Title of Invention	"A 4-AMINO, 6-PIPERIDINYL PYRIMIDINE COMPOUND AND A PROCESS FOR PREPARING THE SAME"
Abstract	Novel vitronectin receptor antagonists of formula I are described, wherein: Rl, R2, R3, R4 and G are such as defined in the description. The compounds have potentially valuable pharmaceutical properties for the treatment of osteoporosis and cancer.

Full Text

A subject of the present invention is new antagonist derivatives of the vitronectin receptor, their preparation process, their use as medicaments and the pharmaceutical compositions containing them. A subject of the invention is the compounds of formula (I): G 0 R4 R2 H N N (I) NH N .—N R3 Ri in which R1, R2, R3, R4 and G have the meanings indicated below as well as their physiologically acceptable salts and their prodrugs. The compounds of formula (I) are compounds having a pharmacological activity and can therefore be used as medicaments. They are antagonists of the vitronectin receptor and cell adhesion inhibitors and they inhibit bone resorption mediated by the osteoc lasts. They are therefore useful for the therapeutic or prophylactic treatment of diseases which are caused at least in part by an undesirable increase in bone resorption, for example osteoporosis. A subject of the invention is also the processes for preparing the compounds of formula (I), their use, in particular as a medicament, and the pharmaceutical compositions containing them. Bone is constantly subjected to a dynamic process which includes bone resorption and bone formation. These processes are mediated via specialized cells. Bone formation is the result of the deposit of a mineral matrix by the osteoblasts and bone resorption is the result of the dissolution of this bone matrix by the osteoclasts. The majority of bone disorders are caused by a disturbed equilibrium between bone formation and bone resorption. Osteoporosis is characterized by a dry loss of this bone matrix. An activated mature osteoclast resorbs the bone after adhesion to the bone matrix via the secretion of proteolytic enzyme, and protons inside the adhesion zone, resulting in depressions or hollows in the bone surface which appear when the osteoclast detaches itself fro iii ihebone. Studies have shown that the fixation of the osteoclast on the bone is mediated by receptors: the integrins. Integrins are a superfamily of receptors mediating the cell/cell and more particularly cell/matrix adhesion process, including in particular cLLIbI33 as a blood platelet receptor (fibrinogen) and a~f33 as a vitronectin receptor. The peptides containing the RGD unit as well as the anti ci~f33 antibodies are known for their ability to inhibit resorption of dentin and prevention of osteoclast adhesion on the mineralized matrices (Horton et al. Exp. Cell. Res. (1991), 195, 368). The peptide Echistatine, isolated from snake venom also contains an RGD unit and is described as an inhibitor of the adhesion of osteoclasts to the bone and is a powerful inhibitor 3, of bone resorption in tissues cultured in vitro (Sato et al. J. Cell. Biol. (1990), Ill, 1713) and in vivo in the rat (Fisher et al. Endocrinology (1993), 132, 1411). The UvI33 receptor is a transmembrane glycoprotein which is expressed in a large number of cells including endothelial cells, smooth muscle cells, osteoclast and cancerous cells which thus leads to a pluripotentiality of the compounds of formula (I) according to the invention. In fact, the ct~~33 receptors expressed in the membrane of the osteoclasts are the basis of the adhesion/resorption process, contribute to the organization of the cell cytoskeleton, and are involved in osteoporosis. The a~f33 receptors expressed in thc smooth muscle cells of the aorta, stimulate their migration towards the neointima, which leads to the formation of arteriosclerosis and the occurrence of post~ angioplastic recurrence of stenosis (Brown et al., cardiovascular Res. (1994), 28., 1815). The endothelial cells secrete growth factors which are mitogens for the endothelium and can contribute to the formation of new blood vessels (Angiogenesis). The antagonists of cIVI33 integrin can therefore lead to a regression of cancerous tumors by inducing apoptosis of the angiogenic blood vessels. (Brook et al. Cell (1994) 79, 1157). Cheresh et al (Science 1995, 270, 1500) have described anti-u~r33 antibodies or antagonists of the Uvf33 receptor which inhibit the process of angiogenesis induced by bFGP in the rat eye, a property which can be used for the treatment of retinopathies, in particular in diabetics. The Patent Application WO-A-94/12181 describes aromatic or non-aromatic substituted systems and WO-A-94/08577 describes substituted heterocycles as antagonists of the fibrinogen receptor and inhibitors of platelet aggregation. EP-A528586 and EP-A-528587 describe phenylalanine derivatives substituted by an aminoalkyl or a heterocycle and WO-A-95/327 10 describes aryl derivatives as inhibitors of bone resorption by the osteoclasts. WO-A-96/00574 describes benzodiazepines and WO-A-96/00730 describes compounds which inhibit the fibrinogen receptor, in particular benzodiazepines which are linked to a ring with 5 nitrogenous members as antagonists of the vitronectin receptor. WO9800395, W099/32457 and W099/3 7621 describe tyrosine derivative antagonists of the vitronectin receptor. EP0820991 claims cycloalkyl derivatives as antagonists of the vitronectin receptor. Other investigations have made it possible to show that the derivatives of formula (I) show marked activity as antagonists of the vitronectin receptor and of bone resorption mediated via the osteoclasts. A subject of the invention is the compounds of formula (I): G 0 R4 R2 H N N (I) NH N ~—N R3 Ri in all their isomeric forms, alone or in a mixture, as well as their physiologically acceptable addition salts, in which - G represents R7R8N-C(=NR6)-NH-CO- Het-NH-CO-; Het-NH-CH2-, Het-, Het representing a monocyclic or polycyclic system, each ring being constituted by 4 to 10 aromatic or non aromatic members, the ring or at least one of the rings containing 1 to 4 nitrogen atoms, substituted or non substituted by one or more R9 groups - represents a hydrogen atom ; a (C5-C14)-aryl ; (Cs-C14)-aryl-(C1-C4)-alkyl- group ; an amino radical non substituted or monosubstituted or disubstituted by an alkyl radical and/or an acyl radical containing 1 to 4 carbon atoms; - R2 represents a hydrogen atom ; a halogen atom ; a nitro group ; an alkyl radical containing I to 4 carbon atoms ; an amino radical non substituted or monosubstituted or disubstituted by an alkyl and/or an acyl containing I to 4 carbon atoms; a—(CH2)o2-C02R5 group ; or a—(CH2)o2-0R5 group; - a hydrogen atom - a -C02R5 radical, - an —502R5 radical or - a monocyclic or polycyclic system, each ring being constituted by 4 to 10 aromatic or non aromatic members, the ring or at least one of the rings containing 1 to 4 heteroatoms chosen from N, 0 or 5, substituted or non substituted by one or more R9 radicals, - represents OH ; (Ci-C8)-alkoxy- ; (C5-C14)-aryl-(Ct-C4)-alkyloxy- ; (C5-C14)-aryloxy- ; (C3-C12)-cycloalkyloxy ; (C3-C12)-cycloalkyl-(C1-C4)-alkyloxy- ; (C1-Cs)-alkylcarbonyloxy-(C1 -C4)-alkyloxy- ; (C5-C1 4)-aryl-(C1 -C4)-alkylcarbonyloxy-(C1 -C4) alkyloxy- ; i-C8)dialkylaminocarbonylmethyloxy- ; (C5-C1 4)-aryl-(Ci -C4)-dialkylaminocarbonylmethyloxy- ; an amino radical non substituted or monosubstituted or disubstituted by a (Ci-C4)-alkyl and/or (Cs-C14)-aryl and/or (C5- 5 C14)-aryl-(C1-C4)-alkyl- radical and/or a (Ci-Cs)-acyl radical ; or the remainder of an amino acid D or L; - R5 represents (C1-C8)-alkyl ; (C5-C14)-aryl ; (C5-C14)-aryl-(C1-C4)-alkyl-(C3-C 12)-cycloalkyl or (C3-C1 2)-cycloalkyl-(C1-C4)-alkyl-, bicyeloalkyl-(C1 -C4)-alkyl-, tricycloalkyl-(C1-C4)-alkyl-, said aryl, alkyl, cycloalkyl, bicycloalkyl and tricycloalkyl radicals being non substituted or substituted by one or more chosen R9 groups; - R6 represents a hydrogen atom ; a hydroxyl ; nitro, (C1-C6)-alkyl-O-CO- ; or (Ci-C6)-alkyl-O-CO-O- group; 7 - R and R8, independently of one another represent a hydrogen atom or a (Ci-C6)-alkyl radical non substituted or substituted by R9; - R9 represents halogen ; amino ; nitro ; hydroxyl, (Ci-C4)-alkyloxy- ; (C1-C4)-alkylthio- ; carboxy ; (C1-C4)-alkyloxycarbonyl- ; (C1-C8)-alkyl non substituted or substituted by one or more halogen atoms, (C5-C14)-aryl ,(Cs-C14-aryl-(C1-C4)-alkylAll the radicals which can be found several times in the compounds of formula (I), for example the R3 radical, are independent of one another and can be identical or different. The alkyl radicals can be linear or branched, saturated or mono- or polyunsaturated. This also applies when they carry a substituent or when they are included in groups such as for example alkoxy, alkoxycarbonyl, aralkyl or heteroarylalkyl. By (C1-C8)-alkyl is meant the methyl, ethyl, propyl, butyl. pentyl, hexyl, heptyl, octyl, nonyl radicals, the n-isomers of these radicals, isopropyl, isobutyl, isopentyl, neopentyl, isohexyl, 3 -methylpentyl, 2,3 ,4-trimethylhexyl, sec-butyl, tertbutyl, tert-pentyl. Among the preferred radicals the (Ci-C4)-alkyl groups can be mentioned such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tertbutyl. Preferably alkyl represents methyl or ethyl. The cycloalkyl radicals can be monocyclic, bicyclic or tricyclic. They are for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotetradecyl or cyclooctadecyl radicals which if appropriate can be substituted for example by an alkyl containing 1 to 4 carbon atoms. As substituted cycloalkyl radicals, there can be mentioned 4-methylcyclohexyl and 2 ,3-dimethylcyclohexyl. The bicycloalkyl and tricycloalkyl radicals can be non-substituted or substituted in any position, for example by one or more oxo groups and/or 1 or more identical or different alkyl groups such as methyl or isopropyl and preferably methyl. The junction bond of the bi or tricyclic radical can be situated in all positions of the 6 molecule. The bond can be situated at the bridged carbon atom or one of the other carbon atoms. This bond can also take any position from the point of view of the stereochemistry, for example exo or endo. As examples of bicycloalkyl or tricycloalkyl radicals, there can be mentioned camphanyl, bornyl, adamantyl such as 1-adamantyl or 2-adamantyl, caranyl, epii-sobomyl, epibornyl, norbornyl or norpinanyl. By halogen is meant fluorine, chlorine, bromine or iodine. By the term (Cs-C14)-aryl is meant - either the heterocyclic (C5-C14)-aryl radicals (9~ (Cs-C14)-heteroaryl), in which one or more carbon atoms of the ring are replaced with a heteroatom such as nitrogen, oxygen or sulphur, - or the carbocyclic (C6-C14)-aryl radicals. Among the carbocyclic (C6-C14-aiyl radicals, phenyl, naphthyl, biphenylyl, anthryl or fluorenyl and quite particularly I -naphthyl, 2-naphthyl and phenyl can be mentioned. Unless indicated otherwise, the aryl radicals, in particular phenyl, can be non-substituted or substituted by one or more identical or different radicals chosen from (Cj-Cs)-alkyl, in particular (C1-C4)alkyl, hydroxyl,(C1-C8)-alkoxy, C1-C8)-alkoxylthio, halogen such as fluorine, chlorine and bromine, nitro, amino, (C1-C4)alkylamino, di-(C1-C4)alkylamino, tri fluoromethyl, hydroxyl, methylenedioxy, cyano, aminocarbonyl, (C1 -C4alkylaminocarbonyl, di-(Ci -C4)alkylaminocarbonyl, carboxy,(C1 -C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. In the case of monosubstituted phenyl, the substituent can be situated in position 2, 3 or 4, and preferably in position 3 or 4. In the case where the phenyl is disubstituted, the substituents can be in position 2, 3 or 2, 4 or 2, 5 or 2, 6 or 3, 4 or 3, 5. Preferably, in the disubstituted phenyls, the two substituents are in position 3,4. 'When this phenyl is trisubstituted, the positions are as follows: 2, 3, 4 or 2, 3, 5 or 2, 3, 6 or 2, 4, 5 or 2, 4, 6 or 3, 4, 5. In the same way, the naphthyl radicals or other aryl radicals can be substituted in any position, for example the 1 -naphthyl radical in position 2-, 3-, 4-, 5-, 6-, 7-, and 8 and the 2-naphthyl radical in position 1-, 3-, 4-, 5-~ 6-, and 7. The (C5-C14)-aryl group can also represent a monocyclic or polycyclic aromatic system in which 1, 2, 3, 4 or 5 carbon atoms of the ring are replaced with heteroatoms, in particular identical or different from the group constituted by nitrogen, oxygen and sulphur. Among the heterocyclic (C5-C14)-aryl (=(C5-C14)-heteroaryl) groups there can be mentioned the 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, im idazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, 7 phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, f3-carbolinyl groups or also benzocondensed, cyclopenta- cyclohexa- or cyclohepta~. condensed derivatives of these radicals. The heterocyclic system can be substituted by the same substituents mentioned above for the carbocyclic system. The optically active carbon atoms contained in the compounds of formula (I) can independently from one another show the R configuration or the S configuration. The compounds of formula (I) can be in the form of pure enantiomers or pure diastereoisomers or in the form of a mixture of enantiomers, for example in the form of racemates or mixtures of diastereoisomers. A subject of the present invention is therefore pure enantiomers, mixtures of these enantiomers, pure diastereoisomers and mixtures of these diastereoisomers. The invention relates to mixtures of two or more than two stereoisomers of formula (I) and all the ratios of these stereoisomers in said mixtures. The compounds of formula (I) can, if appropriate, be present in the form of E isomers or Z isomers. A subject of the invention is therefore the pure F isomers, the pure Z isomers and the E/Z mixtures in any ratio. The invention also relates to all the tautomer forms of the compounds of formula (I), relating for example to the form represented by formula (I), with G = R7R8N-C(=NR6)-NH-CO- the form in which acylguanidine is present in the form of a -CO-N=C(NHR1)-NR2R7 group, and all the other forms which differ by the different position of the hydrogen atom are considered. The diastereoisomers, including the E/Z isomers, can be separated into individual isomers, for example by chromatography. The racemates can be separated into two enantiomers by standard methods such as chiral phase chromatography or by resolution methods. The physiologically acceptable salts of the compounds of formula (I) are in particular salts which can be used pharmaceutically or non-toxic salts or salts which can be used physiologically. When the compounds of formula (I) contain an acid group such as carboxylic acid, they are for example salts of alkali or alkaline earth metals such as sodium, potassium, magnesium, calcium salts, and also the salts formed with physiologically acceptable quatemary ammonium ions and the addition salts with acids such as ammonia and physiologically acceptable organic amines such as for example triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. When the compounds of formula (I) contain a basic group, they can form an addition salt with acids, for example with inorganic acids such as hydrochloric, sulphuric, phosphoric acid or with organic carboxylic acids such as acetic, trifluoroacetic, citric, benzoic, maleic, fumaric, tartaric, methanesulphon ic or para toluene sulphonic acid. The compounds of formula (I) which comprise a basic group and an acid group, such as for example guanidino and carboxylic, can be present in the form of Zwitterions (betaines), which are also included in the present invention. When appropriate a physiologically acceptable Q anion can be contained in the compounds of formula (I) containing a charged ammonium group. It is preferably a monovalent anion or an equivalent of a polyvalent anion of an organic or inorganic non-toxic, physiologically acceptable and in particular pharmaceutically acceptable acid, for example the anion or an anion equivalent of one of the acids mentioned above, useful for the formation of the addition salts. can be for example one of the anions (or anion equivalent) of a group chosen from chlorine, sulphate, phosphate, acetate, trifluoroacetate, citrate, benzoate, maleate, fumarate, tartrate, methanesulphonate and paratoluenesulphonate. The salts of the compounds of formula (I) can be obtained by standard methods known to a person skilled in the art, for example by combining a compound of formula (I) with an organic or inorganic acid or a base in a solvent or a dispersant or from another salt by cation or anion exchange. The invention also includes all the salts of the compounds of formula (I) which, because of their low physiological acceptability, cannot be used directly as medicaments, but can be used as intermediate products to implement subsequent chemical modifications in the compounds of formula (I) or as starting products for the preparation of physiologically acceptable salts. The present invention also includes all the solvates of the compounds of formula (I) for example the hydrates, the solvates formed with alcohols, and all the derivatives of the compounds of formula (I), for example the esters, prodrugs and other physiologically acceptable derivatives, as well as the metabolites of the compounds of formula (I). A more particular subject of the invention is the compounds of formula (1) in which G represents a Het, Het-NHCO-, or Het-M-I-CH2- group in which Het represents I K— N N R9 N H H N N HH If.4 N H R9 N H N R9 N H N N H N R9 N N H R9~7 N H R9 N H N N HH N R9 N H QQ H N N H H (CH2)n R9 N N H A more particular subject of the invention is the compounds of formula (I) as defined above in which R3 is - a heterocycle chosen from 1c~ N N H N N N.. N—N H N S N N 0 — ~ N —~-~ ~ 0 N 0 N N 0 N 0 as well as their pharmaceutically acceptable addition salts. A more particular subject of the invention is the compounds of formula (I) as defined above in which R3 is a benzyloxycarbonyl group, as well as their pharmaceutically acceptable addition salts. A more particular subject of the invention is the compounds of formula (I) as defined above in which R2 is a hydrogen, an alkyl radical containing 1 to 4 carbon atoms, and quite particularly methyl and ethyl, or a fluorine atom as well as their pharmaceutically acceptable addition salts. A more particular subject of the invention is the compounds of formula (1) as defined above in which: G represents N N NHCOH c4 N NHCOH as well as their pharmaceutically acceptable addition salts. A more particular subject of the invention is the compounds of formula (I) as defined above in which G represents N N NHCOH C3~ N NHCOH R1 represents a hydrogen atom R2 represents a hydrogen atom, a fluorine atom, a methyl radical or an ethyl radical, R3 represents a benzyloxycarbonyl group /1 R4 represents a hydroxy or (Ci-C4)-alkyloxy group, As well as the pharmaceutically acceptable addition salts A particular subject of the invention is the compounds of formula (I) the names of which follow: 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl )- I -piperidinyl]-4-pyrimidinyl]amino]-N- [(phenylmethoxy)carbonyl]alanine 3-[[5-ethyl-6-[4-[( 1 ,2,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyl}- 1-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl] alanine 3 -[[6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyljalanine 3-[[6-[4-[(1 ,2 , 3,4,5, 6-hexahydro-2-pyrimidinyl)iminocarbonylj-l-piperidinyl]- 5-methyl-4-pyrimidinyl]aminoJ -N-[(phenylmethoxy)carbonyljalanine ethyl 3-[[5 -ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1-piperidinyl] -4-pyrimidinyl]amino]-N- L(phenylmethoxy)carbonyl Jalaninate isopropyl 3-[[6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinylj-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alan mate (1,1 -dimethylethyl)3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)-I -piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate (1,1 -dimethylethyl)3-[[5-methyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)-l -piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl jalaninate (1,1 -dimethylethyl) 3-[[5-ethyl-6-~4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)-1 -piperidinyl]-4-pyrimidinyl]amino]-N-( 1 -naphthalenesulphonyl)alaninate (R) configuration or (5) configuration or their mixtures, as well as their addition salts. A subject of the present invention is also a process for the preparation of the compounds of formula (I). The compounds can generally be prepared, for example during convergent synthesis by coupling two or more fragments which can be derived by retrosynthesis of the compounds of formula (I). In order to avoid the functional groups leading to undesirable or secondary reactions during each stage of synthesis, it can be advantageous or necessary during the synthesis of the compounds of formula (I), to introduce the functional groups in the form of precursors which are then converted into the desired functional groups or to temporarily block these functional groups by implementing a protective group strategy appropriate for the synthesis which is known to a person skilled in the art (Greene, Wuts Protective Group in Organic Synthesis, Wiley 1991). Thus the compounds of formula (I) can be prepared, according to the following diagram: N ~—N Ri 12- R2 HO OH N ...-N Ri G 0 R4 R2 H N N N.. NH N ...-N R3 (i) Ri G N. G (III) NH Q H 2 R2 x x N ~-N Ri (V) R4 R2 H X N N.. NH N ...—N (II) R3 Ri 0 R (?~PQNH 0 H3hI (IV) R3 A subject of the invention is therefore a process for the preparation of the compounds of formula (I) in which a compound of formula (II) (II) R2 0 R4 H X N NH R3 N .~-N Ri I 2 3 in which R , R , R and R4 are as defined previously is reacted, a) with a compound of formula (III) (III) G NH in which G is as defined previously in the presence of a base or a transition metal coupling reagent b) then the compound of formula (I) is subjected, optionally with cleavage of the R3-NH- function in order to regenerate the free amine, followed by condensation N ..—N Ri '-3 of the R3 radicals of—C02-R5 or -502-R5 structure, and/or if appropriate to the hydrolysis and optionally to esterification or to amidification and/or to salification. By way of a variant, a subject of the invention is also a process for the preparation of the compounds of formula (I) in which a) a compound of formula (II) as defined previously is reacted with a compound of formula (lila): 0 (lila) RO NH in order to obtain the intermediate compound of formula (IV): RO (IV) b) then a compound of formula I-let-NH2 is reacted, in order to obtain the compounds of formula (I) with G representing a Het-NHCO- group, c) then the compound of formula (I) obtained is subjected, optionally with cleavage of the R3-NH- function in order to regenerate the free amine, followed by condensation of radicals R3 of—C02-R5 or -502-R5 structure, and/or if appropriate, to esterification or to amidification and/or to salification. Coupling of a compound of formula (II) with a piperidine derivative of formula (III) or (lila) can be carried out in the presence of a hindered strong base under reflux. In particular diisopropylethylamine is used. The reaction can vary from 4 to 12 hours under reflux. At the level of the compound of formula (IV), when OR is a hydroxyl, therefore if a guanidine of formula (Het-NH2) is reacted with a carboxylic acid of formula (IV), then the carboxylic acid is firstly activated. Activation can be carried out for example with dicyclohexylcarbodiimide (DCCI) or with the O-((cyano(ethoxycarbonyl)-methylene)amino)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU; K~5nig et al, Proc. 21st Europ. Peptide Symp. 1990 (Eds Giralt, Andreu), Escom, Leiden 1991, p.24K3) or another activation agent currently used in peptide synthesis. Apart from the free guanidines of formula (Het-NH2), the guanidine salts can also be used in the reaction with the compounds of formula (IV), the free guanidines being formed in situ or by a separate stage by means of a base. The reaction of an activated carboxylic acid derivative of formula (IV) with the guanidine (or derivative) of formula (Het-NH2) is preferably carried out in a manner known per se in an organic protic or aprotic but inert solvent. In this case, solvents are used such as methanol, isopropanol, tert-butanol, dimethylformarnide, dichloromethane or tetrahydrofuran at temperatures ranging from 00C to the reflux temperature of these solvents, in particular during the reaction of the methyl or ethyl esters (OR is a methoxy or an ethoxy) with guanidines. The reactions of the compounds of formula (IV) with the free guanidines are advantageously carried out in an inert aprotic solvent such as dimethylformamide, tetrahydrofuran, dimethoxyethane or dioxane, if appropriate by adding a base such as for example potassium tert-butoxide, sodium methoxide or an inorganic base such as N-methylmorpholine. However, water can also be used as a solvent in the reactions of the compounds of formula (IV) with the guanidines of formula (I-let-NH2), for example by using a base such as sodium hydroxide. The reaction mixture is then treated and if desired the reaction product is purified according to the methods known to a person skilled in the art. The protective groups optionally present in the compounds of formula (I) obtained from the compounds of formulae (IV) with the amines or guanidines of formula Het-NH2 or from the compounds of formula (II) with the compounds of formula (III) are then eliminated by standard processes ; for example the tert-butyl ester groups are converted to carboxylic acid by treatment with trifluoroacetic acid, the benzyl groups are eliminated by hydrogenation or also the fluorenylmethoxycarbonyl groups are eliminated in the presence of secondary amine and other reactions are carried out using standard processes, for example by acylation reactions. The hydrolysis reactions in order to obtain a derivative of acid (COR4 = CO2H), the esterification reactions in order to obtain an ester or a prodrug (particularly COR4 = alkyloxycarbonyl or aryloxycarbonyl starting from the corresponding acid) or the amidification reactions (COR4 = mono or disubstituted aminocarbonyl starting from the corresponding acid) are carried out according to the usual methods known to a person skilled in the art. In particular the hydrolysis is carried out in an acid medium, in the presence of trifluoracetic acid for example, in a halogenated organic solvent such as dichloromethane for example. If necessary, the conversion to physiologically acceptable salts is carried out by processes known to a person skilled in the art. The starting compounds of formula (II) can be prepared according to the processes described in the literature or also are accessible by analogy. The 15 preparation of the compounds of formula (II) is illustrated in the diagram described above, it being understood that the present invention is not restricted to these syntheses or these starting products. It is not a major difficulty for a person skilled in the art to envisage modifications to the syntheses described in our Application for the preparation of other compounds of formula (II) according to the invention. Therefore a subject of the invention is the process for the preparation of the compounds of formula (II) characterized in that a compound of formula (V): R2 x -~ x (V) N ..—N Ri in which R' and R2 are as defined previously, and X represents a halogen preferably chlorine is reacted with a compound of formula (VI): 0 H2N R4 (VI) HN R3 in which R3 and R4 are as defined previously, in the presence of a strong base. In general, a hindered strong base is used such as diisopropylethylamine under reaction conditions known to a person skilled in the art for the implementation of nucleophilic substitution. Preferably the operation takes place in the presence of dimethylformamide and at reflux temperature. Moreover the COR4 group will preferably represent a hindered ester group such as the tertbutyloxycarbonyl group. According to another variant of the invention, the products of formula (I) can also be prepared according to the following diagram: 16 R2 R2 HO OH X X N. N. -~ N .-N (V) Ri Ri G (Ill) NH 0 G G H2N R4 R2 N. N X HN~ N. R3 (VI) Ri (Ila) According to the invention, the process for the preparation of the products of formula (I) consists of a) the reaction of a product of formula (Ila) G R2 N X N. N-N Ri (Ila) 1 2 in which R , R , G and X are as defined previously, with a product of formula (VI) 0 H2N R4 HN~R3 (VI) in which R3 and R4 are as defined previously, either in the presence of a strong base, or by catalysis with palladium, b) then the product of formula (I) is subjected , optionally to cleavage of the R3-NH- function in order to regenerate the free amine, followed by condensation of the R3 radicals of—C02-R5 or -502-R5 structure, and/or if appropriate to hydrolysis and optionally to esterification or to amidification and/or to salification. The reaction of the pyrimidine of formula (Ila) with the amine of general formula (VI) is carried out under conditions similar to the conditions described '7 previously for the reaction of a pyrimidine of formula (V) with the amine of general formula (VI). In particular, it is possible to operate in diisopropylethylamine in an organic solvent such as an amide (dimethylacetamide, dimethylformamide for example), at a temperature comprised between 900C and the reflux temperature of the reaction mixture. It is also possible to operate by catalysis with palladium (for example tris(dibenzylideneacetone) dipalladium) in the presence of cesium fluoride, at the reflux temperature of the reaction mixture. It is understood that the functions which could interfere with the reaction are protected. The protection and release of these functions is carried out according to the usual methods which do not alter the remainder of the molecule. The condensation of the R3 radicals of—C02-R5 or -502-R5 structure on the free amine, and the hydrolysis are carried out as described previously. The pyrimidine derivatives of formula (ha) can be prepared by the action of a product of formula (III) G (Ill) NH in which G is defined as previously, on a dihalogenated derivative of the pyrimidine of formula (V) R2 x -~ x N —N (V) Ri in which R1, R2 and X are defined as previously. The reaction is advantageously carried out in the presence of a hindered strong base, at the reflux temperature of the reaction mixture. The operation is carried out under the conditions described hereafter in the examples and in particular in the presence of a hindered amine such as diisopropylethylamine, in an amide such as dimethylacetamide for example. It is understood that the functions which could interfere with the reaction are protected. The protection and release of these functions is carried out according to the usual methods which do not alter the remainder of the molecule. The compounds of formula (I) are compounds having a pharmacological activity and can thus be used as medicaments in particular in the treatment or prevention of diseases of the bone, tumorous diseases as well as cardiovascular disorders. 17' Therefore a subject of the present invention is the compounds of formula (I) and/or their physiologically acceptable salts as a medicament. The compounds of formula (I) as well as their physiologically acceptable salts and their prodrugs can be administered to animals, preferably mammals and in particular human beings as therapeutic or prophylactic medicaments. They can be administered as they are or in a mixture with one or more other compounds of formula (I) or also in the form of a pharmaceutical preparation (pharmaceutical composition) which allows enteral or parenteral administration and which contains an effective dose of at least one compound of formula (I) and/or its physiologically acceptable salts as active ingredient as well as current and pharmaceutically inert supports and/or additives. The pharmaceutical compositions according to the invention allow enteral or parenteral administration, containing an effective dose of at least one compound of formula (I) and/or its physiologically acceptable salts as active ingredient as well as one or more pharmaceutically inert supports and/or one or more usual additives. Therefore a subject of the invention is the pharmaceutical compositions containing a compound of formula (I) as defined previously as well as one or more excipients. The medicaments can be administered orally, for example in the form of pills, tablets, coated tablets, film-encased tablets, granules, gelatin capsules and soft capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. The administration can however be carried out by rectal route, for example in the form of suppositories, by parenteral route, for example in the form of injectable solutions, infusions, microcapsules or implants, by percutaneous route, for example in the form of an ointment, solutions, pigments or colorants, by transdermal route in the form of patches, or by other routes such as in the form of an aerosol or nasal spray. The pharmaceutical preparations according to the invention are prepared according to methods known per se, pharmaceutically inert organic or inorganic supports, being added to the compounds of formula (I) and/or their physiologically acceptable salts. For the production of pills, tablets, coated tablets and hard gelatin capsules, it is possible to use for example lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. Suitable supports for soft gelatin capsules or for suppositories are for example fats, waxes, semi-solid or liquid polyols, natural or modified oils, etc. Appropriate vehicles for the preparation of solutions, for example injectable solutions, emulsions or syrups are for example water, alcohols, glycerol, polyols, sucrose, inverted sugars, glucose, vegetable oils, etc. Suitable supports for microcapsules or implants are for example glyoxilic acid and lactic acid copolymers. The pharmaceutical preparations normally contain from 0.5 % to 90 00 by weight of the compounds of formula (I) and/or their physiologically acceptable salts. In addition to the active ingredients and supports, the pharmaceutical preparations can contain additives such as, for example, diluting agents, disintegration agents, binding agents, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, colouring agents, flavouring or aromatizing agents, thickeners, buffering agents, and also solvents or solubilizing agents or agents to obtain a delayed release effect and also salts for modifying the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of formula (I) and/or their physiologically acceptable salts. Moreover, in addition to at least one or more compounds of formula (I) and/or their physiologically acceptable salts, they can contain at least one or more active ingredients which can be used for therapeutic or prophylactic uses. The pharmaceutical preparations (pharmaceutical compositions) normally contain 0.2 to 500 mg, and preferably 1 to 200 mg of the compound of formula (1) and/or their physiologically acceptable salts and/or their prodrugs. The compounds of formula (I) are quite particularly antagonists of the vitronectin receptors and are therefore capable for example of inhibiting the adhesion of osteoclasts on the surface of the bone and thus bone resorption by the osteoclasts. The action of the compounds of formula (I) can be demonstrated for example in a test in which the inhibition of the binding of vitronectin to the cells which contain the vitronectin receptor is determined. Further information about this test is given below. As antagonists of the vitronectin receptor, the compounds of formula (I) and their physiologically acceptable salts are in general suitable for the treatment or prevention of diseases linked to the interactions between the vitronectin receptors and their ligands, in the process of cell-cell or cell-matrix interaction or which can be influenced by the inhibition of interactions of this type, to relieve or cure when inhibition of interactions of this type is desired. As explained at the beginning, such an interaction plays an important role in bone resorption, in angiogenesis or in cell proliferation of the vascular smooth muscle cells. Bone diseases the treatment or prevention of which require the use of the compounds of formula (I) are in particular osteoporosis, hypercalcemia, osteopenia, for example caused by bony metastases, dental disorders for example parodontitis, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, and Paget's disease. Moreover the compounds of formula (I) can be used to relieve, prevent or treat bone disorders which are caused by treatments with glucocorticoids, therapies linked to taking steroids or corticosteroids or male or female sex hormone deficiencies. All these disorders are characterized by bone loss, which is caused by a lack of equilibrium between bone formation and bone destruction and which can be favourably influenced by the inhibition of bone resorption by the osteoclasts. Besides this use as an inhibitor of bone resorption mediated via the osteoclasts, the compounds of formula (I) and their physiologically acceptable salts are used as inhibitors of tumorous growth or of cancerous metastases, in the treatment of inflammatory disorders, for the treatment or prevention of cardiovascular disorders. such as arteriosclerosis or restenosis, or the treatment or prevention of nephropathy or retinopathy such as for example diabetic retinopathy. The compounds according to the invention can also have an activity with respect to other integrmns which interact with their ligands via the tripeptide sequence RGD (a431, O.v~5, ~HbP3), giving them pharmacological properties which can be used to treat pathologies associated with these receptors. This activity vis-~-vis the integrins therefore makes the compounds of formula (I) of use in the prevention or treatment of numerous diseases such as those mentioned above or in the publication by Dermot Cox DN§P 8(4) May 1995, 197— 205 the content of which is incorporated in the present Application. Therefore a more particular subject of the present invention is a compound of formula (I) and/or its physiologically acceptable salts as defined above as a medicament having an antagonist activity on the vitronectin receptor. Therefore a more particular subject of the present invention is a compound of formula (I) and/or its physiologically acceptable salts and/or its prodrugs as defined above as a medicament having an inhibitory activity on bone resorption or for the treatment or prevention of osteoporosis. Therefore a more particular subject of the present invention is a compound of formula (I) and/or its physiologically acceptable salts as defined above as a medicament having an inhibitory activity on tumorous growth or cancerous metastases. Therefore a more particular subject of the present invention is a compound of formula (I) and/or its physiologically acceptable salts as defined above as a medicament having an anti-inflammatory activity or for the treatment or prevention of cardiovascular disorders, restenosis, arteriosclerosis, nephropathies or retinopathies. A subject of the present invention is also the use of the compounds of formula (I) and/or their physiologically acceptable salts as defined above for the preparation of medicaments intended for the prevention or treatment of osteoporosis. 21 A subject of the present invention is also the use of the compounds of formula (I) and/or their physiologically acceptable salts as defined above for the preparation of medicaments intended to inhibit tumorous growth or cancerous metastases. A subject of the present invention is also the use of the compounds of formula (I) and/or their physiologically acceptable salts as defined above for the preparation of medicaments intended for the prevention or the treatment of cardiovascular disorders, restenosis, arteriosclerosis, nephropathies or retinopathies. When the compounds of formula (I) are used, the doses can vary within broad limits and must be set according to the person treated. This depends for example on the compound used and the nature and severity of the disease to be treated, whether the conditions are serious or acute and if a prophylactic treatment is used. In the case of administration by oral route, the daily dose in general varies from 0.01 to 100 mg/kg and preferably from 0.1 to 50 mg/kg, in particular from 0.1 to 5 mg/kg. For example, for an adult weighing 75 kg, a daily dose can be envisaged varying from 0.3 to 0.5 mg/kg. In the case of administration by intravenous route, the daily dose varies approximately from 0.01 to 100 mg/kg and preferably from 0.05 to 10 mg/kg. The daily dose can be divided, in particular in the case of the administration of a large quantity of active ingredient, into several, for example 2, 3 or 4 parts. If appropriate, depending on individual behaviour, it may be necessary to administer different increasing or decreasing doses. Apart from the use of the compounds of formula (I) as medicaments, it is also possible to envisage their use as a vehicle or support for active ingredients in order to deliver these active compounds specifically towards the target (Drug targeting, see Targeted Drug Delivery, R.C. Juliano, Handbook of Experimental Pharmacology, Vol 100, Ed. Born, G.V.R. et al, Springer Verlag). The active ingredients which can be delivered are in particular those used for the treatment or prevention of the diseases mentioned above. The compounds of formula (I) and their salts can also be used as a diagnostic agent, for example for in vitro methods or as auxiliaries in biochemical studies in which blocking the vitronectin receptor or influencing cell-cell or cell-matrix interactions are desired. They can moreover be used as an intermediate for the preparation of other compounds, in particular other active ingredients, which are accessible from the compounds of formula (I), for example by modification or introduction of radicals or functional groups. 22-. EXAMPLES The products were identified by mass spectrum (MS), infrared (IR) and/or NMR spectrum. The compounds which were purified by chromatography using an eluent which contains for example acetic or trifluoroacetic acid, and which are then dried or in which, during the last synthesis stage, for example trifluoroacetic acid was used in order to eliminate a tert-butyl protective group, sometimes contain, depending on the manner in which the product was dried, the acid originating from the eluent or the last synthesis stage and are therefore found partially or completely in the form of the salt of the acid used, for example in the form of an acetic or trifluoroacetic acid salt. They can also be more or less hydrated. Abbreviations/chemical names optionally used: AcOEt: ethyl acetate; EDCI: 1 -(3 -dimethylaminopropyl)-3 -ethyl-carbodi imide hydrichloride ; DMF: dimethylformamide; DIPEA: Diisopropylethylamine ; MeOH: methanol ; TEA: triethylamine ; TFA: trifluoroacetic acid ; THF: tetrahydrofuran MCPBA: meta-chloroperoxybenzoic acid ; DBU: I ,8-diazabicyc lo[5 .4.0]undec-7-ene ; PTSA: paratoluenesulphonic acid; DPPA: diphenylphosphorylazide ; DMSO: dimethylsulphoxide ; Pd/C Palladium on carbon ; Boc: terbutoxycarbonyl ; CBz: benzyloxycarbonyl ; DCC 1 ,3-dicyclohexylcarbodiimide ; BrTMS: bromotrimethylsi-lane ; TMSI: trimethylsilane iodide. IR: Infrared ; NMR: Nuclear Magnetic Resonance ; MS: Mass Spectrum ; PES: Positive mode electrospray ; sh.: shoulder ; 5: strong ; 5: singlet ; d: doublet ; t: triplet; quad: quadruplet ; quint: quintuplet ; b: broad ; m: multiplet ; J: coupling constant; Rf: retention factor (chromatography). It is understood that in the examples which follow the products of Examples I to S are in racemic form, the products of Examples 6 to 9, 11, and 13 to 41 as well as their ester precursors are in (5) form on the asymmetrical centre of the 3-amino alanine and Examples 10 and 12 and if appropriate their ester precursors are in (R) form on the asymmetrical centre of the 3-amino alanine. Preparation I Synthesis of 4,6-dichloro-5-ethyl-pyrimidine (Compound of formula (V). HO N. OH POGI3/PhNEt2 N. N N A mixture of 5 g (35.7 mmoles) of 5-ethyl-4,6-dihydroxy-pyrimidine (marketed by Aldrich) in 30 ml of phosphorus oxychloride is taken to reflux for 1 hour. After returning to ambient temperature, a mixture of 4 ml of N,Ndiethylaniline in 10 ml of phosphorus oxychloride is added dropwise and the reaction 23 medium is taken to reflux for 4 hours. After returning to ambient temperature, the reaction medium is poured into a mixture of ice and water, followed by extracting with ethyl acetate, washing the organic phases with 2N hydrochloric acid, drying over magnesium sulphate and evaporating to dryness under vacuum. 6 g (Yield 95 %) of a brown oil of expected product is obtained used as it is for the following. TLC Rf=0.5 (silicagel, eluent: dichloromethane-methanol 90-10) Example 1 3-[[5-ethyl-6-[4-( 1 ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinylj-4-pyrimidinyl]aminoj-N-[(phenylmethoxy) carbonyljalanine, bis(trifluoroacetate) Stai~e a) Synthesis of (1,1 -dimethylethyl) 3-[(6-chloro-5-ethyl-4-pyrimidinyl)amino]-N— [(phenylmethoxy)carbonyl] alaninate. 0 0 o o ci ci HN H I + 2 NH DIPEA/DMF CI N NH N N o o — N~>N ~ 10 ml of diisopropylethylamine is added to a mixture of 3.8 g (21 mmoles) of 4,6-dichloro-5-ethyl-pyrimidine and 4.4 g (15 mmoles) of (l,l-dimethylethyl)3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem.(200 1), 44(8), 1158-1176) in 50 ml of dimethylformamide, then this mixture is heated at 1200C for 6 hours. Then the dimethylformamide is eliminated under vacuum and the residue is taken up in a mixture of ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is decanted then dried over magnesium sulphate and the solvent is eliminated by evaporation under vacuum. The residue is chromatographed on silicagel eluting with a gradient of 100 % heptane to heptane-ethyl acetate 50-50. 4.7 g (Yield = 70 %) of expected product is obtained in the form of an oil. TLC Rf=0.2 (silicagel, eluent: heptane-ethyl acetate 70-30) IR (CHCI3) 3411 (NH) ; 1718 (C=O) ; 1571;1498 cm-l (Heterocycle±Aromatic±Amide) 1H-NMR (DMSO.-d6) 6 1.02 (t, 3H, CH2-CH3) ; 1.30 (s, 9H, tBu) ; 2.57 (q, 2H CH2-CH3); 3.74 (in, 2H NH-CH2-CH-NH) ; 4.29 (bq, JH, NH-CH2-CH-NH); 5.00 and 5.06 (syst. AB, 2H, O-CH2-Ph) ; 7.22 (bt, lH, NH-CH2-CH-NH) ; 7.34 (in, SH, Ph) ; 7.64 (bd, 1H, NH-CH2-CH-NH) ; 8.16 ppm (s, IH, N=CH-N) HPLC/MS (tr=26 mm): 435 (MH±) ; 379 (MH-tBu±). Sta2e b) Synthesis of (1,1 -dimethylethyl) 3-[[5 -ethyl-6-f4-( 1,2,3 ,4-tetrahydro- I 98 naphthyridin-7-yl)- I -piperidinyl]-4-pyrimidinyl]amino] -N[(phenylmethoxy)carbonyl]alaninate. DIPEA NH N ~N A mixture of 1.68 g (3 mmoles) of l,2,3,4-tetrahydro-7-(4-piperidinyl)-1,8— naphthyridine, tris(trifluoroacetate) (prepared according to Patents EP1065207 or WO 0078317) and 7.5 g (14.1 mmoles base equivalents) of aminomethyl polystyrene (Polymer Labs 1.88 mmoles/g) in 200 ml of a solution of dichloromethane-methanol 50-50 is stirred at ambient temperature for 1 hour. The mixture is filtered, the resin is washed with methanol and dichloromethane and the filtrate is concentrated to dryness under vacuum producing 630 mg of free amine. 651 mg (1.5 mmoles) of (1,1 -dimethylethyl) 3- [(6-chloro-5 -ethyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy) carbonyllalaninate and 2 ml of diisopropylethylamine are added to this residue and the reaction medium taken to reflux for 8 hours, followed by evaporating to dryness under vacuum and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent evaporated off under vacuum. The residue is chromatographed on silicagel eluting successively with pure dichioromethane, a mixture of dichloromethane-methanol 90-10 then a mixture of dichloromethanemethanol-water-acetic acid 90-10-1-1. 115 mg (Yield = 12 %) of expected product is obtained in the form of oil. Another 280 mg (43 %) of chlorinated starting compound is also recovered. TLC Rf= 0.55 (alumina, eluent: heptane-ethyl acetate 50-50). IR (CHCI3) 3438 (NH 1717 (C=O) ; 1583 ; 1500 cm-I (Heterocycle+Aromatic+Amide). 1H-NMR (DMSO-d6) 6 1.06 (t, 3H, CH2-CH3); 1.31 (s, 9H, tBu) ; 1.77 (ni, 211, CH2-CH2-CFI2-NH); 1.78 (in, 4H, CH2-CH-CH2) ; 2.43 (q, 2H, CH2-CH3) ; 2.51 (in, 111, CFI2-CH-CH2) ; 2.61 (in, 211, CH2-CH2-CH2-NII) ; 2.82 and 3.44 (2m, 411, CH2-CH2-N-CH2-CH2) ; 3.23 (in, 211, CH2-CH2-CH2-N1J) ; 3.72 (in, 2H, NH-CH2- CH-NH) ; 4.23 (in, lH, NH-CH2-CH-NH) ; 5.03 (bd, 2H, CH2-Ph) ; 6.22 (in, lH, C[12- CH2-CH2-NII) ; 6.30 and 7.05 (2m, 211, H naphthyridine) ; 6.35 (in, lH, NH—CH2- CH-NH) ; 7.34 (in, 511, Ph); 7.60 (in, 111, NH-CH2-CH-NH) ; 8.11 ppm (N=CH-N). 2 CF3000H 25 HPLC/MS: (rt = 14 mm): 616 (MH+). Stare c) Synthesis of 3 -[[5 -ethyl-6-[4-( I ,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1-piperidinyl]-4-pyrimidinyljaininoj-N-[(phenylinethoxy)carbonyl]alanine, bis(trifluoroacetate). 0 OH H N NH 0A0 7 110 mg (0.18 minoles) of (1,1-diinethylethyl) 3-[[5-ethyl-6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 5 ml of dichloroinethane is stirred with 1 ml of trifluoroacetic acid at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: C112C12-MeOH-1120-AcOH 90-10-1 -1). Toluene is added and the reaction medium is evaporated to dryness under vacuum. The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 108 ing (Yield = 76 %) of expected product is obtained in the form of an amorphous solid. TLC Rf=0.33 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1) IR (CHCI3) 1677 (C=O) ; 1626 ; 1586 ; 1500 cm-I (Heterocycle±Aromatic±Amide). 1H-NMR (DMSO-d6) 6 1.07 (t, 3H, CH2-C113); 1.77 and 1.94 (2m, 411, NCH2-C112-CH-); 1.84 (in, 211, NH-CH2-C112-CH2-) ; 2.45 (q, 211, CH2-CH3) ; 2.75 (t, 211, NH-CH2-C112-CH2-) ; 2.85 (t, 111, N-C112-CH2-CH-) ; 2.98 and 3.53 (2m, 411, N-CH2-CH2-CH-) ; 3.43 (in, 211, N-CH2-CH2-CH2-) ; 3.61 and 3.85 (2m, 211, NH-C112-CH-NH) ; 4.32 (q, 111, NH-CVI2-CH-NH) ; 4.99 and 5.04 (syst NB, 211, 0- CH2-Ph) ; 6.67 (d, 111, 11 naphthyridine) ; 7.22 (bs, 111, NH-C112-CH-NH) ; 7.35 (in, 511, Ph) ; 7.60 (d, 11-I, NH-C112-CH-NH) ; 7.64 (d, 111, 11 naphthyridine), 8.26 (s, 111, N9=CH-N); 8.29 ppm (bs, 111, NH-CH2-C112-CH2-). HPLC/MS (rt = 8.0 mm): 560 (MH+) ; 427 (M11-Naphthyridine±) ; 280 (M+2H±+) Microanalysis: theoretical C=5 1.84% ; 11=4.99% ; N12.45 %; found C=52.0 %; 11=5.2 % ; N=12.4 %; Example 2 3-1t5-ethyl-6-14-I(1,2,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyll- 1- piperidinyll-4-pyrimidinyllaminol-N-I(phenylmethoxy)carbonyll alanine. Stage a) Synthesis of (1,1 -diinethylethyl) 3 -[[5-ethyl-6-[4-(methoxycarbonyl)- 1-. piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylmethoxy)carbonyl Jalaninate. 0 0 I ~ ow 0 0 H OIPEA 0 Ci N H N0 N NH N N NH NH N~N N~N o~ 7 7 A mixture of 1.2 g (2.8 minoles) of(1,1-dimethylethyl) 3-[(6-chloro-5-ethyl-4-pyriinidinyl)ainino]-N-[(phenyl methoxy)carbonyl]alaninate, 5 ml of methyl 4-piperidinylcarboxylate and 1 ml of isopropylethylamine is heated between 110 and 1200C for 4 hours. After cooling down to ambient temperature, the reaction medium is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate then concentrated to dryness under vacuum. The residue is chromatographed on silicagel with a gradient of pure heptane to pure ethyl acetate. 260 ing (Yield = 17 %) of expected product is obtained in the form of an oil. TLC : Rf=0.36 (silicagel, eluent: heptane-ethyl acetate 50-50). IR (CHCI3) : 3422 (NH) ; 1725 (C0) ; 1582 ; 1499 cm-l (Heterocycle±Aroinatic+Ainide) lH-NMR (DMSO-d6) : 6 1.05 (t, 3H, CH2-C113); 1.30 (s, 911, tBu); 1.67 and 1.88 (2m, 411, N-C112-C112-CH) ; 2.40 (q, 211, C112-CH3) ; 2.50 (in, 111, N-C112-- C112-CH) ; 2.81 and 3.33 (2m, 411, N-C112-C112-CH) ; 3.62 (s, 311, O-CH3) ; 3.71 (in, 211, NH-C112-CH-NH) ; 4.22 (q, 111, NH-CH2-CH-N11) ; 5.02 (s, 211, O-C112- Ph) ; 6.36 (t, 111, NH-C112-CH-NH) ; 7.34 (in, 511, Ph); 7.64 (d, 111, N11-CH2-CH- NH); 8.10 ppm (s, 111, N=CH-N). HPLC/MS: (rt = 12mm): 564 (MNa±) ; 542 (MH±) ; 486 (M11-tBu±). Stage b) Synthesis of 3-[[5-ethyl-6-[4-[( 1,2,3 ,4,5,6-hexahydro-2-pyrimidinyl)iininocar-bonyll- I -piperidinyl]-4-pyriinidinyl] amino]-N-[(phenylinethoxy)carbonylj alanine. N NH 0 OH H 2 H NH CH202 o~"o 7 A mixture of 250 ing (0.46 minoles) of 1,1-dimethylethyl) 3-[[5-ethyl-6-[4-(inethoxycarbonyl)- 1 -piperidinyl] -4-pyrimidinyl]amino]-N- [(phenylinethoxy)carbonyl]alaninate and 200 mg (2.0 minoles) of 2-ainino-l.4,5,6-tetrahydropyriinidine (prepared according to R. F. Evans J. Chein. Soc. 1964, 2450-245 5) in 15 ml of dichloroinethane is stirred for 24 hours at ambient temperature. After evaporation to dryness under vacuum, the residue is chroinatographed on silicagel eluting with a gradient of pure dichloroinethane to a dichloromethane-methanol-water-acetic acid mixture 85-15-2-2. After evaporation of the solvent of useful fractions, the residue is taken up in the minimum amount of a mixture of inethanol-dichloromethane 50-50 and the acid precipitates by the addition of ethyl ether. After filtration and drying under vacuum 18 mg (Yield = 7 %) of expected product is obtained in the form of an amorphous solid. TLC Rf=0.5 (silicagel, eluent: dichloroinethane-methanol-acetic acid 70-20-10) IR (CHCI3) : 3287 (OH/NH) ; 1700 ; 1600 (C=O) ; 1582 ; 1499 cm-l (Heterocycle± Aroinatic±Ainide). 1H-NMR (DMSO-d6) : 6 1.05 (t, 311, CH2-C113); 1.67 and 1.86 (2in,4H, NC112-CH2-CH-); 1.80 (in, 211, NH-C112-C112-C112-NH) ; 2.26 (in, 111, N-CH2- C112-CH-) ; 2.38 (in, 211, C112-CH3) ; 2.78 and 3.33 (2in, 411, N-C112-C112-C11-) 3.24 (in, 411, NH-C112-CH2-CH2-NH) ; 3.42 and 3.75 (2m, 2H, N11-CH2-CH-NH); 4.08 (in, 111, NH-C112-CH-NH) ; 4.95 and 5.00 (syst AB, 211, O-CH2-Ph) ; 6.10 (bt, 111 NH-C112-CH-NH) ; 6.74 (bs, 111, NH-CH2-CH-NH) ; 7.30 (in, 511, Ph) ; 8.05 (s, 111, N=CH-N) ; 8.55 ppm (bs, 211, NH-C112-C112-CH2-N11). HPLC/MS : (rt = 6mm): 553 (MI-I-I-) ; 364 (MIH-tBu-PhCH2+) ; 320 (MI-I-tBu-Z+). Example 3 3-f f6-f4-( 1 ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyll -5-methyl-4-pyrimidinyll aminol-N-I(phenylmethoxy) carbonyll alanine Stage a) Synthesis of (1,1 -diinethylethyl)3-[(6-chloro-5-inethyl-4-pyrimidinyl)aininoj-N-[(phenylmethoxy)carbonyl] alaninate. 0 0 ci ci H2N DIPEA/DMF NH _________ + N~N o o N$ DIPEA A mixture of 325 mg (2 inmoles) of 4,6-dichloro-5-inethyl-pyrimidine (marketed by SPECS), 600 ing (2 inmoles) of (1,1-diinethylethyl) 3-amino-N-[(phenylmethoxy)carbonyll alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176) in 3 ml of diinethylformainide and 3 ml of diisopropylethylainine is heated at 1200C overnight. The reaction medium is concentrated to dryness under vacuum and the residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. The residue is chroinatographed on silicagel eluting with a gradient of heptane (100 %) to a mixture of heptane-ethyl acetate (50-50). 450 ing (Yield = 53 00) of expected product is obtained in the form of an oil. TLC : Rf=0.5 (silicagel, eluent: ethyl acetate-heptane( 25-75) 1II-NMR (CDC13) 6 1.48 (s, 9H, tBu) ; 2.08 (s, 311, C113) 3.80 and 3.97 (2in, 211, NH-C112-CH-NH) ; 4.50 (in, IH, NH-CH2-C11-NI-I) ; 5.08 and 5.15 (syst AB, 211, O-CH2-Ph) ; 5.86 (bd, 111, NH-CH2-CH-NH) ; 6.12 (bs 111 NH-C112-CH- NI-I) ; 7.35 (in, 511, Ph); 8.30 ppm (s, 111, N=C11-N). MS (FAB) : 421 (MH+) ; 365 (MH-tBu). Stage bi Synthesis of (1,1 -diinethylethyl) 3-j46-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-5-inethyl-4-pyriinidinyl]ainino]-N- [(phenylinethoxy)carbonyl]alaninate. 7 N 0 N N H N N N~N o 0 'N. K A mixture of 370 mg (0.88 minoles) of (1,1-diinethylethyl) 3-[(6-chloro-5-inethyl-4-pyriinidinyl)ainino]-N-[(phenylinethoxy)carbonyll alaninate and 1.0 g (1.79 ininoles) of 1,2,3 ,4-tetrahydro-7-(4-piperidinyl)- I ,8-naphthyridine, tris (trifluoroacetate) (prepared according to Patents EP 1065207 or WO 0078317) in 1 ml of diisopropylethylainine is heated at 1200C for 2 hours. Then 10 ml of xylene is added and the medium is taken to reflux for 4 hours. The reaction medium is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum and the residue is chroinatographed on silicagel with a gradient of 100 % ethyl acetate to a mixture of ethyl acetate-methanol~ triethylainine-dichloroinethane 50-10-10-SO. 32 mg (Yield = 6 %) of expected product is obtained and 200 ing (54 %) of chlorinated starting product is recovered. TLC Rf=0.6 (silicagel, eluent: ethyl acetate-dichloroinethane-inethanol 50-40-10) 1H-NMR (CDCI3) : 6 1.49 (s, 911, tBu); 1.97 (in, 211, NH-CH2-C112-C112); 2.01 (s, 311, CH3) ; 2.18 (in, 4H, N-CH2-C112-CH) ; 2.79 (in, 211, NH-CH2-CH2- C112) ; 2.98 (in, 111, N-C112-CH2-CH) ; 3.39 and 3.89 (2m, 411, N-C112-C112-CII) 3.52 (in, 211, NH-C112-CH2-C112); 3.77 and 4.09 (2in, 211, NH-C112-CH-NH) ; 4.47 (in, 111, NH-CH2-CH-NH) ; 5.13 (bs, 211, O-C112-Ph) ; 5.92 (bs, 111, NH-CH2-CH- NFL) ; 6.47 (bd, 111, H naphthyridine) ; 7.37 (in, 51-I, Ph) ; 7.38 (in, III, H naphthyridine) ; 8.41 ; 8.68 and 14.80 ppm (3bs, 311, N=CH-N and mobiles). MS : 602 (MH+) ; 546 (MH-tBu+). Stare ci Synthesis of 3-[[6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidi nyl 5-inethyl-4-pyriinidinyl]ainino]-N-[(phenylinethoxy)carbonyl]alanine. GF3c001-vQ-t2a2 0 OH ___________ H NH NH 'N K A mixture of 38 mg (0.06 ininoles) of (1,1-dimethylethyl) 3-[[6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-5-inethyl-4-pyriinidinyl]ainino]-N-[(phenyl inethoxy)carbonyllalaninate and 2 ml of trifluoroacetic acid in 10 ml of dichioroinethane is stirred at ambient temperature for 3 hours. Then 5 ml of toluene is added followed by evaporating the mixture to dryness. 26 mg (Yield = 76 %) of expected product is obtained in the form of an amorphous solid. TLC Rf=0.8 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1). 1H-NMiR (DMSO-d6) 6 1.84 (in, 211, NH-CH2-C112-C112) ; 1.92 (s, 311, CH3) ; 1.75 and 1.91 (2m, 411, N-CH2-C112-CH) ; 2.74 (in, 211, NH-C112-CH2- CH2) ; 2.84 (in, LH, N-C112-CH2-C11) ; 2.92 and 3.67 (2in, 411, N-CH2-C112-CH); 3.44 (in, 2H, NH-CH2-CH2-C112); 3.63 and 3.82 (2in, 211, NH-C112-CH-NH) ; 4.29 (in, 111, NH-CH2-CLI-NH) ; 5.02 (bs, 211, O-C112-Ph) ; 6.68 (d, 111, H naphthyridine); 7.20 to 7.40 (in, 511, Ph) ; 7.64 (bd, 111, NH-C112-C11-N11); 7.65 (d, 111, H naphthyridine) ; 7.82 and 8.21 ppm (2bs, 311, N=CH-N and mobiles). HPLC/MS : (rt = 7mm) 546 (MH+) ; 273 (M-i-211++). 3d Example 4 3-116-14-1(1,2 ,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyll -1- piperidinyll-5-methyl-4-pyrimidinyll aminol-N-t(phenylmethoxy)carbonyll alanine Sta2e a) Synthesis of (1,1 -diinethylethyl) 3-[[6-[4-(inethoxycarbonyl)- 1 -piperidinyl]-5--inethyl-4-pyriinidinyl]ainino]-N-[(phenylmethoxy)carbonyl]alaninate. + Ci N __________ 'N NH N~N 0~N.0 ~ 7 0 N. 0 NH 0 DIPEA N.0 H N N 'N NH N~N 0~1N.0 'N. K A mixture of 80 mg (0.19 minoles) of (1,1-diinethylethyl) 3-[(6-chloro-5-inethyl-4-pyriinidinyl)ainino]-N-[(phenylinethoxy) carbonyl] alaninate and 3 ml of methyl 4-piperidinylcarboxylate is heated under refiux for 3 hours. After cooling down the reaction medium is taken up in water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent eliminated under vacuum. The residue is chroinatographed on silicagel eluting with a gradient of heptane (100 %) to heptaneethyl acetate (50-50). 25 mg (Yield = 25 %) of the expected product is obtained in the form of oil. TLC: Rf=0.3 (silicagel, eluent: ethyl acetate-heptane 50-50) IR (CHCI3) : 3421(NH); 1724(C=O); 1585; 1501 cin-l(C=C, C=N) 1H-NMR (DMSO-d6) : 6 1.31 (s, 911, tBu) ; 1.68 (bq, 2H, C112-CH(C=O)); 1.87 (in, 211, CH2-CH(C=O)); 1.87 (s, 311, CH3-C=) ; 2.51 (masked, lH, -CH2-CH- C112-) ; 2.80 (bt, 211, -N-(CH2)2-(C112)2-) ; 3.44 (bd, 211, -N-(C112 2-(C112)2-) 3.62 (s, 311, CH3-O) ; 3.71 (in, 211, NH-CH2-CH-NH-) ; 4.22 (in, 111, NH-C112-CH- NH-) ; 5.03 (bs, 211, O-C112-Ph) ; 6.35 bs, 111, NH-CH2-CH-NH-) ; 7.34 (in, 511, Ph) ; 7.63 (bd, 111, NH-C112-CH-NH-) ; 8.08 ppm (s, 111, N=C11-N). HPLC/MS (rt = I 7mm) 528 (MH±) ; 472 (MH-tBu±) Stare b) Synthesis of 3-[[6-[4-[( 1 ,2,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyl]- 1-piperidinyl]-5 -inethyl-4-pyriinidinyl]aininoj-N-[(phenylinethoxy)carbonyl]alanine. NH 0 N NH2 N N H H CH2CI2 0 N N 'N NH N~N 'N 7 O OH H N NH 'N 7 2 I-C 31 A mixture of 100 mg (0.19 ininoles) of (1,1-diinethylethyl) 3-[[6-[4-(inethoxycarbonyl)- I -piperidinyl]-5 -methyl-4-pyriinidinyl] ainino]-N[(phenylinethoxy) carbonyl]alaninate and 150 ing (1.5 inmoles) of 2-ainino-1.4,5,6-tetrahydropyrimidine (prepared according to R. F. Evans J. Chein. Soc. 1964, 2450-245 5) in 10 ml of dichloroinethane is stirred at ambient temperature for S hours. The reaction medium is evaporated to dryness under vacuum and the residue is chroinatographed on silicagel eluting with a dichloroinethane-inethanol-water-acetic acid mixture 85-15-2-2. 10 ing (Yield = 10 %) of expected product is obtained in the form of an amorphous solid. TLC : Rf=0.4 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 85-15-2-2) 1H-NMR (DMSO-d6) : 6 1.64 and 1.74 (2m, 411, N-C112-C112-CH); 1.77 (in, 211, NH-C112-C112-C112-NH); 1.85 (s, 311, CH3) ; 2.11 (in, 111, N-C112-CH2-C11); 3.17 (in, 411, NH-CH2-C112-CH2-NH) ; 2.68 and 3.42 (2m, 411, N-C112-CH2-CH); 3.30 and 3.62 (2m, 211, 11N-C112-CH-NH) ; 3.73 (in, lI-I, N-CH2-CH-NH); 5.00 (in, 211, O-C112-Ph) ; 6.54 (bd, 111, NH-C112-CH-N11) ; 6.77 (bs, 111, NH-C112-CH- NH) ; 7.33 (in, 511, Ph) ; 8.04 ppm (s, 111, N=CH-N). HPLC/MS : (rt = 1.9mm) 1077 (2M11+) ; 539 (MH±) ; 440 (MHaininotetrahydro pyriinidine+) Examnle 5 ethyl 3-1 15-ethyl-6-14-(1 ,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperi-dinyll-4-pyrimidinyll aminoJ-N-j(phenylmethoxy)carbonylj alaninate, dihydrochioride 0 ce S~X~2IEtOH H NI NI 'N 'N 7 7 160 iil (2.19 ininoles) of thionyl chloride is added to 4 ml of ethanol cooled down to —120C under a nitrogen atmosphere and the mixture is stirred for 30 minutes. Then a solution of 354 ing (0.45 inmoles) of 3-[[5-ethyl-6-[4-(l ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylinethoxy)carbonyl]alanine, bis(trifluoroacetate) in 13 ml of ethanol is added. The mixture is stirred for 30 minutes at —120C then left to return to ambient temperature and finally heated at 400C for 4 hours under nitrogen. The reaction 3d.. medium is evaporated to dryness under vacuum and the residue crystallizes from a mixture of diisopropyl ether and of pentane and the solid is filtered. 284 mg (Yield = 95 %) of expected product is obtained in the form of an amorphous beige solid. TLC : Rf=0.4 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1) IR (CHCI3) : 3400-3000(011, NH); 1719(C=O) ; 1654 ; 1623 ; 1580 ; 1504 cin-l(C=C, C=N, aromatic) 1H-NMR (DMSO-d6) 6 1.09 (t, 311, CH2-C113); 1.14 (t, 311, O-CH2-C113); 1.85 (in, 211, N11-C112-C112-C112); 1.85 and 2.00 (2in, 411, N-CH2-C112-CH) ; 2.48 (in, 211, CH2-C113) ; 2.75 (t, 211, NH-C112-C112-C112) ; 2.92 (in, 111, N-C112-C112- C11) ; 3.03 and 3.57 (2in, 411, N-C112-CH2-CH) ; 3.44 (t, 211, N-C112-CH2-CH2) 3.76 and 3.87 (2in, 211, NH-C112-CH-NH) ; 4.07 (q, 211, O-CH2-CH3) ; 4.39 (q, 111. NH-CH2-CH-NH) ; 5.03 (s, 211, O-CH2-Ph) ; 6.62 (d, 111, 11 naphthyridine) ; 6.86 (bs, lH NH-C112-CH-NH) ; 7.30 (in, 511, Ph) ; 7.33 (bs, lH, NH-C112-CH-NH) 7.58 (d, 111, 11 naphthyridine) ; 8.20 ppm (s, 111, NCH-N). HPLC/MS : (rt = 6.2mm) 588 (MH±) ; 454 (MH-COOCH2Ph±) ; 437 (M11-NHCOOCH2Ph±). Example 6 Synthesis of 4,6-dihydroxy-5-inethyl-pyriinidine. ~K— + H3N~NH EtONa HO OH O 0 0 EIOH N~N 102 ml (282 inmoles) of a solution of sodium ethylate at 21 % in ethanol is added to a solution of 7.5 g (94 ininoles) of formamidine hydrochloride in 250 ml of ethanol cooled down to 00C and the mixture is stirred for 30 minutes ; then a solution of 13 ml (94 inmoles) of diethyl methyl inalonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and acetic acid in order to adjust the pH to 6. The precipitate is filtered then washed successively with water, isopropanol, diethyl ether and finally with pentane. 7 g (Yield = 60 %) of expected product is obtained in the form of a beige solid. TLC : Rf=0.20 (silicagel, eluent: ethyl acetate- dichloromethane-inethanol 50-40-10) 1H-NMR (DMSO d6): ppm 1.73 (s, 311, C-CH3) ; 7.88 (s, N=CH-N). MS:127 (M11+); 125 (M-H-). -3-2:37 Synthesis of 4,6-dibroino-5-inethyl-pyrimidine. HO OH POBr3 Br N. Br N. N .~ N N N A mixture of 6 g (47.6 ininoles) of 5-methyl-4,6-dihydroxy-pyriinidine in 18 g of phosphorus oxybroinide is taken to 2000C for 3 hours. After returning to ambient temperature, the reaction mixture is taken up in a mixture of iced water and sodium bicarbonate and extraction is carried out with ethyl acetate, followed by washing the organic phases with water, drying over magnesium sulphate and evaporating to dryness under reduced pressure (2 kPa). 9 g (Yield = 75 %) of a beige solid is obtained. TLC : Rf=0.27 (silicagel, eluent: dichloromethane-pentane 50-50) 1H-NMR (CDC13): ppm 2.58 (s, 311, C-CHi) ; 8.51 (s, N=CH-N). MS : 253-255 (MH±). Synthesis of 6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl )- I -piperidinyl]-5-inethyl-4-bromo-pyriinidine: Br Br DMA/DIPEA N. N N Br 70 ml diinethylacetamide, 7.56 g (30 minoles) of 4,6-dibroino-5-inethyl-pyriinidine in solution in 40 ml of dimethylacetainide and 14 ml of diisopropylethylamine are added into a single-necked flask containing 8 g (36.8 inmoles) of 4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidine released from its salt. This mixture is heated at 1400C for 4 hours then concentrated to dryness under reduced pressure (2 kPa). The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). The solid obtained is washed several times with diisopropyl ether then with pentane, 7.7 g of the expected product is obtained in the form of a light brown powder. The filtrate is concentrated to dryness then chroinatographed on silicagel eluting with a gradient of ethyl acetate (100 %) then ethyl acetate- methanol (95-5). 533 ing of expected product is obtained in the form of a yellow powder. (Overall yield = 70 %) Preparation of naphthyridine in free amine form: 3?, 22 g of naphthyridine is displaced from its salt by 6 mass equivalents of basic ainberlyst A2 1 resin (resin of R-NMe2 type) in a CH2Cl2 / MeOH /AcOEt mixture 1/1/1 under stirring for 30 minutes. The resin is washed beforehand and left to swell for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the displacement of the salt to be complete. After filtration of the resin and evaporation of the solvents, 8 g (36.8 inmoles) of free naphthyridine is obtained. TLC Rf=0.33 (silicagel, eluent: ethyl acetate (100 %)). 1H-NMR (DMSO-d6) : 6 1.7 to 1.85 (in, 611, NH-C112-C112-C112, N-CH2- CH2-CH-CH2) ; 2.23 (s, 311, C113-) ; 2.60 (in, 311, C112-CH-CH2, NH-CH2-C112- CH2) ; 3.23 (in, 211, NH-C112-C112-C112) ; 2.97 and 3.92 (2in, 411, CH2-C112-N- C112-CH2) ; 6.3 and 7.05 (2d 211 CH=CH naphthyridine) ; 8.28 (s, 111, N=CH-N). MS (FAB): 388(M) ; 389(MH±) Synthesis of (1,1 -diinethylethyl) 3-[[5 -inethyl-6- [4-( 1,2,3 ,4-tetrahydro-. 1,8 -naphthyridin-7-yl)- I -piperidinyl]-4-pyriinidinyl]amino]-N- [(phenylinethoxy)carbonyl]alaninate. S(-)~NAP 7 Pd2LtB~ N 00 N N-I H H N N (~F "~ NI 'N Oc~u N~N 17 A mixture of 620 mg (1.6 mmoles) of 4-bromo-5-inethyl-6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-pyriinidine, 565 ing (1.92 ininoles) of (1,1 -dimethylethyl) 3-amino-N-[(phenylinethoxy)carbonyl]alaninate (prepared according to J. Med. Chem.(2001), 44(8), 1158-1176), 340 ing (2.25 ininoles) of caesiuin fluoride, 73 ing (0.08 mmoles) of tris(dibenzylideneacetone) dipalladiuin(0), 100 ing (0.16 minoles) of S(-)2,2'-bis(diphenyl-phosphino)-1,l'-binaphthyl in 50 ml of dioxane is heated under reflux for S hours. After cooling down another 280 ing (0.96 minoles) of (1,1 -diinethylethyl)3-ainino-N-[(phenylinethoxy)carbonyl] alaninate, 340 mg (2.25 inmoles) of caesiuin fluoride, 73 ing (0.08 minoles) of tris(dibenzylideneacetone) dipalladiuin(0),and 100 ing (0.16 inmoles) of S(-)2,2'-bis(diphenyl-phosphino)- 1,1 '-binaphthyl are then added and the reaction mixture is heated under reflux for 5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chroinatographed a first time on silicagel eluting with a gradient of ethyl acetate-methylene chloride-triethylamine-inethanol from 50-50-0-0 35 to 50-50-2-2. The product obtained is chroinatographed a second time on alumina eluting with a mixture of heptane-inethylene chloride 50-50 then with ethyl acetatediisopropyl ether 50-5 0. 360 ing (Yield = 37 %) of expected product is obtained in the form of an amorphous white solid. TLC Rf= 0.20 (silicagel, eluent: methylene chloride -methanol 95-5). IR (CHCI3) : 3435 (NH) ; 1717 (C=O) ; 1583.l555.l50l cm-I (Heterocycle+Aromatic±Ainide). 1H-NMR (CDCI3) : 6 1.47 (s, 911, tBu); 1.94 (s, 311, C-C113); 1.75 to 2.05(in, 611, CH2-CH2-CH2-NH and CH2-CH-CH2) ; 2.60 to 2.77 (in, 3H, CH2-CH-CH2 and CH2-CH2-CH2-NH) ; 2.93 and 3.90 (2in, 411, C112-CH2-N-C112-CH,) ; 3.42 (in, 211, CH2-CH2-CH2-NH) ; 3.66 (in, 211, NH-CH2-CH-NH) ; 4.45 (in, 111, NH-C112-CH- Nil) ; 4.95, 5.25 and 6.20 (3m, 311 CH2-CH2-CH2-NH NH-CH2-C11-NH, NH-CH2- CH-NH); 5.12 (s, 211, CH2-Ph); 7.3S (in, 511, Ph); 8.29 ppm (s, N=CH-N). MS: 602 (MH+); 546 (MH-tBu±) ; 412 (MH-COOC112Ph±). IciDi (0.625 % EtOH): ~4•5o Synthesis of 3-[[5-inethyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1-piperidinylj-4-pyriinidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(trifluoroacetate). cF3c021-va-Q02 ~ 'N 2(2F3(XX1~A-I N~N o~~"o 'N 7 7 350 mg (0.58 mmoles) of (1,1-diinethylethyl) 3-[[5-methyl-6-[4-(1,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylinethoxy)carbonyl]alaninate in 15 ml of dichloroinethane is stirred with 3 ml of trifluoroacetic acid at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH-H20-AcOH 90-10-1-I). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloroinethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 330 ing (Yield = 73 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid. TLC : Rf=0.44 (silicagel, eluent: dichloroinethane-methanol-water-acetic acid 90-10-1-1) 1H-NMR (CDCI3) 6 1.96 (s, 3H C-CH3); 1.80 to 2.05 (in, 611, CH2-CH2-CH2-NFI and CH2-CH-CH2) ; 2.76 (t, 211, NH-C112-C112-CH2-) ; 2.96 (t, lH, N- 36 CH2-CH2-CH-) ; 3.21 and 3.83 (2in, 411, N-CH2-C112-CH-) ; 3.50 (in, 211, N-C112- CH2-C112-); 3.83 and 4.05 (2in, 211, NH-C112-CH-NH) ; 4.54 (q, 111, NH-CH2-CH- NH); 5.50 (s, 2H, O-C112-Ph); 6.40 (d, 111, 11 naphthyridine); 6.55 (bd, 111, NH); 7.28 (in, 511, Ph) ; 7.45 (ml 111 NH) ; 8.22 (d, 111, 11 naphthyridine), 8.22 (s, 111, N=CH-N); 9.62 ppm (bs, 111). MS : 546 (MH±) ; 412 (MH-COOCH2Ph±) ; 544- (M-11-) ; 436- (544-OCH2 Ph-); 1089- (2M-H-) IaDl (0.60 % MeOH) : -14.0. Example 7 Preparation of naphthyridine in free amine form: 22 g of naphthyridine is displaced from its salt by 6 mass equivalents of basic ainberlyst A2 I resin (resin of R-NMe2 type) in a CH2CI2 / MeOH /AcOEt mixture 1/1/1 under stirring for 30 minutes. The resin is washed beforehand and left to swell for 20 minutes in this solvent mixture. This operation must be repeated 3 times for displacement of the salt to be complete. After filtration of the resin and evaporation of the solvents, 8 g (36.8 ininoles) of free naphthyridine is obtained. TLC : Rf=0.33 [silicagel, eluent: ethyl acetate (100 %)] 1H-NMR (DMSO-d6) : 6 1.7 to 1.85 (in, 611, NH-C112-CH2-CH2, N-CH2- CH2-CH-CH2);2.23 (s, 311, CH3-) ; 2.60 (in, 3H, C112-CH-C112, NH-C112-CH2- CH2) ; 3.23 (in, 211, NH-C112-C112-CH2) ; 2.97 and 3.92 (2in, 411, C112-CH2-N- CH2-CH2) ; 6.3 and 7.05 (2d 211 CH=CH_naphthyridine); 8.28 (s, 111, N'CH-N). MS (FAB) (rt = 0.50 mm and 2.80 mm): 388(M) ; 389(MH±) Synthesis of ethyl N-(alpha)-Z-L,2-3 -diaininopropionate. 0 0 H2N OH H2N 0 HN ~ + HN 7- 12 ml (168 minoles) of thionyl chloride is added dropwise and at 00C into a single-necked flask containing 26 ml of absolute ethanol. This mixture is stirred for about twenty minutes at AT then 2 g (8.4 inmoles) of N-(alpha)-Z-L,2-3-diainino-propionic acid is added to it in small quantities, a white cloudiness appears. The reaction mixture is then taken to reflux (780C) for 2 hours (after heating for a few minutes, the solution becomes clear). 37 After cooling down the solution is concentrated to dryness, a yellow liquid is obtained to which isopropyl ether is added. The expected product solidifies, then the supernatant is removed and the residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuuin. 1.4 g of a pale yellow oil is obtained, it is the ester in free amine form (Yield = 63 %). TLC Rf= 0.41 [ Silicagel, eluent: inethylene chloride-methanol (85-15)and 2 % of water-acetic acid(1-l). LH-NMR (CDCI3): 1.33 (t, 31-I, CH3-C112-O) ; 2.53 (in, 211, NH2-C112-CH) 3.15 (in, 211, N142-CH2-C11) ; 4.22 (q, 211, C113-C112-O) ; 4.42 (in, 111, N112-CH2-C11-NH); 5.85 (m,IH, CH-N11-CO) ; 5.15 (s, 211, O-C112-Ph); 7.35 (in, 511, Ph) MS (FAB) : (rt =0.51 mm and 1.2 mm): 267(MH+) ; 533(2MH±) laiD (CHCI3) = ±6.336 Synthesis of ethyl 3-[[6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinylJ-5-inethyl-4-pyriinidinyl]ainino]-N-[(phenylinethoxy)carbonyl~Jalaninate. 0 0 N 0 No / 0 N IN _____________ N N — N—' Pd,dba,/CsF/BINAP N 'N DivE - A mixture of 1.9 g (4.9 ininoles) of 6-[4-(l,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)- 1 -piperidinyl]-5-inethyl-4-broino-pyriinidine and 1.62 g (6.08. ininoles) of ethyl 3-ainino-N-[(phenylmethoxy)carbonyl] alaninate, is heated under reflux for 4 hours in the presence of 1.06 g (6.86 ininoles) of caesiuin fluoride, 310 ing (490 ~imoles)of (2,2'-bis(diphenylphosphino)- 1,1 '-binaphthyl and 230 ing (245 liinoles) of tris(dibenzylideneacetone) dipalladium(o) in 40 ml of 1 ,2-diinethoxyethane. The reaction mixture is then taken to temperature for the addition of 230 ing (245 jtinoles) of tris(dibenzylideneacetone)dipalladiuin(o), then again taken to reflux for 16 hours. After cooling down the solution is concentrated to dryness then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silicagel with 100 % ethyl acetate. 1.15 g of expected product is obtained in the form of a pale yellow oil (yield =40 %) TLC : Rf= 0.16 (silicagel eluent: 100 % ethyl acetate LH-NMR (CDCI3) 6 1.25 (t, 311, C113-C112-O) ; 1.80 to 2.05 (in, 911, NHCH2-C112-C112, N-CH2-C112-CH-CH2, CH3~C9C~) ; 2.72 (in, 311, CH2-CH-CH2 NH-CH2-CH2-C112) ; 2.95 and 3.93 (2in, 411, CH2-C112-N-C112-CH2) ; 3.45 (in, 211, NH-C112-CH2-CH2) ; 3.68 (d, 211, NI-1-CH2-CH-NH) 4.23 (t, 2H, CH3-CH2- 0), 4.45 (in, 111, NH-CH2-CH-N11); 5.10 and 5.17 (syst AB, 211, O-CH2-Ph) ; -6.41 and 7.18 (2d, 211, CH=CH naphthyridine) ; 7.35 (in, 511, Ph); 8.27 (s, 111, N=CH-N). HPLC/MS: (rt = 0.48 mm and 2.9 mm): 574 (MH±) ; 440 [MH - Z+] ; 287 [MH - (tBu - Z±)] ~cLID (C11C13) = ± 0.788 Formation of the hydrochloride: 0 N N.' 0 N N N / ~N ,HCI N W =610.15 M F =C31H39N704,HCI 1.15 g of ethyl 3-[[6-[4-( I ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-5-inethyl-4-pyriinidinyl]ainino]-N- [(phenylmethoxy)carbonyl]alaninate are solubilized in a minimum amount of methylene chloride. This solution is poured into ethyl ether, the solution must remain clear. Then, 2.65 ml of 2N HCI diluted in a little ethyl ether is added dropwise, under stirring. The hydrochloride solidifies, the supernatant is removed, then the residue crystallizes from isopropyl ether. Then a solid is obtained which is filtered, rinsed with ether then with pentane. After drying, 890 mg of a pale yellow powder is obtained. (Yield = 73 %) Example 8 Preparation of naphthyridine in free amine form: 22 g of naphthyridine is displaced from its salt by 6 mass equivalents of basic amberlyst A2 I resin (resin of R-NMe2 type) in a C112C12 / MeOH /AcOEt mixture 1/1/1 under stirring for 30 minutes. The resin is washed beforehand and left to swell for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the displacement of the salt to be complete. After filtration of the resin and evaporation of the solvents, 8 g (36.8 ininoles) of free naphthyridine is obtained. 37 TLC Rf=O.33 [silicagel, eluent: ethyl acetate (100 %)] LH-NMR (DMSO-d6) : 6 1.7 to 1.85 (in, 611, NH-C112-CH2-C112, N-C112- C112-CH-CH2);2.23 (s, 311, C113-); 2.60 (in, 3H, CH2-CH-CH2, NH-C112-CH2- CH2) ; 3.23 (in, 211, NH-CH2-CH2-CH2) ; 2.97 and 3.92 (2in, 411, C112-CH2-N- C112-C112) ; 6.3 and 7.05 (2d 211 CH=CH naphthyridine); 8.28 (s, 111, N=CH-N). MS (FAB) (rt = 0.50 mm and 2.80 mm): 3 88(M) ; 389(MH+) Synthesis of isopropyl N-(alpha)-Z-L,2-3-diaininopropionate. 0 0 H2N OH H2N 0 HN HN OH CI CI 46 ml (840 minoles) of thionyl chloride is added dropwise and at 00C into a single-necked flask containing 125 ml of isopropanol. This mixture is stirred for about twenty minutes at AT then 10 g (42 inmoles) of N-(alpha)-Z-L,2-3-diainino-propionic acid is added to it in small quantities, a white cloudiness appears. The reaction mixture is then taken to reflux (780C) for 2 hours (after a heating for a few minutes, the solution becomes clear). After cooling down the solution is concentrated to dryness, a yellow liquid is obtained to which isopropyl ether is added. The expected product solidifies, then the supernatant is removed and the residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. 7.4 g of a white powder is obtained, it is the ester in free amine form (Yield =42 %). TLC Rf = 0.5 [ Silicagel, eluent: methylene chloride-methanol (85-l5)and 2 % of water-acetic acid(l-l). 1H-NMR (CDCI3) 6 1.25 (d, 611, CH3-CH-C113); 1.60 (in, 211, N112-C112-CH) 3.10 (in, 211, N112-C112-CH) ; 4.35 (in, 111, N112-C112-CH-NH) 5.10 (in, 111, CH3-CH-CH3); 5.15 (s, 2H, O-CH2-Ph) ; 5.2 (m,lH, CH-NH-CO), 7.37 (in, 511, Ph) MS (FAB): (rt =0.52 mm and 2.09 mm): 281(MH±) ; 239(MH-ipr+) laiD (CHCI3) = +15.02 Synthesis of isopropyl 3-[[6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1-piperidinyl]-5-methyl-4-pyriinidinyl]amino]-N-[(phenylinethoxy)carbonyl]alaninate. 0 o N0 N B, /JN. N IN — N N Pd2dba,/CsF/BINAP / '\ N OME — / N A mixture of 1.5 g (3.86 inmoles) of 6-[4-(1,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)-1-piperidinyl]-5-inethyl-4-broino-pyriinidine and 1.30 g (4.63 minoles) of isopropyl 3-ainino-N-[(phenylmethoxy)carbonyl] alaninate, is heated under reflux for 5 hours and 30 minutes in the presence of 825 mg (5.41 inmoles) of caesiuin fluoride, 241 ing (386 pinoles)of (2,2'-bis(diphenylphosphino)-1,l '-binaphthyl and 180 mg (193 ~imoles) of tris(dibenzylideneacetone) dipalladium(o) in 40 ml of 1,2-dimethoxyethane. The reaction mixture is then taken to temperature for the addition of 180 mg (245 jtmoles) of tris(dibenzylideneacetone) dipalladiuin(o), then again taken to reflux for 16 hours. The next day, the reaction mixture is heated for another 9 hours after having added 180 mg (193 ~tmoles) of tris(dibenzylidcneacetone) dipalladiuin(o. After cooling down the solution is concentrated to dryness then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chroinatographed on silicagel with 100 % ethyl acetate. 1.52 g of expected product is obtained in the form of crystals yellow pale (yield = 50 %) TLC : Rf = 0.18 (silicagel eluent: 100 % ethyl acetate 1H-NMR (CDCI3) 6 1.27 (d, 611, C113-CH-CH3); 1.83 to 2.05 (in, 911, NHCH2-C112-C112, N-C112-CH2-CH-CH2, C113-C=C-) ; 2.72 (in, 311, CH2-CH-C112 NH-CH2-C112-C112) ; 2.95 and 3.93 (2in, 411, C112-C112-N-C112-CH2) ; 3.45 (in, 211, NH-CH2-CH2-C112) ; 3.68 (d, 211, NI-I-CH2-C11-NH), 4.50 (in, 111, N11-C112- CH-NH); 5.07 (in, 1H, CH3-CH-C113) ; 5.12 (s, 211, O-C112-Ph) ; 6.42 and 7.18 (24, 211 C11=CH naphthyridine) ; 7.35 (in, 511, Ph) ; 8.28 (s, 111, N=CH-N). HPLC/MS: (rt = 0.48 mm and 3.03 mm): 588 (MH+) ; 454 [MH - Z+] ; 412 [MH — (ipr — Z)±] lain (CHCl3) + 0.765 5 Formation of the hydrochloride: N ~ N .4, 0 0 N >~0 N.' 0 N N N /~N HCI — NJ M W =624.19 M F =C32H41N704,HCI 3.8 g of isopropyl 3-[[6-[4-( 1 ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-5-methyl-4-pyriinidinyl]amino]-N-[(phenylinethoxy)carbonyl]alaninate is solubilized in 20 ml of inethylene chloride. This solution is poured into ethyl ether, the solution must remain clear. Then, 3.23 ml of 2N HCI diluted in a little ethyl ether is added dropwise, under stirring. The hydrochloride solidifies, the supernatant is removed, then the residue is crystallized from isopropyl ether. Then a solid is obtained which is filtered, rinsed with ether then with pentane. After drying, 3.44 g of a white powder is obtained. (Yield = 85 %) Example 9 Synthesis of 4,6-dibroino-5-ethyl-pyrimidine OH POBr3 Br ~ Br N N A mixture of 2.8 g (20 mmoles) of 5-ethyl-4,6-dihydroxy-pyriinidine (marketed by Aldrich) and 8.85 g (31 minoles) of phosphorus oxybroinide is taken to I 600C for 1 hour. After returning to ambient temperature, the reaction mixture is poured into a mixture of ice, a saturated solution of sodium bicarbonate and ethyl acetate. After decanting, the organic phase is washed with a saturated solution of sodium bicarbonate, followed by drying over magnesium sulphate and the solvent is eliminated by evaporation under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of 100 % heptane to heptaneethyl acetate 50-50. 3.92 g (Yield = 74 %) of a light brown solid of expected product is obtained which is used as it is for the following. TLC RP=0.5 (silicagel, eluent: heptane-ethyl acetate 90-10) IR (CHCl3):1538; 1503 (C=C, C=N) 1II-NMR (DMSO-d6) 6 1.16 (t, 311, C112-C113) ; 2.86 (q, 211, C112-CH3) 8.63 ppm (s, 111, N=CH-N) MS 266 (M11+) ; 249 (MH-CH3±); 184 (MH-HBr+). Synthesis 4-bromo-5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyll-pyrimidine 7 7 N. [TV'A N.' N N N N H H N + ~ 'N N N~N I 1 N~N A mixture of 3.67 g (6.45 ininoles) of 1,2,3 ,4-tetrahydro-7-(4-piperidinyl)- 1,8— naphthyndine, tris(trifluoroacetate) (prepared according to Patents EP 1065207 or WO 0078317) and of 25 g of Ainberlyst A-2 1 resin (origin Fluka 06424 washed beforehand with a dichloroinethane-ethyl acetate-methanol solution 1- i-I) in 150 ml of solution of dichloroinethane-ethyl acetate-methanol 1-1-I is stirred at ambient temperature for 1 hour. The mixture is filtered and the resin is washed with the ternary solution. The filtrate obtained is stirred at ambient temperature for 1 hour in the presence of 25 g of Ainberlyst A-2 1 resin treated as previously ; this operation is carried out three times. The filtrate thus obtained is concentrated to dryness under reduced pressure (2 kPa) producing 1.4 g of free amine. 2.06 g (7.74 ininoles) of 4,6-dibroino-5-ethyl-pyrimidine, 200 ml of dimethylacetainide and 5 ml of diisopropylethylamine are added to this residue followed by heating at 1000C for 3.5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of 100 % heptane to heptaneethyl acetate 50-50. 1.5 g (Yield = 58 %) of expected product is obtained in the form of a beige solid. TLC : Rf=O.5 (alumina, eluent: heptane-ethyl acetate 50-50) IR (CHCI3) : 3440 (NH) ; 1596, 1586, 1547, 1508, 1480 cin-l (Heterocycle+Aroinatic) 1H-NMR (DMSO-d6) : 6 1.23 (t, 311, CH2-CH3) ; 1.75 (in, 611, CH2-C112-CH2-NH, C112-CH-CH2) ; 2.67 (in 511 CH2-CH3 CH2-~jj-CH2 CH2-CH2-C112-NH) ; 3.02 (t, 211, CH2-CH2-N) ; 3.23 (in, 211, CH2-C112-C112-N11) ; 3.90 (d, 211, CH2-~jj2-N) ; 6.20 (s, IH, CH2-CH2-CH2-NH) ; 6.30 and 7.04 (2d, 211, H naphthyridine); 8.27 ppm (s, N'CH-N). MS : 403 (MH+). 2~3 Synthesis of (1,1 -dimethylethyl)3 -[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]aininoj-N- [(phenylinethoxy)carbonyl]alaninate. 0 0 S(-)BINAP N N + H2N~>..~t Pd2dba, 0 H N Br NH ___ CsF 0~O ~ N~~N 00 Dioxane A mixture of 317 mg (0.79 minoles) of 4-broino-5-ethyl-6-[4-(1,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1 -piperidinyl]-pyriinidine, 279 ing (0.95 ininoles) of (1,1 -diinethylethyl) 3 -ainino-N-[(phenylinethoxy)carbonyl]alaninate (prepared according to J. Med. Chein.(2001), 44(8), 1158-1176), 168 mg (1.11 ininoles) of caesiuin fluoride, 36 mg (0.04 inmoles) of tris(dibenzylideneacetone)dipalladiuin(0), 49 ing (0.08 ininoles) of S(-)2,2'-bis(diphenyl-phosphino)-l,l'-binaphthyl in 11 ml of dioxane is heated under reflux for 21 hours. After cooling down another 140 mg (0.48 minoles) of (1,1 -diinethylethyl) 3-amino-N-[(phenylinethoxy)carbonyl] alaninate, 168 ing (1.11 ininoles) of caesiuin fluoride, 36 ing (0.04 ininoles) of tris(dibenzylideneacetone)dipalladium(0),and 49 ing (0.08 ininoles) of S(-)2,2'-bis(diphenyl-phosphino)-1,l '-binaphthyl in 2 ml of dioxane are added and the reaction medium is heated under reflux for 3.5 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol 50-50-0, 25-75-0, 0-100-0, and finally 0-100-3. 400 ing (Yield = 83 %) of expected product is obtained in the form of an oil. TLC Rf= 0.55 (silicagel, eluent: ethyl acetate-inethanol-triethylainine 95-2-2). IR (CHCI3) 3435 (NH) ; 1717 (C=O) ; 1583.1555.1501 cm-I (Heterocycle±Aroinatic±Amide). 1H-NMR (DMSO-d6) : 6 1.06 (t, 311, CH2-C113); 1.31 (s, 911, tBu); 1.75 (in, 2H, CH2-CH2-CH2-NH) ; 1.77 (in, 411, C112-CH-CH2) ; 2.46 (in, 211, CH2-CH3) 2.53 (in, 111, CH2-CH-CH2) ; 2.62 (t, 2H, C112-CH2-CH2-NH) ; 2.83 and 3.44 (2in, 411, CH2-CH,-N-CH2-CH2) ; 3.24 (in, 211, CH2-CH2-C112-NH) ; 3.72 (in, 2H, NHC112-CH-NH) ; 4.23 (q, lH, NH-C112-CI-I-NH) ; 5.02 (s 211 C112-Ph) ; 6.24 (s, 111, CH2-CH2-CH2-NH) ; 6.30 and 7.06 (2d, 211, H naphthyridine) ; 6.36 (in, 111, NH CH2-CH-NH) ; 7.34 (in, SH, Ph) ; 7.62 (d, 111, NII-C112-CH-NH) ; 8.11 ppm (s, N=CH-N). 2 GF3000H N~N -43*4 MS: 616 (MH+); 560 (MH-tBu±) ; 426 (MH-COOCH2Ph±). IaDl (1 % CHCI3) IcLDI (1.05 % EtOH) ~6.1o Synthesis of 3-[[5-ethyl-6- [4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl )- 1-piperidinyl]-4-pyriinidinyl]amino]-N-[(phenylinethoxy)carbonyl]alanine, bis(trifluoroacetate). 475 mg (0.77 inmoles) of 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylinethoxy) carbonyl]alaninate of (1,1 -diinethylethyl) in 15 ml of dichloroinethane with 3.5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product has disappeared according to TLC (silicagel, eluent: C112C12-MeOH-1120-AcOH 90-10- 1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloroinethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 368 mg (Yield = 61 % expressed as ditrifluoroacetate) of expected product is obtained in the form of an amorphous solid. TLC Rf=0.33 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1) IR (CHCI3) 1677 (C=O) ; 1625 ; 1587 ; 1492 cm-i (Conjugated systein±Aroinatic). 1H-NMR (DMSO-d6) : ~ 1.04 (t, 311, CH2-CH3); 1.77 and 1.90 (2in, 411, NCH2-C112-CH-); 1.81 (in, 211, NH-CH2-C112-C112-) ; 2.45 (q, 211, CH2-C113) ; 2.73 (t, 211, NH-C112-CH2-C112-) ; 2.78 (t, 111, N-CH2-C112-CH-) ; 2.87 and 3.48 (2in, 411, N-CH2-C112-CH-) ; 3.23 (in, 211, N-CH2-C112-CH2-) ; 3.58 and 3.83 (2in, 211, NH-CH2-CH-NH) ; 4.28 (q, 111, NH-CH2-CH-NH) ; 5.01 (syst AB, 211, O-CH2- Ph); 6.65 (d, 111, 11 naphthyridine) ; 6.55 (bs 111 N11-CH2-CH-NH) ; 7.33 (in, 511, Ph) ; 7.68 (d, 111, NH-CH2-CH-NH) ; 7.58 (d, 111, 11 naphthyridine) ; 8.15 (s, 111, N=CH-N) ; 6.24 ppm (bs, 111 NH-C112-C112-C112-). MS : 560 (MH+) ; 426 (MH-COOCH2Ph+) ; 558- (M-H-) ; 450- (55 8-OCH2Ph-); 1117- (2M-H-) IaDI (1 % CHC13) : ±2.40 45 ExamDIe 10 (i~,i,4int~yle.thyi) N4(phenylipethoxy)~arbonyIj~i1aninate 0~.OIJ Q 0 H2N~ ~. H'2N ACOtBu/HCIQ. . 0 0 7- I ml of perchloric acid is auu'.-u dropwise to 480 ing (2 minoles) of N[(phenylinethoxy)carbonyl] alanic acid in 15 ml of terbutyl acetate. The biphasic mixture is stirred for 24 hours at ambient temperature. The mixture is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chroinatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol 100-0-0, 0-100-0, and finally 0-95-05. 50 ing (Yield = 10 %) of expected product is obtained in the form of an oil. TLC : Rf=0.20 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1) fcLDI (1.25 % CHC13) : Synthesis of (1,1 diinethylethyl) 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N- [(phenylmethoxy)carbonyl]alaninate. 0 0 S(-)BINAP + H2N ~" NH Pd2dba, H CsF N Dioxane 0 o N.. I— A mixture of 200 mg (0.5 inmole) of 4-broino-5-ethyl-6-[4-(1,2,3,4-tetrahydro- l,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 50 ing (0.17 ininole) of (1,1 diinethylethyl) (D) 3-ainino-N-[(phenylmethoxy)carbonyl]alaninate, 40 ing (0.26 minole) of caesium fluoride, 15 mg (0.0 16 ininole) of tris(dibenzylideneacetone)dipalladiuin(0), 20 mg (0.032 minole) of 2,2'-bis(diphenyl-phosphino)- 1,1 '-binaphthyl in 20 ml of dioxane is heated under reflux for 5 hours. After cooling down another 15 ing (0.016 ininole) of tris(dibenzylideneacetone)dipalladium(0) is then added and the reaction mixture heated under reflux for 15 hours, followed by evaporating to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over 46 magnesium sulphafe and the solvent i~ evaporated off under reduced pressure (2 kPa). The residue is chroinatographed a first time on alumina eluting xvith a gradient of ethyl acetate-diisopropyl ether-inethylene chloride 50-50-50, 10-50-50, and finally 10-2Q-~70 then on silicagel eluting with cihyl acetate. 40 ing (Yield I 38 %) of expected product is obtained in the form of an oil. TLC Rf= 0.25 (silicagel, eluent: ethyl acetate). MS : 616 (MH±) ; 560 (MH-tBu±). laoI (1.0 % CHCl3) : -2.4 Synthesis of 3-[[5-ethyl-6-[4-( I ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylinethoxy)carbonyl]alanine, bis(trifluoroacetate). 0 ~ [N.. CF3GOOH/CH2CI2 0 OH 'NH H N~N 0~'N.0 2CF3COOH N~N 'NH 'N 7 40 mg (0.77 ininoles) of (1,1 -diinethylethyl) 3-[[5-ethyl-6-[4-( 1,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate in 10 ml of dichloromethane with I ml of trifluoroacetic acid is stirred at ambient temperature until the starting product has disappeared according to TLC (silicagel, eluent: C112C12-MeOH-1120-AcOH 90-10- 1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is chroinatographed on silicagel eluting with a C112C12-MeOH-H20-AcOH mixture 90-10-1-1. 25 mg (Yield = 48 % expressed as ditrifluoroacetate) of expected product is obtained in the form of an amorphous solid. TLC : Rf=0. 10 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1) MS : 560 (MH+) ; 426 (MH-COOCH2Ph+) ; 558- (M-H-) ; 450- (558-OCH2Ph-); 1117- (2M-H-) tctDI (1.75 % CHC13) : -6.0 Example 11 ethyl 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1 -piperidinyl]4-pyrimidinyl]ainino]-N-[(phenylinethoxy)carbonyl]alaninate, dihydrochloride N N O~~ H HN.7J,,~ SOCI2/EtOH N ____________ NH N .~N 2 HOI .47 160 p.1 (2.19 minol~s) of thionyl chloride is added to 5 ml of ethanol cooled down to -120C under a nitrogen atmosphere and the mixture is stirred for 30 minutes. Then a solution of 354 rug (0.45 ininoles) of 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-l,8-naphthyridin-7-yl); I -piperidinyl]-4-pyrimidinyl]ainino]-N- [(phenylinethoxy)carbonyl]alanine, bis(trifluoroacetate) in 13 ml of ethanol is added. The mixture is stirred for 30 minutes at -120C then left to return to ambient temperature and finally heated at 400C for 4 hours under nitrogen. The reaction mixture is evaporated to dryness under reduced pressure (2 k.Pa) and the residue crystallizes from a mixture of diisopropyl ether and pentane and the solid is filtered. 284 ing (Yield = 95 %) of expected product is obtained in the form of an amorphous beige solid. TLC Rf=0.4 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1) IR (CHCI3) : 3400-3000(011, NH) ; 1719(C=O) ; 1654 ; 1623 ; 1580 ; 1504 cm-1(C=C, C=N, aromatic) 1H-NMR (DMSO-d6) 6 1.09 (t, 311, C112-CH3); 1.14 (t, 311, O-C112-CH3); 1.85 (in, 211, NH-CH2-C112-C112); 1.85 and 2.00 (2m, 411, N-C112-C112-CH) ; 2.48 (in, 211, CH2-C113) ; 2.75 (t, 211, NH-CH2-C112-CH2) ; 2.92 (in, 111, N-C112-C112- CH); 3.03 and 3.57 (2in, 411, N-C112-C112-CH) ; 3.44 (t, 211, N-C112-CH2-C112) 3.76 and 3.87 (2in, 211, NH-CH2-CH-NII) ; 4.07 (q, 211, O-CH2-CH3) ; 4.39 (q, IH, NH-CH2-CH-NH) ; 5.03 (s, 211, O-C112-Ph) ; 6.62 (d, 111, H naphthyridine) ; 6.86 (bs, 111, NH-CH2-CH-NII) 7.30 (in, 511, Ph) ; 7.33 (bs, IH, NH-C112-CH-NH) 7.58 (d, 111, H naphthyridine); 8.20 ppm (s, 111, N"~C11-N). MS: 588 (MH+) ; 454 (MH-COOCH2Ph+) ; 426 (454-C2H4+). jaDJ (1 % CHCI3) : ±4 Example 12 ethyl N-[(phenylmethoxy)carbonyl]alaninate 0 OH o OEt H2N ~~INH SOCI2/EtOH H2N 'NH ~ 1~ 6 ml (63 ininoles) of thionyl chloride is added to 12 ml of ethanol cooled down to 00C under a nitrogen atmosphere and the mixture is stirred for 20 minutes at ambient temperature. Then a solution of 950 ing (4 ininoles) of N[(phenylmethoxy)carbonyl]alanic acid in 5 ml of ethanol is added. The mixture is stirred under reflux for 1 hour under nitrogen. The reaction mixture is evaporated to H N~N dryness under reduced pressure (2 kPa) and the residue crystallizes from a mixture of diisopropyl ether and p~ntane and the solid is filtered. The solid obtained is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. 535 ing (Yield = 50 %) of expected pn5duct is obtained in the form of a colourless oil. TEC Rf=~0.4 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-I) HPLC/MS : (rt 0.5 and 1.4 mm) 267 (MH±). laDi (1.0 % CHCI3) -11.2 Synthesis of ethyl 3-[[5-ethyl-6-[4-( 1 ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)-1 -piperidinyl]-4-pyrimidinyl]ainino]-N-[(phenylmethoxy)carbonyl]alaninate. 0 %.— ~,sI 0 +H2N 'NI Ri4~3 N N H H N N C~sF 'N Fl-I 'N I Eioxa~ N~N 7 7 A mixture of 320 mg (0.8 ininole) of 4-broino-5-ethyl-6-[4-(1,2,3,4-tetrahydro-I ,8-naphthyridin-7-yl)- 1 -piperidinyl]-pyrimidine, 215 mg (1.04 inmole) of ethyl (D) 3-ainino-N-[(phenylinethoxy)carbonyl]alaninate, 190 mg (1.25 inmoles) of caesiuin fluoride, 37 mg (0.04 ininole) of tris(dibenzylideneacetone)dipalladiuin(0), 50 ing (0.08 ininole) of S(-)2,2 -bis(diphenyl-phosphino)- 1,1' -binaphthyl in 15 ml of dioxane is heated under reflux for 5 hours. After cooling down another 37 ing (0.04 ininole) of tris(dibenzylideneacetone)dipalladiuin(0) is then added and the reaction mixture is heated under reflux for 7 hours, followed by evaporating to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a gradient of ethyl acetate-diisopropyl ether-inethylene chloride 50-50-50, 10-50-50, and finally 10-20-70. 260 mg (Yield = 55 %) of expected product is obtained in the form of an oil. TLC : Rf= 0.25 (silicagel, eluent: ethyl acetate). 1H-NMR (CDCI3) 6 1.16 (t, 311, C112-CH3) ; 1.27 (t, 311, O-CH2-C113) 1.85 to 2.00 (in, 611, N-CH2-C112-CH and NH-CH2-CH2-CH2) ; 2.46 (in, 211, C112-C113) ; 2.75 (t, 311, NH-C112-C112-CH2 and N-C112-CH2-CH) ; 3.89 (t, 211, N-C112-C112-CH2) ; 3.47 and 3.61 (2in, 411, N-CH2-C112-CH) ; 3.00 and 3.98 (2in, 211, NH-CH2-CH-NH) ; 4.22 (in, 211, 0-CH2-C113) ; 4.54 (in, 111, NH-CH2-C11-NH) ; 5.13 (s, 211, O-CH2-Ph) ; 6.43 (d, 111, 49 H naphthyridine) ; 7.22 (d, 111, H naphthyridine) ; 7.35 (in, 511, Ph) ; 8.27 ppm (s, 111, N=CH-N). MS : 588 (MH+) ; 454 (MH-COOCH2Ph+). laDi (1.3 % CHCI3) : -6.0 Example 13 Synthesis of 6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-5 -ethyl-4-chloro-pyriinidine: ci DMA I DIPEA N C~ 80 ml diinethylacetainide, 11.8 g (30 minoles) of 4,6-dichloro-5-ethyl-pyrimidine solubilized in 40 ml of diinethylacetainide and 24 ml of diisopropylethylainine are added into a single-necked flask containing 12.5 g (57.5 inmoles) of 4-( I ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -pipendine released from its salt. This mixture is heated at 1400C for 5 hours then concentrated to dryness under vacuum. The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum in order to produce 15.5 g of an orange oil. This oil is solubilized in a minimum amount of methylene chloride and precipitated from isopropyl ether, 9 g of the expected product is obtained in the form of a beige powder. The filtrate is concentrated to dryness then chroinatographed on silicagel eluting with a gradient of cyclohexane (100 %), ethyl acetate-cyclohexane (50-50) then ethyl acetate-cyclohexane (70-30). 3 g of expected product is obtained in the form of a pale yellow powder. (Overall yield 58 %) Preparation of the naphthyridine in free amine form: 28.5 g of naphthyridine is displaced from its salt by 6 mass equivalents of basic amberlyst A2 1 resin (resin of R-NMe2 type) in a C112C12 / MeOH /AcOEt mixture 1/1/i under stirring for 30 minutes. The resin is washed beforehand and left to swell for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the displacement of the salt to be complete. After filtration of the resin and evaporation of the solvents, 12.5 g (57.5 ininoles) of free naphthyridine is obtained. TLC : Rf~'0.32 [silicagel, eluent: ethyl acetate (100 %)J Pd2dba, (CsF I BINAP DME 1H-NMR () 6 1.32 (t, 311, CH3-C112); 1.81 to 2.05 (in, 611, NH-C112-C112-C112, N-C112-CH2-CH-CH2)__2.70 (in, 511 C112-C11-C112, NH-C112-CH2-CH2, C113-CH2); 3.43 (in, 2H, NH-C112-C112-CH2); 3.OS and 3.97 (2in, 411, C112-CH2-N-C112-CH2) ; 6.4 and 7.12 (2d, 211, CH=CH naphthyridine); 8.37 (s, 111, N=CH-N). HPLC / MS : (rt = 0.51 mm and 2.93 mm): 358 (MH+) Synthesis of isopropyl 3-[[6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-5-ethyl-4-pyrimidinyl]ainino]-N-[(phenylmethoxy)carbonyl]alaninate. 0 CI 0 N0 0 N IN N N N N 'N A mixture of 1 g (2.79 ininoles) of 6-[4-(l,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-l-piperidinyl]-5-ethyl-4-chloro-pyriinidine and 940 ing (3.35 inmoles) of isopropyl 3-amino-N-[(phenylinethoxy)carbonyl] alaninate is heated under reflux for 5 hours, in the presence of 594 ing (3.91 ininoles) of caesiuin fluoride, 174 ing (279 p.moles)of (2,2'-bis(diphenylphosphino)-l,1 '-binaphthyl and 130 mg (140 p.inoles) of tris(dibenzylideneacetone) dipalladiuin(o) in 35 ml of 1 ,2-diinethoxyethane. The reaction mixture is then taken to temperature for the addition of 180 mg (140 p.moles) of tris(dibenzylideneacetone)dipalladiuin(o), then again taken to reflux for 16 hours. After cooling down the solution is concentrated to dryness then taken up a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silicagel with 100 % ethyl acetate. 1.07 g of expected product is obtained in the form of pale yellow crystals (yield 64 %) TLC Rf= 0.20 (silicagel eluent: ethyl acetate 100 % 1H-NMR (CDCI3) : 6 1.18 (t 311 C113-C112); 1.25 (d, 611, C113-CH-CH3); 1.83 to 2.05 (in, 611, NH-C112-CH2-CH2, N-CH2-C112-C11-CH2) ; 2.45 (q, 211, CH3-CH2) ; 2.72 (in, 311, C112-CH-CH2, NH-C112-CH2-C112) ; 2.97 and 3.93 (2m, 411, C112-C112-N-C112-C112) ; 3.45 (in, 211, N11-C112-C112-C112) ; 3.60 (d, 211, NHCH2-CH-NII), 4.50 (in, 111, NH-C112-CH-NH) ; 4.97 to 5.20 (in, 311, C113-CH- 5! CH3, O-C112-Ph) ; 6.43 and 7.18 (2d, 211, CH=CH naphthyridine) ; 7.35 (in, 511, Ph) ; 8.28 (s, 111 N"CH-N). HPLC/MS : (rt = 0.50 mm and 3.14 mm): 602 (MH+) ; 468 [MH - Z+] ; 426 [MH — (ipr — Z)±] laiD (CHCI3) = + 2.175 Formation of the hydrochloride: 0 o N / N.WO 'N 0 N N N /~N .HCI - NJ M W =638.22 M F =C33H43N704.HGI 3.2 g (5.3 mmoles) of isopropyl 3-[[6-[4-(l,2,3,4-tetrahydro-1,8-naphthyridin- 7-yl)- 1 -piperidinyl]-5-ethyl-4-pyrimidinyl]ainino]-N-[(phenylinethoxy)carbonyl]alaninate is solubilized in a minimum amount of inethylene chloride. This solution is poured into ethyl ether, the solution must remain clear. Then, 2.65 ml of 2N HCl in ethyl ether is added dropwise, under stirring. The hydrochloride solidifies, the supernatant is removed, then the residue is recrystallized from isopropyl ether. Then a solid is obtained which is filtered, rinsed with ether then with pentane. After drying, 3.5 g of an off-white powder is obtained. (Yield = quantitative). Example 14 Synthesis of terbutyl 2-(2-benzyloxycarbonylamino-3- { 5-ethyl-6-[4-(5 ,6,7,8-tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- I -yl]-pyriinidin-4-ylainino } -propinylamino)-4-methylpentanoate. 0 0 NH, 0 NH 2 CF3COOH N~N EDAC-NORT JLJ~ NMM-TEA-DMF O 0 '- K— 80 mg (0.15 ininole) of 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin- 7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylinethoxy)carbonyl]alanine, 45 ing (0.20 mmole) of terbutyl L-leucinate hydrochloride, 22 ing (0.16 ininole) of 1- hydoxy benzotriazole, 30 ing (0.16 inmole) of 1 -[3-(diinethylamino) propyl]-3-ethyl carbodiimide hydrochloride, 0.050 ml (0.45 inmole) of N-inethhylinorpholine and 0.070 ml (0.50 mmole) of triethylainine in 5 ml of diinethylformainide are stirred for 0 0 0 OH NH 0 2 CF3ccXDI-I 5~2- 24 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of ethyl acetate-inethylene chloride-methanol of 50-50-0 to 50-45-S. 60 ing (Yield = 55 %) of expected product is obtained in the form of a white solid. TLC Rf=0.66 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 85-15-2-2) 1H-NMR (CDCI3) : 6 0.91 (t, 311, CH2-C113) ; 1.16 (d, 61-1, CHCH2CH(CH3)2) ; 1.28 (bt, 211, CHCH2CH(C113)2) ; 1.41 to 1.57 (in, 111, CHCH2C11(CH3)2) ; 1.48 (s, 911, tBu) ; 1.80 to 2.05 (in, 611, CH2-C112-CH-NH, C112-CH-C112) ; 2.49 (in, 211, C112-CH3) ; 2.67 (tt, 111, C112-CH-CH2) ; 2.73 (t, 21-I, C112-CH2-CH2-N11) ; 2.98 and 3.66 (bq and in, 411, CH2-C112-N-C112-C112); 3.43 (in, 211, CH2-C112-C112-NH) ; 3.70 and 4.16 (2in, 211, NH-C112-CH-NH) ; 4.32 (in, 111, NH-CH2-CH-NH) ; 4.49 (in, 111, CONH-CHCH2CH(CH3)2)-CO) ; 5.13 (in, 21-I, C112-Ph) ; 5.42, 6.83 and 7.92 (311, mobile Hs) ; 6.43 and 7.15 (2d, 211, 11 naphthyndine); 7.37 (in, 511, Ph) ; 8.2 ppm (s, 111, N=CH-N). MS: 729 (MH+). Synthesis of 2-(2-benzyloxycarbonylainino-3 - {5-ethyl-6-[4-(5,6,7,8-tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- 1 -yl]-pyriinidin-4-ylainino --propinylamino)-4-methylpentanoic acid. cr3cocl-~ci-i~a, 60 ing (0.083 minoles) of terbutyl 2-(2-benzyloxycarbonylamino-3- 5-ethyl-6-[4-(5 ,6,7,8-tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- 1 -yl]-pyriinidin-4-ylamino}-propinylamino)-4-inethylpentanoate in 5 ml of dichloroinethane with 0.5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: C112C12-MeOH-H20-AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The R:\Brev,t021500\21565US.doc -28 f&,ne~ 2005 - 51/110 S3 precipitate is filtered. 55 ing (Yield = 74 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid. TLC Rf=0.52 (silicagel, eluent: dichloromethane-inethanol-water-acetic acid 85-15-2-2) MS : 673 (MH+). Example 15 - Synthesis of 4,6-dihydroxy-5-propyl-pyriinidine. O~7- + HN 0 0 Ci EtOH N ..~. N 102 ml (282 inmoles) of a solution of 21 % sodium ethylate in ethanol is added to a solution of 7.5 g (94 ininoles) of formainidine hydrochloride in 200 ml of ethanol cooled down to 00C and the mixture is stirred for 30 minutes ; then a solution of 19.5 ml (94 minoles) of diethyl propyl inalonate in 50 ml of ethanol is added and the reaction mixture is stirred overnight at ambient temperature, followed by evaporating to dryness under reduced pressure (2 kPa). The residue is taken up in 100 ml of a saturated solution of sodium chloride and extraction is carried out with 800 and 200 ml of n-butanol. The organic phases are dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). 7.3 g (Yield 50 %) of expected product is obtained in the form of a beige solid. 1H-NMR (DMSO d6) 0.85(t, 3H,C112-CH2-CH3) ; 1.39(sext, 211, Cl-I2-C112-C113); 2.23(t, 211, CH2-CH2-C113) ; 7.85 ppm (s, N=CH-N). MS:155 (MH+); 159 (M-11-). Synthesis of 4,6-dichloro-5 -propyl-pyrimidine P 0 C 13/P h N E t2 HO . OH CI N ...-. N N ..~-. N A mixture of 3 g (19.5 mmoles) of 5-propyl-4,6-dihydroxy-pyriinidine in 20 ml of phosphorus oxychloride is taken to reflux for 1 hour. After returning to ambient temperature, a mixture of 3 ml of N,N-diethylaniline in 10 ml of phosphorus oxychloride is added dropwise and the reaction mixture is taken to reflux for 4 hours. After returning to ambient temperature, the reaction mixture is poured into a mixture of ice and water then sodium bicarbonate is added slowly to a basic pH, followed by extracting with ethyl acetate, drying over magnesium sulphate and evaporating to 54 dryness under reduced pressure (2 kPa). The residue is chroinatographed on alumina eluting with a gradient of heptane-inethylene chloride 100-0 to 80-20. 2 g (Yield 54 %) of expected product is obtained in the form of a blueish solid. TLC: Rf=O.35 (silicagel, eluent: heptane-ethyl acetate 90-10). Synthesis of 6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-5-propyl-4-chloro-pyrimidine: DMA / DIPEA 50 ml dimethylacetainide, 2g (10.5 inmoles) of 4,6-dichloro-5-propyl-pyriinidine and 4 ml of diisopropylethylainine are added into a single-necked flask containing 1.6 g (7.4 inmoles) of 4-(l,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-l-piperidine released from its salt. This mixture is heated at 1400C for 5 hours then concentrated to dryness under reduced pressure (2 kPa). The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of heptane-inethylene chloride-ethyl acetate of 50-50-0 to 0-0-100. 875 ing of expected product is obtained in the form of an amorphous solid. (Yield = 50 %) TLC: Rf=0.25 [silicagel, eluent: ethyl acetate (100 %)] 1H-NMR (CDCI3) S l.02(t, 311,C-CH2-CH2-C113) ; l.72(sext, 211 C-C11~- CH,-C113) ; 1.81 to 2.07 (in, 611, NH-CH2-C112-C112, N-C112-C112-CH-CH2) 2.64(t, 211 C-C112-CH2-C113) ; 2.73 (in, 311, CH2-CH-C112, NH-C112-C112-CH2); 3.46 (t, 211, NH-CH2-CH2-CH2) ; 3.06 and 3.96 (in and d, 411, C112-CH2-N-CH2- CH2) ; 5.00 (in, 211, NH-CH2-C112-C112) ; 6.40 and 7.14 (2d, 211, CH=CH naphthyridine); 8.38 (s, 111, N=CH-N). MS: 372.374 (MH±). Synthesis of (1,1 -diinethylethyl)3 -[[5-propyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- I -pipendinyl]-4-pyrimidinyl]ainino]-N- [(phenylmethoxy)carbonyl]alaninate. BINAP I N3Th ___ + H, Pd,dba, N N NH H CsF N.. N1 Dioxane N.~N A mixture of 600 ing (1.62 ininoles) of 4-chloro-5-propyl-6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-pyriinidine, 590 ing (2 ininoles) of (1,1 -diinethylethyl) 3-ainino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chein.(2001), 44(8), 1158-1176), 380 ing (2.51 ininoles) of caesiuin fluoride, 7~ ing (0.083 inmole) of tris(dibenzylideneacetone)dipalladiuin(0), 102 ing (0.163 ininole) of 2,2'-bis(diphenyl-phosphino)-l,l'-binaphthyl in 50 ml of dioxane are heated under reflux for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chroinatographed on alumina eluting with a gradient of inethylene chloride-diisopropyl ether- ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0 then 0-0-100-0 and finally 0-0-90-10. 620 ing (Yield = 61 %) of expected product is obtained in the form of an amorphous yellow solid. TLC Rf= 0.12 (silicagel, eluent: ethyl acetate). 1H-NMR (CDCI3) 6 0.90(t, 211, C-C112-CH2-CH3); 1.0 l(t, 3H,C-C112-CH2- C113) ; 1.48 (s, 911, tBu) ; 1.81 to 2.07 (in, 611, NH-CH2-CH2-CH2, N-C112-CH2- CH-C112) ; 2.39(t, 211, C-CH2-C112-C113 ) ; 2.65 (bt, 111, C112-C11-CH2) ; 2.73 (t, 211, NH-CH2-CH2-C112) ; 2.97 and 3.55 (bt and bd, 411, C112-CH2-N-C112-C112); 3.44 (in, 211, NH-CH2-C112-C112) ; 3.85 and 3.93 (2m, 211, NH-CH2-C11-NH) ; 4.46 (in, 111, NH-C112-C11-NH) ; 5.14 (s, 211, C112-Ph) ; 6.16 (d, 111 C112-CH2-CH2-N11); 6.44 (d, 111, H naphthyridine) ; 7.15 (d, 111,11 naphthyridine), 7.37 (in, 511 CH2Ph); 8.29 (s, 111, N=CH-N); MS : 630 (MH±) ; 574 (MH-tBu+) ; 440 (MH-COOC112Ph±). Synthesis of 3 -[[5-propyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1-piperidinyl]-4-pyriinidinyl]amino]-N- [(phenylinethoxy)carbonyl]alanine, bis(trifluoroacetate). 7 N N H N. ___________ NH O 0 N. 610 ing (0.97 inrnole) of (1,1-diinethylethyl) 3-[[5-propyl-6-[4-(1,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylmethoxy)carbonyl]alaninate in 50 ml of dichloroinethane with 5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH-1120-AcOH 90-10-1-I). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloroinethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 400 mg (Yield = 51 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a beige solid. TLC Rf=0.40 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 85-15-2-2) 1H-NMR (DM50 d6) .5 0.93(t, 311,C-C112-CH2-C113); l.48(in, 211, C-CH2- CH2-C113); 1.67 to 2.00(in, 611, CH2-C112-C112-NH and C112-C11-C112) ; 2.40(t, 211, C-CH2-C112-CH3) ; 2.65 to 2.96 (in, 511, NH-CH2-C112-CH2-, N-CH2-CH2-CH- NC112-CH2-CH-) ; 3.32 to 3.51 (in, 4H, N-CH2-CH2-CH- and NH-CH2-C112-C112-) - 3.56 and 3.84 (2m, 211, NH-CH2-CH-NH) ; 4.31 (q, 111, NH-CH2-CH-N11); 5.02 (s, 211, O-C112-Ph) ; 6.68 (d, 111, H naphthyridine) ; 7.33 (in, 511, Ph) ; 7.61 (in, 111, 1-1 naphthyridine) ; 8.20 (s, 111, N=CH-N). MS 574 (MH+) ; 440 (MH-COOCH2Ph±) ; S72- (M-H-) ; 464- (572-OCH2Ph-); 1145- (2M-H-) IaDI (1.20 % CHCI3) : -17.7. ExamDle 16 Synthesis of 4,6-dihydroxy-5-isobutyl-pyriinidine. E tO N a + HO OH H,N~NH CI EtON N. N ..~. N 0 0 102 ml (282 inmoles) of a solution of 21 % sodium ethylate in ethanol is added to a solution of 7.5 g (94 minoles) of formamidine hydrochloride in 200 ml of ethanol cooled down to 00C and the mixture is stirred for 30 minutes ; then a solution of 20.6 ml (94 minoles) of diethyl propyl malonate in 50 ml of ethanol is added and the reaction mixture is stirred overnight at ambient temperature, followed by evaporating to dryness under reduced pressure (2 kPa). The residue is taken up in 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phases are dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). 13.7 g (Yield = 86 %) of expected product is obtained in the form of a beige solid. TLC Rf=0.53 (silicagel, eluent: dichloromethane-inethanol-water-acetic acid 85-15-2-2) -5-7 1H-NMiR (DM50 d6) .5 0.81(d, 6H,C112-C11-(C113)2) ; 1.85 (in, 111, --C112-CH-(CH3)2) ; 2.13(d, 211, -C112-CH-(CH3)2) ; 7.81 ppm (s, N=CH-N). MS:169 (MH+); 167 (M-H-). Synthesis of 4,6-dichloro-5-isobutyl-pyriinidine HO OH POCI3/PhNEI2 CI . CI N ~ N N ~—~- N A mixture of 3 g (17.9 minoles) of 5-isobutyl-4,6-dihydroxy-pyriinidine in 20 ml of phosphorus oxychloride is taken to reflux for 1 hour. After returning to ambient temperature, a mixture of 3 ml of N,N-diethylaniline in 10 ml of phosphorus oxychloride is added dropwise and the reaction mixture is taken to reflux for 4 hours. After returning to ambient temperature, the reaction mixture is poured into a mixture of ice and water then sodium bicarbonate is added slowly to basic PH, followed by extracting with ethyl acetate, drying over magnesium sulphate and evaporating to dryness under reduced pressure (2 kPa). The residue is chroinatographed on alumina eluting with a gradient of heptane-inethylene chloride 100-0 to 80-20. 0.9 g (Yield = 2S %) of a brown oil is obtained. TLC : Rf=0.25 (silicagel, eluent: heptane-ethyl acetate 95-5). Synthesis of 6- [4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyli-5 -isobutyl-4-chloro-pyriinidine: DMA /DIPEA 25 ml diinethylacetamide, 0.9g (4.4 inmoles) of 4,6-dichloro-5-isobutyl-pyrimidine and 2 ml of diisopropylethylamine are added into a single-necked flask containing 0.95 g (4.4 inmoles) of 4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1-piperidine released from its salt. This mixture is heated at 1200C for 5 hours then concentrated to dryness under reduced pressure (2 kPa). The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kiPa). The residue is chroinatographed on silicagel eluting with a gradient of heptane-inethylene chloride- N~N -5-if ethyl acetate from 50-50-0 to 0-0-100. 1 g of expected product is obtained in the form of a beige solid. (Yield = 60 %) TLC Rf= 0.25 [silicagel, eluent: ethyl acetate (100 %)] 1H-NMR (CDCI3) : .5 0.89(d, 611,C112-CH-(CH3)2); 1.77 to 2.12 (in, 711, NHC112-CH2-CH2, N-CH2-CH2-C11-CH2 and C112-CH-(C113)2) ; 2.66 (d, 211, -C112-- CH-(C113)2); 2.73 (t, 211, NH-CH2-CH2-C112) ; 2.61 to 2.77 (111, masked, CH2-CH- CH2); 3.44 (in, 211, NH-CH2-C112-CH2) ; 3.03 and 3.87 (t and d, 411, C112-CH2-N- CH2-CH2) ; 5.11 (in, 211 NH-C112-CH2-C112) ; 6.41 and 7.15 (2d, 211, CH CII naphthyridine); 8.40 (s, 111, N=CH-N). MS: 386.388 (MH+). Synthesis of (1,1 -diinethylethyl)3-[[5-isobutyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylinethoxy)carbonyl]alaninate. RiA~3 + NI 17 A mixture of 450 mg (1.17 minoles) of 4-chloro-5-isobutyl-6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-pyriinidine, 413 mg (1.4 inmoles) of (1,1 -diinethylethyl) 3-ainino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chein.(2001), 44(8), 1158-1176), 275 ing (1.81 ininoles) of caesium fluoride, 55 mg (0.060 minole) of tris(dibenzylideneacetone)dipalladiuin(0), 75 ing (0.12 minole) of 2,2'-bis(diphenyl-phosphino)-l,l'-binaphthyl in 35 ml of dioxane is heated under reflux for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chroinatographed on alumina eluting with a gradient of methylene chloride-diisopropyl ether- ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0 then 0-0-100-0 and finally 0-0-90-10. 630 mg (Yield = 83 %) of expected product is obtained in the form of an amorphous yellow solid. TLC : Rf= 0.12 (silicagel, eluent: ethyl acetate). 1H-NMR (CDCI3) .5 0.9 l(d, 6H,CH2-CH-(CH~)2); 1.49 (s, 911, tBu); 1.77 to 2.07 (in, 711, -C112-C11-(CH3)2), NH-CH2-CH2-CH2 and N-CH2-C112-CH-CH2); 2.32(d, 211, -C112-CH-(CH3)2) ; 2.65 (bt, 111, CH2-CH-C112) ; 2.73 (t, 211, NI-I-C112- C112-C112) ; 2.95 (bt, 211 CH2-CH2-N-C112-C112) ; 3.44 (in 411, CH2-C112-N-C112- C112 and NH-CH2-CH2-CH2) ; 3.85 and 3.92 (2in, 211, NH-CH-,-CH-NH) ; 4.45 (in, 111, NH-C112-CH-NH) ; 5.14 (s, 211, C112-Ph) ; 6.12 (d, IH C112-CH2-C112-NH) 6.43 (d, 111,11 naphthyridine); 7.16 (d, 111, H naphthyridine), 7.37 (in, 511, CH2Ph); 8.31 (s, 111, N=CH-N); MS: 644 (MH+) ; 588 (MH-tBu+) ; 4S4 (MH-COOCH2Ph+). Synthesis of 3-[[5-isobutyl-6-[4-( 1 ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1-piperidinyl]-4-pyriinidinyl]ainino]-N-[(phenylmethoxy)carbonyl]alanine, bis(trifluoroacetate). N N 'f TN.. GF3000H/0H202 H N ______ N~N 0 o N. 7 7 620 mg (0.96 inmole) of (1,1-diinethylethyl) 3-[[5-isobutyl-6-[4-(1,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N- [(phenylinethoxy)carbonyl]alaninate in 50 ml of dichloroinethane with 5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2CI2-MeOH-H20-AcO11 90-10- 1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloroinethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 525 mg (Yield = 67 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a beige solid. TLC : Rf=0.40 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2) 1H-NMR (DMSO d6) 0.83(d, 6H,CH2-CH-(~1j3}2); 1.60 to 2.OS (in, 711, - C112-CH-(C113)2), N11-CH2-CH2-C112 and N-C112-C112-CH-CH2) ; 2.3 5(in, 211, - CH2-CH-(C113)2) ; 2.65 to 2.87 (in, 311, CH2-CH-C112 and NH-CH2-C112-C112); 2.91 (bt, 2H CH2-CH2-N-CH2-C112) ; 3.42 (in 4H, CH2-C112-N-CH2-CH2 and NHC112-C112-CH2); 3.57 and 3.84 (2m, 211, NH-C112-CH-NH) ; 4.32 (in, 111, NH-CH2- CH-NH) ; 5.0 (s, 211, CH2-Ph) ; 6.68 (d, 111, H naphthyridine) ; 7.37 (in, 5H, CH2Ph); 7.66 (d, 111, H naphthyridine) ; 7.59 (d, 111 C112-CH2-CH2-NH) ; 8.27 (s, 111, N=CH-N). MS : 588 (MH+) ; 454 (MH-COOCH2Ph±) ; 586- (M-11-) ; 478- (586-OCH2Ph-); 1173- (2M-11-) IULDI (0.75 % CHC13) : ±1.0. Example 17 Synthesis of 5-inethoxy-4,6-dihydroxy-pyrimidine: OH 0 KNH2 HOI + 0 0 EtONadansEtOH ~. N ~ N. 7 EtOM o 7- N OH 0 S g (6.2 ininoles)of formainidine hydrochloride is added at 00C and in small quantities into a single-necked flask containing 30 ml of absolute ethanol and 90 ml of a solution of sodium ethylate at a concentration of 1.7 inol/l in ethanol. Stirring is maintained at ambient temperature for about twenty minutes, then 8.5 ml of diinethyl methoxymalonate is added dropwise. Stirring is maintained for 16 hours. The reaction mixture is then acidified with pure acetic acid to a pH between 4 and 5, then concentrated to dryness in the presence of cyclohexane. After impasting the crude product obtained is chroinatographed on silicagel eluting with a mixture of inethylene chloride-methanol (85-15)and 2 % water-acetic acid(l-l). 9.5 g of the expected product is obtained containing a small quantity of sodium acetate salts. TLC Rf= 0 [ Silicagel, eluent: inethylene chloride-methanol (85-l5)and 2 % of water-acetic acid( 1-1). 1H-NMR (MeOD) .5 3.67 (s, CH3-O); 7.73 (s, IH, N=CH-N) 2.00 (s, 311, CH3-COO-) HPLC / MS: (rt = 0.5 mm) Synthesis of 4,6-dichloro-5-inethoxy-pyriinidine: OH ci 0 POGI3 N 'N. N'NNN. N OH A mixture of 5 g (35.2 inmoles) of 5-methoxy-4,6-dihydroxy-pyriinidine and 40 ml of phosphorus oxychloride, is taken to reflux for one hour. After returning to ambient temperature, a mixture of 4.8 ml of N,N-diethylaniline and 18 ml of phosphorus oxychloride is added dropwise. The mixture is again taken to reflux for 4 hours 30 minutes. After cooling down, the reaction mixture is poured slowly into a mixture of ice and water then neutralized by a saturated solution of sodium bicarbonate. This aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum. The residue obtained is purified on silica eluting with a mixture of cyclohexane and acetate (95-5). 2.5 g (Yield = 40 %) of expected product is obtained in the form of a white powder. TLC : Rf= 0.48 [Silicagel, eluent: cyclohexane-ethyl acetate(80-20)] 1H-NMR (MeOD) .5 4.00 (s, C113-O) ; 8.55 (s, 111, N=CH-N) HPLC/MS : rt = 1.3 mm Synthesis of 6- [4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1 -piperidinyl]-5 -inethoxy-4-chloro-pyriinidine: CI N 0 ,N OMA/ DIPEA N N C~ 2.2 g (12.3 minoles) of 4,6-dichloro-5-methoxy-pyriinidine solubilized in 25 ml of diinethylacetamide and 3640 p.1 of diisopropylethylainine are added into a single-necked flask containing 800 mg (3.68 ininoles) of 4-( I ,2,3,4-tetrahydro- 1,8-naphthyridin-7-yl)- I -piperidine released from its salt. This mixture is heated at 1300C for 2 hours then concentrated to dryness under vacuum. The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. The residue is chroinatographed on alumina eluting with a mixture of cyclohexane and acetate (80-20). 900 mg (Yield 68 %) of expected product is obtained in the form of a yellow powder. Preparation of the naphthyridine in free amine form: 2.4 g of naphthyridine is displaced from its salt by 6 mass equivalents of basic amberlyst A2 I resin (resin of R-NMe2 type) in a C112C12 / MeOH /AcOEt mixture 1/1/1 under stirring for 30 minutes. The resin is washed beforehand and left to swell for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the displacement of the salt to be complete. After filtration of the resin and evaporation of the solvents, 800 ing (3.68 minoles) of free naphthyridine is obtained. (Yield = 88 %). TLC : Rf=0.4 [alumina, eluent: ethyl acetate cyclohexane (30-70)] 1H-NMR (MeOD) : 6 1.75 to 1.95 (in, 611, NH-C112-CH2-CH2, N-C112-C112-CH-CH2) ; 2.70 (t, 111, CH2-CH-CH2) ; 2.8 (in, 211, NH-CH2-CH2-CH2) ; 3.15 and 3.75 (2in, 411, CH2-CH2-N-CH2-C112) ; 3.75 (s, C113-O) ; 6.4 and 7.15 (2d, 211, CH=CH naplithyridine); 8.1 (s, 111, N=CH-N). IIPLC / MS (rt = 0.53 mm and 2.56 mm): 359(M) ; 360(MH±) ; 361 (M±2H±±). Synthesis of (1,1 -dimethylethyl) 3-[[6-[4-( 1,2,3 ,4-tetrahydro- 1, 8-naphthyridin-7-yl)- 1 -piperidinyl]-5-inethoxy-4-pyrimidinyl]amino]-N- [(phenylmethoxy)carbonyl]alaninate. / C' N N N /N Pd,dba, I CsF I BINAP Dioxane A mixture of 300 ing (0.83 minoles) of 6-[4-(l,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)- 1 -piperidinyl]-5 -inethoxy-4-chloro-pyriinidine and 295 ing (I. inmole) of (1,1 -dimethylethyl) 3 -ainino-N-[(phenylinethoxy)carbonyl] alaninate (prepared according to J. Med. Chein. (2001), 44(8), 1158-1176), is heated under reflux for 3 hours 30 minutes in the presence of 177 mg (1.17 ininoles) of caesiurn fluoride, 52 ing (83 p.inoles)of (2,2'-bis(diphenylphosphino)-1,l'-binaphthyl and 40 mg (42 p.inoles) of tris-dibenzylideneacetone) dipalladiuin(o), in 10 ml of dioxane. The reaction mixture is then taken to temperature then 0.5 ininoles of (1,1-dimethylethyl) 3-amino-N-[(phenylinethoxy)carbonyl] alaninate and 1.17 minoles of caesium fluoride, 83 p.moles of (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and 42 p.moles of tris-dibenzylideneacetone) dipalladiuin(o) are added then the reaction mixture is taken to reflux for another 8 hours. After cooling down the solution is concentrated to dryness then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chroinatographed on alumina with a gradient of isopropyl ether and ethyl acetate (70-30, 60-40, 50-50) ending with 100 % ethyl acetate. The fractions containing the expected product are combined for a second purification on silicagel with a gradient of 100 % ethyl acetate. The expected product is obtained in the form of a pale yellow oil which is taken up in an isopropyl ether and pentane mixture in order to produce 220 mg (Yield = 43 %) of a white powder. TLC Rf= 0.3 (alumina eluent: isopropyl ether-ethyl acetate 60-40) 1H-NMR (MeOD):.5 1.46 (s, 911, tBu); 1.80 (in, 211, NH-CH2-CH2-C112); 1.90 (in, 411, N-CH2-CH2-CH-CH2) ; 2.65 (in, 111, C112-CH-C112) ; 2.69 (t, 211, NH-CH2-CH2-C112) ; 2.95 and 3.78 (2in, 411, C112-C112-N-C112-CH2) ; 3.38 (t, 211, NH-CH2-C112-CH2) ; 3.59 (s, CH3-O) ; 4.35 (in, 111, NH-CH2-CH-NH) ; 4.45 (d, ':3 211, NH-C112-CH-NH); 5.03 and 5.12 (syst AB, 211, O-CH2-Ph) ; 6.38 and 7.15 (2d, 211, CH=CH naphthyridine) ; 7.32 (in, 511, Ph); 7.90 (s, 111, NCH-N). HPLC/MS (rt = 3.4 mm): 618 (MH±);562 (MH —tBu) ; 428 [MH -(tBu-Z±)] Synthesis of corresponding acid: 0 oH 0 'N CF,COOH / CH,CI, o N 'N I ___________________ "11 I 0 0 N N N I N 0 0 / ~ N / N ~CF,COOH - NJ A mixture of 200 ing (0.32 minoles) of (1,1-dimethylethyl) 3-[[5-inethoxy-6-[4-( 1 ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-5-methyl-4-pyriinidinyl]amino]-N-[(phenyl methoxy)carbonyl]alaninate and 1.5 ml of trifluoroacetic acid in 15 ml of dichloromethane is stirred at ambient temperature for 8 hours. Then toluene is added and the mixture is evaporated to dryness. 350 mg of a yellow oil is obtained, this oil is taken up in a minimum amount of inethylene chloride and precipitated from isopropyl ether, in this way the impure trifuoroacetate salt is obtained. Precipitation is repeated from ether to purification (checked by TLC). Finally 156 ing of the expected product (Yield = 71 %) is obtained in the form of a white powder. TLC Rf=0.4 (silicagel, eluent: dichloromethane-inethanol-water-acetic acid 90-10-1-1). 1H-NMR (MeOD) : .5 1.85 (in, 211, NH-CH2-CH2-CH2) ; 2.00 (in, 411, NC112-CH2-CH-CH2); 2.83 (t, 211, NH-CH2-C112-CH2) ; 3.90 (in, 111, CH2-CH- C112) ; 3.12 and 3.72 (2in, 411, CH2-CH2-N-C112-CH2) ; 3.52 (t, 211, NH-C112- C112-C112); 3.62 (s, 311, CH3-O) ; 4.52 (in, 211, NH-CH2-CH-NH) ; 4.60 (in, 111, NH-C112-CH-NH) ; 5.06 and 5.10 (syst AB, 211, O-CH2-Ph) ; -6.65 and 7.62 (2d, 211 CH=CH naphthyridine) ; 7.43 (in, 511, Ph); 8.00 (s, 111, No~CH~N). HPLCIMS : (rt = 0.5 mm and 2.75 mm): 562 (MH±) ; 428 [MH -(tBu-Z±)] ; 428 Example 18 Synthesis of 4,6-dibroino-5-fluoro-pyriinidine. F O ~ ~ + H,N...~NH 1/ EtONa-EtOH Br Br o o CH,C02 2/ POBr3 N~N 1/ 60.7 ml (168 mmoles) of a solution of sodium ethylate to 21 % in the ethanol is added to a solution of 5.83 g (56 ininoles) of formamidine acetate in 300 ml of ethanol cooled down to 00C and the mixture is stirred for 30 minutes then a solution of 10 g (56 ininoles) of diethyl fluoro inalonate in 25 ml of ethanol is. added at ambient temperature and the reaction mixture is stirred overnight, followed by cooling down to 00C then 17.85 ml of concentrated hydrochloric acid is added in order to adjust the pH to 6. The precipitate is filtered then washed successively with water, isopropanol, diethyl ether and finally pentane. 14.2 g (theory = 7.3g) of expected product and mineral salts are obtained used as they are for the following. 2/ A mixture of 14.2 g (56 ininoles) of 5-fluoro-4,6-dihydroxy-pyriinidine in 21 g of phosphorus oxybroinide is taken to 2000C for 3 hours. After returning to ambient temperature, the reaction mixture is taken up in a mixture of iced water and sodium bicarbonate and extracted with ethyl acetate, the organic phases are washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of inethylene chloride-heptane from 0-100 to 100-0. 850 mg (Yield = 06 %) of expected product is obtained in the form of beige solid used as it is for the following. TLC : Rf=0.50 (silicagel, eluent: dichloroinethane-heptane 50-SO) Synthesis 4-broino-5 -fluoro-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-pyriinidine A mixture of 840 mg (1.5 ininoles) of l,2,3,4-tetrahydro-7-(4-piperidinyl)-l,8-naphthyridine, tris(trifluoroacetate) (prepared according to the Patents EP1065207 or WO 0078317) and S g of Ainberlyst A-2 1 resin (origin Fluka 06424 washed beforehand with a dichloroinethane-ethyl acetate-methanol solution 1-1-1) in 100 ml of a dichloromethane-ethyl acetate-methanol solution 1-1-1 is stirred at ambient temperature for 1 hour. The mixture is filtered and the resin washed with the ternary solution. The filtrate obtained is stirred at ambient temperature for 1 hour in the presence of 5 g of Amberlyst A-2 1 resin treated as previously. The filtrate thus obtained is concentrated to dryness under reduced pressure (2 kPa) producing 320 ing of free amine. 384 ing (1.5 ininoles) of 4,6-dibromo-5-fluoro-pyriinidine, 6 ml of dimethylacetamide and 1.5 ml of diisopropylethylainine are added to this residue and the reaction mixture is taken to 1300C for 1.5 hours, followed by evaporating to dryness under reduced pressure (2 kPa). The residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with heptaneethyl acetate 50-50. 300 mg (Yield = 52 %) of expected product is obtained in the form of an amorphous solid. TLC Rf=0. 15 (silicagel, eluent: heptane-ethyl acetate 50-50). IR (CHCI3) 3440 (NH); 1573, 1542, 1503 cm-i (Heterocycle) 5 1H-NMR (CDCI3):.5 1.82, 1.92 and 2.02(dt, t and d 611, CJ-12-CH2-C112-NH and ~R-CH-CH2) ; 2.72 (t, 211, C112-CH2-CH2-NH) ; 2.80 (bt, 111, C112-CH-C112); 3.13 and 4.68 (bt and d, 411, C112-C112-N-CH2-C112) ; 3.42 (in, 211, C112-C112-C112- NH) ; 5.00 (in, 111 NH) ; 6.37 (d, 111, naphthyridine) ; 7.14 (d, 111, naphthyridine); 8.11 ppm (s, N=CH-N). MS: 392 (MH±). Synthesis of (1,1 -diinethylethyl) 3-[[5-fluoro-6-[4-( 1 ,2,3,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]ainino]-N- [(phenylmethoxy)carbonyl]alaninate. 5(-)BINAP - N' ~CxON1 + ~ N N FY> N-I H HIJ I N ~ A mixture of 280 mg (0.72 inmole) of 4-broino-5-fluoro-6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-pyriinidine, 253 ing (0.86 ininole) of (1,1 -diinethylethyl) 3 -ainino-N-[(phenylinethoxy)carbonyl]alaninate (prepared according to J. Med. Chem.(2001), 44(8), 1158-1176), 152 ing (1.00 ininole) of caesium fluoride, 33 mg (0.036 ininole) of tris(dibenzylideneacetone)dipalladiuin(0), 45 mg (0.072 inmole) of 2,2'-bis(diphenyl-phosphino)-l,l'-binaphthyl in 50 ml of dioxane is heated under reflux for 6 hours. The reaction medium is cooled down then another 125 ing (0.43 minole) of (1,1 -diinethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl] alaninate, 152 mg (1.0 ininole) of caesiuin fluoride, 33 mg (0.036 ininole) of tris(dibenzylideneacetone)dipalladiuin(0), and 45 mg (0.072 minole) of 2,2'-bis(diphenyl-phosphino)- 1,1 '-binaphthyl are added and the reaction mixture is heated under reflux for 4 hours, followed by evaporating to dryness under reduced pressure (2 kPa). The residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol from 100-0-0 to 0-100-0 and finally 0-95-5. The product obtained is chroinatographed a second time on alumina eluting with a heptane-inethylene chloride mixture 50-50 then with an ethyl acetate-diisopropyl ether mixture 50-50. 300 mg (Yield = 70 %) of expected product is obtained in the form of a yellow oil. TLC Rf= 0.35 (silicagel, eluent: ethyl acetate. IR (CHCI3) 3439 (NH) ; 1718 (C=O) ; 1609.1503 cm-i (Heterocycle±Aromatic±Ainide). N~N 66 1H-NMR (CDCI3) .5 1.47 (s, 911, tBu); 1.70 to 2.05(in, 611, CH2-CH2-CH2- NH and C112-CH-CH2) ; 2.73 (t, 211, C112-C112-C112-NH) ; 2.80 (bt, 111, C112-CH- CH2); 3.01 and 3.90 (bt and in, 411, CH2-C112-N-CH2-CH2) ; 3.43 (in, 211, C112-CH2- CH2-NH); ; 4.42 (in, 111, NH-C112-CH-NTI) ; 4.51 (bd., 211, NH-CH2-CH-NH); 5.11 (in, 111 NH); 5.14 (s, 211, CH2-Ph) ; 6.12 (in, 111 C112-CH2-CH2-NH ) ; 6.37 (d, 111, naphthyridine); 7.16 (d, 111, naphthyridine); 7.35 (in, 511, Ph) ; 7.98 ppm (s, N=CH-N). MS 606 (MH±); 550 (MH-tBu±) ; 416 (550-COOCH2Ph±), 604- [(M-H)]-, 650- [(604±HCOOH)]-, 496- [(604-OCH2Ph)]-. fanj (1.0 % CHCI3) ±4.4 Synthesis of 3-[[5-fluoro-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- Ipiperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, bis(trifluoroacetate). 7 CF3COOH/CH2CI2 N N N H N 2 CF3COOH NN.~N~N. 7 290 mg (0.48 minole) of (1,1-diinethylethyl) 3-[[5-fluoro-6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylinethoxy)carbonyl]alaninate in 40 ml of dichloromethane with 4 ml of trifluoroacetic acid stirred at ambient temperature until the disappearance of the starting product according to TLC (silicagel, eluent: C112C12-MeOH-H20-AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 310 mg (Yield = 83 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid. TLC Rf=0.44 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1) MS 550 (MH±) ; 416 (MH-COOCH2Ph±) ; 548- (M-H-) ; 440- (548-OCH2Ph-); 1097- (2M-H-) IcLDI (0.30 % MeOH) -9.3. Example 19 Synthesis of (1,1 -dimethylethyl) 3-[5-ethyl-6-[4-( 1 ,2,3,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]ainino]alaninate. '7 H2 Pd/C ______________ n AcOH AcOH 150 ml of 100 % acetic acid and 300 mg of activated palladium on carbon (5- 10 %) are loaded into a single-necked flask containing 3 g (4.87 ininoles) of 3-[[6-[4-(1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]- 5-ethyl-4- pyrimidinyl]ainino]-N-[(phenylmethoxy) carbonyl]alanine. This mixture is purged under reduced pressure (2 kPa) then left under stirring at ambient temperature and under atmospheric pressure of hydrogen for 22 hours. The heterogeneous medium obtained is filtered on clarcel. The filtrate is concentrated to dryness then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is extracted with ethyl acetate and dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). 1.95 g of a pale yellow oil is obtained. TLC : Rf= 0.65 (silicagel, eluent: ethyl acetate-inethanol-triethylainine 90-5-5) 1H-NMR (CDCI3) :.5 1.09 (t, 311, CH2-CH3); 1.35 (s, 911, tBu); 1.7S (in, 611, C112-CH-CH2_and C112-C112-CH2-NH) ; 2.44 (in, 211, C112-C113) ; 2.60 (t, 211, CH2- CH2-CH2-NII) ; 2.81 (in, 211, CH2-CH-CH2 and NH-CH2-CH-NH) ; 3.23 (in, 211, CH2-CH2-CH2-NH); 3.41 (in, 411, CH2-CH2-N-C112-C112) ; 3.42 and 3.57 (2in, 211, NH-CH2-CH-NH); 6.25 (in, 211, CH2-C112-CH2-NH_and NH-C112-CH-NH) ; 6.30 and 7.04 (2d, 211, 11 naphthyridine) ; 8.08 ppm (s, 111, N=CH-N). IR (CHCI3) : 3439 (NH); 1726 (C0); 1580, 1502 cm-I (heterocycle). MS : 482k [MH]~ ; 426k [MH~ - tBu]~; 339k [MH~ - CH2CH(NH2)CO2tBu ]i; 241.7k [M±2H]2 laDi :-3(1 %CHCl3) Synthesis of (1,1 -diinethylethyl) 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]amino]-N- [(adamantylinethoxy)carbonyl]alaninate. CH2CI2 o N1K. TEA o 0 N N HY 0 H N N~N N..~2~'.NH ~ ~N~N)NO 0~NO NyC H N~N A mixture of 239 mg (0.49 inmoles) of (1,l-dimethylethyl)3-[5-ethyl-6-[4-(1 ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]amino] alaninate, 152 mg (0.49 ininoles) of N-adainantylinethoxycarbonyloxysucciniinide and 0.104 ml (0.75 ininoles) of triethylainine in 50 ml of inethylene chloride is stirred for 5 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chroinatographed on silicagel eluting with a gradient of methylene chloride 100 % to inethylene chloride-methanol 90-10. 77 ing (Yield = 17 %) of expected product is obtained in the form of a beige solid. TLC : Rf = 0.45 (silicagel, eluent: inethylene chloride-methanol-acetic acid-water 90-10-1-1). IR(CHCI3):3437 (NH); 1711 (C=O); 1583, 1556, 1501 cm-l (Heterocycle) 1H-NMR (DMSO-d6) : .5 1.08 (t, 311, C112-CH3) ; 1.45 to 1.92 (in, 1511, adainantyl); 1.32 (s, 911, tBu); 1.77 (in, 611, CH2-CH-C112 and C112-C112-CH2-NH); 2.44 (q, 211, CH2-CH3) ; 2.50 (in, 111, C112-C11-CH2) ; 2.61 (t, 211, C112-C112-C112-NH) ; 2.82 and 3.44 (2m, 411, CH2-CLI2-N-C112-C112) ; 3.22 (in, 211, C112-C112-CH2-NH) ; 3.56 (s, 211, O-CH9-adain) ; 3.66 (in, 211, NH-CH2-CH-NH) ; 4.17 (q, 111, NHC112-f I-I-NH) ; 6.24 (s, 111, CH2-CH2-CH2-NH) ; 6.30 and 7.05 (2d, 211, H naphthyridine) ; 6.37 (t, 111 NH-CH2-CH-NH) ; 7.44 (d, 111, NH-C112-CH-NH) 8.10 ppm (s, N=CLI-N). MS : 674 (MH±) ; 618 (MH-tBu±) ; 426 (618-COOC112adain±) ; 337.7 (M2H±±) ; 718- (M-H-HCOOH) ; 672- (M-H). laiD : ±2.5 (1 % CHCI3). Synthesis of 3-[[5-ethyl-6-[4-( I ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1-piperidinyl]-4-pyrimidinyl]ainino]-N- [(adainantylmethoxy)carbonyl]alanine GF/n2H 130 mg (0.19 ininoles) of (1,1 -dimethylethyl) 3-[[5-ethyl-6-[4-( 1,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl] -4-pyrimidinyl]ainino]-N-[(adainantylmethoxy)carbonyl]alaninate in 20 ml of dichloroinethane with 2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: C112C12-MeOH-H20-AcO11 90-10- 1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloroinethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 368 ing (Yield 61 % expressed as ditrifluoroacetate) of expected product is obtained in the form of an amorphous solid. TLC Rf=0.35 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-l-l) IR (CHCI3) 3401 (NH); 1668 (C=O); 1581, 1492 cm-i (Heterocycle) 1H-NMR (DMSO-d6) .5 1.08 (t, 311, C112-C113) ; 1.45 to 1.92 (in, 1511, adainantyl) ; 1.76 (in, 611, C112-CH-C112 CH2-C112-CH2-NH) ; 2.43 (q, 2H CH~CH3) ; 2.50 (in, 111, CH2-CH-CH2) ; 2.60 (t, 2H CH,-CH2-CH2-NH) ; 2.82 and 3.45 (2m, 4H, CH2-~1j2-N-CH2-CIi2) ; 3.23 (in, 211, CH2-C112-CH2-NH) ; 3.49 and 3.58 (in, 211, O-CH,-adam) ; 3.56 and 3.76 (in, 211, NH-C112-CH-NH); 4.18 (in, lH, NHCH2-CH-NH) ; 6.26 (s, 111, CH2-CH2-CH2-NH) ; 6.30 and 7.05 (2d, 211, H naphthyridine) ; 6.44 (in, 111 NH-CH2-CH-NH); 7.25 (d, 111, NH-CH2-C11-NH) 8.11 ppm (s, N=CH-N). MS 618 (MH±) ; 426 (MH-COOCH2Ph±); 1235 (2M11±) ; 309.8 (M211±±); 616- (M-H-) IcEDI (0.7 % CH3OH): -2.8 Example 20 Synthesis of (1,1 -diinethylethyl) 3 -[5 -ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyrimidinyl]amino]alaninate. 0 0 H2 H Pd/C N _____________ ~NH, AAcOH H N NH 6' AcOH N N/RN — N~~~' ~ 150 ml of 100 % acetic acid and 300 ing of palladium on activated carbon (5- 10 %) is loaded into a single-necked flask containing 3 g (4.87 mmoles)of 3-[[6-[4-(1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1 -piperidinyl]-5-ethyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy) carbonyl]alanine. This mixture is purged under reduced pressure (2 kPa) then left under stirring at AT under atmospheric pressure of hydrogen for 22 hours. The heterogeneous medium obtained is filtered on clarcel. The filtrate is concentrated to dryness under reduced pressure (2 kPa) then taken up in a mixture of 0' water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is extracted with ethyl acetate and dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). 1.95 g of a pale yellow oil is obtained. TLC rf= 0.65 (silicagel eluent AcOEt-MeOH-TEA = 90-5-5) (7Ld=-3(l %CHCl3) 1H-NMR (CDCI3):.5 1.09 (t, 311, C112-C113); 1.35 (s, 911, tBu); 1.75 (in, 611, CH2-CH-C112 and C112-C112-C112-NH) ; 2.44 (in, 211, C112-C113) ; 2.60 (t, 211, CH2- C112-C112-NH) ; 2.81 (in, 211, CH2-CH-C112 and NH-C112-CH-NH) ; 3.23 (in, 211, CH2-C112-C112-NH); 3.41 (in, 411, C112-C112-N-C112-C112) ; 3.42 and 3.S7 (2in, 211, N11-CH2-CH-NH) ; 6.25 (in, 211, CH2-C112-CH2-NH_and NH-C112-CH-NH) ; 6.30 and 7.04 (2d, 211, H naphthyridine) ; 8.08 ppm (s, 111, NCH-N). IR (CHCI3) 3439 (NFL); 1726 (C=O); 1580— 1502 (heterocycle) HPLC I MS 482~ [MH]~ ; 426' [MH~ - tBu]t ; 339k [MW -C112CH(NH2)CO2tBu V ; 24l.7~ [M±211]2 ExamDies 21 to 31 ExamDIe 28 Stai~e a) Synthesis of (1,1 -dimethylethyl)3-[[5-ethyl-6-[4-( I ,2,3,4-tetrahydro- 1,8- naphthyridin- 7-yl)- I -piperidinyl]-4-pyriinidinyl]ainino]-N-(4-methoxy-benzenesulphonyl)alaninate. 0 — pyi-idine, CH,CI, + ,iS \ / 0 64.3 mg (0.31 inmoles)of 4-methoxy-benzenesulphonyl chloride in solution in 3 ml of dichloroinethane is added to a mixture of 150 ing (0.31 inmoles) of (1,1-diinethylethyl) 3- [5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphtiridin-7-yl)- 1-piperidinyl]-4-pyrimidinyl]amino]alaninate in solution in 6 ml of dichloroinethane and 650 p.1 of pyridine. The reaction mixture is stirred at ambient temperature for S hours. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silicagel with the following eluent: ethyl acetatedichloromethane/methanol(95/5) 50-SO to ethyl acetate-methanol 90-10. 55.8 ing (Yield = 28 %) of expected product is obtained. CFJCOOt-1. CH,CI, 2 CF,COOH ~7T TLC Rf=0.63 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2) 1H-NMR (CDCI3) : .5 1.21 (t, 311, CH2-CH3) ; 1.30 (s, 911, tBu) ; 1.92 and 2.02 (2in, 611, N-CH2-CH2-CH-CH2-CH2, CH2-C112-CH2-NH) ; 2.48 (q, 211, C112- CH3) ; 2.72 (in, 311, N-CH2-CH2-CH-C112-CH2, CH2-C112-C112-NH) ; 2.97 and 3.61 (2m, 411, N-C112-CH2-CH-C112-C112) ; 3.45 (in, 211, C112-CH2-CH2-NH); 3.74 and 3.86 and 3.95 (3m, 611, NH-C112-CH-NH, OCH3) ; 4.95 (t, 111, mobile NH); 5.92 (bd, 111, mobile NH) ; 6.43 and 7.20 (2d, 2H, CH=CH naphthiridine) 6.95 and 7.79 (2d, 411, CH=CH benzene) ; 8.29 (s, 111, N=CH-N). MS: 652(MH±). Sta2e b) Synthesis of 3-[[5-ethyl-6-[4-( I ,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyriinidinyl]ainino]-N-(4-inethoxy-benzenesulphonyl)alanine. 55.8 mg (0.086 ininoles) of (1,1 -diinethylethyl) 3-[[5-ethyl-6-[4-( 1,2,3,4-tetrahydro- 1, 8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]ainino] -N-(4- inethoxy-benzenesulphonyl)alaninate in 5 ml of dichloroinethane with 0.5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: C112C12-MeO11-1120-AcOH 85-15- 2-2). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 59.8 mg (Yield = 85 % expressed as ditrifluoroacetate) of expected product is obtained. TLC : Rf=0. 33 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2). 1H-NMR (MeOD) : .5 1.22 (t, 311, C112-CH3) ; 1.96 and 2.10 (2in, 611, NC112-CH2-CH-CH2-C112, C112-C112-C112-NH) ; 2.55 (q, 211, C112-CH3) ; 2.85 (t, 211, CH2-CH2-C112-NH) ; 2.95 (in, 111, N-CH2-CH2-CH-CH2-C112) ; 3.20 and 3.67 and 3.92 (3m, 611, N-CH2-CH2-CH-C112-CH2, NH-CH2-CH-NH) ; 3.51 (in, 211, CH2-C112-C112-NH) ; 4.24 (in, 111, NH-CH2-CH-NH) ; 6.71 and 7.64 (2d, 211, CH=CH naphthiridine) ; 6.99 and 7.74 (2d, 411, CH=CH benzene) ; 8.27 (s, 111, N=CH-N). 7L MS: 596(MH±). General operating method for the preparation of sulphonainides Stai~e a) 0 + CI~-~R pyrid~ne, CH,GI, II 0 0.31 inmoles (mass in~) of sulphonyl chloride in solution in 3 ml of dichloroinethane is added to a mixture of 150 mg (0.31 inmoles) of (1,1-diinethylethyl)3-[5 -ethyl-6-[4-( 1,2,3 ,4-tetrahydro- l ,8-naphtiridin-7-yl)- 1- piperidinyl]-4-pyriinidinyl]ainino]alaninate in solution in 6 ml of dichloroinethane and 650 p.1 of pyridine. The reaction mixture is stirred at ambient temperature for S hours. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silicagel with the following eluent: ethyl acetatedichloroinethane/ inethanol(95/5) 50-50 to ethyl acetate-methanol 90-10. A mass of expected product is obtained. TLC : Rf(eluent: diebloroinethane-methanol-water-acetic acid 85-15-2-2). Sta2e bi GF,COOH. CH,CI, 2 CF,COOH A mass my of (1,1 -dimethylethyl) 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyriinidinyl]ainino]-N-(R-sulphonyl)alaninate in 5 ml of dichloroinethane with 0.5 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH-1120-AcOH 85-15-2-2). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. A mass m~ of expected product is obtained. TLC : Rf (eluent: dichloromethane-inethanol-water-acetic acid 85-15-2-2). 92- 73 My: mass of ester obtained R:\Brevets'21500\21565US.doc -28 f~vrier 2005- 72/110 71~. mass of acid obtained mass of ester obtained 7-5- Example 32 Synthesis of (1,1 -dimethylethyl) 3-[[5-ethyl-6-[4-( 1 ,2,3,4-tetrahydro- I ,8 naphthyndin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]amino]-N-( 1-naphthalenesulphonyl)alaninate. THF 7 >~- TEA 7 N' 0 0 NI 00 Cg N N N.)~NH N N NNJI~NH ~ H H H N o~~o~— N N. N N ~N N~N / / A mixture of 239 mg (0.49 mmoles) of (1,1-dimethylethyl) 3-[5-ethyl-6-~4-(1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyrimidinyl]amino] alaninate, 113 mg (0.5 mmoles) of l-naphthalenesulphonyl chloride and 0.104 ml (0.75 mmoles) of triethylamine in 50 ml of tetrahydrofuran is stirred for S hours al ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a gradient of heptane-ethyl acetate 75-25 to 0-100. 220 mg (Yield = 67 %) of expected product is obtained in the form of a white solid. TLC Rf = 0.10 (silicagel, eluent: methylene chloride-methanol-acetic acid-water 90-10-1-I). IR (CHCI3) 3440 (NH) ; 1728 (C=O) ; 1583, 1555, 1503 cm-I (Heterocycle±aromatic) 1H-NMR (CDCI3) 6 1.02 (t, 3H, CIJ2CH3) ; 1.15 (s, 911, tBu) ; L81 to 2.03(m 611 CH2-CH-CH2_and_CH2-CH9-CH2-NH) ; 2.23 and 2.31 (2q, 211, CH2- CU3) ; 2.67 (t, 111, CH2-CH-CH2) ; 2.72 (t, 2H, C112-CH2-CH2-NI-I) ; 2.93 and 3.56 (bt and bd, 4H, CLI2-CH2-N-C112-CLI2) ; 3.43 (in, 2H, CH2-CH2-C112-NH) ; 3.66 and 3.76 (2m, 211, NH-CH9-CH-NH) ; 3.97 (in, 111, NH-CH2-CH-NH) ; 4.73 (t, 111, t, 111, NH-CH2-CH-NH) ; 6.55 (s,1H, CH2-C112-CH2-NIT) ; 6.42 and 7.05(2d, 211, 11 naphthyridine) ; 7.51 (t, 111, 113 1-SO2naphthyl); 7.57 and 7.62 (2t, 2H, H6 and H7 1-SO2naphthyl) ; 7.90 (d, 111, H2 1-SO2naphthyl) ; 8.02 (d, 111, H4 ISO2naphthyl); 8.22 (in, 211 N=CH-N and 115 l-SO2naphthyl); 8.61 ppm (in, 111, 118 1 -SO2naphthyl). MS 672 (MH+) ; 426 (61 6-SOOnaphth+) ; 670- (M-H). laiD +3.3 (1 % CHCI3). Synthesis of 3-[[5-ethyl-6-[4-( I ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1-piperidinylj-4-pyrimidinyl]amino]- N-( I -naphthalenesulphonyl)alanine 7 N N N N 0 CH2CI2 N N 0 OH H N H N _________ ~NH N~N ~-S CF3C02H N~N 0-~ ~ / Oo/ / 220 mg (0.33 mmoles) of (1,1-dimethylethyl) 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyrimidinyl]amino]-N-( 1- naphthalenesulphonyl)alaninate in 20 ml of dichloromethane with 2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2CI2-MeOH-1120-AcOH 90-10- 1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloroinethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 230 mg (Yield = 82 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid. TLC Rf=0. 10 (silicagel, eluent: dichloroinethane-inethanol-water-acetic acid 90-10-1-1) IR (CHCI3) 3412-3257(OH, NH) ; 1668(C=O) ; 1628, 1582, 1505 cm1(C=C, C=N, aromatic) 1H-NMR (DMSO-d6) : 60.87 (t, 311, C112-CH3); 1.77 (in 611 C112-CH-CH2 C112-C112-C112-NH) ; 2.OS (q, 111, ~jj2-CH3) ; 2.16 (q, 111, CH2-C113) ; 2.62 (t, 211, CH2-C112-C112-NH) ; 2.73 and 3.50 (2m, 411, C112-C112-N-C112-C112) ; 2.80 (in, 111, C112-C11-CH2) ; 3.20 (in, 211, CH2-CH2-CH2-NH) ; 3.50 (in, 211, CH-CH2-CH2-N); 3.66 and 3.76 (2in, 211, NH-CH,-CH-N11) ; 3.97 (t, 111, NH-CH2-CH-NH) ; 6.26 (s, 111, C112-C112-C112-NH) ; 6.31 and 7.06 (2d, 211, H naphthyridine) ; 7.55 (t, 111, 113 I-SO2naphthyl) ; 7.62 (in, 211, 116 and 117 l-SO2naphthyl) ; 7.96 ppm (s N=CHN); 8.02 (in, 111, 115 l-SO2naphthyl) ; 8.08 (d, 111, 112 1-SO2naphthyl) ; 8.14 (d, 111, 114 1-SO2naphthyl); 8.58 (in, 111, 118 1-SO2naphthyl). MS: 616 (MH+) ; 426 (MH-SOOnaphth+); 1231 (2MH+) ; 308.8 (M211++); 614- (M-H-) IcLDI:(O.4 % CH3OH):+7.0 Example 33 Synthesis of (1,1 -diinethylethyl) 3 -[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]amino]-N-(2-pyridinyl)alaninate '7 >2 ____ 0>2 N N N N N..XNH N.~~NH2 N F N,~N N~N N. A mixture of 240 ing (0.50 rnmole) of (1,1-diinethylethyl) 3-[5-ethyl-6-[4-(1 ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]amino] alaninate and 3 ml of 2-fluoropyridine is stirred for 24 hours under reflux. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a mixture of ethyl acetate-methylene chloride-methanol 80-16-4. 13 mg (Yield = 05 %) of expected product is obtained in the form of an oil. TLC Rf= 0.40 (silicagel, eluent: methylene chloride-methanol 90-10). MS: 559 (MH±). Synthesis of 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1-pipendinyl]-4-pyrimidinyl]amino]- N-(2-pyridinyl)alanine 7 >2 I 0 0 CH2CI2 0 OH N N NJNH NN)NH H N ______ N~N 7 N CF3002H N~N 7 N 13 mg (0.023 minole) of (1, 1-dimethylethyl) 3-[[5-ethyl-6-[4-(l ,2,3,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyrimidinyl]ainino]-N-(2-pyridinyl)alaninate in 2 ml of dichloroinethane with 0.2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2CI2-MeOH-1120-AcO11 90-10-1-I). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane then poured into diisopropyl ether. The precipitate is filtered. 13 mg (Yield = 76 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a beige solid. TLC Rf=0.35 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2) MS: 503 (MH+); 501- (M-H-) 76 Example 34 Synthesis of (1,1 -dimethylethyl) 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyll-4-pyriinidinyl]aininol-N-(2-benzothiazolyl)alaninate. 7' >2 0 0 N N H~Y H N ~ N~N Py idine __ >2 0 0 ~N. N 5 A mixture of 200 mg (0.42 minole) of (1,1-dimethylethyl) 3-[5-ethyl-6-[4-(1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyriinidinyl]amino] alaninate and 90 mg (0.6 minole) of 2-fluorobenzothiazol in 5 ml of pyridine is stirred for 2 hours at 1000C. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed a first time on silicagel eluting with a gradient of inethylene chloride-ethyl acetate-methanol 100-0-0 to 0-100-0 then 0-95-5 ; then a second time on reversed-phase RP8 eluting with a gradient of methanol-water 80-20 to 100-0. 50 ing (Yield = 19 %) of expected product is obtained in the form of a pink solid. TLC Rf= 0.20 (silicagel, eluent: ethyl acetate-methanol 98-2). 1H-NMR (CDCI3) 5 1.06 (t, 311, C112C11~) ; 1.49 (s, 911, tBu) ; 1.77 to 2.01(in 611 C112-CH-CH2 and C112-C112-C112-NH) ; 2.41 (q, 211, C112-C113) ; 2.61 (t, 111, CH2-CH-CH2) ; 2.72 (t, 211, C112-C112-C112-N11) ; 2.92 and 3.51 (bq and bt, 411, CH2-CH2-N-C112-C112); 3.42 (in, 211, CH2-CH2-CH2-NH) ; 3.9S and 4.09 (2in, 211. NH-~j~-CH-NH) ; 4.88 (in, 111, NH-CH2-CH-NH) ; 4.98 and 5.63 (in and t, 211, NH-C112-CH-NH and NH-CH2-CH-NH) ; 6.67 (bs,lH, C112-CH2-CH2-NH) ; 6.41 and 7.13(2d, 211, H naphthyridine) ; 7.12, 7.31 and 7.57 (t masked, t and bt 411, 11 benzothiazol); 8.32ppin (s, 111, N=CH-N). MS 615 (MH+) ; 559 (MH-tBu±) ; 613- (M-H-). Synthesis of 3-[[5-ethyl-6-[4-( I ,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1-piperidinyl]-4-pyriinidinyl]amino]- N-(2-benzothiazolyl)alanine 0 CH2CI2 0 OH H NH N NH N~S CF3CO2H N S o 45 ing (0.073 minole) of (1,1-dimethylethyl) 3-[[5-ethyl-6-[4-(l,2,3,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- I -piperidinyl]-4-pyrimidinyl]ainino]-N-(2-benzothiazolyl)alaninate in 10 ml of dichloromethane with 1 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: C112C12-MeOH-H20-AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 60 ing (Yield = 97 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid. TLC Rf=0.45 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 85-15-2-2) 1H-NMR (CDCI3) 6 1.15 (t, 311, C112-C113); 1.75 to 2.07(m, 611, C112-CH- NH); 2.96 (in, 111, C112-CH-CH2) ; 3.20 and 3.73 (2m, 411, CH2-C112-N-C112-C112); 3.51 (in, 211, C112-C112-CIrI2-NH) ; 4.23 (in, 211, NH-CH2-CH-NH) ; 4.67 (in, 111, NH-CH2-CH-NH) ; 6.38 and 7.35(2d, 211, 11 naphthyridine) ; 7.20, 7.35, 7.47 and 7.54 (t, t masked, bd and bd 411, 11 beuzothiazol) ; 7.73 and 10.05 (2m, 2H, mobile Hs); 8.36 ppm (s, 111, N=CH-N). MS: 559 (MH+); 557- (M-11-) Example 35 Operating by analogy with Example 34, starting from (1,1-dimethylethyl) 3-[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1 ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]amino] alaninate, 3-[[5-ethyl-6-[4-( 1,2,3 ,4-tetrahydro- I ,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]aininol-N-[2-(4-methoxybenzyinidazolyl)jalanine is prepared in the form of a beige solid. TLC Rf=0.40 (silicagel, eluent: dichloroinethane-methanol-water-acetic acid 85-15-2-2) 1H-NMR (CDCI3) : 6 1.12 (in, 3H, C112C113j); 1.65 to 2.07 (in, 6H, CH,-CHCFI2 and CI-12-C112-CH2-NH) ; 2.47 (in, 211, CH2-CH3) ; 2.74 (in, 211, CH2-CH2-CH2-NH); 2.92 (in, 111, C112-CU-CH2) ; 3.17 and 3.73 (2m, 411, C112-CH2-N-CH2-CH2); 3.52 (in, 211, C112-C112-C112-NH) ; 3.79 (s, 111, 0C113) ; 4.18 (in, 211, NH-CH2-CH- NH) ; 4.81 (in, 1H, NH-C112-CFI-NH) ; 6.35 and 7.36c (2d, 211, 11 naphthyridine) 6.72 and 7.18 (2d, 211, NC(C)CHC11C(CH)0C113) ; 6.87 (s, 111,NC(C)C11C(CH)OCH3) ; 6.37, 7.70 and 9.84 (mobile 311s) ; 8.32ppin (s, 111, N=CH-N). MS: 572 (M11+); 570- (M-H-) Example 36 Synthesis of terbutyl 2-(2-benzyloxycarbonylamino-3 - { 5 -inethyl-6-[4-(5 ,6,7,8-tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- I -yl]-pyriinidin-4-ylamino } -propinylamino)-propionate. N N H N. 2 CF3COOH NH2 EDAC-HOBT NMM-TEA-DMF 0% N' 0~~~NH N H H HI N ~ N~A~ N~N NH 0 0 N. K— 170 mg (0.30 minole) of 3-[[5-inethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1,8-naphthyridin-7-yl)- 1 -piperidinyl]-4-pyriinidinyl]amino]-N-[(phenylinethoxy)carbonyl]alanine, 150 mg (1.0 minole) of terbutyl L-alaninate, 66 mg (0.48 inmole) of 1-hydoxy benzotriazole, 90 mg (0.48 minole) of l-[3-(dimethylainino) propyl]-3-ethyl carbodiimide hydrochloride, 0.015 ml (0.135 inmole) of N-inethhylmorpholine and 0.2 10 ml (1.50 rnmoles) of triethylamine in 10 ml of dimethylforniamide are stirred for 24 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chroinatographed on silicagel eluting with a mixture of ethyl acetate-inethylene chloride-methanol 50-50-10. 120 ing (Yield 60 %) of expected product is obtained in the form of a white solid. TLC Rf=0.40 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 90-10-1-1) MS 673 (MH±). Synthesis of 2-(2-benzyloxycarbonylamino-3- { 5-methyl-6-[4-(5 ,6,7,8-tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- I -yl]-pyriinidin-4-ylainino } -propinylamino)-propionic acid. N~N 2 CF3COOH 2 CF3COOH N~N gj y~o% __ N N H N. CF3COOH-CH2CI2 120 ing (0.179 minoles) of terbutyl 2-(2-benzyloxycarbonylamino-3- {5-methyl-6-[4-(5 ,6,7,8-tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- I -yl]-pyrimidin-4-ylainino}-propinylamino)-propionate in 5 ml of dichloromethane with I ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: C112C12-MeOH-1120-AcO11 90-10-- 1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 95 mg (Yield = 63 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid. TLC Rf=0.45 (silicagel, eluent: dichloromethane-inethanol-water-acetic acid 8 5-15-2-2) MS 616 (MH+). Example 37 Synthesis of terbutyl 2-(2-benzyloxycarbonylainino-3- { 5 -ethyl-6-[4-(5 ,6,7,8— tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- 1 -yl]-pyrimidin-4-ylamino } -propinylamino)-propionate. ___ y~0% NH2 NH EDAC-HOST NMM-TEA-DMF 80 mg (0.15 minole) of 3 -[[5 -ethyl-6-[4-( 1,2,3 ,4-tetrahydro- 1, 8-naphthyridin- 7-yl)- 1 -piperidinyl]-4-pyrimidinyl]amino]-N- II(phenylmethoxy)carbonyl]alanine, 32 mg (0.20 inmole) of terbutyl L-alaninate, 22 mg (0.16 inmole) of 1-hydoxy benzotriazole, 30 mg (0.16 inmole) of 1-[3-(dimethylainino) propyl]-3-ethyl carbodiimide hydrochloride, 0.050 ml (0.45 minole) of N-methhylinorpholine and 0.070 ml (0.50 inmole) of triethylamine in S ml of diinethylformainide are stirred for 24 hours at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of ethyl acetate-methylene chloride-methanol from 50-50-0 to 50-45-5. 55 ing (Yield = 53 %) of expected product is obtained in the form of a white solid. TLC Rf=0.30 (silicagel, eluent: dichloroinethane-methanol-water-acetic acid 90-10-1-I) 1H-NMR (CDCI3) 6 0.91 (t, 311, C112-CH3) ; 1.38 (d, 311, CONHCH(C113)-CO) ; 1.48 (s, 911, tBu) ; 1.79 to 2.07 (in, 611, CH2-CH,-CH2-NH, CU2- CU-CU,) ; 2.49 (in, 211, C11,-C113) ; 2.66 (in, 111, C112-CH-CH2) ; 2.73 (t, 211, CU2- C112-C112-NH) ; 2.97 and 3.63 (2m, 411, C112-C112-N-C112-C112) ; 3.42 (in, 211, CH,C112-C112-NH); 3.73 and 4.14 (2m, 211, NH-C112-CH-NH) ; 4.31 (in, 111, NH-C112- CU-NH) ; 4.44 (q, 111, CONH-CH(C113)-CO) ; 5.14 (in 211 CH2-Ph); S.35, 6.92 and 7.89 (311, mobile Hs) ; 6.42 and 7.14 (2d, 211, H naphthyridine) ; 7.36 (in, 511, Ph) ; 8.29 ppm (s, 111, N=CH-N). MS 687 (MH+). Synthesis of 2-(2-benzyloxycarbonylamino-3- { 5-ethyl-6-[4-(5,6,7,8-tetrahydro-[ 1.8] naphthyridin-2-yl)-piperidin- 1 -yl]-pyrimidin-4-ylamino } -propinylamino)-propionic acid. 0 0 7 0 N' NH N N ____________ H NH N ~ N.~MH N~N N~N 7 2 CF3000H 50 ing (0.073 minoles) of terbutyl 2-(2-benzyloxycarbonylamino-3- {5-ethyl-6-[4-(5,6,7,8-tetrahydro- [1.8] naphthyridin-2-yl)-piperidin- 1 -yl]-pyriinidin-4-ylamino}-propinylamino)-propionate in 5 ml of dichloroinethane with 0.S ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH-H20-AcOH 90-10- 1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 lcPa). The residue is solubilized in the minimum amount of dichloroinethane with a little methanol then poured into diisopropyl ether. The precipitate is filtered. 53 ing (Yield = 85 % expressed as ditrifluoroacetate) of expected product is obtained in the form of a white solid. TLC Rf = 0.12 (silicagel, eluent: dichloromethane-inethanol-water-acetic acid 90-10-1-1) IH-NMR (CDC13) 6 1.16 (t, 311, CH2-CH3) ; 1.41 (d, 311, CONH CH(CH3)-CO); 1.80 to 2.10 (in, 611, C112-C112-C112-NH, CH2-CH-CH2) ; 2.48 (ni, 211 CU2-CU3) ; 2.79 (in, 211 C11~-CH2-CH2-NH) ; 3.00 (bt, 111, C112-CH-C112) 3.28 and 3.84 (2m, 411, C112-CH,-N-C112-C112) ; 3.52 (in, 211, CH2-CH2-~Jj2-NH); 3.78 and 4.13 (2m, 2H, NU-C112-CH-NH) ; 4.46 (in, 111, NH-CH2-CU-N11) ; 4.59 (in, 111, CONU-CU(CH3)-CO) ; 5.05 (in, 211, CU2-Ph) ; 6.41 and 7.38 (2d, 211, I-I naphthyridine) ; 6.68, 7.20, 7.95 and 9.68 (411, mobile Us); 7.31 (in, 511, Ph) ; 8.28 ppm (s, 111, N~fi-N). MS 631 (MU+). ExamDle 38 1St) Synthesis of tert-butyl 4-hydroxy- 1 -piperidinecarboxylate 1: 3 aBH 4 6N4 K) 2 Y N EtOH N 95% commercial I 1 g (5 inmol)of tert-butyl 4-oxo- 1 -piperidinecarboxylate (marketed by Aldrich) is dissolved in 5 ml of ethanol. This solution is cooled down to 00C using an ice bath and 200 mg (7.56 inmol) of sodium tetraborohydride is added by portions and the reaction mixture is stirred for 4 hours at ambient temperature. A saturated aqueous solution of aininonium chloride is added. The ethanol is evaporated off under reduced pressure (2 kPa) then the reaction mixture is taken up in ethyl acetate. The organic phase is separated from the aqueous phase. This extraction is repeated one more time and then the organic phases are combined and dried over magnesium sulphate, followed by concentrating under reduced pressure (2 kPa) and in this way 1.OS g (Yield 100 %) of a colourless oil is recovered. TLC Rf= 0.5 (silicagel, eluent: C112C12/ MeOU 90:10 1H-NMR (CDCI3) 6 1.47 (s, 911, tBu) and (ni, 211 ; -CHH-C112-N-C112-CHU-); 1.87 (in, 211, -CHH-C112-N-C112-CUH-) ; 3.04 (in, 211 -CUH-N-CHH-); 3.85 (in 211 -CHU-N-CUH-) and (in 111 -CH-011) 2nd) Synthesis of tert-butyl 4-iodo-l-piperidinecarboxylate 2: 12 OH PPh3 im idazole cH3CN 70% 2 2.15 g of triphenylphosphine(8.2 minole) and 2.08 g of iodine (8.2 inmole) are dissolved in 30 ml of acetonitrile. The reaction mixture is stirred for 10 minutes at ambient temperature then 918 mg of imidazole (13.5 ininol) is added and stirring is maintained for another 10 minutes at ambient temperature. Then I g (5 minol) of tert-butyl 4-hydroxy-1-piperidinecarboxylate of the preceding stage is added and stirring is maintained for 24 hours at ambient temperature. The reaction is treated by adding an aqueous solution of sodium thiosulphate and the acetonitrile is evaporated off under reduced pressure (2 kPa), followed by taking up in ethyl acetate, extracting and washing with an aqueous solution of sodium thiosulphate. The organic phases are dried over MgSO4, filtered and the ethyl acetate is evaporated off under reduced pressure (2 kPa). After chromatography on Silicagel eluting with dichloromethane then dichloromethane/methanol 90:10, 1.1 g (yield = 70 %) of a colourless oil is recovered. TLC Rf= 0.8 (silicagel, eluent: C112C12/ MeO11 90:10 1H-NMR (CDCI3): 6 1.47 (s, 911, tBu) ; 2.03 (in, 4H, -CH2-CHI-CH2- ) 3.30 and 3.60 (2in, 411, -CH2-N-CH2-) ; 4.46 (in, I H —CIII-) 3rd) Synthesis of 2-broino-6(2,5-dimethyl-pyrol- 1 -yl)-pyridine 3: 0 4 Dean.Stark H2N N Br ~ (9N N Br Toluene commercial Reflux 5 hours 3 90% 1 g (5.78 mmol) of 2-amino-6-broinopyridine marketed by Aldrich in 30 ml of toluene is placed in a 100 ml flask surmounted by a Dean Stark apparatus. 0.3 ml of acetic acid and 0.8 ml (6.78 minol) of acetonylacetone marketed by Aldrich are added. The reaction medium is heated under reflux of the toluene for 5 hours, then left to return to ambient temperature and the toluene is evaporated off under reduced pressure (2 kPa). Water is added and extraction is carried out with ethyl acetate. The organic phases are combined and dried over magnesium sulphate . The ethyl acetate is evaporated off under reduced pressure(2 kPa) and the crude residue is purified by chromatography on silica gel eluting with dichloroinethane. 1 g (Yield = 90 %) of a yellow powder is recovered. TLC Rf= 0.7 (silicagel, eluent: CU2Cl2) I; 1H-NMR (CDCI3) 5 2.20 (s, 611, -CH3CCU-CU~CCH3-) ; 5.90 (s, 211, -CH3C=CH-CH=CCH3-) ; 7.08 (d, 111, 113 or 115 ) ; 7.16 (d, 111, 113 or 115 ) ; 7.29( t, 111, 114) th 4 ) Synthesis of 6-(2,5-Dimethyl-pyrrol- 1 -yl)-3',4',5',6-tetrahydro-2'11- [2,4']bipyridinyl-1'-carboxylic acid tert-butyl ester 4: Activated Zn 8r~~~~Br Znl (5 TMSCI (5 N THF from 600C to AT 5 Pd2(dba)3 I (/~N N THF 600C 2 hours 4 284 ing (4.34mmol)of electrolytic zinc is put into suspension under an argon atmosphere, to which 0.033 ml of 1-2 dibromoethane and I ml of tetrahydrofuran are added. After stirring for 3 minutes at 600C the reaction medium is left to return to ambient temperature. 0.047 ml of trimethylsilyl chloride is added and stirring is carried out for 30 minutes at ambient temperature. 1 g (3.2mmol) of 2 solubilized beforehand in 2 ml of tetrahydrofuran is added. This reaction mixture is stirred for 45 minutes at ambient temperature and it is added to a solution containing 30 mg (0.03 2 inmol)of tris(dibenzylideneacetone) dipalladium marketed by Aldrich and 30 mg (0.13 mmol) of tris(2-furyl)phosphine marketed by LANCASTER. Then I g (4 inmol) of 3 solubilized beforehand in 10 ml of tetrahydrofuran is added. The reaction mixture is left under magnetic stirring at 600C for 2 hours, then left to return to ambient temperature, filtered on clarcel and extracted between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. After extracting the aqueous phase twice with ethyl acetate, the organic phases are combined and dried over magnesium sulphate. The ethyl acetate is evaporated off under reduced pressure(2 kPa) and the crude residue is purified by chromatography on silicagel eluting with a heptane/ ethyl acetate mixture 4:1. 350 mg (yield = 30 %) of expected product is recovered in the form of a yellow oil. TLC Rf= 0.2 (silicagel, eluent: Ueptane/ Ethyl acetate 90:10) 4 4 3 86 1H-NMR (CDCI3) 6 1.50 (s, 9H, tBu); 1.78 and 1.97 (in, 411, -CH2-CH2-N-CH2-CH2-) ; 2.18 (s, 611 -CH3C=CH-CH=CCH3-); 2.85 and 2.95 (in, 311 CHCH2-CHU-N-CHH-C112-) ; 4.28 (in, 211, -C112-CUH-N-CHH-C112-) ; 5.92 (s, 211, -CH3C=CH-CH=CCH3-);7.08 (d, 111, 113 or 115 ) ; 7.16 ( d, 111, 113 or 1-15 ) 7.29( t, 111, 114) 5th) Synthesis of 6-(2,5-dimethyl-pyrrol- I -yl)- 1 ',2',3 t,4',5',6'-hexahydro-[2,4']bipyridinyl 4 TFA ~ ~- ~ N CH2CI2 NH _ 92% 5 330 mg (0.928 minol) of 4 is solubilized in 3 ml of dichloromethane to which 0.3 ml of trifluoroacetic acid is added. The reaction medium is stirred for 2 hours at ambient temperature. The dichloroinethane is evaporated off under reduced pressure (2 kPa). The residue obtained is taken up in water, the reaction medium is basified to p11 = 10 with concentrated ammoniuin hydroxide and the product is extracted with dichloroinethane. The organic phase is dried over magnesium sulphate and the dichloroinethane is evaporated off under reduced pressure (2 kPa). 220 mg (Yield = 92 %) of a yellow oil is recovered. TLC: Rf= 0.3 (silicagel, eluent: CH2CI2/ MeOH 90:10) 1H-NMR (CDCI3) 6 1.90 and 2.08 (in, 411, -CH2-C112-N-CH2-CH2- ) 2.18 (s, 611, -CH3C=CU-CU=CCH3-) ; 2.88 and 3.34 (in, 411, -C112-CH2-N-CH2- C112- ) ; 2.95,(m 111 CH-C112-C112-N-CH2-) ; 4.10 (in, 111, NH) ; 5.92 (s, 211, - CH3C=CH-CH=CCU3-);7.08 (d, 111, 113 or US ); 7.16 ( d, 111, 113 or 115 ); 7.29( t, 111, 114) MS 2S6 (MU+) 6th) Synthesis of 1 '-(6-chloro-5-inethyl-pyrimidin-4-yl)-6-(2,5-dimethyl-pyrrol- 1 -yl)- 1 ',2',3',4',5 ',6'-hexahydro-[2,4~]bipyridinyl: &>ONN N c~ DIEA DMA 5 csr g7 220 mg (0.860 minol) of S is dissolved in 2 ml of dimethylacetamide to which 140 ing (0.860 mmol) of 4,6-dichloro-5-inethyl-pyrimidine marketed by SPECS and 0.2 ml of diisopropylethylainine are added. The mixture is heated at 1 100C under magnetic stirring for one hour. The mixture is left to return to ambient temperature and the diinethylacetamide is evaporated off under reduced pressure(0.2 kPa). The crude residue is taken up in ethyl acetate and washed with water. The aqueous phase is extracted twice with ethyl acetate, the organic phases are combined and dried over magnesium sulphate. The ethyl acetate is evaporated off under reduced pressure (0.2 kPa) and 330 mg of a brown resin is recovered which is used for the following stage without purification. TLC Rf=0.4 (silicagel, eluent: CH2Cl2) 1H-NMR (CDCI3) ~ 2.02 and 2.10 (in, 411, -CH2-C112-N-C112-CH2- ) 2.18 (s 611 -CH3C=CH-CU=CCH3-) ; 2.30( s, 311, C113); 3.08 and 4.01 (in, 411, - C112-C112-N-C112-CH2-) ; 3.02,(m 111 CH-C112-C112-N-C112-); 5.92 (s, 211, - CH3CCH-CH'CC113-);7.09 (d, 111, 113 or 115 ) ; 7.20 ( d, 111, 113 or 115 ); 7.29( t, 111, 114); 8.41 (s, 111, N-CHN) 7th) Synthesis of 2-benzyloxycarbonylamino-3 - { 6- [6-(2 ,5-diinethyl-pyrrol- I - yl)-3',4',5',6'-tetrahydro-2'U-[2,4t]bipyridinyl- 1 '-yl]-5-inethyl-pyrimidin-4-ylainino } -propionic acid tert-butyl ester 7: A BINAP 6 Pd2(dba), DME 90c 330 mg (0.866 inmol) of the preceding stage is solubilized in 5 ml of dimethoxyethane. 286 ing (1 inmol) of (1,1-dimethylethyl) 3-amino-N-[(~phenylmethoxy)carbonyl] alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 184 ing (1.21 inmol) of caesiuin fluoride, 54mg(10 % mol) of rac-2,2'-bis(diphenylphosphino)-1, I '-Binaphthyl marketed by Aldrich, and 40 ing (5 %mol) of tris(dibenzylideneacetone) dipalladiuin marketed by Aldrich are added successively. This mixture is heated at 1 000C for 18 hours under magnetic stirring. Another 54 ing (10 % inol) of rac-2,2'-Bis(diphenylphosphino)-l, I '-binaphthyl, 40 mg (5 % mol) of tris(dibenzylideneacetone)dipalladiuin are added and heating is carried out for another 2 hours at 1000C. The reaction medium is left to return to ambient temperature and the dimethoxyethane is evaporated off under reduced pressure(2 kPa). The residue obtained is taken up in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The aqueous phase is extracted with ethyl acetate, the organic phases are combined and dried over magnesium sulphate . The ethyl acetate is evaporated off under reduced pressure (2 kPa). The residue obtained is purified by chromatography on silicagel eluting with a heptane/ethyl acetate mixture 1:1. 200 mg of a yellow solid is recovered. TLC Rf = 0.2 (silicagel, eluent: heptane / ethyl acetate 1:1) 1H-NMiR (CDCI3) ~ 1.50 (s, 911, tBu); l.97(s, 311, C113) ; 2.02 to 2.1O(m, 411, -CH2-C112-N-CU2-CH2- ) ; 2.18(s, 611, -CH3C=CH-CH=CCH3-) ; 3.20 and 3.78( in, 411, -CH2-CH2-N-CH2-CH2- ) ; 3.O0(m, 111, CH-C112-C112-N-C112-) ; of 3.85 to 4.00 (m,211, NU-CH2-CUCOOtBuNH) ; 4.47(in, 111, NU-CU2CH- COOtBuNH); 5.12(211, -O-CH2-Phenyl) ; 5.92 (s, 211, -CU3CCH-CH=CCH3-); 6.12(m, mobile 111); 7.09(d, 111, 113 or 115); 7.2 1(d, 111, 113 or 115); 7.78(t, 111, 114); 7.45(in, aromatic 511); 8.32(s, 111, =N-CU=N) MS 641 (MU±),584(MH-tBu±) 8th) Synthesis of 3-[6-(6-Amino-3',4',5',6'-tetrahydro-2'11-[2,4']bipyridinyl- 1'-yl)-5-methyl-pyrimidin-4-ylamino]-2-benzyloxycarbonylamino-propionic acid tertbutyl ester 8: 4 ~ N 3 N H2N N NH2OH ~IH N N. EtOI-4 N~N oAo I~NH N~N O1~N Eau refiux 7...— 8 100 ing ( 0.15 inmol) of 7 is dissolved in 3 nil of ethanol and 0.3 ml of water. 50 mg (0.75 minol) of hydroxylamine hydrochloride marketed by ACROS is added and the reaction medium is heated for 18 hours at 900 C. The solvents are evaporated off under reduced pressure (2 kPa) and the crude residue is purified by chromatography on silicagel eluting with a C112C12/MeOU mixture 90:10. 30 ing (36 %) of expected product is obtained in the form of a colourless resin. TLC Rf= 0.5 (silicagel, eluent: C112C12/ MeOH 90:10) 1H-NMR (CDCI3) ~ 1.50 (s, 911, tBu) ; 1.97(s, 311, C113) ; 2.02 to 2.l0(m, 411, -CH2-C112-N-C112-CH2- ) ; 2.18(s, 611, -CH3C=CU-CU=CCH3-) ; 3.20 and 3.78( in, 411, -C112-C112-N-CH2-C112-); 3.00(m, 111, CH-C112-C112-N-C112-) ; of 3.85 to 4.OO(in,211, NU-CH2-CHCOOtBuNU);4.47(m, I U,NH-CU2CH- COOtBuNU); 5.12(211,-O-CH2-Phenyl); 5.92 (s, 211, -CH3C=CH-CH=CCU3-); 6.18, 6.57,6.62(3d,113 and US ± mobile 111); 7.45(in, aromatic 511); 7.60(t, 111, 5 3 MS: 562 (MU±),372(MU-tBu and —CO-O-benzyl±) 9tb) Synthesis of 3 -[6-(6-Ainino-3 9,4e,5 ',6'-tetrahydro-2t11-[2,4']bipyridinyl- 1'- yl)-5-methyl-pyriinidin-4-ylamino]-2-benzyloxycarbonylamino-propionic acid 9 4 K H,N N HO 0 N~N o~o ~ CH2CI2 30 mg (0.053 inmol) of ~ prepared previously is solubilized in 2 ml of dichloroinethane and 0.2 ml of trifluoroacetic acid. Stirring is maintained for 9 hours at ambient temperature. Toluene is added, followed by evaporating to dryness under reduced pressure(2 kPA). The product is purified by chromatography on silicagel eluting with a C112C12/MeOU/acetic acid mixture 90:10:1. 10 mg (Yield = 37 %) of expected product is recovered solidified in the form of a beige solid in a CH2Cl2/isopropyl ether mixture. TLC Rf= 0.2 (silicagel, eluent: C112C12/ MeOH/ acetic acid 90:10:1 1H-NMR (DMSO): 6 1.90 (s, 311, C113); 1.80 to l.85(m, 411 -CH2-C112-N- CH2-CH2-) ; partially masked by water of the DMSO:(4H, -CH2-CH2-N-C112-C112-) and (211, NH-CH2-CHCOOtBuNH) ; 2.80,(m, 111 CH-CH2-CH2-N-C112-) ; 4.l5(in, 111, C112-CH-COOtBuNU-) ; 5.02(211, -O-CH2-Phenyl);6.27 (d, LU, H3 or 115); 6.40 (d, 111, 113 or 115 ) ; 6.52(m, 111, 114); 7.5(m, aromatic 511) ; 8.lO(s, 111, =NCU=N). MS: 506 (MU+), 372 (MH-CO-O-Benzyl±). ExamDIe 39 3 -[5-ethyl-6-[4-(aininoinethyl-2-pyridinyl)- 1 -piperidinyl]-4- pyrimidinylamino]-N-[(phenylmethoxy)carbonyl]alanine, bis(trifluoroacetate). Stare a) Synthesis of (1,1 -diinethylethyl) acid(4-aminomethylpiperidine)- I -carboxylate. 1) benzaldehyde, toluene 2) Boc2O 3) H20. H HN _______________ 0 NH2 N o NH2 9 mL of benzaldehyde (87.5 mmoles)is added to a solution of 10 g (87.S minoles) of 4-aminoinethylpiperidine (marketed by Aldrich) in 110 ml of toluene placed under a nitrogen flow, then this mixture is heated at 1 200C (presence of a Dean-Stark apparatus) for 8 hours. The reaction mixture is left return to ambient temperature then 21 g (96.25 minoles) of di-tert-butyl dicarbonate is added at 00C over 'A of an hour. Stirring is maintained overnight in the presence of nitrogen. The next day, the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) and the oil is taken up in 115 mL of a iN aqueous solution of K11504 and stirred vigorously, under nitrogen for 7 hours. Ethyl acetate is added to the reaction mixture and the aqueous phase is extracted twice with ethyl acetate. Then the mother liquors are basified by the addition of NaOU pellets then the aqueous phase is extracted 3 times with chloroform salting out with NaCI. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). 17.3 g (Yield = 92 %) of expected product is obtained in the form of a yellow oil. TLC Rf= 0.S (alumina, eluent: dichloromethane-inethanol (90-10) 1H-NMR (CDCI3) ~ 1.05 and 1.67 (2in, 411, N-C112-C112-CH-C112-C112); 1.17(s, 2H, N112); 1.42 (s, 1OH,tBu, C112-CH-CH2) ; 2.55 (d, 211, CH2-N112) ; 2.65 and 4.07 (2in, 411, N-C112-C112-CU-C112-C112). MS 215 (MH±); 159 (MH-tBu±). State b) Synthesis of (1,1 -diinethylethyl) acid(4-(2-aininoinethylpyridinyl)-piperidine)-I -earboxylate. F 0 N -~ 0 N + N O NH2 -~ o N H N A mixture of 2.18 g (10.19 inmoles) of (1,1-diinethylethyl) acid(4-aminomethylpiperidine)- 1 -carboxylate in 5 ml of 2-fluoropyridine is taken to refiux for 6 hours. After returning to ambient temperature, the solvent is evaporated off under reduced pressure (2 kPa) and the yellow solid residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted, washed with a saturated solution of sodium chloride then dried over magnesium sulphate and evaporated to dryness under reduced pressure (1.3 kPa). The residue is chromatographed on silicagel with the following eluent: ethyl acetate-cyclohexane 70-30. 1.19 g (Yield = 40 %) of expected product is obtained. TLC Rf= 0.4 (silicagel, eluent: ethyl acetate-cyclohexane 70-30) 1H-NMR (CDCI3) 6 1.20 and 1.80 (2m, 511, N-C112-C112-CU-CH2-C112); 1.47 (s, 911, tBu) ; 2.71 and 4.15 (2m, 411, N-C112-CH2-CH-CH2-C112) ; 3.21 (in, c:~i 211, CU-C112-N11) ; 4.80 (in, 111, CH-C112-NU) ; 6.41 (d, 111, CU=CH pyridine) 6.60 (in, 111, CU=CH pyridine) ; 7.45 (in, 111, CH=CH pyridine) ; 8.07 (in, 111, NCH=CU). MS 292 (MU±); 192 (MH-tBu+). Stare ci Synthesis of 2-(4-methylpiperidinyl)aminopyridine. 0 N — CF3COOH, CH~C12 HN O N N H, N 1.09 g (3.74 inmoles) of (1,1-dimethylethyl) acid(4-(2-aininoinethylpyridinyl)-piperidine)-1-carboxylate in 25 ml of dichloromethane with 6 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: ethyl acetate 100). Then 20 ml of toluene is added and the mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in a mixture of methylene chloride and a 2N aqueous solution of sodium hydroxide. The organic phase is decanted, washed with a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under reduced pressure (2 kPa). The oil obtained is taken up in a little diisopropyl ether and pentane then condensed to dryness under reduced pressure (2 kPa). 590 mg (Yield = 82 %) of expected product is obtained in the form of a yellow solid. TLC Rf=0.2 (silicagel, eluent: dichloromethane-methanol-water-acetic acid 70-30-6-3). 1H-NMR (CDCI3) 6 1.25 and 1.8 (2m, 411, NH-C112-CH2-CH-C112-C112); 1.72 (in, 111, C112-CU-C112) ; 2.62 and 3.15 (2in, 611, NU-CU2-CH2-CH-CH2-CH2 and CU-C112-NH) ; 4.62 (s, 111, mobile NU); 6.37 (d, 111, CUCH pyridine) ; 6.56 (in, 111, CU=CU pyridine) ; 7.41 (in, 111, CU=CU pyndine) ; 8.07 (in, 111, NCH=CU). MS:192 (MU+). Stai~e di Synthesis of 4-bromo-5-ethyl-6-[4-(aininomethyl-2-pyridinyl)- I -piperidinyl]pyriinidine. Br HN H / N~'N. DMA.DiPEA N + _______ N N Br 1.8 ml of diisopropylethylamine is added to a mixture of 657 mg (2.47 minoles) of 4,6-dibroino-5-ethyl-pyrimidine and 450 mg (2.35 minoles) of 2-(4-methylpiperidinyl)aininopyridine in 55 ml of N,N-diinethylacetainide. This mixture is heated at I 100C for 4 hours. Then the solvent is eliminated under reduced pressure (0.2 kPa) and the residue is taken up in a mixture of ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is decanted, dried over magnesium sulphate then condensed under reduced pressure (2 kPa). The brown oil obtained is chromatographed on alumina eluting with the following gradient: heptane-ethyl acetate 80-20 to 70-30. 747 mg (Yield = 84 %) of expected product is obtained in the form of a beige solid. TLC Rf= 0.5 (alumina, eluent: heptane-ethyl acetate SO-SO). 1H-NMR (CDCl3I 6 1.29 (t, 311, C112-CH3); 1.42 and 1.9 (2in, 511, N-CH2- CH2-CU-C112-C112) ; 2.70 (q, 211, C112-C113) ; 2.95 and 3.88 (2m, 411, N-C112- C112-CH-C112-CH2) ; 3.27 (in, 211, CU-C112-NU) ; 4.81 (in, 111, mobile NU) ; 642 (in, 111, CU=CU pyridine) ; 6.60 (in, 111, CH=C11 pyridine) ; 7.46 (in, 111, CH=CH pyridine); 8.09 (in, 111, N-CH=CU) ; 8.31 (s, 111 NCH-N). MS 378 (MH±). Stare ei Synthesis of (1,1 -dimethylethyl) 3- [5-ethyl-6-[4-(aminomethyl-2-pyridinyl)- I -piperidinyl]-4-pyriinidinylainino]-N-[(phenylmethoxy)carbonyl]alaninate. 0 0 N Br H H2N N — NH ______________ N ~ 1N N A mixture of 300 mg (0.79 ininoles) of 4-bromo-5-ethyl-6-[4-(aininomethyl-2-pyridinyl)- 1 -piperidinyl]-pyriinidine, 282.5 ing (0.96 inmoles) (1,1 -diinethylethyl) 3-ainino-N-[(phenylmethoxy) carbonyl]alaninate, 168.6 ing (1.11 ininoles) of caesium fluoride, 49.8 mg (0.08 minoles) of tris(dibenzylideneacetone) dipalladiuin(0) and of 49.8 mg (0.08 minoles) of rac-2,2'-Bis(diphenyl-phosphino)- 1,1 '-binaphthyl in 8 ml of 1 ,4-dioxane is taken to reflux for 7 hours. The reaction mixture is then returned to ambient temperature for the addition of 49.8 ing (0.08 minoles)of tris(dibenzilideneacetone) dipalladiuin(0), then again taken to reflux for 4 hours. After cooling down, the mixture is concentrated under reduced pressure (2 kPa) then the residue obtained is taken up in a mixture of ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is decanted, dried over magnesium sulphate then concentrated under reduced pressure (2 kPa). .2 CF2COOH The residue is chroinatographed a first time on alumina eluting with the following gradient: diisopropyl ether-ethyl acetate 80-20 to 100 % ethyl acetate. The second chromatography is carried out on silicagel with ethyl acetate for eluent. 272 ing (Yield = 58 %) of expected product is obtained. TLC Rf= 0.4 (silicagel, eluent: ethyl acetate). 1H-NMR (CDCI3) 6 1.15 (t, 311, C112-C113); 1.47 and 1.90 (2in, 1311, tBu, N-C112-CH2-CU-CH2-C112); 1.81 (in, 111, N-C112-C112-CH-C112-C112) ; 2.41 (q, 211, C112-C113) ; 2.85 and 3.50(2m, 411, N-CH2-CH2-CH-C112-C112) ; 3.27 (in, 211, CH-C112-NH) ; 3.90 (in, 211, NH-C112-CH-NH) ; 4.45 (in, LU, NH-C112-CH-NH); 4.85 (in, 111, mobile NU); 5.05 (in, 111, mobile NU); 5.12 (s, 211, O-C112-Ph) ; 6.16 (bd, 111, mobile NH) ; 6.42 (d, 111, CH=CU pyridine) ; 6.60 (in, 111, CH=C11 pyridine) ; 7.35 (in, 511, Ph) ; 7.45 (in, 111, CH=CU pyridine) ; 8.07 (bd, 111, NCUCU) ; 8.28 (s, 111, N=C11-N). MS: 590 (MH+) ; 534 (MH-tBu±). taID(CHCI3) = +2.9 Stare 0 Synthesis of 3- [5-ethyl-6-[4-(aininoinethyl-2-pyridinyl)- 1 -piperidinyl]-4-pyrimidinylamino]-N-[(phenylmethoxy)carbonyl]alanine, bis(trifluoroacetate). CF,COOH. CH2CI2 229 ing (0.39 ininoles) of (1,1-dimethylethyl) 3-[5-ethyl-6-[4-(aminomethyl-2-pyridinyl)- 1 -piperidinyl]-4-pyriinidinylainino]-N-[(phenylmethoxy)carbonyl]alaninate in 7.5 ml of dichloromethane with 0.9 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: dichloroinethane-inethanol-wateracetic acid 90-10-1-1). At the end of the reaction, toluene is added to the reaction mixture followed by evaporating to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane with a little methanol then poured into ethyl ether. The precipitate is filtered. 97.4 mg (Yield = 38 %) of expected product is obtained in the form of an amorphous solid. TLC Rf = 0. l(silicagel, eluent: dichioroinethane-inethanol-water-acetic acid 90-10-1-1). 1H-NMR (CDCI3 + 2 drops MeOD) 6 1.12 (t, 311, C112-CU3) ; 1.43 and 1.95 (2in, 511, N-C112-C112-CH-C112-C112) ; 2.41 (q, 211, C112-C113) ; 3.10 and 14- 3.65(2in, 411, N-C112-C112-CU-C112-C112) ; 3.26 (d, 211, CU-C112-NU) ; 3.80 and 4.02 (2m, 211, NH-C112-CU-NU) ; 4.41 (in, 111, NH-C112-CU-N11) ; 5.10 (s, 211,0- C112-Ph) ; 6.74 (t, 111, CU=CH pyridine) ; 6.87 (d, 111, CU=CU pyridine) ; 7.32 (in, 511, Ph) ; 7.81 (in, 211, CU=CH pyridine and N-CH=CH) ; 8.23 (s, 111, N=CH-N). MS 534 (MH+). laiD (CHCI3) = +1.88 Example 40 State ai Synthesis of (1,1 -dimethylethyl) acid 4-[3 -(4-methoxy-2-nitro-phenyl)- thioureidomethyl]-piperidine- 1 -carboxylate. ,0 0—N 0 THF + N N ~ / 0 0 N O NH2 S A mixture of 1 g (4.67 minoles) of (1,1-diinethylethyl) acid 4-aininoinethylpiperidine)- 1 -carboxylate and 1.08 g (6.06 minoles) of 4-methoxy-2-nitrophenyl isothiocyanate in 70 ml of tetrahydrofuran is stirred at ambient temperature, under a nitrogen flow for 5 hours. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silicagel with the following eluent: ethyl acetate-heptane from 20-80 to 3 0-70. 1.66 g (Yield = 84 %) of expected product is obtained. TLC Rf=0.4 (silicagel, eluent: ethyl acetate-heptane 50-50) 1H-NMR (CDCI3) ~ 1.25 and 1.76 (2m, 411, N-CH2-CH2-C11-C112-C112); 1.47 (s, 911, tBu) ; 1.91 (in, 111, N-C112-C112-C11-C112-C112) ; 2.73 and 4.15 (2in, 411, N-CH2-C112-CU-C112-CH2) ; 3.51 (in, 211, CU-C112-NH) ; 3.90 (s, 311, 0- C113); 6.66 (in, 111, CH=CH aromatic) ; 7.22 (in, 111, CH=CH aromatic); 7.59 (in, 111, CU=CU aromatic). MS 425(MU±) ; 325(MH-COOtBu±). State bi Synthesis of (1,1 -diinethylethyl) 4-[(6-methoxy-2- aininomethylbenziinidazole)]-piperidine- I -carboxylate. 0 ¼ 0—N 1)AcOH,Zn — 2) HgCI2, Et3N, DMF 0 0 ii \/ 0 - N N —~ O N o H H N o H eu A mixture of 2 g of activated zinc in a little acetic acid (the zinc is activated by heating with heat gun) is added to a solution of 1.12 g (2.64 inmoles) of (1,1 -diinethylethyl) acid 4-[3-(4-methoxy-2-nitro-phenyl)-thioureidomethyl]-piperidine-1-carboxylate in 100 ml of acetic acid. The reaction mixture is left under stirring for S hours then the clarcel is added to the solution, followed by filtering on clarcel and the solvent is evaporated off under reduced pressure (2 kPa). 1.8 g of the expected product is obtained. This crude product is then solubilized in 100 ml of dimethylforinainide and 10 ml of triethylamine and SOO mg of mercury dichloride are added to it. The reaction mixture is placed under stirring at ambient temperature for 15 hours. Then the solvent is evaporated off under reduced pressure (0.2 kPa) and the residue is taken up in a mixture of water, a saturated solution of sodium bicarbonate and ethyl acetate. The organic phase is decanted, dried over magnesium sulphate and the solvent eliminated by evaporation under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with the following gradient: ethyl acetatedichloromethane/methanol 50-50(100 % C112C12) to 50-50(95/5 C112C12/MeOH). 740 ing (Yield 77 % over 2 stages) of expected product is obtained. TLC Rf 0.4 (alumina, eluent: ethyl acetate-dichloromethane/methanol 50-50(95/5)). 1H-NMR (CDCL3) 6 1.07 and 1.64 (2m, 4H, N-CH2-C112-CH-C112-C112); 1.46 (s, 911, tBu) ; 1.76 (in, 111, N-C112-C112-CH-CH2-CH2) ; 2.61 and 4.05 (2m, 411, NU-C112-CH2-CU-C112-CH2) ; 3.29 (in, 211, CH-CH2-NH) ; 3.81 (s, 311, 0- C113) ; 6.66 and 7.12 (2d, 211, CH=CH benzimidazole) ; 6.88 (s, 111, NH-C=CU-C0C113). MS:361 (MU±) ; 305 (MU-tBu±); 261 (MH-COOtBu±). StaI!e ci Synthesis of 4-(6-inethoxy-2-aininomethylbenziniidazole)piperidine. tri(trifluoroacetate). 0 N ~ CF3COOH, CH2CI2 HN N~I N/I H H N o N o H H 3 CF3COOH 918 ing (2.55 minoles) of (1,1-dimethylethyl) acid 4-[(6-methoxy-2-aminoinethylbenziinidazole)]-piperidine-1-carboxylate in 35 ml of dichloromethane with 6 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: dichloromethane-inethanol 7-4 water-acetic acid 90-10-1-1). Then toluene is added and the mixture evaporated under reduced pressure (2 kPa). 1.15 g of expected product is obtained in the form of the trifluoroacetate salt. TLC Rf = 0.15 (silicagel, eluent: dichloromethane-inethanol-water-acetic acid 90-10-1-I). 1H-NMR (MeOD) :6 1.50 and 2.05 (2m, 511, NH-C112-C112-CH-C112-CH2); 3.00 and 3.43 (2m, 411, NH-CH2-C112-CU-CH2-C112) ; 3.35 (d, 211, CH-C112-NH); 3.81 (s, 311, O-C113) ; 6.8S and 7.25 (2in, 211, CH=CU benzimidazole) ; 6.91 (s, lB. NU-C=CH-C-OCU3). MS 261 (MU±). State di Synthesis of 4-bromo-5 -ethyl-6-[4-(6-methoxy-2-aininomethylbenzimidazole)-1 -piperidinyl]pyrimidine. Br H HN N —~ -~ DMA, DIPEA N / + _____ H H K Br 4 N 0 N N 35 ml of N,N-dimethylacetainide, 381.84 ing (1.43 inmoles) of 4,6-dibromo-5-ethyl-pyrimidine in solution are added into a single-necked flask containing 356 mg (1.37 minoles) of 4-(6-methoxy-2-aminomethylbenzimidazole)piperidine, freed from its salt, , then 1.2 ml of diisopropylethylamine is added. This mixture is heated at 1 100C for 3 hours then concentrated under reduced pressure (0.2 kPa). The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered then the solvent is evaporated off under reduced pressure (2 kPa). The product obtained is chroinatographed on silicagel eluting with a gradient of dichloromethane-methanol 95-S then dichloromethane-methanol 90-10). 383 mg (Yield = 63 %) of expected product is obtained. Preparation of 4-(6-methoxy-2-aminoinethyl benzimidazole)piperidine in free amine form: 700 mg of 4-(6-inethoxy-2-aminomethylbenzimidazole)piperidine is displaced from its salt by 6 mass equivalents of basic amberlyst A2 1 resin (resin of R-NMe2 type) in a C112C12—MeOH-AcOEt 1-1-1 mixture under stirring for 30 minutes. The resin is washed beforehand and left to swell for 20 minutes in this solvent mixture. This operation must be repeated 3 times for the displacement of the salt to be complete. After filtration of the resin and evaporation of the solvents, 356 mg (1.37 minoles) of free 4-(6-inethoxy-2-aminomethylbenziinidazole)piperidine is obtained. TLC Rf = 0.23 (silicagel, eluent: dichloromethane-methanol 90-10). 1H-NMR (CDCL3) 6 1.27 (t, 311, C112-C113) ; 1.32 and 1.80 (2m, 411, NC112-C112-CH-C112-C112); 1.89 (in, 111, N-C112-C112-CU-C112-C112); 2.63 (q, 211, C112-C113) ; 2.85 and 3.82 (2m, 711, N-C112-C112-CU-C112-C112, O-CH3) ; 3.37 (in, 211, CH-C112-NU) ; 6.67 and 7.15 (2d, 211, CU=CH benziinidazole) ; 6.90 (s, 111, NU-C=CU-C-OCH3) ; 8.27 (s, 111, N=~C11-N). MS 446 (MH+). Stare ei Synthesis of (1,1 -diinethylethyl)benzimidazole)- 1 -piperidinyl]pyrimidine 4-bromo-5-ethyl-6-[4-(6-methoxy-2-aminomethyl- 1 -carboxylate. 0. Boc~0. CH,C12 pyridine 1.5 ml of pyridine then 471 mg (2.16 minoles) of di-tert-butyldicarbonate are added to a mixture of 159.7 mg (0.36 minoles) of 4-Broino-5-ethyl-6-114-(6-inethoxy- 2-aminoinethylbenziinidazole)- I -piperidinyl]pyrimidine in 15 ml of dichloromethane. The reaction medium is left under stirring at ambient temperature overnight. A little toluene is added to the reaction mixture then the solvent is evaporated off under reduced pressure (2 kPa). The residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted, dried over magnesium sulphate then condensed under reduced pressure (2 kPa). The crude product obtained is chromatographed on silicagel eluting with the following gradient: heptane-ethyl acetate 60-40 to 50-50. 136 mg (Yield 69 %) of expected product is obtained (in the form of 2 regioisomers distinguished by NMR with a ratio of 50/SO). TLC Rf= 0.5 (silicagel, eluent: dichloromethane-methanol 90-10). 1H-NMR (CDCL3) 6 1.30 (t, 611, C112-C113) ; 1.47 and 1.96 (2in, 811, NC112-C112-CU-C112-C112); 1.72 (2s1, 2011, tBu, N-C112-C112-CU-C112-C112 ) ; 2.70 (q, 411, C112-C113) ; 2.97 and 3.89(2m, 811, N-C112-C112-CU-C112-C112) ; 3.52 (in, 4H, CU-C112-NU) ; 3.82 (s, 611, OCH3) ; 6.62 and 6.82 and 7.31 and 7.46 (4d, 411, C11C11 benzimidazole) ; 7.00 and 7.26 (2s, 211, NH-C=CU-C-0C113); 8.31 (s, 2H, N=CU-N). MS: 545/547 (MU+). Stare f) Synthesis of (1,1 -dimethylethyl) 3-[5-ethyl-6-[4-(6-inethoxy-2- aininomethylbenzimidazole- I -carboxylate (1,1 -dimethylethyl))- 1 -piperidinyl]-4- pyriinidinylamino]-N-[(phenylmethoxy)carbonyl]alaninate. Br~ FU~fr~ ~vE A mixture of 136 mg (0.25 mmoles) of (l,1-dimethylethyl)benzimidazole)-l --piperidinyl]pyriinidine 4-bromo-5-ethyl-6-[4-(6-inethoxy-2-aminomethyl- I -carboxylate, 88.5 mg (0.30 minoles) of (l,1-dimethylethyl)3-amino-N-[(phenylmethoxy)carbonyl]alaninate, S3.2 mg (0.35 minoles) of caesium fluoride, 11.4 mg (0.0 12 minoles) of tris(dibenzylideneacetone)dipalladiuin(O) and 15.6 mg (0.025 mmoles) of rac-2,2'-bis(diphenyl-phosphino)-1,1 '-binaphthyl in 6 ml of 1,2-diinethoxyethane is taken to reflux for 24 hours. During the reaction, 11.4 mg of tris(dibenzilideneacetone)dipalladiuin(0) is added. After cooling down, the mixture is concentrated under reduced pressure (2 kPa) then the residue obtained is taken up in a mixture of ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is decanted, dried over magnesium sulphate then concentrated under reduced pressure (2 kPa). The residue is chromatographed a first time on silicagel eluting with the following gradient: ethyl acetate-heptane 40-60 to 100 % ethyl acetate. The second chromatography is carried out on alumina eluting with the following gradient: ethyl acetate-dichloromethane-inethanol SO-SO-0 to SO-SO-2 %. 58 mg (Yield = 30 %) of expected product is obtained (in the form of 2 regioisomers distinguished by NMR with a ratio of 50/SO). TLC Rf= 0.4 (silicagel, eluent: ethyl acetate). 1H-NMIR (CDCI3) 6 1.1S (t, 611, C112-C113); 1.46 and 1.91 (2m, 2611, tBu, N-C112-C112-CU-C112-C112); 1.72 (in, 2011, tBu, N-C112-CH2-CH-C112-C112); 2.41 (q, 411, C112-C113) ; 2.87 and 3.5 l(2in, 1211, N-C112-C112-CU-C112-C112, Cl-IC112-NH) ; 3.82 (s, 611, 0C113) ; 3.90 (in, 411, NH-C112-CH-NH) ; 4.43 (in, 211, NUC112-CU-NH); 5.12 (s, 411, O-CH2-Ph) ; 6.12 (bd, 211, mobile NU) ; 6.61 (d, 111, CHCH benzimidazole) ; 6.82 (in, 111, CH=CU benzimidazole) ; 7.00 (bs, 111, NUC=CU-C-0C113) ; 7.35 (in, 1211, Ph, CH=CU benzimidazole) ; 7.45 (d, 111, CU=CU benzimidazole); 8.29 (s, 211 N=CH-N). WE CLAIM: 1) The 4-amino, 6-piperidinyl pyrimidine compounds of formula (I): (Formula Removed) in all their isomeric forms, alone or in mixture, as well as their physiologically acceptable addition salts, in which - G represents R7R8N-C(=NR6)-NH-CO- Het-NH-CO-; Het-NH-CH2-, Het-, Het representing a monocyclic or polycyclic system, each ring being constituted by 4 to 10 aromatic or non aromatic members, the ring or at least one of the rings containing I to 4 nitrogen atoms, substituted or non substituted by one or more R9 groups; - R1 represents a hydrogen atom; a (C5-C14)-aryl; (C5-C14)-aryl-(C1-C4)-alkyl-group; an amino radical non substituted or monosubstituted or disubstituted by an alkyl radical and/or an acyl radical containing 1 to 4 carbon atoms; - R2 represents a hydrogen atom; a halogen atom; a nitro group; an alkyl radical containing 1 to 4 carbon atoms; an amino radical non substituted or monosubstituted or disubstituted by an alkyl radical and/or an acyl radical containing 1 to 4 carbon atoms; a-(CH2)0-2-CO2R5 group; or a -(CH2)0-2-OR5 group; - R3 represents a hydrogen atom, a-C02R5 radical, a-S02R5 radical or a monocyclic or polycyclic system, each ring being constituted by 4 to 10 aromatic or non aromatic members, the ring or at least one of the rings containing 1 to 4 heteroatom s cnosen from N, O or S, substituted or non substituted by one or more R9 radicals, - R4 represents OH; (C1-C8)-alkoxy-; (C5-C14)-aryl-(C1-C4)-alkyloxy-; (C5-C14)-aryloxy-; (C3-C12)-cycloalkyloxy; (C3-Ci2)-cycloalkyl-(C1-C4)-alkyloxy-; (C1-C8)-a!kylcarbonyloxy-(Ct -C4)-alkyloxy-; (C5-C14)-aryl-(C 1 -C4)-alkylcarbonyloxy-(C1-C4)-alkyloxy-; (C1-C8)-dialkylaminocarbonylmethyloxy-; (C5-C14)-aryl-(C1-C4)-dialkylaminocarbonylmethyloxy-; an amino radical non substituted or monosubstituted or disubstituted by a (C1C4)-alkyl and/or (C5-Ci4)-aryl and/or (C5-C14)-aryl-(C1-C4)-alkyl-radical and/or a (C1-C5)-acyl radical; or the remainder of an amino acid D or L; - R5 represents (C1-C8)-alkyl; (C5-C14)-aryl; (C5-C14)-aryl-(C1-C4)-alkyl-; (C3-C12)-cycloalkyl or (C3-C12)-cycloalkyl-(C1-C4)-alkyl-, bicycloalkyl-(C1-C4)-alkyl-, tricycloalkyl-(C1-C4)-alkyl-, the said aryl, alkyl, cycloalkyl, bicycloalkyl and tricycloaikyl radicals being non substituted or substituted by one or more chosen R9 groups; - R6 represents a hydrogen atom; a hydroxyl; nitro, (C1-C6)-alkyl-0-CO-; or (C1-C6)-alkyl-0-CO-0- group; - R7 and R8, independently of one another represent a hydrogen atom or a (C1-C6) alkyl radical non substituted or substituted by R9; - R9 represents halogen; amino; nitro; hydroxyl, (C1-C4)-alkyloxy-; (C1-C4)-alkylthio-; carboxy; (C1-C4)-alkyloxycarbonyl-; (C1-C8)-alkyl non substituted or substituted by one or more halogen atoms, (C5-C14)-aryl, (C5-C4)-aryl-(C1-C4)-aIkyl- it being understood that the aryl radicals can be non substituted or substituted by one or more identical or different radicals chosen from (C1-C8)-alkyl, in particular (C1-C4)-alkyl, hydroxyl, (C1-C8)-alkyloxy, (C1-C8)-alkylthio, halogen chosen from fluorine, chlorine and bromine, nitro, amino, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, trifluoromethyl, methylenedioxy, cyano, aminocarbonyl, (C1-C4)-alkylaminocarbonyl, di-(C1-C4)-alkylaminocarbonyl, carboxy, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl and benzyloxy. 2) The compounds of formula (I) as claimed in claim 1 in which G represents a Het, Het-NHCO, or Het-NH-CH2- group with Het representing the following heterocycles: (Formula Removed) 3) The compounds of formula (I) as claimed in any one of claims 1 to 2 in which R is: -a heterocycle chosen from (Formula Removed) as well as their pharmaceutically acceptable addition salts. 4) The compounds of formula (I) as claimed in any one of claims 1 to 2 in which R3 i:-a benzyloxycarbonyl group, as well as their pharmaceutical ly acceptable addition salts. 5) The compounds of formula (I) as claimed in any one of claims 1 to 4 in which R2 is a hydrogen, an alkyl radical containing 1 to 4 carbon atoms or a fluorine atom as well as their pharmaceutically acceptable addition salts. >2 • 6) The compounds of formula (I) as claimed in claim 5 in which R is a methyl or ethyl. 7) The compounds of formula (I) as claimed in any one of claims 1 to 6 in which: - G represents (Formula Removed) as well as their pharmaceutically acceptable addition salts. 8) The compounds of formula (I) as claimed in any one of claims 1 to 7 in which: - G represents (Formula Removed) R represents a hydrogen atom - R2 represents a hydrogen atom, a fluorine atom, a methyl radical or an ethyl radical, - R represents a benzyloxycarbonyloxy group - R4 represents a hydroxy group as well as the pharmaceutically acceptable addition salts. 9) The compounds of formula (I) as claimed in any one of claims 1 to 8 the names of which follow: 3-[[5-ethyl-6-[4-(l,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)-l-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine, 3-[[5-ethyl-6-[4-[(l,2,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyl]-l-oiperidinyl]4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine 3-[[6-[4-( 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1 -piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine 3-[[6-[4-[(l,2,3,4,5,6-hexahydro-2-pyrimidinyl)iminocarbonyl]-l-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alanine ethyl 3-[[5-ethyl-6-[4-(l,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)-l-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate isopropyl 3-[[6-[4-(l,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)-l-piperidinyl]-5-methyl-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate (l,l-dimethylethyl)3-[[5-ethyl-6-[4-(l,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)-l-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate (1,1 -dimethylethyl)3-[[5-methyl-6-[4-( 1,2,3,4-tetrahydro-l ,8-naphthyridin-7-yl) l-piperidinyl]-4-pyrimidinyl]amino]-N-[(phenylmethoxy)carbonyl]alaninate (l,l-dimethylethyl)3-[[5-ethyl-6-[4-(l,2,3,4-tetrahydro-l,8-naphthyridin-7-yl)-l-piperidinyl]-4-pyrimidinyl]amino]-N-(l-naphthalenesulphonyl)alaninate in (R) configuration or (S) configuration or their mixtures, as well as their addition salts. 10) A process for the preparation of the compounds of formula (I) as claimed in one of claims 1 to 9, characterized in that a) a product of general formula (11a) (Formula Removed) in which R1 , R2 , G are as defined previously and X represents a halogen, is reacted with a product of formula (VI) (Formula Removed) in which R3 and R4 are as defined previously, either in the presence of a strong base, or by catalysis with palladium, b) then the product of formula (I) is subjected , optionally to cleavage of the R -NH- function in order to regenerate the free amine, followed by condensation of the R3 radicals of-CO2-R5 or -SO2-R5 structure, and/or if appropriate to hydrolysis and optionally to esterification or to amidification and/or to salification. 11) A composition of formula (I) as claimed in any one of claims, 1 to 9, as and when used for the preparation of a pharmaceutical composition. 12) A compound of Formula (I) and a process for preparation thereof, substantially as herein described as illustrated in the foregoing examples.

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1749-DELNP-2005-Abstract-(16-09-2008).pdf

1749-DELNP-2005-Abstract-04-04-2008.pdf

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1749-DELNP-2005-Description (Complete)-04-04-2008.pdf

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1749-DELNP-2005-Form-2-04-04-2008.pdf

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1749-DELNP-2005-Petition-137-04-04-2008.pdf