MXPA01007330A

MXPA01007330A - Fused ring heteroaryl and heterocyclic compounds which inhibit leukocyte adhesion mediated by vla-4

Info

Publication number: MXPA01007330A
Application number: MXPA/A/2001/007330A
Authority: MX
Inventors: Francine S Grant; Andrei W Konradi; Michael A Pleiss; Eugene D Thorsett
Original assignee: Elan Pharmaceuticals Inc
Priority date: 1999-01-22
Filing date: 2001-07-19
Publication date: 2002-05-09

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

HETEROCICLIC COMPOUNDS AND HETEROARILOS OF FUSED RING WHICH INHIBIT THE ADHESION OF THE LEUKOCYTE MEDIATED BY ALPHA4 BETA1 INTEGRINE AND CD49d / CD29 (VLA-4) BACKGROUND OF THE INVENTION Field of the Invention This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.

References The following publications, patents and patent applications are cited in this application as index numbers overwritten: 1"Hemler and Takada, European Patent Applicati on 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 ) 3 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) REF: 131119 Mulligan, et al., J. Immunology, 150: 2407 (1993) Cybulsky, et al., Science, 251: 788 (1991) Li, et al., Arterioscler. Throm., 13: 197 (1993) 11 Sassevill, et al., Am. J. Path. , 144: 27 (1994) 12 Yang, et al., Proc. Nat. Acad. Science (USA), 90: 10494 (1993) 13 Burkly, et al., Diabetes, £ 3: 529 (1994) 14 Baron, et al., J. Clin. Invest., 93: 1700 (1994) Hamann, et al., J. Immunology, 152: 3238 (! 994) 16 Yednock, et al., Nature, 356: 63 (1992) 17 Baron, et al., J. Exp. Med., 177: 57 (1993) 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., 8_9: 1445 (1991) 22 Paul, et al., Transpl. Proceed. , 25: 813 (! 993) 23 Okarhara, et al., Can. Res., 54: 3233 (1994) 2 Paavonen, et al., Int. J. Can., _58: 298 (1994) 2b Schadenforf, et al., J. Path., 170: 429 (1993) 26 Bao, et al., Diff., 52239 (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., North American Pa tent No. 5, 510, 332, issued April 23, 1996 30 Publication of International Patent Application No. WO 96/01644 All publications, patent applications and patents are incorporated herein for reference in their entirety to the same extent as if each individual publication, patent application or patent is individually and specifically indicated to be incorporated for reference in its entirety.

STATUS OF THE TECHNIQUE VLA-4 (also referred to as αβ integrin and CD49d / CD29), first identified by Hemler and Takada1 is an element of the ßl integrin family of cell surface receptors, each of which comprises two subunits , a string a and a string ß. The VLA-4 contain a chain a.4 and a chain ßl. There are at least nine integrins, all from the same chain ßl and each has 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 to non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed in the endothelial cells of the human umbilical vein activated by the cultured cytokine. The different epitopes of VLA-4 are responsible for the binding activities of fibronectin and VCAM-1 and each activity has been shown to be independently inhibited.2 Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimuli, activated vascular endothelial cells express molecules that are adhesive to leukocytes. The adhesion mechanics of the leukocyte to the endothelial cells involve, in part, the recognition and binding of cell surface receptors in leukocytes to the corresponding cell surface molecules in endothelial cells. Once bound, the leukocytes migrate through the wall of the blood vessel to enter the injured site and release the chemical mediators to fight the infection. For review of adhesion receptors of the immune system, see, for example, Springer3 and Osborn. Inflammatory disorders of the brain, such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), and meningitis, are examples of central nervous system disorders in which the adhesion mechanism of the endothelium / leukocyte results in the destruction of another form of healthy brain tissue. Large numbers of leukocytes migrate through the blood-brain barrier (BBB) in subjects with these inflammatory diseases. The toxic mediators of leukocyte release cause extensive tissue damage resulting in impaired nerve conduction and paralysis. In other organ systems, 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 following myocardial ischemia to the heart tissue can be further complicated by the entrance of the leukocyte to the injured tissue, causing still further attack (Vedder et al.5). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma6-8, Alzheimer's disease, atherosclerosis9-10, AIDS dementia11, diabetes12-14 (including 'early juvenile diabetes onset), inflammatory bowel disease15 ( including ulcerative colitis and Crohn's disease), multiple sclerosis16-17, rheumatoid arthritis18-21, tissue transplantation22, tumor metastasis23-28, meningitis, encephalitis, strokes, and other brain traumas, nephritis, retinitis, atopic dermatitis, psoriasis, ischemia myocardial and acute lesion of the lung mediated by leukocyte such as that which occurs in the respiratory distress syndrome in adults. In view of the above, assays for the determination of the level of the VLA-4 in a biological sample containing the VLA-4 could be useful, for example, diagnose the conditions mediated by the VLA-. Additionally, neglecting 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 is directed to these and other needs BRIEF DESCRIPTION OF THE INVENTION This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to test the presence of VLA-4 in a sample and in pharmaceutical compositions to inhibit cell adhesion mediated by VLA-4, for example, by binding a VCAM to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC50 of about 15 μM or less (measured using the procedures described in Example A below) the compounds are defined by the formula la and Ib later: the Ib wherein, in formula la, R1 and R2, together with the carbon atom and W to which they are attached respectively, are combined to form a fused ring heterocyclic group or a fused ring heteroaryl optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; in formula Ib, R1 and R2, together with the carbon atom and W to which they are respectively attached, are combined to form an optionally fused ring heterocyclic group containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen , nitrogen and sulfur; and further wherein the fused ring heterocyclic or fused ring heteroaryl group of the formula Ia or Ib is optionally substituted, at any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl , alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-a, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol , thioalkyl, thioalkyl or substituted, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (02) -alkyl, -OS (0) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02) -substituted heteroaryl, -0S (02) -heterocyclic, -OS (02) -substituted heterocyclic, -0S (02) -NRR wherein each R is independently hydrogen or alkyl, NRS (02) -alkyl, -NRS (02) - substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, -NRS (02) -heteroaryl, NRS (02) -sheteroaryl substituted, -NRS (02) -heterocyclic, NRS (02) -heterocyclic substituted, -NRS (02) -NR-alkyl, NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR- substituted heteroaryl, -NRS (02) -NR-heterocyclic, -NRS (02) - NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R1] 2 and -N [S (02) -NR! ] 2 wherein each R 'is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, 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, amino mono- and di-heterocyclic, amino mono- and di-heterocyclic substituted, di-substituted asymmetric 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 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 -S02NRR where R is hydrogen or I rent; R3 is selected from the group consisting of: (a) - (CH2) X-Ar-R35 where R35 is selected from the group consisting of -0-Z-NR36R36 'and -O-Z-R37 in. wherein R36 and R36 'is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and wherein R36 and R36' are combined to form a heterocycle or a substituted heterocycle, R37 is selected of the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C (O) - and -S02-, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of 1 to 4; and (b) Ar1-Ar2-C? _? 0alkyl-, Ar1-Ar2-C2_? 0alkenyl- and Ar1-Ar2-C2_? 0alkynyl-, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is substituted optionally with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra; RJ is selected from the group consisting of hydrogen, alkyl of 1 to ID-carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, aryl, arylalkyl of 1 to 1 carbon atoms, heteroaryl , and heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; Q is selected from the group consisting of -O-, -S-, -S (O) -, -S (0) 2-, and -NR4-; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R 4 and R1 or R4 and R2, together with the atoms to which they are attached, are combined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group; W is selected from the group consisting of nitrogen and carbon; and W is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S (0), and S (0) 2; X is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenexy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and -NR "R" wherein each R "is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Ra is selected from the group consists of Cy, -0Rd, -N02, halogen, -S (0) mRd, -SRd, -S (0) 20Rd, -S (0) mNRdRe, -NRdRe, -0 (CRfRg) nNRdRe, -C (0) ) R, -C02Rd, -C02 (CRfRg) nC0NRdRe, -0C (0) Rd, -CN, -C (0) NRdRe, -NRdC (0) Re, -0C (0) NRdRe, -NRdC (0) 0Re , -NRdC (0) NRdRe, -CRd (N-0Re), CF3, and -0CF3, where Cy is optionally substituted with one to four substituents selected indepe of Rc; Rb is selected from the group consisting of Ra, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, heteroaryl, 1 to 10 carbon atoms, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc; Rc is selected from the group consisting of halogen, amino, carboxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms, hydroxy, CF3, and aryloxy; Rd and Re are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, Cy and Cy-C? -? 0alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 elements containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and R9 are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, Cy and Cy-C? -alkyl; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 elements containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; and pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are represented by the following formula II: wherein R3, R3 ', Q and X are as defined above; ring A forms a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic ring; Ring B forms an aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; and pharmaceutically acceptable salts thereof. The most preferred compounds of this invention are represented by the formula Illa posterior: wherein R3, R3 'and X are as defined above; And it is oxygen, sulfur, -S (O) -, -S (0) 2-, > NR5 or > N-S (0) 2R6; R4 'is selected from the group consisting of hydrogen and alkyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl; Rd is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted-cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic; heteroaryl and substituted heteroaryl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-a, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, carboxylheteroaryl substituted, carboxylheterocyclic, substituted carboxylheterocyclic, substituted 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 (02) -alkyl, OS (0) 2-substituted alkyl, -OS (0) ) 2-aryl, -OS (02) -substituted aryl, -OS (0) -heteroaryl, -OS (02) -substituted heteroaryl, -OS (02) -heterocyclic, -OS (02) -substituted heterocyclic, -0S (02) -NRR wherein each R is independently hydrogen or alkyl, -NRS (0) -alkyl, -NRS (02) -substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, NRS ( 02) -heteroaryl, -NRS (02) -substituted heteroaryl, NRS (02) -heterocyclic, -NRS (02) -substituted heterocyclic, NRS (02) -NR-alkyl, -NRS (02) -NR-substituted alkyl, NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR-substituted heteroaryl, -NRS (02) -NR-heterocyclic , -NRS (02) -NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R1] 2 and -N [S (02) -NR '] 2 wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and dialkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and substituted di-heteroarylamino, amino mono- and di-heterocyclic amino, substituted mono- and di-heterocyclic amino, disubstituted asymmetric amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and heterocyclic substituted and substituted alkyl groups having amino groups blocked by the conventional blocking groups such as Boc, Cbz, formyl, and the like, or substituted alkyl / alkyl groups with -S02-alkyl, -S02-alkyl subst ituido, 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; W "is selected from the group consisting of nitrogen and carbon (i.e., CH), and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of this invention are represented by the following formula Illb: wherein, R4 ', R7, R8, W ", X and Y are as defined above, R9 is selected from the group consisting of -OZ-NR1 ^ 11' and -OZ-R12 wherein R11 and R11 'are selected independently of the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R11 and R11 'are combined to form a heterocycle or a substituted heterocycle, R12 is selected from the group which consists of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C (O) - and -S02-, x is an integer from 1 to 4, and pharmaceutically acceptable salts thereof.

Other preferred compounds of this invention include those having the formula lile: wherein R, R, R, R, R and X are as defined herein; and R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxyheterocyclic , carboxilheterocíclico substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfona, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl I, thiocycloalkyl, substituted thiocycloalkyl I, thioheteroaryl, substituted thioheteroaryl I, thioheterocyclic, substituted thioheterocyclic, heteroaryl, heteroaryl replaced it do, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, • oxythiocarbonylamino, -OS (02) -alkyl, -OS (O) 2-substituted alkyl, -OS (O) 2-aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02) -substituted heteroaryl, -0S (02) -heterocyclic, -OS (02) -substituted heterocyclic, -OS (02 ) -NRR wherein each R is independently hydrogen or alkyl, - NRS (02) -alkyl, -NRS (02) -substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, -NRS (02) ) -heteroaryl, NRS (02) -substituted heteroaryl, -NRS (02) -heterocyclic, NRS (02) -substituted heterocyclic, -NRS (02) -NR-alkyl, NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR- substituted heteroaryl, -NRS (02) -NR-heterocyclic, -NRS (02) - NR-substituted heterocyclic where R is hydrogen or alkoxy uilo, -N [S (02) -R '] 2 and -N [S (02) -NR'] 2 where each R 'is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl , substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono - and substituted di-heteroarylamino, amino mono- and di-heterocyclic amino, substituted mono- and di-heterocyclic amino, di-substituted asymmetric 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 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 -S02NRR where R is hydrogen or alkyl; and pharmaceutically acceptable salts thereof.

Still other preferred compounds of this invention are represented by formula IVa and IVb below: IVa rvb wherein, in the formula IVa, R1 and R2, together with the carbon atom and to which they are attached respectively, combine to form a fused ring or fused ring heterocyclic heterocyclic group, optionally containing 1 to 3 heteroatoms additional selected from the group consisting of oxygen, nitrogen and sulfur; in formula IVb, R1 and R2, together with the carbon atom and W, to which they are respectively linked, combine to form a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of of oxygen, nitrogen and sulfur; and further, wherein said fused ring heterocyclic or fused ring heteroaryl group of formula IVa or IVb is optionally substituted, at any ring atom capable of being substituted, with 1-3 substituents selected from the group consisting of alkyl , substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone , thiol, thioalkyl, thioalq substituted uilo, 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 (02) -alkyl, -OS (0) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02 ) -substituted heteroaryl, -0S (02) -heterocyclic, -OS (02) -substituted heterocyclic, -OS (02) -NRR wherein each R is independently hydrogen or alkyl, -NRS (02) -alkyl, -NRS (02) ) -substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, -NRS (02) -heteroaryl, NRS (02) -substituted heteroaryl, -NRS (02. -heterocyclic, NRS (02) -substituted heterocyclic, -NRS (02) -NR-alkyl, NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR-heteroaryl substituted, -NRS (02) -NR-heterocyclic, -NRS (02) -NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R '] 2 and -N [S (02) - NR '] 2 wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di- (alkyl) substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, amino mono- and di-heterocyclic substituted , di-substituted asymmetric amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and group s substituted alkyl having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted alkyl / alkyl groups 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 -S02NRR where R is hydrogen or alkyl; R13 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, Cy, and Cy-C? -aoalkyl, wherein the alkyl is optionally substituted with one to four substituents independently selected from Ra; and Cy is optionally substituted with one to four substituyontes independently selected from Rb; R14 is selected from the group consisting of (a) - (CH2) X-Ar-R35 where R35 is selected from the group consisting of -0-Z-NR36R36 'and -OZ-R37 wherein R36 and R36' are selected independently of the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and wherein R36 and R36 'are combined to form a heterocycle or a substituted heterocycle, R37 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C (O) - and -S02-, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; and (b) Ar1-Ar2-C? _? 0alkyl-, Ar1-Ar2-C2-? 0alkenyl- and Ar1-Ar2-C2-? oalkynyl-, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra; R15 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, aryl, arylalkyl of 1 to 10 carbon atoms, heteroaryl, and heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; R is selected from the group consisting of Cy, ORd, -N02, halogen, -S (0) mRd, -SRd, -S (0) 20Rd, -S (0) mNRdRe, -NRdRe, -0 (CRfRg) nNRdRe , -C (0) R, -C02Rd, ~ C02 (CRfRg) nC0NRRe, -0C (0) Rd, -CN, -C (0) NRdRe, -NRdC (0) Re, -0C (0) NRdRe, - NRdC (0) 0Re, -NRdC (0) NRRe, -CRd (N-0Re), CF3, and -0CF3; wherein Cy is optionally substituted with one to four substituents independently selected from Rc; Rb is selected from the group consisting of Ra, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, heteroaryl, 1 to 10 carbon atoms, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc; Rc is selected from the group consisting of halogen, amino, carboxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms, hydroxy, CF3, and aryloxy; Rd and Re are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, Cy and Cy-C? _? 0alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or R and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 elements containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and Rg are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, Cy and Cy-Ci-? 0alkyl; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 elements containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Rh is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cyano, aryl, arylalkyl of 1 to 10 carbon atoms, heteroaryl, heteroarylalkyl of 1 to 10 carbon atoms, or -S02Ri; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from Ra; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb; R1 is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, and aryl; wherein alkyl, alkenyl, and aryl are each optionally substituted with one to four substituents independently selected from Rc; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; W is selected from the group consisting of carbon and nitrogen; W is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S (0) and S (0) 2; X 'is selected from the group consisting of C (0) 0Rd, -P (0) (0Rd) (0Re), -P (0) (Rd) (0Re), -S (0) m0Rd, C (0) NRdRh, and 5-tetrazolyl; and pharmaceutically acceptable salts thereof.

Other preferred compounds of this invention are represented by the formula Va: wherein W ", Y, R7, R8, R13, R14, R15 and X 'are as defined above, and pharmaceutically acceptable salts thereof Other preferred compounds are those of the formula Vb: R '"Ris wherein R7, R8, R10, R13, R14, R15 and X' are as defined above, and pharmaceutically acceptable salts thereof.

Still other preferred compounds include those represented by the formula Via and VIb: Via VTb where, in the formula Via, R1 and R2, together with the carbon atom and W to which they are respectively bound, combine to form a fused ring or fused ring heterocyclic heterocyclic group optionally containing 1 to 3 selected heteroatoms from the group consisting of oxygen, nitrogen and sulfur; in formula VIb, R1 and R2, together with the carbon atom and W to which they are respectively linked, combine to form a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consisting of of oxygen, nitrogen and sulfur; and further, wherein said fused ring heterocyclic or fused ring heteroaryl group of formula Vía or VIb is optionally substituted, at any ring atom capable of being substituted, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, thioalq substituted uilo, 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 (02) -alkyl, -OS (O) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02) -substituted heteroaryl, -0S (02) -heterocyclic, -OS (02) -substituted heterocyclic, -0S (02) -NRR wherein each R is independently hydrogen or alkyl, NRS (02) -alkyl, -NRS (02) - substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, -NRS (02) -heteroaryl, NRS (02) -sheteroaryl substituted, -NRS (02) -heterocyclic, NRS (02) -heterocyclic substituted, -NRS (02) -NR-alkyl, NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR-substituted heteroaryl, -NRS (02) -NR- heterocyclic, -NRS (02) -NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R? 2 and -N [S (02) -NR '] 2 wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, substituted mono- and di-heterocyclic amino, di-substituted asymmetric amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and groups substituted alkyl having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted alkyl / alkyl groups 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 -S02NRR where R is hydrogen or alkyl; R23 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms optionally substituted with one to four substituents independently selected from Ra; and Cy is optionally substituted with one to four substituents independently selected from Rb; R24 is selected from the group consisting of Ar1-Ar2-C? -? 0alkyl, Ar1-Ar2-C2_? 0alkenyl and Ar1-Ar2-C2_alkalkynyl, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra; R25 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, aryl, arylalkyl of 1 to 10 carbon atoms, heteroaryl, and heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; Ra 'is selected from the group consisting of Cy, -ORd', -N02, halogen, -S (0) mRd ', -SRd', -S (0) 2ORd ', -S (O) mNRd'Re', -NRd'Re ', -0 (CRf'Rg') nNRd'Re ', -C (0) Rd', -C02Rd ', C02 (CRf, Rg') nC0NRd'Re ', -0C (0) Rd' , -CN, -C (O) NRd'Re ', -NRd'C (O) Re', -OC (0) NRd'Re ', -NRd'C (0) ORe', -NRd'c (O) ) NRd'Re ', -CRd' (N-ORe '), CF3, and -OCF3; wherein Cy is optionally substituted with one to four substituents independently selected from Rc '; Rb 'is selected from the group consisting of Ra', alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc '; Rc is selected from the group consisting of halogen, amino, carboxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms, hydroxy, CF3, and aryloxy; R 'and Re' are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, Cy and Cy-C? -? Oalkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc '; or Rd 'and Re' together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 elements containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf 'and Rg' are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, Cy and Cy-C? _alkyl; or Rf 'and Rg together with the carbon to which they are attached form a ring of 5 to 7 elements containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Rh 'is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cyano, aryl, arylalkyl of 1 to 10 carbon atoms , heteroaryl, heteroarylalkyl of 1 to 10 carbon atoms, or -S02R1 '; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from Ra '; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb '; R1 'is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents selected from Rc '; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X 'is selected from the group consisting of C (0) ORd', -P (O) (ORd ') (ORe'), -P (O) (Rd ') (ORe'), -S (0) mORd ', C (0) NRd'Rh', and 5-tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and pharmaceutically acceptable salts thereof.

Yet another preferred set of the compounds of this invention are those represented by the formula Vlla posterior: wherein R7, R8, R23, R24, R25, W ", Y are as defined above X" is selected from the group consisting of -C (0) ORd, -P (O) (ORd) (ORe), - P (O) (Rd) (ORe), S (0) mORd, -C (0) NRdRh, and 5-tetrazolyl; and pharmaceutically acceptable salts thereof.

Other preferred compounds are those of the formula Vllb: wherein R7, R8, R10, R23, R24, R25 and X "are as defined above, and pharmaceutically acceptable salts thereof.

In formula Ia-b, II, Illa-c above, when X is different than -OH the pharmaceutical salts thereof, X is a substituent which will convert (eg, hydrolyze, metabolize, etc.), in vivo to a compound where X is -OH or a salt thereof. Accordingly, suitable groups X are any of the pharmaceutically acceptable groups recognized in the art, which will hydrolyze or otherwise convert in vivo to a hydroxyl group or a salt thereof, including, by way of example, esters (X is alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, alkenoxy, substituted alkenoxy, cycloalkenoxy, substituted cycloalkenexy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocycle, substituted heterocycle, and the like). In the compounds of formula Ia-b, IVa-b, Vla-b above, R1 and R2 are preferably combined to form a benzimidazolyl, benzoxazolyl, benzothiazolyl, substituted benzimidazolyl, substituted benzoxazolyl, substituted benzothiazolyl, quinazolinyl or substituted quinazolinyl group. In the formula Illa-b, W is preferably nitrogen.

In a preferred embodiment of this invention, R is selected from all possible isomers resulting from substitution with the following groups: 3- (CH3) 2NC (0) 0-] benzyl, 4- (CH3) 2NC (0) 0 -] benzyl, 4- (CH 3) 2 NS (O) 20 -] 'benzyl, 4- (piperidin-1' -yl) 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 '-formyloxypiperidin-1' -yl) C (O) O-] benzyl, 4- (4'-ethoxycarbonylpiperidin-1'-yl) C (O) O-] benzyl, 4- (4'-carboxypiperidine) -1 '-il) C (O) O-] benzyl, 4- (3'-hydroxymethylpiperidin-1'-yl) C (O) O-] benzyl, 4- (4'-hydroxymethylpiperidin-1'-yl) C (O) O-] benzyl, 4- (4'-pheny1-1 '-Boc-piperidin-4' -yl) C (0) 0-] benzyl, 4- (4'-piperidon-1'-yl) ethylene ketal) C (O) O-] benzyl, 4- (piperazin- 'yl) -C (O) O-] benzyl, 4- (1' -Boc-piperazin-4 '-yl) -C (O ) O-] benzyl, 4- (4'-methylpiperazin-1'-yl) C (O) 0-] benzyl, 4- (4'-methylhomo) piperazin-1 '-yl) C (O) O-] benzyl, 4- (4' - (2-hydroxyethyl) piperazin-1'-yl) C (O) O-] benzyl, 4- (4'-phenylpiperazine) -1 '-yl) C (O) O-] benzyl, 4- [(4' - (pyridin-2-yl) piperazin-1 '-yl) C (O) O-] benzyl, 4- [(' - (4-trifluoromethylpyridin-2-yl) piperazin-1'-yl) C (0) 0-] benzyl, 4- [('- (pyrimidin-2-yl) piperazin-1-yl) C (O) O-] benzyl, -4- [(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' -yl) C (0) 0-] benzyl, 4- [(4 '- (phenylNHC (0) -) piperazin-1' -yl) C (0) 0-] benzyl, 4- [(4 '- (phenylNHC (S) -) piperazin-1' -il ) C (O) 0-] benzyl, 4- [('-methansulfonylpiperazin-1' -il-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-1-yl) -C (0) 0-] benzyl, 4- [(thiomorpholine- 4 '-il) C (0) 0-] benzyl, 4- [(thiomorpholin-4'-yl sulfone) -C (0) 0-] benzyl, (alternative nomenclature 4- [(1,1-dioxothiomorpholin-4) - il) -C (0) 0-] benzyl), 4- [(pyrrolidin-1-iDC (O) O-] 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 (O) 0-] benzyl, 4- [(2'- (N, N-dimethylamino) ethyl) (CH3) NC (O) O-] benzyl, 4- [(2 '- (N-methyl-N-toluene-4-sulfonylamino) ethyl ) (CH3) NC (O) 0-] benzyl, 4- [(2 '- (morpholin-4' -yl) ethyl) (CH3) NC (O) O-] benzyl, 4- [(2 '- ( hydroxy) ethyl) (CH3) NC (O) O-] benzyl, 4- [(bis (2 '- (hydroxy) ethyl) NC (O) O-] benzyl, 4- [(2' - (formyloxy) ethyl) ) (CH3) NC (O) 0-] benzyl, 4- [(CH3OC (O) CH2) HNC (O) O-] benzyl, 4- [2 '- (phenylNHC (O) O-) ethyl-] HNC (O) O-] benzyl, 3-chloro-4- [(CH3) 2NC (O) 0-] benzyl, 3-chloro-4- [(4'-methylpiperazin-1'-yl) C (O) O -] benzyl, 3-chloro-4- [(4 '- (pyridin-2-yl) piperazin-1' -yl) C (O) O-] benzyl, 3-chloro-4- [(thiomorpholin-4 ' -yl) C (O) 0-] benzyl, and 3-fluoro-4- [(CH 3) 2 NC (0) 0-] benzyl.

In this embodiment, Ar is preferably aryl or substituted aryl and, even more preferably, is phenyl or substituted phenyl. Preferably, x is 1. In another preferred embodiment, R3 corresponds to group R6, (including preferred embodiments) found in International Patent Application Publication No. WO 98/53817, the application is incorporated for reference in its entirety. In this embodiment, R3 is preferably -CH2-A ^ -Ar1.

Preferably, in the compounds of formula Ia-b, II, Illa, c above, R3 'is preferably hydrogen. Preferably, in the compounds of formula Ia-b, II, Illa, c above, R4 and R4 'are preferably hydrogen and X is preferably hydroxyl or alkoxy. Preferably, in the compounds of the formula Illa-b, Va and Vlla above, R5 is -CH2-C (0) X, where X is as defined. Preferably, in the compounds of the formula Illa-b, Va and Vlla above, R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl. Even more preferably, R6 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2- (methoxycarbonyl) phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3, 4-dichlorophenyl, 3,4-dimethoxyphenyl, 4- (CH 3 C (O) H-) phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl) phenyl, 4-t-butylphenyl , 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, lN-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, lN-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, -methylamidophenyl, 4- [CH3SC (= NH)] phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, lN-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-l, 3,4-thiadiazol-2-yl, 4- [H2NC (S)] phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidine- 2-yl, 4- (3 '-dimethylamino-n-propoxy) -phenyl, and l-methylpyrazol-4-yl. In another preferred embodiment, R6 in the compounds of the formula Illa-b, Va and Vllb above is selected to correspond to the group R1, including the preferred embodiments, described in International Patent Application Publication No. WO 98/53814 the application is incorporated for reference in its entirety. In the compounds of the formula IVa-b and Va-b, R14 is selected from all possible isomers resulting from the substitution with the following groups: 3- (CH3) 2NC (O) 0-] benzyl, 4- (CH3 ) 2NC (0) 0-] benzyl, 4- (CH 3) 2NS (O) 20-] benzyl, 4- (piperidin-1'-yl) C (O) O-] benzyl, 4- (piperidin-4 ' -yl) C (O) O-] benzyl, 4- (1 '-methylpiperidin-4' -yl) C (O) O-] benzyl, 4- ('-hydroxypiperidin-1' -il) C (O) 0-] benzyl, 4- (4 '-formyloxypiperidin-1' -yl) C (O) 0-] benzyl, 4- (4'-ethoxycarbonylpiperidin-1'-yl) C (0) 0-] encyl, ( 4'-carboxypiperidin-1'-yl) C (O) 0-] benzyl, (3'-hydroxymethylpiperidin-1'-yl) C (O) O-] benzyl, ('-hydroxymethylpiperidin-1'-yl) C (O) O-] benzyl, 4- (4'-phenyl-1 '-Boc-piperidin-4' -yl) C (O) O-] benzyl, 4- (4'-piperidon-1'-ethyl) ketal) C (O) O-] 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 '-methylhomopi) perazin-1 '-yl) C (O) O-] benzyl, 4- (4' - (2-hydroxyethyl) piperazin-1 * -yl) C (O) O-] benzyl, 4- (4'-phenylpiperazine) -1 '-il) C (O) O-] benzyl, 4- (4' - (pyridin-2-yl) piperazin-1'-yl) C (O) O-] benzyl, 4- (4 '- (4-trifluoromethylpyridin-2-yl) piperazin-l '-il) C (0) 0-] b. ncilo, 4- (4 '- (pyrimidin-2-yl) piperazin-1' -yl) C (O) O-] benzyl, 4- (4'-acetylpiperazin-1'-yl) C (O) 0- ] benzyl, 4- (4 '- (phenylC (O) -) piperazin-1' -yl) C (O) O-] benzyl, 4- (4 '- (pyridin-4-ylC (O) -) piperazin -1 '-il) C (O) O-] benzyl, 4- (4 * - (phenylNHC (O) -) piperazin-1' -yl) C (O) O-] benzyl4- (4 '- (phenylNHC (S) -) piperazin-1' -yl) C (O) O-] benzyl, 4- (4'-methanesulfonylpiperazin-1 '-il-C (O) 0-) benzyl, - [(4'-trifluoromethanesulfonylpiperazin-1 '-il-C (0) 0-) benzyl, - [(morpholin-1-yl) C (0) 0-] benzyl, -nitro-4- [(morpholine) -4 '-il) -C (0) 0-] benzyl, - [(thiomorpholin-4' -yl) C (0) 0-] benzyl, - [(thiomorpholin-4'-yl sulfone) -C (0 ) 0-] benzyl, (alternative nomenclature 4- [(1, 1-dioxothiomorpholin-4-yl) -C (0) 0-] benzyl), - [(pyrrolidin-1 '-yl) C (O) O- ] benzyl, - [(2'-methylpyrrolidin-1-yl) C (0) 0-] benzyl, - [(2 '- (methoxycarbonyl) pyrrolidin-1'-yl) C (0) 0-] benzyl, - [(2 '- (hydroxymethyl) pyrrolidin-1' -yl) C (0) 0-] benzyl, - [(2 '- (N, N-dimethylamino) ethyl) (CH3) NC (0) 0-] benzyl, - [(2 '- (N-methyl-N-toluene-4-sulfonylamino) ethyl) (CH3) NC (0) 0-] benzyl, - [(2' - (morpholin-4! -yl) ethyl] ) (CH3) NC (0) 0-] benzyl, - [(2 '- (hydroxy) ethyl) (CH3) NC (0) 0-] benzyl, - [(bis (2' - (hydroxy) ethyl) NC (0) 0-] benzyl, - [(2 '- (formyloxy) ethyl) (CH3) NC (0) 0-] benzyl, - [(CH30C (O) CH2) HNC (0) O-] benzyl, - [2 '- (phenylNHC (0) 0-) ethyl-] HNC ( 0) 0-] benzyl, -chloro-4- [(CH3) 2NC (0) 0-] encyl, -chloro-4- [(4'-methylpiperazin-1'-yl) C (0) 0-] benzyl , -chloro-4- [(4 '- (pyridin-2-yl) piperazin-1' -yl) C (O) O-] benzyl, 3-chloro-4- [(thiomorpholin-4'-yl) C (O) 0-] benzyl, and 3-fluoro-4- [(CH3) 2NC (O) 0-] benzyl.

In this embodiment, Ar is preferably aryl or substituted aryl and, even more preferably, is phenyl or substituted phenyl. Preferably, x is 1. In another preferred embodiment, R14 corresponds to group R6, (including preferred embodiments) found in International Patent Application Publication No. WO 98/53817, the application is incorporated for reference in its entirety. In this embodiment, R14 is preferably -CH2-Ar2-Ar2. R15 is preferably hydrogen. In the compounds of the formula Vla-b, and VII, the groups R23, R24 and R25 correspond to the groups R5, R6 and R7, respectively, found in International Patent Application Publication No. WO 98/53817 the application it is incorporated for reference in its entirety. In a preferred embodiment, in the compounds of formula IVa-b and Vlla-b, R24 is -CHz-A ^ -Ar1 and R25 is hydrogen. This invention also provides methods for binding VLA-4 to a biological sample. The method comprises contacting the biological sample with a compound of formula I-VII above under the conditions wherein the compound binds to VLA-4. . Certain compounds of formula I-VII 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 effective amount of one or more of the compounds of formula I-VII above. Preferably R3 and R3 'are derivatives of L-amino acids or other starting materials configured in a similar manner. Alternatively, the racemic mixtures can be used. The pharmaceutical compositions can be used to treat the conditions of diseases mediated by VLA-4. Such disease conditions, include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including the principle of acute juvenile diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis , rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, seizures and other brain traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as occurs in the syndrome of respiratory stress in adults. Other disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter's syndrome, systemic lupus erythematosus, progressive systemic sclerosis, dermatomyositis, Wegner's granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis , chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary cirrhosis, autoimmune aplastic anemia, chronic persistent hepatitis and thyroiditis. Accordingly, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4 methods comprising administering to the patient the pharmaceutical compositions described above. Preferred compounds of this invention include those described in Table I below: Table I Accordingly, this invention is also directed to each of the following compounds: N- [1- (ethoxycarbonylmethyl) benzimidazol-2-yl] -L-4- (N, N-dimethylcarbamyoxy) phenylalanine tert-butyl ester, N - [1- (ethoxycarbonylmethyl) benzimidazol-2-yl] -L-4- (N, N-dimethylcarbamyoxy) phenylalanine, N- (benzoxazol-2-yl) -L-4- (N-tert-butyl ester, N-dimethylcarbamyloxy) phenylalanine, N- (benzoxazol-2-yl) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine, N- (benzothiazol-2-yl) -L-4- tert-butyl ester ( N, N-dimethylcarbamyloxy) phenylalanine, N- (benzothiazol-2-yl) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine, N- (2-cyclohexylquinazol-4-yl) -L- tert-butyl ester 4- (N, N-dimethylcarbamyloxy) phenylalanine, N- (2-cyclohexylquinazol-4-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine, N- [2- (piperid-1-tert-butyl ester -yl) quinazol-4-yl) -L-4- (N, -dimethylcarbamyloxy) phenylalanine, N- [2- (piperid-1-yl) quinazol-4-yl) -L-4- (N, N- dimethylcarbamyloxy) phenylalanine, and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION As above, this invention relates to compounds which inhibit the adhesion of leukocytes and, in particular, the adhesion of leukocyte mediated by VLA-4. However, before describing this invention in more detail, the following terms will be defined first.

Definitions As used herein, "alkyl" refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like. "Substituted alkyl" refers to an alkyl group, preferably 1 to 10 carbon atoms, having 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl -substituted cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl , thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2-alkyl, OS (0) 2-alkyl substituted, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (0) 2-heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, - OS (0) 2-substituted heterocyclic, -OS02-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 (O) 2-NR-alkyl, NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR- heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and dialkylamino, mono- and di (substituted alkyl) amino, mono- and di-arylamino, mono- and diarylamino substituted, mono - and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, substituted amino- and di-heterocyclic amino, disubstituted asymmetric amines having different substituents selected from alkyl, substituted-alkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and alkyl groups substituted which have 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 -S02NRR , where R is hydrogen or alkyl. "Alkoxy" refers to the group "alkyl-O-", which includes by way of example, methoxy, ethoxy, n-propoxy, iso-prcpoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy , n-hexoxy, 1,2-dimethylbutoxy and the like. "Alkoxy substituted" refers to the group "alkyl-0-substituted". "Alkenoxy" refers to the group "alkenyl-O-". "Alkenoxy substituted" refers to the group "alkenyl-O-substituted". "Acyl", refers to the groups HC (O) -, alkyl-C (0) -, alkyl-C (O) -substituted, alkenyl-C (0) -, alkenyl-C (0) -substituted, alkynyl -C (0) -, C (0) alkynyl-C (0) -substituted cycloalkyl, C (0) -substituted cycloalkyl, aryl-C (O), aryl-C (O) -substituted, heteroaryl-C (0) -, heteroaryl-C (0) -substituted, heterocyclic-C (0) - and heterocyclic-C (O) -substituted, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl , substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, are as defined.

"Acylamino" refers to the group -C (0) -NRR, wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl , substituted cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and wherein each R is combined to form together with the nitrogen atom, a substituted heterocyclic or 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. "Thiocarbonylamino", refers to the group -C (S) NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl , substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and wherein each R is combined to form, together with the nitrogen atom, a substituted heterocyclic or 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. "Acyloxy" refers to the groups alkyl-C (O) O-, alkyl-C (0) 0-substituted, alkenyl-C (0) 0-, alkenyl-C (0) 0 -substituted, alkynyl-C (0) 0-, C (0) O-substituted alkynyl, aryl-C (0) 0-, aryl-C (O) 0- substituted, cycloalkyl-C (O) 0-, cycloalkyl-C (0) 0- substituted, heteroaryl-C (0) 0-, heteroaryl-C (0) 0 -substituted, heterocyclic-C (0) 0-, and heterocyclic-C (O) -substituted, wherein alkyl, substituted alkyl, alkenyl , substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined. "Alkenyl" refers to the lkenyl 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 alkenyl unsaturation sites. "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, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxyl-aryl substituted, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioarylsubstituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (0) 2-alkyl, OS (0) 2-substituted alkyl, -OS (0) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2-heterocyclic, -OS (O) 2 -substituted heterocyclic, -OS (0) 2-NRR, where R is hydrogen or alkyl, -NRS (0) 2 -alkyl, -NRS (O) 2-substituted alkyl, -NRS (0) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, NRS (O) 2 -substituted heteroaryl, -NRS (O) 2-heterocyclic, NRS (0) 2-substituted heterocyclic, -NRS (0) 2-NR-alkyl, NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (O) 2-NR-substituted aryl, -NRS (O) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (O) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono and di-alkylamino, mono- and di- (alkyl) substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, amino mono- and di-heterocyclic substituted , asymmetric di-substituted amines, having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz , formyl and the like or substituted alkenyl / alkenyl groups, substituted with -S02-alkyl, -S02-substituted alkyl, -S02-alken ilo, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cycloalkyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02 -substituted heteroaryl, -S02-heterocyclic, -S02-heterocyclic substituted and -S02NRR wherein R is hydrogen or alkyl. "Alkynyl" refers to the alkynyl group, preferably having 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably 1-2 alkynyl unsaturation sites. "Substituted alkynyl" refers to alkynyl groups having from 1 to 5 substituents selected from the groups consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, • carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, carboxyl- substituted aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, substituted carboxylheterocyclic, substituted carboxyl-heterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, tiohe substituted heterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, OS (O) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS ( O) 2-heterocyclic, -OS (O) -heterocyclic substituted, -OS (0) 2-NRR, where R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (O) 2 -substituted alkyl, -NRS (0) 2- aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, NRS (O) 2 -substituted heteroaryl, -NRS (O) 2 -heterocyclic, NRS (O) 2-substituted heterocyclic, -NRS (0) .2-NR-alkyl, NRS (0) 2-NR-substituted alkyl, -NRS (0) 2-NR-aryl, -NRS (0) 2-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-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono - and di-heterocyclic, substituted amino- and di-heterocyclic amino, di-substituted asymmetric amines, having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and 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 -S02NRR where 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 (O) 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) -sheteroaryl substituted , -NRC (0) -heterocyclic, and -NRC (0) -heterocyclic substituted, wherein R is hydrogen alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, aryl substituted, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, are as defined. "Aminocarbonyloxy" refers to 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 (O) O-substituted cycloalkyl, -NRC (0) 0-aryl, -NRC (0) 0 -substituted aryl, -NRC (0) O -heteroaryl, -NRC (O) O-substituted heteroaryl, -NRC (O) O-heterocyclic, and -NRC (O) O-substituted heterocyclic, where "R is hydrogen or alkyl and wherein alkyl, substituted alkyl, substituted alkenyl , alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined. "Oxycarbonylamino" refers to the groups 0C (0) NH2, -0C (0) NRR, -OC (0) NR-alkyl, -OC (0) NR-substituted alkyl, -OC (O) NR-alkenyl, -OC (0) NR-substituted alkenyl , -OC (0) NR-alkynyl, -OC (0) NR-substituted alkynyl, -OC (O) NR-cycloalkyl, -OC (O) NR-substituted cycloalkyl, -OC (0) NR-aryl, -OC (0) NR-substituted aryl, OC (O) NR-heteroaryl, -OC (0) NR-substituted heteroaryl, OC (0) NR-heterocyclic and -OC (0) NR-substituted heterocyclic, where R is hydrogen, alkyl , or wherein each R is combined to form, together with the nitrogen atom, a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined. "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) R substituted heterocyclic, wherein R is hydrogen, alkyl or where each R is combined to form, together with the nitrogen atom, a substituted heterocyclic or heterocyclic ring, 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. "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 (0) NR-substituted cycloalkyl, -NRC (0) NR-heteroaryl, -NRC (0) NR-substituted heteroaryl, -NRC (O) NR-heterocyclic and -NRC (0) NR-substituted heterocyclic, where each R it is independently hydrogen, alkyl or where each R is combined to form, together with the nitrogen atom, a substituted heterocyclic or heterocyclic ring, as well as also 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, substituted alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, -heteroaryl substituted, heterocyclic and heterocyclic are as defined. "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, wherein each R is independently hydrogen, alkyl or where each R is combined to form together with the nitrogen atom, a substituted heterocyclic or heterocyclic ring, as well as also where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl and the like, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined. "Aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms, which has a single ring (eg, phenyl), or multiple fused rings (eg, naphthyl or anthryl), rings condensates 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, which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxy , 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 , substitute thioaryl gone, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, substituted 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 (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 (O) 2 -heterocyclic, -S (O) 2 -substituted heterocyclic, -OS (O) 2 -alkyl, -OS (O) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (O) 2-substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2 -heterocyclic, OS (O) 2 -substituted heterocyclic or, -OS (0) 2-NRR, where R is hydrogen or alkyl, -NRS (O) 2-alkyl, -NRS (O) 2 -substituted alkyl, -NRS (O) 2-aryl, -NRS (O) 2-substituted aryl, NRS (O) 2-heteroaryl, -NRS (O) 2 -substituted heteroaryl, NRS (0) 2-heterocyclic, -NRS (0) 2-substituted heterocyclic, -NRS (O) 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 (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, mono - and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, substituted mono- and di-heterocyclic amino, asymmetric di-substituted amines, having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups in the substituted aryl, blocked by the 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 aryl-O- group, which includes, by way of example, phenoxy, naphthoxy, and the like. "Substituted aryloxy" refers to the aryl-O-substituted groups. "Aryloxyaryl" refers to the -aryl-O-aryl group. "Substituted aryloxyaryl" refers to the aryloxyaryl groups, substituted with 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy , substituted heterocyclyloxy, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, carboxylamido, cyano, thiol, thioalkyl , thioalkyl subs substituted, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -S (0) 2-alkyl, -S (O) 2 -substituted alkyl, -S (O) 2-cycloalkyl, S (O) 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 (O) 2-heterocyclic, -S (0) 2-substituted heterocyclic, -OS (0) 2-alkyl, -OS (0) 2-substituted alkyl, -OS (0 ) 2-aryl, -OS (0) 2-substituted aryl, -OS (0) 2-heteroaryl, -OS (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic or, OS (0) 2-substituted heterocyclic, -OS02-NRR, where R s 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 (O) 2-NR-substituted heterocyclic, where R is hydrogen or alkyl, mono- and di- -alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, -mono- and di-heteroarylamino substituted, amino mono and di-heterocyclic, substituted mono- and di-heterocyclic amino, asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and the groups amino in 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 multi-ring alkyl groups such as adamantanil, etc. "Cycloalkenyl" refers to the cyclic alkenyl groups of 3 to 8 carbon atoms, which have multiple or simple instaurations but which are not aromatic. "Substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups, preferably from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (= 0), thioxo (= S) alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, thioaryl sub substituted, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O ) 2-alkyl, OS (0) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -heteroaryl substituted, -OS (O) 2-heterocyclic, -OS (O) 2-substituted heterocyclic, -OS02-NRR wherein R is hydrogen or alkyl, -NRS (0) 2-alkyl, -NRS (O) 2-alkyl substituted, -NRS (0) 2-aryl, -NRS (O) 2 -substituted aryl, -NRS (O) 2 -heteroaryl, NRS (O) 2 -substituted heteroaryl, -NRS (O) 2 -heterocyclic, NRS ( O) 2-substituted heterocyclic, -NRS (O) 2-NR-alkyl, NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (O) 2-NR-aryl substituted, -NRS (O) 2-N R-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 dialkylamino , mono- and di (substituted alkyl) amino, "mono- and di-arylamino, mono- and diarylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, mono amino - and substituted di-heterocyclic, unsubstituted 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 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-a ryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, and -S02NRR, where R is hydrogen or alkyl. "Cycloalkoxy" refers to the -0-cycloalkyl groups.

"Substituted cycloalkoxy" refers to the -O-substituted cycloalkyl groups. "Cycloalkeneoxy" refers to the -0-cycloalkenyl groups. "Substituted cycloalkenexy" refers to substituted -O-cycloalkenyl groups. "Guanidino" refers to the groups -NRC (= NR) NRR, -NRC (= NR) NR-alkyl, -NRC (= NR) NR-substituted alkyl, NRC (= NR) NR-alkenyl, -NRC (= NR) NR-substituted alkenyl, NRC (= NR) NR-alkynyl, -NRC (= NR) R-alkynyl substituted, 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, wherein each R is independently hydrogen and alkyl as well as also one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined.

"Guanidinosulfone" refers to the groups NRC (= NR) NRS02-alkyl, -NRC (= NR) NRS02-substituted alkyl, -NRC (= NR) NRS02-alkenyl, -NRC (= NR) NRS02-substituted alkenyl, - NRC (= NR) NRS02-alkynyl, -NRC (= NR) NRS02-substituted alkynyl, -NRC (= NR) NRS02-aryl, -NRC (= NR) NRS02-substituted aryl, -NRC (= NR) NRS02-cycloalkyl , NRC (= NR) NRS02-substituted cycloalkyl, -NRC (= NR) NRS02-heteroaryl, and -NRC (= NR) NRS02-substituted heteroaryl, NRC (= NR) NRS02- heterocyclic and -NRC (= NR) NRS02- substituted heterocyclic, wherein each R is independently hydrogen and alkyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic They are as defined. "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine and is preferably either chlorine 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 (for example, pyridyl or furyl) or condensed multiple rings (for example, indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl. "Fused ring heteroaryl" refers to a heteroaryl group having two or more fused rings. The fused ring heteroaryl groups include indolyl, lH-indazolyl, benzimidizolyl, purinyl, benzoxazolyl, benzothiazolyl and the like. "Substituted heteroaryl" refers to heteroaryl groups, which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy ,. alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy , heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, substituted carboxyl-alkyl, alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxyheteroaryl, substituted carboxyl-heteroaryl, carboxyheterocyclic, carboxy-heterocyclic substituted, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guani dinosulfone, 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 (O) 2-cycloalkyl, S (O) 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 (O) 2 -heterocyclic, -S (0) 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 (0) 2 -substituted heteroaryl, -OS (0) 2-heterocyclic, OS (0) 2-substituted heterocyclic, -0S (0) 2-NRR, where R is hydrogen or alkyl, -NRS (0) 2 -alkyl, -NRS (0) 2 -substituted alkyl, -NRS (0) 2 -aryl, -NRS (0) 2-substituted aryl, NRS (O) 2 -heteroaryl, -NRS (O) 2 -substituted heteroaryl, NRS (O) 2 -heterocyclic, -NRS (O) 2 -substituted heterocyclic, NRS (0) 2-NR-alkyl, -NRS (O) 2-NR-substituted alkyl, NRS (0) 2-NR-aryl, -NRS (O) 2-NR-substituted aryl, -NRS (0) 2-NR-heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic, -NRS (0) 2-NR-substituted heterocyclic, where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, mono and di-heterocyclic amino, substituted mono- and di-heterocyclic amino, asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups in 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. "Heteroaryloxy", refers to the group -O-heteroaryl and "substituted heteroaryloxy", refers to the -O-substituted heteroaryl group.

"Heterocycle" or "heterocyclic", refers to a saturated or unsaturated group having a single ring or condensed multiple rings, from 1 to 10 carbon atom and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring, wherein in the fused ring systems, one or more of the rings may be aryl or heteroaryl. "Fused ring heterocycle" refers to a heterocyclic group having two or more fused rings. Preferred fused ring heterocyclic groups include indolinyl, 1,2,3,4-tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl and the like. "Substituted heterocyclic" refers to the heterocyclic groups, which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (= 0), thioxo (= S) alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino , acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl , carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxyl-aryl, carboxylheteroaryl, substituted carboxyl-heteroaryl, carboxylheterocyclic, substituted carboxyl-heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, thiol ? substituted aryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, thioh substituted heteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted oxy heteroaryl, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (O) 2 -alkyl, OS ( ) 2-substituted alkyl, -OS (O) 2-aryl, -OS (O) 2 -substituted aryl, -OS (O) 2 -heteroaryl, -OS (O) 2 -substituted heteroaryl, -OS (O) 2 -heterocyclic, -OS (O) 2-substituted heterocyclic, -OS02-NRR where R is hydrogen or alkyl, NRS (0) 2-alkyl, -NRS (O) 2-substituted alkyl, -NRS (0) 2-aryl , -NRS (O) 2-substituted aryl, -NRS () 2 -heteroaryl, -NRS (O) 2 -substituted heteroaryl, -NRS (O) 2 -heterocyclic, NRS (0) 2 -substituted heterocyclic, -NRS ( O) 2-NR-alkyl, NRS (0) 2-NR-substituted alkyl, -NRS (O) 2-NR-aryl, -NRS (0) 2-NR-substituted aryl, -NRS (O) 2-NR -heteroaryl, -NRS (0) 2-NR-substituted heteroaryl, -NRS (0) 2-NR-heterocyclic , -NRS (0) 2-NR-substituted heterocyclic, wherein R is hydrogen or alkyl, mono- and dialkylamino, mono- and di (substituted alkyl) amino, mono- and di-arylamino, mono- and di-arylamino substituted , mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, substituted amino- and di-heterocyclic amino, asymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkynyl groups having amino groups blocked by conventional blocking groups, such as Boc, Cbz, formyl, and the like or 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 -S02NRR, where R is hydrogen or alkyl. Examples of heterocycles and heteroaryls, include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisocyanoline, 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 group -0-heterocyclic and "substituted heterocyclyloxy", refers to the -O-substituted heterocyclic group. "Tiol" refers to the group -SH. "Thioalkyl" refers to the -S-alkyl groups. "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 the pharmaceutically acceptable salts of a compound of formula I, the salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium , magnesium, ammonium, tetralkylammonium and the like; and when the molecule contains a basic functionality, the salts of organic or inorganic acids, such as, hydrochloride, bromohydrate, tartrate, mesylate, acetate, maleate, oxalate and the like.

Preparation of compounds 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 the typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of the reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless it is established. otherwise. The optimum reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from experiencing undesired reactions. Protective groups suitable for the various functional groups as well as suitable conditions for protecting and deprotecting the particular functional groups are well known in the art. For example, the numerous protective groups are described in T.W. Greene and G. M. Wust, Protecting Groups in Organic Syn Thesis, Second Edition, Wiley, New York, 1991, and references cited here. In addition, the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual diastereomers or enantiomers, or as enriched mixtures of stereoisomers. All stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, using, for example, chiral column chromatography, chiral resolving agents and the like. In a preferred method of synthesis, the compounds of this invention are prepared by coupling an amino acid derivative of formula 1: where R3, R3 'and X are as defined with a fused ring heteroaryl heterocyclic intermediate with suitable functionality, such as a compound of formula 2: where R7, R8 and Y are as defined above, to form a coupled reaction product, such as a compound of formula 3: This reaction is typically conducted by contacting a molar equivalent of the heteroaryl or heterocyclic intermediate, such as 2, with at least one molar equivalent of the amino acid derivative 1 in an inert diluent, such as DMSO, at a temperature ranging from about 60 °. C at around 250 ° C for about 12 to about 48 hours. Until the completion of the reaction, the resulting coupled product 3 is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. In addition to the chlorine derivative 2, heteroaryl intermediates having other suitable leaving groups, such as bromine, iodine, tosyl, mesyl and the like, can also be employed in the coupling reaction. The amino acid derivatives 1 used in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic methods. For example, amino acid derivatives can be prepared by C-alkylation of the commercially available diethylamide 2-acetamidomalonate (Aldrich, Milwakee, Wisconsin, USA) with a substituted alkyl or alkyl halide. This reaction is typically conducted by treating diethyl 2-acetamidomalonate with at least one equivalent of sodium oxoxide and at least one equivalent of an alkyl halide or substituted alkyl in refluxing ethanol for about 6 to about 12 hours. The resulting C-alkylated malonate is deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt. Examples of amino acid derivatives of formula 1 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-iodothyrosine methyl ester , ß- (4-hydroxy-naphth-l-yl) -L-alanine methyl ester, β- (6-hydroxy-naphth-2-yl) -L-alanine methyl ester, L-4- ethyl ester (N, N-dimethylcarbamyloxy) phenylalanine and the like. If desired, other esters or amides of the compounds described above may also be used in passing. Similarly, the heteroaryl or heterocyclic intermediates employed in the coupling reaction are either commercially available or can be prepared from commercially available starting materials using methods and reagents well known in the art. For example, the synthesis of 2-chloro-3-nitroquinoline is described in Chem. Pharm. Bull. 1959, 7, 273. Preferred heteroaryl intermediates for use in this reaction include 2-chlorobenzimidazole derivatives, 2-chlorobenzoxazole derivatives, 2-chlorobenzothiazole derivatives and 4-chloroquinazoline derivatives. When compound 2 is a 2-chlorobenzimidazole derivative (ie, Y is -NH-), the nitrogen atom can be easily alkylated, if desired, prior to coupling with amino acid derivative 1. Typically, this alkylation reaction is conducted by contacting the 2-chlorobenzimidazole with a base, such as potassium carbonate, in the presence of an alkylating agent, such as ethyl chloroacetate, in an inert diluent at a temperature ranging from about 0 ° C to about Í00 ° C for around 6 to around 48 hours. The alkylated product is then used in the coupling reaction described above. Alternatively, a 2-chlorobenzimidazole derivative can be sulfonated prior to the coupling reaction by reacting the 2 with a sulfonyl chloride of the formula: R6-S (0) 2-C1, where R6 is as defined, to provide a Sulfonamide intermediate This reaction is typically conducted by reacting the 2-chlorobenzimidazole derivative with at least one equivalent, preferably 1.1 to about 2 equivalents, of a sulfonyl chloride in an inert diluent such as dichloromethane and the like. Generally, the reaction is conducted at a temperature ranging from about -70 ° C to about 40 ° C for about 1 to about 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. Until the completion of the reaction, the resulting sulfonamide is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like. The sulfonyl chlorides used in the above reaction are either known compounds or compounds that can be prepared from known compounds, by conventional synthetic methods. Such compounds are typically prepared from the corresponding sulfonic acid, i.e., from the compounds of formula R6-S03H, wherein R6 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 the temperature in the range of about 0 ° C. at about 80 ° C for about 1 to 48 hours to produce the sulfonyl chloride. Alternatively, the sulfonyl chloride can be prepared from the corresponding thiol compound, ie, from the compounds of formula R6-SH where R6 is as defined, by treatment of the thiol with chlorine (Cl2) and low water conventional reaction conditions. Examples of sulfonyl chlorides suitable for use in this invention, include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, sodium 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-trifluoromethylbenzene chloride lfonilo, 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-pyrazolysulfonyl, 3-pyridinesulfonyl chloride, 2-pyrimidine sulfonyl chloride and the like. If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride can be used in place of the sulfonyl chloride in the above reaction to form the sulfonamide intermediate. In another preferred embodiment, the compounds of this invention can be prepared by displacement of the leaving group as shown in Reaction Scheme 1: Reaction Scheme 1 where R3, Q and X are as defined; A 'is heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; B 'is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic; and L1 is a leaving group, such as chlorine, bromine, iodine, sulfonate ester and the like. Typically, this reaction is conducted by combining approximately stoichiometric equivalents of 4 and 5 in a suitable inert diluent, such as water, dimethisulfoxide (DMSO) and the like, with an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to drag the acid generated by the reaction. The reaction is preferably conducted from about 25 ° C to about 100 ° C until the completion of the reaction which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Patent No. 3,598,859, which is incorporated herein by reference in its entirety. Until the completion of the reaction, the product 6 is recovered by conventional methods including, precipitation, chromatography, filtration and the like. In yet another alternative embodiment, the compounds of this invention, wherein Q is NR4, can be prepared by reductive amidation of a 2-oxocarboxylic acid ester, 8, such as a pyruvate ester, as shown in the Reaction Scheme. 2: Reaction Scheme 2 where A ', B', R3 and X are as defined. Generally, this reaction is conducted by combining equimolar amounts of 7 and 8 in an inert diluent such as methanol, ethanol and the like under conditions, which provide imine formation (not shown). The formed comma is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H2 / palladium on carbon and the like to form the product 9. In a particularly preferred embodiment, the reducing agent is H2 / palladium on carbon , which is incorporated in the initial reaction medium, thereby allowing the reduction of the imine in situ in a one step procedure to provide the. the reaction is preferably conducted from about 20 ° C to about 80 ° C at a pressure of from 1 to 10 atmospheres until the completion of the reaction, which typically occurs within 1 to about 24 hours. Until the completion of the reaction, the product 9 is recovered by conventional methods including, chromatography, filtration and the like. Alternatively, certain compounds of this invention can be prepared via a rhodium catalyzed insertion reaction as shown in Reaction Scheme 3: Reaction Scheme 3 wherein A ', B', R and X (preferably alkoxy) are as defined. Typically, this reaction is conducted using the rhodium acetate dimer, Rh2 (OAc) 4, in an inert diluent such as toluene at the temperature ranging from about 25 ° C to about 80 ° C for about 1 to 12 hours to produce 12. This reaction is further described in BR Henke et al., J. Med. Chem. 1998, 41, 5020-5036 and the references cited here. Similarly, certain compounds of this invention can be prepared by the copper catalyzed coupling reaction shown in Reaction Scheme 4: Reaction Scheme 4 where A ', B', R3 and X (preferably alkoxy) are as defined, and X3 is halogen, such as chlorine, bromine or iodine (preferably iodine). Typically, this reaction is conducted using copper iodide (Cul) and potassium carbonate in an inert diluent such as N, N-dimethyl acetamide (DMA) at a temperature ranging from about 60 ° C to about 120 ° C for about 12 at 36 hours to produce 12. This reaction is further described in D. Ma et al., J. Am. Chem. Soc. 1998, 120, 12459-12467 and the references cited here. For the ease of synthesis, the compounds of formula I-VII are typically prepared as an ester, that is, wherein X is an alkoxy or substituted alkoxy group and the like. If desired, the ester group can be hydrolyzed using conventional conditions and reagents to provide the corresponding carboxylic acid. Typically, this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a varying temperature. from about 0 ° C to about 24 ° C for about 1 to about 12 hours. Alternatively, the benzylic esters can be removed by hydrogenolysis using palladium catalyst, such as palladium on carbon, and the tert-butyl esters can be removed using formic acid to produce the corresponding carboxylic acid.

As will be apparent to those skilled in the art, other functional groups present in any of the substituents of the compounds of the formula I-VII, in addition to the carbamate-like functionality, can be easily modified or derivatized either before or after the synthetic reactions described above using well-known synthetic procedures. For example, a nitro group present in a substituent of a compound of the formula I-VII 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 group corresponding amino. This reaction is typically conducted at a temperature from about 20 ° C to about 50 ° C for about 6 to about 24 hours in an inert diluent, such as methanol. The compounds having a nitro group in the substituent R3 and / or R3 'can be prepared, for example, by the use of 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 an acidic diluent to provide the corresponding piperidinyl analogue. In general, this reaction is conducted by treatment of the pyridine compound with hydrogenation at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperature of about 20 ° C. about 50 ° C for about 2 to about 24 hours in an acidic diluent, such as a mixture of methanol and aqueous hydrochloric acid. Additionally, when the substituent R3 and / or R3 'of a compound of the formula I-VII or an intermediate thereof, contain a primary or secondary amino group, such amino groups can be derivatized either before or after coupling reactions above to provide (in addition to the carbamate-type functionality), by way of example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like. Compounds having a primary amino group in the substituent R3 and / or R3 'can be prepared, for example, by reduction of the corresponding nitro compound as described above. By way of illustration, a compound of the formula I-VII or an intermediate thereof having a substituent contains a primary or secondary amino group, such as wherein R 3 is a (4-aminophenyl) methyl group, they can be easily N- acylated using conventional acylation reagents and conditions to provide the corresponding amide. This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent (benzotriazole hexafluorophosphonate). -1-yloxy-tris (dimethylamino) phosphonium) 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 approximately 4 to approximately 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-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid , N-tert-butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert-butyloxycarbonyl-norpecic acid, N-tert-butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N- (toluene-4-sulfonyl) -L-proline and the like. Alternatively, a compound of the formula I-VII or an intermediate thereof containing a primary or secondary amino group can be N-acylated, using an acyl haloalide or a carboxylic acid anhydride to form the corresponding amide. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or the 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 purify the acid generated during the reaction. Suitable bases include purifying 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 may be conducted under Schotten-Baumann type conditions using aqueous alkali, such as sodium hydroxide and the like. Examples of suitable acyl halides and carboxylic acid anhydrides for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl, 2-trifluoromethylbenzoyl chloride, isonicotinyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride and the like. Carbamyl chlorides, such as N, N-dimethylcarbamyl chloride, βJ / γ-diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas. Similarly, dicarbonates such as i-tert-butyldicarbonate, can be employed to provide carbamates. In a similar manner, a compound of the formula I-VII or an intermediate thereof containing a primary or secondary amino group can be N-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride. Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like. Similarly, sulfamoyl chlorides such as dimethylsulfamoyl chloride can be used to provide sulfonamides (e.g., >; N-S02-N < ). Additionally, a primary or secondary amino group present in a substituent of a compound of the formula I-VII or an intermediate thereof, can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent such as toluene and the like, at a temperature ranging from about 24 ° C. about 37 ° C for about 12 to about 24 hours. The isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures. For example, isocyanates and thioisocyanates are easily prepared by reacting the appropriate amine with phosgene or thiophosgene. Examples of isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, thioisocyanate methyl, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3- (N, N-diethylamino) propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer) I) and similar. In addition, when a compound of formula I-VII or an intermediate thereof contains a primary or secondary amino group, the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group. This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperature ranging from about 0 ° C to about 50 ° C for about 1 to about 72 hours. Suitable aldehydes and ketones for use in this reaction include, by way of example, benzaldehydes, 4-chlorobenzaldehydes, valeraldehydes and the like. In a similar manner, when a compound of formula I-VII or an intermediate thereof has a substituent containing a hydroxyl group, the hydroxyl group may further be modified or derivatized either before or after the above coupling reactions to provide, by way of example, ethers, carbamates and the like. Compounds having a hydroxyl group in substituent R3 for example, can be prepared using an amino acid derivative derived from tyrosine and the like in the reactions described above. By way of example, a compound of the formula I-VII or an intermediate thereof having a substituent containing a hydroxyl group, such as where R 3 is a (4-hydroxyphenyl) methyl group, can be easily O-alkylated to form ethers. This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group. This salt is not generally isolated, but is reacted in-house with at least one equivalent of an alkyl or substituted alkyl halide or a sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to provide the ether. In general, this reaction is conducted at a temperature ranging from about 60 ° C to about 150 ° C for about 24 hours 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 a-bromophenylacetate, 2- (N-ethyl-N-phenylamino) ethyl, 2- (N, N-ethylamino) ethyl chloride, 2- (N, N-diisopropylamino) ethyl chloride, 2- (?, N-dibenzylamino) chloride ethyl, 3- (N, N-ethylamino) propyl chloride, 3- (N-benzyl-N-ethylamino) propyl chloride, N- (2-chloroethyl) morpholine chloride, 2- (hexamethylene imino) ethyl chloride, 3- (N-methylpiperazin) propyl chloride, 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine, 2- (4-hydroxyl-4-phenylpiperidine) ethyl chloride, N-tert-butyloxycarbonyl tosylate -3-piperidinylmethyl and the like. Alternatively, a hydroxyl group present in a substituent of a compound of the formula I-VII or an intermediate thereof, may be O-alkylated using the Mitsunobu reaction. In this reaction, an alcohol, such as 3- (N / N-dimethylamino) -1-propanol and the like, are reacted with from 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 are 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 way, a compound of the formula I-VII or an intermediate thereof, which contain a hydroxyaryl group can be reacted with an aryl iodide to provide diaryl ether. Generally, this reaction is conducted by the formation of the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent such as xylenes at a temperature of about -25 ° C to about 10 ° C. ° C. The salt is then treated with from about 1.1 to about 1.5 equivalents of the 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 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-VII or an intermediate thereof, are contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperature ranging from about -25 ° C to about 0 ° C for about 0.5 to about 2.0 hours. Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine, provides the carbamate . Examples of suitable amines for use in this reaction include but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like. Alternatively, in another method for preparing carbamates, a hydroxy-containing compound is contacted with from 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. about 70 ° C for about 2"to about 72 hours Typically, this reaction is conducted in the presence of a suitable base to purify 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. Carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride or, diethylcarbamyl chloride, and the like. Similarly, when a compound of formula I-VII or an intermediate thereof contains a primary or secondary hydroxyl group, such hydroxyl groups can be easily converted to a residual group and displaced to form, for example, amines, sulfides and fluorides . Generally, when a chiral compound is employed in these reactions, the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically reversed. These reactions are typically conducted by first converting the hydroxyl group to a residual 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. This reaction is generally conducted at a temperature from about 0 ° C to about 70 ° C for about 1 to about 48 hours. The resulting tosylate 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 (-? H2). Similarly, a tosylate group can be easily displaced by a linden to form a sulfide. This reaction is typically conducted by contacting the tosylate with at least one equivalent of a linden, such as thiophenol, in the presence of a suitable base, such as 1,8-diazabicyl [5.4.0] undec-7-ene (DBU ), in an inert solvent, such as N, N-dimethylformamide, at a temperature from about 0 ° C to about 37 ° C for about 1 to about 12 hours to provide the sulfide. Additionally, treatment of a tosylate with morpholinosulfide 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 provides the corresponding fluoro compound. In addition, a compound of formula I-VII or an intermediate thereof having a substituent containing an iodoaryl group, for example, when R 3 is a (4-iodophenyl) methyl group, can be easily converted either before or after the previous coupling reactions in a biaryl compound. Typically, this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2- (methoxycarbonyl) phenylzinc iodide, in the presence of a palladium catalyst, such as tetra (triphenylphosphine) ) 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. Additional methods for preparing biaryl derivatives are described in International Application Number WO 98/53817, published December 3, 1998, a description of which is incorporated herein by reference in its entirety. In some cases, the compounds of formula I-VII, or intermediates thereof, may contain substituents having one or more sulfur atoms. 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 typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperature ranging from about -50 ° C to about 75 ° C for about 1 to approximately 24 hours. The resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate, and the like. Alternatively, the sulfone can be prepared directly by the sulfide contact with at least two equivalents, and preferably an excess of the oxidant reagent. Such reactions are further described in March, "Advanced Organic Chemistry," 4th. Ed. Pp. 1201-1202. Wiley Publisher, 1992. Other methods and reaction conditions for preparing the compounds of this invention are described in the examples set forth above.

Pharmaceutical Formulations When used as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are effective both as injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I-VII above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or included within such a carrier, which may be in the form of a capsule, pouch, 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, dragees, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing, for example, up to 10 % by weight of the active compound, soft or hard gelatin 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 ordinarily ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by the grind to provide a substantially uniform distribution in the formulation for example, approximately 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 methylcellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxy benzoates, sweetening agents; and flavoring agents. The compositions of the invention can be formulated in this manner to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing methods known in the art. The compositions are preferably formulated in a unit dosage form, each dosage contains from about 5 to about 100 mg, more usually about 10 to about 30 mg of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of the 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 dosages and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound currently administered will be determined by a specialist, in view of the relevant circumstances, including the condition to be treated, the chosen route of administration, the current 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 the solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, so that the composition can easily be subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the present invention may be coated or otherwise constituted to provide a dosage form providing the advantage of prolonged action. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a cover on the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the internal component to pass intact in the duodenum or be delayed in the release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as lacquers, cetyl alcohol and cellulose acetate. The liquid forms in which new compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions, with edible oils, such as seed oil. cotton, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in aqueous or organic, pharmaceutically acceptable 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. The compositions in preferably pharmaceutically acceptable solvents can be nebulized by the use of inert gases. The nebulized solutions can be breathed directly from nebulizing devices or the nebulizing device can be attached to a face mask chamber, or intermittent positive pressure breathing machine. The solution, suspension or powder compositions can be administered, preferably orally or nasally, of devices which supply the formulation in an appropriate manner. The following examples illustrate the pharmaceutical compositions of the present invention.

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

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

Formulation Example 3 A powder inhaler-dry formulation containing the following components was prepared: Ingredient% in Weight Active ingredient 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 were prepared, each containing 30 mg of the active ingredient, as follows: Ingredient Quantity (mg / capsule) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in water) 4.0 mg sodium carboxymethyl starch 4.5 mg magnesium stearate 0.5 mg talc 1.0 mg Total 120 mg The active ingredient, starch and cellulose, are passed through a U.S. 20 mesh and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. 16. The granules thus produced are dried from 50 ° to 60 ° C and passed through a U.S. sieve. mesh 16. Sodium carboxymethylstarch, magnesium stearate, and talcum are passed through a No. 30 mesh US sieve, and are then added to the granules, which, after mixing, are compressed into a tablet forming machine to provide the tablets, each weighing 150 mg.

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

Formulation Example 6 Suppositories were prepared as follows, each containing 25 mg of the medicament: Ingredient Quantity Active ingredient 25 mg Fatty acid glycerides Saturated to 2,000 mg The active ingredient is passed through a U.S. sieve. No. 60 mesh, and is suspended in the glycerides of saturated fatty acids previously combined using the minimum heat required. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7 Suspensions were prepared as follows, each containing 50 mg of the drug per 5.0 ml of dose: Ingredient Quantity Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethylcellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Taste and Color c.v. Purified water at 5.0 ml The drug, sucrose and xanthan are combined, passed through a U.S. sieve. No. 10 mesh, and then mixed with a previously made solution of microcrystalline cellulose and carboxymethylcellulose in water.

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

Formulation Example 8 Ingredient Quantity (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, cellulose, starch, magnesium stearate are combined, passed through a U.S. No. 20 mesh, and filled into hard gelatin capsules in amounts of 560 mg.

Formulation Example 9 An intravenous formulation can be prepared as follows: Ingredient Quantity Active ingredient 250.0 mg Isotonic saline 1000 ml Formulation Example 10 It can be prepared as follows. a topical formulation: Ingredient Quantity Active ingredient 1-10 mg Emulsifying wax 30 g Liquid paraffin 20 g White soft paraffin up to 100 g The white soft paraffin is heated until melted. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and the stirring is continued until dispersed. The mixture is then cooled until solidified. 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. 5,023,252, published June 11, 1991, incorporated herein by reference. Such patches can be constructed for continuous, pulsatile or demand delivery of pharmaceutical agents. Direct or 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 divide the blood barrier in the brain. 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 the compositions to provide drug latency by the conversion of the hydrophilic drugs into soluble drugs to the lipids. Latency is generally achieved by blocking the hydroxy, carbonyl, sulfate and primary amine groups present in the drug to provide the drug with the most lipid soluble and receptive for transport through the blood brain barrier. Alternatively, the supply of hydrophilic drugs may be increased by the intra-arterial infusion of hypertonic solutions which may temporarily open the blood barrier of the brain.

Utility The compounds of this invention can be used to bind VLA-4 (integrin a4β) in biological samples and, consequently, have utility in, for example, the testing of such samples for VLA-4. In such assays, the compounds can be bound to a solid support and the VL4 sample added thereto. The amount of VLA-4 in the sample can be determined by conventional methods such as the use of an ELISA assay. Alternatively, labeled VLA-4 can be used in a competitive assay to measure the presence of VLA-4 in the sample. Other suitable assays are well known in the art.

In addition, certain compounds of this invention inhibit the in vivo adhesion of leukocytes to endothelial cells mediated by VLA-4 and, consequently, can be used in the treatment of conditions mediated by VLA-4. Such conditions include inflammatory conditions in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including early acute juvenile diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, strokes, and cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia, and acute leukocyte-mediated lung injury such as that which occurs in the syndrome of adult respiratory distress. The biological activity of the compounds identified above can be tested in a variety of systems. For example, a compound can be immobilized on a solid surface and the adhesion of cells expressing VLA- can be measured. Using such formats, large numbers of compounds can be selected. Suitable cells for this assay include any leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils. A number of leukocyte cell lines can also be used, examples include Jurkat and U937. The test compounds can also be tested for the ability to competitively inhibit the binding between VLA-4 and VCAM-1, or between VLA-4 and a labeled compound known to bind to VLA-4 such as a compound of this invention or antibody to VLA-4. In these assays, VCAM-1 can be immobilized on a solid surface. VCAM-1 can also be expressed as a recombinant fusion protein having an Ig end (e.g., 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. In assays to measure the ability to block adhesion to brain endothelial cells, the assays described in International Patent Application Publication No. WO91 / 05038 are particularly preferred. This application is incorporated herein for reference in its entirety. Many trained trials use labeled test components. Labeling systems can be in a variety of forms. The label can be coupled directly or indirectly to the desired component of the assay in accordance with methods well known in the art. A wide variety of labels can be used. The component can be labeled by any one of several methods. The most common method of detection is the use of autoradiography with compounds labeled with 3H, x I, 35S, 14C, or 32P, or the like. Non-radioactive labels include ligands which bind labeled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies, which can serve as elements of specific binding pairs for a labeled ligand. The choice of label depends on the required sensitivity, ease of conjugation with the compound, stability requirements and available instrumentation. Appropriate models in vivo 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 a4 integrins. Compounds having the desired biological activity can be modified as necessary to provide the desired properties such as improved pharmacological properties (e.g., in vivo stability, bioavailability), or the ability to be detected in diagnostic applications. For example, the infusion of one or more D-amino acids in the sulfonamides of this invention typically increases the stability in vivo. The stability can be tested in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or plasma or human serum. A number of such protein stability assays have been described (see, for example, Verhoef et al., Eur. J. Drug Metab, Pharmacokinet., 1990, 15 (2): 83-93). For diagnostic purposes, a wide variety of labels can be linked to the compounds, which can directly or indirectly provide a detectable signal. Thus, the subject compounds of the invention can be modified in a variety of ways for a variety of final purposes, while still remaining, biological activity. In addition, several reactive sites can be introduced to the terms to link to particles, solid substrates, macromolecules or the like. The labeled compounds can be used in a variety of in vivo or in vitro applications. A wide variety of labels can be used, such as • radionuclides (eg, radioisotopes that emit gamma, such as tecnetiu-99 or indium-111), fluorescers (eg, fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like. Those of ordinary skill in the art will know of other suitable labels to link to the complexes, or will be able to ascertain such using routine experimentation. Linkage of these labels is achieved using standard techniques common to those of ordinary skill in the art. In vi tro uses include diagnostic applications such as the monitoring of inflammatory responses by the detection of the presence of leukocytes expressing VLA-4. The compounds of this invention can also be used for the isolation or labeling of such cells. In addition, as mentioned above, the compounds of the invention can be used to test potential inhibitors of VLA-4 / VCAM-1 interactions. For in vivo diagnostic imaging to identify, for example, sites of inflammation, radioisotopes are typically used in accordance with well-known techniques. 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 be labeled with a paramagnetic isotope for purposes of in vivo diagnosis, such as magnetic resonance imaging (MRI) or electron spinning resonance (ESR), both of which are well known. In general, any conventional method for displaying diagnostic images can be used. Usually, radioisotopes that emit positron and gamma are used for camera imaging and paramagnetic isotopes are used for MRI. Thus, the compounds can be used to monitor the course of the decline 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 reducing the condition is effective. The pharmaceutical compositions of the present invention can be used to block or inhibit cell adhesion associated with a number of conditions and disorders. . For example, a number of inflammatory disorders are associated with integrins or leukocytes. The treatable disorders include, for example, transplant rejection (eg, allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including onset of acute juvenile diabetes), retinitis, cancer metastasis, rheumatoid arthritis, acute leukocyte-mediated lung (eg, adult respiratory distress syndrome), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease (including Crohn's disease and ulcerative colitis) . In preferred embodiments, the pharmaceutical compositions are used to treat inflammatory brain disorders, such as multiple sclerosis (MS), viral meningitis and encephalitis. Inflammatory bowel disease is a collective term for two similar conditions referred to as Crohn's disease and ulcerative colitis. Crohn's disease is an idiopathic, chronic ulceroconstrictive inflammatory disease, characterized by the delimited shape and typically transmural involvement of all layers of the stomach wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, can be involved, although the condition most commonly affects terminal ileus and / or colon. Ulcerative colitis is an inflammatory response largely limited by the mucosa and colonic submucosa. Lymphocytes and macrophages are numerous in inflammatory bowel disease lesions and may contribute to inflammatory injury. Asthma is a condition characterized by the increased sensitivity of the tracheobronchial tree to several stimuli that enhance the paroxysmal constriction of the bronchial airways. The stimulus causes release of several mediators of inflammation from mast cells coated with IgE including histamine, eosinophilic and neutrophilic chemotactic factors, leukotrienes, prostaglandin activating factor and platelets. The release of these factors recruits the basophils, eosinophils and neutrophils, which cause the inflammatory lesion.

Atherosclerosis is a condition of arteries (for example, coronary, carotid, aorta and iliac). The basic lesion, the atheroma, consists of a raised focal plate within the intima that has a lipid core and a fibrous coating layer. Atheromas include arterial blood flow and weakened affected arteries.

Myocardial and cerebral infarcts are a major consequence of this condition. Macrophages and leukocytes are recruited in the atheromas and contribute to the inflammatory lesion. Rheumatoid arthritis is a chronic, recurrent inflammatory condition that mainly causes deterioration and destruction of the joints. Rheumatoid arthritis usually affects the lower joints of the hands and feet first, but can later involve wrists, elbows, ankles, and knees. Arthritis results from the interaction of synovial cells with leukocytes that infiltrate the circulation in the synovial lining of the joints. See, for example, Paul, Immunology (3rd Ed. Raven Press, 1993). Another indication for the compounds of this invention is in the treatment of the organ or graft rejection mediated by VLA-4. During 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 permanent problem is the lack of satisfactory agents to induce immunotolerance in the recipient to the transplanted organ or allograft. When the allogenic cells or organs are transplanted into a host (ie, the tamer and the donee are different individuals of the same species), the host's immune system probably specks an immune response to the foreign antigens in the transplant (host disease) against graft), leading to the destruction of the transplanted tissue. CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplanted tissues. The compounds of this invention which bind to the alpha-4 integrin are used inter alia to block the immune responses induced by the alloantigen in the donee, thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. . See, for example, Paul et al., International Transplant 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georcyznski et al., Transplant. Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994). A related use for compounds of this invention which binds to VLA-4 is in the modulation of the immune response involved in "graft-versus-host" (GVHD) conditions. See for example, Schlegel et al., J. Immunol. 155, 3856-3865 (1995). GVHD is a potentially fatal condition that occurs when immunologically competent cells are transferred to an allogeneic vessel. In this situation, the immunocompetent cells of the donor can attack tissues in the recipient. The tissues of the skin, epithelium of the intestine and liver, are frequent targets and can be destroyed during the course of GVHD. The condition presents a particularly severe problem when the immune tissue is transplanted, such as in the transplantation of the bone marrow; but less severe GVHD have also been reported in other cases, as well, including heart and liver transplants. The therapeutic agents of the present invention are used inter alia to block the activation of donor T cells, thereby interfering with their ability to dissolve target cells in the host.

An additional use of the compounds of this invention is to inhibit tumor metastasis. It has been reported that several tumor cells express VLA-4 and compounds which bind to 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 thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating covering that lines the nerve fibers. In an animal model for multiple sclerosis, murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothelium, thus preventing 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, Mace Publishing Company, Philadelphia, P.A. 17th Ed. (1985). To increase the serum half-life, the compounds can be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques can be employed, which provide an extended serum half-life of the compounds. A variety of methods are available to prepare 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 administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the manner of administration and the like. In therapeutic applications, the compositions are administered to a patient who already suffers from a condition in an amount sufficient to cure or at least partially reduce the symptoms of the condition and its complications. An adequate amount to accompany this is defined as "therapeutically effective dose". The effective amounts for this use, will depend on the condition of the condition to be treated, as well as the judgment of the specialist who attends it, depending on factors such as the severity of the inflammation, the age, weight and general condition of the patient. , and similar. The compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or they can be sterile filtered. The resulting aqueous solutions can be packaged to be used as they are, or lyophilized, the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the compound preparations will typically be between 3 and 11, more preferably from 5 to 9 and more preferably from 7 to 8. It will be understood that the use of certain of the excipients mentioned above, carriers or solubilizers, will result in the formation of the pharmaceutical salts. The therapeutic dosage of the compounds of the present invention will vary according to for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the specialist it prescribes it. For example, for intravenous administration, the dose will typically be in the range of about 20 μg to about 500 μg per kilogram of body weight, preferably about 100 μg to about 300 μg per kg of body weight. The dosage ranges suitable for intranasal administration are generally from about 0.1 pg to 1 mg per kilogram of body weight. Effective doses can be extrapolated from dose response curves derived from test systems of animal or in vitro models. The compounds of this invention are also capable of binding or antagonizing the actions of integrins a6ß ?, 9ß ?, a4ß7, adß2, c7, (although aβ and a9β are preferred in this invention). Accordingly, the compounds of this invention are also employed to prevent or reverse the symptoms, alterations or conditions induced by the binding of these integrins to their respective ligands. For example, International Application Number WO 98/53817, published December 3, 1998 (description of which is incorporated herein by reference in its entirety) and references cited herein describe disorders a4β7. This reference also describes an assay for determining antagonism of a4ß7 dependent on binding to the VCAM-Ig fusion protein. Additionally, the compounds that bind to adß2 and cß7 integrins are particularly used for the treatment of asthma and related lung conditions. See for example, M. H. Grayson et al., J. Exp. Med. 1998, 188 (11) 2187-2191. Compounds that bind to integrin acß7 are also used for the treatment of systemic lupus erythematosus (see for example, M. Pang et al., Arthritis Rheum, 1998, 42 (8), 1456-1463); Crohn's disease, ulcerative colitis and inflammatory bowel disease (IBD) (see for example, D. Elewaut et al., Scand J. Gastroenterol 1998, 33 (7) 743-748); Sjogren's syndrome (see for example, U. Kroneld et al., Scand J. Gastroenterol 1998, 27 (3), 215-018); and rheumatoid arthritis (see for example, Scand J. Gastroenterol 1996, 44 (3) 293-298). And compounds that bind aßßi can be used in the prevention of fertilization (see for example, H. Chen et al., Chem. Biol. 1999, 6, 1-10). The following synthetic and biological examples are offered to illustrate this invention and are not constructed in any way to limit the scope of this invention. Unless stated otherwise, all temperatures are in degrees Celsius.

EXAMPLES In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, its meaning has been generally accepted. ac or ac = aqueous AcOH = acetic acid bd = broad doublet bm = broad multiplet bs = broad singlet Bn = benzyl Boc = N-tert-butoxycarbonyl Boc20 = di-tert-butyldicarbonate BOP = benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate Cbz = carbobenzyloxy CHCI3 = chloroform CH2C12 = dichloromethane (COCÍ) 2 = oxalyl chloride d = doublet dd = doublet of doublets dt = doublet of triplets DBU = 1, 8-diazabicyclo [5.4.0] undec-7-ene DCC = 1 , 3-dicyclohexylcarbodiimide DMAP = 4-N, N-dimethylaminopyridine DME = ethylene glycol dimethyl ether DMF = N / N-dimethylformamide DMSO = dimethylsulfoxide EDC = l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Et 3 N = triethylamine Et 20 = diethyl ether EtOAc = ethyl acetate EtOH = ethanol eq or eq. = equivalent Fmoc = N- (9-fluorenylmethoxycarbonyl) FmocONSu = N- (9-fluorenylmethoxycarbonyl) -succinimide g = grams h = hour H20 = water HBr = hydrobromic acid HCl = hydrochloric acid HOBT = 1-hydroxybenzotriazole hydrate hr = hour K2C03 = potassium carbonate L = liter m = multiplet MeOH = methanol mg = milligram MgSO4 = magnesium sulfate mL = milliliter mm = millimeter mM = millimolar mmol = millimole Pf = melting point N = normal NaCl = sodium chloride Na2C03 = carbonate sodium NaHC03 = sodium bicarbonate NaOEt = sodium ethoxide NaOH = ammonium hydroxide NH4C1 = ammonium chloride NMM = N-methylmorpholine Phe = L-phenylalanine Pro = L-proline psi = pounds per square inch Pt02 = platinum oxide q = quartet quint. = quintet ta = room temperature s = singlet sat = saturated t = triplet t-BuOH = tert-butanol TFA = trifluoroacetic acid THF = tetrahydrofuran TLC or tic = thin layer chromatography Ts = tosyl TsCl = tosyl chloride TsOH = tosylate μL = microliter The following methods can be used to prepare the compounds of this invention.

Method A Method of Preparation of Methyl Ester Methyl amino acid esters can be prepared using the method of Brenner and Huber Helv. Chim. Acta 1953, 36, 1109.

Method B BOP Coupling Process The desired dipeptide ester was prepared by reaction of a carboxylic acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy-tris (dimethylamino) hexafluorophosphate ) fos onio [BOP] (2.0 equivalents), triethylamine (1.1 equivalent), and DMF. The reaction mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography to provide the dipeptide ester.

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

Method D 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 desired carboxylate salt.

Method E Method II of Ester Hydrolysis To a cooled THF / H20 solution (0 ° C) (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 mixture 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 F Ester Hydrolysis Procedure II 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 sodium salt of the desired carboxylate.

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

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

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

Method J Coupling Procedure II EDC To a solution of DMF (5-20 mL) of a carboxylic acid (1 equivalent), the ester hydrochloride of the appropriate amino acid (1 equivalent), Et3N (1.1 equivalent) and 1-hydroxybenzotriazole (2) equivalents) were mixed, placed in a cold bath and l- (3-dimethylaminopropyl) -3-ethyl carbodiimide (1.1 equivalents) was added. The reaction was allowed to reach room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and H20 and the organic phase was washed with 0.2 N citric acid, H20, sat. NaHC03, brine, dried (MgSO4 or Na2SO4), filtered and concentrated. The crude product was purified by column chromatography or preparative TLC.

Method K Tere-Butyl Ester Hydrolysis Procedure II 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 produce the desired product.

Method L Carbamate Formation Procedure I 15.2 mmol were combined in a reaction flask. 1. 0 eq. of the resulting hydroxy compound (typically a tyrosine derivative) and 1.86 g (15.2 mmol, 1.0 eq) of DMAP.

Then methylene chloride (50 mL), triethylamine (2.12 mL, 1.54 g, 15.2 mmol, 1.0 eq), and dimethylcarbamyl chloride (1.68 mL, 1.96 g, 18.2 mmol), 1.2 eq) were added.

The bottle was capped tightly, and the reaction solution was stirred to obtain a homogeneous solution. The reaction solution was then heated to 40 ° C. After 48 h, the TLC of the resulting colorless solution indicated that the conversion was complete. Removal of the reaction solution was as follows: 50 mL of EtOAc and 50 mL of hexanes were added to the reaction mixture, and the resulting mixture was washed with 0.5 M citric acid (3 x 50 mL), water (2). x 50 mL), 10% K2C03 (2 x 50 mL), and sat. NaCl. (1 x 50 mL); dried with MgSO, filtered and evated to provide the desired compound. Method M Carbamate Formation Process II In a reaction flask were combined 84.34 mmol (1.0 eq) of the initiator hydroxy compound (typically a tyrosine derivative) and 17.0 g (84.34 mmol, 1.0 eq) 4-nitrophenyl chloroformate. Methylene chloride (700 mL) was added and the bottle was capped with a septum. A nitrogen line was fixed and the flask was immersed in a 4: 1 water / ethanol cooled ice suspension with stirring to cool it to -15 ° C. Triethylamine (29.38 mL) was added, 21.33 g, 210.81 mmol, 2.5 eq), over five minutes with stirring and stirring was continued at -10 to -15 ° C for 1 h. N-methylpiperazine (9.35 mL, 8.45 g, 84.34 mmol, 1.0 eq) was added for three minutes with stirring and stirring was continued overnight, while warming to room temperature. The reaction mixture was diluted with 700 mL of hexanes and the resulting mixture was washed repeatedly with 10% K2CO3, until no yellow (4-nitrophenol) color was observed in the aqueous layer. The mixture was then washed with sat. NaCl, dried over anhydrous MgSO4, filtered and evaporated. The residue was dissolved in 500 mL of ethanol and evaporated to remove the triethylamine. The residue was redissolved in 500 mL of ethanol and evaporated to remove the triethylamine. The residue was then dissolved in 400 mL of ethanol and 600 mL of water was added with stirring to precipitate in solid or oil. If an oil is formed, the oil is vigorously stirred to induce solidification. The solid is then isolated by filtration. Dissolution, precipitation, and filtration were repeated once and the resulting solid was rinsed with water to remove remains of the yellow color. The solid is then subjected to high vacuum until the mass remains constant, thereby providing the desired carbamyloxy compound.

Example 1 Synthesis of N- [l- (ethoxycarbonylmethyl) benzimidazol-2-yl] -L-4- (N, N-dimethylcarbamyoxy) phenylalanine tert-butyl ester The 2-chlorobenzimidazole was treated with potassium carbonate and ethyl chloroacetate to produce 1- (ethoxycarbonylmethyl) -2-chlorobenzimidazole. This compound (1 eq.) Was combined with the tert-butyl ester of L-4- (N, N-dimethylcarbamyoxy) -phenylalanine (1.1 eq., Prepared as described in Method L) and 2 drops of acetonitrile in a The tube was sealed and the reaction was heated for two days at 120 ° C and the resulting mixture was purified by column chromatography (1: 3 ethyl acetate / hexanes) to yield the title compound.

The NMR data were as follows: XH NMR (CDCl 3) d = 7.51 (d, 1H), 7.15 (m, 3H), 7.07 • (m, 1H), 6.97 (m, 1H), 5.26 (m, 1H) , 4.98 (m, 1H), 4.60 (m, 2H), 4.22 (q, 2H), 3.32 (m, 2H), 3.07 (s, 3H), 2.99 (s, 3H), 1.43 (s, 9H), 1.26 (t, 3H). 13C NMR (CDCI3): d = 171.4, 167.8, 153, 150.51, 134.57, 133.4, 130.64, 121.84, 121.49, 120.14, 116.94, 107.15, 82.47, 62.19, 56.54, 44.21, 36.94, 36.57, 36.33, 27.9, 13.88.

Example 2 Synthesis of N [1- (ethoxycarbonylmethyl) benzimidazol-2-yl] -L-4-. (N / N-dimethylcarbamyloxy) phenylalanine The title compound was prepared from the product of Example 1 using the procedure described in Method H. The data? MR were as follows: ^? MR (CD3OD) d = 7.3 (m, 4H), 7.1-6.9 (m , 4H), 4.2 (m, 2H), 3.1 (m, 4H), 2.95 (m, 4H).

EXAMPLE 3 Synthesis of tert-butyl ester of N- (benzoxazol-2-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine 2-Chlorobenzotriazole, tert-butyl ester of L-4- (N, N-dimethylcarbamyloxy) phenylalanine (prepared as described in Method L), and Hunig's base (diisopropylethylamine) were mixed in a reaction vessel and stirred under reflux for 18 h. The organic layer was washed several times with water and brine, dried over MgSO4 to yield the title compound. The MR data were as follows: XH? MR (CDC13) d = 7.4 (d, 1H), 7.19 (m, 3H), 7.07 (m, 3H), 5.54 (bs, 1H), 4.75 (bs, 1H) , 3.33 (ddd, 2H), 3.18 (s, 3H), 3.07 (s, 3H), 1.47 (s, 9H). 13C? MR (CDCI3): d = 170.26, 160.84, 150.71, 1148.72, 142.80, 132.61, 130.45, 123.95, 121.71, 121.19, 116.67, 108.91, 82.86, 56.7, 37.04, 36.55, 36.3, 27.82.

Example 4 Synthesis of N- (benzoxizole-2-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine The title compound was prepared from the product of Example 3 using the procedure described in Method H. The data NMR were as follows: XH NMR (CD30D): d = 7.22 (m, 4H), 7.14 (m, 2H), 6.92 (m, 2H), 4.57 (m, 1H), 3.28 (m, 2H), 2.95 (m, 2H), s, 3H), 2.84 (s, 3H). 13C NMR (CD30D): d = 156.96, 151.88, 149.74, 143.33, 135.83, 131.40, 125.24, 122.92, 122.46, 116.76, 109.96, 37.94, 36.77, 36.61.

Example 5 Synthesis of N- (benzothiazol-2-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine tert-butyl ester The title compound was prepared following the procedures described by the preparation of Example 3, substituting 2-chlorobenzothiazole for 2-chlorobenzoxazole.

Example 6 Synthesis of N- (benzothiazol-2-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine The title compound was prepared from the product of Example 5 using the procedure described in Method H. The data NMR were as follows: XH NMR (CDC13) d = 7.57 (m, 1H), 7.4 (m, 1H), 7.29 (m, 3H), 7.02 (m, 3H), 4.94 (m, 1H), 3.32 (m, 1H), 3.13 (m, 1H), 3.07 (s, 3H), 2.95 (s, 3H).

Example 7 Synthesis of N- (2-cyclohexylquinazol-4-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine tert-butyl ester Step A - Preparation of 2- (Cyclohexylcarbonylamino) benzamide The anthranilamide was treated with cyclohexanecarbonyl chloride and triethylamine in dichloromethane, followed by washing (10% citric acid, water, sodium bicarbonate sat, and sodium chloride sat.) And it was evaporated to give a near quantitative yield of 2- (cyclohexylcarbonylamino) benzamide as a white solid, which is used immediately in the next step.

Step B - Preparation of 2-cyclohexyl-4-hydroxyquinazoline The 2- (cyclohexylcarbonylamino) benzamide was stirred for 16 hours in a mixture of excess 1M NaOH and EtOH, and the resulting solution was treated with HCl at pH = 7 causing the formation of a precipitate. The precipitate was collected by filtration, washed (with water and hexane), and dried under vacuum to give a near quantitative yield of 2-cyclohexyl-4-hydroxyquinazoline as a white solid, which was used immediately in the next step.

Step C - Preparation of 2-cyclohexyl-4-chloroquinazoline The 2-cyclohexyl-4-hydroxyquinazoline was treated with phosphorus oxychloride and N, N-dimethylaniline according to the procedure described in S. Lee et al., J. Med. Chem. . 1995, 38 (18), 3457, to give a near quantitative yield of 2-cyclohexyl-4-chloroquinazoline as a yellow solid, which was used immediately in the next step.

Step D - Preparation of tert-Butyl Ester of N- (2-cyclohexylquinazol-4-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine To a solution of 2-cyclohexyl-4-chloroquinazoline (0.42 g, 1.7 mmol) in a mixture of 3 mL of dichloromethane and 3 mL of methanol, 4-methylmorpholine (0.29 mL, 0.26 g, 2.6 mmol) and tert-butyl ester of L-4- (N, N-dimethylcarbamyloxy) phenylalanine ( 0.62 g, 2.0 mmol). The mixture was stirred and heated at 40 ° C for 16 h, and then the volatiles were evaporated. The residue was purified by flash chromatography using EtOAc / hexanes on silica gel to give the title compound (0.40 g, 0.77 mmol, 45%) as a clear oil.

Example 8 Synthesis of N- (2-cyclohexylquinazol-4-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine The tert-butyl ester of N- (2-cyclohexylquinazol-4-yl) -L-4- (N, N-dimethylcarbamyloxy) -phenylalanine (0.10 g, 0.19 mmol) was dissolved in 3 mL of 96% formic acid and then the mixture was heated at 40 ° C for 16 h, at which time the TLC indicated the conversion of the initiator material. The majority of the formic acid was evaporated under a stream of nitrogen and then the residue was placed under high vacuum for 48 h to give the title compound (0.97 g, 0.19 mmol, 100%) as a clear oil.

Example 9: Synthesis of tert-butyl N- [2- (piperid-1-yl) quinazol-4-yl] -L-4- (N, N-dimethylcarbamyoxy) phenylalanine ester Step A - Preparation of 2,4-dichloroquinazoline Benzoylenurea was treated with phosphorus oxychloride and N, N-dimethylamine according to the procedure described in R, Ife et al., J. Med. Chem. 1995, 38 (14), 2763, to give a near quantitative yield of 2,4-dichloroquinazoline as a whitish solid, which was used immediately in the next step.

Step B - Preparation of tert-butyl ester of N- (2-chloroquinazol-4-yl) -L-4- (N ^ -dimethylcarbamyoxy) phenylalanine To a solution of 2,4-dichloroquinazoline (2.55 g, 13 mmol) in 30 mL of DMF was added tert-butyl ester of L-4- (N / N-dimethylcarbamyloxy) phenylalanine (4.32 g, 14 mmol) and diisopropylethylamine (3.3 mL, 2.48 g, 19 mmol) and the resulting solution was stirred for 2 hours. h, at such time, the TLC indicated the conversion of the initiator material. The volatiles were evaporated and the residue was dissolved in 200 mL of EtOAc. The resulting solution was washed (pH = 4.5 buffer, sat. Sodium bicarbonate, sat. Sodium chloride), dried (MgSO.sub.4), filtered and evaporated to give tert-butyl ester of N- (2-chloroquinazol-4). -yl) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine (3.2 g, 7.1 mmol, 54%) as a yellow oil, which was used immediately in the next step.

Step C - Preparation of tert-Butyl Ester of? - [2- (piperid-1-yl) quinazol-4-yl] -L-4- (N, N-dimethylcarbamyoxy) phenylalanine To a solution of the tert-butyl ester of N- (2-chloroquinazol-4-yl) -L-4-. { N, N-dimethylcarbamyloxy) phenylalanine (0.35 g, 0.75 mmol) in 2 mL of ethanol was added piperidine (0.22 mL, 0.19 g, 2.25 mmol) and the resulting solution was heated to 110 ° C in a sealed tube for 20 h, at that time the TLC indicated the conversion of the initiator material. The volatiles were evaporated and the residue was dissolved in 6 mL of EtOAc. The resulting solution was washed (pH = 4.5 buffer, sat'd sodium bicarbonate, sat'd sodium chloride) dried (MgSO4), filtered and evaporated to give the residue which was purified by flash chromatography on silica gel using EtOAc / hexanes to give the title compound (0.30 g, 76%) as a clear oil.

Example 10 Synthesis of N- [2- (piperid-1-yl) quinazol-4-yl] -L-4- (N, N-dimethylcarbamyloxy) phenylalanine The tert-butyl ester of N- [2- (piperid-1-yl) quinazol-4-yl] -L-4- (N, N-dimethylcarbamyloxy) -phenylalanine (0.12 g, 0.23 mmol) was dissolved in 3 mL of 96% formic acid and then the mixture was heated at 40 ° C for 16 h, at which time the TLC indicated the conversion of the initiator material. The majority of the formic acid was evaporated under a stream of nitrogen and then the residue was placed under high vacuum for 48 h to give the title compound (0.117 g, 0.23 mmol, 100%) as a clear oil.

Example A 'In Vitro Test to Determine the Link of Candidate Compounds to VLA-4 An in vi tro assay was used to assess the binding of the a4β? Integrin candidate compounds. The compounds which bind in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays (eg, competitive assays). This assay is sensitive to IC50 values as low as 1 nM. The activity of integrin 4β? was measured by the interaction of soluble VCAM-1 with Jurkat cells (eg, American Type Culture Collection No. TIB 152, TIB 153, and CRL 8163), a human T cell line which expresses high levels of a4β integrin ? VCAM-1 interact with the cell surface in a manner dependent on integrin a4β? (Yednock, et al., J. Biol. Chem., 1995, 270: 28740). Recombinant soluble VCAM-1 is expressed as a chimeric fusion protein that contains the seven extracellular domains of the VCAM-1 in the N-terminus and the human IgGi heavy chain constant region in the C-terminus. The VCAM-1 fusion protein was made and purified by the manner described by Yednock, supra. Jurkat cells were grown in RPMl 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutamine as described by Yednock, supra. Jurkat cells were incubated with 1.5 mM of MnCl2 and 5 μg / mL of antibody 15/7 for 30 minutes on ice. Mn + 2 activates the receptor to increase the binding of the ligand, and 15/7 is a monoclonal antibody that recognizes an activated occupied conformation / ligands of the integrin a4β? and encloses the molecule in this conformation, thereby stabilizing the interaction VCAM-1 / integrin a4ß !. Yednock, et al., Supra. Antibodies similar to antibody 15/7 have been prepared by other investigators (Luque, et al., 1996, J. Biol. Chem. 271: 11067) and can be used in this assay. The cells were then incubated for 30 minutes at room temperature with candidate compounds, in various concentrations ranging from 66 μM to 0.01 μM using standard serial dilution of 5 points. 15 μL of soluble recombinant VCAM-1 fission protein were then added to 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 IgG Fe F (ab ') 2 conjugate PE (Immunotech, Westbrook, ME) at 1: 200 and incubated on ice, in the dark, for 30 minutes. minutes The cells were washed twice and analyzed with a standard fluorescent activated cell ("FACS") distributor assay as described in Yednock, et al., Supra. Compounds having an IC50 of less than about 15 μM have binding affinity for a4β ?. When tested in this assay, each of the compounds prepared in the above examples have or are expected to have an IC 50 of 15 μM or less (or are expected to be active in vivo).

Example B Saturation Test In vi tro to Determine the Link of Candidate Compounds to a4ß? The following describes an in vi tro assay to determine the plasma levels needed for a compound to be active in the Encephalomyelitis model Experimental Autoimmune ("EAE"), described in the following sample, or in other models in vivo. Jurkat registration growth cells were washed and resuspended in normal animal plasma containing 20 μg / ml of antibody 15/7 (described in the previous example).

Jurkat cells were diluted twice in either normal plasma samples containing candidate compounds in various concentrations ranging from 66 μM to 0.01 μM, using a standard serial dilution of 12 points for a standard curve, or in plasma samples obtained from the peripheral blood of animals treated with the candidate compound. The cells were then incubated for 30 minutes at room temperature, washed twice with phosphate-buffered saline ("PBS") containing 2% fetal bovine serum and 1 mM each of calcium chloride and magnesium chloride (medium test) to remove the unbound 15/7 antibody. The cells are then exposed to goat anti-mouse IgG Fe F (ab ') conjugated to picoerythrin (Immunotech, Westbrook, ME) which has been absorbed by some non-specific cross-linked reactivity by co-incubation with 5% serum from of the animal species that has been studied, in 1: 200 and incubated in the dark at 4 ° C for 30 minutes. The cells were washed twice with the test medium and suspended again in the sample. They were then analyzed with a standard fluorescent activated cell ("FACS") distributor assay 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 form. The dose levels that result in the superior stabilization of the curve represent the levels necessary to obtain efficacy in an in vivo model. This assay can also be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as the agßi integrin, which is the integrin most closely related to aß? (Palmer et al, 1993, J. Cell Bio., 123: 1289). Such links are predictive of in vivo utility for inflammatory conditions mediated by integrin a4ß ?, which includes, by way of example, hyper-sensitivity of the airways and occlusion that occur with chronic asthma, proliferation of soft muscle cells in atherosclerosis, vascular occlusion followed by angioplasty, fibrosis and glomerular scars as a result of renal disease, aortic stenosis, hypertrophy of synovial membranes in rheumatoid arthritis, and inflammation and scars that occur with the progress of ulcerative colitis and Crohn's disease. Accordingly, the assay described above can be performed with a human colon carcinoma cell line, SW 480 (ATTC # CCL228) transfected with cDNA encoding a9 integrin (Yokosaki et al., 1994, J. Biol. Chem. , 269: 26691), instead of the Jurkat cells, to measure the binding of the a4β integrin ?. As a control, the SW480 cells which express other subunits a and ßi can be used. Accordingly, another aspect of this invention is directed to a method for the treatment of a condition in a mammalian patient, said condition is mediated by a9β ?, and in which, the method comprises administering to said patient a therapeutically effective amount of a compound of this invention. Such compounds are preferably administered in a pharmaceutical composition described hereinabove. The effective daily dose will depend on the age, weight, condition of the patient in which, the factors can be easily verified by the specialist's attention.

However, in a preferred embodiment, the compounds are administered at 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 to reduce motor deterioration in rats or guinea pigs. The reduction in motor deterioration is based on the blocking of blood adhesion between leukocytes and the endothelium and correlates with the anti-inflammatory activity in the candidate compound. This model has been previously described by Keszthelyi et al., Neurology, 1996, 47: 1053-1059, and measures the delay in onset of the condition. The brain and spine of Hartley adult guinea pigs were homogenized in an equal volume of buffered phosphate salt. An equal volume of the complete Freund adjuvant (100 mg mycobacterium tuberculosis plus 10 ml of incomplete Freund's adjuvant) was added to the homogenized. The mixture was emulsified by circulation repeatedly through a 20 ml syringe with a peristaltic pump for approximately 20 minutes. Female rats Lewis (2-3 months of age, 170-220 g) or Hartley guinea pigs (20 days of age, 180-200 g) were anesthetized with isoflurane and three injections of the emulsion, 0.1 ml each, were made on each side a. Motor deterioration begins to be seen in approximately 9 days. One begins with the treatment of the candidate compound on day 8, just before the onset of symptoms. The compounds are administered subcutaneously ("SC"), orally ("PO") or intraperitoneally ("IP"). The doses are given in a range of 10 mg / kg to 200 mg / kg, given, for 5 days, with a typical dosage of 10 to 100 mg / kg SC, 10 to 50 mg / kg PO, and 10 to 100 mg / kg IP. The GG5 / 3 andy against integrin 4β? (Keszthelyi et al., Neurology, 1996, 47: 1053-1059), which delays the onset of symptoms, is used as a positive control and injected subcutaneously at 3 mg / kg on day 8 and 11. Body weight and motor deterioration are measured daily. Motor impairment is provided with the following clinical record: o no change 1 weakness or paralysis of the tail weakness of the hind limb paralysis of the dying or dead hind limb A candidate compound is considered active if it delays the onset of symptoms, for example, they produce clinical records no greater than 2 or decreased body weight loss compared to the control.

Example D Asthma Model Inflammatory conditions mediated by integrin a4β? they include, for example, hyper-sensitivity of the airways and occlusion that occurs with chronic asthma. The following describes an asthma model which can be used to study the in vivo effects of the compounds of this invention for use in the treatment of asthma.

Following the procedures described by Abraham et al, J. Clin. Invent, 93: 776-787 (1994) and Abraham et al, Am J. Respir Crit Care Med, 156: 696-703 (1997), both of which are incorporated by reference in their entirety. The compounds of this invention are formulated in an aerosol and administered to sheep which are hypersensitive to the antigen Ascaris suum. Compounds which decrease the early bronchial response induced by the antigen and / or block the responses of the "late phase" airways, for example, which have a protective effect against late responses induced by antigen and hypersensitivity of the pathways Respiratory ("AHR"), are considered to be active in this model.Allergic sheep, which are shown to develop both early and late bronchial responses to inhaled Ascaris suum antigen, were used to study the respiratory tract effects of candidate compounds Following the topical anesthesia of the nasal passage with 2% lidocaine, a balloon-shaped catheter is advanced through a nostril in the lower esophagus.The animals are then intubated with an impotent endotracheal tube through another window. of the nose with a flexible fiber optic bronchoscope as a guide.Penuronal pressure is stimulated the according to Abraham (1994). The aerosols (see formulations below) are generated using a disposable medical nebulizer that provides an aerosol with an average mass aerodynamic diameter of 3.2 μm determined with an Andersen cascade impactor. The nebulizer is connected to a dosimeter system consisting of a solenoid valve and a compressed air source (20 psi). The total output of the nebulizer is directly on a plastic part T, one end of which is connected to the inspiratory port of a piston respirator. The solenoid valve is activated for 1 second at the beginning of the respirator's inspiratory cycle. The aerosols are released at Vt of 500 ml and at a ratio of 20 breaths / minute. A 0.5% sodium bicarbonate solution is only used as a control. To assess bronchial sensitivity, cumulative concentration response curves for carbachol can be generated according to Abraham (1994). The bronchial biopsy can be taken before and after the initiation of the treatment and 24 hours after the change of the antigen. The bronchial biopsy can be transformed according to Abraham (1994). A study of adhesion within alveolar macrophages can also be carried out in accordance with Abraham (1994), and a percentage of the adherent cells is calculated.

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

A. Preparation of a 0.5% Sodium Bicarbonate / Saline Base Solution: 100.0 mL Procedure: 1. Add 0.5 g of sodium bicarbonate in a 100 mL volumetric flask. 2. Approximately 90.0 mL of saline are added and sonicated until dissolved. 3. Sufficient quantity at 100.0 mL of saline and mix thoroughly.

B. Preparation of 30.0 mg / mL of Compound Candidate: 10.0 mL Procedure: 1. 0.300 g of the candidate compound are added in a 10.0 mL volumetric flask. 2. Approximately 9.7 mL of the sodium bicarbonate / saline base solution is added at 0.5%. 3. Sonicate until the candidate compound is completely dissolved. 4. Sufficient amount at 10.0 mL with 0.5% sodium bicarbonate / Saline Base solution and mix thoroughly.

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

Example E Allograft Model The rejection of the allograft, associated with the infiltration of inflammatory cells, is the obstacle leading to the survival of the long-term allograft. Cell surface adhesion molecules facilitate in vitro recognition and may be critical for lymphocyte trafficking in vivo. The following describes a model which can be studied by the in vivo effects of the compounds of this invention in the control of allograft rejection. The following procedures are described in Coito et al., Transplantation (1998) 65 (6): 699-706 and in Korom et al., Transplantation (1998) 65 (6): 854-895, both of which are incorporated by reference in its entirety. Following the procedures described in Coito and Corom, adult male rats weighing approximately 200-250 g were used in this model. Lewis rats were used as recipients of cardiac allografts of Lewis X Brown Norway rats. The hearts were transplanted into the large abdominal receptacles, using standard microvascular techniques. A candidate compound was administered to the transplant recipient in a suitable pharmaceutical carrier for a course of 7 days of treatment starting on the day of grafting. The doses vary from 0.3 to 30 mg / kg / day. The control vessels received only the pharmaceutical carrier. The rats were euthanized and their cardiac allografts were analyzed as described in Coito and Korom. Using conventional formulations, the compounds of this invention may be active in this model.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the contents of the following claims are claimed as property:

1. A compound of formula la and Ib: the Ib characterized in that, in the formula la, R1 and R2, together with the carbon atom and W to which they are respectively attached, are combined to form a fused ring heterocyclic group or a fused ring heteroaryl optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; in the formula Ib, R1 and R2, together with the carbon atom and W 'to which they are attached respectively, are combined to form an optionally fused ring heterocyclic group containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and further wherein the fused ring heterocyclic or fused ring heteroaryl group of the formula Ia or Ib is optionally substituted, at any ring atom capable of substitution, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, thioalkyl substituted, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino , -OS (02) -alkyl, -OS (O) -substituted alkyl, -OS (0) 2-aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02) -heteroaryl substituted, -OS (02) -heterocyclic, -OS (02) -substituted heterocyclic, -0S (02) -NRR wherein each R is independently hydrogen or alkyl, NRS (02) -alkyl, -NRS (02) -substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, -NRS (02) -heteroaryl, - • NRS (02) -sheteroaryl substituted , -NRS (02) -heterocyclic, NRS (02) -substituted heterocyclic, -NRS (02) -NR-alkyl, NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS ( 02) - 'NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR-substituted heteroaryl, -NRS (02) -NR-heterocyclic, -NRS (02) -NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R '] 2 and -N [S (02) -NR'] 2 where each R 'is independently selected from the group consisting of alkyl, substituted alkyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di- di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic ', amino mono- and di-heter substituted ocicy, di-substituted asymmetric 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 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 -S02NRR where R is hydrogen or alkyl; R3 is selected from the group consisting of: (a) - (CH2)? -Ar-R35 where R35 is selected from the group consisting of -0-Z-NR36R36 'and -OZ-R37 wherein R36 and R36' is selected independently of the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and wherein R36 and R36 'are combined to form a heterocycle or a substituted heterocycle, R37 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C (0) - and -S02-, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; and (b) Ar1-Ar2-C? -? 0alkyl-, Ar1-Ar2-C2_10alkenyl- and Ar1- Ar2-C2-? 0alkynyl-, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra; R3 'is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, aryl, arylalkyl of 1 to 10 carbon atoms, heteroaryl , and heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; Q is selected from the group consisting of -0-, -S-, -S (0) -, -S (0) 2-, and -NR4-; R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R 4 and R1 or R4 and R2, together with the atoms to which they are attached, are combined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group; W is selected from the group consisting of nitrogen and carbon; and W 'is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S (O), and S (0) 2; X is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenexy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and -NR "R" wherein each R "is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Ra is selected from the group consists of Cy, 0R, -N02, halogen, -S (0) mRd, -SRd, -S (O) 2ORd, -S (0) mNRdRe, -NRdRe, -0 (CRfRg) nNRdRe, -C (0) Rd, -C02Rd, -C02 (CRfRg) nCONRdRe, - OC (0) Ra, -CN, -C (0) NR, daRnee, -NRaC (0) Re, -0C (0) NRdaRnee, -NRaC (0) ORe, -NRdC (0) NRdRe, -CRd (N-ORe), CF3, and -OCF3; wherein Cy is optionally substituted with one to four selected substituents independently of Rc; Rb is selected from the group consisting of Ra, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, heteroaryl, 1 to 10 carbon atoms, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc; Rc is selected from the group consisting of halogen, amino, carboxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms, hydroxy, CF3, and aryloxy; Rd and Re are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, Cy and Cy-C? -? Oalkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 elements containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and Rg are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, Cy and Cy-Ci-loalkyl; or Rf and R9 together with the carbon to which they are attached form a ring of 5 to 7 elements containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, characterized in that R3 is - (CH2) X-Ar-R35.

3. The compound according to claim 2, characterized in that Ar is phenyl and x is 1.

4. The compound according to claim 3, characterized in that Q is -NR4- where R4 is hydrogen and X is -OH.

5. The compound according to claim 1, characterized in that R3 'is hydrogen and R3 is selected from the group consisting of: 3- [(CH3) 2NC (0) 0-] benzyl, 4- [(CH3) 2NC ( 0) 0-] benzyl, 4- [(CH3) 2NS (0) 20-] benzyl, 4- [(piperidin-1 '-yl) C (0) 0-] benzyl, 4- [(piperidin-4' -yl) C (0) 0-] benzyl, 4- [(1 '-methylpiperidin-4' -yl) C (O) 0-] benzyl, 4- [('-hydroxypiperidin-1' -il) C ( O) 0-] benzyl, 4- [(4'-formiloxipiperidin-1 '-yl) C (0) 0-] benzyl, 4- (4'-etoxicarbonilpiperidin-1' -yl) C (O) O-] benzyl, '4- (4 * -carboxilpiperidin-1' -yl) C (O) O-] benzyl, 4- (3 '-hidroximetilpiperidin-1' -yl) C (O) O-] benzyl, 4- ( 4 '-hydroxymethylpiperidin-1-yl) C (O) 0-] benzyl, 4- (' -phenyl-1 '-Boc-piperidin-4' -yl) C (O) 0-] benzyl, 4- ( 4 '-piperidon-1' -yl ethylene ketal) C (O) O-] benzyl, 4- (piperazin-4 '-yl) -C (O) 0-] benzyl, 4- (1-Boc-piperazine) -4 '-yl) -C (O) O-] benzyl, 4- (' -methylpiperazin-1'-yl) C (O) 0-] benzyl, 4- (4'-methylhomopiperazine-1-yl) C ( O) 0-] benzyl, 4- (4 '- (2-hydroxyethyl) piperazin-1'-yl) C (O) O-] benzyl, 4- (4'-phenylpiperazin-1'-yl) C (O ) O-] benzyl, 4- (4 '- (pyridin-2-yl) piperazin-1' -yl) C (O) O-] benzyl, 4- (4 '- (4-trifluoromethylpyridin-2-yl) piperazin-1 '-il) C (O) 0-] b ncilo, 4- (4' - (pyrimidin-2-yl) piperazin-1 '-yl) C (O) O-] benzyl, 4- (4 '-acetylpiperazin-1' -yl) C (O) O-] benzyl, 4- (4 '- (phenylC (O) -) piperazin-1' -yl) C (O) 0-] benzyl, 4- ( 4 '- (pyridin-4-ylC (0) -) piperazin-1' -yl) C (O) O-] benzyl, 4- (4 '- (phenylNHC (O) -) piperazin-1' -il) C (O) O-] benzyl, (4 '- (fenilNHC (S) -) piperazin-1 * -yl) C (O) O-] benzyl, 4- (4'-metansulfonilpiperazin-1' -yl-C (O) 0-) benzyl, 4- (4'-trifluorometansulfonilpiperazin-1 '-yl-C (O) O-) benzyl, 4- [(morpholin-4' -yl) C (O) 0-] benzyl, 3-nitro-4- [(morpholin-4 '-yl) -C (0) 0-] benzyl, 4- [(thiomorpholin-4' -yl) C (0) 0-] benzyl, 4- [(thiomorpholine) -4 '-il sulfone) -C (0) 0-] benzyl, (alternative nomenclature goes 4- [(1, l-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) (CH 3) NC (0) 0-] benzyl, 4- [(2 '- (N-methyl-N-toluene-4-sulfonylamino) ethyl) (CH3) NC (0) 0-] benzyl4- [(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 (O) 0-] benzyl , 4- [(CH30C (0) CH2) HNC (0) 0-] benzyl, 4- [2 '- (phenylNHC (O) O-) ethyl-] HNC (0) 0-] benzyl, 3-chloro- 4- [(CH3) 2NC (0) 0-] benzyl, 3-chloro-4- [(4'-methylpiperazin-1'-yl) C (O) 0-] benzyl, 3-chloro-4- [( 4 '- (pyridin-2-yl) piperazin-1' -yl) C (0) 0-] benzyl, 3-chloro-4- [(thiomorpholin-4 '-yl) C (0) 0-] benzyl, and 3-f luoro-4- [(CH 3) 2 NC (O) 0-] benzyl.

6. A compound of formula II characterized in that R3, R3 ', Q and X are as defined in claim 1; ring A forms a heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic ring; Ring B forms an aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring; and pharmaceutically acceptable salts thereof.

7. The compound according to claim 6, characterized in that R3 is - (CH2) X-Ar-R35.

8. The compound according to claim 7, characterized in that Ar is phenyl and x is 1.

9. The compound according to claim 6, characterized in that Q is -NR4- where R is hydrogen and X is -OH.

10. The compound according to claim 6, characterized in that R3 'is hydrogen and R3 is selected from the group consisting of: 3- (CH3) 2NC (O) 0-] benzyl, 4- (CH3) 2NC (0) 0-] benzyl, 4- (CH 3) 2 NS (O) 20-] benzyl, 4- (piperidin-1'-yl) C (O) 0-] benzyl, 4- (piperidin-4'-yl) C ( O) 0-] benzyl, 4- (1 '-methylpiperidin-4' -yl) C (0) 0-] benzyl, 4- (4 '-hydroxypiperidin-1' -yl) C (0) 0-] benzyl 4- (4 '-formyloxypiperidin-1' -yl) C (O) 0-] benzyl, 4- (4'-ethoxycarbonylpiperidin-1'-yl) C (O) 0-] benzyl, 4- (4 ') -carboxylpiperidin-1 '-yl) C (0) 0-] benzyl, 4- (3' -hydroxymethylpiperidin-1'-yl) C (0) 0-] benzyl, 4- (4'-hydroxymethylpiperidin-1 '- il) C (0) 0-] benzyl, 4- (4 '-phenyl-1' -Boc-piperidin-4 '-yl) C (0) 0-] benzyl, 4- (4'-piperidon-1' -ethyl ethylene ketal) C (O) 0-] benzyl, 4- (piperazin-4 '-yl) -C (0) 0-] benzyl, 4- (1' -Boc-piperazin-4 '-il) - C (0) 0-] benzyl, 4- (4'-methylpiperazin-1'-yl) C (0) 0-] benzyl, 4- [(4'-methylhomopipe razin-1 '-il) C (O) O-] benzyl, 4- [(4' - (2-hydroxyethyl) piperazin-1 '-yl) C (0) 0-] benzyl, 4- [(4' phenylpiperazin-1 '-yl) 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- [(4'-acetylpiperazin-1'-yl) C (O) O-] benzyl, 4- [(4 '- (phenylC (O) -) piperazin-1' -yl) C (O) 0-] benzyl, 4- [(4 '- (pyridin-4-ylC (0) -) piperazin-1'-yl) C (0) 0-] benzyl, 4- [( 4 '- (phenylNHC (0) -) piperazin-1' -yl) C (0) 0-] benzyl, 4- [(4 '- (phenylNHC (S) -) piperazin-1' -il) C (0 ) 0-] benzyl, 4- [(4'-methanesulfonylpiperazin-1 '-il-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-1-yl) C (0) 0-] benzyl, 4- [(thiomorpholin-4'-yl sulfone) -C (0) 0- ] benzyl, (alternative nomenclature 4- [(1, l-dioxothiomorpholin-4-yl) -C (0) 0-] benzyl), 4- [(pyrrolidin-1 '-yl) C (O) 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 (O) O -] benzyl, 4- [(2 '- (N-methyl-N-toluene-4-sulfonylamino) ethyl) (CH3) NC (O) 0-] benzyl, 4- [(2' - (morpholin-4 ' -yl) ethyl) (CH3) NC (O) 0-] benzyl, 4- [(2 '- (hydroxy) ethyl) (CH3) NC (O) 0-] benzyl, 4- [(bis (2'- (hydroxy) ethyl) NC (O) 0-] benzyl, 4- [(2 '- (formyloxy) ethyl) (CH3) NC (0) 0-] benzyl, 4- [(CH30C (0) CH2) HNC ( 0) 0-] benzyl, 4- [2 '- (phenylNHC (O) 0-) ethyl-] HNC (O) O-] benzyl, 3-chloro-4- [(CH3) 2NC (0) 0-] benzyl, 3-chloro-4- [(4'-methylpiperazin-1 '-yl) C (O) O-] benzyl, 3-chloro-4- [(4' - (pyridin-2-yl) piperazin-1 '-il) C (O) 0-] benzyl, 3-chloro-4- [(thiomorpholin-4' -yl) C (O) 0-] benz ilo, and 3-fluoro-4- [(CH3) 2NC (O) 0-] benzyl.

11. A compound of the formula Illa: characterized in that R3, R3 'and X are as defined in claim 1; And it is oxygen, sulfur, -S (O) -, -S (0) 2-, > NR5 or > N- S (0) 2R6; R4 'is selected from the group consisting of hydrogen and alkyl; R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; R6 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, cycloalkenyl. substituted, heterocyclic, substituted heterocyclic; heteroaryl and substituted heteroaryl; R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, carboxylheteroaryl substituted, carboxylheterocyclic, substituted carboxylheterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosu_fona, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heter oaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (02) -alkyl, OS (0) 2-substituted alkyl, -OS (O ) 2-aryl, -OS (02) -aryl substituted:., -OS (02) -heteroaryl, -OS (02) -substituted heteroaryl, -OS (02) -heterocyclic, -OS (02) -heterocyclic substituted .. -OS (02) -NRR wherein each R is independently hydrogen alkyl, -NRS (02) -alkyl, -NRS (02) -substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl , NRS (02) -heteroaryl, -NRS (02) -substituted heteroaryl, NRS (02) -heterocyclic, -NRS (02) -substituted heterocyclic, NRS (02) -NR-alkyl, -NRS (02) -NR- substituted alkyl, NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR-substituted heteroaryl, -NRS (02) - NR-heterocyclic, -NRS (02) -NR-substituted heterocyclic wherein R is hydrogen or alkyl, -N [S (02) -R '] 2 and -N [S (02) -NR'] 2 wherein each R 'is independently selected from the group consisting of alkyl, substituted alkyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and dialkylamino, mono- and di- (alkyl 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, substituted mono- and di-heterocyclic amino, disubstituted asymmetric amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl , substituted heterocyclic and 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 with -S02-alkyl, -S02-alkyl the substituted, 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 wherein R is hydrogen or alkyl; W "is selected from the group consisting of nitrogen and carbon (i.e., CH), and pharmaceutically acceptable salts thereof 12.

The compound according to claim 11, characterized in that R3 is - (CH2) X-Ar- R35 13.

The compound according to claim 12, characterized in that Ar is phenyl and x is

1. The compound according to claim 13, characterized in that Q is -NR4- where R4 is hydrogen and X is -OH.

15. The compound according to claim 11, characterized in that R3 'is hydrogen and R3 is selected from the group consisting of: 3- [(CH3) 2NC (0) 0-] benzyl, 4- [(CH3) 2NC ( O) 0-] benzyl, 4- [(CH3) 2NS (0) 20-] benzyl, 4- [(piperidin-1-yl) C (O) O-] benzyl, 4- [(piperidin-4 ' -yl) C (0) 0-] benzyl, 4- [(1 '-methylpiperidin-4' -yl) C (O) 0-] 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 (O) 0 -] benzyl, 4- [(4'-carboxypiperidin-1'-yl) C (0) 0-] benzyl, 4- [(3'-hydroxymethylpiperidin-1'-yl) C (0) 0-] benzyl, 4- [(4'-Hydroxymethylpiperidin-1 '-yl) C (0) 0-] benzyl, 4- [(4'-phenyl-1' -Boc-piperidin-4 '-yl) C (0) 0- ] benzyl, 4- [(4'-piperidon-1 '-yl ethylene ketal) C (0) 0-] benzyl, 4- [(piperazin-4' -yl) -C (0) 0-] benzyl, - [(1-Boc-piperazin-4 '-yl) -C (0) 0-] benzyl, 4- [(4'-methylpiperazin-1' -yl) C (0) O-] benz ilo, 4- [(4 '-methylhomopiperazin-1' -yl) C (0) 0-] benzyl, 4- [(4 '- (2-hydroxyethyl) piperazin-1' -il) C (0) 0- ] benzyl, 4- [(4'-phenylpiperazin-1-yl) 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) piperazine] -1 '-il) C (0) O-] benzyl, 4- [(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' -yl) C (0) 0-] benzyl, 4- [(4 '- (phenylNHC (0) -) piperazin-1' -yl) C (O) 0-] benzyl, 4- [(4'- (phenylNHC (S) -) piperazin-1'-yl ) C (0) 0-] benzyl, (4'-methanesulfonylpiperazin-1 '-il-C (O) O-) benzyl, 4- (4'-trifluoromethanesulfonylpiperazin-1'-yl-C (O) O-) benzyl, 4- (morpholin-4 '-yl) C (O) 0-] benzyl, 3-nitro-4- [(morpholin-4' -yl) -C (O) O-] benzyl, A- (thiomorph- 4 '-il) C (O) O-] benzyl, 4- [(thiomorfoiin-4'-yl sulfone) -C (O) O-] benzyl, (alternative nomenclature 4- [(1, l-dioxothiomorpholin-4 - il) -C (0) 0-] benzyl), 4- (pyrrolidin-1'-yl) C (O) O-] benzyl, 4- (2'-methylpyrrolidin-1'-yl) C (O) O-] benzyl, 4- (2 '- (methoxycarbonyl) pyrrolidin-1'-yl) C (O) 0-] benzyl, 4- (2' - (hydroxymethyl) pyrrolidin-1'-yl) C (O) O-] benzyl, 4- (2 '- (N, N-dimethylamino) ethyl) (CH3) NC (O) O-] benzyl, 4- (2' - (N-methyl-N-toluene-4-sulfonylamino ) ethyl) (CH3) NC (O) 0-] benzyl, (2 '- (morpholin-4' -yl) ethyl) (CH3) NC (O) O-] benzyl, (2 '- (hydroxy) ethyl) (CH3) NC (O) O-] benzyl, (bis (2'-nidroxy) ethyl) NC (O) 0-] benzyl, (2 '- (forr, loxi) ethyl) (CH3) NC (O) O -] benzyl, A- (CH3OC (0) ': -2) HNC (O) O-] benzyl, 2' - (phenylKKC (O) O-) ethyl-] HNC (O) O-] benzyl, -chloro-4- [(CH3) 2NC (O) O-] benzyl, 3-chloro-4- [(4'-m) ethylpiperazin-1 '-yl) C (O) O-] benzyl, 3-chloro-4- [(' - (pyridin-2-yl) piperazin-1 '-yl) C (O) 0-] benzyl, 3 -chloro-4- [(thiomorpholin-4 '-yl) C (O) 0-] benzyl, and 3-fluoro-4- [(CH 3) 2 NC (O) 0-] benzyl.

16. A compound of the formula Illb: characterized in that, R4 ', R7, R8, W ", X and Y are as defined in claim 11, R9 is selected from the group consisting of -OZ-NR11R11' and -OZ-R12 wherein R11 and R11 'are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and wherein R 11 and R 11 'are combined to form a heterocycle or a substituted heterocycle, R 12 is selected from group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C (O) - and -S02-, x is an integer from 1 to 4, and pharmaceutically acceptable salts thereof,

17. A compound of the formula lile: characterized in that R3, R3 ', R4', R7, R8 and X are as defined in claim 11; and R10 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxyheterocyclic , substituted carboxylheterocyclic, substituted cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl substituted, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (02) -alkyl, -OS (O) 2-substituted alkyl, -OS (0) 2 -aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02) -substituted heteroaryl, -0S (02) -heterocyclic, -OS (02) -substituted heterocyclic, -OS (02) -NRR where each R is independently hydrogen or alkyl, NRS (02) -alkyl, -NRS (02) -substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, -NRS (02) -heteroaryl, NRS (02) -substituted heteroaryl, - NRS (02) -heterocyclic, NRS (02) -substituted heterocyclic, -NRS (02) -NR-alkyl, NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR-substituted heteroaryl, -NRS (02) -NR-heterocyclic, -NRS (02) -NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R '] 2 and -N [S (02) -NR'] 2 wherein each R 'is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl , heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino , mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, amino mono- and di-heterocyclic co substituted, di-substituted asymmetric 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 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 -S02NRR where R is hydrogen or alkyl; and pharmaceutically acceptable salts thereof.

18. The compound according to claim 17, characterized in that R3 is - (CH2) X-Ar-R35.

19. The compound according to claim 18, characterized in that Ar is phenyl and x is 1.

The compound according to claim 19, characterized in that Q is -NR4- where R4 is hydrogen and X is -OH.

21. The compound according to claim 17, characterized in that R3 'is hydrogen and R3 is selected from the group consisting of: 3- (CH3) 2NC (O) O-] benzyl, 4- (CH3) 2NC (O) 0-] benzyl, 4- (CH 3) 2NS (O) 20-] benzyl, 4- (piperidin-1'-yl) C (O) O-] benzyl, 4- (piperidin-4'-yl) C ( O) 0-] benzyl4- (1 '-methylpiperidin-4' -yl) C (O) 0-] benzyl, 4- (4 '-hydroxypiperidin-1' -yl) C (O) O-] benzyl, 4- (4 ') -formyloxypiperidin-1 '-yl) C (O) O-] benzyl, 4- (4'-ethoxycarbonylpiperidin-1'-yl) C (O) O-] benzyl, 4- (4'-carboxypiperidin-1' - il) 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' -yl) C (0) 0-] benzyl, A- (4'-piperidon-1-yl-ethylene) ketal) C (0) 0-] benzyl, 4- [(piperazin-4 '-yl) -C (0) O-] benzyl, 4- [(1' -Boc-piperazin-4 '-yl) -C (O) 0-] benzyl, 4- [(4'-methylpiperazin-1'-yl) C (0) 0-] 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-yl) C (0) O-] benzyl, 4- [(4 '- (pyridin-2-yl) piperazin-1-yl) C (0) 0-] benzyl, 4- [(4' - (4-trifluoromethylpyridin-2-yl ) piperazin-1 '-il) C (0) 0-] benzyl, 4- [(4' - (pyrimidin-2-yl) piperazin-1-yl) C (0) 0-] benzyl, 4- [(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' -il-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- '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, A- (2'- (hydroxymethyl) pyrrolidin-1-yl) C (0) 0-] benzyl, 4- [(2 '- (N, N-dimethylamino) ethyl) (CH 3) NC (0) 0 -] benzyl, 4- [(2 '- (N-methyl-N-toluene-4-sulfonylamino) ethyl) (CH3) NC (O) 0-] benzyl, 4- [(2' - (morpholin-4 ' -yl) ethyl) (CH 3) NC (0) 0-] benzyl, A- (2 '- (hydroxy) ethyl) (CH 3) NC (0) 0-] benzyl, 4- [(bis (2' - (hydroxy) ethyl) NC (0) 0-] benzyl, 4- [(2 '- (formyloxy) ethyl) (CH3) NC (O) 0-] benzyl, A- l (CH3OC (0) CH2) HNC ( 0) 0-] benzyl, 4- [2 '- (phenylNHC (0) 0-) ethyl-] HNC (0) 0-] benzyl, 3-chloro-4- [(CH3) 2NC (0) 0-] benzyl, 3-chloro-4- [(4'-methylpiperazin-1 '-yl) C (0) O-] benzyl, 3-chloro-4- [(4' - (pyridin-2-yl) piperazin-1 '-il) C (0) 0-] benzyl, 3-chloro-4- [(thiomorpholin-4' -yl) C (0) 0-] benzyl, and 3-fluoro-4- [(CH 3) 2NC ( 0) 0-] benzyl

22. A compound of formula IVa and IVb: rva rvb characterized in that, in the formula IVa, R1 and R, together with the carbon atom and W to which they are attached respectively, combine to form a fused ring or fused ring heterocyclic heterocyclic group, optionally containing 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; in formula IVb, R1 and R2, together with the carbon atom and W ', to which they are attached respectively, combine to form a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consists of oxygen, nitrogen and sulfur; and further, wherein said fused ring heterocyclic or fused ring heteroaryl group of formula IVa or IVb is optionally substituted, at any ring atom capable of being substituted, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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 carboxyl-alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxylheterocyclic, substituted carboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, thioalk substituted ilo, thioaryl, substituted thioaryl, thiocycloalkyl, thiocycloalkyl. substituted, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, -OS (02) -alkyl, - OS (O) 2-substituted alkyl, -OS (O) 2-aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02) -sheteroaryl substituted, -0S (02) -heterocyclic , -OS (02) -substituted heterocyclic, -OS (02) -NRR wherein each R is independently hydrogen or alkyl, NRS (02) -alkyl, -NRS (02) -substituted alkyl, -NRS (02) -aryl, -NRS (02) -substituted aryl, -NRS (02) -heteroaryl, NRS (02) -substituted heteroaryl, -NRS (02) -heterocyclic, NRS (02) -substituted heterocyclic, -NRS (02) -NR-alkyl , NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS ( 02) -NR-substituted heteroaryl, -NRS (02) -NR-heterocyclic, -NRS (02) -NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R '] 2 and -N [S (02) -NR '] 2 wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di- (alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, substituted mono- and di-heterocyclic amino, di-substituted asymmetric 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 the conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted alkyl / alkyl groups 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 -S02NRR where R is hydrogen or alkyl; R13 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, Cy, and Cy-C? -? 0alkyl, wherein the alkyl is optionally substituted with one to four substituents independently selected from Ra; and Cy is optionally substituted with one to four substituents independently selected from Rb; R14 is selected from the group consisting of (a) - (CH2) x-Ar-R »3J50 where RJ is selected from the group consisting of -0-Z-NR36R36 'and -OZ-R37 wherein R36 and R36' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R36 and R36 'are combined to form a heterocycle or a substituted heterocycle, R37 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C (0) - and -S02-, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer from 1 to 4; and Ar2-C2_? 0alkynyl-, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra; R15 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, aryl, arylalkyl of 1 to 10 carbon atoms, heteroaryl, and heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; Ra is selected from the group consisting of Cy, -ORd, -N02, halogen, -S (0) mRd, -SR, -S (0) 2ORd, -S (0) mNRdRe, -NRdRe, -0 (CRfRg) nNRdRe, -C (0) Rd, -C02Rd, -C02 (CRRg) nCONRdRe, -0C (0) Rd, -CN, -C (0) NRdRe, -NRdC (0) Re, -0C (0) NRdRe, -NRdC (0) ORe, -NRdC (0) NRdRe, -CRd (N-0Re), CF3, and -0CF3; wherein Cy is optionally substituted with one to four substituents independently selected from Rc; Rb is selected from the group consisting of Ra, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, heteroaryl, alkyl from 1 to 10 carbon atoms, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc; Rc is selected from the group consisting of halogen, amino, carboxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms, hydroxy, CF3, and aryloxy; Rd and Re are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, Cy and Cy-C? -? Oalkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 elements containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and Rg are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, Cy and Cy-C? _alkyl; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 elements containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Rh is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cyano, aryl, arylalkyl of 1 to 10 carbon atoms, heteroaryl, heteroarylalkyl of 1 to 10 carbon atoms, or -S02R1; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from Ra; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from Rb; R1 is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, and aryl; wherein alkyl, alkenyl, and aryl are each optionally substituted with one to four substituents independently selected from Rc; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; W is selected from the group consisting of carbon and nitrogen; W 'is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S (O) and S (0) 2; X 'is selected from the group consisting of -C (0) ORd, -P (O) (ORd) (ORe), -P (O) (Rd) (ORe), -S (0) mORd, C (0) ) NRdRh, and 5-tetrazolyl; and pharmaceutically acceptable salts thereof.

23. Some compounds of the formula Va characterized in that W ", Y, R7, R8, R13, R14, R15 and X 'are as defined in claims 11 and 22, and pharmaceutically acceptable salts thereof

24. Compounds of the formula Vb: characterized in that R7, R8, R10, R13, R14, R15 and X 'are as defined in claim 23; and pharmaceutically acceptable salts thereof.

25. A compound of the formula Via and VIb: Via VTfa characterized in that, in the formula Via, R1 and R2, together with the carbon atom and W to which they are respectively bound, combine to form a fused ring or fused ring heterocyclic heterocyclic group optionally containing 1 to 3 selected heteroatoms from the group consisting of oxygen, nitrogen and sulfur; in formula VIb, R1 and R2, together with the carbon atom and W 'to which they are respectively linked, combine to form a fused ring heterocyclic group optionally containing 1 to 3 additional heteroatoms selected from the group consists of oxygen, nitrogen and sulfur; and further, wherein said fused ring heterocyclic or fused ring heteroaryl group of formula Vía or VIb is optionally substituted, at any ring atom capable of being substituted, with 1-3 substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonyl-amino, 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, carboxyl-substituted alkyl, carboxyl-cycloalkyl, substituted carboxyl-cycloalkyl, carboxylaryl, substituted carboxylaryl, carboxylheteroaryl, substituted carboxylheteroaryl, carboxyheterocyclic, substituted carboxylheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, thioalkyl substituted, thioaryl, substituted thioaryl, ticcycloalkyl, 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 (02) -alkyl, -OS (0) 2 -substituted alkyl, -OS (0) 2 -aryl, -OS (02) -substituted aryl, OS (02) -heteroaryl, -OS (02) - substituted heteroaryl, -0S (02) -heterocyclic, -OS (02) -h substituted heterocyclic, -OS (02) -NRR wherein each R is independently hydrogen or alkyl, -NRS (02) -alkyl, -NRS (02) -substituted alkyl, -NRS (02) -aryl, -NRS (02) - substituted aryl, -NRS (02) -heteroaryl, NRS (02) -substituted heteroaryl, -NRS (02) -heterocyclic, NRS (02) -substituted heterocyclic, -NRS (02) -NR-alkyl, NRS (02) -NR-substituted alkyl, -NRS (02) -NR-aryl, -NRS (02) -NR-substituted aryl, -NRS (02) -NR-heteroaryl, -NRS (02) -NR-heteroaryl substituted, -NRS (02) -NR-heterocyclic, -NRS (02) -NR-substituted heterocyclic where R is hydrogen or alkyl, -N [S (02) -R '] 2 and -N [S (02) - NR '] 2 wherein each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, mono- and di-alkylamino, mono- and di- ( alkyl substituted) amino, mono- and di-arylamino, mono- and di-arylamino substituted, mono- and di-heteroarylamino, mono- and di-heteroarylamino substituted, amino mono- and di-heterocyclic, amino mono- and di-heterocyclic substituted, di-substituted asymmetric 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 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 -S02NRR wherein R is hydrogen or alkyl; _. R23 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms optionally substituted with one to four substituents independently selected from Ra; and Cy is optionally substituted with one to four substituents independently selected from Rb; R24 is selected from the group consisting of Ar1-Ar2-C? _10alkyl Ar1-Ar2-C2-? 0alkenyl and Ar1-Ar2-C2_alkalkynyl, wherein Ar1 and Ar2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from Rb; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from Ra; R25 is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, aryl, arylalkyl of 1 to 10 carbon atoms, heteroaryl, and heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and aryl and heteroaryl are optionally substituted with one to four substituents independently selected from Rb; Ra 'is selected from the group consisting of Cy, -ORd', -N02, halogen, -S (0) mRd ', -SRd', -S (0) 2ORd ', -S (O) mNRd'Re', -NRd'Re ', -0 (CRf'Rg') nNRd'Re ', -C (0) Rd', -C02Rd ', C02 (CRf, Rg') nCONRd, Re ', -0C (0) Rd' , -CN, -C (O) NRd'Re ', -NRd'C (O) Re', -OC (0) NRd'Re ', -NRd'C (0) 0Re', -NRd'C (O) ) NRd'Re ', -CR' (N-ORe '), CF3, and -OCF3; wherein Cy is optionally substituted with one to four substituents selected independently from R is selected from the group consisting of Ra ', alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, arylalkyl of 1 to 10 carbon atoms, heteroarylalkyl of 1 to 10 carbon atoms, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from Rc '; Rc 'is selected from the group consisting of halogen, amino, carboxy, alkyl of 1 to 4 carbon atoms, ~ alkoxy of 1 to 4 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms, hydroxy, CF3, and aryloxy; Rd 'and Re' are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, Cy and Cy-C? _? 0alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from Rc; or R 'and Re' together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 elements containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf 'and R9' are independently selected from hydrogen, alkyl of 1 to 10 carbon atoms, Cy and Cy-Ci-loalkyl; or Rf 'and Rg' together with the carbon to which they are attached form a ring of 5 to 7 elements containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; Rh 'is selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, cyano, aryl, arylalkyl of 1 to 10 carbon atoms , heteroaryl, heteroarylalkyl of 1 to 10 carbon atoms, or -S02R1 '; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from Ra '; and aryl and heteroaryl is each optionally substituted with one to four substituents independently selected from Rb '; R1 'is selected from the group consisting of alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents selected from Rc '; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; X 'is selected from the group consisting of C (0) 0Rd', -P (0) (ORd ') (0Re'), -P (O) (Rd ') (0Re'), -S (0) m0Rd ', C (0) NRd'Rh', and 5-tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and pharmaceutically acceptable salts thereof.

26. Some compounds of the formula Vlla erior: characterized in that R7, R8, R23, R24, R25, W ", Y are as defined in claims 11 and 25 and X" is selected from the group consisting of -C (0) 0R, P (0) (0Rd) (0Re), -P (0) (Rd) (ORe), -S (0) mORd, -C (0) NRdRh, and 5-tetrazolyl; and pharmaceutically acceptable salts thereof.

27. A compound of the formula Vllb: characterized in that R7, R8, R10, R23, R24, R25 and X "are as defined in claim 26, and pharmaceutically acceptable salts thereof

28. A compound characterized in that it is selected from the group consisting of: N- [l- (ethoxycarbonylmethyl) benzimidazol-2-yl] -L-4- (N, N-dimethylcarbamyoxy) phenylalanine butyl, N- [1- (ethoxycarbonylmethyl) benzimidazol-2-yl] -L-4- ( N, N-dimethylcarbamyloxy) phenylalanine, N- (benzoxazol-2-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine tert-butyl ester, N- (benzoxazol-2-yl) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine, N- (benzothiazol-2-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine tert-butyl ester, N- (benzothiazol-2-yl) -L-4 - (N, N-dimethylcarbamyloxy) phenylalanine, N- (2-cyclohexylquinazol-4-yl) -L-4- (N, N-dimethylcarbamyoxy) phenylalanine tert-butyl ester, N- (2-cyclohexylquinazol-4-yl) ) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine, N- [2- (piperid-1-i) tert-butyl ester l) quinazol-4-yl) -L-4- (N, N-dimethylcarbamyloxy) phenylalanine, N- [2- (piperid-1-yl) quinazol-4-yl) -L-4- (N, N- dimethylcarbamyloxy) phenylalanine, and pharmaceutically acceptable salts thereof.

29. A method for binding the VLA-4 in a biological sample characterized in that the method comprises contacting the biological sample with a compound of claims 1-28 under the conditions wherein the compound binds to the VLA-4.

30. A pharmaceutical comtion characterized in that it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of a compound of claims 1-28.

31. A method for the treatment of an inflammatory disease in a patient mediated by the VLA-4 characterized in that the method comprises administration to. patient of the pharmaceutical comtions of claim 30.