MXPA02006599A

MXPA02006599A - Nonpeptidyl inhibitors of vla4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases

Info

Publication number: MXPA02006599A
Application number: MXPA/A/2002/006599A
Authority: MX
Inventors: Allen Jacob Duplantier; Anthony John Milici; Louis Stanley Chupak; Wan Fang Lau
Original assignee: Pfizer Products Inc
Priority date: 1999-12-28
Filing date: 2002-06-28
Publication date: 2003-02-07

Abstract

There is disclosed a genus of nonpeptidyl compounds, wherein said compounds are VLA4 inhibitors useful in treating inflammatory, autoimmune, and respiratory diseases, and wherein said compounds comprise a compound of formula (1.0.0) and pharmaceutically acceptable salts and other prodrug derivatives thereof.

Description

NON-PEPTIDE INHIBITORS OF THE CELLULAR UNION DEPENDENT OF VLA-4 USEFUL IN THE TREATMENT OF INFLAMMATORY, AUTOIMMUNE AND RESPIRATORY DISEASES REFERENCE TO PATENT REQUESTS IN PROCESSING TOGETHER WITH THE PRESENT Reference is made herein to the co-pending U.S. patent application. Serial No. 09/403846 (agent's file No. PC10112B), filed on October 26, 1999, which is a continuation of the US document. Serial No. 09/338832 (agent's file No. PC10112A), filed on June 23, 1999, which is a continuation of the US provisional application. Serial No. 60/091180 (file of Agent No. PC10112) filed on June 30, 1998, and currently abandoned; and reference is also made to the corresponding international application PCT / IB99 / 00973 (file of agent No. PC10112A PCT), filed on May 31, 1999, and published as WO 00/00477 on January 6, 2000. The present invention it refers to compounds that are non-peptidic in structure and are active as potent inhibitors of very late antigen 4 binding (VLA-4, a4ß ?, CD49d / CD29) to proteins such as the vascular cell adhesion molecule 1 (VCA - 1), the Hepll / llICS domain (CS-1 region) of fibronectin and osteopontin. As such they are useful in iti-íinüt inhibition of cell adhesion and consequent or associated pathogenic processes subsequently 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 asthma.

BACKGROUND OF THE INVENTION One of the most fundamental processes necessary for the normal defense of the host is the regulated circulation of leukocytes outside the vasculature. This system is designed to allow the normal recirculation of leukocytes, although because it allows a rapid extravasation of leukocytes to wound sites, it is one of the central pathogenic mechanisms of inflammatory, respiratory and autoimmune diseases in mammals. Cell adhesion is a key factor in this process and is particularly relevant for the present invention with respect 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, called integrins, which are non-covalent heterodimer complexes consisting of a subunit a and a β subunit (Hemler, Ann. Rev. Immunol., 8, p. 365, 1990). Eighteen different subunits have been identified and marked as a-ia-io. CCL. OCM, ax, ao, CXLRI, dine, av and OCE; while eight different β subunits have been identified and marked as β-rßß- Each integrin molecule can be categorized within a subfamily based on the type of its subunits a and β. The integrin a β- ?, VLA-4, is an integrin that constitutively expresses all leukocytes (eg, monocytes, lymphocytes, basophils, eosinophils, mast cells and macrophages) except polymorphonuclear leukocytes. The binding of this integrin to one of its ligands has a series of known cell adhesion and activation 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); for the alternatively spliced and spliced forms of the extracellular matrix protein fibronectin (FN) containing the CS-1 domain (Ruegg et al., J. Cell Biol., 117 pp. 179, 1991; Wayner et al, J. Cell. Biol., 105, pp. 1873, 1987, Kramer et al., J. Biol. Chem., 264, pp. 4684, 1989, Gehlsen et al., Science, 24, pp. 1228, 1988) and for the protein of extracellular matrix osteopontin (Bayless, K.l. et al., J. Cell Science, 111, p. 1165-1174, 1998). The importance of cell adhesion interactions of VLA-4 has been established by the use of monoclonal antibody (mAb) antagonists specific to the α-subunit of VLA-4, which have been shown to inhibit VLA-dependent cell adhesion -4 prevent or inhibit numerous pathological inflammatory, respiratory and autoimmune ailments (Chisholm, et al., Eur. J. Immunol., 23, p.682, 1993; Lobb et al., J. Clin. Invest., 94, p. 1722, 1994; Richards et al., Am. J. Respir. Cell. Mol. Biol., 15, p. 172, 1996; Soiluhanninen et al., J. Neuroimmunol., 72, p. 95, 1997; Sagara et al., Int. Arch. Allergy Immunol., 112, p. 287, 1997; Fryer et al., J. Clin. Invest., 99, p. 2036, 1997). In addition, confirmation has been observed that these pathological processes can be inhibited with agents other than antibodies in animal models following treatment with a synthetic CS-1 peptide or a peptide inhibitor of small molecule VLA-4 (Ferguson et al. , Proc. Nati, Acad. Sci., 88, p.8072, 1991; Wahl et al., J. Clin. Invest., 94, p.655, 1994; Molossi et al., J. Clin. Invest., 95, pp. 2601, 1995; Abraham et al., Am. J. Respir. Crit. Care Med., 156, pp. 696, 1997; Jackson et al., J. Med. Chem., 40, pp. 3359 , 1997). - 3.0 Description of the state of the art The investigation of mAb antagonists and VLA-4 peptide antagonists in the art has already been indicated above. By defining the binding site for αβ, it has been observed that lymphoid cells can bind to two different sites in fibronectin (Bernardi et al., J. Cell Biol., 105, p 489, 1987). A component of this cell binding activity has been previously identified as the tripeptide Arg-Gly-Asp (RGD), which binds to the integrin a5β-? (VLA5). Subsequently, the minimum amino acid sequence required to bind and antagonize the activity of VLA-4 on leukocytes at the alternately cut and spliced site on fibronectin was determined (Humphries et al., J. Biol. Chem., 266, p.6886 , 1987; García-Pardo et al., J. Immunol., 144, pp. 3361, 1990; Komoriya et al., J. Biol. Chem., 266, pp. 15075, 1991). It has been discovered that the binding domain of VLA-4 to the CS-1 region of fibronectin (FN) comprises the octapeptide: Glu-lle-Leu-Asp-Val-Pro-Ser-Thr, as well as two pentapeptides that are superponene: Glu-lle-Leu-Asp-Val and Leu-Asp-Val-Pro-Ser. All these peptides inhibit FN-dependent cell adhesion, leading to a first conclusion that the minimum amino acid sequence required for inhibition would be Leu-Asp-Val (LDV). In fact, the minimal inhibitory sequence LDV has been 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., 116, p. 489, 1992). It is believed that various integrins bind to extracellular matrix proteins at the Arg-Gly-Asp recognition site (RGD). Cyclic peptides based on RGD have been prepared that appear to inhibit both the binding of a4β? like that of asßi to FN (Nowlin et al., J. Biol. Chem., 268, page 20352, 1993, PCT / US91 / 04862), even though the primary recognition in FN for c ßi is LDV. The cyclic peptide can be represented by the formula (0.0.1): Arg- Cys- Asp- TPro- Cys (0.0.1) in which TPro indicates 4-thioproline. Other peptide inhibitors of VLA-4 are those referred to in Arrhenius et al., "CS-1 Peptidomimetics", WO 95/15973, which is assigned to Cytel Corporation and is related to the two US patents. indicated below. A representative compound of the type described is the peptide of formula (0.0.2): N-phenylacetyl-Leu-Asp-Phe-NCy3 (0.0.2) in which NCy3 is selected from, among others, morpholinamido, thiomorpholinemido, 4- (thiadioxo) piperidinamido and D-2- (carboxamide) pyrrolidinamido, piperidinamido and piperidinamido replaced. WO 95/15973 ... US 5821231 ... US 5936065 ... Cytel Corporation More works by Arrhenius et al., Involving cyclic CS-1 peptidomimetics are disclosed in WO 96/06108 assigned to Cytel Corporation, which is related to U.S. Pat. indicated below. WO 96/06108 ... US 5869448 ... Cytel Corporation The Arrhenius group has also discovered non-peptide inhibitors of VLA-4-dependent cell binding, as described in He et al., WO 98/42656. The inhibitors described therein are of the general formula (0.0.3): (0.0.3) A typical inhibitor is represented by the formula (0.0.4) WO 98/42656 ... Cytel Corporation The tripeptide Leu-Asp-Val has been used as the nucleus of a group of VLA-4-dependent cell adhesion inhibitors described in Adams et al., WO 96/22966, which is assigned to Biogen, Inc. These inhibitors can be represented by the formula (0.0.5): (0.0.5) wherein R1 may be 4- (N '- (2-methylphenyl) urea) phenylmethyl, Y may be C = O, R2 may be H, R3 may be isobutyl, and R14 may be 1, 3 -benzodioxol-5-yl. An example of a typical inhibitor of this type is that of formula (0.0.6): WO 96/22966 ... Biogen, Inc. The Adams group has also discovered semi-peptide cell adhesion inhibitors for the treatment of inflammatory and autoimmune diseases, described in Lin et al., WO 97/03094.

These inhibitors can be represented by the formula (0.0.7): Z- (Y1) - (Y2) - (Y3) nX (0.0.7) wherein 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. A typical inhibitor of this type is shown in the formula (0.0.8) WO 97/03094 ... Biogen, Inc. The Adams group has also stated, in Zheng et al., WO 98/04247, the discovery that existing integrin inhibitor compounds llb / llla they can be converted into VLA-4 inhibitory compounds, and that the llb / IIIa inhibitor compounds can be prepared by combining a unique VLA-4 integrin structure with a determinant of llb / Illa specificity. These cell adhesion inhibitors can be considered to comprise a compound of the formula: AB, A comprising a determinant of specificity of VLA-4 that does not provide significant integrin inhibitory activity llb / llla, and B is an integrin structure derived from an inhibitor of llb / llla. A three-dimensional pharmacophoric model of the compound with VLA-4 activity is also described. The compounds of formula (0.0.9) and (0.0.10) are representative of the inhibitors thus derived: (0.0.10) WO 98/04247 ... Biogen, Inc. See also Singh et al., WO 98/04913, which relates to a three-dimensional pharmacophoric model of a compound with VLA-4 inhibitory activity, comprising characteristics defined in a tolerance table and the three dimensional coordinates x, y and z. The following compound, representative of the referred ones, can be represented by the formula (0.0.11): WO 98/04913 ... Biogen, Inc. Another type of VLA-4 dependent cell adhesion inhibitor is that described in Head et al., "Antiinflammatory Tyrosine Deivatives", WO 98/54207, which may be represented by formula (0.0.12): ) n (0.0.12) wherein R1 is an optionally substituted alkyl or aromatic group, X2 is -C (= O) -, -C (= O) 0-, -C (= O) NH- or -S (= O) 2-, and R7 is an optionally substituted alkyl or aryl group. A typical compound of this type of inhibitors can be represented by the formula (0.0.13): (0.0.13) WO 98/54207 ... Celltech Therapeutics Ltd. The Head group has also discovered a related group of VLA-4 dependent cell adhesion inhibitors, described in Head et al., "Phenylalanine Derivatives Useful As Pharmaceutical Agents ", WO 99/37618, which are of general formula (0.0.14): (0.0.14) where L is an atom or linker group, A is a chain - [C (R7) (R8)] pY- [C (R9) (R10)] q-, and L2 is a group of crimp selected from - C (= 0) -, -C (= 0) 0-, -S (= 0) -, -S (= 0) 2 or -C (= 0) N (R11) -. An example of this type of inhibitor is the compound of formula (0.0.15): (0.0.15) WO 99/35163 ... Celltech Therapeutics, Ltd. Another closely related group of VLA-4 inhibitors discovered by the Head group is described in Head et al., "Novel Phenylalanine Deivatives Useful as Integrin Antagonists ", WO document 99/37618, which is characterized by the general formula (0.0.16): (0.0.16) A representative example of these inhibitory compounds is that of formula (0.0.17): (0.0.17) WO 99/37618 ... Celltech Therapeutics, Ltd. Yet another group of related compounds discovered by the group of Head that are inhibitors of VLA-4 dependent cell adhesion is described in Head et al., " Phenylalanine Derivatives As Inhibitors of Alpha4 Integrins ", WO 99/43642, and can be characterized by the general formula (0.0.18): (0.0.18) Inhibitors of the type described are illustrated by the formula (0.0.19): (0.0.19) WO 99/43642 ... Celltech Therapeutics, Ltd. Previous work has also been done in the discovery of VLA-4 dependent cell adhesion by Plesii and Thorsett and their collaborators, for example, as described in Thorsett et al. to the., "Inhibitors of Leukocyte Adhesion", WO 96/01544, assigned to Athena Neurosciences, Inc. These inhibitors comprise inhibitors that block cell adhesion mediated by VLA-4 and are used to treat a number of inflammatory diseases, especially cerebral inflammatory diseases. Non-peptide inhibitors, ie, small VLA-4 inhibitory molecules have also been discovered by the Pleiss and Thorsett group, for example as described in Thorsett "Carbamoyloxy Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4", WO document 99/06390, assigned to Athena Neurosciences, Inc. Inhibitors of this type can be represented by the general formula (0.0.20): (0.0.20) wherein R 1 is alkyl, aryl, cycloalkyl, heterocyclyl or heteroaryl, all of which being optionally substituted; R2 is defined similarly to R1 and may be combined with this and the moiety -S (= 0) 2- to form an optionally substituted heterocyclic group; R3 is defined similarly to R1 and is optionally taken with the nitrogen atom attached to R2 and the carbon atom attached to R3 to form an optionally substituted heterocyclyl group; R7 is -H or alkyl, Ar is aryl or optionally substituted heteroaryl; and R5 is -0-Z-NR8R8 or -OZ-R12, wherein Z is -C (= 0) - or -S (= 0) 2, R8 and R8 are -H or optionally substituted alkyl, cycloalkyl or heterocyclyl , or R8 and R8 can be joined to form an optionally substituted heterocycle, and R12 is an optionally substituted heterocycle. A representative example of the above-described VLA-4 inhibitors is the compound of formula (0.0.21): (0.0.21) WO 99/06390 ... Athena Neurosciences, Inc. In Yednock and Pleiss, "Alpha-9 IntegrinAntagonists and Anti-inflammatory Compositions thereof", WO 99/06391 assigned to Athena Neurosciences, the use of the inhibitory compounds of the document is described. WO 99/06390 cited above in ailment treatment procedures involving the binding of a-9 integrin, particularly the adhesion of macrophages or neutrophils.The conditions that are indicated as susceptible to treatment include hyperresponsiveness and airway occlusion, which appear together with chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular occlusion following angioplasty, fibrosis and glomerular scarring as a result of renal disease, aortic stenosis, hypertrophy of the synovial membranes in rheumatoid arthritis and inflammation and scarring that appear with progression of ulcerative colitis and Crohn's disease, Thorset's group ty Pleiss has discovered a group of inhibitors of VLA-4 that is described in Thorsett et al., "Substituted Phenylalanine Type Compounds Which Inhibit Leukocye Adhesion Mediated by VLA-4", WO 99/06431, assigned to Athena Neurosciences, Inc. American Home Products Corporation, which can be represented by the general formula (0.0.22): (0.0.22) wherein R, R2, R3, R7 and Ar have substantially the same meaning as described above with respect to WO 99/06390; and R5 is an optionally substituted member selected from the group consisting of -NHC (= 0) R, alkoxyaryl, aryl, heteroaryl, -NRR ', alkoxy-NRR', alkenyl, alkynyl, aryloxy, heteroaryloxy, alkoxyheterocyclyl, O-heterocyclyl, tetrazolyl , -NRS (= 0) 2-alkyl, alkenylsulfonylamino, alkynylsulfonylamino, alkoxy, amidine, -C (= 0) NRR ', -NRC (= 0) R', -S (= 0) 2-aryl, S (= 0) 2-heteroaryl, -NRC (= 0) NRR ', -NRC (= 0) OR', aminocarbonyl- (N-formylheterocyclyl) and alkyl-C = 0) NH-heterocyclyl. A compound illustrating the type of inhibitors of VLA-4 described is that of formula (0.0.23): WO 99/06431 ... Athena Neurosciences, Inc. A group of related inhibitor compounds is disclosed which has also been discovered by the group of Thorsett and Pleiss in Thorsett et al., "Dipeptide and Related Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4", WO 99/06432 assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by the general formula (0.0.24): (0.0.24) wherein R1, R2, R3 and R7 have substantially the same meaning as described above with respect to WO 99/06390 and WO 99/06431, and R5 is -ALQ-X or = CH-Y, where X is defined and Y to mean a wide variety of groups, all of which are optionally substituted. An example of this type of VLA-4 inhibitor is the compound of formula (0.025): (0.0.25) WO 99/06432 ... Athena Neurosciences, Inc. Another group of related VLA-4 inhibitor compounds that has also been discovered by the Thorsett and Pleiss group is described in Dappen et al, "Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA -4", WO 99/06433, assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by the general formula (0.0.26): (0.0.26) wherein R1, R2, R3 and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431 and WO 99/06432; and X is -H, -OH, acylamino, -C (= 0) OH and alkyl, alkoxy, aryl, aryloxy, aryloxyaryl, carboxyalkyl, carboxycycloalkyl, carboxiaryl, carboxyhearyaryl, carboxyheterocyclyl or optionally substituted cycloalkyl. The type of VLA-4 inhibitor described in the immediately preceding paragraph can be represented by the compound of formula (0.0.27): WO 99/06433 ... Athena Neurosciences, Inc. Yet another group of related VLA-4 inhibitory compounds that has been discovered by the Thorsett and Pleiss group is described in Ashwell et al., "4-Amino-Phenylalanine Type Compounds. Which? Inhibit Leukocyte Adhesion Mediated by VLA-4", WO 99/06434 assigned to Athena Neurosciences, Inc. and American Home Products Corporation The inhibitor compounds of this type are characterized by the general formula (0.0.28): (0.0.28) ) wherein R1, R2, R3 and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431, WO 99/06432 and WO 99/06433; and R is -H, alkyl or aryl; X is O, S or NR; and Y is NRR 'or heterocycle, and all of them are optionally substituted with a wide variety of groups. This other type of VLA-4 inhibitor can be illustrated by the compound of formula (0.0.29): (0.0.29) WO 99/06434 ... Athena Neurosciences, Inc. Another group of VLA-4 inhibitors structurally related to the groups of VLA-4 inhibitors described above, which has been discovered by the Thorsett and Pleiss group , is described in Thorsett et al., "Dipeptide Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4", WO 99/06435 assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by the general formula (0.0.30): (0.0.30) wherein R1, R2, R3 and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433 and WO 99/06434; R5 has substantially the same meaning as described above with respect to WO 99/06432; and R 4 is -H, and optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; and R1 and R2 can be taken together, or R2 and R3 can be taken together, or R3 and R4 can be taken together to form cycloalkyl or heterocyclyl groups. This type of VLA-4 inhibitor can be illustrated by the compound of formula (0.0.31): WO 99/06435 ... Athena Neurosciences, Inc. Yet another structurally related group of inhibitors of cell adhesion dependent on VLA-4, which has been discovered by the group of Thosett and Pleiss, is described in Thorsett et al. "Benzyl Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4", WO 99/06436, assigned to Athena Neurosciences, Inc. and to American Home Products Corporation. The inhibitory compounds of this type are characterized by the general formula (0.0.32): (0.0.32) wherein R1, R2, R3 and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433 and WO 99/06434; and Ar is aryl or heteroaryl. This type of VLA-4 inhibitor can be illustrated by the compound of formula (0.0.33): (0.0.33) WO 99/06436 ... Athena Neurosciences, Inc. There is another description of compounds that are structurally related to those described above in WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433. , WO 99/06434, WO 99/06435 and WO 99/06436, but which are distinguished from them by multiple provisos, which are described in Thorsett et al., "Sulfonylated Dipeptide Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4", WO 99/06437. Three of said inhibitory compounds are those of formulas (0.0.34) or (0.0.36). (0.0.34) (0.0.35) (0.0.36) WO 99/06437 ... Athena Neurosciences, Inc. The group of Stilz and Wehner has discovered a different class of compounds that possess inhibitory activity with respect to cell adhesion mediated by VLA-4. These inhibitory compounds are described, for example, in Stilz et al., "5-Ring Heterocycles As Inhibitors of Leukocyte.

Adhesion and As VLA-4 Antagonists ", document EP 842943 assigned to Hoechst AG, which can be characterized by the general formula (0.0.37): (0.0.37) wherein R is 4-aminophenyl, 4-guanidinophenyl, 4-aminomethylphenyl, 3-aminopropyl or 3-guanidinopropyl; R1 is methyl or benzyl; R2 is -H, methyl, ethyl, optionally substituted benzyl or naphthylmethyl; R3 is a mono-, di- or tripeptide; R 4 is -H, methyl or butyl; and R5 is -H, alkyl, cycloalkyl or optionally substituted aryl. A representative compound that falls within the scope of the aforementioned class of VLA-4 inhibitors is that of formula (0.0.38): EP 842 943 ... Hoechst AG group Stilz and Wehner has also discovered inhibitory compounds which are structurally similar to those described in the aforementioned document EP 20 842 943, and described in Stilz et al., "Heterocycles As Inhibitors of Leukocyte Adhesion and As Antagonists of VLA-4", EP 842944. These compounds can be characterized by the general formula (0.0.39): ** "* •" - - general formula (0.0.39): (0.0.39) wherein R4 is methyl or 4-R3-phenyl, and R3 is 4,5-dihydroimidazol-2-yl or -C (= 0) NH2; R2 is phenyl, pyridyl or optionally substituted naphthyl; and R 4 is -H, ethyl, n-butyl or isobutyl. A representative example of this type of inhibitor compound is that of formula (0.0.40): EP 842944 ... Hoechst AG.

Other inhibitory compounds structurally similar to those of the previously described document EP 842944, are described in Stilz et al., EP 842945, which may be characterized by the general formula (0.0.41): (0.0.41) wherein R is 4-R2-phenyl, and R2 is -CN, -N02, -NH2C (= 0) NH optionally substituted or -NH2C (= 0) NHCH2; and R2 is optionally substituted phenyl. A representative example of this type of inhibitor compound is that of the formula (0.0.42): (0.0.42) EP 842945 ... Hoechst AG The Stilz and Wehner group has also discovered VLA-4-dependent cell adhesion inhibitors that are described in Wehner et al., "Imidazolidine Derivatives with VLA-4 Antagonist Activity Useful for the Treatment of Diseases Mediated by Leukocyte Adhesion", EP document 903353, assigned to Hoechst Marión Roussel Deutschland GmBH. Compounds of this type are characterized by the general formula (0.0.43): 0 M-R5 I R4 X-N ^ XR1 (0.0.43) wherein A is an alkenylene, phenylene, phenylalkylene or alkylenephenyl- optionally substituted; L and M are a bond or -CH2-; X is - CH (R7) - or -C (= CHR7) - optionally substituted, where R7 is an alkyl, phenyl, optionally substituted furyl, thienyl, pyrrolyl, indazolyl or pyridinyl; R1 is -H, optionally substituted cycloalkyl, alkyl, aryl or heterocyclyl, -C (= 0) R6 or -S02R6, where R6 is -H, cycloalkyl, alkyl, aryl or heterocyclyl optionally substituted; R2 is -NH2, -C (= 0) NH2 or -C (= 0) OH; R3 is -H, alkyl, optionally substituted aryl or heterocyclyl; and R5 is -C (= 0) OH, tetrazolyl, -S03 H or -S02NH2.

A typical VLA-4 inhibitor that falls within the class of The above-described compound is illustrated by the formula (0.0.44): EP 903353 ... Hoechst Marion Roussel Deutschland GmbH Another group of inhibitory compounds closely related to the structure of those previously described, has been discovered by the group of Stilz and Wehner and is described in Wehner et al. "Substituted Imidazolidie Derivatives with VLA-4 Antagonist Activity", EP 918059. The aforementioned group can be illustrated by the general formula (0.0.45): (0.0.45) where R is methyl or phenyl, R1 is tert-butyl, propyl, isopropyl, benzyl, or phenyl ciciohexilo optionally substituted, R3 is adamantyl, -CH (CH3) CH2C (C = 0) OH, - CH (phenyl) CH2C (= 0) OH or -CH (phenyl) CH2C (= 0) OH optionally substituted; R4 is -H or isobutyl. An example of a compound illustrating class of VLA-4 inhibitors is that of formula (0.0.46): EP 918059 ... Hoechst Marion Roussel Deutschland GmbH. Yet another class of VLA-4 inhibitors has been discovered by the Chan group, for example as described in Chen et al., "Novel B-Aroulphenylalanine Derivatives As Integrin Antagonists", WO99 / 10312 assigned to F. Hoffman- La Roche AG. This class of inhibitors can be illustrated by the general formulas (0.0.47) and (0.0.48): There are two subclasses of compounds based on different A rings as shown above. In addition, rings A and B can be replaced by various heterocycle, although an ortho-substituted ring B is preferred. A representative example of compound that falls within this class of inhibitors is that of formula (0.0.49): (0.0.49) WO 99/10312 ... F. Hoffman-La Roche AG. A closely related group of inhibitors discovered by the Chen group is described in Chen et al., WO 99/10313 assigned to F. Hoffman-La Roche AG, which can be illustrated by the general formulas (0.0.50) and (0.0 .51): (0.0.50) (0.0.51) There are two subclasses of compounds as described above in the case of formulas (0.0.47) and (0.0.48). In addition, the three R groups attached to the amide linker combine to form a quaternary center. A typical compound representative of VLA-4 inhibitors of this class is that of formula (0.0.52): (0.0.52) WO 99/10313 ... F. Hoffaman-La Roche AG. Another class of inhibitors of cell adhesion dependent on VLA-4 is that discovered by Hagmann et al., As described in Durette and Hagmann, "Heterocyclic Amide Compounds as Cell Adhesion Inhibitors ", WO 98/53814, which was granted to Merck &Co., Inc.

This kind of compound can be illustrated by the general formula (0.0.53): (0.0.53) wherein X is -C (= 0) OH or acid isostere, and is -C (= 0) or -S (= 0) 2; from R1 to R8 are selected from a wide variety of well-known substituents; and A, B and Z are selected so as to provide heterocycles of different ring types and sizes. An example of an inhibitor compound that is representative of this class is that of formula (0.0.54): (0.0.54) WO 99/53814 ... Merck & Co., Inc. Another class of structurally related inhibitory compounds discovered by the Hagmann group is described in Durette et al., "Biarylalkanoic Acids As Cell Adhesion Inhibitors", WO 98/53817 assigned to Merck & Co., which can be illustrated by the general formulas (0.0.55) and (0.0.56): (0.0.55) (0.0.56) wherein X, Y and from R1 to R7 have substantially the same meaning as defined above for the formula (0.0.53), except that R2 and R3 can be taken together with the atoms to which they are attached to form a ring of 4 to 7 members containing 0-2 additional heteroatoms selected from O, S and N; and R b is optionally substituted alkyl, alkenyl, alkynyl, arylalkyl or heteroarylalkyl. A representative example of compound that falls within the scope of this class of VLA-4 inhibitors is that of formula (0.057): (0.0.57) WO 98/53817 .... Merck & Co., Inc. Another class of inhibitory compounds discovered by the Hagmann group, and closely related in structure to those described immediately above, is described in Durette et al., "Sulfonamides As Cell Adhesion Inhibitors", WO 98 / 53818 assigned to Merck & Co., Inc. These compounds can be illustrated by the general formulas (0.0.57) and (0.0.58): Amino Amino acid 1 acid 2 (0.0.57) (0.0.58) In which Rb and R1 to R7 have the same meaning as defined above for formulas (0.0.55) and (0.0.56). A representative inhibitory compound that falls within the class described above is that of formula (0.0.59): (0.0.59) WO 98/53818 ... Merck & Co., Inc. Yet another class of VLA-4 inhibitory compounds structurally related to those described above has been discovered by Hagmann's group and is described in Delaszlo, "Azapeptide.

Acids As Cell Adhesion Inhibitors ", WO 99/20272. This class of inhibitors can be illustrated by the general formula (0.0.60): (0.0.60) where m and n are from 0 to 2, and X, Y and from R1 to R6 have the same meaning as defined above for formulas (0.0.55) and (0.0.56). The representative inhibitory compounds that fall within the class described above are those of formulas (0.0.61) and (0.0.62): (0.0.61) (0.0.62) WO 99/20272 ... Merck & Co., Inc. Another class of inhibitors of VLA-4-dependent cell adhesion discovered by the Hagmann group is described in Delaszlo and Hagmann, "4-Substituted-4-Piperidine Carboxamide Derivatives Useful in the Treatment of Asthma, Inflammation and Multiple Sclerosis ", WO 99/25685, assigned to Merck & Co., Inc. Compounds of this class can be illustrated by the general formula (0.063): (0.0.63) wherein X is a bond or a substituted carbon atom; Z is -C (= 0) OH or acid isostere, L is -C (= 0) -, -S (= 0) 2-; and from R1 to R5 have substantially the same meaning as defined above for formulas (0.0.55) and (0.0.56). A typical inhibitor compound of VLA-4 of this class is that of formula (0.0.64): (0.0.64) WO 99/25685 ... Merck & Co., Inc. Another class of VLA-4 inhibitors closely related in structure to those described above is described in Chang e4t al. "Cyclic AminoAcids As Cell Adhesion Inhibitors", WO 99/26615 assigned to Merck & Co., Inc. Inhibitory compounds of this class are illustrated by the general formula (0.0.65): (0.0.65) where R indicates ring size and X, Y and R1a R7 have the same meaning as defined above for formulas (0.0.55) and (0.0.56). A representative example of an inhibitor compound of this class is that of formula (0.0.66): WO 99/26615 ... Merck & Co., Inc. A class of VLA-4 dependent cell adhesion inhibitors has been discovered which differs from those described in WO 98/53814 described above only with respect to the terminal amino acid, which is a β-amino acid. Accordingly, reference can be made to the general formula (0.0.53) above. These β-amino acids are described in Durette et al., "Substituted β-Alanine Derivatives As Cell Adhesion Inhibitors", WO 99/26921, assigned to Merck & Co., Inc.

The inhibitors (0.0.67) and (0.0.68): (0.0.67) (0.0.68) WO 99/26921 ... Merck & Co., Inc. Yet another class of VLA-4 dependent cell adhesion inhibitors structurally related to those described above has been discovered by the Hagmann group and is described in Chang et al., "Substituted Pyrrole Deivates As Cell Adhesion Inhibitors. ", WO 99/26922, assigned to Merck 6 Co., Inc. This class of inhibitors is illustrated by the general formula (0.0.69): (0.0.69) where Y and from R1 to R7 have the same meaning as defined above for formulas (0.0.55) and (0.0.56), and X and Z have the same meaning as defined above for the formula (0.0.63), except that the meanings are inverted because -XZ- in (0.0.63) have been changed to -AX- in (0.0.69). An example of an inhibitor compound that falls within this class is illustrated by the formula (0.0.70): (0.0.70) WO 99/26922 ... Merck & Co., Inc. Another class of VLA-4 inhibitor compounds discovered by the Hagmann group, and closely related to the foregoing, is that described in Delaszlo and Hagmann, "Para-Adminomethylaryl Carboxamide Derivatives", WO 99/26923, assigned to Merck & Co., Inc., and that can be represented by the general formula (0.0.71): (0.0.71) wherein L, X Z and from R1 to R6 have substantially the same meaning as defined above for formulas (0.0.55) and (0.0.56). Ar is a substituted aryl or heteroaryl residue 1.4. A typical compound that falls within the scope of this class of VLA-4 inhibitors is illustrated by the formula (0.0.72): (0.0.72) WO 99/2623 ... Merck & Co., Inc. A different group has discovered a new class of VLA-4 antagonists which is described in Wattanasin and von Matt, "VLA-4 Antagonists", WO 99/37605, assigned to Novartis. The inhibitory compounds of this new class can be represented by the general formula (0.0.73): (0.0.73) where Y is -C (= 0) -, -S (= 0) 2- or -P (= 0) 2-; Z is - (CH2) n-, - CHR- or -NR-; W is -CH- or -N-; X is -C (= 0) OH or acid isostero; and from R1 to R4 are a wide variety of customary substituents. A representative example of VLA-4 inhibitor of this class is illustrated by the formula (0.0.74): WO 99/37605 ... Novartis • * -'- • »& '* - • * • - < ..

Another different group has discovered the other new class of compounds that inhibit VLA-4-dependent cell adhesion, which is described in Astles et al., "Substituted Anilides and Theri Use in the Treatment of Various Disease States including inflammation, arthritis and atherosclerosis. ", WO 99/23063, assigned to Rhone-Poulenc Rorer Ltd. This class of VLA-4 inhibitors can be represented by the general formula (0.0.75): (0.0.75) wherein X1, X2 and X3 are -N- or -CR-; Ar1 is aryl or heteroaryl; L2 is an optionally substituted alkylene linkage; Y is carboxy, an acid bioisostere or -C (= 0) NRR; and R1 is -H, halo, -OH, lower alkyl or lower alkoxy. A representative example of an inhibitor compound that falls within this class is illustrated by the formula (0.0.76): (0.0.76) WO 99/23063 ... Rhone-Poulenc Rorer Ltd. Another class of VLA-4 inhibitors, which is closely related in structure to those described immediately above, is described in Artles et al., " Biaryl ß-Alanine Derivatives Useful As VLA-4 Antagonists ", WO 99/33789, assigned to Rhone-Poulenc Rorer Ltd. The members of this class of inhibitors can be represented by the general formula (0.0.77): (0.0.77) in which X1, X2 and Y have the same meaning as defined previously for the formula (0.0.75). R 4 is aryl or heteroaryl or optionally substituted alkyl, alkenyl or alkynyl. A representative example of an inhibitor compound within this class is illustrated by the formula (0.0.78): (0.0.78) WO 99/33789 ... Rhone-Poulenc Rorer Ltd. Another different group has also discovered a new class of VLA-4 dependent cell adhesion inhibitors, which is described in Lobl et al., "Cyclic Peptide Inhibitors of ß-i and ß2 Integrin-Mediated Adhesion ", WO 96/40781, assigned to Tanabe Seiyaku Co., Ltd. Inhibitors are cyclic peptides containing a free acid. WO 96/40781 ... Tanabe Seiyaku Co., Ltd. Another class of VLA-4 inhibitors discovered by the same group is described in Lobl et al., "Inhibitors of a? ß4 Meidated Cell Adhesion", WO 98 / 58902, assigned to Tanabe Seiyaku Co., Ltd. and Pharmacia & Upjohn Company. The members of this other class of VLA-4 inhibitors can be represented by the general formula (0.0.79): (0.0.79) wherein R1 is acid or amide; X is phenyl and Z is amide or methylene ether. A representative example of an inhibitor compound of this class is that of formula (0.0.80): (0.0.80) WO 98/58902 ... Tanabe Seiyaku Co., Ltd. Another class of VLA-4 inhibitors discovered by the same group is described in Sircar et al., "Inhibitors of a4 Mediated Cell Adhesion", WO 99/36396, sold to Tanabe Seiyaku Co., Ltd. Members of this class of VLA-4 inhibitors can be characterized by the general formula (0.0.81): (0.0.81) in which from R1 to R6, except R4, are selected from a wide variety of common substituent groups; R4 is acid, acid isosteroid or amide; A is aryl or heteroaryl; Q is a bond, -C (= 0) - or substituted alkylene; n is from 0 to 2; and W is -O-, -S-, -CH = CH- or -N = CH-. A representative member of this class of VLA-4 inhibitors is illustrated by the formula (0.0.82): (0.0.82) WO 99/36393 ... Tanabe Seiyaku Co., Ltd.

Another different group has also discovered a new class of VLA-4 dependent cell adhesion inhibitors, which are described in Kogan et al., "Process to Inhibit Binding of the Integrin alpah 4 beta 1 to VCAM-1 or Fibronectin", WO 96/00581, assigned to Texas Biotechnology Corporation. This class of VLA-4 antagonists comprises cyclic peptides of 5 to 13 residues modeled according to a portion of the peptide CS1, which also contains a free acid. WO 96/00581 ... Texas Biotechnology Corporation Yet another different group has also discovered a new class of VLA-4 antagonists, which is described in Dutta, "Fibronectine.

Adhesion Inhibitors ", WO 95/20216 assigned to Zeneca Limited This class of VLA-4 inhibitors comprises cyclic peptides containing a free acid.

WO 96/00581 ... Zeneca Limited A related class of VLA-4 antagonists disclosed by the same group in Dutta, "Cyclic Tetrapeptide Diemrs Useful As Fibronectin Inhibitors", is disclosed, WO 97/02289, assigned to Zeneca Limited. This class of VLA-4 antagonists comprises cyclic dimeric peptides in which a peptide 1 and a peptide 2, which independently represent a tetrapeptide, are juxtaposed in parallel or antiparallel orientation by means of two binding residues L1 and L2. WO 97/02289 Zeneca Limited Another related class of VLA-4 antagonists discovered by the same group is described in Dutta, "Cyclic Octapeptide Derivatives That Are Integrin Antagonists", WO 97/49731, assigned to Zeneca Limited. This class of VLA-4 antagonists comprises a series of cyclic octapeptides containing a free acid. WO 97/49731 ... Zeneca Limited The same group has also discovered a non-peptide class of VLA-4 antagonists that is described in Brittain and Johnstone, "Chemical Compunds ", WO 99/24398, assigned to Zeneca Limited Members of this class can be represented by the general formula (0.0.83) where Y is -O-, -S-, or -S (= 0) 2-; R1 is urea; R11 is acid or acid isostere; and m is 0 or 1 and when m is 0, then n is 1 a, and when m is 1, then n is 0. A representative member of this class of VLA-4 antagonists is illustrated by the formula (0.0.84). ): (0.0.84) WO 99/24398 ... Zeneca Limited None of the references discussed above describes or suggests the compounds of the present invention. Despite the advances in the art described above with respect to inhibitors of cell adhesion mediated by VLA-4, one skilled in the art will readily recognize that peptide inhibitors tend to low absorption and low absorption and low solubility and they are subject to metabolism in vivo (both systemically and locally when administered directly to the lung), reducing their chance of appreciably affecting the course of an inflammatory, respiratory or autoimmune disease. Those of the above-described VLA-4 antagonists which are non-peptidic, ie, which can be considered as small molecules, can therefore avoid the tendencies of the peptide agents as discussed above. However, for the small molecule VLA-4 antagonists known in the art, as described in detail above, it has not yet been established that they possess sufficiently high levels of the desired potency with low levels of acceptable side effects, together with adequately manageable pharmacokinetic and absorption profiles, such as those that would enable such compounds to become suitable therapeutic agents for use in the treatment of the diseases and conditions discussed herein. Accordingly, there is still a need in the art for non-peptidic or semi-peptide therapeutic agents that can effectively treat or prevent such pathological conditions.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compositions that inhibit VLA-4 dependent cell adhesion in a mammal. The present invention therefore relates to a compound of formula (1.0.0): (1.0.0) and to salts and other pharmaceutically acceptable prodrugs thereof, wherein: -A is (Ci-Cß) alkyl, cycloalkyl , aryl, heteroaryl or heterocyclyl as defined above; said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with 0 to 3 R9; or is a member selected from the group consisting of the following radicals: A1-NHC (= 0) NH-A2-, A1-NHC (= 0) 0-A2-, A1-OC (= 0) NH-A2-, A1 -NHS02NH-A2-, A1-NHC (= 0) -A2-, A1-C (= 0) NH-A2-, A1-NHS02-A2-, A1-S02NH-A2-, A1- (CH2) rA2- , A1-CH (R1) -0-A2-, A1- (CH2) rO-A2-, A1-0- (CH2) rA2-, A1-0- (CH2) rNH-A2-, A1-NH (CH2 ) rA2- and A1- (CH2) rS (= 0) q-A2-, A1 and A2 each being independently selected from the group consisting of hydrogen, aryl, alkyl (Ci-Cß), alkenyl (C2-Cß), alkynyl (C2-Cß), cycloalkyl, heteroaryl and heterocyclyl; said aryl, alkyl, cycloalkyl, heteroaryl or heterocyclyl group being substituted with 0 to 3 R9; -B is a member selected independently of the group constituted by the following: (1.1.18) (1.1.19) (1.1.20) (1.1.23) in which the symbol "*" indicates the point of union of the rest represented for each partial formula (1.1.0) to (1.1.23) to the rest "CR2R3" of the formula (1.0.0), and the symbol "- >" indicates the point of union of the rest represented by each partial formula ( 1.1.0) to (1.1.23) to the remainder "E" of the formula (1.0.0). Each of the formulas (1.1.0) to (1.1.23), with the exception of the formulas (1.1.10), (1.1.17) and (1.1.23), may optionally be substituted with R9; -E is a single bond, -O-, NR10-, -CH = CH-, -C = C-, -S (= 0) q, -CR11R12NR10-, or -CR11R12-; -X is -O-, -C (= 0) -, -S (= 0) q- or -NR10-; -X1, X2 and X3 are each independently selected from the group consisting of CH, CR9 or N; -And it is a simple link, -C (= 0) -, -C (= S) - or -S (= 0) 2-; -k is an integer selected independently of 0, 1 and 2; -m is an integer selected independently of 0 and i: -n is an integer selected independently of 0, 1 and 2; -p is an integer selected independently of 0 and 1, with the proviso that p must be selected as 1 when B is selected as the partial formula (1.1.0) to (1.1.11); -q is an integer selected independently of 0, 1 and 2; -r is an integer selected independently of 0, 1 and 2; -R1 is (C-1-C3) alkyl substituted with 0 or 1 F, CF3, OCF3 or cyano groups; R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl (CrC6) substituted with 0 to 3 R13, alkenyl (C2-C6) substituted with 0 to 3 R13, a carbocyclic ring system (C3-C14) substituted with 0 to 3 R13, a heterocyclic ring as defined herein substituted with 0 to 3 R13, alkyl (C6) -OR5 substituted with 0 to 3 R13, alkyl (C6) -SR5 substituted with 0 to 3 R13, alkyl (C? -C6) -S02R5 substituted with 0 to 3 R13, a heteroaryl ring as defined herein substituted with 0 to 3 R13, an aryl ring as defined herein substituted with 0 to 3 R13; -conditional that- R2 and R3 are as defined above, or 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 cycloalkyl or heterocyclyl 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 attached to form a heteroaryl group or Hexycyclyl, as defined herein, substituted with 0 to 3 R13; -R4 is hydrogen or (C? -C6) alkyl optionally substituted with R13, or R4 may be taken together with R2 or R3 to form a carbocyclic or heterocyclic ring; -R5 and R6 are independently hydrogen, alkyl (CrCß), alkenyl (C2-C6), alkynyl (C2-C6), CF3, aryl, cycloalkyl, heteroaryl or heterocyclyl, said alkyl, alkenyl alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclyl substituted with 0 to 3 R13; -R7 is alkyl (C6), (CH2) kOR5, (CH2) kC (= 0) R5, (CH2) kC (= 0) NR6R5, (CH2) kNR6C (= 0) R5, (CH2) kNR6C (= 0) OR5, (CH2) kNR6S02R5, (CH2) kNR6R5, F. CF3, OCF3, aryl substituted with 0 to 3 R9, heterocyclyl substituted with 0 to 3 R9, heteroaryl substituted with 0 to 3 R9, cycloalkyl substituted with 0 to 3 R9, or R7 it can be taken together with R8 to form a cycloalkyl or heterocyclyl ring, or R7 can be taken together with R11 to form a cycloalkyl or heterocyclyl ring; -R8 is hydrogen, F, CN, (C6) alkyl or (C6C6) alkoxy: -R9 is halogen, (Ci-C3) alkyl, (Ci-C3) alkoxy, (C3-C6) cycloalkyl, cycloalkoxy (C3-C6), cyano, (CH2) kOH, C (= 0) R5, (CH2) kC (0) NR5R6, (CH2) kNR5R6, (CH2) kNR5S02R6, CF3, OCF3, S02NR5R6, (CH2) mC ( = 0) OR5; when R9 is attached to a saturated carbon atom, R9 can be = 0 or = S; when R9 is attached to a sulfur atom, R9 can be = 0; -R10 is hydrogen, C (= 0) R5, C (= 0) OR5, alkyl (C Ce), aryl, heterocyclyl, heteroaryl, cycloalkyl or SO2R5; -R11 and R12 are independently hydrogen, (C -Cß) alkyl, hydroxy, cyano, alkoxy (CrCe). NR6C (= 0) R5, NR6S02R5, NR6R5, CF3, F, aryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkoxy; or R11 can be taken together with R12 to form a cycloalkyl or heterocyclyl ring; -R13 is independently selected from the group consisting of halogen, CF3, alkyl (CrCß), aryl, heteroaryl, heterocyclyl, hydroxy, cyano, alkoxy (CrCß), cycloalkyl (C3-C6), cycloalkoxy (C3-C6), alkynyl (C2) -C6), alkenyl (C2-C6), -NR6R5, -C (= 0) NR5R6, S02R5, hydroxy, cyano, (C6) alkoxy. NR6C (= 0) R5, NR6S02R5, NR6R5, CF3, F, aryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkoxy; or R11 can be taken together with R12 to form a cycloalkyl or heterocyclyl ring; -R13 is independently selected from the group consisting of halogen, CF3, alkyl (CrCß), aryl, heteroaryl, heterocyclyl, hydroxy, cyano, alkoxy (CrCß), cycloalkyl (C3-C6), cycloalkoxy (C3-C6), alkynyl (C2) -C6), alkenyl (C2-C6), -NR6R5, -C (= 0) NR5R6, S02R5. The present invention also relates to pharmaceutical compositions comprising one or more of the compounds of the present invention, as described above, together with a pharmaceutically acceptable carrier of the aforementioned compound (s), the amount being present of the aforementioned compound (s) effective to prevent, inhibit, suppress or reduce cell adhesion and the consequent or associated pathogenic processes subsequently mediated by VLA-4. The present invention also relates to pharmaceutical compositions which, in addition to containing a compound of the present invention, 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 inflammatory, autoimmune or respiratory diseases by inhibiting cell adhesion and the consequent or associated pathological processes subsequently mediated by VLA-4, which comprises administering to a mammal in need of said 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 of an organ transplant, atherosclerosis and other diseases mediated by or associated with VLA-4.

DETAILED DESCRIPTION OF THE IVNENTION The present invention relates to compounds that inhibit cell adhesion and the consequent pathogenic processes mediated by VLA-4. These compounds, which are therefore useful in the treatment of many inflammatory, autoimmune and respiratory diseases, can be illustrated by formula (1.0.0): (1.0.0) For the compounds of formula (1.0.0), the terminal group identified as A has the meaning of alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0 to R9; or is a member selected from the group consisting of the following radicals A1-NHC (= 0) NH-A2-, A1-NHC (= 0) 0-A2-, A1-OC (= 0) NH-A2-, A1- NHS02NH-A2-, A1-NHC (= 0) -A2-, A1-C (= 0) NH-A2-, A1-NHS02-A2-, A1-S02NH-A2-, A + 1- (CH2) rA2 -, A1CH (R1) -0-A2-, A1- (CH2) rO-A2-, A1-0- (CH2) rA2-, A1- (CH2) rNH-A2-, A1-NH (CH2) rA2- and A1- (CH2) S (= 0) q-A2-, A1 and A2 each being independently selected from the group consisting of hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl and heterocyclyl; said aryl, alkyl, alkenyl, cycloalkyl, heteroaryl or heterocyclyl group being substituted with 0 to 3 R9. The term "alkyl" as used with reference to "A", as well as in other contexts throughout the present specification, and whether used separately or combined, represents a straight or branched chain alkyl radical containing the indicated number of carbon atoms, usually from 1 to 6, but often from 1 to 4, carbon atoms. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl and hexyl. The term "cycloalkyl" as used with reference to "A", as well as in other contexts throughout the present specification, and whether used separately or combined, represents a cyclic alkyl radical containing from 3 to 6. carbon atoms. Examples of said cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "aryl" as used with reference to "A", as well as in other contexts throughout the present specification, is meant to represent a carbocyclic aromatic group that is a member selected from the group consisting essentially of phenyl, naphthyl , indenyl, indenyl and fluorenyl. It is preferred, however, that when "A" is "aryl" it is phenyl.

The term "heteroaryl" as used with reference to "A", as well as in other contexts throughout the present specification, is understood to represent a heterocyclic aromatic group that is a member selected from the group consisting essentially of furyl, thienyl , pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, midazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, bezo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1H-indazolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8- naphthyridinyl, pteridinyl, carbazolyl, acridinyl, 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, benzoimidazolyl or quinolinyl. More preferably "A" is pyridyl. The terms "heterocyclic" and "heterocyclyl" as used with reference to "A", as well as in other contexts throughout the present specification, are understood to mean both a non-aromatic carbocyclic ring of 3 to 10 members in the that at least one of the ring carbon atoms has been replaced by a heteroatom selected from N, O or S. Two heteroatoms are preferably present, and more preferably one heteroatom, except in the case of nitrogen, from which nitrogen may be present. heteroatoms. The heterocyclyl group may comprise one or two fused rings, and may further include a fused aryl ring. In a preferred meaning, "heterocyclyl" represents 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. It is preferred, however, that when "A" is "heterocyclyl" it is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. When "A" is defined as a residue selected from the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups defined above, said moiety may be substituted with 0 to 3 R9. The choice of "O" simply indicates that there are no substituents, with substitution optional. When substitution occurs, preferably there are two substituents, and more preferably there is only one substituent. When a substituent R9 is used, it will be independently selected from the group consisting essentially of halogen, alkyl (CrCß), alkoxy (CrCß), cycloalkyl (C3-Cß), cycloalkoxy (C3-Cß), cyano, hydroxy, C (= 0) R5, C (0) NR5R6, NR5R6, NR5S02R6, CF3, OCF3, S02NR5R6, C (= o) OR5; when R9 is attached to a saturated carbon atom, R9 can be = 0 or = S, when R9 is attached to a sulfur atom, R9 can be = 0; R5 and R6 being as defined herein. However, preferably, there is only one substituent and it is F, Cl, OH, methyl, methoxy, cyclohexyl, acetyl, cyclopropyloxy or F3C-. The term "alkoxy" as used with reference to the substituents "R9" on the "A" group, as well as in other contexts throughout the present specification, using both separately and in combination, represents an alkyl ether radical, the term "alkyl" being as defined above. Examples of suitable alkyl ethers include, but are not limited to, methoxy, ethoxy, n-propoxy, iopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. The term "cycloalkoxy" as used with reference to substituents "R9" over group "A", as well as in other contexts throughout the present specification, used both separately and in combination, represents a cycloalkyl ether radical, the term "cycloalkyl" being as defined above. Examples of suitable cycloalkoxy radicals include, but are not limited to, cyclopropoxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. A preferred meaning of "A" is that of a divalent radical which is a member selected from the group consisting of the following radicals: A1-NHC (= 0) NH-A2-, A1-NHC (= 0) 0-A2-, A1-OC (= 0) NH-A2-, A1-NHS02NH-A2-, A1-NHC (= 0) -A2-, A1-C (= 0) NH-A2-, A1-NHS02-A2-, A1 -S02NH-A2-, A1- (CH2) r A2-, A1-CH (R1) -0-A2-, A1- (CH2) r-0-A2-, A1-0- (CH2) A2-, A1 - (CH2) rNH-A2-, A1-NH (CH2) rA2- and A1- (CH2) rS (= 0) qA-2, wherein A1 and A2 are each independently selected from the group consisting of hydrogen, aryl, alkyl ( CrCβ), cycloalkyl, heteroaryl and heterocyclyl, said aryl, alkyl, cycloalkyl, heteroaryl or heterocyclyl group being substituted with 0 to 3 R 9. The alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group that is attached to one or both sides of the ureido radical is selected according to the definitions given above, such as the 0 to 3 substituents R9. It is preferred that an aryl group be covalently attached to both sides of the ureido radical, and it is more preferred that this aryl group is phenyl. It is most preferred that said phenyl group has a single substituent which is preferably F, Cl, methyl, methoxy or F3C-. Examples of preferred meanings of "A" are shown in the partial formulas (4.0.0) through (4.0.11): (4.0.0) (4.0.1) (4.0.2) (4.0.3) (4.0.1) (4.0.5) (4.0.6) (4.0.7) (4.0.8) cnrüy (4.0.9) (4.0.10) (4.0.11) The component of the compounds of formula (1.0.0) that is immediately adjacent to compound "A" is a single bond or a methylene or ethylene bridging element where n = 0, 1 or 2, respectively. It is preferred that n = 1 and that there be a methylene bridge. Accordingly, within the context of the above-mentioned preferences for the meaning of the "A" component, and with the addition of the methylene bridge, the following most preferred terms including the "A" component, may be represented by the following partial formulas (4.1 .0) to (4.1.23): 4- [N '- (4- H3C CH3 (4.1.15) isopropylphenyl) urea] phenylmethyl- or c- 6-methoxy-5- [N '- (o- (4.1.16) toluyl) urea] -2-pyridylmethyl- 4- [N '- (3-cyclopentyl-2- (4.1.17) pyridyl) urea [phenylmethyl- 4- [N '- (2-cyclopentyl) urea] - (4.1.18) phenylmethyl- 4- [N '- (3-cyclopropyloxy-2- (4.1.19) pyridyl) urea [phenylmethyl] 4- [N '- (o-toluyl) urea] -pyrid-5- (4.1.20) ilmethyl- 4- [3- (4-methylpyridin-3- (4.1.21) il) ureido] -phenylmethyl- It will further be observed that in the partial structural formulas the preferred methylene bridge is also preferably linked to the group N, N'-diphenylureide in relation to the point of attachment of the divalent ureide group to the phenyl group involved. The "Y" component of formula (1.0.0) can be -C (= 0) -, -C (= S) -o -S (= 0) 2-. However, in general, it is most preferred that "Y" be a carbonyl residue, that is, that "Y" is the remainder -C (= 0) -. The next component of the compounds of formula (1.0.0) is -NR4CR2R3-. In this component, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl (CrC6) substituted with 0 to 3 R13, alkenyl (C2-C6) substituted with 0 to 3 R13, a carbocyclic ring system (C3-) CH) substituted with 0 to 3 R13, a heterocyclic ring as defined herein substituted with 0 to 3 R13, alkyl (CrC6) -OR5 substituted with 0 to 3 R13, alkyl (CrC6) -SR5 substituted with 0 to 3 R13 , alkyl (C Cß) -S? 2R5 substituted with 6 to 3 R13, a heteroaryl ring as defined herein substituted with 0 to 3 R13, an aryl ring as defined herein substituted with 0 to 3 R13. R2 and R3 can also be taken together according to an optional definition of R2 and R3, in which case they form a cycloalkyl or heterocyclyl ring substituted with 0 to 3 R13. For example, when R2 and R3 are taken together to form a cyclopropyl, cyclobutyl or cyclopentyl spirocyclic group, the resulting compounds of the present invention will include moieties such as those of partial formulas (1.2.0) to (1.2.2): Another preferred subgroup of compounds of the present invention is that formed when R2 or R3 are taken together with R4 and the carbon and nitrogen atoms to which they are respectively attached to form a heteroaryl or heterocyclyl group as defined herein. Said heteroaryl or heterocyclyl group may in turn be substituted with 0 to 3 R13. 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): 5 in which the symbol "*" indicates the point of union of the rest represented by the partial formula (1.3.0) to the rest "Y" in the formula ( 1.0.0), and the symbol "->" indicates the point of union of the rest represented by the partial formula (1.3.0) to "B" in the formula (1.0.0), defined by the partial formulas (1.1.0) to (1.1.22). The substituent "R273" indicates the presence of the substituent R2 or substituent R3. Both can not be present, since one or the other has already been selected to be taken together with R4 to form the heteroaryl or heterocyclyl group of partial formula (1.3.0), represented below: It will be understood that if R2 or R3 is present, it will have the meaning of hydrogen, alkyl or methyl. Accordingly, this subgroup of the group "-NR4CR2R3B- 20" represented by the partial formula (1.3.0) includes, but is not limited to, the embodiments that are represented by the partial formulas (1.3.1) to (1.3.20) ): i.-HÉÍl- = g &-g-ti-k-H- «(1.3.1) (1.32) (13.3) (1.3.10) (1.3.11) (1.3.17) (1.3.18) in which the symbol "*" indicates the point of union of the rest represented by each partial formula (1.3.1) to (1.3.20) to the rest "Y" in the formula ( 1.0.0), and the symbol "->" indicates the point of union of the rest represented by each partial formula (1.3.1) to (1.3.20) to the remainder "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 meant that R13 is not present or is present as a single substituent selected from halogen, CF3, alkyl (CrCß), aryl, heteroaryl, heterocyclyl, hydroxy, cyano, alkoxy (CrCß), a carbocyclic ring system (C3-C14) ), (C3-C6) cycloalkoxy, (C2-C2) alkynyl, (C2-C2) alkenyl, -NR6R5, -C (= 0) NR5R6, S02R5-, C (= 0) R5, NR5S02R6, NR5C (= 0) ) R6, C (= 0) NR5S02R6, NR5C (= 0) OR6 and S02NR5. With reference to the optional R13 substituent, but also with reference to the remainder of the present specification, the term "alkynyl", separately or in combination, represents a straight 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, and the like. With reference to the definition of R13, the term "alkenyl" separately or in combination represents a straight or branched chain alkenyl radical containing from 2 to 6, preferably from 2 to 4, carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl and E- and Z-pentenyl. The term "carbocyclic ring system (C3-C14)" as used with reference to R2 and R3, as well as in other contexts throughout the present specification, used separately or in combination, is meant to represent cycloalkyl groups and cycloalkenyl consisting of one, two or three condensed rings containing a total of three to fourteen carbon atoms. The term "2-cycloalkyl", in turn, means a cyclic alkyl radical containing from 3 to 8, preferably from 3 to 6 carbon atoms Examples of said cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl and the like The term "cycloalkenyl", on the other hand, represents a cyclic carbocycle containing from 4 to 8, preferably 5 or 6 carbon atoms and one or more double bonds Examples of said cycloalkenyl radicals include, but are not limited to, they are limited to them, cyclopentenyl, cyclohexenyl and cyclopentadienyl When two or three fused rings are present, one of the rings may be a cycloalkyl ring system, while one of the other or the other two rings may 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 hydrogen, methyl, ethyl, propyl, butyl and is obutyl, hydroxymethyl, methoxymethyl, allyl, propenyl, E- and Z-isobutenyl and E- and Z-pentenyl, cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl, cyclohexenylmethyl, benzyl, benzyloxymethyl and phenoxymethyl, 2- (methylthio) ethyl, 3- (hydroxypropylthio) methyl, 2- (methylsulfonyl) ethyl, 4- (acetylamino) butyl, 4- (methylsulfonylamino) butyl and 4-ethoxycarbonylamino) butyl. The next component, the "B" group of the compounds of formula (1.0.0), is one of the most important parts of the molecule and is a key element in providing the unexpectedly good biological properties possessed by the compounds of the present invention . Group "B" comprises a member selected from the group consisting of the partial formulas (1.1.0) to (1.1.22): in which the symbol "*" indicates the point of union of the rest represented by each partial formula (1.1.0) to (1.1.22) to the rest "CR2R3" in the formula (1.0.0), and the symbol "- >; "indicates the point of union of the rest represented by each partial formula (1.1.0) to (1.1.22) to the remainder" E "in the formula (1.0.0) All the partial formulas (1.1.0) a ( 1.1.22) above are illustrated as fragments in the manner described above, the junction points at each end of a particular fragment being indicated by the symbols "*" and "- > "In the previous partial formulas that define the component B of the compounds of formula (1.0.0), the rest "X" can be oxygen, sulfur (q = 0) and sulfur to which are bound two oxygen atoms (q = 2), ie sulfonyl; or NH (R10 = hydrogen) or nitrogen that is substituted (R10 = alkyl) (CrCβ), (C 3 -C β) cycloalkyl, heterocyclyl, heteroaryl or aryl). It is preferred, however, that "X" is simply oxygen, sulfur or NH.

Attached to component B in the compounds of formula (1.0.0) are the remaining structural elements, which can be represented by the partial formula (1.4.0): (1.4.0) It will be observed firstly that the rest represented by the partial formula (1.4.0) is directly bonded to component B in the general compound of formula (1.0.0). E is a single bond, oxygen, -NR10-, -CH = CH-, or -CR11R12-. When a substituent R10 is used, it will be independently selected from the group consisting essentially of hydrogen, C (= 0) R5, alkyl (CrCß), aryl, heterocyclyl, heteroaryl, cycloalkyl or S02R5. When the substituents R11 and R12 are used, they will be independently selected from the group consisting essentially of hydrogen, alkyl (d-Cß), hydroxy, alkoxy (CrCß), NR6COR5, NR6S02R5, NR6R5, CF3, F, aryl, heterocyclyl, heteroaryl, cycloalkyl and cycloalkoxy. R11 can be taken together with R12 to form a cycloalkyl or heterocyclyl ring. R5 and R6 are independently hydrogen, alkyl (CrCβ), CF 3, aryl, cycloalkyl, heteroaryl or heterocyclyl.

The alkyl (CrCß), alkoxy (CrCß), aryl, heterocyclyl, heteroaryl, cycloalkyl and cycloalkoxy groups have already been defined in detail above. Within the meaning of these groups, it is preferred that R11 and R12 are independently selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, methoxy, cyclopropoxy, cyclopropyl, phenyl, morpholinyl, piperidinyl and pyridyl. In the parts of the compounds of the present invention represented by the partial formula (1.4.0) above, the residue E is followed by an optional methylene bridge: (-CH2-) m, where m is a whole number independently selected of 0 and 1. The next component of the formula (1.0.0) is represented by "- (CR7R8) P-", in which "p" is selected from the integers 0 and 1, with the proviso that " p "must be selected as 1 when" B "is selected as the partial formulas (1.1.0) to (1.1.11). The substituent R7 is selected from the group consisting of alkyl (C? -C6), hydroxy, alkoxy (CrC6), NHC (= 0) R5, NHS02R5, NR6R5, F, CF3, OCF3, aryl, heterocyclyl, heteroaryl, cycloalkyl; or R7 can be taken together with R8 to form a cycloalkyl or heterocyclyl ring. The substituent R8 is selected from hydrogen, F, alkyl (CrCβ) or alkoxy (CrC 6). The final component of the formula (1.0.0) is the group "- C (= 0) OR", where R is hydrogen.

The component represented by the partial formula (1.4.0) includes, but is not limited to, the embodiments that are presented by the partial formulas (1.4.1) to (1.4.20): (1.4.17) (1.4.18) d -4.19) (1.4.20) The pharmaceutically acceptable derivatives of the compounds of formula are included within the scope of the present invention. (1.0.0). The term "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt of a compound of formula (1.0.0). In addition, any other compound that, when administered to a patient, is capable of directly or indirectly providing a compound of formula (1.0.0) is included in the scope of the present invention. said compounds are referred to as prodrugs, and a series of established procedures are available for the preparation of said prodrug forms of the compounds of formula (1.0.0). The term "patient" as used above and throughout the present specification, represents mammals, including humans. And when the term "cell" is used, represents mammalian cells, including human cells unless otherwise specified. Also included within the scope of the present invention are the metabolites or residues of the compounds of formula (1.0.0) which possess biological activity such as that of inhibiting cell adhesion and the consequent or associated pathological processes subsequently mediated by VLA-4. After being 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 vivo and in vitro assays which are described in detail below. The desired biological activity of the compounds of formula (1.0.0) can also be improved by adding to these the appropriate functionalities, which will work by enhancing the existing biological properties of the compound, improving the selectivity of the compound by the existing biological activities, or adding to the activities biological processes, or by adding other desirable biological activities to existing biological activities. Such modifications are known in the art and include those that increase biological penetration in a given biological system, for example blood, lymphatic system and central nervous system, which increase oral availability, which increase the solubility to allow to the injection administration, those that alter the metabolism and those that alter the rate of excretion of the compound of formula (1.0.0). In view of the above definitions and others throughout the present specification, other chemical and biological terms currently used by those skilled in the art may be readily understood. The defined terms can be used separately or in any combination of these. Preferred and more preferred chain lengths of the radicals that have been specified herein apply to all of these combinations. Continuing with the above descriptions of certain more preferred subgeneric and subgeneric preferred definitions of the compounds of formula (1.0.0), an enumeration of the preferred and more preferred species is provided to provide a further illustration of the present invention. Compounds including the remainder of partial formula (1.1.0): 3- [2- (1 -. {2- 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} 3-. methyl-butyl) -4,5-dihydro-oxazol-5-yl] -2-methylpropionic acid, 2-acetylamino-3- [2- (1 -. {2- [3-methoxy-4- (3-o- tolylureido) phenyl] acetylamino.} - 3-methylbutyl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [2- (1-. {2- [3-methoxy -4- (3-o-tolylureido) phenyl] acetylamino.} - 3-methylbutyl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2,2-difluoro-3- acid. { 2- [1- (methyl { [6- (3-o-tolylureidod) pyridin-3-yl] acetyl} amino) ethyl] -4,5-dihydro-oxazol-5-yl} propionic, 2,2-dimethyl-3- [2- [1 -. { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2-allyloxycarbonylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydro-oxazol-5-yl} propionic, 2- (butane-1-sulfonylamino) -3- (2- {[[methyl- (. {4- [3- (3-methylpyridin-2-ylureido] piperidin-1-yl} acid. acetyl) amino] methyl.}. 4,5-dihydro-oxazol-5-yl) propionic acid, 2-methyl-3- [2- (1- { [4- (2-methylbenzyloxy) phenyl] acetyl acid .}. pyrrolidin-2-yl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2-formylamino-3- { 2- [1- (biphenl-4-yl-acetyl) pyrrolidin-2-yl] -4,5-dihydrothiazol-5-yl.} propionic acid, 2-methyl-3- (2- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolid; n-2-yl.} - 4,5-dihydro-oxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- (2- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-acid il.} -4,5-dihydro-oxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- [2- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl, pyrrolidin-2-yl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [2- (3-methyl-1 - { [5- ( 3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2-acetylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4-methyl-4, 5-dihydro-oxazol-5-yl} propionic, 2-acetylamino-3- acid. { 2 - [( { [3-methyxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydrothiazol-5-yl} propionic, 3-acetylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydro-3H-imidazol-4-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydro-oxazol-5-yl} propionic Compounds including the remainder of partial formula (1.1.1): 3- [2- (1-. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} -3 acid - methylutil) -4,5-dihydro-oxazol-4-yl] -2-methylpropionic acid, 2-acetylamino-3- [2- (1 -. {2- [3-methoxy-4- (3-o)] - tolylureido) phenyl] acetylamino.} - 3-methylbutyl) -4,5-dihydro-oxazol-4-yl] propionic acid, 2-methanesulfonylamino-3- [2- (1-. {2- 2- 3 -methoxy-4- (3-o-tolylureido) phenyl] acetylamino.} - 3-methylbutyl) -4,5-dihiro-oxazol-4-yl] propionic acid, 2,2-d-fluo-3-acid. { 2- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) etl] -4,5-dihydro-oxazole-4- il} propionic acid, 2,2-dimethyl-3- [2- (1 - { [6- (3-phenylurido) pyridin-3-yl] acetyl] pyrrolidin-2-yl) -4,5- dihydro-oxazol-4-yl] propionic acid, 2-allyloxycarbonylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl} methylamino) methyl] -4,5-dihydro-oxazol-4-yl} propionic, 2- (butane-1-sulfonylamino) 3- (2. {[[methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acid} acetyl) amino] methyl} -4,5-dihydro-oxazol-4-yl) propionic acid, 15 _ 2-methyl-3- [2-) 1- acid. { [4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) -4,5-dihydro-oxazol-4-yl] propionic acid, 2-acetylamino-3- acid. { 2- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -4,5-dihydrothiazol-4-yl} propionic acid, 2-methyl-3- (2- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl} -4,5-20-dihydro-oxazol-4-yl) propionic acid , 2-benzenesulfonylamino-3- (2. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} -4,5-dihydro-oxazol-4-yl) propionic acid, ^^^^^ 2-Benzenesulfonylamino-3- [2- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl] propionic acid, 2-methanesulfonylamino-3- [2- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl acid} pyrrolidin-2-yl.} -4,5-dihydro-oxazol-4-yl] propionic acid, 2-acetylamino-3-. {2 - [( { [3-methoxy-4- ( 3-o-tolylureido) phenyl] acetyl.} Methylamino) methyl] -5-methyl-4,5-dihydro-oxazole-4-ylpropionic acid, 2-acetylamino-3-. {2 - [( { [ 3-methoxy-4- (3-o-tolylureido) phenyl] -acetyl} -methylamino) methyl] -4,5-dihydrothiazol-4-yl.} Propionic acid 2- (2,6-dichlorobenzoylamino) -3 - {2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydro-oxazol-4-yl}. Compounds including the remainder of partial formula (1.1.2): 3- [2- (1-. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acid] acetylamino.} - 3-methylbutyl) oxazol-5-yl] -2-methylpropionic acid, 2-acetylamino-3- [2- (1-. {2- [3-methoxy-4- (3-o- tolilure gone) phenyl] acetylamino} -3-methylbutyl) oxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [2- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino]. .3-methylbutyl) oxazol-5-yl] propionic, 2,2-difluoro-3- acid. { 2- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] oxazol-5-yl} propionic acid, 2,2-dimethyl-3- [2- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) oxazol-5-yl] propionic, 2-allyloxycarbonylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-5-yl} propionic, 2- (butane-1-sulfonylamino) -3- (2- {[[methyl- (. {4- [3- (3-methylpyridin-2-ylureido] piperidin-1-yl} acid. acetyl) amino] methyl.} oxazol-5-yl) propionic acid, 2-methyl-3- [2- (1 - { [- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl acid ) oxazol-5-yl] propionic acid, 2-acetylamino-3 { 2- [1 (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] thiazol-5-ylpropionic acid, 2-methyl-3- ( 2- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl.}. Oxazol-5-yl) propionic acid, 2.-benzenesulfonylamino-3- (2- { 1 - [ (4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl.}. Oxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- [2- (1- { [3-methoxy-4- (3-o)} -tolylureido) phenyl) acetyl} pyrrolidin-2-yl.} oxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [2- (3-methyl-1- {[5- (3-oxo-tolylurethane) pyridin-2-yl] acetyl} pyrrolidin-2-yl) oxazol-5-yl] propionic acid, 2-acetylamino-3-. {2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] -acetyl} -methylamino) methyl] -4-methyloxazol-5-yl}. Propionic or, 2-acetylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] thiazol-5-yl} propionic, 3-acetylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl} -3H-imidazol-4-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-5-yl} propionic Compounds including the remainder of partial formula (1.1.3): 3- [2- (1-. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino acid} - 3-methylbutyl) oxazol-4-yl] -3-meitylpropionic acid, 2-acetylamino-3- [2- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] .} - 3-methylbutyl) oxazol-4-yl] propionic acid, 2-methanesulfonylamino-3- [2- (1-. {2- [3-methoxy-4- (3-o-tolylureido) phenyl]] acetylamino.} - 3-methylbutyl) oxazol-4-yl] propionic acid, 2,2-difluoro-3- acid. { 2- [1 - (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] oxazol-4-yl} propionic acid 2,2, -dimethyl-3- [2- (1 -. {[[6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) oxazol-4-yl] propionic, 2-allyloxycarbonylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-4-yl} propionic acid, 2- (butane-1-sulfonylamino) -3- (2- {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-2-yl} acetyl) amino] -methyl} oxazol-4-yl) propionic acid, 2-methyl-3- [2- (1. {[[4- (2-methylbenzyloxy) phenyl] -acetyl} acid. pyrrolidin-2-yl) oxazol-4-yl] propionic acid, 2-formylamino-3- acid. { 2- [1 - (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl] thiazol-4-yl} propionic, 2-methyl-3- (2- { 1 - [(4-o-tolyloxyphenyl) acetyl] -pyrrolidin-2-yl} oxazol-4-yl) propionic acid, 2-benzenesulfonylamino-3 acid - (2- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl.} - oxazol-4-yl, propionic acid, 2-benzenesulfonylamino-3- [2- (1 - { [ 3-methoxy-4- (3-o-tolylureido) phenyl) acetyl} pyrrolidin-2-yl}. Oxazol-4-yl] propionic2-methanesulfonylamino-3- [2- (3-methyl-1- {[[5- (3-o-tolylurethane) pyridin-2-yl] acetyl} pyrrolidin-2-yl} acid} oxazole-4-yl] propionic acid, 2-acetylamino-3. {2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino acid ) methyl] -5-methyloxazol-4-yl.} propionic acid, 2-acetylamino-3-. {2 - [( { [3-methoxy-4- (3-oxo-tolylureido) phenyl] acetyl] .) methylamino) methyl] thiazol-4-yl.} propionic acid 2- (2,6-dichlorobenzylamine) -3-. {2 - [( { [3-methoxy-4- (3- o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-4-yl.}. propionic acid, 3- [2- (1- {[4- (4-chlorobenzyloxy) -3-fluorophenyl] - acetyl, pyrrolidin-2-yl) thiazol-5-yl] propionic acid, 3- [2- (1- {[[3-fluoro-4- (3-methoxybenzyloxy) phenyl] acetyl} pyrrolidin- 2-yl) thiazol-5-yl] propionic acid, 3- [2- (1- { [3-Chloro-4- (4-chlorobenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) thiazole- 5-yl] propionic acid, 3- [2- (1- {[[4- (4-chlorobenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) thiazol-5-yl] propionic acid, 3- [ 2- (1 - [(4-benzyloxy-3-chlorophenyl) acetyl] -3-methylpyrrolidin-2-yl} thiazol-5-yl) propionic acid, 3- [2- (1- {[[4- (4-chlorobenzyloxy) phenyl] acetyl} -3-methylpyrrolidin-2-yl) thiazol-5-yl] propionic acid , 3- (2- { 1 - [(4-benzyloxyphenyl) acetyl] -3-methylpyrrolidin-2-yl} thiazol-5-yl) propionic acid, 3- (2- {. 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl} thiazol-5-yl) propionic acid, and 3- (2. {1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl} .}. isoxazol-5-yl) propionic acid. Compounds including the remainder of partial formula (1.1.4): 3- [3- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} acid. -3- methylbutyl) -4,5-dihydroisoxazol-5-l] -2-methylpropionic acid, 2-acetylamino-3- [3- (1 -. {2- 2- [3-methoxy- (3-o-tolylureido]] ) phenyl] acetylamino.} - 3-methylbutyl) -4,5-dihydroisoxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-15-tolylureido) phenyl] -acetylamino, -3-methylbutyl) -4,5-dihydroisoxazol-5-yl] propionic acid, 2,2-difluoro-3- acid. { 3- [1- (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl-4,5-dihydroisoxazol-5-yl} propionic acid, 2,2-dimethyl-3- [3 - ([1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) -4,5-dihiroisoxazole- 5-yl] propionic acid, 2-allyloxycarbonylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydroisoxazole 5-yl} propionic, 2- (butane-1-sulfonylamino) -3- (3- {[[methyl] [4 - {3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acetyl) amino] -methyl] -4,5-d-hiroisoxazol-5-yl) propionic, α ^^^ H 2-Methyl-3- [3- (1- {[[4- (2-methylbenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) -4,5-dihydroisoxazol-5-yl acid ] propionic, 2-formylamino-3- acid. { 3- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -4,5-dihydroisothiazol-5-yl} propionic acid, 2-meitl-3- (3- { 1 - [(4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl} -4,5-dihydroisoxazol-5-yl) propionic acid, acid 2-Benzenesulfonylamino-3- (3-. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} -4,5-dihydroisoxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- [3] - (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl) acetyl} pyrrolidin-2-yl) -4,5-dihydroisoxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1 - { [5- (3-o-tolylureido)] pyridin-2-yl] acetyl} pyrrolidin-2-yl) -4,5-dihydroisoxazol-5-yl] propionic acid, 2-acetylamino acid, 3- [3 - [( { [3-methoxy-4 - (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4-methyl-4,5-dihydroxyisoxazol-5-ylpropionic acid, 2-acetylamino-3 acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl} methylamino) methyl] -4,5-dihydroisothiazol-5-yl} propionic, 3-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -3,4-dihydro-2H-pyrazol-3-yl} propionic, 2- (2,6-dichlorobenzylamine) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydroisoxazol-5-yl} propionic Compounds including the remainder of partial formula (1.15): 3- [3- (1-. {2- [3-methoxy-4- (3-o-tollylureido) phenyl] acetylamino} -3-methylbutyl acid ) -4,5-dihydropyrazol-1-yl] -2-methylpropionic acid, 2-acetylamino-3- [3- (1 -. {2- 2- [3-methoxy-4- (3-o-tolylure Phenyl) acetylamino, -3-methylbutyl) -4,5-dihydropyrazol-1-yl] propionic acid, 2-methanesulfonylamino-3- [3- (1-. {2- [3-methoxy- 4- (3-o-tolylureido) phenyl] acetylamino,} - 3-methylbutyl) -4,5-dihydropyrazol-1-yl] propionic acid, 2,2-difluoro-3- acid. { 3- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl {amino) ethyl} -4,5-dihydropyrazol-1-yl} propionic acid, 2,2-dimethyl-3- [3 - ([1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) -4,5- dihydropyrazol-1-yl-propionic acid, 2- (butane-1-sulfonylamino) -3- (3. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin- 1-yl.} Acetyl) -amino] methyl. {-4,5-dihydropyrazol-1-yl) propionic acid, 2-methyl-3- [3- (1- { [4- (2 -methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) -4,5-dihydropyrazol-1-yl] propionic acid, 2-acetylamino-3- acid. { 3- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -4,5-dihydropyrazol-1-yl} propionic acid, 2-methyl-3- (3- {1 - [(4-o-tolyloxyphenyl) acetyl] -prolidin-2-yl} -4,5-dihydropyrazol-1-yl) propionic acid, acid 2-Benzenesulfonylamino-3- (3. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} -4,5-dihydropyrazol-1-yl) propionic acid, 2-benzenesulfonylamino-3-acid [3- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl) acetyl} pyrrolidin-2-yl) -4,5-dihydropyrazol-1-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin) -2-yl] acetyl} pyrrolidin-2-yl) -4,5-dihydropyrazol-1-yl] propionic acid, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methyl-4,5-dithiazole-1-yl-5-propionyl , 2-formylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydropyrazol-1-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl} methylamino) methyl] -4,5-dihydropyrazol-1-yl} propionic Compounds including the remainder of partial formula (1.1.6): 3- [3- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} acid. -3- methylbutyl) isoxazol-5-yl] -2-methylpropionic acid, 2-acetylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl]] acetylamino.} - 3-methylbutyl) isoxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (1-. {2- [3-methoxy-4- (3-o-tolylureido)] phenyl] acetylamino.} - 3-methylbutyl) isoxazol-5-yl] propionic acid, 2,2-difluoro-3- acid. { 3- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] isoxazol-5-yl} propionic, 2,2-dimethyl-3- [3- (1 - { [6-3-phenylureido) pyridin-3-yl] acetyl acid} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-allyloxycarbonylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isoxazol-5-yl} propionic, ^ .. ^ _ ,,. ^ _. 2- (Butane-1-sulfonylamino) -3- (3. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acid. acetyl) amino] -methyl.] isoxazol-5-yl) propionic acid, 2-methyl-3- [3- (1- {[[4- (2-methylbenzyloxy) -phenyl] -acetyl} pyrrolidin- 2-yl) isoxazol-5-yl] propionic, 2-acetylamino-3- acid. { 3- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] isothiazol-5-yl} propionic, 2-methyl-3- (3. {1 - [(4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl} isoxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3 acid - (3- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl.} - isoxazol-5-yl}. Propionic acid, 2-benzenesulfonyl-amino-3- [3- (1 -. { . [3-methoxy-4- (3-o-tolylureido) phenyl) acetyl] pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl- 1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-formylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl} methylamino) methyl] -4-methylisoxazol-5-yl} propionic, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isothiazol-5-yl} propionic, 3-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl} methylamino) methyl] -2H-pyrazol-3-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isoxazol-5-yl} propionic, 3- [3- (1-. {[4- (pyridin-4-ylmethoxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3] acid - (1- {[[4- (pyridin-3-ylmethoxy) -phenyl] -acetyl} - {pyrrolidin-2-yl) -isoxazol-5-yl] propionic acid, 3- [3- ( 1 - { [4- (pyridin-2-ylmethoxy) -phenyl] -acetyl} - { Pyrrolidin-2-yl) -isoxazol-5-yl] -propionic acid, 3- (3-. {1- [(6-benzyloxypyridin-3-yl) acetyl] pyrrolidin-2-yl.] Isoxazol-5-yl) propionic acid, 3- (3. {1 - [(5-benzyloxypyridin-2-yl) acetyl] ] pyrrolidin-2-yl.}. isoxazol-5-yl) propionic acid, 3- (3. {1 - [(4-benzodiphenyl) acetyl] pyrrolidin-2-yl]. isoxazol-5-yl) -2-phenylaminopropionic acid, 3- (3 { 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl.}. Isoxazol-5-yl) -3- (pyridin-2-ylamino) propionic acid ,. 3- (3 { 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl}. isoxazol-5-yl) -2- (pyridin-3-ylamino) propionic acid, 3- (3 - { 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl.}. Isoxazol-5-yl) -2- (pyridin-4-ylamino) propionic acid, 3- [3- (1- (1 { [4- (5-chlorothiophen-2-ylmethoxy) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- (3. {1 - [(4-benzyloxyphenyl)} acetyl] pyrrolidin-2-yl.}. isoxazol-5-yl) propionic, • -. - - * - 3- [3- (1- { [4- (4-Chlorobenzyloxy) -3-fluorophenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3-acid - [3- (1- { [3-fluoro-4- (3-methoxy-benzyloxy) -phenyl] -acetyl} - pyrrolidin-2-yl) -isoxazol-5-yl] -propionic acid, 3- [3-] (1- { [3-methoxy-4- (4-methoxybenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1 -. { . [3-methoxy-4- (3-methoxybenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- ( 4-chlorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (3-chlorobenzyloxy) -3} -methoxyphenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- {[[4- (2-chlorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1 - { [4- (4-fluorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin- 2- il) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (3-fluorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl) isox. azol-5-yl] propionic acid, 3- [3- (1-. { [4- (2-flurobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- {[[3-chloro-4- (3-methoxybenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl} ) isoxazol-5-yl] propionic acid, 2-acetylamino-3- [3- (1 - { [3-chloro-4- (3-methoxybenzyloxy) phenyl] acetyl] pyrrolidin-2-yl) isoxazole -5-yl] propionic acid, 2-acetylamino-3- (3 { 1 - [(4-benzyloxy-3-methoxy-phenyl) -acetyl] -pyrrolidin-2-yl}., -soxazol-5-yl ) propionic acid, 3- [3- (1- {[[4- (5-tert-butyl- [1, 2,4] oxadiazol-3-ylmethoxy) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- [3- (1 - { [3-chloro-4- (4-chlorobenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) isoxazole- 5-yl] propionic acid, 3- [3- (1- {[[3-chloro-4- (4-chlorobenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic, 3- [3- (1- { [4- (2-Cyanobenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3-1. { [4 -? (4-cyanobenzyloxy) -phenyl] -acetyl} -pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- (3. {1 - [(4-benzyloxy-3-fluorophenyl) -acetyl] pyrrolidin-2-yl} isoxazole-5 acid -yl) propionic acid, 3- (3 { 1 - [(4-benzyloxy-3-chlorophenyl) -acetyl] pyrrolidin-2-yl} isoxazol-5-yl) propionic acid, 3- (3 - { 1 - [2- (4-benzyloxyphenyl) -acetylamino] -3-methylbutyl}. Isoxazol-5-yl) propionic acid, 2-acetylamino-3- [3- (1 - { [4 - (3-Cyanobenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- [3- (1 - { [4- (4-chlorobenzyloxy)] ) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- (3. {1 - [(4-benzyloxyphenyl) -acetyl] pyrrolidin-2-acid) il.] isoxazol-5-yl) propionic acid, 3- (3. {1 - [(4-p-tolyloxymethylphenyl) -acetyl] pyrrolidin-2-yl}. isoxazol-5-yl) propionic acid, 3- (3 { 1 - [(4-M-Tolyloxymethylphenyl) -acetyl] pyrrolidin-2-yl.}. isoxazol-5-yl) propionic acid, 3- (3- {1- [3- (4-o-tolyloxymethylphenyl) -acetyl] pyrrolidin-2-yl.] Isoxazol-5-yl) propionic acid, 3- [3- (1- { [4- (4-methoxybenzyloxy) -phenyl] acetyl acid} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (3-methoxybenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazole-5 -yl] propionic, 3- [3- (1-. {[4- (2-methoxybenzyloxy) -phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino acid -3- [3- (3-methyl-1 - { 2- [4- (2-methylbenzyloxy) phenyl] acetylamino.} Butyl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- ( 3- { 1- [2- (4-benzyloxyphenyl) -acetylamino] -3-methylbutyl}. Isoxazol-5-yl) propionic acid, 3- [3- (1- { [4- (4 -fluorobenzyl) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- {[[4- (3-fluorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- {[[4- (2-fluorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazole- 5-yl] propionic acid, 3- [3- (1 - { [4- (2-Chlorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3-yl. - [3- (1- { [4- (3-chlorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] pr opionic, 3- [3- (1-. { [4- (4-chlorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (3-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazole- 5-yl] propionic, 3- [3- (1- { [4- (4-methylbenzyloxy) phenyl) -acetyl acid} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (2-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazole- 5-yl] propionic, 3- (3. {3-methyl-1- [2- (4-phenoxyphenyl) -acetylamino] butyl} isoxazol-5-yl) propionic acid, 2-allyloxycarbonylamino-3 acid - [3- (1-Benzoyl-pyrrolidin-2-yl] -20) isoxazol-5-yl) propionic acid, 3- (3. {1 - [(4-benzyloxy-3-methoxyphenyl) -acetyl] pyrrolidine] -2- il.} Isoxazol-5-yl) propionic, -li ^ aite4A-a-t 3- (5- { 1 - [(4-benzyloxyphenyl) -acetyl] pyrrolidin-2-yl.} -2H-pyrazol-3-yl) propionic acid, and acid 3- (3- { 1- [3- (2-methylbenzyloxy) benzoyl] -pyrrolidin-2-yl}. Isoxazol-5-yl) propionic acid. Compounds including the remainder of partial formula (1.1.7): 3- [3- (1-. {2- 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino acid} - 3-methylbutyl) pyrazol-1-yl] -2-methylpropionic acid, 2-acetylamino-3- [3- (1 -. {2- 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino acid .3. -3-methylbutyl) pyrazol-1-ylpropionic acid, 2-methanesulfonylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino acid} -3-methylbutyl) pyrazol-1-ylpropionic acid, 2,2-difluoro-3- acid. { 3- [1- (methyl- { [6 - (- o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] pyrazol-1-yl} propionic acid, 2,2-dimethyl-3- [3- (1 -. {[[6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) pyrazol-1-yl ] propionic acid, 2- (butane-1-sulfonylamino) -3- (3. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1- il.}. acetyl) amino] -methyl}. pyrazol-1-yl) propionic acid, 2-methyl-3- [3- (1. {[4- (2-methylbenzyloxy) phenyl] -acetyl acid} pyrrolidin-2-yl) pyrazol-1-ylpropionic acid, 2-formylamino-3- acid. { 3- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] pyrazol-1-yl-propionic acid, 2-methyl-3- (3-. {1 - [(4-o-tolyloxyphenyl) - acetyl] pyrrolidin-2-yl.}. irazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- (3. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. p. Razol-1-yl) propionic acid, 2-benzenesulfonylamino-3- [3- (1- {[[3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl acid ) pyrazole-1-ylpropionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1. {[[5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidine] n-2-yl) pyrazol-1-yl] propionic acid, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl} -5-methylpyrazole-1-ylpropionic acid, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] pyrazol-1-ylpropionic acid, 2- (2,6-dichlorobenzoylamino) 3-3 -. { 3 - [( { [3-methoxy-4- (3-o-tolylureido (phenyl] acetyl} methylamino) methyl] pyrazol-1-ylpropionic Compounds including the remainder of partial formula (1.1.8) : 3- [4- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} -3-methylbutyl) oxazol-2-yl] -2- methylpropionic acid, 2-acetylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino-3-methylbutyl) oxazol-2-yl] propionic acid, 2-metalenylfonylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino] -3-methyl-butyl) -oxazol-2-yl] -propionic acid , 2,2-difluoro-3- { 4- [1 - (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] oxazole-2 acid -yl.} propionic acid, 2,2-dimethyl-3- [4- (1- {[[6- (3-phenylureido) pyridin-3-yl] acetyl] {pyrrolidin-2-yl) oxazole} -2-il] propionic, -. &J 2-allyloxycarbonylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazole-2-yl} propionic acid, 2- (butane-1-sulfonylamino) -3- (4-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1- il.}. acetyl) amino] -methyl}. oxazol-2-yl) propionic acid, 2-methyl-3- [4- (1 - { [4- (2-methylbenzyloxy) phenyl] -acetyl acid} pyrrolidin-2-yl) oxazol-2-yl] propionic acid, 2-formylamino-3-acid. { 4- [1- (b-phenyl-4-yl-acetyl) pyrrolidin-2-yl] thiazol-2-yl} propionic acid, 2-methyl-3- (4- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl.}. oxazol-2-yl) propionic acid, 2-benzenesulfonylamino- 3- (4- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. Oxazol-2-yl) propionic acid, 2-benzenesulfonylamino-3- [4- (1 - { [3-methoxy-4- (3-o-tolylurethane) phenyl] acetyl} pyrrolidin-2-yl) oxazol-2-yl) propionic acid, 2-methanesulfonylamino-3- [4- (3-methyl) -1- { [5- (3-o-tolyluretho) pyridin-2-yl] acetyl {pyrrolidn-2-yl) oxazol-2-yl] propionic acid 2-acetylamino-3-. { 4 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl} methylamino) methyl] -5-methyloxazol-2-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] thiazol-2-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methy1] oxazol-2-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl} methylamino) methyl] -1 H -imidazol-2-yl} proponic Compounds including the remainder of partial formula (1.1.)): 3- [4- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} - 3-methylbutyl) imidazol-1-yl-2-methylpropionic acid, 2-acetylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) pheny] acetylamino] -3-methylbutyl) imidazole- 1-propionic acid, 2-methanesulfonylamino-3- [4- (1 -. {2- 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) imidazole -1-propylionic acid, 2,2-difluoro-3- acid. { 4- [1 - (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] imidazol-1-ylpropionic acid, 2,2-dimethyl-3 acid - [4- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) imidazol-1-ylpropionic acid, 2- (butane-1-) sulfonylamino) -3- (4-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acetyl) aminojmethyl} imidazole- 1 -yl) propionic acid, 2-methyl-3- [4- (1- {[[4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) imidazol-1-ylpropionic acid, 2-methyl-3- [4- (1. -formylamino-3-. { 4- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] imidazol-1-ylpropionic acid, 2-methyl-3- (4-. {1 - [(4-o-tolyloxyphenyl)) - acetylpyrrolidin-2-yl-imidazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- (4-. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl-imidazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- (4. -benzenesulfonylamino-3- [4- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) imidazol-1-ylpropionic acid, 2-methanesulfonylamino -3- [4- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) imidazol-1-ylpropionic acid; -acetylamino-3-. { 4 - [( { [3-methoxy-4-3-o-tolylureido) phenyl] acetyl} methylamino) methyl-5-methylimidazol-1-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] imidazol-1-ylpropionic acid, 2- (2,6-dichlorobenzoylamino) -3- . { 4 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl} methylamino) methyl] imidazol-1-ylpropionic acid. Compounds including the remainder of partial formula (1.1.10): 3- [3- (1-. {2- 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} -3 acid -methylbutyl) - [1,4-oxadiazol-5-yl] -2-methylproionic acid, 2-acetylamino-3- [3- (1 -. {2- [3-methoxy-4- (3- o-tolylureido) phenyl] acetylamino.} - 3-methylbutyl) - [1, 2,4] oxadiazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (1 -. {2- 2- [ 3-methoxy-4- (3-o-tolylureido) phenyl-5-acetylamino] -3-methylbutyl) - [1, 2,4] oxadiazol-5-yl] propionic acid, 2,2-difluoro-3- acid. { 3- [1 - (methyl-. {1 - (methyl- {[[6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] - [1, 2.4 ] oxadiazol-5-yl.} propionic acid, 2,2-dimethyl-3- [3- (1- {[[6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin- 2-yl) - [1, 2,4] oxadiazol-5-yl] propionic acid, 2-allyloxycarbonylamino-3-. {3 - [( { [3-methoxy-4- (3-o-tolylureido ) phenyl] acetylmethylamino) methyl] - [1,14] oxaidazol-5-yl-1-propionic acid, 2- (butane-1-sulfoniamino) -3- (3- {[methyl- (. {4- [3- (3-Methylpyridin-2-yl) ureido] pyridin-1-yl}. Acetyl) amino] methyl.} - [1, 2,4] oxadiazol-5-yl) propionic acid, 2-methyl- 3- [3- (1- { [4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) - [1,2,4] oxadiazol-5-yl] propionic acid 2- formylamino-3- {3- [1 - (biphenl-4-yl-acetyl) pyrrolidin-2-yl] - [1, 2,4] thiadiazol-5-yl}. propionic acid 2-methyl-3- (3- { 1 - [(4-o-tolyloxyphenyl) acetyl] -pyrrolidin-2-yl} - - [1,4] oxadiazol-5-yl) propionic acid 2-Benzenesulfonylamino-3- (3- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolid in-3-yl.} - [1, 2,4] oxadiazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- [3- (1 -. { [3-methoxy-4- (3-o-tolylureido) phenyl) acetyl} pyrrolidin-2-yl) - [1,4-oxadiazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1 - { [5- (3-o- tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) - [1,4] oxadiazol-5-yl] propionic acid, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tlilureido) phenyl] acetyl} methylamino) methyl] -5-methyl- [1, 2,4] oxadiazol-5-yl} propionic, 2-formylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] - [1,4] thiadiazol-5-yl} propionic acid, 3-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenylJacetyl. {Methylamino) methyl] -2H- [1, 2,4] triazol-3-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylured)) phenyl] acetyl} methylamino) methyl] - [1,4] oxadiazol-5-yl} propionic Compounds including the remainder of the partial formula (1.1.11): 3- [3- (1-. {2- [3-methoxy-4- (3-o-tolylurethane) pheny]] - acetylamino.} - 3-methylbutyl) - [1, 2,4] thiazol-1-yl] -2-methylpropionic acid, 2-acetylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido)] phenyl [acetylamino.] - 3-methylbutyl) - [1, 2,4-tetrazol-1-ylpropionic acid, 2-methanesulfonylamino-3- [3- (1-. {2- [3-methoxy-4 - (3-o-tolylureido) phenyl] acetylamino.] - 3-methylbutyl) - [1, 2,4] triazol-1-ylpropionic acid, 2,2-difluoro-3-acid. { 3- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] - [1, 2,4] triazol-1-ylpropionic acid 2,2-dimethyl-3- [3- (1- { [6- (3-phenylureido) pyridin-3-yl] acetyl}. -pyrrolidin-2-yl) - [1, 2,4] triazol-1-ylpropionic acid, 2-allyloxycarbonylamino-3-acid. { 3 - [( { [3-methoxy-4- (3-o-f-tolylureido) phenyl] -acetyl} -methylamino) methyl] - [1,4-triazol-1-yl]} propionic, 2- (butane-1-sulfonylamino) -3- (3. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acid} acetyl) amino] methyl.} - - [1, 2,4] triazol-1-yl) propionic acid, 2-methyl-3- [3- (1- { [4- (2-methylbenzyloxy)} phenyl] acetyl, pyrrolidin-2-yl) - [1,4] triazol-1-ylpropionic acid, 2-acetylamino-3- acid. { 3- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-ylj- [1, 2,4] triazol-1-ylpropionic acid, • 2-methyl-3- (3-. {1- 1- (4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl.} - 20 [1, 2,4] triazol-1-ylpropionic acid, 2-benzenesulfonylamino-3- (3-. {1 - [( 4- phenoxymethylphenyl) acetyl] pyrrolidin-2-yl.} - [1, 2,4-triazol-1-yl) propionic acid, 2-benzenesulfonyl-amino-3- [3- (1 - { [3 -methoxy-4- (3-o-tolylureido) phenyljacetyl} pyrrolidin-2-yl.} - [1,4-triazol-1-ylpropionic acid, 2-methanesulfonylamino-3- [3- (3 -methyl-1 - { [5- (3-o-tolyluretho) pyridin-2-yl] acetyl} pyrrolidin-2-yl} - - [1,4] triazole -1-phenylpropionic acid, 2-acetylamino-3- { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] -acetyl} -methylamino) methyl] - 4-methyl- [1, 2,4-] triazol-1-ylpropionic acid, 2-acetylamino-3-. {3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl) acetyl] -methylamino) methyl] - [1, 2,4] triazol-1-ylpropionic acid, 2- (2,6-dichlorobenzoylamino) -3-. {3 - [( { [ 3-methoxy-4- (3-o- 10 t) olilureido) phenyl] acetyl} methylamino) methyl] - [1, 2,4] triazol-1-ylpropionic acid. Compounds including the remainder of partial formula (1.1.12): 3- [4- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} -3- acid - methylbutyl) thiophen-2-yl] -2-methylpropionic acid, 2-acetylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-15-tolylureido) phenyl] -acetylamino acid .} - 3-methylbutyl) furan-2-yl] propionic acid, 2-methanesulfonylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o- tolylureido) phenyl] acetylamino.} - 3-methylbutyl) thiophen-2-yl] propionic acid, 2,2-difluoro-3- acid. { 4- [1- (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] -1 H -pyrrol-2-yl} propionic acid, 2,2-dimethyl-3- [4- (1- {[[6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) thiophen-2 acid -yl] propionic, 2- (butane-1-sulfonylamino) -3- (4-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureidoJpiperidin-1) acid -IJacetyl) -amino] methyl.}. Furan-2-yl) propionic acid, 2-methyl-3- [4- (1- {[[4- (2-methylbenzyloxy) phenyl] -acetyl}. pyrrolidin-2-yl) -1 H-pyrrol-2-ylpropionic acid, 2-formylamino-3- acid. { 4- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -thiophen-2-yl} propionic acid, 2-methyl-3- (4- { 1 - [(4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl} -1H-pyrrol-2-yl) propionic acid 2-Benzenesulfonylamino-3- (4- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} furan-2-yl) propionic acid, 2-benzenesulfonylamino-3- [4- ( 1 - { [3-methoxy-4- (3-o-10-tolylurethane) phenyl] -acetyl} pyrrolidin-2-yl) thiophen-2-yl] propionic acid, 2-methanesulfonylamino -3- [4- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) -1 H -pyrrol- 2-yl] propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methyl-1 H-pyrrol-2-yl} propionic, 2-acetylamino-3-acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] thiophen-2-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acids. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] furan-2-yl} proponic Compounds including the remainder of partial formula (1.1.13): 3- [5- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} - acid 3- methylbutyl) thiophen-3-yl] -2-methylpropionic acid, 2-acetylamino-3- [5- (1-. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino acid .} - 3-methylbutyl) furan-3-yl] propionic acid, 2-methanesulfonyl-3- (5- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl]] acetylamino.) - 3-methylbutyl) thiophen-3-ylpropionic acid, 2,2-difluoro-3- acid. { 5- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] -1 H -pyrrol-3-yl} propionic acid, 2,2-dimethyl-3- [5- (1- { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) thiophene -3-yl] propionic acid, 2- (butane-1-sulfonylamino) -3- (5-. {[[Methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido]] piperidin-1-yl.}. acetyl) amino] methyl.}. furan-3-yl) propionic, 2-methyl-3- [5- (1- {[4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) -1 H-pyrrol-3-yl] propionic acid, 2 -formylamino-3-. { 5- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -thiophen-3-yl} propionic acid, 2-methyl-3- (5- { 1 - [(4-o-tolyloxy-phenyl) -acetyl] -pyrrolidin-2-yl} -1H-pyrrol-3-yl) propionic acid, 2-Benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. Furan-3-yl.} Propionic acid, 2-benzenesulfonylamino-3-acid [5- (1- { [3-methoxy-4- (3-o-tolylureido) phenyl) -acetyl} pyrrolidin-2-yl) thiophen-3-ylpropionic acid, 2-methanesulfonylamino acid -3- [5- (3-methyl-1- { [5- (3-o-20-tolylureido) pyridin-2-yl] -acetyl} pyrrolidin-2-yl) -1 H -pyrrole-3 -l] propionic, 2-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -2-methyl-1 H-pyrrol-3-yl} propionic, 2-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyljthiophen-3-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl-acetyl} -methyllamino) methyl] furan-3-yl} propionic Compounds including the remainder of partial formula (1.1.14): 3- [5- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} acid. -3- methylbutyl) thiophen-2-yl] -2-methylpropionic, • 2-acetylamino-3- [5- (1 -. {2- [3-methoxy-4- (3-o-tolylurethane ) phenyl] acetylamino.} - 3-methylbutyl) furan-2-yl] propionic acid, 2-methanesulfonylamino-3- [5- (1- { 2- [3-methoxy-4- (3- o-tolylureido) phenyl] acetylamino.} - 3-methylbutyl) thiophen-2-yl] propionic, f 2,2-difluoro-3- acid. { 5- [1 - (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] -1 H -pyrrol-2-yl} propionic, 2,2-dimethyl-3- [5- (1 -. {[[6- (3-phenylureido) pyridin-3-yl] acetyl] pyrrolidin-2-yl) thiophen-2 acid -yl] propionic, 2- (butane-1-sulfonylamino) 3- (5. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin- 2-yl.) Acetyl) amino] methyl.} Furan-2-yl) propionic acid, 2-methyl-3- [5- (1- {[[4- (2-methylbenzyloxy) phenyl] acetyl]. {pyrrolidin-2-yl) - • 1 H-pyrrol-2-yl] propionic acid, 2-formylamino-3- acid. { 5- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -thiophen-2-yl} propionic acid, 2-methyl-3- (5- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl}. -1 H- pyrrol-2-yl) propionic acid, 2- Benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} furan-2-yl}. propionic acid, 2-benzenesulfonylamino-3- [5- (1 - { [3-methoxy-4- (3-o-tolitureido) phenyljacetyl} pyrrolidin-2-yl) thiophen-2-yl] propionic acid, 2-methanesulfonylamino-3- [5- ( 3-methyl-1- {[5- (3-o-tolylideido) pyridin-2-yl-acetyl} pyrrolidin-2-yl) -1 H -pyrrol-2-yl] propionic acid 2-Acetylamino-3- { 5 - [( { [3-methoxy-4- (3-o- • tolylimideido) phenyl] -acetyl} -methyllamino) methyl] -2-methylene- 1 H, pyrrol-2-yl.} Propionic acid, 2-acetylamino-3. {5 - [( { [3-methoxy-4- (3-o-10-tolyluret)) phenyl] -acetyl acid .) methylamino) methyl] thiophen-2-yl.} propionic acid 2- (2,6-dichlorobenzoylamino) -3-. {5 - [( { [3-methoxy-4- ( 3-o-tolylureido) phenyl] acetyl} methylamino) methyl] furan-2-yl) propionic acid. Compounds including the remainder of partial formula (1.1.15): 3- [5- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} - 3- 15 methylbutyl) isoxazol-3-ylj-2-methylpropionic acid, 2-acetylamino-3- [5- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] .} - 3-methylbutyl) isoxazol-3-yl] propionic acid, 2-methanesulfonylamino-3- [5- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl]] acetylamino.) - 3-methylbutyl) isoxazol-3-yl] propionic acid, 2,2-difluoro-3- acid. { 5- [1 - (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] isoxazol-3-yl} propionic, 2,2-dimethyl-3- [5- (1- {[[6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) isoxazole-3-acid il] propionic, 2-allyloxycarbonylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl-acetyl} -methylamino) methyl] isoxazol-3-yl} propionic, 2- (butane-1-sulfonylamino) -3- (5-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-2-yl} acid} acetyl) amino] methylene] isoxazol-3-yl) propionic acid, 2-methyl-3- [5- (1 - { [4- (2-methylbenzyloxy) phenyl] acetyl acid .}. pyrrolidin-2-yl) isoxazol-3-yl] propionic acid, 2-acetylamino-3- (5- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-ylj- • isothiazol-3-yl.} propionic acid, 2-methyl-3- (5- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl}. isoxazole-10- il) propionic, 2-benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} isoxazol-3-yl) propionic acid, 2-benzenesulfonylamino-3- [5-] (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-3-yl] propionic acid, 2-methanesulfonylamino-3- [5] - (3-methyl-1- { [5- (3-otolyluretho) pyridin-2-yl] acetyl] pyrrolidin-2-yl) -soxazol-3-yl] propionic acid , 2-formylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] -acetyl} -methylamino) -methyl] -4-methylisoxazole-3-yl} propionic, 2-acetylamino acid, 3-. { 5 - [( { [3-methoxy-4- (3-o-20-tolylureido) phenyl] -acetyl} -methylamino) -methyl] -isothiazol-3-yl} propionic, 3-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -2H-pyrazol-5-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isoxazol-3-yl} propionic Compounds including the remainder of partial formula (1.1.16): 3- [5- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} - 3-5-methylbutyl) -oxazol-2-yl] -2-methylpropionic acid, 2-acetylamino-3- [5- (1 - { 2- [3-methoxy-4- (3-o-tolylureido)) L-acetylamino.} - 3-methylbutyl) oxazol-2-yl] propionic acid, 2-methanesulfonylamino-3- [5- (1 -. {2- 2- [3-methoxy-4- (3-o-folylureido (phenyl) acetylamino,} - 3-methylbutyl) oxazol-2-yl] propionic acid, 2,2-difluoro-3-. {5- [1- (methyl- { [6- (3- o-tolylureido (pyridin-3-yl) acetyl} amino) ethyl] oxazol-2-yl.} propionic acid, F 2,2-dimethyl-3- [5- (1-. {[[6-] (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) oxazol-2-yl] propionic acid, 2-allyloxycarbonylamino-3. {5 - [( { [ 3-methoxy-4- (3-o- tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-2-yl} propionic, 2- (butane-1-alphaphonylamino) 3-3 [5-. { [methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl}. acetyl) -amino] methyl} oxazol-2-yl) propionic acid, 2-methyl-3- [5- (1- { [4- (2-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) oxazole-2 acid -yl] propionic acid, 2-formylamino-3- acid. { 5 - [- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] thiazole-2-ylpropionic acid, 2-methyl-3- (5-. {1 - [(4-o-tolyloxyphenyl) -acetyl acid ] pyrrolidin-2-yl.}. oxazol-2-yl { propionic acid, 2-benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. oxazol-2-yl.} propionic acid, 2-benzenesulfonylamino-3- [5- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidine- 2-yl.) Oxazol-2-ylpropionic acid, 2-methanesulfonylamino-3- [5- (3-methyl-1- {[[5- (3-o-tolylureido) pyridin-2-yl] acetyl}. pyrrolidin-2-yl) oxazol-2-yl] propionic acid, 2-acetylamino-3-. {5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methyloxazol-2-yl.} propionic acid, 2-acetylamino-23-. {5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl) -methyl-amino) -methyl] -thiazol-2-yl} -propionic acid, 2- (2,6-dichlorobenzoylamino) 3-. {5 - [( { [3-methoxy-4 - (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-2-yl.} Propionic acid, 2-acetylamin o-3- [5- ( { 2- [4- (3-o-tolylureido) phenyl-acetylamino} methyl) -1 H-imidazol-2-yl] propionic. Compounds including the remainder of the partial formula (1.1.17): 3- (5- { 1 - [(4-benzyloxy-3-methoxyphenyl) -acetyljpyrrolidin-2-yl.} - [1, 3] , 4] thiazdiazol-2-yl) propionic acid, 3- [5- (1- { [4- (4-chlorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) - [1, 3, 4] thiadiazol-2-yl] propionic acid, and 3- (5-. {1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl] - - [1,4] thiadiazole -2-il) propionic. Compounds that include the rest of partial formula (1.1.18), (1.1.19) and (1.1.20): 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl] (meth) amino) methyl] phenol} propionic, 2-formylamino-3- acid. { 6- [1- ( { [3-methoxy-4- (3- (3-methylpyridin-2-yl) ureido] phenyl} acetyl) pyrrolidin-2-yl] pyridin-2-yl .}. propionic acid, 3- {4- [1- (. {3-ethyl-4- [3- (3-methylpyridin-2-yl) ureido] phenyl} acetyl) pyrrolidin -2-yl] pyrimidin-2-yl.} Propionic acid, 2-acetylamino-3- [3- (1- { [3-methoxy-4- (3-o-i-tolylureido) phenyl] acetyl, pyrrolidin-2-yl) phenyljpropionic acid, 2-acetylamino-3- [3- (. {2- [3-methoxy-4- (3-o-10-tolylureido) phenyl]] acetylamino, methyl) phenyl] propionic acid, 2- {2 - [( { [3-methoxy-4- (3-o-pholylureido) phenyl] acetyl} methylamino) methyl] pyridine- 4-ylmethyl} -4-methyl-pentanoic acid, 3- {2 - [(methyl- {[4- (3-o-tolylureido) phenyl] -acetyl} {amino} methyl} pyridine} 4-yl.} Propionic acid, 2-methanesulfonylamino-3- { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl}. methylamino) methyl] - [1, 3,5] triazin-2-yl.}. propionic acid, 1 - [4- (1 - { [6- (3-pyridin-2-hydride) pyridin -3-yl] acetyl.}. Pyrrolidin-2-yl) pyridin-2-ylmethi l] cyclopropanecarboxylic acid, 3- [3- (1- (3. { [6- (3-pridin-2-ylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) phenyl] butyric acid, 2- (btuano-1-sulfonylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] phenyl} propionic acid, 2-benzenesulfonylamino-3- [3- ( { [2-methoxy-2'-methylbiphenyl-4-yl) acetyl] methylamino acid} methyl) phenyl] propionic. 2- (3 { [2- (4-benzyloxyphenyl) acetylamino] methyl} benzyl) malonic acid, 2- [3- (. {- [4- (4-chlorobenzyloxy) phenyl] - 5 acid acetylamino, methyl) benzyl] malonic acid, 3- [3- (. {2- [4- (3-fluorobenzyloxy) phenyl] acetylamino] methyl) phenyl] -2- (propane-1) -sulfonylamino) propionic, 3- [3- ( { 2- [3-Chloro-4- (4-chlorobenzyloxy) phenyl] -acetylamino} methyl) phenyl] -2- (propane-1-sulfonylamino) propionic acid, acid 3 - (3- { [2- (4-benzyloxy-3-chlorophenyl) acetylamino] -methyl] phenyl) -2- (proan-1-sulfonylamino) propionic, 3- [3- ( {2- [4- (3-Chlorobenzyloxy) phenyl] acetylamino.} Methyl) phenyl-2- (propane-1-sulfonylamino) propionic acid, 3- [3- (. {2 - [4- (4-chlorobenzyloxy) phenyl] acetylamino.] Methyl) phenyl] -2-15 (propane-1-suifonylamino) propionic acid, 3- (3 { [2- (4-benzyloxy-3 -methoxyphenyl) acetylamino] methyl] phenyl) -2- (propane-1-sulfonylamino) propionic acid, 3- [3- (. {2- 2- [4- (4-methylbenzyloxy) phenyl] acetylamino}. methyl) -2- acetylamino-3- (3. {[2- (4-benzloxyphenyl) -acetylamino] methyl} phenyl) propionic, 3- [3- ( { 2- (4-benzyloxyphenyl) acetylamino] -methyl} phenyl) -2- (propane-1-sulfonylamino) propionic acid, 2- (propane-1-sulfonylamino) -3- acid. { 3 - [(2-m-tolylacetylamino) methyl] phenyl} propionic, 3- (3 { [2- (4-hydroxymethylphenyl) acetylamino] -methyl} phenyl) -2- (propane-1-sulfonylamino) propionic acid, and 3- [3- (phenylacetylaminomethyl)] phenyl] -2- (propane-1-sulfonylamino) propionic. Compounds including the remainder of partial formula (1121): 3- [4- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} -3- acid methyl-butyl) -pyrrol-1-yl] -2-methylpropionic acid,. 2-Acetylamino-3- [4- (1-. {2- [3-methoxy-4- (3-o-tolylurethane) phenyl] acetylamino] -3-methylbutyl) pyrrol-1-yl acid ] propionic acid, 2-methanesulfonylamino-3- [4- (1- {2- [3-methoxy-4- (3-o-tolylureido) pheny] acetylamino} -3-methylbutyl ) pyrrol-1-ylpropionic acid, f 2,2-difluoro-3- acid. { 4- [1 - (methyl- { [6- (3-o-tolylureido) pyridn-3-yl] acetyl} amino) ethyljpyrrol-1-yl} propionic, 2,2-dimethyl-3- [4- (1 -. {[[6- (3-phenylureido) pyridin-3-yl] acetyl] pyrrolidin-2-yl) pyrrole-1 acid -ylpropionic acid, 2- (butane-1-sulfonylamino) -3- (4-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) uredodopiperidin-1-yl} .}. acetyl) -amino] methyl.}. pyrrol-1-yl) propionic acid, 2-methyl-3- [4- (1 - { [4- (2-methylbenzyloxy) phenyl] -acetic acid pyrrolidin-2-yl) pyrrol-1-ylpropionic acid, 2-formylamino-3- acid. { 4- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] pyrrol-1-ylpropionic acid, 2-methyl-3- (4-. {1 - [(4- o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl}. pyrrol-1-yl) propionic acid, 2-benzenesulfonyl-amino-3- (4. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin- 2-yl.) Pyrrol-1-ylpropionic acid, 2-benzenesulfonylamino-3- [4- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin- 2-yl.) Pyrrol-1-ylpropionic acid, 2-methanesulfonylamino-3- [4- (3-methyl-1- {[[5- (3-o-tolylureido) pyridin-2-yl} acetylpyrrolidin-2-yl) pyrrol-1-ylpropionic acid, 2-acetylamino-3-. {4 - [( { [3-methoxy-4- (3-o- • tolylureido) phenyl] acetylmethylamine) methyl -5-methylpyrrol-1-ylpropionic acid, 2-acetylamino-3- { 4 - [( { [3-methoxy-4- (3-o-10-tolylureido) phenyl-acetyl-methylamine) -methyl] -pyrrol-1-yl-propionic acid , 2- (2,6-dichlorobenzoylamino) -3-. {4 - [( { [3-methoxy-4- (3-o-thylureido) phenyl-acetyl} -methylamino) methylpyrrolidone-1 - iljpropionic.Compounds that include the rest of partial formula (1.1.22): 3- [4- (1-. { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} -3- 15 methylbutyl) pyrazol-1-yl] -2-methylpropionic acid, 2-acetylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) pyrazol-1-ylpropionic acid, 2-methanesulfonylamino-3- [4- (1 -. {2- 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino-3-methylbutyl} pyrrazol-1-ylpropionic acid, 2,2-difluoro-3- acid. { 4- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl-amino) ethyl] pyrazol-1-yl} propionic, 2,2-dimethyl-3- [4- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) pyrazol-1-ylpropionic acid , 2- (butane-1-sulfonylamino) -3- (4-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acid} acetyl) amino] -methyljpyrazol-1-yl) propionic acid, 2-methyl-3- [4- (1- {[[4- (2-methylbenzyloxy) phenyl] -acetyljpyrrolidin-2-yl) pyrazol- 1 -ylpropionic acid, 2-formylamino-3- acid. { 4- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] pyrazol-1-ylpropionic acid, 2-methyl-3- (4-. {1 - [(4- o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl.}. pyrazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- (4. {1 - [(4-phenoxymethylphneyl) acetyl] pyrrolidin-2-acid) il.} pyrazol-1-yl) propionic, 2-benzenesulfonylamino-3- [4- (1 - { [3-methoxy-4- (3-o-tolylurethane) phenyl] acetylpyrrolidin-2-yl) pyrazol-1-yl] propionic acid, 2-methanesulfonylamino-3- [4- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl] pyrrolidin-2 -yl) p -razol-1-yl] propionic acid, 2-acetylamino-3- [4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methylpyrazol-1-ylpropionic acid, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetylmethylmethyl) methyl] pyrazol-1-ylpropionic acid, and 2- (2,6-dichlorobenzoylamino) -3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] -acetyl- {(methylamino) methyl] pyrazol-1-yl-propionic acid. Compounds including the remainder of partial formula (1.1.23): 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl-methylamino) methyl-benzo-oxazole-6-carboxylic acid, 2- [1 - (2- {3-methoxy-4- [3- (3-methylpyridin-2-yl) ureido] phenyl} acetylamino) -3-methylbutyl] -3H-benzoimidazole- 5-carbolylyl, 2- (1 - { [4- (3-pyridin-2-ylureido) phenyl] acetyl-pyrrolidin-2-yl) -1 H- imidazo [4,5-c] pyridine-6-carboxylic acid, 2- (1 - { [3-ethoxy-4- (3-pyridin-2-ylureido) phenyl] acetyl} pyrrolidin-2-yl) benzothiazole-6-carboxylic acid , 2 - [( { [3-methoxy-4- (3-o- • tolylurethane) phenyl] acetylmethylmethyl) methyl] benzothiazole-6-carboxylic acid, 2 - [( { [4 -benzyloxyphenyl) acetyl] methylaminoj-methy1) oxazolo [5,4-10 bjpyridine-5-carboxylic acid, 3-methyl-2- acid. { 1 - [(4-Phenoxyphenyl) acetyl] pyrrolidin-2-ylj-3H-f-benzoimidazole-5-carboxylic acid. The above described compounds of the present invention 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. Said 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, hemisucinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxyethane sulfonate, setionate, laccase, 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, sulfonsalicylate, tartrate, thiocyanate, thiomalate, tosylate and undecanoate. Base salts of the compounds of the present invention include, but are not limited to, ammonium salts, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts with organic bases such such as dicyclohexylamine, meglumine, N-methyl-D-glucamine, tris- (hydroxymethyl) methylamine (tromethanin) and salts with amino acids such as arginine, lysine, etc. The compounds of the present invention comprising basic nitrogen-containing groups can be quaternized with agents such as (C 1 -C 4) alkyl halide, for example methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides.; dialkyl (C1-C4) sulfates, for example dimethyl, diethyl and diamyl sulfates; alkyl halides (C-io-Cis), for example decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides and arylalkyl (C1-C4) halides, for example benzyl chloride and phenethyl bromide. Said salts allow the preparation of compounds of the present invention soluble in water and soluble in oil.

Among the salts mentioned above, those preferred include, but are not limited to, acetate, mesylate, citrate, fumarate, gluconate, hemisucinate, hipurate, hydrochloride, hydrobromide, isothionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and trimethylamine. Multiple forms of salts are included within the scope of the present invention when a compound of the present invention contains • more than one group capable of forming said pharmaceutically acceptable salts. Examples of multiple forms of typical salts include, but are not limited to them, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trichlorhydrate. The pharmaceutical compositions of the present invention comprise one or more of the above-described inhibitory compounds of the present invention, or a pharmaceutically acceptable salt thereof.

These, as also described above, together with a pharmaceutically acceptable carrier according to the properties and expected activity of successful carriers, are well known in the pertinent art. The term "carrier" as used herein, includes diluents, excipients, adjuvants and acceptable carriers. The carriers Pharmaceutically acceptable compounds 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 porteins, 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, sodium acid phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts, colloidal silica, magnesium trisilicate, prolivinylpyrrolidone; 5 substances based on cellulose, for example carboxymethylcellulose; polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers and wool grease. • More particularly, the diluents, excipients, adjuvants and vehicles used in the pharmaceutical compositions herein The invention comprises members selected from the groups consisting essentially of the following: acidifying and alkalinizing agents added to borage a desired or predetermined pH comprise acidifying agents, for example acetic acid, glacial acetic acid, malic acid and propionic acid; and alkalizing agents, for example edetol, carbonate potassium, potassium hydroxide, sodium borate, sodium carbonate and sodium hydroxide; necessary aerosol impellers when the pharmaceutical composition is to be delivered in aerosol form at a significant pressure, for example, acceptable halogenated hydrocarbons, nitrogen or • a volatile hydrocarbon such as butane, propane, isobutane or mixtures of these; antimicrobial agents, including antibacterial, antifungal and antiprotozoal agents added when the pharmaceutical composition is topically applied, for example antimicrobial agents such as benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenylmercury acetate, potassium sorbate and sorbic acid, and antifungal agents such as acid benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben and sodium benzoate; antimicrobial preservatives added to the pharmaceutical compositions to protect them against the growth of potentially harmful microorganisms, for example alkyl esters of p-hydroxybenzoic acid, propionate salts, phenoxyethanol, sodium methylparaben, sodium propylparaben, sodium dehydroacetate, benzalkonium chloride, benzethonium chloride and benzyl alcohol; added antioxidants to protect all the ingredients of the pharmaceutical composition from damage or degradation by oxidizing agents present in the composition itself or in the environment of use, for example anoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulphite, propyloctyl and dodecyl gallate, sodium metabisulfite, sulfur dioxide and tocopherols; buffering agents used to maintain the desired pH of a composition after establishment, 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 to bind destructive compounds and metals and effectively remove them, for example dipotassium edetate, disodium edetate and edetic acid. Dermatologically active agents are added to the pharmaceutical compositions of the present invention which are applied topically, for example wound healing agents such as peptide derivatives, _-ß-_ yeast, patenol, hexylresorcinol, phenol, tetracycline hydrochloride, lamin and kinetin, glucocorticosteroids for the treatment of inflammation, for example hydrocortisone, dexamethasone, betamethasone, triamcinolone, fluocinolone and methylprednisolone, retinoids for the treatment of acne, 5 psoriasis, skin aging and skin cancer, for example retinol, tretinoin, isotretinoin, etretinate, acitretin and arotinoid, immunosuppressive agents for the treatment of inflammation, for example dapsone • and sulfasalazine; mild antibacterial agents, for example resorcinol, salicylic acid, benzoyl peroxide, benzoyl peroxide-erythromycin, erythromycin, clindamycin and mupirocin; antifungal agents, for example griseofulvin, azoles such as miconazole, econazole, itraconazole, fluconazole and ketoconazole and allylamines such as naftifin and tertinaphine; 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 pramoxine hydrochloride, topical analgesics, for example methyl salicylate, camphor, menthol and resorcinol; topical antiseptics for the prevention of infection, for example benzalkonium chloride and povidone-iodine; vitamins and derivatives thereof such as tocopherol, acetate tocopherol, 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: suspending and suspending agents, for example polygen, providone and silicon dioxide; emollients, for example oils and hydrocarbon waxes, esters of trilglicerides, acetylated monoglycerides, methyl esters and other alkyl esters of C-io-5 C2o fatty acids, C?-C2o fatty acids, C? 0-C2o 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 laurocapram and ether polyethylene glycol monomethyl; humectants, for example sorbitol, glycerin and hyaluronic acid; ointment bases, 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 chloride Benzalkonium, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, derivatives of hindatoin, cetylpyridinium chloride, propylparaben, quaternary ammonium compounds such as potassium benzoate and thimerosal; sequestering agents that comprise cyclodextrins; • solvents, for example acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene stearyl ether-15 , propylene glycol, propylene glycol diacetate, sesame oil, and purified water; stabilizers, for example calcium saccharate and thymol; surfactants, for example lapyrium chloride, laureth 4, ie a-dodecyl-omega-hydroxypiol (oxy-1,2-ethanediyl) or polyethylene glycol monododecyl ether. According to this invention, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile aqueous or oleaginous injectable suspension. This suspension can be formulated according to techniques known in the art, using suitable dispersing agents or humectants 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 in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and an isotonic solution of sodium chloride. In addition, sterile, non-volatile oils are conveniently employed as a solvent or suspension medium. To this end, any insipid non-volatile oil, including synthetic mono- or diglycerides, can be employed. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol as a diluent or as a dispersant, such as Rh, HCIX 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, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in the form of a capsule, • Useful diluents include lactose and desired corn starch. When aqueous suspensions are needed for oral use, the active ingredient is 1 10 combines with emulsifying and suspension agents. If desired, certain sweetening, flavoring or coloring agents may also be added. As an alternative, the pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a non-irritating excipient It is suitable that it is solid at room temperature, but liquid at the rectal temperature, and therefore it melts in the rectum releasing the drug. These materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention can • also administered by topography, especially when the purpose of the treatment includes areas or organs easily accessible by topical application, including diseases of the eyes, skin or lower intestinal tract. 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 carriers. The 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 compounds, emulsifying wax and water. Alternatively, the pharmaceutical compositions f can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Acceptable carriers include, but not are limited thereto, mineral oil, sorbitan monostearate, polysorbate, wax of cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions may • formulated as a micronized suspension in isotonic saline sterile with adjusted pH, or preferably, as solutions in sterile exit solution with adjusted pH, with or without preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention can also be administered by nasal spray or by inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Said 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 the • bioavailability, hydrofluorocarbon compounds and / or other conventional solubilizing or dispersing agents. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary f depending on the host treated, and the particular mode of administration. It should be understood, however, that the specific dose and treatment regimen for a particular patient will depend on a number of factors, including the activity of the specific compound used, age, body weight, health status, sex, diet, period of administration, rate of excretion, combination of drugs and the judgment of the attending physician and the severity of the particular disease that is being treated. The amount of active ingredient may also depend on the therapeutic agent or prophylactic, if any, with which the ingredient is co-administered. The dosage and dose rate of the compounds of this invention effective to prevent, inhibit, suppress or reduce cell adhesion and the consequent or associated pathogenic 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 doctor in charge. For example, when the dosage form is oral, for example a tablet or capsule, suitable dosage levels of the compounds of formula (1.0.0) will be between about 1.0 μg and about 10.0 mg / kg of body weight per day, preferably between about 5.0 μg and about 5.0 mg / kg of body weight per day, more preferably between about 10.0 μg and about 2.0 mg / kg of body weight per day, and more preferably between about 20.0 μg and about 0.5 mg / kg of body weight per day. body weight per day of the active ingredient. When the dosage form is administered topically to the bronchi and lungs, for example by means of a powder inhaler or nebulizer, the appropriate dosage levels of the compounds of formula (1.0.0) will be between about 0.1 μg a about 1.0 mg / kg of body weight per day, preferably between about 0.5 μg and about 0.5 mg / kg of body weight per day, more preferably between about 2.0 μg and about 0.1 mg / kg of body weight per day, and more preferably between about 2.0 μg and about 0.05 mg / kg of body weight per day of the active ingredient.

Using representative body weights of 10 kg and 100 kg to illustrate the range of daily topical dosages that could be used as described above, the appropriate dosage levels of the compounds of formula (1.0.0) will be between about 1.0-10.0 μg and 10.0 -100.0 mg per day, preferably between approximately 5.0-50.0 mg per day, more preferably between approximately 10.0-100.0 μg and 1.0-10.0 mg per day, and more preferably between approximately 20.0-200.0 μg and approximately 0.5-5.0 mg per day of the active ingredient comprising a compound of formula (1.0.0). These ranges of dosage amounts represent the total dosage amounts of the active ingredient per day for a given patient. The number of times a day a dose is administered will depend on pharmacological and pharmacokinetic factors such as the half-life of the active ingredient, which reflects its rate of cartbolism and elimination, as well as minimum and optimal levels in the blood plasma or other fluid of the said active ingredient obtained in the patient, which are necessary for therapeutic efficacy. Many more factors must be considered to decide the number of doses per day and the amount of active ingredient per dose that will be administered. The no less important of these other factors is the individual response of the patient to be treated, so, for example when the active ingredient is used to treat or prevent asthma and is administered topically by inhalation of aerosol in the lungs, they will be administered from one to four doses constituted by activations of a dispensing device, ie "bursts" of one inhibitor, per day, each dose containing from about 50.0 μg to about 10.0 mg of the active ingredient. Included in the scope of the present invention are embodiments comprising compositions containing, in addition to a > the present invention as an active ingredient, additional active ingredients as therapeutic agents selected from the group consisting essentially of anti-inflammatory corticosteroids, bronchodilators,• anti-asthmatics, non-steroidal anti-inflammatory drugs, immunosuppressants, immunostimulants, ammetabolites, antipsoriatics and antidiabetics. The specific compounds from each of these classes may be selected from those listed in the appropriate chapters of Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, England, p. 970-986 (1990); and in The Pharmacological Basis of Therapeutics by Goodman and Gilman, 9th edition, Hardman, J.G. and Limbird, L.E., Eds., McGraw Hill, 1996, whose descriptions are incorporated herein by reference in their entirety. Especially preferred active ingredients 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 pathological processes subsequently mediated by VLA-4. As already indicated, cell adhesion associated with VLA-4 plays a central role in a series of inflammatory, immune and autoimmune diseases. Thus, the inhibition of cell adhesion by the compounds of this invention can be used in methods of treatment or prevention of inflammatory, immune and autoimmune diseases, Preferably, the diseases to be treated with the • Methods of this invention are selected from asthma, arthritis, psoriasis, transplant rejection, multiple sclerosis, diabetes and the disease of the inflamed intestine. The above described treatment methods of the present invention can employ the compounds of formula (1.0.0) in monotherapy form, although the said methods can also be used in the form of multiple therapy in which one or more compounds of Formula (1.0.0) are co-administered in combination with an anti-inflammatory, immunomodulatory, immunostimulant or immunosurgery agent known. The terms "co-administered" or "co-administration" as used herein, are understood to mean the therapeutic use of one or more compounds of formula (1.0.0) combined with one or more additional therapeutic agents, including, but not limited to, administering the combination of therapeutic active agents in a single dosage form or in multiple dosage forms, representing the same or different administration routes, the aforementioned multiple dosage forms being administered substantially at the same time or at different times. Following the synthesis of any of the above-mentioned preferred species of the present invention, or of any other compound that falls within the scope of the present invention, the biological activities related to the specificities of VLA-4 of said compounds can be determined. using one or more of the numerous in vitro or in vivo assays that have been described so far in the technical literature of the pertinent art. For example, some of the test procedures and models, now well established, that relate to the measurement of VLA-4 activity by determining the concentration of a candidate inhibitor assay, require blocking the binding of the cells that express VLA-4 to plates coated with fibronectin or CS-1. In this assay, the microtiter wells are coated with fibronectin (containing the sequence CS-1), with peptide CS-1 or with soluble VCAM-1. After coating the wells, variable concentrations of the test compound are added along with cells expressing VLA-4, appropriately marked. Alternatively, the test compound can be added first and allowed to incubate with the coated wells before the addition of the cells. The cells are allowed to incubate in the wells for at least 30 minutes. After incubation, the wells are emptied and washed. The inhibition of the binding is measured by quantification of the fluorescence or of the 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 tests mentioned below for the determination of VLA-4 activity of the compounds of formula (1.0.0). Cells expressing VLA-4 that can be used in this assay include Ramos cells, Jurkat cells, melanone A375 cells, as well as human peripheral blood lymphocytes (PBL). The cells used in • This assay may be fluorescent or radioactively labeled.

To evaluate the inhibitory specificity of VLA-4 of the compounds of The assay can be performed for other major groups of integrins, ie β2 and β3, as well as for other β-i integrins, such as VLA-5, VLA-6 and cc4β7- These assays can be similar to inhibition assays. the adhesion and direct binding described above, substituting the cell expressing the appropriate integrin and the ligand corresponding. For example, morphonuclear cells (PMN) express β2 integrins on their surface and bind to ICAM, whereas β2 integrins are involved in platelet aggregation and inhibition can be measured in a conventional platelet aggregation assay. VLA-5 binds specifically to Arg-Gly-Asp sequences, while VLA-6 binds to laminin. In addition, c ß 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 that - «-» _-. ».. * .- *. it uses CS-1, VCAM or MAdCAM-1 and a cell line that expresses ct4β, but not VLA-4, such as RPMI-8866 cells.

After identifying the specific inhibitors of VLA-4, they can further be characterized by in vivo assays. One of said 5 tests verifies the inhibition of airway hyperresponsiveness induced by allergens and the cellular influx, as described in Hederson et al., "Blockade of CD49d (a4 integrin) on intrapulmonary / but not circulating leukocytes inhibits. airway inflammation and hyperesponsiveness in a mouse model of asthma ", J. Clin. Invest., 100 (12), p. 3083-92 (1997). In this In the assay, the mice are sensitized by intraperitoneal exposure to an irritant, such as ovalbumin. After a period of recovery, the mice • spray the allergen. Prior to aerosol exposure, mice are administered various doses of the VLA-4 inhibitor by intrathecal injection. In vivo inhibition of cell adhesion associated with Inflammation is evaluated by measuring the number of cells and cytokines in the bronchial alveolar lavage fluid. In this manner, those inhibitors of this invention that are most suitable for the inhibition of inflammation can be identified.

Another in vivo test that can be used is the asthma test of primates. This test is performed essentially as described in Turner, C.R. et al. "Characterization of a primate model of asthma using anti-asthma agents", Inflammation Research, 45 (5), p. 239-45 (1996), the description of which is incorporated herein by reference in its entirety. This assay measures the inhibition of late-phase airway responses and airway hyperresponsiveness induced by the Ascaris antigen in allergic primates, after the administration of anti-allergy / anti-asthma agents.

The compounds of the present invention can be formulated in. pharmaceutical compositions which can be administered orally, parenterally, by inhalation (metered dose inhaler, dry powder inhaler or nebulizer), topical, rectal, nasal, intraocular, buccal, vaginal or by an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, 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 that are non-peptidic or semi-peptidic in nature. A number of different procedures are available which are fully described in the technical literature and with which the person skilled in the art will be familiar. The description below of several of said synthesis schemes is representative only and is not supposed to be limiting in any way. A series of abbreviations are used in the aforementioned description to save space. Although these abbreviations are also good M > Means known to the person skilled in the art are immediately described below for reasons of clarity and convenience: BOP benzotriazol-1-yloxytris (dimethylamino) phosphonic hexafluorophosphate DAST diethylaminosulfur trifluoride DIEA diisopropylethylamine DMF dimethylformamide EDCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBT 1 -hydroxybenzotriazole • 10 THF tetrahydrofuran SYNTHESIS SCHEME 1 STAGE A C-Oo 2E. t 2. 0.0 2.0.1 irii-MuMiiii-Tlr - 'The synthesis of compounds of formula 1.0.0 in which component "B" is an isoxazole ring and component "Y" is -S02- is illustrated in scheme 1, steps A to G. In scheme 1, step A, the starting material, diethylamino malonate, is commercially available, for example in Aldrich Chemical Company, Milwaukee, Wl 53233. The amide product (2.0.1), wherein R5 is hydrogen, methyl or phenyl, is also commercially available. • Other amides, where R5 is alkyl, aryl, heterocyclyl or heteroaryl, are readily available through the reaction of the chloride of appropriate acid with the amine (2.0.0) using conditions that are well described in the literature (for example March, J. "Advanced Organic • Chemistry ", 3rd edition, 1985.) Under similar conditions, the amine (2.0.0) can be converted to its corresponding sulfonamide by the reaction of 2.0.0 with an alkyl- or arylsulfonyl chloride.The carbamate product (2.0.1 ), Wherein R5 is alkoxy or aryloxy, is prepared from amine 2.0.0 according to the procedures described in Paik, Yi Hyon; Dowd, Paul; J. Organic Chem., 1986, 51 (15), 2910-2913; and Kawai Masao; Nyfeler, Rolf; Berman, Judd M .; Goodman, Munrray; J. Med Chem., 1982, 25 (4), 397-402. • SYNTHESIS SCHEME 1 STAGE B In scheme 1, stage B, intermediate 2.0.3 is prepared starting from oxime 2.0.2. Oxime 2.0.2 is prepared from its corresponding aldehyde by procedures well known to those skilled in the art (eg, Chung, Yong Jung, Ryu, Eun Jung, Keum, Byochang, Kim, Byeang Hyean, Bioorg. Med. Che., 1996, 4 (2), 209-226; and Kim, Byeang Hyean; Chung, Yong Jun; Keum, Gyochang; Kim, Jaheon; Kim, Kimoon, Tetrahedron Lett., 1992, 33 (45); 6811-6814). The oxime 2.0.2 becomes the 'Soxazol 2.0.3. by oxidation with a suitable oxidant such as Sodium hypochlorite, tert-butyl hypochlorite or N-chlorosuccinimide in a suitable solvent such as THF, chloroform or methylene chloride, reacting the resulting nitrile N-oxide with propargyl bromide. This [2 + 3] cycloaddition reaction is well known in the literature as a method for preparing α -oxazole ring structures. See, for example, Synthesis, 508.9, 1982.

** - - * ^ "~ - ~ - ~ - SYNTHESIS SCHEME 1 STAGE C 2. 0.3 2.0.1 2.0.4 In scheme 1, stage C, intermediate bromide 2.0.3 is converted into component 2.0.4 containing isoxazole. The bromide 2.0.3 is reacted with an optionally substituted malonate (2.0.1) in a suitable solvent such as DMF, DMSO or methylene chloride in the presence of a base such as triethylamine or cesium carbonate. DMF is the preferred solvent and cesium carbonate is the preferred base. The reaction is carried out at a temperature between 0 and 30 ° C for a period of 1 to 16 hours. The reaction of bromide 2.0.3 with malonate 2.0.1 in scheme 1, stage C is not limited to 2-aminomalonates, but may be extended to include malonates of formula [EtOC (= 0) CHR7C (= 0) Oet ], in which R7 is defined above in the definition of formula 1.0.0.

SYNTHESIS SCHEME 1 STAGE D 2. 0.4 2.0.5 The synthesis of the intermediate monoester 2.0.5 is illustrated in scheme 1, stage D. The diethyl malonate 2.0.4 is converted into its intermediate half ester by reaction with one equivalent of one base.

Suitable such as sodium hydroxide or aqueous lithium hydroxide in a solvent such as THF, methanol, tert-butanol or dioxane. The use of aqueous sodium hydroxide in dioxane is preferred. The reaction is carried out at a temperature between 0 and 50 ° C for a period of time between 1 and 16 hours. Three hours are preferred at room temperature. Becomes Subsequently, this intermediate half ester to the monoester 2.0.5 in situ by heating in a suitable solvent such as benzene, toluene or • dioxane at a temperature between 0 and 200 ° C for a period between 1 and 16 hours. Heating at 125 ° C for 3 hours in dioxane is preferred. ** - "-« - ^ "" tf- --- SYNTHESIS SCHEME 1 STAGE E 2. 0.5 2.0.6 • The synthesis of intermediate amine 2.0.6 is illustrated in scheme 1, stage The tert-butyloxycarbamate 2.0.5 intermediate is reacted with an acid such as pure trifluoroacetic acid, or a solution of hydrochloric acid in its suitable non-aqueous solvent such as dioxane. The reaction is carried out at a temperature between 0 and 50 ° C for a period of time between 1 and 16 hours. The preferred conditions are hydrochloric acid in dioxane at room temperature for 1 hour. Those skilled in the art will recognize that the tert-butyloxycarbonyl group functions as a protecting group for the amine and that other suitable protecting groups may be employed. HE will also recognize that the removal procedures of these protective groups must be compatible with all the functionalities present in R5 These methods are well known in the technical literature of the relevant art. For example, see Greene, T.W., Wuts, P.G.M. Protective Group in Organic Synthesis, John Wiley & Sons; New York, 1991. twenty .- ^ - «? J-. - ..

SYNTHESIS SCHEME 1 STAGE F 2. 0.6 2.0.7 The synthesis of sulfonamide intermediate 2.0.7 is described in scheme 1, step F. The amine 2.0.6 is reacted with a sulfonyl chloride [A (CH2) n-S02CI, wherein "A" and "n" are defined above in the definition of formula 1.0.0] in a solvent such as dichloromethane, water or pyridine with or without a base such as sodium carbonate or diisopropylethylamine. The reaction is carried out at a temperature between 0 and 50 ° C for a period of between 1 and 16 hours. The preferred conditions are sodium carbonate in water at room temperature for 16 hours.

SYNTHESIS SCHEME 1 STAGE G 2. 0.8 2.0.7 The carboxylic acid product is prepared from the ester intermediate 2.0.7 as illustrated in scheme 1, step G. The intermediate ester 2.0.7 is reacted with a suitable aqueous base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent such as tert-butanol, methanol and / or THF. The reaction is carried out at a temperature between 0 and 50 ° C for a period of time between 0.5 and 24 hours. Preferred conditions are aqueous lithium hydroxide in a mixture of THF and methanol at room temperature for 1 hour. The synthesis described above is broadly applicable to the compounds of formula (1.0.0). To make this synthesis even clearer, the synthesis scheme 1-a, steps A to G, is described below, with reference to a particular compound of the present invention.

SYNTHESIS SCHEME 1-a 2.1.5 2.1.4 The following schematic synthesis diagram illustrates a generalized preparation procedure for compounds of formula 1.0.0 in which the "Y" component is C = 0: SYNTHESIS SCHEME 2 STAGE A CH Cl A1-NCO + N ^ -A2-CH2C02H 2 2 > A, NHC (0) NH-? -CH2C02H 2. 0.9 2.0.10 2.0.11 > The starting material A1-NC0 is an isocyanate in which "A1" has the same definition as component A of formula (1.0.0) with respect to • of the aryl, heteroaryl and heterocyclyl radicals substituted with 0 to 3 R9. The isocyanate starting materials for the preparation of component A, such As phenyl isocyanate, o-tolyl isocyanate, 2-fluorophenyl isocyanate and 2-chlorophenyl isocyanate are commercially available, for example, from F * Aldrich Cehmical Company, Milwaukee, Wl 53233. Alternatively, the isocyanate starting materials can be easily prepared from their corresponding amines using the procedures described in bibliography (eg March, J. "Advanced Organic Chemistry", 3rd edition) 1985). The pyridyl analogs of the above phenyl isocyanates can 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 made react with an amine of formula 2.0.10. The addition of amines to Isocyanates is a well-known reaction that provides substituted ureas In a simple way. The reaction can be carried out in a solvent such as methylene chloride with triethylamine at slightly elevated temperatures. The disubstituted urea (2.0.11), prepared as in the scheme of above-stated reaction, which forms the reagent that will eventually give rise to component A of the compounds of formula (1.0.0), is then react with an amine of the formula "-NR4CR2R3-B", wherein "B" is defined as one of the partial formulas (1.1.0) - (1.1.22).

SYNTHESIS SCHEME 2 STAGE B A1 NHC (O) NH-A2-CH2CO2H 2.0.11 2.0.6 One skilled in the art will recognize that the reaction between the reagent that forms component A (2.0.11) and amine 2.0.6 implies the acylation of an amine by a carboxylic acid, which can be performed in good yield at room temperature or slightly above it by the use of coupling agents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( EDCl) and 1-hydroxybenzotriazole (HOBT), dicyclohexylcarbodiimide (DCCI), N'.N'-carbonyldiimidazole, tetrafluoroate of N.N.N'N'-tetramethyl (succinimido) uronium and hexafluorophosphate of benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium (BOP). The amine component 5 (2.0.6) is available as described in scheme 1. This reaction can be illustrated in the above schematic synthesis diagram, which provides a generalized preparation procedure for • compounds of formula (1.0.0). To prepare the final product of formula (1.0.0) in the form of an acid, an additional step is required, as shown in the following reaction scheme: ^ SYNTHESIS SCHEME STAGE C LiOH (ac) THF methanol 20 - ~ # ******* - - The final acid product (2.0.13) is prepared from ester 2.0.12 as illustrated in the previous scheme. The intermediate is reacted with a suitable aqueous hydroxide base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent system comprising tert-butanol, methanol or THF and methanol. The reaction is carried out at a temperature between 0 ° C and 50 ° C for 0.5 to 16 hours. Preferred conditions are lithium hydroxide in THF, methanol and water at room temperature for 1 hour. The synthesis described above is broadly applicable to the compounds of formula (1.0.0). To make the synthesis even clearer, the synthesis scheme 2-a, steps A to C, is described below with reference to a particular compound of the present invention: SYNTHESIS SCHEME 2-a 2. 1.15 LiOH (aq) methanol water H 2. 1.16 métítitmtia? 1 ** "* - ---- - - - - - • •> ^ ^ n ^ Sia An alternative synthesis of compounds of formula (1.0.0) is illustrated in synthesis scheme 3 , Steps A to O The synthesis of intermediate amine 2.0.14 is illustrated in Scheme 3, step A. The tert-butyloxycarbamate 2.0.4 intermediate is reacted with an acid such as pure trifluoroacetic acid, or a solution of hydrochloric acid in a suitable non-aqueous solvent such as dioxane The reaction is carried out at a temperature between 0 and 50 ° C for a period of time between 1 and 16 hours.Preferred conditions are hydrochloric acid in dioxane at room temperature for 1 hour. Those skilled in the art will recognize that the tert-butyloxycarbonyl group functions as a protective group for the amine and that other suitable protecting groups can be employed It will also be recognized that the methods of removing these protective groups must be compatible with all functionality is present in R5 These procedures are well known in the technical literature of the relevant art. For example, see Greene, T.W., Wuts, P.G.M. Protective Group ¡n Organic Synthesis, John Wiley & Sons; New York, 1991.

SYNTHESIS SCHEME 3 STAGE A 2. 0.4 2.0.14 SYNTHESIS SCHEME 3 STAGE B 2. 0.14 EDCl 2.0.15 HOBT trieti lamina DMF In scheme 3, step B, the amine 2.0.14 is reacted with acid 2.0.15 under the same conditions as synthesis scheme 2, stage B.

To prepare the final product of formula (1.0.0) in the form of acid, an additional stage is required, as the following scheme of reaction: SYNTHESIS STRUCTURE 3 STAGE C 2. 0.16 2.0.17 Prepare the final acid product (2.0.17) from ester 2.0.16 as illustrated in the previous scheme. The intermediate is reacted with a suitable aqueous hydroxide base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent system comprising tert-butanol, methanol or THF and methanol. The reaction is carried out at a temperature between 0 and 50 ° C for a period of 0.5 to 16 hours. Preferred conditions with lithium hydroxide in THF, methanol and water at room temperature for 1 hour. 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 3-a, step A to C, is described below with reference to a particular compound of the present invention: SYNTHESIS SCHEME 3-a 2 1 19 2.1 20 üsmí ^ - .a * .Í. V? .

An alternative mode of synthesis of compound of formula (1.0.0) is illustrated in synthesis scheme 4, steps A to D.

SYNTHESIS SCHEME 4 STAGE A In scheme 4, step A, oxime 2.0.2 is converted to isoxazole 2.0.18 by oxidation with a suitable oxidant such as sodium hypochlorite, tert-butyl hypochlorite or N-chlorosuccinimide in a suitable solvent such as THF, chloroform or methylene chloride; and reacting the resulting nitrile N-oxide with a 2,2-disubstituted methyl pent-4-inoclate. This [2 + 3] cycloaddition reaction is well known in the literature as a method for preparing the ring structure of soxazole. See, for example, Synthesis, 508-9, 1982.

SYNTHESIS SCHEME 4 STAGE B 2. 0.18 2.0.19 The synthesis of intermediate amine 2.0.19 in the above reaction scheme is illustrated using the same conditions as scheme 3, step A, The starting material is the tert-butyloxycarbamate intermediate 2.0.18.

SYNTHESIS SCHEME 4 STAGE C H 2.0.15 2.0.19 In synthesis scheme 4, step C, the amine 2.0.19 is reacted with acid 2.0.15 under the same conditions as synthesis scheme 2, step B. This reaction can be illustrated in the above schematic synthesis diagram, which provides a generalized preparation process for the compounds of formula (1.0.0). To prepare the final product of formula (1.0.0), in the form of acid, an additional step is required, as shown by the following reaction scheme: SYNTHESIS SCHEME 4 STAGE D The final acid product 2.0.21 was prepared from ester 2.0.20, as illustrated in the above scheme, using the procedure of scheme 3, step C. The synthesis described above is broadly applicable to compounds of formula (1.0 .0). to make the said synthesis even clearer, the synthesis scheme 4-a, steps A to C, is described below with reference to a particular compound of the present invention: twenty ¡¡¡ASiMaM¡ gg ^ g ^^ j ^ j ^ ______ __ ^ ___ ^ -__--- SYNTHESIS SCHEME 4-a 2. 1.26 An alternative way is illustrated for the synthesis of compounds of formula (1.0.0) in synthesis scheme 5, steps A to D. wp? «fí-? l_- i? É-rirf IÍ - r T - * ¿- * - -. - l í - »? *? áta ^? SYNTHESIS SCHEME 5 STAGE A Bromide 2.0.22 is commercially available from, for example, Aldrich Chemical Company, Milwaukee, WL 53233. Bromide 2.0.22 is converted to the desired component 2.0.23 containing a diester, as shown in the above scheme. The bromide is reacted with an aminomalonate under the conditions described in scheme 1, step C.

SYNTHESIS SCHEME 5 STAGE B The nitrile 2.0.23 is converted into the desired 2.0.24 amine as illustrated in the above reaction scheme. The nitrile 2.0.23 is reduced to the corresponding amine 2.0.24 by hydrogenation, as described in the literature (for example March, J. "Advanced Organic Chemistry", 3rd edition, 1985).

The synthesis described above is broadly applicable to the compounds of formula (1.0.0). To make the aforementioned synthesis even clearer, describe the synthesis scheme 5-a below: SYNTHESIS SCHEME 5-a 2. 1.29 Pd on carbon methanol H2HCI EDC HOBT 15 triethylamine DMF LiOH (aq.) 20 methanol THF The synthesis of bicyclic compounds of formula (1.0.0) is illustrated in synthesis scheme 6, steps A to D. The starting materials are acid and amines available from commercial sources, for example Aldrich Chemical Company, Milwaukee, Wl 53233.

SYNTHESIS SCHEME 6 STAGE A 2. 0.22 2.0.23 EDC HOBT triethylamine DMF The person skilled in the art will recognize that the reaction illustrated in the above scheme involves the acylation of an amine 2.0.22 by a carboxylic acid 2.0.23, which can be performed in good yield at room temperature or slightly above it by the use of coupling agents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl) and 1-hydroxybenzotriazole (HOBT), dicyclohexylcarbodiimide (DCCI), N.N '-carbonyldiimidazole, POCI3, TiCl4, SO2CIF Ti8Obu), P2I4, Bu3N, benzotriazol-1-yl diethylphosphate, N, N, N', N'-tetramethyl (succinimido) uronium tetrafluoroborate and preferably di-isopropylethylamine (DIEA) and Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP).

SYNTHESIS SCHEME 6 STAGE B 1. Acetic acid 2. 4 N HCl in dioxane 2. 0.26 The synthesis of intermediate amine 2.0.26 in the above reaction scheme is illustrated. The starting material is a mixture of the tert-butyloxycarbamate intermediates 2.0.24 and 2.0.25. Intermediates 2.0.24 and 2.0.25 are reacted with an acid such as hydrochloric or acetic acid with or without a suitable solvent such as dioxane. The reaction is carried out at a temperature between 0 and 100 ° C for 1 to 16 hours. Acetic acid is preferred in the absence of additional solvent at 80 ° C for 1.5 hours. Those skilled in the art will recognize that these conditions achieve both cyclization to form the desired bicyclic ring system and elimination of the tert-butyloxycarbonyl group. Those skilled in the art will also recognize that the tert-butyloxycarbonyl group functions as an amine protecting group and that other suitable protecting groups can be employed. It will also be recognized that the procedures for the elimination of these protective groups must be compatible with all the functionalities present in Intermediate 2.0.26. These methods are well known in the technical literature of the relevant art, for example, see Greene, T.W., Wuts, P.G.M. Protective Group in Organic Synthesis, John Wiley & Sons; New York, 1991. 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 6-a is described below, with reference to a particular compound of the present invention: SYNTHESIS SCHEME 6-a 2. 1.39 LiOH (aq.) Methanol THF 2. 1.40 An alternative way is illustrated for the synthesis of compounds of formula (1.0.0) in synthesis scheme 7, steps A to C. These steps describe an alternative route for component B used in the coupling reaction, as described in reaction scheme 2, stage B. _- r - »... .. ..-_ _ i" SYNTHESIS SCHEME 7 STAGE A The preparation of intermediate bromide 2.0.29 was described in synthesis scheme 1 stage A. The intermediate bromide 2.0.29 was reacted with commercial imine 2.0.30 available in a suitable solvent such as toluene, methylene chloride or DMF, with a base such as cesium carbonate, cesium hydroxide or potassium hydroxide, in the presence of an additive such as tetrabutylammonium bromide, tetrabutylammonium chloride or tetraphenylammonium bromide. The reaction was carried out at a temperature between -78 and 50 ° C for a period of time from 1 to 16 hours. The reaction of the Intermediate bromide 2.0.29 with imine 2.0.30 in toluene at room temperature in the presence of tetrabutylammonium bromide for 1 hour.

SYNTHESIS SCHEME 7 STAGE B & _- »_,., & t. , _? ... ? * -. .. ..! .. - > :., .-. . -. .IX -, -, t The synthesis of intermediate amine 2.0.32 in the above reaction scheme is illustrated. The intermediate imine 2.0.31 can be transformed into amine 2.0.32 by a series of procedures well known to those skilled in the art and described in the literature. For example, Wolfe, John P .; Ahman, Jens; Saidghi, Joseph P .; Singer, Robert A .; Buchwaid, Stephen L; Tetrahedron Lett., 1997, 38 (36), 6367-6370; and Corey, E.J .; Xu, Feng; Noe, Mark C; J. Am. Chem. Soc. 1997, 119, 12414-12415. In the preferred process, the intermediate imine 2.0.31 is treated with a mixture of ethyl acetate and hydrochloric acid for three hours at room temperature.

SYNTHESIS SCHEME 7 STAGE C The synthesis of intermediate amide 2.0.33 in the above reaction scheme is illustrated. The amine is reacted with or without a solvent, such as dichloromethane, chloroform benzene, water or pyrifine, with an acid anhydride or an acid chloride with or without the addition of a base such as sodium carbonate, pyridine or diisopropylethylamine. The reaction is carried out at a temperature between 0 and 50 ° C for a period of 1 to 16 hours. The _ * --_. _. ___ ____. . . ... ___ ^ __ a_ & i, preferred conditions employ dichloromethane and pyridine at room temperature for 16 hours. The synthesis described above is widely applied to the compounds of formula (1.0.0). To make the aforementioned synthesis even clearer, the synthesis scheme 7-a is described below: SYNTHESIS SCHEME 7-a 2. 1.46 ILLUSTRATION OF PREFERRED EMBODIMENTS The following examples further illustrate the compounds, compositions and methods of treatment of the present invention, but are not to be understood as limiting the scope of the present invention. A series of abbreviations are used in the following examples to save space. Although these abbreviations are well known to those skilled in the art, they are immediately described below for reasons of clarity and convenience with respect to the reader: BOP benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate DAST diethylaminosulfur trifluoride DIEA diisopropylethylamine DMF dimethylformamide EDCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBT 1 -hydroxybenzotriazole THF tetrahydrofuran EXAMPLE 1 A. 2-Allyloxycarbonylamino-3- acid. { 3- [1- (3,5-dichlorobenzenesulfonyl) pyrrolidin-2-yl] isoxazol-5-yl} propionic * • - * - • * * • • - * * *. * A solution of the 2-allyloxycarbonylamino-3-ethyl ester was stirred. { 3-. { 1- (3,5-dichlorobenzene-sulfonyl) pyrrolidin-2-yl] isoxazolo-5-yl} propionic (59 mg, 0.108 mmol) in tetrahydrofuran (1.0 ml) and methanol (0.5 ml) with 2 M aqueous lithium hydroxide (0.5 ml) at room temperature for 40 minutes. The reaction was acidified to pH 1 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and concentration in vacuo afforded the title compound as a white solid (51 mg, 91%). MS (Cl) (Chemical ionization mass spectrometry) m / z 518 (M + 1). B. 2-Allyloxycarbonylamino-3-ethyl ester. { 3- [1- (3,5-dichlorobenzenesulfonyl) pyrrolidin-2-yl] isoxazol-5-yl} propionic 2-ethyl ester hydrochloride was dissolved - * »• - > * - * -, -, * ia .- ^ * & allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) propionic acid (110 mg, 0.294 mmol) and sodium carbonate (93.5 mg, 0.882 mmol) in water (1.5 ml) and 3.5-chloride was added. -dichlorobenzenesulfonyl (86.7 mg, 0.353 mmol). This mixture was stirred overnight. The reaction was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (59 mg, 37%). MS (Cl) m / z 545.7 (M + 1). O 2-Allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) propionic acid ethyl ester chlorohydrate The 2- [5- (2-allyloxycarbonylamino-2-ethoxycarbonylethyl) isoxazol-3-yl] pyrrolidine-1-carboxylic acid tert -butyl ester (3.44 g, 7.86 mmol) was dissolved in 4M hydrochloric acid in dioxane (10%). ml) and stirred at room temperature for 2 hours. The reaction was then concentrated in vacuo and co-evaporated with dichloromethane to provide the desired product as a waxy brown solid. MS (Cl) m / z 509.9 (M + 1). D. 2- [5- (2-Allyloxycarbonylamino-2-ethoxycarbonylethyl) isoxazol-3-yl] pyrrolidine-1-carboxylic acid tert-butyl ester --_-.-- ** **. ** > A mixture of the 2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonylpyrrolidin-2-yl) isoxazol-5-methylmethonic malonic acid ester and 2-allyloxycarbonylamino-2-acid diethyl ester was dissolved. 3- (1-tert-butoxycarbonylpyrrolidin-2-yl) isoxazol-5-ylmethyl] malonic acid (10.4 g, 21.5 mmol) in dioxane (130 mL) and heated in an oil bath at 125 ° C for 3 hours. HE eliminated dioxane under vacuum. The residue was dissolved in ethyl acetate, washed with saturated sodium carbonate and brine, dried over magnesium sulfate and concentrated. The crude material was chromatographed on a 40 M Biotage Flash column, eluting with ethyl acetate / hexanes (1: 4), affording the title compound as a clear oil. (5.12 g, 56% in 2 stages). MS (Cl) m / z 338.0 (M-99). The diethyl ester of 2-allyloxycarbonyl-amino-2- [3- (1-tert-butoxycarbonylpyrrolidin-2-yl) isoxazol-5-ylmethyl] malonic acid (2.96 g, 27%) was recovered. MS (Cl) m / z 509.9 (M + 1), 409.9 (M-99). E. 2-Allyloxycarbonylamino-2- [3- (1-tert-20-butoxycarbonylpyrrolidin-2-yl) isoxazol-5-ylmethyl] malonic acid monoethyl ester M i ??? rtrr ?? ^^ lia-iMtta '- * - 1 -' "- -» - * '- > - *** - * »* • .. 1 M sodium hydroxide (21.5 ml, 21.5 mmol) was added in portions over 30 minutes to a solution of 2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonylpyrrolidin-2-yl) isoxazole-5-diethyl ester. methylmethylmalonic (10.95 g, 21.5 mmol) in dioxane (22 ml). After stirring overnight, it was found that the reaction had not come to an end. Another 0.2 eq of 1 M sodium hydroxide (4.2 ml, 4.2 mmol) was added and stirring was continued for 3 hours. The reaction was diluted with ethyl acetate (50 ml) and 1 M sulfuric acid (23 ml) was added dropwise at 0 ° C. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate and concentrated in vacuo to provide the title compound. The crude product is directly used in the next stage without separation of the unreacted diester. MS (Cl) m / z 382.2 (M-99). F. 2-Allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonylpyrrolidin-2-yl) isoxazol-5-ylmethyl] malonic acid diethyl ester A solution of 2- (5-bromomethylisoxazol-3-yl) pyrrolidin-1 -carboxylic acid tert -butyl ester (7.29 g, 56 mmol) and 2-allyloxycarbonylaminomalonic acid diethyl ester (8.25 g) was cooled to 0 ° C. 32 mmol) in ^^^^ m ^ dimethylformamide (260 ml) and cesium carbonate (25.41 g, 78 mmol) was added. The reaction was allowed to warm to room temperature and was stirred for 3 hours. The reaction mixture was then poured into diethyl ether (2 L) and washed with water (5 x 200 ml) and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with ethyl acetate: hexane (3: 7) to afford the title compound as a clear, colorless oil (10.95 g, 83%). MS (Cl) m / z 260.1 (M-99). G. 2-Allyloxycarbonyl-aminomalonic acid diethyl ester A solution of diethylaminomalonate hydrochloride (47.0 g, 226 mmol) in methylene chloride (1.0 L) was cooled to 0 ° C and pyridine (45 mL, 564 mmol) was added. The previously insoluble solids were dissolved by adding the pyridine. Allyl chloroformate (20 ml, 188 mmol) was slowly added dropwise to maintain the reaction temperature below 5 ° C. After completing the reaction, the reaction was stirred at 0 ° C for 15 minutes. The reaction was washed with 1 M hydrochloric acid (6 x 100 ml), dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (46.78 g,lirThiilii t-iia riiiiiii r • i - • - * ^ - < *. * IM * »- - -« -. * t ~ "a *" 8 80%). The crude product was used without further purification, MS (Cl) m / z 260.1 (M + 1). H. 2- (5-Bromomethylisoxazol-3-yl) pyrrolidin-1-carboxylic acid tert-butyl ester The title compound was prepared in the manner described for Examples 7H and 71, using 2- (hydroxyimnomethyl) pyrrolidin-1-carbamic acid tert -butyl ester in step 71.

EXAMPLE 2 A. 2-Allyloxycarbonylamino-3- (3- {1 - [(4-nitrophenyl) acetyl] pyrrolidin-2-yl} isoxazol-5-yl) propionic acid Hydrolysis of the 2-allyloxycarbonylamino-3- (3- {1 - [(4-nitrophenyl) acetyl] -pyrrolidin-2-yl} -isoxazole-5-ethyl ester was carried out ^ A • »-.» *. ? * L. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -. MS (Cl) m / z 472.6 (M + 1), 471.7 (M + 1). B. 2-Allyloxycarbonylamino-3- (3. {1 - [(4-nitrophenyl) acetyl] pyrrolidin-2-yl] -isoxazol-5-yl) propionic acid ethyl ester A solution of 4-nitrophenylacetic acid (1.61 g, 8.87 mmol) in dimethylformamide (82 ml) was stirred with 4-hydroxybenzotriazole monohydrate (1.40 g, 10.4 mmol) for 10 minutes. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.86 g, 9.72 mmol) was added and the mixture was stirred until all of the 1- (3-dimethylaminopropyl) -3-15-ethylcarbodiimide hydrochloride was dissolved. To this solution was added 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-ylisoxazol-5-yl) propionic acid ethyl ester hydrochloride of Example 1C (3.16 g, 8.25 mmol) and the mixture was stirred for 30 minutes, followed by the addition of triethylamine (1.26 ml, 9.04 mmol). After stirring the reaction at room temperature overnight, it was poured over water and was extracted with ethyl acetate three times. The combined extracts were washed with a saturated solution of sodium bicarbonate, water (2x) and brine. The organic portion was dried over magnesium sulfate and concentrated. The resulting residue was chromatographed on a Biotage column iitfíifíii tiiiliMif - "* -« ** - - - Flash 40S, eluting with ethyl acetate / hexanes (5: 1), affording the title compound as a yellow oil (674 mg, 15%). Cl) m / z 501.3 (M + 1) In addition, the starting material, the 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) propionic acid ethyl ester (2.15 g, 75%). MS (Cl) m / z 338.1 (M + 1).

EXAMPLE 3 A. 2-Allyloxycarbonylamino-3- [3- (1- {[[4- (2,6-dichlorobenzoylamino) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid Hydrolysis of the 2-allyloxycarbonylamino-3- [3- (1- {[4- (2,6-dichlorobenzoylamino) phenyl] acetyl} pyrrolidin-2-yl) isoxazole- ethyl ester was carried out. 5-yl] propionic according to the same protocol as that of example 1A, providing the title compound (77 mg, 75%). MS (Cl) m / z 616.7 (M + 1), 612.5 (M + 1). B. 2-Allyloxycarbonylamino-3- [3- (1- {[[4- (2,6-dichlorobenzoylamino) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid ethyl ester A solution of 2-allyloxycarbonylamino-3- (3. {1 - [(4-aminophenyl) acetyl]] - pyrrolidin-2-yl ethyl ester was cooled to 0 ° C} 6-dichlorobenzoyl) (39 mg, 0.187 mmol) was added. The mixture was stirred for 15 minutes, then pyridine (28 μL, 0.34 mmol) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1 M sodium hydroxide and brine. The organic portion was dried over magnesium sulfate and concentrated to give the title compound (84 mg, 78%). MS (Cl) m / z 635.3 (M + 1), 632.5 (M-1). Or 2-allyloxycarbonylamino-3- (3. {1 - [(4-aminophenyl) acetyl] pyrrolidin-2-yl.] Isoxazol-5-yl) propionic acid ethyl ester A solution of 2-allyloxycarbonylamino-3- (3. {1 - [(4-nitrophenyl) -acetyl] pyrrolidin-2-yl] isoxazole-5-ethyl ester was heated to reflux. . _ "- 4-_ ... ..., - t - t -----.. ----- ..-- *. * ^^ M il) propionic (2B) (565 mg, 1.13 mol) and iron (0) powder (384 mg, 6.98 mmol) in ethanol / water (5 ml, 1: 1). 1 M hydrochloric acid (0.29 ml, 0.29 mmol) was added dropwise and the reaction was heated at reflux for 45 minutes. It was then neutralized with 1 M sodium hydroxide and filtered through Celite. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a Biotage Flash 40S column, eluting with ethyl acetate / hexanes (6: 1), to afford the title compound as a yellow oil (240 mg, 51%). MS (Cl) m / z 471.0 (M + 1).

EXAMPLE 4 A. 2-Allyloxycarbonylamino-3- [3- (1- {[[4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid Hydrolysis of the 2-allyloxycarbonylamino-3- [3- (1- {[4- (3-o-tolylureido) -phenyl] -acetyl} pyrrolidin-2-yl) isoxazole ethyl ester was carried out -5-yl] propionic according to the same protocol as that of example 1A, providing the title compound. MS (Cl) m / z 576.0 (M + 1), 573.9 (M-1). '"* - * • - * •• - * • -" - »> - - -. t * iteü! ii? & Jga B. 2-Allyloxycarbonylamino-3- [3- (1. {[[4- (3-o-tolylureido) pheny] acetyl] ethyl ester. pyrrolidin-2-yl) -isoxazol-5-yl] propionic acid The title compound was prepared in the manner described in Example 2B, using [4- (3-o-tolylureido) -phenyl] acetic acid. MS (Cl) m / z 604.0 (M + 1).

EXAMPLE 5 A. 3- (3- { 1 - [(Acetylaminophenyl) acetyl] pyrrolidin-2-yl.}. Isoxazol-5-yl) -2-allyloxycarbonylaminopropionic acid The hydrolysis of 3- (3. {1 - [(4-acetylaminophenyl) acetyl] pyrrolidin-2-yl}. Isoxazol-5-yl) -2-allyloxycarbonylaminopropionic acid ethyl ester was carried out according to the same protocol than that of Example 1A, providing the title compound. MS (Cl) m / z 485.3 (M + 1), 483.0 (M-1). B. 3- (3 { 1 - [(4-Acetylaminophenyl) acetyl] pyrrolidin-2-yl}. Isoxazol-5-yl) -2-allyloxycarbonylaminopropionic acid ethyl ester The title compound was prepared in the manner described in Example 3B, using acetyl chloride in place of 2,6-dichlorobenzoyl chloride. MS (Cl) m / z 513.0 (M + 1).

EXAMPLE 6 A. 2-tert-Butoxycarbonylamino-3- [3- (1- {[[4- (3-o-tolylureido) phenyl] acetyl) pyrrolidin-2-yl) isoxazol-5-yl] propionic acid The hydrolysis of the methyl ester of 2-tert-butoxycarbonylamino-3- [3- (1- {[4- (3-o-tolylurethodo) phenyl] acetyl} pyrrolidinone was carried out. 2- il) isoxazol-5-yl] propionic according to the protocol of example 1A, provided the title compound. MS (Cl) m / z 590.2 (M-1), 492.2 (M-99). B. 2-tert-Butoxycarbonylamino-3- [3- (1- {[4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) isoxazole-5-yl methyl ester propionic A solution of 1- (4- {2- [2- (Hydryl-iminomethyl) pyrrolidin-1-yl] -2-oxoethyl} phenyl) -3-o-tolylurea (300 mg) was stirred for 5 minutes. 0.789 mmol), 2-tert-butoxycarbonylamino-4-ionic acid methyl ester (359 mg, 1182 mmol, crude mixture) and triethylamine (12.9 μl) in dichloromethane (2 ml). A solution of 5.25% sodium hypochlorite, 2 ml) was added. The reaction was stirred at room temperature overnight. The aqueous portion was extracted 4 times with dichloromethane. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated. Chromatography of the crude mixture on a Biotage column W - i - - "- • '* > * • - - - j« fe-- ..

Flash 40S, eluting with ethyl acetate / hexanes 1: 5, gave the title compound (68 mg, 14%). MS (Cl) m / z 604.5 (M-1), 505.9 (M-99). O 2-tert-butoxy-carbonyl-aminopent-4-inoic acid methyl ester Potassium carbonate (1687 g, 12.2 mmol) was added to a solution of 2-tert-butoxycarbonylamino-4-oxobutyric acid benzyl ester (1875 g, 6.10 mmol) in anhydrous methanol (91.5 mL) and the reaction was stirred for 10 minutes. minutes Dimethyl ester of (1-diazo-2-oxopropyl) phosphonic acid (1,407 g) was added, 7.32 mmol) and the reaction was stirred at room temperature for 1 hour. The ratio was poured into diethyl ether and washed 4 times with 5% sodium bicarbonate, dried over magnesium sulfate and concentrated (1.05 g, crude product mixture). The crude product was used directly in the next step. 1 H NMR (400 MHz, CDCl 3) d 5.39-5.31 (m, 1H), 4.49-4.41 (m, 1H), 3.77 (s, 3H), 2.79-2.65 (m, 2H), 2.03 (s, 1H) , 1.59 and 1.44 (2 singlets, rotamers, 3H). D. 2-tert-Butoxycarbonylamino-4-oxobutyric acid benzyl ester ? _rMiffl were cooled to 0 ° C a solution of tert-butoxycarbonylamino-4-hydroxybutyric 2 (13.58 g, 43.9 mmol) in dimetiisulfóxido (10 ml) and triethylamine (18.35 mL, 131.7 mmol) benzyl ester. Sulfur trioxide pyridine (21.0 g, 131.7 mmol) in dimethyl sulfoxide (80 ml) was added in a continuous stream. The cooling bath was removed and the reaction was removed for 1.5 hours. The reaction was poured into 130 ml of ice water and extracted with diethyl ether (2 x 180 ml and 100 ml). The combined organic portion was washed sequentially with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was chromatographed on silica gel (900 ml), eluting with ethyl acetate / hexanes (1: 4), affording the title compound as a clear, colorless oil (9.20 g, 70%). MS (Cl) m / z 208.9 (M-99).

EXAMPLE 7 A. 2-Acetylamino-4- (3- { 1 - [2- (4-benzyloxyphenyl) -acetylamino] -3-methylbutyl}. Isoxazol-5-yl) propionic acid * -H.fc « *. ~ »-í * ^ ** *!» * «< g »nÉ" ^ ^. . _____ A solution of 2-acetylamino-4- (3- {1- [2- (4-benzyloxyphenyl) acetylamino] -3-methylbutyl} isoxazol-5-yl) propionic acid ethyl ester was combined (92 mg, 0.17 mmol) in methanol / tetrahydrofuran 1: 2 (9 ml) with 2M aqueous lithium hydroxide (3 ml) at room temperature with stirring for 3 hours. After acidifying the reaction to pH = 1 with 1 N hydrochloric acid, it was extracted to the acyl portion with ethyl acetate (2 × 50 ml). combined over sodium sulfate organic portions they were dried, and concentrated to afford 2-acetylamino-4- (1- [2- (4-beceiloxifeil) acetylamino] 3- {-.. 3-methylbutyl) isoxazol-5- il) propionic in the form of a white crystalline solid (83 mg, 95%). MS (Cl) m / z 508.1 (M + 1), 506.1 (M-1). B. Ethyl ester + 2-acetylamino-4- (3- {1- [2- (4-benzyloxyphenyl) acetylamino] -3-methylbutyl} isoxazol-5-yl) propionic acid A solution of (4-benzyloxyphenyl) acetic acid (125 mg, 0.29 mmol, 1.00 eq) and hydrate 1-hydroxybenzotriazole (48 mg, 0.36 mmol, 1.23 eq) in dimethylformamide (5 ml) was stirred at room temperature for 15 minutes . 1- (3-Dimethylaminopropyl) -3-ethylcaabodiimide (64 mg, 0.33 mmol, 1.15 eq) was added and the reaction was stirred for 15 minutes. Hydrochloride of 2-acetylamino-3- [3- (1-amino-3-ethyl) ethyl ester was added ».u .. i- *. -.- **. -fc .. ja-at. «t__jfe,? & . . . . . methylbutyl) isoxazol-5-yl] propionic acid (100 mg, 0.29 mmol, 1.00 eq) and the reaction was stirred for 25 minutes. Triethylamine (43 μl, 0.31 mmol, 1.07 eq) was added. The reaction was stirred at room temperature overnight, then diluted with ethyl acetate (30 ml) and extracted with 1N hydrochloric acid (2 x 30 ml), saturated sodium bicarbonate (2 x 30 ml) and brine ( 30 ml). The organic portion was dried over sodium sulfate and the solvent was removed in vacuo. The residue was chromatographed on a 40S Biotage column (ethyl acetate) to provide the title compound as a clear, colorless oil (94 mg, 61%). MS (Cl) m / z 536.2 (M + 1). C. 2-Acetylamino-3- [3- (1-amino-3-methylbutyl) isoxazol-5-yl] propionic acid ethyl ester hydrochloride ethyl ester 2-acetylamino-3- [3- (1-tert-butoxycarbonylamino-3-methylbutyl) isoxazol-5-yl] propionic acid (7F) (5.95 g, 14.5 mmol) was stirred in 4N hydrochloric acid in dioxane (25 ml) at room temperature overnight. The product was concentrated and dried under high vacuum to provide the title compound as a white solid (5.38 g, 100%). MS (Cl) m / z 312.2 (M + 1 for the free base). D. (4-benzyloxyphenyl) acetic acid a solution of acetic acid methyl ester (4-benzyloxyphenyl) 81.35 g, 5.27 mmol) in methanol / was combined tetrahydrofuran 1: 2 (60 ml) with aqueous lithium hydroxide 2M (20 ml) at room temperature, and stirred the reaction during the night. The reaction was acidified to pH 1 with 1N hydrochloric acid and extracted with ethyl acetate (2 x 50 ml). The organic portions were dried over sodium sulfate and the solvent was removed in vacuo to give the title compound as a white crystalline solid (1.25 g, 98%). NMR-H (300 MHz, CDCl 3) d 3.63 (s, 2H), 5.09 (s, 2H), 6.96-6.99 (d, 2H), 7.22-7.25 (d, 2H), 7.3-7.5 (m, 5H) . E. (4-benzyloxyphenyl) acetic acid methyl ester Cesium carbonate (5.35 g, 16.4 mmol, 3.00 eq) was added to a solution of methyl 4-hydroperoxyphenylacetate (1.00 g, 6.02 mmol, 1.10 eq) and benzyl bromide (0.65 mL, 5.47 mmol, 1.00 eq) in dichloromethane. (40 ml) at 0 ° C. The mixture was allowed to warm to room temperature and stirred vigorously overnight. The reaction was extracted with hydrochloric acid 1 ,. - * & * - *.? .-. .... *., ** .i .. ^ t? _- lfl go »11 - • - - ******? J N (2 x 100 ml) and brine (100 ml). The resulting portion was dried over sodium sulfate and the solvent was removed in vacuo. The resulting oily solid was chromatographed on a 40S Biotage column (20% ethyl acetate / hexanes) to give the title ester as a clear, colorless oil (1.35 g, 96%). 1 H NMR (400 MHz, CDCl 3) d 3.56 (s, 2H), 3.67 (s, 3H), 5.04 (s, 2H), 6.91-6.94 (d, 2H), 7.17-7.19 (d, 2H), 7.3 -7.4 (m, 5H). F. 2-Acetylamino-3- [3- (1-tert-butoxycarbonylamino-3-methylbutyl) isoxazol-5-yl] propionic acid ethyl ester 1 N sodium hydroxide (20.5 ml 20.5 mmol, 1.10 eq) was added to a solution of 2-acetylamino-2- [3- (1-tert-butoxycarbonylamino-3-methylbutyl) isoxazol-5-ylmethyl] diethyl ester] Malonic acid (8.99 g, 18.6 mmol, 1.0 eq) in dioxane at room temperature for 30 minutes, and the reaction was stirred overnight. The reaction was diluted with ethyl acetate (200 ml) and acidified to pH = 1-1.5 with 1 N hydrochloric acid. The organic portion was washed with brine (200 ml) and dried over sodium sulfate. The solvent was removed in vacuo affording 8.58 g of a 1: 1 mixture (according to 1 H-NMR) of the 2-acetylamino-2- [3- (1-tert-butoxycarbonylamino-3-methylbutyl) isoxazole-2-monoethylester -ylmethyl] malonic [MS (Cl) m / z 356.3 j tJ- * Í * i *? - * -. -1 ----.- > . -. *. - .- - - - - * * - ----- J--. -..- ». .. - - * ---, - - _. . - - - - - - _M_É_ta-Í-l-j_ (M-99)] and of the decarboxylated title compound [MS (Cl) m / z 412.3 (M + 1), 312.2 (M-99), 410.3 (M -1)]. The mixture was refluxed in dioxane (150 ml) overnight and concentrated to give an orange oil which was chromatographed using a Biotage column (40M, 50% ethyl acetate / hexanes) to provide the title compound as a dense orange solid (6.72 g, 88%). MS (Cl) m / z 412.3 (M + 1), 312.2 (M-99). G. 2-acetylamino-2- [3- (1-tert-butoxycarbonylamino-3-methylbutyl) isoxazola-5-ylmethyl] -mononic acid diethyl ester Cesium carbonate (18.28 g, 56.1 mmol, 3.0 eq) was added to a solution of [1- (5-bromomethyl-isoxazol-3-yl) -3-methylbutyl] carbamic acid tert-butyl ester (6.48 g, 18.7 mmol, 1.00 eq) and diethylacetamide malonate (4.86 g, 22.4 mmol, 1.20 eq) in dimethylformamide (300 ml) at 0 ° C. The mixture was stirred at room temperature for 5 hours. The reaction was poured into diethyl ether (200 ml) and extracted with water (5 x 200 ml) and brine (200 ml). The organic portion was dried over sodium sulfate and the solvent was removed in vacuo to give the title compound as a viscous oil (8.99 g, 99.4%). MS (Cl) m / z 484.0 (M + 1), 384.1 (M-99).

H. [1- (5-Bromomethyl-isoxazol-3-yl) -3-meitlbutyl] carbamic acid tert-butyl ester N-chlorosuccinimide (5.80 g, 43.4 mmol, 1.00 eq), [1- (hydroxyiminomethyl) -3-methylbutyl] carbamic acid tert-butyl ester (10.00 g, 43.4 mmol, 1.00 eq) and pyridine (0.70 ml) were stirred. in chloroform (70 ml) at room temperature for 1 hour. Propargyl bromide (4.83 ml, 54.3 mmol, 1.25 eq) and the reaction was heated to 45 ° C. Triethylamine (6.35 ml, 45.6 mmol, 1.05 eq) was added dropwise over 20 minutes at 45 ° C. The reaction was stirred for another hour, then diluted with water (200 ml) and extracted with dichloromethane (2 x 200 ml). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 200 ml) and brine (200 ml). The organic portion was dried over sodium sulfate. Evaporation of the solvent gave a brown residue which was subjected to flash chromatography on silica gel, affording the title compound as a white solid (6.48 g, 43%). MS (Cl) m / z 247.0 (M-99). I. 1- (Hydroxyiminomethyl) -3- 20 methylbutylcarbamic acid tert-butyl ester The mixture was stirred vigorously with a mixture of tert-butyl ester of (1-formyl-3-methylbutyl) carbamic acid (2.13 g), hydroxylamine hydrochloride (0.71 g, 10.2 mmol) and NaOAc (HCl). 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 organic phases were washed with water and brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by chromatography using a Flash 40 column of silica gel and eluting with 15-25% EtOAc / hexane provided 1.5 g of the title compound as a white solid mp 156-157 ° C.

EXAMPLE 8 A. 2-Allyloxycarbonylamino-3- [3- (1-benzoyl pyrrolidin-2-yl) isoxazol-5-yl] propionic acid The hydrolysis of compound 8B was carried out according to the protocol of example 1A, affording the title compound, MS (Cl) m / z 414.2 (M + 1), 412.2 (M-1). ...- * -i ... - = -. a ^ "_-_, - ___, ___, - _._ | - mi: Tt-A ^ Jt-- ». . t ^. -. ,. i * £ «aaa * s.- - B. 2-Allyloxycarbonylamino 3- [3- (1-benzoylpyrrolidin-2-yl) isoxazol-5-yl] propionic acid ethyl ester Benzoyl chloride (21 μL, 0.18 mmol, 1.0 eq) was added in one portion to a solution of 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) propionic acid ethyl ester hydrochloride solution (1C) ) (74 mg, 0.20 mmol, 1.1 eq) in pyridine (29 μl, 0.36 mmol, 2.0 eq) and dichloromethane (2 ml) at 0 ° C. The reaction was stirred at room temperature for 4 hours and then diluted with ethyl acetate (30 ml). The reaction was extracted with 1 N hydrochloric acid (30 ml) and brine (30 ml). The organic portion was dried over sodium sulfate and concentrated in vacuo to give the title compound (66 mg, 84%). MS (Cl) m / z 442.3 (M + 1).

EXAMPLE 9 A. 2-Allyloxycarbonylamino-3- acid. { 3- [1-biphenyl-4-carbonyl) pyrrolidin-2-yl] isoxazol-5-yl} propionic ..TO..

The hydrolysis of compound 9B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 490.0 (M + 1), 487.8 (M-1). B. Ethyl ester of 2-allyloxocarbonylamino-3- acid. { 3- [1- (biphenyl-4-carbonyl) pyrrolidin-2-yl] soxazol-5-yl} propionic Prepared using the same procedure described in example 8B. MS (Cl) m / z 518.0 (M + 1).

EXAMPLE 10 A. 2-Acetylamino-3- (3. {3-methyl-1- [2- (4-naphthalen-2-ylphenyl) acetylamino] butyl} isoxazol-5-yl) propionic acid The hydrolysis of compound 10B was carried out using the protocol of Example 1A to provide the title compound MS (Cl) m / z 528.0 (M + 1), 525.8 (M-1). B. 2-Acetylamino-3- (3. {3-methyl-1- [2- (4-naphthalen-2-yl-phenyl) -acetylamino] -butyl} -isoxazol-5-yl) -propionic acid Prepared from 84-naphthalen-2-ylphenyl) acetic acid in the manner described in Example 7B.

'* * * • -' - "*» »** - * • - ~ - ~ - J * ¿**: *.. ~." ^. ** j .. t C. Acid (4-naphthalene- 2-ylphenol) acetic 2 M Lithium hydroxide (3.0 mL) was added to a solution of (4-naphthalen-2-ylphenyl) acetic acid methyl ester (270 mg, 0.977 mmol) in 2: 1 tetrahydrofuran: methanol (9.0 mL). The resulting mixture was stirred at room temperature for 1 hour, the reaction was acidified to pH = 1 with 1M hydrochloric acid and extracted 2 times with ethyl acetate. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to provide the title compound as a white solid (233 mg, 91%). 1 H NMR (400 MHz, CDCl 3) d 8.01-7.39 (m, 11H), 3.72 (s, 2H). D. (4-naphthalen-2-ylphenyl) acetic acid methyl ester Tetrakyl (triphenylphosphine) palladium (65 mg, 7.4 mol%) was added to a solution of (4-trifluoromethanesulfonyloxyphenyl) acetic acid methyl ester (447 mg, 1.5 mmol), 2-naphthaleneboronic acid (286 mg, 1.67 mmol). and cesium fluoride (505 mg, 3.33 mmol) in dimethoxyethane (5.4 ml). The reaction was bubbled with nitrogen and heated in a 100 ° C oil bath with stirring for 3 hours. It was diluted after . The reaction was carried out with ethyl acetate and extracted with water, 1 M sodium hydroxide, water and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with 5% ethyl acetate in hexanes to provide the title compound as a clear oil (273 mg, 66%). 1 H-NMR (400 MHz, CDCl 3) d 8.01-7.38 (m, 11 H), 3.72 (s, 3 H), 3.69 (2 H). B. (4-Trifluoromethane-sulfonyloxyphenyl) acetic acid methyl ester Trifluoromethanesulfonic anhydride (32.2 mmol) was added dropwise over 5 minutes to a solution of the methyl ester of (4-hydroxyphenyl) acetic acid (5.35 g, 32.2 mmol) in pyridine (70 mL) at -40 ° C. The reaction was stirred at -40 ° C for 10 minutes and then at 0 ° C for 2 hours. The reaction was diluted with diethyl ether and washed with water and 2N hydrochloric acid. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed on a 40 M Biotage Flash column with ethyl acetate / hexanes (1: 4) to give the title compound as a clear, colorless oil, which crystallized on standing 9.27 g, 97%. 1 H NMR (400 MHz, CDCl 3) d 7.37-7.34 (m, 2H), 7.24-7.21 (m, 2H), 3.70 (3H), 3.64 (2H).

EXAMPLE 11 A. 2,2-Dimethyl-3- [3- (3-methyl-1 -. {2- [4- (3-o-tolylureido) phenyl] acetylamino] butyl) isoxazol-5-yl] acid propionic The hydrolysis of compound 11B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 521.2 (M + 1), 519.1 (M-1). B. 2,2-Dimethyl-3- [3- (3-methyl-1- {2- [4- (3-o-tolylureido) phenyl] -acetylamino} butyl) -isoxazole-5-methyl ester -il] propionic Prepared from 3- [3- (1-tert-butoxycarbonylamino-3-methylbutyl) isoxazol-5-yl] -2,2-dimethylpropionic acid methyl ester in two steps following the procedure described in examples 1C and 2B . MS (Cl) m / z: 535.1 (M + 1), 535.1 (M-1). ___ ^ _ ^ _ ^^ _ M_f ___%. i, -éi * (t-1í "*" !? - '- - • "= -" • - »- - - ~~. - ______.._.

C- 3- [3- (1-tert-Butoxycarbonylamino-3-methylbutyl) -isoxazol-5-yl] -2,2-d-methylpropionic acid methyl ester Prepared from the [1- (hydroxyiminomethyl) -3-methylbutyl] carbamic acid tert-butyl ester (71) and the 2,2-dimethylpent-4-ynoic acid methyl ester according to the procedure described in Example 6A. MS (Cl) m / z: 313.2 (M-tBu), 269.3 (M-99).

EXAMPLE 12 A 3- (3- (3-Methyl-1- {2- [4- (3-o-tolylureido) phenyl] -acetylamino} butyl) isoxazol-5-yl] -2-phenylproionic acid bikini -.-,.

The hydrolysis of compound 12B was carried out by using the protocol of Example 1A to provide the title compound. B. 3- [3- (3-Methyl-1- {2- [4- (3-o-tolylureido) phenyl] -acetylamino} butyl) -isoxazol-5-yl] -2- methyl ester phenylpropionic The title compound was prepared from 3- [3- (1-tert-butoxycarbonylamino-3-methylbutyl) isoxazol-5-yl] -2-phenylpropionic acid methyl ester in the manner described in Example 11B. O 3- [3- (1-tert-Butoxy-carbonylamino-3-methylbutyl) isoxazol-5-yl] -2-phenylpropionic acid methyl ester The title compound of 2-phenylpent-4-enoic acid methyl ester was prepared in the manner described in Example 6A. D. 2-Phenylpent-4-Niconic Acid Methyl Ester Diisoropylethylamine (5.9 ml, 42 mmol) was dissolved in tetrahydrofuran (30 ml). 2.5 M butyl lithium was added slowly in hexanes (16.8 ml, 42 mmol) was added to a solution of phenylacetic acid (2.72 g, 20 mmol) in tetrahydrofuran (20 ml) by a dropping funnel for 20 minutes. The reaction was stirred for 25 minutes. Propargyl bromide was added as an 80% by weight solution in toluene (2.3 ml, 21.0 mmol). The reaction was stirred for 1.5 hours and 4 N hydrochloric acid (15 ml) was added.

The mixture was diluted with ethyl acetate (50 ml). The organic portion was concentrated in vacuo. The residue was dissolved in diethyl ether and extracted with water (3x) and hydrochloric acid (3x). The organic portion was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting yellow solid (1.7 g) was dissolved in methanol (50 ml) and cooled to 0 ° C. Acetyl chloride (2 ml) was added and the reaction allowed to warm to room temperature.

After stirring the reaction for 18 hours, the solvent was removed in vacuo. The residue was dissolved in diethyl ether. The solution was extracted with saturated sodium bicarbonate, water and brine. The organic portion was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was chromatographed on silica gel with 10% ethyl acetate in hexanes to afford the title compound as an oil (0.58 g, 15%).

EXAMPLE 13 A. 2-Acetylamino-3- [3- (1- {[[4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid The hydrolysis of compound 13B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 534.2 (M + 1), 532.4 (M-1). B. 2-Acetylamino-3- [3- (1- {[[4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid ethyl ester The title compound was prepared from 2- [5- (2-acetylamino-2-methoxy-carbonyl-ethyl) -isoxazol-3-yl] pyrrolidin-1-carboxylic acid tert-butyl ester as described in Example 11B. MS (Cl) m / z 562.1 (M + 1). O 2- [5- (2-Acetylamino-2-methoxycarbonylethyl) isoxazol-3-yl] pyrrolidine-1-carboxylic acid tert-butyl ester The title compound was prepared from 2- (hydroxyiminomethyl) pyrrolidin-1-carbamic acid tert-butyl ester and 2-acetylaminopent-4-ynoic acid methyl ester as described in Example 6B. MS (Cl) m / z 296.0 (M-99).

EXAMPLE 14 A. 2- (2,6-Dichlorobenzoylamino) -3- [3- (1- { [4- (3-o-tolylureido) phenyl-acetyl} -pyrrolidin-2-yl) -isoxazol-5-yl] acid propionic The hydrolysis of compound 14B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 663.8 (M + 1) B. Ethyl 2- (2,6-dichlorobenzoylamino) -3- [3- (1- { [4- (3-o-tolylureido) ethyl ester) phenyl] acetyl) pyrrolidin-2-yl) -isoxazol-5-yl] propionic acid.

The title compound was prepared from the tert-butyl ester of 2- acid. { 5- [2- (2,6-Dichlorobenzoylamino) -2-ethoxycarbonylethyl] isoxazole-3-yl} pyrrolidin-1-carboxylic acid in a manner similar to that described in 11B. MS (Cl) m / z 691.8 (M + 1), 689.7 (M-1). Or 2- tertiary butyl ester. { 5- [2- (2,6-Dichlorobenzoylamino) -2-ethoxycarbonylethyl] isoxazol-3-yl} pyrrolidin-1-carboxylic acid The title compound was prepared from 2- [5- (2-amino-2-ethoxycarbonylethyl) isoxazol-3-yl] pyrrolidin-1-carboxylic acid tert-butyl hydrochloride and 2,6-dichlorobenzoyl chloride. in the manner described in Example 3B. MS (Cl) m / z 525.9 (M + 1), 425.9 (M-99). D. 2- [5- (2-Amino-2-ethoxycarbonylethyl) isoxazol-3-yl] pyrrolidin-1-carboxylic acid tert -butyl ester hydrochloride The tert-butyl ester of 2- acid was stirred. { 5- [2- (Benzhydrylideneamino) -2-ethoxycarbonylethyl] isoxazol-3-yl) pyrrolidin-1-carboxylic acid (700 mg, 1.35 mmol) in a mixture of ethyl acetate (20 ml) and 1 N hydrochloric acid (100 ml) ) during 3 hours. The reaction was neutralized by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with diethyl ether. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The resulting oil (200 mg) was used directly in Example 14C. E. Tertiary butyl ester of acid 2 { 5- [2- (Benzhydrylideneamino) -2- ethoxycarbonyl-ethyl] -isoxazol-3-yl} pyrrolidin-1-carboxylic acid The 2- (5-bromomethylisoxazol-3-yl) pyrrolidin-1-carboxylic acid tert -butyl ester (1.0 g, 3 mmol) and the N- (diphenylmethylene) glycine ethyl ester (1.0 g, 3.74 mmol) were dissolved. ) in toluene (10 ml). 18 M aqueous potassium hydroxide (0.25 ml, 4.5 mmol) and tetrabutylammonium bromide (97 mg, 0.30 mmol) were added. After stirring the reaction at room temperature for 1 hour, 1N hydrochloric acid (4.5 ml) was added. The organic phase was extracted with 1N hydrochloric acid, saturated sodium bicarbonate and brine. The organic portion was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was chromatographed with 15% ethyl acetate in hexanes on a Biotage 40S column to provide the title compound (700 mg, 45%). MS (Cl) m / z 518.0 (M + 1).

EXAMPLE 15 A. 2-Allyloxycarbonylamino-3- acid. { 3- [1- (Toluene-4-sulfonyl) pyrrolidin-2-yl] isoxazol-5-yl} propionic The hydrolysis of compound 15B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 464.0 (M + 1), 461.9 (M-1). B. 2-Allyloxycarbonylamino-3-ethyl ester. { 3- [1- (Toluene-4-sulfonyl) pyrrolidin-2-yl] isoxazol-5-yl} propionic The title compound was prepared according to the procedure described in Example 1B. MS (Cl) m / z 492.0 (M + 1).

EXAMPLE 16 A. 2-Allyloxycarbonylamino-3- [3- (1. {[[4- (2,6-dimethoxy-benzoylamino) pheny] acetyl] pyrrolidin-2-yl) isoxazole-5-acid il] propionic The hydrolysis of compound 16B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 606.7 (M + 1), 605.1 (M1). B. 2-Allyloxycarbonylamino-3- [3- (1- {[[4- (2,6-dimethoxybenzoyllamine) phenyl] acetyl] pyrrolidin-2-yl) isoxazole-5-ethyl ester -il] proponic The title compound was prepared according to the procedure described in Example 3B, using 2,6-dimethoxybenzoyl chloride in place of 2,6-dichlorobenzoyl chloride. MS (Cl) m / z 635.3 (M + 1), 632.5 (M-1).

EXAMPLE 17 A. 2-Allyloxycarbonylamino-3-acid. { 3- [1- (3,4-dimethoxybenzenesulfonyl) pyrrolidin-2-yl] -soxazole-5-yl} propionic The hydrolysis of compound 17B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) 507.6 (M-1). B. 2-Allyloxycarbonylamino-3-ethyl ester. { 3- [1- (3,4-dimethoxybenzenesulfonyl) pyrrolidin-2-yl] isoxazol-5-yl} proponic The title compound was prepared according to the procedure described in Example 1B, using 3,4-dimethoxybenzenesulfonyl chloride. MS (CI) m / z 537.8 (M + 1).

EXAMPLE 18 A. 2-Allyloxycarbonylamino-3- [3- (1-cyclopropanecarbonylpyridinidin-2-yl) isoxazol-5-yl] propionic acid The hydrolysis of compound 18B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 378.2 (M + 1), 376.2 (M-1). B. 2-Allyloxycarbonylamino-3- [3- (1-cyclopropanecarbonylpyrrolidin-2-yl) isoxazol-5-yl] propionic acid ethyl ester The title compound was prepared according to the procedure described in Example 3B, using the appropriate reagents. MS (Cl) m / z 406.1 (M * 1).

EXAMPLE 19 A. 2-Acetylamino-3t [3- (3-methyl-1 -. {2- [4- (2-methylbenzoylloxy) phenol] acetylamino] butyl) isoxazole-5 acid il] prop¡ón¡co The hydrolysis of compound 19B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 508.1 (M + 1), 506.1 (M-1). B. 2-Acetylamino-3- [3- (3-methyl-1 -. {2- [4- (2-methylbenzoyloxy) phenyl] acetylamino} butyl) isoxazol-5-yl] propionic acid ethyl ester The title compound was prepared according to the procedure described in Example 7B, using [4- (2-methylbenzyloxy) phenyl] acetic acid. MS (CI) m / z 550.2 (M + 1). B. [4- (2-meitlbenzyloxy) phenyl] acetic acid The title compound was prepared according to the procedure described in Example 7D. 1 H-NMR (300 MHz, CDCl 3) d 2.40 (s, 3H), 3.65 (s, 2H), 5.05 (s, 2H), 6.98-7.01 (d, 2H), 7.02-7.30 (m, 5H), 7.42. -7.44 (d, 1H). D. [4- (2-Methylbenzyloxy) -phenyl] acetic acid methyl ester The title compound was prepared according to the procedure described in Example 7E. 1 H NMR (400 MHz, CDCl 3) d 2.35 (s, 3 H), 3.56 (s, 2 H), 3.67 (s, 3 H), 5.00 (s, 2 H), 6.92-6.94 (d, 2 H), 7.18-7.26 (m, 5H), 7.37-7.39 (d, 1H).

EXAMPLE 20 A. 2-Acetylamino-3- (3. {1 - [2- (4'-ethylbiphenyl-4-yl) acetylamino] -3-methylbutyl} isoxazol-5-yl) propionic acid The hydrolysis of compound 20B was carried out using the protocol of example 1A to provide the title compound. MS (Cl) m / z 506.1 (M + 1), 504.0 (M-1). B. 2-Acetylamino-3- (3 { 1- [2- (4'-ethylbiphenyl-4-yl) acetylamino] -3-methylbutyl} -isoxazol-5-yl) propionic acid ethyl ester The title compound was prepared according to the procedure described in Example 7B, using (4'-ethylbiphenyl-4-yl) acetic acid. MS (Cl) m / z 534.2 (M + 1). C. Acid (4'-ethylbiphenyl-4-yl) acetic acid The title compound was prepared according to the procedure described in Example 10B. MS (Cl) m / z 239.0 (M + 1). D. Methyl ester of 4 (4'-ethylbiphenyl-4-yl) acetic acid The title compound was prepared according to the procedure described in Example 10C. NMR-1H (400 MHz, CDCl 3) d 7.63 d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 3.79 (s, 3H), 3.75 (s, 3H), 2.78 (q, J = 7.5 Hz, 2H), 1.37 (t, J = 7.5 Hz, 3H).

EXAMPLE 21 A. 2-Acetylamino-3- (3 { 1 - [(4-benzyloxyphenyl) -acetyl] pyrrolidin-2-yl}. Isoxazol-5-yl) propionic acid The title compound was prepared from 2-acetylamino-2- (3. {1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl.] Isoxazol-5-ylmethyl acid diethyl ester. ) malonic using the procedure of Example 1D, MS (Cl) m / z 492.2 (M + 1), 490.3 (M-1). B. 2-Acetylamino-2- (3 { 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl}. Isoxazol-5-ylmethyl) malonic acid diethyl ester MS (Cl) m / z 602.0 (M + 1) EXAMPLE 22 A. 2-Acetylamino-3- [3- (1- {[[4- (4-chlorobenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid The title compound was prepared from compound 22B, according to the procedure described in Example 21 A. MS (Cl) m / z 526.2 (M + 1), 524.2 (M-1). B. 2-Acetylamino-3- [3- (1- {[[4- (4-chlorobenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) -soxazol-5-ylmethyl) malonic acid diethyl ester The title compound was prepared according to the procedure described in Example 21 B, using [4- (4-chlorobenzyloxy) phenyl] acetic acid. MS (CI) m / z 626.0 (M + 1). O Acid [4- (4-chlorobenzyloxy) phenyl] acetic acid The title compound was prepared according to the procedure described in Example 7D. 1 H-NMR (400 MHz, dimethylsulfoxide) d 3.44 (s, 2 H), 5.05 (s, 2 H), 6.88-6.92 (m, 2 H), 7.11-7.14 (m, 2 H), 7.42 (s, 4 H), 12.20 (s, 1 H). ^ a ^^? 13 C-NMR (100 MHz, dimethylsulfoxide) d 68.9, 115.2, 128.1, 129.1, 130.1 (2 overlapping peaks), 131.1, 133.0, 136.9, 157.5, 173.6. D. [4- (4-Chlorobenzyloxy) -phenyl] acetic acid methyl ester The title compound was prepared according to the procedure described in Example 7E. 1 H-NMR (400 MHz, CDCl 3) d 3.55 (s, 2 H), 3.67 (s, 3 H), 5.00 (s, 2 H), 6.88-6.90 (d, 2 H), 7.17-7.19 (d, 2 H), 7.34 (s, 4H).

EXAMPLE 23 A. 2-Acetylamino-3- [3- (1- {[[4- (3-phenylalyl) phenyl] -acetyl} pyrrolidin-2-yl) -soxazol-5-yl] propionic acid The title compound was prepared from compound 23B according to the procedure described in Example 22A. MS (Cl) m / z 502.2 (M + 1), 500.2 (M-1).

B. 2-Acetylamino-3- [3- (1- {[[4- (3-phenylalkyl) phenyl] acetyl} pyrrolidin-2-yl) isoxazole-5-yl acid diethyl ester methyl) malonic The title compound was prepared from [4- (3-phenylallyl) phenyl] acetic acid according to the procedure described in Example 22B. MS (Cl) m / z 602.0 (M + 1). c. [4- (3-Phenylalkyl) phenyl] acetic acid The title compound was prepared from [4- (3-phenylallyl) phenyl] acetic acid according to the procedure described in Example 10B. 1 H-NMR (400 MHz, CDCl 3) d 3.51 (d, 2 H), J = 7 Hz), 3.62 (s, 2 H), 6.28-6.46 (m, 2 H), 7.18-7.37 (m, 9 H). D. [4- (3-phenylalyl) phenyl] acetic acid The (4-trifluoromethanesulfonyloxyphenyl) acetic acid methyl ester (500 mg, 1.68 mmol, 1.00 eq), palladium (II) chloride (15 mg, 5 mol%), bis (diphenylphosphine) were heated at 80 ° C for 3 hours. ethane (50 mg, 5 mol%), bis (pinacolato) diboro (469 mg, 1.85 mmol, 1.10 eq) and potassium acetate (495 mg, 5.04 mmol, 3.00 eq) in dimethylformamide (10 ml). The black reaction mixture was cooled to room temperature. Palladium (II) chloride (15 mg, 5 mol%), bis (diphenylphosphine) ethane (50 mg, 5 mol%), cinnamyl bromide (660 mg, 3.35 mmol, 2.00 eq), sodium carbonate (890) were added. mg, 8.40 mmol, 5.00 eq) and water (4 ml). The reaction mixture was heated at 80 ° C overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 ml). The mixture was extracted with saturated sodium bicarbonate (2 x 50 ml), water (2 x 50 ml) and brine (50 ml). The organic portion was dried over sodium sulfate. Evaporation of the solvent gave a black oily residue which was chromatographed on a Biotage column (5% ethyl acetate / hexanes), affording a 9: 1 mixture of the title compound and the 3-phenylallyl ester of acetic acid (200 mg, Four. Five%). 1 H-NMR (400 MHz, CDCl 3) d 3.52 (dd, 2 H, J = 7, 1.2 Hz), 3.60 (s, 2 H), 3.68 (s, 3 H), 6.24-6.38 (m, 1 H), 6.43-6.47 (d, 1H), 7.1-7.4 (m, 9H). This material was used in Example 23C without further purification.

EXAMPLE 24 A. 2- (3-Methyl-1 - { 2- [4- (3-o-tolylureido) phenyl] -acetylamino.} Butyl) -1H-benzoimidazole-4-carboxylic acid The title compound was prepared from compound 24B according to the procedure described in example 1A. MS (Cl) m / z 514.1 (M + 1), 512.2 (M-1). B. 2- (3-Methyl-1 -. {2- [4- (3-o-tolylureido) phenyl] acetylamino} butyl) -1H-benzoimidazole-4-carboxylic acid methyl ester The title compound was prepared from compound 24C according to the procedure described in example 2B. MS (Cl) m / z 528.0 (M + 1), 526.2 (M-1). O 2- (1-amino-3-methylbutyl) -1H-benzoimidazole-5-carboxylic acid methyl ester hydrochloride . . . . . -t. «Cfc» «ej« « A solution of 4-amino-3- (2-tert-butoxycarbonylamino-4-methylpentanoylamino) benzoic acid methyl ester (690 mg, 1.82 mmol) in acetic acid (9 ml) was heated at 70 ° C with stirring. 1.5 hours The acetic acid was removed in vacuo and the crude mixture was dissolved in 4 M hydrochloric acid in dioxane (9 ml) and stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo to provide the title compound. MS (Cl) m / z 262.0 (M + 1), 260.1 (M-1). E. 4-Amino-3- (2-tert-butoxycarbonyl-amino-4-methylpentanoylamino) benzoic acid methyl ester Hydroxybenzotriazole monohydrate (760 mg, 5.62 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (973 g, 5.07 mmol) were added to a solution of N-tert-butoxycarbonyl-L-leucine (1.06). g, 4.57 mmol) in dimethylformamide (30 ml). The mixture was stirred until all the 1- (3-dimethylaminopropyl) -3-ethylcarbodiomide hydrochloride was dissolved. Methyl 3,4-diaminobenzoate (759 mg, 4.57 mmol) in dimethylformamide (10 ml) and triethylamine (0.68 ml, 4.89 mmol) were added sequentially. The reaction was stirred at room temperature overnight and poured into water. This mixture was extracted with ethyl acetate three times. The organic portion was extracted with a saturated solution of sodium bicarbonate, water (2x) and brine. The organic portion was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column, eluting with ethyl acetate / hexanes (2: 3), which afforded the title compound (690 mg, 40%). MS (Cl) m / z 380.0, (M + 1), 378.2 (M-1).

EXAMPLE 25 A. 2- (2,6-Dichlorobenzoylamino) -3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylurethane) phenyl] acetylamino) -3-methylbutyl acid -isoxazol-5-yl] propionic A mixture of compound 25B (56 mg, 0.13 mol) in tert-butanol (1 ml) and 1 N sodium hydroxide (0.27 ml) was stirred at reflux. After 30 minutes the mixture was concentrated under reduced pressure, the resulting residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give an off white solid. P.f .: 102-104 ° C, MS (m / z) 710.3 and 713.3 (M + 1). B. 2- (2,6-Dichlorobenzoylamino) -3- [3- (1-. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] methyl ester. -3-methylbutyl) -soxazol-5-yl] propionic The title compound was prepared in the manner described in Example 2B using 3-methoxy-4- (3-o-tolylueido) phenylacetic acid and 3- [3- (1-amino-3-methylbutyl) methyl ester hydrochloride. ) isoxazol-5-yl] -2- (2,6-dichlorobenzoylamino) propionic acid. 51% yield, white solid. MS (m / z) 724.2 and 726.2 (M + 1). C. 3- [3- (1-Amino-3-methylbutyl) isoxazol-5-yl] -2- (2,6-dichlorobenzoylamino) propionic acid methyl ester hydrochloride The title compound was prepared from compound 25D in the same way as in example 1C. MS (m / z) 428.3 and 430.3 (M + 1). D. 3- [3- (1-tert-Butoxy-carbonyl-amino-3-methylbutyl) -isoxazol-5-yl] -2- (2,6-dichlorobenzoylamino) propionic acid methyl ester The title compound was prepared from compounds 25E and 71 in the same manner as in Example 7H. MS (m / z) 526.2 and 528.0 (M-1). E. 2- (2,6-dichlorobenzoylamino) -pent-4-inoic acid methyl ester The title compound was prepared from the 2-aminopent-4-ynoic acid methyl ester and the 2,5-dichlorobenzoyl chloride in the same manner as in Example 3B. MS (m / z) 300.2 and 302.2 (M + 1).

EXAMPLE 26 A. 2- [3- (1- {2- [3-Methoxy-4- (3-o-tolylureido) -phenyl] -acetylamino} - 3-methylbutyl) -soxazol-5-ylmethyl] - acid 4-methylpentanoic The title compound was prepared in the same manner as in Example 25, steps A-D, using the methyl ester of 4-methyl-2-propargylpentanoic acid in step D. MS (m / z) 577.3 (M-1).

EXAMPLE 27 A. 2-Acetylamino-3- [3- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} -3-methylbutyl) -isoxazol-5-yl acid propionic The title compound was prepared in the same manner as in example 7A and 7B, using 3-methoxy-4- (3-o-tolylureido) phenylacetic acid in step B. White solid, Mp: 123-125 ° C, MS (m / z) 578.1 (M-1).

EXAMPLE 28 A. 2-Acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} amino) methyl] phenyl} propionic The title compound was prepared in the same manner as in Example 25, Steps A and B, using 28B in step 25B. MS (m / z) 633 (M + 1).

B. 2-Acetylamino-2 - [(3-aminomethylphenyl) methyl] malonic acid diethyl ester A mixture of compound 28C (1.15 g, 3.5 mmol), 10% Pd on carbon (0.15 g) and concentrated HCl (0.3 ml) in ethanol (50 ml) was placed in a Parr stirrer at 3.06 atm of hydrogen during 6 hours. The mixture was filtered through Celite and concentrated under reduced pressure to give 1.2 g of the title compound as a white solid. MS (m / z) 337.3 (M + 1). Or 2-Acetylamino-2 - [(3-cyanophenyl) methyl] malonic acid diethyl ester The title compound was prepared from alpha-bromo-meta-toluenenitrile in the same manner as in Example 7G. MS (m / z) 333 (M + 1).

EXAMPLE 29 Binding of biotinylated CS-1 to isolated VLA-4 The binding-VLA-4 / bCS-1 receptor ligand assay described herein tests the ability of a compound to specifically inhibit VLA-4-dependent binding.

A. Preparation of VLA-4 coated plates VLA-4 coated plates were prepared the day before carrying out the assay. The stock solution of Jurkat cells expressing VLA-4 was isolated according to the protocol of Makarem et al., J. Biol. Chem. 269, 4005-4011 (1994) and diluted in 50 mM NaHCO 3 (pH 8.8) to a concentration final 0.4 mg / ml. Aliquots of 100 ml of this stock solution were then added to each well of a 96-well U-bottom Microfluor "B" plate (No. Dynatech 0010107205) and incubated overnight at 4 ° C. The coating solution was removed by aspiration and the wells were inactivated for 0.5 hours with PBS plus 1% fat-free dried milk containing 1 mM MnCl (22 ml / well, 37 ° C). The dried milk was removed by aspiration immediately before the addition of the biofinylated CS-1. B. Binding of biotinylated CS-1 to isolated VLA-4- Biotinylated CS-1 peptide (bCS-1) was prepared. This peptide was diluted with PBS plus 0.1% fat-free dried milk containing 1 mM MnCl (PBSB) to a final concentration of 5 mg / ml. 200 ml aliquots are 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 that it confers 0.1% DSMO for 60 minutes (37 ° C). The plate is washed three times with 200 ml / well of PBSB to remove unbound bCS-1. Following this, 100 ml of a 1: 5000 dilution of streptavidin poly-HRP in PBSB is added to each well for 60 minutes (37 ° C). Unbound streptavidin poly-HRP was removed by aspiration and the plate was washed three times with PBSB (200 ml / well). Following the final wash, 100 ml of TMB substrate was added to each well to react with the bound streptavidin poly-HRP and the OD of each well of the plate was determined in the Emax plate reader (650). The results were based on the mean of the determinations in duplicate.

EXAMPLE 30 Cellular binding of THP1 dependent on VLA-4 to sVCAM of baculovirus The cell binding assay of THP1 to baculovirus sVCAM tests the ability of a compound to inhibit sVCAM binding dependent on VLA-4.

A. Preparation of sVCAM coated plates Baculovirus sVCAM coated plates were prepared the day before the experiment was carried out. PanVera baculovirus sVCAM stock solution was diluted in mM NaHCO350 (pH 8.8) to a final concentration of 5 mg / ml. Aliquots of 50 ml of this stock solution were then added to each well of a 96-well U-bottom Microfluor "B" plate (No. Dynatech 0010107205) and incubated overnight (4 ° C). The coating solution was removed by aspiration and the wells were inactivated for 1 hour with PBS containing desired milk free of 5% fat (105 ml / well, 4 ° C). The dried milk was removed by shock discharge immediately before the addition of the biotinylated CS-1.

B. Labeling and Binding of THP1 Cells THP1 cells were obtained from the American Type Culture Collection (ATCC, Rockville, MD) and cultured in RPMI 1640 media containing 1 mM 10% MnCl2 for 20 minutes (37 ° C). Confinement of activation with MnCl2, the cells were centrifuged (at approximately 500 xg for 5 minutes) and resuspended twice in serum-free basal media (EBM, 37 ° C). The cells were then incubated in serum-free media (2 x 106 / ml) with 5 mM calcein AM for 30 minutes at 37 ° C. Following labeling, all cells were centrifuged (at approximately 500 xg for 5 minutes) and resuspended twice in RPMI 1640 containing 10% FBS to remove all 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 each well 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). Another 150 ml (100,000 cells) were removed from each well and transferred to the appropriate wells of a plate coated with sVCAM baculovirus inactivated for 45 minutes (37 ° C). Unattached cells were removed by aspiration and the plates were washed three times with DPBSB (100 ml / well). Following the final wash, 100 ml of DPBSB was added to each well and the plate read on a Cytofluor II fluorescent plate reader. Three readings were taken per well at an excitation wavelength of 480 nm and an emission wavelength of 530 nm. The results were based on the mean of the determinations in duplicate. The mean background fluorescence of the white wells of each sample was subtracted, providing a corrected fluorescence intensity value for each sample. Having described the invention as above, the content of the following claims is declared as property. ... ^ a ^ B__

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula (1.0.0):

(1.0.0) and salts and other pharmaceutically acceptable prodrug derivatives thereof, wherein: -A is (C-i-Cß) alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl as defined above; said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with 0 to 3 R9; or is a member selected from the group consisting of the following radicals: A1-NHC (= 0) NH-A2-, A1-NHC (= 0) 0-A2-, A1-OC (= 0) NH-A2-, A1 -NHS02NH-A2-, A1-NHC (= 0) -A2-, A1-C (= 0) NH-A2-, A1-NHS02-A2-, A1-S02NH-A2-, A1- (CH2) rA2- , A1-CH (R1) -0-A2-, A1- (CH2) rO-A2-, A1-0- (CH2) rA2-, A1-0- (CH2) rNH-A2-, A1-NH (CH2) ) r-A2- and A1- (CH2) rS (= 0) q-A2-, A1 and A2 each being independently selected from the group consisting of hydrogen, aryl, alkyl (C? -C6), alkenyl (C2-C6) ), (C2-C2) alkynyl, cycloalkyl, heteroaryl and heterocyclyl; said aryl, alkyl, cycloalkyl, heteroaryl or heterocyclyl group being substituted with 0 to 3 R9; -B is a member selected independently from the group constituted by

following:

(1.1.15) (1.1.16) < 1-1-7 >

(1.1.21) < 1-1-22 > d-1-23) < __, _ -.-_.

in which the symbol "*" indicates the point of union of the rest represented by each partial formula (1.1.0) to (1.1.23) to the rest "CR2R3" of the formula (1.0.0), and the symbol "- > "indicates the point of attachment of the remainder represented by each partial formula (1.1.0) to (1.1.23) to the remainder" E "of the formula (1.0.0). Each of the formulas (1.1.0) to (1.1.23), with the exception of the formulas (1.1.10), (1.1.17) and (1.1.23), may optionally be substituted with R9; -E is a single bond, -O-, NR10-, -CH = CH-, -C = C-, -S (= 0) q, -CR11R12NR10-, or -CR11R12-; -X is -O-, -C (= 0) -, -S (= 0) q- or -NR10-; -X1, X2 and X3 are each independently selected from the group consisting of CH, CR9 or N; -And it is a simple link, -C (= 0) -, -C (= S) - or -S (= 0) 2-; -k is an integer selected independently of 0, 1 and 2; -m is an integer selected independently of 0 and l; -n is an integer selected independently of 0, 1 and 2; -p is an integer selected independently from 0 and 1, with the proviso that p must be selected as 1 when B is selected as the partial formula (1.1.0) to (1.1.11); -q is an integer selected independently of 0, 1 and 2;

- • • • • IftHtlIi -r is an integer selected independently from 0, 1 and 2; -R1 is (C1-C3) alkyl substituted with 0 or 1 F, CF3, OCF3 or cyano groups; R2 and R3 is selected each one independently of the group consisting of hydrogen, (Ci-Cβ) alkyl substituted with 0 to 3 R13, (C2-C6) alkenyl substituted with 0 to 3 R13, a carbocyclic ring system (C3-C14) substituted with 0 to 3 R13 , a heterocyclic ring as defined herein substituted with 0 to 3 R13, alkyl (C6) -OR5 substituted with 0 to 3 R13, alkyl (C6) -SR5 substituted with 0 to 3 R13, alkyl (C? C6) -S02R5 substituted with 0 to 3 R13, a heteroaryl ring as defined herein substituted with 0 to 3 R13, an aryl ring as defined herein substituted with 0 to 3 R13, -with the proviso that- R2 and R3 are as defined above, or are taken together as defined below, or one of them is taken together with R4 as defined below, in which case the ot ro has the meaning of hydrogen or methyl; -R2 and R3 are taken together to form a cycloalkyl or heterocyclyl 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 attached to form a heteroaryl group or Hexycyclyl, as defined herein, substituted with 0 to 3 R13;

J ^ j ^ fi -R4 is hydrogen or alkyl (CrC6) optionally substituted with R13, or R4 can be taken together with R2 or R3 to form a carbocyclic or heterocyclic ring; -R5 and R6 are independently hydrogen, alkyl (CrCß), alkenyl (C2-Ce), alkynyl (C2-C6), CF3, aryl, cycloalkyl, heteroaryl or heterocyclyl, said alkyl, alkenyl alkynyl, aryl, cycloalkyl, heteroaryl being or heterocyclyl substituted with 0 to 3 R13; -R7 is alkyl (CrCe), (CH2) kOR5, (CH2) kC (= 0) R5, (CH2) kC (= 0) NR6R5, (CH2) kNR6C (= 0) R5, (CH2) kNR6C (= 0 ) OR5, (CH2) kNR6S02R5, (CH2) kNR6R5, F. CF3, OCF3, aryl substituted with 0 to 3 R9, heterocyclyl substituted with 0 to 3 R9, heteroaryl substituted with 0 to 3 R9, cycloalkyl substituted with 0 to 3 R9 , or R7 can be taken together with R8 to form a cycloalkyl or heterocyclyl ring, or R7 can be taken together with R11 to form a cycloalkyl or heterocyclyl ring; -R8 is hydrogen, F, CN, alkyl (Ci-Cß) or alkoxy (Ci-Cß): -R9 is halogen, alkyl (Ci-Cß), alkoxy (Ci-Cß), cycloalkyl (C3-C6), cycloalkoxy (C3-C6), cyano, (CH2) kOH, C (= 0) R5, (CH2) kC (0) NR5R6,

(CH2) kNR5R6, (CH2) kNR5S02R6, CF3, OCF3, S02NR5R6, (CH2) mC (= 0) OR5; when R9 is attached to a saturated carbon atom, R9 can be = 0 or = S; when R9 is attached to a sulfur atom, R9 can be = 0; -R10 is hydrogen, C (= 0) R5, C (= 0) OR5, (C6) alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl or S02R5;

-R11 and R12 are independently hydrogen, (C-iC) alkyl, hydroxy, cyano, (C6C) alkoxy. NR6C (= 0) R5, NR6S02R5, NR6R5, CF3, F, aryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkoxy; or R11 can be taken together with R12 to form a cycloalkyl or heterocyclyl ring; -R13 is independently selected from the group consisting of halogen, CF3 > (C -? - C6) alkyl, aryl, heteroaryl, heterocyclyl, hydroxy, cyano, alkoxy (Ci-Cß), cycloalkyl (C3-C6), cycloalkoxy (C3-C6), alkynyl (C2-Ce), alkenyl (C2) -C6), -NR6R5, -C (= 0) NR5R6, S02R5, hydroxy, cyano, (C6C) alkoxy. NR6C (= 0) R5, NR6S02R5, NR6R5, CF3, F, aryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkoxy; or R11 can be taken together with R12 to form a cycloalkyl or heterocyclyl ring; -R13 is independently selected from the group consisting of halogen, CF3, alkyl (CrCß), aryl, heteroaryl, heterocyclyl, hydroxy, cyano, alkoxy (CrCß), cycloalkyl (C3-C6), cycloalkoxy (C3-C6), alkynyl (C2) -Ce), alkenyl (C2-C6), -NR6R5, -C (= 0) NR5R6, S02R5.

2. The compound according to claim 1, further characterized in that when A is heteroaryl, it is a member 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, bezo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1H- indazolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, 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, further characterized in that A is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo [b] furanyl, benzoimidazolyl or quinolinyl.

4. The compound according to claim 3, further characterized in that A is pyridyl.

5. The compound according to claim 1, further characterized in that A is heterocyclyl, is a member selected from the group consisting of oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, benzodioxolane and 1, 3 -benzodioxol-5-yl.

6. The compound according to claim 5, further characterized in that A is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

7. The compound according to claim 1, further characterized in that A and a radical selected from the group consisting of the radicals: A1-NHC (= 0) NH-A2-, A1-NHC (= 0) 0-A2- , A1-OC (= 0) NH-A2-, A1-NHS02NH-A2-, A1-NHC (= 0) -A2-, A1-C (= 0) NH-A2-, A1- NHS02-A2-, A1-S02NH-A2-, A1- (CH2) rA2-, A1-CH (R1) -0-A2-, A1- (CH2) rO-A2-,

A -0- (CH2) rA2-, A1-0- (CH2) rNH-A2-, A1-NH (CH2) rA2- and A1- (CH2) rS (= 0) q-A2-, A1 and A2 being each independently selected from the group consisting of hydrogen, aryl, alkyl (CrCβ), alkenyl (C 2 -Ce), alkynyl (C 2 -C 6), cycloalkyl, heteroaryl and heterocyclyl; said aryl, alkyl, cycloalkyl, heteroaryl or heterocyclyl group being substituted with 0 to 3 R9.

8. The compound according to claim 7, further characterized in that A1 and A2 are both aryl or heteroaryl.

9. The compound according to claim 8, further characterized in that said aryl is phenyl and said heteroaryl is pyridyl., each of which is independently substituted with 0 or 1 substituents R9, which is a member selected from the group consisting of F, Cl, F3C-, methyl, methoxy, hydroxy, isopropyl, cyclopropyloxy and cyclopentyl.

10. The compound according to claim 9, further characterized in that n is the integer 1 that results in a methylene bridge.

11. The compound according to claim 10, further characterized in that said component A and said methylene bridge attached thereto comprises 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 '- (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) phenylmethyl-, 3-methoxy-4- (N' - (3-methyl-2-pyridyl) ureaphenylmethyl-, 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-isopropylphenyl) urea) phenylmethyl-, 6- methoxy-5- (N '- (o-toluyl) urea) -2-pyridylmethyl-, 4- (N' - (3-cyclopropyloxy-2-pyridyl) urea) phenylmethyl- and 4- (N '- (o-toluyl) urea) pyrid-5-ylmethyl-. 5 12.- The compound according to claim 9, further characterized in that Y is -C (= 0) -. 13. The compound according to claim 12, further characterized in that for the component of the formula (1.0.0) - NR CR2CR3-, R4 is hydrogen, R2 is hydrogen and R3 is hydrogen. 14. The compound according to claim 12, further characterized in that for the component of the formula (1.0.0) - NR4CR2CR3-, R4 is hydrogen, R2 is hydrogen and R3 is isobutyl. 15. The compound according to claim 12, further characterized in that for the component of the formula (1.0.0) -15 NR4CR2CR3-, R4 is hydrogen, R2 is hydrogen and R3 is hydrogen. 16. The compound according to claim 12, further characterized in that for the component of the formula (1.0.0) - NR4CR2CR3-, R4 is hydrogen, R2 is hydrogen, R3 is sobutyl and R5 is methyl. 17. The compound according to claim 12, further characterized in that for the component of the formula (1.0.0) - NR4CR2CR3-, R4 is taken together with R2 or R3 to form pyrrolidinyl,

-aia- ili-il-tt-fc-fetii-Mt. , -,. * *. .. . . **. *. **. * .. ^ .. «M_I ..., .a» ^ .-- * * - whereupon R4 is methylene or ethylene, one of R2 or R3 is hydrogen and the other R2 or R3 is ethylene or methylene. 18. The compound according to claim 12, further characterized in that B is a member selected from the group consisting of the partial formulas (1.1.2), (1.1.6), (1.1.17), (1.1.18) , (1.1.19) and (1.1.22):

1. 1.18 1.1.19 1.1.22

wherein the symbol "*" and the symbol "->" are as defined above, X is oxygen, S (= 0) q or nitrogen, and X1, X2 and X3 are each independently selected from the group consisting of - CH-, -CR9- and -N-. 19. The compound according to claim 18, further characterized in that B has as formula the partial formula (1.1.6). 20. The compound according to claim 19, further characterized in that in the partial formula (1.1.6), X is -O-.

21. - The compound according to claim 18, further characterized in that B has the formula as partial formula (1.1.22). 22. The compound according to claim 21, further characterized in that in the partial formula (1.1.22) X is -NR10-, where R10 -H, and each X1, X2 and X3 being a group -CH-. 23.- The compound of. according to claim 12, further characterized in that p is 1, m is 0 or 1 and E is -CR11R12-. 24. The compound according to claim 23, further characterized in that p is 1, m is 0, R11 is -H and R12 is -H. 25. The compound according to claim 12, further characterized in that said compound includes a partial formula residue (1.1.0) and is a member selected from the group consisting of: 3- [2- (1-. { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino, 3-methylbutyl) -4,5-d-hydroxy-oxazol-5-yl] -2-methylpropionic acid, 2- acetylamino-3- [2- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) -4,5-dihydro-oxazole-5 -yl] propionic acid, 2-methanesulfonylamino-3- [2- (1-. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) -4 , 5-dihydro-oxazol-5-yl] propionic acid, 2,2-difluoro-3- acid. { 2- [1 - (methyl { [6- (3-o-tolylureidod) pyridin-3-l] acetyl} amino) ethyl] -4,5-dihydro-oxazol-5-yl} propionic, 2,2-dimethyl-3- [2- [1 -. { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2-allyloxycarbonylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydro-oxazol-5-yl} propionic, 2- (butane-1-sulfonylamino) -3- (2- {[[methyl- (. {4- [3- (3-methylpyridin-2-yl]] piperidine -1-yl.} Acetyl) amino] methyl} -4,5-dihydro-oxazol-5-yl) propionic acid, 2-methyl-3- [2- (1 - { [ 4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) -4,5-dihydro-oxazol-5-yl] propionic acid, 2-formylamino-3-. {2- 2- [1- ( biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -4,5-dihydrothiazol-5-yl.} propionic acid, 2-methyl-3- (2- {1- [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl] -4,5- 10 dihydro-oxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- (2-. {1 - [(4-Phenoxymethylphenyl) acetyl] pyrrolidin-2-yl] -4,5-dihydro-oxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- [2- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl) -acetyl} pyrrolidin-2-yl) -4,5-dihydro-oxazol-5-yl] propionic acid -methanesulfonylamino-3- [2- (3-methyl-1. {[[5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) -4.5 -dihydro-oxazol-5-yl] propionic acid, 2-acetyl acid lamino-3-. { 2 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl} methylamino) methyl] -4-methyl-4,5-dihydro-oxazole-5-ylpropionic, 20 2-acetylamino-3 acid. { 2 - [( { [3-methyxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydrothiazol-5-yl} propionic, 3-acetylamino-3- acid. { 2 - [( { [3-Methoxy-4- (3-o-tolylurethane) phenyl] -acetyl} -methylamino) -methyl] -4,5-dihydro-3H-imidazol-4-yl} propionic,

2- (2,6-dichlorobenzoylamino) -3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydro-oxazol-5-yl} proponic 26. The compound according to claim 1, further characterized in that said compound includes a moiety of partial formula (1.1.1) and is a member selected from the group consisting of: 3- [2- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino.} - 3-methylutil) -4, 5-dihydro-oxazol-4-yl] -2-methylpropionic acid, 2-acetylamino-3- [2- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl]] acetylamino.} - 3-methylbutyl) -4,5-dihydro-oxazol-4-yl] propionic acid, 2-methanesulfonylamino-3- [2- (1-. {2- [3-methoxy-4- (3-o-tolylurethane) phenyl] acetylamino,} - 3-methylbutyl) -4,5-dihiro-oxazol-4-yl] propionic acid, 2,2-difluoro-3- acid. { 2- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] -4,5-dihydro-oxazol-4-yl} propionic acid, 2,2-dimethyl-3- [2- (1-. {[[6- (3-phenylimido) pyridin-3-yl] acetyl] pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl] propionic acid, 2-allyloxycarbonylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl} methylamino) methyl] -4,5-dihydro-oxazol-4-yl} propionic, 2- (butane-1-sulfonylamino) 3- (2. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] p -peridin-1-yl} acetyl) amino] methyl} -4,5-dihydro-oxazol-4-yl) propionic acid, 2-methyl-3- [2-) 1 - acid. { [4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) -4,5-dihydro-oxazol-4-yl] propionic acid, 2-acetylamino-3- acid. { 2- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -4,5-dihydrothiazol-4-yl} propionic,

«» A, a »_g, ^ _ f -« _. ^ _. ._...

2-Methyl-3- (2- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl.} -4,5- dihydro-oxazol-4-yl) propionic acid, acid 2-Benzenesulfonylamino-3- (2- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} -4,5-dihydro-oxazol-4-yl) propionic acid, 2-benzenesulfonylamino- 3- [2- (1- { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) -4,5-dihydro- oxazol-4-yl] propionic acid, 2-methanesulfonylamino-3- [2- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl acid} pyrrolidin-2-yl.} -4,5-dihydro-oxazol-4-yl] propionic acid, 2-acetylamino-3-. {2 - [( { [3-methoxy-4- ( 3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methyl-4,5-dihydro-oxazole-4-ylpropionic acid, 2-acetylamino-3-. {2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydrothiazol-4-yl} propionic acid, 2- (2,6 -dichlorobenzoylamino) -3- { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dih Dro-oxazol-4-yl.}. Propionic or 27. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.2) and is a member selected from the group consisting of: acid

3- [2- (1- { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} - 3-methylbutyl) oxazol-5-yl] -2-methylpropionic acid 2-Acetylamino-3- [2- (1 -. {2- [3-methoxy-4- (3-o-tolylurethane) pheny] acetylamino] -3-methylbutyl) oxazole-5- il] propionic acid, 2-methanesulfonylamino-3- [2- (1-. {2- 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) oxazole -5-yl] propionic, 2,2-difluoro-3- acid. { 2- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] oxazol-5-yl} propionic, 2,2-dimethyl-3- [2- (1-. {[[6- (3-phenylureido) pyridin-3-yl] acetyl] pyrrolidin-2-yl) oxazole-5-acid; 1] propionic, 2-allyloxycarbonylamino-3-acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-5-yl} propionic, 2- (butane-1-sulfonylamino) -3- (2- {[[methyl- ( { 4- [3- (3-methylpyridin-2-ylureido] piperidin-1-yl} acid} acetyl) amino] methyl.} oxazol-5-yl) propionic acid, 2-methyl-3- [2- (1- { [- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2 acid -yl) oxazol-5-yl] propionic acid, 2-acetylamino-3. {2- 2- [1 (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] thiazol-5-ylpropionic acid, 2-methyl-3-acid - (2- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl}. Oxazol-5-yl) propionic acid, 2.-benzenesulfonylamino-3- (2- { - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl.} - oxazol-5-yl) propionic acid, 2-benzenesulfonylamino-3- [2- (1 - { [3-methoxy-4-] (3-o-tolylureido) phenyl) acetyl} pyrrolidin-2-yl.} Oxazole-5-yl] propionic acid, 2-methanesulfonylamino-3- [2- (3-methyl-1 -. [5- (3-oxo-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) oxazol-5-yl] propionic acid, 2-acetylamino-3-. {2 - [( {. [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl] -methylamino) methyl] -4-methyloxazol-5-yl}. ion, 2-acetylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] thiazol-5-yl} propionic, 3-acetylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] -acetyl} -methyllamino) methyl} -3H-imidazol-4-yl} propion, 2- (2,6-dichlorobenzoylamino) -3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl] -methyllamino) methyl] oxazol-5-yl} propionic 28. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.3) and is a member selected from the group consisting of: 3- [2- (1- {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino.} - 3-methylbutyl) oxazol-4-yl] -3-meitylpropionic acid, 2-acetylamino-3- [2- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) oxazol-4-yl] propionic acid, 2-methanesulfonylamino -3- [2- (1 - { 2- [3-methoxy-4- (3-o-tolylurethodo) phenyl] acetylamino} - 3-methylbutyl) oxazol-4-yl] propionic acid 2,2-difluoro-3-. { 2- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] oxazol-4-yl} propionic acid 2,2, -dimethyl-3- [2- (1- { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) oxazole-4- il] propionic, 2-allyloxycarbonylamino-3- acid. { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-4-yl} propionic,

2- (Butane-1-sulfonylamino) -3- (2- {[[methyl- (. {4- [3- (3-methylpyridin-2-yl) uredo] piperidine- 2-yl.}. Acetyl) amino] -methyl.}. Oxazol-4-yl) propionic2-Methyl-3- [2- (1- {[[4- (2-methylbenzyloxy) phenyl] -acetyl] pyrrolidin-2-yl) oxazol-4-yl] propionic acid -formylamino-3-. { 2- [1 - (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl] thiazol-4-yl} propionic acid, 2-methyl-3- (2- { 1 - [(4-o-tolyloxyphenyl) acetyl] -pyrrolidin-2-yl}. oxazol-4-yl) propionic acid, 2-benzenesulfonylamino- 3- (2- { 1 - [(4-phenoxymethyl-phenyl) -acetyl] -pyrrolidin-2-yl} -oxazol-4-yl, propionic acid, 2-benzenesulfonylamino-3- [2- (1 - {. [3-methoxy-4- (3-o-tolylurethane) phenyl) -acetyl} pyrrolidin-2-yl} -oxazol-4-yl] propionic acid, 2-methanesulfonylamino-3- [2] - (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl} oxazol-4-yl] propionic acid 2 - acetylamino-3- {2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methyloxazol-4-yl}. Ion, 2-acetylamino-3- { 2 - [( { [3-methoxy-4- (3-oxo-tolylureido) phenyl] acetyl} methylamino) methyl] thiazole-4-yl The propionic acid 2- (2,6-dichlorobenzylamine) -3-. {2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl}. methylamino) methyl] oxazole-4-yl] propionic acid, 3- [2- (1- {[[4- (4-chlorobenzyloxy) -3-fluorophenyl] -a] cetyl.}. pyrrolidin-2-yl) thiazol-5-yl] propionic,

3- [2- (1- { [3-Fluoro-4- (3-methoxybenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) thiazol-5-yl] propionic acid, 3- [3- 2- (1- { [3-chloro-4- (4-chlorobenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) thiazol-5-yl] propionic acid, 3- [2- (1 - { [4- (4-chlorobenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) thiazol-5-yl] propionic acid, 3- [2- (1 - [(4-benzyloxy-3) chlorophenyl) acetyl] -3-methylpyrrolidin-2-yl.} thiazol-5-yl) propionic acid, 3- [2- (1- {[[4- (4-chlorobenzyl) phenyl] acetyl} .3-Methylpyrrolidin-2-yl) thiazol-5-yl] propionic acid, 3- (2- { 1 - [(4-benzloxyphenyl) acetyl] -3-methylpyrrolidin- 2-yl.) Thiazol-5-yl) propionic acid, 3- (2. {1 - [(4-benzylloxyphenyl) acetyl] pyrrolidin-2-yl.} Thiazole-5-yl) propionic, and 3- (2- { 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl}. isoxazol-5-yl) propionic acid. 29. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.4) and is a member selected from the group consisting of: 3- [3- (1-. { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino] -3-methylbutyl) -4,5-dihydroisoxazol-5-l] -2-methylpropionic acid, 2-acetylamino- 3- [3- (1 - { 2- [3-methoxy] - (3-o-tolylureido) phenyl] acetylamino} - 3-methylbutyl) -4,5-dihydroisoxazol-5-yl] propionic,

-_ ..! ....... Jt-ai_- 2-methanesulfonylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) - 4,5-dihydroisoxazol-5-yl] propionic acid, 2,2-difluoro-3- acid. { 3- [1- (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl-4,5-dihydroisoxazol-5-yl} propionic acid, 2,2-dimethyl-3- [3 - ([1-. {[[6- (3-phenylureido) pyridin-3-yl] acetyl] pyrrolidin-2-yl) - 4,5-dihiroisoxazol-5-yl] propionic, 2-allyloxycarbonylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihidoisoxazol-5-yl} Propionate, 2- (butane-1-sulfonylamino) -3- (3. {[[methyl] - {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1 acid -yl.} acetyl) amino] -methyl] -4,5-dihydroxisoxazol-5-yl) propionic acid, 2-methyl-3- [3- (1-. {[4- (2-methylbenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) -4,5-dihydroisoxazol-5-yl] propionic acid, 2-formylamino-3- acid. { 3- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -4,5-dihydroisothiazol-5-yl} propionic, 2-meitl-3- (3-. {1 - [(4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl} -4,5-dihydroisoxazol-5-yl) propionic acid, acid 2-Benzenesulfonylamino-3- (3. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} -4,5-dihydroisoxazol-5-yl) propionic acid, 2-benzenesulfonylamino- 3- [3- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl) acetyl} pyrrolidin-2-yl) -4,5-dihydroisoxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin) -2-yl] acetyl} pyrrolidin-2-yl) -4,5-dihydroisoxazol-5-yl] propionic acid,

2-Acetylamino acid, 3- [3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4-methyl-4,5-dihydroxyisoxazole- 5-IJpropionic acid, 2-acetylamino-3 acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl] methylammon) methyl] -4,5-dihydroisothiazol-5-yl} propionic, 3-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl] methylammonyl) methyl] -3,4-dihydro-2H-pyrazole-3- il} propionic, 2- (2,6-dichlorobenzylamine) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl} methylamino) methyl] -4,5-dihydroisoxazol-5-yl} propionic 30. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.5) and is a member selected from the group consisting of: 3- [3- (1-. { 2- [3-methoxy-4- (3-o-tollylureido) phenyl] acetylamino] -3-methylbutyl) -4,5-dihydropyrazol-1-yl] -2-methylpropionic acid, -acetylamino-3- [3- (1-. {-2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) -4,5-dihydropyrazol- 1-yl] propionic acid, 2-methanesulfonylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) - 4,5-dihydropyrazol-1-yl] propionic acid, 2,2-difluoro-3- acid. { 3- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} {amino) ethyl] -4,5-dihydropyrazol-1-ylpropionic acid 2.2 -dimethyl-3- [3 - ([1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) -4,5-dihydropyrazol-1-yl] propionic,

H ^ -tÉfAn, n (m-_a - 6 --- a - ^ --- ÉI - fc - l ------- M ^ 2- (butane-1-sulfonylamino) -3- (3- { [Methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] p-peridin-1-yl.} Acetyl) -amino ] methyl. {-4,5-dihydropyrazol-1-yl) propionic acid, 2-methyl-3- [3- (1. {[[4- (2-methylbenzyloxy) phenyl] acetyl] acid} pyrrolidin-2-yl) -4,5-dihydropyrazol-1-yl-propionic acid, 2-acetylamino-3- { 3- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl} ] -4,5-dihydropyrazol-1-ylpropionic acid, 2-methyl-3- (3. {1 - [(4-o-tolloxyphenyl) acetyl] -prolidin-2-yl} -4 , 5-dihydropyrazol-1-ylpropionic acid, 2-benzenesulfonylamino-3- (3. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl] -4,5-dihydropyrazole-1-yl ) propionic acid, 2-benzenesulfonyl-3- (3- (1- {[[3-methoxy-4- (3-o-tolylureido) phenyl) -acetyl} pyrrolidin-2-yl) -4, 5-dihydropyrazol-1-ylpropionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl acid} pyrrolidin-2-yl) -4,5-dihydropyrazol-1-yl] p ropion, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylurethane) phenyl] acetyl} methylamino) methyl] -5-methyl-4,5-dihydropyrazol-1-ylpropionic acid, 2-formylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -4,5-dihydropyrazol-1-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylurethane) phenyl [acetyl]} methylamino) methyl] -4,5-dihydropyrazol-1-yl} propionic 31. The compound according to claim 1, further characterized in that said compound includes a residue of formula

- L-U-b? partial (1.1.6) and is a member selected from the group consisting of: 3- [3- (1- { 2- [3-methoxy-4- (3-o-tolylurethane) phenyl] -acetylamic acid No.} - 3-methylbutyl) isoxazol-5-yl] -2-methylpropionic acid, 2-acetylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o)] -tolylureido) phenyl] acetylamino.} - 3-methylbutyl) isoxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (1 -. {2- 2- [3-methoxy-4- (3- o-tolylurethane) phenyl] acetylamino.} - 3-methylbutyl) isoxazol-5-yl] propionic acid, 2,2-difluoro-3- acid. { 3- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) etl] isoxazol-5-yl} propionic acid, 2,2-d.methyl-3- [3- (1- { [6-3-phenylureido) pyridin-3-yl] acetyl acid} pyrrolidin-2-yl) -soxazol-5-yl] propionic acid, 2-allyloxycarbonylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isoxazol-5-yl} propionic, 2- (butane-1-sulfonylamino) -3- (3. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl] acid} acetyl) amino] -methyl}. isoxazol-5-yl) propionic acid, 2-methyl-3- [3- (1. {[[4- (2-methylbenzyloxy) -phenyl] acetyl acid} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- acid. { 3- [1 - (b \ phenyl] -4-yl-acetyl) pyrrolidin-2-yl] isothiazol-5-yl} propionic, 2-methyl-3- (3. {1 - [(4-o-tolyloxy-phenyl) -acetyl] -pyrrol-id-2-yl} -isoxazol-5-yl) -propionic acid, 2-Benzenesulfonylamino-3- (3. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. isoxazol-5-yl.} propionic acid,

U- a Í - tjfcajb - - *? *? A * A.M ", - ^ ?: 2-Benzenesulfonyl-amino-3- [3- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl) -acetyl acid} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1 -. {[[5- (3-o-tolylureido) pyridin-2-acid] L] acetyl} pyrrolidin-2-yl) -soxazol-5-yl] propionic acid, 2-formylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl [acetyl} methylamino) methyl] -4-methyl-oxazol-5-yl} propionic acid, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isothiazol-5-yl} propionic, 3-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-10-tolylureido) phenyl [acetyl} methylamino) methyl] -2H-pyrazol-3-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -soxazol-5-yl} propionic acid, 3- [3- (1- {[[4- (pyridin-4-ylmethoxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3-] acid 3- (1- { [4- (pyridin-3-ylmethoxy) -phenyl] -acetyl} - {pyrrolidin-2-yl) -isoxazol-5-yl] -propionic acid, 3- [3] - (1- {[[4- (pyridin-2-ylmethoxy) -phenyl] -acetyl} - {pyrrolidin-2-yl) -isoxazol-5-yl} -propionic acid, 3- (3-. 1 - [(6-benzyloxypyridin-3-yl) acetyl] pyrrolidin-2-yl.}. Isoxazole-5-yl) propionic acid, 3- (3. {1 - [(5-benzyloxyipyrin) -2-yl) acetyl] pyrrolidin-2-yl.}. Isoxazole-5-yl) propionic,

iMpir- "* '-"' • - - - * - - - * - - - ****** - = i ^ * w * "acid 3- (3- { 1 - [(4-benciox Phenyl) acetyl] pyrrolidin-2-yl.}. Isoxazol-5-yl) -2-phenylaminopropionic acid, 3- (3. {1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl}. isoxazol-5-yl) -3- (pyridin-2-ylamino) propionic acid, 3- (3- {1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl} isoxazole-5- il) -2- (pyridin-3-ylamino) propionic acid, 3- (3. {1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl.] isoxazol-5-yl) - 2- (Pyridin-4-ylamino) propionic acid, 3- [3- (1- {[[4- (5-chlorothiophen-2-ylmethoxy) phenyl] acetyl} pyrrolidin-2-yl) isoxazole -5-yl] propionic acid, 3- (3 { 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl] isoxazol-5-yl) propionic acid, 3- [3 - (1- {[[4- (4-chlorobenzyloxy) -3-fluorophenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1 - { [3-fluoro-4- (3-methoxy-benzyloxy) -phenyl] -acetyl} pyrrolidin-2-yl) -isoxazol-5-yl] -propionic acid, 3- [3- (1 - { [3 -methoxy-4- (4-methoxybenzyloxy) phenyl-acetyl, pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1 -. { [3-methoxy-4- (3-methoxybenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- {[[4- (4-chlorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl} isoxazol-5-yl] propionic,

.._ ti.-The s. * - * £ * 3- [3- (1- { [4- (3-Chlorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, acid 3- [3- (1- { [4- (2-Chlorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidn-2-yl) isoxazol-5-yl] propionic acid - [3- (1 - { [4- (4-fluorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidi-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (3-Fluorobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3-] (1- {[[4- (2-flurobenzyloxy) -3-methoxyphenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [3-chloro-4- (3-methoxybenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- [3- (1 - { [ 3-Chloro-4- (3-methoxybenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- (3-. {1 - [(4- benzyloxy-3-methoxy-phenyl) acetyl] pyrrolidin-2-yl.}. isoxazol-5-yl) propionic acid, 3- [3- (1 - { [4- (5-tert. -butyl- [1, 2,4] oxadiazol-3-ylm ethoxy) phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- [3- (1 -. { [3-chloro-4- (4-chlorobenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) -soxazol-5-yl] propionic acid, 3- [3- (1- {[[3-chloro-4- (4-chlorobenzyl) -phenyl] -acetyl}. pyrrolidin-2-yl) isoxazol-5-yl] propionic,

1 -- . 1 - "* • ** - - - aiüflülün & tik ^^^ f & ^ -g _____________ acid 3- [3- (1- { [4- (2-cyanobenzyloxy) -phenyl] acetyl}. pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3-1 { [4 -? (4-cyanobenzyloxy) -phenyl] -acetyl] -pyrrolidin-2- il) isoxazol-5-yl] propionic acid, 3- (3. {1 - [(4-benzyloxy-3-fluorophenyl) -acetyl] pyrrolidin-2-yl] -isoxazol-5-yl) propionic, 3- (3 { 1 - [(4-benzyloxy-3-chlorophenyl) -acetyl] pyrrolidin-2-yl}. isoxazol-5-yl) propionic acid, 3- (3-. 1 - [2- (4-benzyloxyphenyl) -acetylamino] -3-methylbutyl}. Isoxazol-5-yl) propionic acid, 2-acetylamino-3- [3- (1 - { [4- (3 -cyanobenzyloxy) - phenyl] acetyl} pyrrolidn-2-yl) isoxazol-5-yl] propionic acid, 2-acetylamino-3- [3- (1 - { [4- ( 4-chlorobenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazole-5-yl] propionic acid, 2-acetylamino-3- (3. {1 - [(4-benzyloxyphenyl) -acetyl acid ] pyrrolidin-2-yl.] isoxazol-5-yl) propionic acid, 3- (3. {1 - [(4-p-tolyloxymethylphenyl) -acetyl] pyrro] lidin-2-yl.) isoxazol-5-yl) propionic acid, 3- (3-. { 1 - [(4-m-Tolyloxymethylphenyl) -acetyl] pyrrolidin-2-yl} isoxazol-5-yl) propionic acid, 3- (3. {1 - [(4-o-tolyloxymethylphenyl) -acetyl] pyrrolidin-2-yl}. isoxazol-5-yl) propionic acid,

i -? - í '"- - - ... -» »i * .r ** to" 1 __it -1 | f | i | - ^ M- * "'- - - -' - - ~ *? *? -i 3- [3- (1- { [4- (4-methoxybenzyloxy) -phenyl] acetyl} pyrrolidine -2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- {[[4- (3-methoxybenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1 - { [4- (2-methoxybenzyloxy) -phenyl] acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, acid 2-Acetylamino-3- [3- (3-methyl-1 - { 2- [4- (2-methylbenzyl) phenyl] acetylamino} butyl) -soxazol-5-yl] propionic acid -acetylamino-3- (3- {1- [2- (4-benzyloxyphenyl) -acetylamino] -3-methylbutyl} isoxazol-5-yl) propionic acid, 3- [3- (1- { [4- (4-Fluorobenzyl) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1) acid - { [. [4- (3-Fluorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (2-fluorobenzyloxy) ) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- {[[4- (2-chlorobenzyloxy) phenyl] -acetyl} pyrrolidine -2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (3-Chlorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazole-5- il] propionic acid, 3- [3- (1- {[[4- (4-chlorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid,

. . Ui i * i 3- [3- (1- { [4- (3-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1- { [4- (4-methylbenzyl) phenyl) -acetyl} pyrrolidin-2-yl) isoxazol-5-yl] propionic acid, 3- [3- (1 - { [4- (2-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) isoxazole-5 -yl] propionic acid, 3- (3. {3-methyl-1- [2- (4-phenoxy-phenyl) -acetylamino] butyl] -isoxazol-5-yl) propionic acid, 2-allyloxycarbonylamino- 3- [3- (1-benzoyl-pyrrolidin-2-yl) isoxazol-5-yl) propionic acid, 3- (3. {1 - [(4-benzyloxy-3-methoxyphenyl) -acetyl] pyrrolidin- 2-yl.] Isoxazol-5-yl) propionic acid, 3- (5- { 1 - [(4-benzyloxyphenyl) -acetyl] pyrrolidin-2-yl.} -2H-pyrazol-3-yl] ) propionic, and 3- (3- {1- [3- (2-methylbenzyloxy) benzoyl] -pyrrolidin-2-yl} -isoxazol-5-yl) propionic acid, 3- [5] acid - (1- { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino.} - 3-methylbutyl) oxazol-2-yl] -2-methylpropionic acid, 2-acetylamino acid -3- [5- (1- { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino.} - 3-methylbutyl) oxazol-2-ylpropionic acid, 2-methanesulfonylamino- 3- [5- (1 -. {2- [3-methoxy-4- (3-o-tolylurethane) pheny] acetylamino] 3-3-methylbutyl) oxaz ol-2-yl] propionic, 2,2-d-fluoro-3- acid. { 5- [1- (methyl- { [6- (3-oxo-tolylureido) pyridin-3-yl] acetyl} amino) etl] oxazol-2-yl} propionic, 2,2-dimethyl-3- [5- (1-. {[[6- (3-phenylureido) pyridin-3-yl] acetyl] {pyrrolidin-2-yl) oxazole-2-acid il] propionic, 2-allyloxycarbonylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazole-2-

. * t . { Il-propionic, 2- (butane-1-sulfonylamino) -3- (5-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1 - il.}. acetyl) -amino] methyl.}. oxazol-2-yl) propionic acid, 2-methyl-3- [5- (1- { [4- (2-methylbenzyloxy) phenyl] -acetyl}. pyrrolidin-2-yl) oxazol-2-yl] propionic acid, 2-formylamino-3- acid. { 5- [1 - (biphenl-4-yl-acetyl) pyrrolidin-2-yl] thiazol-2-yl} propionic acid, 2-methyl-3- (5-. {1 - [(4-o-tolloxyphenyl) -acetyl] pyrrolidin-2-yl} oxazol-2-yl}. propionic acid, acid 2-Benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. Oxazol-2-yl}. Propionic acid, 2-benzenesulfonylamino-3- [5-] (1- {[[3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl} oxazol-2-yl] propionic acid, 2-methanesulfonylamino-3- [ 5- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl} oxazol-2-yl] propionic , 2-acetylamino-3. {5 - [( { [3-methoxy-4- [3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methyloxazole-2 acid -yl.} propionic acid, 2-acetylamino-3 { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] thiazole- 2-yl.) Propionic acid 2- (2,6-dichlorobenzoylamino) -3-. {5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-2-yl.} propionic acid and 2-acetylamino-3- [5- (. {2- 2- [4- (3-o-tolylureido) -phenyl] acetylamino] .) methyl) -1 H-imidazol-2-yl] propionic. 32. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.7) and is a member selected from the group consisting of: 3- [3- (1-. { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino] -3-methyl-butyl) pyrazol-1-yl] -2-methylpropionic,

r-tfc.

2-Acetylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino] -3-methylbutyl) pyrazol-1-yl-propionic acid, acid 2-methanesulfonylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino] -3-methyl-butyl) -pyrazol-1-yl] -propionic acid, 2,2-difluoro-3- acid. { 3- [1 - (methyl- { [6 - (- o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] p-aceol-1-ylpropionic acid, 2,2-dimethyl acid -3- [3- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) pyrazol-1-yl] propionic acid - (butane-1-sulfonylamino) -3- (3. {[[methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acetyl) amino] -methyl.} pyrazol-1-ylpropionic acid, 2-methyl-3- [3- (1- {[[4- (2-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-acid il) pyrazol-1-yl] propionic acid, 2-formylamino-3-. {3- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] pyrazol-1-ylpropionic acid, 2-methyl acid -3- (3- { 1 - [(4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl}. Irazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- (3-) acid {. 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. Pyrazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- [3- (1 -. {[3- methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) pyrazol-1-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1 - . { . [5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) pyrazol-1-ylpropionic,

. ** 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl} -5-methylprazole-1-ylpropionic acid, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] pyrazol-1-yl} propionic acid 2- (2,6-dichlorobenzoylamino) 3-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido (pheny] acetyl} methylamino) methyl] pyrazol-1-yl} propionic. with claim 1, further characterized in that said compound includes a partial formula residue (1.1.8) and is a member selected from the group consisting of: 10 3- [4- (1-. {2- 2- 3- methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} -3-methylbutyl) oxazol-2-yl] -2-methylpropionic acid, 2-acetylamino-3- [4- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} -3-methylbutyl) -oxazol-2-yl] -propionic acid, 2-methanolephonylamino-3- [4] - (1 - { 2- [3-methoxy-4- (3-o-15-tolylureido) phenyl] -acetylamino} - 3-methyl-butyl) -oxazol-2-yl] -propionic acid 2,2- difluoro-3- { 4- [1- (methyl. {[[6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] oxazol-2-yl}. propionic , 2,2-dimethyl-3- [4- (1 -. {[[6- (3-phenylureido) pyridin-3-yl] acetyl] {pyrrolidin-2-yl) oxazol-2-yl acid ] propionic acid, 2-allyloxycarbonylamino-3-. 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-2-yl} propionic, 2- (butane-1-sulfonylamino) -3- (4-. {[[methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-acid il.}. acetyl) amino] -methyl.}. oxazol-2-yl) propionic,

2-Methyl-3- [4- (1-. {[4- (2-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) oxazol-2-yl] propionic acid, 2-acid formyl-3-. { 4- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] tiazol-2-yl} propionic, 2-methyl-3- (4- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl} oxazol-2-yl) propionic acid, 2-benzenesulfonylamino-3-acid (4- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl.}. Oxazol-2-yl) propionic acid, 2-benzenesulfonylamino-3- [4- (1 - { [3 -methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) oxazol-2-yl) propionic acid, 2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolylureido) pyridin-2-yl] acetyl, {pyrrolidin-2-yl) oxazol-2-yl] propionic acid, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl} methylamino) methyl] -5-methyloxazol-2-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] thiazole-2-yl} propionic acid, 2- (2,6-dichlorobenzoylamino) -3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-2-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -1 H -imidazol-2-yl} propionic 33. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.9) and is a member selected from the group consisting of: acid

^ üá 3- [4- (1- { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino.} - 3-methylbutyl) imidazol-1-yl] -2 -methylpropionic acid, 2-acetylamino-3- [4- (1 -. {-2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino} -3-methylbutyl) imidazole-1 - 1-Propionic acid, 2-methanesulfonylamino-3- [4- (1-. {2- 2- [3-methoxy-4- (3-o-tolylurethane) phenyl] acetylamino] -3-methylbutyl) im Dazol-1 -ylpropionic acid, 2,2-difluoro-3- acid. { 4- [1- (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] imidazol-1-ylpropionic acid, 2,2-dimethyl-3- [ 4- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) imidazol-1-ylpropionic acid, 2- (butane-1-sulfonylamino) no) -3- (4-. {[[methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acetyl) amino] methyl. imidazol-1-ylpropionic acid, 2-methyl-3- [4- (1- {[[4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) imidazol-1-ylpropionic acid, acid 2-formylamino-3-. {4- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl-imidazol-1-yl-propionic acid, 2-methyl-3- (4-. 1 - [(4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl}. Imidazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- (4-. {1 - [(4-phenoxymethyl)] lphenyl) acetyl] pyrrolidin-2-yl.}. imidazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- [4- (1 - { [3-methoxy-4- (3- o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) imidazol-1-yl] propionic,

** 2-methaneonylamino-3- [4- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-yl) imidazol-1-ylpropionic acid, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4-3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -5-methylimidazol-1-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylurethane) phenyl-acetyl} -methylamino) methyl] imidazol-1-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylideido) phenyl] acetyl} methylamino) methyl] imidazol-1-ylpropionic acid. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.10) and is a member selected from the group consisting of: 3- [3- (1-. { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) - [1,4] oxadiazol-5-ylj-2-methylproionic acid, 2-acetylamino acid -3- [3- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) - [1,2,4] oxadiazole -5-yl] propionic acid, 2-methaneonylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) pheny] acetylamino} - 3-methylbutyl) - [1, 2,4] oxadiazol-5-yl] propionic, 2,2-difluoro-3- acid. { 3- [1 - (methyl-. {1 - (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] - [1 , 2,4] oxadiazol-5-yl.}. Propionic acid, 2,2-dimethyl-3- [3- (1- {[[6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) - [1,4-oxadiazol-5-yl] propionic acid, 2-allyloxycarbonylamino-3-. {3 - [( { [3-methoxy-4- ( 3-o-tolylureido) phenyl] acetyl} methylamino) methyl] - [1,14] oxaidazol-5-yl.} Propionic acid 2- (butane-1-oniamino) -3- (3-. { . [methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl}. acetyl) amino] methyl.} - [1,4] oxadiazole- 5-yl) propionic acid, 2-methyl-3- [3- (1- { [4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) - [1,2,4] Oxadiazol-5-yl] propionic acid, 2-formylamino-3-. {3- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl- [1, 2,4-thiadiazol-5-yl] .}. propionic acid, 2-methyl-3- (3. {1 - [(4-o-tolyloxyphenyl) acetyl-pyrrolidin-2-yl] - [1, 2,4] oxadiazole-5-acid il) propionic acid, 2-benzeneonylamino-3- (3. {1 - [(4-phenoxymethylphenyl) acetyl]] pyrrolidin-3-yl.}. - [1, 2,4] oxadiazol-5-yl) propionic acid, 2-benzeneonylamino-3- [3- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl) acetyl acid} pyrrolidin-2-yl) - [1,2,4] oxadiazol-5-yl] propionic acid, 2-methaneonylamino-3- [3- (3-methyl-1 - { [5- (3-o- tolylureido) pyridin-2-yl] acetyl] pyrrolidin-2-yl) - [1,4] oxadiazol-5-yl] propionic acid, 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tlilureido) phenyl] acetyl} methylamino) methyl] -5-methyl- [1, 2,4] oxadiazol-5-yl } propionic, 2-formylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] - [1,4] thiadiazol-5-yl} propionic, 3-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) pheny] acetyl, {methylamino) methyl] -2H- [1, 2,4] triazol-3-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureid) pheny] acetyl} methylamino) methyl- [1, 2,4] oxadiazol-5-yl} propionic

* .l .l * \

36. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.11) and is a member selected from the group consisting of: 3- [3- (1-. {2 - [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino.} - 3-methylbutyl) - [1,4] tirazol-1-yl-2-methylpropionic acid, 2-acetylamino- 3- [3- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl [acetylamino.} - 3-methylbutyl) - [1,4] triazole-1 - 6-methaneonylamino-3- [3- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl] - [1-methaneonylamino-3- [3- (1 - { , 2,4] triazol-1-ylpropionic, acid 2,2, -difluoro-3-. { 3- [1 - (methyl- {[[6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] - [1,4] triazole-1-ylpropionic acid 2,2-Dimethyl-3- [3- (1- {[[6- (3-phenyl) -pyridin-3-yl] -acetyl} pyrrolidin-2-yl) - [1,4-triazole] -1-propylionic acid, 2-allyloxycarbonylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] - [1,4-] triazole-1-ylpropionic acid, 2- (butane) -1-onyl-amino) -3- (3- {[[methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl} acetyl ) amino] methyl.} - - [1, 2,4-triazol-1-yl) propionic acid, 2-methyl-3- [3- (1- { [4- (2-methylbenzyloxy) phenyl] acetyl} pyrrolidin-2-yl) - [1, 2,4] triazol-1-ylpropionic acid, 2-acetylamino-3-acid. { 3- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-ylj- [1, 2,4] triazol-1-ylpropionic acid, 2-methyl-3- (3-. {1- [(4-o-tolyloxy-phenyl) -acetyl] pyrrolidin-2-yl- [1, 2,4-thiazole-1-yl] -propionic acid,

^ SSSMu ^ a__sS ms m 2-benzenesulfonylamino-3- (3 { 1 - [(4-phenoxymethylphenyl) acetylpyrrolidin-2-yl] - [1, 2,4] triazol-1-yl} ) propionic, 2-benzenesulfonyl-amino-3- [3- (1 - { [3-methoxy-4- (3-o-tolylureido) phenylJacetyl} pyrrolidin-2-yl} - - [1,2] , 4] triazol-1-yl] propionic acid, 2-methanesulfonylamino-3- [3- (3-methyl-1- {[[5- (3-o-tolylureido) pyridin-2-yl]] acetyl, pyrrolidin-2-yl.} - [1, 2,4] triazol-1-ylpropionic acid, 2-acetylamino-3-. {3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] -acetyl} -methyl-amino) -methyl-4-methyl- [1, 2,4-] triazol-1-yl-propionic acid, 2-acetylamino-3-. ( { [3-methoxy-4- (3-o-10-tolylureido) phenyl] -acetyl} -methylamino) -methyl] - [1,4-triazol-1-yl-propionic acid, 2- (2,6 -dichlorobenzoylamino) -3- { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] - [1,2,4] 37. The compound according to claim 1, further characterized in that the aforementioned compound or includes a partial formula residue (1.1.12) and is a member selected from the group consisting of: 3- [4- (1-. { 2- [3-methoxy-4- (3-o-tolylurethane) phenyl] acetylamino} -3-methylbutyl) thiophen-2-yl-2-methylpropionic acid, 2-acetylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino.) - 3-methylbutyl) furan-2-ylpropionic acid, 2-methanesulfonylamino-3- [4- (1-. {2- [3-methoxy-4- (3-o-tolylureido]] ) phenylJacetylamino.} - 3-methylbutyl) thiophen-2-yl] propionic acid, 2,2-difluoro-3- acid. { 4- [1- (methyl. {[6- (3-o-tolylurethane) pyridin-3-yl] acetyl-Jamino) ethyl] -1 H -pyrrol-2-yl} propionic,

2,2-Dimethyl-3- [4- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) thiophen-2-yl] propionic acid Co, 2- (butane-1-sulfonyl-lane) -3- (4-. {[[methyl- (. {4- [3- (3-methylpyridin-2-yl) urethane} ] piperidin-1-yl.} acetyl) -amino] methyl} furan-2-yl) propionic acid, 2-methyl-3- [4- (1 - { [4- (2-methylbenzyloxy)] ) phenyl] -acetyl} pyrrolidin-2-yl) -1 H -pyrrol-2-ylpropionic acid, 2-formylamino-3- acid. { 4- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl-thiophen-2-yl-propionic acid, 2-methyl-3- (4-. {1 - [(4-o-tol)] Loxyphenyl) -acetyl] pyrrolidin-2-yl.} -1 H-10-pyrrol-2-yl) propionic acid, 2-benzenesulfonylamino-3- (4- { 1 - [( 4- phenoxymethylphenyl) acetyl] pyrrolidin-2-yl.}. Furan-2-yl) propionic acid, 2-benzenesulfonylamino-3- [4- (1- { [3-methoxy-4- (3-o- tolylureido) phenyl] acetyl} pyrrolidin-2-yl) thiophen-2-yl] propionic acid, 2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o - tolylureido) pyridin-2-yl] acetyl] pyrrolidin-2-yl) -1 H -pyrrol-2-yl] propionic acid, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl] methylammonyl) methyl] -5-methyl-1H-pyrrol-2-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-20-tolylureido) phenyl] -acetyl} -methylamino) -methyl] -thiophen-2-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acids. { 4 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl} methylamino) methyl] furan-2-yl} propionic

38. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.13) and is a member selected from the group consisting of: 3- [5- (1-. {2 - [3-methoxy-4- (3-o-tolylurethane) phenyl] acetylamino] -3-methylbutyl) thiophen-3-yl-5-methylpropionic acid, 2-acetylamino-3- [5] - (1 - { 2- [3-methoxy-4- (3-o-tolylurethane) phenyl-5-acetylamino] -3-methylbutyl) furan-3-yl] propionic acid, 2-methanesulfonyl-3- (3- 5- (1 - { 2- [3-methoxy-4- (3-o-tolyluredo) phenyl] acetylamino} - 3-methylbutyl) thiophen-3-yl] propionic acid 2.2 -difluoro-3-. { 5- [1 - (methyl- { [6- (3-o-tolyluretho) pyridin-3-yl] acetyl} amino) ethyl] -1 H -pyrrol-3-yl} propionic, 2,2-dimethyl-3- [5- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) thiophen-3-acid; l-propionate, 2- (butane-1-sulfonyl-amino) -3- (5-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin} -1-yl.}. Acetyl) amino] methyl.}. Furan-3-yl) propionic acid, 2-methyl-3- [5- (1- { [4- (2-methylbenzyloxy) phenyl] acetyl, pyrrolidin-2-yl) -1 H-pyrrol-3-ylpropionic acid, 2-formylamino-3-acid. { 5- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl-thiophen-3-yl} propionic acid, 2-methyl-3- (5- { 1 - [(4-o-tolyloxyphenyl) -acetyl] pyrrolidin-2-yl}. -1 H- pyrrol-3-yl) propionic acid , 2-benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl} furan-3-yl} propionic acid,

g * ^ or 2-benzenesulfonylamino-3- [5- (1 - { [3-methoxy-4- (3-o-tolylurethane) phenyl) acetyl acid} pyrrolidin-2-yl) thiophen-3-yl] propionic acid, 2-methanesulfonylamino-3- [5- (3-methyl-1 - { [5- (3-o-tolylureido) pyridinic acid) 2-yl] acetyl} pyrrolidin-2-yl) -1 H-pyrrol-3-yl] propionic acid, 2-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl] methylamino) methyl] -2-methylene-1 H-pyrrole-3 -il} propionic, 2-acetylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylurethane) phenyl] acetyl] methylamino) methyl] thiophen-3-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] furan-3-yl} propionic 39.- The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.14) and is a member selected from the group consisting of: 3- [5- (1-. { 2- [3-methoxy-4- (3-o-tolylureido) phenyl-acetylamino] -3-methylbutyl) thiophen-2-yl] -2-methylpropionic acid, 2-acetylamino-3- [5- ( 1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino,} -3-methylbutyl) furan-2-yl] propionic acid, 2-methanesulfonylamino-3- [5- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino] -3-methylbutyl) thiophen-2-yl] propionic acid 2,2- difluoro-3-. { 5- [1- (methyl { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] -1 H -pyrrol-2-yl} propionic acid, 2,2-dimethyl-3- [5- (1 - { [6- (3-phenyluretho) pyridin-3-yl] acetyl} pyrrolidin-2-yl) thiophen-2-acid Il-propionic, 2- (butane-1-sulfonylamino) 3- (5. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] p-peridin-2-yl} .) acetyl) amino] methyl.}. furan-2-yl) propionic acid, 2-methyl-3- [5- (1-. {[4- (2-methylbenzyloxy) phenyl] acetyl (pyrrolidin-2-yl) -1 H-pyrrol-2-yl-propionic acid, 2-formylamino-3-acid. { 5- [1 - (biphenyl-4-yl-acetyl) pyrrolidin-2-yl-thiophen-2-yl} propionic, 2-methyl-3- (5- { 1 - [(4-o-tolyloxyphenyl) acetyl] pyrrolidin-2-yl}. -1 H-pyrrol-2-yl) propionic acid, acid 2-Benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. Furan-2-yl}. Propionic acid, 2-benzenesulfonylamino- 3- [5- (1 - { [3-methoxy-4- (3-o-tolitureido) phenyl] acetyl} pyrrolidin-2-yl) thiophen-2-yl] propionic acid, 2-methanesulfonylamino- 3- [5- (3-methyl-1 - { [5- (3-o-tolylureido) pyridin-2-yl] acetyl] pyrrolidin-2-yl) -1 H -pyrrole-2 -yl] propionic acid, 2-acetylamino-3 { 5 - [( { [3-methoxy-4- (3-o-tolylurethane) phenyl] acetyl} methylamino) methyl -2-methyl-1 H, pyrrol-2-yl.}. Propionic, 2-acetylamino-3. {5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl} acetyl] -methyllamino) methyl] thiophen-2-yl}. propionic acid, 2- (2,6-dichlorobenzoylamino) -3-. {5 - [( { [3-methoxy -4- (3-o-20-tolylureido) phenyl] -acetyl} -methylamino) methyl] furan-2-yl) propionic acid. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.15) and is a member selected from the group consisting of: acid

MM * > W > '^ - - 1 -. ^. I-Hi-y - ^ - M 3- [5- (1- { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} -3-methylbutyl) isoxazol-3-yl] -2-methylpropionic acid, 2-acetylamino-3- [5- (1 -. {2- [3-methoxy-4- (3-o- tolylureido) phenyl] acetylamino.} - 3-methylbutyl) isoxazol-3-yl] propionic acid, 2-methanesulfonylamino-3- [5- (1- { 2- [3-methoxy-4- (3-o -tolylurethane) phenyl] acetylamino.} - 3-methylbutyl) isoxazol-3-ylpropionic acid, 2,2-difluoro-3- acid. { 5- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyljisoxazol-3-yl} propionic acid, 2,2-dimethyl-3- [5- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) isoxazol-3-yl] propionic, 2-allyloxycarbonylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) pheny] acetyl} methylamino) methyl] isoxazol-3-yl} propionic acid, 2- (butane-1-sulfonylamino) -3- (5-. {[[meth] l- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidin- 2-yl) acetyl) amino] methyl.} Isoxazol-3-yl) propionic acid, 2-methyl-3- [5- (1 - { [4- (2-methylbenzyloxy) phenyl] acetyl acid .}. pyrrolidin-2-yl) isoxazol-3-yl] propionic acid, 2-acetylamino-3- (5- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] -isothiazole- 3-yl.} Propionic, 2-methyl-3- (5-. {1 - [(4-o-tolloxyphenyl) acetylpyrrolidin-2-yl] isoxazole-3-acid; l) propionic acid, 2-benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetylpyrrolidin-2-yl}. isoxazol-3-yl) propionic acid, 2-benzenesulfonylamino-3- [5- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidin-2-yl) isoxazole-3 acid -yl] propionic acid, 2-methanesulfonylamino-3- [5- (3-methyl-1 - { [5- (3-otolylureido) pyridin-2-yl] acetyl} pyrrolidin-2-acid L) isoxazol-3-yl] propionic, 2-formylamino-3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methylj-4-methylisoxazol-3-yl} propionic acid, 2-acetylamino acid, 3-. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isothiazol-3-yl} propionic, 3-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] -2H-pyrazol-5-yl} propionic, 2- (2,6-dichlorobenzoylamino) -3- acid. { 5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] isoxazol-3-yl} propionic 41. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.16) and is a member selected from the group consisting of: 3- [5- (1-. { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino] -3-methylbutyl) oxazol-2-yl] -2-methylpropionic acid, 2-acetylamino-3- [5- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} - 3-methylbutyl) oxazol-2-yl] propionic acid, 2-methanesulfonylamino-3- [5 - (1- { 2- [3-methoxy-4- (3-o-folylidene (phenyl-5-ylamino) -3-methyl-butyl) -oxazol-2-yl] propionic acid, 2,2-difluoro-3-acid - { 5- [1- (methyl- { [6- (3-o-tolylureido (pyridin-3-yl] acetyl} amino) ethyl-oxazol-2-yl}. Propionic acid 2, 2-dimethyl-3- [5- (1 - { [6- (3-phenyl-ureido) -pyridin-3-yl] -acetyl} pyrrolidin-2-yl) -oxazol-2-yl] -propionic acid 2- allyloxycarbonylamino-3- {5 - [( { [3-methoxy-4- (3-o-tolylureido) pheny] acetyl} methylamino) methyl] oxazol-2-yl}. propionic acid, 2- (butane-1 acid -lfalylamino) 3-3 [5-. { [methyl- (. {4- [3- (3-methylpyridin-2-yl) ureido] piperidin-1-yl}. acetyl) -amino] methyl} oxazol-2-yl) propionic acid, 2-methyl-3- [5- (1- { [4- (2-methylbenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) oxazol-2-yl acid ] Propionic, 2-formylamino-3- acid. { 5 - [- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] thiazol-2-ylpropionic acid, 2-methyl-3- (5-. {1 - [(4-o-tolyloxyphenyl) -acetylpyrrolidine] -2-yl.) Oxazole-2-.l. {Propionic acid, 2-benzenesulfonylamino-3- (5- { 1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. oxazole-2-yl. propionic acid, 2-benzenesulfonylamino-3- [5- (1- { [3-methoxy-4- (3-o-tolyluret)) phenyl] acetyl acid} pyrrolidin-2-yl.}. oxazol-2-yl] propionic acid, 2-methanesulfonylamino-3- [5- (3-methyl-1- {. [5- (3-o-tolylureido) pyridin-2} il] acetyl} pyrrolidin-2-yl) oxazol-2-yl] propionic acid, 2-acetylamino-3-. {5 - [( { [3-methoxy-4- (3-o-tolylureido)] ) phenylal] acetyl} methylamino) methyl] -5-methyloxazol-2-yl} propionic acid, 2-acetylamino-23-. {5 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] -acetyl} - methylamino) methyl] tiazol-2-yl.] Propionic acid, 2- (2,6-dichlorobenzoylamino) 3-. {5- [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] oxazol-2-yl}. Propionic acid 2-acetyl amino-3- [5- ( { 2- [4- (3-o-tolylureido) phenyl] acetylamino} methyl) -1 H-imidazol-2-yl] propionic. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.17) and is a member selected from the group consisting of: 3- (5-. {1- [(4-benzyloxy-3-methoxyphenyl) -acetyl] pyrrolidin-2-yl] - - [1,4] triazodiazol-2-yl) propionic acid 3- [5- ( 1 - { [4- (4-Chlorobenzyloxy) phenyl] -acetyl} pyrrolidin-2-yl) - [1,4] thiadiazol-2-yl] propionic acid and 3- (5- { 1 - [(4-benzyloxyphenyl) acetyl] pyrrolidin-2-yl.} - [1, 3,4] thiadiazol-2-yl) propionic acid. 43.- The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.18), (1.1.1)) and (1.1.20) and is a member selected from the group constituted by: 2-acetylamino-3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl- {methylamino) methyl] phenyl} propionic acid, 2-formylamino-3- acid. { 6- [1 - ( { [3-methoxy-4- (3- (3-methylpyridin-2-yl) uredo] phenyl} acetyl) pyrrolidin-2-yl] pyridin-2-yl .}. propionic acid, 3- {4- [1 - (. {3-ethyl-4- [3- (3-methylpyridin-2-yl) uredo] phenol} acetyl) pyrrolidin-2-yl] pyrimidin-2-yl}. propionic acid, 2-acetylamino-3- [3- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl]] acetyl, pyrrolidin-2-yl) phenyl-propionic, 2-acetylamino-3- [3- (. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] acetylamino} methyl) phenyl] propionic acid, 2- . { 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] pyridin-4-ylmethyl} -4-methyl-pentanoic acid, 3-. { 2 - [(methyl- { [4- (3-o-tolylureido) phenyl] acetyl, {. Amino) methyl] pyridin-4-yl} propionic, 2-methanesulfonylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolyluredo) phenyl] acetyl] -methylamino) methyl] - [1, 3,5] triazin-2-yl} propionic acid 1- [4- (1-. {[[6- (3-pyridin-2-ylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) pyridin 2-ylmethyl] cyclopropanecarboxylic acid, 3- [3- (1- {[[6- (3-pridin-2-ylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) phenyl] butyric, 2- (btuano-1-sulfonylamino) -3- acid. { 3 - [( { [3-methoxy-4- (3-o-tolylurethane) phenyl] acetyl] methylamino) methyl] phenyl} propionic acid, 2-benzenesulfonylamino-3- [3- ( { [2-methoxy-2'-methylbiphenyl-4-yl) acetyl] methylamino acid} methyl) phenyl] propionic. 2- (3 { [2- (4-benzyloxyphenyl) acetylamino] methyl] benzyl) malonic acid, 2- [3- (. {- [4- (4-chlorobenzyloxy)] phenyl-acetylammonyl, methyl) benzyl] malonic acid, 3-3- [3- (. {2- [4- (3-fluorobenzyloxy) phenyl] acetylamino] methyl) phenol] - 2- (propane-1-sulfonylamino) propionic acid, 3- [3- ( { 2- [3-Chloro-4- (4-chlorobenzyloxy) phenyl] -acetylamino} methyl) phenyl] -2- ( propane-1-sulfonylamino) propionic acid, 3- (3 { [2- (4-benzyloxy-3-chlorophenyl) acetylaminoj-methyl} phenyl) -2- (proan-1-sulfonyl-amino) propionic acid, 3- [3- (. {2- [4- (3-Chlorobenzyloxy) phenyl] acetylamino} methyl) phenyl] -2- (propane-1-sulfonylamino) propionic acid, 3- [3-] acid ( { 2- [4- (4-chlorobenzyloxy) phenyl-acetylamino} methyl) phenyl] -2- (propane-1-sulfonylamino) propionic acid, 3- (3- { [2- (4 -benzyloxy-3-methoxyphenyl) acetylamino] methyl.}. phenyl) -2- 10 (propane-1-sulfonylamino) propionic acid, 3- [3- (. {2- 2- [4- (4-methylbenzyloxy) phenyl] acetylamino.} methyl) -2- acetylamine-3- (3- { [2- (4-be n-yloxyphenyl) -acetylamino] methyl} phenyl) propionic acid, 3- [3- (. {2- (4-benzyloxy-phenyl) -acetylamino] -methyl} phenyl) -2- (propane-1-sulfonylamino) propionic acid, 2- (propane-1-sulfonylamino) -3-. { 3 - [(2-m-tolylacetylamino) methyl] phenyl} propionic, 3- (3 { [2- (4-hydroxymethylphenyl) acetylamino] -methyl} phenyl) -2- (propane-1-sulfonylamino) propionic acid, and 3- [3- ( phenylacetylaminomethyl) phenyl] -2- (propane-1-20-sulphonylamino) propionic acid. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.21) and is a member selected from the group consisting of: acid

l? l-ll? lliilllíiiiii? ill? .l? IIL? 1 l il ii 3- [4- (1- { 2- [3-methoxy-4- (3-o-tolilureido) phenyl] acetylamino .} - 3-methylbutyl) pyrrol-1-ylj-2-methylpropionic acid, 2-acetylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-tolylureido)] phenyl] acetylamino.} - 3-methylbutyl) pyrrol-1-ylpropionic acid, 2-methanesulfonylamino-3- [4- (1-. {2- [3-methoxy-4- (3-o-tolylure Phenyl) acetylamino, -3-methylbutyl) pyrrol-1-ylpropionic acid, 2,2-difluoro-3- acid. { 4- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl-acetyl} amino) ethyl] pyrrol-1-ylpropionic acid, 2,2-dimethyl-3- acid [4- (1 - { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) pyrrol-1-ylpropionic acid, 2- (butane-1-) acid sulfonylamino) -3- (4-. {[[methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] piperidn-1-yl.} acetyl) -amino] methyl.}. pyrrol-1-yl) propionic acid, 2-methyl-3- [4- (1- {[[4- (2-methylbenzyloxy) phenyl] -acetyl} pyrrolidy] n-2-yl) pyrrol-1-ylpropionic acid, 2-formylamino-3- acid. { 4- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-yl] pyrrole-1-yl] -propionic acid, 2-methyl-3- (4-. {1 - [(4-o-tolyloxyphenyl) -acetyl-pyrrolidin} -2-yl.) Pyrrol-1-yl) propionic acid, 2-benzenesulfonyl-amino-3- (4. {1 - [(4-phenoxymethylphenyl) acetyl] pyrrolidin-2-yl}. pyrrol-1-yl.} propionic acid, 2-benzenesulfonylamino-3- [4- (1 - { [3-methoxy-4- (3-o-tolylureido) pheny] acetyl} pyrrolidine yl} -2-pyrrol-1 -iljpropiónico, methanesulfonylamino-2-3- [4- (3-methyl-1 -.... {[5- (3-o- tolilure¡do) pirid¡n-2 -yl] acetyl-1-pyrrolidin-2-yl) pyrrol-1-ylpropionic acid, 2-acetylamino-3-. {4 - [( { [3-methoxy-4- (3-o- tolilureido) fen¡l] acetyl} methylamino) met¡l] -5--iljpropiónico met¡lp¡rrol-1, 2-acetylamino-3- 5- {4 -.... [({[3-.. methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] pyrrol-1-ylpropionic acid, 2- (2,6-dichlorobenzoylamino) -3-. {4 - [( { [3-methoxy-4- (3-o-tlylureido) phenyl] acetyl} methylamino) methyl] pyrrol-1-ylpropionic acid. In accordance with claim 1,

10 further characterized in that said compound includes a partial formula residue (1.1.22) and is a member selected from the group consisting of: acid

3- [4- (1- { 2- [3-methoxy-4- (3-o-tolilureido) phenyl] -acetilam¡no.}. -3-methylbutyl) pyrazol-1 ¡lj- 2-methylpropionic, 2-Acetylamino-3- [4- (1 -. {2- [3-methoxy-4- (3-o-tolylureido) phenyl] -acetylamino-3-methylbutyl) pyrazol-1-yl-propionic acid, 2- methanesulfonylamino-3- [4- (1 - { 2- [3-methoxy-4- (3-o-tolylureido) phenyl-ketathylamino} -3-methylbutyl) pyrazol-1-ylpropionic acid, 2,2-difluoro acid -3-. { 4- [1- (methyl- { [6- (3-o-tolylureido) pyridin-3-yl] acetyl} amino) ethyl] p-aceol-1-yl} propionic acid, 2,2-dimethyl-3- [4- (1- { [6- (3-phenylureido) pyridin-3-yl] acetyl} pyrrolidin-2-yl) p -razol- 1 -ylpropionic acid, 2- (butane-1-sulfonylamino) -3- (4-. {[[Methyl- ( { 4- [3- (3-methylpyridin-2-yl) ureido] pperiod] n-1-yl.} acetyl) amino-methyl.} pyrazol-1-yl) propionic,

^^^ m ^ 2-methyl-3- [4- (1- { [4- (2-methylbenzyloxy) fenilj-acetyl.}. Pyrrolidin-2-yl) pyrazol-1 -iljpropiónico acid, 2 -formylamino-3-. { 4- [1- (biphenyl-4-yl-acetyl) pyrrolidin-2-ylpyrazole-1-ylpropionic acid, 2-methyl-3- (4-. {1 - [(4-o-tolyloxy) phenyl) - acetyl] pyrrolidin-2-yl.}. pyrazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- (4- { 1 - [(4-phenoxymethylphneyl) acetyl] pyrrolidin-2-yl acid} pyrazol-1-yl) propionic acid, 2-benzenesulfonylamino-3- [4- (1 - { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} pyrrolidine- 2-yl) pyrazol-1 -iljpropiónico, methanesulfonylamino-2-3- [4- (3-methyl-1- { [5- (3-o-tolilure¡do) pirid¡n-2yl] acetyl, pyrrolidin-2-yl) pyrazole-1-ylpropionic acid, 2-acetylamino-3- [4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acet} I.) methylamino) methyl] -5-methylpyrazole-1-yl} propionic, 2-acetylamino-3- acid. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} - methylamino) methyl] pyrazol-1-ylpropionic acid, and 2- (2,6- dichlorobenzoylamino) -3-. { 4 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl, {(methylamino) methyl] pyrazol-1-yl} propionic 46. The compound according to claim 1, further characterized in that said compound includes a partial formula residue (1.1.23) and is a member selected from the group consisting of: 2 - [( { [3- methoxy-4- (3-o-tolylureido) phenyl] acetyl} - methylamino) methyl] benzooxazole-6-carboxylic acid,

"- ** - £ - ** - • 2- [1 - (2. {3-methoxy-4- [3- (3-methylpyridin-2-yl) ureido] phenyl} acetylamino) -3-methylbutyl] -3H-benzoimidazole-5-carbolylic acid, 2- (1 - { [4- (3-pyridin-2-ylureido) phenyl] acetyl} - pyrrolidin-2-yl) -1 H-imidazo [4,5-cjpyridine-6-carboxylic acid, 2- (1. {[[3-ethoxy-4- (3-pyridin-2-ylureido) phenyl] acetyl} pyrrole. Din-2-yl) benzothiazole-6-carboxylic acid, 2 - [( { [3-methoxy-4- (3-o-tolylureido) phenyl] acetyl} methylamino) methyl] benzothiazole-6 acid carboxylic acid, 2 - [( { [4-benzyloxyphenyl) acetyl] methylamino} -methyl) oxazolo [5,4-bjpyridine-5-carboxylic acid, 3-methyl-2- acid. { 1 - [(4-phenoxyphenyl) acetyl] pyrrolidin-2-yl} -3H-benzoimidazole-5-carboxylic acid. 47.- 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, wherein the amount of said compound present is effective to prevent , inhibit, suppress or reduce cell adhesion and the consequent or associated pathological processes subsequently mediated by VAL-4. 48. The pharmaceutical composition according to claim 47, further characterized in that it comprises one or more therapeutic agents. 49.- The pharmaceutical composition according to claim 48, further characterized in that said additional therapeutic agent or agents is selected from the group consisting essentially of anti-inflammatory corticosteroids, bronchodilators, antiasthmatic agents, non-steroidal anti-inflammatory agents, immunosuppressants, immunostimulant agents, antimetabolites, antipsoriatics and antidiabetics. 50.- The pharmaceutical composition according to claim 45, further characterized in that said therapeutic agent is a member selected from the group consisting essentially of theophylline salbutamol, salmeterol, mometasone, fluticasone, arillo, motelukast, sulfasalazine, cyclosporine aminosilicates, FK-506 , repamicin, clofosfamide, methotrexate and interferons. 51.- The use of a compound of the formula (1.0.0) as claimed in claim 1 or a pharmaceutical composition as defined in claim 48, for the preparation of a medicament for treating or preventing inflammatory, autoimmune or Respiratory factors inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4 in a mammal. 52. The use as claimed in claim 51, 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 followed by organ transplantation, atherosclerosis and other diseases mediated by or associated with VLA-4.

ÉMW íii if r * --- • - .. .. ^ k * _ié¡a- «t-É SUMMARY OF THE INVENTION

A genus of non-peptide compounds is described, said VLA-4 inhibitor compounds being useful in the treatment of inflammatory, autoimmune and respiratory diseases and said compounds comprising a compound of formula (1.0.0):

(1.0.0) and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein: A is alkyl (CrC6), cycloalkyl, aryl, heteroaryl or heterocyclyl optionally substituted with 0 to 3 R9, or is a member selected from the group constituted by the following radicals: A1-NHC (= 0) NH-A2-, A1-NHC (= 0) 0-A2-, A1-OC (= 0) NH-A2-, A1-NHS02NH-A2-, A1- NHC (= 0) -A2-, A1-C (= 0) NH-A2-, A1-NHS02-A2-, A1-S02NH-A2-, A1- (CH2) rA2-, A1-CH (R1) - 0-A2-, A1- (CH2) r-0-A2-, A1-0- (CH2) rA2-, A1-0- (CH2) rNH-A2-, A1-NH (CH2) rA2- and A1- (CH2) rS (= 0) q-A2-, A1 and A2 each being independently selected from the group consisting of hydrogen, aryl, alkyl (CrC6), alkenyl (C2-C6), alkynyl (C2-C6), cycloalkyl, heteroaryl and heterocyclyl substituted with 0 to 3 R9;

2 /. 11 B is a member selected independently from the group consisting of the following:

E is a single bond, -O-, NR1U-, -CH = CH-, -C = C-, -S (= 0) q, -CR11R12NR10-, or -CR11R12-; X is -O-, -C (= 0) -, -S (= 0) q- or -NR10-; -X1, X2 and X3 are each independently selected from the group consisting of CH, CR9 or N; And it is a simple bond, -C (= 0) -, -C (= S) - or -S (= 0) 2- R7 is alkyl (CrC6), (CH2) kOR5, (CH2) kNR6C (= 0) R5, (CH2) kNR6C (= 0) OR5, (CH2) kNR6S02R5, (CH2) kNR6R5, F. CF3, OCF3, aryl substituted with 0 to 3 R9, heterocyclyl substituted with 0 to 3 R9, heteroaryl substituted with 0 to 3 R9, cycloalkyl substituted with 0 to 3 R9, or R7 may be taken together with R8 to form a cycloalkyl or heterocyclyl ring, or R7 may be taken together with R11 to form a cycloalkyl or heterocyclyl ring or heterocyclyl; and R8 is

_ ^ ______ to ____ ?? _ U __ ^ __ a_ffiM__?