyl; E. when R1 is p-methylphenyl, R2 is pte * tyl, R5 is methyl, R3 is -hydroxymethyl, Q is -C (0) NH-, then R6 is not -O-methyl; Y F. when R1 is p-methylphenyl, R2 is methyl, R3 is methyl or t-butyl, R5 is p-hydroxybenzyl, Q is -C (0) NH-, then R6 is not -O-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-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (CH 3 C (O) H-) phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, lN-methyl- 3-methyl-5-chloropyrazol-4-yl, phenethyl, lN-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- [CH3SC (= NH)] phenyl, 5-chloro-2 -thienyl, 2, 5-dichloro-4-thienyl, lN-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1, 3, 4-thiadiazol-2-yl, 4- [H2NC (S)] phenyl , 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4- (3'-dimethylamino-n-propoxy) -phenyl, Y l-methylpyrazol-4-yl.

5. A compound according to claim 1 or 2, characterized in that, R2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, - (CH2) 2-2-thienyl, and - (CH2) 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 the group S02 attached to R1 are linked to form a heterocyclic group or substituted heterocyclic group.

7. A compound according to claim 1 or 2, characterized in that, R3 is selected from the group consisting of methyl, phenyl, benzyl, diphenylmethyl, -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 are bonded to form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group.

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 or 2, characterized in that, R5 is selected from the group consisting of benzyl, (N-benzylimidazol-4-yl) methyl, (pyridin-2-yl) methyl, (pyridin-3) -yl) methyl, (pyridin-4-yl) methyl, 4- [2- (pyridin-2-yl) ethynyl] benzyl, 4- [2- (3-hydroxyphenyl) ethynyl] benzyl, 4-iodobenzyl, 4- cyanobenzyl, 4- (2-bromobenzamido) benzyl, 4- (pyridin-4-yl-C (0) NH-) benzyl, and 4-hydroxybenzyl.

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

12. A compound characterized in that it is selected from the group consisting of N- (toluene-4-sulfonyl) - (2S-indolin-2-carbonyl) -L-phenylalanine N- (toluene-4-sulfonyl) -2S-1, 2, 3, 4-tetrahydroisoquinoline-3-carbonyl-L-phenylalanine N- (toluene-4-sulfonyl) glycyl-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-L-f-enylalanine N- (toluene-4-sulfonyl) -L-alanyl-L-phenylalanine N- (2-methoxycarbonylbenzenesulfonyl) glycyl-L-phenylalanine N- (2-methoxycarbonylbenzenesulfonyl) L-alanyl-L-phenylalanine N- (saccharin-2-yl) -L-alanyl-L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine "^ I ^ .: 3 = s?, - ^ E.í'iS? .., -» *, N- (toluene-4-sulfonyl) -N-methyl-L-phenylalanyl-D, L-phenylalanine N- (toluene-4-sulfonyl) -L-diphenylalanyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-diphenylalanyl-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-L- (N-benzyl) histidine N- (toluene-4-sulfonyl) sarcosyl-D, L-β- (3-pyridyl) alanine N- (toluene-4-sulfonyl) sarcosyl-D, L-β- (4-pyridyl) alanma N- (toluene-4-sulfonyl) sarcosyl-L-β- (2-pyridyl) alanine N- (toluene-4-sulfonyl) -D, L-phenylsarcosyl-L-phenylalanine N- (toluene-4-sulfonyl) -L-aspartyl-L-phenylalanine N- (toluene-4-sulfonyl) - (2S- 1,2,3,4-tetrahydroisoquinoline-3-carbonyl) -L- benzyl ester phenylalanine Benzyl ester of N- (toluene-4-sulfonyl) - (2S-indolin-2-carbonyl) -L-phenylalanine Benzyl ester of N- (toluene-4-sulfonyl) -L-alani1-L-phenylalanine Benzyl ester of N- (toluene-4-sulfonyl) sarcosi1-L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylglycine-L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -N-methyl-L- (O-benzyl) seryl-L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -N-methyl-L- (O-benzyl) seryl-L-phenylalanine ethyl ester Benzyl ester of N- (toluene-4-sulfonyl) -L-diphenylalani1-L-phenylalanine 1. ? tttr ^ J ^ JSSS N- (toluene-4-sulfonyl) -N-phenylglycyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-D, L-phenylglycyl-L-phenylalanine ethyl ester Methyl ester of N- (toluene-4-sulfonyl) sarcosyl-L- (N-benzyl) histidine ? - (Toluene-4-sulfonyl) -N-methyl-L-seryl-L- (N-benzyl) histidine methyl ester Benzyl ester of? - (toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine Benzyl ester of? - (toluene-4-sulfonyl) -N-methyl-D, L-phenylglycine-L-phenylalanine Methyl ester of? - (toluene-4-sulfonyl) -N-benzylglici1-L-phenylalanine ? - (toluene-4-sulfonyl) -N-benzylglycyl-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [2- (pyridin-2-yl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [2- (3-hydroxyphenyl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosi1-D, L-4- (iodo) phenylalanine Methyl ester of N- (toluene-4-sulfonyl) -N- (2-thienylethyl) glycyl-L-phenylalanine ? - (toluene-4-sulfonyl) -N- (2-thienylethyl) glycyl-L-phenylalanine Methyl ester of? - (toluene-4-sulfonyl) -N-methyl-L-seryl-L- (N-benzyl) histidine ? - (Toluene-4-sulfonyl) -N- (2-phenylethyl) glycyl-L- (N-benzyl) histidine methyl ester ? - (toluene-4-sulfonyl) -N- (2-phenylethyl) glycyl-L-phenylalanine * - **! ** -. 'you. .. 'I ^ S.f. 'ZSS. N- (toluene-4-sulfonyl) l sarcosyl-D, L-4-cyanophenylalanine N- (toluene-4-sulfonyl) -L- erc-butylglycyl-L-phenylalanine Methyl ester of N- (saccharin-2-yl) -D, L-alamnyl-L-4- (isonicotinamido) phenylalanine and pharmaceutically acceptable salts thereof as well as any of the ester compounds mentioned above wherein one ester is substituted with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, ester n-butyl, isobutyl ester, sec-butyl ester and tert-butyl ester.

13. A method for linking VLA-4 in a biological sample, characterized in that it comprises, contacting the biological sample with a compound of claims 1 or 2 ba or conditions wherein said compound binds to VLA-4.

14. The method according to claim 13, characterized in that, R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl.

15. The method according to claim 13, characterized in that, R is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,, 6-trimethylphenyl, 2- (methoxycarbonyl) phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3, -dimethoxyphenyl, 4- (CH 3 C (O) NH-) phenyl , 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-butylphenyl, 4-butoxyphenyl, 4-nitrophenyl, 2-thienyl, lN-methyl-3-methyl-5- chloropyrazol-4-yl, phenethyl, lN-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- [CH3SC (= NH)] phenyl, 5-chloro-2-thienyl, 2.5 -dichloro-4-thienyl, lN-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1, 3, 4-thiadiazol-2-yl, 4- [H2NC (S)] phenyl, 4-aminophenyl, 4 -fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, 4- (3'-dimethylamino-n-propoxy) -phenyl, and l-methylpirate zol-4-yl.

16. The method according to claim 13, characterized in that, R2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, - (CH2) 2-2-thienyl, and - (CH2) 2-f.

17. The method according to claim 13, characterized in that, R1 and R2 together, with the nitrogen atom attached to R2 and the group S02 bound to R1 are linked to form a heterocyclic group or substituted heterocyclic group.

18. The method according to claim 13, characterized in that, R3 is selected from the group consisting of methyl, phenyl, benzyl, diphenylmethyl, -CH2CH2-COOH, -CH2-COOH, 2-amidoethyl, isobutyl, t-butyl, -CH20-benzyl and hydroxymethyl.

19. The method according to claim 13, characterized in that, R2 and R3 together, with the nitrogen atom attached to R2 and the carbon atom attached to R3 are bonded to form an unsaturated heterocyclic group or an unsaturated substituted heterocyclic group.

20. The method according to claim 13, characterized in that Q is -C (0) NH- or -C (S) NH-.

21. The method according to claim 13, characterized in that, R5 is selected from the group consisting of benzyl, (N-benzylimidazol-4-yl) methyl, (pyridin-2-yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, 4- [2- (pyridin-2-yl) ethynyl] benzyl, 4- [2- (3-hydroxyphenyl) ethynyl] benzyl, 4- iodobenzyl, 4-cyanobenzyl, 4- (2-bromobenzamido) benzyl, 4- (pyridin-4-yl-C (O) NH-) benzyl, and 4-hydroxybenzyl.

The method according to claim 13, characterized in that, R6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy , isopropoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso-propyl-4-b-methylcyclohexoxy, 2-b-isopropy1-4-b-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2COOH, -NHCH2CH2COOH, -NH-adamantyl, -NHCH2CH2COOCH2CH3, -NHS02-p-CH3-f, -NHOR8 wherein R8 is hydrogen, methyl, isopropyl or benzyl, O- (N-succinimidyl), -0-cholest- 5-en-3-ß-ilo, -OCH2-OC (0) C (CH3) 3, -0 (CH2) zNHC (0) W wherein z is 1 or 2 and W is selected from the group consisting of of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, -NR "C (0) -R 'wherein R' is aryl, heteroaryl or heterocyclic and R "is hydrogen or -CH2C (0) 0CH2CH3.

23. The method according to claim 13, characterized in that the compound is selected from the group consisting of: N- (toluene-4-sulfonyl) - (2S-indoline-2-carbonyl) -L- phenylalanine N- (toluene-4-sulfonyl) -25-1, 2, 3, 4-tetrahydroisoquinoline-3-carbonyl-L -phenylalanma N- (toluene-4-sulfonyl) glycyl-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-L-f enylamine N- (toluene-4-sulfonyl) -L-alanyl-L-phenylalanine N- (2-methoxycarbonylbenzenesulfonyl) glycyl-L-phenylalanine N- (2-methoxycarbonylbenzenesulfonyl) L-alanyl-L-phenylalanine N- (saccharin-2-yl) -L-alanyl-L-phenylalanine N- (toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-phenylalanyl-D, L-phenylalanine N- (toluene-4-sulfonyl) -L-diphenylalanyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-L-diphenylalanyl-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-L- (N-benzyl) histidine N- (toluene-4-sulfonyl) sarcosi1-D, L-β- (3-pyridyl) alanine N- (toluene-4-sulfonyl) sarcosi1-D, L-β- (4-pyridyl) alanine N- (toluene-4-sulfonyl) sarcosyl-L-β- (2-pyridyl) alanine N- (toluene-4-sulfonyl) -D, L-phenylsarcosyl-L-phenylalanine N- (toluene-4-sulfonyl) -L-aspartyl-L-phenylalanine N- (toluene-4-sulfonyl) - (2S-1,2,3,4-tetrahydroisoquinoline-3-carbonyl) -L-phenylalanine benzyl ester N- (toluene-4-sulfonyl) benzyl ester - (2S- indolin-2-carbonyl) -L-phenylalanine Benzyl ester of N- (toluene-4-sulfonyl) -L-alani1-L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-L-phenylalanine benzyl ester N- (toluene-4-sulfonyl) -D, L-phenylglycine-L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -N-methyl-L- (O-benzyl) seryl-L-phenylalanine ethyl ester N- (toluene-4-sulfonyl) -N-methyl-L- (O-benzyl) seryl-L-phenylalanine ethyl ester Benzyl ester of N- (toluene-4-sulfonyl) -L-diphenylalani1-L-phenylalanine N- (toluene-4-sulfonyl) -N-phenylglycyl-L-phenylalanine N- (toluene-4-sulfonyl) -N-methyl-D, L-phenylglycyl-L-phenylalanine ethyl ester Methyl ester of N- (toluene-4-sulfonyl) sarcosyl-L- (-benzyl) histidine Methyl ester of N- (toluene-4-sulfonyl) -N-methyl-L-seryl-L- (N-benzyl) histidine Benzyl ester of? - (toluene-4-sulfonyl) -D, L-phenylglycyl-L-phenylalanine Β-benzyl ester (toluene-4-sulfonyl) -N-methyl-D, L-phenylglycyl-L-phenylalanine Methyl ester of? - (toluene-4-sulfonyl) -N-benzylglici1-L-phenylalanine ? - (toluene-4-sulfonyl) -? J-benzylglycyl-L-phenylalanine ? - (toluene-4-sulfonyl) sarcosyl-4- [2- (pyridin-2-yl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-4- [2- (3- hydroxyphenyl) ethynyl] -D, L-phenylalanine N- (toluene-4-sulfonyl) sarcosyl-D, L-4- (iodo) phenylalanine Methyl ester of N- (toluene-4-sulfonyl) -N- (2-thienylethyl) glycyl-L-phenylalanine ? - (toluene-4-sulfonyl) -N- (2-thienylethyl) glycyl-L-phenylalanine Methyl ester of? - (toluene-4-sulfonyl) -N-methyl-L-seryl-L- (N-benzyl) histidine ? - (Toluene-4-sulfonyl) -N- (2-phenylethyl) glycyl-L- (N-benzyl) histidine methyl ester ? - (toluene-4-sulfonyl) -N- (2-phenylethyl) glycyl-L-phenylalanine ? - (toluene-sulfonyl) sarcosyl-D, L-4-cyanophenylalanine N- (toluene-4-sulfonyl) -L- erc-butylglycyl-L-phenylalanine Methyl ester of N- (saccharin-2-yl) -D, L-alaninyl-L-4- (isonicotinamido) phenylalanine and pharmaceutically acceptable salts thereof as well as any of the ester compounds mentioned above wherein one ester is substituted with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, ester n-butyl, isobutyl ester, sec-butyl ester and tert-butyl ester.

24. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of claims 1 or 2.

25. A method for the treatment of an inflammatory disease in a mammalian patient, said disease is mediated by VLA-4, the method is characterized in that it comprises administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 24.

26. The method according to claim 25, characterized in that, the inflammatory condition is selected from the group consisting of asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including early juvenile diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, seizures or strokes, and other brain traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and injury acute of the leukocyte-mediated lung such as that which occurs in the respiratory distress syndrome in an adult.