MXPA00012625A

MXPA00012625A - Non-peptidyl inhibitors of vla-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases

Info

Publication number: MXPA00012625A
Application number: MXPA/A/2000/012625A
Authority: MX
Inventors: Allen Jacob Duplantier; Anthony John Milici; Louis Stanley Chupak
Original assignee: Pfizer Products Inc
Priority date: 1998-06-30
Filing date: 2000-12-15
Publication date: 2001-07-31

Abstract

Compounds of Formula (1.0.0) are described, wherein A is for example aryl, heteroaryl or heterocyclyl, Y is preferably -C(=O)-;B is independently selected from a group of moieties, the most preferred of which are those of partial Formulas (1.1.2) and (1.1.6), and E is a single bond;oxygen;1,1-cyclopropyl;C(CH3)2;CF2;or a bridging moiety of partial Formula (1.9.0), where R1a is hydrogen when R1 has the meaning of a mono-valent substituent;and R1a is a single bond when R1 has the meaning of a di-valent substituent. Said compounds are useful in methods of treating or preventing an inflammatory, autoimmune or respiratory disease by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4.

Description

NON-PEPTIDILIC INHIBITORS OF THE UNION TO THE VLA-4 DEPENDENT CELLS USEFUL IN THE TREATMENT OF INFLAMMATORY, AUTOIMMUNE AND RESPIRATORY DISEASES The present invention relates to compounds that have a non-peptidyl structure and are active as potent inhibitors of very late antigen-4 binding (VLA-4; 4β; CD49d / CD29) to proteins such as cell adhesion molecule 1 ( VCAM-1), the Hepll / MICS domain (CS-1 region) of fibronectin and osteopontin. As such, they are very useful in the inhibition of cellular adhesion and of pathogenic processes associated with cell adhesion mediated by VLA-4. The compounds and pharmaceutical compositions of this invention can be used in the treatment of many inflammatory, autoimmune and respiratory diseases, especially in asthma.

BACKGROUND OF THE INVENTION One of the most important processes necessary for the normal defense of the host is the regulated transit of leukocytes outside the vasculature. This system is designed to allow the normal recirculation of leukocytes, because it allows the rapid extravasation of leukocytes towards sites of injury and is one of the central pathogenic mechanisms of inflammatory, respiratory and autoimmune diseases in mammals. Cell adhesion is an important factor in this process and is particularly relevant for the present invention with regard to cell / cell and cell / matrix binding of hematopoietic cells containing VLA-4. VLA-4 is a member of a superfamily of cell surface macromolecular receptors termed integrins, which are non-covalent heterodimer complexes formed by a subunit a and a β subunit (Hemler, Ann, Rev. Immunol., 8, p 365, 1990). Eighteen different subunits have been identified and have been designated a? -a10, a? _, CC, oc? Oto, OCLRI, anB. «V and OIE! whereas nine different ß subunits have been identified that have been called ßi ß9. Each integrin molecule can be classified into a subfamily according to the type of its subunits a and β. The integrin β ?, VLA-4 is an integrin constitutively expressed by all leukocytes (for example, monocytes, lymphocytes, basophils, eosinophils, mast cells and macrophages) except for polymorphonuclear lymphocytes. The binding of this integrin to one of its ligands has a series of known activation and cell adhesion functions (Hemler, Ann, Rev. Immunol., 8 pp. 365, 1990; Walsh et al., Clin and Exp. Allergy, 25, pp. 1128, 1995; Huhtala et al., J. Cell Biol., 129, pp. 867, 1995). In particular, it is a receptor for the cytokine-inducible endothelial cell surface protein known as vascular cell adhesion molecule-1 (VCAM-1) and for the alternatively spliced and spliced forms of extracellular protein fibronectin (FN). containing the CS-1 domain (Ruegg et al., J. Cell. Biol., 177, pp. 179, 1991; Wayner et al., J. Cell. Biol., 105, pp. 1873, 1987; Kramer er al., J. Biol., Chem., 264, pp. 4684, 1989; Gehlsen et al., Science, 24, pp. 1228, 1988). The importance of the interactions of cell adhesion with VLA-4 has been determined by the use of specific monoclonal antibody (mAb) antagonists of the α-subunit of VLA-4, which have shown that inhibitors of VLA-dependent cell adhesion 4 prevent or inhibit numerous pathological inflammatory, respiratory and autoimmune disorders (Chisholm er al., Euro J. Immunol., 23, p682, 1993; Lobb et al., J. Clin. Invest., 94, p. 1722 1994; Richards et al., Am J. Respir Cell. Mol. Biol., 15, page 172, 1996; Soiluhanninen et al., J. Neuroimmunol., 72, page 95, 1997; Sagara et al. ., Int. Arch. Allergy Immunoi, 1 12, p.287, 1997; Fryer et al., J. Clin. Invest., 99, p.2036, 1997). In addition, confirmation that these pathological processes can be inhibited with agents other than antibodies has been observed in animal models after treatment with a synthetic CS-1 peptide or small peptide inhibitor molecule of VLA-4 (Fergus m et al., Proc. Nati, Acad. Sci., 88, pp. 8072, 1991; Wahl et al., J. Clin. Invest., 94, pp. 655, 1994; Molossi et al., J. Clin. Invest., 95 , page 2601, 1995, Abraham et al., Am. J. Respir. Crit. Care Med., 156, p.769, 1997; Jackson et al., J. Med. Chem., 40, p.3359, 1997).

DETAILED DESCRIPTION OF THE TECHNIQUE The investigation of mAbs and peptide VLA-4 antagonists in the art has already been indicated above. In defining the binding site for a4ßt, it was observed that lymphoid cells can bind at two different sites on fibronectin (Bemardi et al., J. Cell, Biol., 105, pp. 489, 1987). A component of this cell-binding activity has previously been identified as the tripeptide Arg-Gly-Asp (RGD) that binds to the c44 integrin? (VLA-5). Next, the minimum amino acid sequence required to bind and antagonize the activity of VLA-4 on leukocytes to the alternately cut and spliced site on fibronectin was determined (Humphries et al., J. Biol. Chem., 266, page 6886 , 1987; Garda-Pardo et al., J. Immunol., 144, pp. 3361, 1990; Komoriya et al., J. Biol. Chem., 266, pp. 15075, 1991). It was discovered that the binding domain to VLA-4 in the CS-1 region of fibromectin (FN) was formed by the octapeptide: Glu-lle-Leu-Asp-Val-Pro-Ser-Thr, as well as by two pentapeptides that overlapped: Glu-lle-Leu-Asp-Val and Leu-Asp-Val-Pro-Ser. All of these peptides inhibited FN-dependent cell adhesion, leading to the premature conclusion that the minimum amino acid sequence required to inhibit was Leu-Asp-Val (LDV). In fact, the minimal inhibitory sequence LDV was found to be as effective as the full-length CS-1 fragment in binding to the activated form of VLA-4 (Wayner et al., J. Cell. Biol., 16 , page 489, 1992).

It is believed that various integrins bind to the extracellular matrix proteins at the Arg-Gly-Asp (RGD) recognition site. Cyclic peptides based on RGD have been prepared that are said to inhibit the binding of 4β? and as-i to FN (Nowlin et al., J. Biol. Chem., 268, page 20352, 1993; Document PCT / US91 / 04862) although the primary recognition in FN for ß? It is LDV. The cyclic peptide is Arg - Cys - Asp - TPro - Cys where TPro represents 4-thioproline. Other peptide inhibitors of VLA-4 are those cited in Arrhenius, T. S .; Elices, M. J .; Gaeta; F. C. A .; "CS-1 Peptidomimetics", WO 95/15973, where a representative compound of the aforementioned type is the following: N-Phenylacetyl-Leu-Asp-Phe-NCy3 where NCy3 is selected, inter alia, from morpholinemido, thiomorpholinemido, 4- (tiadioxo) p -peridinamido and D-2- (carboxamide) -pyrrolidinamido, piperidinamido and piperidinamido substituted. The tripeptide Leu-Asp-Val has been used as the nucleus of a group of inhibitors of cell adhesion dependent on VLA-4 of the formula wherein R1 can be 4- (N '- (2-methylphenyl) urea) phenylmethyl; And it can be C = O; R2 can be H; R3 can be isobutyl; and R 4 can be 1,3-benzodioxol-5-yl. See Adams, S.P .; Lin, K. C; Lee W. C; Castro, A. C; Zimmerman, C. N .; Hammond, C. E .; Liao, Y. S .; Cuervo, J. H .; Singh, J .; "Cell Adhesion Inhibitors", WO 96/22966, which refers to compounds such as the following: other peptide inhibitors of cell adhesion mediated by VLA-4 that have been described include those of the formula Z- (Y1) - (Y2) - (Y3) n -X where Z can be 4- (N, - (2- methylphenyl) urea) phenylacetyl; (Y1) - (Y2) - (Y3) n represents a series of amino acids that form a peptide chain; and X can be OH. See Lin, K. C; Adams, S. P .; Castro, A. C; Zimmerman, C.

N .; Cuervo, J. H .; Lee, W. C; Hammond, C. E .; Carter, M. B .; Almquist, R. G .; Ensinger, C. L .; "Cell Adhesion Inhibitors", WO 97/03094, which refers to compounds such as the following: See also Zheng, Z .; Ensinger, C. L .; Adams, S. P .; WO 98/04247 which refers to inhibitors of cell adhesion comprising a compound of formula: A-B, wherein A comprises a determinant specificity that does not impart significant activity llb / Illa, and B comprises a supporting integrin. The following compound is representative of those cited: See also Singh, J .; Zheng, Z., Sprague, P., Van Vlijmen, H. W. T .; Castro A .; Adams, S. P .; "Molecular Model for VLA-4 Inhibitors", WO 98/04913, which refers to a three-dimensional pharmacophore model of a compound having VLA-4 inhibitory activity, comprising the characteristics defined by a three-dimensional tolerance and coordinate table x, y, z. The following compound is representative of the aforementioned: In spite of the advances described above in the art with respect to inhibitors of cell adhesion mediated by VLA-4, the skilled artisan will quickly recognize that these peptidyl inhibitors are prone to low absorption, low solubility and are subject to metabolism in vivo (both systemically and locally when administered directly to the lung), decreasing its opportunity to appreciably affect the development of an inflammatory, respiratory or autoimmune disease. Accordingly, there is still a need in the art for non-peptidyl or semi-peptidyl therapeutic agents that can effectively treat or prevent such pathological disorders.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compositions that inhibit VLA-4 dependent cell adhesion in a mammal. The present invention thus relates to a compound of formula (1.0.0): (1.0.0) and its pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein -A is aryl, heteroaryl or heterocyclyl as defined herein, said aryl, heteroaryl or heterocyclyl being substituted with 0 to 3 R10; or is a member selected from the group consisting of divalent radicals: -A1NHC (= O) NH-A2-, -A1NHC (= O) O-A2-, and -A1NH (NCN) NH-A2-, each selected from A1 and A2 independently of the group consisting of hydrogen, aryl, heteroaryl and heterocyclyl as defined herein, said aryl, heteroaryl or heterocyclyl being substituted with 0 to 3 R10; -B is a member selected independently from the group consisting of the following: (1.1.3) (1.1.4) (1.1.5) (1.1.12) (1 .1.13) (1.1.14) where the symbol "*" indicates the point of union of the radical represented by each of the partial formulas (1.1.0) to (1.1.14), to the radical "Y" in the formula (1.0.0); and the symbol "-» "indicates the point of attachment of the radical represented by each of the partial formulas (1.1 .0) to (1.1.14) to the radical" E "of the formula (1.0.0); -E is a simple link; -OR-; -CH = CH-; or a radical of formula (1.9.0): (1 .9.0) wherein R1a is hydrogen when R1 has the meaning of a monovalent substituent; and R a is a single bond when R 1 has the meaning of a divalent substituent; -X is -O-; -S (= 0) q-; or -N (R14) -; -And it is -C (= O) -; -C (= S) -; -S (= O) 2-; or -CH (Ra) -; -m is an integer selected independently of 0, 1 and 2; n is a selected integer independent of 1 and 2; -p is a selected integer independent of 1 and 2, with the proviso that p must be selected as 1 when B is selected as the partial formula (1.1.2), (1.1.3), (1.1.5), ( 1.1.6), (1.1.7), (1.1.8), (1.1.9), (1.1.10), (1.1.11), (1.1.12), (1.1.13), or (1.1) .14); -q is an integer selected independently of 0 and 2; -R is independently selected from the group consisting of -tetrazolyl; -C (= O) -OR5; -C (= O) (CH2) kC (= O) OR5; -C (= O) NO; -C (= O) -NH-S (= O) 2R5; -S (= O) 2-NR 14 R 5; -C (= O) -NHS (= O) 2R6; and a radical of the partial formula (3.0.0); (3.0.0) where -k is an integer selected independently of 0, 1 and 2; -R is independently selected from the group consisting of hydrogen; = O; = S; F; C -? - C6 alkyl substituted with 0 to 3 R10; C2-C6 alkenyl substituted with 0 to 3 R10; C2-C6 alkynyl substituted with 0 to 3 R10; a C3-d4 carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; and aryl (C1-C4 alkyl), said aryl and alkyl being substituted with O to 3 R12; heterocyclyl as defined herein, substituted with O to 3 R12; and heterocyclyl (C 1 -C 4 alkyl) as defined herein, said heterocyclyl and alkyl being substituted with O 3 R 12; C (= O) NR8R9; and C (= O) R8; -R2 and R3 are each independently selected from the group consisting of hydrogen; C? -C alkyl substituted with 0 to 3 R 3; C2-C6 alkenyl substituted with 0 to 3 R13; a C3-C carbocyclic ring system substituted with 0 to 3 R13; (C 1 -C 4 alkoxy) carbonylamino (C 1 -C 4 alkyl); (C 1 -C 4 alkyl) t 1 - (C 1 -C 4 alkyl) -; (C 1 -C 4 alkyl) sulfonyl (C 1 -C 4 alkyl) -; hydroxy (C 1 -C 4 alkyl) thio- (C 1 -C 4 alkyl) -; (C 1 -C 4 alkyl) carbonylamino (C 1 -C 4 alkyl) -; (C 1 -C 4 alkyl) sulfonylamino (C 1 -C 4 alkyl) -; (C 1 -C 4 alkyl) sulfonylaminocarbonyl (C 1 -C 4 alkyl) -; and a heterocyclic ring as defined herein, substituted with 0 to 3 R13; with the proviso that R2 and R3 are each as defined above; or they are taken together as defined below; or one of them is taken together with R4 as defined below, in which case the other has the meaning of hydrogen or methyl; -R2 and R3 are taken together forming a carbocyclic ring C3-C-? Spirocyclic substituted with 0 to 3 R13; or -R2 or R3 are taken together with R4 and the carbon and nitrogen atoms to which they are respectively bonded to form a heteroaryl or heterocyclyl group as defined herein, substituted with 0 to 3 R12; -R5 is hydrogen; alkyl 0 ^ 4; C3-Cβ cycloalkyl; or aryl; -R6 is hydrogen; C1-C4 alkyl; (CH2) (C3-C6 cycloalkyl); or (CH2) s-aryl; where -r and s are each independently an integer selected from 0, 1 and 2; -R8 and R9 are each independently selected from the group consisting of hydrogen; C1-C4 alkyl substituted with 0 to 3 R10; a C3-Cu carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; and aryl (C 1 -C 4 alkyl), said aryl and alkyl being substituted with 0 to 3 R 12; heterocyclyl as defined herein, substituted with 0 to 3 R12; and heterocyclyl (C 1 -C 4 alkyl) as defined herein, said heterocyclyl and alkyl substituted with 0 to 3 R 12; -R10 is independently selected from the group consisting of F; Cl; -C (= O) OR14; -OH; nitro; cyano; Not me; di (alkyl CrC4) amino; C1-C4 alkyl; C1-C4 alkoxy; (alkyl d-C4) thio; phenoxy; trifluoromethoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; (C3-C6 cycloalkoxy) carbonyl; (C 1 -C) alkylcarbonylamino; (C 1 -C) alkyl sulfonylamino; (C 1 -C 4 alkyl) urea; and C 1 -C 4 alkyl and C 1 -C 4 alkoxy each substituted by 1 to 3 substituents independently selected from F and Cl; -R 2 when it is a substituent on a carbon atom, is independently selected from the group consisting of F; Cl; C -? - C4 alkyl; C3-C6 cycloalkyl; C4 alkoxy; -C (= O) OR14; -OH; alkyl d-C4 and C 1 -C 4 alkoxy, each substituted by 1 to 3 substituents independently selected from F and Cl; (C 1 -C 4 alkoxy) carbonyl; (C 1 -C 4 alkyl) carbonyl; (C 1 -C 4 alkyl) carbonyloxy; and a heteroaryl or heterocyclyl group as defined herein, having 5 or 6 links; or -R12 when two groups R12 are attached to adjacent carbon atoms of a carbocyclic, aryl, heteroaryl or heterocyclic ring, can be a chain of 3 or 4 carbon atoms forming a fused ring of 5 or 6 links, said ring being of 5 or 6 links optionally mono- or di-substituted on the aliphatic carbon atoms thereof by F, Cl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or hydroxy; or -R12 when R13 is attached to a saturated carbon atom, can be = O u = S; or when R12 is attached to a sulfur atom, it can be = O; -R12 when it is a substituent on a nitrogen atom, is independently selected from the group consisting of hydroxy; hydroxy (C1-C4 alkyl); C1-C4 alkoxy; C3-C6 cycloalkyl; (C 1 -C 4 alkyl) carbonyl; and aryl; -R13 is independently selected from the group consisting of aryl; heteroaryl; heterocyclyl; C1-C4 alkoxy; C3-C6 cycloalkyl; C2-C6 alkynyl; -OR14; heterocyclic il-carbonyl; (alkyl d-C4) thio; -NR6R5; and -C (= O) -NR14R5; and R is hydrogen; hydroxy; C1-C4 alkyl; C3-C6 cycloalkyl; or aril. The present invention further relates to pharmaceutical compositions comprising one or more of the compounds of the present invention as described above, together with a pharmaceutically acceptable carrier for said compound (s), said amount being (s) ) compound (s) effective to prevent, inhibit, suppress or reduce cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. The present invention further relates to pharmaceutical compositions which, in addition to containing a compound of the present invention, further comprise one or more therapeutic agents selected from the group consisting essentially of anti-inflammatory corticosteroids, non-steroidal anti-inflammatory agents, bronchodilators, antiasthmatic agents and immunosuppressive agents. The present invention further relates to a method of treating or preventing an inflammatory, autoimmune or respiratory disease by inhibiting cell adhesion and the consequent or associated processes subsequently mediated by VLA-4 which comprises administering to a mammal in need of such treatment a therapeutically effective amount. of a pharmaceutical composition of the present invention. The pharmaceutical compositions of the present invention can be used in the treatment of many inflammatory, autoimmune and respiratory diseases, including, but not limited to, asthma, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, host rejection after an organ transplant, atherosclerosis and other diseases mediated by or associated with VLA-4.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds that inhibit cell adhesion and the consequent pathogenic processes mediated by VLA-4. These compounds, which are thus useful in the treatment of many inflammatory, autoimmune and respiratory diseases, can be illustrated by the formula (1.0.0.): (1.0.0) for the compounds of formula (1.0.1), the terminal group identified as A has the meaning of aryl, heteroaryl or heterocyclyl substituted with 0 to 3 R10, or is a member selected from the group consisting of divalent radicals: -A1NHC (= O ) NH-A2-, -A1NHC (= O) O-A2-, and -A1NH- (NCN) NH-A2-, each of A1 and A2 being selected from the group consisting of hydrogen, aryl, heteroaryl and heterocyclyl, said aryl, heteroaryl or heterocyclyl substituted with 0 to 3 R10.

The term "aryl" when used with reference to "A", as well as in other contexts of the present specification, refers to a carbocyclic aromatic group that is a member selected from the group consisting essentially of phenyl, naphthyl, indenyl, indanyl and fluorenyl. However, it is preferred that when "A" is "aryl", it is phenyl. The term "heteroaryl" when used with reference to "A", as well as in other contexts of the present specification, refers to a heterocyclic aromatic group that is a member selected from the group consisting essentially of furyl, thienyl, pyrrolyl, oxazolyl , Soxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1 H-indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl , acridinium, phenazinyl, phenothiazinyl, phenoxazinyl and pyrazolo [1,5-c] triazinyl. However, it is preferred that when "A" is "heteroaryl" it is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo [b] furanyl, benzimidazolyl or quinolinyl. More preferably "A" is pyridyl. The terms "heterocyclic" and "heterocyclyl" when used with reference to "A", as well as in other contexts of the present specification, both refer to a non-aromatic carbocyclic ring of 3 to 10 links in which at least one of the carbon atoms of the ring has been replaced by a heteroatom selected from N, O or S. Preferably, two and more preferably one heteroatom are present, except in the case of nitrogen, in which up to four N heteroatoms may be present. The heterocyclyl group may comprise one or two fused rings, and may further include an aryl fused ring. In a preferred definition, "heterocyclyl" refers to a member selected from the group consisting essentially of oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and benzodioxolane, especially 1,3-benzodioxol-5-yl. However, it is preferred that when "A" is "heterocyclyl", it is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. When "A" is defined as a radical selected from the aryl, heteroaryl or heterocyclyl groups defined above, said radical may be substituted with 0 to 3 R10. The choice of "0" simply indicates that there are no substituents, with the substitution being optional. When substitution exists, there are preferably two substituents and more preferably there is only one substituent. When a substituent R10 is used, it will be independently selected from the group consisting of F; Cl; -C (= O) OR14; -OH; nitro; cyano; Not me; di (CrC4 alkyl) amino; alkyl d-C; C4-C4 alkoxy; Cs-Ce cycloalkyl; C3-C6 cycloalkoxy; (alkyl C? -C) thio; phenoxy; trifluoromethoxy; (C3-C6carbonylcycloalkoxy; (d-C4 alkyl) carbonylamino; (C1-C4 alkyl) sulfonylamino; (alkyl dC) urea; and C1-C4 alkyl and dd alkoxy each substituted by 1 to 3 substituents independently selected from F and Cl being R14 as defined herein, however, preferably there is a single substituent and this is F, Cl, OH, methyl, methoxy, cyclohexyl, cyclopropyloxy or F3C- The term "alkyl" when used with reference to the substituents "R10" in the group "A", as well as in other contexts of the present specification and when used alone or in combination, refers to a straight or branched chain alkyl radical containing the indicated number of carbon atoms. carbon, usually from 1 to 6, although they are frequently from 1 to 4. Examples of such radicals include, but are not limited to methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, urea-butyl, pentyl, / so-amyl and hexyl The term "alkoxy" when used with reference aa the substituents "R10" in the group "A", as well as in other contexts of the present specification, and if used alone or in combination, refers to an alkyl ether radical, the term "alkyl" being the same as defined before. Examples of suitable alkyl ether radicals include, but are not limited to methoxy, ethoxy, n-propoxy, / so-propoxy, n-butoxy, / so-butoxy, sec-butoxy and tert-butoxy. The term "cycloalkyl" when used with reference to substituents "R10" in group "A", as well as in other contexts of the present specification, and if used alone or in combination, refers to a cycloalkyl radical containing from 3 to 6 carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkyloxy" when used with reference to substituents "R10" in group "A", as well as in other contexts of the present specification, and if used alone or in combination, refers to a cycloalkyl ether radical , the term "cycloalkyl" being as defined above. Examples of such cycloalkyloxy radicals include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. A preferred meaning of "A" is that of a ureido radical, more preferably a divalent radical which is a member selected from the group consisting of -A1NHC (= O) NH-A2-, -A1NHC (= O) O-A2- and -A1NH (NCN) NH-A2-, each being selected from A1 and A2 independently of the group consisting of hydrogen, aryl, heteroaryl and heterocyclyl, said aryl, heteroaryl or heterocyclyl being substituted with 0 to 3 R10. The aryl, heteroaryl or heterocyclyl group which is attached to both of the ureido radical is selected according to the definitions set forth above, such as the 0 to 3 substituents R10. It is preferred that an aryl group be covalently attached to both sides of the ureido radical, and it is further preferred that this aryl group is phenyl. Most preferred is that said phenyl group has a single substituent which is preferably F, Cl, methyl, methoxy or F3C-. Examples of the preferred meanings of "A" are shown in the partial formulas (4.0.0) to (4.0.1 1): .0.3) (4.0.4) .0.5) (4.0.6) (4.0.7) ( 4.0.8) .0.9) .0.10) .0.11) the component of the compounds of formula (1.0.0) which is immediately adjacent to component "A" is the methylene or ethylene bridge element, where n = 1 or 2, respectively. It is preferred that n = 1 and that a methylene bridge exists. Therefore, within the context of the preferences indicated above for the meaning of the "A" component and adding the methylene bridge, the following most preferred terms including the "A" component can be represented by the partial formulas (4.1.0) a ( 4.1.23) below: 4-hydroxyphenyl- 4.1.0) 3. -methoxy-4- (N'-phenylurea) -phenylmethyl- (4.1.1) H 4- (N'-phenylurea) -phenylmethyl- Cpr (4.1 2) 4- [N '- (2-methylphenyl) -urea] -phenylmethyl- 4- [N '- (2-methoxyphenyl) -urea] -phenylmethyl- 3-methoxy-4- [N '- (2-methylphenyl) -urea] -phenylmethyl- 4- [N '- (2-pyridyl) -urea] -phenylmethyl- 6-methoxy-5- [N '- (2-methylphenyl) -urea] -2-pyridylmethyl- 4- [N '- (3-methyl-2-pyridyl) -urea] -2-phenylmethoxy- 3-methoxy-4- [N '- (3-methyl-2-pyridyl) -urea] -phenylmethyl- 3-methoxy-4- [N '- (2-pyridyl) -urea] -phenylmethyl- 4- [N '- (2-pyridyl) -urea] -phenylmethyl- 4- [N, - (2-fluorophenyl) -urea] -phenylmethyl- 4- [N '- (2-chlorophenyl) -urea] -phenylmethyl- 4- [N '- (2-chlorophenyl) -urea] -3-methoxyphenylmethyl- 4- [N '- (4- / so-propylphenyl) -urea] -phenylmethyl- 6-methoxy-5- [N '- (o-toluyl) -urea] -2-pyridylmethyl- 4- [N '- (3-cyclopentyl-2-pyridyl) -urea] -phenylmethyl- 4- [N '- (2-cyclopentyl) -urea] -phenylmethyl- 4- [N '- (3-cyclopropyloxy-2-pyridyl) -urea] -phenylmethyl- 4- [N '- (o-toluyl) -urea)] - pyrid-5-ylmethyl-CH 3 O 4- [3- (4-methy1-pyridin-3-yl) -ureido] -phenylmethyl-? (4 1 21) (4 1 22) 4- [3- (2,6-dichloro-phenyl) -ureido] -phenylmethyl- 4- [3- (2,6-dimethyl-phenyl) -ureido] -phenylmethyl- (4 1 23) It will be further appreciated in partial structural formulas that the preferred methylene bridge is further preferably linked to the N, N'-diphenylureido group in a relationship for the point of attachment of the divalent ureide group to the phenyl group involved. The "Y" component of the formula (1.0.0) can be -C (= O) -; -C (= S) -; -S (= O) 2-; or -CH (Ra) -; having Ra the meaning of hydrogen or d-C4 alkyl. When "Y" is the radical -CH (Ra) -, it is preferred that Ra has the meaning of hydrogen or methyl. In general, however, it is most preferred that "Y" be a carbonyl radical, that is, that "Y" be the radical -C (= O). The next component, group "B", of the compounds of formula (1.0.0) is one of the most important parts of the molecule and is a fundamental element to provide the unexpectedly good biological properties of the compounds of the present invention . The group "B" comprises a member selected from the group consisting of the partial formulas (1.1.0) to (1.1.14): (1.1.0) (1 -1.1) (1.1.2) (1.1.3) (1.1.4) (1.1.5) (1.1.6) (1.1.7) (1.1.8) (1.1.9) (1.1.10) (1.1.11) (1.1.12) (1.1.13) (1.1.14) where the symbol "*" indicates the point of union of the radical represented by each of the partial formulas (1.1.0) to (1.1.14), to the radical "Y" in the formula (1.0.0); and the symbol "-" indicates the point of union of the radical represented by each of the partial formulas (1.1.0) to (1 .1.14) to the radical "E" of the formula (1.0.0). All the above partial formulas (1.1.0) to (1.1.14), both included, are illustrated as fragments in the manner described above, with the points of attachment at either end of a particular fragment being indicated by the symbols "* " Y "?". In the above partial formulas defining component B of the compounds of formula (1.0.0), the radical "X" may be oxygen; sulfur (q = 0) and sulfur to which two oxygen atoms are attached (q = 2), that is, sulfonyl; or nitrogen (R14 = hydrogen) or nitrogen that is substituted (R14 = alkyl d-d; C3-Cβ cycloalkyl; or aryl). However, it is preferred that "X" is simply oxygen, sulfur or nitrogen. In the above partial formulas defining component B of the compounds of formula (1.0.0), R2 and R3 are independently selected from the group consisting of hydrogen; substituted d-C4 alkyl from 0 to 3 R13; C2-C6 alkenyl substituted with 0 to 3 R13; a C3-d4 carbocyclic ring system substituted with 0 to 3 R13; (C 1 -C) alkoxycarbonylamino (d-C alkyl); (alkyl dC) thio- (C1-C4 alkyl); (C 1 -C 4 alkyl) sulfonyl (d-d alkyl) -; hydroxy (alkyl C? -d) t, o- (alkyl dC) -; (alkyl d-C4) carbonyl amine (d-C4 alkyl) -; (CrC4 alkyl) suiofilamino (alkyl dC) -; (alkyl Ci-dsulfonylaminocarbonyl (alkyl dd) -; and a heterocyclic ring substituted with 0 to 3 R13, with the proviso that R2 and R3 are not both hydrogen at the same time.This condition is also fulfilled when R2 and R3 are taken together according to an optional definition of R2 and R3, in which case they form a C3-d spirocyclic ring substituted with 0 to 3 R. For example, when R2 and R3 are taken together to form a spirocyclic group cyclopropyl, cyclobutyl or cyclopentyl, the resulting compounds of the present invention will include radicals such as those of the partial formulas (1.2.0) to (1.2.2): (1.2.0) (1.2.1) (1.2.2) Another preferred subgroup of compounds of the present invention is formed when R2 or R3 are taken together with R4 and the carbon and nitrogen atoms to which they are attached respectively forming a heteroaryl or heterocyclyl group as defined herein. Said heteroaryl or heterocyclyl group can, in turn, be substituted with 0 to 3 R12. According to the aforementioned condition, when R2 or R3 are taken together with R4, the other must be hydrogen or methyl. The subgroup can be represented by the following partial formula (1.3.0): (1.3.0) in which the symbol "*" indicates the point of union of the radical represented by the partial formula (1.3.0) to the radical "Y" in the formula (1.0.0); and the symbol "?" indicates the point of attachment of the radical represented by the partial formula (1.3.0) to the remaining portion of the radical "B" in the formula (1.0.0), defined by the formulas (1.1.0) to (1.1.14) . The substituent "R273" indicates the presence of the substituent R2 or the substituent R3. These may not be present, since one or the other has already been selected to be taken together with R 4 and to form the heteroaryl or heterocyclyl group of partial formula (1.3.0), depicted below: it will be understood that if R2 or R3 is present, it will have the meaning of hydrogen or methyl. Therefore, this subgroup of group "B" represented by the partial formula (1.P-.0) includes, although it is not limited to the modalities that are represented by the partial formulas (1.3.1) to (1.3.20) : (1.3.17) (1.3.18) (1.3.19) (1.3.20) in which the symbol "*" indicates the point of union of the radical represented by each of the partial formulas (1.3.1) to (1.3.20) to the radical "Y" in the formula (1.0.0); and the symbol "?" indicates the point of union of the radical represented by each of the partial formulas (1.3.1) to (1.3.20) to the radical "E" in the formula (1.0.0). With reference to the optional substituent R13 that may be present on substituents R2 and R3 of component B, R13 is not present when "0" is selected. It is preferred that R13 is not present, or is it as a single substituent selected from aryl; heteroaryl; heterocyclyl; alkoxy d-d; C3-C6 cycloalkyl; C2-Cß alkynyl; -OR14; heterocyclyl carbonyl; (alkyl d-C4) thio; NR14R5; and -C (= O) NR14R14 '. With reference to the optional R13 substituent, but also with reference to the radical of the present invention, the term "alkynyl" alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing from 2 to 6, preferably from 2 to 4 carbon atoms. Examples of such radicals include, but are not limited to ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl-like. The term "alkylthio", alone or in combination with other terms, is used herein to refer to a thioether radical of the formula alkyl-S-, where the alkyl component thereof is a straight-chain or branched-chain alkyl radical containing from 1 to 4 carbon atoms, and preferably from 1 to 2 carbon atoms. Thus, an example of said alkylthio substituent includes, but is not limited to, methylthio and / so-butylthio. With respect to the definitions of substituents R2 and R3 in component B, the term "alkoxycarbonylaminoalkyl", alone or in combination, refers to a radical of formula alkyl-OC (= O) NH-alkyl-, both being "alkyl" "as defined earlier. The term "alkylthioalkyl", used alone or in combination, refers to a thioester radical attached to component B by an alkyl radical, of the formula alkyl-S-alkyl, both terms being "alkyl" as defined above. The term "alkylsulfonylalkyl", alone or in combination, refers to a radical of formula alkyl-S (= O) 2 -alkyl-, both terms being "alkyl" as defined above. The term "alkylcarbonylamino", alone or in combination, refers to a radical of formula alkyl-C (= O) NH-alkyl-, both terms being "alkyl" as defined above. The term "alkylsulfonylaminoalkyl", alone or in combination, refers to a radical of formula alkyl-S (= O) 2-NH-alkyl-, both terms being "alkyl" as defined above. The term "(C 1 -C) alkylsulfonylaminocarbonyl-C 1 -C 4 alkyl-" alone or in combination, refers to a radical of the formula alkyl-S (= O) 2-NH-C (= O) alkyl, both terms being "alkyl" as defined above. With reference to component "B" of the compounds of formula (1.0.0), the term "alkenyl" used therein, as well as in other contexts in the present specification, used alone or in combination, refers to a straight chain or branched chain alkenyl radical containing from 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. Examples of such radicals include, but are not limited to ethenyl, E- and Z-propenyl, / so-propenyl, E- and Z-butenyl, E- and Z- / so-butenyl and E- and Z-pentyl. The term "C3-Cu carbocyclic ring system" when used with reference to "B", as well as in other contexts in the present specification, used alone or in combination, refers to cycloalkyl and cycloalkenyl groups formed by one, two or three condensed rings containing a total of three to fourteen carbon atoms. The term "cycloalkyl" in turn means a cyclic alkyl radical containing from 3 to 8, preferably from 3 to 6 carbon atoms.

Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. On the other hand, the term "cycloalkenyl" refers to a cyclic carbocycle containing from 4 to 8, preferably 5 or 6, carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to cyclopentyl, cyclohexenyl and cyclopentadienyl. When two or three condensed rings are present, one of the rings can be a cycloalkyl ring system, while the other ring (s) can be cycloalkenyl ring systems. It is preferred that when one of R2 and R3 is hydrogen, the other is selected from the group consisting essentially of / so-propyl, sec-butyl, / so-butyl and urea-butyl; E- and Z- / so-butenyl and E- and Z-pentenyl; cyclopentyl and cyclohexyl; cyclohexenyl and cyclopentadienyl; phenyl, indenyl and indanyl; 2- (methylthio) ethyl; 3- (hydroxypropylthio) methyl; 2- (methylsulfonyl) ethyl; 4- (acetylamino) butyl; 4- (methylsulfonylamino) butyl; and 4- (ethoxycarbonylamino) butyl. The radical of structural elements, which can be. represented by the partial formula (1.4.0) is bonded to component B in the compounds of formula (1.0.0): (1.4.0) it will be appreciated that the radical represented by the formula (Ib) is directly linked to the component B in the general compound of formula (1.0.0) and that p is an integer independently selected from 1 and 2, so that one or two of the radicals of formula (1.4.0) may be attached to component B. Normally, in the preferred embodiments of the compounds of formula (1.0.0) "p" will be selected as the integer 1. In addition, in certain partial formulas (1.1.2), etc. the definitions of B do not allow "p" to be selected as the integer 2. Therefore, the definition of "p" implies the condition that "p" must be selected as 1 when B is selected as the partial formulas (1.1 .2), (1.1.3), (1.1.5), (1.1.6), (1.1.7), (1.1.8), (1.1.9), (1.1.10), (1.1.1) 1), (1.1.12), (1.1.13), or (1.1.14). However, there are embodiments of the compounds of formula (1.0.0) in which "p" will be selected as an integer "2". An example of said compound will be represented by the formula (1.6.0): (1.6.0) E is a simple link; oxygen; 1,1-cyclopropyl; C (CH3) 2; CF2; or is a radical bridge of partial formula (1.9.0): R1 I - c - R1a (1 .9.0) where E is defined as a single bond, a particular group of compounds of formula (1.0.0) is provided for which it is characterized by a terminal carboxylic acid or a fragment of carboxylic acid of reduced size. So, when "m" is selected as the integer 0, the terminal attached to component B comprises the radical: [-R] p wherein "p" is preferably it would be selected as the integer 1. However, in most preferred embodiments of the present invention, E is defined as a bridging radical of partial formula (1.9.0) above. This radical bridge comprises a substituted methylene group to which the substituent R1 and R1a are attached, where R1a is hydrogen when R1 has the meaning of a monovalent substituent; and R1a is a single bond when R1 has the meaning of a divalent substituent. In the most preferred embodiments, when R1 is a divalent substituent, it has the meaning = O. A representative compound of the present invention in which E has the meaning of the partial formula (1.9.0), R1a is a single bond and R1 has the meaning of a divalent substituent = O, in which it is represented by the formula ( 1.4.2): (1.4.2) In the portions of the compounds of the present invention represented by the partial formula (1.4.0) above, the radical E is followed by an optional methylene or ethylene bridge: - (CH2-), where m is an integer independently selected from 0, 1 and 2. It is preferred that an ethylene bridge be present, and it is even more preferred that a methylene bridge be present. In fact, the preferred compounds of the present invention have an ethylene or propylene bridge between the components "B" and "R" of the formula (1.0.0) and the substituent R1 is therefore bound at the a-position of this ethylene bridge. or propylene. It is possible that the substituent R1 is not present, ie, so that R1 is hydrogen, and this is the preferred structure - in many of the compounds of formula (1.0.0). However, there is a series of compounds other than formula (1.0.0) in which it is preferred that the substituent R1 is present. Therefore, in addition to hydrogen, R1 is selected from the following: = O, = S; F; CF3: d-C6 alkyl substituted with 0 to 3 R10; C2-C6 alkenyl substituted with 0 to 3 R10; C2-C6 alkynyl substituted with 0 to 3 R10; a C3-d carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12 and aryl (C1-C4 alkyl) said alkyl and aryl being substituted with 0 to 3 R12; heterocyclyl substituted with 0 to 3 R12; and heterocyclyl (d-C4 alkyl), said heteroaryl and alkyl being substituted with 0 to 3 R12; and C (= O) NR8R9 and C (= O) R8. The d-C6 alkyl and C2-C6 alkenyl groups have already been defined in detail before. From the meaning of these groups, it is preferred that R1 is methyl, ethyl, / so-propyl, urea-butyl, 2-propenyl or 1-, 2- or 3-butenyl. R1 can also be C2-C6 alkynyl. The term "alkynyl" when used with reference to "R1", as well as in other contexts of the present specification, using alone or in combination, refers to a straight chain or branched chain alkynyl radical containing from 2 to 6. carbon atoms. Examples of such radicals include, but are not limited to ethynyl (acetylenyl), 1-propynyl, propargyl (2-propynyl), butynyl and hexynyl. When R1 is alkynyl, it is preferred that it is ethynyl or propargyl. R1 may also be a C3-Cu carbocyclic ring system substituted with 0 to 3 R 2. The meaning of "C3-d carbocyclic ring system" has already been described in detail before, although it is preferred that when R1 is selected from this group, this is cyclopropyl or cyclopentyl. R1 may also be aryl substituted with 0 to 3 R12; or aryl (C1-C4 alkyl), said aryl and alkyl being substituted with 0 to 3 R12. The meaning of "aryl" and "C 1 -C 4 alkyl" has already been described in detail before, although it is preferred that when R 1 is selected from this group, it is phenyl, phenylmethyl or phenylethyl. Preferred embodiments of these definitions are those that include one or two R12 groups as substituents. The choice of the R12 substituent depends on the position of the R12 substituent. In this case, the substituent R12 is located in an aryl or arylalkyl group and thus will be attached to a carbon atom. When R12 is a substituent on a carbon atom, it is independently selected as a member among several groups, one of which is essentially F-formed; Cl; C? -C4 alkyl; C3-C6 cycloalkyl; alkoxy d-d; -C (= O) OR14; -OH; C1-C4 alkyl and C1-C4 alkoxy, each substituted with 1 to 3 substituents independently selected from F and Cl; (Cr C) carbonyl alkoxy; (C 1 -C 4 alkylcarbonyl; and (C 1 -C 4 alkyl) carbonyloxy. Particularly preferred substituents of this group are methyl, methoxy, F, Cl and -OH. Another group whose members can define R12 when attached to a carbon atom is essentially formed by a 5- or 6-membered heterocyclic or heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur: and a chain of 3. or 4 carbon atoms attached to the adjacent carbons when an aryl ring forms a 9 or 10-membered fused ringsaid condensed ring of 9 or 10 links being optionally mono- or di-substituted on the aliphatic carbon atoms thereof with F, Cl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or hydroxy. Preferred heteroaryl substituents comprising R12 in this group are furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, oxadiazolyl, thiadiazolyl, parathiazinyl, indolyl, benzo [b] furanyl, benzimidazolyl, benzothiazolyl. , quinolinyl and isoquinolinyl. More preferably, R12 is pyrrolyl, imidazolyl, oxazolyl or indolyl. Preferred heterocyclic substituents comprising R12 in this group are oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and benzodioxolane, especially 1,3-benzodioxol-5-yl. Most preferred is when R12 is heterocyclyl, this is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. When R12 is attached to a saturated carbon atom, it may be = O u = S; or when R12 is attached to a sulfur atom, this may be = O. Ketones formed from heterocyclyl substituents are especially preferred, for example, pyrrolidinones, pyrazolidinones, imidazolidinones, tetrazolindinones, piperidones and piperazinones. When R12 is attached to a sulfur atom and is defined as (= O)? 6 2, it is preferred that there are two (= O), providing a sulfonyl group. When R12 is a substituent on a nitrogen atom, it is independently selected from the group consisting essentially of hydroxy; hydroxy (alkyl dC); alkoxy d-d; C3-C6 cycloalkyl; (alkyl d-d) carbonyl; and aril. The above-mentioned substituent R1 in formula (1.9.0), which in turn represents one of the meanings of the basic component E of the compounds of formula (1.0.0), can be further defined as heterocyclyl substituted 0 to 3 R12; and heterocyclyl (C 1 -C 4 alkyl), said heterocyclyl and alkyl being substituted 0 to 3 R 12. Optional R12 substituents on these heterocyclyl and heterocyclylalkyl groups are as described above in more detail. A particular and preferred meaning of heterocyclyl is a benzocondensed ring system comprising a dioxolane, for example, when R 1 is 1,3-benzodioxol-5-yl. This particular heterocyclyl group is structurally analogous to a 3,4-dimethoxyphenyl group, a 3,4-difluorophenyl group or a benzo-1,4-dioxanyl group, as illustrated by its partial formulas (3.1.0), (3.1. 1), (3.1.2) and (3.1.3) respectively. (3.1.0) (3.1.1) (3.1.2) (3.1.3) The basic component R1 of the compounds of formula (1.0.0) can also be C (= O) NR8R9 or C (= O) R8, R8 and R9 being independently selected from hydrogen; C1-C4 alkyl substituted with 0 to 3 R10; a C3-Cu carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; an aryl (d-C4 alkyl), said aryl and alkyl being substituted with 0 to 3 R12; heterocyclyl substituted with 0 to 3 R12; and heterocyclyl (alkyl d-d), said heterocyclyl and alkyl being substituted with 0 to 3 R12. The substituents R10 and R12 are as described above.

Finally, the "R" component of formula (1.0.0) is independently selected from the group consisting of -tetrazolyl; -C (= O) -OR5; -C (= O) (CH2) kC (= O) OR5; -C (= O) NO, -C (= O) -NH-S (= O) 2R5; -S (= O) 2-NR 14 R 5; -C (= O) NHS (= O) 2R6; and a radical of partial general formula (3.0.0): (3.0.0) It is preferred that R is C (= O) -OH. However, in addition to said simple carboxylic acids, other embodiments of R include α-, β- and ce-keto acids included within the scope of the partial formula: -C (= O) (CH 2) - -C (= O) OR 5. When k is 0, an α-keto acid is included as pyruvic acid. When k is 1, β-ketoacid is included as acetoacetic acid. When k is 2, a? -aceto acid is included as levulinide acid. The R component also includes radicals derived from sulfamic acid, H2NSO2H, defined by the partial formula: S (= O) 2-NR14R5, as well as the sulfonamidocarbonyl radicals defined by the partial formulas -C (= O) -NH-S (= O) 2R5 and -C (= O) NHS (= O) 2R6. Pharmaceutically acceptable derivatives of the compounds of formula (1.0.0) are included within the scope of the present invention. The term "pharmaceutically acceptable derivative" as used in the present specification indicates any pharmaceutically acceptable salt of a compound of formula (1.0.0). Furthermore, any other compound which, after administration to a patient, can directly or indirectly provide a compound of formula (1.0.0) is included within the scope of the present invention. Such compounds are known as prodrugs, and a number of known methods for preparing such prodrugs of the compounds of formula (1.0.0) are available. The term "patient", as used before and throughout the specification, refers to mammals, including humans. And when the term "cell" is used, unless otherwise indicated; it is used to refer to mammalian cells, including cells from humans. Also included within the scope of the present invention are metabolites or radicals of the compounds of formula (1.0.0) which possess biological activity such that they can inhibit cell adhesion and subsequent or associated pathogenic processes subsequently induced by VLA-4. Once synthesized, the inhibitory activities and specificities for VLA-4 of the compounds of formula (1.0.0) according to this invention can be determined using in vitro and in vivo assays which are described in detail below. The desired biological activity of the compounds of formula (1.0.0) can also be improved by joining the same functional groups that act by enhancing the established biological properties of the compound, improving the selectivity of the compound by the established biological activities or by adding other desirable biological activities to the established biological activities. Such modifications are known in the art and include those that increase biological penetration in a given biological system, for example, the blood, the lymphatic system and the central nervous system; increase oral bioavailability, increase solubility allowing administration by injection; they alter the metabolism, and alter the rate of excretion of the compound of formula (1.0.0). In view of the above definitions and others throughout the specification, it can be easily understand the meaning of other chemical and biological terms used herein by those skilled in the art. The defined terms can be used alone or in any combination thereof. The preferred and most preferred chain lengths of the radicals that have been specified herein apply to all such combinations. As regards the above descriptions of certain preferred subgeneric definitions and max. Preferred of the compounds of formula (1.0.0), the preferred and more preferred species are listed below in order to further illustrate the present invention. Compounds including the partial formula radical (1.1.0): 3- [2- (3-Methyl-1 -. {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-oxazol-5-yl] propionic; 3- [2- (3-Methyl-1 -. {2- [4- (3. {2-fluorophenyl)} -ureido) -phenyl] -acetylamino} -butyl) -4 acid 5-dihydro-oxazol-5-yl] -propionic acid; 2- [2- (3-Methyl-1- {2- [4- (3. {2-cyclopentylphenyl} -ureido) -phenyl] -acetylamino} -butyl) -4 acid 5-dihydro-oxazol-5-yl] -acetic; 4- [2- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-oxazol-5-yl] -butyric acid; 3- [2- (3-Methyl-1 - { 2- [4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -4,5- acid dihydro-oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1 -. {-2- [3-methyl-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino acid}. -butyl) -4,5-dihydro-thiazol-5-yl] -propionic acid; 2- [2- (3-Methyl-1- {2- [3-fluoro-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -4,5-dihydro-thiazol-5-yl] -acetic; 3- [2- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1,1-dioxo-4,5-dihydro-thiazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1- {2- [3-methyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-imidazol-5-yl] -propionic acid; 4- [2- (3-Methyl-1- {2- [3-fluoro-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-imidazol-5-yl] -butyric acid; 3- [2- (3-Methyl-1- {2- [3-methyl-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-imidazol-5-yl] -propionic acid; 2- [2- (3-Methylene-1- {2- [3-fluoro-4- (3. {3-cyclopentyl-pyrid-2-yl} -ureido) -phenyl acid ] -acetylamino.} - butyl) -4,5-dihydro-imidazol-5-yl] -acetic acid; Acid 3-. { 2- [1- (2- { 4- [3- (2-chloro-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; Acid 3-. { 2- [1- (2- { 4- [3- (2-methoxy-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; Acid 3-. { 2- [1- (2- { 4- [3- (2-fluoro-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; Acid 3-. { 2- [1 - (2- {4- [3- (2,6-dichloro-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; Acid 3-. { 2- [1 - (2- {4- [3- (2,6-dimethyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; Acid 3-. { 2- [1 - (2- { 4- [3- (2-chloro-6-methyl-phenyl) -ureido) -phenyl} -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; 3- [2- (3-Methyl-1- {2- [4- (3-phenyl-ureido) -phenyl] -acetylamino} -butyl) -thiazol-5-yl] propionic acid; N-hydroxy-3- [2- (3-methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) thiazol-5-yl} -propionamide; 3- [2- (1- { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -but-3-enyl) -thiazol-5-yl] -propionic; 3- [2- (1- { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -thiazol-5-yl] -propionic acid; N-. { 1- [5- (3-methanesulfonylamino-3-oxo-propyl) -thiazol-2-yl] -3-methyl-butyl} -2- [4- (3-o-tolyl-ureido) -phenyl] -acetamide; 2-. { 4- [3- (2-Chloro-phenyl) -ureido] -phenyl} -N- { 1- [5- (3-methanesulfonylamino-3-oxo-propyl) -thiazol-2-yl] -3-methyl-butyl} -acetamide; 3- [2- (. {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -methyl) -thiazol-5-yl] -propionic acid; and Acid 3-. { 2 - [(2- {4- [3- (2-chloro-phenyl) -ureido] -phenyl} - acetylamino) -methyl] -thiazol-5-yl} -propionic Compounds including the partial formula radical (1.1.1): 3- [2- (3-Methyl-1. {2 - [4- (3-o-tolyl-ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-oxazol-4-yl] -propionic acid; 4- [2- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-oxazol-4-yl] -butyric acid; 3- [2- (3-Methyl-1- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -4,5- acid dihydro-oxazol-4-yl] -propionic acid; 3- [2- (3-Methyl-1- {2- [3-methyl-4- (3. {Pyrid-2-yl} -ureido) -phenyl] - acid acetylamino.} - butyl) -4,5-dihydro-thiazol-4-yl] -propionic acid; 3- [2- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-methoxypyrid-2-yl} -ureid'-phenyl] -acetylamino acid} -butil) -1,1-dioxo-4,5-dihydro-thiazol-4-yl] -propionic acid; [2- (3-methyl-1 -. {2- [3-methyl- 4- (3- ({3-methylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} - butyl) -4,5-dihydro-midazol-4-yl] -propionic acid; and 2- [2- (3-Methyl-1 - { 2- [3-fIuoro-4- (3. {3-cyclopentylpyrid-2-yl.}. -ureido) -phenyl] -acetylamino acid. .} - butyl) -4,5-dihydro-imidazol-4-yl] -acetic compounds which include the radical of partial formula (1.1.2): 3- [2- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1 -. {2- [4- (3. {2-methoxyphenyl) -ureidyl) -phenyl] -acetylamino} -butyl) -oxazole- 5-yl] -propionic; 3- [2- (3-Methyl-1 -. {2- [4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid) - oxazol-5-yl] -propionic; 4- [2- (3-Methyl-1- {2- [4- (3. {3-methoxy-pyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -oxazol-5-yl] -butyric acid; 2- [2- (3-Methyl-1 -. {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -oxazole-5- acid il] -acetic; 3- [2- (3-Methyl-1- {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazole-5- acid il] -propionic; 3- [2- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino acid}. -butyl) -oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1 - { 2- [3-methyl-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1,1-dioxo-thiazol-5-yl] -propionic acid; 4- [2- (3-Methyl-1- {2- [3-fluoro-4- (3. {3-methoxy-pyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -thiazol-5-yl] -butyric acid; 3- [2- (3-Methy1-1- { 2- [3-methoxy-4- (3. {3-methoxy-pyrid-2-yl}. -ureido) -phenyl acid ] -acetylamino.} - butyl) -imidazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1- {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazole-5-1-propionic; 3- [2- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazol-5-yl] -propionic; 3- [2- (3-Methyl-1 - { 2- [3-trifluoromethyl-4- (3. {3-cyclopentyl-pyrid-2-yl}. -ureido) -phenyl acid ] -acetylamino.} - butyl) -imidazol-5-yl] -propionic acid; Acid 3-. { 2- [1- (2- { 4- [3- (2-chloro-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; Acid 3-. { 2- [1 - (2- {4- [3- (2,6-dichloro-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; Acid 3-. { 2- [1- (2- { 4- [3- (2-fluoro-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; 3- [2- (1- { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -3-methyl-butyl) -thiazole-5-yl] -propionic acid; Acid 3-. { 2- [1- (2- {4- [3- (2-dimethyl-phenyl} -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; 3- ({2- [1 - (2- {4- [3- (2-chloro-6-methyl-phenyl) -ureido] -phenyl} -acetylamino) - 3-Methyl-butyl] -thiazol-5-yl.} -propionic acid: 3- {2- [1- (2- {4- [3- (2-methoxy-phenyl) -ureido}] -phenyl.}. -acetylamino) -3-methyl-butyl] -thiazol-5-yl.} -propionic acid: 3- { 2- [1- (2- { 4- [3- ( phenyl) -ureido] -phenyl.}. -acetylamino) -3-methyl-butyl] -thiazol-5-yl}. -propionic acid; 8 3- [2- (1- { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -3-butenyl) -thiazol-5-yl acid} -propionic; Acid 3-. { 2- [1- (2- { 4- [3- (2-methyl-phenyl) -ureido] -phenyl} -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -prop-2-enoic; Acid 3-. { 2- [1 - (2- {4- [3- (2-methyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -1-hydroxyiminopropionic acid; Acid 3-. { 2- [1- (2- { 4- [3- (2-methyl-phenyl) -ureido] -phenyl] -acetylamino) -n-butyl] -thiazol-5-yl} -propionic; and 3-. { 2- [1- (2- { 4- [3- (2-methyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -1-methylsulfonyl-propionamide. Compounds including the partial formula radical (1.1.3): 3- [2- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino acid} -butyl) -oxazol-4-yl] -propionic acid; 4- [2- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -oxazol-4-yl] -butyric acid; 3- [2- (3-Methyl-1- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazole-4- acid il] -propionic; 3- [2- (3-Methyl-1- {2- [3-methyl-4- (3. {Pyrid-2-yl} -uredode] -phenyl] - acid acetylamino.} - butyl) -thiazol-4-yl] -propionic acid; 3- [2- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1, 1-rdioxo-thiazol-4-yl] -propionic; 3- [2- (3-Methyl-1- {2- [3-methyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazol-4-yl] -propionic; and 2- [2- (3-Methyl-1- {2- [3-fluoro-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid .} - butyl) -imidazol-4-yl] -acetic acid. Compounds including the radical of partial formula (1.1.4): 3- [3- (3-Methyl-1 - { Í2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-isoxazol-5-yl] -propionic acid; 3- [3- (3-Methyl-1 - { 2- [4- (3. {2-fluorophenyl). -ureido) -phenyl] -acetylamino} -butyl) -4 acid. 5-dihydro-isoxazol-5-yl] -propionic; 2- [3- (3-Methyl-1- {2- [4- (3. {2-cyclopentylphenyl} -ureido) -phenyl] -acetylamino} -butyl) -4 acid 5-dihydro-isoxazol-5-yl] -acetic; 4- [3- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-isoxazol-5-yl] -butyric acid; 3- [3- (3-Methyl-1- {2- [4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-isoxazol-5-yl] -propionic acid; and 3- [3- (3-Methyl-1 -. {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -4 acid 5-dihydro-isoxazol-5-yl] -propionic acid. Compounds including the radical of the general formula (1.1.5): 3- [3- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1- {2- [4- (3. {2-methoxyphenyl} -ureido) -phenyl] -acetylamino} -butyl) -4 acid 5-dihydro-pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1 -. {2- [4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid) - 4,5-dihydro-pyrazol-1-yl] -propionic; 4- [3- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-pyrazol-1-yl] -butyric; 2- [3- (3-Methyl-1 -. {2- [3-metii-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -4,5- acid dihydro-pyrazol-1-yl] -acetic; 3- [3- (3-Methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamine] -butyl) -4.5- acid dihydro-pyrazol-1-yl]; 3- [3- (3-Methyl-1- {2- [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; 4- [3- (3-Methyl-1 - { 2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-pyrazol-1-yl] -butyric acid; 3- [3- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl acid] -acetylamino.} - butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1 -. {2- (3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl-acetylammonic acid .} - butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid 3- [3- (3-methyl-1 -. {2- [3-methoxy-4- (3- {.3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino.} - butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; and 3- (3-) acid (3-Methyl-1- {2- [3-trifluoromethyl-4- (3. {3-cyclopentyl-pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl ester ) -4,5-dihydro-pyrazol-1-yl] -propionic Compounds including the partial formula radical (1.1.6): 3- [3- (3-methyl-1 -. {2- [3- 4- (3-o-tolyl-ureido) -phenyl] -acetylamino.} - butyl) -isoxazol-5-yl] -propionic acid 3- [3- (3-methyl-1 -. {2- [4- (3- {2-fluorophenyl} -ureido) -phenyl] -acetylamino} -butyl) -isoxazol-5-yl] -propionic acid; 2- [3- (3-Methyl-1- {2- [4- (3- ({2-cyclopentylphenyl} -ureido) -pheno] -acetylamino} -butyl) -isoxazole- acid 5-yl] -acetic; 4- [3- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -isoxazol-5-yl] -butyric acid; 3- [3- (3-Methyl-1 - { 2- [4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} -butyl acid ) -isoxazol-5-yl] -propionic acid; 3- [3- (3-Methyl-1- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -isoxazole-5- acid il] -propionic; 3- [3- (3-Methyl-1- (2- {4- [3- (4-methyl-pyridin-3-yl) -ureido] -phenyl} -acetylamino) -butyl] - acid isoxazol-5-yl.}. -propionic acid 3- [3- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl acid ) -isoxazol-5-yl] -acrylic acid; 3- ({3- [1- (2- {4- (3- (2-chloro-phenyl) -ureido) -phenyl} acid. -acetylamino) -3-methyl-butyl] -isoxazol-5-yl} -propionic; Ethyl ester of 3- acid. { 3- [1- (2- { 4- [3- (2-chloro-phenyl) -ureido] -phenyl] -acetylamino?) - 3-methyl-butyl] -isoxazol-5-yl} -3-oxo-propionic; Ethyl 3- [3- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -isoxazole-5-yl ethyl ester ] -2-oxo-propionic; and 3- [3- (3-Methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -isoxazol-5-yl] acid prop-2-enoic. Compounds including the partial formula radical (1.1.7): 3- [3- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino acid} -butil) -pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1 - { 2- [4- (3. {2-methoxyphenyl} -ureido) -phenyl] -acetylamino} -obutyl) -butyl acid) - pyrazol-1-yl] -propionic; 3- [3- (3-Methyl-1 -. {2- [4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid) - pyrazol-1-yl] -propionic; 4- [3- (3-Methyl-1 - { 2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -pyrazol-1-yl] -butyric; 2- [3- (3-Methyl-1 -. {-2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -pyrazol-1- acid il] -acetic; 3- [3- (3-Methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -pyrazol-1-acid il]; 3- [3- (3-Methyl-1- {2- [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -pyrazol-1-yl] -propionic; 4- [3- (3-Methyl-1 - {2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -pyrazol-1-yl] -butyric acid; 3- [3- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -pyrazol-1-yl] -propionic; 3- [3- (3-Methyl-1- {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -pyrazol-1-yl] -propionic; 3- [3- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-cyclopentyl-pyrid-2-yl) -ureid) -phenyl] - acid acetylamino.} - butyl) -pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1 - {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] - acid. acetylamino.} - butyl) -pyrazol-1-yl] -propionic acid. Compounds that include the radical of partial formula (1.1.8): 3- [4- (3-MethyI-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazole-2-acid il] -propionic; 3- [4- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazol-2-yl] -propionic acid; 3- [4- (3-Methyl-1 - { 2- [4- (3. {2-methoxyphenyl}. -ureido) -phenyl] -acetylamino} -butyl) -oxazole- acid. 2-yl] -propionic; 3- [4- (3-Methyl-1 - { 2- [4- (3 { Pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid) - oxazol-2-yl] -propionic acid; 4- [4- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -oxazol-2-yl] -butyric acid; 2- [4- (3-Methyl-1 -. {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazole-2-acid il] -acetic; 3- [4- (3-Methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -oxazole-2-acid il] -propionic; 3- [4- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino acid}. -butyl) -thiazol-2-yl] -prc-ionic; 3- [4- (3-Methyl-1- {2- [3-methyl-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -1,1-dioxo-thiazol-2-yl] -propionic acid; 4- [4- (3-Methyl-1 - { 2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -thiazol-2-yl] -butyric acid; 3- [4- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-methylpyrid-2-yl.] -uret) -phenyl] acid -acetylamino.} - butyl) -imidazol-2-yl] -propionic acid; 3- [4- (3-Methyl-1- {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazol-2-yl] -proponic; 3- [4- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazol-2-yl] -propionic; 3- [4- (3-Methyl-1 - { 2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -imidazol-2-yl] -propionic acid. Compounds including the partial formula radical (1.1.9): 3- [4- (3-Methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino acid} -butil) -imidazol-1-yl] -propionic; 3- [4- (3-Methyl-1 - { 2- [4- (3. {2-methoxyphenyl}. -ureido) -phenyl] -acetylamino} -butyl) -imidazole- acid. 1-yl] -propionic; 3- [4- (3-Methyl-1 - { 2- [4- (3 { Pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid) - imidazol-1-yl] -propionic; 4- [4- (3-Methyl-1- {2- [4- (3. {3-methoxy-pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -imidazol-1-yl] -butyric acid; 2- [4- (3-Methyl-1 -. {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -imidazole-1- acid L] -acetic; 3- [4- (3-Methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -imidazole-1- acid il]; 3- [4- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino acid}. -butyl) -imidazol-1-yl] -propionic; 4- [4- (3-Methyl-1 - { 2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazol-1-yl] -butyric; 3- [4- (3-Met.l-1- { 2- [3-methoxy-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl acid. ] -acetylamino.} - butyl) -imidazol-1-yl] -propionic acid; 3- [4- (3-Methyl-1- {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] - acid acetylamino.) - butyl) - midazol-1-yl] -proponic; 3- [4- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -imidazol-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -imidazol-1-yl] -propionic. Compounds including the radical of partial formula (1.1.10): 3- [3- (3-methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] - acid acetylamino.) - butyl) -1, 2,4-oxadiazol-5-yl] -propionic acid; 3- [3- (3-Methyl-1 -. {2- [4- (3. {2-fluorophenyl)} -ureido) -phenyl] -acetylamino} -butyl) -1 acid, 2,4-oxadiazol-5-yl] -propionic; 2- [3- (3-Methyl-1 - { 2- [4- (3. {2-cyclopentyl-phenyl} -ureido) -phenyl] -acetylamino} -butyl acid) - 1, 2,4-oxadiazol-5-yl] -acetic; 4- [3- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -1, 2,4-oxadiazol-5-yl] -butyric; 3- [3- (3-Methyl-1- {2- [4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -1, 2,4-oxadiazol-5-yl] -propionic; 3- [3- (3-Methyl-1 -. {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -4,5- acid 1, 2,4-oxadiazol-5-yl] -propionic. Compounds that include the radical of partial formula (1.1.1 1): 3- [4- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -1H-1, 2,4 acid -triazol-1 -yl] -propionic; 3- [4- (3-Methyl-1 -. {2- [4- (3. {2-methoxyphenyl)} -ureido) -phenyl] -acetylamino} -butyl) -1H acid -1, 2,4-triazol-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid) - 1 H-1, 2,4-triazol-1-yl] -propionic; 4- [4- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -1 H-1, 2,4-triazol-1-yl] -butyric; 2- [4- (3-Methyl-1 -. {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -1H-1 acid. , 2,4-triazol-1-yl] -acetic; 3- [4- (3-Methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -1H-1 acid. , 2,4-triazol-1 -yl]; 3- [4- (3-methyl-1- {2- [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] - acid acetylamino.} - butyl) -1 H-1, 2,4-triazol-1-yl] -propionic acid; 4- [4- (3-Methyl-1 -. {2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -pheni] -acetylamino acid} -butyl) -1 H-1, 2,4-triazol-1-yl] -butyric; 3- [4- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,4-triazol-1-yl] -proponic; 3- [4- (3-Methyl-1- {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,4-triazol-1-yl] -propionic; 3- [4- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-cyclopentyl-pyrid-2-yl}. -ureido) -phenyl] - acid. acetylamino.} - butyl) -1 H-1, 2,4-triazol-1-yl] -propionic acid; 3- [4- (3-Methyl-1- {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,4-triazol-1-yl] -propionic. Compounds including the partial formula radical (1.1.12): 3- [4- (3-Methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamine acid} -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 3- [4- (3-Methyl-1 -. {2- [4- (3. {2-methoxyphenyl)} -ureido) -phenyl] -acetylamino} -butyl) -1H acid -1, 2,3,4-tetrazol-1-yl] -propionic; 3- [4- (3-Methyl-1 - { 2- [4- (3 { Pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid) - 1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 4- [4- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -1 H-1, 2,3,4-tetrazol-1-yl] -butyric; 2- [4- (3-Methyl-1 -. {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -1H-1 acid. , 2,3,4-tetrazol-1-yl] -acetic; 3- [4- (3-Methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -1H-1 acid. , 2,3,4-tetrazol-1-yl]; 3- [4- (3-Methyl-1- {2- [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 4- [4- (3-Methyl-1 - { 2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -butyric; 3- [4- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl] acid -acetylamino.} - butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-cyclopenty-pyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 3- [4- (3-MethyI-1- {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic. Compounds including the radical of partial formula (1.1.13): 3- (3-Iso-butyl-2-oxo-4- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl acid .}. -piperazin-1-yl) -propionic; 3- (3-iso-butyl-2-oxo-4- { [4- (3- { 2-methoxyphenyl.}. Ureido) -phenyl] -acetiI.}. -piperazine-1- il) -propionic; 3- (3-Isobutyl-2-oxo-4-. {[[4- (3 { Pyrid-2-yl} -uretdo) -phenyl] -cetyl} acid .piperazin-1-yl) -propionic; 4- (3-Isobutyl-2-oxo-4-. {[[4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetyl} acid. piperazin-1-yl) -butyric; 2- (3-α-Butyl-2-oxo-4- { [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1-yl. )-acetic; 3- (3-iso-butyl-2-oxo-4- { [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetyl.}. -piperazin-1-yl) -propionic; 3- (3-Isobutyl-2-oxo-4- { [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetyl acid} -piperazin-1-yl) -propionic; 4- (3-Isobutyl-2-oxo-4- { [3-fluoro-4- (3. {3-methoxypyrid-2-yl.) -uredo] -phenyl] -acetyl} -piperazin-1-yl) -butyric acid; 3- (3-Isobutyl-2-oxo-4- { [3-methoxy-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl] -acetyl acid .}. -piperazin-1-yl) -propionic; 3- (3-Isobutyl-2-oxo-4- { [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetyl acid .}. -piperazin-1-yl) -propionic; 3- (3-Isobutyl-2-oxo-4- { [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino acid .}. - p.perazin-1-yl) -propionic; 3- (3-iso-butyl-2-oxo-4- { [3-trifluoromethyl-4- (3- { 3-ciclopentilpirid-2yl.}. Ureido) -phenyl] -acetyl .}. -piperazin-1-yl) -propionic acid. Compounds including the partial formula radical (1.1.14): 3- (3-α-Butyl-6-oxo-4-. {[4- (3-o-tolyl-ureido) -phenyl] - acetyl,} -piperazin-1-yl) -propionic acid; 3- (3-Isobutyl-6-oxo-4-. {[[4- (3. {2-methoxyphenyl} -ureido) -phenyl] -acetyl} -piperazin-1- acid il) -propionic; 3- (3-Isobutyl-6-oxo-4- { [4- (3 { Pyrid-2-yl.}. -ureido) -phenyl] -acetyl} -piperazine- acid 1 -yl) -propionic; 4- (3-Isobutyl-6-oxo-4-. {[[4- (3. {3-methoxypyrid-2-yl} -ureido) -fenii] -acetyl} acid. piperazin-1-yl) -butyric; 2- (3-Isobutyl-6-oxo-4- { [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1-yl acid) -acetic; 3- (3-Isobutyl-6-oxo-4- { [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1- acid il) -propionic; 3- (3-α-Butyl-6-oxo-4- { [3-methoxy-4- (3. {Pyrid-2-yl} -ureido) -phenyl] -acetyl acid} -piperazin-1-yl) -propionic acid; 4- (3-Isobutyl-6-oxo-4- { [3-fluoro-4- (3-. {3-methoxypyrid-2-yl.] -ureido) -phenyl] -acetyl acid .} - piperazin-1-yl) -butyric acid; 3- (3-α-Butyl-6-oxo-4- { [3-methoxy-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl] - acetyl,} -piperazin-1-yl) -propionic acid; 3- (3-Isobutyl-6-oxo-4- { [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl] -acetyl acid .}. -piperazin-1-yl) -propionic; 3- (3-α-Butyl-6-oxo-4- { [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl acid ] -acetylamino.} - piperazin-1-yl) -propionic; 3- (3-Isobutyl-6-oxo-4- { [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl.) -ureido) -phenyl] - acetyl,} -piperazin-1-yl) -propionic acid. Compounds including the partial formula radical (1.3.0): 3- [2- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2 acid -yl) -thiazol-5-yl] -propionic acid; 3- [2- (5-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] acid] -propionic; 3- [2- (5,5-Dimethyl-1. {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole- acid 5-yl] -propionic; 3- [2- (3-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] acid] -propionic; 3- [2- (3,3-Dimethyl-1. {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5- acid il] -propionic; 3- [2- (4-Methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5-yl] acid] -propionic; 3- [2- (4-Hydroxy-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] acid] -propionic; 3- [2- (4-Hydroxy-4-methyl-1- {[[4- (3-o-tolyl-uredo) -phenyl] -acetyl} -pyrrolidin-2-yl) acid thiazoI-5-yl] -propionic; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - azepan-2-yl) -thiazol-5-yl] -propionic acid; 3- [2- (4-Oxo-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] acid] -propionic; 3- [2- (4-amino-1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl] -pyrrolidin-2-yl) -thiazole-5-yl] acid] -propionic; 3- [2- (4-Methylamino-1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5 acid -il] -propionic; 3- [2- (4- (Ethyl-methyl-amino) -1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) - acid thiazol-5-yl] -propionic; 3- [2- (2-Methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] acid] -proponic; 3- [2- (3-. {[4- (3-o-Tolyl-ureido) -phenyl] -acetyl} -oxazolidin-4-yl) -thiazol-5-yl] -propionic acid; Acid 3- (3, - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2 ', 3', 4 ', 5, -tetrahydro- [2,4' ] b.t.azolyl-5-yl) -propionic acid; 3- [2- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1-, 2,3,6-tetrahydro-pyridin-2-yl) acid thiazol-5-yl] -propionic; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperidin-2-yl) -thiazol-5-yl] -propionic acid, acid 3- [2- (2- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1, 2,3,4-tetrahydro-isoquinolin-3-yl) -thiazole -5-iI] -propionic; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - azetidin-2-yl) -thiazol-5-yl] -propionic acid; 3- [2- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - azetidin-2-yl) -oxazol-5-yl] -propionic acid; 3- [2- (1- { [4- (3-o-tolyl-yuryl) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] -propionic acid; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - azepan-yl) -oxazol-5-yl] -propionic acid; 3- [2- (5-Methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (5,5-Dimethyl-1. {[[4- (3-o-tolii-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazole-5- acid il] -propionic; 3- [2- (3-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (3,3-Dimethyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazole-5- acid il] -propionic; 3- [2- (4-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (4-Hydroxy-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (4-Hydroxy-4-methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazole- 5-yl] -propionic; 3- [2- (4-Oxo-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (4-amino-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl acid ] -propionic; 3- [2- (4-Methylamino-1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl] -pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (4- (Ethyl-methyl-amino) -1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) - acid oxazol-5-yl] -propionic; 3- [2- (2-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (3-. {[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -oxazolidin-4-yl) -oxazol-5-yl] -propionic acid; 3- [2- (3-. {[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -thiazolidin-4-yl) -oxazol-5-y!] - propionic acid; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1-, 2,3,6-tetrahydro-pyrrolidin-2-yl) acid oxazol-5-yl] -propionic; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperidin-2-yl) -oxazol-5-yl] -propionic acid; 3- [2- (2- { [4- (3-o-tol-yl-u-yido) -phenyl] -acetyl} - 1, 2, 3, 4-tetrahydroquinolicyn- 3-yl) -oxazol-5-yl] -propionic; 3- [3- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] -propionic acid; 3- [2- (5-Methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] acid] -propionic; 3- [3- (5,5-Dimethyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole-5- acid il] -propionic; 3- [3- (1- { [4- (3-o-Tolyl-ureido) -phenyl] -acetyl} - azepan-2-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (3-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] acid] -propionic; 3- [2- (3,3-Dimethyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole-5- acid il] -propionic; 3- [3- (4-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] acid] -propionic; 3- [3- (4-Hydroxy-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] acid] -pro-ionic; 3- [2- (4-Hydroxy-4-methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -isoxazol-2-yl) -thiaazole acid -5-il] -propionic; 3- [3- (4-Oxo-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -isoxazol-5-yl] acid -propionic; 3- [3- (4-amino-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole acid -5-il] -propionic; 3- [3- (4-Methylamino-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole-5-ii acid] -propionic; 3- [3- (4- (Ethyl-methyl-amino) -1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) - acid isoxazol-5-yl] -propionic acid; 3- [3- (2-Methyl-1 - { [4- (3-o-toyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole- acid 5-yl] -propionic; 3- [3- (3. {[4- (3-o-Tolyl-ureido) -phenyl] -acetyl} -oxazolidin-4-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (3- {[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -thiazolidin-4-yl) -isoxazol-5-yl] - acid propionic; 3- [3- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl] -1-, 2,3,6-tetrahydro-pyridin-2-yl) - acid Soxazol-5-yl] -propionic; 3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperidin-2-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1-, 2,3,4-tetrahydro-isoquinolin-3-yl) acid isoxazol-5-yl] -propionic acid; and 3- [3- (1-. {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -azatidin-2-yl) -isoxazol-5-yl] -propionic acid. The compounds of the present invention described above can be used in the form of acids, esters or other chemical classes of compounds to which the disclosed compounds belong.

It is also within the scope of the present invention to use said compounds in the form of pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to procedures well known in the art. Such well-known pharmaceutically acceptable salts include, but are not limited to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, besylate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate., ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, isethionate, lactate, lactobionate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate , oxalate, oleate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, salicylate, sodium phosphate, stearate, succinate, sulfate, sulfosalicylate, tartrate, thiocyanate, thiomalate, tosylate and undecanoate. Base salts of the compounds of the present invention include, but are not limited to, ammonium salts; salts of alkaline metals such as sodium and potassium; salts of alkaline earth metals such as calcium and magnesium, salts with organic bases such as dicyclohexylamine, meglumine, N-methyl-D-glucamine, tri- (hydroxymethyl) -methylamine (tromethamine) and salts with amino acids such as arginine, lysine, etc. The compounds of the present invention comprising basic nitrogen-containing groups can be quatemarized with agents such as d-C4 alkyl halides, for example, methyl, ethyl, / so-propyl and urea-butyl chlorides, bromides and iodides; di (C1-C4 alkyl) sulfate, for example, dimethyl, diethyl and diamyl sulfates; Cι-de alkyl halides, for example, decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl halides (C 1 -C 4 alkyl), for example, benzyl chloride and phenethyl bromide. Such salts allow the preparation of water-soluble and oil-soluble compounds of the present invention. Among the salts mentioned above, those which are preferred include, but are not limited to, acetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, Sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine. Multiple salt forms are included within the scope of the present invention in which a compound of the present invention contains more than one group capable of forming such pharmaceutically acceptable salts. Examples of multiple salt forms include, but are not limited to, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trichlorhydrate. The pharmaceutical compositions of the present invention comprise any one or more of the above described inhibitory compounds of the present invention, or a pharmaceutically acceptable salt thereof also described above, together with a pharmaceutically acceptable carrier according to the properties and expected behavior of such vehicles. , which are well known in the corresponding art.

The term "carrier" as used herein, includes diluents, excipients and adjuvants. Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchange compositions; alumina; aluminum stearate; lecithin; serum proteins, for example, human serum albumin; phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; Water; salts or electrolytes, for example, prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; for example sodium carboxymethyl cellulose; polyethylene glycol; polyacrylates, waxes; polyethylene-polyoxypropylene block polymers; and anhydrous lanolin. More particularly, the diluents, excipients, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the group consisting essentially of the following: the acidifying and alkalizing agents added to obtain a desired or predetermined pH comprise acidifying agents, example, acetic acid, glacial acetic acid, malic acid and propionic acid and the alkalizing agents, for example, edetol, potassium carbonate, sodium hydroxide, sodium borate, sodium carbonate and sodium hydroxide; aerosol propellants needed when the pharmaceutical composition is to be released in the form of a spray under significant pressure, for example, acceptable halogenated hydrocarbons; nitrogen; or a volatile hydrocarbon such as butane, propane, isobutane or mixtures thereof, antimicrobial agents including antibacterial, antifungal and antiprotozoal agents added when the pharmaceutical composition is to be administered topically, for example, antimicrobial agents such as benzyl alcohol, chlorobutanol, alcohol phenylethyl, phenylmercuric acetate, potassium sorbate and sorbic acid, and antifungal agents such as benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben and sodium benzoate; antimicrobial preservatives added to the pharmaceutical compositions in order to protect them against the growth of potentially dangerous microorganisms, for example alkyl esters of p-hydroxybenzoic acid, propionate salts, phenoxyethanol, sodium methylparaben, propylparaben sodium, sodium dehydroacetate, benzalkonium chloride , benzethonium chloride and benzyl alcohol; antioxidants added to protect all the ingredients of the pharmaceutical composition from damage or degradation by oxidizing agents present in the composition itself or the environment of use, for example, anoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulfite, octyl, propyl or dodecyl gallate, sodium metabisulfite, sulfur dioxide and tocopherols; buffering agents used to maintain the desired pH of a composition once achieved, for example, calcium acetate, potassium metaphosphate, potassium phosphate monobasic and tartaric acid; and chelating agents used to help maintain the ionic strength of the pharmaceutical composition and efficiently bind and remove destructive compounds and metals, for example, dipotassium edatate, disodium edetate, and edetic acid. To the pharmaceutical compositions of the present invention to be applied topically are added dermatologically active agents, for example, wound healing agents such as peptitic derivatives, yeast, panthenol, hexylresorcinol, phenol, tetracycline hydrochloride, lamin and kinetin. , glucocorticosteroids for the treatment of inflammation, for example, hydrocortisone, dexamethasone, betamethasone, triamcinolone, fluocinolone and methylprednisolone, retinoids for treating acne, psoriasis, skin aging and skin cancer, for example, retinol, tretinoin, isotretinoin, etretinate, acitretin and arotinoid, immunosuppressive agents to treat inflammation, for example, dapsone and sulfasalazine; weak antibacterial agents, for example, resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide, erythromycin, clindamycin and mupirocin, antifungal agents, for example, griseofulvin, azoles such as miconazole, econazole, traconazole, fluconazole and ketoconazole and allylamines such as naftifine and terphinephine, antiviral agents, for example, acyclovir, famciclovir and valaciclovir, antihistamines, for example, diphenhydramine, terfenadine, astemizole, loratadine, cetirizine, acrivastine and temelastin, topical anesthetics, for example, benzocaine, lidocaine, dibucaine and hydrochloride pramoxine, topical analgesics, for example, methyl salicylate, camphor, menthol and resorcinol; topical antiseptics to prevent infection, for example, benzalkonium chloride and povidone iodine; vitamins and derivatives thereof such as tocopherol, tocopherol acetate, retinoic acid and retinol. Other examples of diluents, excipients, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the groups consisting essentially of the following: dispersing and suspending agents, eg, polygen, povidone and silicon dioxide; emollients, for example, oil and hydrocarbon waxes, triglyceride esters, acetylated monoglycerides, methyl esters and other C10-C20 fatty acid alkyls, C? 0-C2o fatty acids, C10-C20 fatty alcohols, lanolin and derivatives, esters of polyhydric alcohols such as polyethylene glycol (200-600), esters of polyoxyethylene sorbitan fatty acids, esters of waxes, phospholipids and sterols; emulsifying agents used to prepare oil-in-water emulsions; excipients, for example, laurocaprama and polyethylene glycol monomethyl ether; humectants, for example, sorbitol, glycerol and hyaluronic acid; bases of ointments, for example, petrolatum, polyethylene glycol, lanolin and poloxamer; penetration enhancers, for example dimethyl isosorbide, diethyl glycol monoethyl ether, 1-dodecylazacycloheptan-2-one and dimethylsulfoxide (DMSO); preservatives, for example, benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, propylparaben, quaternary ammonium compounds such as potassium benzoate and thimerosal; sequestering agents comprising cyclodextrins; solvents, for example, acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerol, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, methylene chloride, mineral oil, peanut, phosphoric acid, polyethylene glycol, polyoxypropylene stearyl ether, propylene glycol, propylene glycol diacetate, sesame oil and purified water; stabilizers, for example, sodium saccharate and thymol; surfactants, for example, lapirio chloride, laureth 4, ie, α-dodecyl-β-hydroxy-poly (oxy-1,2-ethanediyl) or polyethylene glycol monododecyl ether. In accordance with the present invention, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as the solvent or suspending medium. For these purposes, any insipid non-volatile oil, including synthetic mono- or di-glycerides, may be employed. In the preparation of injectables, fatty acids such as oleic acid and its glyceride derivatives are useful, as are pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol based diluent or dispersant, such as Rh, HClX or a similar alcohol. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, vehicles that are normally used include lactose and corn starch. Typically, lubricating agents are also used, like magnesium stearate. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with the emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring materials may also be added. Alternatively, the pharmaceutical compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention can also be administered topically, especially when the subject of treatment includes areas or organs easily accessible by topical application, including eye, skin or lower intestinal tract diseases. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application to the lower intestinal tract may be effected in a rectal suppository formulation, as described above, or in a suitable enema formulation. Topically active transdermal patches can also be used. For topical applications, the pharmaceutical compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more vehicles. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions can be formulated in the form of a micronized suspension in isotonic sterile saline with adjusted pH or, preferably, as solutions in sterile isotonic saline solution with adjusted pH, with or without a preservative such as benzalkonium chloride . Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. The pharmaceutical compositions of this invention can be further administered by aerosol or nasal inhalation with a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well known in the pharmaceutical formulating art and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons and / or other solubilizing or dispersing agents. conventional The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. It will be understood, however, that a specific dose and specific treatment regimen for any given patient will depend on a number of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, the rate of excretion, the combination of drugs and the criteria of the attending physician and the severity of the particular disease being treated. The amount of active ingredient may also depend on the therapeutic or prophylactic agent, if any, with which the ingredient can be administered. The dosage and rate of dose of the compounds of this invention effective to prevent, inhibit, suppress or reduce cell adhesion and the consequent or associated processes subsequently mediated by VLA-4 will depend on a number of factors such as the nature of the inhibitor, the weight of the patient, the purpose of the treatment, the nature of the pathology in question, the specific pharmaceutical composition used and the observations and conclusions of the attending physician. For example, when the dosage form is oral, for example, a tablet or a capsule, suitable dosage levels of the compounds of formula (1.0.0) will vary from about 1.0 μg to about 10.0 mg / kg of body weight per day, preferably from about 5.0 μg to about 5.0 mg / kg of body weight per day, more preferably from about 10.0 μg to about 1.0 mg / kg of body weight per day and, most preferably, from about 20.0 μg to about 0.5 mg / kg of body weight per day of active ingredient. When the dosage form is administered topically to the bronchi or lungs, for example, by means of a nebulizer powder inhaler, the appropriate dose levels of the compounds of formula (1.0.0) will vary from about 0.1 μg to about 1.0 mg / kg of body weight per day, preferably from about 0.5 μg to about 0.5 mg / kg of body weight per day, more preferably from about 1.0 μg to about 0.1 mg / kg of body weight per day and, most preferably , from about 2.0 μg to about 0.05 mg / kg of body weight per day of active ingredient. Using representative body weights of 10 kg and 100 kg in order to illustrate the range of daily topical doses that could be used as described above, the appropriate dose levels of the compounds of formula (1.0.0) will vary from about 1.0. -10.0 μg to 10.0 -100.0 mg per day, preferably from about 5.0 -50.0 μg to 5.0-50.0 mg per day, more preferably from about 10.0 - 100.0 μg to 1.0 -10.0 mg per day and, most preferably, from about 20.0 - 200.0 μg to 0.5 - 5.0 mg per day of active ingredient comprising a compound of formula (1.0.0). These ranges of dosage amounts represent the amounts of total dosages of active ingredient per day for a given patient. The number of times per day that a dose is administered will depend on pharmacological and pharmacokinetic factors such as the half-life of the active ingredient, which reflects the rate of catabolism and clearance, as well as the minimum and optical levels in blood plasma or other body fluid of said ingredient. active achieved in the patient that is required for therapeutic efficacy. Numerous additional factors should also be considered when deciding the number of doses per day and the amount of active ingredient per dose to be administered. The individual response of the patient being treated is not the least important of such factors. Thus, for example, when the active ingredient is used to treat or prevent asthma, and is administered topically by an aerosol inhalation in the lungs, one to four doses consisting of actuations of a dispensing device will be administered each day, i.e. , "applications" of an inhaler, each dose containing from about 50.0 μg to about 10.0 mg of active ingredient. Within the scope of the present invention are embodiments comprising compositions containing, in addition to a compound of the present invention as an active ingredient, other therapeutic active ingredients selected from the group consisting essentially of anti-inflammatory corticosteroids.; bronchodilators; antiasthmatics; non-steroidal anti-inflammatories; immunosuppressants; immunostimulants; antimetabolites; antipsoriatic and antidiabetic. The specific compounds within each of these classes may be selected from those listed under the appropriate headings in Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, England, pages 970-986 (1990); and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman, J. G. and Limbird, L. Editors, McGraw-Hill, 1996, the disclosure of which is incorporated herein by reference in its entirety. Especially preferred ingredients for inclusion for use in combination with the compounds of formula (1.0.0) are anti-inflammatory compounds such as theophylline, sulfasalazine and aminosalicylates; immunosuppressants such as cyclosporin, FK-506 and rapamycin; antimetabolites such as cyclophosphamide and methotrexate; and immunomodulators such as interferons. Other embodiments of the present invention relate to a method for treating or preventing an inflammatory, autoimmune or respiratory disease by inhibiting cell adhesion and the consequent or associated pathogenic processes subsequently mediated by VLA-4. As mentioned above, cell adhesion associated with VLA-4 plays a major role in a number of inflammatory, immune and autoimmune diseases. Thus, the inhibition of cell adhesion by the compounds of the present invention can be used in methods for treating or preventing inflammatory, immune and autoimmune diseases. Preferably, the diseases to be treated with the methods of the invention are selected from asthma, arthritis, psoriasis, rejection of transplants, multiple sclerosis, diabetes and inflammatory bowel disease. The above-described treatment methods of the present invention can employ the compounds of formula (1.0.0) in monotherapy form, although such methods can also be used in the form of multiple therapy in which one or more compounds of formula are co-administered (1.0.0) combined with an anti-inflammatory agent, immunomodulator, immunostimulant or immunosuppressant. The terms "co-administered" or "co-administration" as used herein, mean the therapeutic use of one or more compounds of formula (1.0.0) in combination with one or more additional therapeutic agents, including, but not limited to, limited to the administration of the combination of active therapeutic agents in a single dosage form or in multiple dosage forms representing the same or different administration routes, said multiple dosage forms being administered at substantially the same time or at different times. After the synthesis of any of the above-mentioned preferred species of the present invention or of any other compound falling within the scope of the present invention, the biological activities relative to the specificities for VLA-4 of said compounds can be determined using one or more than the numerous in vivo or in vitro assays that have been described so far in the technical literature corresponding to the technical field. For example, some of the well-established assay methods and models presently involve measuring the activity of VLA-4 by determining the concentration of a candidate inhibitor assay required to block the binding of VLA-4 expressing cells to coated plates. fibronectin or CS-1. In this assay, they are coated with fibronectin (containing the CS-1 sequence), soluble CS-1 peptide or VCAM-1 assay microtiter wells. Once the wells have been coated, various concentrations of test compound are then added, along with appropriately labeled VLA-4 expressing cells. Alternatively, the test compound can be added first and allowed to incubate with the coated wells before adding the cells. The cells are allowed to incubate in the wells for at least 30 minutes. After the incubation, the wells are emptied and washed. The inhibition of binding is measured by quantifying the fluorescence or radioactivity bound to the plate for each of the various concentrations of the test compound, as well as for the controls that do not contain test compound. However, the described assay is less preferred than other assays cited below to determine the VLA-4 activity of the compounds of formula (1.0.0). Cells that express VLA-4 that can be used in this assay include Ramos cells, Jurkat cells, melanoma cells A375, as well as lymphocytes of peripheral human blood (PBL). The cells used in this assay can be fluorescently or radioactively labeled. In order to assess the inhibitory specificity of VLA-4 of the test compounds, tests can be performed for other important integrin groups, ie β2 and β3, as well as ßi integrins such as VLA-5, VLA-6 and a4ß7- These assays may be similar to the adhesion inhibition and direct binding assays described above, substituting the cell expressing the appropriate integrin and the corresponding ligand. For example, polymorphonuclear cells (PMM) express β2 integrins on their surface and bind to ICAM; whereas ß3 integrins are involved in platelet aggregation and inhibition can be measured in a conventional platelet aggregation assay. VLA-5 binds specifically to the Arg-Gly-Asp sequences. While VLA-6 binds to laminin. In addition, a ß7 is a recently discovered homolog of VLA-4 that also binds fibronectin and VCAM, as well as MadCAM-1. The specificity with respect to α7 is determined in a binding assay using CS-1, VCAM or MAdCAM-1 and a cell line expressing at β7, but not VLA-4 as the RPMI-8866 cells. Once the VLA-4 inhibitors have been identified, these can be further characterized in in vivo assays. One such assay assesses the inhibition of allergen-induced airway hypersensitivity and cell entry, as described by Henderson et al., "Blockade of CD49d (a4 integrin) on intrapulmonary / but not circulating leukocytes inhibits airway. inflammation and hyperresponsiveness in a mouse model of asthma ", J. Clin. Invest., 100 (12), pages 3083-3092 (1997). In this assay, mice are sensitized by intraperitoneal exposure to an irritant such as ovalbumin. After a recovery period, the mouse is stimulated in a manner caused by exposure to the allergen with an aerosol. Before exposure to the aerosol, various doses of the VLA-4 inhibitor are administered to the mouse by intratracheal injection. In vivo inhibition of inflammation associated with cell adhesion is assessed by measuring the number of cells and cytokines in the bronchial alveolar lavage fluid. In this way, the inhibitors of this invention which better adapt to the inhibition of inflammation can be identified.

Another in vivo assay that can be used is the asthma test in primates. This assay is performed essentially as described in Turner, CR et al., "Characterization of a primate model of asthma using anti-allegy / anti-asthma agents", Inflammation Research, 45 (5), pages 239-245 (1996). , the description of which is incorporated herein by reference in its entirety. This assay measures the inhibition of late-phase airway responses induced by Ascaris antigen and airway hypersensitivity in allergic primates after administration of antiallergic / antiasthma agents. The compounds of the present invention can be formulated into pharmaceutical compositions which can be administered orally, parenterally, by inhalation (metered dose inhaler, dry powder inhaler or nebulizer), topical, rectal, nasal, intraocular, sublingual, vaginal or for an implanted deposit. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intraestemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. The compounds of formula (1.0.0) can be prepared according to well-known procedures for carrying out the synthesis of organic compounds having non-peptidyl or semi-peptidyl nature. There are a number of different procedures available that are fully described in the technical literature and with which the expert will be familiar. The following description of several such synthesis schemes is merely illustrative and is not intended to be in any way limiting. In said description a series of abbreviations are used in order to save space. Although these abbreviations are also known to the expert, for reasons of clarity and convenience are described below: BOP benzotriazole-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate DAST diethylaminosulfur trifluoride DIEA diisopropylethyl amine DMF dimethylformamide EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBT 1-Hydroxybenzotriazole THF tetrahydrofuran A group of preferred A components of the compounds of formula (1.0.0) have been described by partial formulas (IVb) to (IVu) above. The most basic of these components is that of formula (IVc), that is, 4- (N'-phenylurea) phenylmethyl. The following schematic synthesis diagrams illustrate a general preparation process for the compounds of formula (1.4.0) to (1.4.20): SYNTHESIS SCHEME I-STAGE A CHCl2 Ar-NCO + NH2-Ar-CH2C? 2H - - > ArNHC (O) NH-Ar-CHsCQ H Et3N (2.1.0) (2.1.1) (2.1.2) The starting material Ar-NCO is an isocyanate in which "Ar" has the same definition as component A of formula (1.0.0) with respect to the aryl, heteroaryl and heterocyclyl radicals substituted with 0 to 3 R10. The isocyanate starting materials for preparing component A as represented by the partial formulas (1.4.1) to (1.4.20) are commercially available, for example, from Aldrich Chemical Company, Milwaukee, Wl 53233, as follows: isocyanate of phenyl (1.4.1); 2-methoxyphenyl isocyanate (1.4.2) (1.4.4) o-tolyl isocyanate (1.4.3); 2-fluorophenyl socianate (1.4.5); (1.4.7); (1.4.16), (1.4.12) (1.4.20) isocyanate of 4-iso-propylphenyl isocyanate 2-chlorophenyl (1.4.15) (1.4.13); (1.4.14) Pyridyl analogs of the above phenyl isocyanates can be used to prepare the corresponding compounds of formula (1.0.0) in which component A contains a pyridyl group. One of the isocyanates described above is reacted with an aryl-heteroaryl- or heterocyclic-il-acetic acid having an amine group in the 4-position. The addition of amines to isocyanates is a well-known reaction that provides substituted ureas in a simple manner . The reaction can be carried out in a solvent such as methylene chloride with triethylamine at slightly elevated temperatures. The reactant used to produce most of the components A illustrated as the partial formulas (1.4.1) to (1.4.20) is 4-aminophenylacetic acid, commercially available from Aldrich Chemical Company, cited above. The disubstituted urea (2.1.2) prepared as in the aforementioned reaction scheme, which forms the reactant which finally gives the component A of the compounds of formula (1.0.0), is then reacted with the reactant which finally gives component B, one of the partial formulas (1.1.0) to (1.1.14). for example, the reactant component B may be that of the partial formula (1.7.0) illustrated below in the formula (lllo-a): (1.7.0) The reactant components B of the type illustrated in the formula (lllo-a) can be prepared according to procedures well known in the technical literature of the corresponding technical field. For example, see Bhatt, U .; Mohamed, N .; Just, G .; Tetrahedron Lett. 1997, 38 (21), 3679-3682; and Sugihara, H. et al., J. Med. Chem. 1998, 41, 489-502. The reaction between the reactant forming component A and the reactant forming component B will be known to the person skilled in the art to be one which involves the acylation of an amine by a carboxylic acid which can be carried out in a good yield at room temperature. or slightly higher using coupling agents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT); dicyclohexylcarbodiimide (DCCI); N, N'-carbonyldiimidazole; POCI3; TiCl4; SO2CIF; Ti (OBu) 4; P2U; Bu3N; benzotriazol-1-yl diethyl phosphate; N, N, N ', N'-tetramethyl (succinimido) uronium tetrafluoroborate; and preferably diisopropylethylamine (DIEA) and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP). This reaction can be illustrated in the following schematic synthesis diagram that provides a generalized method of preparing the compounds of formulas (1.0.0): SYNTHESIS SCHEME I-STAGE B The piperazinyl reactant (2.1.3) for component B is used in the form of a C1-C4 alkyl ester of an acid, which serves as a blocking group to prevent reaction of the carboxylic acid group with the secondary amine group forming part of the piperazinyl radical of other reactants (2.1.3) present in the reaction mixture. The coupling agents promote the condensation of the reactants (2.1.2) and (2.1.3) by providing the intermediate (2.1.4) which is composed of the formula (1.0.0) in which R is defined as O (alkyl). -C6). To prepare the final product of formula (1.0.0) in acid form an additional step is required, as shown in the following reaction scheme: REACTION SCHEME I-STAGE C The saponification of the aqueous hydroxide is carried out in an alcohol as solvent, preferably urea-butanol as indicated. The subsequent neutralization is preferably carried out using 1 N HCl as aqueous mineral acid and the reaction is conveniently carried out at room temperature. The synthesis described above is broadly applicable to the compounds of formula (1.0.0). In order to make said synthesis even clearer, the synthesis scheme 1-a, steps A to C, is shown below, with reference to a particular compound of the present invention: SYNTHESIS SCHEME l-a Compounds of formula (1.0.0) in which component B is a radical of partial formula (1.1.4), ie, an isoxazolyl group, can be prepared by a process in which the two final stages are similar to the two final stages, steps B and C of the process illustrated in the synthesis scheme I. The preparation of the amine reactant that produces component B of the partial formula (1.4.4) is illustrated generally for the compounds of formula (1.0 .0) in the following synthesis scheme II-stage A: SYNTHESIS SCHEME ll-STAGE A .1.6) (2.1.7) In step A of this synthesis, the starting material is a 1-formyl derivative of a carbamic acid having a protecting group R and having the desired R2 and R3 substituents of the formula: ROC (= O) NHC (R2) (R3) CH (= O). This aldehyde starting material is reacted with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as water and methanol, to prepare the corresponding oxime according to the well known procedure involving the addition of carbonyl and the elimination of water in which it is maintained. an optimum pH of approximately 4.

SYNTHESIS SCHEME ll-STAGE B The intermediate oxime (hydroxyiminomethyl) (2.1.7) is converted into the desired component B containing isoxazolyl of partial formula (lile), intermediate (2.1 .8) by oxidizing (2.1.7) to its corresponding N-oxide nitrile with sodium hypochlorite in a suitable solvent such as THF or methylene chloride; and reacting the N-oxide nitrile in situ with an appropriate terminal alkyl alkanoate. This cycloaddition reaction [2 + 3] is well known in the literature as a method for preparing the isoxazoline ring structure. See for example Synthesis, 508-509, 1982.

SYNTHESIS SCHEME ll-STAGE C (2.1.9) Benzyl carbamate (2.1.8) is converted to the primary amine (2.1.9) using one of the following reagents using the procedures published in the literature: H2 / Pd-C. { Ber., 65, page 1192, 1932); HBr, AcOH (J. Org. Chem., 17, page 1564, 1952); 70% HF, pyridine. { J. Chem. Soc, Chem. Commun., Page 451, 1976) or CF3SO3H (J. Chem. Soc, Chem. Commun., Page 107, 1974). The synthesis described above is broadly applicable to the compounds of formula (1.0.0). In order to make said synthesis even clearer, the synthesis scheme II, steps A to D, is shown below, with reference to a particular compound of the present invention (stage D being analogous to steps B and C of the scheme I): SYNTHESIS SCHEME H-a Compounds of formula (1.0.0) in which component B is a radical of partial formula (1.1.6), ie, an isoxazole group, can be prepared by a process in which the final steps are similar to those Steps B and C of the process illustrated in synthesis scheme I. The preparation of the amine reactant producing component B of partial formula (1.1.6) is illustrated generally for the compounds of formula (1.0.0) in the following synthesis scheme: SYNTHESIS SCHEME III-STAGE A (2.1.11) The intermediate oxine (hydroxyiminomethyl) (2.1.7) is converted into the component B containing the desired isoxazole of partial formula (1.1.6), intermediate (2.1.11), oxidizing (2.1.7) to its corresponding N-oxide nitrile with sodium hypochlorite in a solvent such as THF or methylene chloride; and reacting the N-oxide nitrile in situ with an appropriate terminal alkyl alkanoate. This [2 + 3] cycloaddition reaction is well known in the literature as a method for preparing the isoxazole ring structure. See for example Synthesis 508-509, 1982.

SYNTHESIS SCHEME IH-STAGE B The benzyl carbamate (2.1.1 1) is converted to the primary amine (2.1.12) using one of the following reagents using the procedures published in the literature: H2 / Pd-C. { Ber., 65, page 1 192., 1932); HBr, AcOH. { J. Org., Chem., 17, page 1564, 1952); 70% HF, pyridine. { J. Chem. Soc, Chem. Commun., Page 451, 1976) or CF3SO3H. { J. Chem. Soc, Chem. Commun., Page 107, 1974). The synthesis described above is broadly applicable to the compounds of formula (1.0.0). In order to make said synthesis even clearer, the synthesis scheme III, steps A to C, is shown below, with reference to a particular compound of the present invention (stage C being analogous to steps B and C of the scheme I): SYNTHESIS SCHEME lll-a Compounds of formula (1.0.0) in which component B is a radical of partial formula (1.1.0), ie, an oxazoline group, can be prepared by a method illustrated gener in the following synthesis scheme : SYNTHESIS SCHEME IV-STAGE A ArN The condensation of the carboxylic acid (2.1.2) and the amine (2.1.14) to give the tert-butyl ester (2.1.15) is shown in step A and is analogous to the reaction of synthesis scheme I, step B. The ether-butyl ether is converted into its corresponding acid (2.1.16) by subjecting it to acidic conditions such as HCl in a solvent such as dioxane at room temperature or close to it. The transformation of (2.1.15) in (2.1.16) is shown below in stage B.

SYNTHESIS SCHEME IV - STAGE B HCl, dioxane The intermediate acid (2.1.16) is condensed with the amine (2.1.17) to provide the amide (2.1.18) as shown below in step C and is analogous to the reaction of synthesis scheme I, step B. The intermediate amide (2.1.18) is cyclized to oxazoline (2.1.19) in the presence of diethylaminosulfur trifluoride (DAST) as shown below in step D using literature procedures (Pinto et al., Tetrahedron Lett 30, page 3349, 1989); Jones went to., Tetrahedron Lett. 31, page 3649, 1989).

SYNTHESIS SCHEME IV - STAGE C SYNTHESIS SCHEME IV - STAGE D Fin, the desired acid (2.1.20) is obtained from the ester (2.1.19) in the presence of aqueous base as shown in the next step E and is analogous to the reaction of synthesis scheme I, step C.

SYNTHESIS SCHEME IV - STAGE E The above synthesis is broadly applicable to the compounds of formula (1.0.0). In order to make said synthesis even clearer, the synthesis scheme IV, steps A to E, is shown below with reference to a particular compound of the present invention: SYNTHESIS SCHEME IV - a H2 ™ | ^ [T ^ CHp, 3 HOBT, EDCI, DEA, CH2Cl2 (2.2.17) The compounds of formula (1.0.0) in which component B is a radical of partial formula (1.1.2), ie, an oxazole group, can be prepared by a method illustrated gener in the following scheme of analysis : SYNTHESIS SCHEME V - STAGE A The intermediate acid (2.1.22) is condensed with the amine (2.1.23) providing the amide (2.1.24) as shown in step A and is analogous to the reaction of synthesis scheme I, step B. The amide intermediate (2.1.24) is cyclized to oxazole (2.1.25) in the presence of phosphorous oxychloride in a solvent such as toluene at temperatures from room temperature to 110 ° C as shown below in step B. { J. Org. Chem., 55, page 386, 1990).

SYNTHESIS SCHEME V - STAGE B The benzyl carbamate (2.1.25) is converted to the primary amine (2.1.26) using one of the following reagents using the procedures published in the literature: H2 / Pd-C. { Ber., 65, page 1 192, 1932); HBr, AcOH. { J. Org. Chem., 17, page 1564, 1952); 70% HF pyridine. { J. Org. Soc, Chem. Commun., Page 451, 1976) or CF3SO3H. { J. Org. Soc, Chem. Commun., Page 107, 1974). The intermediate amine (2.1.26) is converted to the compounds of formula (1.0.0) using analogous reactions to synthesis scheme I, steps B and C. 02 SYNTHESIS SCHEME V - STAGE C The synthesis described above is broadly applicable to the compounds of formula (1.0.0). In order to make said synthesis even clearer, the synthesis scheme V, steps A to C, is shown below, with reference to a particular compound of the present invention: SYNTHESIS SCHEME V - The compounds of formula (1.0.0) in which component B is a radical of partial formula (1.1.2) ie, a thiazole group, can be prepared by a method illustrated generally in the following synthesis scheme: SYNTHESIS SCHEME VI - STAGE A The intermediate amide (2.1.24) is cyclized to thiazole (2.1.27) using the conditions of the Lawesson reagent literature [2,4-bis (4-methoxyphen!!) -1,3-dithia-2,4 -difosphetane-2,4-disulfide] in a solvent such as toluene at temperatures from room temperature to 110 ° C as shown in step A. The benzyl carbamate (2.1.27) is converted to the primary amine (2.1. 28) as shown in step B using one of the following reagents using the procedures published in the literature: H2 / Pd-C. { Ber., 65, page 1192, 1932); HBr, AcOH (J. Org. Chem., 17, page 1564, 1952); 70% HF pyridine. { J. Chem. Soc, Chem. Commun., Page 451, 1976) or CF3SO3H (J. Chem. Soc, Chem. Commun., Page 107, 1974). The intermediate amine (2.1.28) is converted to the compounds of formula (1.0.0) using analogous reactions to synthesis scheme I, steps B and C.

SYNTHESIS SCHEME VI - STAGE B The synthesis described above is broadly applicable to the compounds of formula (1.0.0). In order to make said synthesis even clearer, the synthesis scheme VI, steps A to C, is shown below, with reference to a particular compound of the present invention: SYNTHESIS SCHEME VI - a Compounds of formula (1.0.0) in which component B is a radical of partial formula (1.3.0) for example, a pyrrolidin-2-ylthiazol-5-yl group, can be prepared by an illustrated procedure in a general way in the following synthesis scheme: SYNTHESIS SCHEME Vil - STAGE A The pyrrolidine dicarboxylic acid (2.3.0) in the form of protected diester is condensed with the amine (2.3.1) to give the amide (2.3.2) under reaction conditions which are analogous to those described above in the synthesis scheme I , Step B. The amide (2.3.2) is then cyclized to the thiazole (2.3.3) using a Lawesson's reagent under conditions well known in the art and described in more detail herein. This reaction is illustrated by synthesis scheme VII, stage B, as follows: SYNTHESIS SCHEME Vil - STAGE B The thiazole (2.3.3) prepared as described above now contains the pyrrolodin-2-yl-thiazol-5-yl component which is a fundarpental part of the compounds of formula (1.0.0) in which the component B is a radical of partial formula (1.3.0). The radical of components of a compound of formula (1.0.0) is prepared in successive stages illustrated below. The nitrogen atom of the pyrrolidinyl group is deprotected to form the pyrrolidinyl-thiazole (2.3.4), followed by the condensation of (2.3.4) with an o-tolyl-ureido-phenyl-acetic acid (2.3.5) as reactant, which provides the left portion of a compound of the present invention. An "R" ester of a compound of formula (1.0.0), (2.3.6), is thus formed, as shown in synthesis scheme VII, step C below: SYNTHESIS SCHEME Vil - STAGE C In a final step, the ester (2.3.6) is reduced provided the corresponding carboxylic acid (2.3.7) according to well-known procedures. This stage is illustrated as a synthesis scheme VII, stage D as follows: SYNTHESIS SCHEME Vil - STAGE D EXAMPLIFICATION OF PREFERRED MODALITIES The following examples further illustrate the compounds, compositions and methods of treatment of the present invention, although they are not intended to limit the scope of the present invention. In the following examples a series of abbreviations are used in order to save space. Although these abbreviations are well known to the expert, are presented below for reasons of clarity and convenience of the reader: BOP benzotriazol-1-yliloxytris (diethylamino) phosphonium hexafluorophosphate DAST diethylaminosulfur trifluoride DIEA diisopropylethyl amine DMF dimethylformamide EDCI 1- (3-dimethylaminopropyl) hydrochloride 3-ethylcarbodiimide HOBT 1 -hydroxybenzotriazole THF tetrahydrofuran EXAMPLE 1 A. 3- (3-Isobutyl-2-oxo-4-ir4- (3-o-tolyl-ureido) -phenin-acetyl> -p8perazin-1-yl-) butyric acid A solution of 3- (3-isobutyl-2-oxo-4-. {[4- (3-o-tolyl-ureido) -phenyl] -acetyl acid methyl ester was stirred for 16 hours at room temperature} -piperazin-1-yl-) butyric acid (20 mg, 0.038 mmol) by mixing with 1 ml of 0.1 N NaOH and 1 ml of fer-butanol. The reaction mixture was then concentrated under reduced pressure, dissolved in water (5 ml) and extracted with ether (5 ml x 2). The aqueous portion was then acidified to pH < 3 with 1N HCl and extracted with ethyl acetate. The combined organs were washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give 16 mg of the title compound as a sticky yellow oil.

MS [M + 1] + 509.3; 1 H NMR (400 MHz, CD3OD) d 0.88-1.70 (m, 12H), 2.25 (s, 3H), 2.34-4.96 (m, 10H), 6.98 (t, J = 7.4 Hz, 1 H), 7.1 1 -7.40 (m, 6H), 7.59 (d, J = 7.5 Hz, 1 H).

B. 3- (3-Isobutyl-2-oxo-4-fr4- (3-o-tolyl-ureido) -phenyl-acetyl) -piperazin-1-yl) -butyric acid methyl ester 3- (3-Isobutyl-2-oxo-piperazin-1-yl) -butyric acid methyl ester (50 mg, 0.19 mmol) was added to a stirred mixture of acid [4- (3-o-tolyl-ureido)] phenyl] -acetic (55 mg, 0.19 mmol), dipossoylethylamine (0.17 ml), BOP (86 mg, 0.19 mmol) in DMF (1 ml). After stirring 16 hours at room temperature, the solution was diluted with water and extracted into ethyl acetate. The combined organics were washed with 5% citric acid, saturated NaHCO3 and brine; dried over MgSO 4, filtered and concentrated under reduced pressure. Column chromatography on silica gel eluting with 2% MeOH / CH2Cl2 gave 20 mg of the title compound as an amorphous yellow solid. MS [M + 1] +523.3.

C. [4- (3-o-tolyl-ureido) -phenoacetic acid Triethylamine (13.8 ml) was added to a stirred mixture of 4-aminophenylacetic acid (15.0 g) and o-tolyl isocyanate (10.2 ml) in CH2Cl2 (200 ml). After one hour, the resulting homogeneous solution was concentrated under reduced pressure, dissolved in water (100 ml) and acidified to pH 2 with 1 N HCl. The off-white precipitate was filtered, suspended in THF (200 ml) and filtered. they added 10 ml of concentrated HCl. The resulting homogeneous solution was concentrated under reduced pressure and recrystallized from EtOAc (800 mL) to provide 22 g of the title compound as a white solid. P.F. 221-222 ° C; MS [M + 1] +285.2; Analysis calculated for C 16 H 16 N 2 O 3: C (67.59), H (5.67), N (9.85). Found: C (67.22), H (5.78), N (9.69).

D. 3- (3- (Isobutyl-2-oxo-p-piperazin-1-y-butyric acid methyl ester: MS [M + 1J + 257.3 The title compound can be prepared by those skilled in the art using one of the following literature references: (a) Bhatt, U; Mohamed, N; Just, G, Tetrahedron Lett. 1997, 38 (21), 3679-3682; or (b) Sugihara, H. et al., J. Med. Chem., 1998, 41, 489-502.

EXAMPLE 2 A. Acid 3-r3- (3-methyl-1-f2-r4- (3-o-tolyl-ureido) -phenin-acetylamino> -butyne-isoxazole-5-ip-propionic acid A mixture of 3- [3- (3-methyl-1 -. {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -3- methyl ester was stirred at room temperature. butyl) -isoxazol-5-yl] -propionic acid (17 mg) in tert-BuOH (1 ml) and 0.1 N NaOH (1 ml).

After 20 hours, the mixture was concentrated under reduced pressure, dissolved in water (5 ml) and extracted with EtOAc (5 ml x 3). The aqueous layer was then acidified to pH 3 with 1N HCl and extracted with EtOAc. The combined organics were washed with brine; dried over Na2SO; they were filtered and concentrated under reduced pressure to give the title compound as an amorphous white solid: M.p. =?; MS [M + 1] +493.2; 1 H NMR (400 MHz, CD3OD) d 0.81 (d, 3 H), 0.91 (d, 3 H), 1.53-1.66 (m, 3 H), 2.26 (s, 3 H), 2.64 (t, J = 7.4 Hz, 2 H ), 2.97 (t, J = 7.5 Hz, 2H), 3.44 (s, 2H), 5.08 (m, 1 H), 6.00 (s, 1 H), 6.99 (t, 1 H), 7.11-7.36 (m , 6H), 7.59 (d, J = 7.9 Hz, 1 H).

B. 3-R3- (3-Methyl-1- {2-r4- (3-o-tolyl-ureido) -phenyl-1-acetylamino-butyl) -isoxazole-5-yl-1-propionic acid methyl ester A solution of 3- [3- (1-amino-3-methyl-butyl) -isoxazol-5-yl] -proponic acid methyl ester hydrobromide (272 mg, 0.85 mmol) in CH2Cl2 (12 ml) was added. ) to a stirred solution of [4- (3-o-tolyl-uredio) -phenyl] -acetic acid (305 mg, 1.07 mmol), DIEA (1.3 ml), HOBT (120 mg, 0.89 mmol) and EDCI (170 mg, 0.89 mmol) in CH2Cl2 (8 mL) at room temperature. After stirring for 16 hours at room temperature, the mixture was diluted with CH2Cl2 (20 ml) and poured into water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (20 ml X 3). The combined organics were dried over MgSO; they filtered; and concentrated under reduced pressure. The residue was purified by flash chromatography using a column of silica gel and eluting with 65% EtOAc / hexane to give 220 mg of the title compound as an amorphous white solid. P.f. = 153-154 ° C; MS [M + 1] +507.2; 1 H NMR (400 MHz, CD3OD) d 0.88 (d, J = 6.4 Hz, 6H), 1.53-1.66 (m, 3H), 2.21 (s, 3H), 2.66 (t, J = 7.6 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 3.49 (s, 2H), 3.68 (s, 3H), 5.15 (dt, J = 6.2 and 8.7 Hz, 1 H), 5.85 (s, 1 H), 6.11 (d, J = 8.5 Hz, 1 H), 6.65 (s, 1 H)), 7.00 (s, 1 H), 7.05-7.24 (m, 7H), 7.53 (, 1 H); Analysis calculated for C28H34N4O5: C (66.39), H (6.76), N (11.05). Found: C (66.29), H (7.11), N (11.11).

C. 3-f3- (1-amino-3-methyl-butyl) -isoxazole-5-ip-propionic acid methyl ester bromide.

A stirred suspension of 3- [3- (1-benzyloxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl] -propionic acid methyl ester (320 mg, 0.85 mmol) m in 30% HBr was gently stirred until homogeneous. % / AcOH (3 ml). After 4 hours at room temperature, the orange solution was concentrated to give 275 mg of the title compound as a bright orange amorphous solid. MS [M + 1] +241.2.

D. 3-R3- (1-Benzyloxycarbonylamino-3-methyl-butyl) -isoxazole-5-ip-propionic acid methyl ester Triethylamine (0.2 ml) was added, followed by Clorox bleach (80 ml) to a stirred solution of [1- (hydroxyimino-methyl) -3-methyl-butyl-carbamic acid benzyl ester (6.0 g, 22.7 mmol) and ester methyl pent-4-inoic acid (3.8 g, 34 mmol) in CH2Cl2 (80 mL). After 4 hours at room temperature, the organic phase was separated and the acid phase was extracted with CH2Cl2 (25 ml x 3). The combined organics were dried over MgSO 4; they were filtered and concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography using a column of silica gel and elution with 10-20% EtOAc / hexane gave 2.5 g of the title compound as a waxy pale yellow solid: MS [M + 1] +375.3; (400 MHz, CDCI3) d 0.91 (m, 6H), 1.51 -1.76 (m, 3H), 2.67 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 3.67 (s, 3H), 4.89 (m, 1 H), 5.08 (m, 3H), 5.92 (s, 1 H), 7.31 (m, 5H).

E. Benzyl ester of ri- (hydroxyimino-methyl) -3-methyl-butifl-carbamic acid Vigorously stirred to a mixture of (1-formyl-3-methyl-butyl) -carbamic acid benzyl ester (2.13 g, 8.5 mmol), hydroxylamine hydrochloride (0.71 g, 10.2 mmol) and NaOAc (2 g, 24.4 mmol). ) in MeOH (20 ml) and water (20 ml). After 24 hours, the mixture was diluted with water (60 ml) and extracted with EtOAc (50 ml x 3). The combined organics were washed with water and brine; dried over MgSO; they were filtered and concentrated under reduced pressure. Purification by flash chromatography using a column of silica gel and elution with 15-25% EtOAc / hexane yielded 1.5 g of the title compound as a waxy white solid: MS [M + 1] +265.

EXAMPLE 3 A. Acid r2- (3-methyl-1-l2-r4- (3-o-tolyl-ureido) -phenin-acetylamino> -butin-4,5-dihydro-oxazol-5-ill-acetic acid A mixture of [2- (3-methyl-1- {2- (4- (3-o-tolyl-ureido)] benzyl ester was stirred in a Parr apparatus at 2.07 x 105 Pa of H2 for 2 hours. ) -phenyl] -acetylamino.} - butyl) -4,5-dihydro-oxazol-5-yl] -acetic acid (120 mg) and palladium hydroxide (40 mg) in 10 ml of THF and 10 ml of MeOH. The mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The residue was suspended in EtOAc and concentrated under reduced pressure. Trituration with hot EtOAc gave 93 mg of the title compound as a light pink solid. MS [M + 1] +481.3; 1 H NMR (400 MHz, DMSO-dd) d 0.77-0.87 (m, 6H), 1.39-1.59 (m, 3H), 2.10-2.33 (m, 4H, including sa 2.21, 3H), 2.40-5.08 (m , 7H, including qa 3.36, J = 14.2 Hz, 2H), 6.90 (t, J = 7.4 Hz, 1 H), 7.08-7.14 (m, 4H), 7.35 (d, J = 6.8 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1 H), 7.95-8.45 (m, 2H), 9.13-9.23 (m, 1 H).

B. Benzyl ester of f2- (3-methyl-1-. {2-r4- (3-o-tolyl-ureido) -pheno-acetylamino) -butyl-4,5-dihydro-oxazole-5 acid -il1-acetic DAST (0.245 ml) was added to a stirred suspension of 3-hydroxy-4- (4-methyl-2-. {2- [4- (3-o-tolyl-ureido) -phenyl] - benzyl ester. acetylamino.}. phenylamino) -butyric acid (0.73 g) in CH2Cl2 (100 ml) and THF (100 ml) at room temperature. After 2 hours an additional 0.245 ml of DAST was added. After 2 hours, the resulting homogeneous solution was diluted with CH2Cl2 (600 mL), washed with 100 mL of saturated NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography using a column of silica gel and elution with 5% MeOH / CH2Cl2 yielded a solid which was recrystallized from EtOAc to give 0.255 g of the title compound as a light yellow solid. MS [M + 1] +571.2; 1 H NMR (400 MHz, DMSO-d 6) d 0.73-0.81 (m, 6H), 1.42-1.51 (m, 3H), 2.18 (s, 3H), 2.59-2.70 (m, 2H), 3.26-3.42 ( m, 3H), 3. 81 (m, 2H), 4.44 (m, 1 H), 8.45 (m, 1 H), 5.08 (s, 2H), 6.88 (t, 1 H), 7.06-7.13 (m, 4H), 7.27-7.33 (m, 6H), 7.79 (d, 1 H), 7.83 (s, 1 H), 8.27-8.30 (m, 1 H), 8.91 (s, 1 H).

C. 3-Hydroxy-4- (4-methyl-2- (2-r4- (3-o-tolyl-ureido) -phenyl-1-acetylamino) -pentanoylamino) -butyric acid benzyl ester EDCI (1.63 g) was added to a stirred solution of 4-methyl-2- acid. { 2- [4- (3-o-tolyl-uredo) -phenyl] -acetylamino} pentanoic acid (3.6 g), benzylic ester hydrochloride of 4-amino-3-hydroxy-butyric acid (1.6 g), triethylamine (1 ml) and HOBT (1.06 g) in DMF (50 ml) at room temperature. After stirring 16 hours, the mixture was poured into 1500 ml of ice water and stirred for 20 minutes. The resulting precipitate was filtered and dried to give a cream colored solid. Recrystallization from EtOAc gave 2.1 g of the title compound as a white solid. MS [M + 1] +589.2; NMR of 1 (400 MHz, DMSO-d6) d 0.73-0.81 (m, 6H), 1.37-1.49 (m, 3H), 2.19 (s, 3H), 2.20-2.28 (m, 1 H), 2.46-2.49 (m, 1 H), 2.99-3.09 (m, 2H), 3.33 (q, J = 13.8 Hz, 2H), 3.90 (m, 1 H), 4.19-4.23 (m, 1 H), 5.05 (s, 2H), 6.88 (t, 1 H), 7.06-7.12 (m, 4H), 7.26-7.34 (m, 6H), 7.75 (d, J = 8.1 Hz, 1 H), 7.92 (dt, 1 H), 8.06 (s, 1 H), 8.10 (d, J = 8.1 Hz, 1 H), 9.13 (s, 1 H).

D. Benzyl ester hydrochloride of amino-3-hydroxy-butyric acid A mixture of 4-tert-butoxycarbonylamino-3-hydroxy-butyric acid benzyl ester (2.1 g) in 4N HCl / dioxane was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give 1.6 g of the title compound as an amorphous white solid. MS [M + 1] +210.1; 1 H- NMR (400 MHz, DMSO-d 6) d 2.44-2.50 (m, 1 H), 2.61-2.74 (m, 2 H), 2.88 (dd, 1 H), 4.11 (m, 1 H), 5.09 ( s, 2H), 5.59 (d, J = 5.6 Hz, 1 H), 7.35 (m, 5H), 8.01 (broad s, 3H).

E. Tert-butyrocarbonylamino-3-hydroxy-butyric acid benzyl ester K2CO3 (2.8 g) was added to a solution of 4-tert-butoxycarbonylamino-3-hydroxy-butyric acid (2.0 g) in dry DMF (30 ml) at room temperature. After 15 minutes, benzyl bromide (1.7 g) was added. After 16 hours, the mixture was poured into 200 ml of water and extracted into EtOAc (200 ml x 2). The combined organics were washed with 1 N NaOH (40 ml); water (40 ml x 2), brine (40 ml); dried over MgSO4; they were filtered and concentrated under reduced pressure to give an oil. Purification by flash chromatography using a column of silica gel and eluting with 30% EtOAc / hexane gave 2.1 g of the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d 1.43 (s, 9 H), 2.53 (m, 2 H), 3.07-3.14 (m, 1 H), 3.30-3.34 (m, 1 H), 4.09-4.13 (m, 1 H), 4.95 (s, broad, 1 H), 5.14 (s, 2H), 7.34 (m, 5H).

F. tert-butoxycarbonylamino-3-hydroxy-butyric acid A mixture of 4-amino-3-hydroxy-butyric acid (2.9 g), 1 N NaOH (72 ml) and di-fer-butyl dicarbonate (6.6 g) in dioxane (72 ml) was stirred at room temperature. After 16 hours, the mixture was poured into 200 ml of water and extracted with EtOAc (200 ml x 2). The aqueous layer was acidified to pH 4 with 3N HCl and extracted with CH2Cl2 (200 mL x 2). The combined organics were washed with water (40 ml); dried over MgSO4; they were filtered and concentrated under reduced pressure providing 2.05 of the title compound as a colorless oil. MS [M-1] 218.2; 1 H- NMR (400 MHz, DMSO-d 6) d 1.33 (s, 9 H), 2.07 (dd, 1 H), 2.30 (dd, J = 4.1 and 15.3 Hz, 1 H), 2.87 (t, J = 5.9 Hz, 2H), 3.79 (m, 1 H), 6.70 (broad t, 1 H).

Methyl-2-f2-r4- (3-o-tolyl-ureido) -phenyl-1-acetylamino) -pentanoic acid A mixture of the benzyl ester of 4-methyl-2- acid was stirred in a Parr apparatus under 2.07 x 105 Pa of H2. { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylaminoj-pentanoic acid (4.0 g) and palladium hydroxide on carbon (1.0 g) in 200 ml of MeOH and 200 ml of THF. After 2 hours, the mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give 3.6 g of the title compound as a white solid. MS [M + 1] +398.3; 1 H- NMR (400 MHz, DMSO-d 6) d 0.79 (d, J = 6.4 Hz, 3 H), 0.86 (d, J = 6.4 Hz, 3 H), 1.44-1.63 (m, 3 H), 2.21 (s, 3H), 3.36-3.40 (m, 2H), 4.15-4.20 (m, 1 H), 6.91 (t, 1 H), 7.09-7.14 (m, 4H), 7.33 (d, 2H), 7.81 (d, 1 H), 7.89 (s, 1 H), 8.26 (d, 1 H), 8.97 (s, 1 H).

H. Benzyl Ester of Meti-2-f2- | "4- (3-o-tolyl-ureido) -phenin-acetylamino) -pentanoic acid EDCI (2.4 g) was added to a stirred solution of [4- (3-o-tolyl-ureido) -phenyl] -acetic acid (3.0 g), benzyl ester of L-leucine (4.2 g), triethylamine (1). .6 ml) and HOBT (1.6 g) in dry DMF (50 ml) at room temperature. After 16 hours, the mixture was poured into water (400 ml) and extracted with EtOAc (400 ml x 2). The combined organics were washed with 5% citric acid (100 ml); Saturated NaHCO3 (100 ml); water (100 ml), brine (100 ml); dried over MgSO4; they were filtered and concentrated under reduced pressure to approximately 100 ml. The resulting suspension was filtered to provide 4.0 g of the title compound as a white solid. MS [M + 1] +488.2; 1 H- NMR (400 MHz, DMSO-d 6) d 0.79 (d, J = 6.4 Hz, 3 H), 0.86 (d, J = 6.4 Hz, 3 H), 1.45-1.63 (m, 3 H), 2.21 (s, 3H), 3.37 (s, 2H), 4.26-4.31 (m, 1 H), 5.07 (s, 2H), 6.91 (t, 1 H), 7.09-7.15 (m, 4H), 7.29-7.37 (m, 7H), 7.81 (s, 1 H), 8.44 (d, 1 H), 8.93 (s, 1 H).

EXAMPLE 4 A. Acid (3-benzyl-2-oxo-4 ~ f r4- (3-o-tolyl-ureido) -phenin-acetyl> piperazin-1-yl) -propionic A solution of 3- (3-benzyl-2-oxo-4-. {[[4- (3-o-toyl] -phenyl] -phenyl] -acetyl acid tert-butyl ester was stirred at room temperature} -piperazin-1-yl) -propionic acid (0.7 g) in 10 ml of 4N HCl / dioxane. After 2 hours, the solution was concentrated under reduced pressure and the residue was dissolved in NaOH 1 N (50 ml) and extracted with EtOAc (20 ml x 2). The aqueous phase was acidified to pH 2 with 6N HCl and extracted with EtOAc (20 ml x 3). The combined organics were washed with brine; dried over Na2SO4; they were filtered and concentrated under reduced pressure to give 0.54 g of the title compound as an amorphous white solid. P.f.103-105 ° C; MS (M-1) 527.

B. (3-Benzyl-2-oxo-4- { R4- (3-o-tolyl-ureidoVfeniH-acetyl) -piperazin-1-i0-propionic acid tert-butyl ester The title compound (amorphous white solid; MS (M-1) 583.4) was prepared analogously to Example 1B, using 3- (3-benzyl-2-oxo-piperazin-1-yl) tert-butyl ester. -propionic as amine reactant, which can be prepared by those skilled in the art using the procedure referenced in example 1 D.

EXAMPLE 5 3-BenzoH, 31-dioxol-5-yl-3-isobutyl-2-oxo-4-ir4- (3-o-tolyl-ureido) -pheniphenyl) -piperazin-1-yl acid) -propionic The title compound (amorphous solid, MS [M + 1] + 615) was prepared analogously to Example 4, using 3-benzo [1, 3] dioxol-5-yl-3-tert-butyl ester (3-isobutyl-2-oxo-piperazin-1-yl) -propionic as amine reactant in part B, which can be prepared by those skilled in the art using the procedure referenced in example 1 D.

EXAMPLE 6 3-R5- (2-carboxy-ethyl) -3- 3-methyl-1-y2-r4- (3-o-tolyl-ureido) -phene-acetylamino) -butiD-4,5- acid dihydro-isoxazole-5-p-propionic The compound of the title [M + 1] + was prepared analogously to example 2, using [1- (hydroxyimino-methyl) -3-methyl-butyl-carbamic acid benzyl ester and 4-methylene-heptanedioic acid diethyl ester as starting materials in part D. Amorphous white solid; P.f. 173-175 ° C; MS [M + 1] + 567.2; Analysis calculated for C30H38N4O7: C (63.59), H (6.76), N (9.88). Found: C (63.07), H (7.21), N (9.70).

EXAMPLE 7 3-r3- (3-Methyl-1-l2-r4- (3-o-tolyl-uredo) -phenin-acetylamino-butin-4,5-dihydro-isoxazole-5-in-propionic acid The title compound was prepared analogously to example 2, using [1- (hydroxyimino-methyl) -3-methyl-butyl-carbamic acid benzyl ester and methyl 4-pentanoate as starting materials in part D. Solid light amber; 1 H NMR (400 MHz, DMSO-d 6) d 0.79 (d, J = 6.0 Hz, 3 H), 0.84 (d, J = 5.8 Hz, 3H), 1.48-1.67 (m, 5H), 2.19-2.24 (m, 2H), 2.20 (s, 3H), 2.46-2.54 (m, 1 H), 2.93 (dt, J = 10.6 and 17.1 Hz, 1 H), 3.32 (s, 2H), 4.43 (m, 1 H), 4.62 (m, 1 H), 6.90 (t, J = 7.5 Hz, 1 H), 7.0Í-7.13 (m, 4H), 7.33 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.3 Hz, 1 H), 7.85 (s, 1 H), 8.22-8.25 (m, 1 H), 8.93 (s, 1 H); MS (M + 1) 495.2.

EXAMPLE 8 A. Acid r2- (3-methyl-1-f2-r4- (3-o-tolyl-ureido) -phenin-acetylamino> -butyn-oxazole-5-in-propionic acid The title compound was prepared analogously to example 2 A-C, using 3- [2- (1-benzyloxycarbonylamino-3-methyl-butyl) -oxazol-5-yl] -propionic acid methyl ester as starting material. White solid; P.f. 168-170 ° C; 1 H NMR (400 MHz, DMSO-d 6) d 0.77 (d, J = 6.4 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3H), 1.44-1.63 (m, 3H), 2.19 (s, 3H), 2.50 (t, J = 7.4 Hz, 2H), 2.79 (t, J = 7.3 Hz, 2H) , 3.34 (d, 2H), 4.92 (q, J = 8.0 Hz, 1 H), 6.72 (s, 1 H), 6.89 (t, J = 7.4 Hz, 1 H), 7.07-7.13 (m, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1 H), 7.84 (s, 1 H), 8.54 (d, J = 8.3 Hz, 1 H), 8.91 (s, 1 H); MS (M +) 493.2.

B. R 2 - (1-Benzyloxycarbonyl-amino-3-methyl-butyl) -oxazole-5-n-propionate methyl ester A mixture of 5- (2-benzyloxycarbonylamino-4-methyl-pentanoylamino) -4-oxo-pentanoic acid methyl ester (300 mg) and POCI3 (351 mg) in toluene (10 ml) was heated at reflux for 3 hours. An additional 351 mg of POCI3 was added and the mixture was heated to reflux for another 2 hours. The mixture was cooled to room temperature, poured into aqueous bicarbonate and extracted with EtOAc (2 x 100 ml). The combined organics were washed with water (20 ml) and brine (20 ml) and dried over MgSO4. The resulting mixture was filtered and concentrated under reduced pressure to provide an oil. Purification by flash chromatography using a column of silica gel and eluting with 2.5% MeOH in CH 2 Cl 2 gave 100 mg of the title compound as an oil. MS (M +) 375.

C. 2- (Benzyloxycarbonylamino-4-methyl-pentanoylamino) -4-oxo-pentanoic acid methyl ester TEA (0.7 mL) was added, followed by EDCI (1.05 g) to a stirred solution of 2-benzyloxycarbonylamino-4-methyl-pentanoic acid (1.3 g), 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride. (0.90 g) and HOBT (0.67 g) in DMF (15 ml) at room temperature. After stirring for 16 hours, the mixture was poured into water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organics were washed with 5% citric acid (20 ml), saturated aqueous bicarbonate (20 ml) and water (20 ml); dried over MgSO4; they filtered; and concentrated under reduced pressure to provide an oil. Purification by flash chromatography using a: column of silica gel and eluting with 2.5% MeOH / CH2Cl2 gave 0.53 g of the title compound as an oil. MS [M + 1] + 293.

EXAMPLE 9 Acid 3-r3- (1-l2- (3-o-tom-ureido) -phenylactylamino> -cyclopentip-isoxazole-5-in-propionic acid The title compound was prepared analogously to Example 2, using [1- (hydroxyimino-methyl) -cyclopentyl] -carbamic acid benzyl ester and methyl pent-4-inoclate as starting materials in part D. White solid; P.f. 195-197 ° C; MS [M + 1] + 491.3; Analysis calculated for C27H3oN4O5: C (66.11), H (6.16), N (11.42). Found: C (65.85), H (6.22), N (11.24).

EXAMPLE 10 A. r3- (3-Methyl-1-f2-r4- (3-pyridin-2-yl-ureido) -pheno-acetylamino) -butyl-isoxazole-5-ip-propionic acid The title compound was prepared in a manner analogous to Example 2, using [4- (3-pyridin-2-yl-ureido) -phenyl] -acetic acid in part B. White solid; P.f. 159-161 ° C; 1 H NMR (400 MHz, CD3OD) d 0.87 (d, J = 6.0 Hz, 3 H), 0.91 (d, J = 6.2 Hz, 3 H), 1.56-1.73 (m, 3 H), 2.64 (t, J = 7.3 Hz, 2H), 2.98 (t, J = 7.3 Hz, 2H), 3.47 (s, 2H), 5.06-5.10 (m, 1 H), 6.01 (s, 1 H), 6.96-6.99 (m, 1 H ), 7.14 (d, 1 H), 7.22 (d, 2H), 7.45 (d, 2H), 7.67-7.72 (m, 1 H), 8.25 (m, 1 H); MS [M + 1] + 480.3.

B. R (3-pyridin-2-yl-ureido) -phenoacetic acid H The title compound was prepared analogously to Example 1 C, using 2-pyridyl isocyanate and 4-aminophenylacetic acid as starting materials. EM [M + 1] + 272.2 EXAMPLE 11 A. r2- (3-Methyl-1-2-r4- (3-pyridin-2-yl-ureido) -phenyl-1-acetylamino-1-butyl) -thiazole-5-ill-propionic acid The title compound was prepared analogously to example 2 AC, using [4- (3-pyridin-2-yl-ureido) -phenyl] -acetic acid in 2B and methyl 3- [2- ( 1-benzyloxycarbonylamino-3-methyl-butyl) -thiazol-5-yl] -propionic acid in 2C. Whitish solid. P.f. 173-175 ° C; 1 H NMR (400 MHz, CD3OD) d 0.88 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 1.60-1.77 (m, 3H), 2.59 (t, J = 7.3 Hz, 2H), 3.05 (t, J = 7.3 Hz, 2H), 3.50 (s, 2H), 5.19 (q, 1 H), 6.96-6.99 (m, 1 H), 7.14 (d, 1 H), 7. 24 (d, 2H), 7.38 (s, 1 H), 7.46 (d, 2H), 7.67-7.71 (m, 1 H), 8.25 (d, 1 H), 8.69 (d, 1 H); MS [M + 1] + 469.2 B. F2- (1-benzyloxycarbonyl-amino-3-methyl-butyl) -thiazole-5-n-propionic acid methyl ester A mixture of 5- (2-benzyloxycarbonylamino-4-methyl-pentanoylamino) -4-oxo-pentanoic acid methyl ester (0.96 g) and Lawesson's reagent [2,4-bis (4-methoxyphenyl) - was heated to reflux. 1, 3-dithia-2,4-diphosptane-2,4-disulfide] (2.4 g) in 200 ml of anhydrous toluene. After 5 hours, the mixture was poured into water (200 ml) and extracted with EtOAc (2 x 200 ml). The combined organics were washed with water (40 ml) and brine (40 ml), dried over MgSO 4, filtered and concentrated under reduced pressure to an oil. Purification by flash chromatography using a column of silica gel and eluting with 2.5% MeOH / CH2Cl2 gave 0.39 g of the title compound as a colorless oil. MS [M + 1] + 391.

EXAMPLE 12 Acid 4-f3- (3-methyl-1-2-r4- (3-o-tolyl-ureido) -phenin-acetylamino > -butyl) -isoxazole-5-ill-butyric acid The title compound was prepared in a manner analogous to Example 2, using [1- (hydroxymethyl-methyl) -3-methyl-butyl-carbamic acid benzyl ester and methyl hex-5-inoclate as starting materials in the Stage D. White solid. 1 H NMR (400 MHz, DMSO-d 6) d 0.81 (d, J = 5.8 Hz, 3 H), 0.85 (d, J = 5.8 Hz, 3 H), 1.50-1.82 (m, 5 H), 2.21 (s, 3 H) ), 2.25 (t, J = 7.3 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 3.35 (s, 2H), 4.92-4.98 (m, 1 H), 6.10 (s, 1 H) , 6.91 (t, 1 H), 7.09-7.15 (m, 4H), 7.34 (d, 2H), 7.81 (d, 1 H), 8.43 (d, 1 H), 8.94 (s, 1 H); MS [M + 1] + 507.3.

EXAMPLE 13 3-r2- (3-Methyl-1-f2-r4- (3-o-tolyl-uredo) -phenin-acetylamino-buthithiazole-5-in-propionic acid The title compound was prepared analogously to Example 11 using the appropriate starting materials and reactants. White solid: 1 H NMR (400 MHz, DMSO-d 6) d 0.81 (d, J = 6.4 Hz, 3 H), 0.87 (d, J = 6.4 Hz, 3H), 1.56-1.74 (m, 3H), 2.21 (s, 3H), 2.53 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.3 Hz, 2H), 3.36 (d, J = 14 Hz, 1 H), 3.41 (d, J = 14 Hz, 1 H), 5.03 (q, 1 H), 6.91 (t, 1 H), 7.09-7.15 (m, 4H), 7.35 (d, 2H), 7.39 (s, 1 H), 7.81 (d, 1 H), 7.87 (s, 1 H), 8.69 (d, 1 H), 8.95 (s, 1 H); MS [M + 1] + 509.2.

EXAMPLE 14 Acid 3- < 3-R3-Methyl-1- (2-l4-R3-4-methyl-pyridin-3-yl) -ureido-1-phenyl-acetylamino) -butyl-isoxazole-5-yl-propionic acid The title compound was prepared analogously to Example 2 using acid. { 4- [3- (4-methyl-pyridin-3-yl) -ureido] -phenyl} -acetic in part B. White solid; MS [M + 1] + 492.

EXAMPLE 15 Acid 3 2-ri- (2-f4-r3- (2-chloro-phenyl) -ureido-1-phenyl-3-acetylamino-3-methyl-butip-thiazol-5-yl) -propionic acid The title compound was prepared analogously to Example 11 using the appropriate starting materials and reactants. White solid. P.f. 173-175 ° C; MS [M + 1] + 527; Analysis calculated for C26H29CIN4O4S: C (59.03), H (5.52), N (10.59). Found: C (58.89), H (5.60), N (10.49).

EXAMPLE 16 3-f2-Ri- (2- {4-R3- (2-methoxy-phenyl) -ureido-1-phenyl} -acetylamino-3-methyl-butyl-thiazol-5-yl-3-f-3 acid The title compound was prepared analogously to Example 11 using the appropriate starting materials and reactants. White solid. P.f. 197-198 ° C; MS [M-1] + 523; Analysis calculated for C27H32N4O5S: C (62.90), H (6.26), N (10.87). Found: C (62.09), H (6.33), N (9.91).

EXAMPLE 17 Acid 3 ~ f2-p- (2- {4-r3- (2-fluoro-phenyl) -ureido-1-phenyl} -acetylamino-3-methyl-but-p-thiazol-5-yl) - proponic The title compound was prepared analogously to Example 11 using the appropriate starting materials and reactants. White solid. P.f. 83-85 ° C; MS [M + 1] + 511.1.

EXAMPLE 18 3-r3- (3-Methyl-l-2-r4- (3-o-tolyl-ureido) -pheno-acetylamino-butyne-isoxazole-5-i-2-acrylic acid The title compound was prepared analogously to Example 2 using 3- [3- (1- (benzyloxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl] -acrylic acid ethyl ester as the starting material in the C. White solid; Mp 136-138 ° C; MS [M-1] + 489 B. 3-l3- (1- (benzyloxycarbonyl-amino-3-methyl-butyl) -isoxazole-5-yl-1-acrylic acid ethyl ester A stirred mixture of [1- (5-formyl-isoxazol-3-yl) -3-methyl-butyl] -carbamic acid benzyl ester (407 mg, 1.3 mmol), pyridine (10 mL) was heated to 55 ° C. and ethyl hydrogen malonate (255 mg, 1.9 mmol). After 2 days, the mixture was cooled to room temperature, poured into water and extracted into EtOAc (3 x). The combined organics were washed with 1 N HCl, water and brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give 480 mg of a yellow oil. Purification by flash chromatography (small) eluting with EtOAc / hexane 1: 3 gave 220 mg of the title compound as a light yellow oil. MS [M + 1] + 387.

C. Benzyl ester of f1- (5-formyl-isoxazole-3-i0-3-methyl-butyl-carbamic acid A stirred mixture of [1- (5-diethoxymethyl-isoxazol-3-yl) -3-methyl-butyl] -carbamic acid benzyl ester (920 mg, 2.4 mmol), acetone (50 ml) and H2SO4 was heated to reflux. (10 drops) After 35 minutes, the mixture was cooled to room temperature, neutralized with solid NaHCO3 and concentrated under reduced pressure. The resulting paste was suspended in EtOAc; washed with water and brine; dried over Na2SO4; it leaked; and concentrated under reduced pressure giving a light yellow oil. Purification by flash chromatography (small) eluting with EtOAc / hexane 1: 3 gave 407 mg of the title compound as a light yellow oil: MS [M + 1] + 317.

D. H- (5-diethoxymethyl-isoxazol-3-yl) -3-methyl-butyl-carbamic acid benzyl ester A mixture of [1- (hydroxyimino-methyl) -3-methyl-butyl] -carbamic acid benzyl ester (1.2 g, 4.5 mmol), 3,3-diethoxy-propyne (1.5 g, 11.4 g) was stirred until homogeneous. mmoles), CH2Cl2 (40 ml) and TEA (6 drops) and then Clorox bleach (20 ml) was added. After vigorous stirring for 12 hours, the layers were separated and the aqueous layer was extracted with (3 x). The combined organics were dried over Na2SO4; they filtered; and concentrated under reduced pressure to give a yellow oil. Purification by flash chromatography (small) eluting with 10% EtOAc in hexanes gave 920 mg of the title compound as a colorless oil. MS [M + 1] + 391.

EXAMPLE 19 Acid 3-f2-ri- 2 ~ f4-r3- (2,6-dichlorophenip-uredodo-1-phenyl-acetylamino) -3-methyl-but-n-thiazol-5-yl > -propionic The title compound was prepared in a manner analogous to Example 11 using the appropriate starting materials and reactants. White solid; p.f. 148-150 ° C; MS [M + 1] + 561.

EXAMPLE 20 Acid 3-f2-ri - (2-f4-r3- (2,6-dimethyl-phen-n-ureido-1-phenyl > -acetylamino) -3-methyl-but-p-thiazol-5-yl}. -propionic The title compound was prepared in a manner analogous to Example 1 1 using the appropriate starting materials and reactants. White solid; p.f. 125-127 ° C; MS [M + 1] + 521.

EXAMPLE 21 Acid 3-f2-p- (2-f4-r3-2-chloro-6-methyl-phenyl-ureido-1-phenyl > -acetylamino) -3-methyl-butyl-thiazol-5-yl > -propionic The title compound was prepared in a manner analogous to Example 11 using the appropriate starting materials and reactants. White solid; p.f. 160-162 ° C; MS [M-1] + 541.

EXAMPLE 22 3-r2- (3-Methyl-l-2-r4- (3-phenyl-ureido) -phenin-acetylamino-g-butyl) -thiazole-5-in-propionic acid The title compound was prepared in a manner analogous to Example 11 using the appropriate starting materials and reactants. White solid; p.f. 146-148 ° C; EM [M-1j + 495.3.

EXAMPLE 23 N-Hydroxy-3-r2- (3-methyl-1-f2-r4- (3-o-tolyl-ureido-phenylacetylamino> -butynthiazole-5-in-propionamide Hydroxylamine hydrochloride (6.96 g) was suspended in methanol (35 ml) and heated to 90 ° C. This solution was added to potassium hydroxide (8.34 g) dissolved in methanol (21 ml). After 15 minutes of stirring, the solution was filtered and 3- [2- (3-methyl-1- {2 - [4- (3-o-tolyl-ureido) -phenyl] methyl ester was added. -acet.lamino.}. -butyl) -thiazol-5-yl] -propionic acid (0.80 g, 1.53 mmoles). The reaction was stirred at room temperature for 15 minutes, 1 N HCl (50 mL) was added and the methanol was removed in vacuo. The residue was partitioned between ethyl acetate and hydrochloric acid (1 N). The organic portion was dried over sodium sulfate and the solvent was removed in vacuo. The title compound (0.175 g, 17%) was isolated by crystallization from a mixture of ethyl acetate and methanol. MS [M + 1] 524.1.

EXAMPLE 24 Acid 3-f3-ri- (2-f4-r3- (2-Chloro-phenin-ureido-1-phenyl) -acetylamino) -3-methyl-but-p-isoxazol-5-yl) -propionic acid The title compound was prepared in a manner analogous to Example 2 using the appropriate starting materials and reactants. White solid; p.f. 143-145 ° C; MS [M + 1] + 511.2.

EXAMPLE 25 Acid 3-r2- (1-f2-r4- (3-o-tolyl-ureido) -phenin-acetylamino> -but-3-enip-thiazole-5-p-propionic acid The title compound was prepared in a manner analogous to Example 11 using the appropriate starting materials and reactants. Amorphous white solid; MS [M + 1] + 493.

EXAMPLE 26 A. 3-J3-H- (2- {4-R3- (2-chlorophen-n-ureido-1-phenyl-2-acetylamino) -3-methyl-but-p-isoxazole- ethyl ester 5-yl) -3-oxo-propionic The title compound was prepared in a manner analogous to Example 2 using 3- [3- (1-amino-3-methyl-butyl) -isoxazol-5-yl] -3-oxo-propionic acid ethyl ester hydrochloride in Stage B. White solid; p.f. 150-152 ° C; MS [M + 1] + 555.5.

B. 3-R3- (1-amino-3-methyl-butyl) -isoxazole-5-ill-3-oxo-propionic acid ethyl ester hydrochloride A solution of 3- [3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl] -3-oxo-propionic acid ethyl ester (1.4 g, 3.9 mmol) was stirred at room temperature. in 4M HCl in dioxane (5 ml). After 3 hours, the mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid. MS [M + 1] + 269.0.

C. 3-R3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazole-5-ip-3-oxo-propionic acid ethyl ester The title compound was prepared from 3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazole-5-carboxylic acid by treatment with carbonyldiimidazole, followed by the magnesium salt of monoethyl malonate, such as is described in Angew. Chem., Int. Ed. Eng., 18 (1979), page 72.

EXAMPLE 27 Acid 3-r2- (1-l2-r4- (3-o-tolyl-ureido) -phenin-acetylamino-butin-thiazole-5-propionic acid The title compound was prepared in a manner analogous to Example 11 using the appropriate starting materials and reactants. White solid; MS [M + 1] + 493.

EXAMPLE 28 N-f1-f5- (3-methanesulfonylamino-3-oxo-propyl) -thiazole-2-yn-3-methyl-butyl -2- [- (3-o-tolip-urethane) -phenyl- acetamide A mixture of 3- [2- (3-methyl-1 -. {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) - was stirred at room temperature. thiazol-5-yl] -propionic (example 13) (91 mg, 0.2 mmol), DMF (5 ml), EDCI (48 mg, 0.2 mmol) and DMAP (26 mg, 0.2 mmol). After 10 minutes, methane sulfonamide (51 mg, 0.5 mmol) was added. After stirring 16 hours, the solution was diluted with EtOAc and washed with 1 N HCl (2 x). The organic layer was dried over Na2SO; it was filtered, and concentrated under reduced pressure. The resulting solid was purified by flash chromatography 12 eluting with 10% AcOH in EtOAc and providing 30 mg of the title compound as a white amorphous solid. MS [M-1] + 584.

EXAMPLE 29 2- (4-r3- (2-Chloro-phenyl) -ureido-1-phenyl-N-> f1-r5- (3-methanesulfonylamino-3-oxo-propyl) -thiazole-2-yn-3 methyl-butyl-acetamide The title compound was prepared in a manner analogous to Example 28 from acid 3-. { 2- [1- (2- { 4- [3- (2-chloro-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic Colorless oil; MS [M + 1] + 607.

EXAMPLE 30 3-r2- 2-r4- (3-o-tolyl-ureido) -fenip acetylamino -3-methylene-thiazole-5-propionic acid The title compound was prepared in a manner analogous to Example 11 using the appropriate starting materials and reactants. White solid; MS [M + 1] + 453.

EXAMPLE 31 Acid 3-f2-r (2-f4-r3- (2-chloro-phenyl) -ureidol-phenyl) -acetylamino) -methin-thiazol-5-yl-propionic acid The title compound was prepared in a manner analogous to Example 11 using the appropriate starting materials and reagents. White solid; MS [M + 1] + 473.

EXAMPLE 32 3-r2- (1- r4- (3-o-tolyl-ureido) -phenylane-acetyl) -pyrrolidin-2-yl) -thiazole-5-propionic acid A solution of 3- [2- (1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazoyl- methyl ester was prepared. 5-yl] -propionic acid (0.33 g, 0.65 mmol) in methanol (4 ml), tetrahydrofuran (8 ml) and aqueous lithium hydroxide (2M, 4 ml). The solution was stirred for 4 hours and partitioned between aqueous hydrochloric acid (1 N, 30 ml) and ethyl acetate (100 ml). The aqueous portion was extracted with ethyl acetate (50 ml). The combined organic portions were extracted with brine (20 ml) and the solvent was removed in vacuo to give the title compound (0.3 g, 94%). 1 H NMR (400 MHz, CD3OD): d 7.60 (d, J = 7.3 Hz, 1 H), 7.46 (s, 0.3H), 7.39 (d, J = 8.5 Hz, 2.7H), 7.29 (d, J = 8.5 Hz, 0.6), 7.18 (m, 3H), 6.99 (m, 1.4H), 5.40 (d, J = 7.0 Hz, 0.3H), 5.34 (d, J = 6.0 Hz, 0.7H), 3.4- 3.8 (m, 4H), 3.05 (m, 2H), 2.60 (m, 2H), 2.27 (s, 3H), 1.9-2.2 (m, 4H). MS: Calculated for C25H26N4O4S: 492.18. Found (M + 1) 492.9.

B. 3-r2- (1- (r4- (3-o-tolyl-ureido) -phenyl-acetyl-pyrrolidin-2-yl) -thiazole-5-ill-propionic acid methyl ester A solution of 3- (2-pyrrolidin-2-yl-thiazol-5-yl) -propionic acid methyl ester (approximately 1.09 mmol) in dimethyl formamide was prepared. To this solution were added [4- (3-o-tolyl-ureido) -phenyl] -acetic acid (0.38 g, 1.3 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.33 g, 1.7 mmol). ) and 1-hydroxybenzotriazole (0.24 g, 1.8 mmol). The reaction was stirred 1 hour and triethylamine (0.15 g, 1.46 mmol) was added. After stirring the reaction overnight (approximately 16 hours), this was poured into water (100 ml) and extracted on ethyl acetate (3 x 50 ml). The combined organic portion was extracted with saturated sodium bicarbonate (30 ml), water (2 x 15 ml) and brine (20 ml) and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column with methane-acetic acid: ethyl acetate (1: 1: 98) to give the title compound (0.33 g, 65%): Calculated MS for C26H28N4O4S: 506.20.

Found: (M + 1) 507.2 and (M-1) 505.3.

C. 3- (2-Pyrrolidin-2-yl-thiazol-5-yl) -propionic acid methyl ester A solution of 2- [5- (2-methoxycarbonyl-ethyl) -thiazol-2-yl] -pyrrolidine-1-carboxylic acid tert -butyl ester (0.37 g, 1.09 mmol) was stirred at room temperature for 1 hour. a solution of hydrochloric acid in dioxane (4 N, 10 ml). The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The methylene chloride was removed in vacuo and the residue redissolved in methylene chloride. The solvent was removed in vacuo and the residue was used without purification. MS: Calculated for CnH16N2O2S: 204.09. Found (M + 1): 241.2.

D. 2-R5- (2-methoxycarbonyl-ethyl) -thiazole-2-y-pyrrolidine-1-carboxylic acid tert-butyl ester The solution of 2- (4-methoxycarbonyl-2-oxo-butylcarbamoyl) -pyrrolidine-1-carboxylic acid tert -butyl ester (0.57 g) was prepared, 1.66 mmoles) in toluene (15 ml) and Lawesson's reagent (0.405 g, 1.0 mmoles) was added. The reaction was refluxed for 3 hours and poured into water (150 ml). This mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic portion was extracted with saturated sodium bicarbonate (2 x 30 ml) and brine (30 ml) and then dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on a Biotage 40s column with ethyl acetate: hexanes (1: 1) to give the title compound (0.37 g, 65%). 1 H NMR (400 MHz, CDCl 3) d 7.37 (s, 1 H, thiazole), 5.18 (m, 0.4H), 5.05 (m, 0.6H), 3.67 (s, 3H), 3.35-3.60 (m, 2H) ), 3.10 (m, 2H), 2.64 (t, J = 7.5 Hz, 2H), 2.20 (m, 2H), 1.90 (m, 2H), 1.62 (s wide, 1 H), 1.46 (s wide 4H) , 1.31 (broad s, 5H). MS: calculated for C 16 H 24 N 2 O 4 S: 304.15. Found (M + 1) 341.0 E. 2- (4-Methoxycarbonyl-2-oxo-butylcarbamoyl) -pyrrolidine-1-carboxylic acid tert-butyl ester 2-Tert-butyl ester of pyrrolidine-1,2-dicarboxylic acid, ester 1- (2,5-dioxo-pyrrolidin-1-yl) (1.03 g 3.3 mmol) was dissolved in DMF (30 ml) and salt was added. 5-amino-4-oxo-pentanoic acid methyl ester hydrochloride (0.60 g, 3.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. Triethylamine was added and stirring was continued overnight (approximately 16 h). The reaction was poured into water (300 ml) and extracted with ethyl acetate (3 x 70 ml). The combined organic portion was extracted with saturated aqueous sodium bicarbonate (60 ml), water (2 x 30 ml) and brine (50 ml). The organic portion was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting yellow oil was chromatographed on a Biotage 40s column with ethyl acetate: hexanes (4: 1) to give the title compound (0.57 g, 50%). 1 H NMR (400 MHz, CDCl 3) d 4.2 (m, 3 H), 3.65 (s, 3 H), 3.43 (m, 1, 5H), 3.35 (m, 0, 5H), 2.70 (m, 2H), 2.62 (m, 2H), 2.25 (s wide, 0.25H), 2.15 (wide s 0.75H), 1.88 ( m, 2H), 1.70 (s broad, 1 H), 1.25 (broad s, 9H). MS: Calculated for CnH 8N2O (M-BOC): 242.13. Found (M-BOC + 1) 243.0 EXAMPLE 33 Binding of biotinylated CS-1 to VLA-4 isolated The receptor ligand-binding assay VLA-4 / bCS-1 described herein evaluates the ability of a compound to inhibit the specific form of VLA-4-dependent binding.

A. Preparation of the VLA-4 coated plates VLA-4 coated plates were prepared the day before the test was carried out. The stock solution expressing VLA-4 was isolated from Jurkat cells according to the protocol of Makarem et al., J. Bio. Chem., 269, 4005-4011 (1994) and diluted in 50 mM NaHCO3 (pH 8.8) to a final concentration of 0.4 mg / ml. Aliquots of 100 ml of this stock solution were then added to each of the wells of a 96-well plate with U-bottom Microfluor "B" (Dynatech No. 0010107205) and incubated overnight at 4 ° C. The coating solution was removed by aspiration and the wells were quenched for 0.5 hour with PBS plus 1 ml of 1 mM MnCl containing 1% defatted milk powder (200 ml / well, 37 ° C). The milk powder was removed by aspiration immediately before the addition of the biotinylated CS-1.

B. Binding of biotinylated CS-1 to isolated VLA-4 The biotinylated CS-1 peptide (bCS-1) was prepared. This peptide was diluted with PBS plus 1 mM MnCl containing 1% defatted milk powder (PBSB) to a final concentration of 5 mg / ml. 200 ml aliquots were added to the wells of a 96-well polypropylene transfer plate containing the compounds (32, 10, 3, 2, 1, 0.32 and 0.1 mM), vehicle or antibodies (0.5 mg / ml) in PBSB containing 0.1% DMSO for 60 minutes (37 ° C). The plate is washed three times with 200 ml / well of PBSB to remove the unbound bCS-1. Next, 100 ml of a 1: 5000 dilution of streptavidin poly-HRP in PBSB is added to each well for 60 minutes (37 ° C). The unbound poly-HRP streptavidin is removed by aspiration and the plate washed three times with PBSB (200 ml / well). After the final wash, 100 ml of TMB substrate was added to each well to react the linked HRP streptavidin HRP and the OD of each well of the plate was determined in the Emax plate reader (650). The results were based on the average of determinations in duplicate.

EXAMPLE 34 Union of THP1 cells dependent on VLA-4 to baculovirus sVCAM The binding assay of THP1 cells to baculovirus sVCAM assesses the ability of a compound to inhibit sVCAM binding dependent on VLA-4.

A. Preparation of the sVCAM coated plates The sVCAM baculovirus coated plates were prepared the day before the experiment was carried out. PanVera sVCAM baculovirus stock solution was diluted in 50 mM NaHCO3 (pH 8.8) to a final concentration of 5 mg / ml. Aliquots of 50 ml of this stock solution were then added to each of the wells of a 96-well plate with U-bottom Microfluor "B" (Dynatech No. 0010107205) and incubated overnight at 4 ° C. The coating solution was removed by aspiration and the wells were quenched for 1 hour with PBS containing 5% defatted milk powder (150 ml / well, 4 ° C). The milk powder was removed by a sudden discharge immediately before the addition of the biotinylated CS-1.

B. Marking and Binding of THP1 Cells THP1 cells were obtained from the American Type Culture Collection (ATCC, Rockville MD) and reproduced in RPMI 1640 medium containing 1 mM 10% MnCl 2 for 20 minutes (37 ° C). After activation with MnC, the cells were centrifuged (approximately 500 g for 5 minutes) and resuspended twice in serum-free basal medium (EBM, 37 ° C). Cells in the serum-free medium (2 x 106) were then incubated with 5 mM Calcein AM for 30 minutes at 37 ° C. After labeling, all cells were centrifuged (approximately 500 g for 5 minutes) and resuspended twice in RPMI 1640 containing 10% FBS to break the free AM calcein. The cells were then resuspended twice in DPBS (+ 1 mM CaCl2 and 1 mM MgCl2) containing 1 mg / ml BSA (DPBSB) and diluted to 667,000 cells / ml. 200 ml aliquots were added to the wells of a 96-well polypropylene transfer plate containing the test compounds (10, 5, 1 and 0.1 mM), vehicle or antibodies (0.5 mg / ml) in DPBSB containing DMSO at 0.1% for 30 minutes (37 ° C). Next, 150 ml (100,000 cells) were removed from each well and transferred to appropriate wells of an sVCAM baculovirus-coated plate extinguished for 45 minutes (37 ° C). The unbound cells were removed by aspiration and the plate was washed three times with DPBSB (100 ml / well). After the final wash, 100 ml of DPBSB was added to each well and the plate was read on a Cytoflour II fluorescent plate reader. Three readings were taken for each well at an excitation of 480 and emission of 530. The results were based on the mean of determinations in duplicate. The mean background fluorescence of the white wells was subtracted from each sample to provide the corrected fluorescence intensity value for each sample.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (1.0.0): and their pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein -A is aryl, heteroaryl or heterocyclyl as defined herein, said aryl, heteroaryl or heterocyclyl being substituted with 0 to 3 R10; or is a member selected from the group consisting of divalent radicals: -A1NHC (= O) NH-A2-, -A1NHC (= O) O-A2-, and -A1NH (NCN) NH-A2-, each selected from A1 and A2 independently of the group consisting of hydrogen, aryl, heteroaryl and heterocyclyl as defined herein, said aryl being heteroaryl > or heterocyclyl substituted with 0 to 3 R10; -B is a member selected independently from the group consisting of the following: (1.1.0) (1.1.1) (1.1.2) (1.1.6) (1.1.7) (1.1.8) (1.1.9) (1.1.10) (1.1.11) (1.1.12) (1.1.13) (1.1.14) where the symbol "*" indicates the point of union of the radical represented by each of the partial formulas (1.1.0) to (1.1.14), to the radical "Y" in the formula (1.0.0); and the symbol "->" indicates the point of union of the radical represented by each of the partial formulas (1.1.0) to (1.1.14) to the radical "E" of the formula (1.0.0); -E is a simple link; -OR-; -CH = CH-; or a radical of formula (1.9.0): R1 I C Ri- I .9.0) wherein R1a is hydrogen when R1 has the meaning of a monovalent substituent; and R1a is a single bond when R1 has the meaning of a divalent substituent; -X is -O-; -S (= O) q-; or -N (R14) -; -And it is -C (= O) -; -C (= S) -; -S (= O) 2.M i -CH (Ra) -; -m is a selected integer independently of 0, 1 and 2; -n is an integer selected independently of 1 and 2; -p is an integer selected independently of 1 and 2, with the proviso that p must be selected as 1 when B is selected as the partial formula (1.1.2), (1.1.3), (1.1.5), ( 1.1.6), (1.1.7), (1.1.8), (1.1.9), (1.1.10), (1. 1.11), (1.1.12), (1.1.13) or (1.1. 14); -q is an integer selected independently of 0 and 2; -R is independently selected from the -tetrazolyl-forming group; -C (= O) -OR5; -C (= O) (CH2) kC (= O) OR5; C (= O) NO-; -C (= O) -NH-S (= O) 2R5; -S (= 0) 2-NR14R5; -C (= O) -NHS (= O) 2R6; and a radical of the partial formula (3.0.0); (3.0.0) where: -K is an integer selected independently of 0, 1 and 2; -R1 is independently selected from the group consisting of hydrogen; = O; = S; F; C -? - C6 alkyl substituted with 0 to 3 R10; C2-C6 alkenyl substituted with 0 to 3 R10; C2-C6 alkynyl substituted with 0 to 3 R10; a C3-Cu carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; and aryl (C 4 alkyl), said aryl and alkyl being substituted with 0 to 3 R 12; heterocyclyl as defined herein, substituted with 0 to 3 R12; and heterocyclyl (C? -C alkyl) as defined herein, said heterocyclyl and alkyl being substituted with 0 to 3 R12; C (= O) NRßRa; and C (= O) Rβ; - R¿ and R? each is independently selected from the group consisting of hydrogen; C C alkyl substituted with 0 to 3 R13; C2-C6 alkenyl substituted with 0 to 3 R13; a carbocyclic ring system C3-C-? substituted with 0 to 3 R 13, (C 1 -C 4 alkoxy) carbonylamino (C 1 -C 4 alkyl); (C 1 -C 4 alkyl) thio- (d-C 4 alkyl) -; (C 1 -C 4 alkyl) sulfonyl (C 1 -C 4 alkyl) -; hydroxy (C 1 -C 4 alkyl) thio- (C 1 -C 4 alkyl) -; (C 1 -C 4 alkyl) carbonylamino (C 1 -C 4 alkyl) -; (C 1 -C 4 alkyl) sulfonylamino (C 1 -C 4 alkyl) -; (C 1 -C 4 alkyl) sulfonylaminocarbonyl (C 1 -C 4 alkyl) -; and a heterocyclic ring here is defined, substituted with 0 to 3 R13; - with the proviso that R2 and R3 are each as defined above; or they are taken together as defined below; or one of them is taken together with R4 as defined below, in which case the other has the meaning of hydrogen or methyl; -R2 and R3 are taken together to form a C3-Cu spirocyclic carbocyclic ring substituted with 0 to 3 R13; or - R2 or R3 are taken together with R4 and the carbon and nitrogen atoms to which they are respectively bonded to form a heteroaryl or heterocyclyl group as defined herein, substituted with 0 to 3 R12; -R5 is hydrogen; C1-C4 alkyl; C3-C6 cycloalkyl; or aryl; -R6 is hydrogen; C1-C4 alkyl; (CH2) r- (C3-C6 cycloalkyl); or (CH2) s-aryl; where -r and s are each independently an integer selected from 0, 1 and 2; -R8 and R9 are each independently selected from the group consisting of hydrogen; C1-C4 alkyl; substituted with 0 to 3 R10; a C3-C carbocyclic ring system substituted with 0 to 3 R12; aryl substituted with 0 to 3 R12; and aryl (C 1 -C 4 alkyl), said aryl and alkyl being substituted with 0 to 3 R 12; heterocyclyl as defined herein, substituted with 0 to 3 R12; and heterocyclyl (C 1 -C 4 alkyl) as defined herein, said heterocyclyl and alkyl being substituted with 0 to 3 R 12; -R10 is independently selected from the group consisting of F; Cl; -C (= O) OR14; -OH; nitro; cyano; Not me; di (C 1 -C 4 alkyl) amino; C -? - C4 alkyl; C4-C4 alkoxy; (C 1 -C 4 alkylthio); phenoxy; trifluoromethoxy; C3-C6 cycloalkyl; C3-C6 cycloalkoxy; (C3-C6 cycloalkoxy) carbonyl; (C 1 -C 4 alkyl) carbonylamino; (Cr C4 alkyl) sulfonylamino; (CrC4 alkyl) urea; and C 1 -C 4 alkyl and C 1 -C 4 alkoxy each substituted by 1 to 3 substituents independently selected from F and Cl; -R12 when it is a substituent on a carbon atom, is independently selected from the group consisting of F; Cl; C1-C4 alkyl; C3-C6 cycloalkyl; C1-C4 alkoxy; C (= O) OR14; -OH; C4 alkyl and alkoxy ^ -04, each substituted by 1 to 3 substituents independently selected from F and Cl; (C 1 -C 4 alkoxy) carbonyl; (C 1 -C 4 alkylcarbonyl; (alkyl C -? - C4) carbonylloxy; and a heteroaryl or heterocyclyl group as defined herein, having 5 or 6 links; or -R12 when two groups R12 are attached to adjacent carbon atoms of a carbocyclic, aryl, heteroaryl or heterocyclic ring, can be a chain of 3 or 4 carbon atoms forming a fused ring of 5 or 6 links, said ring being of 5 or 6 links optionally mono- or di-substituted on the aliphatic carbon atoms thereof by F, Cl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or hydroxy; or -R12 when R12 is attached to a saturated carbon atom, can be = O u = S; or when R12 is attached to a sulfur atom, it can be = O; -R12 when it is a substituent on a nitrogen atom, is independently selected from the group consisting of hydroxy; hydroxy (C1-C4 alkyl); C -? - C alkoxy; C3-Cβ cycloalkyl; (C 4 alkyl) carbonyl; and aryl; -R13 is independently selected from the group consisting of aryl; heteroaryl; heterocyclyl; C1-C4 alkoxy; OrCß cycloalkyl; C2-C6 alkynyl; -OR14; heterocyclyl; (C 4 alkyl) thio; -NR6R5; and -C (= O) -NR14R5; and -R14 is hydrogen; hydroxy; C1-C4 alkyl; C3-Cβ cycloalkyl; or aril.

2. The compound according to claim 1, wherein, when A is heteroaryl, it is selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1 H -indazolyl, benzimidazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and pyrazolo [1,5-c] ] triazinyl.

3. The compound according to claim 2, wherein A is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo [b] furanyl, benzimidazolyl or quinol? Nilo.j

4. The compound according to claim 3, wherein A is pyridyl.

5. The compound according to claim 1, wherein, when A is heterocyclyl, it is a member selected from the group consisting of oxirane, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, benzodioxolane and 1,3-benzodioxol-5-yl.

6. The compound according to claim 5, wherein A is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

7. The compound according to claim 1, wherein A is a divalent radical selected from the group consisting of divalent radicals: -A1 NHC (= O) NH-A2, -A1 NHC (= O) O-A2- and -A1NH (NCN) NH-A2-, each of A1 and A2 being independently selected from the group consisting of hydrogen, aryl, heteroaryl and heterocyclyl, said aryl, heteroaryl or heterocyclyl being substituted with 0 or 1 R10.

8. The compound according to claim 7, wherein A1 and A2 are both aryl or heteroaryl.

9. The compound according to claim 8, wherein said aryl is phenyl and said heteroaryl is pyridyl, each of which is independently substituted by 0 or 1 substituents R10, which is a member selected from the group consisting of , Cl, F3C-, methyl, methoxy, hydroxyl, / 'so-propyl, cyclopropyloxy and cyclopentyl.

10. The compound according to claim 9, wherein n is the integer 1, which gives rise to a methylene bridge.

The compound according to claim 10, wherein said component A and said methylene bridge attached thereto comprise a member selected from the group consisting of 4-hydroxyphenyl-; 3-methoxy-4- (N'-phenylurea) -phenylmethyl-; 4- (N'-phenylurea) -phenylmethyl-; 4- [N '- (2-methylphenyl) -urea] -phenylmethyl-; 4- [N '- (2-methoxyphenyl) -urea] -phenylmethyl-; 3-methoxy-4- [N '- (methylphenyl) -ureaj-phenylmethyl-; 4- [N '- (2-pyridyl) -urea] -phenylmethyl-; 6-methoxy-5- [N '- (2-methylphenyl) -urea] -2-pyridylmethyl-; 4- [N '- (3-methyl-2-pyridyl) -urea] -2-pyridylmethyl-; 3-methoxy-4- [N '- (3-methyl-2-pyridyl) -urea] -phenylmethyl-; 3-methoxy-4- [N, - (2-pyridyl) -urea] -phenylmethyl-; 4- [N '- (2-pyridyl) -urea] -phenylmethyl-; 4- [N '- (2-fluorophenyl) -urea] -phenylmethyl-; 4- [N '- (2-chlorophenyl) -urea] -phenylmethyl-; 4- [N '- (2-chlorophenyl) -urea] -3-methoxyphenylmethyl-; 4- [N '- (4- / so-propylphenyl) -urea] -phenylmethyl-; 6-methoxy-5- [N '- (o-toluyl) -urea] -2-pyridylmethyl-; 4- [N '- (3-cyclopentyl-2-pyridyl) -urea] -phenylmethyl-; 4- [N '- (2-cyclopentyl) -urea] -phenylmethyl-; 4- [N '- (3-cyclopropyloxy-2-pyridyl) -urea] -phenylmethyl-; and 4- [N, - (o-toluyl) -urea)] - pyrid-5-ylmethyl-.

12. The compound according to claim 9, wherein Y is -C (= O) -.

13. The compound according to claim 12, wherein B is a member selected from the group consisting of the partial formulas (1.1.2) and (1.1.6): (1.1.2) (1.1.6) where the symbol "*" and the symbol "?" they are as defined above; and where X is oxygen, sulfur or nitrogen.

14. The compound according to claim 16, wherein one of R2 and R3 is hydrogen and the other is selected from the group consisting essentially of / so-propyl, sec-butyl, / so-butyl and fer-butyl; E- and Z- / so-butenyl and E- and Z-pentenyl; cyclopentyl and cyclohexyl; cyclohexenyl and cyclopentadienyl; phenyl, indenyl and indanyl; 2- (methylthio) ethyl; 3- (hydroxypropylthio) methyl; 2- (methylsulfonyl) ethyl; 4- (acetylamino) butyl; 4- (methylsulfonylamino) butyl; and 4- (ethoxycarbonylamino) butyl.

15. The compound according to claim 13, wherein p is 1, m is 1 or 2; and E is a radical partial formula bridge (1.9.0): where R1a is hydrogen when R1 has the meaning of a monovalent substituent; and R1a is a single bond when R1 has the meaning of a divalent substituent; and wherein R1 is a member selected from the group consisting essentially of methyl; ethyl; / so-propyl; urea-butyl; 2-propenyl; 1-, 2- or 3-butenyl; ethynyl; propargyl; cyclopropyl; cyclopentyl; phenyl; phenylmethyl; phenylethyl; and heterocyclyl.

16. The compound according to claim 15, wherein R1 is independently substituted by 1 or 2 substituents R12.

17. The compound according to claim 15, wherein R1 is heterocyclyl substituted with 1 or 2 R12; or heterocyclyl (C 1 -C 4 alkyl), said heterocyclyl and alkyl being substituted with 1 or 2 R 12.

18. The compound according to claim 13, wherein R1 is 1,3-benzodioxol-5-yl; 3,4-dimethoxyphenyl; 3,4-difluorophenyl; or benzo-1,4-dioxanyl; respectively of the partial formulas (1.2.1), (1.2.2), (1.2.3) and (1.2.4): (1.2.1) (1.2.2) (1.2.3) (1.2.4)

19. The compound according to claim 13, wherein R is COOH.

20. The compound according to claim 1, wherein said compound is: 3- [2- (3-methyl-1- { 2- [4- (3-o-tolyl-ureido)] - phenyl] -acetylamino.} - butyl) -4,5-dihydro-oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1 - { 2- [4- (3. {2-fIuophenyl-phenyl} -ureido) -phenyl] -acetylamino} -butyl) -4, 5-dihydro-oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1 -. {2- [4- (3. {2-cyclopentylphenyl) -ureidyl) -phenyl] -acetylamino} -butyl) -4- acid, 5-dihydro-oxazol-5-yl] -acetic; 4- [2- (3-methyl-1 - { 2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-oxazol-5-yl] -butyric acid; 3- [2- (3-Methyl-1 - {2- [4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1 -. {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -4,5- acid dihydro-oxazol-5-yl] -propionic acid; 3- [2- (3-Methyl-1 -. {-2- [3-methyl-4- (3. {pyridin-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -4,5-dihydro-tol-5-yl] -propionic acid; 2- [2- (3-Methyl-1 -. {2- [3-fluoro-4- (3. {pyrid-2-yl} -ureido-phenyl] -acetylamino acid} - butyl) -4,5-dihydro-tol-5-yl] -acetic acid 3- [2- (3-methyl-1 -. {2- [3-methoxy-4- (3- {3-methoxypyrid-2-yl}. -ureido) -phenyl] -acetylamino.} - butyl) -1,1-dioxo-4,5-dihydro-tol-5-yl] -propionic acid; - [2- (3-methyl-1 - {2- [3-methyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino}. -butyl) -4,5-dihydro-midazol-5-yl] -propionic acid 4- [2- (3-methyl-1 -. {2- [3-fluoro-4- (3-. { 3-methylpyrid-2-yl.} -ureido) -phenyl-acetylamino.} - butyl) -4,5-dihydro-imidazol-5-yl] -butyric acid 3- [2- (3-methyl -1- {2- [3-methyl-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} -butyl) -4.5- dihydro-imidazol-5-yl] -propionic acid 2- [2- (3-methyl-1-. {2- [3-fluoro-4- (3. {3-cyclopentylpyrid-2-yl} (solid) -phenyl] -acetylamino.) - butyl) -4,5-dihydro-imidazol-5-yl] -acetic acid, 3-. {2- 2- [1 - (2- { 4- [3- (2-chloro-phenyl) -ureido] -phenyl.}. -acetylamino ) -3-methyl-butyl-tol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (2-methoxy-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -tol-5-yl} -propionic; acid 3-. { 2- [1- (2- { 4- [3- (2-fluoro-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -tol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (2,6-dichloro-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -tol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (2,6-dimethyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -tol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (2-chloro-6-methyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -tole-5- il} -propionic; 3- [2- (3-Methyl-1- {2- [4- (3-phenyl-ureido) -phenyl] -acetylamino} -butyl) -tol-5-yl] -propionic acid; N-hydroxy-3- [2- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -tole-5-yl ] -propionamide; 3- [2- (1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -but-3-enyl) -tol-5-yl] -propionic acid; 3- [2- (1- { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -tol-5-yl] -propionic acid; N-. { 1- [5- (3-methanesulfonylamino-3-oxo-propyl) -tol-2-yl] -3-methyl-butyl} -2- [4- (3-o-tolyl-ureido) -phenyl] -acetamide; 2-. { 4- [3- (2-chloro-phenyl) -ureido] -phenyl} -N- { 1- [5- (3-methanesulfonicamino-3-oxo-propyl) -tol-2-yl] -3-methyl-butyl} -acetamide; 3- [2- (. {2- 2- (4- (3-o-tolyl-ureido) -phenyl] -acetylamino} - methyl) -tol-5-yl] -propionic acid; acid 3-. { 2 - [(2- {4- [3- (2-chloro-phenyl) -ureido] -phenyl} acetylamino) -methyl] -tol-5-yl} -propionic; 3- [2- (3-Methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -4,5-dihydro-oxazole- 4-yl] -propionic; 4- [2- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-oxazol-4-yl] -butyric acid; 3- [2- (3-Methyl-1- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -actylamino} -butylH.d-dihydro-ox ^ acid zoM-yl-propionic acid 3- [2- (3-methyl-1 -. {2- 2- [3-methyl-4- (3. {pyrid-2-yl} -ureido) -phenyl ] -acetylamino.} - butyl) -4,5-dihydro-tol-4-yl] -propionic acid 3- [2- (3-methyl-1-. {2- [3-methoxy-4- (3- {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl) -1,1-dioxo-4,5-dihydro-tol-4-yl] - propionic, 3- [2- (3-methyl-1- {2- [3-methyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl acid ] -acetylamino.} - butyl) -4,5-dihydro-imidazol-4-yl] -propionic; 2- [2- (3-Methyl-1 -. {2- [3-fluoro-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -4,5-dihydro-imidazol-4-yl] -acetic; 3- [2- (3-Methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -oxazol-5-yl] -propionic, 3- [2- (3-methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazol-5-yl acid ] -propionic; 3- [2- (3-Methyl-1 - { 2- [4- (3. {2-methoxyphenyl}. -ureido) -phenyl] -acetylamino} -butyl) -oxazole -5-il] -propionic; 3- [2- (3-Methyl-1 -. {2- [4- (3 { pyrid-2-yl}. -ureido) -phenyl] -acetylamino} -butyl acid l) -oxazol-5-yl] -propionic; 4- [2- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -oxazol-5-yl] -butyric; 2- [2- (3-Methyl-1 -. {-2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazole-5- acid il] -acetic; acid 3-. { 2- (3-methyl-1 - { 2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazol-5-yl] -propionic; 3- [2- (3-Methyl-1 -. {-2- [3-methoxy-4- (3. {pyrid-2-yl} -ureido-phenyl] -acetylamino acid} - butyl) -thiazol-5-yl] -propionic acid 3- [2- (3-methyl-1- {2 - [3-methyl-4- (3. {3-methoxypyrid-2-yl} .}. -.-solid) -phenyl] -acetylamino.] - butyl) -1,1-dioxo-thiazol-5-yl] -propionic acid, 4- [2- (3-methyl-1-. {2 - [3-fluoro-4- (3- ({3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} - butyl) -thiazol-5-yl] -butyric acid; - [2- (3-methyl-1 - { 2- [3-methoxy-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl-acetylamino}. butyl) -imidazol-5-yl-propionic acid 3- [2- (3-methyl-1 -. {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino.} - butyl) -imidazol-5-yl] -propionic acid 3- [2- (3-methyl-1. {2- [3-methoxy-4 - (3- {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylmaine} - butyl) -imidazol-5-yl] -proponic acid 3- [2- ( 3-methyl-1- {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} -butyl) -imidazole -5-il] -propioni co; 3- [2- (3-methyl-1 - acid. { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -oxazol-4-yl] -propionic; 4- [2- (3-Methy1-1- { 2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylmaine}. -butyl) -oxazol-4-yl] -butyric acid; 3- [2- (3-Methyl-1 -. {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -oxazole-4- acid il] -propionic; 3- [2- (3-Methyl-1 -. {2- [3-methyl-4- (3-. {pyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -thiazol-4-yl] -propionic; 3- [2- (3-Methyl-1 -. {-2- [3-methoxy-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1, 1-dioxo-thiazol-4-yl] -propionic; 3- [2- (3-Methyl-1 -. {-2- [3-methyl-4- (3. {3-methy1-pyrid-2-yl} -ureido) -phenyl] - acid acetylamino.} - butyl) -imidazol-4-yl] -propionic acid; 2- [2- (3-Methyl-1- {2- [3-fluoro-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazol-4-yl] -acetic; 3- [3- (3-Methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -4,5-dhydro- Soxazol-5-yl] -propionic; 3- [3- (3-Methyl-1- {2- [4- (3- {2-fluorophenyl} -ureido} -phenyl] -acetylamino} -butyl) - acid 4,5-dihydro-isoxazol-5-yl] -propionic acid 2- [3- (3-methyl-1 - { 2- [4- (3. {2-cyclopentylphenyl} -ureido ) -phenyl] -acetylamino.} - butyl) -4,5-dihydro-isoxazol-5-yl] -acetic acid, 4- [3- (3-methyl-1- { 2- [4- ( 3- ({3-methylpyrid-2-yl} -ureido) -phenyl] -acetylmaino] -butyl) -4,5-dihydro-isoxazol-5-yl] -butyric acid 3- [3- ( 3-methyl-1 - {2- [4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} -butyl) -4.5 -dihydro-isoxazol-5-yl] -propionic acid 3- [3- (3-methyl-1 -. {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] ] -acetylamino.} - butyl) -4,5-dihydro-isoxazol-5-yl] -propionic acid 3- [3- (3-methyl-1- { 2- [4- (3-o -tolyl-ureido) -phenyl] -acetylamino.} - butyl) -4,5-dihydro-pyraz-1-l] -propionic acid 3- [3- (3-methyl-1-. {2 - [4- (3. {2-methoxyphenyl} -ureido) -phenyl] -acetylamino} - butyl) -4,5-d-hydroxy-pyrolol-1-yl] -propionic acid; 3- [3- (3-methyl-1 -. {2 - [4- (3- { Pyrid-2-il} -ureido) -phenyl] -acetylamino} -butyl) -4,5-dihydro-pyrazol-1-yl-propionic acid; 4- [3- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -4,5-dihydro-pyrazol-1-yl] -butyric acid; 2- [3- (3-Methyl-1- {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl-4,5-dihydro acid -pyrazol-1-yl] -acetic acid, 3- [3- (3-methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino]} -butyl) -4,5-dihydro-pyrazol-1-yl]; 3- [3- (3-methyl-1- {2 - [3-methoxy-4- (3-. pyrid-2-yl.}. -ureido) -phenyl] -acetylamino.} - butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid, 4- [3- (3-methyl-1 - { 2- [3-fluoro-4- (3. {3-methoxy-pyrid-2-yl}. -ureido) -phenyl] -acetylamino} -butyl) -4, 5-dihydro-pyrazol-1-yl] -butyric acidXaZ ; 3- [3- (3-Methyl-1 - [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} - butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1 - {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl] - acid acetylamino, butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1 -. {-2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] - acid acetylamino.} - butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; acid 3-. { 3- (3-methyl-1 -. {2- [3-trylfuoromethyl-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino}. -butyl) -4,5-dihydro-pyrazol-1-yl] -propionic acid; 3- [3- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl] -isole-5- acid il] -propionic; 3- [3- (3-Methyl-1 - { 2- [4- (3. {2-fluorophenyl} -ureidyl) -phenyl] -acetylamino} -butyl) -isole- 5-l] -propionic; 2- [3- (3-Methyl-1 - { 2- [4- (3. {2-cyclopentylphenyl} -ureido) -phenyl] -acetylamino} -butyl) -isole- 5-yl] -acetic; 4- [3- (3-methyl-1 - { 2- [4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -isol-5-yl] -butyric acid; 3- [3- (3-Methyl-1- {2- [4- (3. {3-cyclopentylpyr-2-yl} -ureido) -phenyl] -acetylamino} acid; butyl) -isol-5-yl] -propionic acid; 3- [3- (3-Methyl-1 -. {-2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) - Sol-5-yl] -propionic; acid 3-. { 3- [3-methyl-1 - (2- {4- [3- (4-methyl-pyridin-3-yl) -ureido] -phenyl} - acetylamino} - butyl) -isole- 5-yl] -propionic; 3- [3- (3-Methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -isol-5-yl] -acrylic acid; acid 3-. { 3- [1 - (2- {4- [3- (2-chloro-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -sole-5 -il} -propionic; 3-ethyl ester. { 3- [1- (2- { 4- [3- (2-chloro-phenyl) -ureido) -phenyl} -acetylamino) -3-methyl-butii] -isol-5-yl} -3-oxo-propionic; 3- [3- (3-Methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -pyrazol-1-yl] -prop acid Ionic; 3- [3- (3-Methyl-1- {2- [4- (3. {2-methoxyphenyl} -ureido) -phenyl] -acetylamino} -butyl) -pyrazol- acid 1-yl] -propionic; 3- [3- (3-Methyl-1 - { 2- [4- (3 { pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl) - pyrazol-1-yl-propionic; 4- [3- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -pyrazol-1-yl] -butyric; 2- [3- (3-Methyl-1 -. {-2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -pyrazol-1-acid il] -acetic; 3- [3- (3-Methyl-1- {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -pyrazol-1- acid il]; 3- [3- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamine acid} -butil) -pyrazol-1-yl] -propionic; 4- [3- (3-Methyl-1. {2 - [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -pyrazol-1-yl] -butyric acid; 3- [3- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -pyrazol-1-yl-propionic; 3- [3- (3-Methyl-1 - { 2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -pyrazol-1-yl-propionic; 3- [3- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] - acid acetylamino.} - butyl) -pyrazol-1-yl-propionic acid; 3- [3- (3-Methyl-1 -. {-2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl-acetylamino acid .} - butyl) -pyrazol-1-yl-propionic acid; 3- [4- (3-methyl-1- { 2- [4- (3-o-tolyl-ureido) -phenyl-acetylamino} -butyl) -ol-2-yl] -propionic acid; 3- [4- (3-methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -ol-2-yl] -propionic acid; 3- [4- (3-Methyl-1- {2- [4- (3. {2-methoxyphenyl} -ureido) -phenyl] -acetylamino} -butyl) -ole- 2-ilj-prop¡ón¡co; 3- [4- (3-Methyl-1- {2- [4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl) acid ol-2-yl] -propionic; 4- [4- (3-Methyl-1- {2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl acid ) -ol-2-yl] -butyric acid; 2- [4- (3-Methyl-1 -. {-2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -ole-2- acid ilj-acetic; 3- [4- (3-Methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -ole-2- acid il] -propionic; 3- [4- (3-Methyl-1- {2- [3-methoxy] -4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino acid} .butyl) -thiazol-2-yl] -propionic; 3- [4- (3-Methyl-1- {2- [3-methyl-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl-acetylamino acid} -butyl) -1, 1-dioxo-thiazol-2-yl] -propionic; 4- [4- (3-Methyl-1. {2 - [3-fluoro-4- (3. {3-methoxy-pyrid-2-yl} -ureido) -phenyl] - acetylamino] -butyl) -thiazol-2-yl] -butyric acid; 3- [4- (3-Methyl-1 -. {-2- [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl-acetylamino acid} -butyl) -imidazol-2-yl] -propionic acid; 3- [4- (3-Methyl-1 - { 2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] - acetylamino.} - butyl) -imidazol-2-yl] -proponic acid; 3- [4- (3-methyl-1 - { 2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl-acetylamino acid .} - butyl) -imidazol-2-yl-propionic acid; 3- [4- (3-Methyl-1- {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} acid .}. -butyl) -imidazol-2-yl] -propionic acid; 3- [4- (3-Methyl-1 - {2 [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -imidazol-2-yl] -propionic acid 3- [4- (3-methyl-1- {2- [4- (3-. {2-methoxyphenyl} -ureido) -phenyl] -acetylamino} -butyl) -imidazole-1 -ilj-propionic; 3- [4- (3-methyl-1 -. {2- [4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl) acid imidazol-1-yl-propionic; 4- [4- (3-Methyl-1 - { 2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -imidazol-1-yl] -butyric acid; 2- [4- (3-Methyl-1 -. {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -imidazole-1 - acid ilj-acetic; 3- [4- (3-Methyl-1- {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -imidazole-1- acid il]; 3- [4- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -imidazol-1-yl-propionic acid; 4- [4- (3-Methyl-1 -. {2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazol-1-yl] -butyric; 3- [4- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -imidazole-1-yl-propionic acid; 3- [4- (3-Methyl-1 - {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butil) -imidazol-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [3-methoxy] -4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid .} - butyl) -imidazol-1-yl-propionic acid; 3- [4- (3-Methyl-1 - { 2- [3-trifluoromethyl-4- (3. {3-cyclopentyl-pyrid-2-yl}. -ureido) -phenyl acid ] -acetylamino.} -butyl) -midazol-1-yl-propionic acid; 3- [3- (3-methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl-acetylamino} -butyl) -1,2,4-oxadiazole-5 acid -il] -propionic; 3- [3- (3-Methyl-1- {2- [4- (3. {2-fluorophenyl} -ureido) -phenyl] -acetylamino} -butyl) -1 acid, 2,4-oxadiazol-5-yl-propionic acid; 2- [3- (3-Methyl-1 - { 2- [4- (3. {2-cyclopentylphenyl} -ureido) -phenyl-acetylamino} -butyl) -1, 2 acid , 4-oxadiazol-5-yl] -acetic; 4- [3- (3-Methyl-1- {2- [4- (3. {3-methylpyrid-2-yl} -uredodo) -phenyl] -acetylamino} acid. -butyl) -1, 2,4-oxadiazol-5-yl] -butyric acid; 3- [3- (3-Methyl-1 - { 2- [4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino} acid. -butyl) -1, 2,4-oxadiazol-5-yl] -propionic; 3- [3- (3-Methyl-1- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -4,5- 1, 2,4-oxadiazol-5-yl] -propionic acid; 3- [4- (3-Methyl-1 -. {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -1 H-1, 2,4 acid -triazol-1-yl-propionic; 3- [4- (3-Methyl-1 - { 2- [4- (3. {2-methoxyphenyl}. -ureido) -phenyl] -acetylamino} -butyl) -1 H acid -1, 2,4-triazol-1-yl-propionic; 3- [4- (3-methyl-1 -. {2- [4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl) acid 1 H-1, 2,4-triazol-1-yl-propionic; 4- [4- (3-Methyl-1 - { 2- [4- (3. {3-methoxypyrid-2-yl}. -ureido) -phenyl-acetylamino} -butyl) -1 H-1, 2,4-triazol-1-yl] -butyric; 2- [4- (3-Methyl-1- {2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -1 H-1 acid , 2,4-triazol-1-yl] -acetic; 3- [4- (3-methyl-1 -. {2- [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyl) -1 H-1 acid , 2,4-triazol-1-yl]; 3- [4- (3-Methyl-1 -. {2- [3-methoxy-4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -1 H-1, 2,4-triazol-1-yl-propionic acid; 4- [4- (3-Methyl-1 - { 2- [3-fluoro-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butl) -1 H-1, 2,4-triazol-1-yl] -butyric; 3- [4- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,4-triazol-1-yl] -propionic; 3- [4- (3-Methyl-1 - {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetic acid lamino.}. -butyl) -1 H-1, 2,3,4-triazol-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-triazol-1 -yl] - propionic; 3- [4- (3-Methyl-1- {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-triazoM-yl-propionic; 3- [4- (3-methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -1 H-1, 2,3 acid , 4-tetrazoM-yl] -propionic; 3- [4- (3-Methyl-1 - { 2- [4- (3. {2-methoxyphenyl}. -ureido) -phenyl] -acetylamino} -butyl) -1 H acid -1, 2,3,4-tetrazol-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino} -butyl) acid 1 H-1, 2,3,4-tetrazol-1-yl-propionic acid; 4- [4- (3-Methyl-1 - { 2- [4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -, acetylamino} - butyl) -1 H-1, 2,3,4-tretrazol-1-yl] -butyric acid; 2- [4- (3-Methyl-1 - { 2- [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -1 H-1 acid , 2,3,4-tetrazol-1-yl] -acetic; 3- [4- (3-methyl-1 -. {2- [3-fIuoro-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -1 H-1 acid , 2,3,4-tetrazol-1-yl]; 3- [4- (3-Methyl-1 -. {-2- [3-methoxy-4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetylamino} acid. -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 4- [4- (3-Methyl-1. {2 - [3-fluoro-4- (3. {3-methoxypyrid-2-yl}. -ureido) -phenyl] - acetylamino.} - butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -butyric acid; 3- [4- (3-Methyl-1 - { 2- [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butiI) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 3- [4- (3-Methyl-1 - {2- [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-tetrazoI-1-yl] -propionic; 3- [4- (3-Methyl-1- {2- [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl} -ureido) -phenyl acid] -acetylamino.} - butyl) -1 H-1, 2,3,4-tetrazoM -yl] -propionic; 3- [4- (3-Methyl-1 -. {2- [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl] -ureide) -phenyl] -acetylamino acid} -butyl) -1 H-1, 2,3,4-tetrazol-1-yl] -propionic; 3- (3-α-Butyl-2-oxo-4- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1-yl) -propionic acid; 3- (3-α-Butyl-2-oxo-4. {[[4- (3. {2-methoxyphenyl} -ureido) -phenyl] -acetyl} -piperazin-1 acid -il) -propionic; 3- (3-Isobutyl-2-oxo-4-. {[[4- (3 { pyrid-2-yl} -ureido) -phenyl] -acetyl} -p. perazin-1-yl) -propionic; 4- (3-Iso-butyl-2-oxo-4-. {[[4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetyl}. piperazin-1-yl) -butyric; 2- (3-Isobutyl-2-oxo-4-. {[3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1-yl) -acetic; 3- (3-Isobutyl-2-oxo-4- { [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1 - il) -propionic; 3- (3-α-Butyl-2-oxo-4- { [3-methoxy-4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetyl} -piperazin-1-yl) -propionic acid; 4- (3-Isobutyl-2-oxo-4- { [3-fluoro-4- (3-. {3-methoxypyrid-2-yl}. -ureido) -phenyl] -acetyl .} - piperazin-1-yl) -butyric; 3- (3-Iso-butyl-2-oxo-4- { [3-methoxy-4- (3. {3-methylpyrid-2-yl} -ureido) -phenyl] -acetyl .}. -piperazin-1-yl) -propionic; 3- (3-Isobutyl-2-oxo-4- { [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl] -acetyl .}. -piperazin-1-yl) -propionic acid; 3- (3-Isobutyl-2-oxo-4- { [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl.) -uredo] -phenyl] -acetyl amino) -piperazin-1-yl) -propionic; 3- (3-Isobutyl-2-oxo-4- { [3-trifluoromethyl-4- (3-. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetyl .}. -piperazin-1-yl) -propionic; 3- (3-Isobutyl-6-oxo-4- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - piperazin-1-yl) -propionic acid; 3- (3-Iso-butyl-6-oxo-4- { [4- (3. {2-methoxyphenyl}. -ureido) -phenyl] -acetyl} -piperazine-1 - il) -propionic; 3- (3-Isobutyl-6-oxo-4- { [4- (3 { pyrid-2-yl} -ureido) -phenyl] -acetyl} -piperazine- 1 -yl) -propionic; 4- (3-Isobutyl-6-oxo-4. {[[4- (3. {3-methoxypyrid-2-yl} -ureido) -phenyl] -acetyl} - piperazin-1-yl) -butyric; 2- (3-Isobutyl-6-oxo-4- { [3-methyl-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1-yl) -acetic; 3- (3-Iso-butyI-6-oxo-4- { [3-fluoro-4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperazin-1-yl) -propionic; 3- (3-α-Butyl-6-oxo-4- { [3-methoxy-4- (3. {pyrid-2-yl} -ureido) -phenyl] -acetyl} -piperazin-1-yl) -propionic; 4- (3-α-Butyl-6-oxo-4- { [3-fluoro-4- (3. {3-methoxypyrid-2-yl}. -ureido) -phenyl] - acetyl.}. - p.perazin-1-yl) -butyric; 3- (3-Isobutyl-6-oxo-4- { [3-methoxy-4- (3. {3-methy1-pyrid-2-yl.) -uret) -phenyl ester ] -acetyl} -piperazin-1-yl) -propionic; 3- (3-Isobutyl-6-oxo-4- { [3-cyclopentyl-4- (3. {3-methylpyrid-2-yl}. -ureido) -phenyl] -acetyl} .}. -piperazin-1-yl) -propionic; 3- (3-Iso-butyl-6-oxo-4- { [3-methoxy-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetylamino acid .}. -piperazin-1-yl) -propionic; 3- (3-iso-butyl-6-oxo-4- { [3-trifluoromethyl-4- (3. {3-cyclopentylpyrid-2-yl}. -ureido) -phenyl] -acetyl .}. -piperazin-1 -yl) -propir nico; acid 3-. { 2- [1- (2- { 4- [3- (2-chloro-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (2,6-dichloro-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (2-fluoro-phenyl) -ureido] -phenyl} -acetylamino) -3-methyl-butyl] -thiazole-5- il} -propionic; 3- [2- (1- { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -3-methyl-butyl) -thiazol-5-yl] -propionic acid; acid 3-. { 2- [1 - (2- {4- [3- (2-dimethyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (2-chloro-6-methyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazole-5- il} -propionic; acid 3-. { 2- [1- (2- { 4- [3- (2-methoxy-phenyl) -ureido] -phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- [3- (phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -propionic; acid 3-. { 2- [1 - (2- {4- (3-o-toyl-ureido) -phenyl-acetylamino} -3-butenyl) -thiazol-5-yl] -propionic acid; acid 3-. { 2- [1 - (2- {4- [3- (2-methyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -prop-2-enoic; acid 3-. { 2- [1- (2- { 4- [3- (2-methyl-phenyl) -ureido] -phenyl} - acetylamino) -3-methyl-butyl] -thiazol-5-yl} -1-Hydroximino-propionic; acid 3-. { 2- [1 - (2- {4- [3- (2-methyl-phenyl) -ureido] -phenyl} - acetylamino) -n-butyl] -thiazol-5-yl} -propionic; 3-. { 2- [1- (2- { 4- [3- (2-methyl-phenyl) -ureidoj-phenyl] -acetylamino) -3-methyl-butyl] -thiazol-5-yl} -1-methylsulfonyl-propionamide; 3- [3- (3-Methyl-1 -. {2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino] -butyI) -isoxazole-5-Ionic acid ethyl ester ] -2-oxo-propionic; 3- [3- (3-methyl-1 - { 2- [4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -butyl) -isoxazol-5-yl] -prop acid -2-enoic; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5-yl] -propionic acid; 3- [2- (5-methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -thiazol-5-yl] acid] -propionic; 3- [2- (5,5-Dimethyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5- acid il] -propionic; arid 3- [2- (3-methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -thiazol-5-yl] -propionic; 3- [2- (3,3-Dimethyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5- acid il] -propionic; 3- [2- (4-Methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5 acid -l] -propionic; 3- [2- (4-hydroxy-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] -propionic; 3- [2- (4-Hydroxy-4-methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl} - thiazol-5-yl] -propionic; 3- [2- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - azepan-2-yl) -thiazol-5-yl] -propionic acid; 3- [2- (4-Oxo-1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] -propionic; 3- [2- (4-amino-1 - { [4- (3-o-toyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazole-5 acid -il] -propionic; 3- [2- (4-methylamino-1 - { [4- (3-o-tolyI-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -thiazol-5-yl] -propionic; 3- [2- (4- (ethyl-methyl-amino) -1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) - thiazol-5-yl-propionic; 3- [2- (2-methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -thiazol-5-yl] acid] -propionic; 3- [2- (3. {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -oxazolidin-4-yl) -thiazol-5-yl] -propionic acid; 3- (3'- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -2 ', 3', 4 ', 5'-tetrahydro- [2,4'] acid ] -thiazolyl-5-l3-propionic acid 3- [2- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1, 2,3,6 -tetrahydro-pyridin-2-yl) -thiazol-5-yl] -propionic acid 3- [2- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl .}. -piperidin-2-yl) -thiazole-5-yl] -propionic acid 3- [2- (2 { [4- (3-o-tolyl-ureido) - phenyl] -acetyl} -1, 2,3,4-tetrahydro-isoquinolin-3-yl) -thiazol-5-yl] -propionic acid 3- [2- (1 - { [4- ( 3-o-tolyl-ureido) -phenyl] -acetyl} - azetidin-2-yl) -thiazol-5-yl] -propionic acid 3- [2- (1 - { [4- (3 -o-tolyl-ureido) -phenyl] -acetyl} - azetidin-2-yl) -oxazol-5-yl] -propionic acid 3- [2- (1 - { [4- (3- o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazol-5-yl] -propionic acid 3- [2- (1- { [4- (3-o -tolyl-ureido) -phenyl] -acetyl}. -azepar-2-yl) -oxazol-5-yl] -propionic acid 3- [2- (5-methyl-1 - { [4- ( 3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazol-5-yl] -propionic acid; 3- [2- (5,5-Dimethyl-1-. { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl-propionic acid; 3- [2- (3-Methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] -propionic; 3- [2- (3,3-Dimethyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazole-5- acid il] -propionic; 3- [2- (4-methyl-1 - { [4- (3-o-tolii-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (4-Hydroxy-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazol-5-yl] -propionic; 3- [2- (4-Hydroxy-4-methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazole- 5-yl] -propionic; 3- [2- (4-Oxo-1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] acid] -propionic; 3- [2- (4-amino-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazol-5-yl] -propionic; 3- [2- (4-Methylamino-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -oxazol-5-yl] -propionic; 3- [2- (4- (ethyl-methyl-amino) -1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) - oxazol-5-yl] -propionic; 3- [2- (2-methyl-1 - { [4- (3-o-tolyl-uredo) -phenyl] -acetyl} -pyrrolidin-2-yl) -oxazole-5- acid il] -propionic; 3- [2- (3. {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -oxazolidin-4-yl) -oxazol-5-yl] -propionic acid; 3- [2- (3. {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -thiazolidin-4-yl) -oxazol-5-yl] -propionic acid; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1-, 2,3,6-tetrahydro-pyridin-2-yl) - acid oxazol-5-yl] -propionic; 3- [2- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperidin-2-yl) -oxazol-5-yl] -propionic acid; 3- [2- (2- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1-, 2,3,4-tetrahydro-isoquinolin-3-yl) acid oxazol-5-yl] -propionic; 3- [3- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (5-Methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl-acetyl} - pyrrolidin-2-yl) -isoxazol-5-yl] - acid pror, ionic; 3- [3- (5,5-dimethyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole-5- acid il] -propionic; 3- [3- (1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - azepan-2-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (3-methyl-1- {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole- 5-yl] -propionic; 3- [3- (3,3-dimethyl] -1- { [4- (3-o-tolyl-uredo) -phenyl] -acetyl} -pyrrolidin-2-acid; l) -isoxazol-5-yl] -propionic; 3- [3- (4-methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} - pyrrolidin-2-yl) -isoxazol-5-yl] -proponic; 3- [3- (4-hydroxy-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazole-5- acid il] -proponic; 3- [3- (4-hydroxy-4-methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -isoxazol-2-yl) -t azol-5-yl] -propionic; 3- [3- (4-Oxo-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] -propionic; 3- [3- (4-amino-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] -propionic; 3- [3- (4-methylamino-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-y) -isoxazole-5 acid -il] -propionic; 3- [3- (4- (ethyl-methyl-amino) -1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl acid ) -isoxazol-5-yl] -propionic; 3- [3- (2-methyl-1 - { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] -propionic; 3- [3- (3. {[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -oxazolidin-4-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (3. {[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -thiazolidin-4-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1-, 2,3,6-tetrahydro-pyridin-2-yl acid ) -isoxazol-5-yl] -propionic; 3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -piperidin-2-yl) -isoxazol-5-yl] -propionic acid; 3- [3- (2- { [4- (3-o-tolyl-ureido) -phenyl] -acetyl} -1-, 2,3,4-tetrahydro-isoquinolin-3-yl) - acid isoxazol-5-yl] -propionic; and 3- [3- (1-. {[[4- (3-o-tolyl-ureido) -phenyl] -acetyl} -azetidin-2-yl) -soxazole-5-yl] -propionic acid.

21. A pharmaceutical composition comprising a compound of formula (1.0.0) as defined in claim 1, together with a pharmaceutically acceptable carrier for said compound, the amount of said compound being effective to prevent, inhibit, suppress or reduce cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4.

22. The pharmaceutical composition according to claim 21, further comprising one or more therapeutic agents.

23. - The pharmaceutical composition according to claim 22, wherein said one or more therapeutic agent (s) is selected from the group consisting essentially of anti-inflammatory cosicosteroids; non-steroidal anti-inflammatory agents; bronchodilators, antiasthmatic agents; immunosuppressive agents; Immunostimulates; antimetabolites; antipsoriatics; and antidiabetics.

24. The pharmaceutical composition according to claim 23, wherein said therapeutic agent is a member selected from the group consisting essentially of theophylline, sulfasalazine, aminosalicylates; ciclosporin, FK-506, rapamycin, clofosfamide, methotrexate and interferons.

25. The use of a compound of formula (1.0.0) as defined in claim 1, or a pharmaceutical composition as defined in claim 21 for the manufacture of a medicament for treating or preventing an inflammatory disease, autoimmune or respiratory, inhibiting cell adhesion and pathogenic processes > consequently or associated subsequently mediated by VLA-4 in a mammal.

26. The use as claimed in claim 25, wherein said inflammatory, autoimmune or respiratory disease is a member selected from the group consisting essentially of asthma, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis , rejection of the host after organ transplantation, atherosclerosis and other diseases induced by or associated with VLA-4. SUMMARY OF THE INVENTION Compounds of formula (1.0.0) are disclosed wherein A is, for example, aryl, heteroaryl or heterocyclyl, Y is preferably -C (= O) -; B is independently selected from a group of radicals, the most preferred of which being those of the partial formulas (1.1.2) and (1.1.6): and E is a simple link; oxygen; 1,1-cyclopropyl; C (CH3) 2; CF2; or a bridging radical of partial formula (1.9.0): R1 I - c - R1. (1.9.0) wherein R1a is hydrogen when R1 has the meaning of a monovalent substituent; and R1a is a single bond when R1 has the meaning of a divalent substituent; said compounds are useful in methods for treating or preventing an inflammatory, autoimmune or respiratory disease by inhibiting cell adhesion and the consequent or associated pathogenic processes subsequently mediated by prolactin-4. - c go PFIZER / All * P00 / 1618F