MXPA01007394A - 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 THAT INHIBIT THE ADHESION OF MEDIUM LEUKOCYTES THROUGH ALFA4 BETA1 INTEGRINE AND CD49d / CD29 (VLA-4) BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to compounds that inhibit the adhesion of leukocyte and in particular the adhesion of moderate leukocyte by means of VLA-4.

REFERENCES The following publications, patents and patent applications are cited in this application as superscripts: 1 Hemler and Takada, European Patent Application Publication No. 330,506, published August 30, 1989 2 Elices, et al., Cell, 60: 577-584 (1990) 3 Springer, Nature, 346: 425-434 (1990) 4 Osborn, Cell, 62: 3-6 (1990) 5 Vedder, et al., Surgery 106: 509 (1989) 6 Pretolani, et. al., J. Exp. Med., 180: 795 (1994) 7 Abraham, et al., J. Clin. Invest., 93: 776 (1994) 8 Mulligan, et al., J. Immunology 150: 2407 (1993) 9 Cybulsky et al., Science, 251: 788 (1991) 10 Li, et al., Arterioscler. Thromb., 13: 197 (1993) 11 Sasseville, et al., Am. Path., 144: 27 (1994) REF: 131118 12 Yang, et al., Proc. Nat. Acad. Science (USA), 90: 10494 (1993) 13 Burkly et al., Diabetes, _43: 529 (1994) 14 Baron, et al., J. Clin. Invest., 93: 1700 (1994) 15 Hammann, et al., J. Immunology 152: 3238 (1994) 16 'Yednock, et al., Nature, 356: 63 (1992) 17 Baron, et al., J. Exp. Med., 177: 57 (1993) 18 van Dinther-Janssen, et al., J. Immunology 147: 4207 (1991) 19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52: 672 (1993) 20 Elices, et al., J. Clin. Invest., 93: 405 (1994) 21 Postigo, et al., J. Clin. Invest., 89: 1445 (1991) 22 Paul, et al., Transpl. Proceed., 25: 813 (1993) 23 Okarhara, et al., Can. Res., 54: 3233 (1994) 24 Paavonen, et al., Int. J. Can., 58: 298 (1994) 25 Schadendorf, et al., J. Path., 170: 429 (1993) 26 Bao, et al., Diff., 52: 239 (1993) 27 Lauri, et al., British J. Cancer, 68: 862 (1993) 28 Kawaguchi, et al., Japanese J. Cancer Res., 83: 1304 (1992 ) 29 Kogan, et al., U.S. Patent No. 5,510,332, issued April 23, 1996 30 International Patent Application, Publication No. WO 96/01644 -Eb-dM ^ -VH- All publications, patents and prior patent applications are hereby incorporated by reference in their entirety, to the same extent as if each publication, patent or individual patent application was specifically and individually indicated to be incorporated by reference in its entirety.

STATE OF THE ART VLA-4 (also referred to as a4β integrin and CD49d / CD29), first identified by Hemler and Takada1 is a member of the ßl integrin family of cell surface receptors, each of which comprises two subunits, a chain α a string ß. VLA-4 contains an a4 chain and a ßl chain. There are at least nine integrins, all sharing the same chain ßl and each having a different chain. These nine receptors all link a different complement to the various molecules of the cell matrix, such as fibronectin, laminin and collagen. VLA-4, for example, binds to fibronectin. VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on human umbilical vein endothelial cells, activated with cytosine, in culture. Different epitopes of VLA-4 are sensitive for fibronectin and the binding activities of VCAM-1 and each activity has been shown to be independently inhibited2. Moderate intercellular adhesion by VLA-4 and other cell surface receptors is associated with a variety of inflammatory responses. At the site of a lesion or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive to leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once linked, leukocytes migrate through the wall of the blood vessel to enter the damaged site and release chemical mediators to fight the infection. For reviews of adhesion receptors of the immune system, see, for example, Springer3 and Osborn 4. Inflammatory diseases of the brain, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of nervous system disorders central in which the leukocyte / endothelium adhesion mechanism results in the destruction of otherwise healthy brain tissue. Large numbers of leukocytes migrate through the blood-brain barrier (BBB) in subjects with these inflammatory diseases. Leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis. In another organ system, tissue damage also occurs via an adhesion mechanism that results in the migration or activation of leukocytes. For example, it has been shown that the initial attack after myocardial ischemia to the heart tissue can be further complicated by the entrance of leukocyte to the damaged tissue causing the still further attack (Vedder et al5). Other inflammatory conditions mediated by an adhesion mechanism include, as an example, asthma6-8, Alzheimer's disease, Atherosclerosis9"10, AIDS dementia11, diabetes12" 14 (including acute juvenile onset diabetes), inflammatory bowel disease15 (which includes ulcerative colitis and Crohn's disease), multiple sclerosis16-17, rheumatoid arthritis18"21, tissue transplantation22, tumor metastasis23" 28, meningitis, encephalitis, cerebrovascular accident and other traumas, nephritis, rhinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury, such as that presented in the respiratory distress syndrome in adults.

In view of the above, analyzes to determine the level of VLA-4 in a biological sample containing VLA-4 would be useful, for example for the diagnosis of conditions mediated by VLA-4. Additionally, despite 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 This invention provides compounds that bind to VLA-4. Such compounds can be used, for example, for the analysis for the presence of VLA-4 in a sample and in pharmaceutical compositions that inhibit cell adhesion mediated by VLA-4, for example, the binding of VCAM-1 to VLA-4. . The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC 50 of about 15 μm or less (measured as described in Example A then herein) compounds that are defined by formula I shown below : wherein R1 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and R1 and R2 together with the linked nitrogen atom R2 and the group S02 can form a heterocyclic group or a substituted heterocyclic group; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R2 does not form a heterocyclic group with R1, R2 and R3 together with the nitrogen atom linked to R2 and the carbon atom linked to R3 can form a heterocyclic group or a substituted heterocyclic group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R 3 does not form a heterocyclic group or a group heterocyclic substituted with R2, then R3 and R4 together with the carbon atom to which they are attached can form a cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic group; R5 is selected from the group consisting of isopropyl, -CH2-W y = CH-W, where W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl , aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxy, carboxylalkyl, substituted carboxyl-alkyl, carboxy-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxy-heteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic, and hydroxyl with the proviso that when R5 is = CH-W then (H) is separated from the formula and W is not hydroxyl; Q is selected from the group consisting of: (i) wherein X is selected from the group consisting of oxygen, sulfur and NH; (ii) wherein R7 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R8 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R7 or R8 together with the nitrogen atom bonded to R7 and the carbon atom linked to R8 can form a heterocyclic ring or substituted heterocyclic ring; (iii) wherein R9 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R10 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R9 and R10 together with the nitrogen atom linked to R9, the carbon atom linked to R10 and the group -C (X) - can form a heterocyclic group or substituted heterocyclic group; X is selected from the group consisting of oxygen, sulfur and NH; (iv) wherein R11 and R12 together with the nitrogen atom linked to R11 and the group > C = N- linked to R12 form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and V) wherein R13 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R14 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; X is selected from the group consisting of oxygen, sulfur and NH; and pharmaceutically acceptable salts thereof.

In another embodiment, the compounds of this invention can also be provided as pro-drugs that convert (eg, hydrolyze, metabolize, etc.) in vivo to a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid in the compound of formula I is modified to a group which, in vivo, will convert the carboxylic acid (including the salts thereof). In a particularly preferred embodiment, such pro-drugs are represented by compounds of formula IA: wherein R1 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and R 1 and R 2 together with the nitrogen atom The RH linked to R and the S02 group can form a heterocyclic group or a substituted heterocyclic group; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R2 does not form a heterocyclic group with R1, R2 and R3 together with the nitrogen atom linked to R2 and the carbon atom linked to R3 can form a heterocyclic group or a substituted heterocyclic group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and when R 3 does not form a heterocyclic group or a group heterocyclic substituted with R2, then R3 and R4 together with the carbon atom to which they are attached can form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R5 is selected from the group consisting of isopropyl, -CH2-W and = CH-W, wherein W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, aryl substituted, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxy, carboxylalkyl, substituted carboxyl-alkyl, carboxy-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxy-heteroaryl , substituted carboxyl-heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic and hydroxyl, with the proviso that when R5 is = CH-W then (H) is separated from the formula and W is not hydroxyl; R6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, -NHOY wherein Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and -NH (CH2) pCOOY 'where Y' is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and p is an integer from 1 to 8; Q is selected from the group consisting of: (i) wherein X is selected from the group consisting of oxygen, sulfur and NH; (ü) wherein R7 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R8 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R7 and R8 together with the nitrogen atom bonded to R7 and the carbon atom linked to R8 can form a heterocyclic ring or substituted heterocyclic ring; (iü) wherein R9 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R10 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R9 and R10 together with the nitrogen atom linked to R9, the carbon atom linked to R10 and the group -C (X) - can form a heterocyclic group or substituted heterocyclic group; X is selected from the group consisting of oxygen, sulfur and NH; and (iv) wherein R11 and together with the nitrogen atom linked to R11 and the group > C = N- linked to R12 form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and V) wherein R. 13 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R14 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; X is selected from the group consisting of oxygen, sulfur and NH; and pharmaceutically acceptable salts thereof.

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. Still more preferably R1 is selected from the group consisting of methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-methylphenyl, 4-t-butylphenyl, 2,4,6-trimethylphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3- chloro-4-fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-t-butoxyphenyl, 4- (3'-dimethylamino-n-propoxy) -phenyl, -carboxyphenyl, 2- (methoxycarbonyl) phenyl, 4- (H2NC (0) -) phenyl, 4- (H2NC (S) -) phenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3,5-dihydrogen (trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4- (CH3C (O) NH-) phenyl, 4- (PhNHC (O) NH-) phenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4- (CH3SC ( = NH) -) phenyl, 4-chloro-3- (H2NS (O) 2-) phenyl, l-naphthyl, 2-naphthyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, quinolin -8-ilo, 2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-7-yl, morpholin-4-yl, 2-thienyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, lN-methylimidazole- 4-yl, lN-methylpyrazol-3-yl, 1-N-methylpyrazol-4-yl, lN-butylpyrazol-4-yl, lN-methyl-3-methyl-5-chloropyrazol-4-yl, lN-methyl- 5-methyl-3- ^ - ^ g ^^^ * chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-l, 3,4-thiadiazol-2-yl. Preferably, 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 linked to R2 and S02 linked to R1 are linked to form a heterocyclic group or substituted heterocyclic group. Preferred substituted heterocyclic and heterocyclic groups include those having from 5 to 7 ring atoms, having 2 to 3 heteroatoms in the ring, selected from the group consisting of nitrogen, oxygen and sulfur, which ring is optionally fused to another ring such as a phenyl or cyclohexyl ring to provide a fused ring heterocycle of 10 to 14 ring atoms, having 2 to 4 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur. Specifically preferred R 2 -linked groups include, by way of example, benzisothiazolonyl (saccharin-2-yl), N-2, 10-camforsultamyl and 1, l-dioxo-2, 3-dihydro-3, 3-dimethyl-l, 2-benzisothiazol-2-yl. In a preferred embodiment, R2 and R3 together with the nitrogen atom bound to R2 substituent and the carbon atom bonded to the substituent R3, form a heterocyclic group or substituted heterocyclic group of 4 to 6 ring atoms, having 1 to 2 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which ring is optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro, methyl, hydroxy, oxo (= 0), amino, phenyl, thiophenyl , thiobenzyl, (thiomorpholin-4-yl) C (0) 0-, CH3S (0) 2- and CH3S (0) 20-, or may be fused to another ring such as a phenyl or cycloalkyl ring to provide heterocycle ring fused of 10 to 14 atoms in the ring, having 1 or 2 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur. Such heterocyclic rings include azetidinyl (e.g., L-azetidinyl), thiazolidinyl (e.g., L-thiazolidinyl), piperidinyl (e.g., L-piperidinyl), piperazinyl (e.g., L-piperazinyl), dihydroindolyl (e.g., L -2, 3-yl-2-dihydroindole), tetrahydroquinolinyl (e.g., Ll, 2, 3, 4-tetrahydroquinolin-2-yl), tiomofrolinilo (e.g., L-thiomorpholin-3-yl), pyrrolidinyl (e.g. , L-pyrrolidinyl), substituted pyrrolidinyl such as 4-hydroxypyrrolidinyl (e.g., 4-a- (or beta) hydroxy-L-pyrrolidinyl), 4-oxopyrrolidinyl (e.g. 4-oxo-L-pyrrolidinyl), 4- fluoropyrrolidinyl (e.g., 4-a- (or β-) fluoro-L-pyrrolidinyl), 4-4-difluoropyrrolidinyl (e.g., 4,4-difluoro-L-pyrrolidinyl), 4- (thiomorpholin-4-ylC ( 0) 0-) pyrrolidinyl (e.g., 4- (or ß-) - (thiomorph- ^^ ß u lin-4-ilC (O) 0-) -L-pyrrolidinyl, 4- (CH3S (0) 20-) pyrrolidinyl (for example 4-a- (or β-) (CH3S (0) 20- ) -L-pyrrolidinyl, 3-phenylpyrrolidinyl (for example, 3-a- (or β-) phenyl-L-pyrrolidinyl), 3-thiophenyl-pyrrolidinyl (for example, 3-a- (or β-) -thiophenyl-L- pyrrolidinyl), 4-aminopyrrolidinyl (for example, 4-a- (or β-) -amino-L-pyrrolidinyl), 3-methoxypyrrolidinyl (for example 3-a- (or β-) methoxy-L-pyrrolidinyl) , 4, 4-dimethylpyrrolidinyl, substituted piperazinyl such as 4-N-Cbz-piperazinyl and 4- (CH3S (0) 2) -) piperazinyl, thiazolidinyl, substituted thiazolidinyl such as 5,5-dimethylthiazolidin-4-yl, 1, 1-dioxo-thiazolidinyl (eg, Ll, 1-dioxo-thiazolidin-2-yl), 1,1-dioxo-thiazolidinyl substituted such as Ll, 1-dioxo-5,5-dimethylthiazolidin-2-yl, 1, 1-dioxothiomorpholinyl (for example, Ll, l-dioxo-thiomorpholin-3-yl) and the like. Preferably, in the compounds of formula I and IA above, R3 includes all isomers that arise by substitution with hydrogen, methyl, phenyl, benzyl, diphenylmethyl, -CH2CH2-C00H, -CH2-C00H, 2-amidoethyl, isobutyl, t-butyl, -CH20-benzyl and hydroxymethyl. Additionally, in another preferred embodiment, R3 and R2 together with the nitrogen atom linked to R2 can form a heterocyclic group or substituted heterocyclic group.

Preferably in the compounds of formula I and IA above, R 4 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and where R 3 and R 4 are attached together with the carbon atom to which they are attached to form a cycloalkyl group of 3 to 6 carbon atoms or a heterocyclic group of 3 to 8 ring atoms. Preferred alkyl cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Q is preferably -C (0) N (0) -, -CH2NH-, CH (0H) C (0) NH-, -NHC (0) NH-, or tetrazol-1,5-diyl. R5 is preferably selected from all possible isomers that arise by substitution with the following groups: 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl, 4-benzyloxybenzyl, 4- [f-CH (CH3 ) 0-] benzyl, 4- [f-CH (COOH) -] benzyl, 4- [BocNHCH2C (O) NH-] benzyl, 4-chlorobenzyl, 4- (NH2CH2C (0) NH-] benzyl, 4-carboxybenzyl , 4- [CbzNHCH2CH2NH-] benzyl, 3-hydroxy-4- (f-OC (O) NH-) benzyl, 4- [H00CCH2CH2C (0) NH-] benzyl, benzyl, 4- [2'-carboxylphenoxy-] benzyl, 4- [fC (0) NH-] benzyl, 3-carboxybenzyl, 4-iodobenzyl, 4-hydroxy-3,5-diiodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxy-phenyl] -benzyl , f-CH2CH2-, 4-nitrobenzyl, 2-carboxybenzyl, 4- [dibenzylamino] -benzyl, 4- [1'-cyclopropylpiperidin-4 '-yl) C (O) NH-benzyl, 4 - [- NHC (0) CH2NHBoc] benzyl, 4-carboxybenzyl, 4-hydroxy-3-nitroberyl, 4- [-NHC (O) CH (CH3) NHBoc] encyl, 4- [-NHC (O) CH ( CH2f) NHBoc] benzyl, isobutyl, methyl, 4- [CH3C (0) NH-] benzyl, -CH2- (3-indolyl), n-butyl, t-butyl-0C (0) CH2-, t-butyl- OC (O) CH2CH2- H2NC (0) CH2-, H2NC (0) CH2CH2-, B? CNH- (CH2) 4-, t-butyl-OC (O) - (CH2) 2-, HOOCCH2-, H00C ( CH2) 2-, H2N (CH2) 4-, isopropyl, (l-naphthyl) -CH2-, (2-naphthyl) -CH2-, (2-thiophenyl) -CH2-, (f-CH2-0C (O) NH- (CH2) 4-, cyclohexyl-CH2-, benzyloxy-CH2-, HOCH2-, 5- (3-N-benzyl) imidazolyl-CH2-, 2-pyridyl-CH2-, 3-pyridyl-CH2-, 4 -pyridyl-CH2-, 5- (3-N-methyl) imidazolyl-CH2-, N-benzylpiperid-4-yl-CH2-, N-Boc-piperidin-4-yl-CH2-, N- (phenyl-carbonyl) ) piperidin-4-yl-CH2-, H3CSCH2CH2-, lN-benzylimidazol-4-yl-CH2-, iso-propyl-C (0) NH- (CH2) 4-, iso-butyl-C (0) NH- (CH2) -, phenyl-C (0) NH- (CH2) 4-, benzyl-C (0) NH- (CH2) 4-, allyl-C (0) NH- (CH2) 4-, 4- ( 3-N-methylimidazolyl) -CH2-, 4-imidazolyl, 4- [(CH3) 2NCH2CH2CH2-0-] benzyl, 4- [(benzyl)] 2N-] -benzyl, 4-aminobenzyl, allyloxy-C (0) NH (CH2) 4-, allyloxy-C (0) NH (CH2) 3-, allyloxy-C (0) NH (CH2) 2-, NH2C (0) CH2-, f-CH =, 2-pyridyl-C (0) NH- (CH2) 4-, 4-methylpyrid-3-yl-C (0) NH- (CH2) 4-, 3-methylthien -2-yl-C (0) H- (CH2) 4-, 2-pyrrolyl-C (0) NH- (CH2) 4-, 2-furanyl-C (0) NH- (CH2) 4-, 4 -methyl-enyl-S02-N (CH3) CH2C (0) NH (CH2) 4, 4- [cyclopentylacetylenyl] -benzyl, 4- [-NHC (0) - (N-Boc) -pyrrolidin-2-yl) - benzyl, lN-methylimidazol-4-yl-CH2-, lN-methylimidazol-5-yl-CH2-, imide zol-5-yl-CH2-, 6-methylpyrid-3-yl-C (O) NH- (CH2 ) 4-, 4- [2 '-carboxymethyl-phenyl] -benzyl, 4- [-NHC (O) NHCH2CH2CH2-f] -benzyl, 4- [-NHC (0) NHCH2CH2-f] -benzyl, -CH2C (0) NH (CH2) 4f, 4- [f (CH2) 0- ] -benzyl, 4- [-C = Cf-4 'f] -benzyl, 4- [-C = C-CH2-0-S (O) 2-4' -CH3-f] -benzyl 4- [- C = C-CH2NHC (O) NH2] -benzyl, 4- [-C = C-CH2-0-4 '-COOCH2CH3-f] -benzyl, 4- [-C = C-CH (NH2) -cycothexyl] -benzyl, - (CH2) 4NHC (0) CH2-3-indolyl, - (CH2) 4NHC (O) CH2CH2-3-indolyl, - (CH2) 4NHC (O) -3- (5-methoxyindolyl), - (CH2) 4NHC (O) -3- (1-methylindolyl), - (CH2) 4NHC (0) -4 - (- S02 (CH3) - f), - (CH2) 4NHC (O) -4- ( C (O) CH 3) -phenyl, - (CH2) 4NHC (O) -4-f luorofenyl, - (CH2) 4NHC (O) CH20-4-f luorofenyl, 4- [-C = C- (2-pyridyl)] benzyl, 4- [ -C = C-CH2-0-phenyl] benzyl, 4- [-O = C-CH20CH3] benzyl, 4- [-C = C- (3-hydroxyphenyl)] benzyl, 4- [-C = C-CH2 -0-4 '- (-C (0) OC2H5) phenyl] benzyl, 4- [-C = C-CH2CH (C (0) 0CH3) 2] benzyl, 4- [-C = C-CH2NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl) ), 3-aminobenzyl, 4- [-C = C-CH2CH (NHC (0) CH3) C (0) OH] -benzyl, -CH2C (0) NHCH (CH3) f, -CH2C (0) NHCH2- ( 4-dimethylamino) -f, -CH2C (0) NHCH2-4-nitrofenyl, -CH2CH2C (0) N (CH3) CH2-f, -CH2CH2C (0) NHCH2CH2- (N-methyl) -2-pyrrolyl, - CH2CH2C (0) NHCH2CH2CH2CH3, -CH2CH2C (0) NHCH2CH2-3-indolyl, -CH2C (0) N (CH3) CH2f enyl, -CH2C (0) NH (CH2) 2- (N-methyl) -2-pyrrolyl, -CH2C (0) NHCH2CH2CH2CH3, -CH2C (0) NHCH2CH2-3-indolyl, - (CH2) 2C (0) NHCH (CH3) f, - (CH2) 2C (0) NHCH2-4-dimethylaminophenyl, - (CH2) 2C (0) NHCH2-4-nitrofenyl, - (CH2C (0) NH-4- [-NHC (0) CH3-phenyl], -CH2C (0) NH-4-pyridyl, -CH2C (0) NH- 4- [dimethylaminofenyl], -CH2C (0) NH-3-methoxyfenyl, -CH2CH2C (O) NH-4-chlorofenyl, -CH2CH2C (0) NH-2-pyridyl, -CH2CH2C (0) NH-4 -metoxifenyl, -CH2CH2C (0) NH-3-pyridyl, 4- [(CH3) 2NCH2CH20-] benzyl, - (CH2) 3NHC (NH) NH-S02-4-methylfenyl, 4 - [(CH3) 2NHC2CH20 -] benci lo, - (CH2) 4NHC (0) NHCH2CH3, - (CH2) 4NHC (0) NH-f-enyl, - (CH2) 4NHC (0) NH-4-methoxyfyl, -4- [4'-pyridyl-C (0) NH-] benzyl, 4- [3'-pyridyl-C (O) NH-] benzyl, 4- [NHC (0) NH-3 '-methylphenyl] benzyl, 4- [-NHC (0) CH2NHC (0) NH-3 '-methylphenyl] benzyl, 4 - [- NHC (0) - (2', 3'-dihydroindol-2-yl)] benzyl, 4- [-NHC (0) -2 ', 3' -dihydro-N-Boc-indol-2-yl)] benzyl, p- [-OCH2CH2-l '- (4'-pyrimidyl) -piperazinyl] benzyl, 4- [-OCH2CH2- (1'-piperidinyl) benzyl, 4- [-OCH2CH2- (1-pyrrolidinyl)] benzyl, 4- [-OCH2CH2CH2- (l '-piperidinyl)] benzyl, -CH2-3- ( 1, 2,4-triazolyl), 4- [-OCH2CH2CH2-4- (3'-chlorophenyl) -piperazin-1-yl] benzyl, 4- [-OCH2CH2N (f) CH2CH3] benzyl, 4- [-OCH2- 3 '- (N-Boc) -piperidinyl] benzyl, 4- [di-n-pentylamino] benzyl, 4- [n-pentylamino] benzyl, 4- [di-4-propylamino-CH2CH20-] benzyl, 4- [ -OCH2CH2- (N-morpholinyl)] benzyl, 4- [-0- (3 '- (N-Boc) -piperidinyl] benzyl, 4- [-0CH2CH (NHBoc) CH2cyclohexyl] benzyl, p- [OCH2CH2- ( N-piperidinyl] benzyl, 4- [OCH2CH2CH2- (4-m-chlorophenyl) -piperazin-1-yl] benzyl, 4- [-OCH2CH2- (N-homopiperidinyl) benzyl, 4- [-NHC (0) -3 '- (N-Boc) -piperidinyl] benzyl, 4- [-OCH2CH2N (benzyl) 2] benzyl, -CH2-2-thiazolyl, 3-hydroxybenzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, 4- [ -NHC (S) NHCH2CH2- (N-morpholino)] benzyl, 4- [-OCH2CH2N (C2H5) 2] benzyl, 4- [-OCH2CH2CH2N (C2H5] benzyl, 4- [CH3 (CH2) 4NH-] benz ilo, 4- [Nn-butyl, Nn-pentylamino-] benzyl, 4- [-NHC (O) -4'-piperidinyl] benzyl, 4 - [- NHC (0) CH (NHBoc) (CH2) 4NHCbz] benzyl , 4 - [- NHC (0) - (1 ', 2', 3 ', 4'-tetrahydro-N-Boc-isoquinolin-1' -yl] benzyl, P "[-OCH 2 CH 2 CH 2 -l- (4 ' -methyl) -piperazinyl] benzyl, - (CH 2) 4 NH-Boc, 3-OCH 2 CH 2 CH 2 N (CH 3) 2] benzyl, 4-OCH 2 CH 2 CH 2 N (CH 3) 2] benzyl, 3-OCH 2 CH 2 (1'-pyrrolidinyl)] benzyl , 4- -OCH2CH2CH2N (CH3) benzyl] benzyl, 4-NHC (S) NHCH2CH2CH2- (N-morpholino)] benzyl, 4- -OCH2CH2- (N-morpholino)] benzyl, 4-NHCH2- (4 ' -chlorophenyl)] benzyl, 4--NHC (O) NH- (4'-cyanofenyl)] benzyl, 4- -OCH2COOH] benzyl, 4- -OCH2COO-t-butyl] benzyl, 4-NHC (0) -5'-fluoroindol-2-yl] benzyl, 4-NHC (S) NH (CH2) 2-l-piperidinyl] benzyl, 4- N (S02CH3) (CH2) 3-N (CH3) 2] benzyl , 4-NHC (O) CH2CH (C (O) OCH2f) -NHCbz] benzyl, 4- NHS (0) 2CF3] benzyl, 3- O- (N-methylpiperidin-4'-yl) benzyl, - -C (= NH) NH2] benzyl, 4-NHS02-CH2C1] benzyl, 4-NHC (O) - (1 ', 2', 3 ', 4'-tetrahydrois oquinolin-2'-yl] benzyl, 4- NHC (S) NH (CH2) 3-N-morpholino] benzyl, 4-NHC (O) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, 4-C (0) NH2] benzyl, A-Qi 4- [-NHC (O) NH-3 '-methoxyphenyl] benzyl, 4- [-0CH2CH2-indol-3' -yl] benzyl, 4- [-0CH2C (0) NH-benzyl] benzyl, 4- [-0CH2C (0) 0-benzyl] benzyl, 4- [-0CH2C (0) OH] benzyl, 4 - [- 0CH2-2 '- (4', 5'-dihydro) imidazolyl] benzyl, -CH2C (0) NHCH2- (dimethylamino) phenyl, -CH2C (0) NHCH2- (4-dimethylamino) phenyl, 4- [-NHC (0) -L-2 '-pyrrolidinyl-N-S02-4' -methylphenyl ] benzyl, 4- [-NHC (0) NHCH2CH2CH3] benzyl, 4-aminobenzyl] benzyl, 4- [-0CH2CH2-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) piperazinyl] benzyl, - [-0- (N-methylpiperidin-4 '-yl)] benzyl, 3-methoxybenzyl, 4- [-NHC (O) -piperidin-3'-yl] benzyl, 4- [-NHC (0) -pyridin -2 '-yl] benzyl, 4- [-NHCH2- (4'-chlorophenyl)] benzyl, 4- [-NHC (0) - (N- (4' -CH3-f-S02) -L-pyrrolidin- 2'-yl)] benzyl, 4 - [-NHC (0) NHCH2CH2-f] benzyl, 4- [-0CH2C (0) NH2] benzyl, 4- [-0CH2C (0) NH-t-butii] benzyl, 4- [-0CH2CH2-1- (4-hydroxy-4-f-enyl) -piperidinyl] benzyl, 4- [-NHS02-CH = CH2] benzyl, 4- [-NHS02-CH2CH2C1] benzyl, -CH2C (O) NHCH 2 CH 2 N (CH 3) 2, 4- [(1-Cbz-piperidin-4'-yl) C (O) NH-] benzyl, 4- [(1 '-Boc-piperidin-4' -yl) C (O ) NH-] benzyl, 4- [(2 '-bromofenyl) C (O) NH-] benzyl, 4- [-NHC (O) -pyridin-4' -yl] benzyl, 4- [(4'- (CH3) 2NC (0) 0-) phenyl) -C (O) NH-] benzyl, 4- [-NHC (O) -1 '-methylpiperidin-4' -yl] Joencyl, 4- (dimethylamino) benzyl, 4- [-NHC (0 ) - (1'-N-Boc) -piperidin-2'-yl] benzyl, 3- [-NHC (0) -pyridin-4'-yl] benzyl, 4- [(tert-butyl-0 (O)] CCH2-0-benzyl) -NH-] benzyl, [BocNHCH2C (0) NH-] butyl, 4-benzylbenzyl, 2-hydroxyethyl, 4 - [(Et) 2NCH2CH2CH2NHC (S) NH-] benzyl, 4- [ (1 '-Boc-4' -hydroxypyrrolidin-2'-yl) C (0) NH-] benzyl, 4- [fCH2CH2CH2NHC (S) NH-] benzyl, 4- [(perhydroindolin-2'-yl) C ( O) NH-] benzyl, 2- [4-hydroxy-4- (3-methoxy-thien-2-yl) piperidin-1-yl] ethyl, 4- [(1-Boc-perhydroindolin-2'-yl) - C (O) NH-] benzyl, 4- [N-3-methylbutyl-N-trifluoromethanesulfonyl) -amino] benzyl, 4- [N-vinylsulfonyl) amino] benzyl, 4- [2- (2-azabicyclo [3.2. 2] octan-2-yl) ethyl-0-] benzyl, 4- [4 '-hydroxypyrrolidin-2'-yl) C (O) NH-] benzyl, 4- (fNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl, 4- (fCH2NHC (S) NH) benzyl, 3- [(1 '-Boc-piperidin-2' -yl) C (O) NH-] benzyl, 3- [piperidin- 2 '-i lC (O) NH-] benzyl, 4- [(3 '-Boc-thiazolidin-4' -yl) C (O) NH-] benzyl, 4- (pyridin-3'-yl-NHC (S) NH) benzyl, 4- (CH3NHC (S) NH) benzyl, 4- (H2NCH2CH2CH2C (O) NH) benzyl, 4- (BocHNCH2CH2CH2C (0) NH) benzyl, 4- (pyridin-4 '-il-CH2NH) benzyl, - [(N, N-di (4-N, N-dimethylamino) benzyl) -amino] benzyl, 4 - [(1-Cbz-piperidin-4-yl) C (0) NH-] butyl, 4- [ fCH20CH2 (BocHN) CHC (O) NH] benzyl, 4- [(piperidin-4 '-yl) C (O) NH-] benzyl, 4- [(pyrrolidin-2'-yl) C (0) NH-] benzyl, 4- (pyridin-3'-yl-C (O) NH) butyl, 4- (pyridin-4'-yl-C (O) NH) butyl, 4- (pyridin-3'-yl-C ( O) NH) benzyl, 4- [CH3NHCH2CH2CH2C (0) NH-] benzyl, 4- [CH3N (Boc) CH2CH2CH2C (O) NH-] benzyl, 4- (aminomethyl) benzyl, 4- [fCH2OCH2 (H2N) CHC ( O) NH] benzyl, 4- [(1'-4'-di (Boc) piperazin-2'-yl) -C (O) NH-] benzyl, 4- [(piperazin-2'-yl) -C (O) NH-] benzyl, 4- [(N-toluenesulfonylpyrrolidin-2'-yl) C (0) NH-] butyl 4- [-NHC (O) -4'-piperidinyl] butyl, 4- [-NHC (O) -1 '-N-Boc-piperidin-2' -yl] benzyl, 4- [-NHC (O) -piperidin-2'-yl] benzyl, 4- [(1'-N-Boc-2 ', 3'-dihydroindolin-2'-yl) -C ( 0) NH] benzyl, 4- (pyridin-3 '-il-CH2NH) benzyl, 4- [(1' -Cbz-piperidin-4 '-yl) C (O) NH-] benzyl, 4- [(piperidine -1 '-il) C (O) CH3-0-] benzyl, 4- [(CH3) 2NC (0) CH2-0-] benzyl, 4- [HO (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [fCH20 (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [-NHC (O) -2 '-methoxyphenyl] benzyl, 4- [(pyrazin-2'-yl) C (O) NH-] benzyl, 4- [HO (O) C (NH2) CHCH2CH2-C (O) NH-] benzyl, 4- (2'-formyl-l ' , 2 ', 3', 4 '-tetrahydroisoquinolin-3' -il-CH2NH-) benzyl, ^^^^ tag ^ g ^ N-Cbz-NHCH2-, 4- [(4 '-methylpiperazin-1-yl) C (0) 0-] benzyl, 4- [CH3 (N-Boc) NCH2C (0 ) NH-] benzyl, 4- [-NHC (0) - (1 ', 2', 3 ', 4 '-tetrahydro-N-Boc-isoquinolin-3' -yl] benzyl, 4- [CH3NHCH2C (0) NH-] benzyl, (CH3) 2NC (0) CH2-, 4- (N-methylacetamido) benzyl, 4- (1 ', 2', 3 ', 4' -tetrahydroisoquinolin-3 '-yl- CH2NH-) benzyl, 4- [(CH3) 2NHCH2C (0) NH-] benzyl, (l-toluenesulfonylimidizole-4) -yl) methyl, 4- [(1-Boc-piperidin-4 '-yl) C (0) NH-] benzyl, 4-trifluoromethylbenzyl, 4- [(2'-bromophenyl) C (0) NH-] benzyl, 4- [(CH3) 2NC (0) NH-] benzyl, 4- [CH30C (0) NH-] benzyl, 4- [(CH3) 2NC (0) 0-] benzyl, 4-t (CH3) 2NC (0) N (CH 3) -] benzyl, 4- (N-methyltrifluoroacetamido) benzyl, 4- [(1'-methoxycarbonylpiperidin-4-yl) C (0) NH-] benzyl, 4- [(4 '- phenylpiperidin-4 '-yl) C (0) NH-] benzyl, 4- [(4'-phenyl-1' -Boc-piperidin-4 '-yl) -C (0) NH-] benzyl, 4- [ (piperidin-4 '-yl) C (O) 0-] benzyl, 4- [(1' -methylpiperidin-4 '-yl) -0-] benzyl, 4- [(1-methylpiperidin-4-yl) C (O) 0-] benzyl, 4- [(4'-methylpiperazin-1-yl) C (O) NH-] benzyl, 3- [(CH3) 2NC (0) 0-] benzyl, 4- [(4'-phenyl-1 '-Boc-piperidin-4'-yl) -C (0) 0-] benzyl, 4- (N toluenesulfonylamino) benzyl, 4-t (CH3) 3CC (O) NH-] benzyl, 4- [(morpholin-4 '-yl) C (O) NH-] benzyl, 4- [(CH3CH2) 2NC (O ) NH-] benzyl, 4- [-C (O) NH- (4'-pyridinyl)] benzyl, 4- [(2'-trifluoromethylphenyl) C (O) NH-] benzyl, 4- [(2'-methylphenyl) C (O) NH-] benzyl, 4- [(CH3) 2NS (O) 20-] benzyl, 4- [(pyrrolidin-2'-yl) C (O) NH- ] benzyl, 4- [-NHC (O) -piperidin-1-yl] benzyl, 4- [(thiomorpholin-4 '-yl) C (O) NH-] benzyl, 4- [(thiomorpholin-4' - il sulfone) -C (O) NH-] benzyl, 3-Nitro-4- (CH3OC (O) CH20-] benzyl, (2-benzoxazolinon-6-yl) -methyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl -, 4- [(CH3) 2NS (O) 2NH-] benzyl, 4- [(CH3) 2NS (O) 2N (CH3) -] benzyl, 4- [(thiomorpholin-4 * -yl) C (O) 0-] benzyl, 4- [(thiomorpholin-4'-yl sulfone) -C (0) 0-] benzyl, 4- [(piperidin-1-yl) C (0) 0-] benzyl, 4- [ (pyrrolidin-1-yl) C (0) 0-] benzyl, 4- [(4'-methylpiperazin-1-yl) C (O) 0-] benzyl, 4- [(2'-methylpyrrolidin-1) '-il) -, (pyridin-4-yl) methyl-, 4- [(piperazin-4' -yl) -C (O) O-] benzyl, 4- [(1-Boc-piperazin-4 ' -yl) -C (O) 0-] benzyl, 4- [(4'-acetylpiperazin-1-yl) C (O) O-] benzyl, p- [(4'-methanesulfonylpiperazin-1'-yl) -benzyl, 3-nitro-4- [(morpholin-4 '-yl) -C (O) O-] benzyl, 4-. { [CH3) 2NC (S)] 2N-} benzyl, N-Boc-2-aminoethyl-, 4- [(1,1-dioxothiomorpholin-4-yl) -C (O) O-] benzyl, 4- [(CH3) 2NS (0) 2-] benzyl, 4- (imidazolid-2 '-one-1'-yl) benzyl, 4- [(piperidin-1-yl) C (0) 0-] benzyl, lN-benzyl-imidazol-4-yl-CH2-, 3,4-dioxyethylenebenzyl, 3,4-dioxymethylenebenzyl, 4- [-N (S02) (CH3) CH2CH2CH2N (CH3) 2] benzyl, 4- (3'-f-ormilimidazolid-2'-ona-1'-yl) benzyl, 4- tNHC (O) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, [2 * - [4"-hydroxy-4" - (3 '' '-methoxy-2-yl) -yl) piperidin-2' '-yl] ethoxy] benzyl and p- [(CH3) 2-NCH2CH2N (CH3) C (O) O-] benzyl, In a preferred embodiment, R5 is preferably selected from all possible isomers that arise by substitution with the following groups. 3- (CH3) 2NC (O) O-] benzyl, 4- (CH3) 2NC (O) O-] benzyl, 4- (CH3) 2NS (O) 20-] benzyl, 4- (piperidin-1 '- il) C (O) O-] benzyl, 4- (piperidin-4 '-yl) C (O) O-] benzyl, 4- (1-methylpiperidin-4' -yl) C (O) O-] benzyl, 4- (4 '-hydroxypiperidin-1' -yl) C (O) 0-] benzyl, 4- (4 '-formyloxypiperidin-1' -yl) C (O) O-] benzyl, 4- (4 '-ethoxycarbonylpiperidin-1'-yl) C (0) 0-] benzyl, 4- (4'-carboxypiperidin-1'-yl) C (O) O-] benzyl, 4- (3' -hydroxymethylpiperidin-1 ' -yl) C (O) 0-] benzyl, 4- (4'-hydroxymethylpiperidin-1'-yl) C (O) 0-] benzyl, 4- (4'-phenyl-1 '-Boc-piperidin-4) '-il) - C (0) 0-] benzyl, 4- (4' -piperidon-1 '-yl ethylene ketal) - C (0) 0-] benzyl, 4- (piperazin-4' -yl) -C (O) 0-] benzyl, 4- (1 '-Boc-piperazin-4' -yl) -C (O) O-] benzyl, 4- (4 '-methylpiperazin-1'-yl) -C (O ) O-] benzyl, 4- (4 '-methylhomopiperazin-1' -yl) C (O) 0-] benzyl, 4- [(4 '- (2-hydroxyethyl) piperazin-1'-yl) C (0 ) 0-] benzyl, 4- [(4'-phenylpiperazin-1 '-il) C (0) 0-] benzyl, 4- [(4 '- (pyridin-2-yl) piperazin-1'-yl) C (0) 0-] benzyl, 4- [(4' - (4-trifluoromethylpyridin- 2-yl) piperazin-1 '-yl) C (0) 0-] benzyl, 4- [(4'-pyrimidin-2-yl) piperazin-1'-yl) C (0) 0-] benzyl, - [(4-acetylpiperazin-1 '-yl) C (0) 0-] benzyl, 4- [(4- (phenylC (0) -) piperazin-1-yl) C (0) 0-] benzyl, 4- [(4'- (pyridin-4-ylC (0) -) piperazin-1 '- il) C (0) 0-] benzyl, 4- [(4' - (phenylNHC (0) -) piperazin-1'-yl) C (0) 0-] benzyl, 4- [(4 '- (phenylNHC (S) -) piperazin-1'-yl) C (0) 0-] benzyl, 4- [(4'-methanesulfonylpiperazin-1'-yl-C (0) 0-) benzyl, 4- [( 4 '-trifluoromethanesulfonylpiperazin-1' -il-C (0) 0-) benzyl, 4- [(morpholin-4 '-yl) C (0) 0-] benzyl, 3-nitro-4 [(morpholin-4' -yl) -C (0) 0-] benzyl, 4- [(thiomorpholin-4 '-yl) C (0) 0-] benzyl, 4- [(thiomorpholin-4'-yl sulfone) -C (0) 0-] benzyl, (alternative nomenclature 4- [(1,1-dioxothiomorpholin-4-yl) -C (0) 0-] benzyl, 4- [(pyrrolidin-1 'yl) C (0) 0-] benzyl, 4- [(2'-methylpyrrolidin-1'-yl) C (0) 0-] benzyl, 4- [(2' - ( methoxycarbonyl) pyrrolidin-1'-yl) C (0) 0-] benzyl, 4- [(2 '- (hydroxymethyl) pyrrolidin-1'-yl) C (0) 0-] benzyl, 4- [(2' - (N, N-dimethylamino) ethyl) - (CH3) NC (0) 0-] benzyl, 4- [(2 '- (N-methyl-N-toluene-4-sulfonylamino) -ethyl) (CH3) NC (0) 0-] benzyl, 4- [(2 '- (morpholin-4' -yl) ethyl) (CH3) NC (0) 0-] benzyl, 4- [(2 '- (hydroxy) ethyl) ( CH3) NC (0) 0-] benzyl, 4- [bis- (2 '- (hydroxy) ethyl) NC (0) 0-] benzyl, 4- [(2' - (formyloxy) ethyl) (CH3) NC (0) 0-] benzyl, 4- [(CH3) OC (0) CH2) HNC (0) 0-] benzyl, 4- [2 '- (phenylNHC (0) 0-) ethyl-] NHC (0) 0-] benzyl, 3-chloro-4- [(CH3) 2NC (0) 0-] benzyl, 3-chloro-4- [(4'-methylpiperazin-1'-yl) C (0) 0-] benzyl , 3-chloro-4- [(4 '- (pyridin-2-yl) piperazin-1'-lyl) C (0) 0-] benzyl or, 3-chloro-4- [(thiomorpholin-4 '-yl) C (0) 0-] benzyl and 3-chloro-4 - [(CH 3) 2 NC (0) 0-] benzyl.

In the compounds of formula IA, R6 is preferably 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, n- pentoxy, 2-a-iso-propyl-4-ß-methylcyclohexoxy, 2-ß-isopropyl-4-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2COOH, -NHCH2CH2COOH, -NH-adamantyl, NHCH2CH2COOCH2CH2, -NHS02-p-CH3 -f, -NHOR8 where R8 is hydrogen, methyl, iso-propyl or benzyl, 0- (N-succinimidyl), -0-cholest-5-en-3-β-yl, -OCH2-OC (0) C ( CH3) 3, -0 (CH2) ZNHC (0) W where z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl and N-methyl-1,4-dihydro-pyrid -3-yl, -NR "C (0) R 'wherein R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or CH2C (0) 0CH2CH2. Preferred compounds within the scope of Formulas I and IA above include, by way of example: N- [N- (toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl] -L-phenylalanine N- [N- (toluene-4-sulfonyl) - L-prolinyl] -N-hydroxy-L-phenylalanine N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-D-phenylalanine N- [2- (N-toluene-4-sulfonyl ) -L-pyrrolidinyl) -2-hydroxyacetyl] -L-4- (N-benzyloxycarbonyl-isonipecotamido) phenylalanine N- [2- (N- (toluene-r-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl] - L-4- (isonipecotamido) phenylalanine (2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (nitrobenzyl) propionic acid methyl ester of (2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonyl) ynespecpecide) benzyl) propionic acid ( 2S) -2- [5-N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonylisonipecotamido) benzyl) propionic N- [N-] (toluene-4-sulfonyl) pyrrolidin-2-yl] aminocarbonyl] -L-phenylalanine and pharmaceutically acceptable salts eutically thereof, as well as any of the ester compounds mentioned above, wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester. This invention also provides methods for binding VLA-4 to a biological sample, which method comprises contacting the biological sample with a compound of formula I or IA above, under conditions wherein the compound binds to VLA-4.

Some of the compounds of formula I and IA above are also useful in reducing inflammation mediated by VLA-4 in vivo. This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of one or more of the compounds of formula I or IA above, with the exception that R3 and R5 are derivatives of L-amino acids or other starting materials similarly configured. Alternatively, racemic mixtures may be used. The pharmaceutical compositions can 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 (which includes acute juvenile onset diabetes), inflammatory bowel disease (which includes ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, cerebrovascular accident and other 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 acute.

Thus, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4, methods comprising administering to the patient the pharmaceutical compositions described above. Preferred compounds of Formulas I and IA above, include those set forth in Table I below: 1-tetrazolyl, 5-diyl = I and - < N-N DETAILED DESCRIPTION OF THE INVENTION As stated above, this invention relates to compounds that inhibit leukocyte adhesion and in particular, leukocyte adhesion mediated by VLA-4. When the compounds, compositions and methods of this invention are described, the following terms have the following meanings, unless otherwise indicated.

DEFINITIONS As used herein "alkyl" refers to alkyl groups preferably having 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, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, substituted carboxylalkyl, carboxycycloalkyl, carboxycycloalkyl substituted, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxy-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl , substituted thioheteroaryl, thioheterocyclic co, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkylcoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (0) 2-alkyl, OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS (O) 2 -substituted aryl, -OS (0) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2- heterocyclic, -OS (O) 2-substituted heterocyclic, -OS02-NRR where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (O) 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 (0) 2 -heterocyclic substituted, - NRS (O) 2-NR-alkyl, -NRS (0) 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 (0) 2-NR-heterocyclic, -NRS (0) 2-NR-heterocyclic substitute uido, wherein R is hydrogen or alkyl, mono- or di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono - and substituted di-heteroarylamino, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, unsymmetrical disubstituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like or 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 and -S02-N RR, where R is hydrogen or alkyl. "Alkoxy" refers to the group "alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy , 1,2-dimethylbutoxy and the like. "Substituted alkoxy" refers to the group "alkyl-0-substituted". "Acyl" refers to the groups HC (O) -, alkyl-C (0) -, substituted alkyl-C (0), alkenyl-C (0) -, substituted alkenyl-C (0) -, alkynyl-C (0) -, substituted alkynyl-C (0) -, cycloalkyl-C (0) -, substituted cycloalkyl-C (0) -, aryl-C (O) -, substituted aryl-C (0) -, heteroaryl- C (0) -, substituted heteroaryl-C (0) -, heterocyclic-C (0) - and substituted heterocyclic-C (0) -, 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, cycloalkyl, cycloalkyl substituted, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein each R is linked to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Thiocarbonylamino" refers to the group -C (S) NRR, wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, cycloalkyl substituted, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and wherein each R is linked to form, together with the nitrogen atom, a heterocyclic, substituted heterocyclic ring, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic are as defined herein. "Acyloxy" refers to the groups alkyl-C (0) 0-, substituted alkyl-C (0) 0-, alkenyl-C (0) -, substituted alkenyl-C (0) 0-, alkynyl-C (0) ) 0-, substituted alkynyl-C (0) 0-, aryl-C (0) 0-, substituted aryl-C (0) 0-, cycloalkyl-C (0) 0-, cycloalkyl-C-substituted (0) 0 -, heteroaryl-C (0) 0-, substituted heteroaryl-C (0) 0-, heterocyclic-C (0) 0- and substituted heterocyclic-C (0) 0-, wherein alkyl, substituted alkyl, alkenyl, 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 having preferably 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably 1-2 sites of alkenyl unsaturation. "Substituted alkenyl" refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidoino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy , aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted-carboxylaryl, carboxy-heteroaryl, substituted-carboxyl-heteroaryl, carboxy-heterocyclic , substituted carboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (0) 2-alkyl, -OS (O) 2-substituted alkyl, -OS (O ) 2-aryl, -OS (0) 2-substituted aryl, -SO (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, -NRS02-substituted alkyl, -NRS02-aryl, -NRS (0) 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 (O) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (O) 2-NR-substituted heteroaryl, - NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di- - arylamino, mono- and di-arylamino, substituted and di-heteroarylamino mono-, di-heteroarylamino mono- and substituted mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, disubstituted amines unsymmetrical that have different constituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and ejantes or alkenyl groups / substituted alkenyl, substituted -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, and -S02NRR where R is hydrogen or alkyl. "Alkynyl" refers to the alkynyl group having preferably 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably 1-2 sites of alkynyl unsaturation. "Alkynyl substituted" refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy , aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, aryloxy substituted, halogen, hydroxyl, cyano, nitro, carboxyl, carboxyalkyl, I carboxyalkyl substituted, carboxyl-cycloalkyl, carboxyl- substituted cycloalkyl, carboxylaryl, I carboxylaryl substituted, carboxylheteroaryl, I carboxylheteroaryl substituted, 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, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, cycloalkoxy, substituted heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxitiocarbonilamino, -OS (O) 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 (O) 2 -heterocyclic, -OS (O) 2 -heterocyclic substituted, -OS02-NRR, where R is halogen or alkyl, NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NR (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-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di- di-substituted heterocyclic amino, amines, di-substituted unsymmetrical having different selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by blocking groups conventional such as Boc, Cbz, formyl and the like, or substituted alkynyl / alkynyl 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, and -S02-NRR 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) -, where R is hydrogen or alkyl. "Aminoacyl" refers to the groups NRC (0) alkyl, -NRC (0) substituted alkyl, NRC (0) 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, -NRC (0) -heteroaryl, -NRC (0) substituted heteroaryl, -NRC (0) heterocyclic and -NRC (0) substituted heterocyclic, where R is hydrogen or alkyl, 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) O-alkyl, -NRC (0) O-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 -aryl substituted, -NRC (0) O-heteroaryl, NRC (0) O-substituted heteroaryl, -NRC (0) O-heterocyclic and -NRC (0) O-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, substituted heterocyclic are as defined herein. "Oxycarbonylamino" refers to the groups 0C (0) NH2-, -0C (0) NRR, -OC (0) NR-alkyl, -OC (0) NR-substituted alkyl, -0C (0) NR-alkenyl, -OC (0) NR-substituted alkenyl, -OC (O) NR-alkynyl, -OC (0) NR-substituted alkynyl, -OC (0) NR-cycloalkyl, -OC (0) NR-substituted cycloalkyl, -0C (0) NR-aryl, -OC (0) NR-substituted aryl, 0C (0) NR-heteroaryl, -OC (0) NR-substituted heteroaryl, OC (O) NR-heterocyclic and -OC (0) NR- substituted heterocyclic, wherein R is hydrogen, alkyl or where each R is attached to form, together with the nitrogen atom, a heterocyclic, 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. "Oxithiocarbonylamino" refers to the groups -OC (S) NH2-, -OC (S) NRR, -OC (S) NR-alkyl, -OC (S) NR-substituted alkyl, -OC (S) NR-alkenyl , -OC (S) NR-substituted alkenyl, -OC (S) NR-alkynyl, -OC (S) NR-substituted alkynyl, -OC (S) NR-cycloalkyl, -OC (S) NR-substituted cycloalkyl, - OC (S) NR-aryl, -OC (S) NR-substituted aryl, OC (S) NR-heteroaryl, -OC (S) NR-substituted heteroaryl, OC (S) NR-heterocyclic and -OC (S) NR -substituted heterocyclic, wherein R is hydrogen, alkyl or where each R is linked to form together with the nitrogen atom a heterocyclic, 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 (0) NR-cycloalkyl, -NRC (O) ) NR-substituted cycloalkyl, -NRC (0) NR- a ^^ tBüMÉatttfi? heteroaryl and -NRC (0) NR-substituted heteroaryl, -NRC (0) NR-heterocyclic and -NRC (0) -heterocyclic substituted, wherein each R is independently hydrogen, alkyl or where each R is attached to form together with the atom of nitrogen a heterocyclic or substituted heterocyclic ring, as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , substituted cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. "Aminothiocarbonylamino" refers to the groups -NRC (S) NRR, -NRC (S) NR-alkyl, -NRC (S) NR-substituted alkyl, -NRC (S) NR-alkenyl, -NRC (S) NR- substituted alkenyl, NRC (S) NR-alkynyl, -NRC (S) NR-substituted alkynyl, NRC (S) NR-aryl, -NRC (S) NR-substituted aryl, -NRC (S) NR-cycloalkyl, -NRC (S) NR-substituted cycloalkyl, -NRC (S) NR-heteroaryl and -NRC (S) NR-substituted heteroaryl, -NRC (S) NR-heterocyclic and -NRC (S) NR-substituted heterocyclic, where each R is independently hydrogen, alkyl or where each R is bonded to form together with the nitrogen atom a heterocyclic, heterocyclic ring thus substituted, such as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic ico and substituted heterocyclic are as defined herein. "Aryl" or "Ar" refers to an aromatic, unsaturated carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl) fused rings which they may or may 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 that are substituted with 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, alkylamidoino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, ^ gg carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxylheterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, thioheteroaryl substituted, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (O) 2 -alkyl, S (O) 2-substituted alkyl, -S (O) 2-cycloalkyl, -S (0) 2-substituted cycloalkyl, -S (O) 2-alkenyl, -S (O) 2 -substituted alkenyl, -S ( 0) 2-aryl, -S (0) 2 -substituted aryl, -S (0) 2 -heteroaryl, -S (O) 2 -substituted heteroaryl, -S (0) 2 -heterocyclic, -S (O) 2 -substituted heterocyclic, -OS (0) 2-alkyl, -OS (O) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (0) 2 -substituted aryl, -OS (0) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2 -heterocyclic, -OS (0) 2 -substituted heterocyclic, -0S02-NRR, where R is hydrogen or alkyl , NRS (0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-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 -substituted aryl, -NRS (0) 2 -heteroaryl, -NRS (0) 2 -substituted heteroaryl, -NRS (0) 2-NR -substituted heteroaryl , -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and dialkyl substituted amino, mono- and di- arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, non-symmetrical disubstituted amines having different s substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or substituted with -S02NRR where R is hydrogen or alkyl. "Aryloxy" refers to the group aryl-O- which includes, by way of example, phenoxy, naphthoxy and the like. "Substituted aryloxy" refers to aryl-0-substituted groups. "Aryloxyaryl" refers to the -aryl-O-aryl group.

"Substituted aryloxyaryl" refers to aryloxyaryl groups substituted with 1 to 3 substituents on any or both of the 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, amino, 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 carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxylheterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioaryl their substituted, 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 (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) 2-aryl, -0S (0) 2-substituted aryl, -OS (0) 2-heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2 -substituted heterocyclic, -0S02 -NRR, where R is hydrogen or alkyl, NRS (0) 2-alkyl, -NRS (0) 2 -substituted alkyl, -NRS (0) 2 -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) 2NR-heteroaryl, -NRS (0) 2NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, substituted mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, non-symmetrical di-substituted amines having different substituents selected from alkyl, & amp; substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or substituted with -S02NRR where R is hydrogen or alkyl. "Cycloalkyl" refers to cyclic alkyl groups of 3 to 8 carbon atoms having 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 rings such as adamantanil, etc. "Cycloalkenyl" refers to cyclic alkenyl groups of 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic. "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups, preferably 3 to 8 carbon atoms, having 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 carboxylalkyl, carboxycycloalkyl, substituted carboxylcycloalkyl, carboxylaryl, substituted carboxylaryl , substituted carboxylheteroaryl, carboxylheteroaryl, carboxylheterocyclic, substitutedcarboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, heteroaryl substituted, 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 (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 (O ) 2-aryl, -NRS (0) 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 (O) 2 -substituted aryl, -NRS ( O) 2-heteroaryl, -NRS (O) 2 -heteroaryl 6 substituted, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, where R is hydrogen or alkyl, mono- and di-alkylamino , mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, unsymmetrical disubstituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by groups of conventional blocks such as Boc, Cbz, formyl and the like, or substituted alkynyl / alkynyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02 -substituted cycloalkyl, -S02-aryl, -S02-aryl substituted, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic and -S02-NRR, where R is hydrogen or alkyl. "Cycloalkoxy" refers to -O-cycloalkyl groups. "Substituted cycloalkoxy" refers to substituted -0-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) R-alkynyl, -NRC (= NR) NR-substituted alkynyl, NRC (= NR) NR-aryl, -NRC (= NR) NR-substituted aryl, -NRC ( = NR) NR-cycloalkyl, -NRC (= NR) NR-heteroaryl, -NRC (= NR) NR-substituted heteroaryl, -NRC (= NR) NR-heterocyclic and NRC (= NR) NR-substituted heterocyclic, where each R is independently hydrogen and alkyl as well as wherein 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, 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) RS02-cycloalkyl , NRC (= NR) NRS02-substituted cycloalkyl, -NRC (= NR) NRS02-heteroaryl and -NRC (= NR) NRS02-substituted heteroaryl, NRC (= NR) NRS02-heterocyclic and -NRC (= NR) RS02-heterocyclic substituted, 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, substituted heterocyclic was as define in the present. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and is preferably either color or bromine. "Heteroaryl" refers to an aromatic carbocyclic group of 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups may have a single ring (eg, pyridyl or furyl) or multiple fused rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl. "Substituted heteroaryl" refers to heteroaryl groups that are substitutable with 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, thioheteroaryl , thiohetero substituted aryl, 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 (O) 2 -substituted alkyl, -S (O) 2 -cycloalkyl, S (O) 2 -substituted cycloalkyl, -S (O) 2 -alkenyl , -S (0) 2-substituted alkenyl, -S (O) 2 -aryl, -S (0) 2 -substituted aryl, -S (O) 2 -heteroaryl, -S (O) 2 -substituted heteroaryl, - S (0) 2-heterocyclic, -S (O) 2 -substituted heterocyclic, -0S (0) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (O) 2 -aryl, -OS (0 ) 2-substituted aryl, -OS (O) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (0) 2 -substituted heterocyclic, -0S02-NRR, where R is hydrogen or alkyl, NRS ( 0) 2-alkyl, -NRS (0) 2-substituted alkyl, -NRS (0) 2-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, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di- substituted arylamino, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, unsymmetrical di-substituted amines having different substituents selected from alkyl, alkyl substituted, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the aryl s is blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or substituted with -S02NRR where R is hydrogen or alkyl. "Heteroaryloxy" refers to the group -O-heteroaryl and "substituted heteroaryloxy" refers to the group -0-substituted heteroaryl. "iaat-" heterocycle "or" heterocyclic "refers to a saturated or unsaturated group having a single ring or multiple fused rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring, wherein, in fused ring systems, one or more of the rings may be aryl or heteroaryl. "Substituted heterocyclic" refers to heterocycle groups that are substituted with 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, substituted aryloxy, aryloxyaryl, aryloxyaryl substituted, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxylaryl substituted O, 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, thioheterocyclic substituted, 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 (0) 2-heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, -OS (O ) 2-substituted heterocyclic, -OS02-NRR, where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (O) 2 -substituted alkyl, -NRS (O) 2 -aryl, -NRS (0) ) 2-substituted aryl, -NRS (O) 2-he teroaryl, -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 (O) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (O) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, substituted mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono- and di-heterocyclic amino, mono- and di-heterocyclic substituted amino, non-symmetric amines di- substituted which have different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, or substituted alkynyl / alkynyl 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, and -S02-NRR, where R is hydrogen or alkyl. Examples of heterocycles and heteroaryls include, but are not limited to, acetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalizine, naphthylpyridine. , quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, penantridine, 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, thiophene, benzo [b] thiophene, morpholino, thiomorpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl and the like.

"Heterocyclyloxy" refers to the -0-heterocyclic group and "substituted heterocyclyloxy" refers to the -O-substituted heterocyclic group. "Tiol" refers to the group -SH. "Thioalkyl" refers to the group -S-alkyl. "Substituted thioalkyl" refers to the group -S-substituted alkyl. "Thiocycloalkyl" refers to the -S-cycloalkyl groups. "Substituted thiocycloalkyl" refers to the group -S-substituted cycloalkyl. "Thioaryl" refers to the group -S-aryl and "substituted thioaryl" refers to the group -S-substituted aryl. "Thioheteroaryl" refers to the group -S-heteroaryl and "substituted thioheteroaryl" refers to the group -S-substituted heteroaryl. "Thioheterocyclic" refers to the group -S-heterocyclic and "substituted thioheterocyclic" refers to the group -S-substituted heterocyclic. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of formula I, salts that are derived from a variety of organic and inorganic counter ions well known in the art and includes, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkyl ammonium and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Preparation of the Compound The compounds of this invention can be prepared from readily available starting materials using the following methods and general procedures. It will be appreciated that where common or preferred process conditions (ie, reaction temperatures, times, mole ratios of reagents, solvents, pressures, etc.) are given, other process conditions may also be used unless it is established from another way. Optimal reaction conditions may vary with the particular reagents or solvents used, but such conditions may be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from being subjected to undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T.W. Greene and G.M Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley New York, 1991 and the references cited therein. In addition, the compounds of this invention will commonly contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, that is, as individual enantiomers or disteriomers or as mixtures enriched with stereoisomers. All 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 resolving agents and the like. In a preferred embodiment, the compounds of formula I and IA wherein Q is a portion of tetrazole-1,5-diyl are readily prepared by contacting the corresponding amide, ie, where Q is -C (0) NH- , with an equimolar amount of phosphorus pentachloride (PC15) in an anhydrous inert solvent, such as benzene, followed by treatment of the resulting imino chloride with hydrazoic acid (HN3). Commonly, this reaction is conducted by contacting the amide with PC15 at room temperature for about 90 minutes. If the resulting imino chloride is not commonly isolated, but is reacted in situ with an equimolar amount of hydrozoic acid at room temperature for about 2 hours to give the tetrazole. The amide intermediates, ie, where Q is -C (0) NH-, used in this reaction are readily prepared by first coupling an amino acid of formula II: wherein R2 and R3 are as defined herein (e.g., in formula I and IIA), with a sulfonyl chloride of formula III: wherein R1 is as defined herein, to provide an N-sulfonyl amino acid of formula IV: wherein R ^ R3 are as defined herein. This reaction is commonly conducted by reacting the amino acid of formula II with at least one equivalent, preferably about 1.1 to about 2 equivalents, of sulfonyl chloride III in an inert diluent such as dichloromethane and the like. In general, the reaction is conducted 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 clean the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base. The completion of the reaction, the resulting N-sulfonylamino acid IV is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like. The amino acids of formula II employed in the above reaction are either known compounds or compounds which can be prepared from known compounds by conventional synthesis methods. Examples of suitable amino acids for use in this reaction include, but are not limited to, L-proline, trans-4-hydroxyl-L-proline, cis-4-hydroxyl-L-proline, trans-3-phenyl-L-proline. , cis-3-phenyl-L-proline, L- (2-methyl) proline, L-pipecolinic acid, L-azetidine-2-carboxylic acid, L-indoline-2-carboxylic acid, acid Ll, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidin-4-carboxylic acid, L- (5,5-dimethyl) thiazolidine-4-carboxylic acid, L-thiamorpholine-3-carboxylic acid, glycine, 2-tert-butylglycine, D, L-phenylglycine, L-alanine, α-methylalanine, N-methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D, L-phenylsarcosine, β-tert-butyl ester of L-aspartic acid, gama-tert ester -butyl of L-glutamic acid, L- (0-benzyl) serine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid (cycloleucine) 1-aminohexanecarboxylic acid, L-serine and the like. If desired, the corresponding carboxylic acid esters of the amino acids of formula II, such as methyl esters, ethyl esters and the like, can be employed in the above reaction with the sulfonyl chloride III. Subsequent hydrolysis of the ester group to the carboxylic acid using conventional reagents and conditions, i.e. treatment with an alkali metal hydroxide in an inert diluent such as methanol / water, then provides the N-sulfonyl amino acid IV. Similarly, the sulfonyl chlorides of formula III employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthesis methods. Such compounds are commonly prepared from the corresponding sulfonic acid, ie, compounds of the formula R1-S03h where 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 either pure or in an inert solvent, such as dichloromethane, at a temperature in the range of about 0. ° C at about 80 ° C for about 1 to about 48 hours to give the sulfonyl chloride. Alternatively, the sulfonyl chlorides of formula III can be prepared from the corresponding thiol compound, ie, of compounds of the formula R1-SH, where R1 is as defined herein, by treating the thiol with chlorine (Cl2) and water under conventional reaction conditions. Examples of sulfonyl chloride 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, α-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-trifluoromethyl chloride encensulfonyl, 4-trifluoromethoxybenzenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonyl chloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonyl chloride, 2, 5-dichloro-4-chloride thiophenesulfonyl, 2-thiazolesulfonyl chloride, 2-methyl-4-thiazolesulfonyl chloride, l-methyl-4-imidazolesulfonyl chloride, l-methyl-4-pyrazolesulfonyl chloride, 5-chloro-1,3-dimethyl chloride, 4-pyrazolesulfonyl, 3-pyridinesulfonyl chloride, 2-pyrimidine sulfonyl chloride and the like. If desired, a sulfonyl chloride, sulfonyl bromide or sulfonic acid anhydride can be used in place of the sulfonyl chloride in the above reaction to form the N-sulfonyl amino acids of formula IV. The intermediate N-sulfonyl amino acids of formula IV can also be prepared by reacting a sulfonamide of formula V: wherein R1 and R2 are as defined herein, with a carboxylic acid derivative of the formula L (R3) CHCOOR, wherein L is a leaving group, such as chlorine, bromine and odo, mesylate, tosylate and the like, R3 is as defined herein and R is hydrogen or an alkyl group. This reaction is commonly conducted by contacting the sulfonamide V with at least one equivalent, preferably 1.1 to 2 equivalents, of the carboxylic acid derivative in the presence of a suitable base, such as triethylamine, in an inert diluent, such as DMF. , at a temperature ranging from about 24 ° C to about 37 ° C for about 0.5 to about 4 hours. This reaction is further described in Zuckermann et al., J. Am. Chem. Soc, 1992, 114, 10646-10647. Preferred carboxylic acid derivatives for use in this reaction are the esters of a-chloro and a-bromocarboxylic acid such as tert-butyl bromoacetate and the like. When a carboxylic acid ester is employed in this reaction, the ester group is subsequently improvised using conventional procedures to give an N-sulfonyl amino acid of formula IV. The amide intermediates where Q is -C (0) NH-then are prepared by coupling the N-sulfonyl amino acid intermediate of formula IV with an amino acid derivative of formula VI: wherein R5 and R6 are as defined herein. This coupling reaction is commonly conducted using well known coupling reagents such as carbodiimides, BOP reagent (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphonate) and the like, suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide ( DCC), l- (3-dimethylamino-propyl) -3-ethylcarbodiimide (EDC) and the like. If desired, carbonate-supported forms of carbodiimide coupling reagents can also be used, including, for example, those described in Tetrahedron Letters, 34 (48), 7685 (1993). Additionally, promoters of ^^ w ^ ^ & ^^^ well known coupling such as N-hydroxysuccinimide, 1-hydroxybenzothiazole and the like, can be used to facilitate coupling reaction. This coupling reaction is commonly conducted by contacting the N-sulfonylamino acid IV with about 1 to about 2 equivalents of the coupling reagent and at least 1 equivalent, preferably about 1.2 equivalents, of amino acid derivative derivative VI in a diluent. inert, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N-dimethylformamide and the like. In general, this reaction is conducted at a temperature ranging from about 0 ° C to about 37 ° C for about 12 to about 24 hours. At the completion of the reaction, the amide is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like. Alternatively, the N-sulfonyl amino acid IV can be converted into an acid halide and the acid halide coupled with the amino acid derivative VI to provide an amide. The VI acid halide can be prepared by contacting VI with an inorganic acid halide, such as thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride or, preferably, with oxalyl chloride under conventional In general, this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at a temperature in the range of about 0 °. C at about 80 ° C for about 1 to about 48 hours. A catalyst, such as DMF, can also be used in this reaction. The N-sulfonyl amino acid IV acid halide is then contacted with at least one equivalent, preferably about 1.1 to about 1.5 equivalents of amino acid derivative VI in an inert diluent, such as dichloromethane, at a temperature ranging from about -70 ° C to about 40 ° C for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to clean the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethyl amine, 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 amide is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like. Alternatively, the amide intermediates wherein Q is -C (0) NH- can be prepared by first forming a diamino acid derivative of formula VII: wherein R2, R3, R5 and R6 are as defined herein.

The diamino acid derivatives of formula VII can be readily prepared by coupling an amino acid of formula II with an amino acid derivative of formula VI using conventional amino acid coupling techniques and reagents, such carbodiimides, BOP reagent and the like, described above. The diamino acid VII can then be sulfonated using a sulfonyl chloride of formula III and using the synthesis methods described above to provide an amide. The amino acid derivatives of formula VI used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthesis process. For example, the amino acid derivatives of formula VI can be prepared by the C-alkylation of commercially available diethylamide 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with an alkyl or substituted alkyl halide. This reaction is commonly conducted by treating diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl halide or substituted alkyl in ethanol at reflux for about 6 to about 12 hours. The resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, commonly as the hydrochloride salt. Examples of amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-tyrosine methyl ester, L-3 methyl ester, 5-diiodotyrosine, L-3 methyl ester iodotyrosine, β- (4-hydroxy-naphthyl-1-yl) -L-alanine methyl ester, β- (6-hydroxy-naphthyl-2-yl) -L-alanine methyl ester and the like. If desired, of course, other esters or amides of the compounds described above may also be employed. In another embodiment, compounds of formula I / IA wherein Q is -CH (OH) C (O) NH- are readily prepared by coupling an α-hydroxy carboxylic acid of formula IVa: with an amino acid derivative of Formula VI using the reagents and coupling procedures described above. The α-hydroxycarboxylic acids of formula IVa are either commercially available or can be prepared from readily available starting materials using conventional reagents and reaction conditions well known to those skilled in the art. Additionally, in another preferred embodiment, compounds of formula I / IA, where Q is -C (0) N (0) - are readily prepared by coupling an N-hydroxy amino acid of formula IV with an H-hydroxy amino acid of formula IVb: wherein R5 and R6 are as defined in qOpresent, using the reagents and coupling procedures described above. The N-hydroxy amino acid of formula IVb can be prepared from corresponding amino acid derivatives of formula IV, wherein R6 is OH, by reaction with sodium nitrite and sodium bromide in aqueous sulfuric acid, diluted (commonly 2.5 N), followed by ~ ¿- - Sa treatment with hydroxylamine. Commonly, this reaction is conducted by first contacting an IV solution and excess potassium bromide in 2.5 N sulfuric acid with excess sodium nitrite at 0 ° C for about 0.25 to 0.5 hours and then at room temperature for 1 hour. The product is then esterified using thionyl chloride and methanol under standard conditions to form the methyl ester. The methyl ester is then immediately contacted with hydroxylamine in methanol and the reaction mixture is heated to reflux for 6 to 24 hours to give the N-hydroxyamino acid of formula IVb. Even in another preferred modality, compounds of formula I / IA where Q is -NHC (0) NH- are readily prepared by contacting an N-sulfonyl amino acid of formula IV with an equimolar amount of diphenylphosphoryl azide in an inert solvent, such as toluene, followed by treatment with a trialkylamine, such as triethylamine, to form the corresponding isocyanate. The intermediate isocyanate, in general, is not isolated, but is reacted in situ with an amino acid derivative of formula VI to give the urea. This reaction is commonly conducted at about 80 ° C for about 6 to about 24 hours to provide the urea. In yet another preferred embodiment, compounds of formula I / IA where Q is -CH (R8) NR7- are conveniently prepared by the reductive alkylation of an amino acid derivative of formula VI using a carbonyl compound of formula IVc: using reagents and reducing, conventional alkylation conditions. Commonly this reaction is conducted by contacting the amino acid derivative VI with an excess of IVc, preferably with 1.1 to 2 equivalents of IVc and an excess, preferably 1.1 to 5 equivalent, of a reducing agent, such as cyanoborohydride. sodium. In general, this reaction is conducted in an essentially inert diluent such as methanol, at a temperature ranging from about 0 ° C to about 50 ° C, preferably at room temperature, for about 0.5 to 3 hours to give the desired product. For ease of synthesis, the compounds of formula I are commonly 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 conventional conditions and reagents to provide the corresponding carboxylic acid. Commonly, this reaction is conducted by treating the ester with at least one equivalent of a metal hydroxide alkaline, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperature ranging from about 0 ° C to about 24 ° C for about 1 to about 12 hours . Alternatively, the benzylic esters can be separated 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, hydroxyamine such as hydroxylamine and N-hydroxysuccinimide, alkoxyamines and substituted alkoxyamines such as O-methylhydroxylamine and O-benzylhydroxylamine and the like, using Conventional coupling conditions and reagents As described above. As will be apparent to those skilled in the art, other functional groups present in any of the substituents of the compounds of formula I can be easily modified or derived either before or after the coupling reactions described above, using well-known synthesis methods . For example, a nitro group present on a substituent on a compound of formula I or an intermediate thereof, can be easily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group . This reaction is commonly conducted at a temperature of about 24 ° C to about 50 ° C for about 6 to about 24 hours in an inert diluent, such as methanol. Compounds having a nitro group on the substituent R5 can be prepared, for example, by 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 platinum catalyst, such as platinum oxide, in a diluent to acidic, to provide the corresponding piperidinyl analog. In general, this reaction is conducted by treating the pyridine compound, with hydrogen at a pressure ranging from about 1.4 Kg / cm2 (20 psi) to about 4.22 Kg / cm2 (60 psi), preferably about 2.81 Kg / cm2 ( 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 easily prepared by using, for example, β- (2-pyridyl) -, β- (3-pyridyl) - or β- (4-pyridyl) -L-alanine derivatives in the reactions of coupling described above.

In addition, when the R5 substituent of a compound of formula I or an intermediate thereof, contains a primary or secondary amino group, such amino groups may be further derivatized either before or after the above coupling reactions to provide, by way of example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like. Compounds having a primary amino group on the substituent R5 can be prepared, for example, by reduction of the corresponding nitro compound as described above. Alternatively, such compounds can be prepared by using an amino acid derivative of formula VI derived from lysine, 4-aminophenylalanine and the like, in the coupling regions described above. By way of illustration, a compound of formula I or an intermediate thereof, having a substituent having a primary or secondary amino group, such as where R 5 is a (4-aminophenyl) methyl group, can be easily N-acylated using reagents and conventional acylation conditions to provide the corresponding amide. This acylation reaction is commonly 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 ^ Mám? coupling reagent, such as a carbodiimide, BOP reagent, (benzotriazol-1-yloxy-tri (dimethylamino) phosphonium hexafluoro-phosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N, N dimethylformamide and the like, at a temperature ranging from about 0 ° C to about 37 ° C for about 4 hours to about 24 hours. Preferably, a promoter, such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and the like, is used to facilitate the acylation reaction. Examples of suitable carboxylic acids for use in this reaction include, but are not limited to, N-tert-butoxycarbonylglycine, N-tert-butyloxycarbonyl-1-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, acid benzoic acid, N-tert-butyloxycarbonylisonipecic acid, N-methylisonipecotic acid, N-tert-butyloxycarbonylpecic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N- (toluene-4-sulfonyl) -L-proline and similar. Alternatively, a compound of formula I or an intermediate thereof, which contains a primary or secondary amino group may be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide. This reaction is commonly conducted by contacting the amino compound with at least one ^^^^^^^^^ equivalent, preferably about 1.1 to about 1.2 equivalents of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperature ranging from about -70 ° C to about 40 ° C for about 1 to about 24 hours. If desired, an acylation catalyst such as 4- (N, N-dimethylamino) pyridine can be used to promote the acylation reaction. The acylation reaction is preferably conducted in the presence of a suitable base to clean the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines such as triethyl amines, diisopropylethylamine such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Alternatively, the reaction can be conducted under Schotten-Baumann type conditions using aqueous alkali, such as sodium hydroxide and the like. Examples of acyl halide 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, chloride. of 2-methylbenzoyl, 2-trifluoromethylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, . u ^ M- picolinoyl, acetic anhydride, succinic anhydride and the like. Carbamyl chlorides, such as N, N-dimethylcarbamyl chloride, N, N-diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas. Similarly, bicarbonates, such as tert-butyl bicarbonate, can be employed to provide carbamates. In a similar manner, a compound of formula I or an intermediate thereof, which contains a primary or secondary amino group can be N-sulfonated to form a sulfonamide using a sulfonyl halide and a sulfonic acid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction, include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride and the like. Similarly, sulfamoyl chlorides, such as dimethylsulfanoyl chloride, can be used to provide sulfamide (eg, > N-S02-N <). Additionally, a primary and secondary amino group present on a substituent of a compound of formula I or an intermediate thereof, can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea respectively. This reaction commonly on0m (5Ua-i is conducted by contacting the amino compound *--*" you.. minus one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperature ranging from about 24 ° C to about 37 ° C for about 12 to about 24 hours . The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from compounds, commercially available using well-known synthesis methods. For example, isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thiisocyanate 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. of methyl, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3- (N, N-dimethylamino) propyl 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 commonly conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalent, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent. , such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature ranging from about 0 ° C to about 50 ° C for about 1 to about 72 hours. Suitable aldehydes and ketones for use in this reaction include, by way of example, benzaldehyde, 4-chloro-benzaldehyde, valeraldehyde and the like. In a similar manner, when a compound of formula I or an intermediate thereof, has a substituent containing a hydroxyl group, the hydroxyl group can be modified or further derivated either before or after the coupling reactions to provide as a example, ethers, carbamates and the like. Compounds having a hydroxyl group on the R5 substituent, for example, can be prepared using an amino acid derivative of formula VI derived from tyrosine and the like, in the regions described above.

By way of example, a compound of formula I or an intermediate thereof having a substituent containing a hydroxyl group, such as where R 6 is a (4-hydroxyphenyl) methyl group, can be easily O-alkylated to form ethers. This O-alkylation reaction is commonly conducted by contacting the hydroxy compound with a suitable alkaline or alkaline earth metal base, such as potassium carbonate in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali metal or alkaline earth salt of the hydroxyl group. This salt, in general, is not isolated, but is reacted in situ with at least one equivalent of an alkyl or substituted alkyl halide or sulfonate, such as an alkyl chloride, bromide and oduro, mesylate or tosylate, for give the ether. In general this reaction is conducted at a temperature ranging from about 60 ° C to about 150 ° C for about 24 to about 72 hours. Preferably, a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is employed in the reaction. Examples of alkyl or substituted alkyl halides and sulfonates, suitable for use in this reaction, include but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl-bromophenylacetate, 2- (N-ethyl-N-phenylamino) ethyl chloride, 2- (N, N-ethylamino) chloride ethyl, 2- (N, N-diisopropylamino) ethyl chloride, 2- (N, N-dibenzylamino) ethyl chloride, 3- (N, N-ethylamino) propyl chloride, 3- (N-benzyl) chloride N-methylamino) propyl, N- (2-chlorophenyl) morpholine, 2- (hexamethyleneimino) ethyl chloride, 3- (N-methylpiperazin) propyl chloride, 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine, 2- (4-hydroxy-4-phenylpiperidine) ethyl chloride, N-tert-butyloxycarbonyl-3-piperidinmethyl tosylate and the like. Alternatively, a hydroxyl group present on a substituent of a compound of formula I or an intermediate thereof, may be O-alkylated using the Mitsonobu reaction. In this reaction, an alcohol, such as 3- (N, N-dimethylamino) -1-propanol and the like, is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in a 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-butyltyrosine 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 48 hours to provide the O-alkylated product. In a similar manner, a compound of formula I or an intermediate thereof containing an aryl hydroxy group can be reacted with an aryl iodide to provide a diaryl ether. In general, this reaction is 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 -25 ° C to about 10 ° C. The salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperature ranging from about 10 ° C to about 30 ° C for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like. The reaction is then heated to about 70 ° C to about 150 ° C for about 2 to about 24 hours to provide the diaryl ether. Additionally, a hydroxy-containing compound can also be easily derivatized to form a carbamate. In a method for preparing such carbamates, a hydroxy compound of formula I or an intermediate thereof ^ U = U 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 approximately 2.0 hours. Treatment of the resulting carbonate with an excess, 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, morpholine, thiomorpholine, pyrrolidine, piperidine and the like. Alternatively, in another method for preparing carbamates, a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent such as dichloromethane, at a temperature ranging from about 25 ° C to about 70 ° C for about 2 to about 72 hours. Commonly, this reaction is conducted in the presence of a suitable base to clean the acid generated during the reaction.

Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like. Additionally, at least one equivalent (based on the hydroxy compound) of 4- (N, N-dimethylamino) pyridine is preferably added to the reaction mixture to facilitate the reaction. Examples of carbamyl chloride suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like. Likewise, when a compound of formula I or an intermediate thereof contains a primary or secondary hydroxyl group, such hydroxyl groups can be easily converted to a leaving group and displaced to form, for example, amine, 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 the nucleophilic displacement of the derivatized hydroxyl group. In general, when a chiral compound is employed in these reactions, the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is commonly reversed. These reactions are commonly conducted by first converting the hydroxyl group to a leaving group, such as a tosylate, by treating the hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-toluenesulfonyl chloride and the like, in pyridine. . In this reaction, it is conducted, in general, at a temperature from about 0 ° C to about 70 ° C for about 1 to about 48 hours. The resulting tosylate can then be easily displaced with 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, a temperature ranging from about 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the corresponding azido compound. The azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino compound (-NH2). Similarly, a tosylate group can be easily displaced by a thiol to form a sulfide. This reaction is commonly conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene ( DBU), in an inert diluent, such as N, N-dimethylformamide, at a temperature from about 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the sulfide. Additionally, the treatment of a tosylate with morpholino-sulfur trifluoride in an inert diluent, such as dichloromethane, at a temperature ranging from about 0 ° C to about 37 ° C for about 12 to about 24 hours gives the corresponding fluoro compound. In addition, a compound of formula I or an intermediate thereof having a substituent containing an iodoaryl group, for example, when R 5 is a (4-iodophenyl) methyl group, can easily be converted either before or after the reactions of previous coupling to a biaryl compound. Commonly, this reaction is conducted to treat 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 until the completion of the reaction. This reaction is further described, for example, in Rieke, J. Org. Chem. 1991, 56, 1445. In some cases, the compounds of formula I or intermediates thereof may contain substituents having one or more sulfur atoms. Such sulfur atoms will be present, for example, when the amino acid of formula II used in the above reactions is derived from L-thiazolidin-4-carboxylic acid, L- (5,5-dimethyl) thiazolidin-4-carboxylic acid, L-thiomorpholine-3-carboxylic acid and the like. When present, such sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions. Suitable reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like. The oxidation reaction is commonly conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperature ranging from about 50 ° C to about 75 ° C. approximately 1 to approximately 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and the like. Alternatively, the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. Such reactions are further described in March, "Advanced Organic Chemistry", 4a. Ed., Pp. 1201-1202, Wiley Publisher, 1992. As described above, compounds of 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 coupling reactions described above. Alternatively, such compounds can be prepared by the N-alkylation of a sulfonamide of formula I or IV (where R2 is hydrogen) using conventional synthesis methods. Commonly, 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 carbonate of potassium, 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 they are not limited to and oduro of methyl and similar. Additionally, the sulfonamides of formula I to 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 commonly conducted by treating 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 an inert diluent, such as tetrahydrofuran, at a temperature ranging from about 0 ° C to about 30 ° C for about 2 to about 48 hours to give the cyclized 1,2-benzisothiazol-3-one derivative. Finally, the compounds of formula I wherein Q contains a thiocarbonyl group (C = S) can be prepared by using an amino thionoacid derivative in place of the amino acid II in the synthetic processes described above. Such amino thioacid derivatives can be prepared by the methods described in Shalaky et al., J. Org. Chem., 61: 9045-9048 (1996) and Brain, et al., J. Org. Chem., 62: 3808-3809 (1997) and references cited therein.

Pharmaceutical Formulations When used as pharmaceutical substances, the compounds of formulas I and IA are usually administered in the form of 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 containing, as the active ingredient, one or more of the compounds of formula I and IA previously associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier such that it 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, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example , up to 10% by weight of the active compound, soft or hard gelatine capsules, suppositories, sterile injectable solutions and sterile packaged powders. In the preparation of a formulation, it may be necessary to grind the active compound to provide the appropriate particle size before combining with the other ingredients. If the active compound is substantially insoluble, it is commonly ground to a mesh particle size of less than 200. If the active compound is substantially soluble in water, the particle size is usually adjusted by milling 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, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone , cellulose, water, syrup and methyl cellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsification and suspension agents; preservatives such as methyl- and propyl-hydroxybenzoates; sweetening agents; flavoring agents. The compositions of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions are preferably formulated in a unit dosage form, each dose containing from about 5 to about 100 mg, more usually, about 10 to about 30 mg of the active ingredient. The term "unit dose forms" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. . The active compound is effective over a wide range of doses and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound actually administered will be determined by a doctor or practitioner, in view of the relevant circumstances, which include the condition to be treated, the selected route of administration, the actual compound administered., the age, weight and response of the individual patient, the severity of the patient's symptoms and the like. For the preparation of 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 homogeneous preformulation compositions, it is understood that the active ingredient is uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dose forms such as tablets, pills and capsules. . This solid preformulation is then subdivided into unit dosage forms of the type described above, which contain, for example, 0.1 to about 500 mg of the active ingredient of the present invention. The tablets and pills of the present invention can be coated or otherwise compounded to provide a dosage form that gives the long-acting advantage. For example, the tablet or pill may comprise an internal dosage and an external dosage component, the latter being in the form of a wrapper over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allow the inner component to pass intact to the duodenum or be delayed in release. A variety of materials can be used for such enteric coatings or coatings, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as lacquer, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention can be incorporated for oral administration or by injection include suitably flavored syrups in aqueous solutions, aqueous or oily suspensions and emulsions flavored with edible oils such as oils, cottonseed. , sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation including solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for the local or systemic effect. Preferably, compositions in pharmaceutically acceptable solvents can be nebulized by the use of inert gases. The nebulized solutions can be breathed directly from the nebulization device or the nebulization device can be attached to a face mask chamber, or a positive pressure, intermittent breathing machine. The compositions in solution, suspension or powder can be administered, preferably orally or nasally, from devices that supply the formulation in an appropriate manner. The following formulation examples illustrate the pharmaceutical compositions of the present invention.

Formulation Example 1 Hard gelatin capsules are prepared containing the following ingredients: 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 tablet formula is prepared using the ingredients set forth below: Ingredient Quantity (mg / tablet) Active ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal Silicon Dioxide 10.0 Stearic Acid 5.0 The components are mixed and compressed to form tablets, each one that weighs 240 mg.

Formulation Example 3 A dry powder inhaler formulation is prepared which contains the following components: Ingredient% by weight Active ingredient 5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a dry powder inhalation device.

Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows: Ingredient Quantity (mg / tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as a 10% solution in water ) Carboxymethyl sodium 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 No. 20 mesh American sieve and mixed thoroughly. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a North American 16 mesh screen. The granules thus produced are dried at 50 ° C at 60 ° C and passed through a North American 16 mesh screen. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 30 mesh American sieve, are then added to the granules which, after mixing, are compressed on a tablet forming machine to produce tablets each one that weighs 150 mg.

Formulation Example 5 Capsules, each containing 40 mg of drug, are made as follows: Ingredient Amount 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 stearate of magnesium are mixed, passed through a No. 20 mesh American sieve and filled into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6. Suppositories, each containing 25 mg of active ingredient, are made as follows: Ingredient Quantity Active ingredient 25 mg Saturated fatty acid glycerides at 2,000 mg The active ingredient is passed through a North American mesh screen No. 60 and suspended in the saturated fatty acid glycerides previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7 Suspensions, each containing 50 mg of medication per 5.0 ml dose, are made as follows: Ingredient Quantity Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 mg Sodium Benzoate 10.0 mg Flavoring and coloring cbp Purified Water at 5.0 ml The drug, sucrose and xanthan gum are mixed, passed through a No. 10 mesh American sieve and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavoring and coloring are diluted with some water and added with agitation. Then enough water is added to produce the required volume.

Example of formulation 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 and magnesium stearate are mixed, passed through a North American mesh sieve No 20 and filled in hard gelatine capsules in quantities 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 10 Formulation example 10 A topical formulation can be prepared as follows: Ingredient Quantity 15 Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g Soft white paraffin at 100 g White soft paraffin is heated until it melts. The liquid paraffin and the emulsifying wax are incorporated and agitated until they dissolve. The active ingredient is added and the stirring is continued until it disperses. The mixture is then cooled until it becomes solid. to sa ^ ».

Another preferred formulation employed in the methods of the present invention employs 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 transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Patent No. 5,023,256 issued June 11, 1991, incorporated herein by reference. Such patches can be constructed for the continuous, pulsatile or on-demand supply of pharmaceutical agents. Direct and indirect placement techniques can be used when it is desirable or necessary to introduce the pharmaceutical composition to the brain. Direct techniques usually involve the placement of a drug delivery catheter into the host ventricular system to cross the blood-brain barrier. Such an implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent No. 5,011,472, which is incorporated herein by reference. Indirect techniques, which are generally preferred, usually involve the formulation of Here are compositions for providing drug latency by converting hydrophilic drugs to liquid soluble drugs. Latency is achieved, in general, through the blocking of the hydroxy, carbonyl, sulfate and primary amine groups present in the drug to make the drug more soluble in lipid and treatable for transportation through the blood-brain barrier. Alternatively, the supply of hydrophilic drugs can be increased by the intra-arterial infusion of hypertonic solutions that can open the blood-brain barrier transiently.

Utility The compounds of this invention can be used to bind VLA-4 (a4β integrin) in biological samples and thus have utility in, for example, the analysis of such samples for VLA-4. In such analyzes, the compounds can be bound or 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 interlaced ELISA assay. Alternatively, labeled VLA-4 can be used in a competitive analysis to measure the presence of VLA-4 in the sample. Other suitable analyzes are well known in the art.

In addition, some of the compounds of this invention inhibit, in vivo, the adhesion of leukocytes to endothelial cells mediated by VLA-4 and thus, 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 (which includes acute juvenile onset diabetes), inflammatory bowel disease (which includes ulcerative colitis and Crohn's disease). , multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, cerebrovascular accident and other traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury, such as that which occurs in respiratory distress syndrome in adults. The biological activity of the compounds identified above can be analyzed in a variety of systems. For example, a compound can be immobilized on a solid surface and the adhesion of cells expressing VLA-4 can be measured. Using such formats, large numbers of compounds can be classified. Suitable cells for this analysis include any of the known leukocytes expressing VLA-4 such as B cells, monocytes, eosinophils and basophils.

A number of leukocyte cell lines can also be used, examples include Jurkat and U937. Test compounds can also be tested for the ability to competitively inhibit the binding between VLA-4 and VCAM-1, or between VLA-4 and a known, labeled compound that binds VLA-4 such as a compound of this invention or antibodies to VLA-4. In these analyzes, VCAM-1 can be immobilized on a solid surface. VCAM-1 can also be expressed as a recombinant fusion protein having an Ig tail (for example IgG), so that the binding to VLA-4 can be detected in an immunoassay. Alternatively, cells expressing VCAM-1 such as activated endothelial cells or fibroblasts transfected with VCAM-1 can be used. For analyzes to measure the ability to block adhesion to brain endothelial cells, the analyzes described in the international patent application, publication No. WO 91/05038 are particularly preferred. This application is incorporated herein by reference in its entirety. Many analysis formats employ marked analysis components. Dialing systems can be in a variety of forms. The tag or tag can be coupled directly or indirectly to the desired component of the assay according to methods well known in the art. A wide variety of brands or labels can be used. The component can be labeled by any of the various methods. The most common method of detection is the use of autoradiography with compounds marked with 3 H, 125 I, 35 S, 1 C or 32 P or the like. Non-radioactive labels or tags include ligands that bind to labeled antibodies, fluorophores, chemiluminescent agents, enzymes, and antibodies that can serve as specific binding members for a labeled ligand. The selection of the brand or label depends on the required sensitivity, ease of conjugation with the compound, stability requirements and available instrumentation. Appropriate in vivo models to demonstrate efficacy in the treatment of inflammatory responses include EAE (experimental autoimmune encephalomyelitis) in mice, rats, guinea pigs or primates, as well as other inflammatory models dependent on integrins. Compounds having the desired biological activity can be modified as necessary to provide 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 commonly increases the stability in vivo. Stability can be analyzed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability analyzes have been described (see, for example, Verhoef et al., Eur. J. Drug Metab.Pharmacokinet., 1990, 15 (2): 83-93. A wide variety of labels or labels can be linked to the compounds, which can provide, directly or indirectly, as a detectable signal, Thus, the compounds of the present invention can be modified in a variety of ways for a variety of final purposes while In addition, several reactive sites can be introduced at the termination for binding to particles, solid substrates, macromolecules or the like.The labeled compounds can be used in a variety of in vivo or in vitro applications. Variety of brands or labels can be used, such as radionuclides (for example, radioisotopes that inhibit gamma rays such as technetium-99 or indium-111), fluores cente (for example, fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds and the like. Those skilled in the art will know of other brands or labels suitable for linking to the complexes, or will be able to find out such, using routine experimentation. The linkage of these marks or labels is achieved using standard techniques common to those skilled in the art. In vitro use includes diagnostic applications such as the verification of inflammatory responses by detecting 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 analysis for potential inhibitors of VLA-4 / VCAM-1 interactions. For in vivo diagnostic imaging to identify, for example, sites of inflammation, radioisotopes are commonly used according to well-known techniques. The radioisotopes can be linked to the peptide either directly or indirectly using intermediate functional groups. For example, chelating agents such as diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metal ion radioisotopes. The complexes can also be labeled with a paramagnetic isotope for purposes of in vivo diagnosis, such as in magnetic resonance imaging (MRI) or electronic spin resonance (ESR), both of which are well known. In general, any conventional method for visualizing diagnostic imaging can be used. Usually, radioisotopes that emit gamma rays and positrons are used for camera imaging and paramagnetic isotopes are used for MRI. Thus, the compounds can be used to verify the course of improvement or relief 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 alleviating the disease is effective. The pharmaceutical compositions of the present invention can be used to block or inhibit cell adhesion associated with a number of diseases and disorders. For example, a number of inflammatory disorders are associated with integrins or leukocytes. Treatable disorders include, for example, rejection of transplants (eg, allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), retinitis, cancer metastasis, rheumatoid arthritis, acute leukocyte-mediated lung injury (eg, respiratory distress syndrome in adult), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease (including Crohn's disease and Ulcerative colitis) . In preferred embodiments, the pharmaceutical compositions are used to treat inflammatory disorders of the brain, such as multiple sclerosis (MS), viral meningitis and encephalitis. Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn's disease and ulcerative colitis. Crohn's disease is an inflammatory, ulceroconstrictive, chronic, ideopathic disease, characterized by the clearly delimited and commonly transmural involvement of all the layers of the intestinal wall by means of a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and / or colon. Ulcerative colitis is an inflammatory response largely limited to the mucosa and colon submucosa. Lymphocytes and macrophages are abundant in inflammatory bowel disease lesions that may contribute to inflammatory injury. Asthma is a disease characterized by increased sensitivity of the tracheobronchial tree to several stimuli that increase the paraoximal constriction of the bronchial airways. The stimuli cause the release of several inflammation mediators of IgE-coated mast cells that include stamina, eosinophilic and neutrophilic chemotactic factors, leukotrienes, prostaglandin and platelet activation factor. The release of these factors provides basophils, eosinophils and neutrophils, which cause inflammatory lesions. Atherosclerosis is a disease of the arteries (for example, coronary, carotid, aorta and iliac). The basic lesion, the atoroma, consists of a focal plate in relief inside the intima, which has a lipid nucleus and a fibrous covering layer. Atheromas jeopardize Artereal blood flow and affected, weakened arteries. Myocardial and cerebral infarcts are a major consequence of this disease. Macrophages and leukocytes are supplied to atheromas and contribute to the inflammatory lesion. Rheumatoid arthritis is a recurrent, chronic inflammatory disease that mainly causes deterioration and destruction of the joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but can then involve the wrists, elbows, ankles and knees. Arthritis results from the interaction of synovial cells with leukocytes that infiltrate the circulation to the synovial lining of the joints. See, for example, Paul, Immunology (3rd Edition, Raven Press, 1993). Another indication for the compounds of this invention is in the treatment of organ or graft rejection mediated by VLA-4. Through recent years, there has been a considerable improvement in the efficiency of surgical techniques for the transplantation of tissues and organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow. Perhaps the main outstanding problem is the lack of satisfactory agents to induce immunotolerance in the allograft receptor or transplanted organ. When allogenic cells or organs are transplanted into a bone (ie, the donor and the donee are different individuals of the same species), the host's immune system is likely to mount an immune response to foreign antigens in the transplant (host disease) -contra-graft) which leads to the destruction of the transplanted tissue. CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues. The compounds of this invention that bind alpha-4-integrin are useful, inter alia, to block the immune responses induced by the alloantigen in the donee, in order to prevent such cells from participating in the destruction of the tissue or organ. -átßíí-fit-t transplanted. See, for example, Paul et al, Tranplant International 9, 420-425 (1996); Georczynski et al., Immunology 87,573-580 (1996); Georcyznski et al., Transplant. Immunol. 3.55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994). A related use for the compounds of this invention that bind to VLA-4 is in the modulation of the immune response involved in the "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 a halogeneic receptor. In this situation, the immunocompetent cells of the donor can attack the tissues in the receiver. The tissues of the skin, epithelium of intestines and liver are frequent targets and can be destroyed during the course of GVHD. The disease presents a particularly severe problem when immune tissue is being transplanted, such as in bone marrow transplantation; but less severe GVHD has also been reported in other cases, including heart and liver transplants. The therapeutic agents of the present invention are used, inter alia, to block the activation of donor T cells to thereby interfere with the ability to cause lysis of target cells in the host.

An additional use of the compounds of this invention is the inhibition of tumor metastasis. Several tumor cells have been reported to express VLA-4 and compounds that bind VLA-4 to block adhesion of such cells to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13, 47-52 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994). 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 believed to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating covering that covers the nerve fibers. In an animal model for multiple sclerosis, murine monoclonal antibodies directed against VLA-4 are shown to block the adhesion of leukocytes to the endothelium and thus prevent inflammation of the central nervous system and subsequent paralysis in animals16. The pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Formulations suitable for use in the present invention are found in Remington's Pharmaceutical Sciences, Philadelphia Mace Publishing Company, P.A. 17a. Edition (1985). In order to increase the half-life period in the serum, the compounds can be encapsulated, introduced into the liposome lumen, prepared as a colloid, or other conventional techniques can be employed which provide a prolonged serum half-life of the compounds A variety of methods are available for the preparation of liposomes, as described in, for example, Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference. The amount administered to the patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or therapy, the patient's condition, 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 partially arrest the symptoms of the disease and its complications. An adequate amount to accomplish this is defined as "therapeutically effective doses". The effective amounts for this use will depend on the condition of the disease being treated as well as on the criteria of the attending clinician 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 can be filtered for sterilization. The resulting aqueous solutions can be packaged for use as they are or freeze-dried, the lyophilized preparation being combined with a sterile aqueous carrier before administration. The pH of the compound preparations will commonly be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that the use of some excipients, carriers or prior 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 made, the manner of administration of the compound, the health and condition of the patient and the judgment of the physician or practitioner. that prescribes. For example, for intravenous administration, the dose will commonly be in the range of about 20 mg to about 500 ig per kilogram of body weight, preferably from about 100 ig to about 300 ig per kilogram of body weight.

The dose ranges suitable for intranasal administration in general are from about 0.1 pg to 1 mg per kilogram of body weight. Effective doses can be extrapolated from dose / response curves derived from in vitro or animal model test systems. The following synthetic and biological examples are presented to illustrate the invention and are not to be considered in any way as limiting the scope of this invention. Unless stated otherwise, all temperatures are in degrees Celsius.

EXAMPLES In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. aq or aq. aqueous AcOH acetic acid bd broad doublet bm broad multiplet bs broad singlet Bn benzyl Boc tert-butoxycarbonyl-N Boc20 = di-tert-butyl BOP = benzotriazol-1-iloxi- tris (dimethylamino) phosphonium hexafluorophosphate Cbz = carbobenzyloxy CHC13 = chloroform CH2C12 = dichloromethane (COCI) 2 = oxalyl chloride d = doublet dd = doublet of doublet dt = doublet of triplets DBU = 1,8-diazabi- cyclo [5.4.0] undec-7-ene DCC = 1, 3- dicyclohexylcarbodiimide DMAP = 4-N, N-dimethylaminopyridine DME = ethylene glycol dimethyl ether DMF = dimethylformamide DMSO = dimetiisulfóxido hydrochloride EDC = l- (3-dimethyl tilaminopropil) -3-ethylcarbodiimide hydrochloride Et3N = triethylamine rflí-MI-É- Et20 diethyl ether EtOAc ethyl acetate EtOH ethane eq or eq. equivalent Fmoc N- (9-fluorenylmethoxycarbonyl) FmocONSu N- (9-fluorenylmethoxycarbonyl) -succinimide g gram h hour H20 water HBr hydrobromic acid HCl hydrochloric acid HOBT 1-hydrate hydroxy- benzotriazole hr hour K2C03 potassium carbonate Liter m multiplet MeOH methanol mg milligram MgSO4 magnesium sulfate ml milliliter mm millimeter mM millimolar mmol millimol mp melting point N normal NaCl sodium chloride Na2C02 sodium carbonate NaHCO3 sodium bicarbonate NaOEt sodium ethoxide NaOH sodium hydroxide NH4C1 ammonium chloride NMM N-methylmorpholine Phe L-phenylalanine Pro L-proline psi pounds / square inch Pt02 platinum oxide quint quartet. quintet rt room temperature s singlet sat saturated t triplet t-BuOH tert-butanol TFA trifluoroacetic acid THF tetrahydrofuran TLC or tic thin layer or thin layer chromatography Ts = tosyl TsCl = tosyl chloride TsOH = tosylate iL = microliter In the later examples, all temperatures are in degrees Celsius (unless otherwise indicated). The following methods were used to prepare the exposed compounds afterwards as indicated.

Method 1 N-Tosylation Procedure The N-tosylation of the appropriate amino acid was conducted via the method of Cupps, Boutin and Rapoport J. Org. Chem. 1995, 50.3972.

Method 2 Methyl ester preparation procedure Methyl amino acid esters were prepared using the method of Brenner and Huber Helv. Chem. Acta 1953, 36,1109.

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

Method 4 Hydrogenation Procedure I Hydrogenation was performed using 10% palladium on carbon (10% by weight) in methanol at 2.1 Kg / cm2 (30 psi) overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to yield the desired amino compound.

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

Method 6 Ester II Hydrolysis Procedure To a cooled THF / H20 (0 ° C) solution (2: 1, 5-10 ml) of the appropriate ester was added LiOH (1.1 equivalents). The temperature was maintained at 0 ° C and the reaction was completed 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 Ester III Hydrolysis Procedure The appropriate ester was dissolved in dioxane / H20 (1: 1) and 0.9 equivalents of 0.5 N NaOH were added. The reaction was stirred for 3-16 hours and then concentrated. The resulting residue was dissolved in H20 and extracted with ethyl acetate. The aqueous phase was lyophilized to yield the desired carboxylate sodium salt.

Method 8 Sulfonylation Procedure I To the appropriately protected aminophenylalanine analogue (11.2 mmol), dissolved in methylene chloride (25 ml) and cooled to -78 ° C, the desired sulfonyl chloride (12 mmol) was added. ) followed by the dropwise addition of pyridine (2 Ml). The solution was allowed to warm to room temperature and stirred for 48 hours. The reaction solution was transferred to a 250 ml separatory funnel with methylene chloride (100 ml) and extracted with 1 N HCl (50 ml x 3), brine (50 ml) and water (100 ml). The organic phase was dried (MgSO 4) and the solvent was concentrated to yield the desired product.

Method 9 Reductive Amination Procedure The 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 Separation Procedure Anhydrous hydrochloride (HCl) gas was bubbled through a methanol solution of the appropriate BOC-amino acid ester at 0 ° C for 15 minutes and the reaction mixture was stirred for 3 hours. The solution was concentrated to a syrup and dissolved in Et20 and reconcentrated. This procedure was repeated and the resulting solid was placed under high vacuum overnight.

Method 11 Hydrolysis Procedure of Ester Tert-Butyl I The tert-butyl ester was dissolved in Ch 2 Cl 2 and treated with TFA. The reaction was complete in 1-3 hr, at which time the reaction mixture was concentrated and the residue was dissolved in H20 and lyophilized to yield the desired acid.

Method 12 Coupling procedure of EDC IA a solution in CH2C12 (5-20 ml) of N- (toluene-4-sulfonyl) -L-proline (1 equivalent), mixed in appropriate amino acid ester hydrochloride (1 equivalent) , N-methylmorpholine (1.1-2.2 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 rise to room temperature and was stirred overnight. The reaction mixture was poured into H20 and the organic phase was washed with sat. NaHC03, brine, dried (MgSO4 or Na2SO), filtered and concentrated. The crude product was purified by column chromatography.

Method 13 Coupling Procedure of EDC III To a solution in DMF (5-20 ml) of the appropriate N-protected amino acid (1 equivalent), the appropriate amino acid ester hydrochloride (1 equivalent), Et3N (1.1 equivalent) and 1 were mixed. -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 rise to room temperature and was stirred overnight. The reaction mixture was partitioned between EtOAc and H20 and the organic phase was washed with 0.2 N nitric acid, H20, sat NaHC03, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. column chromatography or preparative TLC.

Method 14 Sulfonylation procedure II The appropriate sulfonyl chloride was dissolved in CH2C12 and placed in an ice bath. L-Pro-L-Phe-OMe * HCl (1 equivalent) and Et 3 N (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 organic phase was washed with sat. NaHCO3, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. The crude product was purified by column chromatography or preparative TLC.

Method 15 Sulfonylation procedure III To a solution of L-Pro-L-4- (3-dimethylaminopropyloxy) -Phe-OMe [prepared using in the procedure described in Method 10] (1 equivalent) in CH2C12 was added Et3N (5 equivalents) ) followed by the appropriate sulfonyl chloride (1.1 equivalents). The reaction was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was concentrated, dissolved in EtOAc, washed with NaHCO 3 and 0.2 N citric acid. The aqueous phase was made basic with solid NaHCO 3 and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO 4 or Na 2 SO 4), filtered and concentrated. The crude methyl ester was purified by preparative TLC. The corresponding acid was prepared using the procedure described in Method 7.

Method 16 Hydrogenation Procedure II To a methanol solution (10-15 ml) of the azlactone, NaOAc (1 equivalent) and 10% Pd / C were added. This mixture was placed on the hydrogenator at 2.81 Kg / cm2 (40 psi) H2. After 8-16 hours, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to yield the methyl ester of dehydropeptide. The ester was dissolved in dioxane / H20 (5-10 Ml), to which 0.5 N NaOH (1.05 equivalents) was added. After stirring for 1-3 hours, the reaction mixture was concentrated and the residue was redissolved in H20 and washed with EtOAc. The aqueous phase was made acidic with 0.2 N HCl and the produced was extracted with EtOAc. The combined organic phase was washed with brine (1 x 5 ml), dried (MgSO 4 or Na 2 SO 4), filtered and concentrated to yield the acid as a mixture of about 1: 1 of diastereomers.

Method 17 Tert-Butyl II Ester Hydrolysis Procedure The tert-butyl ester was dissolved in CH2C12 (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 concentrated. The residue was redissolved in H20 and lyophilized to yield the desired product.

Example 1 Synthesis of N- [N- (Toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl] -L-phenylalanine N- (Toluene-4-sulfonyl) -L-prolinol (358 mg, 1.41 mmol) is was taken in 7 ml of dry DMSO, with Et3N (3.0 eq, 590 ml) at room temperature, under N2. In a separate flask, pyridine sulfur trioxide complex (3.0 eq, 660 Mg) in 3 ml of DMSO was cooled to 15 ° C under N2. The prolinol solution was added by syringe to the subsequent reaction mixture and allowed to warm to room temperature. The reaction, after a couple of hours, was emptied into cold brine (10 ml), then extracted with ether (2 x 50 ml). The organic layer was washed with 10% citric acid (25 ml), water, saturated NaHCO 3 (25 ml) and brine. In the filtration and evaporation of the solvent under reduced pressure, the desired prolinal was isolated as a fluffy solid. This was then taken in MeOH (4 ml) with benzyl ester of L-phenylalanine and NaCNBH3 (1.0 eq). the pH was maintained at 6.0, with one drop of AcOH. The reaction mixture was stirred overnight at room temperature. EtOAc was added as well as water and brine. The organic layer was washed several times and dried over MgSO4. In the filtration and evaporation of the solvents under reduced pressure, the crude material was eluted on column chromatography (silica gel) with EtOAc / hexane 1: 1. The ester was diluted in EtOAc / EtOH / water 1: 0.5: 0.5, with a catalytic amount of 10% Pd on C and hydrogenated. After filtration over Celite, the title product was isolated as a white foam. The physical data are as follows: A NMR (300 Mhz, CDC13): 5 = 7.76 (m, 2H), 7.39-7.26 (m, 7H), 4.05 (m, ÍH), 3.92 (m, lH), 3.55- 3.12 (m, 5H), 2.82 (m, lH), 2.38 (s, 3H), 1.55 (m, 3H), 1.25 (m, 2H). Mass spectroscopy: (FAB) 403 (M + H) Example 2 Synthesis of N- [N- (Toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-L-phenylalanine Powdered sodium nitrite (1.27 g) was added portion by portion at 0 ° C to a solution of potassium bromide (4,896 g) and D-phenylalanine (2 g) in 2.5 N sulfuric acid (24.2 ml). The reaction mixture was stirred 20 minutes at 0 ° C Mri-l-Í --- ta followed by 1 hour at room temperature. The product was extracted with ether (3 x 15 ml), the combined organic extract was washed with water, brine, dried over MgSO, filtered and evaporated to dryness in vacuo. The product (2.4 g) was used without further purification in the next reaction. The methyl ester was prepared using thionyl chloride and methanol. This product (2 g) was immediately added to a solution of hydroxylamine in methanol (10 ml). Hydroxylamine was prepared by treating HCL hydroxylamine (1.15 g) in methanol (10 ml) with Na (380 mg). The reaction mixture was heated to reflux overnight, evaporated in vacuo and the residue was partitioned between water and chloroform. The separated organic layer was dried and evaporated. The residue was redivided between 2N HCl and ether. The separated aqueous layer was made basic with NaHCO 3, extracted with chloroform, dried over MgSO 4, filtered and evaporated in vacuo to give 400 mg of N-hydroxyl-L-phenylalanine methyl ester. A carbonyl chloride solution of N- (toluene-4-sulfonyl) -L-proline (412 mg) in THF (10 ml) was added dropwise at 0 ° C to the solution of the product of the last reaction (280 mg) in THF (20 ml) containing triethylamine (145 mg). The mixture was stirred for 1 hour at 0 ° C, one hour at room temperature, then evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The separated organic layer was dried over MgSO 4, filtered and evaporated in vacuo. The residue was flash chromatographed on 30 g of silica gel. Elution with chloroform gave 360 mg of N- [N-toluene-4-sulfonyl] -L-prolinyl] -N-hydroxy-L-phenylalanine methyl ester. The title compound was prepared from the product of the latter reaction (1150 mg) in THF (80 ml) which was immediately treated with IN NaOH (2.57 ml). This mixture was stirred at room temperature overnight. The crystallized product was stirred, washed with ether, dried at 0.1 Torr to yield 750 mg of the title compound, mp 202-204 ° C.

EXAMPLE 3 Synthesis of N- [N- (Toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-D-phenylalanine The title compound was prepared using the procedure described for the preparation of Example 2, substituent L-phenylalanine by D-phenylalanine. The physical data were as follows: MS: [(+) FAB], [M + H] +433.

Example 4 Synthesis of N- [2- (N- (Toluen-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl] -L-4- (N-benzyloxycarbonyl-isonipecotamido) phenylalanine 2- (Hydroxyacetyl) pyrrolidine (J Org Chem. (1991), 56, 1624) was N-tosylated and the resulting product was coupled to Zá ^ ^ the appropriately substituted phenylalanine or using the standard peptide synthesis methodology. The title compound was obtained after basic hydrolysis of the ester, mp 92-95 ° C. The physical data were as follows: MS (+) FAB [M + H] + 707 Example 5 Synthesis of N- [2- (N- (Toluen-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl] -L-4- (isonipecotamido) phenylalanine The product of Example 4 was deprotected by hydrogenation over Pd / C in ethanol for 4 hours. The catalyst was filtered and the filtrate was taken up in water and lyophilized to give 240 mg of a white solid. The physical data were as follows: MS (+) FAB [M + H] +573. Calculated for: C28H36N4O7S * CH3CO2H > < 3H20. C: 48.71; H: 5.73; N: 7.57. Found: C: 48.88; H: 5.58; N: 7.45 Example 6 Synthesis of Acid (2S) -2 [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4-nitrobenzyl) propionic N- methyl ester ( toluene-4-sulfonyl-L-propyl-L- (4-nitro) phenylalanine was mixed with an equimolar amount of PCL5 in dry benzene and stirred for 90 minutes.The yellow solution was treated with a solution of hydrazoic acid in benzene and the mixture was stirred at room temperature for 12 hours, then it was diluted with benzene and washed with saturated NaHCO 3 and brine.The organic layer was dried and evaporated to give a clear yellow foam.The title compound was prepared from the product of the last reaction using basic hydrolysis techniques, standards, to produce a whitish spongy solid, mp 150-160 ° C. The physical data were as follows: MS (+) FAB [M + H] +487.

Example 7 Synthesis of (2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert- butoxycarbonyl isonipecotamido) benzyl) propionic The nitro intermediate described in Example 6 was reduced, dissolved in methylene chloride and mixed with N-Boc-isonipecotic acid, HOBT, refrigerated at 5 ° C and treated with DCC. The reaction mixture was allowed to reach room temperature overnight, filtered, evaporated to dryness and the residue was taken up in ethyl acetate. The organic phase was washed as usual, dried and evaporated to give the title compound, mp 92-102 ° C. The physical data were as follows: MS (+) FAB [M + H] +682.

Example 8 Synthesis of (2S) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonyl isonipecotamido)] benzyl) propionic The title compound was prepared from the product of Example 7 using standard basic hydrolysis techniques, mp 180-180 ° C. The physical data was as follows. MS (+) FAB [M + Li] +674.

Example 9 Synthesis of N- [N- (toluene-4-sulfonyl) pyrrolidin-2-yl] aminocarbonyl] -L-phenylalanine N-tosylproline (1 g, 3.71 mmol) was added to a solution of diphenylphosphoryl azide (1.13 g, 3.71 mmol) in 50 ml of toluene under an argon atmosphere. Triethylamine (394 mg, 3.9 mmol) was added, then the mixture was heated at 80 ° C for 2 hours. L-phenylalanine benzyl ester (1.75 g, 4.1 mmol) and triethylamine (394 mg, 3.9 mmol) were added and heated at 80 ° C overnight. The toluene was removed under reduced pressure and the residue was purified by flash column chromatography (silica, hexane: EtOAc, 2: 1) to give the benzyl ester as a white solid (540 mg, 28%). The benzyl ester was removed by hydrogenation (10% Pd / C, EtOH, 2.81 Kg / cm2, 40 psi, H2). The catalyst was removed and the product was recrystallized with EtOH / Et20 to give the title compound as a white solid (75 mg, 40%). The physical data were as follows: C2? H25N3O5S.0.75 H20. Calculated C: 56.68; H: 6.0; N: 9.44. Found C: 56.94; H: 5.68; N: 9.05. Mass spectroscopy [FAB] [M-H] @ M / Z 430 (100%).

Example A In Vitro Analysis to Determine the Linking of Candidate Compounds to VIA-4 An in vitro analysis was used to estimate the binding of candidate compounds to a4β? integrin. Compounds that link in this analysis can be used to estimate levels of VCAM-1 in biological samples by conventional analyzes (eg, competitive analyzes). This analysis is sensitive to IC5o values as low as approximately InM. The activity of the aß? integrin was measured by the interaction of soluble VCAM-1 with Jurkat cells (e.g., American Type Culture Collection Nos. TIB 152, TIB 153 and CRL 8163), a human T cell line expressing high levels of a4β? integrin. VCAM-1 interacts with the cell surface in a manner dependent on aß? integrin (Yednock, et al., J. Biol. Chem., 1995, 270: 28740). Recombinant soluble VCAM-1 was expressed as a chimeric fusion protein containing the seven extracellular domains of VCAM-1 on the N-terminus and the heavy chain constant region of human IgGi on the C-terminus. The VCAM-1 fusion protein was made and purified by the manner described by Yednock, supra. Jurkat cells were cultured in RPMl 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and vitamin as described by Yednock, supra. Jurkat cells were incubated with 1.5 mM of MnCl2 and 5 ig / ml of antibody 15/7 for 30 minutes on ice. Mn + 2 activates the receptor to increase ligand binding and 15/7 is a monoclonal antibody that recognizes an occupied ligand / activated aßj conformation. integrin and closes the molecule in this conformation to stabilize in this way the interaction of VCAM-l / a4β? integrin. 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 analysis. The cells were then incubated for 30 minutes at room temperature with candidate compounds, in various concentrations ranging from 66 mM to 0.01 iM using a standard 5 point serial dilution. 15 ml 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 goat anti-mouse F (ab ') 2 IgG Fc conjugated with PE (Immunotech, Westbrook, ME) at 1: 200 and incubated on ice in the dark for 30 minutes. Cells were washed twice and analyzed with standard fluorescence activated cell sorter analysis ("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 analysis, each of the compounds in Examples 1-9 have an IC50 of 15 iM or less.

Example B Analysis of in vitro saturation to determine the binding of Candidate Compounds to aB ?. The following describes an in vitro analysis to determine the plasma levels necessary for a compound to be active in the experimental autoimmune encephalomyelitis ("EAE") model, described in the following example, or in other in vivo models. Jurkat logarithmic growth cells are washed and resuspended in normal animal plasma containing 20 mg / ml of antibody 15/7 (described in the previous Example). Jurkat cells are diluted twice in either normal plasma samples containing known amounts of candidate compound in various concentrations ranging from 66 mM to 0.01 μM, using a standard 12-point serial dilution for a standard curve or in samples of plasma obtained from the peripheral blood of animals treated with candidate compound. The cells are then incubated for 30 minutes at room temperature, washed twice with pH regulated saline with phosphate ("PBS") containing 2% fetal bovine serum and 1 mM each of calcium chloride and chloride. of magnesium (analysis medium) to separate the unbound 15/7 antibody. The cells are then exposed to goat F (ab ') 2 anti-mouse IgG Fc conjugated with phycoerythrin (Immunotech, Westbrook, ME), which has been absorbed by some non-specific cross-reactivity by co-incubation with 5% serum. the animal species that is studied, at 1: 200 in incubated in the dark at 4 ° C for 30 minutes.

The cells are washed twice with the analysis medium and resuspended therein. These are then analyzed with a standard fluorescence activated cell sorter analysis ("FACS") as described in Yednock et al. J. Biol. Chem. 1995, 270: 28740. The data are then plotted as fluorescence against dose, for example, in a normal dose-response mode. The dose levels that result in the upper plateau of the curve represent the levels necessary to obtain efficacy in an in vivo model. This analysis can also be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as agßi integrin, which is the integrin most closely related to a4β? (Palmer et al., 1993, J. Cell Bio., 123: 1289). Such binding is predictive of in vivo utility for inflammatory conditions mediated by agßi integrin, which includes, by way of example, hypersensitivity of the airway and occlusion that occurs with chronic asthma, proliferation of smooth muscle cells in atherosclerosis , vascular occlusion after angioplasty, fibrosis and glomerular scarring as a result of renal disease, aortic stenosis, synovial membrane hypertrophy in rheumatoid arthritis, and inflammation and scarring that occurs with the progression of ulcerative colitis and Crohn's disease. Thus, the analysis described above can be performed with a human colon carcinoma cell line, SW 480 (ATTC # CCL 228) transfected with á9 integrin encoding cDNA, (Yokosaki et al., 1994, J. Biol. Chem. , 269: 26691), instead of the Jorkat cell, to measure the binding of the integrin ctgßi. As a control, SW 480 cells expressing other a and Bi subunits can be used. Thus, another aspect of this invention is directed to a method for treating a disease in a mammalian patient, a disease that is mediated by ctgßi and a method comprising administering to the patient a therapeutically effective amount of a compound of this invention. Such compounds are preferably administered in a pharmaceutical composition described hereinabove. The effective daily dosage will depend on the age, weight, condition of the patient, factors that can be easily ascertained by the attending clinician. However, in a preferred embodiment, the compounds are administered from about 20 to 500 μg / Kg per day.

EXAMPLE C In Vivo Evaluation The standard multiple sclerosis model, Experimental Autoimmune (or Allergic) Encephalomyelitis ("EAE"), was used to determine the effect of candidate compounds for reducing motor deterioration in rats or guinea pigs. The reduction in motor deterioration is based on the blocking of adhesion between leukocytes and the endothelium and is correlated with the anti-inflammatory activity in the candidate compound. This model has been previously described by Keszthelyi et al., Neurology 1996, 47: 1053-1059 and measures the delay in onset of the disease. Brains and spinal cords from adult Hartley guinea pigs were homogenized in an equal volume of pH regulated saline with phosphate. An equal volume of Freund's complete adjuvant (100 mg of mycobacterium tuberculosis plus 10 ml of incomplete Freund's adjuvant) was added to the homogenate. The mixture was emulsified by repeatedly circulating it through a 20 ml syringe with a peristaltic pump for approximately 20 minutes. Female Lewis rats (2-3 months of age, 170-220 g) or Hartley rabbits (20 days old, 180-200 g) were anesthetized with isofuran and three injections of the emulsion, 0.1 ml each, were made on each flank. He aSh? M¡¡¡ The start of motor deterioration is observed in approximately 9 days. Treatment with the candidate compound started on day 8, just before the onset of symptoms. The compounds were administered subcutaneously ("SC"), orally ("OP") or intraperitoneally ("IP"). The doses were given in a range of 10 mg / Kg to 200 mg / Kg, proposed, for 5 days with a common dosage of 10 to 100 mg / Kg SC, 10 to 50 mg / Kg PO and 10 to 100 mg / Kg IP. Antibody GG5 / 3 against á4β? integrin (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. The weight of the body and motor deterioration were measured daily.The motor deterioration was classified in the following clinical record: 0 no change 1 weakness or paralysis of the tail 2 weakness of the hind limb 3 paralysis of the hind limb dying or dead A candidate compound was considered active if it delayed the onset of symptoms, for example, produced clinical records no greater than 2 or decreased body weight loss as compared to the control.

Example D Asthma Model Inflammatory conditions mediated by á4β? Integrin include, for example, hypersensitivity of the airway and occlusion that occurs with chronic asthma. The following describes an asthma model that can be used to study the in vivo effects of the compounds of this invention for use in the treatment of asthma. Following the procedures described by Abraham et al., J. Clin. Invest, 93: 776-787 (1994) and Abraham et al, Am J. Respir Crit Care Med, 156: 696-703 (1997), both of which are incorporated by reference in their entirety, the compounds of this invention with formulated in an aerosol and administered to sheep that are hypersensitive to the antigen Ascaris suum. Compounds that decrease antigen-induced early bronchial response and / or block the response of late-base airways, for example, have a protective effect against late responses induced by antigen and airway hypersensitivity ("AHR "), are considered to be active in this model. Allergic sheep that show development of both premature and late bronchial responses to inhaled Ascaris suum antigen are used to study the effects on the respiratory tract of candidate compounds.

After atopic anesthesia of the nasal passages with 2% lidocaine, a balloon catheter is advanced through a window of the nose to the lower esophagus. The animals are then intubated with an endotracheal tube with fold through the other nostril with a flexible fiber optic bronchoscope as a guide. Pleural pressure is estimated according to Abraham (1994). The aerosols (see formulation below) are generated using a disposable medical nebulizer that provides an aerosol with an average mass aerodynamic diameter of 3.2 mm as determined with an Andn cascade impactor. The nebulizer is connected to a dosimeter system consisting of a solenoid valve and a compressed air source ((2.1 Kg / cm2) 20 psi). The outlet of the nebulizer is directed to a plastic part T, one end of which is connected to the inspiratory orifice of a piston respirator. The solenoid valve is activated for 1 second at the beginning of the inspiratory cycle of the respirator. The aerosols are supplied at Vt of 500 ml and a ratio of 20 breaths / minute. A 0.5% sodium bicarbonate solution is only used as a control. To estimate the bronchial sensitivity, cumulative concentration / response curves with respect to carbachol can be generated according to Abraham (1994).

Bronchial biopsies can be taken before and after the initiation of treatment and 24 hours after stimulation with antigen. Bronchial biopsies can be preformed according to Abraham (1994). An in vitro adhesion study of alveolar macrophages can also be performed according to Abraham (1994) and a percentage of adherent cells is calculated.

Aerosol Formulation A solution of the candidate compound in 0.5% sodium bicarbonate / saline solution (w / v) at a concentration of 30.0 mg / ml is prepared using the following procedure: A: Preparation of 0.5% Sodium Bicarbonate / solution Salina Base: 100.0 ml Procedure: 1. Add 0.5 g of sodium bicarbonate to a 100 ml volumetric flask. 2. Add approximately 90.0 ml of saline and sonicate until it dissolves. 3. c.bp. to 100.0 ml with saline and mix thoroughly ^ ÜÁMüÉMa B: Preparation of 30.0 mg / ml Compound Candidate: 10.0 ml.

Procedure: 1. Add 0.300 g of the candidate compound to a 10.0 ml volumetric flask. 2. Add approximately 9.7 ml of 0.5% sodium bicarbonate / base saline solution. 3. Sonicate until the candidate compound is completely dissolved. . Q.S. to 10.0 ml with 0.5% sodium bicarbonate / saline base and mix thoroughly. Using a conventional oral formulation, the compounds of this invention would be active in this model. It is noted that, in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (30)

1. bh. CLAIMS Having described the invention as above, property is claimed as contained in the following claims: A compound of formula I: characterized in that: R1 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and R1 and R2 together with the linked nitrogen atom R2 and the group S02 can form a heterocyclic group or a substituted heterocyclic group; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R2 does not form a heterocyclic group with R1, R2 and R3 together with the nitrogen atom linked to R2 and the carbon atom linked to R3 can form a heterocyclic group or a substituted heterocyclic group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and when R 3 does not form a heterocyclic group or a group heterocyclic substituted with R2, then R3 and R4 together with the carbon atom to which they are attached can form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R5 is selected from the group consisting of isopropyl, -CH2-W y = CH-W, where W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl , aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxy, carboxylalkyl, substituted carboxylalkyl, carboxy- = 2 ^ cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic and hydroxyl with the proviso that when R5 is = CH-W then (H) is separated of the formula and W is not hydroxyl; Q is selected from the group consisting of: (i) X II + -C-N- I. Or wherein X is selected from the group consisting of oxygen, sulfur and NH; (ii) wherein R7 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R8 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R7 and R8 together with the nitrogen atom bonded to R7 and the carbon atom linked to R8 can form a heterocyclic or substituted heterocyclic ring; (iii) wherein R9 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R10 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R9 and R10 together with the nitrogen atom linked to R9, the carbon atom linked to R10 and the group -C (X) - can form a heterocyclic group or substituted heterocyclic group; X is selected from the group consisting of oxygen, sulfur and NH; (iv) wherein R11 and R12 together with the nitrogen atom linked to R11 and the group > C = N- linked to R12 form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and V) wherein R13 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R14 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; X is selected from the group consisting of oxygen, sulfur and NH; and pharmaceutically acceptable salts thereof.
2. 2. A compound of formula IA: characterized in that: R1 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and R1 and R2 together with the linked nitrogen atom R2 and the group S02 can form a heterocyclic group or a substituted heterocyclic group; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R2 does not form a heterocyclic group with R1, R2 and R3 together with the nitrogen atom linked to R2 and the carbon atom linked to R3 can form a heterocyclic group or a substituted heterocyclic group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and when R 3 does not form a heterocyclic group or a group heterocyclic substituted with R2, then R3 and R4 together with the carbon atom to which they are attached can form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R5 is selected from the group consisting of isopropyl, -CH2-W y = CH-W, wherein W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl , aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxy, carboxylalkyl, substituted carboxylalkyl, carboxycycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxyheteroaryl, carboxyl- substituted heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic and hydroxyl, with the proviso that when R5 is = CH-W then (H) is separated from the formula and W is not hydroxyl; R6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, -NHOY wherein Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and -NH (CH2) pCOOY 'where Y' is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and p is an integer from 1 to 8; Q is selected from the group consisting of: (i) wherein X is selected from the group consisting of oxygen, sulfur and NH; (or) wherein R7 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R8 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R7 and R8 together with the nitrogen atom bound to R7 and the carbon bonded to R8 can form a heterocyclic ring or substituted heterocyclic ring; (iii) wherein R9 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R10 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R9 and R10 together with the nitrogen atom linked to R9, the carbon atom linked to R10 and the group -C (X) - can form a heterocyclic group or substituted heterocyclic group; X is selected from the group consisting of oxygen, sulfur and NH; and (iv) wherein R11 and R12 together with the nitrogen atom linked to R11 and the group > C = N- linked to R12 form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and V) wherein R13 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R14 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; X is selected from the group consisting of oxygen, sulfur and NH; and pharmaceutically acceptable salts thereof.
3. 3. The 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. 4. The compound according to claim 1 or 2 characterized in that R1 is selected from the group consisting of methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-methylphenyl, 4-t-butylphenyl, 2,4, 6-trimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4- dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-t-butoxyphenyl, 4- (3 '-dimethylamino-n-propoxy) -phenyl, 2-carboxyphenyl, 2- (methoxycarbonyl) phenyl, 4- (H2NC (0) -) phenyl, 4- (H2NC (S) -) phenyl, 4-cyanophenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3,5-di- (trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4- (CH 3 C (O) NH-) phenyl, 4- (PhNHC (O) NH-) phenyl, -amidinophenyl, 4-methylamidinophenyl, 4- (CH3SC (= NH) -) phenyl, 4-chloro-3- (H2NS (O) 2-) phenyl, l-naphthyl, 2-naphthyl, pyrid in-2-yl, pyridin-3-yl, pyrimidin-2-yl, quinolin-8-yl, 2- (trifluoroacetyl) -1,2,3,4-tetrahydroisoquinolin-7-yl, morfo-lin-4- ilo, 2-thienyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, lN-methylimidazol-4-yl, lN-methylpyrazol-3-yl, 1- N -methylpyrazol-4-yl, lN-butylpyrazol-4-yl, lN-methyl-3-methyl-5-chloropyrazol-4-yl, lN-methyl-5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-l, 3,4-thiadiazol-2-yl.
5. 5. The 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. 6. The compound according to claim 1 or 2, characterized in that R2 and R3 together with the nitrogen atom bonded to the substituent R2 and the carbon bonded to the substituent R3 form a heterocyclic or substituted heterocyclic group.
7. 7. The compound according to claim 6, characterized in that R2 and R3 together with the nitrogen atom linked to the substituent R2 and the carbon bonded to the substituent R3 form a substituted heterocyclic ring.
8. The compound according to claim 1 or 2, characterized in that R1 and R2 together with the nitrogen atom linked to R2 and the group S02 linked to R1 are linked to form a heterocyclic ring or a substituted heterocyclic ring.
9. 9. The compound according to claim 1 or 2, characterized in that R3 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, diphenylmethyl, 2-carboxyethyl, 2-amidoethyl, isobutyl, t-butyl, carboxymethyl, - CH20-benzyl and hydroxymethyl.
10. 10. The compound according to claim 1 or 2, characterized in that R4 is selected from the group consisting of hydrogen, methyl, ethyl and phenyl.
11. 11. The compound according to claim 1 or 2, characterized in that Q is selected from the group consisting of -C (0) N (0) -, -CH2NH-, -CH (OH) C (0) NH-, -NHC (0) NH- and tetrazol-1,5-diyl.
12. 12. The compound according to claim 1 or 2, characterized in that R5 is selected from the group consisting of: 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl, 4-benzyloxybenzyl, 4- [f -CH (CH3) 0-] benzyl, 4- [f-CH (COOH) -] benzyl, 4- [BocNHCH2C (0) NH-] benzyl, 4-chlorobenzyl, 4- [NH2CH2C (O) NH-] benzyl , 4-carboxybenzyl, 4- [CbzNHCH2CH2NH-] benzyl, 3-hydroxy-4- (f-OC (O) NH-) benzyl, 4- [H00CCH2CH2C (O) NH-] benzyl, benzyl, 4- [2 ' -carboxylphenoxy-] benzyl, 4- [fC (O) NH-] benzyl, 3-carboxybenzyl, M ** iBitatei-i 4-iodobenzyl, 4-hydroxy-3, 5-diiodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxyphenyl] -benzyl, f-CH2CH2-, 4-nitrobenzyl, 2- carboxybenzyl, 4- [dibenzylamino] -benzyl, 4- [(1'-cyclopropylpiperidin-4 '-yl) C (0) NH-] benzyl, 4- [-NHC (0) CH2NHBoc] benzyl, 4-carboxybenzyl, -hydroxy-3-nitrobenzyl, 4- [-NHC (0) CH (CH3) NHBoc] benzyl, 4- [-NHC (0) CH (CH2f) NHBoc] benzyl, isobutyl, methyl, 4- [CH3C (0) NH-] benzyl, -CH2- (3-indolyl), n-butyl, t-butyl-OC (0) CH2-, t-butyl-OC (0) CH2CH2- H2NC (0) CH2-, H2NC (0) CH2CH2-, BocNH- (CH2) 4-, t-butyl-OC (0) - (CH2) 2-, HOOCCH2-, HOOC (CH2) 2-, H2N (CH2) 4-, isopropyl, (l-naphthyl) -CH2-, (2-naphthyl) -CH2-, (2-thiophenyl) -CH2-, (f-CH2-OC (0) NH- (CH2) 4-, cyclohexyl-CH2-, benzyloxy-CH2-, H0CH2 -, 5- (3-N-benzyl) imidazolyl-CH2-, 2-pyridyl-CH2-, 3-pyridyl-CH2-, 4-pyridyl-CH2-, 5- (3-N-methyl) imidazolyl-CH2- , N-benzylpiperid-4-yl-CH2-, N-Boc-piperidin-4-yl-CH2-, N- (phenyl-carbonyl) piperidin-4-yl-CH2-, H3CSC H2CH2-, lN-benzylimidazol-4-yl-CH2-, iso-propyl-C (O) NH- (CH2) 4-, iso-butyl-C (O) NH- (CH2) -, f-enyl-C ( 0) NH- (CH2) 4-, benzyl-C (0) NH- (CH2) 4-, "* * - + * allyl-C (0) NH- (CH2) 4-, 4- (3-N-methylimidazolyl) -CH2-, 4-imidazolyl, 4- [(CH3) 2NCH2CH2CH2-0-] benzyl, 4- [(benzyl) 2N-] -benzyl, 4-aminobenzyl, allyloxy-C (0) NH (CH2) 4-, allyloxy-C (0) NH (CH2) 3-, allyloxy-C (0) NH ( CH2) 2-, NH2C (0) CH2-, f-CH =, 2-pyridyl-C (0) NH- (CH2) 4-, 4-methylpyrid-3-yl-C (0) NH- (CH2) 4-, 3-methylthien-2-yl-C (0) NH- (CH2) 4-, 2-pyrrolyl-C (0) NH- (CH2) 4-, 2-furanyl-C (0) NH- ( CH2) 4-, 4-methylphenyl-S02-N (CH3) CH2C (0) NH (CH2) 4-, 4- [cyclopentylacetylenyl] -benzyl, 4- [-NHC (0) - (N-Boc) - pyrrolidin-2-yl)] - benzyl-, lN-methylimidazol-4-yl-CH2-, 1-N-methyl-imide zol-5-yl-CH2-, imide zol-5-yl-CH2-, 6- methylpyrid-3-yl-C (0) NH- (CH2) 4-, 4- [2'-carboxymethylphenyl] -benzyl, 4- [-NHC (0) NHCH2CH2CH2-f] -benzyl, 4- [-NHC ( O) NHCH2CH2-f] -benzyl, -CH2C (0) NH (CH2) 4f, 4- [f (CH2) 40-] -benzyl, 4- [-C = Cf-4 'f] -benzyl, 4- [-C = C-CH2-0-S (0) 2-4 * -CH3-f] -benzyl 4- [-C = C-CH2NHC (0) NH2] -benzyl, 4- [-C = C- CH2-0-4 '-C00CH2CH3-f] -benzyl, 4- [-C = C -CH (NH2) -cydohexyl] -benzyl, - (CH2) 4NHC (0) CH2-3-indolyl, - (CH2) 4NHC (0) CH2CH2-3-indolyl, - (CH2) 4NHC (0) -3- (5-methoxyindolyl), - (CH2) 4NHC (0) -3- (1-methylindolyl), - (CH2) 4NHC (0) -4 - (- S02 (CH3) - f), - (CH2) 4NHC ( 0) -4- (C (0) CH3) -phenyl, - (CH2) 4NHC (0) -4-f luorophenyl, - (CH2) NHC (0) CH20-4-f luorofenyl, 4- [-C = C- (2-pyridyl)] benzyl, 4- [-C = C-CH2-0-f-enyl] benzyl, 4 - [-C = C-CH20CH3] benzyl, 4- [-C = C- (3 -hydroxyphenyl)] benzyl, 4- [-C = C-CH2-0-4 '- (-C (0) OC2H5) phenyl] benzyl, 4- [-C = C-CH2CH (C (0) 0CH3) 2 ] benzyl, 4- [-C = C-CH2NH- (4, 5-dihydro-4-oxo-5-phenyl-oxazol-2-yl), 3-aminobenzyl, 4- [-C = C-CH2CH (NHC (O) CH3) C (O) OH] -benzyl, -CH2C (0) NHCH (CH3) f, -CH2C (0) NHCH2- (4-dimethylamino) -f, -CH2C (O) NHCH2-4-nitrof enyl, -CH2CH2C (O) N (CH3) CH2-f, -CH2CH2C (O) NHCH2CH2- (N-methyl) -2-pyrrolyl, -CH2CH2C (O) NHCH2CH2CH2CH3, -CH2CH2C (O) NHCH2CH2-3-indolyl, -CH2C (O) N (CH3) CH2f enyl, -CH2C (O) NH (CH2) 2- (N-methyl) -2-pyrrolyl, -CH2C (O) NHCH2CH2CH2CH3, -CH2C (O) NHCH2CH2-3-indolyl, - (CH2) 2C (0) NHCH (CH3) f, - (CH2) 2C (0) NHCH2-4-dimethylaminophenyl, - (CH2) 2C (0) NHCH2-4-nitrophenyl, - (CH2C (O) NH-4- [-NHC (O) CH3-fenyl], -CH2C (O) NH-4-pyridyl, -CH2C (O) NH- 4- [dimethylaminofenyl], -CH2C (O) NH-3-methoxyfenyl, -CH2CH2C (0) NH-4-chlorophenyl, -CH2CH2C (O) NH-2-pyridyl, -CH2CH2C (O) NH-4- methoxyfine, -CH2CH2C (O) NH-3-pyridyl, 4- [(CH3) 2NCH2CH20-] benzyl, - (CH2) 3NHC (NH) NH-S02-4-methylfenyl, 4- [(CH3) 2NHC2CH20- ] benzyl, - (CH2) 4NHC (0) NHCH2CH3, - (CH2) 4NHC (0) NH-phenyl, - (CH2) NHC (O) NH-4-methoxyphenyl, -4- [4'-pyridyl-C ( O) NH-] benzyl, 4- [3'-pyridyl-C (O) NH-] benzyl, 4- [NHC (O) NH-3 '-methylphenyl] benzyl, 4- [-NHC (O) CH2NHC ( O) NH-3 '-methylphenyl] benzyl, 4 - [- NHC (0) - (2', 3'-dihydroindol-2-yl)] benzyl, 4 - [- NHC (0) -2 ', 3' -dihydro-N-Boc-indol-2-yl)] benzyl, p- [-OCH2CH2-L '- (4'-pyrimidyl) -piperazinyl] benzyl, 4- [-OCH2CH2- (1'-piperidinyl) benzyl, 4 - [- OCH2CH2- (1-pyrrolidinyl)] benzyl, 4- [-OCH2CH2CH2- (l '-piperidinyl)] benzyl, -CH2-3- (l, 2,4-triazolyl), 4- [-OCH2CH2CH2-4- (3'-chlorophenyl) -piperazin-1-yl) ] benzyl, 4- [-OCH2CH2N (f) CH2CH3] benzyl, 4- [-OCH2-3 '~ (N-Boc) -piperidinyl] benzyl, 4- [di-n-pentylamino] benzyl, 4- [n- pentylamino] benzyl, 4- [di-iso-propylamino-CH2CH20-] benzyl, 4- [-0CH2CH2- (N-morpholinyl)] benzyl, 4- [-0- (3 '- (N-Boc) -piperidinyl] ] benzyl, 4- [-0CH2CH (NHBoc) CH2cyclohexyl] benzyl, - "" ** • »p- [OCH2CH2- (N-piperidinyl] benzyl, 4- [OCH2CH2CH2- (4-m-chlorofenyl) -piperazin-1-yl] -benzyl, 4- [-OCH2CH2- (N -homopiperidinyl) benzyl, 4- [-NHC (0) -3 '- (N-Boc) -piperidinyl] benzyl, 4- [-OCH2CH2N (benzyl) 2] benzyl, -CH2-2-thiazolyl, 3-hydroxybenzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, 4- [-NHC (S) NHCH2CH2- (N-morpholino)] benzyl, 4- [-OCH2CH2N (C2H5) 2] benzyl, 4- [-OCH2CH2CH2N (C2H5) 2] benzyl, 4- [CH3 (CH2) 4NH-] benzyl, 4- [Nn-butyl, Nn-pentylamino-] benzyl, 4- [-NHC (0) -4'-piperidinyl] benzyl, 4- [- NHC (0) CH (NHBoc) (CH2) 4NHCbz] benzyl, 4- [-NHC (0) - (1 ', 2', 3 ', 4' -tetrahydro-N-Boc-isoquinolin-1'-yl] benzyl, p- [-0CH2CH2CH2-1'- (4'-methyl) -piperazinyl] benzyl, - (CH2) 4NH-Boc, 3- [-0CH2CH2CH2N (CH3) 2] benzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, 3- [-OCH2CH2 (1'-pyrrolidinyl)] benzyl, 4- [-OCH2CH2CH2N (CH3) benzyl] benzyl, 4- [-NHC (S) NHCH2CH2CH2- (N-morpholino)] benzyl, - "- * -" - - '' - i 4 - [- OCH2CH2- (N-morpholino)] benzyl, 4- [-NHCH2- (4'-chlorophenyl)] benzyl, 4- [-NHC (O) NH- (4'-cyanophenyl)] benzyl, 4- [-OCH2COOH] benzyl, 4- [-OCH2COO-t-butyl] benzyl, 4- [-NHC (O) -5 '-fluoroindol-2-yl] benzyl 4- [-NHC (S) NH (CH2) 2-l-piperidinyl] benzyl, 4- [-N (S02CH3) (CH2) 3-N (CH3) 2] benzyl, 4- [-NHC (O) CH2CH (C (0) 0CH2f) -NHCbz] benzyl, 4- [-NHS (O) 2CF3] benzyl, 3- [-0- (N-methylpiperidin-4 '-yl] benzyl, 4- [-C (= NH) NH2] benzyl, 4- [-NHS02-CH2C1] benzyl, 4- [-NHC (0) - (1 ', 2', 3 ', 4' -tetrahydroisoquinolin-2 'yl] benzyl, 4- [- NHC (S) NH (CH2) 3-N-morpholine] benzyl, 4- [-NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, 4- [-C (O) NH2] benzyl, 4- [-NHC] (0) NH-3 '-methoxyphenyl] benzyl, 4- [-OCH2CH2-indol-3'-yl] benzyl, 4- [-0CH2C (0) NH-benzyl] benzyl, 4- [-0CH2C (O) O-benzyl] benzyl, 4- [-0CH2C (0) OH] benzyl, 4- [-0CH2-2 '- (4', 5'-dihydro) imidazolyl] benzyl, -CH2C (0) NHCH2- (dimethylamino) phenyl, -CH2C (0) N HCH2- (4-dimethylamino) phenyl, 4- [-NHC (0) -L-2 '-pyrrolidinyl-N-S02-4 * - methylphenyl] benzyl, 4- [-NHC (0) NHCH2CH2CH3] benzyl, 4- aminobenzyl] benzyl, 4- [-0CH2CH2-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) piperazinyl] benzyl, 4- [-0- (N-methylpiperidin-4 '-yl)] benzyl , 3-methoxybenzyl, 4- [-NHC (O) -piperidin-3'-yl] benzyl, 4- [-NHC (0) -pyridin-2'-yl] benzyl, 4- [-NHCH2- (4 ' -chlorophenyl)] benzyl, 4- [-NHC (0) - (N- (4 '-CH3-f-S02) -L-pyrrolidin-2'-yl)] benzyl, 4- [-NHC (0) NHCH2CH2 -f] benzyl, 4- [-OCH2C (0) NH2] benzyl, 4- [-0CH2C (0) NH-t-butyl] benzyl, 4- [-0CH2CH2-1- (4-hydroxy-4-phenyl) - piperidinyl] benzyl, 4- [-NHS02-CH = CH2] benzyl, 4- [-NHS02-CH2CH2C1] benzyl, -CH2C (0) NHCH2CH2N (CH3) 2, 4- [(1'-Cbz-piperidin-4 '-il) C (0) NH-] benzyl, 4- [(1-Boc-piperidin-4 '-yl) C (0) NH-] benzyl, 4- [(2'-bromophenyl) C (0) NH-] benzyl, 4- [-NHC (O ) -pyridin-4 '-yl] benzyl, 4- [(4' - (CH3) 2NC (0) 0-) phenyl) -C (0) NH-] benzyl, 4 - [- NHC (0) -l '-methylpiperidin-4' -yl] benzyl, 4- (dimethylamino) benzyl, 4- [-NHC (0) - (1 '-N-Boc) -piperidin-2' -yl] benzyl, 3- [-NHC (0) -pyridin-4 '-yl] benzyl, 4- [(tert-butyl-0 (0) CCH2-0-benzyl) -NH-] benzyl, [BocNHCH2C (0) NH-] butyl, 4-benzylbenzyl, 2-hydroxyethyl, 4 - [(Et) 2NCH2CH2CH2NHC (S) NH-] benzyl, 4- [(1 '-Boc-4' -hydroxypyrrolidin-2 '-yl) C (0) NH- benzyl, 4 - [fCH2CH2CH2NHC (S) NH-] benzyl, 4- [(perhydroindolin-2'-yl) C (0) NH-] benzyl, 2- [4-hydroxy-4- (3-methoxythien-2- il) piperidin-1-yl] ethyl, 4- [(1 '-Boc-perhydroindolin-2'-yl) -C (0) NH-] benzyl, 4- [N-3-methylbutyl-N-trifluoromethanesulfonyl) ami - no] benzyl, 4- [N-vinylsulfonyl) amino] benzyl, 4- [2- (2-azabicyclo [3,2,2] octan-2-yl) ethyl- 0-] benzyl, 4- [4 ' -hydroxypyrrolidin-2 '-yl) C (0) NH-] benzyl, 4- (fNHC (S) NH) benzyl, 4- (EtNHC (S) NH) benzyl, 4- (fCH2NHC (S) NH) benzyl, 3- [(1 '-Boc-piperidin-2' -yl) C (O) NH-] benzyl, 3- [piperidin-2 '-yl-C (O) NH-] benzyl, 4- [(3' -Boc-thiazolidin-4 '-yl) C (O) NH-] benzyl, 4- (pyridin-3' -il-NHC (S) NH) benzyl, 4- (CH3NHC (S) NH) benzyl, 4- (H 2NCH2CH2CH2C (O) NH) benzyl, 4- (B? CHNCH2CH2CH2C (O) NH) benzyl, 4- (pyridin-4 '-il-CH2NH) benzyl, 4- t (N, N-di (4-N, N -dimethylamino) benzyl) amino] benzyl, 4- [(l-Cbz-piperidin-4-yl) C (O) H-] butyl, 4- [fCH2OCH2 (BocHN) CHC (O) NH] benzyl, 4- [(piperidin-4 '-yl) C (O) NH-] benzyl, 4- [(pyrrolidin-2'-yl) C (O) NH-] benzyl, 4- (pyridin-31-yl-C (O) NH) butyl, 4- (pyridin- 4 '-il-C (O) NH) butyl, 4- (pyridin-3'-yl-C (O) NH) benzyl, 4- [CH3NHCH2CH2CH2C (O) NH-] benzyl, 4- [CH3N (Boc) CH2CH2CH2C (O) NH-] benzyl, 4- (aminomethyl) benzyl, 4- [fCH2OCH2 (H2N) CHC (O) NH] benzyl, 4- [(1 '-4' -di (Boc) piperazin-2 '- il) -C (O) NH-] benzyl, 4- [(piperazin-2'-yl) -C (O) NH-] benzyl, 4- [(N-toluenesulfonylpyrrolidin-2 '-yl) C (O) NH-] butyl, 4- [-NHC] (0) -4 '-piperidinyl] butyl, 4- [-NHC (0) -1' -N-Boc-piperidin-2'-yl] benzyl, 4- [-NHC (0) -piperidin-2 '- il] benzyl, 4- [(1-N-Boc-2 ', 3'-dihydroindolin-2'-yl) - C (0) NH] benzyl, 4- (pyridin-3'-yl-CH2NH) benzyl , 4- t (1 '-Cbz-piperidin-4' -yl) C (0) NH-] benzyl, 4- [(piperidin-1 '-yl) C (0) CH3-0-] benzyl, 4- t (CH3) 2NC (0) CH2-0-] benzyl, 4- [HO (0) C (Cbz-NH) CHCH2CH2-C (0) NH-] benzyl, 4- [fCH20 (0) C (Cbz- NH) CHCH2CH2-C (0) NH-] benzyl, 4- [-NHC (0) -2 '-methoxyphenyl] benzyl, 4- [(pyrazin-2' -yl) C (0) NH-] benzyl, 4- [HO (0) C (NH2) CHCH2CH2-C (0) NH-] benzyl, 4- (2'-formyl-1 ', 2', 3 ', 4' -tetrahydroisoquinolin-3'-yl-CH2NH -) benzyl, N-Cbz-NHCH2-, 4- [(4'-methylpiperazin-1'-yl) C (0) 0-] benzyl, 4- [CH3 (N-Boc) NCH2C (0) NH-] benzyl, 4- [-NHC (0) - (1 ', 2', 3 ', 4' -tetrahydro-N-Boc-isoquinolin-3 '-yl] benzyl, 4- [CH3NHCH2 C (0) NH-] benzyl, (CH3) 2NC (0) CH2-, 4- (N-methylacetamido) benzyl, 4- (1 ', 2', 3 ', 4' -tetrahydroisoquinolin-3'-yl- CH2NH-) benzyl, 4- [(CH3) 2NHCH2C (0) NH-] benzyl, (1-toluenesulfonylimidizol-4-yl) methyl, 4- [(1-Boc-piperidin-4 '-yl) C (0 ) NH-] benzyl, 4-trifluoromethylbenzyl, 4- [(2'-bromophenyl) C (0) NH-] benzyl, 4- [(CH3) 2NC (0) NH-] benzyl, 4- [CH30C (0) NH-] benzyl, - [(CH3) 2NC (0) 0-] benzyl, 4- [(CH3) 2NC (0) N (CH3) -] benzyl, 4- (N-methyltrifluoroacetamido) benzyl, 4- [(1'-methoxycarbonylpiperidin- 4-1) C (0) NH-] benzyl, 4- [(4'-phenylpiperidin-4'-yl) C (0) NH-] benzyl, 4- [(4'-phenyl-1-Boc-piperidin-4 '-yl) -C (0) NH-] benzyl, 4- [(piperidin-4'-yl) C (0) 0-] benzyl 4 - [(11-methylpiperidin-4 '-yl) -0-] benzyl, 4- [(1-methylpiperidin-4-yl) C (0) 0-] benzyl, 4- [(4'-methylpiperazin-1 '-yl) C (0) NH-] benzyl, 3- [(CH3) 2NC (0) 0-] benzyl, 4- [(4'-phenyl-1' - Boc-piperidin-4 '-yl) - C (0) 0-] benzyl, 4- (N-toluenesulfonylamino) benzyl, 4- [(CH3) 3CC (0) NH-] benzyl, 4- [(morphine- 4 '-il) C (O) NH-] benzyl, 4- [(CH3CH2) 2NC (O) NH-] benzyl, 4- [-C (O) NH- (4'-pyridinyl)] benzyl, 4- [(2'-trifluoromethylphenyl) C (O) NH-] benzyl, 4- [(2'-methylphenyl) C (O) NH-] benzyl, 4- [(CH3) 2NS (0) 20-] benzyl, 4 - [(pyrrolidin-2 '-yl) C (O) NH-] benzyl, 4- [-NHC (O) -piperidin-1' -yl] benzyl, 4- [(thiomorpholin-4 '-yl) C ( O) NH-] benzyl, 4- [(thiomorpholin-4'-yl sulfone) -C (O) NH-] benzyl, 4- [(morpholin-4 '-yl) C (O) Obencil, 3-nitro- 4- (CH3OC (O) CH20-] benzyl, (2-benzoxazolinon-6-yl) -methyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-, 4- [(CH3) 2NS (0) 2NH-] benzyl, 4- [(CH3) 2NS (0) 2N (CH3) -] benzyl, 4- [(thiomorpholin-4 * -yl) C (O) O-] benzyl , 4- [(thiomorpholin-4'-yl sulfone) -C (O) O-] benzyl, 4- [(p. iperidin-1 '-il) C (O) 0-] benzyl, 4- [(pyrrolidin-1'-yl) C (O) 0-] benzyl, 4- [(4'-methyIpiperazin-1-yl) C (O) O-] benzyl, 4- [(2'-methylpyrrolidin-1'-yl) -, (pyridin-4-yl) methyl-, 4- [(piperazin-4 '-yl) -C (O ) 0-] benzyl, z ^ Í? z? e? j 4- [(1-Boc-piperazin-4 '-il) -C (0) 0-] benzyl, 4- [(4'-acetylpiperazin-1'-yl) C (0) 0-] benzyl, p- [(4'-methanesulfonylpiperazin-1'-yl) -benzyl, 3-nitro-4- [(morpholin-4 '-yl) -C (0) 0-] benzyl , 4-. { [CH3) 2NC (S)] 2N-} benzyl, N-Boc-2-aminoethyl-, 4- [(1, l-dioxothiomorpholin-4-yl) -C (0) 0-] benzyl, 4- [(CH3) 2NS (0) 2-] benzyl, 4- (imidazolid-2 '-one-1'-yl) benzyl, 4- [(piperidin-1-yl) C (0) 0-] benzyl, lN-benzyl-imidazol-4-yl-CH2-, 3,4-dioxyethylenebenzyl, 3,4-dioxymethylenebenzyl, 4- [-N (S02) (CH3) CH2CH2CH2N (CH3) 2] benzyl, 4- (3 ') -formylimidazolid-2 '-one-1' -yl) benzyl, 4- [NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, [2 '- [4"-hydroxy-4" - (3' '' -methoxythien-2 '*' - il) piperidin-2"-l] ethoxy] benzyl and p- [(CH3) 2-NCH2CH2N (CH3) C (0) 0-] benzyl.
13. The compound according to claim 2, characterized in that R6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n- butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso-propyl-4-b-methylcyclohexoxy, 2-b-isopropyl-4-b-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2COOH, -NHCH2CH2COOH, - NH-adamantyl, -NHCH2CH2COOCH2CH3, -NHS02-p-CH3-f, -NHOR8 where R8 is hydrogen, methyl, iso-propyl or benzyl, 0- (N-succinimidyl), -0-colest-5-en- 3-ß-ilo, -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-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) ) OCH2CH2.
14. 14. A compound selected from the group consisting of: N- [N- (toluene-4-sulfonyl) -L-pyrrolidin-2-ylmethyl] -L-phenylalanine; N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-L-phenylalanine; N- [N- (toluene-4-sulfonyl) -L-prolinyl] -N-hydroxy-D-phenylalanine N- [2- (N-toluene-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl] - L-4- (N-benzyloxycarbonyl-isonipecotamido) -phenylalanine N- [2- (N- (toluene-4-sulfonyl) -L-pyrrolidinyl) -2-hydroxyacetyl] -L-4- (isonipecotamido) phenylalanine acid (2S ) -2- [5- (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4-nitrobenzyl) propionic acid ester (2S) -2- [5 - (N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert-butoxy-carbonylisonipecotamido) benzyl) propionic acid (2S) -2- [5 -N- (toluene-4-sulfonyl) pyrrolidin-2-yl) tetrazol-1-yl] -2- (4- (N-tert-butoxycarbonylisonipecota-mido) benzyl) propionic N- [N- (toluene-4- sulfonyl) pyrrolidin-2-yl] aminocarbonyl] -L-phenylalanine and pharmaceutically acceptable salts thereof, as well as any of the ester compounds mentioned above, wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester.
15. 15. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I: wherein: R1 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and R1 and R2 together with the linked nitrogen atom R2 and the group S02 can form a heterocyclic group or a substituted heterocyclic group; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R2 does not form a heterocyclic group with R1, R2 and R3 together with the nitrogen atom linked to R2 and the carbon atom linked to R3 can form a heterocyclic group or a substituted heterocyclic group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R 3 does not form a heterocyclic group or a group heterocyclic substituted with R2, then R and R together with the carbon atom to which they are attached can form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R5 is selected from the group consisting of isopropyl, -CH-W and = CH-W, where W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl , aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxy, carboxylalkyl, substituted carboxylalkyl, carboxycycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxyheteroaryl, carboxyl- substituted heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic, and hydroxyl with the proviso that when R5 is = CH-W then (H) is separated from the formula and W is not hydroxyl; Q is selected from the group consisting of: (i) wherein X is selected from the group consisting of oxygen, sulfur and NH; -EfiMi-lil (ü) wherein R7 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R8 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R7 and R8 together with the nitrogen atom bonded to R7 and the carbon atom linked to R8 can form a heterocyclic ring or substituted heterocyclic ring; (iü) wherein R9 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R10 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R9 and R10 together with the nitrogen atom linked to R9, the carbon atom linked to R10 and the group -C (X) - can form a heterocyclic group or substituted heterocyclic group; X is selected from the group consisting of oxygen, sulfur and NH; (iv) wherein R11 and R12 together with the nitrogen atom linked to R11 and the group > C = N- linked to R12 form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and V) wherein R13 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R14 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; X is selected from the group consisting of oxygen, sulfur and NH; and pharmaceutically acceptable salts thereof.
16. 16. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IA: wherein R1 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and R1 and R2 together with the linked nitrogen atom R2 and the group S02 can form a heterocyclic group or a substituted heterocyclic group; R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and when R2 does not form a heterocyclic group with R1, R2 and R3 together with the nitrogen atom linked to R2 and the carbon atom linked to R3 can form a heterocyclic group or a substituted heterocyclic group; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and when R 3 does not form a heterocyclic group or a group heterocyclic substituted with R2, then R3 and R4 together with the carbon atom to which they are attached can form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; R5 is selected from the group consisting of isopropyl, -CH2-W y = CH-W, wherein W is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl , aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxy, carboxylalkyl, substituted carboxylalkyl, carboxycycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxyheteroaryl, carboxyl- substituted heteroaryl, carboxyheterocyclic, substituted carboxy-heterocyclic and hydroxyl, with the proviso that when R5 is = CH-W then (H) is separated from the formula and W is not hydroxyl; R6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, -NHOY wherein Y is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and -NH (CH2) pCOOY 'where Y' is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl and p is an integer from 1 to 8; Q is selected from the group consisting of: (i) wherein X is selected from the group consisting of oxygen, sulfur and NH; (or) wherein R7 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R8 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R7 and R8 together with the nitrogen atom bonded to R7 and the carbon atom linked to R8 can form a heterocyclic ring or substituted heterocyclic ring; (iü) ^^ AU? ^ m? i wherein R9 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R10 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; or R9 and R10 together with the nitrogen atom linked to R9, the carbon atom linked to R10 and the group -C (X) - can form a heterocyclic group or substituted heterocyclic group; X is selected from the group consisting of oxygen, sulfur and NH; and (iv) wherein R11 and R12 together with the nitrogen atom linked to R11 and the group > C = N- linked to R12 form a heterocyclic, substituted heterocyclic, heteroaryl or substituted heteroaryl ring; and V) wherein R13 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; R14 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; X is selected from the group consisting of oxygen, sulfur and NH; and pharmaceutically acceptable salts thereof.
17. 17. The pharmaceutical composition according to claim 15 or 16, characterized in that R1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl.
18. 18. The pharmaceutical composition according to claim 15 or 16, characterized in that R1 is selected from the group consisting of methyl, isopropyl, n-butyl, benzyl, phenethyl, phenyl, 4-methylphenyl, 4-t-butylphenyl, 2, 4,6-trimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 3,5-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-bromophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-t-butoxyphenyl, 4- (3 '-dimethylamino-n-propoxy) -phenyl, 2-carboxyphenyl, 2- (methoxycarbonyl) phenyl, 4- (H2NC (0) -) phenyl, 4- (H2NC (S) -) phenyl, 4-cyanophenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3,5-di- (trifluoromethyl) phenyl, 4-nitrophenyl, 4-aminophenyl, 4- (CH 3 C (O) NH-) phenyl, 4- (PhNHC (O) NH-) phenyl, -amidinophenyl, 4-methylamidinophenyl, 4- (CH3SC (= NH) -) phenyl, 4-chloro-3- (H2NS (O) 2 ~) phenyl, l-naphthyl , 2-naphthyl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, quinolin-8-yl, 2- (trifluoroacetyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl, morfo -lin-4-yl, 2-thienyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, l-methyl-imidazol-4-yl, l-methyl-pyrazol-3-yl, 1-N-methyl-pyrazole -4-yl, lN-butylpyrazol-4-yl, l-methyl-3-methyl-5-chloropyrazol-4-yl, 1-N-methyl-5-methyl-3-chloropyrazol-4-yl, 2-thiazolyl and 5-methyl-1,3,4-thiadiazol-2-yl.
19. 19. The pharmaceutical composition according to claim 15 or 16, characterized in that R2 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, - (CH2) 2-2-thienyl and - (CH2) 2-f.
20. 20. The pharmaceutical composition according to claim 15 or 16, characterized in that R2 and R3 together with the nitrogen atom bonded to the substituent R2 and the carbon bonded to the substituent R3 form a heterocycle or a substituted heterocyclic group.
21. 21. The pharmaceutical composition according to claim 20, characterized in that R2 and R3 together with the nitrogen atom linked to the substituent R2 and the carbon bonded to the substituent R3 form a substituted heterocyclic ring. j? i?
22. 22. The pharmaceutical composition according to claim 15 or 16, characterized in that R1 and R2 together with the nitrogen atom linked to R2 and the group S02 linked to R1 are linked to form a heterocyclic ring or a substituted heterocyclic ring.
23. 23. The pharmaceutical composition according to claim 15 or 16, characterized in that R3 is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, diphenylmethyl, 2-carboxyethyl, 2-aminoethyl, iso-butyl, t-butyl, carboxymethyl, -CH20-benzyl and hydroxymethyl.
24. 24. The pharmaceutical composition according to claim 15 or 15, characterized in that R4 is selected from the group consisting of hydrogen, methyl, ethyl and phenyl.
25. 25. The pharmaceutical composition according to claim 15 or 16, characterized in that Q is selected from the group consisting of -C (0) N (0) -, -CH2NH-, -CH (0H) C (0) NH- , -NHC (0) NH- and tetrazol-1,5-diyl.
26. 26. The pharmaceutical composition according to claim 15 or 16, characterized in that R5 is selected from the group consisting of: 4-methylbenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-t-butoxybenzyl, 4-benzyloxybenzyl, 4- [ f-CH (CH3) 0-] benzyl, 4- [f-CH (COOH) -] benzyl, 4- [BocNHCH2C (0) NH-] benzyl, 4-chlorobenzyl, 4- [NH2CH2C (O) NH-] benzyl, 4-carboxybenzyl, 4- [CbzNHCH2CH2NH -] benzyl, 3-hydroxy-4- (f-OC (O) NH-) benzyl, 4- [HOOCCH2CH2C (0) NH-] benzyl, benzyl, 4- [2'-carboxylphenoxy] benzyl, 4- [ fC (O) NH-] benzyl, 3-carboxybenzyl, 4-iodobenzyl, 4-hydroxy-3, 5-diiodobenzyl, 4-hydroxy-3-iodobenzyl, 4- [2'-carboxymethyl] benzyl, f-CH2CH2 -, 4-nitrobenzyl, 2-carboxybenzyl, 4- [dibenzylamino] -benzyl, 4- [(1'-cyclopropylpiperidin-4 '-yl) C (O) NH-] benzyl, 4 - [- NHC (0) CH2NHBoc ] benzyl, 4-carboxybenzyl, 4-hydroxy-3-nitrobenzyl, 4- [-NHC (O) CH (CH3) NHBoc] benzyl, 4- [-NHC (O) CH (CH2f) NHBoc] benzyl, isobutyl, methyl, 4- [CH3C (O) NH-] benzyl, -CH2- (3-indolyl), n-butyl, t-butyl-OC (O) CH2-, t-butyl-OC (O) CH2CH2- H2NC (0) CH2-, H2NC (0) CH2CH2-, BocNH- (CH2) 4-, t-butyl-OC (O) - (CH2) 2-, HOOCCH2-, HOOC (CH2) 2-, H2N (CH2) 4-, isopropyl, (l-naphthyl) -CH2-, (2-naphthyl) -CH2-, (2-thiophenyl) -CH2-, ( f-CH2-OC (0) NH- (CH2) 4-, cyclohexyl-CH2-, benzyloxy-CH2-, HOCH2-, 5- (3-N-benzyl) imidazolyl-CH2-, 2-pyridyl-CH2-, 3-pyridyl-CH2-, 4-pyridyl-CH2-, 5- (3-N-methyl) imidazolyl-CH2-, N-benzylpiperid-4-yl-CH2-, N-Boc-piperidin-4-yl-CH2 -, N- (phenyl-carbonyl) piperidin-4-yl-CH2-, H3CSCH2CH2-, lN-benzylimidazol-4-yl-CH2-, iso-propyl-C (0) NH- (CH2) 4-, iso- butyl-C (O) NH- (CH2) 4-, phenyl-C (0) NH- (CH2) -, benzyl-C (0) NH- (CH2) 4-, alii-C (0) NH- ( CH2) 4-, 4- (3-N-methylimidazolyl) -CH2-, 4-imidazolyl, 4- [(CH3) 2NCH2CH2CH2-0-] benzyl, 4- [(benzyl) 2N-] -benzyl, 4-aminobenzyl , allyloxy-C (O) NH (CH2) 4-, allyloxy-C (O) NH (CH2) 3-, allyloxy-C (O) NH (CH2) 2- , NH2C (0) CH2-, _-- la - a - Í - f - CH =, 2-pyridyl-C (O) NH- (CH2) 4-, 4-methylpyrid-3-yl-C (O) NH- (CH2) 4- , 3-methylthien-2-yl-C (0) NH- (CH2) 4-, 2-pyrrolyl-C (0) NH- (CH2) 4-, 2-furanyl-C (0) NH- (CH2) 4-, 4-methylphenyl-S02-N (CH3) CH2C (O) NH (CH2) 4-, 4- [cyclopentylacetylenyl] -benzyl, 4- [-NHC (O) - (N-Boc) -pyrrolidin- 2-yl)] -benzyl-, lN-methylimidazol-4-yl-CH2-, lN-methylimidazol-5-yl-CH2-, imide zol-5-yl-CH2-, 6-methylpyrid-3-yl-C (0) NH- (CH2) 4-, 4- [2 '-carboxymethylphenyl] -benzyl, 4- [-NHC (O) NHCH2CH2CH2-f] -benzyl, 4- [-NHC (O) NHCH2CH2-f] - benzyl, -CH2C (0) NH (CH2) 4f, 4- [f (CH2) 40-] -benzyl, 4- [-C = Cf-4 'f] -benzyl, 4- [-C = C-CH2] -0-S (O) 2-4 '-CH3-f] -benzyl 4- [-C = C-CH2NHC (O) NH2] -benzyl, 4- [-C = C-CH2-0-4' - COOCH2CH3-f] -benzyl, 4- [-CsC-CH (NH2) -cycdohexyl] -benzyl, - (CH2) 4NHC (O) CH2-3-indolyl, - (CH2) 4NHC (O) CH2CH2-3-indolyl , É-MÉÉll-- (CH2) 4NHC (O) -3- (5-methoxyindolyl), - (CH2) 4NHC (O) -3- (1-methylindolyl), - (CH2) 4NHC (0) -4- ( -S02 (CH3) -f), - (CH2) 4NHC (O) -4- (C (O) CH3) -phenyl, - (CH2) 4NHC (O) -4-fluorophenyl, - (CH2) 4NHC (O ) CH20-4-fluorophenyl, 4 - [- C = C- (2-pyridyl)] benzyl, 4- [-C = C-CH2-0-phenyl] benzyl, 4 - [-C = C-CH2OCH3] benzyl , 4- [-C = C- (3-hydroxyphenyl)] benzyl, 4- [-C = C-CH2-0-4 '- (- C (O) OC2H5) phenyl] benzyl, 4- [-C = C-CH2CH (C (O) 0CH3) 2] benzyl, 4- [-C = C-CH2NH- (4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl), 3-aminobenzyl, 4- [-C = C-CH2CH (NHC (O) CH3) C (O) OH] -benzyl, -CH2C (0) NHCH (CH3) f, -CH2C (0) NHCH2- (4-dimethylamino) -f , -CH2C (O) NHCH2-4-Nitrof enyl, -CH2CH2C (0) N (CH3) CH2-f, -CH2CH2C (O) NHCH2CH2- (N-methyl) -2-pyrrolyl, -CH2CH2C (O) NHCH2CH2CH2CH3, -CH2CH2C (O) NHCH2CH2-3-indolyl, -CH2C (O) N (CH3) CH2f enyl, -CH2C (O) NH (CH2) 2- (N-methyl) -2-pyrrolyl, -CH2C (O) NHCH2CH2CH2CH3 , -CH2C (O) NHCH2CH2-3-indolyl, - (CH2) 2C (0) NHCH (CH3) f, - (CH2) 2C (0) NHCH2-4 -dimethylaminophenyl, - (CH 2) 2 C (O) NHCH 2 -4 -nitrofenyl, - (CH 2 C (O) NH 4 - [-NHC (O) CH 3 -phenyl], -CH 2 C (O) NH 4 -pyridyl, -CH2C (O) NH-4- [dimetilaminof enyl], -CH2C (O) NH-3-enyl metoxif, -CH2CH2C (0) NH-4-chlorophenyl, -CH2CH2C (O) NH-2-pyridyl, -CH2CH2C (O) NH-4-methoxy-enyl, -CH2CH2C (O) NH-3-pyridyl, 4- [(CH3) 2NCH2CH20-] benzyl, - (CH2) 3NHC (NH) NH-S02-4-methylphenyl, - [(CH3) 2NHC2CH20-] benzyl, - (CH2) 4NHC (O) NHCH2CH3, - (CH2) 4NHC (O) NH-f enyl, - (CH2) 4NHC (O) NH-4-methoxyphenyl, -4- [4'-pyridyl-C (O) NH-] benzyl, 4- [3'-pyridyl-C (0) NH-] benzyl, 4- [NHC (O) NH-3 '-methylphenyl] benzyl, 4- [-NHC (O) CH2NHC (O) NH-3 '-methylphenyl] benzyl, 4 - [- NHC (0) - (2', 3'-dihydroindol-2-yl)] benzyl, 4-t-NHC ( O) -2 ', 3'-dihydro-N-Boc-indol-2-yl)] benzyl, p- [-OCH2CH2-l' - (4'-pyrimidyl) -piperazinyl] benzyl, 4- [-OCH2CH2- (1'-piperidinyl) benzyl, 4 - [- OCH2CH2- (1-pyrrolidinyl)] benzyl, 4- [-OCH2CH2CH2- (1'-piperidinyl)] benzyl, -CH2-3- (1, 2.4- triazole ilo), 4- [-OCH2CH2CH2-4- (3'-chlorophenyl) -piperazin-1-yl] benzyl, 4- [-OCH2CH2N (f) CH2CH3] benzyl, 4- [-OCH2-3 '- (N- Boc) -piperidinyl] benzyl4- [di-n-pentylamino] benzyl, 4- [n-pentylamino] benzyl, 4- [di-4-propylamino-CH2CH20-] benzyl, 4- [-OCH2CH2- (N-morpholinyl)] benzyl, 4- [-0- (3 '- (N-Boc) -piperidinyl] benzyl, 4- [-0CH2CH (NHBoc) CH2cyclohexyl] benzyl, p- [OCH2CH2- (N-piperidinyl] benzyl, 4- [OCH2CH2CH2- ( 4-m-chlorophenyl) -piperazin-1-yl] -benzyl, 4- [-OCH 2 CH 2 - (N-homopiperidinyl) benzyl, 4 - [- NHC (0) -3 '- (N-Boc) -piperidinyl] benzyl 4- [-0CH2CH2N (benzyl) 2] benzyl, -CH2-2-thiazolyl, 3-hydroxybenzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, 4- [-NHC (S) NHCH2CH2- (N-morpholino )] benzyl, 4- [-OCH2CH2N (C2H5) 2] benzyl, 4- [-OCH2CH2CH2N (C2H5) 2] benzyl, 4- [CH3 (CH2) 4NH-] benzyl, 4- [Nn-butyl, Nn-pentylamino -] benzyl, 4- [-NHC (O) - '-piperidinyl] benzyl, 4- [-NHC (O) CH (NHBoc) (CH2) 4NHCbz] benzyl, 4- [-NHC (O) - (1' , 2 ', 3', 4 '-tetrahydro-N-Boc-isoquinolin-1'-yl] benzyl, p- [-OCH2CH2CH2-l- (4'-methyl) -piperazinyl] benzyl, - (CH2) 4NH -Boc, 3- [-OCH2CH2CH2N (CH3) 2] benzyl, 4- [-OCH2CH2CH2N (CH3) 2] benzyl, 3 - [- OCH2CH2 (1-pyrrolidinyl)] benzyl, 4- [-OCH2CH2CH2N (CH3) benzyl] benzyl, 4- [-NHC (S) NHCH2CH2CH2- (N -morpholino)] benzyl, 4- [-OCH2CH2- (N-morpholino)] benzyl, 4 - [- NHCH2- (4'-chlorophenyl)] benzyl, 4- [-NHC (O) NH- (4'-cyanofenyl)] benzyl, - [-OCH2COOH] benzyl, 4- [-OCH2COO-t-butyl] benzyl, 4- [-NHC (O) -5 '-fluoroindol-2-yl] benzyl, 4- [-NHC (S) NH (CH2 ) 2-l-piperidinyl] benzyl, 4- [-N (S02CH3) (CH2) 3-N (CH3) 2] benzyl, 4- [-NHC (O) CH2CH (C (O) OCH2f) -NHCbz] benzyl , 4- [-NHS (O) 2CF3] benzyl, 3- [-0- (N-methylpiperidin-4 '-yl] benzyl, 4 - [- C (= NH) NH2] benzyl, 4- [-NHS02- CH2C1] benzyl, 4- [-NHC (0) - (1 ', 2', 3 ',' -tetrahydroisoquinolin-2'-yl] benzyl, 4- [-NHC (S) NH (CH2) 3-N- morph olino] benzyl, 4- [-NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, 4- [-C (0) NH2] benzyl, 4- [-NHC (0) NH-3 '-methoxyphenyl] benzyl, 4- [-OCH2CH2-indol-3'-yl] benzyl, 4- [-OCH2C (0) NH-benzyl] benzyl, 4- [-OCH2C (0) 0-benzyl] benzyl, 4- [-0CH2C (0 ) OH] benzyl, 4- [-OCH2-2 '- (4', 5 '-dihydro) imidazolyl] benzyl, -CH2C (0) NHCH2- (dimethylamino) phenyl, -CH2C (0) NHCH2- (4-d) imethylamino) phenyl, 4- [-NHC (0) -L-2 '-pyrrolidinyl-N-S02-4' -methylphenyl] benzyl, 4- [-NHC (0) NHCH 2 CH 2 CH 3] benzyl, 4-aminobenzyl] benzyl, - [-0CH2CH2-1- (4-hydroxy-4- (3-methoxypyrrol-2-yl) -piperazinyl] benzyl, 4- [-0- (N-methylpiperidin-4 '-yl)] benzyl, 3-methoxybenzyl 4- [-NHC (0) -piperidin-3 '-yl] benzyl, 4- [-NHC (O) -pyridin-2'-yl] benzyl, 4- [-NHCH2- (4'-chlorophenyl)] benzyl, 4- [-NHC (0) - (N- (4 * -CH3-f-S02) -L-pyrrolidin-2'-yl)] benzyl, 4- [-NHC (0) NHCH2CH2-f] benzyl 4- [-0CH2C (0) NH2] benzyl, 4- [-0CH2C (0) NH-t-butyl] benzyl, 4- [-OCH2CH2-l- (4-hydroxy-4-phenyl) -piperidinyl] benzyl , 4- [-NHS02-CH = CH2] benzyl, 4- [-NHS02-CH2CH2C1] benzyl, -CH2C (0) NHCH2CH2N (CH3) 2, 4- [(1'-Cbz-piperidin-4 '-il) C (0) NH-] benzyl, 4- [(1-Boc-piperidin-4'-yl) C (0) NH-] benzyl, 4- [(2'-bromophenyl) C (0) NH-] benzyl, 4- [-NHC (0 ) -pyridin-4 '-yl] benzyl, 4- [(4' - (CH3) 2NC (0) 0-) phenyl) -C (0) NH-] benzyl, 4 - [- NHC (0) -l '-methylpiperidin-4' -yl] benzyl, 4- (dimethylamino) benzyl, 4- [-NHC (0) - (1 '-N-Boc) -piperidin-2' -yl] benzyl, 3- [-NHC (0) -pyridin-4 '-yl] benzyl, 4- [(tert-butyl-0 (0) CCH2-0-benzyl) -NH-] benzyl, [BocNHCH2C (0) NH-] butyl, 4-benzylbenzyl, 2-hydroxyethyl, 4 - (Et) 2NCH2CH2CH2NHC (S) NH-] benzyl, 4 - (1 * -Boc-4 '-hydroxypyrrolidin-2' -yl) C (O) NH-benzyl, 4-fCH2CH2CH2NHC (S) NH-] benzyl, 4 - (perhydroindolin-2'-yl) C (O) NH-] benzyl, 2- 4-hydroxy-4- (3-methoxythien-2-yl) piperidin-1 - il] ethyl, 4 - (1 '-Boc-perhydroindolin-2'-yl) -C (O) NH-] benzyl, 4- N -3-methylbutyl-N-trifluoromethanesulfonyl) amino] benzyl, 4-N- vinylsulfonyl) amino] benzyl, 4- 2- (2-azabicyclo [3,2,2] octan-2-yl) ethyl- 0-] benzyl, 4- 4 '-hydroxypyrrolidin-2'-yl) C (O) NH-] benzyl, 4-fNHC (S) NH) benzyl, 4-EtNHC (S) NH) benzyl, 4-fCH2NHC (S) NH) benzyl, 3- (1 '-Boc-piperidin-2' -il) C (O) H-] benzyl, 3-piperidin-2'-yl-C (O) NH-] benzyl, 4 - (3 '-Boc-thiazolidin-4' -yl) C (O) NH-] benzyl , 4-pyridin-3 '-il-NHC (S) NH) benzyl, 4- CH3NHC (S) NH) benzyl, 4-H2NCH2CH2CH2C (O) NH) benzyl, 4-BocHNCH2CH2CH2C (O) NH) benzyl, 4-pyridin-4 '-il-CH2NH) benzyl, .. . -. ^ h - «- 4- (N, N-di (4-N, N-dimethylamino) benzyl) amino] benzyl, 4- (l-Cbz-piperidin-4-yl) C (O) NH-] butyl , 4- fCH2OCH2 (BocHN) CHC (O) NH] benzyl, 4- (piperidin-4 '-yl) C (O) NH-] benzyl, 4- (pyrrolidin-2' -yl) C (O) NH- ] benzyl, 4-pyridin-3'-yl-C (O) NH) butyl, 4-pyridin-4'-yl-C (O) NH) butyl, 4-pyridin-3'-yl-C (O) NH) benzyl, 4- CH3NHCH2CH2CH2C (O) NH-] benzyl, 4- CH3N (Boc) CH2CH2CH2C (O) NH-] benzyl, 4-aminomethyl) benzyl, 4-fCH2OCH2 (H2N) CHC (O) NH] benzyl, 4- (1'-4'-di (Boc) piperazin-2'-yl) -C (O) NH-] benzyl, 4- (piperazin-2'-yl) -C (O) NH-] benzyl, 4- (N-Toluenesulfonylpyrrolidin-2 '-yl) C (O) NH-] butyl, 4-NHC (O) -4'-piperidinyl] butyl, 4-NHC (O) -1' -N-Boc -piperidin-2 '-yl] benzyl, 4- -NHC (O) -piperidin-2'-yl] benzyl4- (1 '-N-Boc-2', 3 '-dihydroindolin-2'-yl) -C (0) NH] benzyl, 4-pyridin-3' -il-CH2NH) benzyl, 4- (1 '-Cbz-piperidin-4' -yl) C (O) NH-] benzyl, 4- (piperidin-1 '-yl) C (O) CH3-0-] benzyl, 4- (CH3) 2NC (O) CH2-0-] benzyl, - ^^ - «iiféatei 4- [HO (O) C (Cbz-NH) CHCH2CH2-C (O) NH-] benzyl, 4- [fCH20 (O) C (Cbz-NH ) CHCH2CH2-C (O) NH-] benzyl, 4- [-NHC (O) -2 '-methoxyphenyl] benzyl, 4- [(pyrazin-2' -yl) C (O) NH-] benzyl, 4- [HO (0) C (NH2) CHCH2CH2-C (0) NH-] benzyl, 4- (2'-formyl-l ', 2', 3 ', 4' -tetrahydroisoquinolin-3'-yl-CH2NH-) benzyl, N-Cbz-NHCH2-, 4- [(4'-methylpiperazin-1 '-yl) C (0) 0-] benzyl, 4- [CH3 (N-Boc) NCH2C (0) NH-] benzyl, 4- [-NHC (0) - (1 ', 2', 3 ', 4' -tetrahydro-N-Boc-isoquinolin-3 '-yl] benzyl, 4- [CH3NHCH2C (0) NH-] benzyl , (CH3) 2NC (0) CH2-, 4- (N-methylacetamido) benzyl, 4- (1 ', 2', 3 ', 4'-tetrahydroisoquinolin-3'-yl-CH2NH-) benzyl, 4- [ (CH3) 2NHCH2C (0) NH-] benzyl, (1-toluenesulfonylimidizol-4-yl) m ethyl, 4- [(1-Boc-piperidin-4'-yl) C (0) NH-] benzyl, 4-trifluoromethylbenzyl, 4- [(2'-bromophenyl) C (0) NH-] benzyl, 4 - [(CH3) 2NC (0) NH-] benzyl, 4- [CH30C (0) NH-] benzyl, 4- [(CH3) 2NC (0) 0-] benzyl, * S ^^^^^ 4- (CH3) 2NC (O) N (CH3) -] benzyl, 4- N-methyltrifluoroacetamido) benzyl, 4- (1'-methoxycarbonylpiperidin-4-yl) C (0) NH -] benzyl, 4- (4'-phenylpiperidin-4 '-yl) C (O) NH-] benzyl, 4- (4'-phenyl-1' -Boc-piperidin-4'-yl) -C (O ) NH-] benzyl, 4- (piperidin-4 '-yl) C (O) 0-] benzyl, 4- [(1'-methylpiperidin-4' -yl) -0-] benzyl, 4- (1 ') -methylpiperidin-4-yl) C (O) 0-] benzyl, 4- (4'-methylpiperazin-1'-yl) C (O) NH-] benzyl, 3- (CH3) 2NC (O) 0-] benzyl, 4- (4 '-phenyl-1' -Boc-piperidin-4 '-yl) - C (0) 0-] benzyl, 4-N-toluenesulfonylamino) benzyl, 4- (CH 3) 3CC (O) H -] benzyl, 4- (morpholin-4 '-yl) C (O) NH-] benzyl, 4- (CH3CH2) 2NC (O) NH-] benzyl, 4-C (O) NH- (4' - pyridinyl)] benzyl, 4- (2'-trifluoromethylphenyl) C (O) NH-] benzyl, 4- (2'-methylphenyl) C (O) NH-] benzyl, 4- (CH3) 2NS (O) 20- ] benzyl, 4- (pyrrolidin-2'-yl) C (O) NH-] benzyl, 4- N-NHC (O) -piperidin-1-yl] -benzyl, 4- (thiomorpholin-4'-yl) C (O) NH-] benzyl, ^ gg ^ g ^ 4- [(thiomorpholin-4'-yl sulfone) -C (0) NH-] benzyl, 4- [(morpholin-4 '-yl) C (0) Obencil, 3-nitro-4- (CH30C (0) CH20-] benzyl, (2-benzoxazolinon-6-yl) -methyl-, (2H-1,4-benzoxazin-3 (4H) -one-7-yl) methyl-, 4-t (CH3) 2NS (0) 2NH-] benzyl, 4- [(CH3) 2NS (0) 2N (CH3) -] benzyl, 4- [(thiomorpholin-4 '-yl) C (0) 0- ] benzyl, 4- [(thiomorpholin-4 '-yl sulfone) -C (0) 0-] benzyl, 4- [(piperidin-1-yl) C (0) 0-] benzyl, 4- [(pyrrolidine -1 '-il) C (0) 0-] benzyl, 4- [(4'-methylpiperazin-1' -yl) C (0) 0-] benzyl, 4- [(2'-methylpyrrolidin-1 '- il) -, (pyridin-4-yl) methyl-, 4- [(piperazin-4 '-yl) -C (0) 0-] benzyl, 4- [(1-Boc-piperazin-4' -il ) -C (0) 0-] benzyl, 4- [(4'-acetylpiperazin-1-yl) C (0) 0-] benzyl, p- [(4'-methanesulfonylpiperazin-1'-yl) -benzyl , 3-nitro-4- [(morpholin-4 '-yl) -C (0) 0-] benzyl, 4-. { [CH3) 2NC (S)] 2N-} benzyl, N-Boc-2-aminoethyl-, 4- [(1,1-dioxothiomorpholin-4-yl) -C (0) 0-] benzyl, 4- [(CH3) 2NS (0) 2-] benzyl, 4- (imidazolid-2 '-one-1'-yl) benzyl, 4- [(piperidin-1-yl) C (0) 0-] benzyl, lN-benzyl-imidazol-4-yl-CH2-, 3,4-dioxyethylenebenzyl, 3,4-dioxymethylenebenzyl, 4- [-N (S02) (CH3) CH2CH2CH2N (CH3) 2] benzyl, 4- (3'-formylimidazolid-2'-ona-1'-yl) benzyl , 4- [NHC (0) CH (CH2CH2CH2CH2NH2) NHBoc] benzyl, [2 '- [4"-hydroxy-4" - (3' '' -methoxy-2''-yl) piperidin-2 ' '-yl] ethoxy] benzyl and p- [(CH 3) 2 -NCH 2 CH 2 N (CH 3) C (0) 0-] benzyl.
27. 27. The pharmaceutical composition according to claim 16, characterized in that R6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n -butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-a-iso-propyl-4-b-methylcyclohexoxy, 2-b-isopropyl-4-b-methylcyclohexoxy, -NH2, benzyloxy, -NHCH2C00H, -NHCH2CH2C00H, -NH-adamantyl, -NHCH2CH2C00CH2CH3, -NHS02-p-CH3-f, -NH0R8 where R8 is hydrogen, methyl, iso-propyl or benzyl, O- (N-succinimidyl), -0-colest-5-en -3-ß-ilo, -0CH2-0C (O) 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 ilo, 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) 0CH2CH2. i ^^ i-M-i-MÍfÍI
28. 28. A method for binding VLA-4 to a biological sample, characterized in that it comprises contacting the biological sample with a compound of claim 1 or 2 under conditions wherein the compound binds to VLA-4.
29. 29. A method for treating an inflammatory condition in a mammalian patient, such a condition is mediated by VLA-4, the method is characterized in that it comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition of claim 15 or 16.
30. 30. The method according to claim 29, characterized in that the inflammatory condition is selected from the group consisting of asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis , meningitis, encephalitis, cerebrovascular accident, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury. ^^^ ^ ^ j ^ MEASURED LEUKOCYTES THROUGH ALFA4 BETA1 INTEGRINE AND CD49d / CD29 (VLA-4) SUMMARY OF THE INVENTION Compounds that bind VLA-4 are described. Some of these compounds also inhibit leukocyte adhesion and in particular, moderate leukocyte adhesion by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian, e.g., human patient, 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 diseases of the brain such as multiple sclerosis.