RU2296753C2 - Derivatives of 3-oxo-1-cyclobutene and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I):

and their salts, solvates, hydrates and N-oxides wherein R¹ represents group of the formula: Ar¹L²Ar²Alk wherein Ar¹ represents aromatic or heteroaromatic group; L² represents a covalent bond or -O-, -NH- or -CONH-; Ar² represents arylene or heteroarylene group; Alk represents chain -CH₂CH(R) or -CH(CH₂R)- wherein R represents -CO₂H or -COOAlk⁷ wherein Alk⁷ represents (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-heterocycloalkyl group and others; X represents group -N(R²)- wherein R² represents hydrogen atom or (C₁-C₆)-alkyl group; V represents oxygen atom; R^x, R^y and R^z represent atom or group -L¹(Alk¹)_n(R³)_v wherein L¹ represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH₃)-; Alk¹ represents aliphatic group; R³ represents hydrogen, halogen atom, group -OR^3a, -SR^3a and others wherein R^3a represents hydrogen atom, (C₁-C₆)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L¹ represents covalent bond then v = 1; or R^z represents atom or group given above, and R^x and R^y taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α₄-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

Description

The present invention relates to derivatives of phenylalanine enamide, to compositions containing these derivatives, to methods for their preparation and to their use in medicine.

Over the past few years, it has become increasingly apparent that the physical interaction of inflammatory leukocytes with each other and with other body cells plays an important role in the regulation of immune and inflammatory responses [Springer, T.A., Nature, 346, 425, (1990); Springer T.A. Cell, 76, 301, (1994)]. Specific cell surface molecules are generally called cell-adhesive molecules that mediate many such interactions.

By their structure, adhesive molecules are divided into various groups. One of the families of adhesive molecules, which obviously plays a particularly important role in the regulation of immune and inflammatory responses, is the integrin family. This family of cell surface glycoproteins has a typical non-covalently bound heterodimeric structure. At least 16 different alpha chains and 8 different integrin beta chains have been identified [Newman, P. et al. Molecular Medicine Today, 304, (1996)]. Members of this family are usually named according to their heterodimeric composition, although trivial nomenclature is widespread in this area. So, for example, integrin α4β1 consists of 4 integrin-alpha chains associated with 1 integrin-beta chain, and in a broader sense it is also called “very late antigen 4” or “VLA-4”. Not all of the possible pairs of integrin alpha chains and beta chains have yet been found in nature, and the integrin family has been subdivided into a number of subgroups based on those pairs that were already known to date [Sonnenberg, A., Current Topics in Microbiology and Immunology, 184, 7 (1993)].

The importance of integrin function in normal physiological responses is especially evident from the existing two diseases associated with its insufficiency and characterized by impaired integrin function. Thus, in a disease called leukocyte adhesion deficiency (DAL), one of the integrin families expressed on leukocytes is deficient [Marlin S.D. et al., J. Exp. Med. 164, 855 (1986)]. In patients suffering from this disease, a reduced ability to recruit white blood cells to the area of inflammation is detected, and in patients suffering from recurrent infections, this disease, in extreme cases, can be fatal. Patients suffering from a disease called Glanzman thrombasthenia (a deficiency of a member of the beta 3 integrin family) have a blood clotting disorder (Hodivala-Dilke, K.M. J. Clin. Invest. 103, 229 (1999)].

The possibility of modifying the function of integrins so that this leads to a favorable modulation of cell adhesion has been widely studied in animal models using specific antibodies and peptides that block the various functions of these molecules [for example, Issekutz, TB, J. Immunol. 149, 3394 (1992); Li, Z. et al, Am. J. Physiol. 263, L723 (1992); Mitjans, F. et al, J. Cell Sci. 108, 2825 (1995); Brooks, PC et al, J. Clin. Invest. 96, 1815 (1995); Binns, RM et al., J. Immunol. 157, 4094 (1996); Hammes, H.-P. et al, Nature Medicine 2, 529 (1996); Srivata, S. et al., Cardiovascular Res. 36, 408 (1997)]. In particular, it was demonstrated that the anti-α ₄ β ₇ antibody produced both clinical and histological attenuation of inflammatory activity and disease severity in non-human primates with a model of inflammatory bowel disease [Hesterberg, PE et al., Gastroenterol, 111, 1373-80 (1996)]. A series of monoclonal antibodies that block integrin function has been investigated on their therapeutic effect in treating a disease in humans, and one ReoPro anti-platelet integrin chimeric antibody αIIbβ3 has been used as a strong antithrombotic agent for administration to a patient with cardiovascular complications after coronary angioplasty.

Integrins recognize both cell-surface ligands and extracellular matrix ligands, and their ligand specificity is determined by a particular combination of alpha and beta subunits of the indicated molecule [Newman, P., ibid.]. One particular integrin subgroup of interest includes the α4 chain, which can pair with two different β-chains β1 and β7 [Sonnenberg, A., ibid.]. The formation of the α4β1 pair occurs on many circulating leukocytes (e.g., lymphocytes, monocytes and eosinophils and basophils), although it does not occur on circulating neutrophils or occurs only at low levels. α4β1 binds to an adhesive molecule (vascular cell-adhesive molecule 1, also called VCAM-1), which in most cases is positively regulated on endothelial cells of inflammatory sites [Osborne, L., Cell, 62, 3 (1990)]. It has also been shown that this molecule binds to at least three sites of the fibronectin matrix molecule [Humphrires, M.J. et al., Ciba Foundation Symposium, 189, 177 (1995)]. Based on the data obtained using monoclonal antibodies in animal models, it is obvious that the interaction between α4β1 and ligands on other cells and with the extracellular matrix plays an important role in the migration and activation of leukocytes [Yednock, T.A. et al., Nature, 356, 63 (1992); Podolsky, D.K. et al., J. Clin. Invest. 92, 372 (1993); Abraham W.M. et al., J. Clin. Invest. 93, 776 (1994)].

The integrin generated by the pairing of α4 and β7 was designated LPAM-1 [Holzmann B. & Weissmann, I.L. EMBO J. 8, 1735 (1989)]. The combination of α4β7 is expressed on some subpopulations of T and B lymphocytes and eosinophils [Erle, D.J. et al., J. Immunol. 153, 517 (1994)]. Like α4β1, α4β7 binds to VCAM-1 and to fibronectin. In addition, α4β7 binds to an adhesive molecule that is apparently involved in the “homing” of leukocytes into mucosal tissue, such as the mucosa of the gastrointestinal tract, and which has been designated MAdCAM-1 [Berlin C. et al, Cell, 74, 185, (1993)]. MAdCAM-1 is expressed primarily in the gastrointestinal tract. The interaction of α4β7 with MAdCAM-1 may also play an important role in areas of inflammation outside the mucosal tissue [Yang X.-D. et al., PNAS, 91, 12604 (1994)].

Regions of the peptide sequence recognized by α4β1 and α4β7 were identified when they bind to their ligands. α4β1 apparently recognizes the peptide sequences of LDV, IDA or REDV in fibronectin and the QIDSP sequence in VCAM-1 [Humphries, M.J. et al., ibid.], while α4β7 recognizes the LDT sequence in MAdCAM-1 [Birskin M.J. et al., J. Immunol. 156, 719 (1996)]. There are several reports of inhibitors of these interactions that have been constructed from modifications of these short peptide sequences [Cardarelli, P.M. et al., J. Biol. Chem. 269, 18668 (1994); Shorff H.N. et al., Bioorganic Med. Chem. Lett. 6, 2495 (1996); Vanderslice P. et al., J. Immunol. 158, 1710 (1997)]. It has also been reported that a short peptide sequence originating from the α4β1 binding site in fibronectin can inhibit the hypersensitivity contact reaction in mice sensitized with trinitrochlorobenzene [Ferguson T.A. et al., PNAS, 88, 8072 (1991)].

Since the subgroup of alpha-4 integrins is expressed mainly on leukocytes, it is assumed that their inhibition can have a beneficial effect in the treatment of a number of immune or inflammatory pathological conditions. However, given the ubiquity and wide range of functions performed by other members of this integrin family, it would be extremely important to identify selective alpha-4 subgroup inhibitors.

The authors of the present invention have discovered a group of compounds that are strong and selective α4 integrin inhibitors. Members of this group are able to inhibit α4 integrins, such as α4β1 and / or α4β7, at concentrations at which they usually do not have an inhibitory effect or have a minimal inhibitory effect on α-integrins of other subgroups. These compounds have other advantages, namely good pharmacokinetic properties, and in particular, low plasma clearance and good absorption properties, which make these compounds especially suitable for oral administration.

Thus, in accordance with one aspect of the present invention, the authors obtained a compound of formula (1):

where R ¹ represents a group Ar ¹ L ² Ar ² Alk ² , in which:

Ar ¹ represents an optionally substituted aromatic or heteroaromatic group;

L ² represents a covalent bond or a linker atom or a linker group;

Ar ² represents an optionally substituted arylene or heteroarylene group; and

Alk represents the chain

in which R represents a carboxylic acid (—CO ₂ H) or a derivative or bioster thereof;

X represents an atom —O— or —S— or a group N (R ² ), where:

R ² represents a hydrogen atom or a C _1-6 alkyl group;

V represents an oxygen atom (O) or sulfur (S);

R ^x , R ^y and R ^z may be the same or different, and each of them represents an atom or group -L ¹ (Alk ¹ ) _n (R ³ ) _v , where L ¹ represents a covalent bond or a linker atom or a linker group, Alk ¹ represents an optionally substituted aliphatic or heteroaliphatic chain, R ³ represents a hydrogen or halogen atom or a group selected from —OR ^3a [where R ^3a represents a hydrogen atom or an optionally substituted straight or branched C _1-6 alkyl group or a C _3-8 cycloalkyl group ], -SR ^3a, -CN or an optionally substituted tsikloalifatiche Coy, heterocycloaliphatic, polycycloaliphatic, geteropolitsikloalifaticheskoy, aromatic or heteroaromatic group, n is zero or an integer 1 and v is the integer 1, 2 or 3, with the proviso that when n is zero, and L ¹ is a covalent bond, then v equal to the integer 1;

or R ^z represents an atom or group as defined above, and R ^x and R ^y taken together form an optionally substituted spiro-linked cycloaliphatic or heterocycloaliphatic group;

and its salts, solvates, hydrates and N-oxides.

It should be noted that the compounds of formula (1) may have one or more chiral centers and may exist as enantiomers or diastereomers. It should be noted that the present invention relates to all such enantiomers, diastereomers and mixtures thereof, including racemates. Compounds of formula (1) and compounds of formulas below are all individual isomers and mixtures thereof, unless otherwise indicated or indicated. In addition, the compounds of formula (1) can exist in the form of tautomers, for example, in the form of (CH ₂ C = O) -enol and (CH = CHOH) -ketone. Compounds of formula (1) and compounds of formulas below are all individual tautomers and mixtures thereof, unless otherwise indicated.

Optionally substituted aromatic groups represented by Ar ¹ , if present in the R ¹ group, are, for example, optionally substituted monocyclic or bicyclic fused C _6-12 aromatic groups such as phenyl, 1- or 2-naphthyl, 1- or 2- tetrahydronaphthyl, indanyl or indenyl groups.

Optionally substituted heteroaromatic groups represented by Ar ¹ , if present in R ¹ , are, for example, optionally substituted C _1-9 heteroaromatic groups containing, for example, one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen. In general terms, said heteroaromatic groups can be, for example, monocyclic or bicyclic fused heteroaromatic groups. Monocyclic heteroaromatic groups are, for example, five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms. Bicyclic heteroaromatic groups are, for example, 8-13 membered fused heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulfur or nitrogen atoms.

Specific examples of heteroaromatic groups of these types are pyrrolyl, furyl, thienyl, imidazolyl, NC _1-6 alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 , 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5 triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, [2,3-dihydro] benzothienyl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo [1,2-a] pyridyl, benzothiazoles , benzoxazolyl, benzisoxazolyl, benzopyranyl, [3,4-dihydro] benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, for example, 2,6-naphthyridinyl or 2,7-naphthyridinyl, pyrido [3,4-b] pyridyl, pyrido [3, 2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl and imidyl, for example, succinimidyl, phthalimidyl or naphthalimidyl, such as 1,8-naphthalimidyl.

Each aromatic or heteroaromatic group represented by Ar ¹ may be, but is not necessarily, substituted at any available carbon atom, or, if present, a nitrogen atom. One, two, three or more identical or different substituents may also be present, and each substituent may be selected, for example, from an atom or a group —L ³ (Alk ² ) _t L ⁴ (R ⁴ ) _u , where each of L ³ and L ⁴ , which may be the same or different, represents a covalent bond or a linker atom or a linker group, t is zero or an integer 1, u is an integer 1, 2 or 3, Alk ² is an optionally substituted aliphatic or heteroaliphatic chain, and R ⁴ represents a hydrogen or halogen atom or a group selected from neobyazate no substituted C _1-6 alkyl or C _3-8 cycloalkyl, -OR ⁵ [wherein R ⁵ represents a hydrogen atom, an optionally substituted C _1-6 alkyl or C _3-8 cycloalkyl group], -SR ^5, -NR ⁵ R ⁶ [where R ⁶ has the meanings just defined for R ⁵ and these values may be the same or different], —NO ₂ , —CN, —CO ₂ R ⁵ , —SO ₃ H, —SOR ⁵ , —SO ₂ R ⁵ , -SO ₃ R ⁵ , -ОСО ₂ R ⁵ , -CONR ⁵ R ⁶ , -OCONR ⁵ R ⁶ , -CSNR ⁵ R ⁶ , -COR ⁵ , -OCOR ⁵ , -N (R ⁵ ) COR ⁶ , N ( R ⁵ ) CSR ⁶ , —SO ₂ N (R ⁵ ) (R ⁶ ), —N (R ⁵ ) SO ₂ R ⁶ , N (R ⁵ ) CON (R ⁶ ) (R ⁷ ) [where R ⁷ represents an atom hydrogen, optionally substituted C _1-6 alkyl or C _3-8 cycloalkyl group], —N (R ⁵ ) CSN (R ⁶ ) (R ⁷ ) or —N (R ⁵ ) SO ₂ N (R ⁶ ) (R ⁷ ), When the proviso that when t is 0, and each of L ³ and L ⁴ is a covalent bond then u is the integer 1, and R ⁴ is not a hydrogen atom.

If L ³ and / or L ^{4 is} present in these substituents as a linker atom or linker group, then it can represent any divalent linker atom or any divalent linker group. Specific examples are —O— or —S— atoms, or —C (O) -, —C (O) O—, —OC (O) -, C (S), —S (O) -, S ( O) ₂ -, —N (R ⁸ ) - [where R ⁸ represents a hydrogen atom or an optionally substituted straight or branched C _1-6 alkyl group], —CON (R ⁸ ) —OC (O) N (R ⁸ ), -CSN (R ⁸ ) -, -N (R ⁸ ) СО-, -N (R ⁸ ) С (О) О-, -N (R ⁸ ) CS-, -S (O) ₂ N (R ⁸ ) -, -N (R ⁸ ) S (O) ₂ -, -N (R ⁸ ) O-, -ON (R ⁸ ) -, -N (R ⁸ ) N (R ⁸ ) -, -N (R ⁸ ) CON (R ⁸ ) -, -N (R ⁸ ) CSN (R ⁸ ) - or N (R ⁸ ) SO ₂ N (R ⁸ ) -. If the specified linker group contains two substituents R ⁸ , then they can be the same or different.

If R ^3a , R ⁴ , R ⁵ , R ⁶ , R ⁷ and / or R ⁸ are present as a C _1-6 alkyl group, this group may be a straight or branched C _1-6 alkyl group, for example C _{1 -3} an alkyl group, such as a methyl, ethyl or isopropyl group. With _3-8 cycloalkyl groups represented by R ^3a , R ⁴ , R ⁵ , R ⁶ and / or R ⁷ are C _3-6 cycloalkyl groups, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. Other substituents that may be present on said alkyl or cycloalkyl groups are, for example, one, two or three substituents, which may be the same or different, and which are selected from halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, or hydroxy or C _1-6 alkoxy groups, for example, methoxy or ethoxy groups.

If both groups R ⁵ and R ⁶ or R ⁶ and R ⁷ represent C _1-6 alkyl groups, then these groups taken together with the N atom to which they are attached form a heterocyclic ring. Such heterocyclic rings may, but need not, be interrupted by other heteroatoms selected from —O—, —S— or —N (R ⁵ ). Specific examples of such heterocyclic rings are piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.

If Alk ^{2 is} present as an optionally substituted aliphatic or heteroaliphatic chain, then this chain may be an optionally substituted aliphatic or heteroaliphatic chain, as defined below for Alk ¹ .

The halogen atoms represented by R ⁴ in the optional Ar ¹ substituents are fluorine, chlorine, bromine or iodine atoms.

Examples of substituents represented by -L ³ (Alk ¹ ) _t L ⁴ (R ⁴ ) _u , if present in Ar ¹ groups in the compounds of the present invention, are atoms or groups-L ³ Alk ² L ⁴ R ⁴ , -L ³ Alk ² R ⁴ , -L ³ R ⁴ , -R ⁴ and -Alk ² R ⁴ , where L ³ , Alk ² , L ⁴ and R ^{4 are as} defined above. Specific examples of such substituents are the groups —L ³ CH ₂ L ⁴ R ⁴ , —L ³ CH (CH ₃ ) L ⁴ R ⁴ , —L ³ (CH ₂ ) ₂ L ⁴ R ⁴ , —L ³ CH ₂ R ⁴ , -L ³ CH (CH ₃ ) R ⁴ , -L ³ (CH ₂ ) ₂ R ⁴ , -CH ₂ R ⁴ , -CH (CH ₃ ) R ⁴ , - (CH ₂ ) ₂ R ^4, and -R ⁴ .

Thus, Ar ¹ in the compounds of the present invention can be, but is not necessarily, substituted by at least one two, three or more halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, and / or groups, such as C _{1 -6} alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, C _3-8 cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C _1-6 hydroxyalkyl, for example hydroxymethyl, hydroxyethyl or —C (OH) (CF ₃ ) ₂ , carboxyC _1-6 alkyl, for example carboxyethyl, C _1-6 alkylthio, for example methylthio or ethylthio, carboxyC _1-6 alkylthio, for example, carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C _1-6 alkoxy, for example, methoxy or ethoxy, hydroxyC _1-6 alkoxy, for example, 2-hydroxyethoxy, halogenC _1-6 alkyl, for example —CF ₃ , —CHF ₂ , —CH ₂ F, haloC _1-6 alkoxy, for example, —OCF ₃ , —OCHF ₂ , —OCH ₂ F, C _1-6 alkylamino, for example methylamino or ethylamino, amino (-NH ₂ ) amino C _1-6 alkyl, for example, aminomethyl or aminoethyl, C _1-6 dialkylamino, for example, dimethylamino or diethylamino, C _1-6 alkylamino C _1-6 alkyl, for example, ethylaminoethyl, C _1-6 dialkylamino C _1-6 alkyl e.g. diethyl oetil, aminoC _1-6 alkoxy, such as aminoethoxy, C _1-6 alkilaminoS _1-6 alkoxy, e.g., methylaminoethoxy, C _1-6 dialkilaminoS _1-6 alkoxy, such as dimethylaminoethoxy, diethylaminoethoxy, diizopropilaminoetoksi or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (—OH), formyl [HC (O) -], carboxyl (—CO ₂ H), —CO ₂ R ⁵ , for example, —CO ₂ CH ₃ or —CO ₂ C (CH ₃ ) ₃ , C _1-6 alkanoyl, e.g. acetyl, thiol (-SH), thioC _1-6 alkyl, e.g. thiomethyl or thioethyl, sulfonyl (-SO ₃ H), -SO ₃ R ⁵ , C _1-6 alkylsulfinyl, e.g. methylsulfinyl , C _1-6 alkylsulfonyl, e.g. methylsulfonyl l, aminosulfonyl (-SO ₂ NH ₂ ), C _1-6 alkylaminosulfonyl, e.g. methylaminosulfonyl or ethylaminosulfonyl, C _1-6 dialkylaminosulfonyl, e.g. dimethylaminosulfonyl or diethylaminosulfonyl, phenylaminosulfonyl, carboxamido (-CONH ₂ ), C _1-6 alkyl e.g., methylaminocarbonyl or ethylaminocarbonyl, C _1-6 dialkylaminocarbonyl, such as dimethylaminocarbonyl or diethylaminocarbonyl, aminoC _1-6 alkylaminocarbonyl, e.g., aminoetilaminokarbonil, C _1-6 alkilaminoS _1-6 alkylaminocarbonyl, e.g., etilaminoetilaminokarbonil, C _{1 -6} dialkilaminoS _1-6 alkylaminocarbonyl, e.g., dietilaminoetilaminokarbonil, aminocarbonylamino, C _1-6 alkylaminocarbonylamino, e.g., methylaminocarbonylamino or ethylaminocarbonylamino, C _1-6 dialkylaminocarbonylamino, e.g., dimethylaminocarbonylamino or dietilaminokarbonilamino, C _1-6 alkilaminokarbonilS _1-6 alkylamino, e.g., methylaminocarbonylmethylamino, aminothiocarbonylamino, C _1-6 alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C _1-6 dialkylaminothiocarbonylamino, e.g. Emer, dimetilaminotiokarbonilamino dietilaminotiokarbonilamino or C _1-6 alkilaminotiokarbonilS _1-6 alkylamino, e.g., etilaminotiokarbonilmetilamino, C _1-6 alkylsulfonylamino, such as methylsulfonylamino or ethylsulfonylamino, C _1-6 dialkilsulfonilamino example dimetilsulfonilamino or dietilsulfonilamino, aminosulfonilamino (-NHSO ₂ NH ₂ ), C _1-6 alkylaminosulfonylamino, for example methylaminosulfonylamino or ethylaminosulfonylamino, C _1-6 dialkylaminosulfonylamino, for example dimethylaminosulfonylamino or diethylamino phonylamino, C _1-6 alkanoylamino, for example acetylamino, amino C _1-6 alkanoylamino, for example aminoacetylamino, C _1-6 dialkylamino C _1-6 alkanoylamino, for example dimethylaminoacetylamino, C _1-6 alkanoylamino C _1-6 alkyl, for example, acetylaminome C _1-6 alkanoilaminoS _1-6 alkylamino, e.g., atsetamidoetilamino, C _1-6 alkoxycarbonylamino, e.g., methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino.

L ² , if present as part of the R ¹ group in the compounds of the present invention, may represent a linker atom or a linker group L ^2a , or a linker - (Alk ³ ) L ^2a -, where Alk ³ means an optionally substituted aliphatic or heteroaliphatic chain, which may be any chain defined below for Alk ¹ , and L ^2a may mean any linker atom or linker group defined below for L ³ .

The optionally substituted arylene groups represented by Ar ² , if present as part of the R ¹ group, are aromatic groups described above for Ar ¹ .

The optionally substituted heteroarylene groups represented by Ar ² , if present as part of the R ¹ group, are the heteroaromatic groups described above for Ar ¹ .

Each divalent arylene or heteroarylene group represented by Ar ² can be attached to the rest of the molecule via any available carbon or nitrogen atom on the ring.

The arylene and heteroarylene groups represented by Ar ² may be, but are not necessarily substituted with one, two or more substituents selected from the atoms or groups -L ³ (Alk ² ) _t L ⁴ (R ⁴ ) _u described herein. These two atoms or these two groups, if present, may be the same or different.

If the R ² group is present in the compounds of the present invention as a C _1-6 alkyl group, then it can, for example, be a straight or branched C _1-6 alkyl group, for example, a C _1-3 alkyl group, such as methyl or ethyl Group.

If the R group is present in R ¹ in the compounds of the present invention as a carboxylic acid derivative, then it may be, for example, an acyclic or cyclic ester or carboxylic acid amide. Particular acyclic esters and amides are the —CO ₂ Alk ⁷ and —CONR ⁵ R ⁶ groups defined herein. If R is a carboxylic acid bioster, then it can be, for example, tetrazole or another acid, such as phosphoric acid, phosphinic acid, sulfonic acid, sulfinic acid or boronic acid, or an acylsulfonamide group.

The ester (-CO ₂ Alk ⁷ ) and amide (-CONR ⁵ R ⁶ ) carboxylic acid derivatives of the group (-CO ₂ H) in the compounds of formula (1) can advantageously be used as prodrugs of the active compound. Such prodrugs are compounds that undergo biological conversion to the corresponding carboxylic acid before their pharmacological action, and therefore the present invention, in particular, relates to prodrugs of acids of the formula (1). Such prodrugs are well known in the art, see, for example, international patent application No. WO 00/23419, Bodor, N. (Alfred Benzon Symposium, 1982, 17, 156-177), Singh, G. et al. (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard, H. (Design of Prodrugs, 1985, Elsevier, Amsterdam).

The esterified carboxyl groups represented by —CO ₂ Alk ⁷ are groups where Alk ⁷ is a straight or branched, optionally substituted C _1-8 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or neopentyl group; an optionally substituted C _2-8 alkenyl group, such as a propenyl group, for example a 2-propenyl group; or a butenyl group, for example a 2-butenyl or 3-butenyl group; an optionally substituted C _2-8 alkynyl group, such as an ethynyl, propynyl group, for example, a 2-propynyl group, or a butynyl group, for example, a 2-butynyl or 3-butynyl group; an optionally substituted C _3-8 cycloalkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; optionally substituted C _3-8 heterocycloalkyl group, such as tetrahydrofuranyl group, for example, tetrahydrofuran-3-yl group, pyrrolidinyl group, for example, 1-methylpyrrolidinyl group, such as 1-methylpyrrolidin-3-yl group, piperidinyl group, for example, 1 a methylpiperidinyl group such as a 1-methylpiperidin-4-yl group, a tetrahydropyranyl group, for example a tetrahydropyran-4-yl group, or a 2-oxo [1,3] dioxol-4-yl group, for example, 5-methyl-2- oxo [1,3] dioxol-4-yl group; an optionally substituted C _3-8 cycloalkyl C _1-8 alkyl group such as a cyclopentylmethyl, cyclohexylmethyl or cyclohexylethyl group; optionally substituted C _3-8 heterocycloalkyl C _1-8 alkyl group such as morpholinyl-N-ethyl group, thiomorpholinyl-N-methyl group, pyrrolidinyl-N-ethyl group, pyrrolidinyl-N-propyl group, piperidinyl-N-ethyl group, pyrazolidinyl-N-methyl group or piperazinyl-N-ethyl group; optionally substituted C _1-6 alkyloxyC _1-6 alkyl group such as metiloksietilnaya or propiloksietilnaya group; an optionally substituted hydroxyC _1-6 alkyl group, such as a hydroxyethyl group, for example, a 2-hydroxyethyl or hydroxypropyl group, for example, a 2-hydroxypropyl, 3-hydroxypropyl or 2,3-dihydroxypropyl group; an optionally substituted C _1-6 alkylthioC _1-6 alkyl group, such as an ethylthioethyl group; optionally substituted C _1-6 alkilsulfinilS _1-6 alkyl group such as metilsulfiniletilnaya group; optionally substituted C _1-6 alkilsulfonilS _1-6 alkyl group such as metilsulfonilmetilnaya group; an optionally substituted C _3-8 cycloalkyloxy C _1-6 alkyl group, such as a cyclohexyloxymethyl group; an optionally substituted C _3-8 cycloalkylthioC _1-6 alkyl group, such as a cyclopentylthiomethyl group; an optionally substituted C _3-8 cycloalkylsulfinyl C _1-6 alkyl group, such as a cyclopentylsulfinylmethyl group; an optionally substituted C _3-8 cycloalkylsulfonyl C _1-6 alkyl group, such as a cyclopentylsulfonylmethyl group; optionally substituted C _1-6 alkiloksikarbonilS _1-6 alkyl group such as izobutoksikarbonilpropilnaya group; optionally substituted C _1-6 alkoksikarbonilS _1-6 alkenyl group such as izobutoksikarbonilpentenilnaya group; optionally substituted C _1-6 alkiloksikarboniloksiS _1-6 alkyl group such as etiloksikarboniloksimetilnaya isopropoxycarbonyloxyethyl group or a group, e.g., 1- (isopropoxycarbonyloxy) ethyl or 2- (isopropoxycarbonyloxy) ethyl group; optionally substituted C _1-6 alkiloksikarboniloksiS _1-6 alkenyl group such as izopropoksikarboniloksibutenilnaya group; an optionally substituted C _3-8 cycloalkyloxycarbonyloxy C _1-6 alkyl group such as a cyclohexyloxycarbonyloxyethyl group, for example a 2- (cyclohexyloxycarbonyloxy) ethyl group; optionally substituted N-di-C _1-8 alkilaminoS _1-8 alkyl group such as a N-dimethylaminoethyl or N-dietilaminoetilnaya group; an optionally substituted N — C _6-12 aryl-N — C _1-6 alkylamino-C _1-6 alkyl group, such as an N-phenyl-N-methylaminomethyl group; an optionally substituted N-di-C _1-8 alkylcarbamoylC _1-8 alkyl group, such as an N-diethylcarbamoylmethyl group; an optionally substituted C _6-12 aryl C _1-6 alkyl group, such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; an optionally substituted heteroC _6-10 aryl C _1-6 alkyl group such as a pyridinyl methyl group, for example a pyridin-4-ylmethyl or imidazolylethyl group, for example, a 2-imidazol-1-yl ethyl group; A C _6-12 aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; A C _6-12 aryloxy C _1-8 alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl or 2-naphthyloxymethyl group; A C _6-12 arylthioC _1-8 alkyl group, such as an optionally substituted phenylthioethyl group; A C _6-12 arylsulfinyl C _1-8 alkyl group, such as an optionally substituted phenylsulfinylmethyl group; A C _6-12 arylsulfonyl C _1-8 alkyl group, such as an optionally substituted phenylsulfonylmethyl group; optionally substituted C _1-8 alkanoiloksiS _1-8 alkyl group such as acetoxymethyl, ethoxycarbonyloxyethyl, pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; an optionally substituted C _4-8 imido C _1-8 alkyl group, such as a succinimidomethyl or phthalamidoethyl group; A C _6-12 aryloxy C _1-8 alkyl group, such as an optionally substituted benzoyloxyethyl or benzoyloxy propyl group, or a triglyceride group, such as a 2-substituted triglyceride group, for example, a 1,3-di-C _1-8 alkyl glyceryl-2-yl group such as a 1,3-diheptylglyceryl-2-yl group. Optional substituents present on the Alk ⁷ group are R ^13a substituents described below.

It should be noted that in the above list of Alk ⁷ groups, attachment to the rest of the compound of formula (1) is carried out by the part of the Alk ⁷ group just described. Thus, for example, a methoxyethyl group may be attached via an ethyl group, and a morpholinyl-N-ethyl group may be attached via an N-ethyl group.

In addition, it should be noted that in the above list of Alk ⁷ groups, unless otherwise indicated, the alkyl groups can be replaced by alkenyl or alkynyl groups, where these groups are defined above for Alk ¹ . In addition, these alkyl, alkenyl or alkynyl groups may, but need not be interrupted by one, two or three linker atoms or groups, where such linker atoms or linker groups have been described above for L ³ .

Other prodrug precursors of compounds of formula (1) are cyclic esters, where X represents a —N (R ² ) - group in which R ² is a chain attached to C _1-6 alkyl, and in particular a —CH ₂ - or - chain CH ₂ CH ₂ -, which is also attached to the acid group R to form a cyclic ester of formula (1a):

If a linker atom or linker group is present in the group R ^x , R ^y and / or R ^z in the compounds of formula (1), then the linker atom or linker group represented by L ¹ can be any linker atom or linker group described above for linker an atom or linker group represented by L ³ . In addition, L ¹ may also represent a -Se- atom.

If Alk ^{1 is} present in the groups R ^x , R ^y and / or R ^z in the compounds of formula (1) as an optionally substituted aliphatic chain, then it may be an optionally substituted C _1-10 aliphatic chain. Specific examples are optionally substituted straight or branched C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene chains.

Specific examples of the aliphatic chains represented by Alk ¹ are optionally substituted chains: —CH ₂ -, - (CH ₂ ) ₂ -, —CH (CH ₃ ) CH ₂ -, - (CH ₂ ) ₂ CH ₂ -, - (CH ₂ ) ₃ CH ₂ -, -CH (CH ₃ ) (CH ₂ ) ₂ -, -CH ₂ CH (CH ₃ ) CH ₂ -, -C (CH ₃ ) ₂ CH ₂ -, -CH ₂ C (CH ₃ ) ₂ CH ₂ -, - (CH ₂ ) ₂ C (CH ₃ ) ₂ CH ₂ -, - (CH ₂ ) ₄ CH ₂ -, - (CH ₂ ) ₅ CH ₂ -, -CHCH-, -CHCHCH ₂ - , CH ₂ CHCH—, —CHCHCH ₂ CH ₂ -, —CH ₂ CHCHCH ₂ -, - (CH ₂ ) ₂ CHCH—, —CC—, CCCH ₂ -, —CH ₂ CC—, —CHCH ₂ CH ₂ -, -CH ₂ CCHS ₂ - or - (CH ₂ ) ₂ CC-.

The heteroaliphatic chains represented by Alk ¹ , if they are present in the groups R ^x , R ^y and / or R ^z in the compounds of formula (1), are aliphatic chains directly described above for Alk ¹ , where each of them, in addition, contains one , two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups are L ⁵ atoms or groups, where L ^{5 is as} defined above for L ³ if L ³ is a linker atom or linker group. Each atom or group L ⁵ can interrupt the aliphatic chain, or it can be located at its terminal carbon atom, linking this chain to an adjacent atom or to an adjacent group. Specific examples are optionally substituted chains —CH ₂ L ⁵ -, —CH ₂ CH ₂ L ⁵ -, —L ⁵ CH ₂ -, —L ⁵ CH ₂ CH ₂ -, —L ⁵ CH (CH ₃ ) CH ₂ -, -L ⁵ CH ₂ CH (CH ₃ ) CH ₂ -, -L ⁵ CH ₂ CH ₂ CH (CH ₃ ) -, -L ⁵ C (CH ₃ ) ₂ CH ₂ -, -CH ₂ L ⁵ CH ₂ CH ₂ -, - (CH ₂ ) ₂ L ⁵ CH ₂ -, - (CH ₂ ) ₃ L ⁵ CH ₂ -, -L ⁵ (CH ₂ ) ₃ -, -L ⁵ (CH ₂ ) ₄ -, -CH ₂ L ⁵ CH ₂ CHL ⁵ CH ₂ - and - (CH ₂ ) ₂ L ⁵ CH ₂ CH ₂ -.

The optional substituents that may be present on the aliphatic or heteroaliphatic chains represented by Alk ¹ are one, two, three or more substituents, where these substituents may be the same or different, and selected from halogen atoms, for example, fluorine, chlorine, bromine or iodine, or —OH, —CO ₂ H, —CO ₂ R ⁹ , where R ⁹ represents an optionally substituted straight or branched C _1-6 alkyl group as defined above for R ⁴ , —CONHR ⁹ , —CON (R ⁹ ) ₂ , -COR ⁹ , for example, -COCH ₃ , C _1-6 alkoxy, for example methoxy or ethoxy and a thiol group, —S (O) R ⁹ , —S (O) ₂ R ⁹ , a C _1-6 alkylthio group, for example, a methylthio or ethylthio group, amino or substituted amino groups. Substituted amino groups are —NHR ⁹ and —N (R ⁹ ) ₂ . If two R ⁹ groups are present in any of the above substituents, then they may be the same or different.

The optionally substituted cycloaliphatic groups represented by the group R ³ , if present in the groups R ^x , R ^y and / or R ^z in the compounds of the present invention, are optionally substituted C _3-10 cycloaliphatic groups. Specific examples are optionally substituted C _3-10 cycloalkyl groups, for example C _3-8 cycloalkyl or C _3-10 cycloalkenyl groups, for example C _3-8 cycloalkenyl groups.

The optionally substituted cycloaliphatic groups represented by the R ³ group, if present in the R ^x , R ^y and / or R ^z groups, are optionally substituted C _3-10 heterocycloaliphatic groups. Specific examples are optionally substituted C _3-10 heterocycloalkyl groups, for example C _3-7 heterocycloalkyl or C _3-10 heterocycloalkenyl groups, for example C _3-7 heterocycloalkenyl groups, where each of these groups contains one, two, three or four heteroatoms or heteroatom-containing L ⁵ groups as defined above.

Optionally substituted polycycloaliphatic groups represented by R ³ , if present in R ^x , R ^y and / or R ^z groups, are optionally substituted C _7-10 bi- or tricycloalkyl or C _7-10 bi or tricycloalkenyl groups. Optionally substituted heteropolycycloaliphatic groups represented by R ³ are the optionally substituted polycycloaliphatic groups described immediately above, wherein each of these groups furthermore contains one, two, three or four atoms or groups of L ⁵ .

Particular examples of cycloaliphatic, polycycloaliphatic, heterocycloaliphatic and geteropolitsikloalifaticheskih groups represented by the group R ^3, are groups such as optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, 2-cyclobuten -1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophen-1-oxide, tetrahydro thiophene-1,1-dioxide, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, e.g. pyrazolinyl , 2-pyrazolinyl, pyrazolidinyl, pyranyl, for example 2- or 4-pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, piperidinyl, piperidinone, dioxanyl, for example, 1,3-di 1,4-dioxanyl, morpholinyl, morpholinone, dithianil, e.g. 1,3-dithianil or 1,4-dithianil, t omorpholinyl, piperazinyl, 1,3,5-trithianil, oxazinyl, for example 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4- oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, for example, o- or p-isoxazinyl, oxathiazinyl, for example, 1,2,5- or 1,2,6-oxathiazinyl or 1,3,5-oxadiazinyl.

Optional substituents that may be present on cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or heteropolycycloaliphatic groups represented by R ³ are one, two, three or more substituents, each of which is selected from halogen atoms, for example, fluorine, chlorine, bromine or iodine atoms, or from groups such as C _1-6 alkyl, for example methyl, ethyl, propyl or isopropyl, halogen C _1-6 alkyl, for example, halogenmethyl or haloethyl, such as difluoromethyl or trifluoromethyl, are optionally substituted hydroxyl, for example, —C (OH) (CF ₃ ) ₂ , C _1-6 alkoxy, for example methoxy, ethoxy or propoxy, halogen C _1-6 alkoxy, for example, halogenmethoxy or haloethoxy, such as difluoromethoxy or trifluoromethoxy, thiol, C _1-6 alkylthio, for example methylthio, ethylthio or propylthio, or from the groups - (Alk ⁴ ) _g R ¹⁰ in which Alk ⁴ represents a straight or branched C _1-3 alkylene chain, g is 0 or an integer of 1, and R ¹⁰ represents —OH, —SH, —N (R ¹¹ ) ₂ , (where R ¹¹ represents an atom or group defined herein for R ⁷ ), —CN, —CO ₂ R ¹¹ , —NO ₂ , —CON (R ¹¹ ) ₂ , -CSN (R ¹¹ ) ₂ , -COR ¹¹ , -CSN (R ¹¹ ) ₂ , -N (R ¹¹ ) COR ¹¹ , -N (R ¹¹ ) CSR ¹¹ , -SO ₂ N (R ¹¹ ) ₂ , -N (R ¹¹ ) SO ₂ R ¹¹ , -N (R ¹¹ ) CON (R ¹¹ ) ₂ , -N (R ¹¹ ) CSN (R ¹¹ ), -N ( R ¹¹ ) SO ₂ N (R ¹¹ ) ₂ , or from an optionally substituted phenyl group. If two atoms or two groups of R ¹¹ are present in these substituents, then they can be the same or different, or taken together, they form a heterocyclic ring, as described above for R ⁵ and R ⁶ bonded together. Optionally substituted phenyl groups is a phenyl group substituted with one, two or three R ¹³ groups described above.

In addition, if the group R ³ represents a heterocycloaliphatic group containing one or more nitrogen atoms, then each nitrogen atom may be optionally substituted with a group - (L ⁶ ) _p (Alk ⁵ ) _q R ¹² in which L ⁶ represents - C (O) -, -C (O) O-, -C (S) -, -S (O) ₂ -, -CON (R ⁸ ) -, -CSN (R ⁸ ) - or -S (O) ₂ N (R ⁸ ) -; p is zero or an integer of 1; Alk ⁵ represents an optionally substituted aliphatic or heteroaliphatic chain; q is zero or an integer 1; and R ¹² represents a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group.

With _1-3 alkylene chains represented by Alk ⁴ , are —CH ₂ -, —CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ -, —CH (CH ₃ ) CH ₂ -, and —CH ₂ CH (CH ₃ ) -chains.

The optionally substituted aliphatic or heteroaliphatic chains represented by Alk ⁵ are the optionally substituted chains described above for Alk ¹ . Optional substituents that may be present on these groups are those described above for Alk ¹ .

Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic or polyheterocycloaliphatic groups represented by R ¹² are groups that were directly defined above for the group R ³ . Optional substituents that may be present on these groups are those described above for R ³ cycloaliphatic groups.

Aromatic or heteroaromatic groups represented by R ¹² are the groups described herein for the Ar ¹ group. Optional substituents that may be present on these groups are optional R ¹³ substituents described below.

If the R ³ group is an optionally substituted aromatic or heteroaromatic group, then it may be, for example, an aromatic or heteroaromatic group described herein for the Ar ¹ group.

Optional substituents that may be present on aromatic or heteroaromatic groups represented by R ³ are one, two, three or more substituents, each selected from an atom or group R ¹³ , where R ¹³ is —R ^13a or Alk ⁶ (R ^13a ) _m , where R ^13a represents a halogen atom or a group such as amino (—NH ₂ ), substituted amino, nitro, cyano, amidino, hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO ₂ H), esterified carboxyl, thiol (-SH), substituted thiol, -COR ¹⁴ [wherein R ¹⁴ is -Alk ⁶ (R ^13a) _m, aryl w or heteroaryl group], -CSR ^14, -SO ₃ H, -SOR ^14, -SO ₂ R ^14, -SO ₃ R ^14, -SO ₂ NH _2, -SO ₂ NHR ^14, SO ₂ N (R ¹⁴⁾ ₂ , -CONH ₂ , -CSNH ₂ , -CONHR ¹⁴ , -CSNHR ¹⁴ , -CON [R ¹⁴ ] ₂ , -CSN (R ¹⁴ ) ₂ , -N (R ¹¹ ) SO ₂ R ¹⁴ , -N (SO ₂ R ¹⁴ ) ₂ , -NH (R ¹¹ ) SO ₂ NH ₂ , -N (R ¹¹ ) SO ₂ NHR ¹⁴ , -N (R ¹¹ ) SO ₂ N (R ¹⁴ ) ₂ , -N (R ¹¹ ) COR ¹⁴ , -N (R ¹¹ ) CONH ₂ , -N (R ¹¹ ) CONHR ¹⁴ , -N (R ¹¹ ) CON (R ¹⁴ ) ₂ , -N (R ¹¹ ) CSNH ₂ , -N (R ¹¹ ) CSNHR ¹⁴ , —N (R ¹¹ ) CSN (R ¹⁴ ) ₂ , —N (R ¹¹ ) CSR ¹⁴ , —N (R ¹¹ ) C (O) OR ¹⁴ , —SO ₂ NHet ¹ [where —NHet ¹ is optionally substituted C _{5 -7 a} cycloamino group optionally containing one or more other —O— or —S— atoms, or one or more groups: —N (R ¹¹ ) -, —C (O) -, —C (S) -, —S ( O) or —S (O) ₂ ], —CONHet ¹ , —CSNHet ¹ , —N (R ¹¹ ) SO ₂ NHet ¹ , —N (R ¹¹ ) CONHet ¹ , —N (R ¹¹ ) CSNHet ¹ , —SO ₂ N (R ¹¹ ) Het ² [where Het ² represents an optionally substituted monocyclic C _5-7 carbocyclic group optionally containing one or more —O— or —S— atoms or one or more —N (R ¹¹ ) -, —C groups (O) - or -C (S) -], -Het ² , -CON (R ¹¹ ) Het ² , -CSN (R ¹¹ ) Het ² , -N (R ¹¹ ) CON (R ¹¹ ) Het ² , - N (R ¹¹ ) CSN (R ¹¹ ) Het ² , an aryl or heteroaryl group; Alk ⁶ is a straight or branched C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene chain optionally interrupted by one, two or three —O— or —S—, or —S (O) _n atoms [where n represents an integer 1 or 2] or a group —N (R ¹⁵ ) - [where R ¹⁵ represents a hydrogen atom or a C _1-6 alkyl group, for example, a methyl or ethyl group]; and m is zero or an integer of 1, 2 or 3. It should be noted that if two R ¹¹ or R ¹⁴ groups are present in one of the above substituents, then these R ¹¹ or R ¹⁴ groups may be the same or different.

If in the group-Alk ⁶ (R ^13a ) _m m is an integer of 1, 2 or 3, it should be noted that in this case the substituent or substituents R ^13a can be present on any suitable carbon atom in -Alk ⁶ . If more than one R ^13a substituent is present, then they may be the same or different and may be present on the same atom or on different atoms in -Alk ⁶ . Obviously, if m is zero and the substituent R ^{13a is} absent, then the alkylene, alkenylene or alkynylene chain represented by Alk ⁶ becomes an alkyl, alkenyl or alkynyl group.

If R ^13a represents a substituted amino group, then such a group may be, for example, a —NHR ¹⁴ group [where R ^{14 is} defined above] or a —N (R ¹⁴ ) ₂ group, where the R ¹⁴ groups may be the same or different.

If R ^13a represents a halogen atom, then such an atom may be, for example, a fluorine, chlorine, bromine or iodine atom.

If R ^13a represents a substituted hydroxyl or substituted thiol group, then such groups may be, for example, the group —OR ¹⁴ or —SR ¹⁴ , or —SC (= NH) NH ₂ , respectively.

The esterified carboxyl groups represented by R ^13a are groups of the formula —CO ₂ Alk ⁸ , where Alk ⁸ represents a straight or branched optionally substituted C _1-8 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups; A C _6-12 aryl C _1-8 alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; A C _6-12 aryl group such as an optionally substituted phenyl, 1-oil or 2-naphthyl group; A C _6-12 aryloxy C _1-8 alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl or 2-naphthyloxymethyl group; optionally substituted C _1-8 alkanoiloksiS _1-8 alkyl group such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C _6-12 aryloxy C _1-8 alkyl group, such as an optionally substituted benzoyloxyethyl or benzoyloxy propyl group. Optional substituents present on the Alk ⁸ group are R ^13a substituents described above.

If Alk ^{6 is} present in the substituent or is itself a substituent, then it can be, for example, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, ethenylene, 2-propenylene, 2- butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or -S (O) -, -S (O) groups ₂ - or - N (R ⁸ ) -.

The aryl or heteroaryl groups represented by the groups R ^13a or R ¹⁴ are mono- or bicyclic optionally substituted C _6-12 aromatic or C _1-9 heteroaromatic groups described above for the Ar ¹ group. These aromatic and heteroaromatic groups can be attached to the rest of the compounds of formula (1) via any carbon atom or heteroatom, for example, nitrogen, if necessary.

If -NHet ¹ or -Het ² forms part of the substituent R ¹³ , then each of them may represent an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. In addition, Het ² may represent, for example, an optionally substituted cyclopentyl or cyclohexyl group. The optional substituents that may be present on -NHet ¹ or -Het ² are the optional substituents described above for aliphatic chains represented by Alk ¹ .

Particularly suitable atoms or groups represented by R ¹³ are fluorine, chlorine, bromine or iodine atoms or groups such as C _1-6 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, for example tert-butiloksikarbonilpiperazinil, pyrrolidinyl, dioxolanyl, dioxanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl or piperidinyl, C _1-6 hydroxyalkyl, e.g., hydroxymethyl or hydroxyethyl carb oxyC _1-6 alkyl, for example, carboxyethyl, C _1-6 alkylthio, for example, methylthio or ethylthio, carboxyC _1-6 alkylthio, for example, carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C _1-6 alkoxy, for example, methoxy or ethoxy, hydroxyC _1-6 alkoxy, for example 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyloxy, phenylthio or pyridylthio, C _4-7 cycloalkyl, for example cyclobutyl, cyclopentyl, C _5-7 cycloalkoxy, for example cyclopentyloxy, halogenC _{1 -6} alkyl, e.g. trifluoromethyl, haloC _1-6 alkoxy, e.g. trifluoromethoxy, C _1-6 al kilamino, for example methylamino, ethylamino or propylamino, C _6-12 arylC _1-6 alkylamino, for example benzylamino, 4-fluorobenzylamino, or 4-hydroxyphenylethylamino, amino (-NH ₂ ), aminoC _1-6 alkyl, for example, aminomethyl or aminoethyl, C _1-6 dialkylamino, for example, dimethylamino or diethylamino, aminoC _1-6 alkylamino, for example aminoethylamino or aminopropylamino, optionally substituted with Het ¹ NC _1-6 alkylamino, for example 3-morpholinopropylamino, C _1-6 alkylamino C _1-6 alkyl, e.g. ethylaminoethyl, C _1-6 dialkylaminoC _1-6 alkyl, e.g. diethylaminoethyl, aminoC _1-6 alkox and, for example, aminoethoxy, C _1-6 alkilaminoS _1-6 alkoxy, e.g., methylaminoethoxy, C _1-6 dialkilaminoS _1-6 alkoxy, such as dimethylaminoethoxy, diethylaminoethoxy, dimethylaminopropoxy or diizopropilaminoetoksi, hydroxyC _1-6 alkylamino, such as 2- hydroxyethylamino, 3-hydroxypropylamino or 3-hydroxybutylamino, imido, such as phthalimido or naphthalimido, for example, 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (-OH), formyl, [HC (O) -], carboxyl ( —CO ₂ H), —CO ₂ Alk ⁸ [where Alk ^{8 is} defined above], C _1-6 alkanoyl, for example acetyl, propyryl or butyryl, optional well-substituted benzoyl, thiol (-SH), thioC _1-6 alkyl, e.g. thiomethyl or thioethyl, -SC (= NH) NH ₂ , sulfonyl (-SO ₃ H), -SO ₃ Alk ⁸ , C _1-6 alkylsulfinyl For example, methylsulfinyl, ethylsulfinyl or propylsulfinyl, C _1-6 alkylsulfonyl, e.g., methylsulfonyl, ethylsulfonyl or propylsulfonyl, aminosulphonyl (-SO ₂ NH _2), C _1-6 alkylaminosulfonyl, e.g., methylaminosulfonyl, ethylaminosulfonyl propylaminosulfonyl or C _1-6 dialkylaminosulfonyl, e.g., dimethylaminosulfonyl or diethylaminosulfonyl, fenilaminosulfonil, carboxamido (-CONH _2), C _1-6 Alki aminocarbonyl, e.g., methylaminocarbonyl, ethylaminocarbonyl and propylaminocarbonyl, C _1-6 dialkylaminocarbonyl, such as dimethylaminocarbonyl or diethylaminocarbonyl, aminoC _1-6 alkylaminocarbonyl, e.g., aminoetilaminokarbonil, C _1-6- alkilaminoS _1-6 alkylaminocarbonyl, e.g., metilaminoetilaminokarbonil, C _{1- 6} dialkylaminoC _1-6 alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C _1-6 alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C _1-6 dialkylaminocarbonyl Mino, e.g., dimethylaminocarbonylamino or dietilaminokarbonilamino, C _1-6 alkilaminokarbonilS _1-6 alkylamino, e.g., metilaminokarbonilmetilamino, aminotiokarbonilamino, C _1-6 alkilaminotiokarbonilamino example metilaminotiokarbonilamino etilaminotiokarbonilamino or C _1-6 dialkilaminotiokarbonilamino example dimetilaminotiokarbonilamino or dietilaminotiokarbonilamino, C _{1 -6} alkilaminotiokarbonilS _1-6 alkylamino, e.g., etilaminotiokarbonilmetilamino, -CONHC (= NH) NH _2, C _1-6 alkylsulfonylamino, such as methylsulfonylamino or ethylsulphonylamino, haloC _1-6 alkylsulfonylamino, e.g., triftormetilsulfonilamino, C _1-6 dialkilsulfonilamino example dimetilsulfonilamino dietilsulfonilamino or optionally substituted phenylsulfonylamino, aminosulfonilamino (-NHSO ₂ NH _2), C _1-6 alkilaminosulfonilamino example metilaminosulfonilamino or etilaminosulfonilamino, With _1-6 dialkylaminosulfonylamino, for example dimethylaminosulfonylamino or diethylaminosulfonylamino, optionally substituted morpholinesulfonylamino or morpholinesulfonylC _1-6 al kilamino optionally substituted fenilaminosulfonilamino, C _1-6 alkanoylamino, for example acetylamino, aminoC _1-6 alkanoylamino, e.g., aminoatsetilamino, C _1-6 dialkilaminoS _1-6 alkanoylamino, e.g., dimetilaminoatsetilamino, C _1-6 alkanoilaminoS _1-6 alkyl, e.g., acetylaminomethyl, C _1-6 alkanoilaminoS _1-6 alkylamino, e.g., atsetamidoetilamino, C _1-6 alkoxycarbonylamino, e.g., methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyl oxycarbonylamino, benziloksikarbonilaminoS _1-6 alkyl, e.g., benzyloxycarbonylaminoethyl, tiobenzil, pyridylmethylthio or tiazolilmetiltio.

If necessary, the two R ¹³ substituents bonded together can form a cyclic group, such as a cyclic ether, for example a C _1-6 alkylenedioxy group, such as methylenedioxy or ethylenedioxy.

It should be noted that if two or more R ¹³ substituents are present, then they do not necessarily represent the same atoms and / or groups. In general, said substituent (s) may be present at any available position on the ring in the aromatic or heteroaromatic group represented by R ³ .

If the groups R ^x and R ^y joined together form an optionally substituted spiro-bonded cycloaliphatic or heterocycloaliphatic group attached to the cyclobutenone ring defined by formula (1), then such groups may be any cycloaliphatic or heterocycloaliphatic group described above for R ³ . Optional substituents that may be present on such spiro-linked cycloaliphatic or heteroaliphatic groups are optional substituents defined for R ³ .

The presence of certain substituents in the compounds of formula (1) may contribute to the formation of salts of these compounds. Suitable salts are pharmaceutically acceptable salts, for example, acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.

Acid addition salts are hydrochlorides, hydrobromides, hydroiodides, alkyl sulfonates, for example, methanesulfonates, ethanesulfonates or isothionates, aryl sulfonates, for example, p-toluenesulfonates, besylates or napsilates, phosphates, sulfates, bisulfates, acetates, trifluoroacetates, trifluoride acetate , malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases are alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.

Particularly suitable salts of the compounds of the present invention are pharmaceutically acceptable salts, and in particular acid addition pharmaceutically acceptable salts.

In the compounds of the present invention, the group R ¹ preferably represents the group Ar ¹ L ² Ar ² Alk -. In compounds of this type, Ar ¹ preferably represents an optionally substituted phenyl, monocyclic heteroaromatic or bicyclic heteroaromatic group. Particularly suitable monocyclic heteroaromatic groups are optionally substituted five- or six-membered heteroaromatic groups described above, and in particular five- or six-membered heteroaromatic groups containing one or two heteroatoms selected from oxygen, sulfur or nitrogen atoms. The most suitable nitrogen-containing groups are, in particular, pyridyl or pyrimidinyl groups. Particularly suitable substituents present on these monocyclic Ar ¹ groups are halogen atoms or an alkyl group, a haloalkyl group and —OR ⁵ , —SR ⁵ , —NR ⁵ R ⁶ , —CO ₂ H, —CO ₂ CH ₃ , —NO groups ₂ , —N (R ⁵ ) COR ⁶ or —CN described above for compounds of formula (1). The most suitable bicyclic heteroaromatic groups represented by Ar ¹ are optionally substituted ten-membered fused heteroaromatic groups containing one, two or three, and in particular one or two heteroatoms, in particular nitrogen atoms. Specific examples are optionally substituted naphthyridinyl, and in particular 2,6-naphthyridinyl, 2,7-naphthyridinyl, quinolinyl and isoquinolinyl groups, in particular the isoquinolin-1-yl group. Particular optional substituents are those described above for monocyclic heteroaromatic groups. In addition, in the compounds of the present invention, X preferably represents a —N (R ² ) - group, and V preferably represents an oxygen atom.

A particularly suitable group of compounds of the present invention has the formula (2a):

where -W = represents -CR ¹⁸ =, -N = or -N (O) =;

each of R ¹⁶ , R ¹⁷ and R ¹⁸ , which may be the same or different, represents a hydrogen atom, or an atom or group —L ³ (Alk ² ) _t L ⁴ (R ⁴ ) _u , where L ³ , Alk ² , t , L ⁴ , R ⁴ and u are as defined above;

L ² , Ar ² , Alk, R ² , R ^x , R ^y and R ^{z are} defined for formula (1);

and their salts, solvates, hydrates and N-oxides.

In one preferred class of compounds of formula (2a), where W is —CR ¹⁸ =, the group R ¹⁸ represents a hydrogen atom. In another of the preferred classes of compounds, R ¹⁸ preferably represents an atom or group as defined above for R ¹⁶ , and in particular C _1-6 alkoxy, in particular a methoxy or ethoxy group.

In another of the preferred classes of compounds of formula (2a), W represents a group —N═ or —N (O) =.

Each R ¹⁶ and R ¹⁷ in the compounds of formula (2a) preferably represents a group described above for compounds of formula (1), which is not a hydrogen atom. The most suitable substituents of R ¹⁶ and R ¹⁷ are halogen atoms, in particular fluorine or chlorine atoms, or groups such as C _1-6 alkyl, in particular methyl, ethyl or isopropyl, halogen C _1-6 alkyl, in particular halogenmethyl most preferably —CF ₃ , —CHF ₂ or —CH ₂ F, C _1-6 alkoxy, in particular methoxy or ethoxy, or halogen C _1-6 alkoxy, in particular halogenmethoxy, most preferably —OCF ₃ , —OCHF ₂ or -OSH ₂ F.

Another most suitable group of compounds of the present invention has the formula (2b):

where g is an integer of 1, 2, 3 or 4;

R ¹⁶ represents an atom or group —L ³ (Alk ² ) _t L ⁴ (R ⁴ ) _u , where L ³ , Alk ² , t, L ⁴ , R ⁴ and u are as defined above;

L ² , Ar ² , Alk, R ² , R ^x , R ^y and R ^{z are} defined for formula (1);

and their salts, solvates, hydrates and N-oxides.

The most suitable R ¹⁶ substituents, if present in the compounds of formula (2b), are halogen atoms, in particular fluorine, chlorine or bromine atoms, or groups such as C _1-6 alkyl, for example methyl, ethyl or isopropyl, halogen _1-6 alkyl, in particular halogenmethyl, most preferably —CF ₃ , C _1-6 alkoxy, in particular methoxy, haloC _1-6 alkoxy, in particular halogenmethoxy, most preferably —OCF ₃ , —CN, —CO ₂ CH ₃ , —NO ₂ , amino (—NH ₂ ), substituted amino (—NR ⁵ R ⁶ ), for example, —NHCH ₃ and —N (CH ₃ ) ₂ , —N (R ⁵ ) COCH ₃ , in particular groups —NHCOCH ₃ or optionally substituted phenyl, furyl, thienyl, imidazolyl, pyridyl and pyrimidinyl.

Another most suitable group of compounds of the present invention has the formula (2c);

where R ¹⁶ , g, L ² , Ar ² , Alk, R ² , R ^x , R ^y and R ^{z are} defined for formula (2b);

and their salts, solvates, hydrates and N-oxides.

Each atom or each group R ¹⁶ in the compounds of formula (2c) can be independently selected from an atom or group —L ³ (Alk ² ) _n L ⁴ (R ⁴ ) _u as defined above for compounds of formula (2b).

Another most suitable group of compounds of the present invention has the formula (2d):

where R ¹⁶ , g, L ² , Ar ² , Alk, R ² , R ^x , R ^y and R ^{z are} defined for formula (2b):

and their salts, solvates, hydrates and N-oxides.

Each atom or each R ¹⁶ group in the compounds of formula (2d) can be independently selected from an atom or group —L ³ (Alk ² ) _t L ⁴ (R ⁴ ) _u as defined above for compounds of formula (2b).

In one preferred class of compounds of formula (2d), at least one atom or one R ¹⁶ group is present at the 3-position of the isoquinoline ring. In a preferred group of compounds of this class, R ¹⁶ represents an optionally substituted phenyl ring. Optional substituents that may be present on the phenyl ring are halogen atoms, in particular fluorine or chlorine atoms, or groups such as C _1-6 alkyl, in particular methyl, ethyl or isopropyl, halogen C _1-6 alkyl, in particular , halogenmethyl, most preferably —CF ₃ , —CHF ₂ or —CH ₂ F, C _1-6 alkoxy, in particular methoxy or ethoxy, or halogen C _1-6 alkoxy, in particular halogenmethoxy, most preferably —OCF ₃ , - OCHF ₂ or -OCH ₂ F.

It should be noted that the compounds of formulas (2a), (2b), (2c) and (2d) include, if necessary, the corresponding hydroxytautomers. In the compounds of the present invention, Alk preferably represents

or, in particular, —CH ₂ CH (R) -.

In one of the preferred classes of compounds of formulas (1), (2a), (2b), (2c) and (2d), R represents a group —CO ₂ N.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R is an esterified carboxyl group of the formula —CO ₂ Alk ⁷ , which can advantageously be used as a prodrug precursor of the active compound. In a compound of this class, Alk ⁷ preferably represents a C _1-8 alkyl group, in particular a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or neopentyl group; an optionally substituted C _3-8 cycloalkyl group, in particular a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; an optionally substituted C _3-8 heterocycloalkyl group, in particular a tetrahydrofuranyl group, for example, a tetrahydrofuran-3-yl group, a pyrrolidinyl group, for example a 1-methylpyrrolidinyl group, such as a 1-methylpyrrolidin-3-yl group, a piperidinyl group, for example A 1-methylpiperidinyl group such as a 1-methylpiperidin-4-yl group, a tetrahydropyranyl group, for example, a tetrahydropyran-4-yl group, or a 2-oxo [1,3] dioxol-4-yl group, for example, 5-methyl-2 an oxo [1,3] dioxol-4-yl group; an optionally substituted C _6-10 aryl group, in particular a phenyl group; an optionally substituted C _6-10 aryl C _1-6 alkyl group, in particular a benzyl group; an optionally substituted heteroC _6-10 aryl-C _1-6 alkyl group, in particular a pyridinyl C _1-3 alkyl group such as a pyridinyl methyl group, for example a pyridin-4-ylmethyl or pyridinyl ethyl group, for example, a pyridin-4-yl ethyl group or an imidazolyl C _1-3 alkyl group such as an imidazolylethyl group, for example a 2-imidazol-1-yl ethyl group or an imidazolyl propyl group, for example a 2-imidazol-1-yl propyl group; an optionally substituted hydroxy-C _1-6 alkyl group, in particular a hydroxyethyl group, for example, a 2-hydroxyethyl or hydroxypropyl group, for example, a 3-hydroxypropyl or 2,3-dihydroxypropyl group; optionally substituted C _3-8 heterocycloalkyl C _1-6 alkyl group, in particular such as a morpholinyl-N-ethyl group, optionally substituted N-di-C _1-8 alkylamino C _1-8 alkyl group, in particular N-dimethylaminoethyl or N-diethylaminoethyl group; or an optionally substituted C _1-6 alkyloxyC _1-6 alkyl group, particularly metiloksietilnuyu group. Particularly preferred esterified carboxyl groups are —CO ₂ CH ₃ , —CO ₂ CH ₂ CH ₃ , —CO ₂ CH ₂ CH ₂ CH ₃ , —CO ₂ CH (CH ₃ ) _2, and —CO ₂ C (CH ₃ ) ₃ groups . The most preferred esterified carboxyl group is —CO ₂ (hydroxyC _1-6 alkyl), in particular —CO ₂ CH ₂ CH ₂ OH.

Basically in compounds of formula (1), if X represents a group —N (R ² ), and in particular in compounds of formulas (2a), (2b) (2c) and (2d), R ² preferably represents a hydrogen atom.

In one preferred class of compounds of formula (2a), L ² preferably represents L ^2a , where L ^2a represents a —CON (R ⁸ ) - group [where R ⁸ preferably represents a hydrogen atom or a C _1-3 alkyl group], in particular a group —CONH—, or a group - (Alk ³ ) L ^2a - for example, a group - (Alk ³ ) O— [where Alk ³ preferably represents a C _1-3 alkyl group], and most preferably a —CH ₂ O— group. In compounds of this class, -W = preferably represents -N = or -N (O) =. Most preferably, W is —N =.

In another preferred class of compounds of formula (2a), L ² preferably represents a covalent bond. In compounds of this class, -W = preferably represents -C (R ¹⁸ ) =, where R ^{18 is as} defined above.

Basically, in the compounds of formulas (2b), (2c) and (2d), L ² preferably represents L ^2a , where L ^2a represents an —O— atom or a group —N (R ⁸ ) - [where R ⁸ preferably represents a hydrogen atom or C _1-3 alkyl group]. A particularly preferred group —N (R ⁸ ) - is —NH—.

The Ar ² group in the compounds of formulas (1), (2a), (2b), (2c) and (2d) preferably represents an optionally substituted phenylene or optionally substituted pyridinediyl group of the formulas:

where a and b are the attachment positions of L ² and Alk, respectively. Most preferably, Ar ² represents an optionally substituted 1,4-phenylene group.

Particularly preferred optional substituents that may be present on Ar ² in the compounds of the present invention are halogen atoms, in particular fluorine, chlorine or bromine atoms, or groups such as C _1-6 alkyl, for example methyl, ethyl or isopropyl, halogen _1-6 alkyl, in particular halogenmethyl, more preferably —CF ₃ , C _1-6 alkoxy, in particular methoxy or halogen C _1-6 alkoxy, in particular halogenmethoxy, most preferably —OCF ₃ , —CN, —CO ₂ CH ₃ , —NO ₂ , amino (—NH ₂ ), substituted amino (NR ⁵ R ⁶ ), in particular, —NHCH ₃ and —N (CH ₃ ) ₂ , and —N (R ⁵ ) CO CH ₃ , in particular, —NHCOCH ₃ .

In one general preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x , R ^y and / or R ^z represent an optionally substituted alkyl group, most preferably an optionally substituted C _1-8 an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-heptyl or n-hexyl group. Particularly preferred optional substituents which may be present on said alkyl groups R ^x , R ^y and / or R ^z are halogen atoms, in particular fluorine or chlorine atoms, C _1-6 alkoxy groups, in particular methoxy, halogen C _1-6 alkoxy groups, in particular —OCF ₃ , —CN, —CO ₂ CH ₃ , —NO ₂ , substituted amino (—NR ⁵ R ⁶ ), in particular —NHCH ₃ and —N (CH ₃ ) ₂ , and optionally substituted phenyl groups where optional substituents are as defined for optional substituents on Ar ² .

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d) R ^z represents a hydrogen atom.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x represents a hydrogen atom.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^z represents a halogen atom, in particular a fluorine, chlorine, bromine or iodine atom, most preferably a chlorine or bromine atom.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^z represents the group —L ¹ (Alk ¹ ) _n R ³ . In compounds of this class, L ¹ preferably represents a covalent bond or an —O—, —S— or —Se— atom or an —S (O) - or —N (R ⁸ ) - group, in particular an —NH— or —N group (CH ₃ ) -. Most preferably, L ¹ represents an —S— atom or a group —S (O) -. In compounds of this class, R ³ preferably represents a hydrogen atom, or an optionally substituted C _3-10 cycloaliphatic group, in particular a C _3-7 cycloalkyl group, most preferably an optionally substituted cyclopentyl, cyclohexyl or cycloheptyl group; or an optionally substituted C _3-10 heterocycloaliphatic group, in particular a C _3-7 heterocycloalkyl group, most preferably an optionally substituted piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, dithianyl or pyrazolidinyl group, or an optionally substituted C _6-12 aromatic group, preferably optionally a phenyl group or an optionally substituted C _1-9 heteroaromatic group, preferably an optionally substituted monocyclic C _1-9 geteroaromatich a group, most preferably a 5- or 6-membered monocyclic heteroaromatic group containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms, in particular an optionally substituted furyl, thienyl, imidazolyl group, for example, 1- methylimidazolyl-2-yl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl or pyrazinyl group. Optional substituents that may be present on said heterocycloaliphatic groups are those described below, if R ^x and R ^y , bonded together form an optionally substituted spiro-linked heterocycloaliphatic group. Optional substituents that may be present on said aromatic and heteroaromatic groups are those described above for R ¹⁶ in the compounds of formula (2a). In one preferred group of compounds of this class, n is zero. In another preferred group of compounds of this class, L ¹ represents a covalent bond and n is zero. In this group of compounds, R ³ preferably represents an optionally substituted C _3-10 cycloaliphatic, C _3-10 heterocycloaliphatic, C _6-12 aromatic or monocyclic C _1-9 heteroaromatic group directly described above. In another preferred group of compounds of this class, n is an integer 1, and Alk ¹ represents an optionally substituted aliphatic chain, most preferably an optionally substituted C _1-6 alkylene chain, in particular —CH ₂ -, —CH ₂ CH ₂ - or —CH ₂ CH (CH ₃ ) chain. In another preferred group of compounds of this class, L ¹ represents a covalent bond, n is an integer of 1, and Alk ¹ preferably represents an optionally substituted aliphatic chain, most preferably an optionally substituted C _1-6 alkylene chain, in particular —CH ₂ -, —CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ - or -CH ₂ CH (CH ₃ ) chain. In another preferred group of compounds of this class, L ¹ is preferably an atom or a group directly described above, most preferably the atom —S—, n is an integer 1, and Alk ^{1 is} preferably an optionally substituted aliphatic chain, most preferably optionally substituted C _1-6 an alkylene chain, in particular a —CH ₂ -, —CH ₂ CH ₂ -, —CH ₂ CH ₂ CH ₂ -, or —CH ₂ CH (CH ₃ ) chain. In compounds of this class, R ³ preferably represents a hydrogen atom.

The most preferred R ^z groups that may be present in the compounds of the present invention are a hydrogen or halogen atom, in particular a fluorine, chlorine, bromine or iodine atom, or a group of the formula -L ¹ (Alk ¹ ) _n R ³ as defined above, in in particular, an alkyl group described above or hydroxyl (—OH); C _1-6 alkoxymethoxy, ethoxy or isopropoxy; C _3-7 cycloalkyl, in particular cyclopentyl or cyclohexyl; C _1-6 alkylsulfanyl, in particular methyl, ethyl or isopropylsulfanyl; C _1-6 alkylsulfinyl, in particular methyl, ethyl or isopropylsulfinyl; C _3-7 heterocycloalkyl, in particular piperidinyl, most preferably piperidin-3-yl, such as 1-methylpiperidin-3-yl or dithianyl, in particular [1,3] dithian-2-yl; C _6-12 aryl selenyl, in particular phenyl selenyl; C _6-12 arylsulfanyl, in particular phenylsulfanyl or pentafluorophenylsulfanyl; monocyclic C _1-9 heteroaromatic sulfanyl, in particular tetrazol-5-ylsulfanyl, most preferably 1-methyl-1H-tetrazol-5-ylsulfanyl or imidazolylsulfanyl, in particular imidazol-2-ylsulfanyl, most preferably 1-methyl-1H- imidazol-2-ylsulfanyl; monocyclic C _1-9 heteroaromatic, in particular pyridinyl, most preferably pyridin-3-yl, 1-methylpyridinium or pyrazinyl, in particular pyrazin-2-yl; or C _6-12 aryl C _1-3 alkyl, in particular a benzyl group.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), each of R ^x and R ^z represents a hydrogen atom.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x represents a hydrogen atom and R ^z represents a halogen atom, in particular a fluorine, chlorine, bromine or iodine atom, and most preferably, a chlorine or bromine atom, or R ^z represents a group of the formula —L ¹ (Alk ¹ ) _n R ³ as defined above.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), each of R ^x and R ^y represents a hydrogen atom, and R ^z represents a halogen atom, in particular a fluorine atom, a chlorine atom , bromine or iodine, most preferably a chlorine or bromine atom, or R ^z represents a group of the formula —L ¹ (Alk ¹ ) _n R ³ as defined above.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x represents a hydrogen atom, and R ^y represents an optionally substituted alkyl group described above for generally preferred alkyl groups .

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), each of R ^x and R ^z represents a hydrogen atom, and R ^y represents an optionally substituted alkyl group described above.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x represents a hydrogen atom, R ^z represents a halogen atom, in particular a fluorine, chlorine, bromine or iodine atom, most preferably a chlorine or bromine atom, or R ^z represents a group of the formula -L ¹ (Alk ¹ ) _n R ³ , in particular the group specifically described above, and R ^y represents an optionally substituted alkyl group described for generally preferred alkyl groups .

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x represents a hydrogen atom, and each of R ^y and R ^z represents an optionally substituted alkyl group described above for, in mainly preferred alkyl groups.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), each of R ^x and R ^y represents an optionally substituted alkyl group as described above for substantially preferred alkyl groups.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), each of R ^x and R ^y represents an optionally substituted alkyl group described above for generally preferred alkyl groups, and R ^z represents a hydrogen atom.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), each of R ^x and R ^y represents an optionally substituted alkyl group described above for generally preferred alkyl groups, and R ^z represents a halogen atom, in particular a fluorine, chlorine, bromine or iodine atom, most preferably a chlorine or bromine atom, or R ^z represents a group of the formula -L ¹ (Alk ¹ ) _n R ³ as defined above.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), each of R ^x , R ^y, and R ^z represents an optionally substituted alkyl group described above for substantially preferred alkyl groups.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x and R ^y , bonded together, form an optionally substituted spiro-linked cycloaliphatic group, in particular a C _3-10 cycloaliphatic group , most preferably C _3-8 cycloalkyl group, particularly an optionally substituted cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a C _3-8 cycloalkenyl group, especially an optionally substituted cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl c PPU. Particularly preferred optional substituents which may be present on said spiro-bonded cycloaliphatic groups are halogen atoms, in particular fluorine or chlorine atoms, C _1-6 alkyl groups, in particular methyl, ethyl, propyl or isopropyl groups, C _1-6 alkoxy groups in particular methoxy or ethoxy groups, haloC _1-6 alkoxy groups, in particular —OCF ₃ , —CN, —CO ₂ CH ₃ , —NO ₂ , and a substituted amino group (—N (R ¹¹ ) ₂ ), in particular groups —NHCH ₃ and —N (CH ₃ ) ₂ . In a preferred group of compounds of this class, R ^z represents a hydrogen atom. In another preferred group of compounds of this class, R ^z represents an alkyl group as described above. In another preferred group of compounds of this class, R ^z represents a halogen atom, in particular a fluorine, chlorine, bromine or iodine atom, most preferably a chlorine or bromine atom, for example, a bromine atom. In another preferred group of compounds of this class, R ^z represents a group of the formula —L ¹ (Alk ¹ ) _n R ³ as defined above.

In another preferred class of compounds of formulas (1), (2a), (2b), (2c) and (2d), R ^x and R ^y , bonded together, form an optionally substituted spiro-linked heterocycloaliphatic group, in particular, optionally substituted C _3-10 a heterocycloaliphatic group, most preferably an optionally substituted C _3-7 heterocycloalkyl group, in particular an optionally substituted C _3-7 heterocycloalkyl group containing one or two heteroatoms -O-, -S-, -S (O) -, -S (O ₂ ) -, -NH- or C (O) - or heteroatom-containing groups. Particularly preferred optionally substituted heterocycloaliphatic groups are optionally substituted 5- and 6-membered heterocycloalkyl groups containing one heteroatom or one heteroatom-containing group described above, in particular, optionally substituted pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene-1-tetrahydrothiophene-1-tetrahydrothiophene-1 1-dioxide, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide or tetrahydrothiopyran-1,1 -dioxide group. Particularly preferred optional substituents which may be present on said spiro-linked heterocycloaliphatic groups are halogen atoms, in particular fluorine or chlorine atoms, C _1-6 alkyl groups, in particular methyl, ethyl, propyl or isopropyl groups, C _1-6 alkoxy groups in particular methoxy or ethoxy groups, haloC _1-6 alkoxy groups, in particular —OCF ₃ , —CN, —CO ₂ CH ₃ , —NO ₂ , and a substituted amino group (—N (R ¹¹ ) ₂ ), in particular groups —NHCH ₃ and —N (CH ₃ ) ₂ . In addition, if the specified spiro-linked heterocycloaliphatic group contains a nitrogen atom, then this group may be substituted by the group - (L ⁶ ) _p (Alk ⁵ ) _q R ¹² , where L ⁶ preferably represents -C (O) - or -S (O ₂ ) -, Alk ⁵ preferably represents an optionally substituted C _1-6 alkylene chain, in particular a —CH ₂ -, - (CH ₂ ) ₂ - or —CH (CH ₃ ) CH ₂ chain, or an optionally substituted heteroC _1-6 an alkylene chain, in particular a —CH ₂ L ⁵ -, —CH ₂ CH ₂ L ⁵ -, —L ⁵ CH ₂ - or —L ⁵ CH ₂ CH ₂ chain, where L ⁵ represents an —O— or —S atom -, or a group -NH- or -N (CH ₃₎ -, and R ¹² represents a hydrogen atom, or an optionally substituted phenyl ring where preferred optional substituents include the atoms and groups defined above for R ¹⁶ in compounds of formula (2b). In one preferred group of compounds of this class, R ^z represents a hydrogen atom. In another preferred group of compounds of this class, R ^z represents an alkyl group described above. In another preferred group of compounds of this class, R ^z represents a halogen atom, in particular a fluorine, chlorine, bromine or iodine atom, most preferably a chlorine or bromine atom. In another preferred group of compounds of this class, R ^z represents a group of the formula —L ¹ (Alk ¹ ) _n R ³ described above.

Particularly preferred compounds of the present invention are:

(2S) -2 - [(3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) hydroxy] phenyl} propanoic acid,

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(2,7) naphthyridin-1-yloxy] phenyl} propanoic acid,

(2S) -2 - [(2-bromo-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- (2,6-dimethoxy- [1,1'-biphenyl] -4-yl) propanoic acid,

(2S) -2 - {(3-oxospiro [3,6] dec-1-en-1-yl) amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-bromo-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - {[4,4-dimethyl-2- (phenylselenyl) -3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid ,

(2S) -2 - [(2-bromo-7-methoxy-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - {(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridine- 1-yl) oxy] phenyl} propanoic acid,

(2S) -2 - {[2- (phenylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid ,

(2S) -2 - [(2-chloro-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-pyridin-3-ylspiro [3,5] non-1-en-1-ylamino ) propanoic acid,

(2S) -2 - [(2-iodo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridine- 2-yl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridine- 2-yl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2- [4,4-dimethyl-2- (1-methyl-1H-tetrazol-5-ylsulfanyl) -3-oxocyclobut-1-enylamino] -3- {4 - [(3,5-dichloroisonicotinoyl ) amino] phenyl} propanoic acid,

(2S) -2 - [(2-bromo-3,7,7-trioxo-7λ ⁶ -thiaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3 , 5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-bromo-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-methylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2- (2-fluoro-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-fluoro-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino) 3- {4 - [(3,5-dichloroisonicotinoyl) amino ] phenyl} propanoic acid,

(2S) -2 - [(4,4-dimethyl-2-methylsulfanyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid ,

(2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid,

(2S) -2 - [(2-isopropylsulfanyl-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridine- 1-ylamino) phenyl] propanoic acid,

(2S) -2 - [(2-bromo-3-oxospiro [3,4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(4,4-dimethyl-3-oxo-2-pentafluorophenylsulfanylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(4,4-dimethyl-3-oxo-2-pyrazin-2-ylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(7-acetyl-2-bromo-3-oxo-7-azaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3, 5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - {[2- (isopropylsulfanyl) -3-oxo-7-oxaspiro [3,5] non-1-en-1-yl)] amino} -3- (2,6-dimethoxy [1 , 1'-biphenyl] -4-yl) propanoic acid,

(2S) -2 - [(2-cyclohexyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxospiro [3,5] non-1-en-1-ylamino) propanoic acid,

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propylspiro [3,5] non-1-en-1-ylamino) propanoic acid,

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxo-7-oxaspiro [3,5] non-1-en-1-ylamino ) propanoic acid,

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propyl-7-oxaspiro [3,5] non-1-en-1-ylamino ) propanoic acid,

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2- [1,3] dithian-2-yl-3-oxospiro [3,5] non-1- en-1-ylamino) propanoic acid,

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-ethyl-3-oxospiro [3,5] non-1-en-1-ylamino) propanoic acid,

(2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (3-oxospiro [3,5] non-1-en-1-ylamino ) propanoic acid,

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl ) amino] phenyl} propanoic acid,

(2S) -2- (2-chloro-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl ) amino] phenyl} propanoic acid,

(2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (2-methanesulfinyl-4,4-dimethyl-3-oxocyclobut-1-enylamino ) propanoic acid,

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4- (3-methyl [2,7] naphthyridin-1-ylamino) phenyl] propanoic acid,

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propane acid,

(2S) -2- (2-bromo-4,4-dimethyl-3-oxocyclobut-1-enylamino] -3- [4- (3-methyl [2,7] naphthyridin-1-yloxy) phenyl] propanoic acid ,

(2S) -2 - [(2-bromo-3-oxospiro [3,5] oct-1-en-1-yl) amino] 3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propane acid and

their salts, solvates, hydrates, N-oxides and esters of carboxylic acids.

Particularly preferred carboxylic acid esters are methyl, ethyl, propyl, isopropyl and tert-butyl esters.

The most preferred compounds of the present invention are:

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-bromo-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-bromo-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - {(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridine- 1-yl) oxy] phenyl} propanoic acid,

(2S) -2 - {[2- (phenylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid ,

(2S) -2 - [(2-chloro-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-pyridin-3-ylspiro [3,5] non-1-en-1-ylamino ) propanoic acid,

(2S) -2 - [(2-iodo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridine- 2-yl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridine- 2-yl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-bromo-3,7,7-trioxo-7λ ⁶ -thiaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3 , 5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-chloro-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-bromo-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-methylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2- (2-fluoro-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2- (2-fluoro-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino ] phenyl} propanoic acid,

(2S) -2- [4,4-dimethyl-2-methylsulfanyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid ,

(2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino] phenyl} propanoic acid

(2S) -2 - [(2-isopropylsulfanyl-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridine- 1-ylamino) phenyl] propanoic acid,

(2S) -2 - [(2-bromo-3-oxospiro [3,4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(7-acetyl-2-bromo-3-oxo-7-azaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3, 5-dichloroisonicotinoyl) amino] phenyl} propanoic acid,

(2S) -2 - [(2-cyclohexyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxospiro [3,5] non-1-en-1-ylamino) propanoic acid,

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propylspiro [3,5] non-1-en-1-ylamino) propanoic acid,

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2- [1,3] dithian-2-yl-3-oxospiro [3,5] non-1- en-1-ylamino) propanoic acid,

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl ) amino] phenyl} propanoic acid,

(2S) -2- (2-chloro-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl ) amino] phenyl} propanoic acid,

and their salts, solvates, hydrates, N-oxides and esters of carboxylic acids.

Particularly preferred carboxylic acid esters are methyl, ethyl, propyl, isopropyl and tert-butyl esters.

Particularly suitable esters of prodrug precursors of the compounds of the present invention are:

ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

isopropyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

tert-butyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

1-methylpiperidin-4-yl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

phenyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoylamino] phenyl} propanoate,

cyclopentyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

2-imidazol-1-yl-ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

neopentyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

tetrahydrofuran-3-yl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

pyridin-4-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

tetrahydropyran-4-yl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-Dichloroisonicotinoyl) amino] phenyl} propanoate,

1-methylpyrrolidin-3-yl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

2,3-dihydroxypropyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate and

tetrahydrofuran-2-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate,

and their salts, solvates, hydrates and N-oxides.

The compounds of the present invention are potent and selective α4 integrin inhibitors. The ability of these compounds to such activity can be easily determined using the tests described in the following examples.

The compounds can be used to modulate cell adhesion, and in particular, for the prevention and treatment of diseases or disorders, including inflammatory disorders, in which leukocyte extravasation plays a role, and therefore the present invention relates to the use of these compounds for these purposes, as well as their use for the preparation of a medicament for the treatment of these diseases or disorders.

Diseases or disorders of this type are inflammatory arthritis, such as rheumatoid arthritis, vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.

For the prevention or treatment of a disease, the compounds of the present invention can be administered in the form of pharmaceutical compositions, and in accordance with another aspect, the present invention relates to a pharmaceutical composition which comprises a compound of formula (1) in combination with one or more pharmaceutically acceptable carriers, excipients or diluents .

The pharmaceutical compositions of the present invention can be made in a form suitable for oral, buccal, parenteral, intranasal, local or rectal administration, or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions can be prepared in the form of, for example, tablets, troches or capsules made by standard methods and containing pharmaceutically acceptable excipients, such as binding agents (for example, corn starch swellable in cold water, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium bisphosphate); lubricants (e.g. magnesium stearate, talc or silicon dioxide); disintegrants (e.g. potato starch or sodium glycolate); or wetting agents (e.g. sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be prepared in the form of, for example, solutions, syrups or suspensions, or they may be prepared as a dry product which is reconstituted with water or another suitable vehicle before use. Such liquid preparations can be prepared by standard methods using pharmaceutically acceptable additives, such as suspending agents, emulsifying agents, anhydrous carriers and preservatives. These preparations may also contain, if necessary, buffering salts, perfumes, colorants and sweetening agents.

Preparations for oral administration can be prepared so that they provide controlled release of the active compound.

For buccal administration, these compositions may be prepared in the form of tablets or lozenges in a standard manner.

The compounds of formula (1) can be prepared for parenteral administration by injection, for example, bolus injection, or infusion. Compositions for injection can be prepared in the form of a single dosage form, for example, in a glass ampoule, or in the form of packages for repeated administration of a medicine, for example, glass vessels. Compositions for injection can be obtained in the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain processing aids, such as suspending agents, stabilizers, preservatives and / or dispersing agents. Alternatively, the active ingredient may be prepared in powder form, which is reconstituted with a suitable vehicle, for example sterile pyrogen-free water, before use.

In addition to the compositions described above, the compounds of formula (1) can be formulated as a depot preparation. Such sustained release formulations may be administered by implantation or by intramuscular injection. For intranasal administration or for administration by inhalation, the compositions of the present invention are usually delivered in the form of an aerosol spray in spray-type packages or in inhalers using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas mixture.

Such compositions may, if necessary, be included in packages or dispensers, which may contain one or more unit dosage forms containing the active ingredient. This package or dispenser may be provided with instructions for administering the drug.

The amount of a compound of the present invention needed to prevent or treat a particular condition may vary depending on the compound selected and the condition of the patient being treated. However, in general, daily doses may range from about 100 ng / kg to 100 mg / kg, for example, from 0.01 to 40 mg / kg body weight, for oral or buccal administration; from about 10 ng / kg to 50 mg / kg body weight for parenteral administration; and from about 0.05 to 1000 mg, for example, from about 0.5 to 1000 mg for intranasal administration or for administration by inhalation or insufflation.

The compounds of the present invention can be obtained in various ways, mainly as described below, and more specifically, as described in the following examples. In the methods described below, the symbols Ar ¹ , Ar ² , Alk, R ¹ , R ² , R ³ , L ¹ , L ² , Alk ¹ , R ^x , R ^y , R ^z and n, if they are present in these formulas , mean groups defined above for compounds of formula (1), unless otherwise indicated. In the reactions described below, it may be necessary that the reactive functional groups, for example, hydroxy, amino, thio, or carboxy groups, the presence of which is desirable in the final product, are protected to prevent undesired reactions. In this case, standard protective groups described in the literature can be used [see, for example, Green, TW, “Protective Groups in Organic Synthesis”, John Wiley and Sons, 1999]. In some cases, the deprotection reaction may be carried out at the final stage of the synthesis of the compound of formula (1), wherein the methods for removing such protecting groups described below are also within the scope of the present invention. For convenience, all of the following methods are described for preparing a compound of formula (1), it being understood that this description applies equally to the preparation of compounds of formula (2).

Thus, in accordance with another aspect of the present invention, a compound of formula (1) in which R represents a —CO ₂ H group can be obtained by hydrolysis of an ester of formula (1a):

where Alk represents a group

[where Alk ⁷ represents an alkyl group, for example, a C _1-6 alkyl group].

Hydrolysis can be carried out using either an acid or a base, depending on the nature of Alk ⁷ , for example, an organic acid, such as trifluoroacetic acid, or an inorganic base, such as lithium, sodium or potassium hydroxide, optionally in an aqueous organic solvent, such as amide for example, a substituted amide such as dimethylformamide; an ether, for example, a cyclic ether, such as tetrahydrofuran or dioxane, or an alcohol, for example methanol, at a temperature from ambient temperature to reflux temperature. If necessary, mixtures of these solvents can be used.

In accordance with another aspect of the present invention, a compound of formula (1) can be obtained by condensation of a compound of formula (3):

where the compounds of formula (3) are present in the form of two tautomeric isomers, (3a) and (3b), in solution with an amine of the formula R ¹ R ² NH, an alcohol of the formula R ¹ OH or with a thiol of the formula R ¹ SH. This reaction can be carried out in an inert solvent or in a mixture of solvents, for example, a hydrocarbon, such as an aromatic hydrocarbon, such as benzene or toluene and / or a halogenated hydrocarbon, such as 1,2-dichloroethane or dichloromethane, at a temperature of from 0 ° C. to boiling temperature under reflux. If necessary, for example, if an amine salt of R ¹ R ² NH is used, an organic base such as diisopropylethylamine can be added.

Any carboxylic acid group present in the intermediate of formula (3), or an amine R ¹ R ² NH, an alcohol R ¹ OH or a thiol R ¹ SH, if necessary, can be protected during the substitution reaction, for example, in the form of ethyl ether. Then the desired acid can be obtained by subsequent hydrolysis, for example, in particular, as described above, and basically, as described below.

The substitution reaction can also be carried out on an intermediate of formula (4) (see below) under the conditions described above.

If necessary, a substitution reaction can be carried out on an intermediate of formula (3), where R ¹ R ² NH, R ¹ OH or R ¹ SH are connected, for example, via a group R, R ¹ or R ³ , with a solid carrier, such as polystyrene resin. After the reaction, the desired compound of formula (1) can be separated from the carrier by any standard method, depending on the selected starting bond.

Intermediates of formula (3), R ¹ R ² NH, R ¹ OH, or R ¹ SH can be prepared from simpler known compounds using one or more standard synthetic methods, including substitution, oxidation, reduction, or cleavage reactions. Specific methods for carrying out the substitution reaction are standard procedures for the alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulfonylation, nitration, formylation and combination. It should be noted that these methods can also be used to obtain or modify other compounds of formula (1) and (2a), (2b), (2c) and (2d), if the corresponding functional groups are present in these compounds.

Thus, intermediate compounds of formula (3) can be obtained by hydrolysis of intermediate compounds of formula (4):

where R ^a represents a C _1-6 alkyl group or a silyl group, such as a tert-butyldimethylsilyl group.

The hydrolysis can be carried out using an acid, for example, an inorganic acid, such as hydrochloric acid, in an organic solvent, such as ether, for example diethyl ether or alcohol, for example ethanol, optionally in the presence of added water at a temperature from about ambient temperature to 80 ° C.

Intermediates of formula (4) can be prepared by a cycloaddition reaction of an intermediate of formula (5):

with a ketone of formula (6):

obtained previously or formed in situ during the cycloaddition reaction from an acid chloride of the formula (7):

This reaction can be carried out in the presence of an organic base such as an amine, for example triethylamine or N, N-diisopropylethylamine or a cyclic amine such as pyridine or N-methylmorpholine, optionally in an organic solvent such as ether, for example diethyl ether or diisopropyl ether.

Chlorides of formula (7) can be prepared from the corresponding acids by a standard halide preparation method, for example by reaction with thionyl chloride or oxalyl chloride under standard conditions well known to those skilled in the art.

Compounds of formula (1a) in which R ^z represents, for example, a halogen atom, can be obtained from compounds of formula (1a), where R ^z represents a hydrogen atom, by reacting with a halogen source such as bromine or halogen succinamide, for example, chlorine - or bromosuccinamide. This reaction can be carried out in a solvent, such as an ether, for example, a cyclic ether, such as tetrahydrofuran, at a temperature of from about 0 to 30 ° C. If bromine is used as the halogen source, this interaction may, but not necessarily, be carried out in the presence of an added base such as an amine, for example triethylamine.

Other compounds of formula (1a) in which R ^z is —L ¹ (Alk ¹ ) _n (R ³ ) _v , where L ¹ is, for example, Se, S, O or N (R ⁸ ), can be prepared by reaction the interaction of the intermediate compounds of formula HL ¹ (Alk ¹ ) _n (R ³ ) _v with the compound of formula (1a), where R ^z represents a hydrogen atom. This reaction can be carried out in an organic solvent, such as an ether, for example, a cyclic ether, such as tetrahydrofuran, at about room temperature, optionally in the presence of a base, such as an amine, for example triethylamine.

Intermediates of formula (4) can also be prepared from squaric acid derivatives by well-known methods described by MacDougall, J. M. et al., J. Org. Chem., 64, 5979-83 (1999); Hergueta, R. A., J. Org. Chem., 64, 5979-83 (1999); Heileman, V. J. et al., J. Am. Chem. Soc., 120, 3801-2 (1998); Yamamoto, Y. et al., J. Org. Chem., 62, 1292-8 (1997); Zhag, D. et al., J. Org. Chem., 61, 2594-5 (1996); Petasis, N. A. et al., Synlett, 155-6 (1996); Petasis, N.A. et al., Tetrahedron Lett., 36, 6001-4 (1995); Tumbull, P. et al., J. Org. Chem., 60, 644-9 (1995); Yerxa, B. R. et al., Tetrahedron, 50, 6173-80 (1994); Ezcurra, J. E. et al., Tetrahedron Lett., 34, 6177-80, (1993); Ohno, M. et al., Tetrahedron Lett., 34, 4807-10 (1993); Yerxa, B. R. et al., Tetrahedron Lett., 33, 7811-14 (1992); Xu, S. L. et al., J. Org. Chem., 57, 326-8 (1992) and Kravs, J. L. et al., Tetrahedron Lett., 28, 1765-8 (1987).

Other compounds of the present invention and their intermediates may be prepared by alkylation, arylation or heteroarylation. Thus, for example, compounds containing the group —L ¹ H or —L ² H (where each of L ¹ and L ² represents a linker atom or linker group) can be treated with a combination agent R ³ (Alk ¹ ) _n X ¹ or Ar ¹ X ^1, respectively, where X ¹ represents a leaving atom or a leaving group, for example, a halogen atom such as a fluorine, bromine, iodine or chlorine atom, or a sulfonyloxy group, such as an alkylsulfonyloxy group, for example, a trifluoromethylsulfonyloxy group or an arylsulfonyloxy group, for example, para-toluenes

This reaction can be carried out in the presence of a base, such as a carbonate, for example cesium or potassium carbonate, an alkoxide, for example potassium tert-butoxide, or a hydride, for example sodium hydride, or an organic amine, for example triethylamine or N, N-diisopropylethylamine or a cyclic amine, such as N-methylmorpholine or pyridine, in a bipolar aprotic solvent, such as an amide, for example, a substituted amide, such as dimethylformamide, or an ether, for example, a cyclic ether, such as tetrahydrofuran.

Compounds of formula Ar ¹ X ¹ can be prepared from alcohols of formula Ar ¹ OH by reaction with a halogenating agent, for example, phosphorus oxyhalide, such as phosphorus oxychloride, at elevated temperatures, for example, at 110 ° C.

Intermediate alcohols of the formula Ar ¹ OH, where Ar ¹ , for example, is 2,6-naphthyridine, can be prepared by methods well known to those skilled in the art, for example, by the method described by T. Sakamoto et al. [Chem. Pharm. Bull., 33, 626-633 (1985)].

Alternatively, alkylating agents of the formula Ar ¹ X ¹ , where, for example, Ar ¹ is 2,6-naphthyridine, can be prepared by reacting N-oxide or N, N'-2,6-naphthyridine dioxide with a halogenating agent, for example, phosphorus oxyhalide such as phosphorus oxychloride to give 1-halogen or 1,5-dihalo-2,6-naphthyridine, respectively. In the case of 1,5-dihalo-2,6-naphthyridine, each halogen atom can be individually substituted with a reagent such as HL ² Ar ² AlkN (R ² ) H or HL ³ (Alk ² ) _t L ⁴ (R ⁴ ) _u corresponding the methods described above.

N-oxides and N, N'-dioxides of 2,6-naphthyridine can be obtained from the corresponding 2,6-naphthyridines by the general methods for the synthesis of N-oxides described below, or they can be synthesized by the methods described by Numata A. et al. (Synthesis, 1999, 306-311).

Other alkylating agents of the formula Ar ¹ X ¹ , where, for example, Ar ¹ is 2,6-naphthyridine, can be obtained by the methods described by Giacomello G. et al. [Tetrahedron Letters, 1117-1121 (1965)], Tan, R. and Taurins, A. [Tetrahedron Lett., 2737-2744 (1965)], Ames, DE and Dodds, WD [J. Chem. Soc. Perkin, 1, 705-710 (1972)] and Alhaique, F. et al. [Tetrahedron Lett., 173-174 (1975)].

Intermediate alcohols of the formula Ar ¹ OH, where Ar ¹ is an optionally substituted 2,7-naphthyridin-1-yl group, can be prepared by methods well known to those skilled in the art, for example, the method described by Sakamoto, T. et al. [Chem. Pharm. Bull., 33 626-633 (1985) or Baldwin, JJ et al. [J. Org. Chem., 43, 4878-4880 (1978)]. For example, the synthesis of intermediate 3-substituted 2,7-naphthyridin-1-yl groups of the formula Ar ¹ OH described in Scheme 1 can be carried out by a modified Baldwin method.

As a result of the interaction of the optionally substituted 4-methyl-3-cyanopyridine of formula (8) with N, N-dimethylformamide di-C _1-6 alkyl acetal, for example, N, N-dimethylformamide diethyl acetal in a bipolar solvent such as an amide, for example, substituted an amide, such as dimethylformamide, at an elevated temperature, for example, 140-150 ° C., a compound of formula (9) or (10) or a mixture thereof is obtained, depending on the nature of the group R ¹⁶ .

Compounds of formula (9) or (10) can be cyclized to produce a 3-substituted 2,7-naphthyridin-1-yl alcohol of formula (11) by treatment with an acid, for example, an inorganic acid such as hydrochloric acid or hydrobromic acid, or acidic gas, such as hydrogen chloride in an organic solvent, for example, in an organic acid, such as acetic acid, optionally in the presence of water, at a temperature from about ambient temperature to 50 ° C.

Alternatively, alkylating agents of the formula Ar ¹ X ¹ , where Ar ¹ is an optionally substituted 2,7-naphthyridin-1-yl group, can be obtained by reacting the N-oxide or N, N'-2,7-naphthyridine dioxide with a halogenating agent, for example, phosphorus oxyhalide, such as phosphorus oxychloride, to give 1-halogen or 1,6-dihalo and / or 1,8-dihalo-2,7-naphthyridine, respectively. In the case of 1,6-dihalo- and / or 1,8-dihalo-2,6-naphthyridines, each halogen atom may be individually substituted with a reagent such as HL ² Ar ² AlkN (R ² ) H or HL ³ (Alk ² ) _t L ⁴ (R ⁴ ) _{u by the} appropriate methods described above.

N-oxides and N, N'-dioxides of 2,7-naphthyridine can be obtained from the corresponding 2,7-naphthyridines by the general methods for the synthesis of N-oxides described below, or they can be synthesized by the methods described by Numata A. et al. (Synthesis, 1999, 306-311).

Other alkylating agents of the formula Ar ¹ X ¹ , where, for example, Ar ¹ is 2,7-naphthyridin-1-yl, can be obtained by the methods described by Wenkert E. et al., J. Am. Chem. Soc., 89, 6741-5 (1967), and Aust. J. Chem. 433 (1972), and Sheffield DJJ Chem. Soc. Perkin. Trans I, 2506 (1972).

Intermediate alcohols of the formula Ar ¹ OH, where Ar ¹ is a 3-substituted isoquinolin-1-yl group, can be prepared by methods well known to those skilled in the art, for example, by the method described by Wu M.-J. et al. Tetrahedron, 55, 13193-200 (1999), Hiebl J. et al. Tetrahedron Lett., 40, 7935-8 (1999), Nagarajan A. et al. Indian J. Chem., Sect. B, 28B, 67-78 (1989), Brun EM et al. Synlett, 7, 1088-90 (1999) and Brun, EM et al. Synthesis, 273-280 (2000).

Other alkylating agents of the formula Ar ¹ X ¹ , where, for example, Ar ¹ represents an isoquinolin-1-yl group, can be obtained by the methods described by Falk H. et al. Monatsch. Chem., 25, 325-33 (1994) and Deady, LW et al. Aust. J. Chem., 42, 1029-34 (1989).

In another example, intermediates of formula R ¹ R ² NH can be prepared by reacting a compound of formula Ar ¹ L ² H with a compound of formula X ¹ Ar ² AlkN (R ² ) H under the reaction conditions described above.

Compounds of the formula Ar ¹ L ² H, where, for example, Ar ¹ is 2,6-naphthyridine and L ² is the group —N (R ⁸ ), can be prepared from substituted 4-cyano-3-cyanomethylpyridines by the methods described by Alhaique, F. et al. (ibid. Gazz. Chim. Ital., 1975, 105, 1001-1009) or from 3-formylpyridines by the methods described by Molina, P. et al. (Tetrahedron, 1992, 48, 4601-4616).

Compounds of the formula Ar ¹ L ² H, where, for example, Ar ¹ represents a 2,7-naphthyridin-1-yl group and L ² represents a —N (R ⁸ ) - group, can be prepared from substituted 4-formylpyridines by the methods described Molina, P. et al. Tetrahedron, 48, 4601-4616 (1992), or by the methods described in US patent No. 3938367.

Compounds of the formula Ar ¹ L ² H, where, for example, Ar ¹ represents a 3-substituted isoquinolin-1-yl group and L ² represents a —N (R ⁸ ) - group, can be prepared by the methods of Bordner, J. et al. J. Med. Chem., 31, 1036-9 (1988), Tovar JD et al. J. Org. Chem., 64, 6499-6504 (1999), Karser EM et al. Synthesis, 11, 805-6 (1974), and Molino, P. et al. J. Chem. Soc. Perkin Trans., 1, 1727-31 (1990).

In another example, compounds containing -L ¹ H or -L ² H or a group as defined above may be functionalized by acylation or thioacylation, for example, by reaction with one of the alkylating agents described above, but in which X ^{1 is} replaced by - C (O) X ² , —C (S) X ² , —N (R ⁸ ) COX ^2, or —N (R ⁸ ) C (S) X ² , where X ² represents a leaving atom or a leaving group described for X ¹ . This reaction can be carried out in the presence of a base, such as a hydride, for example sodium hydride, or an amine, for example triethylamine or N-methylmorpholine, in a solvent such as a halogenated hydrocarbon, for example dichloromethane or carbon tetrachloride or an amide, for example dimethylformamide, for example at ambient temperature. Alternatively, the acylation can be carried out under the same conditions using an acid (for example, one of the alkylating agents described above, where X ^{1 is} replaced by a group —CO ₂ H) in the presence of a condensing agent, for example, a diimide such as 1- (3-dimethylaminopropyl ) -3-ethylcarbodiimide or N, N'-dicyclohexylcarbodiimide, preferably in the presence of a catalyst, such as an N-hydroxy compound, for example, N-hydroxytriazole, such as 1-hydroxybenzotriazole. Alternatively, the acid may be reacted with chloroformate, for example ethyl chloroformate, before the desired acylation reaction is carried out.

In another example, compounds can be prepared by sulfonylation of a compound containing an —OH group, by reaction with one of the above alkylating agents, but where X ^{1 is} replaced by —S (O) Hal or —SO ₂ Hal groups [where Hal represents a halogen atom, such as a chlorine atom] in the presence of a base, for example, an inorganic base, such as sodium hydride in a solvent, such as an amide, for example a substituted amide, such as dimethylformamide, for example, at room temperature.

In another example, compounds containing the group —L ¹ H or —L ² H, as defined above, can be reacted with one of the alkylating agents described above, wherein X ^{1 is} replaced by —OH, in a solvent such as tetrahydrofuran, in the presence of phosphine, for example triphenylphosphine, and an activator, such as diethyl, diisopropyl or dimethyl azodicarboxylate.

In another example, the ester groups —CO ₂ R ⁵ , —CO ₂ R ^11, or CO ₂ Alk ⁷ in these compounds can be converted to the corresponding acid [CO ₂ H] by hydrolysis catalyzed by acid or base, depending on the nature of the R ⁵ groups R ¹¹ or Alk ⁷ . The hydrolysis catalyzed by acid or base can be carried out, for example, by treatment with an organic or inorganic acid, for example trifluoroacetic acid, in an aqueous solvent or in a mineral acid, such as hydrochloric acid in a solvent, such as dioxane or an alkali metal hydroxide, for example lithium hydroxide in aqueous alcohol, for example, in aqueous methanol.

In another example, —OR ⁵ or OR ¹⁴ groups [where each R ⁵ or R ¹⁴ represents an alkyl group such as a methyl group] in the compounds of formula (1) can be cleaved to form the corresponding alcohol —OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, for example dichloromethane, at low temperature, for example at about -78 ° C. Alcohol (-OH) groups can also be obtained by hydrogenation of the corresponding -OCH ₂ R ¹⁴ group (where R ¹⁴ represents an aryl group ) using metal a natural catalyst, for example palladium, on a carrier such as carbon, in a solvent such as ethanol, in the presence of ammonium formate, cyclohexadiene or hydrogen, at a temperature from about ambient temperature to reflux temperature. In another example, —OH groups can be prepared from the corresponding ester of [CO ₂ Alk ⁷ or CO ₂ R ⁵ ] or aldehyde [—CHO] by reduction using, for example, a metal complex hydride, such as lithium aluminum hydride or sodium borohydride, to a solvent such as methanol.

In another example, the —OH alcohol groups in these compounds can be converted to the corresponding —OR ⁵ or —OR ¹⁴ group by reaction with a reagent R ⁵ OH or R ¹⁴ OH in a solvent such as tetrahydrofuran in the presence of phosphine, for example triphenylphosphine and an activator such as diethyl, diisopropyl or dimethyl azodicarboxylate.

The amino-sulfonylamino groups of [-NHSO ₂ NHR ³ or -NHSO ₂ NHAr ¹ ] in these compounds can be obtained in another example by reacting the corresponding amine [-NH ₂ ] with sulfamide R ³ NHSO ₂ NH ₂ or Ar ¹ NHSO ₂ NH ₂ in the presence of organic a base, such as pyridine, at an elevated temperature, for example, at reflux temperature.

In another example, compounds containing the —NHCSAr ¹ , —CSNHAr ¹ , —NHCSR ^3, or —CSNHR ³ groups can be prepared by treating the corresponding compound containing the —NHCOAr ¹ , —CONHAr ¹ , —NHCOR ^3, or —CONHR ³ groups with a reagent, introducing a thia group, such as Lawesson's reagent, in an anhydrous solvent, for example, in a cyclic ether, such as tetrahydrofuran, at an elevated temperature, such as a boiling point under reflux.

In another example, amine groups (—NH ₂ ) can be alkylated by reductive alkylation using an aldehyde and borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as a halogenated hydrocarbon, such as dichloromethane, a ketone, such as acetone, or alcohol, for example, ethanol, if necessary, in the presence of an acid, such as acetic acid, at about ambient temperature.

In another example, the amine groups [-NH ₂ ] in the compounds of formula (1) can be obtained by hydrolysis from the corresponding imide by reacting it with hydrazine in a solvent such as alcohol, for example ethanol, at ambient temperature.

In another example, the nitro group [-NO ₂ ] can be reduced to the amine [-NH ₂ ], for example, by catalytic hydrogenation using, for example, hydrogen, in the presence of a metal catalyst, for example, palladium-supported, such as coal, in a solvent such as an ether, for example tetrahydrofuran or an alcohol, for example methanol, or by chemical reduction using, for example, a metal, for example tin or iron, in the presence of an acid such as hydrochloric acid.

Aromatic halogen substituents in the compounds can be subjected to a halogen-metal exchange reaction using a base, for example, a lithium base such as n-butyllithium or tert-butyl lithium, optionally at a low temperature, for example, at about −78 ° C., in a solvent such like tetrahydrofuran; and then this reaction can be quenched by an electrophile to introduce the desired substituent, for example, a formyl group can be introduced using dimethylformamide as an electrophile, and a thiomethyl group can be introduced using dimethyl sulfide as an electrophile.

In another example, the sulfur atoms in these compounds, for example, if they are present in the linker group L ¹ or L ² , can be oxidized to the corresponding sulfoxide or sulfone using an oxidizing agent such as peroxyacid, for example 3-chloroperoxybenzoic acid, in an inert solvent, such as a halogenated hydrocarbon, for example dichloromethane, at about ambient temperature.

In another example, compounds of the formula Ar ¹ X ¹ (where X ¹ represents a halogen atom such as a chlorine, bromine or iodine atom) can be converted into compounds such as Ar ¹ CO ₂ R ²⁰ (where R ²⁰ is an optionally substituted alkyl, aryl or heteroaryl group), Ar ¹ CHO, Ar ¹ CHCHR ²⁰ , Ar ¹ CCR ²⁰ , Ar ¹ N (R ²⁰ ) H, Ar ¹ N (R ²⁰ ) ₂ for their use, for example, in the synthesis of compounds of formula Ar ¹ L ² Ar ² AlkN (R ² ) H, carried out under well-known and widely used reaction conditions, catalyzed by palladium and described in the general guidelines of Rodd's Chemistry of Carbon Compounds, Volumes 1-15 and Supplementals (Elsevier Science Publishers, 1989), Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al., Volumes 1-8, 1984 and Volumes 1-11, 1994 (Pergamon), Comprehensive Organic Functional Group Transformations, Ed. Katritzky et al., Volumes 1-7, 1995 (Pergamon), Comprehensive Organic Synthesis, Ed. Trost and Flemming, Volumes 1-9 (Pergamon, 1991), Encyclopedia of Reagents for Organic Synthesis, Ed. Paguette, Volumes 1-8 (John Wiley and Sons, 1995), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) and March's Advanced Organic Chemistry (John Wiley and Sons, 1992).

N-oxides of the compounds of formula (1) can be obtained, for example, by oxidizing the corresponding nitrogen base using an oxidizing agent, such as hydrogen peroxide in the presence of an acid, such as acetic acid at elevated temperatures, for example, from about 70 to 80 ° C, or alternatively, by reaction with a peracid, such as peracetic acid in a solvent, such as dichloromethane, at ambient temperature.

Salts of compounds of formula (1) can be prepared by reacting a compound of formula (1) with an appropriate base in a suitable solvent or in a mixture of solvents, for example, in an organic solvent such as ether, for example diethyl ether, or alcohol, for example ethanol, using standard procedures.

If it is necessary to obtain a specific enantiomer of a compound of formula (1), it can be obtained from an appropriate mixture of enantiomers using any suitable standard procedure for the separation of ententiomers.

Thus, for example, diastereomeric derivatives, for example, salts, can be obtained by reacting a mixture of enantiomers of the formula (1), for example, a racemate, with the corresponding chiral compound, for example, a chiral base. Then these diastereomers can be separated by any suitable methods, for example, crystallization, and the desired enantiomer can be isolated, for example, by treatment with an acid, if the specified diastereomer is a salt.

In another separation method, the racemate of formula (1) can be separated using chiral high performance liquid chromatography. Alternatively, if necessary, a particular enantiomer can be obtained using the corresponding chiral intermediate in one of the methods described above. Alternatively, a specific enantiomer can be obtained by carrying out an enzymatic bioconversion specific for a given enantiomer, for example, hydrolyzing an ester using esterase, followed by purification of only the unanti-ester hydrolyzed acid from the unreacted ester antipode.

Chromatography, recrystallization, or other standard separation procedures using intermediates or end products may also be carried out to obtain the specific geometric isomer of the present invention.

The present invention is illustrated by the following examples. All temperatures are given in ° C. The following abbreviations were used:

NMM - N-methylmorpholine

MeOH - methanol

DCM - Dichloromethane

DIPEA - Diisopropylethylamine

Pyr - Pyridine

DMSO - dimethyl sulfoxide

Et ₂ O - diethyl ether

THF - tetrahydrofuran

FMOC - 9-fluorenylmethoxycarbonyl

DBU - 1,8-diazabicyclo [5.4-0] undec-7-ene

DMAP - 4- (dimethylamino) pyridine

NOVT - 1-hydroxybenzotriazole

EtOAc - Ethyl Acetate

BOC - butoxycarbonyl

AcOH - acetic acid

EtOH - Ethanol

Ar - aryl

IPr - Isopropyl

Me - methyl

DMF - N, N-dimethylformamide

All NMR were obtained either at 300 M Hz or at 400 M Hz.

All intermediates and examples were named using Beilstein Autonom (available from MDL Information Systems GmbH, Therdor-Heuss-Allee 108D 60486, Frankfurt, Germany), or names were given that apparently correspond to the names accepted by IUPAC, with the exception of that instead of the trivial name “propionate” the name “propanoate” was given, and instead of the name “pyridine-4-carbonyl” the name “isonicotinoyl” (trivial name) was used.

INTERMEDIATE CONNECTION 1

(+/-) - 3-ethoxy-4-methyl-4-propyl-2-cyclobuten-1-one

The target compound was obtained by a modified method of Wasserman HH et al. [J. Org. Chem., 38, 1451-1455 (1973)]. To a solution of 2-methylpentanoyl chloride (3.91 ml) and etiletinilovogo ether (5g, 40% solution in hexane, 28.6 mmol) in Et ₂ O (35 mL) at room temperature was added with stirring triethylamine (9.9 mL ) The reaction mixture was heated to 50 ° C and stirred for 72 hours, and then cooled and filtered. The filtrate was concentrated in vacuo and the residual oil was chromatographed (SiO ₂ , hexanes: EtOAc 80:20) to give the title compound as a colorless oil (3.71 g, 17.9 mmol, 77%) δH (CDCl ₃ , 300K), 4 84 (1H, s), 4.24-3.98 (2H, m), 2.04 (3H, s), 1.56-1.43 (4H, m), 1.30-1.26 (3H, m), 0.91 (3H, t, J = 7.3 Hz). m / z (ES ⁺ , 70B) 178.1 (MH ⁺ ).

INTERMEDIATE CONNECTION 2

(+/-) - 3-hydroxy-4-methyl-4-propyl-2-cyclobuten-1-one

Intermediate 1 (1 g, 59.5 mmol) and concentrated hydrochloric acid (2 ml) were stirred vigorously at room temperature for 48 hours. The resulting suspension was filtered and the residue washed with water (3 × 10 ml) and dried in vacuo to give the target compound as an off-white powder (620 mg, 44.2 mmol, 74%). δH (CDCl ₃ , 300K), 3.79 (2H, s), 1.59-1.53 (2H, m), 1.41-1.27 (2H, m), 1.18 (3H, s ), 0.85 (3H, t, J = 7.3 Hz). m / z (ES ⁺ , 70B) 140.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 3

3-ethoxy-4,4-dipropyl-2-cyclobuten-1-one

The target compound was obtained by a modified method of Wasserman HH et al. [J. Org. Chem., 38, 1451-1455 (1973)]. Triethylamine (29 ml) was added dropwise to a thoroughly mixed solution of di-n-propylacetyl chloride (13.9 g, 85.8 mmol) and ethyl ethinyl ether (15 g, 40% solution in hexane, 85.7 mmol) in toluene (120 ml) at room temperature. The reaction mixture was heated to 60 ° C and stirred for 48 hours, and then cooled and filtered. The filtrate was concentrated in vacuo and the residual oil was chromatographed (SiO ₂ ; hexanes: EtOAc 80:20) to give the title compound as a brown oil (11.2 g, 57.1 mmol, 67%) δH (CDCl ₃ , 300K), 5 02 (1H, s), 4.32 (2H, q, J, 7.1 Hz), 1.69-1.61 (4H, m), 1.45-1.40 (4H, m), 1 02 (6H, t, J = 7.3 Hz). m / z (ES ⁺ , 70B) 197.1 (MH ⁺ ).

INTERMEDIATE 4

3-hydroxy-4,4-dipropyl-2-cyclobuten-1-one

Intermediate 3 (10.2 mmol) and 6M hydrochloric acid (10 ml) were intensively stirred at 65 ° C for 72 hours. The resulting suspension was diluted with DCM (30 ml) and distilled water (30 ml) and extracted with DCM (3 × 10 ml). The combined extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title compound as a pale yellow oil, which crystallized upon standing (1.49 g, 8.87 mmol, 87%).

INTERMEDIATE CONNECTION 5

3-ethoxy-2-hexyl-4,4-dimethyl-2-cyclobuten-1-one

The target compound was obtained by a modified method of Wasserman HH et al. [J. Org. Chem., 38, 1451-1455 (1973)]. Triethylamine (22 ml) was added dropwise to a thoroughly mixed solution of isobutyryl chloride (7.3 ml, 69 mmol) and 1-ethoxy-1-octin [obtained by Kocienski P. et al., Tetrahedron Lett., 1833, 30 (1989) ] (6.5 g, 63 mmol) in diethyl ether (100 ml) at room temperature. The reaction mixture was heated to 35 ° C and stirred for 96 hours, and then cooled and filtered. The filtrate was concentrated in vacuo and the residual oil was chromatographed (SiO ₂ ; hexanes: EtOAc 80:20) to give the title compound as a brown oil (8.6 g, 38 mmol, 61%) δH (CDCl ₃ , 300K), 4.34 (2H, d, J 7.1 Hz), 2.05 (2H, dd, J 5.6 Hz, 7.3 Hz), 1.44 (3H, t, J 7.1 Hz), 1.27 -1.12 (8H, m), 1.23 (6H, s), 0.89 (3H, t, J = 2.7 Hz). m / z (ES ⁺ , 70B) 225.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 6

2-hexyl-3-hydroxy-4,4-dimethyl-2-cyclobuten-1-one

Intermediate 5 (7.6 g, 34.0 mmol) and 6M hydrochloric acid (10 ml) were stirred vigorously at 100 ° C. for 18 hours. The resulting suspension was diluted with DCM (30 ml) and distilled water (30 ml) and extracted with DCM (3 × 10 ml). The combined extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was triturated with hexane and filtered to give the desired compound as an off-white powder (6.5 g, 33.0 mmol, 98%). δH (CDCl ₃ , 300K), 2.01 (2H, t, J 7.0 Hz), 1.49-1.44 (2H, m), 1.34-1.19 (14H, m), 0 89-0.84 (3H, m), m / z (ES ⁺ , 70B) 197.0 (MH ⁺ ).

INTERMEDIATE 7

(+/-) - 4-benzyl-3-ethoxy-4-methyl-2-cyclobuten-1-one

The target compound was obtained by a modified method of Wasserman HH et al. [J. Org. Chem., 38, 1451-1455 (1973)]. To a stirred solution containing α-methyltetrahydrocinnamoyl chloride (5 g, 27.5 mmol) and ethyl ethylene ether (6 g, 40% solution in hexane, 85.7 mmol), triethylamine (20 ml) was added and the resulting suspension was heated to 35 ° C. within 3 days. Then the crude reaction mixture was filtered and the residue was concentrated in vacuo. The residual oil was chromatographed (SiO ₂ ; EtOAc: hexanes 20:80) to give the title compound as a light brown oil (4.91 g, 86%). δH (CDCl ₃ , 300K), 7.19-7.05 (5H, m), 4.56 (1H, s), 4.09-4.00 (1H, m), 3.97-3.89 (1H, m), 2.86 (1H, d, J 14.0 Hz), 2.86 (1H, d, J 14.0 Hz), 1.30 (3H, t, J 7.1 Hz) 1.24 (3H, s). m / z (ES ⁺ , 70B) 216.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 8

(+/-) - 4-benzyl-3-hydroxy-4-methyl-2-cyclobuten-1-one

Intermediate 7 (4.5 g, 20.9 mmol) and hydrochloric acid (6M, 10 ml) were stirred at room temperature for 48 hours. After filtering the resulting suspension and washing the residue with water (3 × 15 ml), the target compound was obtained in the form of a light brown powder (3.92 g, 20.8 mmol, 99%). δH (CDCl ₃ , 300K), 7.03-6.83 (5H, m), 4.24 (1H, s), 2.52 (2H, s), 0.94 (3H, s). m / z (ES ⁺ , 70B) 189.1 (MH ⁺ ).

INTERMEDIATE CONNECTION 9

3-cyano-4- (2- (N, N-dimethylamino) ethylene-1-yl) pyridine

A solution of 4-methyl-3-cyanopyridine [prepared as described in Prakt. Chem., 338, 663 (1996)] (8.0 g, 67.8 mmol) and N, N-dimethylformamide diethyl acetal (11.0 g, 74.8 mmol) in dry DMF (50 ml) was stirred at 140 ° C in an atmosphere of N ₂ for 2 days. An additional portion of N, N-dimethylformamide diethyl acetal (5 g) was then added and the mixture was stirred at 140 ° C. for 4 hours. Volatiles were removed in vacuo and the resulting dark oil was partitioned between EtOAc (300 ml) and water (50 ml). Then the phases were separated and the aqueous layer was again extracted with EtOAc (3x100 ml). The combined organic extracts were washed with brine (30 ml), dried (Na ₂ SO ₄ ), treated with activated carbon, filtered and evaporated in vacuo to give a substantially pure target compound as a pale orange solid (10.1 g , 85%). δH (CDCl ₃ ), 8.49 (1H, s), 8.25 (1H, d, J 5.9 Hz), 7.29 (1H, d, J 13.2 Hz), 7.09 (1H d, J 5.9 Hz), 5.25 (1H, d, J 13.2 Hz), and 2.99 (6H, s); m / z (ES ⁺ , 70B) 174 (MH ⁺ ).

INTERMEDIATE CONNECTION 10

Hydrochloride salt of 1-hydroxy-2,7-naphthyridine

HCl gas was bubbled through a stirred solution of intermediate 9 (6.2 g, 3.58 mmol) in glacial acetic acid (50 ml) and water (0.64 ml, 3.55 mmol) for 1-2 minutes. The reaction mixture was stirred in a flask with a closed lid at 40 ° C for 18 hours. Volatiles were removed in vacuo to give a dark residue, which was treated with water (3 × 20 ml) and again evaporated in vacuo. The resulting dark semi-solid was treated with 40 ml of warm ethanol, cooled with ice, and an insoluble solid was collected by filtration to obtain the target compound as a green solid (5.2 g, 80%) δH (DMSO-d ⁶ ) 12.5 (1H, broad) s), 9.38 (1H, s), 8.84 (1H, d, J 7.0 Hz), 8.15 (1H, d, J 7.0 Hz), 7.89 (1H, broad dd, J 7.0, 5.0 Hz) and 6.85 (1H, d, J 7.0 Hz); m / z (ES ⁺ , 70B) 147 (MH ⁺ ).

INTERMEDIATE CONNECTION 11

1-chloro-2,7-naphthyridine

Intermediate 10 (5.2 g, 28.5 mmol) was stirred with phosphorus oxychloride (75 ml) at 110 ° C. for 24 hours. Volatiles were removed in vacuo to give a dark oil, which was poured into a mixture of saturated aqueous NaHCO ₃ (100 ml, containing 20 g solid NaHCO ₃ ) and EtOAc (100 ml) cooled in an ice bath. After thoroughly mixing the phases were separated and the aqueous layer was again extracted with EtOAc (2 × 75 ml). The combined organic extracts were washed with brine (15 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the title compound as a yellow solid (4.0 g, 85%) δH (CDCl ₃ ) 9.45 (1H , s), 8.81 (1H, d, J 5.7 Hz), 8.47 (1H, d, J 5.7 Hz), 7.66 (1H, d, J 5.7 Hz) and 7 60 (1H, d, J 5.7 Hz); m / z (ES ⁺ , 70B) 165 and 167 (MH ⁺ ).

INTERMEDIATE CONNECTION 12

Ethyl (2S) -2-amino-3- [4- (2,7-naphthyridin-1-ylamino) phenyl] propanoate

A solution of ethyl (S) -3- [4-aminophenyl] -2- [tert-butoxycarbonylamino] propanoate (638 mg, 2.07 mmol) and intermediate 11 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml ) was stirred at 120 ° C for 15 min and at 100 ° C for 1 hour in a nitrogen atmosphere. Volatiles were removed in vacuo and the dark residue was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO ₃ (10 ml). The phases were separated and the aqueous layer was again extracted with EtOAc (2 × 30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a dark foam. Chromatography (SiO ₂ ; 5-10% MeOH / DCM) gave a mixture of ethyl (S) -3- [4- (2,7-naphthyridin-1-ylamino) phenyl] -2 - [(tert-butoxycarbonyl) amino ] propanoate and a certain amount of the target compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 hour. Volatiles were removed in vacuo and the residue was partitioned between EtOAc (75 ml) and saturated aqueous NaHCO ₃ (20 ml). The phases were separated and the aqueous layer was again extracted with EtOAc (3 × 30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an orange solid. Chromatography (SiO ₂ ; 10% MeOH / DCM) gave the title compound as a straw-colored solid (420 mg, 60% for two steps) δH (CDCl ₃ ) 10.70 (1H, s), 10.31 (1H , s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8 54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, d, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br.s), 3.64 (1H, dd, J 13.5, 6, 4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m / z (ES ⁺ , 70B) 337 (MH ⁺ ).

INTERMEDIATE CONNECTION 13

Methyl (2S) -2-amino-3- [4- (2,7-naphthyridin-1-yloxy) phenyl] propanoate

A mixture of N- (BOC) - (S) -tyrosine methyl ester (1.71 g, 5.80 mmol), potassium carbonate (0.80 g, 5.80 mmol) and intermediate 11 (1.0 g, 6 , 08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 hours and at 40 ° C for 18 hours. DMF was removed in vacuo and the residue was partitioned between EtOAc (80 ml) and 10% aqueous Na ₂ CO ₃ (20 ml). The phases were separated and the aqueous layer was again extracted with EtOAc (2 × 20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a colorless oil. After chromatography (silica; 2.5% MeOH / DCM), a sufficiently pure and N-tert-butoxycarbonyl protected compound was obtained (1.75 g, 71%). This compound was dissolved in EtOAc (40 ml) and gaseous HCl was bubbled through the stirred solution for 1 minute, and then the mixture was stirred for another 0.5 hour. Volatiles were removed in vacuo to give a yellow solid, which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO ₃ (20 ml). The phases were separated and the aqueous layer was again extracted with EtOAc (2 × 20 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The resulting oil was chromatographed (SiO ₂ ; 5% MeOH / DCM) to give the desired compound as an almost colorless oil (0.83 g, 62%) δH (CDCl ₃ ) 9.77 (1H, s), 8.75 (1H d, J 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8 4 Hz), 7.25 (1H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 3.80-3.70 (1H, fuzzy m), 3 , 72 (3H, s), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) and 0.78 ( 2H, broad s); m / z (ES ⁺ , 70B) 324 (MH ⁺ ).

INTERMEDIATE CONNECTION 14

4-acetonyl-3-cyanopyridine

A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) and N, N-dimethylacetamide dimethyl acetal (5.4 g, 40.6 mmol) in dry DMF (20 ml) was stirred at 130 ° C for 7 hour. Volatiles were removed in vacuo to give a dark oil that solidified upon settling. This material was chromatographed (SiO ₂ ; 50% EtOAc / Hexane - 100% EtOAc) to give the title compound as a yellowish solid (3.73 g, 69%). δH (CDCl ₃ ) 8.87 (1H, s), 8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5.2 Hz), 4.00 (2H, s) and 2.36 (3H, s); m / z (ES ⁺ , 70B) 161 (MH ⁺ ).

INTERMEDIATE CONNECTION 15

1-hydroxy-3-methyl-2,7-naphthyridine hydrochloride

HCl gas was bubbled through for several minutes through a stirred solution of intermediate 14 (3.73 g, 23.3 mmol) in glacial acetic acid (40 ml). The flask was closed and the reaction mixture was stirred for 18 hours at ambient temperature. Volatiles were removed in vacuo to give a straw-colored solid. This material was treated twice with water (30 ml portions) and again evaporated to dryness in vacuo to give the desired compound (containing ~ 25% unidentified by-product as an impurity) as a dark straw solid (4.1 g) δH (DMSO) -d ⁶ ) 12.46 (1H, br s), 9.32 (1H, s), 8.71 (1H, d, J 6.5 Hz), 7.98 (1H, d, J 6, 5 Hz), 6.67 (1H, s), and 2.38 (3H, s); m / z (ES ⁺ , 70B) 161 (MH ⁺ ).

This substance was used without further purification.

INTERMEDIATE CONNECTION 16

1-chloro-3-methyl-2,7-naphthyridine

Intermediate 15 (4.1 g) was treated with phosphorus oxychloride (50 ml) at 130 ° C. for 3 hours to obtain a dark solution. Volatiles were removed in vacuo and the resulting dark oil was extracted with Et ₂ O (100 ml). A saturated aqueous solution of NaHCO ₃ (ice-cold and containing an additional 10 g of solid NaHCO ₃ ) was poured (carefully!) Onto the crude product with shaking and cooling in an ice bath. After vigorous shaking, Et ₂ O (80 ml) was added, the mixture was again shaken and the phases were separated. The aqueous layer was again extracted with Et ₂ O (2 × 80 ml) and the combined ether extracts were washed with brine (20 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an orange solid (3.6 g). Chromatography (silica; 70% EtOAc / hexane - 100% EtOAc) gave a more polar by-product (3-methyl-1H-pyrano [3,4-c] pyridin-1-one, (0.7 g)) and target compound as a white solid (2.82 g, 79% of intermediate 14) δH (CDCl ₃ ) 9.66 (1H, s), 8.73 (1H, d, J 5.8 Hz), 7 56 (1H, d, J 5.8 Hz), 7.40 (1H, s) and 2.69 (3H, s); m / z (ES ⁺ , 70B) 179 and 181 (MH ⁺ ).

INTERMEDIATE CONNECTION 17

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) amino] phenyl} propanoate hydrochloride

Acetyl chloride (55 mg, 50 ml, 0.70 mmol) was added to absolute ethanol (25 ml) and stirred for one minute. Then, intermediate 16 (2.50 g, 14.0 mmol) and ethyl (S) -3- [4-aminophenyl] -2- [tert-butoxycarbonyl] propanoate (4.31 g, 14.0 mmol) were added. and the reaction mixture was stirred at 60 ° C for 2.75 hours. Volatiles were removed in vacuo to give a yellow-orange solid. This material was treated with EtOAc (~ 25 ml), heated, and then cooled again and the precipitate was collected by filtration and washed with Et ₂ O to give the title compound as a yellow solid (4.96 g, 73%) δH (CDCl ₃ ) 10, 44 (1H, broad s), 10.33 (1H, broad s), 8.60 (1H, d, J 6.5 Hz), 8.00 (1H, d, J 6.5 Hz), 7.85 (2H, d, J 8.5 Hz), 7.28 (1H, d, J 8.0 Hz), 7.23 (2H, d, J 8.5 Hz), 7.16 (1H , s), 4.19-4.01 (1H, m), 4.08 (2H, q, J 7.0 Hz), 2.97 (1H, dd, J 13.8, 5.4 Hz) 2.86 (1H, dd, J 13.8, 10.0 Hz), 2.50 (3H, s), 1.34 (9H, s) and 1.15 (3H, t, J 7.0 Hz); m / z (ES ⁺ , 70B) 451 (MH ⁺ ).

INTERMEDIATE CONNECTION 18

Ethyl (2S) -2-amino-3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) amino] phenyl} propanoate

HCl gas was bubbled through for 1 to 2 minutes through a stirred solution of intermediate 17 (4.95 g, 10.2 mmol). After 30 minutes stirring at ambient temperature, volatiles were removed in vacuo to give a yellow powder. This powder was treated with saturated aqueous NaHCO ₃ (30 ml) and then extracted with EtOAc (100 ml and 3 × 50 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the title compound as a yellow solid (3.56, 100%) δH (CDCl ₃ ) 9.25 (1H, s), 8.50 (1H, d, J 5.6 Hz), 7.66 (2H, d, J 8.4 Hz), 7.35 (1H, d, J 5.6 Hz), 7, 34 (1H, latent s), 7.14 (2H, d, J 8.4 Hz), 6.81 (1H, s), 4.12 (2H, q, J 7.2 Hz), 3.65 (1H, dd, J 7.8, 5.2 Hz), 3.02 (1H, dd, J 13.7, 5.2 Hz), 2.80 (1H, dd, J 13.7, 7, 8 Hz), 2.48 (3H, s), 1.56 (2H, br s) and 1.21 (3H, t, J 7.2 Hz); m / z (ES ⁺ , 70B) 351 (MH ⁺ ).

INTERMEDIATE CONNECTION 19

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) oxy] phenyl} propanoate

A mixture of N-tert-butyloxycarbonyl- (S) -tyrosine ethyl ester (14.5 g, 46.9 mmol), cesium carbonate (14.05 g, 43.1 mmol) and intermediate 9 (7.0 g, 39 , 2 mmol) in dry DMF (60 ml) was stirred at room temperature for 48 hours. The reaction mixture was diluted with Et ₂ O (150 ml) and filtered. The filtrate was evaporated under high vacuum and the residue was chromatographed (SiO ₂ ; 40% -60% EtOAc / Hexane) to give the title compound as a viscous straw-colored oil (16.2 g, 77%) δH (CDCl ₃ ) 9.56 ( 1H, s), 8.58 (1H, d, J 5.8 Hz), 7.39 (1H, d, J 5.8 Hz), 7.15-7.10 (4H, m), 7, 00 (1H, s), 4.99-4.91 (1H, m), 4.54-4.46 (1H, m), 4.09 (2H, q, J 7.1 Hz), 3, 10-2.99 (2H, m), 2.36 (3H, s), 1.34 (9H, s) and 1.15 (3H, t, J = 7.1 Hz); m / z (ES ⁺ , 70B) 452 (MH ⁺ ).

INTERMEDIATE CONNECTION 20

Ethyl (2S) -2-amino-3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) oxy] phenyl} propanoate

HCl gas was bubbled through a stirred solution of intermediate 19 (16 g) in EtOAc (300 ml) until a stable fine white precipitate formed (~ 2 minutes). After stirring for 0.5 hour, volatiles were removed in vacuo. The resulting solid was partitioned between EtOAc (250 ml) and saturated aqueous NaHCO ₃ (80 ml plus 5 g solid NaHCO ₃ ). The phases were separated and the aqueous layer was again extracted with EtOAc (5 × 50 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an oil. Chromatography (SiO ₂ ; 100% EtOAc - 10% EtOH / EtOAc) gave the target compound as a viscous oil (11.1 g, 89%) δH (CDCl ₃ ) 9.71 (1H, s), 8.70 ( 1H, d, J 5.Hz), 7.50 (1H, d, J 5.8 Hz), 7.31-7.28 (4H, m), 7.11 (1H, s), 4.23 (2H, q, J 7.1 Hz), 3.79-3.72 (1H, m), 3.14 (1H, dd, J 14.1, 5.4 Hz), 2.94 (1H, dd, J 14.1, 7.8 Hz), 2.47 (3H, s), 1.75-1.50 (2H, br.s) and 1.30 (3H, t, J 7.1 Hz ); m / z (ES ⁺ , 70B) 352 (MH ⁺ ).

INTERMEDIATE CONNECTION 21

1-chloro-2,6-naphthyridine

1-hydroxy-2,6-naphthyridine (550 mg) [obtained by Sakamoto, T. et al. [Chem. Pharm. Bull., 33, 626, (1985)] was stirred with phosphorus oxychloride (10 ml) at 110 ° C. for 5 hours. Volatiles were removed in vacuo and the residue was carefully treated with ice. After dilution with water (up to ~ 25 ml), solid NaHCO _{3 was} added to neutralize effectively and the product was extracted with EtOAc (2 × 80 ml). The combined organic extracts were dried (MgSO ₄ ), evaporated in vacuo and the crude product was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a light yellow solid (420 mg, 68%) δH (CDCl ₃ ) 9.35 (1H , s), 8.82 (1H, d, J 5.9 Hz), 8.48 (1H, d, J 5.6 Hz), 8.00 (1H, d, J 5.9 Hz), 7 74 (1H, d, J 5.6 Hz); m / z (ES ⁺ , 70B) 165 and 167 (MH ⁺ ).

INTERMEDIATE CONNECTION 22

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- [4 - ([2,6] naphthyridin-1-ylamino) phenyl] propanoate

Ethyl (S) -3- (4-aminophenyl) -2- [N- (tert-butyloxycarbonyl) amino] propanoate (600 mg, 1.95 mmol), intermediate 21 (350 mg, 2.13 mmol) and DIPEA (276 mg, 372 μl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) was stirred at 130 ° C. under N ₂ for several hours. The reaction mixture was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO ₃ (30 ml). The phases were separated and the aqueous layer was extracted again with EtOAc (3 × 30 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO ₄ ) and evaporated in vacuo to give a dark oil. Chromatography (SiO ₂ ; 3% MeOH / DCM) gave the target compound as a pale orange foam (360 mg, 42%) δH (CDCl ₃ ) 9.19 (1H, s), 8.67 (1H, d, J 5.9 Hz), 8.24 (1H, d, J 5.8 Hz), 7.66 (1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz ), 7.21 (1H, d, J 5.8 Hz), 7.16 (2H, d, J 8.5 Hz), 7.15 (1H, fuzzy s), 5.05-4.97 ( 1H, m), 4.60-4.51 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.17-3.04 (2H, m), 1.44 ( 9H, s), 1.27 (3H, t, J = 7.1 Hz); m / z (ES ⁺ , 70B) 459 (MNa ⁺ ) 437 (MH ⁺ ).

INTERMEDIATE JOINT 23

Ethyl (2S) -2-amino-3- [4 - ([2,6] naphthyridin-1-ylamino) phenyl] propanoate

Intermediate 22 (360 mg) was treated with a solution of trifluoroacetic acid (10 ml) and DCM (10 ml) and stirred at room temperature for 2 hours. Volatiles were removed in vacuo and the residue was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO ₃ (30 ml). The phases were separated and the aqueous layer was again extracted with EtOAc (3 × 30 ml). The combined organic extracts were dried (MgSO ₄ ) and evaporated in vacuo to give the desired compound as a dark orange viscous oil (280 mg, 100%) δH (CDCl ₃ ) 9.18 (1H, s), 8.66 (1H, d, J 5.9 Hz), 8.22 (1H, d, J 5.8 Hz), 7.67 (1H, d, J 5.9 Hz), 7.64 (2H, d, J 8, 5 Hz), 7.22 (2H, d, J 8.5 Hz), 7.19 (1H, d, J 5.8 Hz), 4.20 (2H, q, J 7.1 Hz), 3 73 (1H, dd, J 7.9, 5.1 Hz), 3.10 (1H, dd, J 13.6, 5.2 Hz), 2.87 (1H, dd, J 13.6, 7.9 Hz), 1.70 (3H, br s), 1.28 (3H, t, 7.1 Hz); m / z (ES ⁺ , 70B) 337 (MH ⁺ ).

INTERMEDIATE CONNECTION 24

Methyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- [4 - ([2,6] naphthyridin-1-yloxy) phenyl] propanoate

Intermediate 21 (0.79 g, 4.82 mmol) was added to N- (tert-butyloxycarbonyl) - (S) -tyrosine methyl ester (1.42 g, 4.82 mmol) in dry DMF (10 ml) and cesium carbonate (1.65 g, 5.06 mmol) and the reaction mixture was stirred at 45 ° C in an atmosphere of N ₂ for 2 days. After this, DMF was evaporated, EtOAc was added and washed (3 ×) with water, then dried (MgSO ₄ ) and evaporated in vacuo. The residue was chromatographed (SiO ₂ ; 40% -100% EtOAc / isohexane) to give the title compound as a white foam (1.61 g, 82%) δH (CDCl ₃ ) 9.29 (1H, s), 8.76 ( 1H, d, J 5.74 Hz), 8.17 (1H, d, J 5.74 Hz), 8.11 (1H, d, J 5.8 Hz), 7.43 (1H, d, J 5.8 Hz), 7.22-7.18 (3H, m), 5.03 (1H, br s), 4.61 (1H, br s), 3.75 (3H, s), 3.15-3.05 (2H, m); 1.44 (9H, s); m / z (ES ⁺ , 70B) MH ⁺ 424.

INTERMEDIATE CONNECTION 25

3,5-dichloropyridin-4-carboxylic acid

A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml) was added to a solution of LDA [obtained from nBuLi (2.5 M solution in hexane, 14.9 ml, 37.2 mmol) and diisopropylamine (4.10 g, 5.7 ml, 40.6 mmol)] in THF (25 ml) at −78 ° C. under a nitrogen atmosphere and a tan suspension was obtained. After this, the reaction mixture was stirred for 30 min at -78 ° C, then gaseous CO _{2 was} bubbled into the mixture to obtain a clear brown solution, which slowly precipitated, was heated to room temperature for 2 hours, then quenched with water (20 ml) and partitioned between Et ₂ O (100 ml) and 1M NaOH (100 ml). The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid, and then extracted with 10% MeOH in DCM (100 ml × 3). The combined organic layers were dried (MgSO ₄ ) and the solvent was removed in vacuo to give a brown solid, which was then recrystallized from ethanol and dried in vacuo to give the desired compound as pinkish crystals (2.63 g, 41%). δH (DMSO-d ⁶ ) 8.74 (2H, s). δC (DMSO-d ⁶ ) 163.5, 147.7, 141.0, 126.7.

INTERMEDIATE CONNECTION 26

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A suspension of intermediate 25 (51.2 g, 0.267 mol) in DCM (195 ml) and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5 drops) and refluxed for 4 hours. The reaction mixture was concentrated in vacuo and subjected to azeotropic distillation with toluene (2 × 50 ml), resulting in a yellow solid, which was used without further purification. A solution of ethyl- (S) -3- (4-aminophenyl) -2- (tert-butyloxycarbonylamino) propionate (130.8 g, 0.425 mol) in DCM (800 ml) was cooled to 0 ° C and treated with NMM (56.0 ml, 0.51 mol) was stirred for 5 min, and then a solution of acid chloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwise, keeping the reaction temperature below 5 ° C. The reaction mixture was stirred for 1 hour, the reaction was quenched with NaHCO ₃ solution (500 ml), the organic layer was separated, washed with NaHCO ₃ solution (500 ml), 10% citric acid solution (500 ml) and NaHCO ₃ solution (500 ml), dried (MgSO ₄ ) and concentrated in vacuo to give a yellow solid, which was recrystallized (EtOAc / hexane) to obtain the target compound (140 g, 69%) δH (DMSO d ⁶ ), 8.8 (2H, s), 7, 55 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.0 (3H, m), 3.4 (2H, br s), 2, 9 (1H, m), 2.8 (1H, m), 1.3 (9H, s), 1.25 (3H, t); m / z (ES ⁺ , 70B) 504 (MNa ⁺ ).

INTERMEDIATE CONNECTION 27

Ethyl (2S) -2-amino-3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate hydrochloride

A solution of intermediate 26 (70 g, 0.146 mol) in EtOAc (500 ml) and 1,4-dioxane (50 ml) was treated with a solution of HCl in EtOAc (500 ml, 3M) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give a yellow solid, which was triturated with Et ₂ O, then recrystallized (EtOAc / Hexane) to give the desired compound (59.3 g, 92%) δH (DMSO d ⁶ ), 11.10 (1H , s), 8.70 (2H, s), 7.55 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 4.10 (3H, m ), 3.10 (2H, m); 1.10 (3H, m); m / z (ES ⁺ , 70B) 382 (MH ⁺ ).

INTERMEDIATE CONNECTION 28

3-ethoxy-7-oxaspiro [3,5] non-2-en-1-one

Oxalyl chloride (1.1 eq., 10.9 ml, 0.12 mol) was added dropwise to tetrahydropyranyl-4-carboxylic acid (14.7 g, 0.11 mol) and DMF (0.5 ml) in DCM (150 ml). ) After 1 hour, the reaction mixture was concentrated in vacuo, the residual suspension was diluted with Et ₂ O (200 ml) and the resulting precipitate was removed by filtration. The filtrate was treated with ethoxyacetylene (40 wt.% Solution in hexane, 1.3 eq., 18 ml), then triethylamine (25 ml, 0.19 mol) was added dropwise and the reaction mixture was stirred for 11 days. After filtering and concentrating the obtained filtrate in vacuo, followed by chromatography (SiO ₂ ; EtOAc: hexanes, 5: 1), the target compound was obtained in the form of a light yellow oil (12.1 g, 59%) δH (CDCl ₃ , 300K) 4, 85 (1H, s), 4.23 (2H, q, J, 7.1 Hz), 3.89-3.75 (4H, m), 1.88-1.79 (4H, m), 1, 47 (3H, t, J 7.1 Hz); m / z (ES ⁺ , 70B) 182.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 29

7-oxaspiro [3,5] nonan-1,3-dione

Intermediate 28 (12.1 g, 0.67 mol) and 2M hydrochloric acid (26 ml) were stirred vigorously for 24 hours at room temperature. The resulting solution was concentrated to dryness and the residual suspension was washed with Et ₂ O (25 ml) to obtain the target compound as an off-white powder (8.93 g, 0.062 mol) δH (DMSO d ⁶ , 300K), 4.80 (2H, s ), 3.78 (4H, t, J 5.5 Hz); 2.62 (4H, t, J 5.5 Hz); m / z (ES ⁺ , 70B) 154.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 30

3-ethoxyspiro [3,6] decan-1-one

Triethylamine (20 ml, 0, 0, 0, 0, 14 mol) and the reaction mixture was stirred for 5 days at room temperature. After filtration and concentration of the obtained filtrate in vacuo, followed by chromatography (SiO ₂ ; EtOAc: hexanes, 5: 1), the target compound was obtained in the form of a light yellow oil (10.5 g, 0.054 mol, 87%) δH (CDCl ₃ , 300K ) 4.78 (1H, s), 4.20 (2H, q, J 7.1 Hz), 1.94-1.87 (2H, m), 1.83-1.77 (2H, m) 1.71-1.66 (2H, m); 1.63-1.52 (6H, m); 1.45 (3H, t, J = 7.1 Hz); m / z (ES ⁺ , 70B) 194.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 31

Spiro [3,6] decan-1,3-dione

Intermediate 30 (8.5 g, 0.044 mol) and 2M hydrochloric acid (30 ml) were stirred vigorously for 24 hours at room temperature. The resulting suspension was extracted with EtOAc (3 × 100 ml), the extracts were combined and concentrated in vacuo, and the resulting solid was recrystallized from diethyl ether to give the title compound as an off-white powder (7.1 g, 0.043 mol, 95%) δH (DMSO d ⁶ , 300K), 4.58 (2H, s), 1.75-1.29 (12H, m); m / z (ES ⁺ , 70B) 166.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 32

7-acetyl-3-ethoxy-7-azaspiro [3,5] non-2-en-1-one

Triethylamine (7.6 ml, 55.0) was added dropwise to a solution of 1-acetylpiperidin-4-carbonyl chloride (5.0 g, 26.4 mmol) and ethoxyacetylene (4.0 g, 55.5 mmol) in THF (60 ml). mmol). The resulting suspension was stirred at room temperature for 5 days, and then filtered and the filtrate was concentrated in vacuo. Chromatography (SiO ₂ ; 100% EtOAc - EtOAc: MeOH, 95: 5) gave the target compound as a white powder (3.97 g, 17.8 mol, 67%) δH (CDCl ₃ , 300K) 4.79 ( 1H, s), 4.17 (2H, q, J 7.1 Hz), 3.87-3.81 (1H, m), 3.56-3.42 (3H, m), 2.02 ( 3H, s), 1.85-1.67 (4H, m), 1.39 (3H, t, J = 7.1 Hz); m / z (ES ⁺ , 70B) 223.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 33

7-acetyl-7-azaspiro [3,5] nonan-1,3-dione

Intermediate 32 (700 mg, 0.31 mmol) and hydrochloric acid (2M, 5 ml) were stirred at room temperature for 4 hours. After concentration in vacuo of the resulting straw-colored solution, the target compound was obtained in the form of a light brown water-soluble powder (535 mg, 0.027 mmol, 87%). m / z (ES ⁺ , 70 V) 195.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 34

3-ethoxy-7-methoxyspiro [3,5] non-2-en-1-one

The target compound was prepared from 4-methoxycyclohexanecarbonyl chloride (10 g, 52.1 mmol) and ethoxyacetylene (7.5 g, 0.10 mol) by the method described for preparing intermediate 1 as an isomer mixture of approximately 1: 1, which is light yellow oil (7.2 g, 34.4 mmol, 65%) δH (CDCl ₃ , 300K) 4.81-4.79 (1H, s), 4.22-4.20 (2H, q, J 7.1 Hz), 3.34-3.32 (3H, s), 3.31-3.22 (1H, m), 2.04-1.56 (8H, m), 1.44- 1.43 (3H, t, J = 7.1 Hz); m / z (ES ⁺ , 70B) 211.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 35

7-methoxyspiro [3,5] nonan-1,3-dione

Intermediate 34 (5.0 g, 23.9 mol) and hydrochloric acid (2M, 20 ml) were stirred at room temperature for 18 hours. The resulting suspension was diluted with water (50 ml) and extracted with EtOAc (3 × 25 ml), after which the extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. Recrystallization from diethyl ether gave the target compound as an off-white powder (4.06 g, 22.4 mmol, 94%) δH (CDCl ₃ , 300K) 3.81 (2H, s), 3.25 (4H, m), 1.96-1.90 (2H, m), 1.86-1.79 (2H, m), 1.73-1.66 (2H, m), 1.64-1.56 ( 2H, m); m / z (ES ⁺ , 70B) 182.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 36

Ethyl (2S) -2-amino-3-hydroxypropanoate hydrochloride

A mixture of (2S) -2-amino-3-hydroxypropanoate (25 g, 238 mmol) and acetyl chloride (34 ml, 476 mmol) in absolute ethanol (250 ml) was stirred at 50 ° C for 18 hours. Volatiles were removed in vacuo until the volume was reduced to ~ 100 ml. After cooling, the resulting precipitate was collected, washed with ether and hexane, and the target compound was obtained in the form of a white powder (26.3 g, 65%) δH NMR (DMSO d ⁶ ) 8.47 (3H, br s), 5.58 (1H dd), 4.20 (2H, q), 4.08 (1H, t), 3.81 (2H, dd), 1.23 (3H, t).

INTERMEDIATE CONNECTION 37

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3-hydroxypropanoate

Di-tert-butyl dicarbonate (10.26 g, 47 mmol) was added to a stirred mixture of intermediate 36 (7.98 g, 47 mmol) and NaHCO ₃ (8.70 g, 2.2 eq.) In dioxane / water (1: 1) (80 ml) and this mixture was stirred for 4.5 hours. The main volume of the solvent was removed in vacuo and the resulting suspension was treated with EtOAc (150 ml). Inorganic substances were removed by filtration using EtOAc. The filtrate was washed with 10% citric acid solution (30 ml), water (30 ml), saturated aqueous NaHCO ₃ solution (20 ml) and brine (20 ml), and then dried (Na ₂ SO ₄ ) and evaporated in vacuo to give target compound as a colorless oil (10.3 g, 94%) δH (CDCl ₃ ) 5.45 (1H, broad), 4.36 (1H, broad), 4.26 (2H, q), 3 94 (2H, broad m), 1.47 (9H, s), 1.28 (3H, t); m / z (ES ⁺ , 70B) 233 (MH ⁺ ), 256 (MNa ⁺ ).

INTERMEDIATE CONNECTION 38

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3 - [(methylsulfonyl) oxy] propanoate

Methanesulfonyl chloride (730 μl, 9.43 mmol) was added to a stirred ice-cooled solution of intermediate 37 (2.0 g, 8.5 mmol) and 4-methylmorpholine (1.13 ml, 10.29 mmol) in dry DCM (30 ml) and this mixture was stirred for 6 hours. The solvent was removed in vacuo and the residue was treated with EtOAc (150 ml). The organics were washed with water (40 ml), 10% citric acid solution (20 ml), water (20 ml), saturated aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (10 ml), and then dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a colorless glassy substance that solidified upon standing. This material was treated with hexane and then filtered, washed with hexane and dried under N ₂ to give the desired compound (2.45 g, 92%) δH (CDCl ₃ ) 5.38 (1H, broad), 4.63 (3H , broad m), 4.27 (2H, q), 3.03 (3H, s), 1.48 (9H, s), 1.33 (3H, t); m / z (ES ⁺ , 70B) 333 (MNa ⁺ ).

INTERMEDIATE CONNECTION 39

Ethyl (2R) -2 - [(tert-butoxycarbonyl) amino] -3-iodopropanoate

Intermediate 38 (1.0 g, 3.21 mmol) was stirred in acetone (10 ml) in a foil-coated flask with sodium iodide (723 mg, 4.82 mmol) at room temperature for 18 hours. Acetone was removed in vacuo and the residue was partitioned between EtOAc (100 ml) and water (30 ml). The organics were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a yellow oil. This oil was purified by chromatography (SiO ₂ ; 30% Et ₂ O / hexane) to give the title compound as a colorless oil, which solidified to give a white solid (597 mg, 54%) δH (CDCl ₃ ) 5.36 (1H, broad), 4.50 (1H, broad m), 4.27 (3H, m), 3.59 (2H, m), 1.48 (9H, s), 1.33 (3H, t) ; m / z (ES ⁺ , 70B) 365 (MNa ⁺ ).

INTERMEDIATE CONNECTION 40

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- (5-nitropyridin-2-yl) propanoate

Zinc dust (100 mesh) (581 mg, 8.88 mmol) was heated in vacuo and then cooled in N ₂ atmosphere. After that, 1,2-dibromoethane (32 μl, 0.37 mmol) and dry THF (1 ml) were added, heating to boiling. Then the heating was stopped and the mixture was stirred for 1 min. This heating and stirring was repeated two more times. After that, TMSCI (66 μl, 0.52 mmol) was added and stirred at 50 ° C for ~ 10 min. Then, intermediate 39 (2.54 g, 7.40 mmol) in dry THF (4 ml) was added and the mixture was stirred at ~ 35-40 ° C for 40 min. After that, 2-bromo-5-nitropyridine (1.50 g, 7.30 mmol) and PdCl ₂ (PPh ₃ ) ₂ (260 mg, 0.37 mmol) and dry THF (2 ml) were added and the reaction mixture was stirred at 35 ° C for 2 hours. The reaction mixture was partitioned between EtOAc (150 ml) and saturated aqueous NH ₄ Cl (40 ml). The phases were separated and the aqueous phase was extracted again with EtOAc (50 ml). The combined organic extracts were washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a dark straw oil. Purification by chromatography (SiO ₂ ; 30-70% Et ₂ O / hexane) gave the target compound as a yellow oil (1.52 g, 61%) δH (CDCl ₃ ) 9.34 (1H, s), 8.39 (1H, d), 7.38 (1H, d), 5.58 (1H, broad), 4.75 (1H, broad m), 4.20 (2H, m), 3.47 (2H m) 1.42 (9H, s); 1.23 (3H, t); m / z (ES ⁺ , 70B) 339 (MH ⁺ ).

INTERMEDIATE CONNECTION 41

Ethyl (2S) -3- (5-aminopyridin-2-yl) -2 - [(tert-butoxycarbonyl) amino] propanoate

A stirred solution of intermediate 40 (1.16 g, 3.42 mmol) in absolute EtOH (20 ml) was hydrogenated at atmospheric pressure using 10% Pd-on-carbon (100 mg) for 3.5 hours. The catalyst was removed by filtration through a celite pad using DCM. The filtrate was evaporated in vacuo. The crude target compound was obtained as a straw-colored oil (1.03 g, 98%) and was used without further purification δH (CDCl ₃ ) 8.01 (1H, s), 6.92 (2H, s), 5.83 ( 1H, broad), 4.59 (1H, broad m), 4.13 (2H, m), 3.63 (2H, broad), 3.15 (2H, broad), 1.43 ( 9H, s), 1.21 (3H, t); m / z (ES ⁺ , 70B) 309 (MH ⁺ ).

INTERMEDIATE CONNECTION 42

Ethyl (2S) -2 - [(tert-butoxycarbonyl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} propanoate

3,5-Dichloroisonicotinoyl chloride (0.51 ml, 3.61 mmol) was added to a solution of intermediate 41 (1.06 g, 3.43 mmol) and dry pyridine (0.55 ml) in dry DCM, which was stirred in an ice bath cooled (20 ml) and stirred at room temperature for 1 hour. After evaporation of the solvent, the residue was dissolved in EtOAc (80 ml) and washed with saturated sodium bicarbonate (20 ml), water (10 ml), brine (10 ml), and then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo with obtaining a red-brown glassy substance. Chromatography (silica, 75% Et ₂ O / DCM) gave the target compound as a brownish solid (1.25 g, 75%) δ H NMR (DMSO d ⁶ ), 8.69 (2H, s), 8, 58 (1H, s), 7.92 (1H, d), 7.20 (1H, d), 4.26 (1H, m), 3.97 (2H, m), 2.93 (2H, m ), 1.21 (9H, s), 1.01 (3H, t); m / z (ES ⁺ , 70B) 483 (MH ⁺ ).

INTERMEDIATE CONNECTION 43

Ethyl (2S) -2-amino-3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} propanoate

Acetyl chloride (6 ml) was added to absolute EtOH (20 ml), stirred for 15 minutes and cooled to room temperature, then intermediate 42 (2.74 g, 5.67 mmol) was added and stirred for 3.5 hours . The solvent was removed in vacuo. The resulting yellow residue was treated with saturated sodium bicarbonate (10 ml) and solid sodium bicarbonate until neutralized. After extraction with EtOAc (4 × 50 ml), drying (Na ₂ SO ₄ ) and concentration, the target compound was obtained as a straw-colored foam (2.1 g, 97%) δH NMR (d ⁶ DMSO), 8.67 (2H, s), 8.56 (1H, d), 7.85 (1H, d), 7.16 (1H, d), 3.89 (2H, q), 3.57 (1H, dd), 2, 86 (1H, dd), 2.82 (1H, dd), 1.73 (2H, broad), 1.00 (3H, t); m / z (ES ⁺ , 70B) 383 (MH ⁺ ).

INTERMEDIATE CONNECTION 44

3-ethoxy-7,7-dioxo-7λ ⁶ -thiaspiro [3,5] non-2-en-1-one

To a solution of 1,1-dioxohexahydro-1λ ⁶ -thiopyran-4-carboxylic acid (10.2 g, 57.3 mmol) [obtained in accordance with the procedure described in Org. Prep. Proc. Int. 1977, 94] and DMF (0.3 ml) in DCM (120 ml) at room temperature, oxalyl chloride was added dropwise, and the resulting suspension was stirred for 3 days. The crude reaction solution was then concentrated in vacuo to give an oil, which was again dissolved in THF (100 ml), treated with ethoxyacetylene (10 ml, 50 wt.%) And triethylamine (10 ml), and the resulting suspension was stirred for 10 days at room temperature. After filtration and concentration of the filtrate in vacuo, a crude oil was obtained, which was purified by chromatography (SiO ₂ , 30% EtOAc: hexanes), and the target compound was obtained as a yellow oil (8.9 g, 38.6 mmol, 67%) δH (CDCl ₃ , 300K) 4.88 (1H, s), 4.27 (2H, q, J 7.1 Hz), 3.44-3.37 (2H, m), 3.13-3.05 (2H , m), 2.47-2.40 (2H, m), 2.35-2.29 (2H, m), 1.48 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 230.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 45

3-hydroxy-7,7-dioxo-7λ ⁶ -thiaspiro [3,5] non-2-en-1-one

Intermediate 44 (8.6 g, 37.4 mmol) was stirred with 1M HCl (100 ml) for 3 days and the resulting solution was concentrated in vacuo. The residual solid was triturated with EtOAc to give the title compound as an off-white solid (5.1 g, 25.2 mmol, 68%). m / z (ES ⁺ , 70 V) 202.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 46

3-ethoxyspiro [3,4] octa-2,6-dien-1-one

Oxalyl chloride (3.6 ml, 39.0 mmol) was added dropwise to a solution of cyclopent-3-encarboxylic acid (4.0 g, 36.0 mmol) and DMF (0.25 ml) in DCM (30 ml) at 0 ° C. . After 2 hours, the reaction mixture was concentrated in vacuo, the residual suspension was diluted with Et ₂ O (100 ml), the resulting precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The resulting oil was diluted with Et ₂ O (50 ml), treated with ethoxyacetylene (40 wt.% Solution in hexane), then triethylamine (6 ml, 44.0 mmol) was added dropwise and the reaction mixture was stirred for 7 days. After filtration and concentration of the filtrate in vacuo, chromatography (SiO ₂ , EtOAc: hexanes, 5: 1) was performed and the title compound was obtained as a pale yellow oil (4.3 g, 73%). m / z (ES ⁺ , 70 V) 164.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 47

3-hydroxyspiro [3,4] octa-2,6-dien-1-one

Intermediate 46 (2.0 g, 12.0 mmol) and 2M hydrochloric acid (5 ml) were stirred vigorously for 24 hours at room temperature. The resulting solution was extracted with EtOAc (25 ml), the extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give the target compound as a light brown powder (1.07 g, 7.9 mmol, 65%). δH (DMSO d ⁶ , 300K) 5.54 (4H, s), 4.57 (2H, s), 2.52 (2H, s); m / z (ES ⁺ , 70B) 136.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 48

(+, -) - 3-ethoxy-4-methyl-4-phenylcyclobut-2-enone

Oxalyl chloride (6.4 ml, 0.72 mmol) was added dropwise to a solution of (+, -) - 2-phenylpropionic acid (10.0 g, 0.66 mmol) and DMF (0.3 ml) in DCM (150 ml). . After 1 hour, the reaction mixture was concentrated in vacuo, the residual suspension was diluted with Et ₂ O (100 ml) and the resulting precipitate was removed by filtration. The filtrate was treated with ethoxyacetylene (40 wt.%, Solution in hexane, 18 ml), then triethylamine (25 ml, 0.19 mol) was added dropwise and the reaction mixture was stirred for 7 days at room temperature. After filtration, concentration of the filtrate in vacuo and subsequent chromatography (SiO ₂ , EtOAc: hexanes, 5: 1), the target compound was obtained in the form of a light yellow oil (6.1 g, 45%) δH (CDCl ₃ , 300K) 7.45 -7.24 (5H, m), 5.01 (1H, s), 4.31 (2H, J 7.1 Hz), 1.67 (3H, s), 1.51 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 202.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 49

(+, -) - 3-hydroxy-4-methyl-4-phenylcyclobut-2-enone

Intermediate 48 (4.5 g, 22.2 mmol) was hydrolyzed by the method described for intermediate 29 and the title compound was obtained as an off-white powder (3.29 g, 18.9 mmol, 85%); δH (CDCl ₃ , 300K) 7.53-7.21 (5H, m), 4.04 (1H, d, J 21.7 Hz), 3.93 (1H, d, J 21.7 Hz), 1.62 (3H, s). m / z (ES ⁺ , 70B) 174.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 50

Cyclohexylethynyloxytriisopropylsilane

This compound was obtained by the method described by Kowalski, Sankar Lal & Haque, JACS, 1986, 108, 7127-7128.

INTERMEDIATE CONNECTION 51

2-cyclohexyl-3-triisopropylsilanyloxy-spiro [3,5] non-2-en-1-one

To a stirred solution of the compound of Example 89 (5.6 g, 20 mmol) in tert-butyl methyl ether (50 ml) was added cyclohexylcarbonyl chloride (5.3 ml, 40 mmol) and triethylamine (13 ml, 100 mmol). The resulting mixture was stirred at the boil under reflux for 24 hours, and then left to cool and filtered to remove triethylammonium chloride. The filtrate was concentrated under reduced pressure and chromatographed on silica gel (mobile phase, 3% EtOAc in hexane) to give the title compound as a brown oil (5.8 g, 74%). m / z (ES ⁺ , 70 V) 235.2 (MH ^{+ of} desilylated compound).

INTERMEDIATE CONNECTION 52

2-cyclohexylspiro [3,5] nonan-1,3-dione

Intermediate 51 was stirred with 5 volumes of 2M hydrochloric acid for 14 days and treated with the method described for intermediate 4, whereby the target compound was obtained as a white crystalline solid in 40% yield. m / z (ES ⁺ , 70 V) 235.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 53

1-butoxyprop-1-in

The specified compound was obtained by the method described by Nooi &Arens; Recl. Trav. Chim. Pays-bas; 78; 1959; 284-287.

INTERMEDIATE CONNECTION 54

1-butoxybut-1-in

The specified compound was obtained from the corresponding starting compounds by the method described for intermediate 53.

INTERMEDIATE CONNECTION 55

1-butoxypent-1-in

The specified compound was obtained from the corresponding starting compounds by the method described for intermediate 53.

INTERMEDIATE CONNECTION 56

3-butoxy-2,4,4-trimethylcyclobut-2-enone

The specified compound was obtained from intermediate compound 53 by the method described for intermediate compound 1, yield 45%. δ H NMR (d CHCl ₃ ) 4.35 (2H, t, J 6.5 Hz), 1.79 (2H, m), 1.66 (3H, s), 1.50 (2H, m), 1 22 (6H, s); 0.99 (3H, t, J = 7.4 Hz). m / z (ES ⁺ , 70B) 183.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 57

3-butoxy-2-ethyl-4,4-dimethylcyclobut-2-enone

The specified compound was obtained from intermediate compound 54 by the method described for intermediate compound 1, yield 56%. δ H NMR (d CHCl ₃ ) 4.31 (2H, t, J 6.5 Hz), 2.07 (2H, q, J 7.6 Hz), 1.80 (2H, m), 1.52 ( 2H, m), 1.23 (6H, s), 1.10 (3H, t, J 7.6 Hz), 1.00 (3H, t, J 7.3 Hz); m / z (ES ⁺ , 70B) 197.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 58

3-butoxy-4,4-dimethyl-2-propylcyclobut-2-enone

The specified compound was obtained from intermediate compound 55 by the method described for intermediate compound 1, yield 51%. δ H NMR (d CHCl ₃ ) 4.30 (2H, t, J 6.5 Hz), 2.04 (2H, q, J 7.4 Hz), 1.75 (2H, m), 1.50 ( 4H, m), 1.23 (6H, s), 1.00 (3H, t, J 7.4 Hz). m / z (ES ⁺ , 70B) 211.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 59

2,2,4-trimethylcyclobutane-1,3-dione

The specified compound was obtained from intermediate compound 56 by the method described for intermediate compound 2, yield 85%. δH (d ⁶ DMSO) 1.36 (3H, s), 1.07 (6H, s). m / z (ES ⁺ , 70B) 126.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 60

4-ethyl-2,2-dimethylcyclobutane-1,3-dione

The specified compound was obtained from intermediate compound 57 by the method described for intermediate compound 2, yield 70%. δH (d ⁶ DMSO) 1.85 (2H, q, J 7.6 Hz), 1.07 (6H, s), 0.95 (3H, t, J 7.6 Hz). m / z (ES ⁺ , 70B) 140.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 61

2,2-dimethyl-4-propylcyclobutane-1,3-dione

The specified compound was obtained from intermediate compound 58 by the method described for intermediate compound 2, yield 64%. δH (CDCl ₃ ) 1.96 (2H, t, J 7.3 Hz), 1.50 (2H, m), 1.28 (6H, s), 0.90 (3H, t, J 7.3 Hz). m / z (ES ⁺ , 70B) 154.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 62

3-butoxy-2-methylspiro [3,5] non-2-en-1-one

The specified compound was obtained from intermediate compound 53 by the method described for intermediate compound 1, yield 23%. δH (CDCl ₃ ) 4.34 (2H, t, J 6.5 Hz), 1.77-1.25 (17H, m), 1.00 (3H, t, J 7.4 Hz). m / z (ES ⁺ , 70B) 223.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 63

3-butoxy-2-propylspiro [3,5] non-2-en-1-one

The specified compound was obtained from intermediate compound 55 by the method described for intermediate compound 1, yield 67%. δH (CDCl ₃ ) 4.31 (2H, t, J 6.4 Hz), 2.07 (2H, t, J 7.2 Hz), 1.80-1.40 (13H, m), 1, 00 (3H, t, J 7.1 Hz); 0.93 (3H, t, J 7.3 Hz). m / z (ES ⁺ , 70B) 251.1 (MH ⁺ ).

INTERMEDIATE CONNECTION 64

2-methylspiro [3,5] nonan-1,3-dione

The specified compound was obtained from intermediate compound 62 by the method described for intermediate compound 2, yield 90%. δH (d ⁶ DMSO) 1.56 (10H, m), 1.37 (3H, s). m / z (ES ⁺ , 70B) 166.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 65

2-propylspiro [3,5] nonan-1,3-dione

The specified compound was obtained from intermediate compound 63 by the method described for intermediate compound 2, yield 64%. δH (d ⁶ DMSO) 1.82 (2H, t, J 7.2 Hz), 1.58 (8H, m), 1.41 (2H, m), 1.39 (2H, q, J 7, 4 Hz), 0.85 (3H, t, J = 7.3 Hz). m / z (ES ⁺ , 70B) 195.1 (MH ⁺ ).

INTERMEDIATE CONNECTION 66

3-butoxy-2-methyl-7-oxaspiro [3,5] non-2-en-1-one

The specified compound was obtained from intermediate compound 53 by the method described for intermediate compound 1, yield 48%. δH (CDCl ₃ ) 4.30 (2H, t, J 6.5 Hz), 3.76 (4H, m), 1.70 (6H, m), 1.63 (3H, s), 1.36 (2H, m), 0.92 (3H, t, J = 7.4 Hz). m / z (ES ⁺ , 70B) 225.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 67

3-butoxy-2-propyl-7-oxaspiro [3,5] non-2-en-1-one

The specified compound was obtained from intermediate compound 55 by the method described for intermediate compound 1, yield 79%. δH (CDCl ₃ ) 4.33 (2H, t, J 6.4 Hz), 3.81 (4H, m), 2.09 (2H, t, J 7.7 Hz), 1.81 (6H, m), 1.50 (4H, m), 1.00 (3H, t, J 7.4 Hz), 0.94 (3H, t, J 7.3 Hz). m / z (ES ⁺ , 70B) 253.0 (MH ⁺ ).

INTERMEDIATE CONNECTION 68

2-methyl-7-oxaspiro [3,5] nonan-1,3-dione

The specified compound was obtained from intermediate compound 66 by the method described for intermediate compound 2, yield 51%. δ H NMR (d ⁶ DMSO) 3.67 (4H, m), 1.68 (4H, m), 1.40 (3H, s). m / z (ES ⁺ , 70B) 168.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 69

2-propyl-7-oxaspiro [3,5] nonan-1,3-dione

The specified compound was obtained from intermediate compound 67 by the method described for intermediate compound 2, yield 79%. m / z (ES ⁺ , 70 V) 196.9 (MH ⁺ ).

INTERMEDIATE CONNECTION 70

(3-ethoxyprop-2-ynyl) benzene

To a solution of ethoxyacetylene (9.95 g, 50 wt.% Solution in hexane, 70 mmol) in THF (100 ml) at -78 ° C was added n-butyllithium (31 ml, 2.5 M solution in hexane, 78 mmol). The mixture was stirred at this temperature for 2 hours, and then HMPA (20 ml) was added, stirred for another 15 minutes and benzyl bromide (9.2 ml) was added. The reaction mixture was allowed to warm to room temperature overnight, and then partitioned between EtOAc (300 ml) and water (200 ml). The organic extracts were separated, washed with water (5 × 200 ml) and brine (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the target compound as a mobile brown oil (11.1 g, 99% ) δH (300 M Hz, CDCl ₃ ) 7.15-7.57 (5H, m), 4.12 (2H, q, J = 7.1 Hz), 3.60 (2H, s), 1.41 (3H, t, J = 7.1 Hz); m / z (ES ⁺ , 70B) MH ⁺ 161.

INTERMEDIATE CONNECTION 71

2-benzyl-3-ethoxy-4,4-dimethylcyclobut-2-enone

To a solution of intermediate 70 (11 g, 68 mmol) in THF (200 ml) at room temperature was added isobutyryl chloride (11 ml) and triethylamine (19 ml). The mixture was stirred at this temperature for 65 hours, then filtered, partitioned between EtOAc (400 ml) and water (200 ml), after which the organic extracts were separated, washed with brine (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ ; eluent hexane: diethyl ether, 3: 2) to obtain the desired compound as a viscous clear oil (11.8 g, 75%). δH (300 M Hz, CDCl ₃ ) 7.18-7.32 (5H, m), 4.47 (2H, q, J = 7.1 Hz), 3.43 (2H, s), 1.36 (3H, t, J = 7.1 Hz), 1.28 (6H, s). m / z (ESI, 70B) MH ⁺ 231.

INTERMEDIATE CONNECTION 72

4-benzyl-2,2-dimethylcyclobutane-1,3-dione

Intermediate 71 (11.8 g, 51.3 mmol) was stirred in HCl (200 ml, 6M aqueous) at room temperature overnight. The solid precipitate was filtered and washed with hexane and diethyl ether on a sintered glass funnel, whereby the target compound was obtained in the form of a white powder (9.8 g, 95%). δH (300 M Hz, d ⁶ DMSO) 7.13-7.29 (5H, m), 3.20 (2H, s), 1.11 (6H, s); m / z (ESI, 70B) MH ⁺ 213.

INTERMEDIATE CONNECTION 73

4-bromomethyl-5-methyl-2-oxo-1,3-dioxolene

The specified compound was obtained by the method described by Sakamoto F., Ikeda S. & Tsukamoto G. Chem. Pharm. Bull., 1984, 32, 2241-2248.

INTERMEDIATE CONNECTION 74

Ethyl (2S) -2-tert-butoxycarbonylamino-3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} propanoate

Intermediate 26 (500 mg, 1.04 mmol) and mCPBA (493 mg, 2.0 mmol) in DCM (10 ml) were stirred together at room temperature for 48 hours. Then sodium sulfite (10% solution in water, 20 ml) was added, stirring for 5 minutes, and then partitioned between DCM (50 ml) and sodium bicarbonate solution (50 ml). The organic extracts were washed with sodium bicarbonate solution (2 × 50 ml) and water (1 × 50 ml), dried (MgSO ₄ ) and concentrated in vacuo. The resulting orange solid was recrystallized from EtOAc / hexane to give the title compound as a pale yellow powder (350 mg). δH (DMSO d ⁶ ) 7.78 (2H, s), 6.78 (2H, d, J 8.3 Hz), 6.46 (2H, d, J 8.4 Hz), 3.55 (1H , m), 3.36 (2H, q, J 7.1 Hz), 2.31 (1H, dd, J 5.8 Hz, 13.8 Hz), 2.31 (1H, dd, J 13, 6, 8.9 Hz), 0.60 (9H, s), 0.43 (3H, t, 3H).

INTERMEDIATE CONNECTION 75

(S) -2-amino-3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} propionic acid ethyl ester

Intermediate 74 (330 mg, 0.55 mmol) and HCl in EtOAc (2.6 M) were stirred together at room temperature overnight. Then, the precipitate formed was filtered off, washed with Et ₂ O (3 × 50 ml), and then made basic by partitioning between EtOAc (50 ml) and sodium bicarbonate solution (50 ml). The organic extracts were dried (MgSO ₄ ) and concentrated in vacuo to afford the title compound as a white solid (185 mg). δH (CD ₃ OD) 8.40 (2H, s), 7.43 (2H, d, J 8.6 Hz), 7.05 (2H, d, J 8.6 Hz), 3.98 (2H q, J, 7.1 Hz), 2.85 (2H, m), 1.04 (3H, t, J, 7.1 Hz).

EXAMPLE 1

Ethyl (2S) -2 - [(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (57 mg, 0.51 mmol) [obtained by the method described by Wasserman HH et al., J. Org. Chem., 38, 1451-1455 (1973)] and ethyl ester obtained by the method used to prepare intermediate 13 (164 mg, 0.51 mmol) in 1,2-dichloroethylene (5 ml) was stirred at room temperature within 72 hours. Volatiles were removed in vacuo and the residue was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a white solid (188 mg, 0.45 mmol, 89%). δH (CDCl ₃ , 300K) 9.92 (1H, s), 8.75 (1H, d, J 5.7 Hz), 8.60 (1H, d, J 8.6 Hz), 8.04 ( 1H, d, J 5.8 Hz), 7.82 (1H, d, J 5.6 Hz), 7.47 (1H, d, J 5.8 Hz), 7.27 (2H, d, J 8.5 Hz), 7.16 (2H, d, J 8.5 Hz), 4.31 (1H, s), 4.30-4.21 (1H, m), 3.68-3.63 (2H, q, J 7.1 Hz), 3.17 (1H, dd, J 13.6, 9.4 Hz), 2.95 (1H, dd, J 5.0, 13.6 Hz), 1.01 (3H, s), 0.93 (3H, s). m / z (ES ⁺ , 70B) 418.1 (MH ⁺ ).

EXAMPLE 2

(2S) -2 - [(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoic acid

The compound of example 1 (127 mg, 0.31 mmol) in THF (5 ml) was treated with 1 portion of LiOH · H ₂ O (13 mg, 0.32 mmol) in H ₂ O (1 ml) and the reaction mixture was stirred at room temperature within 2 hours. Then the reaction was quenched by the addition of HOAc (ice-cold, 1 ml) and the volatiles were removed in vacuo. Water (10 ml) was added to the residual foam and mixed thoroughly to precipitate. Then the precipitate was collected by vacuum filtration, and this residue was washed with water (2 × 5 ml). After drying in vacuo, the title compound was obtained in the form of a finely divided white solid (108 mg, 0.27 mmol, 88%). δH (DMSO d ⁶ , 300K) 9.67 (1H, s), 8.78 (1H, d, J 5.7 Hz), 8.51 (1H, d, J 8.6 Hz), 8.09 (1H, d, J 5.8 Hz), 7.86 (1H, d, J 5.6 Hz), 7.50 (1H, d, J 5.7 Hz), 7.21 (2H, d, J 8.4 Hz), 4.17 (2H, d, J 8.4 Hz), 4.34 (1H, s), 4.18-4.14 (1H, m), 3.21 (1H, dd, J 4.9, 13.9 Hz), 2.98 (1H, dd, J 13.9, 9.3 Hz), 1.06 (3H, s), 0.99 (3H, s). m / z (ES ⁺ , 70B) 404.1 (MH ⁺ ).

EXAMPLE 3

Ethyl (2S) -2 - [(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- [4 - ([2,6] naphthyridin-1-ylamino) phenyl] propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (58 mg, 5.1 mmol) and intermediate 23 (1.01 g, 2.7 mmol) in DCM (15 ml) was stirred at room temperature for 48 hours Volatiles were removed in vacuo and the residue was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a white powder (990 mg, 2.3 mmol, 88%). δH (CDCl ₃ , 300K) 9.33 (1H, s), 9.24 (1H, s), 8.69 (1H, d, J 5.9 Hz), 8.63 (1H, d, J 8 5 Hz), 8.42 (1H, dd, J 5.9, 0.8 Hz), 8.15 (1H, dd, J 5.7, 1.3 Hz), 7.85-7.80 (3H, m), 7.31-7.22 (4H, m), 4.39 (1H, s), 4.24-4.21 (1H, m), 4.17 (2H, q, J 7.1 Hz), 3.15 (1H, dd, J 13.8, 5.6 Hz), 3.00 (1H, dd, J 13.8, 9.0 Hz), 1.19 (3H, t, J 7.1 Hz), 1.11 (3H, s), 1.05 (3H, s). m / z (ES ⁺ , 70B) 431.1 (MH ⁺ ).

EXAMPLE 4

(2S) -2 - [(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- [4 - ([2,6]) naphthyridin-1-ylamino) phenyl] propanoic acid

The compound of example 3 (500 mg, 1.16 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound as a finely divided white solid (421 mg, 1.04 mmol, 90%). δH (DMSO d ⁶ , 300K) 9.21 (1H, s), 9.12 (1H, s broad), 8.66 (1H, d, J 5.8 Hz), 8.38 (1H, d , J 5.8 Hz), 8.18 (2H, m), 7.81 (2H, d, J 7.9 Hz), 7.27 (2H, d, J 7.9 Hz), 7.26 (1H, fuzzy s), 4.36 (1H, s), 4.13-4.07 (1H, m), 3.20 (1H, dd, J 14.0, 5.1 Hz), 3, 02 (1H, dd, J 41.0, 8.7 Hz), 1.13 (3H, s), 1.09 (3H, s). m / z (ES ⁺ , 70B) 403.0 (MH ⁺ ).

EXAMPLE 5

Ethyl (2S) -2 - [(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (58 mg, 0.52 mmol) [prepared by the method described by Wasserman HH et al., J. Org. Chem., 38, 1451-1455 (1973)] and the free base of intermediate 27 (200 mg, 5.2 mmol) in DCM (5 ml) was stirred at room temperature for 48 hours. Volatiles were removed in vacuo and the residue was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a white solid (230 mg, 0.48 mmol, 93%). δH (CDCl ₃ , 300K) 8.48 (2H, s), 8.10 (1H, s), 7.51 (2H, d, J 8.2 Hz), 7.04 (2H, d, 8, 2 Hz), 5.91 (1H, s), 4.43 (1H, s), 4.22 (2H, q, J 7.1 Hz), 3.17 (1H, dd, J 14.0, 5.1 Hz), 3.05 (1H, dd, J 14.0, 5.8 Hz), 1.28 (3H, t, J 7.1 Hz), 1.15 (3H, s), 1 14 (3H, s). m / z (ES ⁺ , 70B) 476.0 and 478.0 (MH ⁺ ).

EXAMPLE 6

(2S) -2 - [(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 5 (100 mg, 0.21 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound as a finely divided white solid (76 mg, 0.71 mmol, 81%). δH (DMSO d ⁶ , 350K) 10.5 (1H, s), 8.74 (2H, s), 7.80 (1H, broad s), 7.53 (2H, d, J 8.1 Hz ), 7.25 (2H, d, J 8.1 Hz), 7.26 (1H, fuzzy s), 4.30 (1H, s), 3.88 (1H, m), 3.16 (1H , dd, J 13.5, 4.9 Hz), 3.01 (1H, dd, J 13.5, 3.8 Hz), 1.11 (3H, s), 1.07 (3H, s) . m / z (ES ⁺ , 70B) 448.0 and 449.9 (MH ⁺ ).

EXAMPLE 7

Methyl (2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl] amino-3- {4 - [(3-methyl [2,7] naphthyridine-1 -yl) oxy] phenyl} propanoate

A solution of intermediate 2 (187 mg, 1.33 mmol) and intermediate 20 (450 mg, 1.2 mmol) in chloroform (10 ml) was stirred at 55 ° C for 48 hours. Volatiles were removed in vacuo and the residue was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a white solid (539 mg, 1.17 mmol, 91%) as a mixture of diastereomers, about 1: 1. δH (CDCl ₃ , 300K) 9.69 (1H, s), 8.69 (1H, d, J 5.7 Hz), 7.51 (1H, dd, J 9.3, 0.5 Hz), 7.19-7.11 (4H, m), 5.79 (1H, d, J 7.3 Hz), 4.64 (1H, s), 4.36-4.30 (1H, m), 3.84 and 3.82 (3H, s, diastereomeric CH ₃ ), 3.31-3.15 (2H, m), 2.45 (3H, s), 1.59-1.54 (1H, m ), 1.50-14 (1H, m), 1.34-1.23 (2H, m), 1.28 and 1.27 (3H, s, diastereomeric CH ₃ ), 0.91-0.86 (3H, m). m / z (ES ⁺ , 70B) 460.1 (MH ⁺ ).

EXAMPLE 8

(2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl] amino-3- {4 - [(3-methyl [2,7] naphthyridine-1- il) oxy] phenyl} propanoic acid

The compound of example 7 (230 mg, 0.5 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound as a finely divided white solid (198 mg, 0.44 mmol, 79%), which is a mixture of diastereomers, about 1 :one. δH (DMSO d ⁶ , 300K) 13.0 (1H, s), 9.60 (1H, d, J 9.7 Hz), 8.72 (1H, d, J 5.6 Hz), 8.49 -8.43 (1H, m NH), 7.76 (1H, d, J 4.7 Hz), 7.41-7.34 (2H, m), 7.27-7.21 (2H, m ), 4.47 and 4.43 (1H, s), 4.19-4.13 (1H, m), 3.29-3.23 (3H, s and 1H as fuzzy m), 3.02- 2.97 (1H, m) 2.36 and 2.35 (3H, s), 1.50-1.10 (4H, m), 1.08 and 0.98 (3H, s), 0.84 -0.63 (3H, m), m / z (ES ⁺ , 70B) 446.1 and 447.1 (MH ⁺ ).

EXAMPLE 9

Ethyl (2S) -2 - [(4,4-dipropyl-3-oxo-1-cyclobutenyl) amino] -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoate

A solution of intermediate 4 (180 mg, 1.07 mmol) and ethyl ester of intermediate 13 (362 mg, 1.07 mmol) in chloroform (7 ml) was stirred at room temperature for 96 hours. Volatiles were removed in vacuo and the residue was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a white solid (406 mg, 0.83 mmol, 78%). δH (CDCl ₃ , 300K) 9.72 (1H, s), 8.71 (1H, d, J 5.7 Hz), 8.04 (1H, d, J 5.8 Hz), 7.55 ( 1H, d, J 5.7 Hz), 7.22-7.16 (4H, m), 5.67 (1H, d, J 7.9 Hz), 4.64 (1H, s), 4, 26-4.16 (3H, m), 3.20 (1H, dd, J 14.1, 5.7 Hz), 3.11 (1H, dd, J 14.1, 6.6 Hz), 1 58-1.01 (8H, m); 0.81 (6H, t, J = 7.0 Hz). m / z (ES ⁺ , 70B) 488.1 and 489.1 (MH ⁺ ).

EXAMPLE 10 (2S) -2 - [(3-oxo-4,4-dipropyl-1-cyclobutenyl) amino] -3- [4 - ([2,7]) naphthyridin-1-yloxy) phenyl] propanoic acid

The compound of example 9 was hydrolyzed by the method described in example 2, to obtain the target compound in the form of a fine off-white powder (35 mg, 0.07 mmol, 19%). δH (DMSO d ⁶ , 350K) 9.68 (1H, s), 8.83 (1H, d, J 5.7 Hz), 8.37 (1, d, J 8.5 Hz), 8.14 (1H, d, J 5.8 Hz), 7.91 (1H, d, J 5.7 Hz), 7.55 (1H, d, J 5.8 Hz), 7.39 (2H, d, J 8.4 Hz), 7.28 (2H, d, J 8.4 Hz), 4.53 (1H, s), 4.14 (1H, dd, J 9.8, 4.3 Hz), 3.25 (1H, dd, J 14.0, 4.6 Hz), 3.0 (1H, dd, J 10.3, 14.0 Hz), 1.50-0.64 (14H, m) . m / z (ES ⁺ , 70B) 460.1 and 461.1 (MH ⁺ ).

EXAMPLE 11

Ethyl (2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl] amino-3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl ] propanoate

A solution of intermediate 2 (300 mg, 2.1 mmol) and ethyl ether of intermediate 13 (724 mg, 2.14 mmol) in DCM (15 ml) was stirred at room temperature for 24 hours. The reaction mixture was then diluted with DCM (30 ml) and distilled water (20 ml) and washed successively with 1M aqueous hydrochloric acid (30 ml), water (30 ml) and saturated aqueous sodium bicarbonate (30 ml). After that, the organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residual foam was chromatographed (SiO ₂ , EtOAc) to give the title compound as a white powder (827 mg, 1.8 mmol, 84%), which was a mixture of diastereomers, about 1: 1. δH (CDCl ₃ , 300K) 9.72 (1H, s), 8.71 (1H, d, J 5.7 Hz), 8.04 (1H, d, J 5.8 Hz), 7.55 ( 1H, d, J 5.7 Hz), 7.22-7.12 (5H, m), 5.80 (1H, d, J 7.6 Hz), 4.57 (1H, s), 4, 28-4.20 (3H, m), 3.25-3.07 (2H, m), 1.57-1.21 (7H, m), 1.18 and 1.17 (3H, s) 0 84-0.78 (3H, m). m / z (ES ⁺ , 70B) 460.1 (MH ⁺ ) and 482.0 (MNa ⁺ ).

EXAMPLE 12

(2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl] amino-3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoic acid

The compound of example 11 (600 mg, 1.31 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound as a finely divided white solid (520 mg, 1.21 mmol, 92%), which is a mixture of diastereomers, about 1 :one. δH (DMSO d ⁶ , 300K) 9.61 and 9.58 (1H, s), 8.72 (1H, d, J 5.7 Hz), 8.39-8.33 (1H, m, NH) 8.04-8.00 (1H, m), 7.80-7.79 (1H, m), 7.45-7.33 (1H, m), 7.32-7.25 (2H, m), 7.18-7.12 (2H, m), 4.37 and 4.32 (1H, s), 4.10-4.04 (1H, m), 3.17-3.12 ( 1H, m), 2.94-2.82 (1H, m), 1.41-0.86 (4H, m), 0.99 and 0.91 (3H, s), 0.73 and 0, 63 (3H, t, J 7.2 Hz). m / z (ES ⁺ , 70B) 432.0 (MH ⁺ ).

EXAMPLE 13

Ethyl (2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl) amino] -3- [4 - ([2,6] naphthyridin-1-ylamino) phenyl] propanoate

The target compound, a mixture of diastereomers, about 1: 1, was obtained as a white powder (482 mg, 1.05 mmol, 89%) from intermediate 2 (200 mg, 1.43 mmol) and intermediate 23 (400 mg 1.19 mmol) by the method described for the preparation of the compound of Example 11. δH (CDCl ₃ , 300K) 9.13 (1H, s), 8.61 (1H, d, J 5.9 Hz), 8.17 ( 1H, d, J 5.8 Hz), 7.66-7.60 (3H, m), 7.19-7.04 (5H, m), 5.62 (1H, t, J 4.6 Hz ), 4.51 and 4.49 (1H, s), 4.25-4.19 (3H, m), 3.16-3.05 (2H, m), 1.51-1.16 (7H , m), 0.85-0.77 (3H, m). m / z (ES ⁺ , 70B) 459.1 (MH ⁺ ).

EXAMPLE 14

(2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl] amino-3- [4 - ([2,6] naphthyridin-1-ylamino) phenyl] propanoic acid

The compound of example 13 (600 mg, 1.31 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a light yellow powder (521 mg, 1.21 mmol, 95%) (mixture of diastereomers, about 1: 1 ) δH (DMSO d ⁶ , 300K) 9.10 (1H, s), 8.55-8.53 (1H, m), 8.37 and 8.31 (1H, m, NH), 8.27 (1H d, J 5.9 Hz), 7.72-7.65 (2H, m), 7.15-7.08 (3H, m), 4.30 and 4.25 (1H, s), 3 99-3.94 (1H, m), 3.06-2.99 (1H, m), 2.83-2.76 (1H, m), 1.34-0.96 (4H, m) , 0.94 and 0.86 (3H, s), 0.68 and 0.55 (3H, t, J = 7.0 Hz). m / z (ES ⁺ , 70B) 431.0 (MH ⁺ )

EXAMPLE 15

Ethyl (2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl] amino-3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound, a mixture of diastereomers, about 1: 1, was obtained as a white powder (318 mg, 0.63 mmol, 80%) from intermediate 2 (120 mg, 0.86 mmol) and the free base of intermediate 27 ( 300 mg, 0.79 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 8.56 (2H, s), 8.29 and 8.24 (1H, s NH), 7.61-7 59 (2H, m), 7.16-7.10 (2H, m), 5.82-5.78 (1H, m), 4.56 (1H, s), 4.32-4.26 (3H, m), 3.29-3.23 (1H, m), 3.16-3.09 (1H, m), 1.59-1.13 (7H, m), 0.89-0 84 (3H, m). m / z (ES ⁺ , 70B) 504.0 and 506.0 (MH ⁺ ).

EXAMPLE 16

(2S) -2 - [(4R, S) -4-methyl-3-oxo-4-propyl-1-cyclobutenyl] amino-3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 15 (300 mg, 0.59 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a finely divided white solid (261 mg, 0.55 mmol, 92%) (mixture of diastereomers, about 1: 1 ) δH (DMSO d ⁶ , 300K) 10.90 (1H, s), 8.81 (2H, s), 7.60-7.56 (2H, m), 7.31-7.26 (2H, m ), 4.45 and 4.42 (1H, s), 4.15-4.41 (1H, m), 3.23-3.14 (1H, m), 2.99-2.89 (1H , m), 1.49-1.12 (3H, m), 1.07 and 0.99 (3H, s), 0.84-0.54 (4H, m). m / z (ES ⁺ , 70B) 476.0 & 478.0 (MH ⁺ )

EXAMPLE 17

Ethyl (2S) -2 - [(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound was obtained as a white powder (201 mg, 0.42 mmol, 72%) from intermediate 6 (200 mg, 1.0 mmol) and the free base of intermediate 27 (200 mg, 0.52 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 8.99 (1H, s), 8.42 (2H, s), 7.52 (2H, d, J 8.4 Hz), 7.02 (2H, d, J 7.6 Hz), 5.54 (1H, s), 4.34 (1H, s), 4.19 (2H, q, J 7.1 Hz), 3.07 (2H, broad. s), 1.95-1.81 (2H, br s), 1.27-0.77 (17H, m). m / z (ES ⁺ , 70B) 560.0 and 562.0 (MH ⁺ ).

EXAMPLE 18

(2S) -2 - [(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 17 (80 mg, 0.14 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as an off-white powder (62 mg, 0.12 mmol, 82%). δH (DMSO d ⁶ , 300K) 10.53 (1H, s), 8.73 (2H, s), 7.60-7.56 (2H, m), 7.57 (2H, d, J 8, 4 Hz), 7.30 (2H, d, J 8.4 Hz) 4.14-4.12 (1H, m), 3.17 (1H, dd, J 13.9, 4.8 Hz), 3.03 (1H, dd, J 13.0, 9.1 Hz), 1.87 (2H, t, J 7.3 Hz), 1.41-1.25 (9H, m), 1.15 -0.86 (8H, m). m / z (ES ⁺ , 70B) 532.0 and 534.0 (MH ⁺ )

EXAMPLE 19

Ethyl (2S) -2 - [(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl) amino] -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoate

The target compound was obtained as a white powder (201 mg, 0.42 mmol, 72%) from intermediate 6 (200 mg, 1.0 mmol) and ethyl ester of intermediate 33 (200 mg, 0.59 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 9.72 (1H, s), 8.71 (1H, d, J 5.7 Hz), 8.03 (1H, d, J 5.8 Hz), 7.56-7.51 (1H, m), 7.27-7.17 (4H, m), 5.41 (1H, broad m), 4.39 (1H, broad m), 4, 19 (2H, q, J 7.1 Hz), 3.15-3.12 (2H, m), 1.91-1.75 (2H, m), 1.39-1.09 (18H, m ) 0.81-0.74 (2H, m). m / z (ES ⁺ , 70B) 516.1 (MH ⁺ ).

EXAMPLE 20

(2S) -2 - [(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl) amino] -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoic acid

The compound of example 19 (200 mg, 0.39 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound as a finely divided white solid (161 mg, 0.33 mmol, 85%). δH (DMSO d ⁶ , 360K) 9.62 (1H, s), 8.74 (1H, d, J 5.6 Hz), 8.04 (1H, d, J 5.6 Hz), 7.82 (1H, d, J 5.6 Hz), 7.47 (1H, d, J 5.5 Hz), 7.30 (2H, d, J 8.3 Hz), 7.17 (2H, d, J 8.3 Hz), 4.02 (1H, br s), 3.21-3.18 (1H, m), 2.97-2.91 (1H, m), 1.74 (2H, m), 1.12-0.62 (17H, m). m / z (ES ⁺ , 70B) 488.1 (MH ⁺ ).

EXAMPLE 21

Ethyl (2S) -2 - [(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl) amino] -3- {4 - [(3-methyl- [2,7] naphthyridine-1- il) oxy] phenyl} propanoate

The target compound was obtained as a white powder (331 mg, 0.63 mmol, 73%) from intermediate 6 (200 mg, 1.0 mmol) and intermediate 18 (300 mg, 0.85 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 9.70 (1H, s), 8.70 (1H, d, J 5.8 Hz), 7.51 (1H, d, J 5.8 Hz), 7, 26-7.19 (4H, m), 5.34 (1H, br s), 4.45 (1H, br s), 4.26 (2H, q, J 7.2 Hz), 3, 21 (2H, br s), 2.44 (3H, s), 2.10-1.90 (2H, m), 1.47-1.43 (2H, m), 1.33-1, 12 (12H, m), 0.87-0.84 (3H, m). m / z (ES ⁺ , 70B) 530.1 (MH ⁺ ).

EXAMPLE 22

(2S) -2 - [(4,4-dimethyl-3-oxo-2-hexyl-1-cyclobutenyl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) hydroxy] phenyl} propanoic acid

The compound of example 21 (60 mg, 0.11 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound as a finely divided white solid (42 mg, 0.08 mmol, 74%). δH (DMSO d ⁶ , 360K) 9.59 (1H, s), 8.70 (1H, d, J 5.7 Hz), 7.70-7.68 (1H, m), 7.66 (1H d, J, 9.7 Hz), 7.37 (2H, d, J, 8.6 Hz), 7.31 (1H, s), 7.23 (2H, d, J, 8.6 Hz), 4 , 18-4.16 (1H, m), 3.24 (1H, dd, J 13.9, 4.4 Hz), 3.04 (1H, dd, J 13.9, 9.9 Hz), 2.38 (3H, s), 1.86 (2H, t, J 7.3 Hz), 1.38-1.19 (8H, m), 1.04 (3H, s), 0.99 ( 3H, s), 0.83-0.79 (3H, m). m / z (ES ⁺ , 70B) 502.1 (MH ⁺ )

EXAMPLE 23

Ethyl (2S) - [(4R, S) -4-benzyl-4-methyl-3-oxo-1-cyclobutenyl] amino-3- {4 - [(3-methyl [2,7] naphthyridin-1-yl ) oxy] phenyl} propanoate

The target compound, a mixture of approximately 1: 1 diastereomers, was obtained as a white powder (412 mg, 0.79 mmol, 92%) from intermediate 8 (200 mg, 1.0 mmol) and intermediate 20 (300 mg, 0.85 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 9.70 (1H, d, J 4.9 Hz), 8.71 and 8.70 (1H, d, J 5.8 Hz), 7.51 (1H, d, J 5.8 Hz), 7.31-7.08 (11H, m), 5.88-5.82 (1H, m), 4.60 and 4, 50 (1H, s), 4.33-4.28 (1H, m), 4.26-4.16 (2H, m), 3.25-3.07 (2H, m), 2.98- 2.83 (2H, m), 2.45 and 2.40 (3H, s), 1.35-1.21 (6H, m). m / z (ES ⁺ , 70B) 522.1 (MH ⁺ ).

EXAMPLE 24

(2S) -2 - [(4R, S) -4-benzyl-4-methyl-3-oxo-1-cyclobutenyl] amino-3- {4 - [(3-methyl- [2,7] naphthyridine-1 -yl) hydroxy] phenyl} propanoic acid

The compound of example 23 (250 mg, 0.48 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound as a finely divided white solid (221 mg, 0.45 mmol, 94%), which is a mixture of diastereomers of about 1: one. δH (DMSO d ⁶ , 360K) 9.72 (1H, m), 8.81 (1H, m), 8.03 (1H, m), 7.82-7.77 (1H, broad m), 7.46-7.20 (9H, m), 4.49 and 4.41 (1H, s), 4.21 (1H, m), 3.39-3.30 (1H, m), 3, 21-3.14 (1H, m), 3.01-2.87 (2H, m), 2.51 (3H, s), 1.29 and 1.24 (3H, s). m / z (ES ⁺ , 70B) 494.0 (MH ⁺ )

EXAMPLE 25

Ethyl (2S) -2 - [(4R, S) -4-benzyl-4-methyl-3-oxo-1-cyclobutenyl] amino-3-4 - [(3,5-dichloroisonicotinoyl) amino] phenylpropanoate

The target compound, a mixture of approximately 1: 1 diastereomers, was obtained as a white powder (387 mg, 0.70 mmol, 89%) from intermediate 8 (185 mg, 0.98 mmol) and the free base of intermediate 27 (300 mg, 0.79 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 9.36 and 9.31 (1H, s), 8.36 and 8.35 (2H, s), 7.54 and 7.45 (1H, d, J 8.4 Hz), 7.19-7.02 (8H, m), 6.09-6.03 (1H, m), 4.31 and 4.20 ( 1H, s), 4.22-4.01 (3H, m), 3.07-2.92 (2H, m), 2.76-2.63 (2H, m), 1.35-1, 15 (2H, m), 1.09 and 1.08 (3H, s). m / z (ES ⁺ , 70B) 551.9 and 553.9 (MH ⁺ ).

EXAMPLE 26

(2S) -2 - [(4R, S) -4-benzyl-4-methyl-3-oxo-1-cyclobutenyl] amino-3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 25 (320 mg, 0.58 mmol) was hydrolyzed by the method described in example 12 to obtain the target compound as a finely divided white solid (277 mg, 0.53 mmol, 91%), which is a mixture of diastereomers of about 1: one. δH (DMSO d ⁶ , 360K) 13.05 (1H, br s), 8.83 and 8.82 (2H, s), 8.67 and 8.62 (1H, d, J 8.9 Hz) 7.71 and 7.61 (2H, d, J 8.7 Hz), 7.37-6.89 (9H, m), 4.32 and 4.23 (1H, s), 4.09- 4.00 (1H, m), 3.20-2.64 (4H, m), 1.24-1.07 (3H, m). m / z (ES ⁺ , 70B) 523.9 and 525.9 (MH ⁺ ).

EXAMPLE 27

Ethyl (2S) -2 - [(3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound was obtained as a white powder (512 mg, 0.99 mmol, 95%) from 1-keto-3-hydroxyspiro [3,5] non-2-ene (400 mg, 2.6 mmol) [obtained by described by Wasserman HH et al., J. Org. Chem., 38, 1451-1455, (1973)] and the free amine of intermediate 27 (400 mg, 1.04 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 10.86 (1H, s) 8.78 (2H, d), 8.34 (1H, d, J 8.5 Hz), 7.56 (2H, d, J 8.5 Hz), 7.25 (2H, d, J 8 5 Hz), 4.36 (1H, s), 4.20-4.11 (3H, m), 3.13 (1H, dd, J 13.8, 5.3 Hz), 3.00 ( 1H, dd, J 9.2, 13.8 Hz), 1.67-1.19 (10H, m), 1.17 (3H, t, J 4.1 Hz). m / z (ES ⁺ , 70B) 516.0 and 518.0 (MH ⁺ ).

EXAMPLE 28

(2S) -2 - [(3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of Example 27 (700 mg, 1.36 mmol) was hydrolyzed by the method described in Example 2 to give the title compound as a finely divided white solid (627 mg, 1.28 mmol, 95%). δH (DMSO d ⁶ , 360K) 10.54 (1H, s), 8.73 (2H, s), 7.81 (1H, d, J 8.4 Hz), 7.56 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 4.39 (1H, s), 4.12-4.05 (1H, m), 3.19 (1H, dd , J 13.9, 5.1 Hz), 3.00 (1H, dd, J 13.9, 8.8 Hz), 1.94-1.24 (10H, m). m / z (ES ⁺ , 70B) 488.0 and 490.0 (MH ⁺ ).

EXAMPLE 29

Ethyl (2S) -2 - [(3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl ) oxy] phenyl} propanoate

The target compound was obtained as a white powder (497 mg, 1.02 mmol, 89%) from 1-keto-3-hydroxyspiro [3,5] non-2-ene (400 mg, 2.6 mmol) and intermediate 20 (400 mg, 1.14 mmol) by the method described in example 11. δH (CDCl ₃ , 300K), 9.62 (1H, s), 8.72 (1H, d, J 5.7 Hz), 7, 99 (1H, d, J 8.6 Hz), 7.73 (1H, dd, J 5.7, 0.9 Hz), 7.37-7.34 (3H, m), 7.28-7 24 (2H, m), 4.42 (1H, s), 4.26-4.18 (3H, m), 3.25 (1H, dd, J 14.0, 5.6 Hz), 3 12 (1H, dd, J 14.0, 9.1 Hz), 2.42 (3H, s), 1.72-1.55 (10H, m), 1.25 (3H, t, J 7 , 1 Hz). m / z (ES ⁺ , 70B) 486.1 (MH ⁺ ).

EXAMPLE 30

(2S) -2 - [(3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) hydroxy] phenyl} propanoic acid

The compound of example 29 (300 mg, 0.62 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a finely divided white solid (237 mg, 0.52 mmol, 84%). δH (DMSO d ⁶ , 360K) 9.62 (1H, s), 8.72 (1H, d, J 5.7 Hz), 7.82 (1H, d, J 6.3 Hz), 7.73 (1H, d, J 5.5 Hz), 7.35 (2H, d, J 8.7 Hz), 7.25 (2H, d, J 8.7 Hz), 4.39 (1H, s) 4.12 (1H, dd, J 8.7, 13.2 Hz), 3.34-3.12 (2H, m), 2.42 (3H, s), 1.72-1.53 ( 10H, m). m / z (ES ⁺ , 70B) 458.0 (MH ⁺ ).

EXAMPLE 31

Ethyl (2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

To a solution containing the compound of Example 27 (500 mg, 0.97 mmol) and triethylamine (2 equiv., 270 μl) in THF (10 ml) at 0 ° C., a bromine solution (1.1 equiv., 170 was added dropwise) mg) in THF (5 ml). After 20 minutes, the reaction mixture was allowed to warm to room temperature, and then diluted with EtOAc (100 ml). The crude reaction mixture was washed with saturated aqueous NaHCO ₃ (20 ml) and brine (20 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residual foam was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a white powder (511 mg, 0.86 mmol, 95%). δH (CDCl ₃ , 300K) 8.48 (2H, s), 8.05 (1H, s broad), 7.52 (2H, d, J 8.4 Hz), 7.04 (2H, d, J 8.5 Hz), 5.81 (1 H, doublet, J 8.3 Hz), 4.98-4.91 (1 H, m), 4.21 (2 H, q, J 7.1 Hz) ), 3.21 (2H, d, J 5.3 Hz), 1.70-1.66 (4H, m), 1.53-1.44 (4H, m), 1.28 (3H, t , J 7.1 Hz), 1.20-1.16 (2H, m). m / z (ES ⁺ , 70B) 597.9 and 595.0 (MH ⁺ ).

EXAMPLE 32

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 31 (511 mg, 0.86 mmol) was hydrolyzed by the method described in example 2 (1.3 eq., 50 mg) to obtain the target compound as a white powder (421 mg, 0.74 mmol, 87%) . δH (DMSO d ⁶ , 390K) 10.34 (1H, s), 8.67 (2H, s), 7.53 (2H, s broad), 7.26 (2H, d, J 8.26 Hz ), 4.67 (1H, m), 3.26-3.22 (1H, m), 3.13-3.08 (1H, m), 1.67-1.21 (10H, m). δC (DMSO-d ⁶ , 300K) 23.86, 25.30, 30.75, 37.79, 57.98, 61.94, 67.02, 119.73, 128.47, 130.38, 133 46, 136.86, 142.85, 148.10, 160.11, 171.80, 173.96, 186.93. m / z (ES ⁺ , 70B) 569.9 and 567.9 (MH ⁺ ).

EXAMPLE 33

Ethyl (2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

Bromine (1.1 eq., 0.32 ml) was added dropwise to a stirred solution of the compound of Example 5 (2.7 g, 5.67 mmol) in THF (25 ml) at room temperature. After 25 min, the reaction mixture was diluted with EtOAc (100 ml) and the crude reaction mixture was washed with saturated aqueous NaHCO ₃ (20 ml) and brine (20 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residual foam was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a light yellow powder (2.51 g, 4.53 mmol, 76%). δH (CDCl ₃ , 300K) 8.46 (2H, s), 8.17 (1H, s broad), 7.51 (2H, d, J 8.4 Hz), 7.04 (2H, d, J 8.4 Hz), 6.05 (1H, doublet, J 8.4 Hz), 4.98-4.92 (1H, m), 4.22 (2H, q, J 7.1 Hz ), 3.21 (2H, d, J 5.4 Hz), 1.28 (3H, t, J 7.1 Hz), 1.14 (3H, s), 1.13 (3H, s). m / z (ES ⁺ , 70B) 555.8 and 557.9 (MH ⁺ ).

EXAMPLE 34

(2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 33 (198 mg, 0.36 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound in the form of a white powder (142 mg, 0.27 mmol, 75%). δH (DMSO-d ⁶ , 390K) 10.46 (1H, s), 8.74 (2H, s), 7.63 (2H, d, J 5.74 Hz), 7.35 (2H, d, J 8.26 Hz), 4.80 (1H, broad), 3.32 (1H, dd, J 5.14, 14.2 Hz), 3.14 (1H, dd, J 8.9 Hz , 14.2 Hz), 1.18 (3H, s), 1.15 (3H, s). m / z (ES ⁺ , 70B) 527.9 and 529.8 (MH ⁺ ).

EXAMPLE 35

Ethyl (2S) -2 - [(3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4- [(2,7) naphthyridin-1-yloxy] phenyl} propanoate

A solution of ethyl ester of intermediate 13 (565 mg, 1.68 mmol) and 1-keto-3-hydroxyspiro [3,5] non-2-ene (280 mg, 1.84 mmol) in DCM (20 ml) was stirred at room temperature for 24 hours. After concentration in vacuo and chromatography (SiO ₂ ; EtOAc), the title compound was obtained in the form of a light yellow powder (730 mg, 1.55 mmol, 92%). δH (CDCl ₃ , 300K) 9.82 (1H, s), 8.82 (1H, d, J 5.7 Hz), 8.14 (1H, d, J 5.9 Hz), 7.64 ( 1H, d, J 5.8 Hz), 7.25-7.17 (6H, m), 5.77 (1H, d, J 7.6 Hz), 4.60 (1H, s), 4, 25 (2H, q, J 7.1 Hz), 3.30 (1H, dd, J 5.5 Hz, 13.9 Hz), 3.18 (1 H, dd, J 5.5 Hz, 13.9 Hz), 1.84-1.53 (10H, m), 1.35 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 472.1 (MH ⁺ ).

EXAMPLE 36

Ethyl (2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4- (2,7) naphthyridin-1-yloxy] phenyl} propanoate

To a stirred solution of the compound of Example 35 (300 mg, 0.637 mmol) and triethylamine (1.2 eq., 100 μl), a solution of bromine in DCM (2% w / v, 2.1 ml, 1, 2 equiv.). After 12 hours, the reaction mixture was diluted with DCM (50 ml) and washed thoroughly with saturated aqueous NaHCO ₃ , dried (MgSO ₄ ), filtered and concentrated in vacuo. The residual foam was triturated with diisopropyl ether and the resulting solid was collected and dried in vacuo to give the title compound as a light yellow powder (325 mg, 0.59 mmol, 95%). δH (CDCl ₃ , 300K) 9.83 (1H, s), 8.78 (1H, d, J 5.8 Hz), 8.16 (1H, d, J 5.8 Hz), 7.69 ( 1H, d, J 5.7 Hz), 7.32 (1H, d, J 5.8 Hz), 7.27 (4H, s), 5.87 (1H, d, J 8.4 Hz), 5.10-5.03 (1H, m), 4.30 (2H, q, J 7.1 Hz), 3.38-3.32 (2H, m), 1.85-1.69 (4H , m), 1.67-1.50 (6H, m), 1.36 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 552.0 (MH ⁺ ).

EXAMPLE 37

(2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(2,7) naphthyridin-1-yloxy] phenyl} propanoic acid

The compound of example 36 (220 mg, 0.40 mmol) was hydrolyzed by the method described in example 2, the desired compound was obtained in the form of a white powder (125 mg, 0.24 mmol, 60%). δH (DMSO d ⁶ , 300K) 9.27 (1H, s), 8.88 (1H, d, J 9.4 Hz), 8.83 (1H, d, J 5.4 Hz), 8.12 (1H, d, J 5.8 Hz), 7.90 (1H, d, J 5.7 Hz), 7.55 (1H, d, J 5.8 Hz), 7.38 (2H, d, J 8.4 Hz), 7.27 (2H, d, J 8.4 Hz), 4.83-4.79 (1H, m), 3.08-3.03 (2H, m), 1, 80-1.37 (8H, m), 1.19-1.12 (2H, m). m / z (ES ⁺ , 70B) 523.9 (MH ⁺ ).

EXAMPLE 38

Ethyl (2S) -2 - [(3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

The target compound (3.31 g, 6.38 mmol, 91%) was obtained from 7-oxaspiro [3,5] nonan-1,3-dione (1.2 g, 7.8 mmol) and the free amine of intermediate 27 (2.67 g, 7.0 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 8.61 (1H, s), 8.33 (2H, s), 7.41 (2H, d , J 5 Hz), 6.94 (2H, d, J 8.5 Hz), 6.30 (1H, s broad), 4.35 (1H, s), 4.11 (2H, q, J 7.1 Hz) and (1 H, m fuzzy), 5.72 (4 H, m), 3.07 (1 H, dd, J 14.0, 5.0 Hz), 2.94 (1 H, dd, J 14.0, 6.6 Hz), 1.75-1.66 (2H, m), 1.55-1.48 (2H, m), 1.17 (3H, t, J 7.1 Hz) . m / z (ES ⁺ , 70B) 517.9 (MH ⁺ ).

EXAMPLE 39

Ethyl (2S) -2 - [(2-bromo-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl ) amino] phenyl} propanoate

To a solution of the compound of Example 38 (1.64 g, 3.17 mmol) and triethylamine (0.69 g, 970 μl, 6.8 mmol) in THF (15 ml), a solution of bromine (506 mg, 3 , 1 mmol) in THF (2 ml). After 1 hour, the resulting precipitate was removed by filtration, washed several times with cold EtOAc and dried to obtain the target compound as a white powder (1.53 g, 2.56 mmol, 81%). δH (DMSO d ⁶ , 300K) 10.90 (1H, s), 9.07 (1H, d, J 9.0 Hz), 8.81 (2H, s), 7.60 (2H, d, J 8.4 Hz), 7.28 (2H, d, J 8.4 Hz), 4.85-4.80 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3 81-3.76 (2H, m), 3.63-3.58 (2H, m), 3.23 (1H, dd, J 13.8, 4.8 Hz), 3.05 (1H, dd, J 13.8, 9.4 Hz), 2.07-1.94 (2H, m), 1.52-1.49 (1H, m), 1.34-1.31 (1H, m ), 1.24 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 597.9 and 599.9 (MH ⁺ ).

EXAMPLE 40

(2S) -2 - [(2-bromo-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 39 (575 mg, 0.96 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white powder (283 mg, 0.50 mmol, 52%). δH (DMSO d ⁶ , 390K) 10.88 (1H, s), 8.98 (1H, d, J 9.2 Hz), 8.81 (2H, s), 7.59 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 4.78-4.72 (1H, m), 3.82-3.75 (2H, m), 3.64 -3.54 (2H, m), 3.24 (1H, dd, J 13.9, 4.5 Hz), 3.01 (1H, dd, J 13.8, 9.5 Hz), 2, 08-1.93 (2H, m), 1.52-1.48 (1H, m), 1.30-1.26 (1H, m). m / z (ES ⁺ , 70B) 569.9 and 571.9 (MH ⁺ ).

EXAMPLE 41

Methyl (2S) -2 - {(3-oxospiro [3,5] non-1-en-1-yl) amino} -3- (2,6-dimethoxy- [1,1'-biphenyl] -4- sludge) propanoate

To a solution of methyl (2S) -2-amino-3- (2,6-dimethoxy [1,1'-biphenyl] -4-yl) propanoate (0.80 g, 2.5 mmol) in DCM (10 ml) at room temperature, 1-keto-3-hydroxyspiro [3,5] non-2-ene (0.38 g, 2.5 mmol) was added and the mixture was stirred for 48 hours. Volatiles were removed in vacuo and the residue was purified by column chromatography (SiO ₂ ; EtOAc), whereby the target compound was obtained as a white solid (1.05 g, 92%). δH (CDCl ₃ ): 7.32-7.26 (3H, m), 7.12 (2H, d, J 8.2 Hz), 6.92 (2H, d, J 8.3 Hz), 5 90 (1H, brd. D, J 8.2 Hz), 4.60 (1H, s), 4.33 (1H, br.), 3.86 (3H, s), 3.73 (6H, s), 3.30 (1H, dd, J 13.9, 5.3 Hz), 3.13 (1H, dd, J 13.9, 6.3 Hz), 1.82-1.33 (10H , m). m / z (ES ⁺ , 70B) 450.1 (MH ⁺ ).

EXAMPLE 42

(2S) -2 - {(3-oxospiro [3,5] non-1-en-1-yl) amino} -3- (2,6-dimethoxy- [1,1'-biphenyl] -4-yl ) propanoic acid

The compound of example 41 (0.40 g, 0.9 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white solid (0.19 g, 45%). δH (DMSO d ⁶ ) 8.25 (1H, d, J 8.6 Hz), 7.29-7.19 (3H, m), 7.07 (2H, d, J 7.9 Hz), 6 70 (2H, d, J 8.4 Hz), 4.32 (1H, s), 4.11 (1H, broad), 3.61 (6H, s), 3.18 (1H, dd, J 13.7, 4.7 Hz), 2.93 (1H, dd, J 13.7, 9.9 Hz), 1.67-1.16 (10H, m). m / z (ES ⁺ , 70B) 436.1 (MH ⁺ ).

EXAMPLE 43

Methyl (2S) -2 - {(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino} -3- (2,6-dimethoxy- [1,1'-biphenyl ] -4-yl) propanoate

To a cooled solution (0-5 ° C.) of the compound of Example 41 (0.42 g, 0.93 mmol) and triethylamine (0.14 ml, 1.03 mmol) in THF (10 ml) was added a bromine solution (0.16 g, 1.0 mmol) in DCM (1 ml). The mixture was stirred at this temperature for 1 hour, and then partitioned between EtOAc (100 ml) and sodium hydrosulfite (100 ml, 5% aqueous). The organic extracts were separated, washed with water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product as a light yellow foam. Column chromatography (SiO ₂ ; EtOAc: hexanes, 1: 1) gave the title compound as a white foam (0.45 g, 92%). δH (CDCl ₃ ): 7.32-7.26 (3H, m), 7.13 (2H, d, J 8.1 Hz), 6.66 (2H, d, J 8.4 Hz), 5 80 (1H, broad d, J = 8.6 Hz), 5.15-5.08 (1H, m), 3.87 (3H, s), 3.73 (6H, s), 3.35 (1H, d, J 10.0 Hz), 3.31 (1H, d, J 4.9 Hz), 1.80-1.33 (10H, m). m / z (ES ⁺ , 70B) 529.0 and 530.0 (MH ⁺ ).

EXAMPLE 44

(2S) -2 - {(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino} -3- (2,6-dimethoxy- [1,1'-biphenyl] -4-yl) propanoic acid

The compound of example 43 (0.36 g, 0.7 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white solid (0.23 g, 58%). δH (DMSO d ⁶ ) 8.83 (1H, d, J 9.4 Hz), 7.28 (1H, d, J 8.4 Hz), 7.24-7.20 (2H, m), 7 10 (2H, d, J 8.1 Hz), 6.70 (2H, d, J 8.4 Hz), 4.83-4.77 (1H, broad), 3.61 (6H, s ), 3.25 (1H, dd, J 13.8, 9.8 Hz), 2.95 (1H, dd, J 13.8, 10.3 Hz), 1.78-1.35 (10H, m). m / z (ES ⁺ , 70B) 516.0 and 517.0 (MH ⁺ ).

EXAMPLE 45

Ethyl (2S) -2 - [(3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound (1.1 g, 20.7 mmol, 86%) was obtained from intermediate 31 (400 mg, 2.4 mmol) and the free amine of intermediate 27 (920 mg, 2.4 mmol) by the method described in example 11. δH (CDCl ₃ , 300K) 8.57 (2H, s), 8.28 (1H, s), 7.61 (2H, d, J 8.5 Hz), 7.14 (2H, d, J 8.5 Hz), 5.76 (1H, d, J 7.5 Hz), 4.33-4.23 (3H, m), 3.25 (1H, dd, J 5.3, 14, 0 Hz), 3.12 (1H, dd, J 5.7, 13.9 Hz), 1.95-1.89 (2H, m), 1.79-1.70 (4H, m), 1 71-1.50 (6H, m); 1.36 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 530.0 (MH ⁺ ).

EXAMPLE 46

(2S) -2 - [(3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 45 (257 mg, 0.57 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white powder (257 mg, 0.51 mmol, 89%). δH (DMSO d ⁶ , 390K) 10.83 (1H, s), 8.84 (2H, s), 7.39 (2H, d, J 8.5 Hz), 7.29 (2H, d, J 8.5 Hz), 4.30 (1H, s), 4.12-3.98 (1H, m), 3.15 (1H, dd, J 13.9, 5.2 Hz), 2.97 (1H, dd, J 13.8, 9.5 Hz), 1.85-1.78 (1H, m), 1.77-1.38 (11H, m). m / z (ES ⁺ , 70B) 502.0 (MH ⁺ ).

EXAMPLE 47

Ethyl (2S) -2 - [(2-bromo-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

To a solution of the compound of Example 45 (988 mg, 1.87 mmol) and triethylamine (520 μl, 3.7 mmol) in THF (20 ml), a solution of bromine (330 mg, 2.1 mmol) in THF was added dropwise at 0 ° C ( 2 ml). After 1 hour, the crude reaction mixture was diluted with EtOAc (50 ml), saturated aqueous NaHCO ₃ (15 ml) and saturated aqueous sodium chloride (15 ml) and the crude product was extracted with EtOAc (3 × 20 ml). The combined extracts were dried (MgSO ₄ ), concentrated in vacuo and the crude residue was chromatographed (SiO ₂ , EtOAc: hexanes, 1: 1) to give the title compound as a white powder (965 mg, 1.58 mmol, 85%) . δH (CDCl ₃ , 300K) 8.61 (2H, s), 8.45 (1H, d, J 3.1 Hz), 7.63 (2H, d, J 8.2 Hz), 7.15 ( 2H, d, J 8.2 Hz), 5.91 (1H, d, J 8.1 Hz), 5.05-5.00 (1H, m), 4.30 (2H, q, J 7, 1 Hz), 3.30 (2H, d, J 5.4 Hz), 1.98-1.90 (2H, m), 1.89-1.60 (10H, m), 1.22 (3H , t, J 7.1 Hz). m / z (ES ⁺ , 70B) 609.9 and 611.9 (MH ⁺ ).

EXAMPLE 48

(2S) -2 - [(2-bromo-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 47 (560 mg, 0.92 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white powder (412 mg, 0.71 mmol, 77%). δH (DMSO d ⁶ , 380K) 10.40 (1H, s), 8.67 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.26 (2H, d, J 8.5 Hz), 4.52 (1H, br s), 3.22 (1H, dd, J 14.1, 5.3 Hz), 3.11 (1H, dd, J 13.9, 8 , 0 Hz), 1.82-1.29 (12H, m). m / z (ES ⁺ , 70B) 589.1 and 583.9 (MH ⁺ ).

EXAMPLE 49

Ethyl (2S) -2 - {[4,4-dimethyl-2- (phenylselenyl) -3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

To a stirred solution of the compound of Example 5 (630 mg, 1.41 mmol) in THF (15 ml) was added dropwise a solution of phenyl selenyl chloride (283 mg, 1.48 mmol) at room temperature. After 10 minutes, the crude reaction mixture was diluted with EtOAc (30 ml), saturated aqueous NaHCO ₃ (50 ml) and brine (50 ml). The mixture was extracted with EtOAc (3 × 50 ml), the combined extracts were dried (MgSO ₄ ) and concentrated in vacuo. The residual suspension was chromatographed (SiO ₂ , EtOAc) to give the title compound as a white powder (812 mg, 1.29 mmol, 91%). δH (CDCl ₃ , 300K) 8.58 (2H, s), 7.75 (1H, s), 7.53 (2H, d, J 8.3 Hz), 7.35-7.11 (5H, m), 7.04 (2H, d, J 8.3 Hz), 6.11 (1H, d, J 8.5 Hz), 5.28-5.25 (1H, m), 4.20 ( 2H, q, J, 7.1 Hz), 3.17 (2H, m), 1.31 (6H, s), 1.28 (3H, t, J, 7.1 Hz). m / z (ES ⁺ , 70B) 631.9 (MH ⁺ ).

EXAMPLE 50

(2S) -2 - {[4,4-dimethyl-2- (phenylselenyl) -3-oxo-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 49 (600 mg, 0.95 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white powder (503 mg, 0.83 mmol, 87%). δH (DMSO d ⁶ , 300K) 10.86 (1H, s), 9.11 (1H, d, J 8.9 Hz), 8.81 (2H, s), 7.50 (2H, d, J 8.2 Hz), 7.21 (2H, d, J 8.2 Hz), 4.96-4.92 (1H, br s), 3.13 (1H, dd, J 13.8, 4 5 Hz), 2.94 (1H, dd, J 13.6, 8.7 Hz), 1.22 (3H, s), 1.14 (3H, s). m / z (ES ⁺ , 70B) 603.9 (MH ⁺ ).

EXAMPLE 51

Ethyl (2S) -2 - [(3-oxo-7-acetyl-7-azazpiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl ) amino] phenyl} propanoate

The target compound (143 mg, 0.26 mmol, 67%) was obtained from intermediate 33 (150 mg, 0.77 mmol) and the free amine of intermediate 27 (150 mg, 0.39 mmol) by the method described in example 11. δH (DMSO d ⁶ , 300K) 10.89 (1H, s), 8.89 (2H, s), 8.55-8.48 (1H, m), 7.58 (2H, d, J 7, 9 Hz), 7.25 (2H, d, J 7.9 Hz), 4.47 (1H, s), 4.29-4.23 (1H, m), 4.16 (2H, q, J 7.1 Hz), 3.76-3.72 (1H, m), 3.15 (1H, dd, J 13.8, 5.2 Hz), 3.01-2.89 (2H, m) 2.00 (3H, s), 1.90-1.37 (6H, m), 1.21 (3H, q, J, 7.1 Hz). m / z (ES ⁺ , 70B) 559.0 (MH ⁺ ).

EXAMPLE 52

(2S) -2 - [(3-oxo-7-acetyl-7-azaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 51 (200 mg, 0.35 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white powder (91 mg, 0.16 mmol, 46%). δH (CD ₃ OD, 300K) 8.90 (2H, s), 7.60 (2H, d, J 8.2 Hz), 7.30 (2H, d, J 8.2 Hz), 4.49 (1H, s), 4.33-4.27 (2H, m) 3.85-3.77 (1H, m), 3.57-3.45 (1H, m), 3.37-3, 31 (1H, m), 3.20-3.11 (1H, m), 3.05-2.99 (1H, m), 2.11 (3H, s), 1.97-1.52 ( 4H, m). m / z (ES ⁺ , 70B) 531.0 (MH ⁺ ).

EXAMPLE 53

Ethyl (2S) -2 - [(7-methoxy-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

The target compound as an indivisible mixture of 1: 1 isomers (1.23 g, 2.25 mmol, 87%) was obtained from intermediate 35 (500 mg, 2.77 mmol) and the free amine of intermediate 27 (980 mg, 2, 6 mmol) by the method described in example 11. δH (CDCl ₃ , 300K, 2 isomers) 9.12 / 8.99 (1H, s), 8.51 / 8.50 (2H, s), 7.59 / 7.56 (2H, d, J 8.5 Hz), 7.08 (2H, d, J 8.5 Hz), 6.21 / 5.98 (1H, d, J 7.9 Hz / 7, 6 Hz), 4.46 / 4.43 (1H, s), 4.29 / 4.10 (3H, m), 3.13-3.08 (1H, m), 3.39 (1H, m ), 3.30 / 3.29 (3H, s), 3.23-3.18 (1H, m), 3.13-3.08 (1H, m), 1.97-1.58 (8H , m) 1.35-1.34 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 546.0 (MH ⁺ ).

EXAMPLE 54

(2S) -2 - [(7-methoxy-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 53 (950 mg, 1.7 mmol) was hydrolyzed by the method described in example 2, to obtain the target compound in the form of a white powder, which is a mixture of approximately 1: 1 isomers (812 mg, 1.57 mmol, 92%). δH (DMSO d ⁶ , 300K) 10.57 (1H, s), 8.73 (2H, s), 7.93 (1H, br s), 7.56 (2H, d, J 8.2 Hz ), 7.29-7.21 (2H, m), 4.37 (1H, s), 4.08-4.04 (1H, m), 3.34 (1H, m), 3.25 ( 3H, s), 3.21-3.02 (2H, m), 1.92-1.34 (8H, m). m / z (ES ⁺ , 70B) 518.0 (MH ⁺ ).

EXAMPLE 55

Ethyl (2S) -2 - [(2-bromo-7-methoxy-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl ) amino] phenyl} propanoate

By the method described in example 47, from the compound of example 53 (1.0 g, 1.83 mmol) and bromine (322 mg, 2.0 mmol) the target compound was obtained in the form of a powder (778 mg, 1.24 mmol, 70% ) [Isomer separation at this stage was carried out using chromatography (SiO ₂ ; EtOAc: hexanes - 100% EtOAc, 1: 1)]. δH (CDCl ₃ , 300K, rapidly eluting isomer). δH 10.65 (1H, s), 10.74 (1H, d, J 9.2 Hz), 8.58 (2H, s), 7.36 (2H, d, J 8.6 Hz), 7 06 (2H, d, J 8.6 Hz), 4.54-4.48 (1H, m), 3.18 (1H, m), 3.03-2.98 (1H, m), 3 , 00 (3H, s), 2.78 (1H, dd, J 13.9, 10.0 Hz), 1.18-1.65 (2H, m), 1.61-1.44 (4H, m), 1.18-1.15 (1H, m), 0.92 (1H, m). m / z (ES ⁺ , 70B) 625.9 (MH ⁺ ).

EXAMPLE 56

(2S) -2 - [(2-bromo-7-methoxy-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of example 55 (650 mg, 1.04 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white powder (512 mg, 0.86 mmol, 83%). δH (DMSO d ⁶ , 300K) 10.86 (1H, s), 9.11 (1H, d, J 8.9 Hz), 8.81 (2H, s), 7.50 (2H, d, J 8.2 Hz), 7.21 (2H, d, J 8.2 Hz), 4.96-4.92 (1H, br s), 3.13 (1H, dd, J 13.8, 4 5 Hz), 2.94 (1H, dd, J 13.6, 8.7 Hz), 1.22 (3H, s), 1.14 (3H, s). m / z (ES ⁺ , 70B) 597.9 (MH ⁺ ).

EXAMPLE 57

Ethyl (2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridine -1-yl) oxy] phenyl} propanoate

To the compound of Example 29 (0.54 g, 1.1 mmol) in THF (10 ml), triethylamine (0.2 ml, 1.4 mmol) and a bromine solution (224 mg, 1.4 mmol) in DCM (1 ml). The mixture was stirred overnight and then partitioned between EtOAc (50 ml) and water (50 ml). The organic extracts were separated, washed with sodium hydrosulfite (2 × 50 ml, 5% aqueous), water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude product was subjected to column chromatography (SiO ₂ ; EtOAc) to obtain the target compound as a white solid (0.46 g, 73%). δH (CDCl ₃ ) 9.75 (1H, s), 8.69 (2H, d, J 5.9 Hz), 7.64 (2H, d, J 6.0 Hz), 7.25 (2H, d, J 8.2 Hz), 7.20 (2H, d, J 8.2 Hz), 5.89 (1H, d, J 8.3 Hz), 5.06 (1H, dt, J 5, 4, 8.2 Hz), 4.30 (2H, q, J 7.1 Hz), 3.35 (2H, m), 2.50 (3H, s), 1.84-1.33 (10H , m). m / z (ES ⁺ , 70B) 566.1 and 567.1 (MH ⁺ ).

EXAMPLE 58

(2S) -2 - {(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino} -3- {4 - [(3-methyl [2,7] naphthyridine- 1-yl) oxy] phenyl} propanoic acid

The compound of example 57 (0.32 g, 0.6 mmol) was hydrolyzed by the method described in example 2 to obtain the target compound as a white solid (0.20 g, 66%). δH (DMSO d ⁶ ) 9.61 (1H, s), 8.88 (1H, d, J 9.5 Hz), 8.72 (1H, d, J 5.7 Hz), 7.74 (1H d, J 5.8 Hz), 7.35 (3H, s), 7.24 (2H, d, J 8.6 Hz), 4.77 (1H, m), 3.18 (1H, dd , J 13.7, 4.70 Hz), 3.01 (1H, dd, J 13.7, 10.4 Hz), 2.49 (3H, s), 1.78-1.12 (10H, m). m / z (ES ⁺ , 70B) 537.1 and 538.1 (MH ⁺ ).

EXAMPLE 59

Ethyl (2S) -2 - {[2- (phenylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

To a solution of the compound of Example 5 (340 mg, 0.76 mmol) in THF (25 ml), a solution containing phenylsulfenyl chloride (122 mg, 0.84 mmol) in THF (2 ml) was added dropwise at room temperature. After 10 min, the reaction mixture was poured into a mixture of EtOAc (150 ml) and saturated aqueous NaHCO ₃ solution (50 ml). The organic layer was extracted and washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ ; 100% EtOAc) gave the title compound as a white powder (346 mg, 0.59 mmol, 78%). δH (CDCl ₃ ) 8.45 (2H, s), 8.05 (1H, s), 7.43 (1H, d, J 8.4 Hz), 7.15 (2H, d, J 8.4 Hz), 7.11-7.04 (5H, m), 6.25 (1H, d, J 8.5 Hz), 5.10-5.05 (1H, m), 4.09 (2H, q, J 7.1 Hz), 3.11-3.06 (2H, m), 1.18 (3H, s), 1.15 (3H, s), 1.13 (3H, t, J 7 , 1 Hz). m / z (ES ⁺ , 70B) 584.0 (MH ⁺ ).

EXAMPLE 60

(2S) -2 - {[2- (phenylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of ethyl ether (340 mg, 0.58 mmol) with lithium hydroxide (60 mg, 1.4 mmol) by the method described in example 2, the target compound (296 mg, 0.53 mmol, 90%) was obtained as a white powder . δH (DMSO d ⁶ 390K) 10.30 (1H, br s), 8.68 (2H, s), 7.45 (2H, br s), 7.26-7.22 (2H, m) 7.15-7.08 (7H, m), 4.75-4.66 (1H, m), 3.17 (1H, dd, J 14.0, 5.3 Hz), 3.04 ( 1H, dd, J 14.0, 7.7 Hz), 1.19 (3H, s), 1.16 (3H, s). m / z (ES ⁺ , 70B) 556.0, 557.9 (MH ⁺ ).

EXAMPLE 61

Ethyl (2S) -2 - [(2-chloro-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

A solution of the compound of Example 27 (366 mg, 0.71 mmol) in THF (25 ml) was treated in portions with N-chlorosuccinimide (100 mg, 0.75 mmol) in portions. After 30 minutes, the reaction mixture was poured into a mixture of EtOAc (150 ml) and saturated aqueous NaHCO ₃ solution (50 ml). The organic layer was extracted and washed with brine (25 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , 70% EtOAc: hexanes) gave the title compound as a white powder (312 mg, 0.56 mmol, 80%). δH (CDCl ₃ ) 8.50 (2H, s), 7.73 (1H, s), 7.53 (1H, d, J 8.4 Hz), 7.04 (2H, d, J 8.4 Hz), 5.73 (1H, d, J 8.0 Hz), 4.88-4.81 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.21- 3.16 (2H, m), 1.79-1.65 (4H, m), 1.51-1.36 (6H, m), 1.28 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 550.0 (MH ⁺ ).

EXAMPLE 62

(2S) -2 - [(2-chloro-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 61 (300 mg, 0.54 mmol) with lithium hydroxide (60 mg, 1.4 mmol) by the method described in Example 2, the desired compound was obtained. δH (DMSO d ⁶ , 390K) 10.44 (1H, broad s), 8.69 (2H, s), 8.05-7.85 (1H, s broad), 7.54 (2H, d , J 7.8 Hz), 7.25 (2H, d, J 7.8 Hz), 4.60-4.49 (1H, m), 3.21 (1H, dd, J 14.0, 5 , 3 Hz), 3.04 (1H, dd, J 14.0, 5.1 Hz), 1.80-1.21 (10H, m). m / z (ES ⁺ , 70B) 521.9, 525.9 (MH ⁺ ).

EXAMPLE 63

Ethyl (2S) -2 - [(2-iodo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

To a stirred solution of the compound of Example 27 (1.0 g, 1.9 mmol) in THF (10 ml) at room temperature, N-iodosuccinimide (460 mg, 2.0 mmol) was added in one portion. After 5 minutes, the mixture was concentrated in vacuo and the residue was triturated with a mixture of ether (10 ml) and water (10 ml), and then filtered and washed with ether and water. After drying in an oven, the title compound (802 mg, 66%) was obtained as a yellow solid. δH (DMSO d ⁶ ) 8.90 (1H, d, J 9.1 Hz), 8.78 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.25 (2H d, J 8.5 Hz), 4.91 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.30-3.00 (2H, m), 1.80 -1.24 (10H, m), 1.21 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 642.0 (MH ⁺ ).

EXAMPLE 64

Ethyl (2S) -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} -2- (3-oxo-2-pyridin-3-ylspiro [3,5] non-1- en-1-ylamino) propanoate

A mixture of the compound of example 63 (1.0 g, 1.6 mmol), 10% palladium-on-carbon (15 mg), triphenylphosphine (100 mg, 0.32 mmol), copper iodide (1) (30 mg, 0, 16 mmol) and 3-pyridyltributyltin (560 μl, 1.7 mmol) in DMF (10 ml) were heated to 100 ° C in a nitrogen atmosphere for 2 hours. The solvent was removed by evaporation in vacuo and the residue was purified by column chromatography (SiO _2; EtOAc: hexane: triethylamine 666: 333: 1) to give the title compound as a yellow oil (378 mg, 41%). δH (DMSO d ⁶ ) 8.76 (2H, s), 8.60 (1H, m), 8.30 (2H, br s), 7.94 (1H, d, J 8.0 Hz), 7.54 (2H, m), 7.34 (2H, m), 7.10 (1H, dd, J 8.4 Hz), 4.34 (1H, m), 4.24 (2H, q, J 5.3 Hz), 3.25-2.95 (2H, m), 1.86-1.40 (10H, m), 1.26 (3H, t, J 5.3 Hz). m / z (ES ⁺ , 70B) 593.0 (MH ⁺ ).

EXAMPLE 65

(2S) -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} -2- (3-oxo-2-pyridin-3-ylspiro [3,5] non-1-ene -1-ylamino) propanoic acid

The compound of Example 64 was hydrolyzed by the method described in Example 2, whereby the target compound was obtained as a white solid (76%). δH (DMSO d ⁶ , 400K) 10.28 (1H, s), 8.66 (2H, s), 8.59 (1H, s), 8.34 (1H, m), 7.80 (1H, m), 7.69 (1H, m), 7.51 (2H, m), 7.24 (4H, m), 4.28 (1H, m), 3.25-3.07 (2H, m) ), 1.90-1.50 (10H, m). m / z (ES ⁺ , 70B) 565.0 (MH ⁺ ).

EXAMPLE 66

Ethyl (2S) -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} -2- (2-iodo-4,4-dimethyl-3-oxocyclobut-1-enylamino) propanoate

The target compound in the form of a white solid (72%) was obtained from the compound of Example 5 by the method described in Example 63. δH (DMSO d ⁶ ) 9.17 (1H, d, J 9.1 Hz), 8.79 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.29 (2H, d, J 8.5 Hz), 4.94 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.25-3.00 (2H, m), 1.23 (3H, t, J 7.1 Hz), 1.12 (3H, s), 1.03 (3H, from). m / z (ES ⁺ , 70B) 601.8 (MH ⁺ ).

EXAMPLE 67

Ethyl (2S) -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} -2- (4,4-dimethyl-3-oxo-2-pyridin-3-ylcyclobut-1- enylamino) propanoate

The target compound in the form of a white solid (41%) was obtained from the compound of example 66 by the method described in example 64. δH (CDCl ₃ ) 8.85 (1H, m), 8.57 (1H, m), 8.34 ( 3H, m), 7.92 (2H, m), 7.73 (2H, m), 7.28 (1H, m), 4.33 (1H, m), 4.15 (2H, q, J 7.1 Hz), 3.32-3.09 (2H, m), 1.71 (3H, s), 1.33 (3H, s), 1.27 (3H, t, J 7.1 Hz ) m / z (ES ⁺ , 70B) 553.0 (MH ⁺ ).

EXAMPLE 68

(2S) -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} -2- (4,4-dimethyl-3-oxo-2-pyridin-3-yl-cyclobut-1 -enylamino) propanoic acid

The compound of Example 67 was hydrolyzed by the method described in Example 2, whereby the target compound was obtained as a white solid (43%). δH (DMSO d ⁶ , 400K) 10.28 (1H, br s), 8.66 (3H, m), 8.33 (1H, m), 8.09 (1H, m), 7.75 ( 1H, m), 7.52 (2H, m), 7.27 (3H, m), 4.25 (1H, m), 3.26 (1H, m), 3.14 (1H, m), 1.22 (3H, s); 1.06 (3H, s). m / z (ES ⁺ , 70B) 524.9 (MH ⁺ ).

EXAMPLE 69

(2S) -2 - [(2-iodo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of Example 63 was hydrolyzed by the method described in Example 2, whereby the target compound was obtained as a white solid (98%). δH (DMSO d ⁶ ) 10.87 (1H, s), 8.84 (1H, d, J 9.3 Hz), 8.79 (2H, s), 7.58 (2H, d, J 8, 5 Hz), 7.27 (2H, d, J 8.5 Hz), 4.87 (1H, m), 3.25 (1H, m), 3.02 (1H, m), 1.70- 1.25 (10H, m). m / z (ES ⁺ , 70B) 613.8 (MH ⁺ ).

EXAMPLE 70

(2S) -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} -2- (2-iodine-4,4-dimethyl-3-oxocyclobut-1-enylamino) propanoic acid

The compound of Example 66 was hydrolyzed by the method described in Example 2, whereby the target compound was obtained as a white solid (95%). δH (DMSO d ⁶ ) 10.87 (1H, s), 9.06 (1H, d, J 9.3 Hz), 8.78 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.26 (2H, d, J 8.5 Hz), 4.88 (1H, m), 3.25 (1H, m), 3.04 (1H, m), 1.12 (3H, s), 1.01 (3H, s), m / z (ES ⁺ , 70V) 573.8 (MN ⁺ )

Example 71

Ethyl (2S) -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} -2 - [(3-oxospiro [3.5] non-1-en-1-yl) amino] propanoate

To a solution of intermediate 43 (470 mg, 1.22 mmol) in DCM (10 ml) was added spiro [3.5] nonane-1,3-dione (187 mg, 1.23 mmol), stirring for 18 hours. After evaporation of the solvent, the crude product was purified by chromatography (silica, 3-4% MeOH / DCM) to give the target compound as a white foam (610 mg, 96%). δ H NMR (d ⁶ DMSO) 8.81 (2H, s), 8.70 (1H, s), 8.33 (1H, d), 8.02 (1H, d), 7.32 (1H, d), 4.35 (1H, m), 4.13 (2H, m), 3.23 (2H, m), 1.53 (8H, broad), 1.37 (2H, broad), 1.17 (3H, t). m / z (ES ⁺ , 70V) 517 (MH ⁺ )

Example 72

Ethyl (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2 -yl} propanoate

A solution of NBS (169 mg, 0.94 mmol) in dry DCM (5 ml) was added to a stirred solution of the compound of Example 71 (490 mg, 0.94 mmol) in DCM (10 ml) at 0 ° C. (ice water bath) . After 30 minutes, the solvent was evaporated in vacuo and the residue was partitioned between Et ₂ O (80 ml) and saturated sodium bicarbonate (20 ml). The phases were separated and the aqueous layer was again extracted with Et ₂ O (40 ml). The combined organic extracts were washed with water (2 × 10 ml), brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo, after which the residue was purified by chromatography (silica, 50-80% Et ₂ O / hexane) to obtain the target compound as a colorless glassy foam (501 mg, 88%). δH NMR (d ⁶ DMSO) 11.17 (1H, s), 8.83 (2H, s), 8.73 (1H, s), 8.01 (1H, d), 7.34 (1H, d), 5.06 (1H, dd), 4.20 (2H, q), 3.39-3.20 (2H, broad m), 1.73 (1H, m), 1.57 (8H, broad), 1.34 (1H, broad), 1.22 (3H, t). m / z = (ES ⁺ , 70V) 596 (MH ⁺ )

Example 73

Ethyl (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridine hydrochloride 2-yl} propanoate

The compound of Example 72 (300 mg, 0.50 mmol) was dissolved in EtOAc (20 ml) and gaseous HCl was bubbled for a short period of time. The obtained belm precipitate was collected by filtration, washed with Et ₂ O and dried to obtain the target compound as a white powder (155 mg, 48%). δ H NMR (d ⁶ DMSO) 11.32 (1H, s), 8.84 (2H, s), 8.81 (1H, s), 8.13 (1H, d), 7.43 (1H, d), 5.06 (1H, dd), 4.19 (2H, q), 3.39 (1H, m), 3.28 (1H, m), 1.74 (1H, m), 1.57 (8H, broad), 1.35 (1H, broad), 1.22 (3H, t), m / z (ES ⁺ , 70V) 631 (MH ⁺ )

Example 74

(2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2- silt} propanoic acid

The compound of Example 72 (370 mg, 0.62 mmol) was hydrolyzed by the method described in Example 2, whereby the target compound was obtained as a white solid (200 mg, 56%). δ H NMR (d ⁶ DMSO) 11.16 (1H, s), 8.83 (2H, s), 8.73 (1H, s), 8.05 (1H, d), 7.35 (1H, d), 5.00 (1H, dd), 2.76 (2H, broad m), 1.55 (8H, broad), 1.27 (1H, broad), 1.12 (1H, broad). m / z (ES ⁺ , 70V) 568 (MH ⁺ )

Example 75

Ethyl (2S) -2 - [(2-chloro-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2 -yl} propanoate

A solution of NCS (247 mg, 1.85 mmol) in dry THF (10 ml) was added to a stirred (ice-cooled in a water bath) solution of the compound of Example 71 (800 mg, 1.54 mmol) in THF (10 ml) and DCM (10 ml). After 2 hours, the solvent was evaporated in vacuo and the residue was partitioned between Et ₂ O (250 ml) and saturated sodium bicarbonate (30 ml). The phases were separated and the organic layer was washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo, after which the residue was purified by chromatography (silica, 70-100% Et ₂ O / hexane) to obtain the target compound as white foam (620 mg, 72%). δ H NMR (d ⁶ DMSO) 8.96 (2H, s), 8.86 (1H, s), 8.20 (1H, d), 7.50 (1H, d), 5.08 (1H, m), 4.32 (2H, q), 3.53 -3.31 (2H, broad m), 1.72 (9H, m), 1.50 (1H, broad), 1.34 (3H, t), m / z (ES ⁺ , 70V) 551 (MH ⁺ )

EXAMPLE 76

Ethyl (2S) -2 - [(2-chloro-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridine hydrochloride 2-yl} propanoate

The compound of Example 75 (269 mg, 0.48 mmol) was dissolved in FtOAc (20 ml) and gaseous HCl was bubbled for a short period of time. The resulting precipitate was collected by filtration, washed with Et ₂ O and dried to obtain the target compound (230 mg, 80.3%). δH NMR (d ⁶ DMSO) 11.21 (1H, s), 8.83 (2H, s), 8.75 (1H, s), 8.08 (1H, d), 7.39 (1H, d), 4.95 (1H, m), 4.20 (2H, q), 3.36 (1H, m), 3.26 (1H, m), 1.71 (1H, m), 1.57 (8H, broad), 1.35 (1H, m), 1.21 (3H, t), m / z (ES ⁺ , 70V) 587 (MH ⁺ )

Example 77

(2S) -2 - [(2-chloro-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2- silt} propanoic acid

The compound of example 72 (250 mg, 0.45 mmol) was hydrolyzed by the method described in example 2, whereby the target compound was obtained in the form of a white powder (142 mg, 60%). δH NMR (d ⁶ DMSO) 11.19 (1H, s), 8.83 (2H, s), 8.74 (1H, s), 8.07 (1H, d), 7.35 (1H, d), 4.90 (1H, m), 3.37 (1H, m), 3.19 (1H, m), 1.71-1.28 (10H, broad m). m / z (ES ⁺ , 70V) 523 (MH ⁺ )

Example 78

Ethyl (2S) -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl) -2 - {[(2- (methylsulfanyl) -3-oxospiro [3.5] non-1-en- 1-yl) amino) propanoate

Sulfuryl chloride (49 μl) was added dropwise to a solution of dimethyl sulfide (74 μl) in THF (5 ml), stirred and cooled in an ice bath. The ice bath was removed and the solution was stirred for 45 minutes. This solution was added to a stirred solution of compound 71 (700 mg, 1.35 mmol) in THF (10 ml) and DCM (10 ml) and stirred at room temperature. The reaction mixture was treated by the method described in example 79, whereby the desired compound was obtained.

EXAMPLE 79

Ethyl (2S) -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} -2 - {[(2- (isopropylsulfanyl) -3-oxospiro [3.5] non-1-en- 1-yl) amino} propanoate

Sulfuryl chloride (218 μl) was added dropwise to a solution of isopropyl disulfide (432 μl) in THF (10 ml), stirred and cooled in an ice bath. The ice bath was removed and the mixture was left for 35 minutes. 5 ml of this solution was added to a stirred solution of the compound of Example 71 (700 mg, 1.35 mmol) in THF (10 ml) and DCM (10 ml) and stirred at room temperature for 15 minutes. The solvent was removed and the residue was partitioned between Et ₂ O (130 ml) and saturated sodium bicarbonate (30 ml). The phases were separated and the organic layer was washed with brine (10 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo, after which the residue was purified by chromatography (silica, 2-3% EtOH / DCM) to obtain the target compound as a white foam . m / z (ES ⁺ , 70V) 591 (MH ⁺ ).

Example 80

Ethyl (2S) -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} -2 - {[(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino} propanoate

To a solution of intermediate 43 (792 mg, 2.06 mmol) in DCM (15 ml) and THF (5 ml) was added 2,2-dimethyl-1,3-cyclobutanedione (0.27 g, 2.41 mmol), stirring for 24 hours. After evaporation of the solvent, the crude product was purified by chromatography (silica, 4-8% EtOH / DCM) to give the target compound as a white foam (926 mg, 93%). δ H NMR (d ⁶ DMSO) 8.78 (2H, s), 8.68 (1H, s), 8.53 (1H, d), 7.30 (1H, d), 4.38 (1H, s ), 4.33 (1H, m), 4.11 (2H, q), 3.38-3.10 (2H, m), 1.14 (3H, t), 1.04 (3H, s) 0.94 (3H, s). m / z (ES ⁺ , 70B) 477 (MH ⁺ ).

EXAMPLE 81

Ethyl (2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl } propanoate

The target compound (530 mg, 75%) as a white foam was obtained from the compound of Example 80 (600 mg, 1.25 mmol) by the method described in Example 72. δH NMR (d ⁶ DMSO) 9.20 (1H, s), 8.95 (2H, s), 8.87 (1H, s), 8.20 (1H, d), 7.51 (1H, d), 5.19 (1H, m), 4.32 (2H , q), 3.53-3.30 (2H, m), 1.34 (3H, s), 1.26 (3H, s), 1.13 (3H, s). m / z (ES ⁺ , 70B) 556 (MH ⁺ ).

EXAMPLE 82

Ethyl (2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] -2-pyridinyl hydrochloride } propanoate

The compound of Example 81 was dissolved in EtOAc (10 ml) and gaseous HCl was bubbled for a short period of time. The resulting white precipitate was collected by filtration, washed with EtOAc and Et ₂ O and dried, whereby the target compound was obtained in the form of a white powder (252 mg). δ H NMR (d ⁶ DMSO) 11.30 (1H, s), 9.12 (1H, d), 8.81 (2H, s), 8.80 (1H, s), 8.10 (1H, d ), 7.43 (1H, d), 5.04 (1H, m), 4.18 (2H, q), 3.30 (2H, m), 1.20 (3H, t), 1.12 (3H, s), 1.00 (3H, s). m / z (ES ⁺ , 70B) 592 (MH ⁺ ).

EXAMPLE 83

Ethyl (2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl } propanoic acid

The compound of Example 81 (200 mg, 3.59 mmol) was hydrolyzed by the method described in Example 2, whereby the target compound was obtained as a white amorphous solid (110 mg, 58%). δ H NMR (d ⁶ DMSO) 8.96 (1H, d), 8.81 (2H, s), 8.72 (1H, s), 8.04 (1H, d), 7.34 (1H, d ), 4.96 (1H, m), 3.35-3.15 (2H, m), 1.11 (3H, s), 0.96 (3H, s). m / z (ES ⁺ , 70B) 528 (MH ⁺ ).

EXAMPLE 84

Ethyl (2S) -2 - [(2-chloro-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl } propanoate

A solution of NCS (294 mg, 2.20 mmol) in dry DCM (10 ml) was added to a solution of the compound of Example 80 (869 mg, 1.82 mmol) in THF (10 ml) at a temperature of from -10 to 10 ° C, while stirring within 1.5 hours. After 30 minutes, the solvent was evaporated in vacuo and the residue was purified by chromatography (silica, 4-8% EtOH / DCM) to give the title compound as a pale yellow foam (786 mg, 84%). δ H NMR (d ⁶ DMSO) 11.18 (1H, s), 9.02 (1H, d), 8.83 (2H, s), 8.75 (1H, s), 8.08 (1H, d ), 7.37 (1H, d), 4.99 (1H, m), 4.20 (2H, q), 3.40-3.21 (2H, m), 1.22 (3H, t) 1.13 (3H, s), 1.01 (3H, s). m / z (ES ⁺ , 70B) 511 (MH ⁺ ).

EXAMPLE 85

(2S) -2 - [(2-chloro-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} propanoic acid

The compound of Example 84 (560 mg, 1.09 mmol) was hydrolyzed by the method described in Example 2, whereby the target compound was obtained as an off-white powder (370 mg, 70%). δH NMR (d ⁶ DMSO) 11.17 (1H, s), 9.94 (1H, d), 8.83 (2H, s), 8.75 (1H, s), 8.06 (1H, d), 7.35 (1H, d), 4.91 (1H, m), 3.37-3.16 (2H, m), 1.12 (3H, s), 0.97 (3H, s), m / z (ES ⁺ , 70B) 483 (MH ⁺ ).

Example 86

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- [2- (1-methylpyridin-3-yl) -3-oxospiro [3.5] non-1- iodide salt en-1-ylamino] propanoate

To a stirred solution of the compound of Example 64 (126 mg, 0.21 mmol) in DMF (1 ml) was added iodomethane (14 ml, 0.23 mmol). After 18 hours, the solvent was removed in vacuo to give the crude target compound, which was used without further purification, m / z (ES ⁺ , 70B) 607.0 (MH ⁺ ).

Example 87

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- [2- (1-methylpiperidin-3-yl) -3-oxospiro [3.5] non-1-en- 1-ylamino] propanoate

The compound of Example 86 (127 mg, 0.21 mmol) was dissolved in EtOH (10 ml) and hydrogenated over platinum dioxide (50 mg) at room temperature and under a hydrogen pressure of 1 atmosphere for 5 days. The catalyst was removed by evaporation in vacuo to give the title compound as a yellow oil (129 mg, 100%). δН NMR (d ⁶ DMSO) 10.48 (1Н, br.s), 8.70 (2Н, s), 7.59 (2Н, d, J 8.1 Hz), 7.30 (2Н, d, J 8.1 Hz), 4.25 (1Н, m ), 4.22 (2Н, q, J 4.0 Hz), 3.23 (1Н, m), 3.08 (1Н, m), 1.70-1.50 (22Н, m), 1.26 (3Н, m). m / z (ES ⁺ , 70B) 613.2 (MH ⁺ ).

EXAMPLE 88

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- [2- (1-methylpiperidin-3-yl) -3-oxospiro [3.5] non-1-en-1 -amylamino] propanoic acid

The compound of Example 87 was hydrolyzed by the method described in Example B 2. This product was purified by passing through a short knee (RP-18 silica; 5% aqueous acetonitrile), whereby the desired compound was obtained as a yellow solid (52%). δН NMR (d ⁶ DMSO) 10.47 (1Н, br.s), 8.70 (2Н, s), 7.57 (2Н, d, J 7.7 Hz), 7.27 (2Н, d, J 7.7 Hz), 4.13 (1Н, m ), 3.19 (1Н, m), 3.02 (1Н, m), 2.27 (3Н, s), 1.70-1.30 (10Н, m). m / z (ES ⁺ 70B) 585.1 (MH ⁺ ).

EXAMPLE 89

(2S) -ethyl-2 - [(2-chloro-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A stirred solution of the compound of Example 38 (800 mg, 1.54 mmol) in THF (25 ml) was treated with several portions of N-chlorosuccinimide (226 mg, 1.69 mmol) at room temperature. After 1 hour, the crude reaction mixture was partitioned between EtOAc (150 ml) and brine (100 ml). The organic layers were removed and washed with another 100 ml of brine, and then the organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , 50% EtOAc: hexanes) gave the title compound as a white powder (625 mg, 1.13 mmol, 67%). δH (DMSO d ⁶ , 390K) 10.39 (1H, br s), 8.69 (2H, s), 8.39 (1H, d, J 8.8 Hz), 7.57 (2H, s ), 7.29 (2H, d, J 8.4 Hz), 4.72 (1H, m), 4.24 (2H, q, J 7.1 Hz), 3.83-3.77 (2H , m), 3.73-3.62 (2H, m), 3.28 (1H, dd, J 5.5, 14.2 Hz), 2.04-1.93 (2H, m), 1 54-1.51 (1H, m); 1.44-1.42 (1H, m) 1.27 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 554 (MH ⁺ ).

EXAMPLE 90

(2S) -2 - [(2-chloro-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 89 (525 mg, 0.95 mmol) with lithium hydroxide (80 mg, 1.7 mmol) by the method described in Example 2, the desired compound (412 mg, 0.79 mol, 83%) was obtained. δH (DMSO d ⁶ , 390K) 10.40 (1H, s), 8.68 (2H, s), 8.30 (1H, broad s), 7.55 (2H, d, J 5.8 Hz ), 7.27 (2H, d, J 5.8 Hz), 4.63 (1H, m), 3.80-3.73 (2H, m), 3.69-3.61 (2H, m ), 3.26 (1H, dd, J 4.9, 14.1 Hz), 3.07 (1H, dd, J 9.1, 14.1 Hz), 1.97-1.90 (2H, m), 1.51-1.48 (1H, m), 1.40-1.37 (1H, m). m / z (ES ⁺ , 70B) 524.0 (MH ⁺ ).

EXAMPLE 91

(2S) -ethyl-2 - [(2-chloro-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound in the form of a white powder (625 mg, 1.11 mmol, 74%) was obtained by the method described in example 89 from the compound of example 45 (800 mg, 1.51 mmol) and N-chlorosuccinimide (222 mg, 1.66 mmol). δH (DMSO d ⁶ , 390K) 10.40 (1H, s), 8.70 (2H, s), 8.11 (1H, s broad), 7.57 (2H, s broad), 7, 29 (2H, d, J 8.3 Hz), 4.68 (1H, m), 4.24 (2H, q, J 7.1 Hz), 3.28 (1H, dd, J 5.5, 14.3 Hz), 3.12 (1H, dd, J 9.1, 14.3 Hz), 1.82-1.52 (12H, m), 1.27 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 566.0 (MH ⁺ ).

EXAMPLE 92

(2S) -2 - [(2-chloro-3-oxospiro [3,6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 91 (600 mg, 1.07 mmol) with lithium hydroxide (80 mg, 1.7 mmol) by the method described in Example 2, the desired compound (512 mg, 0.95 mol, 89%) was obtained. δH (DMSO d ⁶ , 390K) 10.37 (1H, s), 8.67 (2H, s), 7.52 (2H, m), 7.25 (2H, d, J 8.3 Hz), 4.44 (1H, m), 3.22 (1H, dd, J 5.2, 14.0 Hz), 3.13 (1H, dd, J 8.0, 13.9 Hz), 1.98 -1.41 (12H, m). m / z (ES ⁺ , 70B) 536.0 (MH ⁺ ).

EXAMPLE 93

(2S) -ethyl-2- [4,4-dimethyl-2- (1-methyl-1H-tetrazol-5-ylsulfanyl) -3-oxocyclobut-1-enylamino] -3- {4 - [(3,5 -dichloroisonicotinoyl) amino] phenyl} propanoate

A stirred solution of the compound of Example 5 (1.03 g, 2.16 mmol) in THF (50 ml) was treated at room temperature with a suspension of 1-methyl-1H-tetrazol-5-ylsulfanyl chloride (360 mg, 2.4 mmol) in DCM ( 2 ml). After 30 minutes, the crude reaction mixture was partitioned between EtOAc (150 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic phase was removed, washed with brine (100 ml), dried (MgSO ₄ ) and concentrated in vacuo. Chromatography (SiO ₂ ; EtOAc) gave the title compound as a white powder (1.12 g, 1.89 mmol, 88%). δH (DMSO d ⁶ , 390K) 10.40 (1H, s), 9.08 (1H, d, J 2.6 Hz), 8.67 (2H, s), 7.55 (2H, d, J 6.2 Hz), 7.24 (2H, d, J 6.2 Hz), 5.06 (1H, m), 4.17 (2H, q, J 7.1 Hz), 4.05 (3H , s), 3.27 (1H, dd, J 5.5, 14.2 Hz), 3.12 (1H, dd, J 8.9, 14.2 Hz), 1.23 (3H, s) 1.22 (3H, t, J = 7.1 Hz); 1.20 (3H, s). m / z (ES ⁺ , 70B) 590.0 (MH ⁺ ).

EXAMPLE 94

(2S) -2- [4,4-dimethyl-2- (1-methyl-1H-tetrazol-5-ylsulfanyl) -3-oxocyclobut-1-enylamino] -3- {4 - [(3,5-dichloroisonicotinoyl ) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 93 (640 mg, 1.08 mmol) with lithium hydroxide (80 mg, 1.7 mmol) by the method described in Example 2, the desired compound (517 mg, 0.92 mol, 85%) was obtained. δH (DMSO d ⁶ , 390K) 10.41 (1H, s), 9.35 (1H, d, J 2.6 Hz), 8.67 (2H, s), 7.51 (2H, d, J 5.9 Hz), 7.22 (2H, d, J 7.5 Hz), 4.93 (1H, m), 3.97 (3H, s), 3.26 (1H, dd, J 5, 5, 14.2 Hz), 3.09 (1H, dd, J 8.9, 14.2 Hz), 1.17 (3H, s), 1.10 (3H, s). m / z (ES ⁺ , 70B) 562.0 (MH ⁺ ).

EXAMPLE 95

(2S) -ethyl-2 - [(3,7,7-trioxo-7λ ⁶ -thiaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5 -dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound in the form of a white powder (712 mg, 1.25 mmol, 23%) was obtained from intermediate 45 (1.1 g, 5.4 mmol) and the free base of intermediate 27 (2.08 mg, 5.5 mmol ) by the method described in example 11. δH (CDCl ₃ , 300K) 8.51 (1H, s), 8.33 (2H, s), 7.37 (2H, d, J 8.2 Hz), 6, 96 (2H, d, J 8.2 Hz), 4.25 (1H, s), 4.10 (2H, q, J 7.1 Hz), 4.01 (1H, m), 3.40 - 3.33 (2H, m), 3.06 (1H, dd, J 4.5, 14.2 Hz), 2.90 (1H, dd, J 14.1, 8.0 Hz), 2.79 -2.75 (2H, m), 2.38-2.31 (2H, m), 1.99-1.96 (1H, m), 1.86-1.81 (1H, m), 1 16 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 565.9 (MH ⁺ ).

EXAMPLE 96

(2S) -ethyl-2 - [(2-bromo-3,7,7-trioxo-7λ ⁶ -thiaspiro [3,5] non-1-en-1-yl) amino] -3- {4- [ (3,5-Dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of the compound of Example 95 (435 mg, 0.77 mmol) in THF (18 ml) at 0 ° C was treated in portions with N-bromosuccinimide (151 mg, 0.85 mmol). After 10 min, the reaction mixture was partitioned between EtOAc (100 ml) and saturated aqueous sodium bicarbonate (50 ml), the organic phase was removed, dried (MgSO ₄ ) and concentrated in vacuo. Chromatography (SiO ₂ , 50% EtOAc: hexanes) gave the title compound as a white powder (411 mg, 0.64 mmol, 83%). δH (DMSO d ⁶ , 390K) 10.43 (1H, s), 9.00 (1H, d, J 8.4 Hz), 8.69 (2H, s), 7.58 (2H, d, J 6.8 Hz), 7.28 (2H, d, J 6.8 Hz), 4.85 (1H, m), 4.23 (2H, q, J 7.1 Hz), 3.37-3 25 (3H, m, overlapping), 3.13-3.03 (3H, m, overlapping), 2.56-2.45 (2H, m), 2.09-1.89 (2H, m) 1.27 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 645.9 (MH ⁺ ).

EXAMPLE 97

(2S) -2 - [(2-bromo-3,7,7-trioxo-7λ ⁶ -thiaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3 , 5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 96 (410 mg, 0.63 mmol) with lithium hydroxide (31 mg, 0.7 mmol) by the method described in Example 2, the target compound (371 mg, 0.60 mol, 95%) was obtained. δH (DMSO d ⁶ , 390K) 10.41 (1H, s), 9.35 (1H, d, J 2.6 Hz), 8.69 (2H, s), 7.55 (2H, d, J 6.7 Hz), 7.27 (2H, d, J 6.7 Hz), 4.70 (1H, m), 3.37-3.25 (5H, m,), 3.05 (1H, dd, J 5.4, 13.3 Hz), 2.3 (2H, m), 2.02 (1H, m), 1.92 (1H, m). m / z (ES ⁺ , 70B) 617.8 (MH ⁺ ).

EXAMPLE 98

(2S) -ethyl-2- [4,4-dimethyl-2- (1-methyl-1H-imidazol-2-ylsulfanyl) -3-oxocyclobut-1-enylamino] -3- {4 - [(3,5 -dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound in the form of a white powder (1.03 g, 1.75 mmol, 83%) was obtained from the compound of Example 5 (1.0 g, 2.1 mmol) and 1-methyl-1H-imidazol-2-yl sulfenyl chloride (340 mg, 2.3 mmol) by the method described to obtain the compound of example 93. δH (DMSO d ⁶ , 390K) 10.84 (1H, s), 9.19 (1H, d, J 9.0 Hz), 8, 79 (2H, s), 7.53 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 1.1 Hz ), 6.88 (1H, d, J 1.1 Hz), 5.46 (1H, m), 4.16 (2H, q, J 7.1 Hz), 3.62 (3H, s), 3.26 (1H, dd, J 5.2, 14.2 Hz), 3.06 (1H, dd, J 8.9, 14.2 Hz), 1.20 (3H, t, J 7.1 Hz), 1.09 (3H, s), 0.97 (3H, s). m / z (ES ⁺ , 70B) 590.0 (MH ⁺ ).

EXAMPLE 99

(2S) -2- [4,4-dimethyl-2- (1-methyl-1H-imidazol-2-ylsulfanyl) -3-oxocyclobut-1-enylamino] -3- {4 - [(3,5-dichloroisonicotinoyl ) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 98 (760 mg, 1.29 mmol) with lithium hydroxide (100 mg, 2.2 mmol) by the method described in Example 2, the target compound (412 mg, 0.74 mol, 57%) was obtained. δH (DMSO d ⁶ , 390K) 10.83 (1H, s), 9.11 (1H, d, J 9.0 Hz), 8.79 (2H, s), 7.51 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 1.1 Hz), 6.90 (1H, d, J 1.1 Hz) , 5.38 (1H, m), 3.63 (3H, s), 3.25 (1H, dd, J 5.2, 14.2 Hz), 3.05 (1H, dd, J 8.9 , 14.2 Hz), 1.07 (3H, s), 0.96 (3H, s). m / z (ES ⁺ , 70B) 562.0 (MH ⁺ ).

EXAMPLE 100

(2S) -ethyl-2 - [(3-thioxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of the compound of example 27 (700 mg, 1.36 mmol) and Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1,2,3,4-dithiadiphosphetane-2,4-disulfide] (561 mg, 1, 38 mmol) in toluene (25 ml) was heated to 80 ° C for 24 hours. The crude reaction mixture was then partitioned between EtOAc (100 ml) and brine (100 ml). The organic phase was separated, dried (MgSO ₄ ) and concentrated in vacuo. Chromatography (SiO ₂ ; EtOAc) gave the title compound as a yellow powder (621 mg, 1.17 mmol, 86%). δH (DMSO d ⁶ , 390K) 10.84 (1H, s), 8.96 (1H, d, J 8.9 Hz), 8.78 (2H, s), 7.56 (2H, d, J 7.9 Hz), 7.25 (2H, d, J 7.9 Hz), 5.48 (1H, s), 4.37 (1H, m), 4.18 (2H, q, J 7, 1 Hz), 3.20 (1H, dd, J 4.9, 13.9 Hz), 3.04 (1H, dd, J 9.9, 13.9 Hz), 1.96-1.87 ( 2H, m), 1.63-1.42 (8H, m), 1.21 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 532.0, 534.0 (MH ⁺ ).

EXAMPLE 101

(2S) -2 - [(3-thioxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 100 (340 mg, 0.66 mmol) with lithium hydroxide (30 mg, 0.67 mmol) by the method described in Example 2, the target compound (287 mg, 0.57 mol, 86%) was obtained. δH (DMSO d ⁶ , 390K) 10.84 (1H, s), 8.87 (1H, d, J 8.8 Hz), 8.77 (2H, s), 7.54 (2H, d, J 8.3 Hz), 7.24 (2H, d, J 8.3 Hz), 5.45 (1H, s), 4.23 (1H, m), 3.21 (1H, dd, J 4, 4, 13.9 Hz), 3.00 (1H, dd, J 9.9, 13.9 Hz), 1.96-1.87 (2H, m), 1.67-1.41 (8H, m). m / z (ES ⁺ , 70B) 562.0 (MH ⁺ ).

EXAMPLE 102

(2S) -2 - [(3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of 3-hydroxyspiro [3,4] oct-2-en-1-one (330 mg, 2.39 mmol) [obtained by the method described by Wasserman HH et al., J. Org. Chem., 38, 1451-1455 (1973)] and the free base of intermediate 27 (911 mg, 2.39 mmol) in DCM (5 ml) was stirred at room temperature for 48 hours. Volatiles were removed in vacuo and the residue was chromatographed. (SiO ₂ ; EtOAc) to obtain the target compound as a white solid (1.03 g, 2.05 mmol, 86%). δH (CDCl ₃ , 300K) 8.97 (1H, s), 8.41 (2H, s), 7.51 (2H, d, J 8.5 Hz), 7.01 (2H, d, J 8 5 Hz), 5.89 (1H, d, J 7.5 Hz), 4.39 (1H, s), 4.21 (3H, fuzzy m), 3.15 (1H, dd, J 5, 3, 14.0 Hz), 3.03 (1H, dd, J 5.8, 14.0 Hz), 1.74-1.49 (10H, m), 1.27 (3H, t, J 7 , 1 Hz). m / z (ES ⁺ , 70B) 502.0 (MH ⁺ ).

EXAMPLE 103

(2S) -2 - [(3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 102 (150 mg, 0.30 mmol) with lithium hydroxide (30 mg, 0.67 mmol) by the method described in Example 2, the desired compound (112 mg, 0.23 mol, 79%) was obtained. δH (DMSO d ⁶ , 390K) 13.08 (1H, s), 10.87 (1H, s), 8.79 (2H, s), 8.39 (1H, d, J 8.5 Hz), 7.57 (2H, d, J 8.2 Hz), 7.26 (2H, d, J 8.2 Hz), 4.39 (1H, s), 4.14 (1H, m), 3, 16 (1H, dd, J 4.7, 13.8 Hz), 2.98 (1H, dd, J 9.4, 13.8 Hz), 1.73-1.58 (10H, m). m / z (ES ⁺ , 70B) 473.9 (MH ⁺ ).

EXAMPLE 104

(2S) -ethyl-2 - [(2-chloro-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound in the form of a white powder (1.13 g, 2.1 mmol, 84%) was obtained from the compound of Example 102 (1.25 g, 2.49 mmol) and N-chlorosuccinimide (333 mg, 2.7 mmol) by the method described in Example 61. δH (DMSO d ⁶ , 390K) 10.41 (1H, s), 8.68 (2H, s), 8.33 (1H, d, J 5.9 Hz), 7.57 (2H, m), 7.27 (2H, m), 4.66 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.26 (1H, dd, J 5, 3, 14.1 Hz), 3.11 (1H, dd, J 9.0, 14.1 Hz), 1.98-1.58 (10H, m), 1.23 (3H, t, J 7 , 1 Hz). m / z (ES ⁺ , 70B) 535.9 (MH ⁺ ).

EXAMPLE 105

(2S) -2 - [(2-chloro-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 104 (1.10 g, 2.05 mmol) with lithium hydroxide (100 mg, 2.2 mmol) by the method described in Example 2, the desired compound (976 mg, 1.92 mol, 94%) was obtained. δH (DMSO d ⁶ , 390K) 10.41 (1H, s), 8.69 (2H, s), 8.26 (1H, s), 7.57 (2H, d, J 6.2 Hz), 7.28 (2H, d, J 6.2 Hz), 4.61 (1H, m), 3.26 (1H, dd, J 5.0, 14.1 Hz), 3.08 (1H, dd , J 9.1, 14.1 Hz), 1.92-1.60 (10H, m). m / z (ES ⁺ , 70B) 509.9 (MH ⁺ ).

EXAMPLE 106

(2S) -ethyl-2 - [(2-bromo-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of the compound of Example 102 (1.25 g, 2.49 mmol) in THF (25 ml) was treated with N-bromosuccinimide (443 mg, 2.49 mmol) at room temperature. After 30 minutes, the reaction mixture was diluted with EtOAc (100 ml), washed with saturated aqueous sodium bicarbonate (50 ml) and the organic phase was separated, dried (MgSO ₄ ) and concentrated in vacuo. Chromatography (SiO ₂ , EtOAc) gave the title compound as a white powder (1.27 g, 2.18 mmol, 87%). δH (DMSO d ⁶ , 390K) 10.43 (1H, s), 8.69 (2H, s), 8.42 (1H, d, J 8.9 Hz), 7.58 (2H, d, J 6.7 Hz), 7.29 (2H, d, J 6.7 Hz), 4.77 (1H, s), 4.22 (2H, q, J 7.1 Hz), 3.26 (1H , dd, J 5.4, 14.1 Hz), 3.12 (1H, dd, J 9.0, 14.1 Hz), 1.98-1.62 (8H, m), 1.25 ( 3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 582.0 (MH ⁺ ).

EXAMPLE 107

(2S) -2 - [(2-bromo-3-oxospiro [3,4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 106 (900 mg, 1.54 mmol) with lithium hydroxide (100 mg, 2.2 mmol) by the method described in Example 2, the target compound (721 mg, 1.3 mol, 84%) was obtained. δH (DMSO d ⁶ , 390K) 10.39 (1H, s), 8.68 (2H, s), 8.12 (1H, s broad), 7.54 (2H, d, J 8.2 Hz ), 7.27 (2H, d, J 8.2 Hz), 4.64 (1H, m), 3.25 (1H, dd, J 5.1, 14.1 Hz), 3.11 (1H dd, J = 8.6, 14.1 Hz), 1.92-1.62 (8H, m). m / z (ES ⁺ , 70B) 553.9 (MH ⁺ ).

EXAMPLE 108

(2S) -ethyl-2 - [(2-methylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

To a solution of the compound of Example 27 (1.0 g, 1.94 mmol) in THF (25 ml) at room temperature was added a solution of methanesulphenyl chloride in DCM (2.13 ml, 1.0 M) [obtained by the method described by Still IWJ, et al ., J. Org. Chem., 1982, 47, 560]. After 20 minutes, the reaction mixture was diluted with EtOAc (100 ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , 60% EtOAc: hexanes) gave the title compound as a white powder (1.03 g, 1.83 mmol, 94%). δH (DMSO d ⁶ , 390K) 10.86 (1H, s), 8.78 (2H, s), 8.70 (1H, d, J 9.2 Hz), 7.57 (2H, d, J 8.4 Hz), 7.26 (2H, d, J 8.4 Hz), 5.11 (1H, m), 4.18 (2H, q, J 7.1 Hz), 3.20 (1H dd, J 4.6, 13.9 Hz), 3.00 (1H, dd, J 9.8, 13.9 Hz), 1.93 (3H, s), 1.66-1.33 ( 10H, m), 1.21 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 562.1 (MH ⁺ ).

EXAMPLE 109

(2S) -2 - [(2-methylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 108 (600 mg, 1.07 mmol) with lithium hydroxide (100 mg, 2.2 mmol) by the method described in Example 2, the target compound was obtained in the form of a white powder (421 mg, 0.79 mol, 73%) ) δH (DMSO d ⁶ , 390K) 10.84 (1H, s), 8.77 (2H, s), 8.44 (1H, d, J 8.8 Hz), 7.54 (2H, d, J 8.4 Hz), 7.23 (2H, d, J 8.4 Hz), 4.90 (1H, m), 3.19 (1H, dd, J 4.4, 13.7 Hz), 2 98 (1H, dd, J 9.1, 13.7 Hz), 1.93 (3H, s), 1.79-1.54 (8H, m), 1.36-1.22 (2H, m). m / z (ES ⁺ , 70B) 534.0 (MH ⁺ ).

EXAMPLE 110

(2S) -ethyl-2 - [(2-fluoro-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of the compound of Example 27 (2.02 g, 3.91 mmol) in THF (55 ml) was treated with Selectfluor ^™ reagent (1.38 g, 3.89 mmol) and heated to 70 ° C. After 48 hours, the reaction mixture was diluted with EtOAc (300 ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , 60% EtOAc: hexanes) gave the title compound as a white powder (1.87 g, 3.50 mmol, 89%). δH (DMSO d ⁶ , 390K) 10.89 (1H, s), 8.81 (2H, s), 8.47 (1H, d, J 8.7 Hz), 7.59 (12H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 4.26 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.21 (1H dd, J 4.9, 13.8 Hz), 2.98 (1H, dd, J 9.8, 13.8 Hz), 1.70-1.38 (10H, m), 1.22 ( 3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 534.1 (MH ⁺ ).

EXAMPLE 111

(2S) -2- (2-fluoro-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 110 (273 mg, 0.51 mmol) with lithium hydroxide (60 mg, 1.3 mmol) by the method described in Example 2, the target compound was obtained in the form of a white powder (197 mg, 0.39 mol, 76% ) δH (DMSO d ⁶ , 390K) 10.87 (1H, s), 8.80 (2H, s), 8.30 (1H, d, J 8.7 Hz), 7.58 (2H, d, J 8.2 Hz), 7.25 (2H, d, J 8.2 Hz), 4.15 (1H, m), 3.19 (1H, dd, J 4.5, 13.8 Hz), 2 96 (1H, dd, J 9.5, 13.8 Hz), 1.92-1.49 (8H, m), 1.37-1.16 (2H, m). m / z (ES ⁺ , 70B) 506.0 (MH ⁺ ).

EXAMPLE 112

(2S) -2 - [(2-fluoro-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

A mixture of the compound of Example 38 (1.0 g, 1.93 mmol) and Selectfluor ^™ reagent (1.0 g, 2.8 mmol) in THF (25 ml) was refluxed for 72 hours. The crude reaction mixture was then diluted with EtOAc (100 ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo to give a gum. Then this resin was again dissolved in THF (20 ml) and treated with lithium hydroxide (80 mg, 1.78 mmol) and water (1 ml), after which it was stirred for 24 hours at room temperature. The mixture was then acidified with several drops of AcOH, then concentrated in vacuo and chromatographed (SiO ₂ , MeOH: DCM: AcOH: H ₂ O, 10: 90: 3: 2), whereby the target compound was obtained in the form of a white powder (561 mg 1.1 mmol, 57%). δH (DMSO d ⁶ , 390K) 10.89 (1H, s), 8.80 (2H, s), 8.58 (1H, d, J 8.8 Hz), 7.59 (2H, d, J 8.4 Hz), 7.27 (2H, d, J 8.4 Hz), 4.23 (1H, m), 3.76 (2H, m), 3.60 (2H, m), 3, 23 (1H, dd, J 4.4, 13.9 Hz), 2.96 (1H, dd, J 9.8, 13.9 Hz), 1.98-1.93 (2H, m), 1 47 (1H, m), 1.30 (1H, m). m / z (ES ⁺ , 70B) 508.0 (MH ⁺ ).

EXAMPLE 113

(2S) -2- (2-fluoro-4,4-dimethyl-3-oxocyclobut-1-enylamino1-3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The target compound in the form of a white powder (1.13 g, 2.1 mmol, 84%) was obtained from the compound of Example 5 (1.25 g, 2.49 mmol), Selectfluor ™ reagent (1.0 g, 2.8 mmol) ) and lithium hydroxide (80 mg, 1.8 mmol) by the methods described in examples 61 and 2. δH (DMSO d ⁶ , 390K) 10.88 (1H, s), 8.80 (2H, s), 8.65 (1H, d, J 8.7 Hz), 7.60 (2H, d, J 8.2 Hz), 7.27 (2H, d, J 8.2 Hz), 4.25 (1H, m), 3.22 (1H, dd, J 4.5, 13.9 Hz), 2.98 (1H , dd, J 9.3, 13.9 Hz), 1.11 (3H, s), 1.03 (3H, s), m / z (ES ⁺ , 70B) 466.0 (MH ⁺ ).

EXAMPLE 114

(2S) -2 - [(4,4-dimethyl-2-methylsulfanyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

A solution of the compound of Example 5 (700 mg, 1.47 mmol) in THF (15 ml) was treated at room temperature with a 1.0 M solution of methanesulphenyl chloride in DCM (1.5 ml, 1.5 mmol). After 30 minutes, the reaction mixture was partitioned between EtOAc (50 ml) and saturated aqueous sodium bicarbonate (25 ml). After separation of the organic phase, followed by drying (MgSO ₄ ), filtration and concentration in vacuo, a solid was obtained which was approximately 90% pure. This crude solid was redissolved in THF (20 ml) and treated with lithium hydroxide (60 mg, 1.3 mmol) and water (1 ml), and then stirred at room temperature for 24 hours. The reaction mixture was acidified with several drops of AcOH and concentrated in vacuo. Chromatography (SiO ₂ , MeOH: DCM: AcOH: H ₂ O, 10: 90: 3: 2) gave the target compound as a white powder (289 mg, 0.59 mmol, 40%). δH (DMSO d ⁶ , 390K) 10.85 (1H, s), 8.87 (1H, d, J 9.2 Hz), 8.80 (2H, s), 7.59 (2H, d, J 8.0 Hz), 7.29 (2H, d, J 8.0 Hz), 5.04 (1H, m), 2.25 (1H, dd, J 3.5, 13.5 Hz), 3 00 (1H, dd, J 9.8, 13.5 Hz), 2.00 (3H, s), 1.11 (3H, s), 1.02 (3H, s). m / z (ES ⁺ , 70B) 493.9 (MH ⁺ ).

EXAMPLE 115

(2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The target compound in the form of a light yellow powder (305 mg, 0.58 mmol, 39%) was obtained in two stages from the compound of Example 5 (700 mg, 1.47 mmol), a 1.0 M solution of isopropylsulfenyl chloride in DCM (1.5 ml , 1.5 mmol) and lithium hydroxide (80 mg, 1.8 mmol) by the method described in example 114. δH (DMSO d ⁶ , 390K) 13.24 (1H, broad), 10.87 (1H, s), 8.92 (1H, d, J 9.5 Hz), 8.80 (2H, s), 7.58 (2H, d, J 8.4 Hz), 7.28 (2H, d, J 8.4 Hz), 5.16 (1H, m), 3.22 (1H, dd, J 3.9, 13.8 Hz), 2.97 (1H, dd, J 9.7, 13, 8 Hz), 2.67 (1H, m), 1.14 (3H, s), 1.06-1.04 (9H, m). m / z (ES ⁺ , 70B) 522.0 (MH ⁺ ).

EXAMPLE 116

(2S) -ethyl-2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

To a stirred solution of the compound of Example 27 (1.0 g, 1.93 mmol) in THF (50 ml), a 1.0 M solution of isopropylsulphenyl chloride in DCM was added dropwise at room temperature until the reaction mixture turned a stable yellow color. Then the reaction mixture was diluted with EtOAc (200 ml) and washed with saturated aqueous sodium bicarbonate (50 ml). The organic phase was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , 100% EtOAc) gave the title compound as a light yellow powder (987 mg, 87%). δH (DMSO d ⁶ , 390K) 10.85 (1H, s), 8.79 (2H, s), 8.73 (1H, d, J 9.5 Hz), 7.56 (2H, d, J 8.5 Hz), 7.25 (2H, d, J 8.5 Hz), 5.20 (1H, m), 4.17 (2H, q, J 7.1 Hz), 3.18 (1H dd, J 4.3, 13.8 Hz), 2.97 (1 H, dd, J 10.2, 13.8 Hz), 2.65 (1 H, m), 1.73-1.57 ( 8H, m), 1.36-1.33 (1H, m), 1.21 (3H, t, J 7.1 Hz), 1.17-1.14 (1H, m), 1.02 ( 6H, d, J 6.6 Hz). m / z (ES ⁺ , 70B) 590.0 (MH ⁺ ).

EXAMPLE 117

(2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 116 (400 mg, 0.68 mmol) with lithium hydroxide (100 mg, 2.2 mmol) by the method described in Example 2, the target compound was obtained in the form of a white powder (333 mg, 0.59 mol, 89%) ) δH (DMSO d ⁶ , 390K) 10.84 (1H, s), 8.78 (2H, s), 8.62 (1H, d, J 9.4 Hz), 7.55 (2H, d, J 8.1 Hz), 7.25 (2H, d, J 8.1 Hz), 5.12 (1H, m), 3.20 (1H, dd, J 3.6, 13.7 Hz), 2 94 (1H, dd, J 10.2, 13.7 Hz), 2.62 (1H, m), 1.91-1.64 (8H, m), 1.59-1.56 (1H, m), 1.36-1.33 (1H, m), 1.02 (6H, d, J = 6.6 Hz). m / z (ES ⁺ , 70B) 562.0 (MH ⁺ ).

EXAMPLE 118

(2S) -ethyl-2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoate

A solution of 3-hydroxy-4,4-dimethyl-2-cyclobutenone (333 mg, 2.97 mmol) and intermediate 12 (1.0 g, 2.98 mmol) in THF (25 ml) was stirred at room temperature for 48 hours Volatiles were removed in vacuo and the residue was chromatographed (SiO ₂ ; EtOAc) to give 970 mg of the coupling reaction product with a purity of approximately 90%. This intermediate was redissolved in THF (35 ml) and treated with a 1.0 M solution of isopropylsulphenyl chloride in DCM (3.0 ml, 3.0 mmol) at room temperature. After 60 minutes, the reaction mixture was diluted with EtOAc (100 ml) and washed with saturated aqueous sodium carbonate (50 ml), the organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , EtOAc) gave the title compound as a white powder (817 mg, 1.62 mmol, 54%). δH (DMSO d ⁶ , 390K) 9.83 (1H, s), 9.52 (1H, s), 9.01 (1H, d, J 9.4 Hz), 8.65 (1H, d, J 5.7 Hz), 8.16 (1H, d, J 5.7 Hz), 7.81 (2H, d, J 8.5 Hz), 7.68 (1H, d, J 5.7 Hz) 7.23 (2H, d, J 8.5 Hz), 7.13 (1H, d, J 5.7 Hz), 5.24 (1H, m), 4.19 (2H, q, J 7 , 1 Hz), 3.20 (1H, dd, J 4.5, 13.8 Hz), 2.97 (1H, dd, J 10.0, 13.8 Hz), 2.76 (1H, m ), 1.22 (3H, t, J 7.1 Hz), 1.13 (3H, s), 1.05 (6H, d, J 6.7 Hz), 1.04 (3H, s). m / z (ES ⁺ , 70B) 505.2 (MH ⁺ ).

EXAMPLE 119

(2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoate

After hydrolysis of the compound of Example 118 (400 mg, 0.79 mmol) with lithium hydroxide (100 mg, 2.2 mmol) by the method described in Example 2, the target compound was obtained in the form of a white powder (231 mg, 0.49 mmol, 62% ) δH (DMSO d ⁶ , 390K) 9.83 (1H, s), 9.51 (1H, s), 8.89 (1H, d, J 9.5 Hz), 8.65 (1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.78 (2H, d, J 8.5 Hz), 7.22 (2H, d, J 8.5 Hz) 7.11 (1H, d, J 5.7 Hz), 5.16 (1H, m), 3.21 (1H, dd, J 4.1, 13.8 Hz), 2.94 (1H, dd, J 6.7, 13.8 Hz), 2.75 (1H, m), 1.13 (3H, s), 1.06 (6H, d, J 6.6 Hz), 1.03 ( 3H, s). m / z (ES ⁺ , 70B) 477.1 (MH ⁺ ).

EXAMPLE 120

(2S) -ethyl-2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridin-1- ilamino) phenyl] propanoate

The target compound in the form of a yellow powder (931 mg, 1.71 mmol, 58%) was obtained in two stages from intermediate 12 (1.0 g, 2.98 mmol), 1-keto-3-hydroxyspiro [3,5] non-2-ena (452 mg, 2.97 mmol) [obtained by the method described by Wasserman HH et al., J. Org. Chem., 38, 1451-1455 (1973)] and a 1.0 M solution of isopropylsulphenyl chloride in DCM (3.5 ml, 3.5 mmol) by the method described in Example 118. (DMSO d ⁶ , 390K) 9.89 (1H , s), 9.58 (1H, s), 8.82 (1H, d, J 9.4 Hz), 8.71 (1H, d, J 5.6 Hz), 8.21 (1H, d , J 5.6 Hz), 7.85 (2H, d, J 8.3 Hz), 7.74 (1H, d, J 5.6 Hz), 7.28 (2H, d, J 8.3 Hz), 7.18 (1H, d, J 5.6 Hz), 5.31 (1H, m), 4.24 (2H, q, J 7.1 Hz), 3.24 (1H, dd, J 4.1, 13.7 Hz), 3.03 (1H, dd, J 10.3, 13.7 Hz), 2.80 (1H, m), 1.80-1.71 (8H, m ), 1.46-1.43 (1H, m), 1.28 (3H, t, J 7.1 Hz), 1.24-1.21 (1H, m), 1.11 (6H, d , J 6.5 Hz). m / z (ES ⁺ , 70B) 545.2 (MH ⁺ ).

EXAMPLE 121

(2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid

After hydrolysis of the compound of Example 120 (900 mg, 1.62 mmol) with lithium hydroxide (150 mg, 3.3 mmol) by the method described in Example 2, the target compound was obtained in the form of a bright yellow powder (790 mg, 1.53 mol, 94%). δH (DMSO d ⁶ , 390K) 9.83 (1H, s), 9.51 (1H, s), 8.67 (1H, d, J 5.6 Hz), 8.65 (1H, d, J 5.6 Hz), 8.15 (1H, d, J 5.7 Hz), 7.77 (2H, d, J 8.4 Hz), 7.68 (1H, d, J 5.7 Hz) 7.23 (2H, d, J 8.4 Hz), 7.12 (1H, d, J 5.7 Hz), 5.20 (1H, m), 3.22 (1H, dd, J 3 9, 13.8 Hz), 2.94 (1H, dd, J 10.4, 13.8 Hz), 1.79-1.66 (8H, m), 1.40-1.35 (1H , m), 1.20-1.15 (1H, m), 1.05 (3H, d, J 6.3 Hz), 1.03 (3H, d, J 6.3 Hz). m / z (ES ⁺ , 70B) 517.2 (MH ⁺ ).

EXAMPLE 122

(2S) -ethyl-2 - [(2-isopropylsulfanyl-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoate

The target compound in the form of a yellow powder (1.15 g, 2.1 mmol, 36%) was obtained in two stages from intermediate 12 (1.96 g, 5.8 mmol), 7-oxaspiro [3,5] nonane- 1,3-dione (1.0 g, 6.5 mmol) [obtained by the method described by Wasserman HH et al., J. Org. Chem., 38, 1451-1455, (1973)] and a 1.0 M solution of isopropylsulphenyl chloride in DCM (5.4 ml, 5.4 mmol) by the method described in Example 118. δH (DMSO d ⁶ , 390K) 9.83 (1H, s), 9.52 (1H, s), 8.94 (1H, d, J 9.5 Hz), 8.65 (1H, d, J 5.6 Hz), 8.15 (1H d, J 5.7 Hz), 7.78 (2H, d, J 8.5 Hz), 7.68 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8 5 Hz), 7.12 (1H, d, J 5.7 Hz), 5.26 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.81-3, 76 (2H, m), 3.64-3.55 (2H, m), 3.20 (1H, dd, J 4.3, 13.8 Hz), 2.96 (1H, dd, J 10, 3, 13.8 Hz), 2.81-2.74 (1H, m), 2.06-1.93 (2H, m), 1.50-1.47 (1H, m), 1.32 -1.28 (1H, m), 1.23 (3H, t, J 7.1 Hz), 1.07 (3H, d, J 6.6 Hz), 1.05 (3H, d, J 6 , 6 Hz). m / z (ES ⁺ , 70B) 547.2 (MH ⁺ ).

EXAMPLE 123

(2S) -2 - [(2-isopropylsulfanyl-3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridine- 1-ylamino) phenyl] propanoic acid

After hydrolysis of the compound of Example 122 (906 mg, 1.66 mmol) with lithium hydroxide (150 mg, 3.3 mmol) by the method described in Example 2, the target compound was obtained in the form of a light yellow powder (801 mg, 1.54 mol, 93%). δH (DMSO d ⁶ , 390K) 9.82 (1H, s), 9.51 (1H, s), 8.86 (1H, d, J 9.5 Hz), 8.65 (1H, d, J 5.5 Hz), 8.14 (1H, d, J 5.6 Hz), 7.76 (2H, d, J 8.1 Hz), 7.68 (1H, d, J 5.5 Hz) 7.28 (2H, d, J 8.1 Hz), 7.12 (1H, d, J 5.6 Hz), 5.24-5.19 (1H, m), 3.78 (2H, m), 3.61 (2H, m), 3.21 (1H, dd, J 3.5, 13.8 Hz), 2.91 (1H, dd, J 10.7, 13.8 Hz), 2.77-2.71 (1H, m), 2.05-1.91 (2H, m), 1.49-1.46 (1H, m), 1.30-1.26 (1H, m) ), 1.07 (3H, s), 1.03 (3H, s). m / z (ES ⁺ , 70B) 519.1 (MH ⁺ ).

EXAMPLE 124

(2S) -ethyl-2 - [(3-oxospiro [3,4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of intermediate 47 (1.0 g, 7.3 mmol) and the free base of intermediate 27 (2.48 g, 7.3 mmol) in DCM (25 ml) was stirred at room temperature for 48 hours. Volatiles were removed in vacuo and the residue was chromatographed (SiO ₂ ; EtOAc) to give the title compound as a white solid (2.14 g, 4.28 mmol, 59%). δH (CDCl ₃ , 300K) 9.02 (1H, s), 8.38 (2H, s), 7.49 (2H, d, 8.5 Hz), 7.00 (2H, d, J 8, 5 Hz), 6.03 (1H, d, J 7.8 Hz), 5.54 (2H, s), 4.41 (1H, s), 4.21 (2H, q, J 7.1 Hz ), 4.20 (1H, m), 3.15 (1H, dd, J 5.2, 14.0 Hz), 3.03 (1H, dd, J 6.1, 14.0 Hz), 1 56-1.51 (2H, m), 2.38-2.34 (2H, m), 1.18 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 500.0 (MH ⁺ ).

EXAMPLE 125

(2S) -2 - [(3-oxospiro [3,4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 124 (970 mg, 1.94 mmol) with lithium hydroxide (100 mg, 2.2 mmol) by the method described in Example 2, the desired compound (896 mg, 1.90 mol, 98%) was obtained. δH (DMSO d ⁶ , 390K) 10.87 (1H, s), 8.80 (2H, s), 8.45 (1H, d, J 8.4 Hz), 7.57 (2H, d, J 8.5 Hz), 7.27 (2H, d, J 8.5 Hz), 5.63 (2H, s), 4.41 (1H, s), 4.11 (1H, m), 3, 17 (1H, dd, J 4.8, 13.9 Hz), 2.98 (1H, dd, J 9.3, 13.9 Hz), 2.46-2.42 (2H, m), 2 36-2.25 (2H, m). m / z (ES ⁺ , 70B) 471.9 (MH ⁺ ).

EXAMPLE 126

(2S) -ethyl-2 - [(2-bromo-3-oxospiro [3,4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound as a white solid (116 mg, 0.20 mmol, 50%) was obtained by brominating the compound of Example 124 (206 mg, 0.41 mmol) with N-bromosuccinimide (75 mg, 0.57 mmol). δH (DMSO d ⁶ , 390K) 10.36 (1H, s), 8.67 (2H, s), 8.45 (1H, d, J 9.0 Hz), 7.58 (2H, d, J 8.5 Hz), 7.28 (2H, d, J 8.5 Hz), 5.67-5.63 (2H, m), 4.50 (1H, broad), 4.23 (2H q, J, 7.1 Hz), 3.28 (1H, dd, J 6.3, 14.1 Hz), 3.15 (1H, dd, J 9.0, 14.1 Hz), 2, 52-2.42 (4H, m), 1.28 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 579.0 (MH ⁺ ).

EXAMPLE 127

(2S) -2 - [(2-bromo-3-oxospiro [3,4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 126 (190 mg, 0.33 mmol) with lithium hydroxide (60 mg, 1.3 mmol) by the method described in Example 2, the target compound (162 mg, 0.29 mol, 88%) was obtained. δH (DMSO d ⁶ , 390K) 10.89 (1H, s), 9.09-9.04 (1H, m), 8.81 (2H, s), 7.62 (2H, d, J 8, 5 Hz), 7.29 (2H, d, J 8.5 Hz), 5.69-5.60 (2H, m), 4.72 (1H, m), 3.03 (1H, dd, J 9.0, 14.1 Hz), 2.98 (1H, dd, J 6.7, 14.1 Hz), 2.62-2.20 (4H, m). m / z (ES ⁺ , 70B) 551.8 (MH ⁺ ).

EXAMPLE 128

(2S) -ethyl-2 - [(4,4-dimethyl-3-oxo-2-pentafluorophenylsulfanylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound in the form of a white powder (459 mg, 0.68 mmol, 64%) was obtained from the compound of example 5 (500 mg, 1.06 mmol) and pentafluorophenyl sulfenyl chloride (273 mg, 1.17 mmol) by the method described in example 93. δH (CDCl ₃ , 300K); 8.41 (2H, s), 7.41 (2H, d, J 8.4 Hz), 6.99 (2H, d, J 8.4 Hz), 5.98 (1H, d, J 8, 8 Hz), 5.18-5.12 (1H, m), 4.12 (2H, q, J 7.1 Hz), 3.17 (1H, dd, J 5.6, 14.1 Hz) , 3.10 (1H, dd, J 5.7, 14.1 Hz), 1.18 (3H, t, J 7.1 Hz), 1.03 (3H, s), 1.01 (3H, from). m / z (ES ⁺ , 70B) 673.9 (MH ⁺ ).

EXAMPLE 129

(2S) -2 - [(4,4-dimethyl-3-oxo-2-pentafluorophenylsulfanylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

After hydrolysis of the compound of Example 128 (440 mg, 0.65 mmol) with lithium hydroxide (60 mg, 1.4 mmol) by the method described in Example 2, the target compound was obtained in the form of a white powder (372 mg, 0.57 mol, 88% ) δH (DMSO d ⁶ , 390K) 13.75 (1H, br s), 10.62 (1H, s), 9.16 (1H, d, J 9.5 Hz), 8.54 (2H, s ), 7.30 (2H, d, J 8.5 Hz), 6.97 (2H, d, J 8.5 Hz), 4.83-4.77 (1H, m), 3.0 (1H , dd, J 4.1, 14.0 Hz), 2.71 (1H, dd, J 10.0, 14.0 Hz), 0.83 (3H, s), 0.75 (3H, s) . m / z (ES ⁺ , 70B) 645.9 (MH ⁺ ).

EXAMPLE 130

(2S) -ethyl-2- (4,4-dimethyl-3-oxo-2-pyrazin-2-ylcyclobut-1-enylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} - propanoate

A solution containing vinyl iodide (500 mg, 0.81 mmol), palladium dichloride (14 mg), triphenylarsine (101 mg), 2-tributyltin-1,4-pyridazine (307 mg) and copper iodide (15 mg) in DMF, heated to 95 ° C for 3 hours. Then the reaction mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and EtOAc (100 ml). The organic phase was removed, dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , 50% EtOAc: hexanes) gave the title compound (127 mg, 0.23 mmol, 28%). δH (CDCl ₃ , 330K); 9.51 (1H, s), 8.72 (1H, s), 8.26 (1H, m), 8.11 (1H, d, J 2.7 Hz), 7.97 (1H, d, J 10.9 Hz), 7.54 (2H, d, J 8.5 Hz), 4.24-4.15 (3H, m), 3.18 (1H, dd, J 5.2, 13, 9 Hz), 3.11 (1H, dd, J 4.6, 13.9 Hz), 1.23 (3H, t, J 7.1 Hz), 1.22 (3H, s), 0.98 (3H, s). m / z (ES ⁺ , 70B) 554.1 (MH ⁺ ).

EXAMPLE 131

(2S) -2- (4,4-dimethyl-3-oxo-2-pyrazin-2-ylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

After hydrolysis of the compound of Example 130 (50 mg, 0.09 mmol) with lithium hydroxide (10 mg, 0.23 mmol) by the method described in Example 2, the target compound was obtained in the form of a white powder (33 mg, 0.064 mmol, 71%). LCMS indicated the presence of two separate atropisomers. δH (DMSO, d ⁶ , 390K, 1 atropisomer) 10.49 (1H, s), 8.90 (1H, broad m), 8.69 (2H, s), 8.42 (1H, broad m ), 8.21 (1H, broad m), 7.43 (2H, d, J 8.3 Hz), 7.21 (2H, d, J 8.3 Hz), 5.95 (1H, broad s), 4.20 (1H, m), 3.27-3.22 (1H, m), 3.06 (1H, m), 1.28 (3H, s), 1.19 (3H, from). m / z (ES ⁺ , 70B) 526.0 (MH ⁺ ).

EXAMPLE 132

(2S) -ethyl-2 - [(4-methyl-3-oxo-4-phenylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound, which is a mixture of diastereomers of about 1: 1 (329 mg, 0.61 mmol, 59%), was obtained as a white powder from intermediate 49 (300 mg, 1.72 mmol) and the free base of intermediate 27 (400 mg, 1.04 mmol) by the method described to obtain the compound of example 11. δH (CDCl ₃ , 300K) 10.95 (1H, s), 10.88 (1H, s), 8.89 (1H, d, J 8.6 Hz), 8.81 (2H, s), 8.80 (2H, s), 8.74 (1H, d, J 8.8 Hz), 7.63 (2H, d, J 8, 5 Hz), 7.59 (2H, d, J 8.5 Hz), 7.34-7.10 (5H, m), 6.89 (2H, d, J 8.5 Hz), 6.85 (2H, d, J 8.5 Hz), 4.71 and 4.66 (1H, s), 4.48-4.42 and 4.38-4.33 (1H, m), 4.21 ( 2H, t, J 7.1 Hz), 3.31-3.01 (2H, m), 1.52 and 1.42 (3H, s), 1.25 (3H, t, J 7.1 Hz) ) m / z (ES ⁺ , 70B) 537.9 (MH ⁺ ).

EXAMPLE 133

(2S) -ethyl-2 - [(4-methyl-3-oxo-4-phenylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The compound of example 132 (100 mg, 0.18 mmol) was hydrolyzed by the method described in example 2, whereby the target compound was obtained in the form of a finely divided white substance, which is a mixture of diastereomers, about 1: 1 (79 mg, 0.15 mmol, 86%). δH (DMSO, d ⁶ , 390K) 10.95 and 10.88 (1H, s), 8.82 and 8.81 (2H, s), 8.65 (1H, d, J 8.7 Hz), 7.63 and 7.59 (2H, d, J 8.5 Hz), 7.23-7.10 (5H, m), 6.88 and 6.85 (2H, d, J 8.5 Hz) 4.70 and 4.63 (1H, s), 4.36-4.25 and 4.25-4.23 (1H, m), 3.31-3.00 (2H, m), 1, 41 and 1.25 (3H, s). m / z (ES ⁺ , 70B) 509.9 (MH ⁺ ).

EXAMPLE 134

(2S) -ethyl-2 - [(7-acetyl-2-bromo-3-oxo-7-azaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [( 3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of the compound of Example 51 (100 mg, 0.18 mmol) in THF (10 ml) was treated with N-bromosuccinimide (32 mg, 0.19 mmol) at room temperature. After 30 minutes, the reaction mixture was diluted with EtOAc (50 ml), washed with saturated aqueous sodium bicarbonate (30 ml) and the organic phase was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , EtOAc) gave the title compound as a white powder (79 mg, 0.12 mmol, 67%). δH (CDCl ₃ , 300K); 9.54 (1H, s), 8.65 (1H, d, J 9.4 Hz), 8.19 (2H, s), 7.49 (2H, d, J 8.4 Hz), 7, 07 (2H, d, J 8.4 Hz), 4.91-4.81 (1H, m), 4.11 (2H, q, J 7.1 Hz), 3.49-3.44 (1H , m), 3.25-2.66 (5H, m), 1.89 (3H, s), 1.86-1.25 (4H, m), 1.18 (3H, t, J 7, 1 Hz). m / z (ES ⁺ , 70B) 639.0 (MH ⁺ ).

EXAMPLE 135

(2S) -2 - [(7-acetyl-2-bromo-3-oxo-7-azaspiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3, 5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of Example 134 (50 mg, 0.078 mmol) was hydrolyzed by the method described in Example 2, whereby the target compound was obtained in the form of a white powder (21 mg, 0.034 mmol,%). δH (DMSO, d ⁶ , 390K) 10.38 (1H, s), 8.96 (2H, s), 7.57 (2H, s broad), 7.28 (2H, d, J 7.9 Hz), 4.78 (1H, m), 3.99-3.96 (2H, m), 3.30-3.06 (4H, m), 2.00 (3H, s), 1.94 -1.84 (2H, m), 1.48-1.21 (2H, m). m / z (ES ⁺ , 70B) 610.9 (MH ⁺ ).

EXAMPLE 136

Ethyl (2S) -2- (2-benzyl-4,4-dimethyl-3-oxocyclobut-1-enylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

A solution of the free acid of intermediate 27 (0.82 g, 2.1 mmol) and intermediate 72 (0.48 g, 2.3 mmol, 1.1 eq.) In nitromethane (8 ml) was treated with acetic acid (1 drop ) The resulting mixture was heated to 100 ° C for 2 hours, and then was distributed between EtOAc (50 ml) and water (25 ml), the organic phases were separated, washed with water (25 ml), Na ₂ CO ₃ (25 ml, saturated aqueous) and brine (25 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude foam. This foam was purified by column chromatography (SiO ₂ ; gradient elution with hexane: EtOAc - EtOAc, 1: 1), whereby the target compound was obtained as a white solid (0.71 g, 59%). δ H NMR (DMSO, d ⁶ , 400 M Hz) 10.87 (1H, s), 8.81 (2H, s), 8.38 (1H, d, J 9.3 Hz), 7.53 (2H d, J 8.4 Hz), 7.33 (2H, m), 7.15 (2H, m), 7.09 (2H, d, J 8.5 Hz), 7.03 (2H, d , J 7.2 Hz), 4.15 (1H, m), 4.04 (2H, d q, J 1.6, 7.1 Hz), 3.19 (2H, m), 3.04 ( 1H, dd, J 13.8, 5.0 Hz), 2.89 (1H, dd, J 9.5, 4.8 Hz), 1.02-1.26 (8H, m). m / z (ESI, 70B) (MH ⁺ ) 566.

EXAMPLE 137

2- (2-benzyl-4,4-dimethyl-3-oxocyclobut-1-enylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

To a solution of the compound of Example 136 (210 mg, 0.4 mmol) in THF (2 ml) was added a solution of lithium hydroxide hydrate (25 mg, 0.6 mmol, 1.5 eq.) In water (1 ml). The solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was again dissolved in water (15 ml) and washed with diethyl ether (10 ml). The aqueous solution was concentrated to approximately 5 ml and acidified with HCl (2M, aqueous) to pH 4. The resulting solid was filtered, washed with water on a sintered glass funnel and diethyl ether, and then dried in vacuum to obtain the target compound as a white solid ( 170 mg, 85%). δH (400 M Hz, DMSO d ⁶ , 380K) 10.42 (1H, broad), 8.70 (2H, s), 7.64 (1H, d, J 9.4 Hz), 7.52 ( 2H, d, J 6.6 Hz), 7.25 (2H, m), 7.13-7.18 (5H, m), 4.13 (1H, m), 3.26 (2H, d, J 2.9 Hz), 3.13 (1H, dd, J 14.0, 4.9 Hz), 2.97 (1H, dd, J 14.0, 9.0 Hz), 1.12 (3H , s), 1.09 (1H, d, J 15.7 Hz). m / z (ESI, 70B) MH ⁺ 538.

EXAMPLE 138

Isopropyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

To a solution of the compound of Example 32 (0.5 g, 0.9 mmol) in DMF (5 ml) was added EDC (185 mg, 1.1 eq.), HOBT (135 mg, 1.1 eq.) And isopropanol (0 5 ml). The mixture was stirred at room temperature for 48 hours, then partitioned between EtOAc (100 ml) and water (50 ml). The aqueous layer was separated, and the organic layers were washed with water (5 × 30 ml), brine (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude solid. This crude material was triturated with diethyl ether to give the title compound as a white powder (0.35 g, 65%). δH NMR (300 M Hz, DMSO d ⁶ ) 10.69 (1H, broad), 8.68 (1H, d, J 9.1 Hz), 8.60 (2H, s), 7.39 (2H , d, J 8.5 Hz), 7.08 (2H, d, J 8.5 Hz), 4.78 (1H, septet, J 6.3 Hz), 4.53 (1H, m), 3 01 (1H, dd, J 4.9, 13.8 Hz), 2.83 (1H, dd, J 9.5, 13.9 Hz), 1.36-1.60 (9H, m), 1.19 (1H, d, J 12.7 Hz), 0.98-1.05 (6H, dd). m / z (ESI, 70B) MH ⁺ 608.

EXAMPLE 139

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) 1-methylpiperidin-4-yl ester ) amino] phenyl} propanoic acid

Using the procedure described for the preparation of the compound of Example 138, from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (185 mg, 1.1 eq.), HOBT (135 mg, 1.1 eq.) , 4-hydroxy-1-methylpiperidine (0.5 ml) and DMF (2 ml) gave the target compound (0.21 g, 36%). δH NMR (300 M Hz, DMSO d ⁶ ) 11.01 (1H, broad), 9.01 (1H, d, J 9.4 Hz), 8.92 (2H, s), 7.71 (2H d, J 8.5 Hz), 7.40 (2H, d, J 8.5 Hz), 4.90 (1H, broad), 3.33 (1H, dd, J 13.8, 4, 8 Hz), 3.16 (1H, dd, J 13.8, 9.6 Hz), 2.55 (2H, broad), 2.40 (2H, broad), 2.24 (3H, d , J 8.0 Hz), 1.64-1.95 (12H, m), 1.50 (2H, d, J 12.1 Hz), 1.23 (2H, broad). m / z (ESI, 70B) MH + 664.

EXAMPLE 140

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino-3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid cyclopentyl ester

Using the procedure described for the preparation of the compound of Example 138, from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (600 mg, 3 equiv.), HOBT (400 mg, 3 equiv.), Cyclopentanol (0 , 5 ml) and DMF (5 ml) received the target compound. δ H NMR (400 M Hz, DMSO d ⁶ ) 10.88 (1H, s), 8.85 (1H, d, J 9.0 Hz), 8.78 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.26 (2H, d, J 8.5 Hz), 5.15 (1H, m), 4.71 (1H, m), 3.18 (1H, dd, J 5.2, 13.9 Hz), 3.02 (1H, dd, J 9.5, 13.9 Hz), 1.17-1.84 (18H, m), 1.14 (1H, m ) m / z (ESI, 70B) MH ⁺ 634

EXAMPLE 141

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino tetrahydrofuran-3-yl ester ] phenyl} propanoic acid

Using the procedure described for preparing the compound of Example 138, from the acidic compound of Example 32 (0.5 g, 0.89 mmol), EDC (600 mg, 3 equiv.), HOBT (400 mg, 3 equiv.), (S ) -3-hydroxytetrahydrofuran (0.5 ml) and dimethylformamide (5 ml) gave the target compound. δ H NMR (300 M Hz, DMSO d ⁶ ) 8.87 (1H, d, J 8.9 Hz), 8.79 (2H, s), 7.58 (2H, d, J 8.4 Hz), 7.27 (2H, d, J 8.5 Hz), 5.30 (1H, m), 4.77 (1H, m), 3.72-3.83 (3H, m), 3.65 ( 1H, d, J 10.4 Hz), 3.20 (1H, dd, J 14.0, 5.1 Hz), 3.04 (1H, dd, J 14.0, 9.7 Hz), 2 , 11-2.27 (1H, m), 1.87-1.99 (1H, m), 1.37-1.78 (9H, m), 1.07-1.17 (1H, m) . m / z (ESI, 70B) MH ⁺ 636.

EXAMPLE 142

2- (2-Bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl 1-methylpyrrolidin-3-yl ester } propanoic acid

Using the procedure described for preparing the compound of Example 138, from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (600 mg, 3 eq.), HOBT (400 mg, 3 eq.), 1-methyl -3-pyrrolidinol (0.6 ml) and DMF (5 ml) gave the target compound. δ H NMR (400 M Hz, DMSO d ⁶ ) 10.88 (1H, s), 8.87 (1H, d, J 9.0 Hz), 8.78 (2H, s), 7.58 (2H, d, J 8.3 Hz), 7.26 (2H, d, J 8.5 Hz), 5.13 (1H, m), 4.74 (1H, m), 3.16 (1H, m) 3.04 (1H, m), 2.43-2.73 (2H, m), 2.07-2.26 (2H, m), 1.55-1.75 (11H, m), 1 11 (1H, m). m / z (ESI, 70B) MH ⁺ 649.

EXAMPLE 143

2- (2-Bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloropyridin-4-carbonyl) amino] phenyl} propane phenyl ether acid

Using the procedure described for the preparation of the compound of Example 138, from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (500 mg, 2.6 eq.), HOBT (350 mg, 2.6 eq.) phenol (0.5 g) and DMF (5 ml) gave the target compound (0.17 g, 29%). δH (300 M Hz, DMSO d ⁶ ) 11.10 (1H, broad), 9.24 (1H, d, J 8.8 Hz), 8.98 (2H, s), 7.81 (2H, d, J 8.5 Hz), 7.47-7.67 (5H, s), 7.31 (2H, dd, J 8.4, 0.9 Hz), 6.93 (1H, d, J 8.1 Hz), 5.20 (1H, broad), 3.59 (1H, dd, J 9.3, 6.0 Hz), 3.40 (1H, dd, J 14.0, 9, 3 Hz), 1.60-1.97 (10H, m). m / z (ESI, 70B) MH ⁺ 644.

EXAMPLE 144

Pyridin-4-ylmethyl ether 2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

Using the procedure described for the preparation of the compound of Example 138, from the compound of Example 32 (0.60 g, 1.1 mmol), EDC (222 mg, 1.1 eq.), HOBT (162 mg, 1.1 eq.) , 4-pyridinomethanol (0.36 g, 3.2 mmol) and DMF (5 ml) gave the target compound (0.48 g, 66%). δH NMR (400 M Hz, DMSO d ⁶ , 380K) 10.43 (1H, broad), 8.69 (2H, s), 8.57 (2H, d, J 6.0 Hz), 8.38 (2H, d, J 8.1 Hz), 7.57 (2H, m), 7.30 (4H, m), 5.26 (2H, s), 4.95 (1H, broad), 3 32 (1H, dd, J 14.2, 5.4 Hz), 3.17 (1H, dd, J 14.1, 9.1 Hz), 1.46-1.71 (9H, m), 1.21 (1H, broad m). m / z (ESI, 70B) MH ⁺ 657.

EXAMPLE 145

Methyl (2S) -2 - [(3-oxo-7-oxaspiro [3,5] non-1-en-1-yl) amino] -3- (2,6-dimethoxy [1,1'-biphenyl] -4-yl) propanoate

Using the procedure described for the preparation of the compound of Example 38, from methyl (2S) -2-amino-3- (2,6-dimethoxy [1,1'-biphenyl] -4-yl) propanoate (2.0 g, 6 , 3 mmol) and 7-oxaspiro [3,5] nonane-1,3-dione (1.1 g, 1.1 eq.) In DCM (30 ml), the title compound was obtained as a white foam (2.4 g , 86%). δ H NMR (300 M Hz, DMSO d ⁶ ) 8.53 (1H, d, J 8.7 Hz), 7.20-7.30 (3H, m), 7.08 (2H, d, J 8, 1 Hz), 6.70 (2H, d, J 8.5 Hz), 4.44 (1H, s), 4.30 (1H, m), 3.72 (3H, s), 3.61 ( 6H, s), 3.32 (1H, dd, J 13.7, 5.0 Hz), 2.98 (1H, dd, J 13.8, 10.1 Hz), 1.74-1.99 (2H, m), 1.48 (1H, d, J 13.6 Hz), 1.31 (1H, d, J 13.0 Hz). m / z (ESI, 70B) MH ⁺ 439.

EXAMPLE 146

Methyl (2S) -2 - {[2- (isopropylsulfanyl) -3-oxo-7-oxaspiro [3,5] non-1-en-1-yl)] amino} -3- (2,6-dimethoxy [ 1,1'-biphenyl] -4-yl) propanoate

The target compound as a white foam (0.42 g, 73%) was obtained from the bromine derivative of Example 145 (0.5 g, 1.1 mmol) by the method described for the preparation of Example 70. δH NMR (400 M Hz, DMSO d ⁶ ) 8.91 (1H, d, J 9.4 Hz), 7.29-7.21 (3H, m), 7.09 (2H, d, J 8.2 Hz), 6.70 (2H d, J 8.4 Hz), 5.32 (1H, broad), 3.74-3.80 (5H, m), 3.54-3.64 (8H, m), 3.28 ( 1H, dd, J 4.2, 16.4 Hz), 2.97 (1H, dd, J 10.8, 13.6 Hz), 2.76 (1H, septet, J 6.7 Hz), 1 99 (1H, dt, J 11.5, 4.8 Hz), 1.84 (1H, dt, J 4.8, 13.0 Hz), 1.48 (1H, d, J 12.1 Hz ), 1.25 (1H, d, J 12.2 Hz), 1.05 (3H, d, J 6.7 Hz), 1.02 (3H, d, J 6.7 Hz). m / z (ESI, 70B) MH ⁺ 526.

EXAMPLE 147

Ethyl (2S) -2 - [(4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- (2,6-dimethoxy- [1,1'-biphenyl] -4-yl) propanoate

The target compound in the form of a white foam (1.8 g, 93%) was obtained from ethyl (2S) -2-amino-3- (2,6-dimethoxy [1,1'-biphenyl] -4-yl) propanoate (1 5 g, 4.5 mol) and 3-hydroxy-4,4-dimethyl-2-cyclobutenone (0.5 g, 4.5 mmol) in DCM (15 ml) by the method described for preparing the compound of Example 41. δH NMR (300 M Hz, DMSO d ⁶ ) 8.68 (1H, d, J 8.6 Hz), 7.22-7.37 (3H, m), 7.18 (2H, d, J 8.3 Hz), 6.78 (2H, d, J 8.4 Hz), 4.46 (1H, s), 4.32 (1H, m), 4.21 (2H, q, J 7.1 Hz) 3.69 (6H, s), 3.24 (1H, dd, J 13.8, 5.9 Hz), 3.09 (1H, dd, J 13.8, 9.1 Hz), 1, 24 (3H, t, J 7.1 Hz), 1.16 (3H, s), 1.08 (3H, s). m / z (ESI, 70B) MH ⁺ 424.

EXAMPLE 148

Ethyl (2S) -2 - {[2- (isopropylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- (2,6-dimethoxy- [1,1'-biphenyl] - 4-yl) propanoate

The target compound in the form of a white foam (0.52 g, 87%) was obtained by the method described for the preparation of the compound of Example 70. δH NMR (400 M Hz, DMSO d ⁶ , 380K) 8.99 (1H, d, J 9.5 Hz), 7.21-7.29 (3H, m), 7.10 (2H, d, J 8.1 Hz), 6.70 (2H, d, J 8.4 Hz), 5.29 ( 1H, m), 4.17 (2H, q, J 7.1 Hz), 3.60 (6H, s), 3.23 (1H, dd, J 13.8, 5.0 Hz), 2, 99 (1H, dd, J 13.8, 10.4 Hz), 2.79 (1H, septet, J 6.6 Hz), 0.99-1.25 (15H, m). m / z (ESI, 70B) MH ⁺ 498.

EXAMPLE 149

(2S) -2 - {[2- (isopropylsulfanyl) -3-oxo-7-oxaspiro [3,5] non-1-enyl) amino} -3- (2,6-dimethoxy [1,1'-biphenyl ] -4-yl) propanoic acid

The target compound in the form of a white powder (0.21 g, 89%) was obtained from the compound of example 146 (0.25 g, 0.46 mmol) by the method described in example 2. δH NMR (400 M Hz, DMSO d ⁶ ) 8 80 (1H, d, J 9.5 Hz), 7.21-7.28 (3H, m), 7.08 (2H, d, J 8.1 Hz), 6.70 (2H, d, J 8.4 Hz), 5.25 (1H, m), 3.76 (2H, m), 3.59 (8H, m), 3.30 (1H), 2.93 (2H, dd, J 10.9, 13.6 Hz), 2.76 (1H, septet, J 6.8 Hz), 1.99 (1H, m), 1.86 (1H, m), 1.46 (1H, d , J 13.1 Hz), 1.23 (1H, d, J 12.7 Hz), 1.06 (3H, d, J 7.8 Hz), 1.03 (3H, d, J 7.8 Hz). m / z (ESI, 70B) MH ⁺ 512.

EXAMPLE 150

(2S) -2 - {[2- (isopropylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- (2,6-dimethoxy [1,1'-biphenyl] -4- sludge) propanoic acid

The target compound in the form of a white powder (0.13 g, 44%) was obtained from the compound of example 148 (0.31 g, 0.64 mmol) by the method described in example 2. δH NMR (400 M Hz, DMSO d ⁶ ) 8 85 (1H, broad d), 7.21-7.29 (3H, m), 7.08 (2H, d, J 8.0 Hz), 6.70 (2H, d, J 8.4 Hz), 5.15 (1H, broad), 3.61 (6H, s), 3.91 (1H, dd, J 13.9, 8.6 Hz), 2.77 (1H, septet), 0.98-1.14 (6H, m). m / z (ESI, 70B) MH ⁺ 470.

EXAMPLE 151

Ethyl (2S) -2 - [(2-cyclohexyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

A mixture of the free amine of intermediate 27 (1000 mg, 2.61 mmol), intermediate 52 (611 mg, 2.61 mmol) and nitromethane (10 ml) was refluxed for 5 hours. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed (SiO ₂ , hexane: EtOAc, 3: 2), whereby the target compound was obtained as a colorless oil (310 mg, 20%). δ H NMR (CDCl ₃ ) 8.51 (2H, s), 7.80 (1H, br s), 7.52 (2H, d, J 8.5 Hz), 7.07 (2H, d, J 8.5 Hz), 5.15 (1H, d, J 7.6 Hz), 4.32 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.07 (2H d, J 5.6 Hz), 1.75-1.40 (20H, m), 1.19 (3H, t, J 7.1 Hz).

EXAMPLE 152

(2S) -2 - [(2-cyclohexyl-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid

The compound of Example 151 was hydrolyzed by the method described in Example 2, whereby the desired compound was obtained in 78% yield. δH NMR (d ⁶ DMSO) 10.84 (1H, br s), 8.78 (2H, s), 7.60 (1H, s), 7.56 (2H, d, J 8.2 Hz) 7.25 (2H, d, J 7.9 Hz), 4.06 (1H, m), 3.12 (1H, dd, J 3.9, 13.6 Hz), 2.92 (1H, dd, J 9.8, 13.4 Hz), 1.80-1.00 (21H, m). m / z (ES ⁺ , 70B) 570.1 (MH ⁺ ).

EXAMPLE 153

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2,4,4-trimethyl-3-oxocyclobut-1-enylamino) propanoate

The target compound with a yield of 70% was obtained from intermediate compound 59 by the method described for preparing the compound of Example 151. δH NMR (CDCl ₃ ) 8.78 (1H, br s), 8.44 (2H, s), 7.52 ( 2H, d, J 8.4 Hz), 7.04 (2H, d, J 8.3 Hz), 5.55 (1H, d, J 9.0 Hz), 4.39 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.07 (2H, m), 1.41 (3H, s), 1.26 (3H, t, J 7.1 Hz), 1, 05 (6H, s). m / z (ES ⁺ , 70B) 490.0 (MH ⁺ ).

EXAMPLE 154

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2,4,4-trimethyl-3-oxocyclobut-1-enylamino) propanoic acid

The compound of example 153 was hydrolyzed by the method described in example 2, to obtain the target compound with a yield of 69%. δ H NMR (d ⁶ DMSO) 7.86 (2H, s), 6.82 (2H, d, J 8.5 Hz), 6.54 (2H, d, J 8.5 Hz), 3.69 ( 1H, m), 2.57 (1H, m), 2.25 (1H, m), 0.68 (3H, s), 0.38 (3H, s), 0.29 (s, 3H). m / z (ES ⁺ , 70B) 462.0 (MH ⁺ ).

EXAMPLE 155

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-ethyl-4,4-dimethyl-3-oxocyclobut-1-enylamino) propanoate

The target compound in 73% yield was obtained from intermediate 60 by the method described for the preparation of the compound of Example 151. δH NMR (d ⁶ DMSO) 8.78 (2H, s), 8.13 (1H, d, J 9.0 Hz) 7.59 (2H, d, J 8.4 Hz), 7.30 (2H, d, J 8.3 Hz), 4.25 (1H, m), 4.17 (2H, q, J 7 , 0 Hz), 3.12 (1H, m), 3.00 (1H, m), 1.83 (2H, m), 1.20 (4H, m), 1.06 (3H, m), 0.98 (3H, s); 0.84 (3H, t, J 7.5 Hz). m / z (ES ⁺ , 70B) 504.0 (MH ⁺ ).

EXAMPLE 156

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-ethyl-4,4-dimethyl-3-oxocyclobut-1-enylamino) propanoic acid

The compound of example 155 was hydrolyzed by the method described in example 2, to obtain the target compound with a yield of 78%. δ H NMR (d ⁶ DMSO) 7.83 (2H, s), 6.81 (2H, d, J 8.5 Hz), 6.51 (2H, d, J 8.4 Hz), 3.52 ( 1H, m), 2.51 (1H, m), 2.21 (1H, m), 1.10 (2H, q, J 7.3 Hz), 0.36 (3H, s), 0.26 (3H, s), 0.10 (3H, t, J 7.5 Hz). m / z (ES ⁺ , 70B) 476.0 (MH ⁺ ).

EXAMPLE 157

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (4,4-dimethyl-3-oxo-2-propylcyclobut-1-enylamino) propanoate

The target compound with a yield of 75% was obtained from intermediate compound 61 by the method described to obtain the compound of example 151. δH NMR (d ⁶ DMSO) 8.80 (2H, s), 8.11 (1H, d, J 9.3 Hz) 7.59 (2H, d, J 8.3 Hz), 7.30 (2H, d, J 8.3 Hz), 4.26 (1H, m), 4.15 (2H, q, J 7 , 1 Hz), 3.12 (1H, m), 3.00 (1H, m), 1.75 (2H, m), 1.23 (2H, m), 1.07 (3H, s), 0.99 (3H, s); 0.73 (3H, t, J = 7.3 Hz). m / z (ES ⁺ , 70B) 518.0 (MH ⁺ ).

EXAMPLE 158

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (4,4-dimethyl-3-oxo-2-propylcyclobut-1-enylamino) propanoic acid

The compound of example 157 was hydrolyzed by the method described in example 2, to obtain the target compound with a yield of 93%. δ H NMR (d ⁶ DMSO) 8.78 (2H, s), 8.05 (1H, d, J 9.2 Hz), 7.58 (2H, d, J 8.3 Hz), 7.30 ( 2H, d, J 8.3 Hz), 4.15 (1H, m), 3.13 (1H, m), 2.95 (1H, m), 1.75 (2H, m), 1.23 (2H, q, J, 7.3 Hz), 1.06 (3H, s), 0.98 (3H, s), 0.72 (3H, t, J, 7.3 Hz). m / z (ES ⁺ , 70B) 490.0 (MH ⁺ ).

EXAMPLE 159

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxospiro [3,5] non-1-en-1-ylamino) propanoate

The target compound in 68% yield was obtained from intermediate 64 in the manner described for the preparation of the compound of Example 151. δH NMR (d ⁶ DMSO) 8.79 (2H, s), 7.93 (2H, d, J, 8.9 Hz) 7.58 (2H, d, J 8.4 Hz), 7.29 (2H, d, J 8.4 Hz), 4.33 (1H, m), 4.16 (2H, q, J 7 , 1 Hz), 3.10 (1H, m), 2.99 (1H, m), 1.60 (10H, m), 1.37 (3H, s), 1.18 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 530.1 (MH ⁺ ).

EXAMPLE 160

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxospiro [3,5] non-1-en-1-ylamino) propanoic acid

The compound of example 159 was hydrolyzed by the method described in example 2, to obtain the target compound with a yield of 86%. δ H NMR (d ⁶ DMSO) 8.82 (2H, s), 7.81 (2H, d, J 9.1 Hz), 7.57 (2H, d, J 8.4 Hz), 7.30 ( 2H, d, J 8.4 Hz), 4.28 (1H, m), 3.13 (1H, m), 2.96 (1H, m), 1.70-1.49 (8H, m) 1.38 (3H, s); 1.14 (2H, m). m / z (ES ⁺ , 70B) 501.9 (MH ⁺ ).

EXAMPLE 161

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propylspiro [3,5] non-1-en-1-ylamino) propanoate

The target compound in 76% yield was obtained from intermediate 65 by the method described for the preparation of the compound of Example 151. δH NMR (CDCl ₃ ) 8.58 (2H, s), 8.44 (1H, s), 7.65 (2H, d, J 8.5 Hz), 7.16 (2H, d, J 8.4 Hz), 5.38 (1H, m), 4.46 (1H, m), 4.30 (2H, q, J 7.1 Hz), 3.17 (2H, m), 1.85-1.42 (14H, m), 1.38 (3H, t, J 7.1 Hz), 0.90 (3H, t, J 7.3 Hz). m / z (ES ⁺ , 70B) 558.1 (MH ⁺ ).

EXAMPLE 162

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propylspiro [3,5] non-1-en-1-ylamino) propanoic acid

The compound of example 161 was hydrolyzed by the method described in example 2, to obtain the target compound with a yield of 84%. δ H NMR (d ⁶ DMSO, 380K) 10.42 (1H, br s), 8.69 (2H, s), 7.57 (2H, d, J 7.3 Hz), 7.28 (d, 2H, J 8.3 Hz), 7.12 (1H, d, J 9.1 Hz), 4.21 (1H, m), 3.20 (1H, dd, J 4.9, 14.0 Hz ), 3.06 (1H, dd, J 8.8, 14.0 Hz), 1.87 (2H, m), 1.72-1.45 (10H, m), 1.36 (2H, m ), 1.23 (1H, m), 0.82 (3H, t, J 7.4 Hz). m / z (ES ⁺ , 70B) 530.1 (MH ⁺ ).

EXAMPLE 163

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxo-7-oxaspiro [3,5] non-1-en-1- ilamino) propanoate

The target compound in 71% yield was obtained from intermediate 68 by the method described for the preparation of the compound of Example 151. δH NMR (d ⁶ DMSO) 8.80 (2H, s), 8.11 (1H, d, J 9.1 Hz) 7.59 (2H, d, J 8.4 Hz), 7.30 (2H, d, J 8.4 Hz), 4.38 (1H, m), 4.17 (2H, q, J 7 , 1 Hz), 3.75 (2H, m), 3.60 (2H, m), 3.15 (1H, dd, J 5.1, 13.7 Hz), 2.99 (1H, dd, J 9.2, 13.6 Hz) 1.90 (2H, m), 1.39 (3H, s), 1.19 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 532.0 (MH ⁺ ).

EXAMPLE 164

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxo-7-oxaspiro [3,5] non-1-en-1-ylamino ) propanoic acid

The compound of example 163 was hydrolyzed by the method described in example 2, to obtain the target compound with a yield of 89%. δ H NMR (d ⁶ DMSO) 8.81 (2H, s), 8.05 (1H, d, J 9.2 Hz), 7.60 (2H, d, J 8.4 Hz), 7.32 ( 2H, d, J 8.4 Hz), 4.25 (1H, m), 3.75 (2H, m), 3.58 (2H, m), 3.13 (1H, dd, J 4.6 , 13.8 Hz), 2.98 (1H, dd, J 9.5, 13.8 Hz) 1.94 (2H, m), 1.40 (3H, s), 1.29 (2H, m ) m / z (ES ⁺ , 70B) 504.0 (MH ⁺ ).

EXAMPLE 165

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propyl-7-oxaspiro [3,5] non-1-en-1- ilamino) propanoate

The target compound with a yield of 59% was obtained from intermediate compound 69 by the method described for obtaining the compound of example 151. δH NMR (d ⁶ DMSO) 8.78 (2H, s), 8.08 (1H, d, J 8.8 Hz) 7.55 (2H, d, J 8.4 Hz), 7.29 (2H, d, J 8.5 Hz), 4.23 (1H, m), 4.16 (2H, q, J 7 , 1 Hz), 3.76 (2H, m), 3.58 (2H, m), 3.15 (1H, dd, J 4.8, 13.6 Hz), 2.98 (1H, dd, J 9.7, 13.6 Hz) 1.80 (2H, m), 1.18 (6H, m), 0.73 (3H, t, J 7.4 Hz). m / z (ES ⁺ , 70B) 560.0 (MH ⁺ ).

EXAMPLE 166

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propyl-7-oxaspiro [3,5] non-1-en-1- ilamino) propanoate

The compound of example 165 was hydrolyzed by the method described in example 2, to obtain the target compound with a yield of 82%. δ H NMR (d ⁶ DMSO, 380K) 10.39 (1H, br s), 8.68 (2H, s), 7.57 (2H, m), 7.33 (3H, m), 4.23 (1H, m), 3.70 (4H, m), 3.21 (1H, dd, J 4.8, 14.0 Hz), 3.04 (1H, dd, J 9.0, 14.0 Hz), 2.10 (1H, s), 1.88 (4H, m), 1.87 (3H, t, J 7.0 Hz), 1.40 (4H, m). m / z (ES ⁺ , 70B) 532.1 (MH ⁺ ).

EXAMPLE 167

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl 2-imidazol-1-yl-ethyl ester) ) amino] phenyl} propanoic acid

The target compound with a yield of 48% was obtained from N-2-hydroxyethylimidazole (obtained by the method described by Yoshino et al., JCS Perkin Trans. 1, 1977, 1266-72] by the method described for obtaining the compound of example 138. δH NMR (d ⁶ DMSO ) 10.88 (1H, s), 8.88 (1H, d, J 9.1 Hz), 8.79 (2H, s), 7.66 (1H, s), 7.58 (2H, d , J 8.5 Hz), 7.29 (2H, d, J 8.5 Hz), 6.89 (1H, s), 4.84 (1H, m), 4.39 (2H, m), 4.29 (2H, m), 3.16 (1H, dd, J 4.6, 13.9 Hz), 2.96 (1H, dd, J 9.7, 13.9 Hz), 1.75 -1.45 (8H, m), 1.35 (1H, m), 1.13 (1H, m). M / z (ES ⁺ , 70B) 662.1 (MH ⁺ ).

EXAMPLE 168

2- (2-bromo-3-oxo-7-oxaspiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl ) amino] phenyl} propanoic acid

The target compound with a yield of 77% was obtained by the methods described here. δ H NMR (d ⁶ DMSO) 8.77 (1H, s), 7.67 (1H, d, J 6.3 Hz), 6.96 (2H, d, J 8.5 Hz), 6.78 ( 1H, d, J 5.8 Hz), 6.45 (2H, d, J 8.5 Hz), 6.14 (1H, s), 4.19 (1H, m), 3.05-2, 85 (4H, m), 2.59 (1H, dd, J 4.4, 14.0 Hz), 2.25 (1H, dd, J 9.7, 13.9 Hz) 1.66 (3H, s), 1.28 (1H, m), 1.16 (1H, m), 0.83 (1H, d, J 13.5 Hz), 0.66 (1H, d, J 13.5 Hz) . m / z (ES ⁺ , 70B) 537.9 (MH ⁺ ).

EXAMPLE 169

Ethyl 3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2- [1,3] dithian-2-yl-3-oxospiro [3,5] non-1-en-1 -amylamino) propanoate

To a solution of the compound of Example 27 (1.5 g, 2.9 mmol) in DCM (100 ml) was added 1,3-dithienium tetrafluoroborate (3 g, 14 mmol) [prepared by Paterson I; Price LG Tet. Lett. 1981, 22 (29), 2829]. The mixture was stirred overnight and then partitioned between EtOAc (200 ml) and sodium carbonate (100 ml, saturated aqueous), after which the organic extracts were separated, washed with water (3 × 50 ml) and brine (50 ml), dried ( Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude product, which was purified by column chromatography (SiO ₂ ; EtOAc: hexane, 4: 1) to obtain the target compound as a pale yellow solid (0.6 g, 86%). δH NMR (400 M Hz, d ⁶ DMSO, 300K) 8.67 (2H, s), 8.15 (1H, d, J 9.5 Hz), 7.67 (2H, d, J 8.5 Hz ), 7.12 (2H, d, J 8.5 Hz), 5.06 (1H, m), 4.65 (1H, s), 1.1 (1H, m), 4.08 (2H, t, J 7.1 Hz) 3.17-2.72 (3H, m), 2.65 (2H, m), 1.95 (1H, m), 1.87 (1H, m), 1, 78-1.46 (11H, m), 1.25 (1H, d, J 12.3 Hz). m / z (ESI, 70B) MH ⁺ 634.

EXAMPLE 170

(2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2- [1,3] dithian-2-yl-3-oxospiro [3,5] non-1- en-1-ylamino) propanoic acid

To a solution of the compound of Example 169 (0.25 g, 0.4 mmol) in THF (2 ml) was added a solution of lithium hydroxide (25 mg, 0.6 mmol) in water (1 ml). The mixture was stirred at room temperature overnight, concentrated in vacuo and the residue was distributed in a minimal amount of water. Then, HCl (2M, aqueous) was added to adjust the solution to pH 4, after which the resulting solid was filtered, washed with ether and ethyl acetate, and the product was obtained as a light yellow solid (0.15 g, 63%). δH NMR (400 M Hz, d ⁶ DMSO, 300K) 10.85 (1H, s), 8.78 (2H, s), 8.28 (1H, d, J 9.9 Hz), 7.55 ( 2H, d, J 8.5 Hz), 7.31 (2H, d, J 8.5 Hz), 5.06 (1H, m), 4.75 (1H, s), 3.21-2, 78 (3H, m), 2.67 (2H, m), 1.99 (1H, m), 1.75 (1H, m), 1.57 (8H, m), 1.22 (1H, d , J 11.9 Hz), 1.08 (1H, m). m / z (ESI, 70B) MH ⁺ 606.

EXAMPLE 171

Ethyl (2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (2-methanesulfinyl-4,4-dimethyl-3-oxocyclobut-1- enylamino) propanoate

A solution of the compound of Example 5 (800 mg, 1.68 mmol) in THF (20 ml) was treated at room temperature with a solution of methanesulphenyl chloride in DCM (1.9 ml, 1.0 M). After 30 minutes, the reaction mixture was partitioned between EtOAc (50 ml) and saturated aqueous sodium bicarbonate (25 ml). After separation of the organic phase, drying (MgSO ₄ ), filtration and concentration in vacuo, a solid was obtained which had a purity of approximately 90%. This crude solid was redissolved in DCM (20 ml) and treated with m-CPBA (1.5 g, purity 57-75%) and sodium bicarbonate (500 mg), and then stirred at room temperature for 24 hours. The reaction mixture diluted with EtOAc (100 ml), washed with H ₂ O (50 ml), separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. Chromatography (SiO ₂ , EtOAc) gave the title compound as a white powder (730 mg, 1.31 mmol, 78%), which was a mixture of diastereomers of approximately 1: 1. δH (CDCl ₃ , 330K) 8.44 and 8.41 (2H, s), 8.35 and 8.17 (1H, s), 7.57 and 7.47 (2H, d, J 8.4 Hz ), 7.15 and 7.08 (2H, d, J 8.4 Hz), 7.04 and 7.01 (1H, d, J 8.9 Hz), 5.24-5.22 (1H, m), 4.25-4.11 (3H, m), 3.31-3.05 (2H, m), 2.97 and 2.93 (3H, s), 1.30-1.16 ( 9H, m). m / z (ES ⁺ , 70B) 553.9 and 556.0 (MH ⁺ ).

EXAMPLE 172

(2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (2-methanesulfinyl-4,4-dimethyl-3-oxocyclobut-1-enylamino ) propanoic acid

The compound of example 171 (300 mg, 0.54 mmol) was hydrolyzed by the method described in example 2, whereby the target compound was obtained in the form of a white powder, which is a mixture of diastereomers of about 1: 1 (239 mg, 0.45 mmol, 83% ) δH (DMSO d ⁶ , 390K) 9.75 (1H, br s), 8.77 (2H, s), 7.56 (2H, d, J 8.5 Hz), 7.25 (2H, d , J 8.5 Hz), 4.99 (1H, m), 3.18-2.98 (2H, m), 2.85 (3H, s) 1.18 (3H, s), 1.06 (3H, s). m / z (ES ⁺ , 70B) MH ⁺ 525.9 and 527.9.

EXAMPLE 173

(2S) -2- [2- (methylsulfanyl) -3-oxospiro [3,5] non-1-en-1-yl] amino-3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid

The ethyl ester of the target compound (1.53 g, 0.30 mmol, 71%) was obtained in two stages from the free amine of intermediate 12 (1.40 g, 0.41 mmol), spiro [3,5] nonan-1, 3-dione (650 mg, 0.42 mmol) [obtained by the method described by Wasserman HH et al., J. Org. Chem. 38, 1451-1455 (1973)] and a 1.0 M solution of methylsulphenyl chloride in DCM (0.5 ml, 0.5 mmol) by the method described in Example 108. This ester was hydrolyzed by the method described in Example 2, whereby target compound in the form of a yellow powder (1.15 g, 0.23 mmol, 57%). δH (DMSO d ⁶ , 390K) 9.81 (1H, s), 8.61 (1H, d, J 5.6 Hz), 8.13 (2H, d, J 5.4 Hz), 7.67 (2H, d, J 8.3 Hz), 7.60 (1H, d, J 5.5 Hz), 7.18 (1H, d, J 8.3 Hz), 7.05 (1H, d, J 5.5 Hz), 4.37 (1H, m), 3.22-3.12 (2H, m), 2.14 (3H, s), 1.85-1.10 (10H, m) . m / z (ES ⁺ , 70B) 489.1 (MH ⁺ ).

EXAMPLE 174

Ethyl (2S) -2- [2- (methylsulfanyl) -3-oxo-7-oxaspiro [3,5] non-1-en-1-yl] amino-3- [4 - ([2,7] naphthyridine -1-ylamino) phenyl] propanoate

The target compound in the form of a yellow powder (1.21 g, 0.23 mmol, 55%) was obtained in two stages from the free amine of intermediate 12 (1.40 g, 0.41 mmol), 7-oxaspiro [3.5] nonane-1,3-dione (650 mg, 0.42 mmol) [obtained by the method described by Wasserman HH et al., J. Org. Chem., 38, 1451-1455, (1973)] and a 1.0 M solution of methylsulphenyl chloride in DCM (0.5 ml, 0.5 mmol) by the method described in Example 108. δH (DMSO d ⁶ , 390K) 9.82 (1H, s), 9.55 (1H, s), 8.93 (1H, d, J 9.2 Hz), 8.65 (1H, d, J 5.6 Hz), 8.15 (1H d, J 5.7 Hz), 7.78 (2H, d, J 8.5 Hz), 7.68 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8 5 Hz), 7.13 (1H, d, J 5.7 Hz), 5.16-5.10 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3, 77 (2H, m), 3.59-3.52 (2H, m), 3.21 (1H, dd, J 4.5 Hz, 13.8 Hz), 2.98 (1H, dd, J 10 , 2 Hz, 13.8 Hz), 1.96 (3H, s), 1.48-1.32 (4H, m), 1.23 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 519.1 (MH ⁺ ).

EXAMPLE 175

(2S) -2- [2- (methylsulfanyl) -3-oxo-7-oxaspiro [3,5] non-1-en-1-yl] amino-3- [4 - ([2,7] naphthyridine- 1-ylamino) phenyl] propanoic acid

After hydrolysis of the compound of Example 174 (650 mg, 0.12 mmol) with lithium hydroxide (30 mg, 0.7 mmol) by the method described in Example 2, the target compound was obtained as a pale yellow powder (501 mg, 0.10 mol, 85%). δH (DMSO d ⁶ , 390K) 9.83 (1H, s), 9.54 (1H, s), 8.70 (1H, d, J 8.9 Hz), 8.65 (1H, d, J 5.6 Hz), 8.14 (1H, d, J 5.7 Hz), 7.75 (2H, d, J 8.5 Hz), 7.68 (1H, d, J 5.6 Hz) 7.21 (2H, d, J 8.5 Hz), 7.11 (1H, d, J 5.7 Hz), 4.92 (1H, m), 3.76-3.73 (2H, m), 3.62-3.54 (2H, m), 3.23 (1H, dd, J 3.9, 13.6 Hz), 2.94 (1H, dd, J 9.9 Hz, 13 6 Hz), 1.91 (3H, s), 1.47-1.28 (4H, m). m / z (ES ⁺ , 70B) 491.1 (MH ⁺ ).

EXAMPLE 176

Methyl- (2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoate

To a stirred solution containing intermediate 13 (300 mg, 0.72 mmol) in THF (10 ml), a 1.0 M solution of bromine in THF (1.0 ml, 1 mmol) was added dropwise at room temperature. After 2 hours, the reaction mixture was diluted with EtOAc (50 ml), washed with saturated aqueous sodium bicarbonate (2 × 25 ml), dried (MgSO ₄ ) and concentrated in vacuo. Chromatography (SiO ₂ , EtOAc) gave the title compound as a white powder (217 mg, 0.43 mmol, 61%). δH (DMSO d ⁶ , 360K) 9.71 (1H, s), 8.71 (1H, d, J 5.7 Hz), 8.04 (1H, d, J 5.8 Hz), 7.56 (1H, d, J 5.7 Hz), 7.23-7.13 (5H, m), 6.19 (1H, d, J 8.1 Hz), 5.06-5.02 (1H, m), 3.79 (3H, s), 3.26 (2H, m), 1.19 (6H, s). m / z (ES ⁺ , 70B) 497.9 (MH ⁺ ).

EXAMPLE 177

(2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] propanoic acid

After hydrolysis of the compound of Example 176 (80 mg, 0.016 mmol) LiOH (10 mg, 0.023 mmol) by the method described in Example 2, the title compound was obtained in the form of a white powder (51 mg, 0.01 mol, 63%). δH (DMSO d ⁶ , 360K) 9.71 (1H, s), 8.81 (1H, d, J 5.5 Hz), 8.14 (1H, d, J 5.4 Hz), 7.87 (1H, d, J 5.2 Hz), 7.52 (1H, d, J 5.4 Hz), 7.38 (2H, d, J 8.5 Hz), 7.28 (2H, d, J 8.5 Hz), 4.87-4.84 (1H, m), 3.31-3.15 (2H, m), 1.18 (3H, s), 1.10 (3H, s) . m / z (ES ⁺ , 70B) 483.9 (MH ⁺ ).

EXAMPLE 178

N ⁴ - (4- [3- (2-bromo-3-oxospiro [3,5] non-1-en-1-yl) -5-oxo-1,3-oxazolan-4-yl] methylphenyl) - 3,5-dichloroisonicotinamide

Chloromethyl pivalate (0.5 ml) was added dropwise to a solution containing the compound of Example 32 (1.0 g, 1.76 mmol), finely divided potassium carbonate (500 mg) and DMAP (50 mg, 0.4 mmol) in DMF (14 ml). ) at room temperature. After 24 hours, the reaction mixture was diluted with EtOAc (150 ml), washed with brine (3 × 50 ml), dried (MgSO ₄ ) and concentrated in vacuo. Chromatography (SiO ₂ , EtOAc: hexanes, 1: 1) gave the title compound as a white powder (475 mg, 0.82 mmol, 47%). δH (DMSO d ⁶ , 390K) 10.97 (1H, s), 8.80 (2H, s), 7.63 (2H, d, J 8.5 Hz), 7.17 (2H, d, J 8.5 Hz), 5.41 (1H, d, J 3.9 Hz), 4.95 (1H, m), 4.69 (1H, d, J 3.9 Hz), 3.39-3 29 (2H, m), 1.99-1.06 (10H, m). m / z (ES ⁺ , 70B) 580.9 (MH ⁺ ).

EXAMPLE 179

3- [2- (isopropylsulfanyl) -3-oxospiro [3,5] non-1-en-1-yl] -4- [4 - ([2,7] naphthyridin-1-ylamino) benzyl] -1, 3-oxazolan-5-one

The target compound in the form of an off-white powder (390 mg, 0.73 mmol, 84%) was obtained from the compound of Example 121 (450 g, 0.88 mmol) by the method described for the preparation of the compound of Example 178. δH (DMSO d ⁶ , 390K ) 9.57 (1H, s), 8.64 (1H, d, J 5.7 Hz), 8.24 (1H, d, J 5.8 Hz), 8.17 (1H, s), 7 74 (2H, d, J 8.4 Hz), 7.53 (1H, d, J 5.6 Hz), 7.16 (2H, d, J 8.4 Hz), 7.06 (1H, d, J 5.8 Hz), 5.20 (1H, broad s), 4.93 (1H, broad s), 4.26 (1H, broad s), 3.58 (1H, broad. s), 3.33 (1H, broad s), 3.27 (1H, m), 1.99-1.06 (16H, m). m / z (ES ⁺ , 70B) 529.2 (MH ⁺ ).

EXAMPLE 180

Neopentyl (2S) -2 - [(2-bromo-3-oxospiro [3,5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl } propanoate

Using the procedure described to obtain the compound of example 138, from the compound of example 32 (0.5 g, 0.89 mmol), EDC (191 mg, 1.0 mmol), HOBT (120 mg, 0.89 mmol), neopentyl alcohol (0.4 g, 4.5 mmol) and DMF (15 ml) were obtained after purification by chromatography (SiO ₂ , EtOAc) the target compound in the form of a white powder (400 mg, 0.63 mmol, 71%). δH (DMSO d ⁶ , 390K) 10.87 (1H, s), 8.92 (1H, d, J 9.1 Hz), 8.79 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.32 (2H, d, J 8.5 Hz), 4.88-4.82 (1H, m), 3.86 (1H, d, J 10.4 Hz), 3 80 (1H, d, J 10.4 Hz), 3.26 (1H, dd, J 13.9, 4.8 Hz), 3.03 (1H, dd, J 13.9, 10.1 Hz ), 1.99-1.06 (10H, m), 0.91 (9H, broad s). m / z (ES ⁺ , 70B) 638.0 (MH ⁺ ).

EXAMPLE 181

Isopropyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxo-7-oxaspiro [3,5] non-1-en-1- ilamino) propanoate

The target compound in 79% yield was obtained from the compound of Example 164 by the method described for the preparation of the compound of Example 138. δH (DMSO d ⁶ ) 10.87 (1H, s), 8.80 (2H, s), 8.10 (1H, d, J 8.9 Hz), 7.59 (d, 2H, J 8.2 Hz), 7.31 (d, 2H, J 8.2 Hz), 4.98 (1H, m), 4, 30 (1H, m), 3.76 (2H, m), 3.60 (2H, m), 3.11 (1H, dd, J 13.7, 5.3 Hz), 3.00 (1H, dd, J 13.2, 9.1 Hz), 2.00-1.80 (2H, m), 1.42 (3H, s), 1.17 (6H, m). m / z (ES ⁺ , 70B) 546.1 (MH ⁺ ).

EXAMPLE 182

5-methyl-2-oxo [1,3] dioxol-4-ylmethyl- (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-Dichloroisonicotinoyl) amino] phenyl} propanoate

To a stirred solution of the compound of Example 32 (1.0 g, 1.76 mmol) and potassium carbonate (484 mg, 3.52 mmol) in DMF (20 ml) at 0 ° C., intermediate 73 (408 mg, 2) was added in one portion. , 12 mmol). The ice bath was removed and the mixture was stirred at room temperature for 3 hours. This mixture was then poured into ice water and extracted with EtOAc. The extract was washed three times with brine, dried (MgSO ₄ ) and the solvent was removed in vacuo to give a yellow solid. Chromatography (SiO ₂ , hexane: EtOAc, 1: 1) gave the target compound as a white solid (686 mg, 57%). δH (DMSO d ⁶ ) 10.90 (1H, s), 8.95 (1H, d, J 8.9 Hz), 8.80 (2H, s), 7.60 (2H, d, J 8, 3 Hz), 7.26 (2H, d, J 8.3 Hz), 4.86 (1H, m), 3.22 (1H, m, J 4.0, 13.6 Hz), 3.06 (1H, m, J 13.2, 10.7 Hz), 2.17 (3H, s), 1.74-1.38 (10H, m). m / z (ES ⁺ , 70B) 680.0 (MH ⁺ ).

EXAMPLE 183

2,3-dihydroxypropyl (2S) - (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound in 48% yield was obtained after chromatography on silica gel from the compound of Example 32 and glycerol in the manner described for the preparation of the compound of Example 138. δH (DMSO d ⁶ ) 10.91 (1H, s), 8.91 (1H, d, J 9.2 Hz), 8.80 (2H, s), 7.60 (2H, d, J 8.5 Hz), 7.28 (2H, d, J 8.3 Hz), 5.01 (1H , m), 4.85 (1H, m), 4.71 (1H, m), 4.20 (1H, m), 4.09 (1H, m), 3.71 (1H, m), 3 , 57 (1H, m), 3.26 (1H, dd, J 13.8, 3.9 Hz), 3.04 (1H, dd, J 13.8, 9.3 Hz), 1.80- 1.45 (10H, m). m / z (ES ⁺ , 70B) 640.0 (MH ⁺ ).

EXAMPLE 184

Tetrahydrofuran-3-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound with a yield of 52% was obtained after chromatography on silica gel from the compound of example 32 and tetrahydrofurfuryl alcohol in the manner described for the preparation of the compound of example 138. δH (DMSO d ⁶ ) 10.88 (1H, s), 8.93 (1H, d, J 9.1 Hz), 8.80 (2H, s), 7.60 (2H, d, J 8.3 Hz), 7.28 (2H, d, J 6.9 Hz), 4.84 ( 1H, m), 4.15 (2H, m), 4.05 (1H, m), 3.23 (1H, dd, J 13.8, 4.4 Hz), 3.04 (1H, dd, J 13.6, 9.6 Hz), 2.00-1.50 (14H, m). m / z (ES ⁺ , 70B) 650.1 (MH ⁺ ).

EXAMPLE 185

Tetrahydropyran-4-yl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound (0.42 g, 74%) was obtained from the compound of Example 32 (0.5 g, 0.89 mmol), EDC (300 mg), HOBT (200 mg) and 4-hydroxytetrahydropyran (0.8 ml) in DMF (5 ml) by the method described to obtain the compound of example 138. δH (300 M Hz, DMSO d ⁶ ) 11.02 (1H, broad), 9.04 (1H, d, J 9.0 Hz), 8 92 (2H, s), 7.73 (2H, d, J, 8.4 Hz), 7.42 (2H, d, J, 8.5 Hz), 5.13 (1H, broad), 4, 93 (1H, broad), 3.87 (2H, broad), 3.60 (2H, broad), 3.36 (1H, dd, J 14.0, 5.1 Hz), 3.18 (1H, dd, J 13.6, 9.3 Hz), 1.61-2.06 (12H, m), 1.52 (2H, d, J 12.6 Hz), 1.26 (2H, broad.). m / z (ES ⁺ , 70B) 652 (MH ⁺ ).

EXAMPLE 186

Isopropyl (2S) -2- (2-bromo-3-oxo-7-oxaspiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

To a solution of isopropyl ether of the compound of Example 40 (0.4 g, 8.1 mmol) [prepared by the method described for the compound of Example 138] in THF (5 ml), NBS (0.3 g) was added at room temperature. The mixture was stirred for 2 hours and then partitioned between water (100 ml) and EtOAc (100 ml), after which the organic extracts were separated and washed with water (3 × 50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude oil. After purification by column chromatography (hexane: EtOAc, 3: 2), the title compound was obtained as a white solid (0.24 g, 52%). δH (400 M Hz, DMSO d ⁶ ) 9.02 (1H, d, J 9.0 Hz), 8.79 (2H, s), 7.59 (2H, d, J 8.5 Hz), 7 , 27 (2H, d, J 8.5 Hz), 4.97 (1H, m), 4.75 (1H, m), 3.80 (2H, m), 3.58 (2H, q, J 11.7 Hz), 3.20 (1H, dd, J 13.0, 5.0 Hz), 3.03 (1H, dd, J 13.0, 9.4 Hz), 1.97 (2H, m), 1.49 (1H, dd J 13.0, 1.6 Hz), 1.33 (1H, dd J 13.2, 1.6 Hz), 1.23 (3H, d J 11.3 Hz), 1.19 (3H, d J, 11.4 Hz). m / z (ES ⁺ , 70B) (MH ⁺ ) 612.

EXAMPLE 187

Ethyl (2S) -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} -2- (4,4-dimethyl-2-methylsulfanyl-3-oxocyclobut-1-enylamino) propanoate

A mixture of intermediate 43 (0.44 g, 1.15 mmol) and 3-hydroxy-4,4-dimethyl-2-cyclobutenone (0.14 g, 1.1 eq.) Was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo and triturated with diethyl ether and the resulting solid was redissolved in THF (10 ml). The solution was treated with a solution of methanesulfenyl chloride at 0-5 ° C. in DCM until a TLC analysis of this mixture indicated that all of the starting material had been consumed. The mixture was partitioned between EtOAc (50 ml) and water (50 ml) and the organic extracts were separated, washed with water (2 × 50 ml) and brine (50 ml), then dried (MgSO ₄ ), filtered and concentrated to give a crude white foam. Purification by column chromatography (EtOAc: hexane, 1: 1) gave the target compound as a white solid (0.55 g, 91%). δH (400 M Hz, DMSO d ⁶ ) 11.16 (1H, broad), 8.87 (1H, d, J 9.0 Hz), 8.82 (s, 2H), 8.72 (1H, d, J 2.5 Hz), 8.05 (1H, dd, J 8.4, 2.5 Hz), 7.35 (1H, d, J 8.4 Hz), 5.33 (1H, m ), 4.18 (2H, q, J 7.1 Hz), 3.36 (1H, dd, J 14.1, 5.0 Hz), 3.32 (3H, s), 3.20 (1H dd, J 14.1, 9.4 Hz), 0.94 (3H, s), 1.09 (3H, s), 1.21 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) MH ⁺ 523.

EXAMPLE 188

Isopropyl (2S) -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2-yl} -2- (4,4-dimethyl-2-methylsulfanyl-3-oxocyclobut-1-enylamino) propanoate

After hydrolysis of the compound of Example 187 (0.35 g, 0.67 mmol) by the method described in Example 2 and re-esterification with isopropanol (EDC, HOBT, DMF), the title compound was obtained as a white solid (65 mg, 18%). δH (400 M Hz, DMSO d ⁶ ) 11.16 (1H, broad), 8.85 (1H, d, J 8.9 Hz), 8.82 (2H, s), 8.72 (1H, d, J 1.8 Hz), 8.04 (1H, m), 7.35 (1H, d, J 8.3 Hz), 5.28 (1H, m), 5.00 (1H, m) , 3.35 (1H, dd, J 14.1, 5.0 Hz), 3.32 (3H, s), 3.18 (1H, dd, J 14.1, 9.3 Hz), 1, 22 (6H, m), 1.09 (3H, d, J 1.2 Hz), 0.95 (3H, d, J 1.2 Hz). m / z (ES ⁺ , 70B) MH ⁺ 537.

EXAMPLE 190

Ethyl (2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (3-oxospiro [3,5] non-1-en-1- ilamino) propanoate

Intermediate 75 (170 mg, 0.42 mmol) and 1-keto-3-hydroxy [3,5] non-2-ene (200 mg, 1.3 mmol) were stirred together at room temperature overnight in THF ( 5 ml). The reaction mixture was diluted with DCM (50 ml), washed with sodium bicarbonate solution (saturated, 2 × 50 ml), dried (MgSO ₄ ) and concentrated in vacuo to give a yellow solid. The residue was chromatographed (SiO ₂ , DCM: methanol, 98: 2) to give the title compound as a white powder (120 mg). δH (CDCl ₃ ) 9.03 (1H, broad), 8.11 (2H, s), 7.64 (2H, d, J 7.9 Hz), 7.18 (2H, d, J 7, 5 Hz), 5.01 (1H, m), 4.22 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.12 (2H, m), 1.45 ( 10H, m), 1.30 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 532.0 (MH ⁺ ).

EXAMPLE 191

(2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (3-oxospiro [3,5] non-1-en-1-ylamino ) propanoic acid

The compound of Example 190 (30 mg, 0.056 mmol) was hydrolyzed by the method described in Example 2, whereby the target compound was obtained in the form of a white powder (20 mg). δH (CD ₃ OD) 8.46 (2H, s), 7.47 (2H, d, J 8.5 Hz), 7.18 (2H, d, J 8.5 Hz), 4.14 (1H , m), 3.21 (1H, m), (hidden by MeOH / water) 2.83 (1H, dd, J 9.6, 4.2 Hz), 1.80-1.10 (9H, m) 1.07 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 505.0 (MH ⁺ ).

EXAMPLE 192

Ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4- carbonyl) amino] phenyl} propanoate

The target compound (80 mg) was obtained from the compound of Example 190 (85 mg, 0.160 mmol) by the method described for the preparation of the compound of Example 31. δH (CDCl ₃ ) 8.94 (1H, br s), 8.14 (2H, s ), 7.62 (2H, d, J 8.4 Hz), 7.13 (2H, d, J 8.3 Hz), 5.88 (1H, m), 5.00 (1H, m), 4.26 (2H, q, J 7.1 Hz), 3.26 (2H, m), 2.03-1.41 (10H, m), 1.35 (3H, t, J 7.1 Hz) ) m / z (ES ⁺ , 70B) 612.0 (MH ⁺ ).

EXAMPLE 193

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl ) amino] phenyl} propanoic acid

The compound of Example 192 was hydrolyzed by the method described in Example 2, whereby the desired compound was obtained. δH (DMSO d ⁶ ) 10.80 (1H, s), 8.73 (2H, s), 7.55 (2H, d, J 8.0 Hz), 7.24 (2H, d, J 8, 4 Hz), 4.65 (1H, m), 3.22 (1H, dd, J 13.8, 4.4 Hz), 3.00 (1H, dd, J 13.7, 4.4 Hz) 1.82-1.00 (11H, m).

EXAMPLE 194

Ethyl 2S) -2- (2-chloro-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl ) amino] phenyl} propanoate

The target compound in the form of a white powder (220 mg) was obtained from the compound of Example 190 (500 mg, 0.94 mmol) and N-chlorosuccinimide (150 mg, 1.13 mmol) by the method described for the preparation of the compound of Example 61. δH 10.85 (1H, s), 8.84 (1H, d, J 9.0 Hz), 8.75 (2H, s), 7.58 (2H, d, J 8.5 Hz), 7.27 (2H d, J 8.5 Hz), 4.68 (1 H, m), 4.20 (2 H, q, J 7.0 Hz), 3.22 (1 H, dd, J 13.8, 4.7 Hz), 3.01 (1H, dd, J 13.7, 9.7 Hz), 1.74-1.55 (9H, m), 1.38 (1H, m), 1.23 (3H, m, J 7.1 Hz), 1.13 (1H, m). m / z (ES ⁺ , 70B) 568.0 (MH ⁺ ).

EXAMPLE 195

(2S) -2- (2-chloro-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl ) amino] phenyl} propanoic acid

The compound of Example 194 was hydrolyzed by the method described in Example 2, whereby the desired compound was obtained. δH (DMSO d ⁶ ) 10.83 (1H, s), 8.75 (m, 3H), 7.57 (2H, d, J 8.4 Hz), 7.26 (2H, d, J 8, 5 Hz), 4.63 (1H, m), 3.22 (1H, dd, J 13.8, 4.5 Hz), 3.00 (1H, m), 1.64-1.55 (9H , m), 1.35 (1H, m), 1.15 (1H, m). m / z (ES ⁺ , 70B) 538.0 (MH ⁺ ).

EXAMPLE 196

Ethyl (2S) -2 - [(2-chloro-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound in the form of a white powder (0.9 mmol, 31%) was obtained from the compound of Example 5 (3.2 mmol) and N-chlorosuccinimide (3.5 mmol) by the method described for the preparation of the compound of Example 61. δH (DMSO d ⁶ , 300K) 9.05 (1H, d, J 9.0 Hz), 8.79 (2H, s), 7.60 (2H, d, J 8.5 Hz), 7.25 (1H, d, J 8.5 Hz), 4.70 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.22 (1H, dd, J 13.9, 5.0 Hz), 3.02 (1H, dd, J 13.9, 9.2 Hz), 1.21 (3H, q, J 7.1 Hz), 1.23 (3H, s), 1.04 (3H, s ) m / z (ES ⁺ , 70B) 512.0 (MH ⁺ ).

EXAMPLE 197

1-methyl-3-pyrrolidinyl (2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino ] phenyl} propanoate

The target compound (0.25 mmol, 40%) was obtained from the compound of Example 34 (0.65 mmol), EDC (0.72 mmol), HOBT (0.72 mmol) and 1-methyl-3-pyrrolidinol (1.95 mmol) in DMF (5 ml) according to the method described for preparing the compound of Example 138. δH (CD ₃ OD) 8.55 (2H, s), 7.52 (2H, d, J 8.5 Hz), 7.20 (2H, d, J 8.5 Hz), 4.92 (1H, dd), 3.38 (1H, dd, MeOH hidden), 2.96 (1H, dd, J 13.9, 9.2 Hz ), 2.50-2.18 (4H, m), 2.18 (3H, s), 1.89-1.56 (m, 4H), 1.12 (3H, s), 1.00 ( 3H, s). m / z (ES ⁺ , 70B) 625.0 (MH ⁺ ).

EXAMPLE 198

Isopropyl (2S) -2- (2-bromo-4,4-dimethyl-3-oxocyclobut-1-enylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate

The target compound (0.25 mmol, 34%) was obtained from the compound of Example 34 (0.65 mmol), EDC (0.84 mmol), HOBT (0.84 mmol) and isopropanol (2.28 mmol) in DMF (5 ml) by the method described for the preparation of the compound of Example 138. δH (DMSO d ⁶ ) 10.88 (1H, s), 9.69 (1H, d, J 9.0 Hz), 8.79 (2H, s), 7.59 (2H, J 8.5 Hz), 7.28 (2H, d, J 8.5 Hz), 4.97 (1H, m), 4.75 (1H, m), 3.20 ( 1H, dd, J 13.9, 5.1 Hz), 3.03 (1H, dd, J 14.0, 9.2 Hz), 1.24 (m, 6H), 1.14 (3H, s ), 1.05 (3H, s). m / z (ES ⁺ , 70B) 570.0 (MH ⁺ ).

EXAMPLE 199

Ethyl (2S) -3- [4- (2,6-dichlorobenzoylamino) phenyl] -2- (3-oxospiro [3,5] non-1-en-1-ylamino) propanoate

The target compound in the form of a yellow powder (1.1 mmol, 66%) was obtained by the method described for preparing the compound of Example 27 (by combining the amino acid ethyl ester (1.68 mmol), dione (1.68 mmol) in DCM (5 ml )). δH (CD ₃ OD) 7.83 (2H, d, J 8.3 Hz), 7.55-7.35 (4H, m), 7.47 (2H, d, J 8.4 Hz), 4 62 (1H, s), 4.50 (3H, m), 3.50 (1H, m), 3.08 (1H, m), 2.05-1.55 (11H, m), 1, 49 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 501.0 (MH ⁺ ).

EXAMPLE 200

Ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4- (2,6-dichlorobenzoylamino) phenyl] propanoate

The target compound in the form of a yellow powder (0.86 mmol, 80%) was obtained from the compound of Example 199 (1.08 mmol) by the method described for the preparation of the compound of Example 72. δH (CD ₃ OD) 7.53 (2H, d, J 8.4 Hz), 7.38-7.15 (4H, m), 7.17 (2H, d, J 8.4 Hz), 5.32 (1H, m), 4.65 (1H, m ), 3.22 (1H, dd, J 13.9, 4.4 Hz), 3.18 (q, 2H, J 7.1 Hz), 2.95 (1H, dd, J 13.9, 9 5 Hz), 1.85-1.20 (14H, m). m / z (ES ⁺ , 70B) 581.0 (MH ⁺ ).

EXAMPLE 201

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4- (2,6-dichlorobenzoylamino) phenyl] propanoic acid

The target compound in the form of a white powder (0.60 mmol, 60%) was obtained from the compound of Example 200 (0.85 mmol) by the method described for the preparation of the compound of Example 2. δH (DMSO d ⁶ ) 13.39 (1H, br s. ), 10.70 (1H, d, J 6.1 Hz), 8.81 (1H, d, J 9.2 Hz), 7.61 (3H, m), 7.56 (1H, m), 7.23 (2H, d, J 8.2 Hz), 3.18 (1H, dd, J 13.9, 4.4 Hz), 2.98 (1H, dd, J 13.8, 9.6 Hz), 2.89-1.20 (11H, m). m / z (ES ⁺ , 70B) 567.0 (MH ⁺ ).

EXAMPLE 202

Isopropyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4- (2,6-dichlorobenzoylamino) phenyl] propanoate

The target compound (0.49 mmol, 63%) was obtained from the compound of Example 201 (0.78 mmol) by the method described for the preparation of the compound of Example 138. δH (DMSO d ⁶ ) 10.71 (1H, s), 8.89 ( 1H, d, J 9.0 Hz), 7.62-7.47 (5H, cm), 4.97 (1H, m), 3.17 (1H, dd, J 4.8 Hz, 13.8 Hz), 3.00 (1H, dd, J 9.7 Hz, 13.8 Hz), 1.79-1.50 (8H, s m), 1.35 (1H, m), 1.24- 1.11 (7H, m). m / z (ES ⁺ , 70B) 609.0 (MH ⁺ ).

EXAMPLE 203

Ethyl (2S) -3- [4- (3-methyl [2,7] naphthyridin-1-ylamino) phenyl] -2- (3-oxospiro [3,5] non-1-en-1-ylamino) propanoate

The target compound in the form of a yellow powder (1.5 mmol, 76%) was obtained by the method described for the preparation of the compound of Example 3. δH (CDCl ₃ ) 9.56 (1H, s), 8.53 (1H, d, J 5, 8 Hz), 7.78 (2H, d, J 8.4 Hz), 7.45 (1H, d, J 5.8 Hz), 7.08 (2H, d, J 8.5 Hz), 6 89 (1H, s), 5.77 (1H, m), 4.57 (1H, s), 4.27 (2H, q, J 7.1 Hz), 3.10 (2H, m), 2.54 (3H, s), 1.84-1.23 (14H, m). m / z (ES ⁺ , 70B) 485.2 (MH ⁺ ).

EXAMPLE 204

Ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4- (3-methyl [2,7] naphthyridin-1-ylamino ) phenyl] propanoate

The desired compound in the form of a yellow powder (0.25 mmol, 40%) was obtained from the compound of Example 203 (0.62 mmol), bromine (0.81 mmol) and triethylamine (0.81 mmol) in DCM (5 ml), described for the preparation of the compound of Example 31. δH (CD ₃ OD) 9.44 (1H, s), 8.34 (1H, d, J 5.8 Hz), 7.43 (1H, d, J 5.8 Hz) ), 7.09 (2H, d, J 8.5 Hz), 6.81 (1H, s), 4.87 (1H, m), 4.89 (1H, m), 4.13 (2H, q, J 7.1 Hz), 3.22 (1H, m), (mostly MeOH is hidden), 2.92 (1H, dd, J 14.0, 9.7 Hz), 2.34 (3H, s ), 1.58-1.26 (10H, m), 1.18 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 564.2 (MH ⁺ ).

EXAMPLE 205

Ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4- (3-methyl [2,7] naphthyridin-1-ylamino ) phenyl] propanoate

The target compound in the form of a yellow powder (0.20 mmol, 90%) was obtained from the compound of example 204 (0.22 mmol) by the method described for obtaining the compound of example 2. δH (DMSO d ⁶ ) 9.76 (1H, s), 9.70 (1H, s), 8.87 (1H, s, J 9.5 Hz), 8.56 (1H, d, J 5.6 Hz), 7.87 (2H, d, J 8, 4 Hz), 7.56 (1H, d, J 5.6 Hz), 7.20 (2H, d, J 8.4 Hz), 6.96 (1H, s), 4.73 (1H, m ), 3.22 (1H, dd, J 13.9 Hz, 4.0 Hz), 2.93 (1H, dd, J 13.5 Hz, 10.1 Hz), 2.42 (3H, s) 1.80-1.00 (11H, m). m / z (ES ⁺ , 70B) 535.0 (MH ⁺ ).

EXAMPLE 206

(2S) -3- [4- (3-methyl [2,7] naphthyridin-1-ylamino) phenyl] -2- (3-oxospiro [3,5] non-1-en-1-ylamino) propanoic acid

The target compound in the form of a white powder (0.27 mmol, 43%) was obtained from the compound of Example 203 (0.62 mmol) by the method described for the preparation of the compound of Example 2. δH (DMSO d ⁶ ) 9.81 (1H, s), 9.52 (1H, s), 8.58 (1H, d, J 5.6 Hz), 8.30 (1H, J 8.6 Hz), 7.86 (2H, d, J 8.4 Hz ), 7.57 (1H, d, J 5.6 Hz), 7.22 (2H, d, J 8.5 Hz), 6.97 (1H, s), 4.08 (1H, m), 4.32 (1H, d), 3.15 (1H, dd, J 13.7, 4.7 Hz), 2.97 (1H, dd, J 13.7, 9.5 Hz), 2.44 (3H, s), 1.74-1.45 (9H, m), 1.24-1.15 (2H, m). m / z (ES ⁺ , 70B) 457.1 (MH ⁺ ).

EXAMPLE 207

Ethyl (S) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] -2- (3-oxospiro [3,5] non-1-en-1-ylamino) propanoate

The target compound in the form of a yellow powder (1.4 mmol, 73%) was obtained by the method described for the preparation of the compound of Example 3. δH (CDCl ₃ ) 9.61 (1H, s), 8.65 (1H, d, J 5, 7 Hz), 8.25 (1H, d, J 5.8 Hz), 7.71 (2H, d, J 8.4 Hz), 7.63 (1H, d, J 8.5 Hz), 7 12 (2H, d, J 8.5 Hz), 7.05 (1H, d, J 5.8 Hz), 5.80 (1H, m), 4.55 (1H, s), 4.29 (2H, q, J, 7.2 Hz), 3.13 (2H, m), 1.87-1.25 (14H, m). m / z (ES ⁺ , 70B) 471.1 (MH ⁺ ).

EXAMPLE 208

Ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoate

The target compound in the form of a yellow powder (0.45 mmol, 76%) was obtained from the compound of Example 207 (0.64 mmol) by the method described for the preparation of the compound of Example 31. δH (CDCl ₃ ) 9.81 (1H, s), 8 64 (1H, d, J 5.7 Hz), 8.29 (1H, d, J 5.8 Hz), 7.75 (2H, d, J 8.3 Hz), 7.60 (1H, d, J 5.8 Hz), 7.12 (2H, d, J 8.4 Hz), 7.08 (1H, d, J 5.7 Hz), 5.91 (1H, m), 5, 03 (1H, m), 4.28 (2H, q, J 7.1 Hz), 3.29 (2H, m), 1.81-1.39 (10H, m), 1.35 (3H, t, J 7.1 Hz). m / z (ES ⁺ , 70B) 550 (MH ⁺ ).

EXAMPLE 209

(S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propionic acid

The target compound in the form of a white powder (0.25 mmol, 64%) was obtained from the compound of example 208 (0.40 mmol) by the method described for obtaining the compound of example 2. δH (DMSO d ⁶ , 300K) 9.90 (1H, s ), 9.56 (1H, s), 8.86 (1H, d, J 9.3 Hz), 8.66 (1H, d, J 5.6 Hz), 8.17 (1H, d, J 5.7 Hz), 7.81 (2H, d, J 8.2 Hz), 7.70 (1H, d, J 5.6 Hz), 7.24 (2H, d, J 8.4 Hz) 7.14 (1H, d, J 5.7 Hz), 4.78 (1H, m), 3.23 (1H, dd, J 13.9, 4.1 Hz), 2.99 (1H, dd, J 13.7, 10.0 Hz), 1.81-1.04 (11H, m). m / z (ES ⁺ , 70B) 522.0 (MH ⁺ ).

EXAMPLE 210

(2S) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] -2- (3-oxospiro [3,5] non-1-en-1-ylamino) propanoic acid

The target compound in the form of a white powder (0.21 mmol, 33%) was obtained from the compound of example 207 (0.64 mmol) by the method described for obtaining the compound of example 2. δH (DMSO d ⁶ , 300K) 9.85 (1H, s ), 9.54 (1H, s), 8.67 (1H, d, J 5.6 Hz), 8.28 (1H, d, J 8.6 Hz), 8.18 (1H, d, J 5.6 Hz), 7.78 (2H, d, J 8.3 Hz), 7.70 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8.4 Hz) , 7.14 (1H, d, J 5.7 Hz), 4.34 (1H, s), 4.08 (1H, m), 3.15 (1H, dd, J 13.8, 4.8 Hz), 2.95 (1H, dd, J 13.8, 9.4 Hz), 1.74-1.39 (9H, m), 1.20 (2H, m). m / z (ES ⁺ , 70B) 443.1 (MH ⁺ ).

EXAMPLE 211

(2S) -3- [4 - ([2,7] naphthyridin-1-yloxy) phenyl] -2- (3-oxospiro [3,5] non-1-en-1-ylamino) propanoic acid

The target compound in the form of a white powder (0.56 mmol, 80%) was obtained by the method described for the preparation of the compound of example 2 (by hydrolysis of the compound of example 35 (0.70 mmol)). δH (DMSO d ⁶ , 300K) 9.70 (1H, s), 8.81 (1H, d, J 5.7 Hz), 8.30 (1H, d, J 8.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.89 (1H, d, J 5.7 Hz), 7.53 (1H, d, J 5.9 Hz), 7.34 (1H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.34 (1H, s), 4.15 (1H, m), 3.21 (1H, dd, J 14 0, 4.8 Hz), 3.00 (1H, dd, J 13.8, 9.7 Hz), 1.71-1.50 (11H, m). m / z (ES ⁺ , 70B) 444.6 (MH ⁺ ).

EXAMPLE 212

Ethyl ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-hydroxy-3-oxospiro [3,5] non-1-en-1-ylamino) propionic acid

To a solution of the compound of Example 27 (1.0 g, 1.9 mmol) in DCM (40 ml) at -40 ° C was added lead tetraacetate (0.94 g, 1.1 eq.). The mixture was allowed to warm to 0 ° C and stirred at this temperature for 8 hours. The reaction mixture was partitioned between EtOAc (200 ml) and water (100 ml), the organic extracts were separated, washed with water (2 × 100 ml) and brine (50 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo to give a crude oils. This crude oil was dissolved in ethanol (10 ml) and treated with NaH (100 mg). The mixture was stirred at room temperature until TLC analysis of this mixture indicated that all of the starting material had been consumed. The reaction was quenched by the addition of NH ₄ Cl (5 ml, saturated aqueous), the mixture was extracted with EtOAc (2 × 20 ml), and then it was washed with water (10 ml) and brine (10 ml), dried (MgSO ₄ ), filtered and concentrated in vacuum to obtain a crude product which was purified by column chromatography (SiO ₂ , EtOAc: hexane, 1: 1), whereby the target compound was obtained as a white foam (0.89 g, 86%). δH (DMSO d ⁶ , 400 M Hz) 10.83 (1H, broad), 8.78 (2H, s), 7.51 (2H, d, J 8.5 Hz), 7.12 (2H, d, J 8.5 Hz), 4.94 (1H, dd, J 11.4, 5.0 Hz), 4.10 (2H, m), 3.33 (1H, dd, J 14.1, 4.9 Hz), 3.14 (1H, dd, J 14.0, 11.4 Hz), 1.40-1.63 (4H, m), 1.19-1.33 (6H, m) 1.16 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 532 (MH ⁺ ).

EXAMPLE 213

Ethyl (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methoxy-3-oxospiro [3,5] non-1-en-1-ylamino) propionoate

To a solution of the compound of Example 212 (0.8 g, 1.5 mmol) in acetone (15 ml) was added K ₂ CO ₃ (5 g) and methyl iodide (2.5 ml). The mixture was stirred at room temperature for 5 days. The mixture was then filtered, concentrated in vacuo, and the residue was purified by column chromatography (SiO ₂ , EtOAc: hexane, 1: 1), whereby the target compound was obtained as a white solid (0.45 g, 55%). δH (DMSO d ⁶ , 400 M Hz) 8.50 (2H, d, J 4.8 Hz), 7.21 (2H, d, J 8.4 Hz), 7.04 (2H, d, J 8 4 Hz), 4.87 (1H, dd, J 11.8, 4.9 Hz), 4.00-4.16 (2H, m), 3.34 (3H, s), 3.26 ( 1H, dd, J 13.9, 4.9 Hz), 3.07 (1H, dd, J 13.9, 11.6 Hz), 1.15-1.66 (10H, m), 1.12 (3H, t, J = 7.0 Hz). m / z (ES ⁺ , 70B) 546 (MH ⁺ ).

EXAMPLE 214

Ethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- (2,4,6-trimethoxy [1,1'-biphenyl] - 4-yl) propanoate

The target compound was prepared by the methods described herein. δH (CDCl ₃ ) 7.19 (2H, d, J 8.1 Hz), 7.04 (2H, d, J 8.1 Hz), 6.14 (2H, s), 5.84 (1H, d, J 8.6 Hz), 4.98 (1H, m), 4.20 (2H, q, J 7.1 Hz), 3.78 (3H, s), 3.62 (6H, s) 3.21 (2H, d), 1.97-1.40 (10H, m), 1.24 (3H, t, J = 7.1 Hz). m / z (ES ⁺ , 70B) 572 (MH ⁺ ).

EXAMPLE 215

(2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- (2,4,6-trimethoxy [1,1'-biphenyl] -4 -yl) propanoic acid

The target compound was obtained from the compound of Example 214 by the method described in Example 2. δH (DMSO d ⁶ ) 12.30 (1H, br s), 8.79 (2H, d, J 10.0 Hz), 7.19 ( 2H, d, J 8.1 Hz), 7.08 (2H, d, J 8.1 Hz), 6.29 (2H, s), 4.78 (1H, m), 3.81 (3H, s), 3.61 (6H, s), 3.27 (1H, m), 2.98 (1H, dd, J 13.4, 10.2 Hz), 1.95-1.00 (10H, m). m / z (ES ⁺ , 70B) 544 (MH ⁺ ).

EXAMPLE 216

Tetrahydrofuran-2-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3,5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloropyridin-4- carbonyl) amino] phenyl} propanoate

In accordance with the procedure described for the preparation of the compound of Example 138, from the compound of Example 32 (0.25 g, 0.44 mmol), EDC (150 mg), HOBT (100 mg) and tetrahydrofurfuryl alcohol (0.5 ml) in DMF (2 ml) gave the target compound (0.15 g, 52%). δH (400 M Hz, DMSO d ⁶ ) 10.88 (1H, s), 8.93 (1H, d, J 9.1 Hz), 8.80 (2H, s), 7.60 (2H, d , J 8.3 Hz), 7.28 (2H, d, J 6.9 Hz), 4.84 (1H, m), 4.15 (2H, m), 4.05 (1H, m), 3.23 (1H, dd, J 13.8, 4.4 Hz), 3.04 (1H, dd, J 13.6, 9.6 Hz), 1.50-2.00 (14H, m) . m / z (ES ⁺ , 70B) 650 (MH ⁺ ).

In order to demonstrate the effectiveness and selectivity of the compounds of the present invention, the following assays were performed. In each of these assays and for each test compound, IC ₅₀ values were determined, which are the concentration of the compound necessary to achieve 50% inhibition of cell adhesion, where 100% = adhesion in the absence of the test compound, and 0% = optical density in cell free wells.

α ₄ β ₁ integrin-dependent adhesion of Jurkat cells to VCAM-Ig

NUNC 96 well plates sensitized with F (ab) ₂ goat anti-human IgG Fcγ-specific antibody fragment [Jackson Immuno Reasearch 109-006-098: 100 μl at 2 μg / ml in 0.1 M NaHCO ₃ , pH 8.4 ] overnight at 4 ° C. These plates were washed (3 ×) in phosphate buffered saline (PBS) and then blocked for 1 hour in PBS / 1% BSA at room temperature on a rotating platform. After washing (3 × in PBS), 9 ng / ml of purified 2d VCAM-Ig diluted in PBS / 1% BSA was added, and the plates were allowed to stand for 60 min at room temperature on a rotating platform. These plates were then washed (3 × in PBS) and analyzed at 37 ° C. for 30 minutes with a total volume of 200 μl containing 2.5 × 10 ⁵ Jurkat cells in the presence or absence of titratable test compounds.

Each plate was washed (2 ×) with medium and adherent cells were fixed with 100 μl of methanol for 10 min, after which they were washed again. Then, 100 μl of 0.25% Bengal pink (Sigma R4507) in PBS was added over 5 minutes at room temperature, and the plates were washed (3 ×) in PBS. After that, 100 μl of 50% (v / v) ethanol was added in PBS and the plates were left for 60 min, after which the optical density (570 nm) was measured.

α ₄ β ₇ integrin-dependent adhesion of JY cells to MAdCAM-Ig

This assay was carried out in the same way as the assay for α ₄ β ₁ , except that instead of 2d VCAM-Ig, MAdCAM-Ig (150 ng / ml) was used, and instead of Jurkat cells, subline β-lymphoblastoid cell line JY was used. For each test compound, IC ₅₀ values were determined as described in the assay for α ₄ β ₁ integrin.

α ₅ β ₁ integrin-dependent adhesion of K562 cells to fibronectin

96-well tissue culture plates were sensitized with plasma fibronectin (Sigma F0895) at a concentration of 5 μg / ml in phosphate buffered saline (PBS) for 2 hours at 37 ° C. The plates were then washed (3 × in PBS) and blocked for 1 hour in 100 μl of PBS / 1% BSA at room temperature on a rotating platform. The blocked plates were washed (3 × in PBS) and analyzed at 37 ° C. in full 200 μl containing 2.5 × 10 ⁵ K562 cells, phorbol-12-myristate-13-acetate at 10 ng / ml, in the presence of or in the absence of titratable test compounds. The incubation time was 30 minutes. Each plate was fixed and stained as described above in the analysis for α ₄ β ₁ integrin.

α _m β _{2 -} integrin-dependent adhesion of human polymorphonuclear neutrophils to plastic

96-well tissue culture plates were coated with RPMI 1640/10% FCS for 2 hours at 37 ° C. Then, 2 × 10 ⁵ freshly isolated human polymorphonuclear neutrophils (PNANs) were completely added to the wells in 200 μl in the presence of 10 ng / ml phorbol-12-myristate-13-acetate and in the presence or absence of test compounds, and incubated for 20 min at 37 ° C, and then for 30 min at room temperature. After this, the plates were washed in medium and 100 μl of 0.1% (w / v) NMB (hexadecyltrimethylammonium bromide, Sigma H5882) in 0.05 M potassium phosphate buffer, pH 6.0 was added to each well. Then the tablets were left for 60 min on a shaker at room temperature. After that, endogenous peroxidase activity was evaluated using tetramethylbenzidine (TMB) as follows: samples of the stain-lysate were mixed with 0.22% H ₂ O ₂ (Sigma) and 50 μg / ml TMB (Boehringer Mannheim) in 0.1 M buffer containing acetate / sodium citrate, pH 6.0, and absorbance was measured at 630 nm.

αIIb / β ₃ -dependent aggregation of human platelets

Human platelet aggregation was evaluated using impedance aggregation on a luminescent aggregometer (Chronolog Whole Blood Lumiaggregometer). Human platelet-rich plasma (PRP) was obtained by centrifugation at 220 × g for 10 min of venous human blood treated with an anticoagulant, 0.38% (v / v) trisodium citrate and diluted to a cell density of 6 × 10 ⁸ / ml autologous plasma. The cuvettes contained equal amounts of PRP and filtered Tyrode buffer (g / liter: NaCl 8.0; MgCl ₂ .H ₂ O 0.427; CaCl ₂ 0.2; KCl 0.2; D-glucose 1.0; NaHCO ₃ 1.0 ; NaHPO ₄ · 2H ₂ O, 0.065). After 2.5 μM ADP (Sigma) was added, aggregation was monitored in the presence or absence of inhibitors.

In the above assays for the preferred compounds of the present invention, such as the compounds described in the examples, the IC ₅₀ values in the α ₄ β ₁ assay were mainly 1 μM and below, and in the α ₄ β ₇ assay they were 5 μM and below. In other assays using α-integrins of other subgroups, the same compounds had IC ₅₀ values of 50 μM or higher, indicating their highly effective and selective action against α ₄ -integrins.

In addition, the compounds of the present invention, such as the compounds described in the examples, have predominant absorption properties, as defined in standard tests, and therefore they are especially suitable for oral administration.

PHARMACOLOGICAL DATA (JC ₅₀ ) for compounds of formula (I) Example No. α ₄ β ₁ (μM) α ₄ β ₇ (μM) 2 0.817 1.929 four 0.243 0.988 6 0.175 0.921 8 0.032 0.807 10 0.284 - 12 0.166 1.366 fourteen 0.068 2.021 16 0.020 0.277 eighteen 0.052 0.423 twenty 0.379 1.924 22 0.166 1.491 24 0.190 - 26 0.042 3.540 28 0.009 0.154 thirty 0.021 0.180 32 0.001 0.028 34 0.024 0.080 37 0.007 0.076 40 0.004 0.032 42 0.228 1.369 44 0.027 0.385 46 0.010 0.120 48 0.002 0.036 fifty 0.008 0.039 52 0.112 0.417 54 0.098 0.369 56 0.011 0.029 58 0.002 0.061 60 0.009 0.034 62 0.003 0.027 65 0.006 0.030 68 0.123 0.313 69 0.001 0.016 70 0.019 0.053 74 0.005 0.024 77 0.012 0.070 83 0.155 0.207 85 0.238 0.432 88 0.088 0.457 90 0.010 0.053 92 0.003 0.054 94 0.055 0.139 97 0.011 0.032 99 0.070 0.228 101 0.021 0.349 103 0.031 0.401 109 0.001 0.007 111 0.007 0.102 112 0.043 0.171 113 0.195 0.529 114 0.016 0.031 115 0.012 0.027 117 0.001 0.002 119 0.022 0.038 121 0.002 0.007 123 0.005 0.007 125 0.113 0.458 127 0.011 0.104 129 0.048 0.285 131 0.079 0.312 133 0.035 0.632 135 0.028 0.056 137 0.061 0.258 149 0.037 0.230 150 0.197 0.381 152 0.001 0.007 154 0.087 0.321 156 0.064 0.257 158 0.106 0.180 160 0.004 0.042 162 0.003 0.049 164 0.017 0.084 166 0.012 0.046 168 0.006 0.168 170 0.001 0.020 172 - 0.050 173 0.005 0.014 175 - 0.014 177 0.120 0.157 191 0.008 0.045 193 0.002 0.007 195 0.002 0.005 205 0.005 0.194 206 0.019 0.678 209 0.013 0.220 210 0.031 0.509 211 0.037 0.236 215 0.013 0.131

Claims (26)

1. The compound of formula (I)

where R ¹ represents a group Ar ¹ L ² Ar ² Alk, in which Ar ¹ represents an optionally substituted aromatic or heteroaromatic group; L ² represents a covalent bond or —O—, —NH— or —CONH—; Ar ² represents an optionally substituted arylene or heteroarylene group and Alk represents the chain —CH ₂ CH (R) - or —CH (CH ₂ R) -, in which R represents a carboxylic acid (—CO ₂ H) or an esterified carboxy group of the formula —COOAlk ⁷ , in which Alk ⁷ represents a C _1-8 alkyl group, an optionally substituted C _3-8 cycloalkyl group, an optionally substituted C _3-8 heterocycloalkyl group optionally substituted C _3-8 heterocycloalkylC _1-6 alkyl group, optionally substituted hydroxyC _1-6 alkyl group, optionally substituted C _1-6 alkyloxy _1-6 alkyl group, optionally substituted N-di-C _1-8 alkylamino C _1-8 an alkyl group optionally substituted a substituted C _6-10 aryl group, an optionally substituted C _6-10 aryl C _1-6 alkyl group, an optionally substituted hetero C _6-10 aryl C _1-6 alkyl group, a pyridinyl C _1-3 alkyl group, an imidazolyl C _1-3 alkyl group; X represents a group —N (R ² ) -, where R ² represents a hydrogen atom or a C _1-6 alkyl group; V represents an oxygen atom (O); R ^x R ^y and R ^z may be the same or different and each of them represents an atom or a group-L ¹ (Alk ¹ ) _n (R ³ ) _v , where L ¹ represents a covalent bond or -O-, -S-, - Se— —S (O) -, —NH— or —N (CH ₃ ) -, Alk ¹ represents an optionally substituted aliphatic group, R ³ represents a hydrogen or halogen atom or a group selected from —OR ^3a [where R ^3a represents an atom hydrogen or optionally substituted straight or branched C _1-6 alkyl group or C _3-8 cycloalkyl group], -SR ^3a or optionally substituted cycloaliphatic, heterocycloaliphatic, aroma matic or heteroaromatic group, n is zero or an integer 1, av is the integer 1, 2 or 3, with the proviso that when n is zero, a L ¹ is a covalent bond, v is the integer 1; or R ^z represents an atom or group as defined above, and R ^x and R ^y taken together form an optionally substituted spiro-linked cycloaliphatic or heterocycloaliphatic group, and its salts, solvates, hydrates and N-oxides. 2. The compound according to claim 1, where R represents a carboxylic acid group (—CO ₂ H). 3. The compound according to claim 1, where R represents an esterified carboxyl group of the formula —CO ₂ Alk ⁷ . 4. The compound according to any one of claims 1 to 3, where R ² represents a hydrogen atom. 5. The compound according to any one of claims ^{1 to 4} , where Ar ² represents an optionally substituted phenylene group or an optionally substituted pyridinediyl group of the formula

where a and b are the attachment positions of L ² and Alk, respectively. 6. The compound according to claim 5, where Ar ² represents a 1,4-phenylene group. 7. The compound according to any one of claims 1 to 6, where Ar ¹ represents an optionally substituted phenyl or 5-, 6- or 10-membered heteroaromatic group. 8. The compound according to claim 7, where Ar ¹ represents an optionally substituted pyridyl, pyrimidinyl, naphthyridinyl, quinolinyl or isoquinolinyl group. 9. The compound of claim 8, where Ar ¹ represents a 2,7-naphthyridinyl group. 10. The compound according to any one of claims 1 to 9, where R ^z represents a halogen atom. 11. The compound of claim 10, where R ^z represents a bromine atom. 12. The compound according to any one of claims 1 to 9, where R ^z represents an optionally substituted C _1-8 alkyl group. 13. The compound according to any one of claims 1 to 9, where R ^z represents a group - L ¹ (Alk ¹ ) _n R ³ , where L ¹ represents an atom -O-, -S-, -Se- or a group -S (O ) -, -NH- or -N (CH ₃ ) -. 14. The compound according to any one of claims 1 to 9, where R ^z represents a group - L ¹ (Alk ¹ ) _n R ³ where L ¹ represents a covalent bond. 15. The compound according to item 13 or 14, where n is 0. 16. The compound of claim 13 or 14, wherein n is an integer of 1, and Alk ¹ is an optionally substituted C _1-6 alkylene chain. 17. The compound of claim 15 or 16, wherein R ³ is a hydrogen atom or an optionally substituted C _3-10 cycloaliphatic, C _3-10 heterocycloaliphatic, C _6-12 aromatic, or C _1-9 heteroaromatic group. 18. The compound according to any one of claims 1 to 17, where each of R ^x and R ^y represents an optionally substituted C _1-8 alkyl group. 19. The compound according to any one of claims 1 to 17, where R ^x and R ^y , bonded together, form an optionally substituted spiro-bonded C _3-10 cycloaliphatic or C _3-10 heterocycloaliphatic group. 20. The compound, which is: (2S) -2 - [(3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1-yl) oxy] phenyl} propanoic acid, (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-4,4-dimethyl-3-oxo-1-cyclobutenyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(2,7) naphthyridin-1-yloxy] phenyl} propanoic acid (2S) -2 - [(2-bromo-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- (2,6-dimethoxy [1,1'-biphenyl] -4- silt) propanoic acid, (2S) -2 - {(3-oxospiro [3.6] dec-1-en-1-yl) amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-bromo-3-oxospiro [3.6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - {[4,4-dimethyl-2- (phenylselenyl) -3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-7-methoxy-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - {(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1- il) oxy] phenyl} propanoic acid, (2S) -2 - {[2- (phenylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-chloro-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-pyridin-3-ylspiro [3.5] non-1-en-1-ylamino) propane acid (2S) -2 - [(2-iodo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2- silt} propanoic acid, (2S) -2 - [(2-chloro-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2- silt} propanoic acid, (2S) -2 - [(2-chloro-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-chloro-3-oxospiro [3.6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2- [4,4-dimethyl-2- (1-methyl-1H-tetrazol-5-ylsulfanyl) -3-oxocyclobut-1-enylamino] -3- {4 - [(3,5-dichloroisonicotinoyl ) amino] phenyl} propanoic acid, (2S) -2 - [(2-bromo-3,7,7-trioxo-7λ ⁶ -thiaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5 -dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-chloro-3-oxospiro [3.4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-3-oxospiro [3.4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-methylsulfanyl-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2- (2-fluoro-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-fluoro-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(4,4-dimethyl-2-methylsulfanyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(2,7) naphthyridin-1-ylamino) phenyl] propanoic acid , (2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid (2S) -2 - [(2-isopropylsulfanyl-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridin-1- ilamino) phenyl] propanoic acid, (2S) -2 - [(2-bromo-3-oxospiro [3.4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid (2S) -2 - [(4,4-dimethyl-3-oxo-2-pentafluorophenylsulfanylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(4,4-dimethyl-3-oxo-2-pyrazin-2-ylcyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid (2S) -2 - [(7-acetyl-2-bromo-3-oxo-7-azaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5- dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - {[2- (isopropylsulfanyl) -3-oxo-7-oxaspiro [3.5] non-1-en-1-yl)] amino} -3- (2,6-dimethoxy [1,1 '-biphenyl] -4-yl) propanoic acid, (2S) -2 - [(2-cyclohexyl-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxospiro [3.5] non-1-en-1-ylamino) propanoic acid, (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propylspiro [3.5] non-1-en-1-ylamino) propanoic acid, (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxo-7-oxaspiro [3.5] non-1-en-1-ylamino) propane acid (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propyl-7-oxaspiro [3.5] non-1-en-1-ylamino) propane acid (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2- [1,3] dithian-2-yl-3-oxospiro [3.5] non-1-en- 1-ylamino) propanoic acid, (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-ethyl-3-oxospiro [3.5] non-1-en-1-ylamino) propanoic acid, (2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (3-oxospiro [3.5] non-1-en-1-ylamino) propane acid (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino ] phenyl} propanoic acid, (2S) -2- (2-chloro-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino ] phenyl} propanoic acid, (2S) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} -2- (2-methanesulfinyl-4,4-dimethyl-3-oxocyclobut-1-enylamino ) propanoic acid, (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- [4- (3-methyl [2,7] naphthyridin-1-ylamino) phenyl] propanoic acid (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid, (2S) -2- (2-bromo-4,4-dimethyl-3-oxocyclobut-1-enylamino] -3- [4- (3-methyl [2,7] naphthyridin-1-yloxy) phenyl] propanoic acid , (2S) -2 - [(2-bromo-3-oxospiro [3.5] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid and its salts, solvates, hydrates, N-oxides and esters of carboxylic acids. 21. The compound, which is: (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-bromo-3-oxospiro [3.6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - {(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3-methyl [2,7] naphthyridin-1- il) oxy] phenyl} propanoic acid, (2S) -2 - {[2- (phenylsulfanyl) -4,4-dimethyl-3-oxo-1-cyclobutenyl] amino} -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-chloro-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-pyridin-3-ylspiro [3.5] non-1-en-1-ylamino) propane acid (2S) -2 - [(2-iodo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2- silt} propanoic acid, (2S) -2 - [(2-chloro-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {5 - [(3,5-dichloroisonicotinoyl) amino] pyridin-2- silt} propanoic acid, (2S) -2 - [(2-chloro-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-chloro-3-oxospiro [3.6] dec-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-3,7,7-trioxo-7λ ⁶ -thiaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5 -dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-chloro-3-oxospiro [3.4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-bromo-3-oxospiro [3.4] oct-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-methylsulfanyl-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2- (2-fluoro-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-fluoro-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2- [4,4-dimethyl-2-methylsulfanyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -2 - [(2-isopropylsulfanyl-4,4-dimethyl-3-oxocyclobut-1-enyl) amino] -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid , (2S) -2 - [(2-isopropylsulfanyl-3-oxospiro [3.5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoic acid , (2S) -2 - [(2-isopropylsulfanyl-3-oxo-7-oxaspiro [3.5] non-1-en-1-yl) amino] -3- [4 - ([2,7] naphthyridin-1- ilamino) phenyl] propanoic acid, (2S) -2 - [(2-bromo-3-oxospiro [3.4] octa-1,6-dien-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid (2S) -2 - [(7-acetyl-2-bromo-3-oxo-7-azaspiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5- dichloroisonicotinoyl) amino] phenyl} propanoic acid, (2S) -2 - [(2-cyclohexyl-3-oxospiro [3.5] non-1-en-1-yl) amino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoic acid , (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2-methyl-3-oxospiro [3.5] non-1-en-1-ylamino) propanoic acid, (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (3-oxo-2-propylspiro [3.5] non-1-en-1-ylamino) propanoic acid, (2S) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} -2- (2- [1,3] dithian-2-yl-3-oxospiro [3.5] non-1-en- 1-ylamino) propanoic acid, (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino ] phenyl} propanoic acid, 2- (2-chloro-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloro-1-hydroxypyridin-4-carbonyl) amino] phenyl} propane acid and its salts, solvates, hydrates, N-oxides and esters of carboxylic acids. 22. The compound, which is a ethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate, isopropyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate, tert-butyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate, 1-methylpiperidin-4-yl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) aminophenyl} propanoate phenyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoylamino] phenyl} propanoate, cyclopentyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate, 2-imidazol-1-yl-ethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino] -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate, neopentyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate, tetrahydrofuran-3-yl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate pyridin-4-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate tetrahydropyran-4-yl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-Dichloroisonicotinoyl) amino] phenyl} propanoate, 1-methylpyrrolidin-3-yl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate, 2,3-dihydroxypropyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate tetrahydrofuran-2-ylmethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- {4 - [(3,5-dichloroisonicotinoyl) amino] phenyl} propanoate and its salts, solvates, hydrates and N-oxides. 23. A pharmaceutical composition having an α ₄ integrin inhibitory activity and comprising the compound of claim 1 in combination with one or more pharmaceutically acceptable carriers, excipients or diluents. 24. Ethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl] propanoate. 25. A pharmaceutical composition having inhibitory activity against α ₄ integrin and containing ethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- [4- ( [2,7] naphthyridin-1-ylamino) phenyl] propanoate in combination with one or more pharmaceutically acceptable carriers, excipients or diluents. 26. Use of ethyl (2S) -2- (2-bromo-3-oxospiro [3.5] non-1-en-1-ylamino) -3- [4 - ([2,7] naphthyridin-1-ylamino) phenyl ] propanoate for the manufacture of a medicament for the treatment and / or prevention of rheumatoid arthritis, multiple sclerosis, asthma and inflammatory bowel disease. The priority of 02.22.2001 according to application 0104418.9 is established according to claims 1 to 26 of the claims. Priorities from 06/08/2001 and 11/16/2001 according to applications 0114000.3 and 0127562.7 are established by the specified features of claims 1-26 of the claims.