# Patent

## Title
Substituted B-amino acid derivatives as CXCR3 receptor antagonists

## Abstract

The present invention relates to compounds of formula 1




that are useful for the preventive and/or therapeutic treatment of diseases caused by abnormal activation of CXCR3 chemokines. The invention relates furthermore to a process for the preparation of said compounds, to pharmaceutical compositions containing said compounds and to novel intermediates used in the preparation of said compounds.

## Background
The present invention relates to compounds that are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of diseases caused by abnormal activation of CXCR3 chemokines.
Chemokines are a large family of small soluble proteins of about 8 to 10 kDa in size. One of the major roles of chemokines is to direct the migration of immune cells. The mechanism by which the movement of cells is guided is the chemical attraction of the cells expressing the relevant chemokine receptor on their surface toward the concentration gradient of the corresponding chemokine.
Some chemokines are homeostatic in function as they regulate the trafficking of cells in a day to day manner. Such homeostatic chemokines, for example direct the homing of lymphocytes to the lymph nodes or they have effect on development by promoting or inhibiting the growth of new blood vessels—thus exerting angiogenic or angiostatic effects.
Other chemokines are expressed in response to inflammation or injury. These inflammatory chemokines regulate the recruitment of specific leukocyte populations into the inflamed tissue that in turn they can elicit the release of specific regulatory and enzymatic factors from the activated immune cells. The expression of these inflammatory chemokines is typically induced by interleukin-1 (IL-1) or interferon-γ (IFN-γ) from various types of cells.
Chemokines exert their function via binding to specific chemokine receptors that are expressed on the cell surface. The chemokine receptors are about 340-360 amino acids long, and they belong to the G-protein coupled receptor (GPCR) super family. To date, approximately 50 chemokines have been identified. Many of them can bind to the same receptor and particular chemokines can also bind to several chemokine receptors. Presently we know altogether 20 different chemokine receptors for these 50 known chemokines [Groom, J. R. and Luster, A. D. 2011. Immunology and Cell Biology, 1-9]. More recently different splice variants have also been described for some chemokine receptors that may have different expression patterns and different physiological or pathophysiological roles.
CXCR3 is an inflammatory chemokine receptor which is predominantly expressed on activated immune cells such as the CD4+ (Th1 helper) and CD8+ (CTL cytotoxic or Tc) T lymphocytes. CXCR3 is absent on naïve T lymphocytes, but its cell surface expression is rapidly induced following T cell activation by dendritic cells. CXCR3 is also expressed on innate lymphocytes such as natural killer cells (NK) and NKT cells, on plasmacytoid dendritic cells (pDC) [Groom, J. R. and Luster, A. D. 2011. Immunology and Cell Biology, 1-9], on inflammatory neutrophils and macrophages.
CXCR3 is selectively activated by three interferon-inducible chemokines, CXCL9 (also termed as Mig), CXCL10 (IP-10) and CXCL11 (I-TAC). Activation of CXCR3 by these endogenous agonists elicits intracellular Ca2+ mobilization via phospholipases C (PLC) and, in addition, activation of both mitogen-activated protein kinase (MAP-kinase) and PI3-kinase [Liu, M; Guo, S; Hibbert, J. M; Jain, V; Sinh, N Wilson, N. O; and Stiles, J. K. 2011. Cytokine & Growth Factor Reviews, 22: 121-130.]. These intracellular events finally result in stimulation of lymphocyte migration and proliferation. CXCR3 plays a key role in selective recruitment of activated immune cells to the site of inflammation. Once recruited, cytotoxic T cells (CTL), through the release of perforin and granzyme B, induce apoptosis, thereby contributing to local tissue damage and subsequent remodelling. At the site of inflammation the recruited Th1 and CTL cells release IFN-gamma that stimulates epithelial cells and macrophages to further release of CXCR3 agonists that leads to a persistent inflammatory activation.
Strong Th1 and CTL responses are beneficial during acute infection, but these responses must be counterbalanced to prevent unwanted tissue destruction and chronic immunopathological changes [Groom, J. R. and Luster, A. D. 2011. Experimental Cell Research 317: 620-631]. In this respect CXCR3 antagonists are suggested to have significant therapeutic relevance.
More recent studies demonstrated that CXCR3 is also expressed on human CD25+FOXP3+ regulatory CD4+ T cells (Treg) and the level of CXCR3 increases on Treg cells following activation [Vandercappellen, J et al, 2011. Cytokine & Growth Factor Reviews 22: 1-18.]. This observation suggests that CXCR3 may participate in mediation of trafficking of Treg cells. Treg cells migrate to the peripheral sites of inflammation, where they exert suppressive activity on CD4+ Th1 and CD8+ CTL cells [Hoerning, A et al 2011. Eur J Immunol, online manuscript, accepted: Apr. 26, 2011. DOI: 10.1002/eji.201041095]. Thus Treg cells are important for suppressing the immune responses, maintaining immune tolerance and preventing autoimmune responses.
For the time being little is known about the expression pattern of CXCR3 on Treg subsets or the association of CXCR3 with Treg immunoregulatory functions. However, this finding may explain some reported variable functional effects of CXCR3 blockade in different animal models [Hoerning, A et al 2011. Eur J Immunol, online manuscript, accepted: Apr. 26, 2011. DOI: 10.1002/eji.201041095] or the variable effects of CXCR3 blockade in different types of allograft rejection.
As of today, there are three splice variants for CXCR3 described in humans: CXCR3-A, CXCR3-B [Romagnani, P; Lasagni, L; Annunziato, F; Serio, M. and Romagnani, S. 2004. TRENDS in Immunology, 25: 201-209.] and CXCR3-alt. CXCR3-A is the most abundant variant, it couples to Gi/o type of G-proteins and it mediates chemotaxis and cell proliferation.
The splice variant CXCR3-B is thought to be expressed on endothelial and vascular smooth muscle cells and mediates angiostatic effects [Strieter, R. M; Burdick, M. D; Gomperts, B. N; Belperio, A.; Keane, M. P. 2011. Cytokine & Growth Factor Reviews 16:593-609.]. CXCR3-B can bind not only the three well known CXCR3 agonists, CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC) but also a forth one, CXCL4 (PF-4), which is a selective, CXCR3-B specific chemokine agonist. Activation of CXCR3-B is supposed to mediate the activation of the Gs, the stimulatory type of G-proteins that in turn causes an intracellular cAMP rise, which finally results in angiostatic effects and inhibition of cell proliferation. More recent studies, however, showed that the alternative CXCR3-B splice variant does not exist in mice [Campanella, G. S. V; Colvin, R. A; and Luster, A. D. 2010. PLoS ONE 5(9): e12700. doi:10.1371/journal.pone.0012700] and, in addition to it, the same authors in their experiments with human endothelial cells also demonstrated that CXCL10 can inhibit endothelial cell proliferation independently of CXCR3 receptors. As of today, there are some controversial observations on the putative roles of the different alternative CXCR3 splice variants and thus further studies are still needed in order to clarify and understand their physiological and pathophysiological roles.
On the other hand, it is widely accepted that T lymphocytes play crucial regulatory function in the immune system [Wijtmans, M; Verzijl, D; Leurs, R; de Esch, I. J. P; and Smit, M. J. 2008. ChemMedChem. 3:861-872.] and [Müller, M; Carter, M. J; Hofert, J; and Campbell, I. L. 2010. Neuropathology and Applied Neurobiology, 36:368-387.]. Their special roles are also indicated by the fact that 15 chemokine receptors out of the 20 known ones, are expressed among the different subpopulations of T lymphocytes [Pease and Williams, Br. J. Pharmacol. 2006. 147, S212]. T cells are implicated in many inflammatory diseases.
Clinical evidences showed significant overexpression of CXCR3 receptor and/or its endogenous agonists (CXCL10, CXCL11) in multiple autoimmune or inflammatory diseases, such as e.g.

    (i) in peripheral airways of COPD patients [Donnelly, L. E. and Barnes, P. J. Trends in Pharmacol Sci 27(10): 564-553.],
    (ii) in skin biopsies from patients with moderate to severe psoriasis [Chen, S-C; Groot, M.; Kinsley, D; Laverty, M; McClanahan, T; Arreaza, M; Gustafson, E. L; Teunissen, M. B. M; Rie, M. A; Jay, S. F; and Kraan, M. 2010. Arch. Dermatol. Rev. 302: 113-123],
    (iii) in lymph nodes and islets of type 1 diabetic patients [Uno, S; Imagawa, A; Saisho, K; Okita, K; Iwahashi, H; Hanafusai, T; and Shimomura, I. 2010. Endocrine Journal. 57(11): 991-996.]
    (iv) in acute allograft rejection (lung, heart, kidney and skin grafts) [Wenczel, J. Lucas, S; Zahn, S; Mikus, S; Metze, D; Stadter, S, et al, 2008. J. Am. Acad. Dermatol. 58:437-442.]
    (v) in colon biopsies of patients with ulcerative colitis [Singh, U. P. Singh, R; Singh, S; Karls, R. K; Quinn, F. D; Taub, D. D; and Lillard Jr J. W. 2008. BMC Immunology 9:25]
    and (vi) in thymus from myasthenia gravis patients [Pease, J. E and Horuk, R. 2009. Expert Opin Ther Patents, 19 (2): 199-221].


In animals, CXCR3-KO mice display blocked T cell migration into bronchoalveolar space following noxious stimuli such as cigarette smoke (murine model of COPD). CXCL10-gene deficient or CXCR3-KO mice showed prolonged allograft survival in murine models of transplant rejection (cardiac and pancreatic island allografts).
Blocking the activation of CXCR3 by antagonists represents a possible approach for the treatment of diseases such as COPD [Hansel, T. T. and Barnes, P. J. 2009. Lancet, 374:744-755], psoriasis [Krueger, J. G. and Bowcock, A. 2005. Ann. Rheum. Dis. 64: Suppl.II.: ii30-ii36.], graft/transplant rejection [Hancock, W. W; Lu, B; Gao, W; Cziszmadia, V; Faia, K; King, J. A; Smileey, S. T; Ling, M; Gearad, N. P; and Gerard, C. 2000. J Exp Med 192:1515-1519.], ophthalmological diseases [Sorensen, T. L; Roed, H; Sellebjerg, F. 2004. Br. J. Opthalmol. 88:1146-1148.], celiac disease [Lammers, K. M; Khandelwal, S; Chaudhry, F; Kryszak, D; Puppa, E. L; Casolaro; V; and Fasano, A. 2010. Immunology, 132:432-440.], inflammatory bowel disease (IBD) [Nishimura, M; Kuboi, Y; Muramato, K; Kawano, T; and Imai, T. 2009. Autoimmunity: Ann N.Y. Acad. Sci. 1173:350-356.], type 1 diabetes [Shimida, A; Oikawa, Y; Yamada, Y; Okubo, Y; and Narumi, S. 2009. Review of Diabetic Studies, 6(2): 81-84], myasthenia gravis (MG) [Pease, J. E and Horuk, R. 2009. Expert Opin Ther Patents, 19 (2): 199-221], multiple sclerosis (MS) and other neuroinflammatory diseases [Müller, M; Carter, M. J; Hofert, J; and Campbell, I. L. 2010. Neuropathology and Applied Neurobiology, 36:368-387.], lupus [Lacotte, S; Brun, S; Muller, S; and Dumortier, H. 2009. Autoimmunity: Ann N.Y. Acad. Sci. 1173:310-317.], rheumatoid arthritis (RA) [Brightling, C; Ammit, A. J; Kaur, D; Black, J. L; Wardlaw, A. J; Hughes, J. M; and Bradding, P. 2005. Am J Respir Crit Care Med. 171: 1103-1108.], lichen planus [Meller, S; Gillier, M; and Homey, B. 2009. J. Investigative Dermatology. 129: 315-319.].
Targeting CXCR3 appears a more straightforward way to treat the condition as this abrogates the effects of all three endogenous CXCR3 chemokines at the same time.
Assorted patent applications and granted patents disclose inhibitors of chemokines or CXCR3 receptor, such as WO2003087063, WO200604924, WO2009094168 and WO2009105435 but the known compounds are structurally very different from the compounds according to the present invention.
We aimed to prepare new CXCR3 receptor antagonist compounds, which have strong antagonistic effect and are selective to the CXCR3 receptor. We also aimed that the stability, bioavailability, metabolism, therapeutic index, toxicity and solubility of the new compounds allow their development into a drug substance. A further aim was that the compounds, due to their favourable enteric absorption, can be administered orally.
Thus, the inventors of the present invention have identified compounds represented by the following formula 1 possessing inhibitory activity against CXCR3 receptors.
The present invention thus provides a compound of formula 1




    
    
        wherein
    
    
    R represents hydrogen, C1-4 alkyl, C3-8 cycloalkyl, C1-4 halogenalkyl or halogenphenyl group;
    R′ represents H, or
    R and R′ represent together with the carbon atom attached a C4 aliphatic ring;
    R1 represents a group selected from the group consisting of






    
    
        wherein
        
            A represents a direct bond or CH2, CH(CH3), C(CH3)2 or C(CH2)2 group;
            R2 represents Cl, Me or CF3;
            R3 represents H, Cl or F;
            R4 represents H or C1-4 alkyl group;
            R5 represents heteroaryl group selected from the group consisting of
        
        
    
    






    X represents O, S or CH2 group;
    Y represents hydrogen, halogen, C1-4 alkyl C1-4 alkoxy or C1-4 hydroxyalkyl group;
    Z represents a C1-4 aliphatic hydrocarbon bridge optionally containing one double bond, and/or one or more heteroatom selected from O, S, NH and N(CH3) or represents a C2-4 aliphatic hydrocarbon bridge optionally containing N fused with a C3-6 cycloalkyl ring optionally containing one or more double bond or with a phenyl ring or represents a C1-4 aliphatic hydrocarbon bridge substituted with a spiro C3-6 cycloalkyl ring optionally containing one or more double bond;
    or a pharmaceutically acceptable salt thereof, stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


According to another aspect of the present invention, there is provided a process for the preparation of a compound of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer, comprising the steps of reductive amination of a benzaldehyde of formula 4




    
    
        wherein X, Y and Z have the meaning as defined above—

with a primary amine of formula 5

R1—NH2   5

        wherein R1 has the meaning as defined above—

reacting the obtained secondary amine of formula 2

    
    






    
    
        wherein X, Y, Z and R1 have the meaning as defined above—

with an aldehyde or cycloalkylketone of formula 3

    
    






    
    
        wherein R and R′ have the meaning as defined above—

and optionally hydrolyzing the obtained ester of formula 1.

    
    


According to another aspect of the present invention there is provided a pharmaceutical composition containing at least one compound of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer and at least one pharmaceutically acceptable excipient.
According to a further aspect the present invention is directed to the compounds of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer for use in the preventive and/or therapeutic treatment of a CXCR3 receptor mediated disease or disorder, especially of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) and lichen planus.
In addition the present invention is directed to a method of treating a CXCR3 receptor mediated disease or disorder, especially of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) and lichen planus comprising administering an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer to a patient in need thereof.
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, are to be understood to have the following meanings:
The C1-4 alkyl group represents a straight or branched alkyl group having 1 to 4 carbon atoms, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and the like.
The C1-4 alkoxy group represents an above identified alkyl group having 1 to 4 carbon atoms and attached through an oxygen atom, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and the like.
The C1-4 hydroxyalkyl group represents an above identified alkyl group having 1 to 4 carbon atoms and bearing one or more hydroxy group, for example, hydroxymethyl group, 1-hydroxy-ethyl group, 2-hydroxy-ethyl group, 1-, 2- or 3-hydroxy-n-propyl group, 1- or 2-hydroxy-isopropyl group, and the like
The C3-8 cycloalkyl group represents a cyclic alkyl group having 3 to 8 carbon atoms in the ring, for example cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctyl group.
The halogen atom represents a fluorine, chlorine, bromine or iodine atom.
The C1-4 halogenalkyl group represents an above identified alkyl group having 1 to 4 carbon atoms and bearing one or more halogen atom, such as fluorine, chlorine, bromine or iodine atom, particularly fluorine or chlorine atom, for example chloromethyl group, fluoromethyl group, 1- or 2-chloro- or -fluoro-ethyl group, 1-, 2- or 3-chloro- or -fluoro-proyl group, 1- or 2-dichloro- or -difluoro-ethyl group, 1-, 2- or 3-dichloro- or -difluoro-propyl group, 1-trichloro- or -trifluoro-ethyl group or 1-trichloro- or -trifluoro-propyl group and the like.
The halogenphenyl group represents a phenyl moiety bearing on the ring one or more halogen atom, such as fluorine, chlorine, bromine or iodine atom, particularly fluorine or chlorine atom in any position, for example o-, m- or p-chloro-phenyl group, o-, m- or p-fluoro-pehnyl group, 2,3-, 2,4- or 2,5-dichloro- or -difluoro-phenyl group, 2,3,4-, 2,4,5- or 3,4,5-trichloro- or -trifluoro-phenyl group, 2-chloro-3-, -4- or -5-fluoro-phenyl group or 2-fluoro-3-, -4- or -5-chloro-phenyl group and the like.
The C4 aliphatic ring represents a cyclobutyl ring.
The C(CH2)2 group means 1,1-cyclopropanediyl group
The C1-4 aliphatic hydrocarbon bridge optionally containing one double bond and/or one or more heteroatom selected from O, S, NH and N(CH3) means an alkandiyl group having 1 to 4 carbon atoms and optionally containing one double bond and/or one or more heteroatom selected from O, S, NH and N(CH3), for example —CH2—CH2—, —CH2—O—, —CH2—S—, —CH2—NH—, —CH2—N(CH3)—, —CH2—CH2—CH2—, —CH═CH—N(CH3)—, —N═CH—N(CH3)—, and the like.
The C2-4 aliphatic hydrocarbon bridge optionally containing N fused with a C3-6 cycloalkyl ring optionally containing one or more double bond or with a phenyl ring means an alkandiyl group having 2 to 4 carbon atoms which optionally contains N as heteroatom, and which is fused with a cycloalkyl ring having 3 to 6 carbon atoms and optionally containing one or more double bond or with a phenyl ring for example —CH(CH2)CH—,




The C1-4 aliphatic hydrocarbon bridge substituted with a spiro C3-6 cycloalkyl ring optionally containing one or more double bond means an alkandiyl group having 1 to 4 carbon atoms and substituted with a spiro cycloalkyl ring having 3 to 6 carbon atoms and optionally containing one or more double bond, means for example




By salts of the compounds of the formula 1 we mean salts formed with inorganic and organic acids. Preferred salts are those given with pharmaceutically acceptable acids as for instance hydrochloric acid, and the like. The salts formed during purification or isolation are also subject of the invention.
The compounds represented by the aforementioned formula 1 may have one or more asymmetric carbon atoms. Thus, they can exist in the form of optical isomers, enantiomers or diastereoisomers. These optical isomers, enantiomers and diastereoisomers as well as their mixtures, including the racemates, are also subject of the invention.
An embodiment of the invention includes the compound of formula 1 wherein

    
    
        R represents hydrogen, C1-4 alkyl, C3-8 cycloalkyl, C1-4 halogenalkyl or halogenphenyl group;
        R′ represents hydrogen or
        R and R′ represent together with the carbon atom attached a C4 aliphatic ring;
        R1 represents a group selected from the group consisting of
    
    






    
    
        wherein
        
            A represents a direct bond or CH2, CH(CH3), C(CH3)2 or C(CH2)2 group;
            R2 represents Cl, Me or CF3;
            R3 represents hydrogen, Cl or F;
            R4 represents hydrogen or C1-4 alkyl group;
            R5 represents heteroaryl group selected from the group consisting of
        
        
    
    






    X represents O, S or CH2 group;
    Y represents halogen, C1-4 alkyl or C1-4 alkoxygroup;
    Z represents (CH2)2, CH2N(CH)3 or CH═CH—N(CH3) group;
    or a pharmaceutically acceptable salt thereof, stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Another embodiment of the invention includes a compound of formula 1, wherein R4 represents hydrogen, or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the invention includes a compound of formula 1, wherein R1 represents a group selected from the group consisting of




    wherein A represents CH2 group;
    
        R2 represents Cl, Me or CF3;
        R3 represents hydrogen, Cl, or F;
        R4 represents hydrogen;
    
    
    or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Another embodiment of the invention includes a compound of formula 1, wherein R1 represents a group selected from the group consisting of




    wherein R2 represents Cl;
    
        R3 represents hydrogen, Cl, or F;
        R4 represents hydrogen;
    
    
    or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Another embodiment of the invention includes a compound of formula 1, wherein X represents an O atom- or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the invention includes a compound of formula 1, wherein Y represents halogen, CH3, C2H5 or OCH3 group or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the invention includes a compound of formula 1, wherein Y represents Cl, F, CH3, C2H5 or OCH3 group or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the invention includes a compound of formula 1, wherein Z represents (CH2)2CH2N(CH3), CH═N(CH3) group or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer. Another embodiment of the invention includes a compound of formula 1, wherein Z represents (CH2)2 group or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.
Another embodiment of the invention includes a compound of formula 1, wherein
R represents hydrogen, C1-4 alkyl group, C3-6 cycloalkyl or fluorophenyl group;
R′ represents hydrogen;

    or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


An other embodiment of the invention includes a compound of formula 1, wherein

    R represents hydrogen, C1-4 alkyl, C3-6 cycloalkyl or fluorophenyl group;
    R′ represents hydrogen;
    R1 represents a group selected from the group consisting of






    wherein A represents CH2 group;
    
        R2 represents Cl, Me or CF3;
        R3 represents hydrogen, Cl, or F;
        R4 represents hydrogen;
    
    
    X represents O, S or CH2 group;
    Y halogen, CH3, C2H5 or OCH3 group;
    Z represents (CH2)2, CH2N(CH)3 or CH═CH—N(CH3) group;
    or a pharmaceutically acceptable salt thereof, stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


Particularly compounds of the present invention represented by formula 1 include compounds selected from the group consisting of:

    1. 3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    1.1 3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethoxy-benzyl}-isobutyl-amino)-propionic acid ethyl ester naphthalene-1,5-disulfonic acid salt
    2. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    3. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid
    4. 3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    5. (S)-3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    6. (R)-3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    7. 3-(4-Chloro-phenyl)-3-(cyclobutyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    8. 1-[(4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-methyl]-cyclopropanecarboxylic acid
    9. (S)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid
    10. (R)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid
    11. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid; hydrochloride
    12. (R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid; hydrochloride
    13. (S)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride
    14. (R)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride
    15. (S)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropyl-ethyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid; hydrochloride
    16. (R)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropyl-ethyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid; hydrochloride
    17. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    18. (R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    19. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid; hydrochloride
    20. (R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid; hydrochloride
    21. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid; hydrochloride
    22. (R)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid; hydrochloride
    23. (S)-3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    24. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid; hydrochloride
    25. (R)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid; hydrochloride
    26. (S)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    27. (R)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    28. (S)-3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    29. (R)-3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    30. (S)-3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    31. (R)-3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    32. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    33. (R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    34. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    35. (R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    36. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    37. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid
    38. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    39. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    40. 3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    41. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid
    42. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    43. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid
    44. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    45. 3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    46. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid
    47. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    48. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    49. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    50. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    51. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid
    52. (R)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-propionic acid
    53. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid
    54. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    55. (R)-3-(4-Chloro-phenyl)-3-(cyclobutylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid
    56. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid
    57. 3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid
    58. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-propionic acid
    59. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid
    60. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid
    61. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid
    62. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-propionic acid
    63. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid
    64. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    65. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    66. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    67. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-ethyl-amino)-propionic acid
    68. 3-(4-Chloro-phenyl)-3-(cyclobutyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    69. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid
    70. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    71. (S)-3-(4-Chloro-phenyl)-3-(cyclobutylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    72. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    73. 3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    74. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    75. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid
    76. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid
    77. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    78. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    79. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid
    80. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid
    81. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    82. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    83. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    84. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    85. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-propionic acid
    86. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-isobutyl-amino)-propionic acid
    87. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    88. (S)-3-(4-Chloro-phenyl)-3-(cyclobutylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    89. 3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    90. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    91. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-propionic acid
    92. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-isobutyl-amino)-propionic acid
    93. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid
    94. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    95. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    96. 3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    97. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-propionic acid
    98. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-isobutyl-amino)-propionic acid
    99. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    100. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    101. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    102. 3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid; hydrochloride
    103. 3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-3-(4-chloro-phenyl)-propionic acid
    104. (S)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclobutylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid
    105. 3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid
    106. 3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropylmethyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride
    107. 3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    108. (S)-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-(3,4-dichloro-phenyl)-acetic acid
    109. (S)-(3,4-Dichloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-acetic acid
    110. (R)-(3,4-Dichloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-acetic acid
    111. (R)-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-(3,4-dichloro-phenyl)-acetic acid
    112. 3-(4-Chloro-phenyl)-3-(ethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    113. 3-(4-Chloro-phenyl)-3-({3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid
    114. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    115. 3-(4-Chloro-phenyl)-3-(ethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    116. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    117. 3-(4-Chloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid
    118. 3-(Butyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    119. 3-(4-Chloro-phenyl)-3-(cyclobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    120. 3-(Cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    121. 3-(2,3-Dihydro-benzofuran-5-yl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    122. 3-(Butyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    123. 3-(2,3-Dihydro-benzofuran-5-yl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid
    124. 3-(Cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    125. 3-(3,4-Dichloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid
    126. 3-(3,4-Dichloro-phenyl)-3-(ethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    127. 3-(Cyclopentylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    128. 3-(Cyclohexylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    129. 3-(4-Chloro-phenyl)-3-[{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid
    130. 3-(4-Chloro-phenyl)-3-[{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid
    131. 3-(Cyclopropylmethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    132. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-propionic acid
    133. 3-(4-Chloro-phenyl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-propyl-amino)-propionic acid
    134. 3-(4-Chloro-phenyl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    135. 3-(Butyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    136. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-propionic acid
    137. 3-(4-Chloro-phenyl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-isobutyl-amino)-propionic acid
    138. 3-(4-Chloro-phenyl)-3-(cyclobutyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-propionic acid
    139. 3-(Cyclopentylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    140. 3-(Butyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    141. 3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    142. 3-(Cyclopropylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    143. 3-(Cyclohexylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    144. 3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid
    145. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    146. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    147. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    148. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    149. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    150. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid
    151. 3-(2,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    152. 3-(4-Chloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-methyl-amino)-2-methyl-propionic acid
    153. 3-(4-Chloro-phenyl)-3-(ethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-2-methyl-propionic acid
    154. 3-(2,3-Dihydro-benzofuran-5-yl)-3-(ethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    155. 3-(2,3-Dihydro-benzofuran-5-yl)-3-({3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid
    156. 3-(Cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid
    157. 3-(4-Chloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid
    158. 3-(2,3-Dihydro-benzofuran-5-yl)-3-(isobutyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    159. 3-(2,4-Dichloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid
    160. 3-(Cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    161. 3-(Butyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    162. 3-(2,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid
    163. 3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid
    164. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid
    165. 3-(4-Chloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-(4-fluoro-benzyl)-amino]-propionic acid; hydrochloride
    166. 3-(4-Chloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-(4-fluoro-benzyl)-amino]-propionic acid; hydrochloride
    167. 3-(3,4-Dichloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid
    168. 1-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-5-chloro-indan-2-carboxylic acid
    169. 5-Chloro-1-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-indan-2-carboxylic acid
    170. 5-Chloro-1-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-indan-2-carboxylic acid
    171. 5-Chloro-1-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-indan-2-carboxylic acid
    172. 5-Chloro-1-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-indan-2-carboxylic acid
    173. 1-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-5-chloro-indan-2-carboxylic acid
    174. 5-Chloro-1-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-indan-2-carboxylic acid
    175. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-ethyl-amino)-2-methyl-propionic acid
    176. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-ethyl-amino)-2-methyl-propionic acid
    177. 3-(Butyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    178. 3-({4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-3-p-tolyl-propionic acid
    179. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-p-tolyl-propionic acid
    180. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-trifluoromethyl-phenyl)-propionic acid
    181. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-trifluoromethyl-phenyl)-propionic acid
    182. (4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-ethyl-amino)-acetic acid
    183. (4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-acetic acid
    184. Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-(4-chloro-phenyl)-acetic acid
    185. (4-Chloro-phenyl)-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-acetic acid
    186. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-2-methyl-propionic acid
    187. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-2-methyl-propionic acid
    188. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid
    189. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid
    190. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid
    191. 3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    192. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-propyl-amino)-propionic acid
    193. 3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    194. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-2-methyl-propionic acid
    195. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-2-methyl-propionic acid
    196. 1-[(4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-methyl]-cyclopropanecarboxylic acid
    197. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-ethyl-amino)-2,2-dimethyl-propionic acid
    198. (S)-3-(Cyclohexylmethyl-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride
    199. (S)-3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    200. (S)-3-(Cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride
    201. (R)-3-({3-Chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-cyclopentylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid
    202. (R)-3-({3-Chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-cyclohexylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid
    203. 3-(5-Chloro-thiophen-2-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid
    204. 3-(2,5-Dimethyl-thiophen-3-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid; hydrochloride
    or a pharmaceutically acceptable salt thereof or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


A particular group of the compounds of the present invention represented by formula 1 include compounds selected from the group consisting of:

    1. 3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    2. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    3. (S)-3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    4. (S)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid
    5. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid; hydrochloride
    6. (S)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride
    7. (S)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropyl-ethyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid; hydrochloride
    8. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    9. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid; hydrochloride
    10. (S)-3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    11. (S)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid; hydrochloride
    12. (S)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    13. (R)-3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    14. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    15. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid
    16. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    17. 3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    18. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid
    19. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid
    20. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid
    21. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid
    22. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    23. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid
    24. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid
    25. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid
    26. 3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    27. 3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-isobutyl-amino)-propionic acid
    28. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid
    29. 3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    30. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid
    31. 3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-propionic acid
    32. 3-(Cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    33. 3-(Cyclopentylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    34. 3-(Cyclopropylmethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    35. 3-(Cyclopentylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    36. 3-(Butyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    37. 3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid
    38. 3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    39. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    40. 3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    41. 3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid
    42. 3-(2,3-Dihydro-benzofuran-5-yl)-3-(ethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid
    43. 3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid
    44. 3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid
    45. 3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid
    or a pharmaceutically acceptable salt thereof or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.


A further embodiment of the invention includes compounds of formula 2




    
    
        wherein
    
    
    R1 represents a group selected from the group consisting of;






    
    
        wherein
        
            A represents a direct bond or, CH2, CH(CH3), C(CH3)2 or C(CH2)2 group;
            R2 represents Cl, Me or CF3;
            R3 represents H, Cl, or F;
            R4 represents Me or Et group;
            R5 represents heteroaryl group selected from the group existing of
        
        
    
    






    X represents O, S or CH2 group;
    Y represents halogen, C1-4 alkyl, or C1-4 alkoxy group;
    Z represents (CH2)2, CH2N(CH)3 or CH═CH—N(CH3) group;
    or a salt thereof.


The intermediates of general formula 2 listed in Table 1 are prepared.









TABLE 1





Example
Structure
Chemical name

















2.1.




3-(2,3-Dihydro-benzofuran-5- yl)-3-{4-[2-(2,5-dioxo- pyrrolidin-1-yl)-ethoxy]-3- methoxy-benzylamino}- propionic acid ethyl ester


 


2.2.




3-(4-Chloro-phenyl)-3-{4-[2- (2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-methoxy- benzylamino}-propionic acid ethyl ester


 


2.3.




3-(2,4-Dichloro-phenyl)-3-{4- [2-(2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-methoxy- benzylamino}-propionic acid ethyl ester


 


2.4.




3-(4-Chloro-phenyl)-3-{3- methoxy-4-[2-(3-methyl-2,6- dioxo-3,6-dihydro-2H- pyrimidin-1-yl)-ethoxy]- benzylamino}-propionic acid ethyl ester


 


2.5.




3-(2,3-Dihydro-benzofuran-5- yl)-3-{4-[2-(2,5-dioxo- pyrrolidin-1-yl)-ethoxy]-3- methyl-benzylamino}- propionic acid ethyl ester


 


2.6.




3-(2,3-Dihydro-benzofuran-5- yl)-3-{3-methyl-4-[2-(3- methyl-2,6-dioxo-3,6-dihydro- 2H-pyrimidin-1-yl)-ethoxy]- benzylamino}-propionic acid ethyl ester


 


2.7.




3-(4-Chloro-phenyl)-3-{3- methyl-4-[2-(3-methyl-2,6- dioxo-3,6-dihydro-2H- pyrimidin-1-yl)-ethoxy]- benzylamino}-propionic acid ethyl ester


 


2.8.




3-(2,3-Dihydro-benzofuran-5- yl)-3-{3-methoxy-4-[2-(3- methyl-2,6-dioxo-3,6-dihydro- 2H-pyrimidin-1-yl)-ethoxy]- benzylamino}-propionic acid ethyl ester


 


2.9.




3-(3,4-Dichloro-phenyl)-3-{3- methoxy-4-[2-(3-methyl-2,6- dioxo-3,6-dihydro-2H- pyrimidin-1-yl)-ethoxy]- benzylamino}-propionic acid ethyl ester


 


2.10.




3-(2,3-Dihydro-benzofuran-5- yl)-3-{4-[3-(2,5-dioxo- pyrrolidin-1-yl)-propyl]-3- methoxy-benzylamino}- propionic acid ethyl ester


 


2.11.




3-(4-Chloro-3-fluoro-phenyl)- 3-{4-[2-(2,5-dioxo-pyrrolidin- 1-yl)-ethoxy]-3-methoxy- benzylamino}-propionic acid ethyl ester


 


2.12.




3-(3,4-Dichloro-phenyl)-3-{4- [2-(2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-methoxy- benzylamino}-propionic acid ethyl ester


 


2.13.




3-(4-Chloro-phenyl)-3-{4-[2- (2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-fluoro- benzylamino}-propionic acid ethyl ester


 


2.14.




3-(4-Chloro-3-fluoro-phenyl)- 3-{4-[2-(2,5-dioxo-pyrrolidin- 1-yl)-ethoxy]-3-fluoro- benzylamino}-propionic acid ethyl ester


 


2.15.




3-(3,4-Dichloro-phenyl)-3-{4- [2-(2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-fluoro- benzylamino}-propionic acid ethyl ester


 


2.16.




3-(4-Chloro-phenyl)-3-{4-[2- (2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-methyl- benzylamino}-propionic acid ethyl ester


 


2.17.




3-(4-Chloro-3-fluoro-phenyl)- 3-{4-[2-(2,5-dioxo-pyrrolidin- 1-yl)-ethoxy]-3-methyl- benzylamino}-propionic acid ethyl ester


 


2.18.




3-(3,4-Dichloro-phenyl)-3-{4- [2-(2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-methyl- benzylamino}-propionic acid ethyl ester


 


2.19.




3-{3-Chloro-4-[2-(2,5-dioxo- pyrrolidin-1-yl)-ethoxy]- benzylamino}-3-(4-chloro- phenyl)-propionic acid ethyl ester


 


2.20.




3-{3-Chloro-4-[2-(2,5-dioxo- pyrrolidin-1-yl)-ethoxy]- benzylamino}-3-(4-chloro-3- fluoro-phenyl)-propionic acid ethyl ester


 


2.21.




3-{3-Chloro-4-[2-(2,5-dioxo- pyrrolidin-1-yl)-ethoxy]- benzylamino}-3-(3,4-dichloro- phenyl)-propionic acid ethyl ester


 


2.22.




3-(4-Chloro-phenyl)-3-{4-[2- (2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-ethyl-benzylamino}- propionic acid ethyl ester


 


2.23.




3-(4-Chloro-3-fluoro-phenyl)- 3-{4-[2-(2,5-dioxo-pyrrolidin- 1-yl)-ethoxy]-3-ethyl- benzylamino}-propionic acid ethyl ester


 


2.24.




3-(3,4-Dichloro-phenyl)-3-{4- [2-(2,5-dioxo-pyrrolidin-1-yl)- ethoxy]-3-ethyl-benzylamino}- propionic acid ethyl ester


 


2.25.




3-{4-[2-(2,5-Dioxo-pyrrolidin- 1-yl)-ethoxy]-3-methyl- benzylamino}-3-p-tolyl- propionic acid ethyl ester


 


2.26.




3-{4-[2-(2,5-Dioxo-pyrrolidin- 1-yl)-ethoxy]-3-methyl- benzylamino}-3-p-tolyl- propionic acid ethyl ester


 


2.27.




3-(4-Chloro-phenyl)-3-{4-[2- (2,5-dioxo-pyrrolidin-1-yl)- ethylsulfanyl]-3-methoxy- benzylamino}-propionic acid ethyl ester


 


2.28.




3-(4-Chloro-3-fluoro-phenyl)- 3-{4-[2-(2,5-dioxo-pyrrolidin- 1-yl)-ethylsulfanyl]-3- methoxy-benzylamino}- propionic acid ethyl ester


 


2.29.




3-(3,4-Dichloro-phenyl)-3-{4- [2-(2,5-dioxo-pyrrolidin-1-yl)- ethylsulfanyl]-3-methoxy- benzylamino}-propionic acid ethyl ester









General Procedures:

Starting materials and solvents used in the synthesis are obtained from chemical vendors such as ABCR, Aldrich, Acros, Apollo, Fluka, Netchem, Lancaster and others.
The crude product is purified by column chromatography or flash chromatography.
In first step the appropriate benzaldehydes (4=4a and 4b) are synthesized in different way depending on the side chain of dioxoamide derivatives. The synthesis of compound formula 4a, wherein X represents oxygen or sulphur atom is done by alkylation of 4-hydroxy- or 4-mercapto-benzaldehydes 6 with dibromoethane and dioxoamide (route via 6a, 7a) or bromo-ethyldioxoamide derivatives (route via 7) in the presence of a base, preferably K2CO3, TEA or sodium hydride using acetonitrile, DMF or MEK as solvent as described on Scheme 1.




Compounds of formula 4b, wherein X represents —CH2— is synthesized by two methods (Scheme 2):
1.) Appropriate aldehyde (6.1) is converted to a triflate (6.1a) then a triple-bound containing intermediate (4c), which is produced in a Sonogashira reaction (Sonogashira, K. et al. Tetrahedron Lett. 1975, 16 (50), 4467), is hydrogenated to saturated aldehyde (4b).
2.) Triflate (6.1a) is protected with ethyleneglycol (6.1b) and coupled in a Suzuki reaction (Suzuki, A. Tetrahedron Lett. 1979, 20 (36), 3437) then the formed vinyl intermediate (4d) is hydrogenated to saturated aldehyde (4b).




In second step synthesized benzaldehydes (4) are reacted with β-aminoacid esters or free acids (5) in mild reductive amination conditions (sodium triacetoxy borohydride in THF or 2-picoline borane complex in EtOH). The resulted secondary amines (2) are reacted with different aldehydes (3, R′=H) or cyclic ketones (3, R and R′=aliphatic ring) in reductive amination step again, the formed esters (1, R4=Me, Et) are hydrolyzed in acidic circumstances. The crude I (R4=H) is purified by chromatography, crystallization or via salt formation (Scheme 3).
The pure enantiomers of 1 are synthesized via chiral separation from racemic 1 or using chiral β-aminoacid esters or acids (5) as starting materials.




Starting materials of formula 3, 5, 6, 7 and 8 are commercially available or can be prepared by known methods.
As mentioned above the compounds of formula 1 or a pharmaceutically acceptable salt, stereoisomer or a pharmaceutically acceptable salt of the stereoisomer can be used as active ingredient of a medicament in the preventive and/or therapeutic treatment of a CXCR3 receptor mediated disease or disorder, especially of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) and lichen planus.
As the active ingredient of the medicament of the present invention, a substance may be used which is selected from the group consisting of the compound represented by the aforementioned formula 1 and pharmacologically acceptable salts, or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer. The substance, per se, may be administered as the medicament of the present invention, however, it is desirable to administer the medicament in a form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient and one or more pharmaceutical additives. As the active ingredient of the medicament of the present invention, two or more of the aforementioned substances may be used in combination. The type of pharmaceutical composition is not particularly limited, and the composition may be provided as any formulation for oral or parenteral administration. For example, the pharmaceutical composition may be formulated, for example, in the form of pharmaceutical compositions for oral administration such as granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or in the form of pharmaceutical compositions for parenteral administrations such as injections for intravenous, intramuscular, or subcutaneous administration, drip infusions, transdermal preparations, transmucosal preparations, nasal drops, inhalants, suppositories and the like. Injections or drip infusions may be prepared as powdery preparations such as in the form of lyophilized preparations, and may be used by dissolving just before use in an appropriate aqueous medium such as physiological saline.
Types of pharmaceutical additives used for the manufacture of the pharmaceutical composition, content ratios of the pharmaceutical additives relative to the active ingredient, and methods for preparing the pharmaceutical composition may be appropriately chosen by those skilled in the art. Inorganic or organic substances, or solid or liquid substances may be used as pharmaceutical additives. Generally, the pharmaceutical additives may be incorporated in a ratio ranging from 1% by weight to 90% by weight based on the weight of an active ingredient.
The dose and frequency of administration of the medicament of the present invention are not particularly limited, and they may be appropriately chosen depending on conditions such as a purpose of preventive and/or therapeutic treatment, a type of a disease, the body weight or age of a patient, severity of a disease and the like. Generally, a daily dose for oral administration to an adult may be 0.01 to 1,000 mg (the weight of an active ingredient), and the dose may be administered once a day or several times a day as divided portions, or once in several days. When the medicament is used as an injection, administrations may preferably be performed continuously or intermittently in a daily dose of 0.001 to 100 mg (the weight of an active ingredient) to an adult.
The present invention will be explained more specifically with reference to the following examples, however, the scope of the present invention is not limited to these examples.
Unless otherwise stated, the following abbreviations have the stated meanings in the examples below:

    abs.=absolute
    AcOH=Acetic acid
    [(C6H5)3P]2PdCl2=Bis(triphenylphosphine)palladium(II) dichloride
    cc. HCl=concentrated hydrogen chloride solution
    CuI=copper1 iodide
    DCM=dichloromethane
    Diazald=N-methyl-N-nitroso-p-toluenesulfonamide
    DMF=N,N-dimethylformamide
    equiv.=equivalent
    Et=ethyl
    EtOH=ethanol
    Et2O=diethyl ether
    EtOAc=ethyl acetate
    HCCOH=formic acid
    HPLC=high performance liquid chromatography
    Ipam=isopropyl amine
    K2CO3=potassium carbonate
    K3PO4=potassium phosphate
    KBr=potassium bromide
    KOH=potassium hydroxide
    LC/MS=liquid chromatography-mass spectrometry
    MEK32 methyl-ethyl ketone
    Me=methyl
    MeOH=methanol
    NaHCO3=sodium bicarbonate
    Na2SO4=sodium sulfate
    NaBH(OAc)3=sodium triacetoxy borohydride
    nM=nanomole
    NaOH=sodium hydroxide
    NMR=nuclear magnetic spectroscopy
    Pd(OAc)2=palladium(II) acetate
    r.t.=room temperature
    TBAB=tetrabutylammonium bromide
    TEA=triethylamine
    THF=tetrahydrofuran
    TsOH=p-toluenesulfonic acid monohydrate


Analytical LC/MS is performed using Waters Alliance 2695+2996 PDA at 220 nm.
A system) MS:Waters LCT Premier XE; Column: Atlantis dC18 (3 μm) 2.1×50 mm; flow 0.7 ml/min of acetonitrile/water/0.05% TFA gradient in ESI+ mode
B system) MS: Micromass ZQ; Column: Purospher-STAR RP18e (3 μm) 4.6×55 mm; flow 1.6 ml/min of water/acetonitrile/20 mM NH4OH gradient or Xterra MS-C18 (3.5 μM) 2.1×50 mm; flow: 1.0 ml/min of water/acetonitrile/20 mM NH4OH gradient in ESI+ mode.
Preparative chiral HPLC is performed using Berger Prep SFC at 210 nm;
C system) Column: Chiralpack IC 250×21 mm (5 μm) Flow: 50 ml/min; CO2/[Methanol/+0.5% Ipam] 70%/30% (other circumstances are detailed in examples).
For structural confirmation NMR spectra are measured for all compounds as well. The NMR spectra are recorded on a Bruker Advance II 400 MHz spectrometer at ambient temperature in DMSO-d6 solution. The chemical shifts are referred to tetramethylsilane (δ, ppm). In some cases not only 1H but 13C, ed-HSQC, zqs-TOCSY and HMBC spectra are also recorded.


PRECURSOR PREPARATIONS
Intermediate 4.1
4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzaldehyde




A method: 6.85 g (45 mmol) of vanilline (6.1) and 10.2 g (49.5 mmol) 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione (7.1) is heated with 8.28 g (60 mmol) K2CO3 in 200 ml of acetonitrile under reflux for 15 h. Precipitated KBr is filtered off, the filtrate is evaporated, the residue is dissolved in 200 ml of dichloromethane, washed with water and 2N NaOH solution, dried with Na2SO4 and evaporated. The remaining oil is triturated with n-hexane to result the desired 4.1 in white crystals. Yield: 6.88 g (55%). (M+H)+=278, Rt (A)=1.90 min, purity 97.6%.
1H-NMR: 2.64 (s, 4H), 3.77 (t, 2H), 2.75 (s, 3H), 4.21 (t, 3H), 7.17 (d, 1H), 7.40 (d, 1H), 7.53 (dd, 1H), 9.84 (s, 1H).




B method: 11.66 g (45 mmol) of 4-(2-bromo-ethoxy)-3-methoxy-benzaldehyde (6.2) and 4.46 g (45 mmol) pyrrolidine-2,5-dione (7.2) is heated with 8.28 g (60 mmol) K2CO3 in 200 ml of acetonitrile for 8 h. After same isolation procedure as in A method 4.1 is given with same purity.
Following the procedure as outlined for intermediate 4.1, the intermediates of general formula 4a listed in Table 2 are prepared.











TABLE 2








Rt
Purity


Intermediate
Structure
(M + H)+
min. (system)
(%)



















4.2




262
2.25 (A)
98.2


 


4.3




276
2.45 (A)
98.3


 


4.4




282
2.26 (A)
98.3


 


4.5




266
3.36 (B)
99.3


 


4.6




293
1.86 (A)
98.7


 


4.7




277
2.28 (A)
98.3


 


4.8




297
2.19 (A)
95.3


 


4.9




305
2.08 (A)
97.9


 


4.10




289
2.35 (A)
99.6


 


4.11




294
2.34 (A)
97.2









Intermediate 4.12
4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzaldehyde




A Method:
Step 1: 6.85 g (45 mmol) vanilline (6.1, Y=OMe) is cooled in a 100 ml of a mixture of DCM-pyridine 4:1, then 9.1 ml (54 mmol) of trifluoromethanesulfonic anhydride in 10 ml DCM is dropped in. The mixture is stirred at r.t. for 2 hours, after evaporated and the residue is triturated with 3×10 ml of EtOAc, the collected organic layer is dried and evaporated. The crude material (6.1a) is used for next step without further purification.
Step 2: The formed crude trifluoro-methanesulfonic acid 4-formyl-2-methoxy-phenyl ester (6.1a), 2.52 ml (45 mmol) of ethylene glycol and 0.77 g (4.5 mmol) TsOH are refluxed in 180 ml of benzene. After evaporation the residue is purified by column chromatography. The desired intermediate is 11 g (80%) of trifluoro-methanesulfonic acid 4-[1,3]dioxolan-2-yl-2-methoxy-phenyl ester (6.1b), as a yellow oil. (M+H)+=329, Rt (A)=3.44 min, purity 93.4%.
Step 3: A mixture of 1.76 g (5 mmol) triflate (6.1b), 2.1 g (15 mmol) of 1-allyl-pyrrolidine-2,5-dione (8.2; Bull. Chem. Soc. Japan, 1984, 57(10), 3021), 0.067 g (0.3 mmol) of Pd(OAc)2, 0.373 g (5 mmol) KCl, 3.22 g (10 mmol) TBAB and 2.12 g (10 mmol) K3PO4 is heated in 10 ml DMF under nitrogen at 120° C. for 8 h. The mixture is diluted with water, extracted with 3×50 ml of EtOAc, the collected organic phase is evaporated and purified by column chromatography (EtOAc-n-hexane 1:1). The desired intermediate (4d) is 1.8 g of 1-[(E)-3-(4-[1,3]dioxolan-2-yl-2-methoxy-phenyl)-allyl]-pyrrolidine-2,5-dione, as an oil. (M+H)+=318, Rt (A)=2.58 min, Rt (B)=4.15 min, purity 71%.
Step 4: Using 3.02 g (9.2 mmol) of triflate (6.1a) a crude protected allyl derivative (4d) is formed (as described in step 2 and 3), which is hydrogenated by H-Cube equipment in full-H2 mode in EtOAc. After evaporation the residue is dissolved in 50 ml of dioxane and stirred with 10 ml of cc. HCl at r.t. for 0.5 h. The mixture is evaporated, the residue is diluted with water, extracted with ethylacetate, dried and removed the solvent. The crude material is purified by flash chromatography. The desired product (Intermediate 4.12) is 1.65 g (65.3%). (M+H)+=276, Rt=2.57 min (A), purity: 97.7%.
1H-NMR: 1.75 (qv, 2H), 2.59-2.62 (m, 6H), 3.38 (t, 2H), 3.86 (s, 3H), 7.40 (d, 2H), 7.47 (dd, 1H), 9.94 (s, 1H).
B Method:
Step 1: A mixture of 4.26 g (15 mmol) triflate (6.1a), 2.47 g (18 mmol) of 1-prop-2-ynyl-pyrrolidine-2,5-dione (8.1), 0.067 g (0.3 mmol) of [(C6H5)3P]2PdCl2, 0.143 g (0.75 mmol) CuI, 0.32 g (0.75 mmol) of 1,4-bis(diphenyl-phosphino)butane and 7 ml (50.5 mmol) of TEA is heated in 40 ml DMF under nitrogen at 100° C. for 3 h. The inorganic salts are removed and DMF is evaporated. The residue is treated with water, extracted 3×50 ml of EtOAc, the collected organic phase is evaporated and purified by flash chromatography (toluene-MeOH 9:1). The intermediate 4c is 1.9 g (44%) of 4-[3-(2,5-dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzaldehyde, as a dark yellow solid. (M+H)+=272, Rt=2.15 min (A), purity: 98.9%. 1H-NMR: 2.71 (s, 4H), 3.89 (s, 3H), 4.44 (s, 2H), 7.47-7.50 (m, 2H), 7.55 (d, 1H), 9.98 (s, 1H).
Step 2: Hydrogenation of 4-[3-(2,5-dioxo-pyrrolidin-1-yl)-prop-1-ynyl]-3-methoxy-benzaldehyde (4c) in same circumstances as described in A method is resulted Intermediate 4.12 in one step. The yield and purity is same as in A method.
Following procedures outlined for intermediate 4.12 the intermediate 4.13 is prepared.
Intermediate 4.13
4-[3-(2,5-Dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzaldehyde




(M+H)+=260, Rt=2.60 min (A), purity: 96.0%.
EXAMPLE 1
3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid




Step 1: 246 mg (0.089 mmol) of 3-amino-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid ethyl ester (5.1) and 250 mg (1.06 mmol) of 4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzaldehyde (4.1) is dissolved in 12 ml of THF, then 60 μl (64 mg, 1.06 mmol) of glacial acetic acid and 751 mg (3.54 mmol) of triacetoxy borohydride is added in at room temperature. After 8 hour stirring the mixture is treated with water and extracted with ethyl acetate. The combined organic phase is dried and purified by flash chromatography. Yield is 309 mg (70%) of 2.1 with 91.3% purity.
Step 2: 400 mg (0.081 mmol) of 2.1 is dissolved in 14 ml of THF and 0.44 ml (349 mg, 4.83 mmol) of 2-methyl-propionaldehyde (3.1) 70 μl (73 mg, 1.21 mmol) of glacial acetic acid and 854 mg (4.03 mmol) of sodium triacetoxy borohydride are added in. The mixture is stirred at room temperature for 4 hours, treated with water, extracted with ethyl acetate and the combined organic phases are dried, evaporated and purified by flash chromatography. Yield is 347 mg (78%) of 1.1 ester. (M+H)+=553, Rt=2.66 min (A), purity: 95.6%.
Salt formation: 101 mg (0.183 mmol) of 1.1 and 66 mg (0.183 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate is dissolved in 2 ml of EtOH, then evaporated, the residue is treated with Et2O and the formed white solid is filtrated, and washed with Et2O. Yield is 158 mg (48%) 1.1 with 1 moles 1,5-naphthalenedisulfonic acid. (M+H)+=553, Rt=2.66 min (A), purity: 95.4%.




Step 3: 227 mg of ester 1.1 is dissolved in 15 ml of dioxane, 5 ml of 2N HCl solution is added, and the mixture is stirred at 80° C. for 8 hours. After cooling the mixture is treated with 2N NaOH solution until pH=7 and extracted with dichloromethane. The combined organic phase is dried, evaporated and purified by flash chromatography.
Yield is 116 mg (54%) of desired product 1. Molecular Formula=C29H36N2O7; (M+H)+=525, Rt=2.36 min (A), purity 98.2%.
1H-NMR: 0.76 (dd, 6H), 1.77 (m, 1H), 2.0 (m, 2H), 2.58 (m, 1H), 2.61 (s, 4H), 2.94-3.00 (m, 2H), 3.17 (t, 2H), 3.67-3.71 (m, 6H), 4.03 (t, 2H), 4.17 (t, 1H), 4.51 (t, 2H), 6.73 (t, 2H), 6.83 (d, 1H), 6.98 (d, 2H), 7.15 (s, 1H), 12.3 (1 s, 1H).
EXAMPLE 2
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid




Following procedures outlined in Example 1 step 1 is accomplished with 3-Amino-3-(4-chloro-phenyl)-propionic acid ethyl ester (5.2) and Intermediate 4.1 then using 2-methyl-propionaldehyde (3.1) in step 2 after acidic hydrolysis and purification the title compound is isolated as a white foam. Molecular Formula=C27H33ClN2O6; (M+H)+=517; Rt=2.53 min (A), purity 98.8%.
EXAMPLE 3
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid




Step 1: 794 mg (3.03 mmol) of the 3-Amino-3-(2,4-dichloro-phenyl)-propionic acid ethyl ester (5.3) and 700 mg (2.52 mmol) of Intermediate 4.1 is dissolved in 30 ml of THF, then 170 μl (182 mg, 3.03 mmol) of glacial acetic acid and 2.14 g (10.10 mmol) of triacetoxy borohydride is added in at room temperature. After 24 hour stirring the mixture is treated with water and extracted with ethyl acetate. The combined organic phase is dried and purified with column chromatography. Yield is 466 mg (35%) of 2.2 with 92.3% purity.




Step 2: 235 mg (0.45 mmol) of 2.2 is dissolved in 10 ml of THF and 0.14 ml (1.35 mmol) of cyclopentane carboxaldehyde (3.2), 40 μl (40 mg, 0.67 mmol) of glacial acetic acid and 381 mg (1.80 mmol) of sodium triacetoxy borohydride is added in. The mixture is stirred at room temperature for 48 hours, treated with water, extracted with ethyl acetate and the combined organic phases are dried and evaporated. Yield is 376 mg (99%) of 1.2 ester (purity: 91.1%).
Step 3: This ester 1.2 is dissolved in 5 ml of dioxane, 3 ml of 2N HCl solution is added, and the mixture is stirred at 80° C. for 12 hours. After cooling the mixture is treated with 2N NaOH solution until pH=7 and extracted with dichloromethane. The combined organic phase is dried, evaporated and purified with chromatography.
Yield is 116 mg (35%) of desired product. Molecular Formula=C29H34Cl2N2O6; (M+H)+=577, Rt=2.80 min (A), purity 98.4%.
EXAMPLE 4
3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid




Following procedures outlined in Example 2 using Intermediate 4.9 after acidic hydrolysis and purification the title compound is isolated as a white foam. Molecular Formula=C28H34ClN3O6; (M+H)+=544; Rt=2.64 min (A), purity 94.7%.
EXAMPLE 5
(S)-3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid




360 mg of Example 4 is separated by preparative chiral column chromatography. The first eluted enantiomer has (S)-configuration ([α]D20=+0.046; c=0.2, EtOH) yield is 132 mg (73%). Molecular Formula=C28H34ClN3O6; (M+H)+=544; Rt=9.30 min (C), purity: 99.6%
EXAMPLE 6
(R)-3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid




360 mg of Example 4 is separated by preparative chiral column chromatography. The second eluted enantiomer has (R)-configuration ([α]D20=−0.033; c=0.2, EtOH) yield is 133 mg (74%). Molecular Formula=C28H34ClN3O6; (M+H)+=544; Rt=10.6 min (C), purity: 99.6%
EXAMPLE 7
3-(4-Chloro-phenyl)-3-(cyclobutyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid




Following procedures outlined in Example 2 step 1 is accomplished with 3-Amino-3-(4-chloro-phenyl)-propionic acid ethyl ester (5.2) and Intermediate 4.10. secondary amine derivative 2.7 is formed.
Step 2: 310 mg (0.62 mmol) of 2.7 is dissolved in 10 ml of EtOH then 52 mg (0.74 mmol) of cyclobutanone (3.3), 54 μl (56 mg, 0.93 mmol) of glacial acetic acid and 80 mg (0.74 mmol) of picoline borane complex is added in. The mixture is stirred at 85° C. for 72 hours, diluted with water, extracted with ethyl acetate and the combined organic phases are dried, evaporated and purified by flash chromatography. Yield is 130 mg (38%) of 1.7 ester. (M+H)+=554, Rt=2.93 min (A), purity: 85.3%.




Step 3: 120 mg (0.22 mmol) of ester 1.7 is dissolved in 2 ml of dioxane, 2 ml of 2N HCl solution is added, and the mixture is stirred at 80° C. for 3 hours. After cooling the mixture is treated with 2N NaOH solution until pH=7 and extracted with dichloromethane. The combined organic phase is dried, evaporated and purified by flash chromatography. Yield is 50 mg (44%) of desired product. Molecular Formula=C28H32ClN3O5; (M+H)+=526, Rt=2.61 min (A), purity 98.1%.
EXAMPLE 8
1-[(4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-methyl]-cyclopropanecarboxylic acid




Synthesis of Intermediate 5.4
Step 1: 9.87 g (46.4 mmol) of 3-(4-Chloro-phenyl)-3-oxo-propionic acid methyl ester (5.4c), 17.44 g (92.8 mmol) of 1,2-dibromoethane and 16 g (115.8 mmol) of K2CO3 is heated in 500 ml of DMF at 90° C. for 2 hours. The mixture is stirred at room temperature at overnight, diluted with water and extracted with DCM. After the evaporation the crude material is purified by flash chromatography. Yield is 2.90 g (26%) of Intermediate 5.4b; (M+H)+=239; Rt=3.21 min (A), purity: 95.8%.
Step 2: 2.26 g (9.47 mmol) of Intermediate 5.4b and 25.5 g (331.5 mmol) of ammonium acetate is refluxed in 100 ml of 2-propanol under inert atmosphere. Then 2.1 g (33.4 mmol) of sodium cyano borohydride is added and refluxed further 3 hours. The solvents is removed, the residue is acidified with 350 ml of 1N HCl solution, then washed with EtOAc, the acidic phase is adjusted with 5N NaOH solution to pH=8, then extracted with EtOAc, dried and evaporated. The crude Intermediate 5.4a is suitable for further step. Yield is 0.77 g (34%) yellow oil. (M+H)+=240; Rt=2.00 min (A), purity: 97.7%.
Step 3: 0.72 g (3 mmol) of Intermediate 5.4a and 16 ml (0.64 g, 16 mmol) of 1N NaOH solution is stirred at 50° C. for 3 hours. After acidification with 1N HCl solution the desired Intermediate 5.4 is separated as a white solid. Yield is 0.59 g (87%). (M+H)+=226; Rt=1.81 min (A), purity: 99.5%.




“One Pot” Synthesis of Example 8: 290 mg (1.29 mmol) Intermediate 5.4 is dissolved in 25 ml of EtOH, 340 mg (1.30 mmol) of Intermediate 4.2, 0.11 ml (116 mg, 1.93 mmol) of glacial acetic acid and 139 mg (1.30 mmol) of 2-picolin boran complex added in. The mixture is stirred at 70° C. for 3.5 hours, then 0.65 ml (523 mg, 9 mmol) of propionaldehyde (3.4) and 352 mg (3.30 mmol) of 2-picolin boran complex is added and the mixture is stirred at 70° C. for 24 hours. After cooling the mixture is treated with 2N NaOH solution until pH=7 and extracted with dichloromethane. The combined organic phase is dried, evaporated and purified by flash chromatography. Yield is 420 mg (64%) of desired product (Example 8).
Molecular Formula=C28H33ClN2O5; (M+H)+=513, Rt=2.65 min (A), purity 97.9%.
EXAMPLE 9
(S)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid




Following procedures outlined in Example 1 using (S)-3-Amino-3-(4-chloro-phenyl)-propionic acid ethyl ester (5.5) and Intermediate 4.2 in the first reductive amination step and propionaldehyde (3.4) in the second step, after acidic hydrolysis and purification the title compound is isolated as a white foam. Molecular Formula=C26H31ClN2O5; (M+H)+=487; Rt=2.48 min (A), purity 98.6%. ([α]D20+0.041; c=0.2, EtOH)
EXAMPLE 10
(R)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid




Following procedures outlined in Example 10 using (R)-3-Amino-3-(4-chloro-phenyl)-propionic acid ester (5.6) title compound is isolated as a white foam. Molecular Formula=C26H31ClN2O5; (M+H)+=487; Rt=2.48 min (A), purity 96.3%. ([α]D20=−0.040; c=0.2, EtOH)
EXAMPLE 11
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid; hydrochloride




Following procedures outlined in Example 1 using (S)-3-Amino-3-(4-chloro-3-fluoro-phenyl)-propionic acid ethyl ester (5.7) and Intermediate 4.1 in the first reductive amination step and cyclopropanecarbaldehyde (3.5) in the second step, after acidic hydrolysis and purification the title compound is isolated as a hydrochloride. Molecular Formula=C27H30ClFN2O6×HCl. (M+H)+=533; Rt=4.26 min (B), purity 100.0%. ([α]D20+0.080; c=0.2, EtOH)
EXAMPLE 12
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid; hydrochloride




Following procedures outlined in Example 11 using (R)-3-Amino-3-(4-chloro-3-fluoro-phenyl)-propionic acid ethyl ester (5.8) title compound is isolated as a white foam. Molecular Formula=C27H30ClFN2O6×HCl. (M+H)+=533; Rt=2.39 min (A), purity 99.3%. ([α]D20=−0.083; c=0.2, EtOH)
EXAMPLE 13
(S)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride




Following procedures outlined in Example 1 using (S)-3-Amino-3-(3,4-dichloro-phenyl)-propionic acid ethyl ester (5.9) and Intermediate 4.5 in the first reductive amination step and cyclopropanecarbaldehyde (3.5) in the second step, after acidic hydrolysis and purification the title compound is isolated as a hydrochloride. Molecular Formula=C26H27Cl2FN2O5×HCl. (M+H)+=537; Rt=4.85 min (B), purity 100.0%. ([α]D20+0.069; c=0.2, EtOH)
EXAMPLE 14
(R)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid; hydrochloride




Following procedures outlined in Example 13 using (S)-3-Amino-3-(3,4-dichloro-phenyl)-propionic acid ethyl ester (5.10) title compound is isolated as a white foam. Molecular Formula=C26H27Cl2FN2O5×HCl. (M+H)+=537; Rt=2.60 min (A), purity 78.5%. ([α]D20=−0.041; c=0.2, EtOH)
EXAMPLE 15
(S)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropylmethyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid; hydrochloride




Following procedures outlined in Example 11 using (S)-3-Amino-3-(4-chloro-3-fluoro-phenyl)-propionic acid ethyl ester (5.7) and Intermediate 4.4 in the first reductive amination step and cyclopropanecarbaldehyde (3.5) in the second step, title compound is isolated as a hydrochloride. Molecular Formula=C26H27Cl2FN2O5×HCl. (M+H)+=537; Rt=4.76 min (B), purity 99.5%. ([α]D20+0.086; c=0.2, EtOH)
EXAMPLE 16
(R)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropylmethyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid; hydrochloride




Following procedures outlined in Example 15 using (S)-3-Amino-3-(4-chloro-3-fluoro-phenyl)-propionic acid ethyl ester (5.8) title compound is isolated as a white foam. Molecular Formula=C26H27Cl2FN2O5×HCl. (M+H)+=537; Rt=2.55 min (A), purity 99.0%. ([α]D20=−0.073; c=0.2, EtOH)
Following the procedures as outlined in Example 1-16 using different amines (5), benzaldehydes (4) and oxo derivatives (3) the compounds listed in Table 3 are prepared.











TABLE 3








Rt






min.
Purity


Examples
Structure
(M + H)+
(system)
(%)



















17.




561
2.70 (A)
97.8


 


18.




561
2.69 (A)
99.8


 


19.




521
4.57 (B)
99.6


 


20.




521
4.57 (B)
99.9


 


21.




523
2.71 (A)
99.2


 


22.




523
2.72 (A)
96.5


 


23.




499
2.52 (A)
96.4


 


24.




519
4.92 (B)
99.6


 


25.




519
4.92 (B)
99.4


 


26.




533
2.64 (A)
98.8


 


27.




533
2.64 (A)
98.7


 


28.




541
2.92 (A)
98.5


 


29.




541
2.91 (A)
98.8


 


30.




556
5.06 (B)
99.1


 


31.




556
5.05 (B)
97.5


 


32.




560
2.79 (A)
99.6


 


33.




560
2.78 (A)
99.7


 


34.




574
2.91 (A)
99.5


 


35.




574
2.91 (A)
99.2


 


36.




515
2.36 (A)
98.2


 


37.




503
2.31 (A)
97.4


 


38.




517
2.61 (A)
98.2


 


39.




543
2.81 (A)
95.4


 


40.




557
2.80 (A)
97.9


 


41.




521
2.36 (A)
99.7


 


42.




535
2.57 (A)
98.5


 


43.




535
2.51 (A)
97.5


 


44.




575
2.84 (A)
98.9


 


45.




549
2.50 (A)
99.0


 


46.




537
2.48 (A)
98.1


 


47.




551
2.69 (A)
98.2


 


48.




551
2.88 (A)
95.7


 


49.




577
3.04 (A)
92.3


 


50.




591
2.95 (A)
99.2


 


51.




503
2.43 (A)
99.2


 


52.




491
2.39 (A)
99.2


 


53.




505
2.59 (A)
99.4


 


54.




505
2.53 (A)
93.9


 


55.




517
2.58 (A)
99.7


 


56.




531
2.75 (A)
99.3


 


57.




545
2.88 (A)
96.0


 


58.




509
2.46 (A)
98.8


 


59.




523
2.60 (A)
98.5


 


60.




549
2.84 (A)
98.4


 


61.




563
3.01 (A)
99.4


 


62.




525
2.57 (A)
84.9


 


63.




539
2.86 (A)
97.2


 


64.




539
2.72 (A)
99.1


 


65.




565
2.95 (A)
99


 


66.




578
3.12 (A)
98.0


 


67.




473
2.49 (A)
99.4


 


68.




499
2.63 (A)
99.8


 


69.




501
2.69 (A)
97.1


 


70.




501
2.76 A)
94.8


 


71.




513
2.65 (A)
99.1


 


72.




527
2.97 (A)
98.4


 


73.




541
3.10 (A)
97.8


 


74.




517
2.56 (A)
99.9


 


75.




505
2.53 (A)
99.6


 


76.




519
2.65 (A)
99.4


 


77.




545
2.84 (A)
98.6


 


78.




559
2.98 (A)
99.2


 


79.




521
3.30 (A)
99.0


 


80.




535
3.67 A)
98.8


 


81.




535
2.99 (A)
99.6


 


82.




561
2.95 (A)
98.5


 


83.




575
5.80 (B)
96.1


 


84.




513
2.63 (A)
99.4


 


85.




501
2.62 (A)
90.8


 


86.




515
2.77 (A)
96.0


 


87.




515
2.75 (A)
97.5


 


88.




527
2.78 (A)
99.0


 


89.




553
3.01 (A)
93.7


 


90.




531
2.66 (A)
98.6


 


91.




519
2.64 (A)
99.5


 


92.




533
2.83 (A)
96.0


 


93.




533
2.76 (A)
99.8


 


94.




559
2.95 (A)
99.0


 


95.




573
3.07 (A)
96.2


 


96.




547
2.76 (A)
99.6


 


97.




534
2.73 (A)
99.2


 


98.




549
2.93 (A)
98.4


 


99.




549
2.85 (A)
99.6


 


100.




575
3.06 (A)
97.4


 


101.




589
3.18 (A)
95.9


 


102.




519
2.49 (A)
98.4


 


103.




507
2.46 (A)
97.1


 


104.




533
2.65 (A)
99.5


 


105.




525
2.54 (A)
97.0


 


106.




553
2.65 (A)
95.4


 


107.




541
2.63 (A)
98.0


 


108.




535
2.35 (A)
83.9


 


109.




537
2.58 (A)
92.7


 


110.




537
2.58 (A)
96.0


 


111.




535
2.36 (A)
89.9


 


112.




500
2.49 (A)
95.8


 


113.




514
2.63 (A)
89.7


 


114.




526
2.66 (A)
88.2


 


115.




516
2.33 (A)
90.5


 


116.




542
2.50 (A)
99.7


 


117.




530
2.47 (A)
99.2


 


118.




544
2.60 (A)
99.5


 


119.




542
2.46 (A)
97.2


 


120.




550
2.33 (A)
91.0


 


121.




552
2.45 (A)
89.9


 


122.




552
2.43 (A)
92.9


 


123.




538
2.30 (A)
93.4


 


124.




576
2.74 (A)
97.7


 


125.




564
2.69 (A)
92.4


 


126.




550
2.55 (A)
97.1


 


127.




578
2.49 (A)
95.0


 


128.




592
2.61 (A)
96.9


 


129.




568
2.95 (A)
97.1


 


130.




584
2.87 (A)
96.8


 


131.




534
2.36 (A)
90.9


 


132.




513
9.08 (B)
86.5


 


133.




501
2.71 (A)
90.3


 


134.




515
2.89 (A)
95.8


 


135.




515
2.86 (A)
89.5


 


136.




540
3.02 (A)
94.5


 


137.




499
2.90 (A)
96.8


 


138.




513
3.22 (A)
84.0


 


139.




549
2.98 (A)
90.8


 


140.




523
2.78 (A)
96.0


 


141.




523
2.80 (A)
95.0


 


142.




505
2.47 (A)
93.4


 


143.




547
2.87 (A)
95.5


 


144.




509
2.64 (A)
93.0


 


145.




509
2.62 (A)
95.2


 


146.




551
2.62 (A)
95.6


 


147.




535
2.80 (A)
98.4


 


148.




565
2.62 (A)
90.2


 


149.




549
2.81 (A)
93.8


 


150.




551
2.54 (A)
93.3


 


151.




551
2.68 (A)
95.2


 


152.




516
2.21 and 2.40 (45% and 51%) (A)
96.4


 


153.




530
2.31 and 2.47 (68% and 30%) (A)
98.4


 


154.




508
2.18 (A)
99.0


 


155.




522
2.32 (A)
98.0


 


156.




576
2.37 (A)
96.5


 


157.




541
3.02 (A)
91.4


 


158.




536
2.48 (A)
96.6


 


159.




564
2.37 (A)
87.7


 


160.




562
2.64 (A)
96.3


 


161.




536
2.46 (A)
95.9


 


162.




535
2.82 (A)
96.0


 


163.




533
2.55 (A)
96.5


 


164.




535
5.11 (B)
96.5


 


165.




569
2.87 (A)
93.6


 


166.




553
5.54 (B)
96.7


 


167.




575
3.46 (A)
90.3


 


168.




529
2.48 (A)
97.2


 


169.




569
2.89 (A)
98.4


 


170.




529
2.56 (A)
97.0


 


171.




555
2.68 (A)
91.0


 


172.




499
2.50 (A)
97.1


 


173.




513
2.61 (A)
96.1


 


174.




513
2.68 (A)
95.7


 


175.




487
2.47 and 2.62 (20% and 78%) (A)
98.5


 


176.




473
2.36 and 2.55 (93% and 6%) (A)
99.5


 


177.




507
2.57 (A)
93.8


 


178.




467
2.45 (A)
98.3


 


179.




523
2.61 (A)
98.4


 


180.




577
2.78 (A)
98.5


 


181.




591
2.91 (A)
97.4


 


182.




475
2.06 (A)
91.3


 


183.




489
2.20 (A)
97.6


 


184.




503
2.36 (A)
98.2


 


185.




487
2.69 (A)
87


 


186.




517
2.44 and 2.60 52% and 47% (A)
99.3


 


187.




529
2.45 and 2.62 64% and 35% (A)
99.3


 


188.




559
2.85 (A)
99.9


 


189.




537
2.59 (A)
99.9


 


190.




577
2.95 (A)
99.2


 


191.




565
2.71 (A)
99.0


 


192.




553
2.69 (A)
99.1


 


193.




567
2.96 (A)
98.4


 


194.




501
2.59 and 2.75 73% and 26% (A)
98.8


 


195.




505
2.58 and 2.71 66% and 33% (A)
99.1


 


196.




527
2.75 (A)
99.2


 


197.




551
2.63 (A)
94.9


 


198.




590
3.02 (A)
96.0


 


199.




542
2.73 (A)
99.6


 


200.




576
2.88 (A)
94.0


 


201.




562
2.75 (A)
99.8


 


202.




576
2.90 (A)
98.7


 


203.




493
2.50 (A)
95.0


 


204.




503
2.30 (A)
90.7









Biological Methods

Compounds according to the invention as described are useful to block the interaction of CXCR3-A and CXCL10 in a radiolabelled binding assay.
Competition radioligand binding assays are performed to determine the in vitro potency of the newly synthesized, unlabeled test compounds to displace the specific binding of the radiolabelled endogenous chemokine, 125I-CXCL10, from the human CXCR3-A receptor. IC50 values are determined for the test compounds and used to explore the structure-activity relationships (SAR). The established SAR is used to feed back the molecular design and to suggest some suitable modifications for groups and structural elements by which the affinity of test compounds for the human CXCR3 receptor would be improved.
Cell Line and Membrane Preparation
CHO cells stably expressing human recombinant CXCR3-A receptors are generated in Sanofi-Aventis (LIT Frankfurt) by transfection of Flp-In-CHO host cells with a plasmid construct of pCDA5-FRT-TO_IRES-Gai4qi4_DEST. This cell line is registered in Sanofi-Aventis cell line bank. Cells are grown in Ham's F12 (PAA) medium supplemented with 10% FCS (PAA, Cat No. E15-898) and 0.6% Hygromycin (PAA) in T175 flasks at 37° C. in a humidified incubator under 5% CO2, 95% air. Cells are harvested from the culture flasks by a short treatment (8-10 minutes) with Versene (Gibco, Cat No. 15040). Cell suspension is diluted with PBS and cells are collected with centrifugation at 230 g for 10 minutes at 10° C. with a Juan centrifuge. Pellets containing approximately 1×108 cells are resuspended in 15 ml of 20 mM HEPES pH=7.4, 10 mM EDTA buffer supplemented with complete protease inhibitor (Roche, Cat No. 11 697 498 001). This suspension is homogenized with a teflon/glass homogenizer (Sartorius potter S) with 3×10 sec pulses in ice cold water bath, and then centrifuged at 300×g for 10 min at 4° C. with a Sigma centrifuge. The supernatant is carefully collected and centrifuged at 100,000×g for 60 min at 4° C. with a Beckman Avanti J30 centrifuge. The resulting pellet is washed once with 15 ml of fresh preparation buffer. The final membrane pellet is resuspended in storage buffer (20 mM HEPES pH=7.4, 0.1 mM EDTA, 250 mM sucrose supplemented with complete protease inhibitor) in a volume ratio of approximately 1×108 cells/1 ml, which gave a protein concentration of 2 to 4 mg/ml. Protein concentration is determined with Bio-Rad protein assay (Cat No 500-0006). Membrane aliquots were stored at −80° C. No degradation is observed until a storage period of approximately 5 months.
125I-CXCL10 Radioligand Binding Study
The composition of the binding assay buffer is determined in a course of detailed optimization procedure. This resulted in a binding assay buffer constituted by the following components: 25 mM Hepes (pH=7.4), 5 mM MgCl2, 1 mM CaCl2, 100 mM NaCl, supplemented with 0.1% of protease free BSA (as a final concentration). Competition binding assay is performed using 125I-CXCL10 (PerkinElmer, NEX348, specific activity 2200 Ci/mmol) radioligand in a final concentration of 50-70 pM. The nonspecific binding is defined by 150 pM of hr-CXCL10 (R&D Systems, Cat No 266-IP). The total assay volume is equal to 150 μl and contained 1% of DMSO (final concentration). Binding reaction is initiated by adding of membranes (10-20 μg proteins, approximately 5×105 cell equivalents) to the reaction mixture. After 60 minutes of incubation at 25° C. the reaction is terminated by rapid filtration over GF/B glass fibre filters that are pre-soaked with 0.5% polyethyleneimine (Fluka Analytical, P3143) for 1 hour, using a Skatron cell harvester device. Filters then are washed with 8 ml of ice-cold wash buffer (modified binding buffer in which BSA is omitted and the concentration of NaCl is adjusted to 500 mM concentration). The radioactivity retained on the filters is measured by a Wizard 1470 Automatic Gamma counter.
Test compounds are dissolved prior to the binding assay at a concentration of 10 mM in DMSO. Stock solutions are stored at −20° C. for not longer than 3 months. On the day of binding assay serial dilutions of test compounds ranging from 10 mM up to 3×10−7 M (or 3×10−9 M) are generated by 8 (or 12) consecutive steps using DMSO as solvent. Before adding these solutions of test compound to the binding reaction mixture, an intermediate dilution procedure is applied, in which 30 μl of each solution sample is transferred into a dilution tube containing 970 μl of binding assay buffer. Then 50 μl of these second dilution series is added to the test tubes and a concentration range of test compounds between 1×10−5 M and 3×10−9 M (or 3×10−11 M) was generated.
The IC50 values and Hill slopes for competition binding data are obtained using nonlinear four-parametric curve fitting method.
The exemplified compounds of the present invention have activities in the above binding assay of less than 20 micromolar, more particularly less than 1 micromolar, and further particularly less than 200 nanomolar 1050. Compounds listed in Table 4 are measured.










TABLE 4







Example #
IC50 (nM)



















1.1
686



1
41



2
34



3
120



4
94



5
23



6
108



7
95



8
677



9
11



10
130



11
19



12
69



13
97



14
374



15
40



16
130



17
54



18
454



19
58



20
282



21
66



22
531



23
42



24
32



25
59



26
39



27
86



28
66



29
31



30
55



31
416



32
69



33
86



34
83



35
75



36
20



37
20



38
45



39
71



40
40



41
107



42
70



43
23



44
43



45
66



46
118



47
143



48
61



49
61



50
98



51
133



52
990



53
125



54
306



55
294



56
52



57
212



58
183



59
109



60
243



61
334



62
503



63
303



64
456



65
186



66
435



67
424



68
118



69
74



70
61



71
54



72
71



73
81



74
34



75
25



76
54



77
61



78
72



79
116



80
81



81
100



82
119



83
302



84
45



85
58



86
12



87
31



88
70



89
51



90
50



91
56



92
66



93
79



94
71



95
144



96
78



97
81



98
130



99
120



100
464



101
292



102
83



103
170



104
145



105
211



106
223



107
570



108
200



109
495



110
786



111
420



112
428



113
123



114
91



115
440



116
91



117
132



118
69



119
152



120
96



121
146



122
122



123
154



124
30



125
72



126
310



127
38



128
118



129
2150



130
1250



131
42



132
192



133
177



134
296



135
116



136
179



137
240



138
190



139
54



140
51



141
43



142
211



143
211



144
80



145
38



146
56



147
46



148
28



149
72



150
140



151
110



152
754



153
635



154
58



155
529



156
120



157
650



158
75



159
354



160
81



161
76



162
263



163
162



164
133



165
75



166
78



167
2440



168
237



169
407



170
345



171
389



172
1350



173
603



174
800



175
266



176
5520



177
255



178
183



179
91



180
198



181
507



182
3900



183
256



184
336



185
467



186
73



187
71



188
31



189
40



190
62



191
20



192
55



193
72



194
272



195
342



196
630



197
295



198
187



199
175



200
234



201
886



202
810



203
105



204
197










Cyclic AMP Accumulation Assay

An in vitro functional assay measuring the changes in the intracellular cyclic adenosine 3′,5′-monophosphate (cyclic AMP, or also called as cAMP) level following either stimulation or activation of CXCR3-A receptor is used to demonstrate the antagonistic functionality of the selected compounds.
Cyclic AMP is one of the most important intracellular second messenger molecules whose level is regulated principally by the G-protein coupled adenylyl cyclase effector enzyme located in the inner surface of the cellular plasma membrane. Receptor dependent, G-protein mediated changes in the cyclic AMP concentration elicit then complex regulatory processes within the cell such as activation of multiple protein kinases and phospholipases, generation of inositol triphosphate and transient rise in the intracellular calcium ion (Ca2+) concentration, ion channel gating, effects on different gene transcriptions.
Upon agonist stimulation, CXCR3-A receptor activates the pertussis toxin (PTX) sensitive G-proteins of the Gi class that mediates a reduction in the intracellular cAMP levels, an increase in the intracellular Ca2+ mobilization and actin polymerization, that finally lead to cytoskeletal rearrangement and directed cell migration (chemotaxis). [Sauty A et al, 2001. J. Immunol. 167: 7084-7093.]
Cyclic AMP accumulation assay is performed with a homogeneous time-resolved fluorescence (HTRF) cAMP femto 2 kit from CisBio International. The measurement is basically carried out by following the manufacturer's instructions.
Since CXCR3-A receptor is coupled to Gi-protein, thus an agonist activation of the receptor will lead to a decrease in the intracellular cAMP level [Crosignani S. et al, 2010. Bioorg. Med. Chem Letters, 20:3614-3617]. Therefore, the cells have to be preactivated by forskolin, a direct activator of the cell adenylyl cyclase enzyme, in order to reach a sufficient cellular basal cAMP level. The agonist induced decrease in cAMP level will be measured by an increase of the Fluorescence Resonance Energy Transfer signal, as the signal is inversely proportional to the concentration of cAMP in the cell.
For the assay, the adherent hr-CXCR3-Flp-In-CHO-IRES-Gai4qi4 cells (the same cell line as used for binding assay) are washed with Ca2+-Mg2+ free PBS and harvested by a short treatment with Acutase (Sigma, A6964). At a time point of 2 min after adding Acutase (3 ml/T175 flask) 7 ml of culture medium is added to the detached cells. Cell suspension is collected and centrifuged at 1,700 rpm for 10 min. (Sigma 2-S table centrifuge). The resulting cell pellet is resuspended in PBS with Ca2+/Mg2+(Invitrogen 14080-048) and subjecting to a second centrifugation step as above. The final cell pellet is resuspended in assay buffer (PBS with Ca2+/Mg2+, supplemented with fatty acid free BSA (Sigma A6003) at a final concentration of 1 mg/ml and with the phosphodiesterase inhibitor Rolipram (Calbiochem 557330) at a final concentration of 10 μM. Cells are transferred to a 96-well microplate (Costar 3694, Half Area flat bottom, non-treated, black polystyrene plate) at a density of 16,000 cells/well.
The cells are incubated in the presence of different concentrations of antagonist compounds (within the range of 10 μM and 0.1 nM) for 10 min at room temperature (R.T.) under continuous shaking the microplate in a plate shaker (Heidolph Titramax 100, at 600 rpm). The final concentration of DMSO in reaction mixture is 0.1%. Then CXCL10 at a final concentration of 20 nM is added and the cells are further incubated for 10 min at R.T., as above. After that forskolin (Sigma F-6886) at 1 μM final concentration is added and an additional incubation period (30 min, R.T., shaking) followed. The final reaction volume is 40 μl. The reaction is stopped by adding the lysis buffer containing the HTRF reagents.
Plates are then incubated for 60 min at R.T. under shaking, and time-resolved FRET signals are measured after excitation at 337 nm. Both the emission signal from the europium cryptate-labelled anti-cAMP antibody (620 nm) and the FRET signal resulting from the labelled cAMP-d2 (665 nm) are recorded using a RubyStar instrument (BMG Labtechnologies).
The results are calculated as a fluorescence ratio (Em.665 nm/Em.620 nm)×10000 and are analysed by calculating the Delta F value which corresponded to the following formula:

DeltaF=(Standard or Sample Ratio−Negative Control Ratio)/(Negative Control Ratio)×100.

The negative control corresponded to the background signal obtained with the cryptate conjugate alone.

FORMULATION EXAMPLES
(1) Tablets
The ingredients below are mixed by an ordinary method and compressed by using a conventional apparatus.
















Compound of Example 1
30 mg



Crystalline cellulose
60 mg



Corn starch
100 mg 



Lactose
200 mg 



Magnesium stearate
4 mg










(2) Soft Capsules

The ingredients below are mixed by an ordinary method and filled in soft capsules.
















Compound of Example 1
30 mg



Olive oil
300 mg 



Lecithin
20 mg










(1) Parenteral Preparations

The ingredients below are mixed by an ordinary method to prepare injections contained in a 1 ml ampoule.
















Compound of Example 1
3 mg



Sodium chloride
4 mg



Distilled water for injection
1 ml










The compounds of the present invention have CXCR3 inhibitory activity and are useful as an active ingredient of a medicament for preventive and/or therapeutic treatment of a disease caused by abnormal activation of CXCR3 such as COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiple sclerosis (MS) and other neuroinflammatory diseases, lupus, rheumatoid arthritis (RA) or lichen planus.

## Claims

1. A compound of formula 1



wherein
R represents hydrogen, —C1-4 alkyl, —C3-8 cycloalkyl, —C1-4 halogenalkyl or halogenphenyl group;
R′ represents hydrogen or
R and R′ represent together with the carbon atom attached a C4 aliphatic ring; and
R1 represents a group selected from the group consisting of





wherein
A represents a direct bond or CH2, CH(CH3), C(CH3)2 or C(CH2)2 group;
R2 represents Cl, Me or —CF3;
R3 represents hydrogen, Cl or F;
R4 represents hydrogen or a —C1-4 alkyl group;
R5 represents a heteroaryl group selected from the group consisting of





X represents O, S or CH2 ;
Y represents hydrogen, halogen or a —C1-4 alkyl, —C1-4 alkoxy or —C1-4 hydroxyalkyl group; and
Z represents a C1-4 aliphatic hydrocarbon bridge optionally containing one double bond, and/or one or more heteroatom selected from O, S, NH and N(CH3) or represents a C2-4 aliphatic hydrocarbon bridge optionally containing N fused with a C3-6 cycloalkyl ring optionally containing one or more double bonds or with a phenyl ring or represents a C1-4 aliphatic hydrocarbon bridge substituted with a spiro C3-6 cycloalkyl ring optionally containing one or more double bonds;
or a pharmaceutically acceptable salt thereof, stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.

2. A compound according to claim 1
wherein
R represents hydrogen or a —C1-4 alkyl, —C3-8 cycloalkyl, —C1-4 halogenalkyl or halogenphenyl group;
R′ represents hydrogen or
R and R′ represent together with the carbon atom attached a C4 aliphatic ring;
R1 represents a group selected from the group consisting of





wherein
A represents a direct bond or a CH2, CH(CH3), C(CH3)2 or C(CH2)2 group;
R2 represents Cl, Me or —CF3;
R3 represents hydrogen, Cl or F;
R4 represents hydrogen or a —C1-4 alkyl group;
R5 represents heteroaryl group selected from the group consisting of





X represents O, S or CH2;
Y represents a halogen or a —C1-4 alkyl or —C1-4 alkoxy group; and
Z represents a (CH2)2, CH2N(CH)3 or CH═CH—N(CH3) group.

3. A compound according to claim 1, wherein R4 represents hydrogen.

4. A compound according to claim 1, wherein R1 represents a group selected from the group consisting of



wherein A represents CH2;
R2 represents Cl, Me or —CF3;
R3 represents hydrogen, Cl or F; and
R4 represents hydrogen.

5. A compound according to claim 1, wherein R1 represents a group



wherein R2 represents Cl;
R3 represents hydrogen, Cl or F; and
R4 represents hydrogen.

6. A compound according to claim 1, wherein X represents an O atom.

7. A compound according to claim 1, wherein Y represents halogen or a —CH3, —C2H5 or —OCH3 group.

8. A compound according to claim 7, wherein Y represents Cl, F or a —CH3, —C2H5 or —OCH3 group.

9. A compound according to claim 1, wherein Z represents a (CH2)2, CH2N(CH3) or CH═N(CH3) group.

10. A compound according to claim 9, wherein Z represents a (CH2)2 group.

11. A compound according to claim 1, wherein
R represents hydrogen or a —C1-4 alkyl, —C3-6 cycloalkyl or fluorophenyl group; and
R′ represents hydrogen.

12. A compound according to claim 1, wherein
R represents hydrogen or a —C1-4 alkyl, —C3-6 cycloalkyl or fluorophenyl group;
R′ represents hydrogen; and
R1 represents a group selected from the group consisting of




wherein A represents a CH2 group;
R2 represents Cl, Me or —CF3;
R3 represents hydrogen, Cl or F;
R4 represents hydrogen;

X represents O, S or CH2;
Y halogen or a —CH3, —C2H5 or —OCH3 group; and
Z represents a (CH2)2, CH2N(CH)3 or CH═CH—N(CH3) group.

13. A compound according to claim 1 selected from the group consisting of
3-(2,3-Dihydro-benzofuran-5-yl)-3-({4[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(S)-3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-phenyl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclobutyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl-ethoxy]-benzyl}-amino)-propionic acid;
1-[(4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-methyl]-cyclopropanecarboxylic acid;
(S)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl) -ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid;
(R)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid;
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
(S)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
(R)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
(S)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropyl-ethyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid;
(R)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropyl-ethyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid;
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid;
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid;
(S)-3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid;
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid;
(S)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
(R)-3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
(S)-3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
(S)-3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(S)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-propionic acid;
3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
(R)-3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid;
(R)-3-(4-Chloro-phenyl)-3-(cyclobutylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-ethyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclobutyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid;
(S)-3-(4-Chloro-phenyl)-3-(cyclobutylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid;
(S)-3-(4-Chloro-phenyl)-3-(cyclobutylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-propionic acid;
3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid;
3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-3-(4-chloro-phenyl)-propionic acid;
(S)-3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclobutylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid;
3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-3-(4-chloro-3-fluoro-phenyl)-propionic acid;
3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-cyclopropylmethyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-({3-Chloro-4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
(S)-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-(3,4-dichloro-phenyl)-acetic acid;
(S)-(3,4-Dichloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-acetic acid;
(R)-(3,4-Dichloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-acetic acid;
(R)-(Cyclopropylmethyl-{ 4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-(3,4-dichloro-phenyl)-acetic acid;
3-(4-Chloro-phenyl)-3-(ethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(ethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid;
3-(Butyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(Cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(2,3-Dihydro-benzofuran-5-yl)-3-(isobutyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(Butyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(2,3-Dihydro-benzofuran-5-yl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid;
3-(Cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-(ethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(Cyclopentylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Cyclohexylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(4-Chloro-phenyl)-3-[{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid;
3-(4-Chloro-phenyl)-3-[{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid;
3-(Cyclopropylmethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-propyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(4-chloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-isobutyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclobutyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-propionic acid;
3-(Cyclopentylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Butyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(Cyclopropylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Cyclohexylmethyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(2,3-Dihydro-benzofuran-5-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid;
3-(2,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-methyl-amino)-2-methyl-propionic acid;
3-(4-Chloro-phenyl)-3-(ethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-2-methyl-propionic acid;
3-(2,3-Dihydro-benzofuran-5-yl)-3-(ethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(2,3-Dihydro-benzofuran-5-yl)-3-({3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid;
3-(Cyclopropylmethyl-{3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid;
3-(2,3-Dihydro-benzofuran-5-yl)-3-(isobutyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
3-(2,4-Dichloro-phenyl)-3-({3-methoxy-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-propyl-amino)-propionic acid;
3-(Cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(Butyl-{3-methyl-4-[2-(3-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-ethoxy]-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-(2,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-propionic acid;
3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid;
3-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-3-(2,4-dichloro-phenyl)-propionic acid;
3-(4-Chloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-(4-fluoro-benzyl)-amino]-propionic acid;
3-(4-Chloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-(4-fluoro-benzyl)-amino]-propionic acid;
3-(3,4-Dichloro-phenyl)-3-[{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-(3,3,3-trifluoro-propyl)-amino]-propionic acid;
1-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-5-chloro-indan-2-carboxylic acid;
5-Chloro-1-(cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-indan-2-carboxylic acid;
5-Chloro-1-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-isobutyl-amino)-indan-2-carboxylic acid;
5-Chloro-1-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-indan-2-carboxylic acid;
5-Chloro-1-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-indan-2-carboxylic acid;
1-(Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-amino)-5-chloro-indan-2-carboxylic acid;
5-Chloro-1-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-isobutyl-amino)-indan-2-carboxylic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-ethyl-amino)-2-methyl-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-ethyl-amino)-2-methyl-propionic acid;
3-(Butyl-{4-[3-(2,5-dioxo-pyrrolidin-1-yl)-propyl]-3-methyl-benzyl}-amino)-3-(2,3-dihydro-benzofuran-5-yl)-propionic acid;
3-({4-[2-(2,5-Dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-3-p-tolyl-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-p-tolyl-propionic acid;
3-(Cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-trifluoromethyl-phenyl)-propionic acid;
3-(Cyclohexylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-3-(4-trifluoromethyl-phenyl)-propionic acid;
(4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-ethyl-amino)-acetic acid;
(4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-acetic acid;
Butyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-(4-chloro-phenyl)-acetic acid;
(4-Chloro-phenyl)-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-acetic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-2-methyl-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-amino)-2-methyl-propionic acid;
3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid;
3-(4-Chloro-3-fluoro-phenyl)-3-(cyclopentylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-propionic acid;
3-(Cyclopropylmethyl-{4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-propyl-amino)-propionic acid;
3-(3,4-Dichloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethylsulfanyl]-3-methoxy-benzyl}-isobutyl-amino)-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-2-methyl-propionic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-fluoro-benzyl}-propyl-amino)-2-methyl-propionic acid;
1-[(4-Chloro-phenyl)-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-ethyl-benzyl}-propyl-amino)-methyl]-cyclopropanecarboxylic acid;
3-(4-Chloro-phenyl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-ethyl-amino)-2,2-dimethyl-propionic acid;
(S)-3-(Cyclohexylmethyl-{3-methoxy-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
(S)-3-(4-Chloro-phenyl)-3-(cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-propionic acid;
(S)-3-(Cyclopentylmethyl-{3-methyl-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-amino)-3-(3,4-dichloro-phenyl)-propionic acid;
(R)-3-({3-Chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-cyclopentylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid;
(R)-3-({3-Chloro-4-[2-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-ethoxy]-benzyl}-cyclohexylmethyl-amino)-3-(4-chloro-phenyl)-propionic acid;
3-(5-Chloro-thiophen-2-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methyl-benzyl}-propyl-amino)-propionic acid; and
3-(2,5-Dimethyl-thiophen-3-yl)-3-({4-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethoxy]-3-methoxy-benzyl}-propyl-amino)-propionic acid,

or a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutically acceptable salt of the stereoisomer.

14. A process for the preparation of a compound according to claim 1, comprising the steps ofreductive amination of a benzaldehyde of formula 4



wherein X, Y and Z have the meaning as defined in claim 1—
with a primary amine of formula 5


R1—NH2   5


wherein R1 has the meaning as defined in claim 1,
reacting the obtained secondary amine of formula 2




with an aldehyde or cycloalkylketone of formula 3




wherein R and R′ have the meaning as defined in claim 1, to obtain an ester of a compoundaccording to claim 1;
and optionally hydrolyzing said ester to obtain a compound according to claim 1.

15. A method for the therapeutic treatment of a disease or disorder selected from the group consisting of COPD, psoriasis, graft/transplant rejection, ophthalmological disease, celiac disease, inflammatory bowel disease (IBD), type 1 diabetes, myasthenia gravis (MG), multiplesclerosis (MS), lupus, rheumatoid arthritis (RA) and lichen planus, the method comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound according to claim 1.

16. A pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable excipient.

17. A compound of formula 2



wherein
R1 represents a group selected from the group consisting of




wherein
A represents a direct bond or a CH2, CH(CH3), C(CH3)2 or C(CH2)2 group;
R2 represents Cl, Me or —CF3;
R3 represents hydrogen, Cl or F;
R4 represents hydrogen or a —C1-4 alkyl group;
R5 represents a heteroaryl group selected from the group consisting of





X represents O, S or a CH2 group;
Y represents halogen or a —C1-4 alkyl, or —C1-4 alkoxy group; and
Z represents a (CH2)2, CH2N(CH)3 or CH═CH—N(CH3) group;
or a salt thereof.