WO1998046599A1 - Novel carboxamides as platelet aggregation inhibitors - Google Patents

Abstract

Compounds of formula (I) and their salts and solvates wherein: one of Y1 or Y2 represents N and the other represents NR5, O or S, or one of Y1 or Y2 represents S and the other represents CR5, wherein R5 represents hydrogen or C1-4 alkyl; m represents 0, 1 or 2; A represents C0-2 alkylene which may be optionally substituted with one or more groups independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4 alkyl, aryl, arylC1-4 alkyl, arylC3-7 cycloalkyl, heteroaryl, heteroarylC1-4 alkyl, R6SO2NR2C1-4 alkyl, R6CONR2C1-4 alkyl, R6OCONR2C1-4 alkyl, R2R7NCONR2C1-4 alkyl, R6SO2C1-4 alkyl, R2R7NSO2C1-4 alkyl, R2R7NCOC1-4 alkyl, R6COC1-4 alkyl, R7OOCC1-4 alkyl, R6OC1-4 alkyl, R2R7NC1-4 alkyl, R8OOC-, or R2R7NCO-; R2 represents independently hydrogen or C1-4 alkyl; B represents carboxy or a metabolically labile ester or amide thereof; R4 represents a group of formula (i) or (ii): wherein the terminal ring in both groups can be optionally substituted with one or more C1-4 alkyl or halogen groups and wherein R1 and R3, as defined in the description, are platelet aggregation inhibitors and are useful for the treatment or prevention of thromboembolic disorders. Pharmaceutical compositions including these compounds and processes for their preparation are also provided.

Description

Novel carboxamides as platelet aggregation inhibitors.

Field of the invention.

The present invention relates to a new series of carboxamides which are platelet aggregation inhibitors. The invention also relates to processes for preparing such compounds, to pharmaceutical compositions containing them and to their use for the treatment of disorders in which platelet aggregation is involved.

Description of the prior art.

Platelet function plays an essential role in the maintenance of blood hemostasis but also in the pathogenesis of a broad range of cardiovascular and cerebrovascular disorders, including unstable angina, myocardial infarction, atherosclerosis, thromboembolism, stroke, restenosis following angioplasty, etc.

The hemostatic plug consists essentially of a mass of platelet aggregates and a net of an insoluble protein known as fibrin. In order to be able to aggregate, platelets must be previously activated and this activation process involves, as a last step, the exposure of certain cell adhesion molecules on the external surface of the platelet membrane. These molecules are glycoproteins

(GP lib /Ilia) belonging to the integrin family, which act mainly as receptors for fibrinogen although they also show affinity for other adhesion molecules such as fibronectin, vitronectin and von Willebrand factor. Fibrinogen (the soluble precusor of fibrin) is able to bind to two molecules of GP Ub/IIIa on adjacent platelets, leading to the formation of the platelet thrombus.

GP Ub/IIIa, like many other integrins, exhibits high affinity for the tripeptide sequence Arg-Gly-Asp, which is present in many adhesion molecules. Several peptidic compounds based on this sequence have been reported which block the binding of fibrinogen to its receptor, thus inhibiting platelet aggregation. However, their therapeutic utility has been severely limited by their low oral bioavailability and metabolic stability. Nonpeptide antagonists of the fibrinogen receptor have also been reported. The present invention discloses new and potent nonpeptide inhibitors of platelet aggregation. It is believed that these compounds act as antagonists of the fibrinogen (GP lib /Ilia) receptor. Description of the invention.

The present invention relates to novel compounds of general formula I:

I wherein: one of Yi or Y₂ represents N and the other represents NR5, O or S, or one of Yi or Y₂ represents S and the other represents CR₅, wherein R₅ represents hydrogen or C₁-₄ alkyl; m represents 0, 1 or 2;

R_l represents hydrogen, C₁-₆ alkyl, C₂-₆ alkenyl, C₂-6 alkynyl, C1-6 alkoxy, C₁-6 haloalkyl, C₃-₇ cycloalkyl, C₃.₇ cycloalkylCi-₄ alkyl, aryl, arylCι-₄ alkyl, arylCi-₄ alkoxy, arylC₃_₇ cycloalkyl, heteroaryl, heteroarylCi-₄ alkyl, R₆SO₂NR₂-, R₆CONR₂-, R₆OCONR₂-, R₂R7NCONR2-, R2R7N-, R₆Sθ2NR₂Cι-4 alkyl, R₆CONR₂Cι-₄ alkyl, R₆OCONR₂Cι-₄ alkyl, R2R7NCONR2C1-4 alkyl, R₆S0₂Ci-4 alkyl, R₂R7NSO₂C₁.₄ alkyl, R₂R7NCOC₁-4 alkyl, R^OC alkyl, R7OOCC1-4 alkyl, R₆OC1-₄ alkyl, or R₂R7NC₁-₄ alkyl;

A represents C₀-₂ alkylene which may be optionally substituted with one or more groups independently selected from Cχ-₆ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, Cι-₆ haloalkyl, C₃-₇ cycloalkyl, C₃-₇ cycloalkylCι-₄ alkyl, aryl, arylCι-₄ alkyl, arylC₃-₇ cycloalkyl, heteroaryl, heteroarylCi-₄ alkyl, R₆SO₂NR₂C₁-₄ alkyl, R₆CONR₂Cι.₄ alkyl, R₆OCONR₂Cι-₄ alkyl, R₂R7NCONR₂C1-₄ alkyl, R₆S0₂Cι- alkyl, R₂R7NSO₂C₁-₄ alkyl, R₂R7NCOC₁-4 alkyl, R COC1-4 alkyl, R7OOCC₁-4 alkyl, R₆OC₁-₄ alkyl, R₂R₇NC₁-₄ alkyl, R₈OOC-, or R₂R7NCO-; R₂ represents independently hydrogen or C₁-₄ alkyl;

R₃ can have any of the meanings disclosed for R and in addition it can represent RsOOC- or R₂R₇NCO-, with the proviso that when A represents Co alkylene, then R₃ cannot represent a group that is bonded through a N atom; B represents carboxy or a metabolically labile ester or amide thereof;

R₄ represents a group of formula (i) or (ii):

wherein the terminal ring in both groups can be optionally substituted with one or more C₁-₄ alkyl or halogen groups; R₆ represents C₁-₆ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, Cι_₆ haloalkyl, Cχ-₄ alkoxyCι-₄ alkyl, C₃-7 cycloalkyl, C₃-₇ cycloalkylCι-₄ alkyl, aryl, arylCι-₄ alkyl, arylcarbonylCi-₄ alkyl, heteroaryl or heteroarylCι-₄ alkyl;

R₇ represents hydrogen or any of the meanings disclosed for R&

R_δ represents hydrogen or C₁-₄ alkyl; p represents 1 or 2;

X_l represents a group of formula:

\ \

N, CH, ₇NN--CCHH₂₂-- ,_ι o_or_r p C H-CH₂-

X₂ represents a group of formula:

/ / / /

N, CH, -CH — N , -CH — CH . — NH-C H , or — O-C H •

\ \ \ \ '

X₃ represents N or CH, with the proviso that when X₃ is N then X₂ cannot represent a group: / / /

N, -CH_?— N I -NH— C H or — O- -C_χH

\

one of Zi or Z₂ represents Z and the other represents CH₂, with the proviso that when X₃ represents N, then Z₂ is CH2; Z represents a group of formula:

O

HN / , (C,.₆ alkyl)N / > (C*.-₆ alkyl)0-C II— N / , (2-pyridyl)— N /

R₉ represents hydrogen or C₁-₄ alkyl;

Rio and Rn independently represent hydrogen or C₁-₄ alkyl, or they can be bonded together forming a C₂-₅ polymethylene chain; aryl in the above definitions represents phenyl or naphthyl which can be optionally substituted with one or more groups independently selected from halogen, C₁-₄ alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, C₁-₄ alkoxy, hydroxy, C₁-₄ haloalkyl, C₁.₄ haloalkoxy, carboxy, cyano, nitro, amino, C .₄ alkylamino, C₁.₄ dialkylamino, C₁-₄ alkylcarbonyl, C₁-₄ alkylcarbonyloxy, C₁-₄ alkoxycarbonyl, C₁-₄ alkylsulfonyl, C₁-₄ alkylsulfinyl, C₁-₄ alkylthio or C₁-₄ alkylcarbonylamino and wherein two substituents on adjacent carbon atoms can be bonded forming a methylenedioxy group; heteroaryl in the above definitions represents an aromatic monocyclic 5- or 6- membered heterocycle or an aromatic bicyclic 9- or 10-membered heterocycle containing from one to four heteroatoms selected from N, O and S, and which can be optionally substituted with one or more groups independently selected from halogen, C₁-₄ alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, C₁-₄ alkoxy, hydroxy, C₁-₄ haloalkyl, C₁-₄ haloalkoxy, carboxy, cyano, nitro, amino, C₁-₄ alkylamino, C₁-₄ dialkylamino, C₁-₄ alkylcarbonyl, C₁-₄ alkylcarbonyloxy, C₁-₄ alkoxycarbonyl,

C₁-₄ alkylsulfonyl, C₁-₄ alkylsulfinyl, C₁-₄ alkylthio or C₁-₄ alkylcarbonylamino.

Also comprised in the present invention are the addition salts of the compounds disclosed herein as well as their solvates and prodrugs. By prodrug it is understood any precursor of a compound of formula I that is capable of releasing a compound of formula I in vivo.

Some compounds of formula I may contain one or more chiral centers, which may give rise to different stereoisomers. The present invention covers each of the individual stereoisomers as well as their mixtures. Moreover, some compounds of the present invention may exhibit cis/trans isomery. The present invention covers each of the geometric isomers as well as their mixtures.

The present invention also provides a pharmaceutical composition which comprises an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof in admixture with a pharmaceutically acceptable excipient.

The invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting platelet aggregation. The invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting the binding of fibrinogen to its receptor.

The invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of thromboembolic disorders.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for inhibiting platelet aggregation.

The invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for inhibiting the binding of fibrinogen to its receptor. The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of thromboembolic disorders.

The invention further provides a method of inhibiting platelet aggregation in a mammal, which comprises administering to a mammal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The invention further provides a method of inhibiting the binding of fibrinogen to its receptor in a mammal, which comprises administering to a mammal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The invention further provides a method for the treatment or prevention of thromboembolic disorders in a mammal, which comprises administering to a mammal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The invention still further provides a process for preparing a compound of formula I, which comprises: (a) reacting a compound of formula II or a reactive derivative thereof

π

wherein Ri, Yi, Y₂ and m have the previously described meaning and R₄ ^* represents a group R₄ as defined above or a group convertible thereto, with an amine of formula HI

m

wherein A, B, R₂ and R₃ have the previously described meaning, followed when necessary by the conversion of R₄ ^* into a group R₄ and/or the removal of any protecting group that may be present; or (b) deprotecting a compound of formula I'

wherein Yj, Y₂, m, A, B, Ri, R₂, R₃ and R₄ have the previously described meaning but at least one of them contains a protecting group; or

(c) converting, in one or a plurality of steps, a compound of formula I into another compound of formula I; or

(d) converting a compound of formula I wherein B represents a carboxy group into a metabolically labile ester or amide thereof; and

(e) if desired, after the above steps, treating a compound of formula I with an acid or a base to give the corresponding addition salt.

Under the nomenclature used throughout this disclosure, the definitions of the substituents are to be read from left to right, so that the terminal portion of each substituent is described always in first place (i.e. to the left) and the point of attachment to the rest of the molecule is described to the right.

In the above definitions, the term Ci-_n alkyl, as a group or part of a group, means a linear or branched alkyl group that contains from one to n carbon atoms. Therefore, when n is 4 it includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. When n is 6 it includes, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, neopentyl and hexyl. A C2-n alkenyl group means a linear or branched alkyl group having from 2 to n carbon atoms and having in addition one or more double bonds. Examples include among others ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl. A C2-n alkynyl group means a linear or branched alkyl group having from 2 to n carbon atoms and having in addition one or more triple bonds. Examples include among others ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl. The term halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.

The term Cι-_n haloalkyl means a group resulting from the substitution of one or more hydrogen atoms of a Cι-_n alkyl group by one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), which can be the same or different. Examples include trifluoromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 1- and 2-chloroethyl, 1- and 2-fluoroethyl, 1- and 2- bromoethyl, 1- and 2-iodoethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1-, 2- and 3-fluoropropyl, 1-, 2- and 3-chloropropyl, 3,3,3- trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-, 2-, 3- and 4- fluorobutyl, 1-, 2-, 3- and 4-chlorobutyl, nonafluorobutyl, 1-, 2-, 3-, 4- and 5- fluoropentyl, 1-, 2-, 3-, 4- and 5-chloropentyl, 1-, 2-, 3-, 4-, 5- and 6-fluorohexyl, and 1-, 2-, 3-, 4-, 5- and 6-chlorohexyl.

The term C3-7 cycloalkyl, as a group or part of a group, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. A Co-2 alkylene group means a bond, methylene or ethylene.

A C2-5 polymethylene chain means ethylene, propylene, butylene or pentylene.

The term Cι-_n alkoxy, as a group or part of a group, means a group derived from the union of a Cι-_n alkyl group to an oxygen atom of an ether functional group. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, terf-butoxy, pentyloxy and hexyloxy.

A Ci-₄ alkoxyCi-₄ alkyl group represents a group resulting from the substitution of a hydrogen atom of a C₁-₄ alkyl group by a C₁-₄ alkoxy group. Examples include among others methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl and butoxybutyl. A C₁-₄ haloalkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a C₁-₄ alkoxy group by one or more halogen atoms, which can be the same or different. Examples include trifluoromethoxy, fluoromethoxy, chloroethoxy, fluoroethoxy, iodoethoxy, 2,2,2-trifluoroethoxy pentafluoroethoxy, fluoropropoxy, chloropropoxy, 2,2,3,3,3- pentafluoropropoxy, heptafluoropropoxy, fluorobutoxy, and nonafluorobutoxy.

A Cι-₄ alkylamino or C₁-₄ dialkylamino group means a group resulting from the substitution of one or two hydrogen atoms respectively of an amino group by one or two C₁-₄ alkyl groups, which can be the same or different. Examples include methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, propylamino, dipropylamino, isopropylamino and diisopropylamino.

A C₁-₄ alkylcarbonyl group represents a group resulting from the union of a C₁-₄ alkyl group to a carbonyl group. Examples include acetyl, propionyl, isopropionyl, and butanoyl.

A C₁-₄ alkylcarbonyloxy group represents a group resulting from the union of a C₁-₄ alkylcarbonyl group to an oxygen atom of an ether functional group. Examples include acetyloxy, propionyloxy, isopropionyloxy, and butanoyloxy. A Cι-₄ alkoxycarbonyl group represents a group resulting from the union of a C -₄ alkoxy group to a carbonyl group. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and terf-butoxycarbonyl. A Cι-₄ alkylsulfonyl group represents a group resulting from the union of a Cι-₄ alkyl group to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. A Cχ-₄ alkylsulfinyl group represents a group resulting from the union of a Ci-₄ alkyl group to a sulfinyl group. Examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, and tert-butylsulfinyl.

A Cι-₄ alkylthio group represents a group resulting from the union of a Cι-₄ alkyl group to a sulphur atom of a thioether funtional group. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, and tert-butylt io.

A Cι-₄ alkylcarbonylamino group represents a group resulting from the substitution of a hydrogen atom of an amino group by a Cχ-₄ alkylcarbonyl group. Examples include acetamido, propanamido and isopropanamido.

The term aryl, as a group or part of a group, represents phenyl or naphthyl, or phenyl or naphthyl substituted with one or more, preferably from one to three, groups independently selected from halogen, C₁-.₄ alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, C₁-₄ alkoxy, hydroxy, C₁-₄ haloalkyl, C₁-₄ haloalkoxy, carboxy, cyano, nitro, amino, C₁-₄ alkylamino, C₁-₄ dialkylamino, C₁-₄ alkylcarbonyl, C₁-₄ alkylcarbonyloxy, C₁-₄ alkoxycarbonyl, C₁-₄ alkylsulfonyl, C₁-₄ alkylsulfinyl, C₁-₄ alkylthio or C₁-₄ alkylcarbonylamino. When there is more than one substituent, these can be the same or different and can be placed on any available position of the aryl group. Moreover, two of the substituents on an aryl group can form together a methylenedioxy group, thus giving rise to a 1,3-benzodioxole ring.

An aryl-Cι-₄ alkyl group represents a group resulting from the substitution of one hydrogen atom of a C₁-₄ alkyl group by an aryl group as defined above. Examples include among others, benzyl, 1-phenylethyl, 3- phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-phenylbutyl and 1-phenylbutyl, wherein the phenyl groups can be substituted as described above in the definition of an aryl group. The term heteroaryl, as a group or part of a group, represents any radical from an aromatic monocyclic 5- or 6-membered or bicyclic 9- or 10-membered heterocycle containing from one to four heteroatoms selected from N, O and S and which is stable and obtainable by synthesis. Examples of aromatic monocyclic heterocycles include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, and pyridazine. Examples of bicyclic heteroaryl groups include benzimidazole, benzofuran, indole, isoindole, benzothiophene, benzothiazole, quinoline, isoquinoline, phthalazine, quinazoline, quinoxaline, cinnoline, naphthyridine, indazole, imidazopyridine, imidazopyrimidine, imidazopyrazine, imidazopyridazine, pyrazolopyrazine, pyrazolopyridine and pyrazolopyrimidine. All these groups can be optionally substituted with one or more groups, preferably from one to three groups, as described above.

In the compounds of the present invention, group B represents a carboxy group or a metabolically labile ester or amide thereof. By metabolically labile it is understood any group that is capable of being split in vivo, releasing the acid group and which acts as prodrugs thereof. Examples of metabolically labile esters include Cι-₆ alkyl esters, for example methyl, ethyl, propyl, isopropyl ester; Cι-₆ alkoxyCι-₄ alkyl esters, for example methoxymethyl, 2- methoxyethyl ester; haloCι-₄ alkyl esters, for example 2-iodoethyl, 2,2,2- trichloroethyl ester; -₆ alkylcarbonyloxyCι-₄ alkyl esters, for example acetoxymethyl, 1-acetoxyethyl or pivaloyloxymethyl ester; arylCi-₄ alkyl esters, for example benzyl ester; arylcarbonyloxyC -₄ alkyl esters, for example benzoyloxymethyl or 1-benzoyloxy ethyl ester; C₃-₇ cycloalkylcarbonyloxyCi-₄ alkyl esters; C₁-₆ alkoxycarbonyloxy C₁-₄ alkyl esters, for example 1- ethoxycarbonyloxyethyl or 1-methoxycarbonyloxyethyl ester; C₃-₇ cycloalkyloxycarbonyloxyCi-₄ alkyl esters; C₁-6 alkoxycarbonylCi-₄ alkyl esters; C₃.₇ cycloalkyloxycarbonylCi-₄ alkyl esters; Ci-6 alkylcarbonylaminoCι-₄ alkyl esters; C₃-₇ cycloalkylcarbonylaminoCι-₄ alkyl esters; and aminoCi-₄ alkyl esters (wherein the amino group can be optionally substituted), for example aminomethyl or 2-N,N-dimethylaminoethyl ester. Examples of metabolically labile amides include amides formed with ammonia and amines such as Cχ-6 alkylamines, for example methyl- or ethylamine; diCι-6 alkylamines, for example dimethylamine or ethylmethylamine; Cι-6 alkoxyCι-6 alkylamines, for example methoxyethylamine; arylCi-4 alkylamines, for example benzylamine; and amino acids, for example glycine, or esters thereof.

Although the present invention includes all the compounds described above, preferred compounds of the invention include those compounds of formula I wherein independently or in any compatible combination:

Yl represents N and Y2 represents S; and /or m represents 0; and /or

A represents methylene which can be optionally substituted, as described above; and /or

R3 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, Ci-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylCι-4 alkyl, aryl, arylCi-4 alkyl, arylCi-4 alkoxy, arylC3-7 cycloalkyl, heteroaryl, heteroarylCι-4 alkyl, R6SO2NR2-,

R₆CONR₂-, R₆OCONR₂-, R2R7NCONR2-, R2R7N-, R₆S0 NR₂Cι^ alkyl,

R₆CONR₂Cι-4 alkyl, R6θCONR₂Cι-₄ alkyl, R2R7NCONR2C1-4 alkyl, R₆Sθ2Cι-₄ alkyl, R2R7NSO2C1-₄ alkyl, R2R7NCOC1-4 alkyl, R6COC1-4 alkyl, R7OOCC₁-4 alkyl, R6OC1.4 alkyl, R2R7NC₁-₄ alkyl, R₈OOC or R2R7NCO-; and /or R₄ represents a group selected from:

Accordingly, a preferred class of compounds of the present invention are those compounds of formula I wherein: m represents 0; and Ri, R₂, R₃, R₄, Yi, Y₂, A and B are as defined above in connection with formula I.

A more preferred class of compounds of the present invention are those compounds of formula I wherein m represents 0 and A represents methylene (which can be optionally substituted as described above), that is those compounds of formula la:

la

wherein:

RA represents independently hydrogen, C₁-6 alkyl, C₂-6 alkenyl, C₂-₆ alkynyl, C₁-₆ haloalkyl, C₃-₇ cycloalkyl, C₃-₇ cycloalkylCi-₄ alkyl, aryl, arylCι-₄ alkyl, arylC₃_₇ cycloalkyl, heteroaryl, heteroarylCι-₄ alkyl, R₆SO₂NR₂C₁-₄ alkyl, R₆CONR₂Cι-₄ alkyl, R₆OCONR₂Ci- alkyl, R2R7NCONR2C1-4 alkyl, R₆S0 Cι-₄ alkyl, R₂R₇NS0₂C₁-₄ alkyl, R₂R7NCOC₁-4 alkyl, R6COCι.₄ alkyl, R7OOCC₁-₄ alkyl, R OC₁-₄ alkyl, R₂R₇NC1-₄ alkyl, RgOOC-, or R2R7NCO-; and Ri, R₂, R₃, R₄, Re, R₇. R_δ, ^γ _l. ^2 and B are as defined above.

A still more preferred class of compounds of the present invention are those compounds of formula la wherein: R₄ represents a group selected from:

and Ri, R_2/ R₃, RA, YI, Y₂ and B are as defined above. An even more preferred class of compounds of the present invention are those compounds of formula la wherein:

R₄ represents a group selected from (a)-(f); Y_l represents N and Y₂ represents S; and Ri, R₂, R₃, RA_. and B are as defined above. A particularly preferred class of compounds of the present invention are those compounds of formula la wherein: R₄ represents a group selected from (a)-(f);

Yl represents N and Y2 represents S;

RA represents hydrogen;

R3 represents C1-6 alkyl, C2-6 alkenyl, C₂-6 alkynyl, Ci-6 alkoxy, -6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylCι-4 alkyl, aryl, arylCι-4 alkyl, arylCι-₄ alkoxy, arylC3-7 cycloalkyl, heteroaryl, heteroarylCι-4 alkyl, R6SO2NR2-, R₆CONR₂-, R₆OCONR₂-, R2R7NCONR2-, R2R7N-, R6SO2NR2C1-4 alkyl, R₆CONR₂Cι-4 alkyl, R₆OCONR₂Ci-4 alkyl, R2R7NCONR2C1-4 alkyl, R₆S0₂Cι-₄ alkyl, R2R7NSO2C1-4 alkyl, R2R7NCOC1-4 alkyl, R COC1-4 alkyl, R7OOC -4 alkyl, R OC1-4 alkyl, R2R7N -4 alkyl, R₈OOC-, or R2R7NCO-; and Ri, R₂, R6/ R7_/ R₈ and B are as defined above.

Another particularly preferred class of compounds of the present invention are those compounds of formula la wherein:

R4 represents a group selected from (a)-(f); Yi represents N and Y2 represents S;

RA independently represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylCι-4 alkyl, aryl, arylCι-4 alkyl, heteroaryl, or heteroarylCi-₄ alkyl, with the proviso that at least one of the RA groups is different from hydrogen; R3 represents hydrogen; and Ri, R2 and B are as defined above.

The compounds of formula I contain one or more basic nitrogen atoms and may contain one or more acid protons and, consequently, they can form salts with acids and bases both organic and inorganic, which salts are also included in the present invention. There is no limitation on the nature of these salts, provided that, when used for therapeutic purposes, they are pharmaceutically acceptable. Examples of these salts include: salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, tartaric acid; as well as other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by reacting the compound of formula I with a sufficient amount of the desired acid or base to produce a salt in the conventional manner. Free compounds and their salts differ in certain physicochemical properties, such as solubility, but they are equivalent for the purposes of the invention. The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of the invention. Some compounds of the present invention can exist as different diastereoisomers and/or optical isomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. The optical isomers can be resolved using any of the conventional techniques of optical resolution to give optically pure isomers. Such a resolution can be performed in any chiral synthetic intermediate as well as in the products of general formula I. Optical resolution techniques include separation by chromatography on a chiral phase or formation of a diastereoisomeric pair, resolution and subsequent recovery of the two enantiomers. The optically pure isomers can also be individually obtained using enantiospecific synthesis. The present invention covers each of the individual isomers and their mixtures (e.g. racemic mixtures), whether as obtained by synthesis or by physically mixing them up.

Furthermore, some of the compounds of the present invention may exhibit cis/trans isomery. The present invention covers each of the geometric isomers and the mixtures thereof.

Some compounds of the present invention may also exhibit tautomery for example those compounds containing an amidino group. All the possible tautomer forms as well as their mixtures are encompassed by the present invention.

The present invention also provides processes for preparing a compound of formula I. The compounds of formula I may be prepared using the methods described below. It will be apparent to those skilled in the art that the precise method used for the preparation of a given compound may vary depending on its chemical structure. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. Moreover, in the majority of the processes described below it will be desirable or necessary to protect reactive or labile groups using conventional protecting groups, for example the groups described below. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art.

In general, the compounds of formula I can be prepared by reaction between an acid of formula II and an amine of formula III, as shown in the following scheme:

R₄ into R₄

wherein Yi, Y_2/ m, A, B, Ri, R₂, R₃ and R₄ are as described above and R₄* represents a group R₄ or a group convertible thereto.

For this process any known method for preparing amide bonds can be used. For example, an acid of formula II can be reacted with an amine of formula HI in the presence of a suitable condensing agent, such as a diimide (e.g. dicyclohexylcarbodiimide), alone or associated with 1- hydroxybenzotriazole, in a suitable solvent; as examples of suitable solvents we can mention substituted amides such as dimethylformamide, and ethers such as dioxane and tetrahydrofuran. When the amine III is used as an addition salt, such as the hydrochloride, the reaction is carried out in the presence of a base, such as triethylamine.

Alternatively, the amide bond can be prepared by reacting amine HI with a reactive derivative of acid II, such as the acid chloride, anhydride or mixed anhydride. In this case, the reaction is carried out in the presence of a proton scavenger base, for example pyridine or triethylamine, in a suitable solvent, for example dichloromethane or chloroform, or the proton scavenger amine itself can be used as the solvent.

As will be evident to those skilled in the art, in order to carry out the reaction between compounds II and III it is necessary that the remaning reactive functional groups that may be present in these compounds are duly protected. As protecting groups can be employed any conventional protecting group known in the art, for example those described in Greene T.W., "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981. Just as examples, as protecting groups of an amino or amidino function the groups tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc) can be used. Carboxy groups can be protected for example as C₁-₄ alkyl esters, such as methyl, ethyl or tert-butyl esters, or arylCι-₄ alkyl esters, such as benzyl ester. In case compounds II or III contain protecting groups, it will be necessary a subsequent deprotection step, which is carried out under usual conditions, for example those disclosed in the above-mentioned reference.

In a compound of formula II, the group R₄ can be present as such or can be present as a precursor group, i.e. a group easily convertible thereto. When in a compound II R₄ ^* represents a group convertible into R₄, after the reaction of II with III it will be necessary to convert this group R₄ ^* into R₄. This conversion is carried out in one or more steps using widely known reactions in organic synthesis, such as those mentioned below and those disclosed in the examples. As examples, thus not being intended to be a limiting list, some of these conversions are listed in the following table:

R, R,

Conversions A, B and D can be carried out in dimethylsulfoxide as solvent in the presence of diisopropylethylamine and heating, or in pyridine at reflux.

Conversion C is carried out under standard alkylation conditions, for example in chloroform in the presence of triethylamine.

Conversion E is carried out under standard reductive amination conditions, for example by treatment with sodium triacetoxyborohydride in tetrahydrofuran/ acetic acid.

Moreover, some compounds of formula I can also be obtained by interconversion from another compound of formula I in one or more steps using widely employed procedures of organic synthesis. Examples of these conversions include alkylations, preparation of esters, amides, sulfonamides, carbamates and ureas, and hydrolysis of esters and amides. These types of reactions are widely described in the literature and are carried out under the standard experimental conditions used in organic chemistry for these type of reactions. Some of them are described in the examples. A compound of the present invention can also be converted to a metabolically labile ester or amide thereof using standard methods, for example by esterification of a compound of formula I under usual experimental conditions or by reaction of an acid, or a reactive derivative thereof, with the desired amine as described above for the reaction of II with III.

The salts of the compounds of formula I can be prepared by conventional methods for example by treatment with an acid such as hydrochloric acid, sulfuric acid, nitric acid, oxalic acid or methanesulfonic acid, or by treatment with a base such as sodium hydroxide or potassium hydroxide. Starting acids of formula II or derivatives thereof are commercially available, widely described in the literature or can be prepared by methods analogous to those known in the art. In general, these methods involve the construction of the 5-membered heterocycle following the procedures widely described in the literature for preparing this type of heterocycles and subsequent deprotection of the carboxy group, usually obtained in protected form as its C₁-₄ alkyl ester. Methods for the preparation of the heterocyclic nucleus can be found for example in: Heterocycles, 1991, 32 (4), 693 and /. Chem. Soc. Perkin Trans. 1, 1991, 2417 for thiazoles; Synthesis, 1984, 275 and Chem . Com m 1990, 20, 2537 for thiophenes; J.Org.Chem. 1996, 16(19), 6496 and

J.Chem.Soc. 1953, 93 for oxazoles; and /. Org.Chem. 1968, 3758 for imidazoles.

When in a compound II the substituent R4^* represents a group R4, this can already be present as such in the starting product used for preparing the heterocyle or alternatively, the heterocyclic nucleus can be prepared first and then the precursor of R4 is converted into R4 using methods analogous to those described above.

The compounds of formula III are commercially available, widely described in the literature or can be prepared by methods analogous to those described starting from commercially available products.

As mentioned above, the compounds of the present invention act by inhibiting the binding of fibrinogen to its receptor. Therefore, they are useful as preventive and therapeutic agents for the treatment of disorders requiring the inhibition of platelet aggregation. This includes the treatment or prevention of thromboembolic disorders such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders including, but not limited to, venous thrombosis, deep vein thrombosis, thrombophlebitis, pulmonary embolism, arterial embolism, renal embolism, transient ischemic attack, stroke, myocardial infarction, unstable and stable angina and atherosclerosis. Other applications of the compounds of the present invention include the prevention of thromboembolism and reocclusion during and after thrombolytic therapy, and the prevention of thromboembolism and reocclusion after angioplasty of the coronary and other arteries.

There are other integrins structurally related to the fibrinogen receptor (fibronectin, vitronectin, osteopontin, collagen, thrombospondin) that are able to recognize the sequence Arg-Gly-Asp, for which reason the compounds of the present invention might also inhibit the adhesion processes where these other integrins are involved and could thus find additional utility as suppressors of the metastasis of cancerous cells and as inhibitors of bone resorption in osteoporosis.

According to the activity of the compounds herein disclosed, the present invention further provides compositions that comprise a compound of the invention together with an excipient and optionally other auxiliary agents, if necessary. The compounds of the present invention can be administered in different pharmaceutical preparations, the precise nature of which will depend, as it is well known, upon the chosen route of administration and the nature of the pathology to be treated. Thus, solid compositions, according to the present invention, for oral administration include compressed tablets, dispersible powders, granules and capsules. In tablets, the active component is admixed with at least one inert diluent such as lactose, starch, mannitol, microcrystalline cellulose or calcium phosphate; granulating and disintegrating agents, for example corn starch, gelatine, microcrystalline cellulose or polyvinylpyrrolidone; and lubricating agents for example magnesium stearate, stearic acid or talc. The tablets may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and, thereby, provide a sustained action over a longer period. Gastric film-coated or enteric film-coated tablets can be made with sugar, gelatin, hydroxypropylcellulose, or acrylic resins. Tablets with a sustained action may also be obtained using an excipient which provides regressive osmosis, such as the galacturonic acid polymers. Formulations for oral use may also be presented as hard capsules of absorbable material, such as gelatin, wherein the active ingredient is mixed with an inert solid diluent and lubricating agents, or pasty materials, such as ethoxylated saturated glycerides. Soft gelatin capsules are also possible, wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

Dispersible powders and granules suitable for the preparation of a suspension by the addition of water provide the active ingredient in admixture with dispersing or wetting agents; suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, xantham gum, gum acacia; and one or more preservatives, such as methyl or π-propyl- p-hydroxybenzoate. Additional excipients, for example sweetening, flavoring and coloring agents may also be present.

Liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, or propylene glycol. Such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening, flavoring, perfuming, preserving agents and buffers. Preparations for injection, according to the present invention, for parenteral administration by bolus injection or continuous infusion include sterile aqueous or non-aqueous solutions, suspensions or emulsions, in a non-toxic parentally-acceptable diluent or solvent. Examples of aqueous solvents or suspending media are distilled water for injection, Ringer's solution, and isotonic sodium chloride solution. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or alcohols such as ethanol. These compositions may also include adjuvants such as wetting, preserving, emulsifying and dispersing agents. They may be sterilized by any known method or manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. When all of the components are sterile, the injectables will maintain the sterility if they are manufactured in sterile environment. The compounds of the present invention can be administered in combination with one or more additional therapeutic agents commonly used for the treatment of the above-mentioned disorders, for example other platelet antiaggregants (such as aspirin, triflusal, ticlopidine, thromboxane inhibitors, thromboxan synthase inhibitors), thrombolytic agents (such as tPA and its derivatives, anistreplase, streptokinase, urokinase, prourokinase), or anticoagulant agents (such as warfarin and heparin). In this case, the therapeutic agents may be formulated together in the same dosage unit or may be administered separately, either at the same time or sequentially, in which case it is not necessary that all components be administered by the same route.

Following are some representative preparations for tablets, capsules and injectables. They can be prepared following standard procedures and they are useful for inhibiting platelet aggregation. Tablets

Compound of formula I 50 mg

Dibasic calcium phosphate 125 mg

Sodium starch glycolate 10 mg

Talc 12.5 mg

Magnesium stearate 2.5 mg

200.0 mg

Hard gelatin capsules

Compound of formula I 50 mg Lactose 197 mg Magnesium stearate 3 mg

250 mg

Injectable Compound of formula I 50 mg

Benzylic alcohol 0.05 m l

Propylene glycol 1 m 1

Water to 5 m l

The activity of the compounds of the present invention as platelet aggregation inhibitors may be tested as follows:

Test 1: inhibition of ADP-induced platelet aggregation in human blood

Human blood was collected from drug-free healthy volunteers into tubes containing 3.16% sodium citrate. Platelet-rich plasma (PRP) was obtained by centrifugation of whole blood at 200 g for 10 min at 4°C. PRP was collected and the remaining blood was subjected to further centrifugation at 700 g for 10 min to obtain platelet-poor plasma (PPP). PRP was adjusted to 2xl0⁸ platelets /sample by diluting with PPP. Platelet aggregation was measured at

37°C by recording the increase in light transmission using a Chronolog aggregometer. Platelet aggregation was initiated by the addition of ADP (5 μM) to 360 mL of PRP under stirring. Tets compounds or vehicle were added 4 min before the addition of ADP. The results are expressed as the IC50 value, i.e. the concentration of test compound required to produce a 50% inhibition of platelet aggregation. The results obtained with representative compounds of the present invention are shown in Table I.

TABLE I

Compound IC50 (μM)

(Example No.)

1 0.65 16 0.61

18 0.07

24 0.021

27 0.012

28 0.043 33 0.005

34 0.005-0.001

36 0.01

40 0.0035

44 0.01

The following examples illustrate, but do not limit, the scope of the present invention. The following abbreviations have been used throughout the examples: DMF: dimethylformamide

EtOAc: ethyl acetate

DMSO: dimethylsulfoxide Hex: hexane

AcOH: acetic acid

THF: tetrahydrofuran

BOC2O: di rf-butyl carbonate NEt3: triethylamine

TFA: trifluoroacetic acid

MeOH: methanol

EtOH: ethanol

Reference example 1 Methyl 3-amino-2(S)-(benzenesulfonylamino)propionate, hydrochloride a) Nα-Benzenesulfonyl-L-asparagine

To a mixture of L-asparagine (10 g, 0.07 mol) in a solution of NaOH (3.4 g) in 50 mL of water and 50 mL of dioxane, cooled with an ice bath, was added dropwise benzenesulfonyl chloride (10.6 mL, 0.08 mol) and the reaction mixture was stirred at this temperature for 1 h. Dioxane was removed, the resulting solution was extracted with EtOAc and the aqueous phase was brought to pH=3 with concentrated HCl. The white precipitate formed was collected by filtration and washed with water, to afford 13.5 g of the desired compound. ¹H NMR (300MHz, D₂0) δ (TMS): 7.80 (d, J=8.4Hz, 2H), 7.56 (m, 3H), 4.66 (s),

4.17 (m, 1H), 2.64 (dd, J=15.2Hz, J=5.1Hz, 1H), 2.54 (dd, J=15.2Hz, J=7.9Hz, 1H). b) 3-Amino-2(S)-(benzenesulfonylamino)propionic acid

To a solution of NaOH (14.7 g, 0.367 mol) in 60 mL of water, cooled to 0 °C, was added Br₂ (3.3 mL, 0.064 mol) and the resulting solution was stirred at that temperature for 5 min. Next, a solution prepared with the compound obtained in step a) (13.5 g, 0.049 mol), NaOH (3.6 g) and 45 mL of water was added, and the reaction mixture was stirred for 20 min at 0 °C and for 30 min at 90 °C. The resulting solution was allowed to cool, was acidified to pH=7 with concentrated HCl and the white solid formed was collected by filtration, to afford 4.5 g of the desired compound.

!H NMR (300MHz, D₂0) δ (TMS): 7.82 (d, J=8.4Hz, 2H), 7.56 (m, 3H), 4.68 (s), 3.79 (m, 1H), 3.28 (dd, J=13.1Hz, J=4.6Hz, 1H), 3.03 (dd, J=13.1Hz, J=8.8Hz, 1H). c) Title compound

To a solution of the compound obtained in step b) (3.5 g, 0.014 mol) in

MeOH (45 mL), cooled to -20 °C, was added thionyl chloride (1.1 mL) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was evaporated to dryness to yield 4.5 g of the title compound.

!H NMR (300MHz, CDC1₃) δ (TMS): 8.24 (s, 2H), 7.96 (d, J=8.4Hz, 2H), 7.72 (d,

J=8.9Hz, IH), 7.51 (m, 3H), 4.57 (m, IH), 3.69 (m, 2H), 3.37 (s, 3H).

Reference example 2 Methyl 3-amino-2(S)-(benzyloxycarbonylamino)propionate, hydrochloride To a solution of 3-amino-2(S)-(benzyloxycarbonylamino)propionic acid

(16.7 g, 0.014 mol) in MeOH (300 mL), cooled to -10 °C, was added thionyl chloride (5.1 mL) and the temperature was then allowed to rise to 0 °C and stirring was maintained at this temperature for 3 h. The resulting solution was evaporated to dryness to yield the title compound. IH NMR (300Mhz, DMSO-d₆) δ (TMS): 8.16 (s, 2H), 7.88 (d, J=8.9Hz, IH), 7.33

(m, 5H), 5.05 (s, 2H), 4.42 (m, IH), 3.66 (s, 3H), 3.20 (m, IH), 3.05 (m, IH).

Reference example 3 Methyl 3-amino-2(S)-(4-methoxybenzenesulfonylamino)propionate, hydrochloride a) Methyl 2(S)-amino-3-(£er£-butoxycarbonylamino)propionate

To a solution of the compound obtained in reference example 2 (19.3 g, 66 mmol) and BOC2O (14.5 g, 66 mmol) in THF (250 mL), cooled to 0 °C, was added dropwise triethylamine (10.2 mL) and the reaction mixture was stirred at room temperature for 18 h. Next, the solvent was removed, EtOAc was added, and the resulting crude product was washed twice with 1% citric acid solution and then with 1% NaHCθ3 solution. The organic phase was dried and concentrated to yield 21.6 g of a crude product. This was purified by chromatography on silica gel (hexane:EtOAc, 3:2) to afford 16.6 g of methyl 2(S)- (benzyloxycarbonylamino)-3-(ter£-butoxycarbonylamino)propionate. This was dissolved in MeOH (200 mL) and was hydrogenated over 10% Pd/C (0.68 g) at atmospheric pressure. The catalyst was filtered off and the solvent was removed to afford 8.9 g (62%) of the desired compound. IH NMR (300MHz, CDC1₃) δ (TMS): 5.03 (m, IH), 3.73 (s, 3H), 3.57 (m, IH), 3.46

(m, IH), 3.23 (m, IH), 1.44 (s, 9H). b) Title compound

To a solution of the compound obtained in step a) (2 g, 9 mmol) and triethylamine (2.55 mL) in CHCI3 (40 mL), cooled to 0 °C, was added in portions 4-methoxybenzenesulfonyl chloride (2 g, 10 mmol) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was washed with water, dried and concentrated, to afford 5 g of a crude product. This was purified by chromatography on silica gel (hexane:EtOAc, 1:1) to yield 3 g of methyl 3-(ter£-butoxycarbonylamino)-2(S)-(4-methoxybenzenesulfonylamino)- propionate. This was deprotected by treatment with HClg/dioxane 2M (30 mL) at room temperature for 2 h, which upon removal of the solvent yielded the title compound.

IH NMR (300MHz, CDCI3) δ (TMS): 8.25 (s, 2H), 7.87 (d, J=8.4Hz, 2H), 7.57 (d, J=8.9Hz, IH), 6.91 (d, J=8.4Hz, 2H), 4.49 (m, IH), 3.80 (s, 3H), 3.69 (m, 2H), 3.44 (s, 3H).

Reference example 4 Methyl 3-amino-2(S)-(2-thienylcarbonylamino)propionate, hydrochloride

Following a similar procedure to that described in reference example la, but using (2-thienyl)carbonyl chloride instead of benzenesulfonyl chloride, and carrying out the degradation of the resulting amide by treatment with iodosobenzene diacetate (J. Org. Chem. 1997, 62, 6918-20) and the esterification as described in reference example lc, the title compound was obtained.

!H NMR (300MHz, CDCl₃+DMSO-d₆) δ (TMS): 8.75 (d, J=7.5Hz, IH), 8.43 (s, 2H), 7.92 (m, IH), 7.48 (m, IH), 6.88 (m, IH), 4.83 (m, IH), 3.58 (s, 3H), 3.33 (m, 2H).

Reference example 5 Methyl 3-amino-2(S)-(phenylacetylamino)propionate, hydrochloride

Following a similar procedure to that described in reference example 3, but using 2-phenylacetyl chloride instead of 4-methoxybenzenesulfonyl chloride, the title compound was obtained. ^lH NMR (300MHz, CDCI3) δ (TMS): 7.18 (m, 5H), 4.67 (m, IH), 4.14 (s, 2H), 3.67 (s, 3H), 3.36 (m, IH), 3.25 (m, IH). Reference example 6

Methyl 3-amino-2(S)-(n-butoxycarbonylamino)propionate, hydrochloride

Following a similar procedure to that described in reference example 4, but using n-butoxycarbonyl chloride instead of (2-thienyl)carbonyl chloride, the title compound was obtained.

IH NMR (300MHz, DMSO-d₆+TFA) δ (TMS): 8.01 (s, 2H), 7.60 (d, J=7.5Hz, IH),

4.37 (m, IH), 3.94 (m, 2H), 3.63 (s, 3H), 3.17 (m, IH), 3.04 (m, IH), 1.52 (m, 2H), 1.27 (m, 2H), 0.83 (t, J=7.9Hz, 3H).

Reference example 7 Methyl 3-amino-2(S)-(benzoylamino)propionate, hydrochloride

Following a similar procedure to that described in reference example 3, but using benzoyl chloride instead of 4-methoxybenzenesulfonyl chloride, the title compound was obtained.

IH NMR (300MHz, CDC1 ) δ (TMS): 8.55 (d, J=7.2Hz, IH), 8.35 (s, 2H), 7.90 (d, J=8.4Hz, 2H), 7.26 (m, 3H), 5.06 (m, IH), 3.58 (s, 3H), 3.57 (m, 2H).

Reference example 8 Methyl 3-amino-2(S)-[2-(2-thienyl)acetylamino]propionate, hydrochloride

Following a similar procedure to that described in reference example 3, but using 2-(2-thienyl)acetyl chloride instead of 4-methoxybenzenesulfonyl chloride, the title compound was obtained.

IH NMR (300MHz, CDCI3) δ (TMS): 7.23 (m, IH), 6.98 (m, 2H), 6.81 (m, IH), 4.87

(m, IH), 4.56 (m, IH), 3.79 (s, 2H), 3.72 (s, 3H), 3.51 (m, 2H).

Reference example 9 Methyl 3-amino-2(S)-(2-methoxyacetylamino)propionate_/ hydrochloride Following a similar procedure to that described in reference example 3, but using 2-methoxyacetyl chloride instead of 4-methoxybenzenesulfonyl chloride, the title compound was obtained. ^lH NMR (300MHz, CDCI3) δ (TMS): 8.18 (s, 2H), 8.03 (d, J=7.4Hz, IH), 5.03 (m, IH), 4.12 (d, J=15.3Hz, IH), 3.98 (d, J=15.3Hz, IH), 3.78 (s, 3H), 3.63 (m, IH), 3.53 (m, IH), 3.43 (s, 3H).

Reference example 10 Methyl 3-amino-2(S)-[3-(4-fluorophenyl)ureido]propionate, hydrochloride Following a similar procedure to that described in reference example 3, but using 4-fluorophenylisocyanate instead of 4-methoxybenzenesulfonyl chloride, the title compound was obtained.

IH NMR (300MHz, CDC1₃) δ (TMS): 7.32 (m, 2H), 7.11 (t, J=8.3Hz, IH), 6.91 (t, J=8.3Hz, IH), 4.58 (m, IH), 4.02 (s, 3H), 3.31 (m, 2H).

Example 1

3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid a) N-tert-Butyl-[4-(4-pyridyl)piperazin-l-yl]carbothioamide To a solution of 4-(4-pyridyl)piperazine (41 g, 0.25 mol) in CHCI3 (350 mL), cooled with an ice bath, was added dropwise tert-butyl isothiocyanate (32 mL, 0.25 mol) and the mixture was stirred at room temperature for 18 h and at reflux for 2 h. To the resulting solution was added pH=7 phosphate buffer solution, and the organic layer was separated and evaporated to dryness, to yield 64 g (92%) of the desired compound.

!H NMR (300MHz, CDCI3) δ (TMS): 8.28 (d, J=6.3Hz, 2H), 6.57(d, J=6.3Hz, 2H),

5.34 (s, IH), 4.00 (m, 4H), 3.53 (m, 4H), 1.58 (s, 9H). b) [4-(4-Pyridyl)piperazin-l-yl]carbothioamide

A solution of the compound obtained in step a) (40.6 g, 0.145 mol) in 48% HBr in AcOH (280 mL) was stirred at room temperature for 18 h and at 40 °C for 2 h. The resulting solution was allowed to cool, the solvents were removed and the resulting solid residue was resuspended in a mixture of EtOAc (250 mL) and IN NaOH (250 mL). The solid was collected by filtration and dried to yield 30.1 g (96%) of the desired compound. IH NMR (300MHz, DMSO-d₆) δ (TMS): 8.17 (d, J=6.3Hz, 2H), 7.51 (s, 2H), 6.86 (d,

J=6.3Hz, 2H), 3.80 (m, 4H), 3.47 (m, 4H). c) Ethyl 4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-carboxylate

A suspension of ethyl 2-chloro-2-isobutyrylacetate (26 g, 0.135 mol, prepared from ethyl isobutyrylacetate and sulfuryl chloride) and the compound obtained in step b) (30 g, 0.135 mol) in EtOH (300 mL) was refluxed for 18 h. The resulting hot solution was filtered, yielding 7.8 g of unreacted starting product, and the filtrate was concentrated to half the initial volume and was allowed to cool, yielding 16.3 g of the desired compound. A second crystallization from the mother liquors yielded an additional 6.4 g of the title compound (47%). lH NMR (300MHz, CDC1₃) δ (TMS): 8.20 (d, J=6.3Hz, 2H), 7.04 (d, J=6.3Hz, 2H), 4.26 (q, J=7.1Hz, 2H), 3.86 (m, 9H), 1.32 (t, J=7.1Hz, 3H), 1.21 (d, J=6.9Hz, 6H). d) 4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-carboxylic acid

To a solution of the product obtained in example c) (27.5 g, 0.076 mol) in EtOH (160 mL) was added a solution of KOH (16.7 g) in H₂0 (160 mL) and the reaction mixture was stirred at 80 °C overnight. Ethanol was removed and the resulting crude product, cooled in an ice bath, was brought to neutral pH with 5N HCl. The resulting precipitate was collected by filtration and dried to afford the desired compound (21.4 g, 85%). ^lH NMR (300MHz, DMSO-d₆) δ (TMS): 8.17 (d, J=6.3Hz, 2H), 6.84 (d, J=6.3Hz,

2H), 3.83 (m, IH), 3.53 (m, 10H), 1.13 (d, J=6.9Hz, 6H). e) tert-Butyl 3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionate

To a solution of the product obtained in step d) (0.67 g, 2.1 mmol) and 1- hydroxybenzotriazole (0.3 g) in anhydrous DMF (15 mL) was added dicyclohexylcarbodiimide (0.45 g) and the reaction mixture was stirred for 1 h at room temperature. The resulting solution was cooled in an ice bath and NEt₃

(0.3 mL) and β-alanine tert-butyl ester hydrochloride (0.38 g, 2.1 mmol) were added. The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The precipitate formed was filtered off and DMF was removed. The resulting crude product was taken up in CHCI₃ and 0.2N aHCθ₃ was added. The aqueous phase was extracted 3x with CHCI₃, and the combined organic extracts were dried and concentrated to afford 1.2 g of a crude product. This was purified by chromatography on silica gel (CHC MeOH, 10%), yielding 0.098 g of the desired compound. f) Title compound A solution of the compound obtained in step e) (0.098 g, 0.2 mmol) in

CH₂CI2 (1.5 mL), cooled in an ice bath, was treated with trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 18 h. Solvents were removed in vacuo, MeOH was added and the resulting solution was evaporated to dryness. Some mL of ether were added and the mixture was allowed to stand in the freezer overnight. The solid formed was collected by filtration, washed with ether and dried to afford the title compound as the trifluoroacetate salt, as a yellow solid (140 mg).

!H NMR (300MHz, CD3OD) δ (TMS): 8.18 (d, J=7.7Hz, 2H), 7.21 (d, J= 7.7Hz, 2H),

4.84 (s, 4H), 3.91 (m, 4H), 3.76 (m, 4H), 3.66 (quint, J= 6.8Hz, IH), 3.54 (t, J= 6.8Hz, 2H), 2.58 (t, J= 6.8Hz, 2H), 1.21 (d, J= 6.8Hz, 6H). Mp: 217-218°C (Cι₉H₂₅N₅θ3S.1.5 CF3COOH). Example 2

3-[N-[[4-Methyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following a similar procedure to that described in example 1, but using methyl 2-chloroacetoacetate instead of ethyl 2-chloro-2-isobutyrylacetate and using β-alanine ethyl ester instead of its tert-butyl ester, and finally hydrolyzing the resulting ethyl ester with IN NaOH in ethanol, the title compound was obtained.

IH NMR (300MHz, CD3OD) δ (TMS): 8.19 (d, J=7.7Hz, 2H), 7.21 (d, J=7.7Hz, 2H), 4.82 (s, 4H), 3.92 (m, 4H), 3.75 (m, 4H), 3.55 (t, J=6.7Hz, 2H), 2.61 (t, J=6.7Hz, 2H), 2.46 (s, 3H). Mp: 272-280 ⁰C(C₁₇H₂ιN5θ₃S.H₂0).

Example 3 3-[N-[[4-tert-Butyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using methyl 2- chloro-4,4-dimethyl-3-oxopentanoate instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained.

Example 4

3-[N-[[4-Cyclopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-3-cyclopropyl-3-oxopropionate instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained. Example 5

3-[N-[[4-(2,2-Dimethylpropyl)-2-[4-(4-pyridyl)piρerazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid

Following the procedure described in example 1, but using ethyl 2- chloro-2-(3,3-dimethylbutyryl)acetate (prepared from 4,4-dimethyl-2-pentanone by treatment with diethyl carbonate in NaH /toluene and subsequent reaction of the resulting product with sulfuryl chloride) instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained.

Example 6 3-[N-[[2-[4-(4-Pyridyl)piperazin-l-yl]-4-trifluoromethylthiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-4,4,4-trifluoro-3-oxobutanoate instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained. Example 7

3-[N-[[4-(3-Furyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-3-(3-furyl)-3-oxopropionate instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.

Example 8 3-[N-[[4-Propyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-2-butyrylacetate instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.

Example 9

3-[N-[[4-Phenyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- benzoyl-2-chloroacetate instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.

Example 10 3-[N-[[4-Benzyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid

Following the procedure described in example 1, but using ethyl 2- chloro-2-(phenylacetyl)acetate (prepared from phenylacetic acid chloride by reaction with monoethyl malonate in BuLi/THF and subsequent reaction of the resulting product with sulfuryl chloride) instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained.

Example 11 3-[N-[[4-(4-Methoxybenzyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid

Following the procedure described in example 1, but using ethyl 2- chloro-4-(4-methoxyphenyl)-3-oxobutanoate (prepared from 4- methoxyphenylacetic acid chloride by reaction with monoethyl malonate in BuLi/THF and subsequent reaction of the resulting product with sulfuryl chloride) instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.

Example 12

3-[N-[[4-(l-Phenylcyclopropyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-3-(l-phenylcyclopropyl)-3-oxopropionate (prepared from 1-phenyl-l- cyclopropanecarboxylic acid chloride by reaction with monoethyl malonate in

BuLi/THF and subsequent reaction of the resulting product with sulfuryl chloride) instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.

Example 13 3-[N-[[4-(2-Phenylethyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-5-phenyl-3-oxopentanoate instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.

Example 14 2-[N-[2-[2-[4-(4-Pyridyl)piperazin-l-yl]thiazol-5-yl]acetyl]amino]acetic acid a) Ethyl 2-[2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]acetate

A mixture of 4-(4-pyridyl)piperazine (1.31 g, 8 mmol) and ethyl 2-(2- bromothiazol-5-yl)acetate (2 g, 8 mmol) in pyridine (20 mL) was heated under reflux overnight. Then, pyridine was removed and the resulting residue was partitioned between 0.5N NaOH and CHCI3, and was extracted three times with CHCI3. The combined organic extracts were dried and concentrated to afford 1.97 g of a crude product that was purified by chromatography on silica gel (CH2CI2: MeOH, 10%) to give the desired product. b) Title compound Following the procedure described in example 1 (steps d, e and f) but starting from the compound obtained in step a) above and using glycine tert- butyl ester instead of β-alanine, the title compound was obtained. IH NMR (300MHz, CD3OD) δ (TMS): 8.17 (d, J=7.7Hz, 2H), 7.21 (d, J=7.7Hz, 2H), 6.66 (s,lH), 4.74 (s, 4H), 3.97 (s, 2H), 3.94 (m, 4H), 3.75 (m, 4H), 3.57 (s, 2H). Mp: 104-106°C (C16H-19N5O3S.I.75CF3COOH).

Example 15 3-[N-[[4-Isopropyl-2-[l-(4-pyridyl)piperidin-4-yl]thiazol-5- yl]carbonyl]amino]propionic acid a) Ethyl 4-isopropyl-2-(4-piperidinyl)thiazol-5-carboxylate Following a similar procedure to that described in example lc, but using l-(tert-butoxycarbonyl)piperidin-4-carbothioamide (prepared from isonipecotamide by treatment with Lawesson's reagent and subsequent protection with BOC₂0) instead of [4-(4-pyridylpiperazin-l-yl]carbothioamide, the desired compound was obtained. b) Ethyl 4-isopropyl-2-[l-(4-pyridyl)piperidin-4-yl]thiazol-5-carboxylate

To a solution of 4-chloropyridine hydrochloride (1.06 g, 7.1 mmol) in xylene (20 mL) was added triethylamine (1.85 mL) and the product obtained in step a) above (2 g, 7.1 mmol), and the mixture was heated at reflux for 24 h. The solvent was removed, IN NaOH was added and it was extracted with CHCI3 (3x). The combined organic extracts were dried and concentrated to afford 2.6 g of a crude product. This was purified by chromatography on silica gel (CHCI3- MeOH, 15%) to give 1.16 g of the desired compound. c) Title compound

Following a similar procedure to that described in example 1 (steps d, e and f), but starting from the compound obtained in step b) above, the title compound was obtained. IH NMR (300MHz, CD₃OD) δ (TMS): 8.04 (d, J=7.8Hz, 2H), 7.13 (d, J= 7.8Hz, 2H), 4.77 (s, 4H), 4.27 (broad d, 2H), 3.56 (m, IH), 3.50 (t, J= 6.7Hz, 2H), 3.39 (m, 3H), 2.53 (t, J= 6.8Hz, 2H), 2.22 (broad d, 2H), 1.83 (broad q, 2H), 1.18 (d, J= 6.8Hz, 6H). Mp: 131-135°C (C20H26N4O3S.CF3COOH).

Example 16 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5- yl]carbonyl]amino]propionic acid a) Ethyl 2-[l'-(tert-butoxycarbonyl)-l,4'-bipiperidin-4-yl]-4-isopropylthiazol-5- carboxylate

To a solution of ethyl 4-isopropyl-2-(4-piperidinyl)thiazol-5-carboxylate (2 g, 7.1 mmol) (prepared as described in example 15a) and l-(tert- butoxycarbonyl)piperidin-4-one (1.41 g, 7.1 mmol) in anhydrous THF (70 mL) was added acetic acid (4 mL). Next, sodium triacetoxyborohydride (1.87 g, 8.8 mmol) was added slowly and the reaction mixture was stirred at room temperature overnight. The resulting solution was evaporated to dryness and the residue was partitioned between 2N Na2Cθ3 and EtOAc. The aqueous phase was extracted again with EtOAc, and the combined organic extracts were dried and concentrated to give 2.9 g of a crude product. This was purified by chromatography on silica gel (Hex-EtOAc, 50%) to afford 1.92 g of the desired product. b) Title compound

Following a similar procedure to that described in example 1 (steps d and e), but starting from the compound obtained in step a) above, and carrying out the final hydrolysis with 6N HCl, the title compound was obtained.

!H NMR (300MHz, CD3OD) δ (TMS): 4.80 (s, H₂0), 4.10 (q, J= 7.1Hz, 2H), 3.8-3.5 (complex signal, 10H), 3.11 (broad t, 2H), 2.60 (t, J= 6.7Hz, 2H), 2.39 (m, 4H), 2.2 (m, 2H), 1.26 (d, J= 6.8Hz, 6H). Mp: 213-214°C (C20H32N4O3S.2HCl.2KbO).

Example 17 3-[N-[[4-Isopropyl-2-[l-[(3-piperidinyl)methyl]piperidin-4-yl]thiazol-5- yl]carbonyl]amino]propionic acid a) l-(ter£-Butoxycarbonyl)-3-(methylsulfonyloxymethyl)piperidine

To a solution of l-(tert-butoxycarbonyl)-3-(hydroxymethyl)piperidine (1 g, 4.6 mmol) (prepared by treatment of 3-hydroxymethylpiperidine with BOC₂0) in CHC1₃ (12 mL) was added NEt₃ (0.65 mL) and methanesulfonyl chloride (0.36 mL) and the reaction mixture was stirred at room temperature overnight. Then, H₂0 was added and it was extracted with CHCI3 (3x). The combined organic extracts were dried and concentrated to afford 1.35 g of the desired product. b) Ethyl 2-[l-[[l-(tert-butoxycarbonyl)-3-piperidinyl]methyl]piperidin-4-yl]-4- isopropylthiazol-5-carboxylate

To a solution of the product obtained in step a) (1.35 g, 4.6 mmol) in CHCI3 (25 mL) and NEt (0.64 mL) was added ethyl 4-isopropyl-2-(4- piperidinyl)thiazol-5-carboxylate (1.30 g, 4.6 mmol, obtained in example 15a) and Nal (0.68 g, 4.6 mmol) and the mixture was refluxed overnight. H₂0 and IN NaOH were added and it was extracted with CHCI3 (3x). The combined organic extracts were dried and concentrated to give 1.8 g of a crude product. This was purified by chromatography on silica gel (CH₂Cl2-MeOH, 5%), to give 1.05 g of the desired product. c) Title compound

The title compound was obtained by hydrolysis of the compound obtained in step b) with IN NaOH in EtOH, subsequent reaction of the resulting carboxylic acid with β-alanine tert-butyl ester as described in example le and finally deprotection of the resulting compound with 6N HCl at room temperature. H NMR (300MHz, CD3OD) δ (TMS): 4.55 (s, 3H), 3.65 (m, 6H), 3.39 (m, 2H), 3.15 (m, 4H), 2.95 (m, IH), 2.86 (m, IH), 2.62 (q, J= 6.7Hz, 2H), 2.40 (m, 5H), 2.00 (m, 3H), 1.46 (m, IH), 1.26 (d, J=6.8Hz, 6H). Mp: 148-157°C (C21H34N4O3S.2HCl.2H2O)

Example 18 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2- methylpropionic acid

Following a similar procedure to that described in example le, but using methyl 3-amino-2-methylpropionate instead of β-alanine tert-butyl ester, and hydrolyzing the resulting methyl ester with IN NaOH in EtOH at room temperature overnight, the title compound was obtained. Mp: 220-221°C (C20H27N5O3S.O.5H2O).

Example 19 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-3- methylbutanoic acid

Following a similar procedure to that described in example le, but using methyl 3-amino-3-methylbutanoate (obtained by treatment of 2,2- dimethylsuccinic anhydride with MeOH at reflux followed by treatment with diphenylphosphorylazide in tert-butanol and hydrolysis with HClg/dioxane) instead of β-alanine tert-butyl ester, and finally hydrolyzing the resulting methyl ester with 6N HCl at room temperature overnight, the title compound was obtained.

!H NMR (300MHz, CD3OD) δ (TMS): 8.16 (d, J=6.8Hz, 2H), 7.08 (d, J=6.8Hz, 2H),

4.85 ( , 2H), 3.70 (m, 9H), 2.38 (s, 2H), 1.49 (s, 6H), 1.20 (d, J=6.7Hz, 6H). Mp: 243- 245°C (C2₁H29N5O3S.H2O) .

Example 20 3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]propionic acid a) [l'-(terf-Butoxycarbonyl)-4_/4'-bipiperidin-l-yl]carbothioamide A mixture of l'-(tert-butoxycarbonyl)-4,4'-bipiperidine (11 g, 42 mmol) and ethoxycarbonyl isothiocyanate (5 mL, 42 mmol) was heated at reflux for 4 h. The mixture was allowed to cool and the solvent was removed. The resulting residue was taken up in ethanol (70 mL) and IN NaOH (70 mL) and was refluxed for 24 h. Upon cooling, a solid precipitated, which was collected by filtration to afford 9.2 g of the desired compound. b) 2-[l'-(tert-Butoxycarbonyl)-4,4'-bipiperidin-l-yl]-4-isopropylthiazol-5- carboxylic acid Following a similar procedure to that described in example lc, but using the compound obtained in step a) instead of [4-(4-pyridyl)piperazin-l- yl]carbothioamide, then treating the resulting compound with BOC2O and IN NaOH in THF-H2O and finally hydrolyzing the ethyl ester as described in example Id, the desired product was obtained.

IH NMR (300MHz, DMSO-d₆) δ (TMS): 3.91 (m, 3H), 3.40 (m, 3H), 2.91 (m, 2H),

2.61 (m, 2H), 1.72 (m, 2H), 1.58 (m, 2H), 1.37 (s, 9H), 1.14 (m, 6H), 1.08 (d, J=6.8Hz, 6H). c) tert-Butyl 3-[N-[[2-[l'-(tert-butoxycarbonyl)-4,4'-bipiperidin-l-yl]-4- isopropylthiazol-5-yl]carbonyl]amino]propionate

Following a similar procedure to that described in example le, but starting from the compound obtained in step b), the desired product was obtained. d) Title compound Following a similar procedure to that described in example If, but starting from the compound obtained in step c), the title compound was obtained.

IH NMR (300MHz, CD3OD) δ (TMS): 4.84 (s, 3H), 4.07 (d, J=12.6Hz, 2H), 3.68 (m,

IH), 3.52 (m, 2H), 3.39 (d, J=12.3Hz, 2H), 3.00 (m, 4H), 2.57 (m, 2H), 1.99 (d, J=10.8Hz, 2H), 1.84 (d, J=12.3Hz, 2H), 1.43 (m, 6H), 1.19 (d, J=6.7Hz, 6H). Mp: 127- 129°C (C20H32N₄θ3S.2CF3COOH.2H₂O).

Example 21 3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]- 2- methylpropionic acid Following a similar procedure to that described in example 20, but using methyl 3-amino-2-methylpropionate instead of β-alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl at room temperature overnight, the title compound was obtained.

^!H NMR (300MHz, CD3OD) δ (TMS): 4.86 (s, 3H), 4.07 (d, J=12.6Hz, 2H), 3.64 (m, IH), 3.43 (m, 2H), 3.00 (m, 4H), 2.65 (m, IH), 2.02 (d, J=10.8Hz, 2H), 1.83 (d, J=12.3Hz, 4H), 1.43 (m, 6H), 1.18 (d, J=6.7Hz, 6H), 1.15 (d, J=6.7Hz, 3H). Mp: 153- 158°C (C₂₁H34N₄0₃S). Example 22

3-[N-[[4-Isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid a) Ethyl 4-isopropyl-2-piperazinylthiazol-5-carboxylate Following a similar procedure to that described in example lc, but using

(4-tert-butoxycarbonylpiperazin-l-yl)carbothioamide instead of [4-(4- pyridyl)piperazin-l-yl]carbothioamide, the desired product was obtained. b) Ethyl 2-[4-[l-(rert-butoxycarbonyl)piperidin-4-yl]piperazin-l-yl]-4- isopropylthiazol-5-carboxylate Following a similar procedure to that described in example 16a, but starting from the compound obtained in step a), the desired product was obtained. c) 2-[4-(l-terf-Butoxycarbonylpiperidin-4-yl)piperazin-l-yl]-4-isopropylthiazol-5- carboxylic acid The title compound was obtained from the compound obtained in step b) by hydrolysis of the ethyl ester as described in example Id.

^!H NMR (300MHz, CD₃OD) δ (TMS): 4.86 (s, IH), 4.15 (d, J=12.6Hz, 2H), 3.86 (m,

IH), 3.64 (m, 4H), 2.87 (m, 4H), 2.83 (m, 2H), 1.95 (d, J=12.6Hz, 2H), 1.47 (m, 3H), 1.45 (s, 9H), 1.18 (d, J=6.8Hz, 6H). d) Title compound

The compound obtained in step c) was allowed to react with β-alanine tert-butyl ester as described in example le, and was finally hydrolyzed with trifluoroacetic acid, as described in example If, to give the title compound.

IH NMR (300MHz, CD3OD) δ (TMS): 4.88 (s, 3H), 3.86 (m, 4H), 3.53 (m, 10H), 3.12 (broad t, J=12.6Hz, 2H), 2.59 (t, J=6.8Hz, 2H), 2.45 (broad d, J=12.6Hz, 2H), 2.03 (m, 2H), 1.22 (d, J=6.9Hz, 6H). Mp: 220-221°C (C19H3iN5O3S.2CF3COOH.H2O).

Example 23 Methyl 2(S)-(benzenesulf onylamino)-3-[N-[[4-isopropyl-2-[4-(4- pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]propionate Following a similar procedure to that described in example le, but using the compound obtained in reference example 1 instead of β-alanine tert-butyl ester, the title compound was obtained.

IH NMR (300MHz, CDC1₃) δ (TMS): 8.32 (d, J=7.5Hz, 2H), 7.85 (d, J=7.5Hz, 2H), 7.55 (m, 3H), 6.70 (d, J=7.5Hz, 2H), 5.94 (t, J=6.0Hz, IH), 4.04 (m, IH), 3.66 (m, 7H), 3.59 (s, 3H), 3.51 (m, 4H), 1.24 (d, J=7.0Hz, 6H). Mp: 92-97°C (C26H32N6O5S2).

Example 24

2(S)-(Benzenesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid The compound obtained in example 23 was hydrolyzed by treatment with 5N HCl in EtOH at room temperature overnight and then at 40 °C for 2 h.

The resulting crude product was purified by chromatography on silica gel

(CHCI3 : MeOH : NH₃ 10:2:1) to afford the title compound.

!H NMR (300MHz, CDCI3+CD3OD) δ (TMS): 8.10 (d, J=7.5Hz, 2H), 7.85 (d, J=7.5Hz, 2H), 7.49 (m, 3H), 7.07 (d, J=7.5Hz, 2H), 4.60 (s, 3H), 3.82 (m, 4H), 3.75 (m, 4H), 3.65 (m, 4H), 1.23 (m, 6H). Mp: 256-257°C (C25H30N6O5S2).

Example 25 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(4-methoxybenzenesulfonylamino)propionic acid Following a similar procedure to that described in example le, but using the compound obtained in reference example 3 instead of β-alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl, the title compound was obtained.

Η NMR (300MHz, DMSO-d₆) δ (TMS): 8.19 (d, J=6.0Hz, 2H), 7.67 (d, J=7.5Hz, 2H), 7.45 (m, 2H), 6.99 (d, J=7.5Hz, 2H), 6.90 (d, J=6.0Hz, 2H), 3.76 (s, 3H), 3.55 (m, 9H), 3.31 ( , 4H), 1.11 (dd, J=6.7Hz, J=2.2Hz, 6H). Mp: 257-258°C (C₂₆H32N₆0₆S2).

Example 26 2(S)-(Benzyloxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid a) Methyl 2(S)-(benzyloxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(4- pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]propionate Following a similar procedure to that described in example le, but using the compound obtained in reference example 2 instead of β-alanine tert-butyl ester, the desired compound was obtained. b) Title compound The methyl ester obtained in step a) was hydrolyzed by treatment with

6N HCl at room temperature overnight and then at 50 °C for 1 h, to give the title compound.

IH NMR (300MHz, CD₃OD) δ (TMS): 8.15 (d, J=6.0Hz, 2H), 7.28 (m, 5H), 6.95 (d,

J=6.0Hz, 2H ), 5.10 (t, J=12.6 Hz, 2H), 4.86 (s, 3H), 4.19 (t, J=7.0Hz, IH), 3.66 (m, 9H), 1.20 (d, J=6.7Hz, 6H). Mp: 203-204°C (C27H32N6O5S.O.5H2O).

Example 27 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(2-thienylcarbonylamino)propionic acid Following a similar procedure to that described in example le, but using the compound obtained in reference example 4 instead of β-alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 5N HCl in EtOH, the title compound was obtained.

*H NMR (300MHz, DMSO-d₆) δ (TMS): 8.61 (d, J=7.1Hz, IH), 8.19 (d, J=6.4Hz,

2H), 7.77 (m, 3H), 7.15 (t, J=4.3Hz, IH), 6.88 (d, J=6.4Hz, 2H), 4.47 (q, J=13.1 Hz, J=7.8Hz, IH), 3.54 (m, 12H), 1.09 (t, J=8.3Hz, 6H). Mp: 263-266°C (C₂₄H₂₈N₆θ4S₂.2H2θ).

Example 28 2(S)-(Ethanesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid a) Methyl 2(S)-amino-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionate

To a solution of the compound obtained in example Id (5.6 g, 16.8 mmol) in CH2CI2 (150 mL) was added N-hydroxysuccinimide (2.1 g, 18 mmol). The mixture was cooled in an ice bath and dicyclohexylcarbodiimide (3.73 g) was added. The reaction mixture was then stirred at room temperature overnight. The precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in boiling EtOAc (100 mL) and was then allowed to cool to room temperature and ^"was finally placed in the freezer for 1 h. The precipitated solid was collected by filtration and dried, to give 5.82 g of the activated acid.

This product was dissolved in CH2CI2 (50 mL) and was added dropwise to a mixture of methyl (S)-2,3-diaminopropionate dihydrochloride (3.5 g) and

NEt3 (6.2 mL) in CH2CI2 (150 mL), cooled in an ice bath. The reaction mixture was stirred at room temperature for 48 h and then at reflux for 2 h. It was then diluted with CH2CI2, 0.5N NaOH was added and it was extracted with CHCI3 at basic pH. The organic phase was dried and concentrated to yield 3.56 g of a crude product. This was purified by chromatography on silica gel (CHCI3 : MeOH : NH₃ 60:5:0.2), to give the desired product (1.4 g). b) Methyl 2(S)-(ethanesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(4- pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]propionate

To a solution of the compound obtained in step a) (0.7 g, 1.62 mmol) and NEt₃ (0.45 mL) in CHCI3 (20 mL) was added ethanesulfonyl chloride (0.23 mL) and the mixture was stirred at room temperature overnight. IN NaOH was added and it was extracted with CHCI3. The organic phase was dried and concentrated to a crude product that was purified by chromatography on silica gel (CHCI3 : MeOH : NH3 60:4:0.2), to yield the desired compound (130 mg). c) Title compound

The compound obtained in step b) was hydrolyzed by treatment with 5N HCl at room temperature overnight and then at 60 °C for 1 h, to give the title compound. ^lH NMR (300MHz, CDCI3+CD3OD) δ (TMS): 8.14 (d, J=7.2Hz, 2H), 6.97 (d, J=7.2Hz, 2H ), 4.27 (m, 3H), 3.86 (m, IH), 3.70 (m, 11H), 3.03 (q, J=14.7Hz, J=7.3Hz, 2H), 1.32 (t, J=7.3Hz, 3H), 1.18 (d, J=6.7Hz, 6H). Mp: 262-263°C (C21H30N6O5S2.2H2O.O.5NH4CI).

Example 29 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(phenylacetylamino)propionic acid a) 2(S)-Amino-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid

A solution of the compound obtained in example 26a (6.6 g, 11.6 mmol) in 48% HBr/AcOH (20 mL) was stirred at room temperature for 3 h. The resulting solution was evaporated to dryness and the residue was partitioned between IN NaOH and CHCI3, and the aqueous phase was again evaporated to dryness. The crude product thus obtained was purified by chromatography on silica gel (CHCI3 : MeOH : NH₃ 10:4:1), to give the desired product (1.3 g). b) Title compound

To a mixture of the compound obtained in step a) (0.6 g, 1.43 mmol) and

NaOH (0.085 g) in H₂0 (2 mL) and dioxane (2 mL), cooled to 0 °C, was added phenylacetic acid chloride (0.2 mL), dropwise. Next, IN NaOH was added until the pH was basic and the reaction mixture was stirred at 0 °C for 1 h and then at room temperature for an additional hour. The resulting solution was treated with 5N HCl until neutral pH and was then evaporated to dryness. The resulting residue was purified by chromatography on silica gel (CHCI3 : MeOH : NH3 10:4:1), to give the desired product (218 mg). IH NMR (300MHz, CDCI3+CD3OD) δ (TMS): 8.12 (d, J=6.0Hz, 2H), 7.18 (m, 5H),

6.87 (d, J=6.0Hz, 2H ), 4.35 (dd, J=7.8 Hz, J=4.8Hz, IH), 4.26 (s, 3H), 3.66 (m, 11H), 3.34 (s, 2H), 1.18 (d, J=6.7Hz, 6H). Mp: 139-141⁰C(C27H₃2N₆θ4S.2H2θ).

Example 30 2(S)-(n-Butoxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid

Following a similar procedure to that described in example le, but using the compound obtained in reference example 6 instead of β-alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl at room temperature overnight and then at 50 °C for 1 h, the title compound was obtained.

IH NMR (300MHz, CD3OD) δ (TMS): 8.23 (d, J=7.2Hz, 2H), 7.23 (d, J=7.2Hz, 2H),

4.87 (m, 3H), 4.42 (m, IH), 4.04 (m, 11H), 3.75 (m, 2H), 1.61 (m, 2H), 1.38 (m, 2H), 1.29 (d, J=6.7Hz, 6H), 0.97 (t, J=7.3Hz, 3H). Mp: 134-151°C

(C24H34N6O5S.HCl.2H2O). Example 31

2(S)-(Benzoylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following a similar procedure to that described in example le, but using the compound obtained in reference example 7 instead of β-alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl at room temperature overnight and then at 50 °C for 1 h, the title compound was obtained.

IH NMR (300MHz, CD₃OD) δ (TMS): 8.14 (d, J=6.3Hz, 2H), 7.85 (d, J=7.0Hz, 2H),

7.49 (m, 3H), 6.93 (d, J=6.3Hz, 2H), 4.85 (m, 3H), 4.60 (m, IH), 3.65 (m, 11H), 1.14 (dd, J=6.7Hz, J=14.7Hz, 6H). Mp: 247-248°C (C26H3oN₆0₄S.0.5H₂0).

Example 32 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-

2(S)-[2-(2-thienyl)acetylamino]propionic acid Following a similar procedure to that described in example le, but using the compound obtained in reference example 8 instead of β-alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl at room temperature overnight and then at 50 °C for 1 h, the title compound was obtained.

*H NMR (300MHz, CD3OD) δ (TMS): 8.15 (d, J=6.8Hz, 2H), 7.20 (m, IH) 6.95 (m, 3H ), 6.89 (m, IH), 4.79 (m, 3H), 4.39 (dd, J=7.5Hz, J=5.2Hz, IH), 3.77 (d, J=2.7Hz, 2H), 3.64 (m, 11H), 1.19 (dd, J=6.7Hz, J=14.7Hz, 6H). Mp: 152-158°C (C₂5H30N₆O₄S₂.2H₂O).

Example 33 2(S)-(Benzenesulfonylamino)-3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-

5-yl]carbonyl]amino]propionic acid a) 2-[l'-(tert-Butoxycarbonyl)-l,4'-bipiperidin-4-yl]-4-isopropylthiazol-5- carboxylic acid

The compound obtained in example 16a was hydrolyzed by treatment with IN NaOH in EtOH at room temperature overnight to give the desired product. ^l NMR (300MHz, CDCI3) δ (TMS): 4.27 (m, 2H), 4.09 ( , IH), 3.42 (m, 2H), 3.27 (m, IH), 3.12 (m, IH), 2.73 (m, 4H), 2.26 (m, 6H), 1.65 (m, 2H), 1.45 (s, 9H), 1.23 (d, J=6.8Hz, 6H). b) Methyl 2(S)-(benze esulfonylamino)-3-[N-[[2-[l'-(ter butoxycarbonyl)-l, ^,- bipiperidin-4-yl]-4-isopropylthiazol-5-yl]carbonyl]amino]propionate

Following a similar procedure to that described in example le, but starting from the compound obtained in step a) and using the compound obtained in reference example 1 instead of β-alanine tert-butyl ester, the desired product was obtained. c) Title compound

The compound obtained in step b) was hydrolyzed by treatment with 6N

HCl at room temperature overnight and the resulting crude product was purified by chromatography on silica gel (CHCI3 : MeOH : NH3 10:5:1), to give the desired compound as the hydrochloride.

IH NMR (300MHz, CD₃OD+D₂0) δ (TMS): 7.82 (d, J=7.0Hz, 2H), 7.55 (m, 3H),

4.73 (H20), 3.78 (m, IH), 3.66 (m, 2H), 3.56 (d, J=13.0Hz, 2H), 3.42 (m, 3H), 3.30 (m, 3H), 3.07 (t, J=13.0Hz, 2H), 2.93 (t, J=8Hz, 2H), 2.29 (d, J=13.0Hz, 4H), 2.01 (m, 4H), 1.26 (d, J=6.7Hz, 6H). Mp: 204-206°C (C26H37N5O5S2.HCl.H2O).

The free base was obtained as described for the hydrochloride salt but treating with 2N NaOH before column purification and dissolving the product eluting from the column in hot EtOAc and then allowing this to precipitate in the freezer. Mp: 235-241°C (C26H37N5O5S2.O.5H2O).

Example 34 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(4- methoxybenzenesulfonylamino)propionic acid Following a similar procedure to that described in example 33, but using the compound obtained in reference example 3 instead of the compound obtained in reference example 1, the title compound was obtained.

^!H NMR (300MHz, CD3OD) δ (TMS): 7.78 (d, J=7.0Hz, 2H), 7.01 (d, J=7.0Hz, 2H),

4.75 (s, 3H), 3.83 (s, 3H), 3.61 (m, 5H), 3.37 (d, J=13.0Hz, 2H), 3.07 (m, 2H), 2.86 (t, J=13.0Hz, 2H), 2.42 (t, J=8Hz, 2H), 2.17 (d, J=13.0Hz, 2H), 2.04 (d, J=13.0Hz, 2H), 1.85 (m, 4H), 1.70 (m, 2H), 1.26 (d, J=6.7Hz, 6H). Mp: 231-234°C (C₂7H39N5θ₆S2.0.5H₂O).

Example 35 3-[N-[[2-(l_/4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(2- thienylcarbonylamino)propionic acid

Following a similar procedure to that described in example 33, but using the compound obtained in reference example 4 instead of the compound obtained in reference example 1, the title compound was obtained.

IH NMR (300MHz, CD₃OD) 6 (TMS): 7.73 (m, IH), 7.63 (m, IH), 7.11 (m, IH),

4.87 (s, 3H), 4.60 (t, J=6.4Hz, IH), 3.77 (d, J=6.5Hz, 2H), 3.58 (m, IH), 3.43 (d, J=13.0Hz, 2H), 3.0 (m, 6H), 2.65 (m, IH), 2.40 (t, J=8Hz, 2H), 2.05 (d, J=12.5Hz, 4H), 2.01 (d, J=12.5Hz, 4H), 1.19 (dd, J= 12.2Hz, J=6.7Hz, 6H). Mp: 173-179°C (C25H35 ₅0₄S₂.H2θ).

Example 36 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-

(phenylacetylamino)propionic acid Following a similar procedure to that described in example 33, but using the compound obtained in reference example 5 instead of the compound obtained in reference example 1, the title compound was obtained.

*H NMR (300MHz, CD3OD) δ (TMS): 7.24 (m, 5H), 4.85 (s, 3H), 4.41 (m, IH), 3.67

(m, 5H), 3.56 (s, 2H), 3.42 (d, J=12.8Hz, 2H), 3.07 (d, J=12.8Hz, 2H), 2.97 (t, J=13.0Hz, 2H), 2.67 (m, IH), 2.42 (t, J=8.0Hz, 2H), 2.10 (t, J=12.5Hz, 4H), 1.80 (m, 4H), 1.23 (dd, J= 4.2Hz, J=6.7Hz, 6H). Mp:152-156°C (C₂₈H₃9N₅0₄S.H₂0).

Example 37 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(n- butoxycarbonylamino)propionic acid Following a similar procedure to that described in example 33, but using the compound obtained in reference example 6 instead of the compound obtained in reference example 1, the title compound was obtained.

!H NMR (300MHz, CD3OD) δ (TMS): 4.85 (s, 3H), 4.19 (m, IH), 4.02 (m, 2H), 3.64

( , 4H), 3.47 (d, J=12.8Hz, 2H), 3.17 (d, J=12.8Hz, 2H), 3.07 (m, IH), 3.01 (t, J=13.0Hz, 2H), 2.85 (m, IH), 2.57 (t, J=8.0Hz, 2H), 2.12 (m, 4H), 1.85 (t, J=12.5Hz, 4H), 1.58 (m, 2H),1.38 (m, 2H), 1.23 (d, J=6.7Hz, 6H), 0.90 (t, J=7.8Hz, 3H). Mp: 147-149°C (C25H41N5O5S.I.5H2O).

Example 38 2(S)-(Benzoylamino)-3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5- yl]carbonyl]amino]propionic acid

Following a similar procedure to that described in example 33, but using the compound obtained in reference example 7 instead of the compound obtained in reference example 1, the title compound was obtained.

IH NMR (300MHz, CD₃OD) 6 (TMS): 7.86 (d, J=6.9Hz, 2H), 7.50 (m, 3H), 4.87 (s,

3H), 4.63 (t, J=6.3 Hz, IH), 3.80 (d, J=6.3Hz, 2H), 3.61 (m, IH), 3.42 (d, J=12.8Hz, 2H), 2.97 (m, 6H), 2.62 (m, IH), 2.38 (t, J=8.0Hz, 2H), 2.05 (m, 4H), 1.76 (m, 4H), 1.23 (dd, J= 15.2Hz, J=6.7Hz, 6H). Mp: 172-180°C (C27H37N5O4S.O.5H2O). Example 39

3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-[2-

(2-thienyl)acetylamino]propionic acid Following a similar procedure to that described in example 33, but using the compound obtained in reference example 8 instead of the compound obtained in reference example 1, the title compound was obtained.

!H NMR (300MHz, CD3OD) δ (TMS): 7.21 (m, IH), 6.94 (m, IH), 6.89 (m, IH),

4.80 (s, 4H), 4.41 (t, J=6.3 Hz, IH), 3.78 (s, 2H), 3.65 (m, 4H), 3.41 (d, J=12.8Hz, 2H), 3.05 (d, J=12.8Hz, 2H), 2.95 (t, J= 12.2Hz, 2H), 2.66 (m, IH), 2.41 (t, J=8.0Hz, 2H), 2.08 (m, 4H), 1.78 (m, 4H), 1.23 (d, J=6.7Hz, 6H). Mp: 223-230°C (C26H37N5O4S2.H2O).

Example 40 2(S)-(Benzenesulfonylamino)-3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-

5-yl]carbonyl]amino]propionic acid Following a similar procedure to that described in example 20, but using the compound obtained in reference example 1 instead of β-alanine tert-butyl ester and in the last step hydrolyzing with 5N HCl instead of with trifluoroacetic acid, the title compound was obtained.

!H NMR (300MHz, CD3OD) δ (TMS): 7.85 (d, J=6.9Hz, 2H), 7.59 (m, 3H), 4.86 (s,

3H), 4.18 (m, 3H), 3.78 (m, 2H), 3.42 (m, 6H), 3.01 (t, J=11.7Hz, 2H), 2.02 (d, J=11.8Hz, 4H), 1.53 (m, 6H), 1.37 (d, J=6.7Hz, 6H). Mp: 167-174°C (C26H37N5O5S2.2H2O.2HCl).

Example 41 3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(4- methoxybenzenesulfonylamino)propionic acid

Following a similar procedure to that described in example 40, but using the compound obtained in reference example 3 instead of the compound obtained in reference example 1, the title compound was obtained.

^!H NMR (300MHz, CD₃OD) δ (TMS): 7.76 (d, J=8.5Hz, 2H),7.02 (d, J=8.5Hz, 2H),

4.86 (s, 3H), 4.14 (m, 3H), 3.85 (s, 3H), 3.74 (m, 2H), 3.40 (m, 6H), 2.97 (t, J=11.7Hz, 2H), 2.02 (d, J=l 1.8Hz, 4H), 1.9-1.0 (m, 6H), 1.34 (d, J=6.7Hz, 6H). Mp: 177-184°C (C27H39N5O6S2.HCl.2H2O). Example 42

3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(2- thienylcarbonylamino)propionic acid Following a similar procedure to that described in example 40, but using the compound obtained in reference example 4 instead of the compound obtained in reference example 1, the title compound was obtained.

IH NMR (300MHz, CD3OD) δ (TMS): 7.73 (m, IH), 7.64 (m, IH), 7.12 (m, IH),

4.86 (s, 3H), 4.58 (t, J=5.9Hz, IH), 4.06 (d, J=12.6Hz, 2H), 3.67 (m, 5H), 3.43 (d, J=11.7Hz, 2H), 2.96 (m, 3H), 1.97 (d, J=11.8Hz, 2H), 1.82 (d, J=11.8Hz, 2H), 1.34 (m, 6H), 1.34 (dd, J=13.1Hz, J=6.7Hz, 6H). Example 43

2(S)-(Benzoylamino)-3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5- yl]carbonyl]amino]propionic acid Following a similar procedure to that described in example 40, but using the compound obtained in reference example 7 instead of the compound obtained in reference example 1, the title compound was obtained. H NMR (300MHz, CD3OD) δ (TMS): 7.89 (d, J=6.9Hz, 2H),7.53 (m, 3H), 4.95 (s,

3H), 4.87 (m, IH), 4.14 (m, 2H), 3.84 (m, 2H), 3.42 (m, 5H), 2.95 (m, 3H), 1.97 (d, J=11.8Hz, 4H), 1.53 (m, 6H), 1.28 (d, J=6.7Hz, 6H). Mp: 172-173°C (C27H37N5O4S.2HCl.2H2O). Example 44

2(S)-(Benzenesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin- l-yl]thiazol-5-yl]carbonyl]amino]propionic acid Following a similar procedure to that described in example 22, but using the compound obtained in reference example 1 instead of β-alanine tert-butyl ester, the title compound was obtained.

IH NMR (300MHz, CD₃OD) δ (TMS): 7.86 (d, J=7.0Hz, 2H), 7.55 (m, 3H), 4.82 (s, 4H), 4.16 (m, IH), 3.83 (m, 4H), 3.45 (m, 4H), 3.40 (m, 6H), 3.09 (t, J=13.7Hz, 2H), 2.40 (d, J=13.7Hz, 2H), 2.01 (m, 2H), 1.25 (d, J=6.9Hz, 6H). Mp: 224-225°C (C25H₃6N₆θ5S2.2CF₃COOH).

Example 45 3-[N-[[4-Isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(2-thienylcarbonylamino)propionic acid

Following a similar procedure to that described in example 22, but using the compound obtained in reference example 4 instead of β-alanine tert-butyl ester and hydrolyzing in the last step with 5N HCl instead of with trifluoroacetic acid, the title compound was obtained. IH NMR (300MHz, CD3OD) δ (TMS): 7.71 (m, IH), 7.61 (m, IH), 7.10 (m, IH),

4.84 (s, 4H), 4.55 (t, J=6Hz, IH), 3.74 (m, 2H), 3.65 (m, IH), 3.48 (m, 7H), 2.99 (t, J=13.7 Hz, 2H), 2.66 (m, 4H), 2.03 (d, J=13.7Hz, 2H), 1.75 (m, 2H), 1.15 (dd, J=6.9Hz, 6H). Mp: 253-259°C (C24H34N6O4S2.4H2O).

Example 46 3-[N-[[4-Isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(4-methoxybenzenesulfonylamino)propionic acid Following a similar procedure to that described in example 22, but using the compound obtained in reference example 3 instead of β-alanine tert-butyl ester and hydrolyzing in the last step with 6N HCl instead of with trifluoroacetic acid, the title compound was obtained. ^lH NMR (300MHz, DMSO-d₆) δ (TMS): 7.71 (d, J=8.4Hz, 2H), 7.04 (d, J=8.4Hz, 2H), 3.82 (m, IH), 3.80 (s, 3H), 3.57 (m, 2H), 3.38 (m, 10H), 3.03 (m, 2H), 3.03 (t, J=13.7Hz, 2H), 2.54 (m, 4H), 1.83 (d, J=13.7Hz, 2H), 1.56 (m, 2H), 1.11 (d, J=6.9Hz, 6H). Mp: 251-257°C (C₂6H3₈N₆0₆S2.H2θ.NH₄Cl). Example 47

3-[N-[[4-Isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(phenylacetylamino)propionic acid Following a similar procedure to that described in example 22, but using the compound obtained in reference example 5 instead of β-alanine tert-butyl ester and hydrolyzing in the last step with 6N HCl instead of with trifluoroacetic acid, the title compound was obtained. IH NMR (300MHz, CD₃OD) δ (TMS): 7.25 (m, 5H), 4.93 (s, 4H), 4.67 (m, IH), 4.25 (m, 2H), 3.69 (m, 12H), 3.58 (s, 2H), 3.15 (t, J=13.7Hz, 2H), 2.51 (d, J=13.7Hz, 2H), 2.11 (m, 2H), 1.31 (m, 6H). Mp: 167-178°C (C27H3sN6O4S.3HCl.2H2O).

Example 48 2(S)-(n-Butoxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin- l-yl]thiazol-5-yl]carbonyl]amino]propionic acid

Following a similar procedure to that described in example 22, but using the compound obtained in reference example 6 instead of β-alanine tert-butyl ester and hydrolyzing in the last step with 6N HCl instead of with trifluoroacetic acid, the title compound was obtained. IH NMR (300MHz, CD3OD) δ (TMS): 4.92 (s, 4H), 4.41 (m, IH), 4.03 (m, 4H), 3.67

(m, 12H), 3.15 (t, J=13.7Hz, 2H), 2.51 (d, J=13.7Hz, 2H), 2.12 (m, 2H), 1.59 (m, 2H),

1.38 (m, 2H), 1.30 (d, J=6.9Hz, 6H), 0.93 (t, J=7.3Hz, 3H). Mp: 165-

176°C(C2₄H40N₆O5S.3HCl.H₂O).

Example 49 2(S)-(Benzenesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(piperazin-l-yl)piperidin- l-yl]thiazol-5-yl]carbonyl]amino]propionic acid a) [4-[4-(tert-Butoxycarbonyl)piperazin-l-yl]piperidin-l-yl]carbothioamide

Following a similar procedure to that described in example 20a, but using 4-[4-(tert-butoxycarbonyl)piperazin-l-yl]piperidine (obtained by reductive amination of l-(tert-butoxycarbonyl)piperazine and 1- benzyloxycarbonylpiperidin-4-one with triacetoxyborohydride as described in example 34a, followed by hydrogenation of the benzyloxycarbonyl group) instead of -(tert-butoxycarbonyl)-4,4'-bipiperidine, the desired compound was obtained. b) 2-[4-[4-(tert-Butoxycarbonyl)piperazin-l-yl]piperidin-l-yl]-4-isopropylthiazol-

5-carboxylic acid Following a similar procedure to that described in example lc, but using the compound obtained in step a) instead of [4-(4-pyridyl)piperazin-l- yl]carbothioamide and hydrolyzing the resulting ester with IN NaOH in EtOH at room temperature overnight, the desired compound was obtained. IH NMR (300MHz, CD₃OD) δ (TMS): 4.86 (s), 4.14 (d, J=12.6Hz, 2H), 3.88 (m,

IH), 3.46 (m, 4H), 3.08 (m, 2H), 2.64 (m, 5H), 1.99 (d, J=12.6Hz, 2H), 1.62 (m, 2H), 1.47 (s, 9H), 1.21 (d, J=6.7Hz, 6H). c) Title compound

Following a similar procedure to that described in example le, but starting from the compound obtained in step b) and using the compound obtained in reference example 1 instead of β-alanine tert-butyl ester, and hydrolyzing the resulting compound with 5N HCl at room temperature overnight and then at 40 °C for 2 h, the title compound was obtained.

IH NMR (300MHz, CD3OD) δ (TMS): 7.86 (d, J=5.1Hz, 2H), 7.56 (m, 3H), 4.94 (s, 4H), 4.38 (d, J=-13.7Hz, 2H), 4.20 (dd, J=8.2Hz, J=5.0Hz, IH), 3.79 (m, 11H), 3.68 (t, J=13.7Hz, 2H), 3.45 (m, IH), 2.52 (d, J=13.7Hz, 2H), 2.19 (m, 2H), 1.38 (d, J=7.5Hz, 6H). Mp: 222-245°C (C25H36N6O5S2.3HCl.4H2O).

Example 50 3-[N-[[4-Isopropyl-2-[4-(piperazin-l-yl)piperidin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(phenylacetylamino)propionic acid

Following a similar procedure to that described in example 49, but using the compound obtained in reference example 5 instead of the compound obtained in reference example 1, the title compound was obtained.

^!H NMR (300MHz, CD3OD) δ (TMS): 7.27 (m, 5H), 4.88 (s, 4H), 4.70 (dd, J=8.2Hz, J=5.0Hz, IH), 4.28 (m, 2H), 3.69 (m, 14H), 3.58 (s, 2H), 2.46 (d, J=13.7Hz, 2H), 2.12

( , 2H), 1.31 (t, J=7.5Hz, 6H). Mp: 160-173°C (C27H3sN6O4S.3HCl.2H2O).

Example 51

3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-

2(S)-(2-methoxyacetylamino)propionic acid Following a similar procedure to that described in example le, but using the compound obtained in reference example 9 instead of β-alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl at room temperature overnight and then at 50 °C for 1 h, the title compound was obtained.

IH NMR (300MHz, CD₃OD) δ (TMS): 8.23 (d, J=7.2Hz, 2H), 7.23 (d, J=7.2Hz, 2H), 4.87 (m, 3H), 4.71 (m, IH), 4.04 (m, 8H), 3.95 (s, 2H), 3.83 (m, IH), 3.75 (m, 2H), 3.44 (s, 3H), 1.35 (d, J=6.7Hz, 6H). Mp: 127-132°C (C22H30N6O5S.2HCl.H2O).

Example 52 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(2-phenyl-2-oxoethylamino)propionic acid Following a similar procedure to that described in example 29, but using phenacyl chloride instead of phenylacetic acid chloride, the title compound was obtained.

IH NMR (300MHz, DMSO-d₆) δ (TMS): 8.28 (d, J=7.2Hz, 2H), 8.03(d, J=7.2Hz,

2H), 7.75 (m, IH), 7.62 (m, 2H), 7.33 (m, 5H), 6.01 (s, 2H), 3.93 (m, 4H), 3.71 (m, IH), 3.67 (m, 2H), 3.56 (m, IH), 3.36 (m, 4H), 1.15 (d, J=6.7Hz, 6H). Example 53

3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(2- methoxyacetylamino)propionic acid Following a similar procedure to that described in example 33, but using the compound obtained in reference example 9 instead of the compound obtained in reference example 1, the title compound was obtained.

^!H NMR (300MHz, CD3OD) δ (TMS): 4.87 (s, 4H), 4.40 (m, IH), 3.89 (s, 2H), 3.77

(m, IH), 3.67 ( , 2H), 3.44 (s, 3H), 3.43 (m, 2H), 3.05 (d, J=12.8Hz, 2H), 3.00 (m, 3H), 2.65 (m, IH), 2.42 (t, J=13.0Hz, 2H), 2.08 (m, 4H), 1.82 (m, 4H), 1.26 (d, J=6.7Hz, 6H). Mp: 137-145°C (C23H37N₅0₅S.H₂0). Example 54

3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(n- butoxycarbonylamino)propionic acid Following a similar procedure to that described in example 40, but using the compound obtained in reference example 6 instead of the compound obtained in reference example 1, the title compound was obtained. H NMR (300MHz, CD3OD) δ (TMS): 4.88 (s, 4H), 4.41 (m, IH), 4.15 (d, J=12.6Hz,

2H), 4.03 (t, J=6.4Hz, 2H), 3.75 (m, 2H), 3.57 (dd, J=11.8Hz, J=8.1Hz, IH), 3.42 (m, 4H), 2.97 (m, 3H), 1.98 (m, 4H), 1.56 (m, 9H), 1.34 (d, J=6.9Hz, 6H), 0.92 (t,

J=7.3Hz, 3H). Mp: 131-142°C (C₂5H₄ιN₅θ5S.HC1.2H₂0).

Example 55

3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-[2- (2-thienyl)acetylamino]propionic acid

Following a similar procedure to that described in example 40, but using the compound obtained in reference example 8 instead of the compound obtained in reference example 1, the title compound was obtained.

IH NMR (300MHz, DMSO-d₆) δ (TMS): 8.89 (m, IH), 8.64 (m, 2H), 8.46 (d, J=7.7Hz, IH), 7.59 (m, IH), 7.31 (m, IH), 6.89 (m, IH), 4.34 (m, IH), 3.81 (m, 5H), 3.73 (s, 2H), 3.23 (d, J=11.7Hz, 2H), 2.96 (m, 2H), 2.75 (m, 2H), 1.73 (m, 4H), 1.37 (m, 6H), 1.10 (d, J=6.7Hz, 6H).

Example 56 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-[3- (4-fluorophenyl)ureido]propionic acid

Following a similar procedure to that described in example 33, but using the compound obtained in reference example 10 instead of the compound obtained in reference example 1, the title compound was obtained.

*H NMR (300MHz, CD₃OD) δ (TMS): 7.42 (m, 2H), 7.21 (t, J=8.7Hz, 2H), 4.90 (s, 5H), 4.43 (t, J=6.3 Hz, IH), 3.75 (m, 9H), 3.30 (m, 2H), 3.13 (t, J=12.8Hz, 2H), 2.41 (m, 4H), 2.23 (m, 2H), 2.07 (m, 2H), 1.25 (dd, J= 15.2Hz, J=6.7Hz, 6H).

Example 57 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2-(2- phenylethyDpropionic acid Following a similar procedure to that described in example le, but using the compound obtained in example 33a instead of the compound obtained in example Id and ethyl 2-(aminomethyl)-4-phenylbutanoate instead of β-alanine tert-butyl ester, and hydrolyzing the resulting ethyl ester with 6N HCl at room temperature overnight and then at 50 °C for 1 h, the title compound was obtained. iH NMR (300MHz, CDC1₃ + CD₃OD) δ (TMS): 7.25 (m, 2H), 7.16 (m, 3H), 4.47 (s,

3H), 3.65 (m, 4H), 3.52 (m, 4H), 3.10 (m, 2H), 2.64 (m, 4H), 2.41 (m, 6H), 2.25 (m, 2H), 2.00 (m, 2H), 1.80 (m, 2H), 1.33 (d, J= 6.9Hz, 6H).

Claims

1.- A compound of formula I:

I wherein: one of Yi or Y2 represents N and the other represents NR5, O or S, or one of Yi or Y2 represents S and the other represents CR5, wherein R5 represents hydrogen or C1-.4 alkyl; m represents 0, 1 or 2;

Rl represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C╬╣_6 alkoxy, C1-6 haloalkyl, C3.7 cycloalkyl, C3-7 cycloalkylC╬╣-4 alkyl, aryl, arylC╬╣-4 alkyl, arylCi-4 alkoxy, arylC3-7 cycloalkyl, heteroaryl, heteroarylC╬╣.₄ alkyl, R SO2 R2-, R₆CONR₂-, R₆OCONR₂-, R2R7NCONR2-, R2R7N-, R₆S╬╕2NR₂Ci-4 alkyl, R₆CONR₂C₁_₄ alkyl, R₆OCONR₂Ci-₄ alkyl, R₂R7NCONR₂C╬╣-₄ alkyl, R₆S0₂C╬╣-₄ alkyl, R2R7NSO2C1-4 alkyl, R₂R NCOC╬╣-₄ alkyl, R6COC1-4 alkyl, R7OOCC1-4 alkyl, R╬▓OC╬╣-4 alkyl, or R2R7NC1-4 alkyl;

A represents C0-2 alkylene which may be optionally substituted with one or more groups independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C₁-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylC╬╣-4 alkyl, aryl, arylC╧ç-4 alkyl, arylC3-7 cycloalkyl, heteroaryl, heteroarylCi-4 alkyl, R6SO2NR2C1-4 alkyl, R₆CONR₂Ci-4 alkyl, R₆OCONR₂C╬╣-₄ alkyl, R₂R₇NCONR₂C╬╣-4 alkyl, R₆S0₂C╬╣- alkyl, R₂R NS0₂C╬╣- alkyl, R₂R NCOC╬╣- alkyl, R6COC1-4 alkyl, R7OOCC1-4 alkyl, alkyl, R₂R₇NC╬╣.₄ alkyl, R₈OOC-, or R7R7NCO-; R2 represents independently hydrogen or C1-4 alkyl;

R3 can have any of the meanings disclosed for Ri and in addition it can represent R₈OOC- or R2R7NCO-, with the proviso that when A represents Co alkylene, then R3 cannot represent a group that is bonded through a N atom; B represents carboxy or a metabolically labile ester or amide thereof;

R₄ represents a group of formula (i) or (ii):

wherein the terminal ring in both groups can be optionally substituted with one or more C₁-₄ alkyl or halogen groups; R represents C₁- alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, Ci-6 haloalkyl, C₁-₄ alkoxyCi-₄ alkyl, C₃-₇ cycloalkyl, C₃-₇ cycloalkylC╬╣-₄ alkyl, aryl, arylC╬╣.₄ alkyl, arylcarbonylC╬╣-₄ alkyl, heteroaryl or heteroarylC╬╣-₄ alkyl;

R₇ represents hydrogen or any of the meanings disclosed for Re;

R₈ represents hydrogen or C₁-₄ alkyl; p represents 1 or 2;

Xi represents a group of formula:

X₂ represents a group of formula:

/ / / /

N, CH, -CH₂ΓÇö N , -CH₂ΓÇö C H , ΓÇö NH-C H , or ΓÇö Q-C H

X₃ represents N or CH, with the proviso that when X₃ is N then X₂ cannot represent a group: / / / N, -CH₂ΓÇö N , -NH-C H , or - -O-C H ΓÇó \ '

one of Zi or Z₂ represents Z and the other represents CH₂, with the proviso that when X₃ represents N, then Z₂ is CH2; Z represents a group of formula:

O

HN / , (C-,.₆ alkyl)N / , (d.₆ alkyl)0-C IIΓÇö N / , (2-pyridyl) ΓÇö N /

R₉ represents hydrogen or C₁-₄ alkyl;

R_lO and Rn independently represent hydrogen or C₁-₄ alkyl, or they can be bonded together forming a C₂-₅ polymethylene chain; aryl in the above definitions represents phenyl or naphthyl which can be optionally substituted with one or more groups independently selected from halogen, C₁-₄ alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, C₁-₄ alkoxy, hydroxy, C₁-₄ haloalkyl, C₁-₄ haloalkoxy, carboxy, cyano, nitro, amino, C₁-₄ alkylamino, C₁-₄ dialkylamino, C₁-₄ alkylcarbonyl, C₁-₄ alkylcarbonyloxy, C₁-₄ alkoxycarbonyl, C₁-₄ alkylsulfonyl, C₁-₄ alkylsulfinyl, C₁-₄ alkylthio or C₁-₄ alkylcarbonylamino and wherein two substituents on adjacent carbon atoms can be bonded forming a methylenedioxy group; heteroaryl in the above definitions represents an aromatic monocyclic 5- or 6- membered heterocycle or an aromatic bicyclic 9- or 10-membered heterocycle containing from one to four heteroatoms selected from N, O and S, and which can be optionally substituted with one or more groups independently selected from halogen, C₁-₄ alkyl, C₂-₄ alkenyl, C₂-₄ alkynyl, C₁-₄ alkoxy, hydroxy, C₁-₄ haloalkyl, C₁.₄ haloalkoxy, carboxy, cyano, nitro, amino, C₁-₄ alkylamino, C₁-₄ dialkylamino, C₁-₄ alkylcarbonyl, C₁-₄ alkylcarbonyloxy, C₁-₄ alkoxycarbonyl,

C╬╣-₄ alkylsulfonyl, C₁-₄ alkylsulfinyl, C₁-₄ alkylthio or C₁-₄ alkylcarbonylamino; or a salt, solvate or prodrug thereof.

2.- A compound as claimed in claim 1 wherein m represents 0.

3.- A compound as claimed in claim 1 or 2 wherein A represents methylene which can be optionally substituted, as described above.

4.- A compound as claimed in any one of claims 1 to 3 wherein R₄ represents a group selected from:

5.- A compound as claimed in any one of claims 1 to 4 wherein Yi represents N and Y₂ represents S.

6.- A compound as claimed in any one of claims 1 to 5 wherein R₃ represents

C╬╣- alkyl, C2-₆ alkenyl, C₂-₆ alkynyl, C₁- alkoxy, C╧ç- haloalkyl, C3-7 cycloalkyl, C₃-₇ cycloalkylC╬╣-₄ alkyl, aryl, arylC╬╣-₄ alkyl, arylC╬╣-₄ alkoxy, arylC₃_₇ cycloalkyl, heteroaryl, heteroarylC╬╣-4 alkyl, R₆S0₂NR₂-, R6CONR₂-, R₆OCONR₂-, R2R7NCONR2-, R2R7N-, R6SO2NR2C1-4 alkyl, R₆CONR₂C╬╣- alkyl, R₆OCONR₂Ci-₄ alkyl, R₂R₇NCONR₂C╬╣- alkyl, R6S0₂C╬╣-₄ alkyl, R₂R₇NS0₂C╬╣-₄ alkyl, R2R7NCOC1-4 alkyl, R COC╬╣-₄ alkyl, R7OOCC1-4 alkyl, R₆OC╬╣-₄ alkyl, R2R7NC1-4 alkyl, RsOOC or R2R7NCO-.

7.- A compound as claimed in claim 1 of formula la

la

wherein: RA represents independently hydrogen, C_\-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylCi-4 alkyl, aryl, arylCi-₄ alkyl, arylC3-7 cycloalkyl, heteroaryl, heteroarylC╬╣-4 alkyl, R6SO2NR2C₁-₄ alkyl, R₆CONR₂Ci-4 alkyl, R₆OCONR₂Ci-4 alkyl, R2R7NCONR2C1-4 alkyl, R₆S0₂Ci-₄ alkyl, R2R7 SO2C1-4 alkyl, R2R7NCO -4 alkyl,

alkyl, R7OOCC₁-4 alkyl, R₆OC╬╣.₄ alkyl, R₂R7NCj_.-₄ alkyl, R₈OOC-, or R2R7NCO-; and Ri, R₂, R3, R4, Re, R7, R₈, Yl/ Y2 and B are as defined in claim 1.

8.- A compound as claimed in claim 7 wherein R4 represents a group selected from:

9.- A compound as claimed in claim 8 wherein Yi represents N and Y2 represents S.

10.- A compound as claimed in claim 9 wherein: RA represents hydrogen; and R3 represents C1-6 alkyl, C₂-6 alkenyl, C₂-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylCi-4 alkyl, aryl, arylC╬╣-4 alkyl, arylC╬╣-₄ alkoxy, arylC3_7 cycloalkyl, heteroaryl, heteroarylCi-4 alkyl, R6SO2NR2-,

R₆CONR₂-, R₆OCONR₂-, R2R7NCONR2-, R2R7N-, R₆S0₂NR₂C╬╣-₄ alkyl,

R₆CONR₂C╬╣-₄ alkyl, R₆OCONR₂C╬╣- alkyl, R2R7NCONR2C1-₄ alkyl, R₆S0₂C╬╣-₄ alkyl, R2R7NSO2C1-4 alkyl, R2R7NCOC1-4 alkyl, R6COC1-4 alkyl, R7OOCC1-4 alkyl, R6OC₁-₄ alkyl, R2R7NC1-4 alkyl, R₈OOC-, or R₂R NCO-.

11.- A compound as claimed in claim 9 wherein:

RA independently represents hydrogen, C1- alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylC╬╣-4 alkyl, aryl, arylCi-4 alkyl, heteroaryl, or heteroarylCi-4 alkyl, with the proviso that at least one of the RA groups is different from hydrogen; and R3 represents hydrogen.

12.- A compound as claimed in claim 1 selected from:

3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid; 3-[N-[[4-methyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid;

3-[N-[[4-tert-butyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid 3-[N-[[4-cyclopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid

3-[N-[[4-(2,2-dimethylpropyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid;

3-[N-[[2-[4-(4-pyridyl)piperazin-l-yl]-4-trifluoromethylthiazol-5-yl]carbonyl]- aminojpropionic acid;

3-[N-[[4-(3-furyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid;

3-[N-[[4-propyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid; 3-[N-[[4-phenyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid;

3-[N-[[4-benzyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- propionic acid;

3-[N-[[4-(4-methoxybenzyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]- amino]propionic acid;

3-[N-[[4-(l-phenylcyclopropyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid;

3-[N-[[4-(2-phenylethyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]- amino]propionic acid; 2-[N-[2-[2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]acetyl]amino]acetic acid;

3-[N-[[4-isopropyl-2-[l-(4-pyridyl)piperidin-4-yl]thiazol-5-yl]carbonyl]- aminojpropionic acid;

3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]propionic acid; 3-[N-[[4-isopropyl-2-[l-[(3-piperidinyl)methyl]piperidin-4-yl]thiazol-5- yl]carbonyl]amino]propionic acid;

3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-2- methylpropionic acid; 3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-3- methylbutanoic acid;

3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]propionic acid; 3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2- methylpropionic acid;

3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5-yl]carbonyl]- amino]propionic acid; methyl 2(S)-(benzenesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)- piperazin-l-yl]thiazol-5-yl]carbonyl]amino]propionate;

2(S)-(benzenesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid;

3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]aminoj-

2(S)-(4-methoxybenzenesulfonylamino)propionic acid; 2(S)-(benzyloxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid;

3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-

2(S)-(2-thienylcarbonylamino)propionic acid;

2(S)-(ethanesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid;

3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-

2(S)-(phenylacetylamino)propionic acid;

2(S)-(n-butoxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid; 2(S)-(benzoylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid;

3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]-

2(S)-[2-(2-thienyl)acetylamino]propionic acid;

2(S)-(benzenesulfonylamino)-3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol- 5-yl]carbonyl]amino]propionic acid;

3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(4- methoxybenzenesulfonylamino)propionic acid; 3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(2- thienylcarbonylamino)propionic acid;

3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-

(phenylacetylamino)propionic acid; 3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(n- butoxycarbonylamino)propionic acid;

2(S)-(benzoylamino)-3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5- yl]carbonyl]amino]propionic acid;

3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-[2-(2- thienyl)acetylamino]propionic acid;

2(S)-(benzenesulfonylamino)-3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-

5-yl]carbonyl]amino]propionic acid;

3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(4- methoxybenzenesulfonylamino)propionic acid; 3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(2- thienylcarbonylamino)propionic acid;

2(S)-(benzoylamino)-3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5- yl]carbonyl]amino]prop ionic acid;

2(S)-(benzenesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin- l-yl]thiazol-5-yl]carbonyl]amino]propionic acid;

3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yi]thiazol-5- yl]carbonyl]amino]-2(S)-(2-thienylcarbonylamino)propionic acid;

3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(4-methoxybenzenesulfonylamino)propionic acid; 3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(phenylacetylamino)propionic acid;

2(S)-(n-butoxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(piperidin-4-yl)piperazin- l-yl]thiazol-5-yl]carbonyl]amino]propionic acid;

2(S)-(benzenesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(piperazin-l-yl)piperidin- l-yl]thiazol-5-yl]carbonyl]amino]propionic acid;

3-[N-[[4-isopropyl-2-[4-(piperazin-l-yl)piperidin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(phenylacetylamino)propionic acid; 3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(2-methoxyacetylamino)propionic acid;

3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(2-phenyl-2-oxoethylamino)propionic acid;

3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(2- methoxyacetylamino)propionic acid;

3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(n- butoxycarbonylamino)propionic acid;

3-[N-[[2-(4,4'-bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-[2-(2- thienyl)acetylamino]propionic acid;

3-[N-[[2-(l,4'-bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2-(2- phenylethyl)propionic acid;

3- [N-[ [2-( 1 ,4'-bipiperidin-4-y l)-4-isopropylthiazol-5-y 1] carbonyl] amino]-2(S)- [3-

(4-fluorophenyl)ureido]propionic acid; or a metabolically labile ester or amide thereof or a salt or solvate thereof.

13.- A process for preparing a compound of formula I as defined in claim 1, which comprises: (a) reacting a compound of formula II or a reactive derivative thereof

wherein Ri, Y , Y₂ and m are as defined in claim 1 and R₄ ^* represents a group R₄ as defined in claim 1 or a group convertible thereto, with an amine of formula III

m

wherein A, B, R₂ and R₃ are as defined in claim 1, followed when necessary by the conversion of R₄ ^* into a group R₄ and/or the removal of any protecting group that may be present; or (b) deprotecting a compound of formula F

wherein Yi, Y₂, m, A, B, Ri, R₂, R₃ and R₄ are as defined in claim 1 but at least one of them contains a protecting group; or

(c) converting, in one or a plurality of steps, a compound of formula I into another compound of formula I; or

(d) converting a compound of formula I wherein B represents a carboxy group into a metabolically labile ester or amide thereof; and

(e) if desired, after the above steps, treating a compound of formula I with an acid or a base to give the corresponding addition salt.

14.- A pharmaceutical composition which comprises an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof in admixture with a pharmaceutically acceptable excipient.

15.- The use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting platelet aggregation.

16- The use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting the binding of fibrinogen to its receptor.

17.- The use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of thromboembolic disorders.

18.- A pharmaceutical composition which comprises a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, a pharmaceutically acceptable excipient and one or more additional therapeutic agents selected from: a platelet antiaggregant agent, a thrombolytic agent or an anticoagulant agent.