HK1051201A - Non-peptidyl inhibitors of vla-4 dependent cell binding useful in treating inflammatory, autoimmune, and respriatory diseases - Google Patents

Description

Non-peptidyl inhibitors of VLA-4 dependent cell binding for the treatment of inflammation, autoimmune diseases and respiratory diseases

Introduction to related applications

Please refer to our related U.S. application No. 09/403846 (attorney Docket No. PC10112B), filed on 26/10/1999; the above application is a continuation of the U.S. application (agency Docket No. PC10112A) filed on 23/6/1999 and filed under the reference number 09/338832; the latter is a continuation of U.S. provisional application 60/091180 (agency Docket number PC10112), filed on 30/6/1998, but now abandoned; further reference is made to the corresponding international application PCT/IB99/00973 (attorney docket number PC10112APCT), filed 5/31/1999, which was published 6/1/2000 and published as WO 00/00477.

The invention relates to compounds of non-peptidyl structure as very late antigen-4 (VLA-4; alpha)₄β₁(ii) a CD49d/CD29) are active with potential inhibitors of binding to proteins such as vascular cell adhesion molecule-1 (VCAM-1), fibronectin and the HepII/IIICS domain of osteopontin (CS-1 region). They are therefore useful in inhibiting VLA-4 mediated cell adhesion and subsequent consequent or related pathological processes. The compounds and pharmaceutical compositions of the invention are useful in the treatment of a variety of inflammatory, autoimmune or respiratory diseases, particularly asthma.

Background

One of the most fundamental processes required for the normal defense of the host is the regulation of the output of leukocytes from the vasculature. This system is used to normally recycle leukocytes and is one of the major pathogenic mechanisms of inflammation, respiratory and autoimmune diseases in mammals because it is capable of rapidly extravasating leukocytes at the site of injury. Cell adhesion is a key factor in this process and is particularly relevant to the cell/cell and cell/matrix binding of the hematopoietic cells comprising VLA-4 of the present invention.

VLA-4 is a member of the superfamily of cell surface macromolecular receptors known as integrins and is a non-covalent heterodimeric complex composed of an alpha and a beta subunit (Hemier, ann. 18 different alpha subunits have been identified, each labeled as alpha ₁-α₁₀，α_L，α_M，α_X，α_D，α_LRI，α_IIB，α_vAnd alpha_E(ii) a At the same time 8 different beta subunits have been identified and marked as beta₁-β₈. Each integrin molecule is classified into subfamilies according to the type of its alpha and beta subunits.

α₄β₁An integrin, VLA-4, is an integrin that can be substantially expressed by all leukocytes other than polymorphonuclear leukocytes (e.g., monocytes, lymphocytes, basophils, eosinophils, mast cells, and macrophages). Binding of this integrin to one of its ligands has many known functions of cell adhesion and activation (Hemler, Ann. Rev. Immunol., 8, p.365, 1990; Walsh et al, Clin. and exp. allergy, 25, p.1128, 1995; Huhtala et al, J.cell. biol., 129, p.867, 1995). It is especially the receptor for a cytokine-induced endothelial cell surface protein known as vascular cell adhesion molecule-1 (VCAM-1) and another spliced form of the extracellular matrix protein Fibronectin (FN) containing the CS-1 domain (Ruegg et al, J.cell. biol., 177, p.179, 1991; Wayner et al, J.cell. biol., 105, p.1873, 1987; Kramer et al, J.biol. chem., 264, p.4684, 1989; Gehlsen et al, Science, 24, p.1228, 1988), and the receptor for the extracellular matrix protein osteopontin (Bayless, K.I. et al, J.cell. Science, 111, p.1165-1174, 1998). The importance of VLA-4 cell adhesion interactions has been established by the use of specific monoclonal antibody (mAb) antagonists of the alpha subunit of VLA-4, which indicate that inhibitors of VLA-4-dependent cell adhesion are capable of preventing or inhibiting a variety of inflammatory, respiratory and autoimmune disorders (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; Soiluhannin et al, J.Neurommnuol.72, p.95, 1997; Sagara et al, int.Arch.Allergy. biol.112, p.203287, 1997; Fryer et al, J.Clin.Invest, 99, p.6, 1997). In addition, this pathological process can be inhibited by drugs other than antibodies, evidence of which has been observed in animal models treated with synthetic CS-1 or small molecule peptide VLA-4 inhibitors (Ferguson et al, Proc. Natl. Acad. Sci., 88, p.8072, 1991; Wahl et al, J.Clin. invest., 94, p.655, 1994; Molossi et al, J.Clin. invest., 95, p.2601, 1995; Abraham et al, am.J.Respir.Crit. Care Med., 156, p.696, 1997; Jackson et al, J.Med. chem., 40, p.3359, 1997). Description of the prior art

The studies of mabs and peptide VLA-4 antagonists in the art have been indicated earlier. In determining alpha₄β₁In the study of binding sites of (a), it has been observed that lymphoid cells can bind fibronectin at two different sites (Bernardi et al, j. cell. biol., 105, p.489, 1987). A component of the cell binding activity was initially identified as being capable of binding to integrin alpha₅β₁(VLA5) binds the tripeptide Arg-Gly-Asp (RGD). The minimum amino acid sequence required to bind and antagonize VLA-4 activity on leukocytes to another splice site in fibronectin was then determined (Humphries et al, j.biol. chem., 266, p.6886, 1987; Garcia-Pardo et al, J.Immunol., 144, p.3361, 1990; Komoriya et al, J.biol. chem., 266, p.15075, 1991). The VLA-4 binding domain in the CS-1 region of Fibronectin (FN) has been found to comprise an octapeptide: Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr, and two overlapping pentapeptides: Glu-Ile-Leu-Asp-Val and Leu-Asp-Val-Pro-Ser. All these peptides were able to inhibit FN-dependent cell adhesion, leading to the early conclusion that the minimum amino acid sequence required for inhibition was Leu-Asp-val (ldv). In fact, it has been observed that the LDV minimal inhibitory sequence is equally effective as a 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 (RGD) recognition site. RGD-based cyclic peptides have been prepared, which are said to inhibit alpha₄β₁And alpha₅β₁Binding to FN (Nowlin et al, J.biol.chem., 268, p.20352, 1993; PCT/US91/04862), albeit at α₄β₁The initial recognition on the FN is LDV. The cyclic peptide is represented by formula (0.01):(0.0.1) wherein Tpro represents 4-thioproline.

Other peptidyl inhibitors of VLA-4 are those compounds known as "CS-1 Peptidomimetics" by Arrhenius et al (WO95/15973, assignee Cytelcorporation, and related to the two U.S. patents listed below). Representative of the compounds involved therein are peptides of formula (0.02):

N-Phenylacetyl-Leu-Asp-Phe-NCy³(0.02) wherein NCy³In particular from morpholino amido; a thiomorpholinoamido group; 4- (thiadioxo) piperidinylamino; and D-2- (carboxamide) -pyrrolidineamido; a piperidineamido group; and substituted piperidinylamino. Us5821231

Further work by Arrhenius et al on cyclic CS-1peptidomimetics is described in WO96/06108, assigned to Cytel Corporation and related to the following U.S. patents.

WO96/06108...............US5869448.............Cytel Corporation

The Arrhenius group also found non-peptidyl inhibitors of VLA-4 dependent cell binding, as described by He et al (WO 98/42656). The inhibitor is a compound of the general formula (0.0.3):(0.0.3)

representative inhibitors are represented by formula (0.0.4):(0.0.4)Wo98/42656……Cytel Corporation

the Leu-Asp-Val tripeptide has been used as the core structure for a group of VLA-4 dependent cell adhesion inhibitors, as described by Adams et al (WO96/22966, assignee Biogen, Inc.). These inhibitors may be represented by formula (0.0.5):(0.0.5) wherein R¹May be 4- (N' - (2-methylphenyl) urea) benzyl; y may be C ═ O; r²Can be H; r³May be an isobutyl group; and R is¹⁴May be a 1, 3-benzodioxol-5-yl group. Typical examples of such inhibitors are represented by formula (0.0.6):(0.0.6)WO96/22966..........Biogen，Inc.

adams groups have also discovered inhibitors of hemi-peptide cell adhesion that are useful in the treatment of inflammatory and autoimmune diseases, as described in Lin et al, WO 97/03094. These inhibitors may be represented by formula (0.0.7):

Z-(Y¹)-(Y²)-(Y³)_n-X

(0.0.7) wherein Z may be 4- (N' - (2-methylphenyl) urea) phenylacetyl; (Y)¹)-(Y²)-(Y³)_nRepresents a series of amino acids capable of forming a peptide chain; and X may be OH. A representative such inhibitor is shown in formula (0.0.8): (0.0.8)WO97/03094..........Biogen，Inc.

Adams groups (Zheng et al, WO98/04247) also found that existing IIb/IIIa integrin inhibitor compounds can be converted to VLA-4 inhibitor compounds, and that IIb/IIIa inhibitor compounds can be prepared by binding a unique VLA-4 integrin scaffold to the IIb/IIIa specific determinant. These cell adhesion inhibitors can be considered to include compounds of formula a-B, wherein a includes the VLA-4 specific determinant, which does not confer significant lib/IIIa integrin inhibitory activity, and B is an integrin scaffold derived from lib/IIIa inhibitors. Also described therein are three-dimensional pharmacophore models of compounds having VLA-4 inhibitory activity. Representative inhibitors derived therefrom are compounds of formulae (0.0.9) and (0.0.10):(0.0.9)(0.0.10)WO98/04247..........Biogen，Inc.

see also, likewise, WO98/04913 to Singh et al, which relates to three-dimensional pharmacophore models of compounds having VLA-4 inhibitory activity, including tolerance lists and three-dimensional pharmacophoresThe coordinates x, y, and z. Representative compounds therein may be represented by the following formula (0.0.11):(0.0.11)WO98/04913..........Biogen，Inc.

another class of VLA-4 dependent cell adhesion inhibitors is described in Head et al, anti-inflammatory tyrosine derivatives (WO98/54207), which may be represented by the general formula (0.0.12): (0.0.12) wherein R¹Is optionally substituted alkyl or aryl; x²is-C (═ O) -; -C (═ O) O-; -C (═ O) NH-; or-S (═ O)₂-; and R is⁷Is an optionally substituted alkyl or aryl group. Typical compounds of such inhibitors may be represented by formula (0.0.13):(0.0.13)WO98/54207..........Celltech Therapeutics Ltd.

the Head group also found a group of related VLA-4 dependent cell adhesion inhibitors, as described by Head et al in "phenylalanine derivatives useful as drugs" (WO 99/37618). They may be represented by the general formula (0.0.14):(0.0.14)

wherein L is¹Is a linking atom or group; a is a chain- [ C (R)⁷)(R⁸)]_p-Y-[C(R⁹)(R¹⁰)]_q-; and L is²Is selected from-C (═ O) -; -C (═ O) O-; -C (═ S) -; -S (═ O)₂or-C (═ O) N (R)¹¹) -a linking group of (a). Examples of such inhibitors are compounds of formula (0.0.15):(0.0.15)WO99/35163..........Celltech Therapeutics，Ltd.

another group of closely related VLA-4 inhibitors discovered by the Head group is described in "novel phenylalanine derivatives useful as integrin antagonists" by Head et al (WO99/37618)Can be characterized by the general formula (0.0.16):(0.0.16)

representative examples of such inhibitor compounds are compounds of formula (0.0.17):(0.0.17)WO99/37618..........Celltech Therapeutics，Ltd.

yet another group of related compounds found by the Head group as inhibitors of VLA-4 dependent cell adhesion is described in Head et al, "phenylalanine derivatives as inhibitors of α 4 integrin" (WO99/43642) and can be characterized by the general formula (0.0.18): (0.0.18)

Inhibitors of the above type may be illustrated by formula (0.0.19):(0.0.19)WO99/43642..........Celltech Therapeutics，Ltd.

early work on VLA-4 dependent cell adhesion inhibitors was done by Pleiss and Thorsett and co-workers, see, e.g., Thorsett et al in "inhibitors of leukocyte adhesion" (WO96/01544, assignee Athena Neurosciences, Inc.). These inhibitors include inhibitors that block VLA-4 mediated cell adhesion and are useful in the treatment of various inflammatory diseases, particularly inflammatory brain diseases.

Also discovered by the Pleiss and Thorsett groups are non-peptidyl, small molecule inhibitors of VLA-4, see, for example, Thorsett, "carbamoyloxy compounds capable of inhibiting VLA-4 mediated leukocyte adhesion" (WO99/06390, assignee Athena Neurosciences, Inc.). Such inhibitors may be represented by the general formula (0.0.20):(0.020) wherein R¹Is alkyl, aryl, cycloalkyl, heterocycle, or heteroaryl, which may be optionally substituted; r²Is defined similarly to R¹But may be combined with it and-S (═ O)₂-the moieties combine to form an optionally substituted heterocyclyl; r³Is defined similarly to R¹And optionally with a link R²And the nitrogen atom to which R is attached³Together form an optionally substituted heterocyclyl; r⁷is-H or alkyl; ar is optionally substituted aryl or heteroaryl; and R is ^5’is-O-Z-NR⁸R^8’or-O-Z-R¹²Wherein Z is-C (═ O) or-S (═ O)₂，R⁸And R^8’Are each-H, or optionally substituted alkyl, cycloalkyl or heterocycle; or R⁸And R^8’May combine to form an optionally substituted heterocyclic ring, and R¹²Is an optionally substituted heterocycle.

Representative examples of such VLA-4 inhibitors are compounds of formula (0.0.21):(0.0.21)WO99/06390..........Athena Neurosciences，Inc.

in Yednock and Pleiss "alpha 9 integrin antagonists and anti-inflammatory compositions thereof" (WO99/06391, assignee Athena Neurosciences, Inc.), the use of the above-described inhibitor compounds of WO99/06390 in methods of treating conditions involving alpha-9 integrin binding, particularly adherent macrophages and neutrophils, is described. Such conditions that may be treated include strong airway responses and obstruction that are associated with chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular obstruction after angioplasty, fibrosis and glomerular scarring caused by renal disease, aortic stenosis, synovial hypertrophy of rheumatoid arthritis, and inflammation and scarring that occur with the progression of ulcerative colitis, and crohn's disease.

The Thorsett and Pleiss group discovered a group of VLA-4 inhibitors, see Thorsett et al, "substituted phenylalanine class compounds capable of inhibiting VLA-4 mediated leukocyte adhesion" (WO99/06431, assignee Athena Neurosciences, Inc. and America Homeproducts Corporation), which may be represented by the general formula (0.0.22): (0.0.22) wherein R¹，R²，R³，R⁷And Ar has substantially the same meaning as described in WO99/06390 above; and R is⁵Is an optional substituent selected from: -NHC (═ O) R; an alkoxyaryl group; an aryl group; a heteroaryl group; -NRR'; alkoxy-NRR'; an alkenyl group; an alkynyl group; an aryloxy group; a heteroaryloxy group; alkoxy-heterocycle; an O-heterocycle; a tetrazolyl group; -NRS (═ O)₂-an alkyl group; an alkenyl sulfonamido group; an alkynyl sulfonylamino group; an alkoxy group; amidines; -C (═ O) NRR'; -NRC (═ O) R'; -S (═ O)₂-an aryl group; s (═ O)₂-a heteroaryl group; -NRC (═ O) NRR'; -NRC (═ O) OR'; aminocarbonyl- (N-formyl heterocycle); and alkyl-C (═ O) NH-heterocyclyl.

Compounds useful for illustration of the above-described VLA-4 inhibitors are of formula (0.0.23):(0.023)WO99/06431..........Athena Neurosciences，Inc.

a related group of inhibitor compounds also discovered by the Thorsett and Pleiss groups is described by Thorsett et al, "dipeptides and related compounds capable of inhibiting VLA-4 mediated leukocyte adhesion" (WO99/06432, assigned to Athena Neurosciences, Inc. and American Home Products Corporation) such inhibitor compounds are characterized by the general formula (0.0.24):(0.0.24) wherein R¹，R²，R³And R⁷Have the meanings essentially as described in WO99/06390 and WO 99/06431; and R is ⁵is-ALK-X or ═ CH-Y, where X and Y represent various groups, all of which are optionally substituted.

Examples of such VLA-4 inhibitors are compounds of formula (0.0.25):(0.0.25)WO99/06432..........Athena Neurosciences，Inc.

another group of related VLA-4 inhibitors, also discovered by the Thorsett and Pleiss groupsSee Dappen "Compounds capable of inhibiting VLA-4 mediated leukocyte adhesion" (WO99/06433, assigned to Athena Neurosciences Inc. and American Home Products Corporation). Such inhibitor compounds are characterized by the general formula (0.0.26):(0.0.26) wherein R¹，R²，R³And R⁷Have the meanings essentially described in WO99/06390, WO99/06431 and WO99/06432 above; and X is-H; -OH; an amido group; -C (═ O) OH; and optionally substituted alkyl; an alkoxy group; an aryl group; an aryloxy group; an aryloxyaryl group; carboxy-alkyl; carboxy-cycloalkyl; carboxy-aryl; carboxy-heteroaryl; carboxy-heterocycle; and cycloalkyl groups. The VLA-4 inhibitors described in the preceding paragraph may be represented by a compound of formula (0.0.27):(0.0.27)WO99/06433..........Athena Neurosciences，Inc.

a further group of VLA-4 inhibitor compounds discovered by the Thorsett and Pleiss groups is described in Ashewell et al, "4-amino-phenylalanine class compounds capable of inhibiting VLA-4 mediated leukocyte adhesion" (WO99/06434, assigned to Athena Neurosciences, Inc. and American Home Products Corporation). Such inhibitor compounds are characterized by the general formula (0.0.28): (0.0.28) wherein R¹，R²，R³And R⁷Have the meanings essentially described in WO99/06390, WO99/06431, WO99/06432 and WO99/06433 above; and R is-H, alkyl, or aryl; x is O, S, or NR; and Y is NRR' or a heterocycle, all of which may be optionally substituted with various groups.

This class of VLA-4 inhibitors is illustrated by formula (0.0.29):(0.0.29)WO99/06434..........Athena Neurosciences，Inc.

the structures found by the Thorsett and Pleiss groups are related to the VLA-4 inhibitor compounds described aboveSee Thorsett et al, "dipeptide compounds capable of inhibiting VLA-4 mediated leukocyte adhesion", WO99/06435 (assigned to athena neurosciences, inc., and American Home Products Corporation). Such inhibitor compounds are characterized by the general formula (0.0.30):(0.0.30) wherein R¹，R²，R³And R⁷Have the meanings essentially as described in WO99/06390, WO99/06431, WO99/06432, WO99/06433, and WO99/06434 above; r⁵Has the meaning substantially as described in WO99/06432 above; r⁴is-H; and optionally substituted alkyl; a cycloalkyl group; an aryl group; a heteroaryl group; a heterocycle; and R is¹And R²Or R²And R³Or R³And R⁴May together form a cycloalkyl or heterocyclic group.

Such VLA-4 inhibitors may be exemplified by compounds of formula (0.0.31): (0.0.31)WO99/06435..........Athena Neurosciences，Inc.

A further group of structurally related VLA-4 dependent cell adhesion inhibitors discovered by the Thorsett and Pleiss groups are described in Thorsett et al, "benzyl compounds capable of inhibiting VLA-4 mediated leukocyte adhesion," WO99/06436 (assigned to Athena Neurosciences, Inc. and American Home Products Corporation). Such inhibitor compounds are characterized by the general formula (0.0.32):(0.0.32) wherein R¹，R²，R³And R⁷Have the meanings essentially as described in WO99/06390, WO99/06431, WO99/06432, WO99/06433, and WO99/06434 above; and Ar is aryl or heteroaryl. Such VLA-4 inhibitors may be exemplified by compounds of formula (0.0.33):(0.0.33)WO99/06436..........Athena Neurosciences，Inc.

thorsett et al further describe compounds related to the structures described in WO99/06390, WO99/06431, WO99/06432, WO99/06433, WO99/06434, WO99/06435 and WO99/06436 above in "sulfonylated dipeptide compounds capable of inhibiting VLA-4 mediated leukocyte adhesion", with the exception of numerous additional limitations. Three such inhibitor compounds are represented by formulas (0.034) - (0.0.36):(0.0.34) (0.0.35)(0.0.36)WO99/06437..........Athena Neurosciences，Inc.

stilz and Wehner groups have discovered different classes of compounds that have activity in inhibiting VLA-4 mediated cell adhesion. See, for example, Stilz et al, "5-ring heterocycles as inhibitors of leukocyte adhesion and as VLA-4 antagonists", EP-842943 (assignee: Hoechst AG). They can be characterized by the general formula (0.0.37): (0.0.37) wherein R is 4-amido-phenyl, 4-guanidino-phenyl, 4-aminomethyl-phenyl, 3-amino-propyl, or 3-guanidino-propyl; r¹Is methyl or benzyl; r²is-H, methyl, ethyl, optionally substituted benzyl, or naphthylmethyl; r³Is a mono-, di-, tri-peptide; r⁴is-H, methyl, or butyl; and R is⁵Is composed of^-HAlkyl, cycloalkyl, or optionally substituted aryl. Representative compounds of the foregoing class of VLA-4 inhibitors are represented by formula (0.0.38):(0.0.38)EP842943..........Hoechst AG.

stilz and Wehner groups have also discovered inhibitor compounds that are structurally closely related to the compounds in EP842943, described above, and described in Stilz et al, "heterocyclic compounds as inhibitors of leukocyte adhesion and VLA-4 antagonistsMaterial ", EP 842944. These compounds are characterized by general formula (0.0.39):(0.0.39) wherein R⁴Is methyl or 4-R³-phenyl, wherein R³Is 4, 5-dihydroimidazol-2-yl or-C (═ O) NH₂；R²Is optionally substituted phenyl, pyridyl, or naphthyl; and R is⁴is-H, ethyl, n-butyl, or isobutyl. Representative examples of such inhibitor compounds are compounds of formula (0.0.40):

(0.0.40)

EP842944..........Hoechst AG.

stilz et al also describe in EP842,945 other inhibitor compounds structurally closely related to the compounds in EP842944 above, which can be characterized by the general formula (0.0.41): (0.0.41) wherein R is 4-R²-phenyl, wherein R²is-CN, -NO₂Optionally substituted-NH₂C (═ O) NH, or-NH₂C(＝O)NHCH₂(ii) a And R is²Is optionally substituted phenyl. Representative examples of such inhibitor compounds are compounds of formula (0.0.42):(0.0.42)EP842945..........Hoechst AG.

stilz and Wehner groups have further discovered VLA-4 dependent cell adhesion inhibitors, see Wehner et al, "imidazolidine derivatives with VLA-4 antagonistic activity useful for the treatment of leukocyte adhesion-mediated diseases," EP903353 (assignee: Hoechst Marion Roussel Deutschland GmBH). Such compounds are characterized by the general formula (0.0.43):wherein A is optionally substituted alkyleneAlkenylene, phenylene, -phenyl-alkylene, or alkylene-phenyl-; l and M are both a bond or-CH₂-; x is optionally substituted-CH (R)⁷) -or-C (═ CHR)⁷) -, wherein R is⁷Is optionally substituted alkyl, phenyl, furyl, thienyl, pyrrolyl, indazolyl or pyridyl; r¹is-H, cycloalkyl, optionally substituted alkyl, aryl, heteroaryl; -C (═ O) R⁶or-SO₂R⁶Wherein R is⁶is-H, cycloalkyl, optionally substituted alkyl, aryl or heteroaryl; r²is-NH₂，-C(＝O)NH₂or-C (═ O) OH; r³is-H, alkyl, optionally substituted aryl, or heterocyclyl; and R is ⁵is-C (═ O) OH, tetrazolyl, -SO₃H or-SO₂NH₂。

Typical VLA-4 inhibitors within the above class of compounds are illustrated by formula (0.0.44):(0.0.44)EP903353..........Hoechst Marion Roussel Deutschland GrnBH

another group of inhibitor compounds which are structurally closely related to the above compounds have been discovered by Stilz and Wehner groups, see Wehner et al, "substituted imidazoline derivatives with VLA-4 antagonistic activity", EP 918059. The group of compounds may be represented by general formula (0.0.45):(0.0.45) wherein R is methyl or phenyl; r¹Is tert-butyl, propyl, isopropyl, benzyl, cyclohexyl, or optionally substituted phenyl; r³Is adamantyl, -CH (CH)₃)CH₂C (═ O) OH, optionally substituted-CH (phenyl) CH₂C (═ O) OH or-CH (phenyl) C (═ O) OH; and R is⁴is-H or isobutyl. Examples of compounds useful for illustrating such VLA-4 inhibitors are compounds of formula (0.0.46):(0.0.46)EP918059..........Hoechst Marion Roussel Deutschland GmBH

another class of VLA-4 inhibitors has been found by Chen et al, see, for example, Chen et al, "novel N-aroylphenylalanine derivatives as integrin antagonists", described in WO99/10312 (assignee: F. Hoffmann-La Roche AG). Such inhibitors may be represented by general formulae (0.0.47) and (0.0.48):(0.0.47) (0.0.48) wherein there are two subclasses of compounds according to the different A rings shown above. In addition, the A and B rings may be substituted with a variety of different heterocycles, but the ortho-substituted B ring is preferred. Representative examples of compounds falling within the scope of such inhibitors are compounds of formula (0.0.49): (0.0.49)WO99/10312..........F.Hoffmann-La Roche AG.

A group of closely related inhibitors found by the Chen group is described in WO99/10313 to Chen et al (assignee: F. Hoffmann-La Roche AG.), and they can be represented by the general formulae (0.0.50) and (0.0.51):(0.0.50) (0.0.51) wherein there are two subclasses of compounds as described in the case of formulas (0.0.47) and (0.0.48) above. Further, the three R groups attached to the amide linker combine to form a four-membered center. Typical examples of such VLA-4 inhibitors are compounds of formula (0.0.52):WO99/10313..........F.Hoffmann-La Roche AG.

a further class of VLA-4-dependent cell adhesion inhibitors was found by Hagmann and co-workers, see for example Durete and Hagmann, "heterocyclic amide compounds as cell adhesion inhibitors", WO98/53814 (assignee: Merck)&Co., Inc.). Such compounds may be represented by the general formula (0.0.53):(0.0.53) wherein X is-C (═ O) OH or an acid isostere; y is-C (═ O) or-S (═ O)₂；R¹-R⁸Selected from various known substituents; a, B and Z are selected to form heterocycles of different types and ring sizes. Representative examples of such inhibitor compounds are compounds of formula (0.0.54): (0.0.54)WO98/53814..........Merck & Co.，Inc.

Another class of structurally related inhibitor compounds discovered by the Hagmann group is found in Durette et al, "diarylalkanoic acid compounds useful as inhibitors of cell adhesion," WO98/53817 (assigned Merck)&Co., Inc.), which may be described by general formulas (0.0.55) and (0.0.56):(0.0.55) (0.0.56) wherein X, Y, and R¹-R⁷Is substantially as described above for formula (0.0.53), except that R²And R³May form, together with the atoms to which they are attached, a 4-7 membered ring containing from 0 to 2 additional heteroatoms selected from O, S and N; and R is^bIs optionally substituted alkyl, alkenyl, alkynyl, aralkyl, or heteroarylalkyl. Representative examples of compounds within the scope of such VLA-4 inhibitors are compounds of formula (0.0.57):(0.0.57)WO98/53817..........Merck & Co.，Inc.

another class of inhibitor compounds which have been discovered by the Hagmann group to be structurally closely related to the above-mentioned compounds is described in Durette et al, "sulfonamide Compounds useful as inhibitors of cell adhesion," WO98/53818 (assignee Merck)&Co., Inc.). These compounds can be represented by general formulae (0.0.57) and (0.0.58):(0.0.57) (0.0.58) wherein R ^bAnd R¹-R⁷The above formulas (0.0.55) and (0.0.56) are defined as above. The compounds of formula (0.0.59) below are representative of the range of inhibitor compounds within the above categories:(0.0.59)WO98/53818..........Merck &yet another class of VLA-4 inhibitor compounds, whose structure is closely related to the above compounds, has been discovered by Hagmann's group, see Delaszlo, "azapeptide acid compounds useful as inhibitors of cell adhesion," WO 99/20272. Such inhibitors may be represented by the general formula (0.0.60):(0.0.60) wherein m and n are 0-2; and X, Y, and R¹-R⁶The above formulas (0.0.55) and (0.0.56) are defined as above. Representative inhibitor compounds within the above classes are compounds of formulae (0.0.61) and (0.0.62):(0.0.61) (0.0.62)WO99/20272..........Merck & Co.，Inc.

another class of VLA-4 dependent cell adhesion inhibitors discovered by the Hagmann group is described in Delaszlo and Hagmann, "4-substituted-4-piperidinecarboxamide derivatives for the treatment of asthma, inflammation and multiple sclerosis", WO99/25685 (assignee Merck)&Co., Inc). Such compounds may be represented by the general formula (0.0.63):(0.0.63) wherein X is a bond or a substituted carbon atom; z is-C (═ O) OH or an acid isostere; l is-C (═ O) -, -S (═ O)₂-; and R is¹-R⁵Are substantially as described above for formulae (0.0.55) and (0.0.56). Typical such VLA-4 inhibitor compounds are of formula (0.0.64): (0.0.64)WO99/25685..........Merck & Co.，Inc.

Another class of VLA-4 inhibitors structurally closely related to the above compounds is found in Chang et al, "Cyclic amino acids as inhibitors of cell adhesion", WO99/26615 (Merck, assignee)&Co., Inc.). Such inhibitor compounds are represented by the general formula (0.0.65):(0.0.65) wherein R represents the ring size, and X, Y, and R¹-R⁷Have the same meaning as described above for formulas (0.0.55) and (0.0.56). Representative examples of such inhibitor compounds are compounds of formula (0.0.66):(0.0.66)WO99/26615..........Merck & Co.，Inc.

a class of VLA-4 dependent cell adhesion inhibitors which differ from the compounds described in WO98/53814 above by the only terminal amino acids has been found to be beta-amino acids. For this purpose, see general formula (0.0.53) above. These beta-amino acids are disclosed in Durette et al, "substituted beta-alanine derivatives for use as cell adhesion inhibitors", WO99/26921 (Merck, assignee)&Co., Inc.). Such typical inhibitors are represented by formulas (0.0.67) and (0.0.68):(0.0.67) (0.0.68)WO99/26921..........Merck & Co.，Inc.

the Hagmann group has discovered another class of VLA-4 dependent cell adhesion inhibitors whose structure is closely related to the above compounds, see Chang et al, "substituted pyrrole derivatives as cell adhesion inhibitors", WO99/26922 (assignee Merck)&Inc.). Such inhibitors are represented by the general formula (0.0.69); (0.0.69) wherein Y and R¹-R⁷Is as defined above for formulae (0.0.55) and (0.0.56), and X and Z are as defined above for formula (0.0.63), but the two meanings must be reversed because of the fact that-X in (0.0.63)-Z-becomes-Z-X-in (0.0.69). Examples of such inhibitor compounds are represented by formula (0.0.70):WO99/26922..........Merck & Co.，Inc.

another class of VLA-4 inhibitor compounds found by the Hagmann group to be structurally closely related to the above compounds is described in Delaszlo and Hagmann, "p-aminomethyl aryl carboxamide derivatives", WO99/26923 (assignee Merck)&Co., Inc.), and may be represented by the general formula (0.0.71):(0.0.71) wherein L, X, Z and R¹-R⁶The meaning of (c) is substantially as described in the above formulae (0.0.55) and (0.0.56). Ar is a 1, 4 substituted aryl or heteroaryl moiety. Typical compounds of such VLA-4 inhibitors are represented by formula (0.0.72):(0.0.72)WO99/26923..........Merck & Co.，Inc.

other groups have discovered a novel class of VLA-4 antagonists, described in Wattanasin and Von Matt, "VLA-4 antagonists", WO99/37605 (assigned to Novartis). This new class of inhibitor compounds can be represented by the general formula (0.0.73):wherein Y is-C (═ O) -, -S (═ O)₂-, or-P (═ O)₂-; z is- (CH)₂)_n-, -CHR-, or-NR-; w is-CH-or-N-; x is-C (═ O) OH or an acid isostere; and R is ¹-R⁴Are various common substituents. Typical examples of such VLA-4 inhibitors are represented by formula (0.0.74):(0.0.74)WO99/37605..........Novartis

another group has discovered a new class of compounds that inhibit VLA-4 dependent cell adhesion, described in Astles et al, "substituted anilides" and their use in the treatment of a variety of conditions including inflammation, arthritis and atherosclerosisThe application in diseases "WO 99/23063 (assignee Rhone-Poulenc Rorer Ltd.). Such VLA-4 inhibitors may be represented by the general formula (0.0.75):(0.0.75) wherein X¹，X²And X³is-N-or-CR-; ar (Ar)¹Is aryl or heteroaryl; l is²Is an optionally substituted alkylene linker; y is carbonyl, an acid isostere, or — C (═ O) NRR; and R is¹is-H, halogen, -OH, lower alkyl or lower alkoxy. Representative examples of suitable such inhibitor compounds are illustrated by formula (0.0.76):(0.0.76)WO99/23063..........Rhone-Poulenc Rorer Ltd.

another class of VLA-4 inhibitors structurally closely related to the compounds described in the previous paragraph is described in Artles et al, "bisaryl beta-alanine derivatives useful as VL-4 antagonists", WO99/33789 (assigned Rhone-Poulenc Rorer Ltd.). Such inhibitors may be represented by the general formula (0.0.77):(0.0.77) wherein X¹，X²And Y is as defined above for formula (0.0.75). R ⁴Is aryl or heteroaryl or is optionally substituted alkyl, alkenyl or alkynyl. Representative examples of such inhibitor compounds are represented by formula (0.0.78):WO99/33789..........Rhone-Poulenc Rorer Ltd.

another group has also discovered a novel class of VLA-4 dependent cell adhesion inhibitors, see Lobl et al, "beta₁And beta₂A cyclic peptide inhibitor of integrin-mediated adhesion "WO 96/40781 (assignee: Tanabe Seiyaku Co., Ltd.). These inhibitors are cyclic peptides containing the free acid.

WO96/40781....................Tanabe Seiyaku Co.，Ltd.

Another one discovered by the groupVLA-4 like inhibitors are described in Lobl et al, "alpha₁β₄Inhibitors of mediated cell adhesion ", WO98/58902 (assignee: Tanabe Seiyaku Co., Ltd., and Pharmacia&Upjohn Company). This class of VLA-4 inhibitors can be represented by the general formula (0.0.79):(0.0.79) wherein R¹Is an acid or an amide; x is phenyl; and Z is an amide or methylene ether. Representative examples of such inhibitor compounds are compounds of formula (0.0.80):(0.0.80)WO98/58902..........Tanabe Seiyaku Co.，Ltd.

a further class of VLA-4 inhibitors found in this group is found in Sircar et al, "inhibitors of α 4-mediated cell adhesion," WO99/36393 (assignee: Tanabe Seiyaku Co., Ltd.). Such VLA-4 inhibitors may be characterized by the general formula (0.0.81):(0.0.81) wherein R¹-R⁶(however, R is not limited thereto⁴Except) are selected from a variety of common substituent groups; r ⁴Is an acid, acid isostere, or amide; a is aryl or heteroaryl; q is a bond, -C (═ O) -, or substituted alkylene; n is 0 to 2; and W is-O-, -S-, -CH ═ CH-, or-N ═ CH-. Representative members of such VLA-4 inhibitors are represented by formula (0.0.82):(0.0.82)WO99/36393..........Tanabe Seiyaku Co.，Ltd.

a further group has also discovered a novel class of VLA-4 dependent cell adhesion inhibitors, see Kogan et al, "methods of inhibiting the binding of integrin α 4 β 1 to VCAM-1 or fibronectin", WO96/00581 (assignee: Texas Biotechnology Corporation). Such VLA-4 antagonists include 5-13 residue cyclic peptides mimicking the CS1 peptide portion, which also contain a free acid.

WO96/00581..............Texas Biotechnology Corporation

A different group has also discovered a novel class of VLA-4 antagonists, see Dutta, "inhibitors of fibronectin adhesion," WO96/20216 (assignee: Zeneca Limited). Such VLA-4 antagonists include cyclic peptides containing the free acid.

WO96/00581...............Zeneca Limited

A related class of VLA-4 antagonists found by this group is described in Dutta, "Cyclic tetrapeptide dimers as fibronectin inhibitors", WO97/02289 (assignee: Zeneca Limited). Such VLA-4 antagonists include cyclic dimeric peptides, in which peptide 1 and peptide 2 independently represent tetrapeptides that are juxtaposed in a parallel or anti-parallel orientation by two linking moieties, L1 and L2.

WO97/02289..............Zeneca Limited

Another related class of VLA-4 antagonists discovered by this group is found in Dutta, "cyclic octapeptide derivatives useful as integrin antagonists", WO97/49731 (assignee: Zeneca Limited). Such VLA-4 antagonists include various cyclic octapeptides containing a free acid.

WO97/49731.............Zeneca Limited

The group also found non-peptide VLA-4 antagonists, see Brittain and Johnstone, "Compounds", WO99/24398 (assignee: Zeneca Limited). Such compounds may be represented by the general formula (0.0.83):(0.0.83) wherein Y is-O-, -S-, or-S (═ O)₂-；R¹Is urea; r¹¹Is an acid or an acid isostere; and m is 0 or 1, and n is 1-4 when m is 0, and n is 0 when m is 1. Representative members of such VLA-4 antagonists are represented by formula (0.0.84):(0.0.84)WO99/24398..........Zeneca Limited

the above documents do not disclose or suggest the compounds of the present invention.

Despite the above advances in the art for VLA-4 mediated inhibitors of cell adhesion, the skilled artisan will quickly recognize that peptidyl inhibitors have a propensity to be poorly absorbed, poorly soluble, and subject to in vivo metabolism (systemic or local metabolism occurring when administered directly to the lung), thereby reducing their potential to significantly affect inflammatory, respiratory, or autoimmune disease processes.

The non-peptidyl, i.e., small molecule VLA-4 antagonists described above thus avoid the disadvantages of the peptide drugs described above. However, the small molecule VLA-4 antagonists known in the art (as discussed above) have not been demonstrated to have a sufficiently high level of desired potency, low levels of acceptable side effects, and a suitably feasible pharmacokinetic and absorption profile to render these compounds suitable therapeutic agents for the treatment of the diseases or conditions described herein. Accordingly, there remains a need in the art for non-peptidyl or semi-peptidyl therapeutic agents that are effective in treating or preventing such pathological conditions.

Summary 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 compounds of formula (1.0.0) and pharmaceutically acceptable salts and other prodrug derivatives thereof:(1.0.0) wherein: a is (C) as defined herein₁-C₆) Alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 0-3R⁹Substitution; or A is a group selected from: a. the¹-NHC(＝O)NH-A²-，A¹-NHC(＝O)O-A²-，A¹-OC(＝O)NH-A²-，A¹-NHSO₂NH-A²-，A¹-NHC(＝O)-A²-，A¹-C(＝O)NH-A²-，A¹-NHSO₂-A²-，A¹-SO₂NH-A²-，A¹-(CH₂)_r-A²-，A¹-CH(R¹)-O-A²-，A¹-(CH₂)_rO-A²-，A¹-O(CH₂)_r-A²-，A¹-(CH₂)_rNH-A²-，A¹-NH(CH₂)_r-A²-, and A¹-(CH₂)_rS(＝O)_q-A²-, wherein A¹And A²Each independently selected from hydrogen, aryl, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, cycloalkyl, heteroaryl, and heterocyclyl, wherein the aryl, alkyl, cycloalkyl, heteroaryl, or heterocyclyl group is substituted with 0-3R ⁹Substitution; -B is a group independently selected from:(1.1.0) (1.1.1) (1.1.2)(1.1.3) (1.1.4) (1.1.5)(1.1.6) (1.1.7) (1.1.8)(1.1.9) (1.1.10) (1.1.11)(1.1.12) (1.1.13) (1.1.14)(1.1.15) (1.1.16) (1.1.17)(1.1.18) (1.1.19) (1.1.20)(1.1.21) (1.1.22) (1.1.23) - -, wherein the symbol "+" represents each of the moiety represented by the formulae (1.1.0) - (1.1.23) and "CR" in the formula (1.0.0)²R³- "the point of attachment of the moiety; the symbol "→" represents a connecting point of the moiety represented by each of the partial formulae (1.1.0) to (1.1.23) and the moiety "E" in the formula (1.0.0); and formulae (1.1.0) - (1.1.23) other than formulae (1.1.10), (1.1.17), and (1.1.23) can each optionally be substituted with R⁹Substitution; -E is a single bond, -O-, -NR¹⁰-，-CH＝CH-，-C≡C-，-S(＝O)_q，-CR¹¹R¹²NR¹⁰-, or-CR¹¹R¹²-, -X is-O-, -C (═ O) -, -S (═ O)_q-, or-NR¹⁰-；-X¹，X²And X³Each independently selected from CH and CR⁹Or N; -Y is a single bond, -C (═ O) -, -C (═ S) -, or-S (═ O)₂-; -k is an integer independently selected from 0, 1 and 2; -m is an integer independently selected from 0 and 1; -n is an integer independently selected from 0, 1 and 2; -p is an integer independently selected from 0 and 1, with the proviso that when B is selected from the sub-formulae (1.1.0) - (1.1.11), p must be selected as 1; -q is an integer independently selected from 0, 1 and 2; -r is an integer independently selected from 0, 1 and 2; -R¹Is 0 or 1F, CF₃、OCF₃Or cyano-substituted (C) ₁-C₃) An alkyl group; -R²And R³Each independently selected from hydrogen by 0-3R¹³Substituted (C)₁-C₆) Alkyl by 0-3R¹³Substituted (C)₂-C₆) An alkenyl group; by 0-3R¹³Substituted (C)₃-C₁₄) Carbocyclic ring system, by 0-3R¹³Substituted heterocyclyl ring, as defined herein, substituted with 0-3R¹³Substituted (C)₁-C₆) alkyl-OR⁵Is substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-SR⁵Is substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-SO₂R⁵Is substituted by 0-3R¹³A substituted heteroaryl ring as defined herein; by 0-3R¹³A substituted aryl ring as defined herein;

-with the proviso that-R²And R³Each as defined above, or they are bound to each other as described below, or one of them is bound to R as defined below⁴In combination with one another, in this case hydrogen or methyl; -R²And R³Are combined with each other to form a quilt with 0-3R¹³A substituted cycloalkyl or heterocyclyl ring; or-R²Or R³And R⁴And the carbon and nitrogen atoms to which they are respectively attached together form a group defined by 0-3R¹³A substituted heteroaryl or heterocyclyl group as defined herein; -R⁴Is hydrogen, or optionally substituted by R¹³Substituted (C)₁-C₆) Alkyl, or R⁴Can be reacted with R²Or R³Together form a carbocyclic or heterocyclic ring; -R⁵And R⁶Independently is hydrogen, (C)₁-C₆) Alkyl radical (C)₂-C₆) Alkenyl (C)₂-C₆) Alkynyl, CF ₃Aryl, cycloalkyl, heteroaryl, or heterocyclyl, wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl is substituted with 0-3R¹³Substitution; -R⁷Is (C)₁-C₆) Alkyl radical (CH)₂)_kOR⁵，(CH₂)_kC(＝O)R⁵，(CH₂)_kC(＝O)NR⁶R⁵，(CH₂)_kNR⁶C(＝O)R⁵，(CH₂)_kNR⁶C(＝O)OR⁵，(CH₂)_kNR⁶SO₂R⁵，(CH₂)_kNR⁶R⁵，F，CF₃，OCF₃Is substituted by 0-3R⁹Substituted aryl radicals, substituted by 0-3R⁹Substituted heterocyclyl, by 0-3R⁹Substituted heteroaryl with 0-3R⁹Substituted cycloalkyl, or R⁷Can be reacted with R⁸Together form a cycloalkyl or heterocyclyl ring; or R⁷Can be reacted with R¹¹Together form a cycloalkyl or heterocyclyl ring; -R⁸Is hydrogen, F, CN, (C)₁-C₆) Alkyl or (C)₁-C₆) An alkoxy group; -R⁹Is halogen, (C)₁-C₆) Alkyl radical (C)₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkoxy, cyano, (CH)₂)_kOH，C(＝O)R⁵，(CH₂)_kC(O)NR⁵R⁶，(CH₂)_kNR⁵R⁶，(CH₂)_kNR⁵SO₂R⁶，CF₃，OCF₃，SO₂NR⁵R⁶，(CH₂)_mC(＝O)OR⁵(ii) a When R is⁹When bound to a saturated carbon atom, R⁹May be either ═ O or ═ S; when R is⁹When bound to a sulfur atom, R⁹May be ═ O; -R¹⁰Is hydrogen, C (═ O) R⁵，C(＝O)OR⁵，(C₁-C₆) Alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, or SO₂R⁵；-R¹¹And R¹²Independently is hydrogen, (C)₁-C₆) Alkyl, hydroxy, cyano, (C)₁-C₆) Alkoxy radicals, NR⁶C(＝O)R⁵，NR⁶SO₂R⁵，NR⁶R⁵，CF₃F, aryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkoxy, or R¹¹Can be combined withR¹²Together form a cycloalkyl or heterocyclyl ring; -R¹³Independently selected from halogen, CF₃，(C₁-C₆) Alkyl, aryl, heteroaryl, heterocyclyl, hydroxy, cyano, (C) ₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkoxy, (C)₂-C₆) Alkynyl (C)₂-C₆) Alkenyl, -NR⁶R⁵，-C(＝O)NR⁵R⁶，SO₂R⁵，C(＝O)R⁵，NR⁵SO₂R⁶，NR⁵C(＝O)R⁶，C(＝O)NR⁵SO₂R⁶，NR⁵C(＝O)OR⁶And SO₂NR⁶R⁵。

The present invention also relates to pharmaceutical compositions comprising one or more of the compounds of the present invention as described above and a pharmaceutically acceptable carrier for said compound, wherein said compound is present in an amount effective to prevent, inhibit, prevent or reduce VLA-4 mediated cell adhesion and subsequent occurrence or associated pathological processes. The invention further relates to pharmaceutical compositions which contain, in addition to a compound of the invention, one or more therapeutic agents selected from the group consisting of anti-inflammatory corticosteroids, non-steroidal anti-inflammatory drugs, bronchodilators, anti-asthmatics and immunosuppressants.

The present invention further relates to a method of treating or preventing inflammatory, autoimmune or respiratory diseases by inhibiting VLA-4 mediated cell adhesion and subsequent or related pathological processes, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the present invention. The pharmaceutical compositions of the present invention may be used to treat a variety of inflammatory, autoimmune or respiratory diseases, including but not limited to asthma, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, host rejection following organ transplantation, atherosclerosis, and other diseases mediated by or associated with VLA-4.

Detailed description of the invention

The present invention relates to compounds that inhibit VLA-4 mediated cell adhesion and the consequent pathological processes. These compounds are therefore useful in the treatment of a variety of inflammatory, autoimmune and respiratory diseases, and they can be represented by the formula (1.0.0):(1.0.0)

for compounds of formula (1.0.0), the end group represented by A is terminated with 0-3R⁹Substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl; or is a group selected from: a. the¹-NHC(＝O)NH-A²-，A¹-NHC(＝O)O-A²-，A¹-OC(＝O)NH-A²-，A¹-NHSO₂NH-A²-，A¹-NHC(＝O)-A²-，A¹-C(＝O)NH-A²-，A¹-NHSO₂-A²-，A¹-SO₂NH-A²-，A¹-(CH₂)_rO-A²-，A¹-O(CH₂)_r-A²-，A¹-(CH₂)_r-A²-, wherein A¹And A²Each independently selected from the group consisting of hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl, wherein the aryl, alkyl, alkenyl, cycloalkyl, heteroaryl, or heterocyclyl group is interrupted by 0-3R⁹And (4) substitution.

The term "alkyl", used either alone or in combination with "A" and in the rest of the specification, refers to a straight or branched chain alkyl group containing the indicated number of carbon atoms, usually 1 to 6, but often 1 to 4 carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl.

The term "cycloalkyl", as used herein in "a" and elsewhere in the specification, whether used alone or in combination, refers to cycloalkyl groups containing from 3 to 6 carbon atoms. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "aryl" as used with respect to "a" and throughout the remainder of this specification refers to a carbocyclic aryl group selected from the group consisting essentially of phenyl, naphthyl, indenyl, 2, 3-indanyl, and fluorenyl. But in the case where "a" is an "aryl" group, a phenyl group is preferred.

The term "heteroaryl" as used with respect to "a" and elsewhere in this specification refers to a heterocyclic aryl group selected from the group consisting essentially of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, p-thiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furyl, 2, 3-dihydrobenzofuryl. Benzo [ b ] thienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, 2, 3-naphthyridinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrazolo [1, 5-c ] triazinyl.

However, in the case where "a" is "heteroaryl", furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo [ b ] furyl, benzimidazolyl or quinolinyl is preferred. More preferably "a" is pyridyl.

The terms "heterocycle" and "heterocyclyl" as used in "a" and elsewhere in this specification, both refer to a non-aromatic 3-10 membered carbocyclic ring in which at least one ring carbon atom is substituted with a heteroatom selected from N, O or S. Preferably two, more preferably one heteroatom are present, except that in the case of nitrogen up to 4 nitrogen heteroatoms may be present. The heterocyclic group may include one or two fused rings, and may further include an aryl fused ring. In a preferred meaning, "heterocyclyl" refers to a group selected from the group consisting essentially of: oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolylalkyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and benzodioxolane, in particular 1, 3-benzodioxol-5-yl.

In the case where "a" is "heterocyclyl", it is preferably pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

When "A" is defined as a group selected from the above alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl groups, the group may be substituted with 0-3R⁹And (4) substitution. The choice of "0" merely indicates no substituents, and substitution is optional. When substitution occurs, preferably two substituents are present, more preferably only one substituent is present.

When the substituent R is used⁹When it is selected from halogen, (C)₁-C₆) Alkyl radical (C)₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkoxy, cyano, hydroxy, C (═ O) R⁵，C(O)NR⁵R⁶，NR⁵R⁶，NR⁵SO₂R⁶，CF₃，OCF₃，SO₂NR⁵R⁶，C(＝O)OR⁵(ii) a When R is⁹When bound to a saturated carbon atom, R⁹May be either ═ O or ═ S; when R is⁹When bound to a sulfur atom, R⁹May be ═ O; wherein R is⁵And R⁶As further defined herein. But preferably a single substituent is present and is F, Cl, OH, methyl, methoxy, cyclohexyl, acetyl, cyclopropoxy, or F₃C-。

For the substituent "R" on the radical "A⁹"and the term" alkoxy "as used throughout the remainder of this specification, whether used alone or in combination, refers to an alkyl ether group, wherein the term" alkyl "is as defined above. Examples of suitable alkyl ether groups include, but are not limited to, methoxy, and the like,Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

For the substituent "R" on the radical "A⁹"and the term" cycloalkoxy "as used in the remainder of the specification, whether used alone or in combination, refers to a cycloalkyl ether group, wherein the term" cycloalkyl "is as defined above. Examples of suitable cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

The preferred meaning of "a" is a divalent radical selected from the group consisting of: a. the¹-NHC(＝O)NH-A²-，A¹-NHC(＝O)O-A²-，A¹-OC(＝O)NH-A²-，A¹-NHSO₂NH-A²-，A¹-NHC(＝O)-A²-，A¹-C(＝O)NH-A²-，A¹-NHSO₂-A²-，A¹-SO₂NH-A²-，A¹-(CH₂)_r-A²-，A¹-CH(R¹)-O-A²-，A¹-(CH₂)_rO-A²-，A¹-O(CH₂)_r-A²-，A¹-(CH₂)_rNH-A²-，A¹-NH(CH₂)_r-A²-, and A¹-(CH₂)_rS(＝O)_q-A²-, wherein A¹And A²Each independently selected from hydrogen, aryl, (C)₁-C₆) Alkyl, cycloalkyl, heteroaryl, and heterocyclyl, wherein the aryl, alkyl, cycloalkyl, heteroaryl, or heterocyclyl group is substituted with 0-3R⁹Substitution; like 0-3 substituents R⁹Similarly, an alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group attached to one or both sides of the ureido group is selected according to the definition above. Preferably, the aryl group is bonded to both sides of the urea group by a covalent bond, and further preferably, the aryl group is a phenyl group. Most preferably, the phenyl group bears a single substituent, which is preferably F, Cl, methyl, methoxy, or F₃C-. An example of a preferred meaning of "A" is represented by the sub-formula (4).0.0) - (4.0. 11) Represents:(4.0.0) (4.0.1) (4.0.2)(4.0.3) (4.0.4) (4.0.5)(4.0.9) (4.0.10) (4.0.11)

the portion of the compound of formula (1.0.0) immediately adjacent to the "a" moiety is a single bond, or a methylene or ethylene bridging moiety, where n is 0, 1 or 2, respectively. Preferably n-1, i.e. a methylene bridge is present. Thus, in addition to the methylene bridge in the above preferred context of the meaning of part "A", the following most preferred end groups including part "A" can be represented by the following partial formulae (4.1.0) - (4.1.23): 4-hydroxyphenyl- (4.1.0) 3-methoxy-4 (N' -phenylurea) -phenylmethyl-(4.1.1)4- (N' -phenylurea) -phenylmethyl-(4.1.2)4- [ N' - (2-methylphenyl) -urea]-phenylmethyl- (4.1.3)4- [ N' -2 (methoxyphenyl) -urea]-phenylmethyl-(4.1.4) 3-methoxy-4- [ N' - (2-methylphenyl) -urea]-phenylmethyl-(4.1.5)4- [ N' - (2-pyridinyl) -urea]-phenylmethyl-(4.1.6) 6-methoxy-5- [ N' - (2-methylphenyl) -urea]-2-pyridylmethyl-(4.1.7) 6-methoxy-5- [ N' - (2-methylphenyl) -urea]-2-pyridylmethyl- (4.1.7)4- [ N' - (3-methyl-2-pyridinyl) -urea]-phenylmethyl-(4.1.8) 3-methoxy-4- [ N' - (3-methyl-2-pyridinyl) -urea]-phenylmethyl-(4.9.9) 3-methoxy-4- [ N' - (2-pyridinyl) -urea]-phenylmethyl-(4.1.10)4- [ N' - (2-pyridinyl) -urea]-phenylmethyl- (4.1.11)4- [ N' - (2-fluorophenyl) -urea]-phenylmethyl-(4.1.12)4- [ N' - (2-chlorophenyl) -urea]-phenylmethyl-(4.1.13)4- [ N' - (2-chlorophenyl) -urea]-3-methoxyphenylmethyl-(4.1.14)4- [ N' - (4-isopropyl-phenyl) -urea ]-phenylmethyl-(4.1.15) 6-methoxy-5- [ N' - (o-toluoyl) -urea]-2-pyridylmethyl-(4.1.16)4- [ N' - (3-cyclopentyl-2-pyridinyl) -urea]-phenylmethyl-(4.1.17)4- [ N' - (2-cyclopentyl) -urea]-phenylmethyl-(4.1.18)4- [ N' - (3-Cyclopropyloxy-2-pyridinyl) -urea]-phenylmethyl- (4.1.19)4- [ N' - (O-toluoyl) -urea]-pyridin-5-ylmethyl-(4.1.20)4- [3- (4-methyl-pyridin-3-yl) -ureido ] -amine]-phenylmethyl(4.1.21)4- [3- (2, 6-dichloro-phenyl) -ureido ] -amide]-phenylmethyl(4.122)4- [3- (2, 6-dimethyl-phenyl) -ureido ]-phenylmethyl (4.1.23)

It should further be noted that the above partial structural formulae, in which the preferred methylene bridge is also preferably attached to the N, N' -diphenylureido group in the para position relative to the point of attachment of the divalent ureido group to the phenyl group in question, are also given.

The moiety "Y" of formula (1.0.0) may be-C (═ O), -C (═ S) -, or-S (═ O)₂-. However, in general, the most preferred "Y" carbonyl moiety, i.e., "Y", is the group-C (═ O) -.

The next moiety in the compound of formula (1.0.0) is-NR⁴CR²R³-. In this moiety, R²And R³Each independently selected from hydrogen by 0-3R¹³Substituted (C)₁-C₆) Alkyl by 0-3R¹³Substituted (C)₂-C₆) Alkenyl by 0-3R¹³Substituted (C)₃-C₁₄) Carbocyclic ring system, by 0-3R¹³Substituted heterocyclic radical as described above, substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-OR⁵Is substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-SR⁵Is substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-SO₂R⁵Is substituted by 0-3R¹³Substituted heteroaryl as defined above, substituted with 0-3R¹³Substituted aryl as described above. R²And R³Can also be according to R²And R³Are linked together, in which case they form a group defined by 0 to 3R¹³Substituted cycloalkyl or heterocyclyl. For example when R²And R³When taken together to form a spirocyclopropyl, cyclobutyl, or cyclopentyl group, the resulting compounds of the invention will include, for example, moieties according to the sub-formulae (1.2.0) - (1.2.2): (1.2.0) (1.2.1) (1.2.2)

When R is²Or R³And R⁴And the carbon and nitrogen atoms to which they are attached, respectively, together form a heteroaryl or heterocyclyl group as defined herein, then form another subgroup of the preferred compounds of the present invention. The heteroaryl or heterocyclyl group may also be substituted by 0-3R¹³And (4) substitution. According to the above conditions, when R²Or R³One and R⁴When joined together, the other must be hydrogen or methyl. This panel can be represented by the following sub-formula (1.3.0):(1.3.0)

wherein the symbol "+" represents the point of attachment of the moiety represented by the partial formula (1.3.0) to the moiety "Y" in the formula (1.0.0); and the symbol "→" represents a connection point of the moiety represented by the partial formula (1.1.0) and "B" in the formula (1.0.0) (as defined by the partial formulae (1.1.0) to (1.1.22)). Substituent "R^2/3"indicates the presence of R²Substituent or R³And (4) a substituent. They cannot both be present at the same time, since one or the other has already been selected with R⁴Together form a heteroaryl or heterocyclyl group represented by the following subformula (1.3.0):it is to be understood that R is either²Or R³If present, they will have the meaning of hydrogen, alkyl or methyl.

Thus, the group of the sub-formula (1.3.0) — NR⁴CR²R³This subgroup of B- "includes, but is not limited to, the moieties represented by the following partial formulae (1.3.1) - (1.3.20):(1.3.1) (1.3.2) (1.3.3) (1.3.4)(1.3.5) (1.3.6) (1.3.7) (1.3.8)(1.3.9) (1.3.10) (1.3.11) (1.3.12)(1.3.13) (1.3.14) (1.3.15) (1.3.16)(1.3.17) (1.3.18) (1.3.19) (1.3.20)

wherein the symbol "×" represents the connection point of the moiety represented by each of the partial formulae (1.3.1) to (1.3.20) and the moiety "Y" in the formula (1.0.0), and the symbol "→" represents the connection point of the moiety "E" in each of the partial formulae (1.3.1) to (1.3.20) and the formula (1.0.0).

With respect to R which may be present in part B²And R³Optional substituents R on the substituents¹³When "0" is selected, R¹³Is absent. Preferably R¹³Is absent or present inIn the form of a single substituent selected from the group consisting of halogen, CF₃，(C₁-C₆) Alkyl, aryl, heteroaryl, heterocyclyl, hydroxy, cyano, (C)₁-C₆) Alkoxy group, (C)₃-C₁₄) A carbocyclic ring system, (C)₃-C₆) Cycloalkoxy, (C)₂-C₆) Alkynyl (C)₂-C₆) Alkenyl, -NR⁶R⁵，-C(＝O)NR⁵R⁶，SO₂R⁵，C(＝O)R⁵，NR⁵SO₂R⁶，NR⁵C(＝O)R⁶，C(＝O)NR⁵SO₂R⁶，NR⁵C(＝O)OR⁶And SO₂NR⁶R⁵. For optional substituent R¹³And other groups in the specification, the term "alkynyl", used alone or in combination, refers to straight or branched chain alkynyl groups containing 2 to 6, preferably 2 to 4, carbon atoms. Examples of such groups include, but are not limited to, ethynyl (ethynyl), propynyl, propargyl, butynyl, hexynyl, decynyl, and the like.

With respect to R¹³The term "alkenyl", employed alone or in combination, means a straight-chain or branched alkenyl group containing 2 to 6, preferably 2 to 4, carbon atoms. Examples of such groups 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.

For R²And R³And the rest of the description, in which the terms "(C) are used alone or in combination ₃-C₁₄) By carbocyclic ring system "is meant cycloalkyl and cycloalkenyl groups consisting of one, two or three fused rings, which in total contain 3 to 14 carbon atoms. The term "cycloalkyl" as such refers to a cyclic alkyl group containing from 3 to 8, preferably from 3 to 6, carbon atoms. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. In another aspect, the term "cycloalkenyl" refers to a carbocyclic ring containing from 4 to 8 (preferably 5 or 6) carbon atoms and one or more double bonds. Examples of such cycloalkenyl groups include, but are not limited toLimited to cyclopentenyl, cyclohexenyl, and cyclopentadienyl.

When two or three fused rings are present, one of the rings can be a cycloalkyl ring system and one or two of the other rings can be a cycloalkenyl ring system.

Preferably, when R is²And R³When one is hydrogen, the other is selected from the group consisting essentially of hydrogen, methyl, ethyl, propyl, butyl, and isobutyl; 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 moiety, the "B" group of the compound of formula (1.0.0), is one of the more important parts of the molecule and is an important element in providing the unexpectedly good biological properties of the compounds of the present invention. The "B" group includes moieties selected from the group consisting of partial formulas (1.1.0) - (1.1.22):(1.1.0) (1.1.1) (1.1.2)(1.1.3) (1.1.4) (1.1.5)(1.1.6) (1.1.7) (1.1.8)(1.1.9) (1.1.10) (1.1.11)(1.1.12) (1.1.13) (1.1.14)

(1.1.15) (1.1.16)(1.1.17) (1.1.18) (1.1.19)(1.1.20) (1.1.21) (1.1.21) -wherein the symbol "+" represents each of the moieties represented by the partial formulae (1.1.0) - (1.1.22) and "CR" in the formula (1.0.0)²R³"attachment point of a moiety; and the symbol "→" represents a connecting point of the moiety represented by each of the partial formulae (1.1.0) to (1.1.22) and the moiety "E" in the formula (1.0.0).

All of the above sub-formulae (1.1.0) - (1.1.22), including both ends, are illustrated by the above-described segments, wherein the points of attachment at either end of a particular segment are indicated by the symbols "+" and "→".

In the above subformulae which define the part of compound B of formula (1.0.0), the moiety "X" may be oxygen, sulphur (q ═ 0) and sulphur with two oxygen atoms attached (q ═ 2), i.e. a sulphonyl group; or NH (R)¹⁰Hydrogen) or substituted nitrogen (R)¹⁰＝(C₁-C₆) An alkyl group; (C)₃-C₆) Cycloalkyl, heterocyclyl, heteroaryl, or aryl). But preferably "X" is simply oxygen, sulfur or NH.

Attached to the B moiety in the compound of formula (1.0.0) is a residual structural unit that may be represented by sub-formula (1.4.0):(1.4.0)

it should first be noted that the moiety represented by sub-formula (1.4.0) is directly attached to the B moiety in the total compound of formula (1.0.0). E is a single bond, oxygen, -NR¹⁰-, -CH ═ CH-, or-CR¹¹R¹²-。

When the substituent R is used¹⁰When it is selected substantially independently from hydrogen, C (═ O) R⁵，(C₁-C₆) Alkyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, or SO₂R⁵。

When the substituent R is used¹¹And R¹²When they are substantially independently selected from hydrogen, (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy radicals, NR⁶COR⁵，NR⁶SO₂R⁵，NR⁶R⁵，CF₃F, aryl, heterocyclyl, heteroaryl, cycloalkyl, and cycloalkoxy. R¹¹Can be reacted with R¹²Together form a cycloalkyl or heterocyclyl ring. R⁵And R⁶Independently is hydrogen, (C)₁-C₆) Alkyl radical, CF₃Aryl, cycloalkyl, heteroaryl, or heterocyclyl.

Group (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, aryl, heterocyclyl, heteroaryl, cycloalkyl and cycloalkoxy are as defined in detail above. Within the meaning of these radicals, preference is given to R¹¹And R¹²Independently selected from the group consisting of methyl, ethyl, propyl, butyl, isobutyl, methoxy, cyclopropoxy, cyclopropyl, phenyl, morpholinyl, piperidinyl and pyridinyl.

In the portion of the compounds of the invention represented by sub-formula (1.4.0) above, moiety E is followed by an optional methylene bridge: (-CH) ₂-)_mWherein m is an integer independently selected from 0 and 1.

The next component of formula (1.0.0) consists of "- (CR)⁷R⁸)_p- "denotes, wherein" p "is selected from the integers 0 and 1, with the proviso that" p "must be selected when" B "is selected from the partial formulae (1.1.0) to (1.1.11)1。

Substituent R⁷Is selected from (C)₁-C₆) Alkyl, hydroxy, (C)₁-C₆) Alkoxy, NHC (═ O) R⁵，NHSO₂R⁵，NR⁶R⁵，F，CF₃，OCF₃Aryl, heterocyclyl, heteroaryl, cycloalkyl; or R⁷Can be reacted with R⁸Taken together to form a cycloalkyl or heterocyclyl ring. Substituent R⁸Selected from hydrogen, F, (C)₁-C₆) Alkyl or (C)₁-C₆) An alkoxy group.

The final component of formula (1.0.0) is a "-C (═ O) OR" group, where R is hydrogen.

Components represented by sub-formula (1.4.0) include, but are not limited to, moieties represented by the following sub-formulae (1.4.1) - (1.4.20):(1.4.1) (1.4.2) (1.4.3) (1.4.4)(1.4.5) (1.46) (1.4.7) (1.4.8)(1.4.9) (1.4.10) (1.4.11) (1.4.12)(1.4.13) (1.4.14) (1.4.15) (1.4.16)(1.4.17) (1.4.18) (1.4.19) (1.4.20)

pharmaceutically acceptable derivatives of the compounds of formula (1.0.0) are included within the scope of the present invention. The term "pharmaceutically acceptable derivative" as used herein refers to any pharmaceutically acceptable salt of the compound of formula (1.0.0). Any other compound capable of directly or indirectly producing a compound of formula (1.0.0) upon administration to a patient is also included within the scope of the present invention. These compounds are referred to as prodrugs, and a variety of accepted methods may be employed to prepare such prodrug forms of the compounds of formula (1.0.0).

The term "patient" as used above and throughout the specification refers to mammals, including humans. And wherein the term "cell" is used to refer to mammalian cells, including human cells, unless otherwise indicated.

Further included within the scope of the present invention are metabolites or residues of compounds of formula (1.0.0) that are biologically active such that they are capable of inhibiting VLA-4 mediated cell adhesion and subsequent consequent or related pathological processes. Once synthesized, the inhibitory activity and VLA-4 specificity of the compounds of formula (1.0.0) of the present invention can be determined using in vitro and in vivo assays as detailed below.

The desired biological activity of the compounds of formula (1.0.0) may also be improved by the introduction of appropriate functional groups which can serve to enhance the existing biological activity of the compound, improve the selectivity of the existing biological activity of the compound, or add other desired biological activity to the existing biological activity. Such modifications are known in the art and include modifications to increase the biological penetration into a given biological system (e.g., blood, lymphatic system, and central nervous system), to increase oral availability, to increase solubility to allow administration by injection, to alter metabolism, and to alter the rate of secretion of the compound of formula (1.0.0).

Other chemical and biological terms used herein will be readily understood by those skilled in the art from the above definitions, as well as from other definitions in this specification. The terms may be used individually or in any combination. Preferred and more preferred chain lengths of the groups already described herein are suitable for all of these combinations.

In light of the foregoing description of certain preferred subclasses and more preferred subclass definitions of compounds of formula (1.0.0), preferred and more preferred compounds are listed below for further illustration of the invention.

A compound comprising the sub-formula (1.1.0): 3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-5-yl ] -2-methyl-propionic acid 2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid 2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -3-methyl-butyl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid 2-methanesulfonamido-3- [2- (1- {2- [ 3-methoxy- Phenyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid 2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-oxazol-5-yl } -propionic acid 2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid 2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -4, 5-dihydro-oxazol-5-yl } -propionic acid 2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-oxazol-5-yl) -propionic acid 2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid 2-carboxamido-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -4, 5-dihydro-thiazol-5-yl } -propionic acid 2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-5-yl) -propionic acid 2-benzenesulfonylamino-3- (2- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-5-yl) -propionic acid 2-benzenesulfonylamino-3- [2- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid 2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-4, 5-dihydro-oxazol-5-yl } -propionic acid 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -4, 5-dihydro-thiazol-5-yl } -propionic acid 3-acetylamino-3- {2- [ ({ [ 3-methyi-l-ureido) -phenyl ] -acetyl } -methyl } -4, 5-dihydro-thiazol-5-yl } -propionic acid 3-acetylamino-3- {2- [ ({ [3- Oxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-3H-imidazol-4-yl } -propionic acid 2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-oxazol-5-yl } -propionic acid

A compound comprising a moiety of the sub-formula (1.1.1): 3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-4-yl ] -2-methyl-propionic acid 2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid 2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -3-methyl-butyl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid 2-methanesulfonamido-3- [2- (1- {2- [ 3-methoxy- Phenyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid 2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-oxazol-4-yl } -propionic acid 2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid 2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -4, 5-dihydro-oxazol-4-yl } -propionic acid 2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-oxazol-4-yl) -propionic acid 2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid 2-acetylamino-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -4, 5-dihydro-thiazol-4-yl } -propionic acid 2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-4-yl) -propionic acid 2-benzenesulfonylamino-3- (2- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-4-yl) -propionic acid 2-benzenesulfonylamino-3- [2- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid 2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-4, 5-dihydro-oxazol-4-yl } -propionic acid 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-thiazol-4-yl } -propionic acid 2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-oxazol-4-yl } -propionic acid

A compound comprising a moiety of the sub-formula (1.1.2): 3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-5-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-5-yl ] -propionic acid; 2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -oxazol-5-yl } -propionic acid; 2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -oxazol-5-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-5-yl) -propionic acid, 2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid, 2-acetylamino-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazole-5-yl ] -propionic acid -yl } -propionic acid; 2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-5-yl) -propionic acid; 2-benzenesulfonylamino-3- (2- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-5-yl) -propionic acid; 2-benzenesulfonylamino-3- [2- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid; 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-oxazol-5-yl } -propionic acid; 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiazol-5-yl } -propionic acid; 3-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -3H-imidazol-4-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-5-yl } -propionic acid;

A compound comprising a moiety of the sub-formula (1.1.3): 3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-4-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-4-yl ] -propionic acid; 2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-4-yl ] -propionic acid; 2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -oxazol-4-yl } -propionic acid; 2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -oxazol-4-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-4-yl) -propionic acid, 2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid, 2-carboxamido-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazole-4-yl ] -propionic acid -yl } -propionic acid; 2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -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-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid; 2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid; 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-oxazol-4-yl } -propionic acid; 2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -thiazol-4-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-4-yl } -propionic acid; 3- [2- (1- { [4- (4-chloro-benzyloxy) -3-fluoro-phenyl ] -acetyl } -pyrrolidin-2-yl) -thiazol-5-yl ] -propionic acid; 3- [2- (1- { [ 3-fluoro-4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid; 3- [2- (1- { [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid; 3- [2- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid; 3- (2- {1- [ (4-benzyloxy-3-chloro-phenyl) -acetyl ] -3-methyl-pyrrolidin-2-yl } thiazol-5-yl) -propionic acid; 3- [2- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -3-methyl-pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid; 3- (2- {1- [ (4-benzyloxy-phenyl) -acetyl ] -3-methyl-pyrrolidin-2-yl } thiazol-5-yl) -propionic acid; 3- (2- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } thiazol-5-yl) -propionic acid; and 3- (2- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } isoxazol-5-yl) -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.4): 3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-isoxazol-5-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid; 2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-isoxazol-5-yl } -propionic acid; 2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -4, 5-dihydro-isoxazol-5-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-isoxazol-5-yl) -propionic acid, 2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl } -propionic acid, 2-carboxamido-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -4, 5-dihydro-isothiazol-5-yl } -propionic acid; 2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-isoxazol-5-yl) -propionic acid 2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-isoxazol-5-yl) -propionic acid; 2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-4, 5-dihydro-isoxazol-5-yl } -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-isothiazol-5-yl } -propionic acid; 3-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -3, 4-dihydro-2H-pyrazol-3-yl } -propionic acid; and 2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-isoxazol-5-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.5): 3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-pyrazol-1-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid; 2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-pyrazol-1-yl } -propionic acid; 2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-pyrazol-1-yl) -propionic acid, 2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid, 2-acetylamino-3- {3- [1- (biphenyl-4-yl-acetyl-) Pyrrolidin-2-yl ] -4, 5-dihydro-pyrazol-1-yl } -propionic acid; 2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-pyrazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-pyrazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-4, 5-dihydro-pyrazol-1-yl } -propionic acid; 2-formylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -4, 5-dihydro-pyrazol-1-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-pyrazol-1-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.6): 3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-5-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-5-yl ] -propionic acid; 2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -isoxazol-5-yl } -propionic acid; 2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -isoxazol-5-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -isoxazol-5-yl) -propionic acid, 2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid, 2-acetylamino-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -isothiazolone- 5-yl } -propionic acid; 2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-carboxamido-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-isoxazol-5-yl } -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isothiazol-5-yl } -propionic acid; 3-acetylamino-3- {5- [ ({ [ 3-methoxy 4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2H-pyrazol-3-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isoxazol-5-yl } -propionic acid; 3- [3- (1- { [4- (pyridin-4-ylmethoxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [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-benzyloxy-pyridin-3-yl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 3- (3- {1- [ (5-benzyloxy-pyridin-2-yl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -2-phenylaminomethyl-propionic acid; 3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -2- (pyridin-2-ylamino) -propionic acid; 3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -2- (pyridin-3-ylamino) -propionic acid; 3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -2- (pyridin-4-ylamino) -propionic acid; 3- [3- (1- { [4- (5-chloro-thiophen-2-ylmethoxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 3- [3- (1- { [4- (4-chloro-benzyloxy) -3-fluoro-phenyl ] -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; phenyl ] -2- (propane-1-sulfonylamino) -propionic acid; 3- [3- (1- { [ 3-methoxy-4- (4-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [ 3-methoxy-4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (4-chloro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (3-chloro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (2-chloro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (4-fluoro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (3-fluoro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (2-fluoro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [ 3-chloro-4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-acetylamino-3- [3- (1- { [ 3-chloro-4- (3-methoxy-benzyloxy) -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-ylmethoxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-acetylamino-3- [3- (1- { [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (2-cyanobenzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (4-cyano-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- (3- {1- [ (4-benzyloxy-3-fluoro-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid, 3- (3- {1- [ (4-benzyloxy-3-chloro-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid, 3- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino ] -3-methyl-butyl } -isoxazol-5-yl) -propionic acid, 2-acetylamino-3- [3- (1- { [4- (3-cyano-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-acetylamino-3- [3- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-acetylamino-3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 3- (3- {1- [ (4-p-tolyloxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 3- (3- {1- [ (4-m-tolyloxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 3- (3- {1- [ (4-o-tolyloxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid; 3- [3- (1- { [4- (4-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (2-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 2-acetylamino-3- [3- (3-methyl-1- {2- [4- (2-methyl-benzyloxy) -phenyl ] -acetylamino } -butyl) -isoxazol-5-yl ] -propionic acid; 2-acetylamino-3- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino ] -3-methyl-butyl ] -isoxazol-5-yl) -propionic acid; 3- [3- (1- { [4- (4-fluoro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (3-fluoro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (2-fluoro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (2-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (3-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (3-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (4-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid; 3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-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-methoxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid, 3- (5- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -2H-pyrazole -3-yl ] -propionic acid; and 3- (3- {1- [3- (2-methyl-benzyloxy) -benzoyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.7): 3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid; 2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -pyrazol-1-yl } -propionic acid; 2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -pyrazol-1-yl) -propionic acid, 2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid, 2-carboxamido-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -pyrazol-1-yl ] -propionic acid -yl } -propionic acid; 2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-pyrazol-1-yl } -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.8): 3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid; 2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -oxazol-2-yl } -propionic acid; 2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-2-yl) -propionic acid; 2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid; 2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazol-2-yl } -propionic acid; 2-methyl-3- (4- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid; 2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid; 2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-oxazol-2-yl } -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -thiazol-2-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid. 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -1H-imidazol-2-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.9): 3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -imidazol-1-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -imidazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -imidazol-1-yl ] -propionic acid; 2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -imidazol-1-yl } -propionic acid; 2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -imidazol-1-yl) -propionic acid; 2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic 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-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -imidazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -imidazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-imidazol-1-yl } -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -imidazol-1-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -imidazol-1-yl } -propionic acid.

A compound comprising a moiety of formula (1.1.10): 3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] oxadiazol-5-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid; 2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid; 2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methyl-amino) -methyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } - [1, 2, 4] oxadiazol-5-yl) -propionic acid; 2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -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-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] oxadiazol-5-yl) -propionic acid; 2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] oxadiazol-5-yl) -propionic acid; 2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid; 2-carboxamido-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] thiadiazol-5-yl } -propionic acid; 3-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -2H- [1, 2, 4] triazol-3-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid.

A compound comprising a moiety of formula (1.1.11): 3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] triazol-1-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] triazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] triazol-1-yl ] -propionic acid; 2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] - [1, 2, 4] triazol-1-yl } -propionic acid; 2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methyl-amino) -methyl ] - [1, 2, 4] triazol-1-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } - [1, 2, 4] triazol-1-yl) -propionic acid; 2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid; 2-acetylamino-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] - [1, 2, 4] triazol-1-yl } -propionic acid; 2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] triazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] triazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl- [1, 2, 4] triazol-1-yl } -propionic acid; 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] triazol-1-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] triazol-1-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.12): 3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -furan-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -propionic acid; 2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -1H-pyrrol-2-yl } -propionic acid; 2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -furan-2-yl) -propionic acid; 2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid; 2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiophen-2-yl } -propionic acid; 2-methyl-3- (4- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -1H-pyrrol-2-yl) -propionic acid; 2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -furan-2-yl) -propionic acid; 2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-1H-pyrrol-2-yl } -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiophen-2-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -furan-2-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.13): 3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-3-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -furan-3-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-3-yl ] -propionic acid; 2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -1H-pyrrol-3-yl } -propionic acid; 2, 2-dimethyl-3- [5- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -thiophen-3-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -furan-3-yl) -propionic acid; 2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-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-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -furan-3-yl) -propionic acid; 2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -thiophen-3-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-3-yl ] -propionic acid; 2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2-methyl-1H-pyrrol-3-yl } -propionic acid; 2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiophen-3-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -furan-3-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.14): 3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -furan-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -propionic acid; 2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -1H-pyrrol-2-yl } -propionic acid; 2, 2-dimethyl-3- [5- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -furan-2-yl) -propionic acid; 2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid; 2-formylamino-3- {5- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiophen-2-yl } -propionic acid; 2-methyl-3- (5- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -1H-pyrrol-2-yl) -propionic acid; 2-benzenesulfonylamino-3- (5- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -furan-2-yl) -propionic acid; 2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid; 2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2-methyl-1H-pyrrol-2-yl } -propionic acid; 2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiophen-2-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -furan-2-yl } -propionic acid.

A compound comprising a moiety of formula (1.1.15): 3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-3-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-3-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-3-yl ] -propionic acid; 2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -isoxazol-3-yl } -propionic acid; 2, 2-dimethyl-3- [5- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid; 2-allyloxycarbonylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -isoxazol-3-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -isoxazol-3-yl) -propionic acid; 2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid; 2-acetylamino-3- {5- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -isothiazol-3-yl } -propionic acid; 2-methyl-3- (5- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-3-yl) -propionic acid; 2-benzenesulfonylamino-3- (5- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-3-yl) -propionic acid; 2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid; 2-carboxamido-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-isoxazol-3-yl } -propionic acid; 2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isothiazol-3-yl } -propionic acid; 3-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2H-pyrazol-5-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isoxazol-3-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.16): 3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid; 2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -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-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid; 2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-2-yl) -propionic acid; 2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid; 2-formylamino-3- {5- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazol-2-yl } -propionic acid; 2-methyl-3- (5- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid; 2-benzenesulfonylamino-3- (5- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid; 2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid; 2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid; 2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-oxazol-2-yl } -propionic acid; 2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiazol-2-yl } -propionic acid; 2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid; and 2-acetylamino-3- [5- ({2- [4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -methyl) -1H-imidazol-2-yl ] -propionic acid.

A compound comprising a moiety of formula (1.1.17): 3- (5- {1- [ (4-benzyloxy-3-methoxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 3, 4] -thiadiazol-2-yl) -propionic acid; 3- [5- (1- { [4- (4-chloro-benzyloxy) -phenyl) -acetyl } -pyrrolidin-2-yl) - [1, 3, 4] -thiadiazol-2-yl ] -propionic acid; 3- (5- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 3, 4] -thiadiazol-2-yl) -propionic acid.

A compound comprising moieties of sub-formulae (1.1.8), (1.1.19) and (1.1.20): 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -phenyl } -propionic acid; 2-formylamino-3- {6- [1- ({ 3-methoxy-4- [3- (3-methyl-pyridin-2-yl) -ureido ] -phenyl } -acetyl) -pyrrolidin-2-yl ] -pyridin-2-yl } -propionic acid; 3- {4- [1- ({ 3-ethyl-4- [3- (3-methyl-pyridin-2-yl) -ureido ] -phenyl } -acetyl) -pyrrolidin-2-yl ] -pyrimidin-2-yl } -propionic acid; 2-carboxamido-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -phenyl ] -propionic acid; 2-acetylamino-3- [3- ({2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -methyl) -phenyl ] -propionic acid; 2- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) phenyl ] -acetyl } -methyl-amino) -methyl ] -pyridin-4-ylmethyl } -4-methyl-pentanoic acid; 3- {2- [ (methyl- { [4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -amino) -methyl ] -pyridin-4-yl } -propionic acid; 2-methanesulfonylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 3, 5] triazin-2-yl } -propionic acid; 1- [4- (1- { [6- (3-pyridin-2-yl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyridin-2-ylmethyl ] -cyclopropanecarboxylic acid; 3- [3- (1- { [6- (3-pyridin-2-yl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -phenyl ] -butyric acid; 2- (butane-1-sulfonylamino) -3- {3- [ ({ { 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -phenyl } -propionic acid; 2-benzenesulfonylamino-3- [3- ({ [ (2-methoxy-2' -methyl-biphenyl-4-yl) -acetyl ] -methyl-amino } -methyl) -phenyl ] -propionic acid; 2- (3- { [2- (4-benzyloxy-phenyl) -acetylamino ] -methyl } -benzyl) -malonic acid; 2- [3- ({2- [4- (4-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -benzyl ] -malonic acid; 3- [3- ({2- [4- (3-fluoro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid; 3- [3- ({2- [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid; 3- [3- ({2- [ 4-benzyloxy-3-chloro-phenyl ] -acetylamino ] -methyl } -phenyl) -2- (propane-1-sulfonylamino) -propionic acid; 3- [3- ({2- [4- (3-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid; 3- [3- ({2- [4- (4-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid; 3- (3- { [2- (4-benzyloxy-3-methoxy-phenyl) -acetylamino ] -methyl } -phenyl) -2- (propane-1-sulfonylamino) -propionic acid; 3- [3- ({2- [4- (4-methyl-benzyloxy) -phenyl ] -acetylamino } -methyl) -2-acetylamino-3- (3- { [2- (4-benzyloxy-phenyl) -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-tolyl-acetylamino) -methyl ] -phenyl } -propionic acid: 3- (3- { [2- (4-hydroxymethyl-phenyl) -acetylamino ] -methyl } -phenyl) -2- (propane-1-sulfonylamino) -propionic acid; and 3- [3- (phenylacetylamino-methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid.

A compound comprising the sub-formula (1.1.21): 3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrrol-1-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrrol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrrol-1-yl ] -propionic acid; 2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -pyrrol-1-yl } -propionic acid; 2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -pyrrol-1-yl) -propionic acid; 2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl ] -propionic acid; 2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -pyrrol-1-yl } -propionic acid; 2-methyl-3- (4- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrrol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrrol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl ] -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-pyrrol-1-yl } -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrrol-1-yl } -propionic acid; and 2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrrol-1-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.22): 3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -2-methyl-propionic acid; 2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid; 2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -pyrazol-1-yl } -propionic acid; 2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid; 2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -pyrazol-1-yl) -propionic acid; 2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid; 2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -pyrazol-1-yl } -propionic 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-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrazol-1-yl) -propionic acid; 2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid; 2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-pyrazol-1-yl } -propionic acid; 2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid; and 2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid.

A compound comprising a moiety of the sub-formula (1.1.23): 2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -benzooxazole-6-carboxylic acid; 2- [1- (2- { 3-methoxy-4- [3- (3-methyl-pyridin-2-yl) -ureido ] -phenyl) -acetylamino) -3-methyl-butyl ] -3H-benzimidazole-5-carboxylic acid; 2- (1- { [4- (3-pyridin-2-yl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-imidazo [4, 5-c ] pyridine-6-carboxylic acid; 2- (1- { [ 3-ethoxy-4- (3-pyridin-2-yl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -benzothiazole-6-carboxylic acid; 2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -benzothiazole-6-carboxylic acid; 2- ({ [ (4-benzyloxy-phenyl) -acetyl ] -methyl-amino } -methyl) -oxazolo [5, 4-b ] pyridine-5-carboxylic acid; and 3-methyl-2- {1- [ (4-phenoxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -3H-benzimidazole-5-carboxylic acid.

The compounds of the invention described above may be used in the form of acids, esters or other chemical species falling within the scope of the compounds. It is also within the scope of the present invention to use these compounds in the form of pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to methods known in the art. Such well-known pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate (benzanesulfonate), benzenesulfonate (besylate), bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactate, lactobionate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, dihydronaphthoate, pectate, persulfate, 3-phenylpropionate, Phosphonates, picrates, pivalates, propionates, salicylates, sodium phosphates, stearates, succinates, sulfates, sulfosalicylates, tartrates, thiocyanates, thiolates, tosylates and undecanoates.

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 salts; alkaline earth metal salts such as calcium and magnesium salts; salts with organic bases, for example dicyclohexylamine, meglumine, N-methyl-D-glucamine, tris- (hydroxymethyl) -methylamine (tromethamine), and salts with amino acids such as arginine, lysine and the like. Compounds of the invention comprising basic nitrogen-containing groups may be quaternized with such agents, e.g. (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; sulfuric acid di (C)₁-C₄) Alkyl esters such as dimethyl sulfate, diethyl ester and diamyl ester; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl- (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. These salts can make water-soluble and oil-soluble compounds of the invention.

Among the above pharmaceutically acceptable salts, preferred include, but are not limited to, acetate, methanesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isothionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiolate, tosylate, and trimethylamine.

Where a compound of the invention contains more than one salt capable of forming such a pharmaceutically acceptable salt, double salt forms are also included within the scope of the invention. Examples of typical double salt forms include, but are not limited to, ditartrate, diacetate, difumarate, diglucamine, diphosphate, disodium and trihydrochloride.

The pharmaceutical compositions of the present invention comprise one or more of the inhibitor compounds of the present invention described above, or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutically acceptable carrier as is well known in the relevant art as required by the nature and desired performance.

The term "carrier" as used herein includes acceptable diluents, excipients, adjuvants and carriers. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchange compositions; alumina; aluminum stearate; lecithin; a serum protein; such as human serum albumin; a phosphate salt; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as sulfated prolamine, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; a cellulose-based substance; such as sodium carboxymethylcellulose; polyethylene glycol; polyacrylates, paraffins; polyethylene-polyoxypropylene block copolymers and lanolin.

More specifically, the diluents, excipients, adjuvants and carriers used in the pharmaceutical compositions of the present invention include materials selected from the group consisting essentially of: adding acidifying and basifying agents, including acidifying agents such as acetic acid, glacial acetic acid, malic acid, and propionic acid, and basifying agents such as edenol (edetol), potassium carbonate, potassium hydroxide, sodium borate, sodium carbonate, and sodium hydroxide, to obtain a desired or predetermined pH; aerosol propellants which are required where the pharmaceutical composition is administered as an aerosol under sufficient pressure, such as acceptable halogenated hydrocarbons; nitrogen gas; or volatile hydrocarbons such as butane, propane, isobutane or mixtures thereof; antimicrobial agents including antibacterial, antifungal and antiprotozoal agents added in cases where the pharmaceutical composition is administered topically, for example, antimicrobial agents such as benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate, potassium sorbate, and sorbic acid, and antifungal agents such as benzoic acid, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, and sodium benzoate; antimicrobial preservatives added to pharmaceutical compositions to protect them from the growth of potentially harmful microorganisms, such as alkyl esters of parahydroxybenzoic acid, propionate salts, phenoxyethanol, sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, sodium dehydroacetate, benzalkonium chloride, benzylethylamine chloride, and benzyl alcohol; adding antioxidants for protecting the ingredients of the pharmaceutical composition from damage or degradation by oxidizing agents present in the composition itself or in the environment of use, such as anoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulfite, propyl, octyl and dodecyl esters of gallic acid, sodium metabisulfite, sulfur dioxide and tocopherol; buffers for maintaining the desired pH of the composition, such as calcium acetate, potassium metaphosphate, potassium dihydrogen phosphate, and tartaric acid; and chelating agents such as dipotassium edetate, disodium edetate, and edetic acid for helping to maintain the ionic strength of the pharmaceutical composition and for binding and effectively removing harmful compounds and metals.

To the topically applied pharmaceutical compositions of the present invention are added dermatologically active substances, for example wound healing agents such as peptide derivatives, yeast, panthenol, hexylresorcinol, phenol, tetracycline hydrochloride, riboflavin and kinetin, glucocorticoids for the treatment of inflammation, for example hydrocortisone, dexamethasone, betamethasone, triamcinolone, fluocinolone and methylprednisolone, retinoic acids for the treatment of acne, psoriasis, skin ageing and skin cancer, for example vitamin a, tretinoin, isotretinoin, etretinate, acitretin and arotinoid (arotinoid); immunosuppressants for the treatment of inflammation, such as dapsone and sulfasalazine; mild antibacterial agents such as resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide, erythromycin, clindamycin, and mupirocin; antifungal agents, for example griseofulvin, azoles such as miconazole, econazole, itraconazole, fluconazole, and ketoconazole; and allylamines such as naftifine and terfenadine (terfinavir), antiviral agents such as acyclovir, famciclovir and valacyclovir, antihistamines such as diphenhydramine, terfenadine, astemizole, loratadine, cetirizine, acrivastine and temustine, topical agents such as benzocaine, lidocaine, octacaine and pramoxine hydrochloride; topical analgesics such as methyl salicylate, camphor, menthol and resorcinol; topical preservatives for the prevention of infection, such as benzalkonium chloride and povidone iodine; vitamins and their derivatives, such as tocopherol, tocopheryl acetate, retinoic acid and retinol.

Other examples of diluents, excipients, adjuvants and carriers for use in the pharmaceutical compositions of the invention include components selected from the group consisting essentially of: dispersing and suspending agents such as poliglenen, povidone and silica; emollients, e.g. hydrocarbon oils and waxes, triglycerides, acetylated monoglycerides, C₁₀-C₂₀Methyl and other alkyl esters of fatty acids, C₁₀-C₂₀Fatty acid, C₁₀-C₂₀Fatty alcohols, lanolin and its derivatives, polyol esters such as polyethylene glycol (200-; an emulsifier for preparing an oil-in-water emulsion; excipients, such as laurocapram  ketone and polyethylene glycol monomethyl ether; humectants, such as sorbitol, glycerol and hyaluronic acid; ointment bases such as petrolatum, polyethylene glycols, lanolin, and poloxamer; penetration enhancers, e.g. dimethyl isosorbide, diethyl-ethanediol-monoethyl ether, 1-dodecylazacycloheptan-2-one and dimethylSulfoxide (DMSO); preservatives, for example benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, propyl p-hydroxybenzoate, quaternary ammonium compounds, for example potassium benzoate and thimerosal; chelating agents, including cyclodextrins; solvents such as acetone, alcohols, amylene hydrate, butanol, corn oil, cottonseed oil, ethyl acetate, glycerol, hexylene glycol, isopropanol, isostearyl alcohol, methanol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol diacetate, sesame oil and purified water; stabilizers, such as calcium saccharinate and thymol; surfactants such as pyrilamine chloride; polyethylene glycol monododecylether 4, i.e., α -dodecyl- ω -hydroxy-poly (oxy-1, 2-ethylene) or polyethylene glycol monododecyl ether.

According to the present invention, the pharmaceutical composition may be in the form of a sterile injectable preparation, for example, an aqueous or oily sterile injectable suspension. Such suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable excipients and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, bland fixed oils which may be employed include synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are also 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 oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as Rh, HCIX or similar alcohols.

The pharmaceutical compositions of the present invention may be administered 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, steroids commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For capsules for oral administration, suitable diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal administration. They can be prepared by mixing the active ingredient with suitable non-irritating excipients which are solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the invention may also be administered topically, particularly where the target of treatment includes a site or organ accessible by topical administration, including diseases of the eye, skin, or lower intestinal tract. For these sites or organs, suitable topical formulations suitable for them are readily prepared.

For topical administration to the lower intestinal tract, this may be accomplished in the form of rectal suppositories or in the form of suitable enema preparations as described above. Topically active transdermal patches may also be used.

For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. In another aspect, the pharmaceutical compositions of the present invention may also be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate, cetyl esters wax, ceteary alcohol, 2-octyldodecyl alcohol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions of the present invention may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably as solutions in isotonic, pH adjusted sterile saline with or without preservatives such as benzalkonium chloride. On the other hand, for ophthalmic use, the pharmaceutical composition may also be formulated as an ointment, such as petrolatum ointment.

The pharmaceutical compositions of the present invention may also be administered by nasal aerosol form, or by inhalation using a nebulizer, dry powder inhaler or metered dose inhaler. Such compositions are prepared by methods well known in the art and may be prepared as physiological saline solutions employing benzyl alcohol or other preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons, and/or other conventional solubilizing or dispersing agents.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. It will be understood, however, that the specific dose and therapeutic regimen appropriate for a particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease undergoing therapy. The amount of active ingredient, if present in the combination, will also depend on the therapeutic or prophylactic agent with which the active ingredient is used in combination.

The dosage and frequency of administration of the compounds of the invention effective for preventing, inhibiting, preventing or reducing VLA-4 mediated cell adhesion and subsequent consequent or related pathological processes will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient's body weight, the goal of the treatment, the nature of the disease being treated, the particular composition used, and the observations and judgments made by the treating physician.

For example, for oral dosage forms such as tablets or capsules, suitable dosage levels of the compound of formula (1.0.0) are from about 1.0 μ g to about 10.0mg/kg body weight/day, preferably from about 5.0 μ g to about 5.0mg/kg body weight/day, more preferably from about 10.0 μ g to about 1.0mg/kg body weight/day, and most preferably from about 20.0 μ g to about 0.5mg/kg body weight/day of the active ingredient.

Where the dosage form is for topical administration to the bronchi and lungs, for example using a powder inhaler or nebulizer, a suitable dosage level for the compound of formula (1.0.0) is from about 0.1 μ g to about 1.0mg/kg body weight/day, preferably from about 0.5 μ g to about 0.5mg/kg carrier/day, more preferably from about 1.0 μ g to about 0.1mg/kg body weight/day, and most preferably from about 2.0 μ g to about 0.05mg/kg body weight/day of active ingredient.

Using representative body weights of 10kg and 100kg to illustrate the above daily dosage ranges for topical administration that may be used, suitable dosage levels for the compound of formula (1.0.0) are about 1.0-10.0 μ g and 10.0-100.0 mg/day, preferably about 5.0-50.0 μ g and 5.0-50.0 mg/day, more preferably about 10.0-100.0 μ g and l.0-10.0 mg/day, and most preferably about 20.0-200.0 μ g and about 0.5-5.0 mg/day including the active ingredient of the compound of formula (1.0.0). These dosage ranges represent the total dose of active ingredient per day for a given patient. The number of daily administrations depends on pharmacological and pharmacokinetic factors such as half-lives reflecting the catabolism and clearance rates of the active ingredients, as well as the minimum and optimal plasma or other body fluid levels reached by the active ingredients in the patient, which are necessary for the therapeutic effect.

Various other factors must also be considered in determining the number of administrations per day and the amount of active ingredient administered per dose. Other factors of greater importance are the individual response of the treated patient. For example, when the active ingredient is used in the treatment or prophylaxis of asthma and is administered topically by aerosol inhalation to the lungs, 1 to 4 doses per day consisting of needle sticks (actuations) of a dispensing device, i.e., a "spray" of an inhaler, each containing from about 50.0 μ g to about 10.0mg of the active ingredient may be administered.

Embodiments included within the scope of the present invention also include pharmaceutical compositions comprising, in addition to the active ingredient of a compound of the present invention, other therapeutically active ingredients selected from the group consisting essentially of anti-inflammatory corticosteroids, bronchodilators, anti-asthmatics, non-steroidal anti-inflammatory drugs, immunosuppressants, immunostimulants, anti-metabolites, anti-psoriasis drugs and anti-diabetic drugs. The specific compounds in each category may be selected from those listed under the appropriate headings in the following documents: comprehensive Medicinal Chemistry, Pergamon Press, Oxford, England, pp.970-986 (1990); and Goodman and Gilman's the pharmacological Basis of Therapeutics, 9 th edition, Hardman, J.G. and Limbird, L.E. ed, McGraw-Hill, 1996, the contents of which are incorporated herein by reference in their entirety. The active ingredients included in combination with the compounds of formula (1.0.0) are particularly preferably anti-inflammatory compounds, such as theophylline, sulfasalazine and para-aminosalicylate; immunosuppressants such as cyclosporin, FK-506 and rapamycin; antimetabolites such as cyclophosphamide and methotrexate; and immunomodulators such as interferons.

Yet another embodiment of the present invention relates to methods of treating or preventing inflammatory, autoimmune or respiratory diseases by inhibiting VLA-4 mediated cell adhesion and subsequent consequent or related pathological processes. As noted above, VLA-4-associated cell adhesion plays a major role in a variety of inflammatory, immune and autoimmune diseases. Thus, inhibition of cell adhesion by the compounds of the present invention may be useful in methods of treating or preventing inflammatory, immune, and autoimmune diseases. The disease to be treated by the method of the invention is preferably selected from the group consisting of asthma, arthritis, psoriasis, transplant rejection, multiple sclerosis, diabetes and inflammatory bowel disease.

The above-described treatment methods of the present invention may use the compound of formula (1.0.0) as a single treatment, but the methods may also be used as multiple treatments, wherein one or more compounds of formula (1.0.0) are administered in combination with known anti-inflammatory, immunomodulatory, immunostimulatory, or immunosuppressive agents. The term "co-administration" as used herein refers to the therapeutic use of one or more compounds of formula (1.0.0) in combination with one or more other therapeutic agents, including, but not limited to, the co-administration of these therapeutically active agents in a single dosage form or in multiple dosage forms capable of administration by the same or different routes, wherein the multiple dosage forms may be administered substantially simultaneously or separately at different times.

After synthesis of any of the above-described compounds of the invention or other compounds falling within the scope of the invention, one or more in vitro and in vivo assays, which have been described in the relevant technical literature, can be used to determine the biological activity associated with the VLA-4 specificity of said compounds. For example, some of the well-established assays and models now involve measuring the activity of VLA-4 by determining the concentration of the test candidate inhibitor required to prevent binding of VLA-4-expressing cells to fibronectin-or CS-coated plates. In this assay, wells of a microtiter plate are coated with fibronectin (containing the CS-1 sequence), a CS-1 peptide, or soluble VCAM-1. After each well was coated, different concentrations of test compound were added along with suitably labeled VLA-4 expressing cells. Alternatively, the test compound can be added first to incubate the coated wells, followed by addition of the cells. Cells were incubated in the wells for at least 30 minutes. After incubation, wells were emptied and washed. Inhibition of binding is determined by measuring fluorescence or radioactivity associated with the plate for different concentrations of test compound and for control groups without test compound. However, the above assay is less preferred over other assays for determining VLA-4 activity of compounds of formula (1.0.0) as described further below.

VLA-4 expressing cells that can be used in this assay include Ramos cells, Jurkat cells, A375 melanoma cells, and human Peripheral Blood Lymphocytes (PBLs). The cells used in the assay may be fluorescently or radioactively labeled.

To evaluate the VLA-4 inhibitory specificity of test compounds, other major group integrins, i.e., β 2 and β 3 and other β 1 integrins, such as VLA-5, VLA-6 and α, can be performed₄β₇The test of (1). These assays are similar to the adhesion inhibition and direct binding assays described above, but are replaced with appropriate integrin-expressing cells and corresponding ligands. For example, polymorphonuclear cells (PMNs) express β 2 integrin on their surface and bind to ICAM; and beta is₃Integrin is associated with platelet aggregation and its inhibition can be measured using standard platelet aggregation assays. VLA-5 specifically binds to the Arg-Gly-Asp sequence, while VLA-6 binds to laminin. Further, α₄β₇Is a recently discovered homologue of VLA-4, which binds equallyFibronectin and VCAM and MAdCAM-1. Alpha is alpha₄β₇The specificity of (A) is determined by using CS-1, VCAM or MAdCAM-1 and expressing alpha₄β₇The cell line of (4) (but not VLA-4), as determined by the binding assay of RPMI-8866 cells.

Once identified, VLA-4 specific inhibitors may be further characterized using in vivo assays. One assay is to test the inhibition of airway hyperresponsiveness and cell influx induced allergens as described by Henderson et al: "blocking CD49d (alpha) on intrapulmonary but non-circulating leukocytes in a mouse asthma model ₄Integrin) inhibits airway inflammation and hyperresponsiveness ", j.clin.invest., 100(12), pp.3083-92 (1997). In this experiment, mice are sensitized by ip contact with a stimulant such as ovalbumin. Mice were challenged after recovery by administration of an allergen aerosol. Different doses of the VLA-4 inhibitor were administered to mice by intratracheal injection prior to aerosol administration. The in vivo inhibition of cell adhesion associated with inflammation was assessed by measuring the number of cells and cytokines in bronchoalveolar lavage fluid. One can thus identify the inhibitors of the invention that are most suitable for inhibiting inflammation.

Another in vivo test that may be used is the primate asthma test. The test is carried out essentially as described by Turner, c.r. et al: "characterization of asthma primate model using anti-allergic/anti-asthmatic drugs", Inflammation Research, 45(5), pp.239-45(1996), the contents of which are incorporated herein by reference in their entirety. This test measures the inhibitory effect of allergy on late airway responses and airway hyperresponsiveness induced by roundworm (Ascaris) antigens in primates following administration of anti-allergy/anti-asthma drugs.

The compounds of the present invention may be formulated into pharmaceutical compositions for oral, parenteral, inhalation (metered dose inhaler, dry powder inhaler or nebulizer), topical, rectal, intranasal, intraocular, buccal, intrathecal or via an implanted depot administration. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

The compound of formula (1.0.0) can be prepared according to a method for synthesizing a non-peptidyl or semi-peptidyl organic compound, which is well known in the art. Various methods well known in the technical literature and familiar to the person skilled in the art can be used. The following description of several synthetic schemes is illustrative only and should not be construed as limiting in any way. Many abbreviations are used in the description for economy of disclosure. Although these abbreviations are also well known to the skilled person, they are listed below for clarity and convenience. BOP benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride DAST diethylaminothio trifluoride HOBT 1-hydroxybenzotriazole DIEA diisopropylethylamine THF tetrahydrofuran DMF dimethylformamide

Synthesis scheme 1 step A

Wherein the moiety of group "B" is an isoxazole ring and the moiety "Y" is "-SO₂The synthesis of the compound of formula (1.0.0) is shown in scheme 1, steps A-G. In scheme 1, step A, the starting diethyl aminomalonate is commercially available, for example from Aldrich chemical company, Milwaukee, WI 53233. Wherein R is ⁵Amide products which are hydrogen, methyl or phenyl (2.0.1) are likewise commercially available. Wherein R is⁵Other amides which are alkyl, aryl, heterocyclyl or heteroaryl groups can be readily prepared by reacting the appropriate acid chloride with an amine (2.0.0) using conditions well described in the literature (e.g., March, j., advanced organic chemistry, 3 rd edition, 1985). Under similar conditions, amines (2.0.0) are converted to the corresponding sulfonamides by reaction with alkyl or arylsulfonyl chlorides. Wherein R is⁵The carbamate product (2.0.1) which is an alkoxy or aryloxy group is prepared from the amine 2.0.0 according to the following method: paik, Yi Hyon; dowd, Paul; chem.1986, 51(15), 2910-2913; and Kawai, Masao; nyfeler, Rolf; berman, Judd m.; the method comprises the following steps of Goodman,Murray；J.Med.Chem.，1982 25(4)，397-402。

synthesis scheme 1 step B

In scheme 1, step B, intermediate 2.0.3 was prepared from oxime 2.0.2. Oxime 2.0.2 is prepared from the corresponding aldehyde using methods well known to those skilled in the art (e.g., Chung, YongJun; Ryu, Eun Jung; Keum, Gyochang; Kim, Byeang Hyean; bioorg.Med.Chem.; 1996, 4(2) 209-226; and Kim, Byeang Hyean; Chung, Yong Jun; Kenm, Gyochang; Kim, Jahenon; Kim, Kimoon; Tetrahedron Lett.; 1992, 33 (45); 6811-6814). Oxime 2.0.2 can be converted to isoxazole 2.0.3 by oxidation with a suitable oxidizing agent such as sodium hypochlorite, t-butyl hypochlorite or N-chlorosuccinimide in a suitable solvent such as THF, chloroform or dichloromethane, and reacting the resulting nitrile N-oxide in situ with propargyl bromide. This [2+3] cycloaddition reaction is well known in the literature as a method for preparing isoxazole ring structures, see, for example, synthesis, 508-9, 1982.

Synthesis scheme 1 step C

In scheme 1, step C, bromide intermediate 2.0.3 is converted to isoxazole containing moiety 2.0.4. The bromide 2.0.3 is reacted with an optionally substituted malonate (2.0.1) in the presence of a base such as triethylamine or cesium carbonate in a suitable solvent such as DMF, DMSO or dichloromethane. DMF is the preferred solvent and the base preferably used is cesium carbonate. The reaction is carried out at 0-30 ℃ for 1-16 hours. Scheme 1, the reaction of bromide 2.0.3 with malonate 2.0.1 in step C is not limited to 2-aminomalonates and can be extended to include compounds of the formula [ EtOC (═ O) CHR⁷C(＝O)OEt]Malonic acid ester of (1), wherein R⁷As described in the definition of formula (1.0.0) above.

Synthesis scheme 1 step D

The synthesis of the monoester intermediate 2.0.5 is shown in scheme 1, step D. Diethyl malonate 2.0.4 is converted to its half-ester intermediate by reaction with one equivalent of a suitable base such as aqueous sodium hydroxide or lithium hydroxide in a solvent such as THF, methanol, tert-butanol or dioxane. Preferably, aqueous sodium hydroxide in dioxane is used. The reaction is carried out at a temperature of 0-50 ℃ for 1-16 hours. The reaction is preferably carried out at room temperature for 3 hours. This half-ester intermediate is then converted in situ to the monoester 2.0.5 by heating in a suitable solvent such as benzene, toluene or dioxane at 0-200 ℃ for 1-16 hours. Preferably at 125 c in dioxane for 3 hours.

Synthesis scheme 1 step E

Synthesis of amine intermediate 2.0.6 is shown in scheme 1, step E. The tert-butoxycarbamate intermediate 2.0.5 is reacted with an acid such as neat trifluoroacetic acid, or with a solution of hydrochloric acid in a suitable non-aqueous solvent such as dioxane. The reaction is carried out at 0-50 ℃ for 1-16 hours. Preferred conditions are 1 hour at room temperature using dioxane of hydrochloric acid. One skilled in the art will recognize that the t-butyloxycarbonyl group functions as an amine protecting group, but other suitable protecting groups may be used. It should further be noted that the process for removing these protecting groups must be compatible with R⁵All functional groups present in (a) are compatible. These methods are well known in the technical literature of the related art. See, for example, Greene, t.w., Wuts, p.g.m.protective Group in organic synthesis; john Wiley& Sons：New York，1991.

Synthesis scheme 1 step F

Sulfonamide intermediates2.0.7 is described in scheme 1, step F. Amines 2.0.6 are reacted with sulfonyl chloride [ A (CH) in a solvent such as methylene chloride, water, or pyridine, with or without a base such as sodium carbonate or diisopropylethylamine₂)_n-SO₂Cl, wherein "A" and "n" are as described above in the definition of formula (1.0.0). The reaction is carried out at 0-50 ℃ for 1-16 hours. Preferred conditions are a reaction with sodium carbonate in water at room temperature for 16 hours.

Synthesis scheme 1 step G

The carboxylic acid product was prepared from ester intermediate 2.0.7 as shown in scheme 1, step G. Ester intermediate 2.0.7 is reacted with a suitable hydrated base such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent such as t-butanol, methanol, and/or THF. The reaction is carried out for 0.5 to 24 hours at the temperature of between 0 and 50 ℃. The preferred conditions are to use hydrated lithium hydroxide in a mixture of THF and methanol for 1 hour at room temperature.

The above synthesis is widely applicable to compounds of formula (1.0.0). To more clearly illustrate the synthesis, the following scheme 1- α, steps a-G, using a particular compound of the invention are given:

synthesis scheme 1-. alpha.

The following synthetic schemes illustrate the general preparation of compounds of formula (1.0.0) wherein "Y" has the composition C ═ O:

synthesis scheme 2-step A

Starting materials A¹NCO is an isocyanate, where "A¹"is as defined for part A in formula (1.0.0)By 0-3R⁹Definitions of substituted aryl, heteroaryl and heterocyclyl. The isocyanate starting materials used to prepare composition A, such as phenyl isocyanate, o-tolyl isocyanate, 2-fluorophenyl isocyanate and 2-chlorophenyl isocyanate, are commercially available, for example, from Aldrich Chemical Company, Milwaukee, WI 53233. On the other hand, the isocyanate starting materials can also be readily prepared from their corresponding amines by methods described in the literature (e.g. March, J. "advanced organic chemistry", 3 rd edition, 1985). The pyridyl analogs of phenyl isocyanate described above can be used to prepare the corresponding compounds of formula (1.0.0) wherein the A moiety contains a pyridyl group.

One of the above isocyanates is reacted 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 mild manner. The reaction is carried out in the presence of triethylamine in a solvent such as dichloromethane at slightly elevated temperature. The disubstituted urea (2.0.11) prepared according to the above reaction scheme constitutes the reactant which ultimately gives part A of the compound of formula (1.0.0), which in turn is reacted with a compound of formula "-NR⁴CR²R³An amine reaction of the formula "B", wherein "B" is defined as one of the partial formulae (1.1.0) to (1.1.22).

Scheme 2-step B

The reaction of the part a forming reactant (2.0.11) with amine 2.0.6 is known to those skilled in the art and can be carried out in good yield at room temperature or slightly elevated temperature, for example, by acylation of the amine with a carboxylic acid, by the use of coupling agents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt), Dicyclohexylcarbodiimide (DCCI), N '-carbonyldiimidazole, N' -tetramethyl (succinimidyl) uronium tetrafluoroborate, and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP). The amine component (2.0.6) was obtained as described in scheme 1. This reaction can be illustrated by the above synthetic schemes which provide a general preparation of the compound of formula (1.0.0).

To prepare the final product of formula (1.0.0) in acid form, additional steps are required as shown in the following reaction scheme:

synthesis scheme 2-step C

The final acid product (2.0.13) was prepared from ester 2.0.12 as shown in the above scheme. The intermediate is reacted with a suitable hydrated hydroxide base (such as lithium hydroxide, potassium hydroxide or sodium hydroxide) in a solvent system consisting of t-butanol, methanol or THF and methanol. The reaction is carried out at 0-50 ℃ for 0.5-16 hours. Preferred conditions are 1 hour at room temperature using lithium hydroxide in THF, methanol and water.

The above synthesis is widely applicable to compounds of formula (1.0.0). To illustrate the synthesis more clearly, the following scheme 2- α, steps a-G, are given for specific compounds of the invention:

synthesis scheme 2-alpha

An alternative synthesis of the compound of formula (1.0.0) is shown in FIG. 3, Steps A-C. The synthesis of amine intermediate 2.0.14 is shown in scheme 3, step a. The tert-butoxycarbamate intermediate 2.0.4 is reacted with a solution of an acid, such as pure trifluoroacetic acid, or hydrochloric acid in a suitable non-aqueous solvent, such as dioxane. The reaction is carried out at 0-50 ℃ for 1-16 hours. Preferred conditions are 1 hour at room temperature using a dioxane solution of hydrochloric acid. One skilled in the art will recognize that the t-butyloxycarbonyl group functions as an amine protecting group, but other suitable protecting groups may be used. It should further be noted that the removal of these protecting groups must be carried out in a manner consistent with R ⁵All functional groups present in (a) are compatible. These methods are well known in the technical literature of the related art. See, for example, Greene, t.w., Wuts, p.g.m.protective Group in Organic Synthesis；John Wiley& Sons：New York，1991.

Synthesis scheme 3 step A

Synthesis scheme 3 step B

In scheme 3, step B, amine 2.0.14 is reacted with acid 2.0.15 under the same conditions described in synthesis scheme 2, step B.

To prepare the final product of formula (1.0.0) in acid form, additional steps are required as shown in the following reaction scheme:

synthesis scheme 3 step C

The final acid product (2.0.17) was prepared from ester 2.0.16 as shown in the above scheme. The intermediate is reacted with a suitable hydrated hydroxide base (such as lithium hydroxide, potassium hydroxide or sodium hydroxide) in a solvent system consisting of t-butanol, methanol or THF and methanol. The reaction is carried out at 0-50 ℃ for 0.5-16 hours. Preferred conditions are 1 hour at room temperature using lithium hydroxide in THF, methanol and water.

The above synthesis is widely applicable to compounds of formula (1.0.0). To illustrate the synthesis more clearly, the following scheme 3- α, steps A-C, are given for specific compounds of the invention:

synthesis scheme 3-alpha

Another way of synthesizing the compound of formula (1.0.0) is shown in FIG. 4, Steps A-D.

Synthesis scheme 4-step A

In scheme 4, step a, oxime 2.0.2 can be converted to isoxazole 2.0.18 by oxidation with a suitable oxidizing agent such as sodium hypochlorite, tert-butyl hypochlorite or N-chlorosuccinic acid imide in a suitable solvent such as THF, chloroform or dichloromethane and reacting the resulting nitrile N-oxide in situ with 2, 2-disubstituted methyl pent-4-ynoate. Such a [2+3] cycloaddition reaction is known in the literature as a method for preparing isoxazole ring structures, see for example Synthesis, 508-9, 1982.

Synthesis scheme 4 step B

Synthesis of amine intermediate 2.0.19 as shown in the synthetic scheme above, the same conditions were used as in scheme 3, step a. Starting from tert-butoxycarbamate intermediate 2.0.18.

Synthesis scheme 4 step C

In scheme 4, step C, amine 2.0.19 was reacted with acid 2.0.15 under the same conditions as described in synthesis scheme 2, step B. This reaction can be illustrated by the above synthetic schemes which provide a general preparation of the compound of formula (1.0.0).

To prepare the final product of formula (1.0.0) in acid form, additional steps are required as shown in the following reaction scheme:

synthesis scheme 4-step D

As shown in the above scheme, the final acid product 2.0.21 was prepared from ester 2.0.20 using the procedure of scheme 3, step C.

The above synthesis is widely applicable to compounds of formula (1.0.0). To illustrate the synthesis more clearly, the following scheme 4- α, steps A-C, are given for specific compounds of the invention:

synthesis scheme 4-alphaAnother method for synthesizing formula (1.0.0) is shown in FIG. 5, Steps A-D.

Synthesis scheme 5 step A

The bromide 2.0.22 is commercially available, for example, from Aldrich chemical company, Milwaukee, WI 53233. The bromide 2.0.22 is converted to the desired diester component comprising component 2.0.23 as shown in the above scheme. The reaction of bromide with an aminomalonate is carried out under the conditions described in scheme 1, step C.

Synthesis scheme step B

The nitrile 2.0.23 can be converted to the desired amine 2.0.24 as shown in the above reaction scheme. Nitrile 2.0.23 is reduced to the corresponding amine 2.0.24 by hydrogenation as described in the literature (e.g., March, j. "advanced organic chemistry", 3 rd edition, 1985).

The above synthesis is widely applicable to compounds of formula (1.0.0). To illustrate the synthesis more clearly, the synthesis scheme 5- α is given below:

synthesis scheme 5-alpha

The synthesis of bicyclic compounds of formula (1.0.0) is shown in FIG. 6, steps A-D. Starting materials are acids and amines available from commercial manufacturers such as Aldrich Chemical Company, Milwaukee, WI 53233.

Synthesis scheme 6 step A

The reactions shown in the above schemes are known to those skilled in the art and include, for example, acylation of amine 2.0.22 with carboxylic acid 2.0.23 by use of coupling reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) and 1-Hydroxybenzotriazole (HOBT), Dicyclohexylcarbodiimide (DCCI), N' -carbonyldiimidazole, POCl₃、TiCl₄、SO₂ClF、Ti(OBu)₄、P₂I₄、Bu₃Benzotriazole-1-yl diethyl phosphate, N' -tetramethyl (succinimidyl) uronium tetrafluoroborate, and preferably Diisopropylethylamine (DIEA) and benzotriazole-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) can be used, and the reaction can be carried out at room temperature or slightly higher temperatures in good yield.

Synthesis scheme 6 step B

The synthesis of amine intermediate 2.0.26 is shown in the reaction scheme above. Starting from a mixture of tert-butoxycarbamate intermediates 2.0.24 and 2.0.25. Intermediates 2.0.24 and 2.0.25 were performed with an acid such as hydrochloric acid or acetic acid in the presence or absence of a suitable solvent such as dioxane. The reaction is carried out at 0-100 ℃ for 1-16 hours. It is preferable to react for 1.5 hours at 80 ℃ using acetic acid without adding a solvent. Those skilled in the art will appreciate that these conditions are capable of effecting cyclization to form the desired bicyclic ring system and removal of the t-butyloxycarbonyl group. It will also be appreciated by those skilled in the art that the t-butyloxycarbonyl group functions as an amine protecting group, but other suitable protecting groups may be used. It should further be noted that the removal method of these protecting groups must be compatible with all functional groups present in intermediate 2.0.26. Such methods are known in the technical literature of the relevant art. See, for example, Greene, t.w., Wuts, p.g.m.protective Group in organic synthesis; john Wiley & Sons: new York, 1991.

The above synthesis is widely applicable to compounds of formula (1.0.0). To more clearly illustrate the synthesis, the following scheme 6- α is given for a specific compound of the invention:

synthesis scheme 6-alpha

Another method for synthesizing the compound of formula (1.0.0) is shown in FIG. 7, Steps A-C. These steps describe an alternative route for the synthesis of part B in the coupling reaction described in step B of scheme 2.

Synthesis scheme 7 step A

The preparation of bromide intermediate 2.0.29 is illustrated in FIG. 1, step A. Intermediate bromide 2.0.29 is reacted with commercially available imine 2.0.30 in the presence of an additive such as tetrabutylammonium bromide, tetrabutylammonium chloride, or tetraphenylammonium bromide in a suitable solvent such as toluene, dichloromethane, or DMF containing a base such as cesium carbonate, cesium hydroxide, or potassium hydroxide. The reaction is carried out at a temperature of-78 ℃ to 50 ℃ for 1 to 16 hours. The reaction of bromide intermediate 2.0.29 with imine 2.0.30 is preferably carried out in the presence of tetrabutylammonium bromide in toluene at room temperature for 1 hour.

Synthesis scheme 7 step B

The synthesis of amine intermediate 2.0.32 is shown in the reaction scheme above. Imine intermediate 2.0.31 can be converted to amine 2.0.32 using a variety of methods well known to those skilled in the art and described in the literature. For example, Wolfe, John p.; ahman, Jens; sadighi, 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 a preferred process, intermediate imine 2.0.31 was treated with a mixture of ethyl acetate and hydrochloric acid for 3 hours at room temperature.

Synthesis scheme 7 step C

The synthesis of amide intermediate 2.0.33 is shown in the above reaction scheme. The amine is reacted with the anhydride or acid chloride in the presence or absence of a solvent such as dichloromethane, chloroform, benzene, water or pyridine, with or without the addition of a base such as sodium carbonate, pyridine or diisopropylethylamine. The reaction is carried out at 0-50 ℃ for 1-16 hours. The preferred reaction conditions are 16 hours at room temperature using dichloromethane and pyridine.

The above synthesis is widely applicable to compounds of formula (1.0.0). To illustrate the synthesis more clearly, scheme 7- α is given below:

synthesis scheme 7-alpha

Preferred embodiment examples

The compounds, compositions and methods of treatment of the present invention are further illustrated by the following examples, which should not be construed as limiting the scope of the invention. And many abbreviations are used in the following examples for economy of disclosure. Although these abbreviations are well known to the skilled artisan, they are listed below for the sake of reader clarity and convenience. BOP benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate DAST diethylaminosulfur trifluoride DIEA diisopropylethylamine DMF dimethylformamide EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride HOBT 1-hydroxybenzotriazole THF tetrahydrofuran Example 1A. 2-allyloxycarbonylamino-3- {3- [1- (3, 5-di-chloro-benzenesulfonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid

2-allyloxycarbonylamino-3- {3- [1- (3, 5-dichloro-benzenesulfonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid ethyl ester (59mg, 0.108mmol) in tetrahydrofuran (1.0mL) was stirred with methanol (0.5mL) at room temperature for 40 min with 2M aqueous lithium hydroxide (0.5 mL). The reaction was acidified with 1M hydrochloric acid to pH1 and extracted with ethyl acetate. The resultant extract was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (51mg, 91%). MS (CI) M/z 518(M + 1). B. 2-allyloxycarbonylamino-3- {3- [1- (3, 5-dichloro-benzenesulfonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid ethyl ester

Ethyl 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) -propionate hydrochloride (110mg, 0.294mmol) and sodium carbonate (93.5mg, 0.882mmol) were dissolved in water (1.5mL) and 3, 5-dichlorobenzenesulfonyl chloride (86.7mg, 0.353mmol) was added. Stirring the mixtureThe mixture was allowed to stand overnight. The reaction was extracted twice with dichloromethane. The organic portion of the synthesis was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (59mg, 37%). MS (CI) M/z545.7(M + 1). C. 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) -propionic acid ethyl ester hydrochloride

Reacting 2- [5- (2-allyloxycarbonylamino-2-ethoxycarbonyl-ethyl) -isoxazol-3-yl]Tert-butyl-pyrrolidine-1-carboxylate (3.44g, 7.86mmol) was dissolved in 4M dioxane (10mL) hydrochloric acid and stirred at room temperature for 2 hours. The reaction was then concentrated in vacuo and evaporated with dichloromethane to give the desired product as a brown waxy solid. MS (CI) M/z 509.9(M + 1). D. 2- [5- (2-allyloxycarbonylamino-2-ethoxycarbonyl-ethyl) -isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonyl-pyrrolidin-2-yl) -isoxazol-5-ylmethyl]-malonic acid monoethyl ester and 2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonyl-pyrrolidin-2-yl) -isoxazol-5-ylmethyl]A mixture of diethyl malonate (10.4g, 21.5mmol) was dissolved in dioxane (130mL) and heated to 125 ℃ in an oil bath for 3 hours. The dioxane was then removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium carbonate and brine, dried over magnesium sulfate and concentrated. Chromatography of the crude product on a Biotag Flash 40M column eluting with ethyl acetate/hexane (1: 4) gave the title compound as a clear, clear oil (5.12g, 56% over two steps). MS (CI) M/z 338.0 (M-99). 2.96g (27%) of 2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonyl-pyrrolidin-2-yl) -isoxazol-5-ylmethyl are recovered ]-malonic acid diethyl ester. MS (CI) M/z 509.9(M +1), 409.9. E. 2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonyl-pyrrolidin-2-yl) -isoxazol-5-ylmethyl]-malonic acid monoethyl ester

To 2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonyl-pyrrolidin-2-yl) -isoxazol-5-ylmethyl was added portionwise within 30 min]To a solution of diethyl malonate (10.95g, 21.5mmol) in dioxane (22mL) was added sodium hydroxide, 1M, (21.5mL, 21.5 mmol). After stirring overnight, the reaction was still incomplete. An additional 0.2 equivalents of 1M sodium hydroxide (4.2mL, 4.2mmol) was added and stirring was continued for 3 hours. The reaction was diluted with ethyl acetate (50mL) and 1M sulfuric acid (23mL) was added dropwise at 0 ℃. The aqueous phase was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate and concentrated in vacuo to afford the title compound. The crude product was used directly in the next step without isolation of the unreacted diester. MS (CI) M/z 382.2 (M-99). F. 2-allyloxycarbonylamino-2- [3- (1-tert-butoxycarbonyl-pyrrolidin-2-yl) -isoxazol-5-ylmethyl]-malonic acid diethyl ester

A solution of tert-butyl 2- (5-bromomethyl-isoxazol-3-yl) -pyrrolidine-1-carboxylate (7.29g, 56mmol) and diethyl 2-allyloxycarbonylamino-malonate (8.25g, 32mmol) in dimethylformamide (260mL) was cooled to 0 deg.C and cesium carbonate (25.41g, 78mmol) was added. The reaction was warmed to room temperature and stirred for 3 hours. The reaction mixture was then poured into diethyl ether (2L) and washed with water (5X 200mL) and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. Chromatography of the crude residue on silica gel eluting with ethyl acetate: hexane (3: 7) gave the title compound as a colorless clear oil (10.95g, 83%). MS (CI) M/z 260.1 (M-99). G. 2-allyloxycarbonylamino-malonic acid diethyl ester

A solution of diethyl aminomalonate hydrochloride (47.0g, 226mmol) in dichloromethane (1.0L) was cooled to 0 deg.C and pyridine (45mL, 564mmol) was added. The previously insoluble solid dissolved upon addition of pyridine. Allyl chloroformate (20mL, 188mmol) was slowly added dropwise to maintain the reaction temperature below 5 ℃. After the addition was complete, the reaction was stirred for 15 minutes at 0 ℃. The reaction was washed with 1M hydrochloric acid (6X 100mL), dried over magnesium sulfate and concentrated in vacuo to give a white solidThe title compound (46.78g, 80%). The crude product was used without further purification. MS (CI) M/z 260.1(M + 1). H. 2- (5-bromomethyl-isoxazol-3-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the methods described for examples 7H and 71 using tert-butyl 2- (hydroxyimino-methyl) -pyrrolidine-1-carbamate in step 71.Example 2A. 2-allyloxycarbonylamino-3- (3- {1- [ (4-nitro-phenyl) -acetyl]-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid

2-allyloxycarbonylamino-3- (3- {1- [ (4-nitro-phenyl) -acetyl group was hydrolyzed according to the same method as in example 1A]-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid ethyl ester to give the title compound. MS (CI) M/z 472.6(M +1), 471.7 (M-1). B. 2-allyloxycarbonylamino-3- (3- {1- [ (4-nitro-phenyl) -acetyl ]-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid ethyl ester

A solution of 4-nitrophenylacetic acid (1.61g, 8.87mmol) in dimethylformamide (82mL) was stirred with 4-hydroxybenzotriazole monohydrate (1.40g, 10.4mmol) for 10 minutes. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.86g, 9.72mmol) was added and the mixture stirred until all 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride had dissolved completely. To this solution was added 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) -propionic acid ethyl ester hydrochloride of example 1C (3.16g, 8.25mmol), the mixture was stirred for 30 minutes, followed by addition of triethylamine (1.26mL, 9.04 mmol). The reaction was stirred at room temperature overnight, poured into water and extracted three times with ethyl acetate. The combined extracts were washed with a saturated solution of sodium bicarbonate, water (2 ×) and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed by Biotage Flash 40S column eluting with ethyl acetate/hexane (5: 1) to giveTo the title compound as a yellow oil (674mg, 15%). MS (CI) M/z501.3(M + 1). An additional starting material, 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) -propionic acid ethyl ester, was recovered (2.15g, 75%). MS (CI) M/z 338.1(M + 1). Example 3A. 2-allyloxycarbonylamino-3- [3- (1- { [4- (2, 6-dichloro-benzoylamino) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

2-allyloxycarbonylamino-3- [3- (1- { [4- (2, 6-dichloro-benzoylamino) -phenyl ] -was hydrolyzed according to the same procedure as in example 1A]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]Ethyl propionate to give the title compound (77mg, 75%). MS (CI) M/z 616.7(M +1), 612.5 (M-1). B. 2-allyloxycarbonylamino-3- [3- (1- { [4- (2, 6-dichloro-benzoylamino) -phenyl) -acetyl ] -methyl-ethyl ester]-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid ethyl ester

Cooling of 2-allyloxycarbonylamino-3- (3- {1- [ (4-amino-phenyl) -acetyl group]-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid ethyl ester (80mg, 0.170mmol) in dichloromethane (1mL) was brought to 0 ℃ and 2, 6-dichlorobenzoyl chloride (39mg, 0.187mmol) was added. The mixture was stirred for 15 min, then pyridine (28. mu.L, 0.34mmol) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1M sodium hydroxide and brine. The organic phase was dried over magnesium sulfate and concentrated to give the title compound (84mg, 78%). MS (CI) M/z635.3(M +1), 632.5 (M-1). C. 2-allyloxycarbonylamino-3- (3- {1- [ (4-amino-phenyl) -acetyl ]-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid ethyl ester

Heating to reflux 2-allyloxycarbonylamino-3- (3- {1- [ (4-nitro-phenyl) -acetyl group]Dissolution of-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid ethyl ester (2B) (565mg, 1.13mmol) and iron (0) powder (384mg, 6.98mmol) in ethanol/water (5mL, 1: 1)And (4) liquid. 1M hydrochloric acid (0.29mL, 0.29mmol) was added dropwise and the reaction heated to reflux for 45 min. Then neutralized with 1M sodium hydroxide and filtered through celite. The filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by Biotage Flash 40S column chromatography eluting with ethyl acetate/hexane (6: 1) to give the title compound as a yellow oil (240mg, 51%). MS (CI) M/z 471.0(M + 1).Example 4A. 2-allyloxycarbonylamino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

2-allyloxycarbonylamino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl ] was hydrolyzed according to the same procedure as in example 1A]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-ethyl propionate to give the title compound. MS (CI) M/z 576.0(M +1), 573.9 (M-1). B. 2-allyloxycarbonylamino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl ]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid ethyl ester

The procedure described in example 2B was followed using [4- (3-o-tolyl-ureido) -phenyl]Acetic acid the title compound was prepared. MS (CI) M/z 604.0(M + 1).Example 5A. 3- (3- {1- [ (4-acetylamino-phenyl) -acetyl group]-pyrrolidin-2-yl } -isoxazol-5-yl) -2-allyloxycarbonylamino-propionic acid

3- (3- {1- [ (4-acetylamino-phenyl) -acetyl ] was hydrolyzed in the same manner as in example 1A]-pyrrolidin-2-yl } -isoxazol-5-yl) -2-allyloxycarbonylamino-propionic acid ethyl ester to give the title compound. MS (CI) M/z 485.3(M +1), 483.0 (M-1). B. 3- (3- {1- [ (4-acetylamino-phenyl) -acetyl group]-pyrrolidin-2-yl } -isoxazol-5-yl) -2-allyloxycarbonylamino-propionic acid ethyl ester

The title compound was prepared according to the procedure described for example 3B, using acetyl chloride instead of 2, 6-dichlorobenzoyl chloride. MS (CI) M/z 513.0(M + 1).Example 6A. 2-Boc-amino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl ] -urea]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

2-tert-Butoxycarbonylamino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl ] was hydrolyzed according to the same procedure as in example 1A]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ]-methyl propionate to give the title compound. MS (CI) M/z 590.2(M-1), 492.2 (M-99). B. 2-tert-Butoxycarbonylamino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl ] -ethyl ester]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid methyl ester

Stirring of 1- (4- {2- [2- (hydroxyimino-methyl) -pyrrolidin-1-yl]-2-oxo-ethyl } -phenyl) -3-o-tolyl-urea (300mg, 0.789mmol), methyl 2-tert-butoxycarbonylamino-pent-4-ynoate (359mg, 1.182mmol, crude mixture) and triethylamine (12.9. mu.L) in dichloromethane (2mL) for 5 min. Sodium hypochlorite solution (5.25%, 2mL) was added. The reaction was stirred at room temperature overnight. The aqueous phase was extracted four times with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The crude mixture was chromatographed by Biotage Flash 40S column eluting with ethyl acetate/hexane 1: 5 to give the title compound (66mg, 14%). MS (CI) M/z 604.5(M-1), 505.9(M-99) C.2-tert-Butoxycarbonylamino-pent-4-ynoic acid methyl ester

To a solution of benzyl 2-tert-butoxycarbonylamino-4-oxo-butyrate (1.875g, 6.10mmol) in dry methanol (91.5mL) was added potassium carbonate (1.687g, 12.2mmol), and the reaction was stirred for 10 min. (1-diaza-2-oxo-propyl) -phosphonic acid dimethyl ester (1.407g, 7.32mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction was poured into diethyl ether Washed 4 times with 5% sodium bicarbonate, dried over magnesium sulfate and concentrated (1.05g, crude product mixture). The crude product was used directly in the next step.¹H NMR(400MHz，CDCl₃) δ 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 singlet, rotamers, 3H). D. 2-Boc-amino-4-oxo-butyric acid benzyl ester

A solution of benzyl 2-tert-butoxycarbonylamino-4-hydroxy-butyrate (13.58g, 43.9mmol) and triethylamine (18.35mL, 131.7mmol) in dimethylsulfoxide (10mL) was cooled to 0 ℃. A solution of pyridine sulfur trioxide (21.0g, 131.7mmol) in dimethyl sulfoxide (80mL) was added in a steady flow. The cooling bath was removed and the reaction stirred for 1.5 hours. The reaction was poured into 130mL of ice water and extracted with diethyl ether (2X 180mL and 100 mL). The combined organic phases were washed successively 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 (900mL) eluting with ethyl acetate/hexane (1: 4) to give the title compound as a clear, colorless oil (9.20g, 70%). MS (CI) M/z 208.0 (M-99).Example 7A. 2-acetylamino-4- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino]-3-methyl-butyl } -isoxazol-5-yl) -propionic acid

2-acetylamino-4- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino]A1: 2 methanol/tetrahydrofuran (9mL) solution of ethyl-3-methyl-butyl } -isoxazol-5-yl) -propionate (92mg, 0.17mmol) was mixed with 2M lithium hydroxide (3mL) and stirred at room temperature for 3 h. After acidifying the reaction with 1N hydrochloric acid to pH 1, the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over sodium sulfate and concentrated to give 2-acetylamino-4- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino ] -acetylamino-e as a white crystalline solid]-3-methyl-butyl } -isoxazol-5-yl) -propionic acid (83mg, 95%). MS (CI) M/z 508.1(M +1), 506.1 (M-1). B. 2-acetylamino-4- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino]-3-methyl-butyl } -isoxazol-5-yl) -propionic acid ethyl ester

A solution of (4-benzyloxy-phenyl) -acetic acid (125mg, 0.29mmol, 1.00 eq) and 1-hydroxybenzotriazole hydrate (48mg, 0.36mmol, 1.23 eq) in dimethylformamide (5mL) was stirred at room temperature for 15 min. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (64mg, 0.33mmol, 1.15 equiv.) was added and the reaction stirred for 15 min. Adding 2-acetamido-3- [3- (1-amino-3-methyl-butyl) -isoxazol-5-yl]Ethyl propionate hydrochloride (100mg, 0.29mmol, 1.00 eq), and the reaction stirred for 25 min. Triethylamine (43. mu.l, 0.31mmol, 1.07 eq.) was added. The reaction was stirred at room temperature overnight, then diluted with ethyl acetate (30mL) and extracted with 1N hydrochloric acid (2X 30mL), saturated sodium bicarbonate (2X 30mL) and brine (30 mL). The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The residue was subjected to column chromatography (ethyl acetate) by 40S Biotage to give the title compound (94mg, 61%) as a colorless transparent oil. MS (CI) M/z 536.2(M + 1). C. 2-acetylamino-3- [3- (1-amino-3-methyl-butyl) -isoxazol-5-yl ]-propionic acid ethyl ester hydrochloride

2-acetylamino-3- [3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl was stirred in 4N dioxane solution of hydrochloric acid (25mL) at room temperature]Ethyl propionate (7F) (5.95g, 14.5mmol) overnight. The product was concentrated and dried under high vacuum to give the title compound as a white solid (5.38g, 100%). MS (CI) M/z 312.2(M +1, free base). D. (4-benzyloxy-phenyl) -acetic acid

A1: 2 methanol/tetrahydrofuran (60mL) solution of (4-benzyloxy-phenyl) -acetic acid methyl ester (1.35g, 5.27mmol) was mixed with 2M aqueous lithium hydroxide (20mL) at room temperature and the reaction was stirred overnight. The reaction was acidified to pH1 with 1N hydrochloric acid and extracted with ethyl acetate (2X 50 mL). The organic phase was dried over sodium sulfate and the solvent was removed in vacuo to yield the title compound as a white crystalline solid (1.25g, 98%).¹H NMR(300MHz，CDCl₃) δ 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-benzyloxy-phenyl) -acetic acid methyl ester

To a solution of 4-hydroxybenzyl acetate (1.00g, 6.02mmol, 1.10 equiv.) and benzyl bromide (0.65mL, 5.47mmol, 1.00 equiv.) in dichloromethane (40mL) at 0 deg.C was added cesium carbonate (5.35g, 16.4mmol, 3.00 equiv.). The mixture was warmed to room temperature and stirred vigorously overnight. The reaction was extracted with 1N hydrochloric acid (2X 100mL) and brine (100 mL). The organic phase was dried over sodium sulfate and the solvent was removed in vacuo. The resulting oily solid was further subjected to column chromatography (20% ethyl acetate/hexane) by 40S Biotage to give the title ester (1.35g, 96%) as a colorless clear oil. ¹HNMR(400MHz，CDCl₃) δ 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-methyl-butyl) -isoxazol-5-yl-1-propanoic acid ethyl ester

2-acetylamino-2- [3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-ylmethyl ester was added to the reaction mixture at room temperature over 30 minutes]To a solution of diethyl malonate (8.99g, 18.6mmol, 1.0 equiv) in dioxane was added sodium hydroxide, 1N, (20.5mL, 20.5mmol, 1.10 equiv). The reaction was diluted with ethyl acetate (200mL) and acidified with 1N hydrochloric acid to pH 1-1.5. The organic phase was washed with brine (200mL) and dried over sodium sulfate. The solvent was removed in vacuo to give 8.58g of 2-acetamido-2- [3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-ylmethyl]-malonic acid monoethyl ester [ MS (CI) M/z 356.3(M-99)]With the decarboxylated title Compound [ MS (CI) M/z412.3(M +1), 312.2(M-99), 410.3(M-1)]1: 1 mixture (according to¹H NMR)。

The mixture was refluxed overnight in dioxane (150mL) and concentrated to give an orange oil which was chromatographed using Biotage column (40M, 50% ethyl acetate/hexane) to afford the title compound as a dark orange solid (6.72g, 88%). MS (CI) M/z412.3(M +1), 312.2 (M-99). G. 2-acetylamino-2- [3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-ylmethyl ]-malonic acid diethyl ester

To [1- (5-bromomethyl-isoxazol-3-yl) -3-methyl-butyl at 0 ℃]To a solution of tert-butyl carbamate (6.48g, 18.7mmol, 1.00 equiv.) and diethyl acetamidomalonate (4.86g, 22.4mmol, 1.20 equiv.) in dimethylformamide (300mL) was added cesium carbonate (18.28g, 56.1mmol, 3.0 equiv.). The mixture was stirred at room temperature for 5 hours. The reaction was poured into diethyl ether (200mL) and extracted with water (5X 200mL) and brine (200 mL). The organic phase was dried over sodium sulfate and the solvent removed in vacuo to give the title compound as a viscous oil (8.99g, 99.4%). MS (CI) M/z 484.0(M +1), 384.1 (M-99). H. [1- (5-bromomethyl-isoxazol-3-yl) -3-methyl-butyl]-carbamic acid tert-butyl ester

N-chlorosuccinimide (5.80g, 43.4mmol, 1.00 equiv.) and [1- (hydroxyimino-methyl) -3-methyl-butyl ] are stirred in chloroform (70mL) at room temperature]Tert-butyl carbamate (10.00g, 43.4mmol, 1.00 equiv.) with pyridine (0.70mL) for 1 hour. Propargyl bromide (4.83mL, 54.3mmol, 1.25 equiv.) was added and the reaction heated to 45 ℃. Triethylamine (6.35mL, 4.56mmol, 1.05 equiv.) was added dropwise at 45 ℃ over 20 minutes. The reaction was stirred for an additional 1 hour, then diluted with water (200mL) and extracted with dichloromethane (2X 200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2X 200mL) and brine (200 mL). The organic phase was dried over sodium sulfate. Evaporation of the solvent gave a brown residue which was flash chromatographed on silica gel to give the title compound as a white solid (6.48g, 43%). MS (CI) M/z 247.0 (M-99). I. 1- (hydroxyimino-methyl) -3-methyl-butyl ]-carbamic acid tert-butyl ester

(1-formyl-3-methyl-butyl) -carbamic acid tert-butyl ester (2.13g), hydroxylamine hydrochloride (0.71g,10.2mmol) and NaOAc (2g, 24.4mmol) in MeOH (20mL) and water (20 mL). After 24 h the mixture was diluted with water (60mL) and extracted with EtOAc (50 mL. times.3). The combined organics were washed with water and brine; drying with magnesium sulfate; filtered and concentrated under reduced pressure. Flash 40 chromatography on silica gel eluting with 15-25% EtOAc in hexane afforded 1.5g of the title compound as a white solid. MP 156-.Example 8A. 2-allyloxycarbonylamino-3- [3- (1-benzoyl-pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

Hydrolysis of 8B using the procedure of example 1A gave the title compound. MS (CI) M/z414.2(M +1), 412.2 (M-1). B. 2-allyloxycarbonylamino-3- [3- (1-benzoyl-pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid ethyl ester

To a solution of 2-allyloxycarbonylamino-3- (3-pyrrolidin-2-yl-isoxazol-5-yl) -propionic acid ethyl ester hydrochloride (1C) (74mg, 0.20mmol, 1.1 equiv.) in pyridine (29 μ l, 0.36mmol, 2.0 equiv.) and dichloromethane (2mL) was added benzoyl chloride (21 μ l, 0.18mmol, 1.0 equiv.) in one portion at 0 ℃. The reaction was stirred at room temperature for 4 hours, then diluted with ethyl acetate (30 mL). The reaction was extracted with 1N hydrochloric acid (30mL) and brine (30 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound (66mg, 84%). MS (CI) M/z 442.3(M + 1). Example 9A. 2-allyloxycarbonylamino-3- {3- [1- (biphenyl-4-carbonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid

Hydrolysis of 9B using the procedure of example 1A gave the title compound. MS (CI) M/z490.0(M +1), 487.8 (M-1). B. 2-allyloxycarbonylamino-3- {3- [1- (biphenyl-4-carbonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid ethyl ester

The preparation was carried out using the same method as described in example 8B. MS (CI) M/z 518.0(M + 1).Example 10A. 2-acetylamino-3- (3- { 3-methyl-1- [2- (4-naphthalen-2-yl-phenyl) -acetylamino]-butyl } -isoxazol-5-yl) -propionic acid

Hydrolysis of 10B using the procedure of example IA provided the title compound. MS (CI) M/z528.0(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 according to the method described for example 7B using (4-naphthalen-2-yl-phenyl) -acetic acid. C. (4-naphthalen-2-yl-phenyl) -acetic acid

To a solution of (4-naphthalen-2-yl-phenyl) -acetic acid methyl ester (270mg, 0.977mmol) in 2: 1 tetrahydrofuran: to a solution of lithium hydroxide in methanol (9.0mL), 2M (3.0mL) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction was acidified with 1M hydrochloric acid to pH 1 and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (233mg, 91%). ¹H NMR(400MHz，CDCl₃) δ 8.01-7.39(m, 11H), 3.72(s, 2H). D. (4-Naphthalen-2-yl-phenyl) -acetic acid methyl ester

To a solution of (4-trifluoromethanesulfonyloxy-phenyl) -acetic acid methyl ester (447mg, 1.5mmol), 2-naphthalene boronic acid (286mg, 1.67mmol) and cesium fluoride (505mg, 3.33mmol) in dimethoxyethane (5.4mL) was added tetrakis (triphenylphosphine) palladium (65mg, 7.4 mol%). The reaction was flushed with nitrogen, heated to 100 ℃ in an oil bath and kept under stirring for 3 hours. The reaction was then diluted with ethyl acetate and extracted with water, 1M sodium hydroxide, water and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed by Biotage Flash 40S using 5% ethyl acetate/hexanes to give the title compound as a clear, clear oil (273mg, 66%).¹HNMR(400MHz，CDCl₃) Δ 8.01-7.38(m, 11H), 3.72(s, 3H), 3.69 (2H). E. (4-Trifluoromethanesulfonyloxy-phenyl) -acetic acid methyl ester

To a solution of (4-hydroxy-phenyl) -acetic acid methyl ester (5.35g, 32.2mmol) in-40 ℃ pyridine (70mL) was added dropwise triflic anhydride (32.2mmol) over 5 min. The reaction was stirred at-40 ℃ for 10 minutes and then at 0 ℃ for an additional 2 hours. The reaction was diluted with diethyl ether and washed with water and 2N hydrochloric acid. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude residue was chromatographed by biotarge flash 40M column eluting with ethyl acetate/hexane (1: 4) to give the title compound as a colorless clear oil which crystallized upon standing (9.27g, 97%). ¹H NMR(400MHz，CDCl₃)δ7.37-7.34(m，2H)，7.24-7.21(m，2H)，3.70(3H)，3.64(2H)。Example 11A. 2, 2-dimethyl-3- [3- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -butyl) -isoxazol-5-yl]-propionic acid

Hydrolysis of 11B using the procedure of example 1A gave the title compound. MS (CI) M/z521.2(M +1), 519.1 (M-1). B. 2, 2-dimethyl-3- [3- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -butyl) -isoxazol-5-yl]-propionic acid methyl ester

The procedure is as described in examples 1C and 2B, starting from 3- [3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl]-2, 2-dimethyl-methyl propionate is prepared in two steps as a raw material. MS (CI) M/z 535.1(M +1), 535.1 (M-1). C. 3- [3- (1-tert-Butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl]-2, 2-dimethyl-propionic acid methyl ester

The procedure is as in example 6A, using [1- (hydroxyimino-methyl) -3-methyl-butyl]-carbamic acid tert-butyl ester (71) and methyl 2, 2-dimethyl-pent-4-ynoate. MS (CI) M/z 313.2(M-tBu), 269.3 (M-99).Example 12A. 3- [3- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -butyl) -isoxazol-5-yl]-2-phenyl-propionic acid

Hydrolysis of 12B using the procedure of example 1A gave the title compound. B. 3- [3- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl ]-acetylamino } -butyl) -isoxazol-5-yl]-2-phenyl-propionic acid methyl ester

The procedure is as in example 11B, using 3- [3- (1-tert-butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl]-2-phenyl-propionic acid methyl ester the title compound was prepared. C. 3- [3- (1-tert-Butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl]-2-phenyl-propionic acid methyl ester

The title compound was prepared according to the procedure described for example 6A using methyl 2-phenyl-pent-4-ynoate. D. 2-phenyl-pent-4-ynoic acid methyl ester

Diisopropylethylamine (5.9mL, 42mmol) was dissolved in tetrahydrofuran (30 mL). Butyllithium, 2.5M hexane solution (16.8mL, 42mmol) was added slowly. A solution of phenylacetic acid (2.72g, 20mmol) in tetrahydrofuran (20mL) was then added slowly over 20 minutes via the addition funnel. The reaction was stirred for 25 minutes. An 80% by weight solution of propargyl bromide in toluene (2.3mL, 21.0mmol) was added. The reaction was stirred for 1.5 h and 4N hydrochloric acid (15mL) was added. The mixture was diluted with ethyl acetate (50 mL). The organic phase was concentrated in vacuo. The residue was dissolved in diethyl ether and extracted with water (3X) and 1N hydrochloric acid (3X). The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting yellow solid (1.7g) was dissolved in methanol (50mL)) And cooled to 0 ℃. Acetyl chloride (2mL) was added and the reaction was warmed to room temperature. After the reaction was stirred for 18 hours, the solvent was removed in vacuo. The residue was dissolved in diethyl ether. The resulting solution was extracted with saturated sodium bicarbonate, water and brine. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was further chromatographed on silica gel, eluting with 10% ethyl acetate/hexane, to give the title compound (0.58g, 15%) as an oil. Example 13A. 2-acetylamino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

Hydrolysis of 13B using the procedure of example 1A gave the title compound. MS (CI) M/z534.2(M +1), 532.4 (M-1). B. 2-acetylamino-3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid ethyl ester

As described in example 11B, 2- [5- (2-acetylamino-2-methoxycarbonyl-ethyl) -isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was prepared. MS (CI) M/z562.1(M + 1). C. 2- [5- (2-acetylamino-2-methoxycarbonyl-ethyl) -isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared as described in example 6B using tert-butyl 2- (hydroxyimino-methyl) -pyrrolidine-1-carbamate and methyl 2-acetamido-pent-4-ynoate. MS (CI) M/z296.0 (M-99).Example 14A. 2- (2, 6-dichloro-benzoylamino) -3- [3- (1- { [4- (3-o-tolyl-ureido) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

Hydrolysis of 14B using the procedure of example 1A gave the title compound. MS (CI) M/z663.8(M + 1). B. 2- (2, 6-dichloro-benzoylamino) -3- [3- (1- { [4- (3-o-tolyl-urea) Phenyl radical]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid ethyl ester

Following a similar procedure as described in 11B, 2- {5- [2- (2, 6-dichloro-benzoylamino) -2-ethoxycarbonyl-ethyl]-isoxazol-3-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester the title compound was prepared. MS (CI) M/z 691.8(M +1), 689.7 (M-1). C. 2- {5- [2- (2, 6-dichloro-benzoylamino) -2-ethoxycarbonyl-ethyl]-isoxazol-3-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester

The procedure is as described in example 3B, using 2- [5- (2-amino-2-ethoxycarbonyl-ethyl) -isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester hydrochloride and 2, 6-dichlorobenzoyl chloride the title compound was prepared. MS (CI) M/z 525.9(M +1), 425.9 (M-99). D. 2- [5- (2-amino-2-ethoxycarbonyl-ethyl) -isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester hydrochloride

2- {5- [2- (diphenylmethylene-amino) -2-ethoxycarbonyl-ethyl ] acetate (20mL) in a mixture of ethyl acetate and 1N hydrochloric acid (100mL) was stirred]-isoxazol-3-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester (700mg, 1.35mmol) for a total of 3 hours. The reaction was neutralized by adding saturated sodium bicarbonate. The aqueous phase was extracted with diethyl ether. The combined organics were dried over magnesium sulfate and the solvent removed in vacuo. The resulting oil (200mg) was used directly in example 14C. E. 2- {5- [2- (diphenylmethylene-amino) -2-ethoxycarbonyl-ethyl ]-isoxazol-3-yl } -pyrrolidine-1-carboxylic acid tert-butyl ester

2- (5-bromomethyl-isoxazol-3-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester (1.0g, 3mmol) and N- (diphenylmethylene) glycine ethyl ester (1.0g, 3.74mmol) were dissolved in toluene (10 mL). Aqueous potassium hydroxide, 18M, (0.25mL, 4.5mmol) and tetrabutylammonium bromide (97mg, 0.30mmol) were added. Stirring at room temperatureAfter 1 hour of reaction, 1N hydrochloric acid (4.5mL) was added. The organic phase was extracted with 1N hydrochloric acid, saturated sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was chromatographed by Biotage 40S column eluting with 15% ethyl acetate/hexanes to give the title compound (700mg, 45%). MS (CI) M/z 518.0(M + 1).Example 15A. 2-allyloxycarbonylamino-3- {3- [1- (toluene-4-sulfonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid

Hydrolysis of 15B using the procedure of example 1A gave the title compound. MS (CI) M/z464.0(M +1), 461.9 (M-1). B. 2-allyloxycarbonylamino-3- {3- [1- (toluene-4-sulfonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid ethyl ester

The title compound was prepared according to the procedure described for example 1B. MS (CI) M/z 492.0(M + 1).Example 16A. 2-allyloxycarbonylamino-3- [3- (1- { [4- (2, 6-dimethoxy-benzoylamino) -phenyl ]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

Hydrolysis of 16B using the procedure of example 1A gave the title compound. MS (CI) M/z606.7(M +1), 605.1 (M-1). B. 2-allyloxycarbonylamino-3- [3- (1- { [4- (2, 6-dimethoxy-benzoylamino) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid ethyl ester

The title compound was prepared according to the procedure described for example 3B, using 2, 6-dimethoxybenzoyl chloride instead of 2, 6-dichlorobenzoyl chloride. MS (CI) M/z 635.3(M +1), 632.5 (M-1).Example 17A. 2-allyloxycarbonylamino-3- {3- [1- (3, 4-dimethoxy-benzenesulfonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid

The title compound was prepared by hydrolysis of 17B using the procedure in example 1A. MS (CI) M/z507.6 (M-1). B. 2-allyloxycarbonylamino-3- {3- [1- (3, 4-dimethoxy-benzenesulfonyl) -pyrrolidin-2-yl]-isoxazol-5-yl } -propionic acid ethyl ester

The title compound was prepared according to the procedure described for example 1B, using 3, 4-dimethoxybenzenesulfonyl chloride. MS (CI) M/z 537.8(M + 1).Example 18A. 2-allyloxycarbonylamino-3- [3- (1-cyclopropanecarbonyl-pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

Hydrolysis of 18B using the procedure in example 1A gave the title compound. MS (CI) M/z378.2(M +1), 376.2 (M-1). B. 2-allyloxycarbonylamino-3- [3- (1-cyclopropanecarbonyl-pyrrolidin-2-yl) -isoxazol-5-yl ]-propionic acid ethyl ester

The title compound was prepared according to the procedure described for example 3B, using the appropriate reagents. MS (CI) M/z 406.1(M + 1).Example 19A. 2-acetylamino-3- [3- (3-methyl-1- {2- [4- (2-methyl-benzyloxy) -phenyl]-acetylamino } -butyl) -isoxazol-5-yl]-propionic acid

Hydrolysis of 19B using the procedure in example 1A gave the title compound. MS (CI) M/z508.1(M +1), 506.1 (M-1). B. 2-acetylamino-3- [3- (3-methyl-1- {2- [4- (2-methyl-benzyloxy) -phenyl]-acetylamino } -butyl) -isoxazol-5-yl]-propionic acid ethyl ester

The procedure is as in example 7B, using [4- (2-methyl-benzyloxy) -phenyl]Acetic acid the title compound was prepared. MS (CI) M/z 550.2(M + 1). C. [4- (2-methyl-benzyl)Oxy) -phenyl]-acetic acid

The title compound was prepared according to the procedure described for example 7D.¹H NMR(300MHz，CDCl₃) δ 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-methyl-benzyloxy) -phenyl]-methyl acetate

The title compound was prepared according to the procedure described for example 7E.¹H NMR(400MHz，CDCl₃)δ2.35(s，3H)，3.56(s，2H)，3.67(s，3H)，5.00(s，2H)，6.92-6.94(d，2H)，7.18-7.26(m，5H)，7.37-7.39(d，1H)。Example 20A. 2-acetylamino-3- (3- {1- [2- (4' -ethyl-biphenyl-4-yl) -acetylamino]-3-methyl-butyl } -isoxazol-5-yl) -propionic acid

Hydrolysis of 20B using the method of example 1A gave the title compound. MS (CI) M/z506.1(M +1), 504.0 (M-1). B. 2-acetylamino-3- (3- {1- [2- (4' -ethyl-biphenyl-4-yl) -acetylamino ]-3-methyl-butyl } -isoxazol-5-yl) -propionic acid ethyl ester

The title compound was prepared according to the procedure described for example 7B, using (4' -ethyl-biphenyl-4-yl) -acetic acid. MS (CI) M/z 534.2(M + 1). C. (4' -Ethyl-biphenyl-4-yl) -acetic acid

The title compound was prepared according to the procedure described for example 10B. MS (CI) M/z 239.0 (M-1). D (4' -ethyl-biphenyl-4-yl) -acetic acid methyl ester

The title compound was prepared according to the method described for example 10C。¹H NMR(400MHz，CDCl₃)δ7.63(d，J＝8.1Hz，2H)，7.60(d，J＝8.1Hz，2H)，7.43(d，J＝8.1Hz，2H)，7.36(d，J＝8.1Hz，2H)，3.79(s，3H)，3.75(s，3H)，2.78(q，J＝7.5Hz，2H)，1.37(t，J＝7.5Hz，3H)。Example 21A. 2-acetylamino-3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl]-pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid

The procedure used in example 1D was followed using 2-acetylamino-2- (3- {1- [ (4-benzyloxy-phenyl) -acetyl]-pyrrolidin-2-yl } -isoxazol-5-ylmethyl) -malonic acid diethyl ester the title compound was prepared. MS (CI) M/z 492.2(M +1), 490.3 (M-1). B. 2-acetylamino-2- (3- {1- [ (4-benzyloxy-phenyl) -acetyl]-pyrrolidin-2-yl } -isoxazol-5-ylmethyl) -malonic acid diethyl esterms(cI)m/z 602.0(m+1)Example 22A. 2-acetylamino-3- [3- (1- { [4- (4-chloro-benzyloxy) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

The title compound was prepared according to the procedure described for example 21A, using 22B. MS (CI) M/z 526.2(M +1), 524.2 (M-1). B. 2-acetylamino-3- [3- (1- { [4- (4-chloro-benzyloxy) -phenyl ]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-malonic acid diethyl ester

The procedure was followed as described in example 21B, using [4- (4-chloro-benzyloxy) -phenyl]Acetic acid the title compound was prepared. MS (CI) M/z 626.0(M + 1). C. [4- (4-chloro-benzyloxy) -phenyl]-acetic acid

The title compound was prepared according to the procedure described for example 7D.¹H NMR (400MHz, dimethylsulfoxide) delta 3.44(s, 2H), 5.05(s, 2H), 6.88-6.92(m, 2H), 7.11-7.14(m，2H)，7.42(s，4H)，12.20(s，1H)。¹³C NMR (100MHz, dimethyl sulfoxide) δ 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-chloro-benzyloxy) -phenyl]-methyl acetate

The title compound was prepared according to the method of example 7E.¹H NMR(400MHz，CDCl₃)δ3.55(s，2H)，3.67(s，3H)，5.00(s，2H)，6.88-6.90(d，2H)，7.17-7.19(d，2H)，7.34(s，4H)。Example 23A. 2-acetylamino-3- [3- (1- { [4- (3-phenyl-allyl) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl]-propionic acid

The title compound was prepared according to the procedure described for example 22A using 23B. MS (CI) M/z502.2(M +1), 500.2 (M-1). B. 2-acetylamino-3- [3- (1- { [4- (3-phenyl-allyl) -phenyl]-acetyl } -pyrrolidin-2-yl) -isoxazol-5-ylmethyl]-malonic acid diethyl ester

The procedure is as in example 22B, using [4- (3-phenyl-allyl) -phenyl ]]Acetic acid the title compound was prepared. MS (CI) M/z 602.0(M + 1). C. [4- (3-phenyl-allyl) -phenyl ]-acetic acid

The procedure is as in example 10B, using [4- (3-phenyl-allyl) -phenyl ]]Acetic acid the title compound was prepared.¹H NMR(400MHz，CDCl₃) δ 3.51(d, 2H, J ═ 7Hz), 3.62(s, 2H), 6.28-6.46(m, 2H), 7.18-7.37(m, 9H). D. [4- (3-phenyl-allyl) -phenyl]-acetic acid

(4-trifluoromethylsulfonyloxy-phenyl) -acetic acid methyl ester (500mg,1.68mmol, 1.00 equiv.), palladium (II) chloride (15mg, 5 mol%), bis-diphenylphosphinoethane (50mg, 5 mol%), bis (pinacolyl) diboron (469mg, 1.85mmol, 1.10 equiv.), and potassium acetate (495mg, 5.04mmol, 3.00 equiv.) for a total of 3 hours. The black reaction mixture was cooled to room temperature. Palladium (II) chloride (15mg, 5 mol%), bis-diphenylphosphinoethane (50mg, 5 mol%), cinnamoyl bromide (660mg, 3.35mmol, 2.00 equiv.), sodium carbonate (890mg, 8.40mmol, 5.00 equiv.), and water (4mL) were added. The reaction mixture was heated to 80 ℃ overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was extracted with saturated sodium bicarbonate (2X 50mL), water (2X 50mL) and brine (50 mL). The organic phase was dried over sodium sulfate. Evaporation of the solvent gave a black oily residue which was further chromatographed by Bioage (5% ethyl acetate/hexane) to give a 9: 1 mixture (200mg, 45%) of the title compound and 3-phenyl-allyl acetate. ¹H NMR(400MHz，CDCl₃) δ 3.52(dd, 2H, J ═ 7, 1.2Hz), 3.60(s, 2H), 3.68(s, 3H), 6.24-6.38(m, 1H), 6.43-6.47(d, 1H), 7.1-7.4(m, 9H). The product was used without further purification in example 23C.Example 24A. 2- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -butyl) -1H-benzimidazole-4-carboxylic acid

The title compound was prepared according to the procedure described for example 1A using 24B. MS (CI) M/z 514.1(M +1), 512.2 (M-1). B. 2- (3-methyl-1- {2- [4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -butyl) -1H-benzimidazole-4-carboxylic acid methyl ester

The title compound was prepared according to the procedure described for example 2B using 24C. MS (CI) M/z 528.0(M +1), 526.2 (M-1). C. 2- (1-amino-3-methyl-butyl) -1H-benzimidazole-5-carboxylic acid methyl ester hydrochloride

Heating 4-amino-3- (2-tert-butoxycarbonylamino-4-methyl group with stirringA solution of-pentanoylamino) -benzoic acid methyl ester (690mg, 1.82mmol) in acetic acid (9mL) was kept at 70 ℃ for 1.5 hours. The acetic acid was removed in vacuo and the crude mixture was dissolved in 4M dioxane (9mL) solution of hydrochloric acid and stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo to afford the title compound. MS (CI) M/z262.0(M +1), 260.1 (M-1). E. 4-amino-3- (2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino) -benzoic acid methyl ester

To a solution of N-tert-butoxycarbonyl-L-leucine (1.06g, 4.57mmol) in dimethylformamide (30mL) was added hydroxybenzotriazole monohydrate (760mg, 5.62mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (973mg, 5.07 mmol). The mixture was stirred until all of the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride had dissolved. A solution of methyl 3, 4-diaminobenzoate (759mg, 4.57mmol) in dimethylformamide (10mL) and triethylamine (0.68mL, 4.89mmol) was added sequentially. The reaction was stirred at room temperature overnight and poured into water. The mixture was extracted three times with ethyl acetate. The organic phase was washed with a saturated solution of sodium bicarbonate, water (2 ×) and brine. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue obtained by column chromatography using Biotage Flash40S was eluted with ethyl acetate/hexane (2: 3) to give the title compound (690mg, 40%). MS (CI) M/z 380.0(M +1), 378.2 (M-1).Example 25A. 2- (2, 6-dichloro-benzoylamino) -3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -3-methyl-butyl) -isoxazol-5-yl]-propionic acid

A mixture of 25B (56mg, 0.13mmol) in t-butanol (1mL) and 1N sodium hydroxide (0.27mL) was stirred at reflux. After 30 minutes the mixture was concentrated under reduced pressure and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified to pH1 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. MP 102-4 ℃; MS (CI) M/z 710.3 and 713.3(M + 1). B. 2- (2, 6-dichloro-benzoyl) Phenylamino) -3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -3-methyl-butyl) -isoxazol-5-yl]-propionic acid methyl ester

The procedure is as in example 2B, using 3-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid and 3- [3- (1-amino-3-methyl-butyl) -isoxazol-5-yl]-2- (2, 6-dichloro-benzoylamino) -propionic acid methyl ester hydrochloride the title compound was prepared. The yield is 51 percent; a white solid. MS (CI) M/z 724.2 and 726.2(M + 1). C. 3- [3- (1-amino-3-methyl-butyl) -isoxazol-5-yl]-2- (2, 6-dichloro-benzoylamino) -propionic acid methyl ester hydrochloride

The title compound was prepared in the same manner as in example 1C using 25D. MS (CI) M/z 428.3 and 430.3(M + 1). D. 3- [3- (1-tert-Butoxycarbonylamino-3-methyl-butyl) -isoxazol-5-yl]-2- (2, 6-dichloro-benzoylamino) -propionic acid methyl ester

The title compound was prepared according to the same method as in example 7H, using 25E and 7I. MS (CI) M/z 526.2 and 528.0(M + 1). E. 2- (2, 6-dichloro-benzoylamino) -pent-4-ynoic acid methyl ester

The title compound was prepared according to the same procedure as in example 3B, using methyl 2-amino-pent-4-ynoate and 2, 5-dichlorobenzoyl chloride. MS (CI) M/z 300.2 and 302.2(M + 1). Example 26A. 2- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -3-methyl-butyl) -isoxazol-5-ylmethyl]-4-methyl-pentanoic acid

The title compound was prepared in the same manner as example 25, Steps A-D using methyl 4-methyl-2-propargylpentanoate in step DA compound is provided. MS (CI) M/z 577.3 (M-1).Example 27A. 2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl]-acetylamino } -3-methyl-butyl) -isoxazol-5-yl]-propionic acid

The title compound was prepared according to the same procedures as examples 7A and B, using 3-methoxy-4- (3-o-tolyl-ureido) -phenylacetic acid in part B. A white solid; MP 123-5 ℃; MS (M/z)578.1 (M-1).Example 28A. 2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl]-acetyl } -amino) -methyl]-phenyl } -propionic acid

The title compound was prepared by the same method as example 25, steps a and B, using 28B in step 25B. MS (M/z)633(M + 1). B. 2-acetylamino-2- [ (3-aminomethyl-phenyl) -methyl]-malonic acid diethyl ester

A mixture of 28C (1.15g, 3.5mmol), 10% Pd on carbon (0.15g), and concentrated hydrochloric acid (0.3mL) in ethanol (50mL) was placed in a Parr shaker under 45 p.s.i. hydrogen pressure for 6 hours. The mixture was filtered through celite and concentrated under reduced pressure to give 1.2g of the title compound as a white solid MS (M/z)337.3(M + 1). C. 2-acetylamino-2- [ (3-cyanophenyl) -methyl ]-malonic acid diethyl ester

The title compound was prepared according to the same procedure as in example 7G, using α -bromo-m-tolylcyanide. MS (CI) M/z 333(M + 1).Example 29 Binding of biotinylated CS-1 to isolated VLA-4

The ability of a compound to specifically inhibit VLA-4 dependent binding was tested using the VLA-4/bCS-1 receptor ligand binding assay described herein. A.Preparation of VLA-4 coated plates

In trialVLA-4 coated panels were prepared prior to the experiments. VLA-4 expression stock was isolated from Jurkat cells according to Makarem et al (J.biol.chem., 269, 4005-₃(pH8.8) to a final concentration of 0.4 mg/ml. A100 ml aliquot of this stock solution was then added to each well of a 96 well Microfluor "B" U-bottom plate (Dynatech No.0010107205) and incubated overnight at 4 ℃. The coating solution was aspirated off and quenched per well with PBS containing 1% skim milk powder +1mM MnCl (200 ml/well, 37 ℃) for 0.5 hour. Skim milk powder was aspirated immediately before addition of biotinylated CS-1. B.Binding of biotinylated CS-1 to isolated VIA-4

Biotinylated CS-1 peptide (bCS-1) was prepared. The peptide was diluted to a final concentration of 5mg/ml with PBS containing 0.1% skim milk powder plus 1mM McCl (PBSB). To each well of a 96-well polypropylene transfer plate, 200ml aliquots of each well containing compounds (32, 10, 3.2, 1, 0.32 and 0.1mM), excipients or antibodies (0.5mg/ml) dissolved in PBSB containing 0.1% DMSO were added and incubated for 60 minutes (37 ℃). The plate was washed three times with 200 ml/well PBSB to remove unbound bCS-1. 100ml of a 1: 5000 dilution of a PBSB solution of streptavidin poly-HRP was then added to each well and incubated for 60 minutes at 37 ℃. Unbound streptavidin poly-HRP was aspirated and the plate washed three times with PBSB (200 ml/well). After the final wash, 100ml of TMB was added to each well to react with unbound streptavidin poly-HRP and the OD of each well on the plate was determined using an Emax plate reader (650). The results are the average of two determinations. Example 30 Binding of VLA-4 dependent THP1 cells to baculovirus sVCAM

The ability of a compound to inhibit VLA-4 dependent binding to sVCAM was tested using the THP1 baculovirus sVCAM cell binding assay. A.Preparation of sVCAM coated plate

sVCAM coated plates were prepared before the assay was run. Baculovirus sVCAM stock from PanVera in 50mM NaHCO₃(pH8.8) to a final concentration of 5 mg/ml. A50 ml aliquot of this stock solution was then added to each well of a 96 well Microfluor "B" U-bottom plate (Dynatech No.0010107205) and incubated overnight (4)Deg.c). The coating solution was aspirated off and each well was quenched with PBS containing 1% skim milk powder (150 ml/well, 4 ℃) for 1 hour. Skim milk powder was removed by tilting rotation just prior to addition of biotinylated CS-1. B.Labelling and binding of THP1 cells

THP1 cells were obtained from the American type culture Collection (ATCC, Rockville, Md.) containing 10% 1mM MnCl₂In RPMI 1640 medium (Bio Rad) for 20 minutes (37 ℃). In the presence of MnCl₂After activation, the pelleted cells were centrifuged (approximately 500g, 5 min) and resuspended twice in serum-free minimal medium (EBM, 37 ℃). Cells in serum-free Medium (2X 10)⁶/ml) was then incubated with 5mM calcein AM for 30 minutes at 37 ℃. After labeling, all cells were pelleted by centrifugation (approximately 500g, 5 min) and resuspended twice in RPMI 1640 containing 10% FBS to lyse any free calcein AM. The cells were then plated at DPBS (+1mM CaCl) containing 1mg/ml BSA ₂And 1mM MgCl₂) (DPBSB) was resuspended twice and diluted to 667,000 cells/ml. To each well of a 96-well polypropylene transfer plate, a 200ml aliquot was added, wherein each well contained compound (10, 5, 1 and 0.1mM), excipient or antibody (0.5mg/ml) in DPBSB (containing 0.1% DMSO), incubated for 30 minutes (37 ℃). An additional 150ml (100,000 cells) was removed from each well and transferred to the appropriate wells of quenched baculovirus sVCAM coated plate and incubated for 45 minutes (37 ℃). Unbound cells were aspirated and the plate was washed three times with DPBSB (100 ml/well). After the last wash, 100ml of DPBSB was added to each well and the plates were read on a Cytoflur II fluorescence plate reader. Three readings were taken per well at 480 excitation and 530 emission wavelengths. The results are based on the average of two determinations. The average background fluorescence of the blank wells was subtracted from each sample to obtain the calibrated fluorescence intensity for each sample.

Claims (53)

1. A compound of formula (1.0.0) and pharmaceutically acceptable salts and other prodrug derivatives thereof:(1.0.0)

wherein:

a is (C)₁-C₆) Alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 0-3R⁹Substitution; or A is a group selected from: a. the¹-NHC(＝O)NH-A²-，A¹-NHC(＝O)O-A²-，A¹-OC(＝O)NH-A²-，A¹-NHSO₂NH-A²-，A¹-NHC(＝O)-A²-，A¹-C(＝O)NH-A²-，A¹-NHSO₂-A²-，A¹-SO₂NH-A²-，A¹-(CH₂)_r-A²-，A¹-CH(R¹)-O-A²-，A¹-(CH₂)_rO-A²-，A¹-O(CH₂)_r-A²-，A¹-(CH₂)_rNH-A²-，A¹-NH(CH₂)_r-A²-, and A¹-(CH₂)_rS(＝O)q-A²-, wherein A¹And A²Each independently selected from hydrogen, aryl, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, cycloalkyl, heteroaryl, and heterocyclyl, wherein the aryl, alkyl, cycloalkyl, heteroaryl, or heterocyclyl group is substituted with 0-3R⁹Substitution;

-B is a group independently selected from:(1.1.0) (1.1.1) (1.1.2)(1.1.3) (1.1.4) (1.1.5)(1.1.6) (1.1.7) (1.1.8)(1.1.9) (1.1.10) (1.1.11)(1.1.12) (1.1.13) (1.1.14)(1.1.15) (1.1.16) (1.1.17)(1.1.18) (1.1.19) (1.1.20)(1.1.21) (1.1.22) (1.1.23)

- - -wherein the symbol "+" represents each of the moieties represented by the partial formulae (1.1.0) to (1.1.23) and "CR" in the formula (1.0.0)²R³- "the point of attachment of the moiety; the symbol "→" represents a connecting point of the moiety represented by each of the partial formulae (1.1.0) to (1.1.23) and the moiety "E" in the formula (1.0.0); and formulae (1.1.0) - (1.1.23) except for sub-formulae (1.1.10), (1.1.17), and (1.1.23) can each be optionally substituted with R9;

-E is a single bond, -O-, -NR¹⁰-，-CH＝CH-，-C≡C-，-S(＝O)q-，-CR¹¹R¹²NR¹⁰-, or-CR¹¹R¹²-，

-X is-O-, -C (═ O) -, -S (═ O)_q-, or-NR¹⁰-；

-X¹，X²And X³Each independently selected from CH and CR⁹Or N;

-Y is a single bond, -C (═ O) -, -C (═ S) -, or-S (═ O) ₂-；

-k is an integer independently selected from 0, 1 and 2;

-m is an integer independently selected from 0 and 1;

-n is an integer independently selected from 0, 1 and 2;

-p is an integer independently selected from 0 and 1, with the proviso that when B is selected from the sub-formulae (1.1.0) - (1.1.11), p must be selected as 1;

-q is an integer independently selected from 0, 1 and 2;

-r is an integer independently selected from 0, 1 and 2;

-R¹is 0 or 1F, CF₃、OCF₃Or cyano-substituted (C)₁-C₃) An alkyl group;

-R²and R³Each independently selected from hydrogen by 0-3R¹³Substituted (C)₁-C₆) Alkyl by 0-3R¹³Substituted (C)₂-C₆) An alkenyl group; by 0-3R¹³Substituted (C)₃-C₁₄) Carbocyclic ring system, by 0-3R¹³Substituted heterocyclic ring as defined herein, substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-OR⁵Is substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-SR⁵Is substituted by 0-3R¹³Substituted (C)₁-C₆) alkyl-SO₂R⁵Is substituted by 0-3R¹³Substituted heteroaromatic rings as defined herein; by 0-3R¹³Substituted aromatic rings as defined herein;

the condition is-

R²And R³Each as defined above; or they are bound to one another as described below, or one of them is bound to R as defined below⁴In combination with one another, in this case hydrogen or methyl;

-R²and R³Are combined with each other to form a quilt with 0-3R¹³A substituted cycloalkyl or heterocyclyl ring; or

-R²Or R³And R⁴And the carbon and nitrogen atoms to which they are respectively attached together form a group defined by 0-3R¹³A substituted heteroaryl or heterocyclyl group as defined herein;

-R⁴is hydrogen, or optionally substituted by R¹³Substituted (C)₁-C₆) Alkyl, or R⁴Can be reacted with R²Or R³Together form a carbocyclic or heterocyclic ring;

-R⁵and R⁶Independently is hydrogen, (C)₁-C₆) Alkyl radical (C)₂-C₆) Alkenyl (C)₂-C₆) Alkynyl, CF₃Aryl, cycloalkyl, heteroaryl, or heterocycleWherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl is substituted with 0-3R¹³Substitution;

-R⁷is (C)₁-C₆) Alkyl radical (CH)₂)_kOR⁵，(CH₂)_kC(＝O)R⁵，(CH₂)_kC(＝O)NR⁶R⁵，(CH₂)_kNR⁶C(＝O)R⁵，(CH₂)_kNR⁶C(＝O)OR⁵，(CH₂)_kNR⁶SO₂R⁵，(CH₂)_kNR⁶R⁵，F，CF₃，OCF₃Is substituted by 0-3R⁹Substituted aryl radicals, substituted by 0-3R⁹Substituted heterocyclyl, by 0-3R⁹Substituted heteroaryl with 0-3R⁹Substituted cycloalkyl, or R⁷Can be reacted with R⁸Together form a cycloalkyl or heterocyclyl ring; or R⁷Can be reacted with R¹¹Together form a cycloalkyl or heterocyclyl ring;

-R⁸is hydrogen, F, CN, (C)₁-C₆) Alkyl or (C)₁-C₆) An alkoxy group;

-R⁹is halogen, (C)₁-C₆) Alkyl radical (C)₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkoxy, cyano, (CH)₂)_kOH，C(＝O)R⁵，(CH₂)_kC(O)NR⁵R⁶，(CH₂)_kNR⁵R⁶，(CH₂)_kNR⁵SO₂R⁶，CF₃，OCF₃，SO₂NR⁵R⁶，(CH₂)_mC(＝O)OR⁵(ii) a When R is⁹When bound to a saturated carbon atom, R⁹May be either ═ O or ═ S; when R is⁹When bound to a sulfur atom, R⁹May be ═ O;

-R¹⁰is hydrogen, C (═ O) R⁵，C(＝O)OR⁵，(C₁-C₆) Alkyl radicalAryl, heterocyclyl, heteroaryl, cycloalkyl, or SO ₂R⁵；

-R¹¹And R¹²Independently is hydrogen, (C)₁-C₆) Alkyl, -OH, -CN, (C)₁-C₆) Alkoxy radicals, NR⁶C(＝O)R⁵，NR⁶SO₂R⁵，NR⁶R⁵，CF₃F, aryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkoxy, or R¹¹Can be reacted with R¹²Together form a cycloalkyl or heterocyclyl ring; and is

-R¹³Independently selected from halogen, CF₃，(C₁-C₆) Alkyl, aryl, heteroaryl, heterocyclyl, hydroxy, cyano, (C)₁-C₆) Alkoxy group, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkoxy, (C)₂-C₆) Alkynyl (C)₂-C₆) Alkenyl, -NR⁶R⁵，-C(＝O)NR⁵R⁶，SO₂R⁵，C(＝O)R⁵，NR⁵SO₂R⁶，NR⁵C(＝O)R⁶，C(＝O)NR⁵SO₂R⁶，NR⁵C(＝O)OR⁶And SO₂NR⁶R⁵。

2. The compound according to claim 1, wherein when a is heteroaryl, it is selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, p-thiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furyl, 2, 3-dihydrobenzofuryl, benzo [ b ] thienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, 2, 3-naphthyridinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, Pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and pyrazolo [1, 5-c ] triazinyl.

3. A compound according to claim 2, wherein a is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo [ b ] furyl, benzimidazolyl or quinolinyl.

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

5. A compound according to claim 1, wherein when a is heterocyclyl, it is a group selected from: oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolylalkyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and benzodioxolane and 1, 3-benzodioxol-5-yl.

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

7. A compound according to claim 1, wherein a is a group selected from: a. the¹-NHC(＝O)NH-A²-，A¹-NHC(＝O)O-A²-，A¹-OC(＝O)NH-A²-，A¹-NHSO₂NH-A²-，A¹-NHC(＝O)-A²-，A¹-C(＝O)NH-A²-，A¹-NHSO₂-A²-，A¹-SO₂NH-A²-，A¹-(CH₂)_r-A²-，A¹-CH(R¹)-O-A²-，A¹-(CH₂)_rO-A²-，A¹-O(CH₂)_r-A²-，A¹-(CH₂)_rNH-A²-，A¹-NH(CH₂)_r-A²-, and A¹-(CH₂)_rS(＝O)_q-A²-, wherein A¹And A²Each independently selected from hydrogen, aryl, (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, cycloalkyl, heteroaryl, and heterocyclyl, wherein the aryl, alkyl, cycloalkyl, heteroaryl, or heterocyclyl group is substituted with 0-3R⁹And (4) substitution.

8. The compound according to claim 7, wherein A is¹And A²Are both aryl or heteroaryl.

9. The compound according to claim 8, wherein said aryl is phenyl and said heteroaryl is pyridyl, each independently substituted with 0 or 1 substituent R⁹Is substituted, and R⁹Is selected from F, Cl, F₃C-, methyl, methoxy, hydroxy, isopropyl, cyclopropoxy and cyclopentyl.

10. A compound according to claim 9, wherein n is the integer 1, resulting in the formation of a methylene bridge.

11. A compound according to claim 10, wherein the a moiety and the methylene bridge to which it is attached together form a group selected from: 4-hydroxyphenyl-, 3-methoxy-4- (N '-phenylureido) -phenylmethyl-, 4- (N' -phenylureido) phenylmethyl-, 4- (N '- (2-methylphenyl) 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) urea-phenylmethyl-, 3-methoxy-4- (N ' - (2-pyridyl) urea) -phenylmethyl-, 4- (N ' - (2-fluorophenyl) urea) -phenylmethyl-, 4- (N ' - (2-chlorophenyl) urea) -3-methoxyphenylmethyl-, 4- (N '- (4-isopropylphenyl) urea) -phenylmethyl-, 6-methoxy-5- (N' - (o-tolyl) urea-2-pyridylmethyl-, 4- (N '- (3-cyclopropoxy-2-pyridyl) urea) -phenylmethyl-, and 4- (N' - (o-tolyl) urea) -pyridin-5-ylmethyl-.

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

13. A compound according to claim 12, wherein for-NR in formula (1.0.0)⁴CR²CR³-a moiety, R⁴Is hydrogen, R²Is hydrogen, and R³Is hydrogen.

14. A compound according to claim 12, wherein for-NR in formula (1.0.0)⁴CR²CR³-a moiety, R⁴Is hydrogen, R²Is hydrogen, and R³It is an isobutyl group.

15. A compound according to claim 12, wherein for-NR in formula (1.0.0)⁴CR²CR³-a moiety, R²Is hydrogen, R³Is hydrogen.

16. A compound according to claim 12, wherein for-NR in formula (1.0.0)⁴CR²CR³-a moiety, R²Is hydrogen, R³Is hydrogen and R⁴Is methyl.

17. A compound according to claim 12, wherein for-NR in formula (1.0.0)⁴CR²CR³-a moiety, R⁴And R²Or R³Together form a pyrrolidinyl group, whereby R⁴Is methylene or 1, 2-ethylene, R²Or R³One is hydrogen and R is²Or R³Is 1, 2-ethylene or methylene.

18. The compound according to claim 12, wherein B is a group selected from the group consisting of partial formulae (1.1.2), (1.1.6), (1.1.17), (1.1.18), (1.1.19) and (1.1.22):1.1.2 1.1.6 1.1.171.1.18 1.1.19 1.1.22

wherein the symbol "+" and the symbol "→" are as defined above; x is oxygen, S (═ O)_qOr nitrogen, and X¹，X²And X³Each independently selected from the group-CH-, -CR ⁹-and-N-.

19. The compound according to claim 18, wherein B is sub-formula (1.1.6).

20. The compound according to claim 19, wherein in the sub-formula (1.1.6), X is-O-.

21. The compound according to claim 18, wherein B is sub-formula (1.1.22).

22. The compound according to claim 21, wherein in the sub-formula (1.1.22), X is-NR¹⁰-, wherein R is¹⁰is-H; and X¹、X²And X³Each is-CH-.

23. A compound according to claim 12, wherein p is 1; m is 0 or 1; and E is-CR¹¹R¹²-。

24. The compound according to claim 23, wherein p is 1; m is 0; r¹¹is-H; and R is¹²is-H.

25. The compound according to claim 1, wherein the compound is:

a compound comprising the sub-formula (1.1.0):

3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-5-yl ] -2-methyl-propionic acid

2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid

2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid

2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-oxazol-5-yl } -propionic acid

2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid

2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -4, 5-dihydro-oxazol-5-yl } -propionic acid

2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-oxazol-5-yl) -propionic acid

2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid

2-carboxamido-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -4, 5-dihydro-thiazol-5-yl } -propionic acid

2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-5-yl) -propionic acid

2-benzenesulfonylamino-3- (2- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-5-yl) -propionic acid

2-benzenesulfonylamino-3- [2- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid

2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-5-yl ] -propionic acid

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-4, 5-dihydro-oxazol-5-yl } -propionic acid

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -4, 5-dihydro-thiazol-5-yl } -propionic acid

3-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-3H-imidazol-4-yl } -propionic acid

2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-oxazol-5-yl } -propionic acid.

26. The compound according to claim 1, wherein the compound is:

a compound comprising a moiety of the sub-formula (1.1.1):

3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-4-yl ] -2-methyl-propionic acid

2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid

2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid

2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-oxazol-4-yl } -propionic acid

2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid

2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -4, 5-dihydro-oxazol-4-yl } -propionic acid

2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-oxazol-4-yl) -propionic acid

2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid

2-acetylamino-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -4, 5-dihydro-thiazol-4-yl } -propionic acid

2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-4-yl) -propionic acid

2-benzenesulfonylamino-3- (2- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-oxazol-4-yl) -propionic acid

2-benzenesulfonylamino-3- [2- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid

2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-oxazol-4-yl ] -propionic acid

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-4, 5-dihydro-oxazol-4-yl } -propionic acid

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-thiazol-4-yl } -propionic acid

2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-oxazol-4-yl } -propionic acid.

27. The compound according to claim 1, wherein the compound is:

a compound comprising a moiety of sub-formula (1.1.2):

3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-5-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-5-yl ] -propionic acid;

2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -oxazol-5-yl } -propionic acid;

2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -oxazol-5-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-5-yl) -propionic acid;

2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid;

2-acetylamino-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazol-5-yl } -propionic acid;

2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-5-yl) -propionic acid;

2-benzenesulfonylamino-3- (2- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-5-yl) -propionic acid;

2-benzenesulfonylamino-3- [2- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-5-yl ] -propionic acid;

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-oxazol-5-yl } -propionic acid;

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiazol-5-yl } -propionic acid;

3-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -3H-imidazol-4-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-5-yl } -propionic acid.

28. The compound according to claim 1, wherein the compound is:

a compound comprising a moiety of sub-formula (1.1.3):

3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-4-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-4-yl ] -propionic acid;

2-methanesulfonylamino-3- [2- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-4-yl ] -propionic acid;

2, 2-difluoro-3- {2- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -oxazol-4-yl } -propionic acid;

2, 2-dimethyl-3- [2- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -oxazol-4-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (2- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-4-yl) -propionic acid;

2-methyl-3- [2- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid;

2-formylamino-3- {2- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazol-4-yl } -propionic acid;

2-methyl-3- (2- {1- [ (4-o-tolyloxy-phenyl) -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-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid;

2-methanesulfonylamino-3- [2- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-4-yl ] -propionic acid;

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-oxazol-4-yl } -propionic acid;

2-acetylamino-3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiazol-4-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-4-yl } -propionic acid;

3- [2- (1- { [4- (4-chloro-benzyloxy) -3-fluoro-phenyl ] -acetyl } -pyrrolidin-2-yl) -thiazol-5-yl ] -propionic acid;

3- [2- (1- { [ 3-fluoro-4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid;

3- [2- (1- { [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid;

3- [2- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid;

3- (2- {1- [ (4-benzyloxy-3-chloro-phenyl) -acetyl ] -3-methyl-pyrrolidin-2-yl } thiazol-5-yl) -propionic acid;

3- [2- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -3-methyl-pyrrolidin-2-yl) thiazol-5-yl ] -propionic acid;

3- (2- {1- [ (4-benzyloxy-phenyl) -acetyl ] -3-methyl-pyrrolidin-2-yl } thiazol-5-yl) -propionic acid;

3- (2- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } thiazol-5-yl) -propionic acid; and

3- (2- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } isoxazol-5-yl) -propionic acid.

29. The compound according to claim 1, wherein said compound comprises a moiety of sub-formula (1.1.4) and is selected from:

3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-isoxazol-5-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid;

2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-isoxazol-5-yl } -propionic acid;

2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -4, 5-dihydro-isoxazol-5-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-isoxazol-5-yl) -propionic acid;

2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid;

2-formylamino-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -4, 5-dihydro-thiazol-5-yl } -propionic acid;

2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-isoxazol-5-yl) -propionic acid

2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-isoxazol-5-yl) -propionic acid;

2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-4, 5-dihydro-isoxazol-5-yl } -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-isothiazol-5-yl } -propionic acid;

3-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -3, 4-dihydro-3H-pyrazol-3-yl } -propionic acid; and

2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-isoxazol-5-yl } -propionic acid.

30. The compound according to claim 1, wherein the compound comprises a moiety of sub-formula (1.1.5) and is selected from:

3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-pyrazol-1-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid;

2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -4, 5-dihydro-pyrazol-1-yl } -propionic acid;

2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -4, 5-dihydro-pyrazol-1-yl) -propionic acid;

2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl ] -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid;

2-acetylamino-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -4, 5-dihydro-pyrazol-1-yl } -propionic acid;

2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-pyrazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -4, 5-dihydro-pyrazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -4, 5-dihydro-pyrazol-1-yl ] -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-4, 5-dihydro-pyrazol-1-yl } -propionic acid;

2-formylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -4, 5-dihydro-pyrazol-1-yl } -propionic acid; and

2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4, 5-dihydro-pyrazol-1-yl } -propionic acid.

31. The compound according to claim 1, wherein the compound comprises a moiety of sub-formula (1.1.6) and is selected from:

3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-5-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-5-yl ] -propionic acid;

2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -isoxazol-5-yl } -propionic acid;

2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methylamino) -methyl ] -isoxazol-5-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -isoxazol-5-yl) -propionic acid;

2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -isothiazol-5-yl } -propionic acid;

2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-carboxamido-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-isoxazol-5-yl } -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isothiazol-5-yl } -propionic acid;

3-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2H-pyrazol-3-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isoxazol-5-yl } -propionic acid;

3- [3- (1- { [4- (pyridin-4-ylmethoxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [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-benzyloxy-pyridin-3-yl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

3- (3- {1- [ (5-benzyloxy-pyridin-2-yl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -diphenylamino-propionic acid;

3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -2- (pyridin-2-ylamino) -propionic acid;

3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -2- (pyridin-3-ylamino) -propionic acid;

3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -2- (pyridin-4-ylamino) -propionic acid;

3- [3- (1- { [4- (5-chloro-thiophen-2-ylmethoxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

3- [3- (1- { [4- (4-chloro-benzyloxy) -3-fluoro-phenyl ] -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;

phenyl ] -2- (propane-1-sulfonylamino) -propionic acid;

3- [3- (1- { [ 3-methoxy-4- (4-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [ 3-methoxy-4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (4-chloro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (3-chloro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (2-chloro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (4-fluoro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (3-fluoro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (2-fluoro-benzyloxy) -3-methoxy-phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [ 3-chloro-4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- [3- (1- { [ 3-chloro-4- (3-methoxy-benzyloxy) -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-ylmethoxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- [3- (1- { [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (2-cyanobenzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (4-cyano-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- (3- {1- [ (4-benzyloxy-3-fluoro-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid;

3- (3- {1- [ (4-benzyloxy-3-chloro-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid;

3- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino ] -3-methyl-butyl } -isoxazol-5-yl) -propionic acid;

2-acetylamino-3- [3- (1- { [4- (3-cyano-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- [3- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- (3- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

3- (3- {1- [ (4-p-tolyloxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

3- (3- {1- [ (4-m-tolyloxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

3- (3- {1- [ (4-o-tolyloxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl) -propionic acid;

3- [3- (1- { [4- (4-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (3-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (2-methoxy-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- [3- (3-methyl-1- {2- [4- (2-methyl-benzyloxy) -phenyl ] -acetylamino } -butyl) -isoxazol-5-yl ] -propionic acid;

2-acetylamino-3- (3- {1- [2- (4-benzyloxy-phenyl) -acetylamino ] -3-methyl-butyl ] -isoxazol-5-yl) -propionic acid;

3- [3- (1- { [4- (4-fluoro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (3-fluoro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (2-fluoro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (2-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (3-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (4-chloro-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (3-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (4-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-5-yl ] -propionic acid;

3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-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-methoxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid;

3- (5- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -2H-pyrazol-3-yl ] -propionic acid, and

3- (3- {1- [3- (2-methyl-benzyloxy) -benzoyl ] -pyrrolidin-2-yl } -isoxazol-5-yl ] -propionic acid;

3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid;

2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -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-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-2-yl) -propionic acid;

2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-formylamino-3- {5- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazol-2-yl } -propionic acid;

2-methyl-3- (5- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- (5- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-oxazol-2-yl } -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiazol-2-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid; and

2-acetylamino-3- [5- ({2- [4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -methyl) -1H-imidazol-2-yl ] -propionic acid.

32. The compound according to claim 1, wherein said compound comprises a moiety of sub-formula (1.1.7) and is selected from

3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid;

2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -pyrazol-1-yl } -propionic acid;

2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl ] -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -pyrazol-1-yl) -propionic acid;

2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2-formylamino-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -pyrazol-1-yl } -propionic acid;

2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-pyrazol-1-yl } -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid.

33. A compound according to claim 1, which is a compound comprising a moiety of sub-formula (1.1.8):

3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid;

2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -oxazol-2-yl } -propionic acid;

2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-2-yl) -propionic acid;

2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazol-2-yl } -propionic acid;

2-methyl-3- (4- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-oxazol-2-yl } -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -thiazol-2-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid.

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -1H-imidazol-2-yl } -propionic acid.

34. The compound according to claim 1, wherein said compound is a compound comprising a moiety of sub-formula (1.1.9):

3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -imidazol-1-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -imidazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -imidazol-1-yl ] -propionic acid;

2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -imidazol-1-yl } -propionic acid;

2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -imidazol-1-yl) -propionic acid;

2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic 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-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -imidazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -imidazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -imidazol-1-yl ] -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-imidazol-1-yl } -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl } -imidazol-1-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -imidazol-1-yl } -propionic acid.

35. The compound according to claim 1, wherein said compound is a compound comprising a moiety of formula (1.1.10):

3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] oxadiazol-5-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid;

2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid;

2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methyl-amino) -methyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } - [1, 2, 4] oxadiazol-5-yl) -propionic acid;

2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -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-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] oxadiazol-5-yl) -propionic acid;

2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] oxadiazol-5-yl) -propionic acid;

2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] oxadiazol-5-yl ] -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid;

2-carboxamido-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] thiadiazol-5-yl } -propionic acid;

3-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -2H- [1, 2, 4] triazol-3-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] oxadiazol-5-yl } -propionic acid.

36. The compound according to claim 1, wherein said compound is a compound comprising a moiety of formula (1.1.11):

3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] triazol-1-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] triazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) - [1, 2, 4] triazol-1-yl ] -propionic acid;

2, 2-difluoro-3- {3- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] - [1, 2, 4] triazol-1-yl } -propionic acid;

2, 2-dimethyl-3- [3- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } methyl-amino) -methyl ] - [1, 2, 4] triazol-1-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (3- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } - [1, 2, 4] triazol-1-yl) -propionic acid;

2-methyl-3- [3- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid;

2-acetylamino-3- {3- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] - [1, 2, 4] triazol-1-yl } -propionic acid;

2-methyl-3- (3- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] triazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- (3- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 2, 4] triazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [3- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) - [1, 2, 4] triazol-1-yl ] -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl- [1, 2, 4] triazol-1-yl } -propionic acid;

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] triazol-1-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 2, 4] triazol-1-yl } -propionic acid.

37. The compound according to claim 1, wherein said compound is a compound comprising a moiety of sub-formula (1.1.12):

3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -furan-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -propionic acid;

2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -1H-pyrrol-2-yl } -propionic acid;

2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -furan-2-yl) -propionic acid;

2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid;

2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiophen-2-yl } -propionic acid;

2-methyl-3- (4- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -1H-pyrrol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -furan-2-yl) -propionic acid;

2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-1H-pyrrol-2-yl } -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiophen-2-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -furan-2-yl } -propionic acid.

38. The compound according to claim 1, wherein said compound is a compound comprising a moiety of sub-formula (1.1.13):

3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-3-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -furan-3-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-3-yl ] -propionic acid;

2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -1H-pyrrol-3-yl } -propionic acid;

2, 2-dimethyl-3- [5- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -thiophen-3-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -furan-3-yl) -propionic acid;

2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-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-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -furan-3-yl) -propionic acid;

2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -thiophen-3-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-3-yl ] -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2-methyl-1H-pyrrol-3-yl } -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiophen-3-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -furan-3-yl } -propionic acid.

39. The compound according to claim 1, wherein said compound is a compound comprising a moiety of sub-formula (1.1.14):

3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -furan-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -thiophen-2-yl ] -propionic acid;

2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -1H-pyrrol-2-yl } -propionic acid;

2, 2-dimethyl-3- [5- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -furan-2-yl) -propionic acid;

2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid;

2-formylamino-3- {5- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiophen-2-yl } -propionic acid;

2-methyl-3- (5- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -1H-pyrrol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- (5- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -furan-2-yl) -propionic acid;

2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -thiophen-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -1H-pyrrol-2-yl ] -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2-methyl-1H-pyrrol-2-yl } -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiophen-2-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -furan-2-yl } -propionic acid.

40. The compound according to claim 1, wherein said compound is a compound comprising a moiety of formula (1.1.15):

3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-3-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-3-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -isoxazol-3-yl ] -propionic acid;

2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -isoxazol-3-yl } -propionic acid;

2, 2-dimethyl-3- [5- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid;

2-allyloxycarbonylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -isoxazol-3-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -isoxazol-3-yl) -propionic acid;

2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid;

2-acetylamino-3- {5- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -isothiazol-3-yl } -propionic acid;

2-methyl-3- (5- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-3-yl) -propionic acid;

2-benzenesulfonylamino-3- (5- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -isoxazol-3-yl) -propionic acid;

2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -isoxazol-3-yl ] -propionic acid;

2-carboxamido-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -4-methyl-isoxazol-3-yl } -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isothiazol-3-yl } -propionic acid;

3-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -2H-pyrazol-5-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -isoxazol-3-yl } -propionic acid.

41. The compound according to claim 1, wherein said compound is a compound comprising a moiety of sub-formula (1.1.6):

3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -oxazol-2-yl ] -propionic acid;

2, 2-difluoro-3- {5- [1- (methyl- { [6- (3-o-tolyl-ureido) -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-tolyl-ureido) -phenyl ] -acetyl ] -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid;

2- (butane-1-sulfonylamino) -3- (5- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -oxazol-2-yl) -propionic acid;

2-methyl-3- [5- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-formylamino-3- {5- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -thiazol-2-yl } -propionic acid;

2-methyl-3- (5- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- (5- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -oxazol-2-yl) -propionic acid;

2-benzenesulfonylamino-3- [5- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-methanesulfonylamino-3- [5- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -oxazol-2-yl ] -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-oxazol-2-yl } -propionic acid;

2-acetylamino-3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -thiazol-2-yl } -propionic acid;

2- (2, 6-dichloro-benzoylamino) -3- {5- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -oxazol-2-yl } -propionic acid;

2-acetylamino-3- [5- ({2- [4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -methyl) -1H-imidazol-2-yl ] -propionic acid.

42. The compound according to claim 1, wherein said compound comprises a moiety of formula (1.1.17) and is selected from the group consisting of:

3- (5- {1- [ (4-benzyloxy-3-methoxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 3, 4] -thiadiazol-2-yl) -propionic acid;

3- [5- (1- { [4- (4-chloro-benzyloxy) -phenyl) -acetyl } -pyrrolidin-2-yl) - [1, 3, 4] -thiadiazol-2-yl ] -propionic acid; and

3- (5- {1- [ (4-benzyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } - [1, 3, 4] -thiadiazol-2-yl) -propionic acid.

43. A compound according to claim 1, wherein said compound comprises moieties of sub-formulae (1.1.8), (1.1.19) and (1.1.20), and is selected from:

2-acetylamino-3- {3- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -phenyl } -propionic acid;

2-formylamino-3- {6- [1- ({ 3-methoxy-4- [3- (3-methyl-pyridin-2-yl) -ureido ] -phenyl } -acetyl) -pyrrolidin-2-yl ] -pyridin-2-yl } -propionic acid;

3- {4- [1- ({ 3-ethyl-4- [3- (3-methyl-pyridin-2-yl) -ureido ] -phenyl } -acetyl) -pyrrolidin-2-yl ] -pyrimidin-2-yl } -propionic acid;

2-acetylamino-3- [3- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -phenyl ] -propionic acid;

2-acetylamino-3- [3- ({2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -methyl) -phenyl ] -propionic acid;

2- {2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) phenyl ] -acetyl } -methyl-amino) -methyl ] -pyridin-4-ylmethyl } -4-methyl-pentanoic acid;

3- {2- [ (methyl- { [4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -amino) -methyl ] -pyridin-4-yl } -propionic acid;

2-methanesulfonylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] - [1, 3, 5] triazin-2-yl } -propionic acid;

1- [4- (1- { [6- (3-pyridin-2-yl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyridin-2-ylmethyl ] -cyclopropanecarboxylic acid;

3- [3- (1- { [6- (3-pyridin-2-yl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -phenyl ] -butyric acid;

2- (butane-1-sulfonylamino) -3- {3- [ ({ { 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -phenyl } -propionic acid;

2-benzenesulfonylamino-3- [3- ({ [ (2-methoxy-2' -methyl-biphenyl-4-yl) -acetyl ] -methyl-amino } -methyl) -phenyl ] -propionic acid;

2- (3- { [2- (4-benzyloxy-phenyl) -acetylamino ] -methyl } -benzyl) -malonic acid;

2- [3- ({2- [4- (4-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -benzyl ] -malonic acid;

3- [3- ({2- [4- (3-fluoro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid;

3- [3- ({2- [ 3-chloro-4- (4-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid;

3- [3- ({2- [ 4-benzyloxy-3-chloro-phenyl ] -acetylamino ] -methyl } -phenyl) -2- (propane-1-sulfonylamino) -propionic acid;

3- [3- ({2- [4- (3-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid;

3- [3- ({2- [4- (4-chloro-benzyloxy) -phenyl ] -acetylamino } -methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid;

3- (3- { [2- (4-benzyloxy-3-methoxy-phenyl) -acetylamino ] -methyl } -phenyl) -2- (propane-1-sulfonylamino) -propionic acid;

3- [3- ({2- [4- (4-methyl-benzyloxy) -phenyl ] -acetylamino } -methyl) -2-acetylamino-3- (3- { [2- (4-benzyloxy-phenyl) -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-tolyl-acetylamino) -methyl ] -phenyl } -propionic acid;

3- (3- { [2- (4-hydroxymethyl-phenyl) -acetylamino ] -methyl } -phenyl) -2- (propane-1-sulfonylamino) -propionic acid; and

3- [3- (phenylacetylamino-methyl) -phenyl ] -2- (propane-1-sulfonylamino) -propionic acid.

44. The compound according to claim 1, wherein said compound comprises a moiety of sub-formula (1.1.21) and is selected from the group consisting of:

3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrrol-1-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrrol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrrol-1-yl ] -propionic acid;

2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -pyrrol-1-yl } -propionic acid;

2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -pyrrol-1-yl) -propionic acid;

2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl ] -propionic acid;

2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -pyrrol-1-yl } -propionic acid;

2-methyl-3- (4- {1- [ (4-o-tolyloxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrrol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- (4- {1- [ (4-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrrol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl 1-propionic acid;

2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -pyrrol-1-yl ] -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-pyrrol-1-yl } -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrrol-1-yl } -propionic acid; and

2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrrol-1-yl } -propionic acid.

45. The compound according to claim 1, wherein said compound comprises a moiety of sub-formula (1.1.22) and is selected from the group consisting of:

3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -2-methyl-propionic acid;

2-acetylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (1- {2- [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetylamino } -3-methyl-butyl) -pyrazol-1-yl ] -propionic acid;

2, 2-difluoro-3- {4- [1- (methyl- { [6- (3-o-tolyl-ureido) -pyridin-3-yl ] -acetyl } amino) -ethyl ] -pyrazol-1-yl } -propionic acid;

2, 2-dimethyl-3- [4- (1- { [6- (3-phenyl-ureido) -pyridin-3-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2- (butane-1-sulfonylamino) -3- (4- { [ methyl- ({4- [3- (3-methyl-pyridin-2-yl) -ureido ] -piperidin-1-yl } -acetyl) -amino ] -methyl } -pyrazol-1-yl) -propionic acid;

2-methyl-3- [4- (1- { [4- (2-methyl-benzyloxy) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2-formylamino-3- {4- [1- (biphenyl-4-yl-acetyl) -pyrrolidin-2-yl ] -pyrazol-1-yl } -propionic 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-phenoxymethyl-phenyl) -acetyl ] -pyrrolidin-2-yl } -pyrazol-1-yl) -propionic acid;

2-benzenesulfonylamino-3- [4- (1- { [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2-methanesulfonylamino-3- [4- (3-methyl-1- { [5- (3-o-tolyl-ureido) -pyridin-2-yl ] -acetyl } -pyrrolidin-2-yl) -pyrazol-1-yl ] -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -5-methyl-pyrazol-1-yl } -propionic acid;

2-acetylamino-3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid; and

2- (2, 6-dichloro-benzoylamino) -3- {4- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -pyrazol-1-yl } -propionic acid.

46. The compound according to claim 1, wherein said compound comprises a moiety of sub-formula (1.1.23) and is selected from the group consisting of:

2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -benzooxazole-6-carboxylic acid;

2- [1- (2- { 3-methoxy-4- [3- (3-methyl-pyridin-2-yl) -ureido ] -phenyl) -acetylamino) -3-methyl-butyl ] -3H-benzimidazole-5-carboxylic acid;

2- (1- { [4- (3-pyridin-2-yl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -1H-imidazo [4, 5-c ] pyridine-6-carboxylic acid;

2- (1- { [ 3-ethoxy-4- (3-pyridin-2-yl-ureido) -phenyl ] -acetyl } -pyrrolidin-2-yl) -benzothiazole-6-carboxylic acid;

2- [ ({ [ 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetyl } -methyl-amino) -methyl ] -benzothiazole-6-carboxylic acid;

2- ({ [ (4-benzyloxy-phenyl) -acetyl ] -methyl-amino } -methyl) -oxazolo [5, 4-b ] pyridine-5-carboxylic acid; and

3-methyl-2- {1- [ (4-phenoxy-phenyl) -acetyl ] -pyrrolidin-2-yl } -3H-benzimidazole-5-carboxylic acid.

47. A pharmaceutical composition comprising a compound of formula (1.0.0) as defined in claim 1 and a pharmaceutically acceptable carrier for said compound, wherein said compound is present in an amount effective to prevent, inhibit, prevent or reduce VLA-4 mediated cell adhesion and consequent or related pathological processes.

48. The pharmaceutical composition according to claim 47, additionally comprising one or more therapeutic agents.

49. The pharmaceutical composition of claim 48, wherein said one or more therapeutic agents are selected from the group consisting essentially of anti-inflammatory corticosteroids, non-steroidal anti-inflammatory drugs, bronchodilators, anti-asthmatics, immunosuppressive agents, immunostimulants, anti-metabolites, anti-psoriasis agents, and anti-diabetic agents.

50. The pharmaceutical composition according to claim 49, wherein the therapeutic agent is selected from the group consisting essentially of theophylline, salbutamol, salmeterol, mometasone, fluticasone, ariflo, montelukast, sulfasalazine, aminosalicylates, cyclosporines, FK-506, rapamycin, cyclophosphamide, methotrexate, and interferon.

51. A method of treating or preventing inflammatory, autoimmune or respiratory diseases by inhibiting VLA-4 mediated cell adhesion and subsequent consequent or related pathological processes, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (1.0.0) as described in claim 1 or a pharmaceutical composition as described in claim 46.

52. The method of claim 51, wherein said inflammatory, autoimmune or respiratory disorder is selected from the group consisting essentially of asthma, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, host rejection following organ transplantation, atherosclerosis, and other disorders mediated by or associated with VLA-4.

53. A compound capable of being converted in vivo to a compound of claim 1.