MX2008009474A - Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors - Google Patents

Abstract

The invention relates to the novel products of formula (I):in which X1 and X2 represent:either one hydrogen and the other alkyl;or one -OCF3or -SCF3and the other NH-CO-alkyl-R3;or X1 and X2 form, with the phenyl radical to which they are attached, an optionally substituted dihydro-indole radical;R represents pyridyl or pyrimidinyl substituted with NR1R2, with R1 representing hydrogen or alkyl, and R2 representing optionally substituted alkyl, cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl, pyridyl, and CO-R3 with R3 representing in particular amine, alkoxy, heterocycloalkyl, aryl, aryloxy and heteroaryl;all these radicals being optionally substituted;and salts thereof.

Description

DERIVES TWO NUMBERS OF CYCLICAL UREA. YOUR PREPA RATION AND YOUR PHARMACEUTICAL UTILIZATION AS INHIBITORS OF KINASES The present invention relates to new cyclic urea derivatives, to their preparation process, to their application as medicaments, to the pharmaceutical compositions containing them and to the pharmaceutical use of such derivatives for the prevention and treatment of conditions capable of being modulated by inhibiting the activity of the protein kinases. The present invention relates to novel cyclic urea derivatives that have inhibitory effects on protein kinases.

The products of the present invention can be used in this way for the prevention or treatment of conditions capable of being modulated by the inhibition of the activity of the protein kinases. The inhibition and regulation of protein kinases are mainly a new potent mechanism of action for the treatment of a large number of solid or fluid tumors. Such are conditions that can treat the products of the present application are, then, very especially solid or liquid tumors. Such protein kinases belong mainly to the group following: EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PLK. PDGFR, tie2, VEGFR, AKT, Raf. Very particularly indicated is protein kinase I GF 1 -R (receptor for growth factor-1 of nonsulin). The present invention thus relates in particular to new inhibitors of the IGF-1 R receptor that can be used for treatments in oncology. Cancer remains a disease for which the treatments that exist are clearly insufficient. Certain protein kinases of which mainly IGF-1 R (insulin growth factor-1 receptor) plays an important role in numerous cancers. The inhibition of such protein kinases is potentially important in the chemotherapy of cancers, mainly to suppress the growth or survival of tumors. The present invention therefore relates to the identification of new products that inhibit such protein kinases. Protein kinases participate in signaling events that control the activation, growth and differentiation of cells in response to either extracellular mediators or medium changes. In general, these substances belong to two groups: those which preferentially phosphorylate the serine and / or threonine residues and those which preferentially phosphorylate the tyrosine residues [S. K. Hanks and T. Hunter, FASEB. J., 1, 1995, 9, pages 576-596]. The serine / threonine kinases are, for example, the isoforms of protein kinases C [A. C. Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases, such as cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-I97]. Tyrosine kinases comprise the receptors for growth factors such as the epidermal growth factor receptor (EGF) [S. Iwashita, M. Kobayashi, Cellular Signaling, 1992, 4, pages 123-132], and cytosolic kinases such as p56tck, p59fYn, ZAP-70 and csk kinases [C. Chan et. al., Ann. Rev. Immunol., 1994, 12, pages 555-592]. Abnormally high levels of protein kinase activity have been implicated in numerous diseases resulting from abnormal cellular functions. This can come either directly or indirectly from a dysfunction in the control mechanisms of the kinase activity, linked for example to a mutation, an overexpression or an inappropriate activation of the enzyme, or by an over- or under-production of cytokines or of the growth factors, equally involved in the transduction of the signals before or after the kinases. In all these cases, a selective inhibition of the action of the kinases allows to expect a beneficial effect. The insulin-like growth factor-1 receptor (IGF-I-R) is a transmembrane receptor with tyrosine kinase activity that binds first to IGF-I but also to IGF-II and to insulin with a weaker affinity. The binding of IGF1 to its receptor causes oligomerization of the receptor, activation of tyrosine kinase, intermolecular autophosphorylation and phosphorylation of cellular substrates (major substrates: IRS1 and Shc). The receptor activated by its ligand induces a mitogenic activity in normal cells. However, IGF-I-R has an important role in the growth called abnormal. Several clinical reports underscore the important role of the IGF-I pathway in the development of human cancers: IGF-IR is often overexpressed in numerous types of tumors (breast, colon, lung, sarcoma, prostate, multiple myeloma; ..) and their presence is often associated with a more aggressive phenotype. Elevated concentrations of circulating IGF1 correlate significantly with a risk of prostate, lung and breast cancer. In addition, it has been extensively documented that IGF-I-R is necessary to create and maintain the transformed phenotype both in vitro and in vivo [Baserga R., Exp. Cell. Res., 1999, 253, pages 1-6]. The kinase activity of IGF-I-R is essentially the transforming activity of several oncogenes: EGFR, PDGFR, the SV40 virus T antigen, activated by Ras, Raf and v-Src. The expression of IGF-I-R in normal fibroblasts induces a neoplastic phenotype, which can then lead to the formation of a tumor in vivo. The expression of IGF-I-R plays an important role in growth independent of the substrate. IGF-I-R has also been shown as a protector in apoptosis induced by chemotherapy, radiotherapy and apoptosis induced by cytokines. In addition, the inhibition of endogenous IGF-I-R by a negative dominant, the formation of a triple helix or the expression of a complementary one causes a suppression of the transforming activity in vitro and the decrease of tumor growth in animal models. Among the kinases for which modulation of activity is sought, FAK (focal adhesion kinase) is also a preferred kinase. FAK is a cytoplasmic tyrosine kinase that plays an important role in the transduction of the signal transmitted by integrins, family of heterodimeric receptors of cell adhesion. FAK and integrins are located in structures of the perimembrane called adhesion plates. It has been demonstrated in numerous cell types that the activation of FAK as well as its phosphorylation in tyrosine residues and in particular its autophosphorylation in tyrosine 397 residues were dependent on the binding of the integrins to their extracellular ligands and, therefore, induced during the cell adhesion [Kornberg L, et al. J. Biol. Chem. 267 (33): 23439-442 (1992)]. The autophosphorylation of FAK on tyrosine 397 represents a binding site for another tyrosine kinase, Src, through its SH2 domain [Schaller et al. Mol. Cell. Biol. 14 :. 1680-1688 1994; Xing et al. Mol. Cell. Biol. 5: 413-421 1994]. Src can then phosphorylate FAK on tyrosine 925, thereby incorporating the Grb2 adapter protein and inducing in some cells the activation of the ras and MAP kinase pathway involved in the control of cell proliferation [Schlaepfer et al. Nature; 372: 786-791 1994; Schlaepfer et al. Prog. Biophy. Mol. Biol. 71: 435-478 1999; Schlaepfer and Hunter, J. Biol. Chem. 272: 13189-13195 1997]. Activation of FAK can also induce the signaling pathway of the NH2-terminal junk kinase (JNK) and produce the evolution of the cells towards the G1 phase of the cell cycle [Oktay ef al., J. Cell. 8/0 / .145: 1461-1469 1999]. The phosphatidylinositol-3-γ-kinase (PI3-kinase) also binds to the FAK on tyrosine 397 and this interaction may be necessary for the activation of the PI3-kinase [Chen and Guan, Proc. Nat. Acad. Sci. USA. 91: 10148-10152 1994; Ling et al. J. Cell. Biochem. 73: 533-544 1999]. The FAK / Src complex phosphorylates different substrates such as paxilin and p130CAS in fibroblasts [Vuori et al. Mol. Cell. Biol. 16: 2606-2613 1996]. The results of numerous studies support the hypothesis that FAK inhibitors may be useful in the treatment of cancer. Studies have suggested that FAK could play an important role in proliferation and / or cell survival in vitro. For example, in CHO cells, some authors have shown that overexpression of p125FAK leads to an acceleration of the transition from G1 to S, suggesting that p125FAK favors cellular proliferation [Zhao J.-H ef al. J. Cell Biol. 143 1997-2008 1998]. Other authors have shown that tumor cells treated with complementary FAK oligonucleotides lose their adhesion and enter apoptosis (Xu et al., Cell Growth Differ., 4: 413-418 1996). It has also been shown that FAK promotes the migration of cells in vitro. Thus, fibroblasts deficient for the expression of FAK (mouse "knockout" for FAK) have a rounded morphology, deficiencies in cell migration in response to chemotactic signals, and these insufficiencies are suppressed by a reexpression of FAK [D. J. Sieg ef al. , J. Cell Science. 12: 2677-91 1 999]. Overexpression of the C-terminal domain of FAK (FRNK) blocks the stretching of adherent cells and reduces cell migration in vitro [Richardson A. and Parsons J. T. Nature. 380: 538-540 1996]. Overexpression of FAK in CHO, COS cells or cells of human astrocytoma favors the migration of cells. The implication of FAK in the activation of the proliferation and migration of cells in numerous cell types in vitro suggests the potential role of FAK in neoplastic processes. A recent study has effectively demonstrated increased proliferation of tumor cells in vivo after induction of FAK expression in human astrocytoma cells [Cary L. A. et al. J. Cell Sci. 1 09: 1787-94 1 996; Wang D ef al. J. Cell Sci. 1 1 3: 4221 -4230 2000]. In addition, immunohistochemical studies of human biopsies have demonstrated that FAK was overexpressed in cancers of the prostate, breast, thyroid, colon, melanoma, brain and lung, the level of FAK expression being directly correlated with tumors presenting the most aggressive phenotype [Weiner T.. et al. Lancet. 342 (8878): 1024-1025 1 993; Owens ef al. Cancer Research. 55: 2752-2755 1995; aung K. ef al. Oncogene 1 8: 6824-6828 1 999; Wang D et al. J. Cell Sci. 1 1 3: 4221 -4230 2000].

AKT protein kinase (also known by the name of PKB) and phosphoinositide 3-kinase (PI3K) are involved in a cell signaling pathway that transmits signals that come from growth factors that activate membrane receptors. This transduction pathway is involved in multiple cellular functions: regulation of apoptosis, control of transcription and translation, glucose metabolism, angiogenesis and mitochondrial integrity. I identified the pricipient as an important activator in the insulin-dependent signaling pathways that regulate metabolic responses, the serine / threonine kinase AKT has been identified as a mediator that plays a key role in survival induced by growth factors. It has been shown that AKT could inhibit death by apoptosis induced by variable stimuli, in a certain number of cell types and tumor cells. Based on these findings, it has been shown that AKT could, phosphorylation of given serine residues, inactivate BAD, GSK3D, caspase-9, the Forkhead transcription factor and activate IKK alpha and e-NOS. It is interesting to note that the BAD protein is recognized hyperphosphorylated in 11 human tumor cell lines in 41 studies. In addition, it has been shown that hypoxia modulated the induction of VEGF in cells transformed by Ha-ras by activating the PI3K / AKT pathway and involving the transcription factor binding sequence HIF-1 (hypoxia inducible factor-1) called HRE for «Element in response to hypoxi». AKT plays a very important role in cancer pathologies. Enlargement and / or overexpression of AKT has been implicated in numerous human tumors such as gastric carcinoma (AKT1 enlargement), ovarian, breast or pancreatic carcinomas (enlargement and overexpression of AKT2) and insufficient breast carcinomas in recipients in estrogens as well as androgen-independent prostate carcinomas (overexpression of AKT3). In addition, AKT is constitutively activated in all PTEN (- / -) tumors, PTEN phosphatase being eliminated or inactivated by mutations in numerous types of tumors such as ovarian, prostate, endometrial, glioblastoma and melanoma carcinomas. AKT is also involved in the oncogenic activation of bcr-abl (References: Khawaja A., Nature 1999, 401, 33-34; Cardone et al. Nature 1998, 282, 1318-1321; Kitada S. er al., Am. J. Pathol. January 1998; 152 (1): 51-61; Mazure NM. ef al. Blood 1997, 90, 3322-3331; Zhong H. et al. Cancer Res. 2000, 60, 1541-1545). The present invention relates to the products general formula (I): wherein: Ra and Rb represent CH3 or form together with the carbon atom to which a cycloalkyl radical is attached, and X2 are such that either one represents hydrogen and the other represents alkyl, either one represents -OCF3 or -SCF3 and the other represents the radical NH-CO-R6, either X1 and X2 form with the phenyl radical to which they are attached a dihydroindole radical occasionally substituted by one or several alkyl radicals and at its nitrogen atom by a radical CO- alkyl-R3, R represents a pyridyl or pyrimidinyl radical substituted by a radical NR ^, where NRTR2 is such that: one of Ri and R2 represents a hydrogen atom or an alkyl radical, and another of R and R2 is selected from the group consisting of atom of hydrogen and alkyl radicals optionally substituted by a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radicals and the piperazinyl itself occasionally substituted on its second nitrogen atom by an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals; and the radical CO-R3 with R3 selected from NR4R5 and the alkoxy, heterocycloalkyl, aryl, aryloxy and heteroaryl radicals, occasionally substituted; R4 and R5, identical or different from R1 and R2, are such as: either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and another of. R4 and R5 is selected from the hydrogen atom and the alkyl radicals optionally substituted by a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radicals and the piperazinyl itself occasionally substituted at its second nitrogen atom by a alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals; either R4 and R5 form, with the nitrogen atom to which they are attached, a cyclic amine containing occasionally another heteroatom selected from N and O, occasionally substituted, all the aryl, phenyl, aryloxy and heteroaryl radicals being present, as well as the cyclic amine NR4R5, optionally substituted by one to three identical or different radicals selected from the halogen atoms, the alkyl radicals, phenyl, NH2, NHAIk, N (Alk) 2, CO-NHAIk and CO-N (Alk) 2; R6 represents alkyl optionally substituted by one or more identical or different radicals selected from the values of said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). It can be seen that when Ra and Rb form together with the carbon atom to which a cycloalkyl radical is attached, this radical is mainly cyclopropyl. The subject of the present invention is thus the products of formula (I) as defined above: wherein: R a and R b represent CH 3, and X 2 have the meaning indicated in claim 1, R represents a substituted pyridyl or pyrimidyl radical radical N R 1 R 2, NR ^ being such that: one of R and R2 represents a hydrogen atom or an alkyl radical, and another of Rt and R2 is selected from the hydrogen atom and alkyl radicals optionally substituted by a radical selected from the hydroxyl radicals , alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or the piperazinyl itself occasionally substituted on its second nitrogen atom by an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals; and the radical CO-R3 with R3 selected from NR4R5 and the alkoxy, piperidyl, phenyl and phenoxy radicals occasionally substituted; R4 and R5, identical or different from Ri and R2, are such as: either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and another of R4 and R5 is selected from the hydrogen atom and the alkyl radicals optionally substituted by a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radicals and the piperazinyl itself occasionally substituted on its second nitrogen atom by an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals; either R and R5 form, with the nitrogen atom to which they are attached, a cyclic amine that occasionally contains another heteroatom selected from N and O, occasionally substituted, all the above radicals phenyl, pyrimidinyl and pyridyl, which are optionally substituted by one to three identical or different radicals selected from halogen atoms, alkyl, phenyl, NH2, N HAIk, N (Alk) 2, CO-NHAIk et al. CO-N (Alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). In the products of the formula (I) and in the part of the text that follows, the terms indicated have the following meanings: - the term "Hal", "Halo" or halogen designates the fluorine, chlorine, bromine or iodine atoms and preferably fluorine and chlorine - the term alkyl radical or alk (Alk) designates a straight or branched radical comprising not more than 12 carbon atoms, chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl radicals, tere-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and likewise heptyl, octyl, nonyl, decyl, undecyl and dodecyl, as well as their isomers of linear or branched position. More specifically, alkyl radicals having at most 6 carbon atoms and, in particular, the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terephthalic radicals are mentioned. butyl, linear or branched pentyl and linear or branched hexyl. the term "alkoxy radical" refers to a straight or branched radical comprising not more than 12 carbon atoms and preferably 6 carbon atoms, chosen, for example, from the methoxy, ethoxy, propoxy, isopropoxy, butoxy-linear, secondary or tertiary radicals, pentoxy, hexoxy and heptoxy, as well as their linear or branched positional isomers. the term "cycloalkyl radical" designates a monocyclic or bicyclic carbocyclic radical comprising from 3 to 10 bonds and primarily designates the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals. - the term "acyl radical" or -CO-r designates a straight or branched radical comprising at most 12 carbon atoms in which the radical r represents an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, these radicals having the values indicated above and are optionally substituted as indicated above: for example, the formyl, acetyl, propionyl, butyryl or benzoyl radicals, or also valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl. It is noted that the radical CO-R3 can be mainly take the values defined above for -CO-r. - the term "aryl radical" refers to unsaturated, monocyclic radicals or constituted by condensed and carbocyclic rings. As examples of such a radical aryl, phenyl or naphthyl radicals may be mentioned.

The phenyl radical is more particularly mentioned. The aryloxy radical designates an O-aryl radical in which the aryl radical has the meaning indicated above. The term "heterocycloalkyl radical" refers to a saturated carbocyclic radical consisting of a maximum of 7 links interrupted by one or more heteroatoms, identical or different, chosen from oxygen, nitrogen or sulfur atoms: as heterocycloalkyl radicals, mention may be made in particular of dioxolane, dioxane radicals , dithiolane, thiooxolane, thioxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholyl nyl or furthermore tetrahydrofuryl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolinyl, piperidinyl, perhydropyranyl, pyrindolinyl, tetrahydroquinoline, tetrahydroisoquinoline or thioazolidinyl , all of these radicals being optionally substituted. Among the heterocycloalkyl radicals, mention may be made more particularly of the optionally substituted piperazinyl radicals, optionally substituted phenyl peridi nyl, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or thioazolidinyl.

The term "heteroaryl radical" refers to a partially or totally unsaturated carbocyclic radical consisting, as a maximum, of 7 links interrupted by one or more heteroatoms, identical or different, chosen from the oxygen, nitrogen or sulfur atoms: between the 5-membered heteroaryl radicals there may be mentioned furyl radicals, such as 2-furyl, thienyl, such as 2-thienyl and 3-thienyl, pyrrolyl, diazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl oxadiazolyl, 3- or 4-isoxazolyl, imidazolyl, pyrazolyl and isoxazolyl. The 6-membered heteroaryl radicals include pyridyl radicals, such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrazolyl. - As condensed heteroaryl radicals containing at least one heteroatom chosen from sulfur, nitrogen and oxygen, there may be mentioned, for example, benzothienyl, such as 3-benzothienyl, benzofuryl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl, purinyl, quinoline, isoquinoline and naphthyridinyl. Among the fused heteroaryl radicals, mention may be made more particularly of the benzothienyl, benzofuranyl, indolyl or quinoline radicals, benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl. , quinazolinyl, 1,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, these radicals being optionally substituted as indicated for the heteroaryl radicals. The term patient designates humans and also other mammals. The term "prodrug" designates a product that can be transformed in vivo by metabolic mechanisms (such as hydrolysis) in a product of formula (I). For example, an ester of a product of the formula (I) containing a hydroxyl group can be converted by hydrolysis in vivo into its parent molecule. Or also, an ester of a product of formula (I) containing a carboxy group can be converted by hydrolysis in vivo into its parent molecule. Mention may be made, as examples, of the esters of the products of the formula (I) which contain a hydroxyl group, such as acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis. -b-hydroxynaphthoates, gentisatos, isethionates, di-p-toluoyltartratos, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. Esters of the especially useful products of formula (I) containing a hydroxyl group can be prepared from acidic moieties, such as those described by Bundgaard et. al., J. Med. Chem., 1989, 32, pages 2503-2507: these esters include especially the substituted (aminomethyl) -benzoates, dialkylamino-methylbenzoates wherein the two alkyl groups may be linked together or may be interrupted by an oxygen atom or an optionally substituted nitrogen atom or an alkylated nitrogen atom or also (morpholino-methyl) benzoates, for example 3- or 4- (morpholinomethyl) -benzoates and (4-alkylpiperazin-1-yl) benzoates, for example 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

The carboxy radical (s) of the products of formula (I) can be salified or esterified by different groups known to those skilled in the art, among which the following compounds can be mentioned as non-limiting examples: Salification, mineral bases such as those formed, for example, with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N- dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, Usin, arginine, histidine and N-methylglucamine, - among the esterification compounds, alkyl radicals to form alkoxycarbonyl groups, such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl , these alkyl radicals may be substituted with radicals chosen, for example, from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for example, in the groups chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl , methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl. Esterified carboxy means, for example, radicals such as alkyloxycarbonyl radicals, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl- or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl. There may also be mentioned radicals formed with the easily degradable ester residues, such as the methoxymethyl or ethoxymethyl radicals; acyloxyalkyl radicals, such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; the alkyloxycarbonyloxyalkyl radicals, such as the methoxycarbonyloxy-methyl or -ethyl radicals and the isopropyloxycarbonyloxy-methyl or -ethyl radicals. A list of such radicals can be found, for example, in European patent EP 0034536. Amidified carboxy is understood to mean radicals of the type: -CO N R4R5 in which the radicals R and. 5 have the meanings indicated above. By "alkylamino radical NHalk" is meant the straight or branched methylamino, ethylamino, propylamino or butylamino, pentylamino or hexylamino radicals. Alkyl radicals having a maximum of 4 carbon atoms are preferred, the alkyl radicals can be selected from the above-mentioned alkyl radicals. By radical dialkylamino N (al k) 2, it is understood the radicals in which alk takes the values defined above: as above, alkyl radicals having at most 4 carbon atoms selected from the above indicated list are preferred. Mention may be made, for example, of the di-methylamino, diethylamino, methylethylamino radicals. The term cyclic amine denotes a cycloalkyl radical containing 3 to 8 links in which a carbon atom is replaced by a nitrogen atom, the cycloalkyl radical having the meaning indicated above and may also contain one or more other heteroatoms selected from O, S, S02, N or NR3, with R3 as defined above: Examples of such cyclic amines include, for example, aziridyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, indolinyl, pyrindolinyl or tetrahydroquinoline radicals, optionally substituted: more specifically the pyrrolidinyl, piperidinyl and morpholine nyl radicals. Salified carboxy is understood to mean salts formed, for example, with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of salts formed with organic bases, such as methylamine, propyl amine, tri-methylamine, diethylamine and triethylamine. The sodium salt is preferred. When the products of formula (I) comprise an amino radical that can be salified with an acid, it is understood that these acid salts also form part of the invention. Mention may be made of the salts obtained with the acids, hydrochloric or methanesulfonic, for example. The addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with the hydrochloric, hydrobromic, hydroiodic acids, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, the alkanomonosulfonic acids such as, for example, methanesulfonic acid, ethanesulfonic acid, acid propanesulfonic, alcandisulfonic acids such as, for example, methandisulfonic acid, alpha, beta-ethanedisulfonic acid, aryl monosulfonic acids, such as benzenesulfonic acid, and aryldisulfonic acids. It may be recalled that stereoisomerism can be defined in a broad sense as the isomerism of compounds that have the same developed formulas, but in which different groups occupy different positions in space, as is particularly the case in monosubstituted cyclohexanes. , in which the substitute me can be in axial or equatorial position, and the different possible rotary configurations of the ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial dispositions of the fixed substituents, either on double bonds or on cycles, which is usually called geometric isomerism or cis-trans isomerism. The term "stereoisomer" is used in the present application in its broadest sense and refers, therefore, to the set of compounds indicated above. The subject of the present invention is also the products of formula (I) as defined above in which: and? 2 are such as: either one represents hydrogen and the other represents an alkyl radical, either one represents -OCF3 or -SCF3 and the other represents the radical NH-CO-Re, either Xi and X2 form with the phenyl radical to which A dihydroindole radical is occasionally bound by one or more alkyl radicals and at its nitrogen atom by the radical COCI H2-NH-cid or alkyl, R represents a pyridyl or pyrimidinyl radical substituted by a radical NR ^, where NRiR2 is such that Ri represents a hydrogen atom or an alkyl radical, and R 2 is selected from the hydrogen atom and alkyl radicals optionally substituted by a hydroxyl, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radical or the piperazinyl itself occasionally substituted at its second nitrogen atom by an alkyl radical; the cycloalkyl radicals having 3 to 6 links; the optionally substituted phenyl radical, the pyrimidinyl radical; the pyridyl radical optionally substituted by a halogen atom; and the radical CO-R3 with R3 selected from NR4R5 and the alkoxy, piperidyl and phenyl radicals occasionally substituted; R4 and R5, identical or different from Ri and R2, are such as: either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and another of R4 and Rs is selected from the group consisting of hydrogen and alkyl radicals optionally substituted by a hydroxyl, aziridyl, azetidinyl, pyrrolidyl, piperidium, morpholyl or piperazinyl radical itself optionally substituted on its second nitrogen atom by an alkyl radical; the cycloalkyl radicals having 3 to 6 links; the optionally substituted phenyl radical; the pyrimidinyl radical; the pyridyl radical optionally substituted by a halogen atom; bi in R 4 and R 5 form with the nitrogen atom to which they are attached an aziridyl, azetidinyl, pyrrolidinyl, piperidium, morpholinyl radical or the piperazinyl itself optionally substituted on its second nitrogen atom by an alkyl radical, all phenyl radicals being optionally substituted by one to three identical or different radicals selected from the halogen atoms, the alkyl radicals and the radicals CO-NHAIk and CO-N (Al k) 2; R6 represents alkyl optionally substituted by one or more identical or different radicals selected from the Ra values. said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). The subject of the present invention is thus the products of formula (I) as defined above in which: X1 and X2 are such as: either one represents hydrogen and the other represents a tere-butyl radical, either one represents -OCF3 or -SCF3 and the other represents the radical NH-CO-CH (NH2) -phenyl, either Xi and X2 they form with the phenyl radical to which they are attached a dihydroindol radical substituted by two methyl radicals and at its nitrogen atom by the radical CO-CH2-NH-cyclopentyl, R represents a pyridyl or pyrimidinyl radical substituted by a radical NR ^, being NR1R2 such that Ri represents a hydrogen atom or an alkyl radical having one or two carbon atoms, and R2 is selected from alkyl radicals having 1 to 4 carbon atoms optionally substituted by a hydroxyl radical; the optionally substituted phenyl radical; the pyrimidinyl radical; the pyridyl radical optionally substituted by a halogen atom; and the radical CO-R3 with R3 selected from piperidyl, optionally substituted phenyl, NH-cycloalkyl, NH2, NH (alk) and N (alk) 2; all phenyl radicals being optionally substituted by one to three identical or different radicals selected from the halogen atoms, the alkyl radicals and the radicals CO-NHAIk and CO-N (Alk) 2; said products of formula (I) being in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (I). The subject of the present invention is therefore the products of formula (I) as defined above in which: Xi and X2 have the meanings indicated in any one of the preceding claims R represents a pyridyl or pyrimidinyl radical substituted by a radical NRi R2 in wherein Ri represents a hydrogen atom and R2 represents a pyrimidinyl or pyridyl radical, or a radical CO-N (CH3) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). The subject of the present invention is mainly the products of formula (I) as defined above in which X1 (X2, Ra, Rb and R have any of the meanings indicated above, and the radicals NR ^ 2 or N R4R5 or well NR- | R2 and N R4R5 are selected from the following radicals named ex 9 a ej ex 31: e | 13 «} 14 «J 15 23 «1 * 4 • 125 e | M eJ 2 * «I» • J 31 said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). The subject of the present invention is mainly the products of formula (I) as defined above in which the radical NR-, R2 is selected from the values ej 9 to ej 31 as defined above. The subject of the present invention is mainly the products of formula (I), as defined above, belonging to formula (la): wherein n and NR4R5 have any of the definitions indicated above and mainly N R4R5 may represent the radicals ex 9 to ex 31, said products of formula (la) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (la). Among the preferred products of the invention, the products of formula (I) as defined above can be more accurately mentioned, which are the following: - 3- (4-tert-butyl-phenyl) -5,5-dimethyl -1 - [2- (pyridin-3-ylamino) -pyrimidin-4-ylmethyl] -imidazolidine-2,4-dione 3- (4- { [3- (4-tert-butylphenyl) -5,5 -dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} pyrimidin-2-yl) -1,1 -dimethylurea-3- [4- (. {3- [1 - (N-cyclopentyl Glycyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl} methyl) pyridin-2 il] -, 1 - dimethylurea-3- [1 - (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-di methyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione - (2R) -2-amino-N- [5- (4,4-dimethyl-2,5-dioxo-3. {[2- (pyridin-3-ylamino) pyridine -4-yl] methyl.}. Imidazolidin-1-yl) -2- (trifluoromethoxy) phenyl] -2-phenylacetamide (2R) -2-amino-N-. { 5- (4,4-Dimethyl-2, 5-dioxo-3 { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. Imidazolidin-1-yl) -2- ( trifluoromethyl) thio] phenyl] -2-phenylacetamide (2R) -2-amino-N-. { 5- [3- (2 - [(Dimethylcarbamoyl) amino] pyridi n-4-yl.] Methyl) -4,4-dimethyl-2,5-dioxoimidazolin-1 -yl] -2- (trifluoromethoxy) phenyl} -2-phenylacetamide (2R) -2-amino-N-. { 5- [3- (2 - [(dimethylcarbamoyl) amino] pyridin-4-yl.] Methyl) -4,4-dimethyl-2,5-dioxoimidazolin-1-yl] -2 - [(trifluoromethyl) thio] phenyl } -2-phenylacetamide-3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione-3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] methyl} i midazolidine-2,4-dione with said products of formula (I) in all the possible racemic, enantiomeric and diastereomeric isomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I).

The products of formula (I) according to the present invention can be prepared according to the usual methods known to those skilled in the art. The products of formula (I) according to the present invention can be prepared by the application or adaptation of known methods and mainly of the methods described in the literature such as, for example, those described by RC Larock in: Comprehensive Organic Transformations, VCH publishers, 1 989. The products according to the present invention can be prepared mainly as indicated in the Synthesis Schemes described below: Scheme for preparation of intermediate products and 4 General Synthesis Schemes: General Scheme 1, General Scheme 2, General Scheme 3 and General Scheme 4 below. The preparations of the examples of the present invention provide illustrations of the schemes below. Such synthesis schemes form part of the present invention: the present invention also has as an object the preparation procedures of the products of formula (i) such as those defined in General Scheme 1, General Scheme 2, General Scheme 3 and General Scheme 4 below. The present invention also has as an object the process for the preparation of intermediate products such as that defined below.

Scheme of preparation of intermediate products: B In the Scheme for preparation of intermediate products: The product D1 can be prepared by brominating the product A in the presence of N-bromosuccinimide in a solvent such as carbon tetrachloride as described by Brown, D. J. et al. (Aust. J. Chem. (1974), 2251). The alcohol C can be prepared by reduction of the ester B with a reducing agent such as sodium borohydride in a solvent such as ethanol at a temperature between 20 ° C and the reflux temperature of the solvent as described by Zanka, A. and cabbage. (Synlett (1999), (10), 1636-1638). The product D2 is prepared by chlorination of the alcohol C as in the conditions described by Fucase K. et al. (Tetrahedron Lett., 1991, 32 (32), 4019-4022) for treatment with thionyl formula in the presence of DMF in a solvent such as dichloromethane at a temperature between 0 ° C and 20 ° C.

General Scheme 1: In General Scheme 1: The alcohol F can be obtained by treating the aldehyde E by a reducing agent such as sodium borohydride, in a solvent such as methanol at a temperature between 0 ° C and 60 ° C as for example in the conditions described by Wang, E. et al. (Heterocycles 2002, 57 (11), 2021-2033.). The chlorinated product G can be obtained from the alcohol F, as in the conditions described for the preparation of the D2 product Hydantoin I can be obtained from isocyanate H by reaction with methyl 2,2-dimethylglycinate in a solvent such as toluene or α, β-dimethylformamide at a temperature between 20 ° C and the reflux temperature of the solvent as described for example Brana MF (J. Het Chem. (2002), 39 (2), 417-420. Product J can be prepared by reaction of products I and G with sodium hydride in tetrahydrofuran or N, N dimethylformamide at a temperature comprised between 0 ° C and 60 ° C as described by Johnson TA et al (J. Am. Chem. Soc. (2002), 124, 11689-11698) The product of general formula K can be prepared by reaction of J with metabenzene perbenzoic acid in solvents such as a dichloromethane / methanol (90:10; v / v) or dichloro-1,2-ethane mixture at temperatures between 0 ° C and 60 ° C as described by Jeong, IH et al (Bull. Korean Chem. Soc. (2002), 23 (12), 1823-1826) The products of general formula L can be prepared by reaction of K with ammonia in solution in water and / or dioxane in a tube sealed in the microwave or heating at temperatures between 40 ° C and 150 ° C as described by Font, D. et al. (Synthesis (2002), (13), 1833-1842). The products of general formula M can be obtained by reaction of L with isocyanate (R4-N = C = 0) using the methods known to those skilled in the art in the art.

The products of formula N can be prepared either by reaction of K with an amine (R2N H2) in solution in dioxane in a microwave sealed tube or by heating at temperatures between 40 ° C and 1 50 ° C as described in preparation of the compound L. Either from L by reaction with an aryl bromide or heteroaryl (R2-Br) in the presence of a palladium-based catalyst such as palladium acetate and a ligand such as xantphos in a solvent such as toluene, dioxane or tert-butanol as for example under the conditions described by BUCHWALD, SL and cois. (J. Org. Chem. 2001, 66 (8), 2560-2565). General Scheme 2: In General Scheme 2: The product O can be prepared by reaction products I and D with the sodium hydride in tetrahydrofuran or N, N-dimethylformamide at a temperature comprised between 0 ° C and 60 ° C as described in the preparation of the compound J. The product P can be prepared from O by reaction with a carbamate (NH2COOR ') in the presence of a palladium-based catalyst such as palladium acetate and a ligand such as xantphos in a solvent such as toluene, dioxane or tert-butanol as for example under the conditions described by BUCHWALD, SL et al. (J. Org. Chem. 2001, 66 (8), 2560-2565). The product M can be prepared either by reaction of the carbamate P with an amine in a solvent such as N-methylpyrrolidinone or toluene at a temperature between 50 ° C and the reflux temperature of the solvent or in the microwave as described by Manov-Yuvenskii V. I et al. (Z / 7, Prikl Khim. (1993), 66 (6), 1319-1327). either from O by reaction with a urea (NH2CON4R5) in the presence of a palladium-based catalyst such as palladium acetate and a ligand such as xantphos in a solvent such as toluene, dioxane or tert-butanol as per example in the conditions described by BUCHWALD, SL et al. (J. Org. Chem. 2001, 66 (8), 2560-2565). The product N can be prepared from O by reaction with an amine (R2-NH2) in the presence of a palladium-based catalyst such as palladium acetate and a ligand such as xantphos in a solvent such as toluene, dioxane or tert-butanol as for example under the conditions described by BUCHWALD, S. L. et al. (J. Org. Chem. 2001, 66 (8), 2560-2565). General Scheme 2 Bis: The product M can also be prepared according to the synthesis described in General Scheme 2 Bis: The product O 'can be prepared by reacting the products I and D with the sodium hydride in tetrahydrofuran or N, N-dimethylformamide at a temperature between 0 ° C and 60 ° C as described in general scheme 2 for product O.

The product P 'can be prepared from O' by reaction with acetamide (NH2COCH3) in the presence of a palladium-based catalyst such as palladium acetate and a ligand such as xantphos in a solvent such as toluene, dioxane or tere- butanol as for example under the conditions described by BUCHWALD, S. L. et al. (J. Am. Chem. Soc. 2002, 1224, 6043-6048). The product P "can be prepared by oxidation of P 'by an oxidant such as metachloroperbenzoic acid in a solvent such as dichloromethane as, for example, under the conditions described by SOLLOGOUB, M. et al (Letters 2002, 43 (Tet. 17), 3121-3123) The product P '"can be obtained by treating the product P" with thiophosgene in the presence of a base such as sodium bicarbonate in a solvent such as ethanol as for example under the conditions described by ROUSSEAU. , D. et al (Can J: Chem. 1977, 55, 3736-3739) The product M can be obtained by treating the product P '"with an amine NHR4R5 in a solvent such as dioxane or dimethyl sulfoxide as for example in the conditions described by OHSAWA, A. et al. (Chem. Pharm. Bull. 1980, 28, 3570-3575).

General Scheme 3: AA In General Scheme 3: The hydantoin R can be obtained from the aniline Q by treatment with diphosgene in a solvent such as dioxane or toluene as for example under the conditions described by Francis, J. E. et al. (J. Meo, Chem. (1991), 34 (1), 281-90), the isocyanate obtained is used as it is then put into reaction with methyl 2,2-dimethyl glycinate in a solvent such as toluene or the ?,? - dimethylformamide at a temperature between 20 ° C and the reflux temperature of the solvent as described for example Brana MF (J. Het Chem. (2002), 39 (2), 417-420.) Product S can be prepared by reaction of the R and D products with the sodium hydride in tetrahydrofuran or N, N-dimethylformamide at a temperature comprised between 0 ° C and 60 ° C as described in the preparation of the product J. The product T can be prepared by reduction of the nitro S in an acid such as hydrochloric acid in the presence of a metal such as zinc at a temperature comprised between 20 ° C and 100 ° C as described by Bryce MR et al. (Tet. Lett. (1987), 28, 577-580) The acid chloride V can be prepared from the acid U by treatment with thionyl chloride in a solvent such as dichloromethane as described by Sener, A. et al (J. Heterocycl. Chem. (2002) , 39 (5), 869-875 The amide W can be prepared by reaction of the acid chloride V with the amine T as ribe Feldman, P. L. et al. (Bioorg, Med. Chem. Lett. (2002), 12 (21), 3215-3218). The product of formula X can be prepared from W by reaction with an amine (R2-NH2) in the presence of a palladium-based catalyst such as palladium acetate and a ligand such as xantphos in a solvent such as toluene , dioxane or tert-butanol as for example under the conditions described by Buchwald, SL et al. . { J. Org. Chem. (2001), 66 (8), 2560-2565).

Product Y may be obtained by treatment of compound X with piperidine in α, β-dimethylformamide as described by Greene T. W. et al. (Protective groups in organic chemistry, John Wiley &Sons 1991, second edition) The product Z can be obtained from W by reaction with a urea (NH2CONR4R5) as in the conditions described for product X. The product AA can be obtained by treatment of the product Z as in the conditions described for the product and General Scheme 4: AM AL In General Scheme 4: The AC product can be obtained by acetylation of AB in acetic anhydride in microwaves or heating at a temperature comprised between 60 ° C and the reflux temperature of the solvent by adding sulfuric acid in catalytic amount as described in Vogel (Textbook of Practical Organic Chemistry, Pearson Prentice Hall, 1989, fifth edition) The product AD can be obtained by alkylating the AC product in solvents such as tetrahydrofuran, N, N-dimethylformamide using a base such as sodium hydride or a mixture of toluene and water in the presence of a phase transfer agent using a base such as sodium hydroxide or carbonate such as, for example, under the conditions described by Ramsay, TW et al. . { Synth Commun, 1995, 25 (24), 4029-4033). The product AE can be prepared by cyclizing the product AD in the presence of a palladium catalyst such as palladium acetate as for example under the conditions described by K.R. Fields. and col. (J. Org. Chem. 2005, 268). The amine AF can be obtained by hydrogenation of the nitro compound AE in the presence of a catalyst such as palladium on carbon, as for example under the conditions described by Rylander P. N. (Catalytic Hydrogenation in Organic Synthesis, Académic press, 1979) The hydantoin AG can be obtained from the aniline AF by treatment with carbonyldiimidazole in a solvent such as tetrahydrofuran as for example under the conditions described by Nefzi A. et al. (J. Comb. Chem. (2002), 4 (2), 175-178). The product AH can be prepared from the product AG and the product D as in the conditions described for product J. The product Al can be deacetylated from the product AH in a solvent such as dioxane as described by Greene T. W. et al. (Protective Groups in Organic Chemistry, John Wiley & amp;; Sons 1 991, second edition) The product AJ can be obtained by acetylation of the product Al in the presence of a base such as triethylamine and in a solvent such as 1,2-dichloroethane as described by Zhao, H.; and you . { Bioorg. Med. Chem. Lett. (2002), 12 (21), 31 1 1 -31 15). The product AK can be prepared by reaction of AJ with different amines which can be used as solvent or in solution in a solvent such as acetonitrile in the presence of a base such as potassium carbonate as described by Zhao, H.; and you (Bioorg, Med. Chem. Lett. (2002), 12 (21), 31 1 1-31 15). The product AL can be prepared from AK by reaction with a urea (NH2CONR4R5) in the presence of a palladium-based catalyst or as described in the preparation of Z. The product AM can be prepared from AK by reaction with a amine (R2-NH2) in the presence of a catalyst based on palladium as described in the preparation of X. In such preparations the products of formula (I) according to the present invention, the starting materials, the intermediates and the products of formula (I), which may be in protected form, they can be subjected, if necessary or if desired, to one or more reactions of following transformations, in any order: a) an esterification reaction of the acid function, b) a saponification reaction of the ester function in acid function, c) an oxidation reaction of the alkylthio group in the corresponding sulfoxide or sulphone, d) a reaction of transformation of the ketone function in oxime function, e) a reduction reaction of the free carboxy function or esterified alcohol function, f) a reaction of transformation of the alkoxy function in hydroxyl function or also of the hydroxyl function in alkoxy function, g) an oxidation reaction of the alcohol function in func aldehyde, acid or ketone ion, h) a reaction of transformation of the nitrile radical into tetrazolyl, i) a reduction reaction of the nitrated compounds in aminated compounds, j) a removal reaction of the protective groups that can carry protected reactive functions, k) a salification reaction with a mineral or organic acid or with a base to obtain the corresponding salt, I) a splitting reaction of the racemic forms in split products, said products of formula (I) being thus obtained in all forms possible isomers, racemic, enantiomeric and di astereoi shallow. It can be noted that such reactions of transformation of substituents in other substituents can also be carried out on the initial products as well as on the intermediates, as defined above, before proceeding with the synthesis according to the reactions indicated in the process described above. . In the reactions described below, it may be necessary to protect reactive functional groups such as for example hydroxy, acyl, free carboxy or even amino and monoalkylamino, imino, thio groups, which may then be protected by the appropriate protecting groups. Conventional protecting groups can be used according to conventional conventional practices such as those described for example by T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1.991. The following non-exhaustive list of examples of protection of reactive functions can be mentioned: hydroxyl groups can be protected for example with alkyl radicals such as tere-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl, the amino groups can be protected, for example, with acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, phthalimido radicals or other known radicals in peptide chemistry, the acyl groups, such as the formyl group, can be protected, for example, in the form of acetals or cyclic or non-cyclic thioketals, such as dimethyl or diethyl acetal or ethylene-dioxyacetal or diethyl thioacetal or ethylene. -dithioacetal, - the acid functions of the products described above, if desired, can be amidated with a primary or secondary amine, for example in methylene chloride in the presence, for example, of 1-ethyl-3- (dimethyl) hydrochloride -amino-propyl) -carbodiimide at room temperature, - the acid functions can be protected, for example, in the form of esters formed with easily digestible esters, such as the benzyl or fer-t-butyl esters or esters known in peptide chemistry . These reactions a) to k) indicated above can be carried out as follows: a) The products described above can, if desired, be subjected to the possible carboxy functions, of esterification reactions which can be carried out according to the usual methods known per se. the experts in the field. b) The optional transformations of the ester functions in The acid function of the products described above, if desired, can be carried out under the usual conditions known to those skilled in the art, mainly by acid or alkaline hydrolysis, for example with soda or potash in alcoholic medium such as, for example, in methanol or also with hydrochloric or sulfuric acid. c) Optional alkylthio groups of the products described above, in which the alkyl radical is optionally substituted with one or more halogen atoms, mainly fluorine, can be converted, if desired, into the corresponding sulfoxide or sulphone functions in usual conditions known to those skilled in the art, such as, for example, peracids, such as peracetic acid or metachloroperbenzoic acid, or also with ozone, oxone, sodium periodate in a solvent such as, for example, methylene chloride or dioxane at room temperature. Obtaining the sulfoxide function can be promoted with an equimolar mixture of the product comprising an alkylthio group and the reactant, such as, in particular, a peracid. The sulfone function can be obtained with a mixture of the product comprising an alkylthio group with an excess of the reactant, such as, in particular, a peracid. d) The reaction of transforming a ketone function into oxyma can be carried out in the usual conditions known to those skilled in the art, such as, in particular, an action in the presence of a hydroxylamine, optionally O-substituted, in an alcohol, such as for example ethanol, at room temperature or by heating. e) The optional free or esterified carboxy functions of the products described above can be reduced, if desired, in alcohol function by methods known to those skilled in the art: eventual carboxy esterified functions can be reduced, if desired, in alcohol function by methods known to those skilled in the art and principally with lithium hydride and aluminum in a solvent such as, for example, tetrahydrofuran or also dioxane or ethyl ether. Optional free carboxy functions of the products described above can be reduced, if desired, to alcohol function especially with boron hydride. f) The optional alkoxy functions, such as primarily methoxy, of the products described above can be converted, if desired, into hydroxyl function under the usual conditions known to those skilled in the art for example with boron tribromide in a solvent, such as for example methylene chloride, with hydrobromide or pyridine hydrochloride or even with hydrobromic or hydrochloric acid in water or with refluxing trifluoroacetic acid. g) The optional alcohol functions of the products described above can be converted, if desired, into aldehyde or acid function by oxidation under the usual conditions known to those skilled in the art, such as for example by the action of manganese oxide to obtain the aldehydes or of the Jones reagent to obtain the acids. h) The optional nitrile functions of the products described above can be transformed, if desired, into tetrazolyl under the usual conditions known to those skilled in the art, such as, for example, by cycloaddition of a metal azide, such as, for example, the azide of sodium, or a trialkyltin azide on the nitrile function, as indicated in the method described in the article whose reference is given below: J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S.- et al. It can be pointed out that the conversion reaction of a carbamate in urea and especially of a sulfonyl carbamate in sulfonyl urea can be carried out, for example, under reflux of a solvent, such as toluene, in the presence of the appropriate amine. It is understood that the reactions described above can be carried out as indicated or, if necessary, according to other usual methods known to those skilled in the art. i) The removal of protective groups such as those indicated above can be carried out under the usual conditions known to those skilled in the art, mainly by acid hydrolysis carried out with an acid such as acid hydrochloric, benzenesulfonic or para-toluenesulfonic, formic or trifluoroacetic or even by catalytic hydrogenation. The phthalimido group can be removed with hydrazine. A list of the different protective groups that can be used, for example, is found in patent BF 2,499,995. j) The products described above, if desired, may be subject to salification reactions, for example with a mineral or organic acid or with a mineral or organic base, according to the usual methods known to those skilled in the art. k) Optional optically active forms of the products described above can be prepared by splitting the racemates according to the usual methods known to those skilled in the art. The optional reactive functions that are optionally protected are mainly the hydroxy or amino functions. They are used to protect the functions of the usual protective groups. Mention may be made, as examples, of the following protective groups of the amino radical: tere-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzydryl, trityl, formyl and benzyloxycarbonyl. As the protective group for the hydroxy radical, radicals such as formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl and tert-butylmethylsilyl can be mentioned. It is understood that the above list is not limiting and that other protective groups, for example, known ones, can be used. in the chemistry of peptides. A list of such protecting groups is found, for example, in French patent BF2,499,995, the content of which is incorporated herein by reference. The optional removal reactions of the protecting groups are carried out as indicated in said patent BF2,499,995. The preferred form of elimination is acid hydrolysis by means of acids selected from the acids, hydrochloric, benzenesulfonic or para-toluenesulphonic, formic or trifluoroacetic acids. Hydrochloric acid is preferred. The optional hydrolysis reaction of the group > C = NH in the ketone group is also preferably carried out by means of an acid such as aqueous hydrochloric acid, for example under reflux. In the examples, an exemplary removal of the tert-butyldimethylsilyl group by means of hydrochloric acid is given below. The optional esterification of a free OH radical is carried out under the conventional conditions. For example, an acid or a functional derivative, for example an anhydride such as acetic anhydride in the presence of a base such as pyridine, can be used. The esterification or optional salification of a COOH group is carried out under the classical conditions known to those skilled in the art. The optional amidification of a free COOH radical is carried out under conventional conditions. A primary or secondary amine may be used on a functional derivative of the acid, for example, a synthetic or mixed anhydride. The starting materials used to prepare the products of formula (I) according to the present invention may be known and available commercially or may be prepared according to methods known to those skilled in the art. The target products of the present invention are endowed with interesting pharmacological properties: it has been found that they have mainly inhibitory properties of protein kinases. Among these proteins, I GF 1R is mainly cited. The tests given below in the experimental part illustrate the inhibitory activity of the products of the present invention against such protein kinases. These properties therefore make it possible for the products of the general formula (I) of the present invention to be used as medicaments for the treatment of malignant tumors. The products of the formula (I) can also be used in the veterinary field. The object of the invention is therefore to apply, in the form of medicaments, products of general formula (I) such as those defined above, said products of formula (I) being in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as The addition salts with acids mineral and organic or with the pharmaceutically acceptable organic and organic bases of said products of formula (I).

The subject of the invention is especially the application, as medicaments, of the products of formula (I), the names of which are the following: 3- (4-tert-butyl-phenyl) -5,5-dimethyl-1 - [2- (pyridin-3-ylamino) -pinmidin-4-ylmethyl] -imidazolidine-2,4-dione 3- (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4 -dioxoimidazolidi n-1 -yl] methyl.} pyrimidin-2-yl) -1,1 -dimethylurea-3- [4- (. {3- [1- (N-cyclopentylglycyl) -3,3-dimethyl} -2,3-dihydro-1 H-indol-6-yl] -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl.} Methyl) pyridin-2-yl] -1,1-dimethyl urea 3- [1 - (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1Hyldol-6-yl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pindin-4-yl] methyl} imidazolidine-2,4-dione (2R) -2-amino-N- [5- (4,4-dimethyl-2, 5-dioxo-3 { [2- (pyridin-3-ylamino) pyridine- 4-yl] methyl.}. Imidazolidin-1-yl) -2- (trifluoromethoxy) phenyl] -2-phenylacetamide (2R) -2-amino-N-. { 5- (4,4-dimethyl-2,5-dioxo-3 { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. Imidazolidin-1-yl) -2- ( trifluoromethyl) thio] phenyl] -2-phenylacetamide (2R) -2-amino-N-. { 5- [3- (2 - [(dimethylcarbamoyl) amino] pyridin-4-yl.] Methyl) -4,4-dimethyl-2,5-dioxoimidazolin-1 -yl] -2- (trifluoromethoxy) phenyl} -2-phenylacetamide - (2R) -2-amino-N-. { 5- [3- (2 - [(dimethylcarbamoyl) amino] pyridine n-4- il} methyl) -4,4-dimethyl-2,5-dioxoimidazolin-1 -yl] -2 - [(trifluoromethyl) thio] phenyl} -2-Phenylacetamide-3- (4-tert-butylphenyl) -5,5-d-methyl-1 -. { [2- (pyrmidin-5-ilarnino) pyridin-4-yl] methyl} Mdazolidi na-2,4-dione-3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (Pyrimidin-5-ylamino) pyrimidn-4-yl] methyl} Midazo-lydrin-2,4-dione with said products of formula (I) in all the possible racemic, enantiomeric and diastereomeric isomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases pharmaceutically acceptable of said products of formula (I). The products can be administered parenterally, orally, perlingually, rectally or topically. Another subject of the invention is pharmaceutical compositions, characterized in that they comprise, as an active principle, at least one of the drugs of general formula (I). These compositions may be in the form of solutions, injectable suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions. These pharmaceutical formulas are prepared according to the usual methods. The active principle can be incorporated into the excipients usually employed in these compositions, such as aqueous or non-aqueous vehicles, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fats of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers and preservatives. The usual dose, variable according to the patient treated and the condition in question, can be, for example, from 10 mg to 500 mg per day in man, orally. The present invention also relates to the use of products of formula (I) as defined above or pharmaceutically acceptable salts of said products of formula (I) for the preparation of drugs intended to inhibit the activity of protein kinases and mainly of a protein kinase. The present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is a protein tyrosine kinase. The present invention thus relates to the use of products of formula (I) as defined above or of the pharmaceutically acceptable salts of said products of formula (I), wherein the protein kinase is selected from the following group : EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1 R, KDR, PDG FR, tie2, VEGFR, AKT and Raf. The present invention thus relates in particular to the use of products of formula (I), as defined above, or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is IGF1 R. The present invention also relates to the use of the products of the formula (I), as defined above, or the pharmaceutically acceptable salts of said products of the formula (I), in which the protein-qui nasa is in a cell culture and also refers to this use in a mammal. The present invention thus relates to the use of products of formula (I), as defined above, or of the pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to prevent or treat a disease characterized by the malfunction of the activity of a protein kinase and, particularly, of such a disease in a mammal. The present invention relates to the use of products of formula (I) as defined above or pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to prevent or treat a disease belonging to the next group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathies, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, diseases in oncology and cancers. The present invention thus relates to the use of products of formula (I) as defined above or pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for treating diseases in oncology. The present invention relates especially to the use of the products of the formula (I) as defined above or the pharmaceutically acceptable salts of said products of the formula (I) for the preparation of a medicament intended to treat cancers . Among these cancers, the present invention relates very especially to the treatment of solid tumors or to the treatment of cancers resistant to cytotoxic agents. Among these cancers, the present invention relates especially to the treatment of breast, stomach, colon, lung, ovarian, uterus, brain, kidney, larynx, lymphatic system, thyroid, thyroid, genitourinary tract, the tube that includes the gallbladder and the prostate, cancer of the bones, pancreas and melanomas. The present invention also relates more especially to the treatment of breast, colon and pulmonary cancer. The present invention also relates to the use of products of formula (I) as defined above or pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended for the chemotherapy of cancers.

As medicaments according to the present invention intended for the chemotherapy of cancers, the products of formula (I) according to the present invention can be used alone or in association with chemotherapy or radiotherapy or alternatively in association with other therapeutic agents. The present invention thus relates mainly to pharmaceutical compositions such as those defined above which also contain active ingredients of other cancer chemotherapy drugs. Such therapeutic agents can be commonly used antitumor agents. Examples of known inhibitors of protein kinases include butyrolactone, flavopiridol, 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, olomucin, Glivec, and Iressa. The products of formula (I) according to the present invention can also be advantageously used in combination with antiproliferative agents: examples of such antiproliferating agents, but without being limited to this list, are aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, active agents on microtubules, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX inhibitors -2, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that decrease the activity of protein-quas nasas and also anti-angiogenic compounds, agonists of gonadorrelin, anti-androgens, bengamides, bisphosphonates and trastuzumab. Mention may also be made, by way of example, of antimicrotubulinic agents such as taxoids, vinca alkaloids, alkylating agents such as cyclophosphamide, DNA intercalating agents such as cs-platinum, agents that interact on topoisomerase as the camptothecin and derivatives, anthracyclines such as adriamycin, antimetabolites such as 5-fluoroacyl and derivatives and analogues. The present invention therefore relates to products of formula (I) as inhibitors of protein kinases, said products of formula (I) being in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as the addition salts with the acids mineral and organic or with the pharmaceutically acceptable mineral and organic bases of said products of formula (I), as well as their prodrugs. The present invention relates especially to the products of formula (I) as defined above as inhibitors of IGF1 R. The present invention relates more specifically to the products of formula (I) such as those defined above as inhibitors of IGF1 R.

The N 1 H NMR spectra are recorded in BRUKER spectrometers at 400 MHz (AVANCE DRX-400) or at 300 MHz (BRUKER ADVANCE DPX-300). The chemical shifts are expressed in ppm (d in ppm) (in solvent of dimethyl sulfoxide) d6 (DM SO-d6) in relation to 2.50 ppm at a temperature of 303K. Mass spectra have been made, either in; electroatomization (ES) in the Q-Tof-2 (Micromass), ZQ (M icromass) and Quattro Premier (Micromass) equipment, either in the electronic impact (IE) equipment; 70 eV; Micromass GCT Premier, either in chemical ionization (IC); reactive gas ammonia; Micromass GCT equipment. LCM S is performed on a Hypersil Gold C 1 8 3x50 mm column with diameter particles: 3 pm Initial conditions: Solvent A: Water for 0.05% TFA 95% Solvent B: Acetonitrile for 0.05% TFA 5% Flow rate 0.9 mi Pressure at t0: 145 bar injected volume: 5 μ? «GRADI ENTE in 7 min Time% A% B 0 95 5 5 5 95 5,5 5 95 6, 5 95 5 7 95 5 Detector U.V. DAD: 200 < ? < 400 nm, the mass is measured by electroatomization (ES +) in a Q-Tof-2 (Micromass) equipment The examples whose preparation follows illustrate the present invention without limiting it, nevertheless. Example 1: 3- (4-tert-Butyl-phenyl) -5,5-dimethyl-1 - [2- (pyridin-3-ylamino) -pyrimidin-4-ylmethyl] -imidazolidine-2,4-dione Phase g : 3- (4-tert-Butyl-phenyl) -5,5-dimethyl-1 - [2- (pyridin-3-ylamino) -pyrimidin-4-ylmethyl] -imidazolidine-2,4-dione To a solution of 0.45 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione obtained in phase f ) in 1 5 ml of dioxane are added successively, under argon, 0.29 g of 3-bromopyridine, 1.51 g of cesium carbonate, 0.085 g of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene. and 0.027 g of palladium acetate. The reaction mixture is heated at 1 20 ° C for 5 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column eluting with dichloromethane to give 76 mg of 3- (4-tert-butyl-phenyl) -5,5-dimethyl-1 - [2- (pyridin-3-ylamino) - pyrimidin-4-ylmethyl] -imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 300 Hz: 1.32 (s, 9H); 1.45 (s, 6H); 2.54 (s, 6H); 4.64 (s, 2H); 7.11 (d, J = 5.0 Hz, 1H); 7.35 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 7.72 (dd, J = 7.5 and 9.0 Hz, 1H); 8.40 (broad d, J = 5.5 Hz, 1H); 8.57 (m, 2H); 9.06 (broad s, 1H); 10.35 (s, 1H). Mass spectrum (ES): m / z = 445 [M + H] + base peak Phase f): 1 - [(2-aminopyrimidin-4-yl) methyl] -3- (4-tert-butylphenyl) - 5,5-dimethylimidazolidine-2,4-dione A solution of 0.45 g of 3- (4-tert-butylphenyl) -5,5-dimethyl-1-. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione obtained in step e) in 2.1 ml of dioxane and 2.1 ml of 30% ammonia is heated in a sealed microwave tube at 120 ° C for 1 hour. After evaporation of the solvents, 0.38 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione are obtained. whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9 H); 1.41 (s, 6H); 4.40 (s, 2H); 6.59 (s, 2H); 6.61 (d, J = 5.0 Hz, 1H); 7.33 (d, J = 8.5 Hz, 2H); 7.50 (d, J = 8.5 Hz, 2H); 8.18 (d, J = 5.0 Hz, 1H).

Mass spectrum (ES): m / z = 368 [M + H] + base peak Phase ex .: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (methylsuifonyl) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione To a solution of 4.1.1 g of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (methylthio) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione obtained in step d) in 130 ml of dichloro-1,2-ethane is added in portions 9.8 g of 3-chloroperbenzoic acid (70-75%). The reaction mixture is stirred at room temperature for 1 5 hours then washed successively 2 times with 1000 ml of a saturated solution of sodium bicarbonate, in water then with saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a silica column eluting with dichloromethane to give 0.8 g of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 46 (s, 6H); 3.41 (s, 3H); 4.85 (s, 2H); 7.33 (d, J = 8.5 Hz, 2H); 7.50 (d, J = 8.5 Hz, 2H); 7.92 (d, J = 5.5 Hz, 1 H); 9.04 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 431 [M + H] + base peak phase d: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (methylthio) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione To a suspension of 1.74 g of sodium hydride (60% strength) 70 ml of tetrahydrofuran are added successively, dropwise under an inert atmosphere of argon, a solution of 4.52 g of 3- (4-tert-butyl-phenyl) -5,5-dimethyl-imidazolidine-2,4-dione. obtained in step c) in 25 ml of tetrahydrofuran followed by a solution of 5.14 g of 4- (chloromethyl) -2- (methylthio) pyrimidine in 50 ml of tetrahydrofuran. After the addition, the reaction mixture is refluxed for 48 hours, cooled to room temperature, poured into distilled water and the aqueous phase washed with ethyl acetate. The organic phase is then washed with water and a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with dichloromethane to give 5.92 g of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (methylthio) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione whose characteristics are the following: 1 H-NMR spectrum at 300 MHz: 1.31 (s, 9H); 1, 43 (s, 6H); 2, 50 (masked, 3H); 4.64 (s, 2H); 7.27 (d, J = 5.0 Hz, 1 H); 7.32 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 8.58 (d, J = 5.0 Hz, 1 H). Mass spectrum (ES): m / z = 399; [M + H] + base peak phase c): 3- (4-tert-butyl-phenyl) -5,5-dimethyl-imidazolidine-2,4-dione To a suspension of 15 g of 4-tert-butyl-phenyl-isocyanate in 200 ml of toluene are added in succession, 31.52 ml of triethylamine and 13.3 g of 2,2-dimethylglycine methyl ester hydrochloride. The reaction mixture is refluxed for 24 h, cooled to room temperature, poured into distilled water and extracted with ethyl acetate. The organic phase is washed successively with water, with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diethyl ether and the solid formed is filtered and dried to give 17.75 g of 3- (4-tert-butyl-phenyl) -5,5-dimethyl-imidazolidine-2,4-dione. whose characteristics are the following: 1 H NMR spectrum at 300 MHz: 1.30 (s, 9H); 1, 39 (s, 6H); 7.26 (d, J = 8.5 Hz, 2H); 7.48 (d, J = 8.5 Hz, 2H); 8.48 (broad s, 1 H). Mass spectrum (I E): m / z = 260 M + Phase b): 4- (chloromethyl) -2- (methylthio) pyrimidine To a solution of 1 3.69 g of [2- (methylthio) pyrimidin-4-yl] methanol obtained in step a) in 250 ml of dichloromethane is added dropwise 7.67 ml of thionyl chloride, then , 91 mi from? ,? -dimethylformamide. The reaction mixture is stirred at room temperature for 15 h and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the solid formed is filtered and dried to give 1 0.28 g of 4- (chloromethyl) -2- (methylthio) pyrimidine whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 2, 52 (s, 3H); 4.72 (s, 2H); 7.33 (d, J = 5.5 Hz, 1 H); 8.68 (d, J = 5, 5 Hz, 1 H). Mass spectrum (CI): m / z = 1 75 [M + H] + base peak Phase a): [2- (methylthio) pyrimidin-4-yl] methanol To a suspension of 20 g of 2-methylthio-pyrimidine-4-carboxaldehyde in 400 ml of methanol at 0 ° C, 9.8 g of sodium borohydride are added in small portions. After the addition, the reaction mixture is stirred at room temperature for 15 h and concentrated under reduced pressure. The residue is collected in dichloromethane and washed successively with water and a saturated solution of sodium chloride, dried over magnesium sulfate and filtered. The solvent is evaporated under reduced pressure to give 16.69 g of [2- (methylthio) pyrimidin-4-yl] methanol whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 2.49 (s, 3H); 4.48 (d, J = 5.5 Hz, 2H); 5.61 (t, J = 5.5 Hz, 1 H); 7.24 (d, J = 5.5 Hz, 1 H); 8, 60 (d, J = 5.5 Hz, 1 H). - Mass spectrum (IE): m / z = 1 56 M + m / z = 1 38 [M -H20] * base peak Example 2: 3- (4- { [3- (4-tert-butylphenyl ) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} - pyrimidin-2-yl) -1, 1 -dimethylurea Step b: 3- (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} - pyrimidin-2-yl) - 1,1-dimethylurea To a solution of 70 mg of phenyl- (4- {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl}. pyrimidin-2-yl) carbamate obtained in step a) above in 3 ml of tetrahydrofuran are introduced under argon, 0.71 ml of a 2M dimethylamine solution. in tetrahydrofuran. After one hour of stirring at room temperature, the reaction medium is concentrated under reduced pressure and the residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane / acetonitrile / methanol (98/1/1 by volume) to give 20 mg of 3- (4. {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyrimidin-2-yl) - 1,1-dimethyl urea in the form of a white powder whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 43 (s, 6H); 2.90 (s, 6H); 4.54 (s, 2H); 7.03 (d, J = 5.0 Hz, 1 H); 7.33 (d, J = 8.5 Hz, 2H); 7.50 (d, J = 8.5 Hz, 2H); 8.46 (d, J = 5.0 Hz, 1 H); 9.25 (s, 1 H) Mass spectrum (ES): m / z = 439 [M + H] * (base peak) m / z = 437 [MH] "(base peak) Phase a: Phenyl- (4- { [3 - (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyrimidin-2-yl) carbamate To a solution of 100 mg of 1 - [(2-aminopyrimidin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione obtained in step f) of the Example 1 in 3 ml of tetrahydrofuran, 0.034 ml of pyridine and 0.045 ml of phenyl chlorocarbonate are added at 0 ° C. The reaction mixture is stirred 4.5 hours at room temperature then it is diluted with ethyl acetate and washed twice with 30 ml of an aqueous solution of 1 N hydrochloric acid then 2 times with 30 ml of water, 2 times with 30 ml of a saturated aqueous solution in sodium bicarbonate and finally with an aqueous solution saturated in sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate / cyclohexane (62/38 by volume) to obtain 70 mg of phenyl- (4- {[3- (4-tert-butylphenyl)) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyrimidin-2-yl) carbamate in the form of a white powder whose characteristics are as follows: Mass spectrum (ES): m / z = 488 [M + H] + (base peak) Example 3: 3- [4- ( { 3- [1 - (N-cyclopentylglyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl.} methyl) pyridin-2-yl] -1, 1 -dimethylurea Step m): 3- [4- ( { 3- [1 - (N-cyclopentylglycyl) -3t3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl- 2,4-dioxoimidazolidin-1-yl.} Methyl) pyridin-2-yl] -1, 1 -dimethylurea To a solution of 0.312 g of [2- (6- { 3 - [(2-chloropi-ridin-4-yl) methyl] -4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl} -3,3-dimethyl-2, 3-dihydro-1 H-indol-1-yl) -2-oxoethyl] -cyclohertylcarbamate obtained in phase I), then in 12 ml of dioxane are added successively under argon, 0.066 g of N, N-di methyl urea, 0.028 g of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 0.022 g of palladium acetate and 0 , 65 g of cesium carbonate. The reaction mixture is refluxed for 4 h and then filtered and concentrated under reduced pressure. The residue is taken up in 10 ml of dioxane, then 12 ml of a 4 N solution of hydrochloric acid in dioxane and the reaction mixture are added. it is stirred at room temperature for 15 h. After concentration under reduced pressure the residue is taken up in 40 ml of water, neutralized by the addition of sodium bicarbonate and extracted with 3 times 20 ml of dichloromethane. The combined organic phases are then washed with water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel column with a mixture of dichloromethane and methanol (90/10 volume) to give 0.08 g of 3- [4- (. {3- [1 - ( N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl-2,4-dioxoimidazolidi n-1-yl.] Methyl) pyridine- 2-yl] -1,1-dimethylurea whose characteristics are the following: MR NMR 1 H at 400 MHz: From 1.28 to 1.78 (m, 8H); 1.32 (s, 6H); 1.40 (s, 6H); 2.94 (s, 6H); 3.09 (m, 1 H); 3.50 (broad s, 2H); 3.91 (s, 2H); 4.58 (s, 2H); 6.99 (broad d, J = 5.5 Hz, 1 H); 7.08 (dd, J = 2.0 and 8.0 Hz, 1 H); 7.37 (d, J = 8.0 Hz, 1 H); 7.83 (broad s, 1 H); 8.05 (broad s, 1 H); 8, 1 8 (d, J = 5.5 Hz, 1 H); 8.79 (s, 1 H). Mass spectrum (ES): m / z = 576 [M + H] +; m / z = 598 [M + Na] + Phase 1): [2- (6- { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-dimethyl-2,5-d Oxoimidazolidin-1-yl.] - 3,3-dmethyl-2,3-dihydro-1 H-indol-1-yl) -2-oxoethyl] tere-butyl cyclopentylcarbamate To a solution of 3.3 g of 1 - [(2-chloropyridin-4-yl) methyl] -3- [1 - (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1H- indol-6-yl] -5,5-dimethylimidazoiidine-2,4-dione obtained in step k) later in 60 ml of dichloromethane are added 1.79 ml of triethylamine followed by 1.5 g of di-tert-butyl ether. Butylcarbonate The reaction mixture is stirred at room temperature for 15 h then it is washed 3 times with 25 ml of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 3.9 g of [2- (6 { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl.} - 3,3-dimethyl-2,3-dihydro -1 H-indol-1-yl) -2-oxoethyl] tere-butyl cyclo-pentacarbamate whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: from 1.20 to 1.85 (m, 29H); 3.95 (broad s, 2H); from 3.98 to 4.45 (extended m, 3H); 4.63 (s, 2H); 7, 10 (dd, J = 2.0 and 8.5 Hz, 1 H); 7.38 (d, J = 8.5 Hz, 1 H); 7.45 (broad d, J = 5.5 Hz, 1 H); 7.58 (broad s, 1 H); 8.08 (broad s, 1 H); 8.38 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 624 [M + H] +; m / z = 646 [M + Na] + m / z = 668 [MH] - + HCOOH Phase k: 1 - [(2-chloropyridin-4-yl) methyl] -3- [1 - (N-cyclopentylglycyl) -3,3-dimethyl-2, 3-dihydro-1 H -indol-6-yl] -5,5-dimethylimidazolidine-2,4-dione A solution of 3,423 g of 3- [1 - (chloroacetyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -1 - [(2-chloropyridin-4-yl) methyl ] -5,5-dimethylimidazolidine-2,4-dione obtained in step j) later in 42 ml of cyclopentylamine is heated at 70 ° C for 4 h. The The reaction mixture is then concentrated under reduced pressure and the residue is taken up in 100 ml of water and extracted 3 times with 60 ml of ethyl acetate. The organic phases gathered, they are then washed with water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 3.5 g of 1 - [(2-chloropyridin-4-yl) methyl] -3- [ 1 - (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethylimidazolidin-2,4-dione whose characteristics are as follows: NMR spectrum 1 H at 400 MHz: from 1.25 to 1.78 (m, 8H); 1.32 (s, 6H); 1.40 (s, 6H); 2, 00 (extended m, 1 H); 3.05 (m, 1 H); 3.48 (s, 2H); 3.91 (s, 2H); 4.63 (s, 2H); 7.09 (dd, J = 1.5 and 8.5 Hz, 1 H); 7.36 (d, J = 8.5 Hz, 1 H); 7.45 (broad d, J = 5.5 Hz, 1 H); 7.58 (broad s, 1 H); 8.08 (broad s, 1 H); 8.38 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 524 [M + H] +; m / z = 568 [MH] - + HCOOH Phase i: 3- [1 - (chloroacetyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -1 - [(2 -chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione A solution of 798 mg of 1 - [(2-chloropyridin-4-yl) methyl] -3- (3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl) -5,5- dimethylimida2olidine-2,4-dione obtained in phase i) later in 40 ml of dichloro-1,2-ethane are introduced 295 μ? of diisopropylamine. The solution is cooled to -20 ° C under argon then 226 mg of chloroacetyl chloride are added dropwise. The reaction mixture is then stirred for 1.5 hours at 0 ° C. After adding diethyl ether, the medium is concentrated under reduced pressure and 1.2 g of a mixture containing mainly 3- [1- (chloroacetyl) -3,3-dimethyl-2,3-dihydro-1 H- is obtained. indol-6-yl] -1 - [(2-chloropyridin-4-ii) methyl] -5,5-dimethylimidazolidine-2,4-dione in the form of a brown paste whose characteristics are as follows: RfCCM silica = 0, 35 [dichloromethane / methanol 95/5 by volume] Phase i: 1 - [(2-chloropyridin-4-yl) methyl] -3- (3,3-dimethyl-2,3-dihydro-1 H-indol-6 -yl) -5,5-dimethylimidazolidine-2,4-dione To a solution of 2.65 g of 3- (1-acetyl-3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5- dimethylamidazolidine-2,4-dione obtained in step h) later in 30 ml of dioxane, 33 ml of an aqueous solution of 1 N hydrochloric acid are added. The reaction mixture is heated at 70 ° C for seventeen hours and concentrated under reduced pressure. The residue is diluted with 30 ml of water and poured into an aqueous solution saturated in sodium bicarbonate, the precipitate formed is filtered, washed four times with 10 ml of water and dried to give 2.3 g of 1 - [ (2-chloropyridin-4-yl) methyl] -3- (3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl) -5,5-dimethylimidazolidine-2,4-dione in the form of a beige solid whose characteristics are the following: LC S: TR = 6.34 min; m / z = 399 [M + H] +; Step h: 3- (1-acetyl-3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5 -dimethylimidazolidine-2,4-dione To 949 mg of sodium hydride, 5 ml of dimethylformamide are added dropwise under argon, then a solution of 6.8 g of 3- (1-acetyl-3,3-dimethyl-2,3-dihydro-1 H-) is added. indol-6-yl) -5,5-dimethylimidazolidine-2,4-dione obtained in step g) a then 40 ml of dimethylformamide. The obtained solution is stirred for 1.5 hours at 25 ° C then 5.24 g of 2-chloro-4-chloromethyl pyridine obtained in step b) is added below. The reaction mixture is stirred at room temperature for 15 hours and diluted with 300 ml of water, the solid formed is filtered, washed three times with 20 ml of water and twice with 20 ml of diethyl ether and dried to give 8 ml of water. , 8 g of 3- (1-acetyl-3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl) -1 - [(2-chloropyridin-4-yl) methyl] -5, 5-dimethylimidazolidine-2,4-dione in the form of a beige solid whose characteristics are the following: Mass spectrum (ES): m / z = 441 [M + H] +; Phase q: 3- (1-acetyl-3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl) -5,5-dimethylimidazolidine-2,4-dione A solution of 6.6 g of 1,1 '-carbonylbis (1 H-imidazole) and of 460 mg of 1 H-imidazole in 50 ml of tetrahydrofuran is stirred under argon and cooled in an ice bath at 0 ° C. To this solution is added a suspension of 6.9 g of 1-acetyl-3,3-dimethylindolin-6-amine obtained in step f) then in 50 ml of tetrahydrofuran. After an hour of agitation, 9.5 ml of triethylamine and 5.2 g of methyl 2-methylalaninate hydrochloride and the mixture is stirred for two hours at room temperature, then refluxed for 7 hours. After returning to room temperature, the mixture is diluted with 800 ml of water, the precipitate formed is filtered, washed four times with 25 ml of water and three times with 15 ml of diethyl ether, then dried to give 8 g. of 3- (1-acetyl-3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl) -5,5-dimethylimidazolidine-2,4-dione in the form of a beige solid whose characteristics are the following: LCMS: TR = 3.19 min; m / z = 316 [M + H] +; m / z = 314 [-H] "Phase f: 1-acetyl-3,3-dimethylindolin-6-amine In a hydrogenation reactor 1.46 g of 10% palladium on carbon, 8.8 g of 1-acetyl-3,3-dimethyl-6-nitroindoline obtained in step e) below and 1 10 ml of ethanol. After the reaction for one hour and ten minutes under 3 bar at a temperature of 25 ° C, the reaction medium is filtered on paper, concentrated under reduced pressure to give 6.9 g of 1-acetyl-3,3- dimethyl indolin-6-amine in the form of a brown solid whose characteristics are as follows: LCMS: TR = 1.12 min; m / z = 205 [M + H] +; Phase e: 1-acetyl-3,3-dimethyl-6-nitroindoline To a solution of 5.2 g of N- (2-bromo-5-nitrophenyl) -N- (2-methylprop-2-en-1-yl) acetamide obtained in step d) below in 140 ml of dimethylformamide 2.12 g of?,?,? - triethyleneteammonium chloride, 1.4 g of sodium formate and 3.4 g of sodium acetate are added. After thirty minutes of stirring under argon at room temperature, 41.0 mg of palladium diacetate is added and the mixture is heated at 80 ° C for five hours. After returning to room temperature, the reaction mixture is diluted with one liter of water, the solid formed is filtered and washed four times with 40 ml of water. The solid is then dissolved in 200 ml of ethyl acetate, dried over magnesium sulfate in the presence of 0.5 g of charcoal, filtered and concentrated under reduced pressure to give 3 g of 1-acetyl-3, 3-dimethyl-6-nitroindoline in the form of a beige-yellow solid whose characteristics are the following: Mass spectrum (IE): m / z = 234 M + Phase d: N- (2-bromo-5-nitrophenyl) -N- (2-methylprop-2-en-1-yl) acetamide To a suspension of 1.34 g of sodium hydride in 10 ml of dimethylformamide under argon is added dropwise at 0 ° C, a solution of 5.8 g of N- (2-bromo-5-nitrophenyl) acetamide obtained in step c) then in 90 ml of dimethylformamide and the reaction medium is stirred at this temperature for 1 hour. 3.3 ml of 3-chloro-2-methylprop-1-ene are then added, then the mixture is heated at 60 ° C for 2 hours. After returning to room temperature, the mixture is diluted with one liter of water and extracted four times with 80 ml of ethyl acetate. The combined organic phases are washed three times with 50 ml of an aqueous solution saturated in sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (80/20 by volume) to give 5.2 g of N- (2-bromo-5-nitrophenyl) -N- ( 2-methylprop-2-en-1-yl) acetamide in the form of a yellow solid whose characteristics are the following: Mass spectrum (IE): m / z = 31 2 M + Phase c: N- (2-bromo-5 -nitrophenyl) acetamide In a microwave oven reactor 2.8 g of 2-bromo-5-nitroaniline are solubilized in 18 ml of acetic anhydride. After sealing the reactor and one hour at 60 ° C under microwave irradiation, the solid is filtered, then washed three times with 10 ml of diethyl ether and dried to give 3 g of N- (2-bromo- 5-nitrophenyl) acetamide in the form of a beige solid whose characteristics are as follows: LCMS: TR = 3.05. min; m / z = 259; 261 [M + H] + (presence of a bromine) Phase b): 2-chloro-4-chloromethyl-pyridine To a solution of 1.1 g of 2-chloro-4-hydroxymethyl-pyridine obtained in step a) in 200 ml of dichloromethane are added dropwise 6.896 ml of thionyl chloride and then 2.1 ml of dimethylformamide. , the reaction mixture is stirred for 3 hours at room temperature, then 50 ml of water are added dropwise. The phases are separated and the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 12.8 g of 2-chloro-4-chloromethyl-pyridine in the form of an amber liquid. used such which without further purification. RfCCM silica = 0.44 (eluent dichloromethane). Phase a): 2-chloro-4-hydroxymethyl-pyridine 78.78 g of 2-chloroisonicotinic acid are added under argon, in portions, to 300 ml of a 2 M solution of dimethylsulfide-borane in tetrahydrofuran. The reaction mixture is stirred for 1 7 hours at room temperature, then treated successively with 20 ml of water dropwise and 20 ml of 5 N hydrochloric acid. 300 ml of ethyl acetate are then added, the phases are separated. and the organic phase is washed 3 times with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is then concentrated under reduced pressure to give 68.6 g of 2-chloro-4-hydroxymethyl-pyridine as a pale yellow solid. RfCCM silica = 0.38 (eluent dichloromethane / methanol 90/10 by volume). Example 4: 3- [1 - (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione To a solution of 0.312 g of [2- (6- { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-dirnethyl-2,5-dioxoirnidazolidin-1-yl.} - 3,3-dimethyl-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -cyclopentylcarbamate tere-butyl obtained in phase I) of example 3 in 12 ml of dioxane are added successively under argon , 0.094 g of 3-aminopyridine, 0.028 g of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 0.022 g of palladium acetate and 0.65 g of carbonate of cesium. The reaction mixture is refluxed for 4 h, then filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 10 ml of dioxane, then 12 ml of a 4 N solution of hydrochloric acid in dioxane are added and the reaction mixture is stirred at room temperature for 15 h. After concentration under reduced pressure the residue is taken up in 40 ml of water, neutralized by the addition of sodium bicarbonate and extracted 3 times with 25 ml of dichloromethane. The combined organic phases are then washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is disaggregated with diethyl ether and the solid obtained is filtered and dried to give 0.12 g of 3- [1- (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1H-indole. -6-yl] -5,5-dimethyl-1-. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: From 1.28 to 1.78 (m, 8H); 1.32 (s, 6H); 1.42 (s, 6H); 2.10 (extended m, 1H); 3.06 (m, 1H); 3.48 (s wide, 2H); 3.91 (s, 2H); 4.55 (s, 2H); 6.82 (broad d, J = 5.5 Hz, 1 H); 6.84 (broad s, 1 H); 7.08 (dd, J = 2.0 and 8.0 Hz, 1 H); 7.28 (dd, J = 5.0 and 8.5 Hz, 1 H); 7.39 (d, J = 8.0 Hz, 1 H); 8.08 (broad d, J = 5.0 Hz, 1 H); 8, 1 3 (d, J = 5.5 Hz, 1 H); 8.21 (broad d, J = 8.0 Hz, 1 H); 8.79 (d, J = 2.0 Hz, 1 H); 9.21 (s, 1 H). Mass spectrum (ES): m / z = 582 [M + H] +; Example 5a: (2R) -2-amino-N- [5- (4,4-dimethyl-2,5-dioxo-3. {[2- (pyridin-3-ylamino) pyridin-4- il] methyl.}. imidazolidin-1-yl) -2- (trifluoromethoxy) phenyl] -2-phenylacetamide Phase ___ el: (2R) -2-amino-N- [5- (4,4-dimethyl-2,5-dioxo-3 { [2- (pyridin-3-ylamino) pyridin -4-yl] methyl.}. Imidazolidin-1-yl) -2- (trifluoromethoxy) phenyl] -2-phenylacetamide To a solution of 33 mg of (2R) -2-amino-N- [5 -. { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl} -2- (trifluoromethoxy) phenyl] -2-phenylacetamide, step d) then in 1 ml of dioxane are added successively under argon, 7 mg of 3-aminopyridine, 3 mg of (9,9-dimethyl-9H-xanthene) -3,6-diyl) bis (diphenylphosphine) (Xantphos), 1.1 mg of palladium acetate and 61 mg of cesium carbonate. The reaction mixture is heated to 110 ° C for 1 h, filtered, washed twice with 10 ml of dioxane, then the filtrate is concentrated under reduced pressure. The residue is taken up in 1 ml of dioxane, then 1 ml of a 4 N solution of hydrochloric acid in dioxane is added and the reaction mixture is stirred at 40 ° C for 2 h. The reaction mixture is then treated with 30 ml of a saturated solution of sodium bicarbonate and extracted 3 times with 30 ml of ethyl acetate. The combined organic phases are then washed with water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 12 mg of (2R) -2-amino-N- [5- (4,4-dimethyl-2,5- dioxo-3- { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. imidazolidin-1-yl) -2- (trifluoromethoxy) phenyl] -2-phenylacetamide whose characteristics are as follows : 1 H NMR spectrum at 400 Hz: 1.42 (s, 6 H); 4.54 (s, 2H); 4.62 (s, 1H); 6.82 (m, 2H); from 7.22 to 7.38 (m, 5H); 7.42 (broad d, J = 8.5 Hz, 2H); 7.60 (broad d, J = 9.0 Hz, 1H); 8.07 (dd, J = 1.5 and 5.5 Hz, 1H); 8.12 (d, J = 5.5 Hz, 1H); 8.19 (ddd, J = 1.5-2.5 and 8.5 Hz, 1H); 8.27 (s, 1H); 8.32 (d, J = 2.5 Hz, 1H); 8.76 (d, J = 2.5 Hz, 1H); 9.17 (s, 1H). Mass spectrum (ES): m / z = 620 [+ H] +; m / z = 1261 [2M + Na] + Phase d): (2R) -2-amino-N- [5-3 - [(2-chloropyridin-4-yl.) methyl] -4,4-dimethyl -2,5-dioxoimidazolin-1-yl] -2- (trifluoromethoxy) phenyl] -2-phenylacetamide To a solution of 0.6 g of DN-Boc-phenylglycine in 12 ml of dimethylformamide is added 0.74 g of O- (benzotriazole-1-N-N-N'-N'-tetramethyluronium tetrafluoroborate (TBTU). After stirring for 5 minutes, 0.837 ml of triethylamine and 0.86 g of 3- [3-amino-4- (trifluoromethoxy) phenyl] -1 - [(2-chloropyridin-4-yl) methyl are successively added. ] -5,5-dimethylimidazolidine-2,4-dione obtained in step c) below. The reaction mixture is heated at 70 ° C for 1 5 hours, then poured into 100 ml of water. The aqueous phase is extracted 3 times with 70 ml of ethyl acetate and the combined organic phases are washed with 50 ml of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and ethyl acetate (70/30 by volume) to give 220 mg of (2R) - (2-amino-N- [5- (3- [ (2-chloropyridin-4-yl) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl.} -2- (trifluoromethoxy) phenyl] -2-phenylacetamide whose characteristics are the following: NMR spectrum 1 H at 400 Hz: 1.40 (s, 15H), 4.62 (s, 2H), 5.53 (broad d, J = 8.0 Hz, 1 H), 7.25 to 7.41 (m, 4H); 7.46 (broad d, J = .5 Hz, 1 H); from 7.48 to 7.56 (m, 4H); 7.59 (broad s, 1 H); 8.00 (d, J = 2.0 Hz, 1 H); 8.37 (d, J = 5.5 Hz, 1 H); 10.0 (s, 1 H). Mass spectrum (ES): m / z = 662 [M + H] +; Step c): 3- [3-amino-4- (trifluoromethoxy) phenyl] -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-midazolidine-2,4-dione To a solution of 4.9 g of 3- [3-amino-4- (trifluoromethoxy) phenyl] -5,5-dimethyl-imidazolidine-2,4-dione obtained in step b) then in 200 ml of dimethylformamide 0.68 g of 60% sodium hydride are added under argon and the stirring is continued 20 minutes at room temperature. In this solution, 2.85 g of 2-chloro-4-chloromethyl pyridine obtained in phase b) of Example 3 are added in solution in 20 ml of dimethylformamide, the reaction mixture is then heated at 70 ° C for 3, 5 hours, then it is poured into 500 ml of ice water and extracted 3 times with 300 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in 500 ml of diethyl ether, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give 6.8 g of 3- [3-amino-4- (trifluoromethoxy) phenyl) ] -1 - [(2-chloropyridin-4-yl) methyl] -5,5- dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.39 (s, 6H); 4.62 (s, 2H); 5.59 (s, 2H); 6.62 (dd, J = 2.5 and 8.5 Hz, 1 H); 6.90 (d, J = 2.5 Hz, 1 H); 7.20 (broad d, J = 8.5 Hz, 1 H); 7.43 (broad d, J = 5.5 Hz, 1 H); 7.56 (broad s, 1 H), 8.37 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 429 [M + H] +; Step b): 3- [3-amino-4- (trifluoromethoxy) phenyl] -5,5-dimethylimidazolidine-2,4-dione To a suspension of 6 g of 5,5-dimethyl-3- [3-nitro-4- (trifluoromethoxy) -phenyl] imidazolidine-2,4-dione obtained in step a) below in 180 ml of concentrated hydrochloric acid 33 g of zinc powder are added per serving. The reaction mixture is heated at 50 ° C for 5 hours then cooled to room temperature and poured into a mixture of 500 ml of ethyl acetate and 200 ml of water. A solution of 5 N sodium hydroxide is then added until pH 8, then the solid formed is filtered on celite and the solid is washed with ethyl acetate. The phases are separated and the aqueous phase is washed with ethyl acetate and the combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 4.96 g of 3- [3- amino-4- (trifluoromethoxy) phenyl] -5,5-d-rimethylimidazolidine-2,4-dione in the form of a beige powder. RfCCM silica = 0.1-8 [dichloromethane / methanol 95/5 by volume] Phase a): 5,5-dimethyl-3- [3-nitro-4- (trifluoromethoxy) phenyl] imidazolidine-2,4-dione To a solution of 15 ml of trichloromethyl chloroformate (diphosgene) in 500 ml of toluene is added 3 g of black 3S. To this suspension cooled to -20 ° C is added 20 g of 3-nitro-4-trifluoromethoxy aniline in solution in 400 ml of toluene. The reaction mixture is heated progressively at room temperature, then it is refluxed for 4 hours. After cooling to room temperature, a suspension of 18 g of dimethyl glycine ethyl ester hydrochloride in 150 ml of toluene is added, followed by 66 ml of triethylamine and the reaction mixture is refluxed for 15 hours. After filtration on celite, the filtrate is concentrated under reduced pressure and the residue is taken up in 500 ml of dichloromethane, washed 3 times with 1000 ml of water, dried over magnesium sulfate, filtered and concentrated under pressure. reduced. The residue is then disaggregated into diethyl ether and the solid formed is filtered and dried to give 7.8 g of 5,5-dimethyl-3- [3-nitro-4- (trifluoromethoxy) phenyl] -imidazolidine-2, 4- diona whose characteristics are the following: 1 H NMR spectrum at 300 Hz: 1, 42 (s, 6H); 7.90 (qd, J = 1.0, and 9.0 Hz, 1 H); 8.00 (dd, J = 3.0 and 9.0 Hz, 1 H); 8.37 (d, J = 3.0 Hz, 1 H); 8, 75 (broad s, 1 H). Mass spectrum (ES): m / z = 332: [-H] "Example 5b: (2R) -2-amino-N-. {5- (4,4-dimethyl-2,5-dioxo-3 - { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. Imidazolidin-1-yl) -2- [(trifluoromethyl) thio] phenyl] -2-phenylacetamide Phase f: (2R) -2-amino-N-. { 5- (4,4-dimethyl-2,5-dioxo-3 { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. Imidazolidin-1-yl) -2- [ (trifluoromethyl) thio] phenyl} -2-phenylacetamide. To a solution 33 mg of (2R) -N- (5- { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl.} -2- [(trifluoromethyl) thio] phenyl) -2 - [(9H-fluoren-9-ylacetyl) amino] -2-phenylacetamide obtained in step e) then in 1 ml of dioxane are added successively under argon, 14 mg of 3-aminopyridine, 3 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 1.1 mg of palladium acetate and 61 mg of cesium carbonate . The reaction mixture is heated to 1 10 ° C for 3 h, it is filtered, washed twice with 10 ml of dioxane, then the filtrate is concentrated under reduced pressure. The residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 5 mg of (2R) -2-amino-N- [5- (4,4-dimethyl-2,5- dioxo-3- { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. imidazolidin-1-yl) -2- (trifluoromethyl) thio] phenyl] -2-phenylacetamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 4.54 (s, 2H); 4.59 (s, 1H); 5.67 (very widespread m, 2H); 6.82 (m, 2H); from 7.22 to 7.31 (m, 2H); 7.34 (broad t, J = 7.5 Hz, 2H); 7.40 (dd, J = 2.5 and 8.5 Hz, 1H); 7.43 (broad d, J = 7.5 Hz, 2H); 7.89 (d, J = 8.5 Hz, 1H); 8.08 (dd, J = 1.5 and 5.5 Hz, 1H); 8.12 (m, H); 8.20 (ddd, J = 1.5-2.5 and 8.5 Hz, 1H); 8.33 (broad s, 1H); 8.43 (d, J = 2.5 Hz, 1H); 8.76 (d, J = 2.5 Hz, 1H); 9.18 (s, 1H). Mass spectrum (ES): m / z = 636 [M + H] +; m / z = 634 [MH] "Phase e): (2R) -N- (5- { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-dimethyl-2,5- dioxoimidazolin-1-yl] -2 - [(trifluoromethyl) thio] phenyl-2 - [(9H-fluoren-9-ylacetyl) amino] -2-phenylacetamide To a solution of 210 mg of 3-. { 3-amino-4 - [(trifluoromethyl) thio] phenyl} -1 - [(2-chloropyridin-4-yl) methyl] -5,5- dimethylimidazolidine-2,4-dione obtained in step d) below and 183 mg of DNF-OC-phenylglycine in 4.5 ml of dichloro-1,2-ethane heated at 95 ° C are added in succession 2 drops of dimethylformamide and 72 μ? of thionyl chloride. The heating is continued for 2.5 hours, then the solvent is concentrated under reduced pressure and the residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (98/2 by volume). The yellow residue obtained is purified again by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 145 mg of (2R) -N- (5-. {3 - [(2-chloropyridin- 4-yl) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl.} -2 - [(trifluoromethyl) thio] phenyl) -2 - [(9H-fluoren-9-ylacetyl) amino] ] -2-phenylacetamide whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.40 (s, 6H); from 4.19 to 4.32 (m, 3H); 4.64 (s, 2H); 5.54 (d, J = 8.0 Hz, 1H); from 7.22 to 7.51 (m, 10H); 7.58 (d, J = 7.5 Hz, 2H); 7.60 (s, 1H); 7.78 (broad m, 2H); from 7.80 to 7.92 (m, 3H); 8.30 (broad d, J = 8.0 Hz, 1H); 8.36 (d, J = 5.5 Hz, 1 HOUR); 10.3 (s, 1H). Mass spectrum (ES): m / z = 800 [+ H] + m / z = 798 [M-H] 'Phase d): 3-. { 3-amino-4- (trifluoromethyl) thio] phenyl} -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-imidazolidine-2,4-dione To a solution of 0.4 g of 3- [3-amino-4- (trifluoromethyl) thio] phenyl} -5,5-dimethylimidazolidine-2,4-dione obtained in step c) then in 20 ml of dimethylformamide are added under argon 53 mg of 60% sodium hydride and stirring is continued for 20 minutes at room temperature. In this solution, 2.85 g of 2-chloro-4-chloromethyl pyridine obtained in phase b) of Example 3 are added in solution in 5 ml of dimethylformamide, the reaction mixture is then heated at 70 ° C for 3 hours., 5 hours, then it is poured into 100 ml of ice water and extracted 3 times with 1 00 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in 100 ml of diethyl ether, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give 500 mg of 3-. { 3-amino-4 - [(trifluoromethyl) thio] phenyl} -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.40 (s, 6H); 4.63 (s, 2H); 6.01 (broad s, 2H); 6.70 (dd, J = 2.5 and 8.0 Hz, 1 H); 6.94 (d, J = 2.5 Hz, 1 H); from 7.40 to 7.50 (m, 2H); 7.58 (broad s, 1 H); 8.39 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 445 [M + H] +; m / z = 443 [M-H] -; m / z = 489 [M-H] + HCOOH Phase gjj. 3-. { 3-amino-4 - [(trifluoromethyl) thio] phenyl} -5,5-dimethylimidazoiidine-2,4-dione To a suspension of 1.75 g of 5,5-dimethyl-3-. { 3-Nitro-4 - ((trifluoromethyl) thio] phenyl.} - imidazolidine-2,4-dione obtained in step b) then in 60 ml of concentrated hydrochloric acid are added, per portion, 7.5 g of zinc powder. The reaction mixture is heated at 50 ° C for 8 hours then cooled to room temperature and poured into a mixture of 100 ml of ethyl acetate and 20 ml of water. A solution of 5 N sodium hydroxide is then added until pH 8, then the solid formed is filtered on celite and the solid is washed with ethyl acetate. The phases are separated and the aqueous phase is washed with ethyl acetate and the combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 400 mg of 3-. { 3-amino-4 - [(trifluoromethyl) thio] phenyl} -5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.39 (s, 6H); 5.98 (s, 2H); 6.62 (dd, J = 2.5 and 8.0 Hz, 1 H); 6.85 (d, J = 2.5 Hz, 1 H); 7.44 (d, J 8.0 Hz, 1 H); 8, 56 (broad s, 1 H). Step bJi 5,5-dimethyl-3-. { 3-Nitro-4- (trifluoromethyl) thio] phenyl} imidazolidine-2,4-dione To a solution of 3.8 g of 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidine-2,4-dione obtained in step a) then in 7 ml of concentrated sulfuric acid a mixture of nitric acid (0.75 ml) in 3 ml of concentrated sulfuric acid is added dropwise at -5 ° C. . After stirring for 4 hours at 0 ° C (ice bath) the mixture is poured onto 1 50 g of ice and the pH is raised to 10 by the addition of concentrated ammonia. The aqueous phase is then extracted 2 times with 1 50 ml of ethyl acetate and the combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 1.8 mg of 5,5-dimethyl-3-. { 3-Nitro-4 - [(trifluoromethyl) thio] phenyl} imidazolidine-2, 4-dione whose characteristics are the following: 1 M NMR spectrum at 400 MHz: 1.41 (s, 6H); 7.80 (d, J = 8.5 Hz, 2H); 8.00 (d, J = 8.5 Hz, 2H); 8.71 (broad s, 1 H).

Step a): 5,5-dimethyl-3-. { 4-f (trifluoromethyl) thiol-enyl} imidazolidine-2,4-dione To a solution of 8.5 ml of trichloromethyl chloroformate (diphosgene) in 250 ml of toluene is added 1.8 g of black 3S. To this suspension cooled to -20 ° C is added 1 g of 4-trifluoromethylthio aniline in solution in 160 ml of toluene. The reaction mixture is heated progressively to room temperature, then brought to reflux for 4 hours. After cooling to room temperature, a suspension of 9.4 g of dimethyl glycine ethyl ester hydrochloride in 90 ml of toluene is added, followed by 38 ml of triethylamine and the reaction mixture is refluxed for 15 hours. After filtration on celite, the filtrate is concentrated under reduced pressure and the residue is taken up in 200 ml of dichloromethane, washed 3 times with 100 ml of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. . The residue is then disaggregated in diethyl ether and the solid formed is filtered and dried to give 12 g of 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidine-2,4-dione whose characteristics are the following: Spectrum R N 1 H at 400 MHz: 1.40 (s, 6H); 7.60 (d, J = 8.5 Hz, 2H); 7.82 (d, J = 8.5 Hz, 2H); 8.65 (broad s, 1 H). Mass spectrum (IE): m / z = 304 [M] +; m / z = 219 [M] + - CONHCH (CH 3) 2; m / z = 150 [219] + -CF3 Example 6a (2R) -2-amino-N-. { 5- [(dimethylcarbamoyl) amino] pyridin-4-yl} methyl) -4,4-dimethyl-2,5-dioxoimidazolin-1 -yl] -2- (trifluoromethoxy) phenyl} -2-phenylacetamide To a solution of 150 mg of (2R) -2-amino-N- [5-. { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl} -2- (trifluoromethoxy) phenyl] -2-phenylacetamide obtained in step d) of example 5a in 10 ml of dioxane are successively added under argon, 30 mg of N, N-dimethylurea, 13 mg of (9.9- dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 5 mg of palladium acetate and 280 mg of cesium carbonate. The reaction mixture is refluxed for 1 h, then filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 10 ml of dioxane, then 5 ml of a 4 N solution of hydrochloric acid in dioxane are added and the reaction mixture is stirred at 40 ° C for 1 h. After concentration under reduced pressure, the residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 45 mg of (2R) -2-amino-N-. { 5 [3- (2- [(dimethylcarbamoyl) amino] pyridin-4-yl} methyl) 4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) -2- (trifluoromethoxy) phenyl} -2-phenylacetamide whose characteristics are the following: NMR spectrum 1 H at 400 MHz: 1.39 (s, 6H); 2, 92 (s, 6H); 4.56 (s, 2H); 4.62 (s, 1 H); 6.98 (dd, J = 1.5 and 5.5 Hz, 1 H); from 7.23 to 7.38 (m, 4H); 7.42 (broad d, J = 8.5 Hz, 2H); 7.58 (broad d, J = 9.0 Hz, 1 H); 7.82 (broad s, 1 H); 8, 15 (d, J = 5.5 Hz, 1 H); 8,19 (s, 1 H); 8.29 (d, J = 2.5 Hz, 1 H); 8.79 (broad s, 1 H). Mass spectrum (ES): m / z = 612 [M-H] '; m / z = 614 [M + H] +; Example 6b: (2R) -2-amino-N-. { 5- [3- (. {2- [(di methylcarbamoM) amino] pyridin-4-yl} methyl) -4,4-d-methyl 1-2,5-d-oxoimidazolidin-1-yl] -2 - [(trifluoromethyl) thio] phenyl} -2-phenylacetamide The product is prepared as in Example 5b by substituting 3-aminopyridine for the α, β-dimethyl urea to give the (2R) -2-amino-N-. { 5- [3- ( {2 - [(dimethylcarbamoyl) -amino] pyridin-4-yl}. Methyl) -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl] -2 - [( trifluoromethyl) thio] -phenyl} -2-phenylacetamide whose characteristics are the following: LCMS: TR = 3.09 min; m / z = 609 [M + H] +; m / z = 607 [M-H] 'Example 7: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (pyrimidin-5- ilamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione Phase d: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione To a solution; of 200 mg of 1 - [(2-aminopyridin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione hydrochloride obtained in step c) below in 5 ml of dioxane, 1 mg of palladium diacetate, 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (xantphos), 777 mg, are successively added under argon, 11 mg. of cesium carbonate and 86.8 mg of 5-bromopyrimidine. The reaction mixture is heated at 100 ° C for 5 h, then filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane, methanol and ammonia (95/4/1 by volume) to give 135 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl- 1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione as a faded white solid whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 42 (s, 6H); 4.58 (s, 2H); 6.88 (broad s, 1 H); 6.90 (broad d, J = 5.5 Hz, 1 H); 7.36 (d width, J = 9.0 Hz, 2H); 7.52 (broad d, J = 9.0 Hz, 2H); 8, 18 (d, J = 5.5 Hz, 1 H); 8.70 (s, 1 H); 9, 13 (s, 2H); 9.44 (s, 1 H) Mass spectrum (ES): m / z = 445 [M + H] + (base peak) Phase c: 1 - [(2-aminopyridin-4-yl) hydrochloride ) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione To a solution of 1.8 g of N- (4- {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyridine- 2-yl) acetamide obtained in step b) then in 20 ml of dioxane, 20.8 ml of a 1 N hydrochloric acid solution are added. The mixture is heated at 75 ° C for six hours, then 42 ml of the 1 N hydrochloric acid solution is added and the stirring is maintained for thirty-six hours at the same temperature. The solution is then concentrated under reduced pressure to give 1.4 g of 1 - [(2-aminopyridin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine hydrochloride. , 4-dione in the form of white powder whose characteristics are the following: LCMS: TR = 3.25 min; m / z = 367 [M + H] + -HCI Phase b: N- (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl ] methyl.}. pyrimidin-2-yl) acetamide To a solution of 400 mg of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a) a Then, in 12 ml of dioxane, 23.3 mg of palladium diacetate, 72 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) [xantphos], 1 are added successively under argon. 18 mg of cesium carbonate and 153 mg of acetamide. After an hour of heating at a temperature close to 90 ° C and chromatography on a silica column eluting with a mixture of diethyl oxide / ethyl acetate (gradient up to 100% ethyl acetate), 370 mg of N- are obtained. (4- {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyridin-2-yl) acetamide in the form of white crystals whose Characteristics are the following: LCMS: TR = 3.95 min; m / z = 409 [M + H] +; Step a: 3- (4-tert-Butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione To a suspension of 1.1 g of sodium hydride in 40 ml of dimethylformamide in argon are added successively 4.9 g of 3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione obtained in step c) of Example 1 and 4.55 g of 2-chloro-4- (chloromethyl) pyridine. The reaction mixture is stirred for 48 h at room temperature, then diluted with 260 ml of water. The solid formed is filtered, rinsed with disproportional ether and dried to give 4.61 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5, 5-Dimethylimidazolidine-2,4-dione in the form of a beige powder whose characteristics are the following: Mass spectrum (ES): m / z = 386 [M + H] +; m / z = 430 [M-H + HCOOH] - Example 8: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione A solution of 150 mg of 1 - [(2-aminopyrimidin-4-yl) methyl] -3- (4-tert-but-methyl) -5,5-dimethylimidazolidine-2,4-dione obtained in step f) of the Example 1 in 10 ml of dioxane are added successively under argon, 18 mg of palladium diacetate, 56 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 505 mg of cesium carbonate and 129 mg of 5-bromopyridine. The reaction mixture is heated at 90 ° C for 8 h, then filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane, acetonitrile and methanol (96/2/2 by volume) to give 45 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl. -1 -. { [2- (pyrimidin-5-ylami no) pyrimidin-4-yl] methyl} imidazolidine-2,4-dione in the form of white crystals whose characteristics are the following: MR spectrum N 1 H at 400 M Hz: 1.31 (s, 9H); 1, 43 (s, 6H); 4.63 (s, 2H); 7.04 (d, J = 5.0 Hz, 1 H); 7, 39 (broad d, J = 8, 5 Hz, 2H); 7.51 (broad d, J = 8.5 Hz, 2H); 8.52 (d, J = 5.0 Hz, 1 H); 8.78 (s, 1 H); 9, 19 (s, 2H); 10.0 (s, 1 H) Mass spectrum (ES): m / z = 446 [M + H] + (base peak); m / z = 444 [M-H] "(base peak) Examples 2 to 8 whose names and structures are described below, are prepared as indicated in the general schemes above in example 1.

The present invention mainly comprises the products of formula (I) which belong to the following formula: that N R4R5 has the meaning indicated above. The products of formula (la) can be prepared mainly as indicated in General Scheme 2 (comds P and M). Examples of products having different NR4R5 radicals according to the present invention are indicated below: these products form part of the invention. eg 9 ex 10 ex 11 ß '1? Example 9: 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) -3 - (3-pyrrolidin-1-ylpropyl) urea Step c: 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) -3 - (3-pyrrolidin-1-ylpropyl) urea To a solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2.4 ] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) then in 2 ml of dimethyl sulfoxide are added 120 mg of 3- pyrrolidin-1-ylpropan-1-amine. The solution is stirred at a temperature of 100 ° C for one hour and forty minutes. After returning to a temperature close to 20 ° C, the reaction medium is diluted with water, the suspension is filtered and the precipitate is purified by chromatography on a column of silica eluting with a dichloromethane / methanol / aqueous ammonia 28% mixture. (gradient from 100/0 to 75/20/5 in volume). There is obtained 1 8.5 mg of 1- (4- {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyridin-2. -yl) -3- (3-pyrrolidin-1-ylpropyl) urea in the form of a pale yellow powder whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.40 (s, 6H); from 1.57 to 1.70 (m, 6H); 2.41 (m, 6H); 3.21 (q, J = 6.5 Hz, 2H); 4.56 (s, 2H); 6.92 (broad d, J = 5.5 Hz, 1 H); 7.31 (broad s, 1 H); 7.34 (broad d, J = 8.5 Hz, 2H); 7.51 (broad d, J = 8.5 Hz, 2H); 8,11 (d, J = 5.5 Hz, 1 H); 8.27 (broad m, 1 H); 9, 1 3 (s, 1 H) Mass spectrum (ES): m / z = 521 [M + H] + (base peak); m / z = 519 [-H] "(base peak) Phase b: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2.4 ] oxadiazolo [2,3-a] (pyridin-7-yl) methyl] imidazolidine-2,4-dione To a solution of 240 mg of N- (4- {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimida2olidin-1-yl] methyl} -1-oxidopyridin -2-yl) acetamide obtained in step a) then in 10 ml of ethanol, 109 mg of sodium bicarbonate and 75 mg of thiocarbonyl dichloride are added. After two hours and thirty minutes of stirring, the solid in suspension is filtered, washed with ethanol and dried. 220 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H-1, 2,4-yl] oxodiazolo [2,3-a] pyridin-7 are obtained -yl) methyl] imidazolidine-2,4-dione in the form of a beige powder having the following characteristics: Mass spectrum (ES): m / z = 425 [M + H] +; m / z = 423 [MH] "Phase a: N- (4- { [3- (4-tert-Butylphenyl) -5,5-d, methyl-2,4-dioxoimidazolidin-1-yl] methyl .}. -1. -oxidopyridin-2-yl) acetamide To a solution of 370 mg of N- (4. {[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2 il) acetamide obtained in step a) of Example 7 in 20 ml of dichloromethane are added under argon and with stirring 704 mg of 3- chlorobenzenecarboperoxide. After one hour and thirty minutes of stirring at a temperature close to 20 ° C, 1 56 mg of 3-chlorobenzenecarbo-peroxide acid is added. The solution is stirred overnight, then diluted with dichloromethane, washed three times with a saturated aqueous solution in sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. After chromatography on a silica column eluting with a mixture of dichloromethane / methanol / 28% aqueous ammonia (gradient from 100/0 to 90/9/1 by volume), 280 mg of N- (4-. {[[ 3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl] methyl} -1-oxypyridin-2-yl) acetamide in the form of a yellow wax whose characteristics are the following: Mass spectrum (ES): m / z = 425 [M + H] +; m / z = 423 [MH] "Example 10: 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl. pyridin-2-yl) -3-cyclopentylurea It can be prepared as in step c) of example 9 but to from 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7- il) methyl] -imidazolidine-2,4-dione obtained in phase b) of example 9, 2 ml of dimethyl sulfoxide and 60 mg of cyclopentanoamine. After chromatography on a silica column, eluting with a mixture of diethyl oxide / ethyl acetate (gradient from 100/0 to 0/100 by volume), 33 mg of 1 - (4-. {[3- (4 -tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. pyridin-2-yl) -3-cyclopentylurea in the form of a white powder whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.40 (s, 6H); 1.40 (masked m, 2H); 1.56 (m, 2H); 1.65 (m, 2H); 1.86 (m, 2H); 4.00 (m, 1H); 4.56 (s, 2H); 6.91 (dd, J = 1.5 and 5.5 Hz, 1H); 7.34 (broad d, J = 8.5 Hz, 2H); 7.36 (broad s, 1H); 7.51 (broad d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.18 (broad m, 1H); 9.09 (s, 1 H) Mass spectrum (ES): m / z = 478 [M + H] + (base peak); m / z = 476 [MH] - Example 1 - (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazoridin-1-yl] methyl.} - pyridin-2-yl) -3- (2-pyrrolidin-1-ylethyl) urea It can be prepared as in a phase c) of example 9 but from 100 mg of 3- (4-tert-butylphenyl) -5,5 -dimethyl-1 - [(2-thioxo-2H- [1,2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] -imidazolidine-2,4-dione obtained in step b) of Example 9, 2 ml of dioxane and 32.3 mg of 2-pyrrolidin-1-ilenamine. After chromatography on a silica column eluting with a mixture of dichloromethane / methanol / 28% aqueous ammonia (95/4/1 in volume) gives 42.4 mg of 1- (4. {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyridine 2-yl) -3- (2-pyrrolidin-1-ylethyl) urea in the form of a white powder whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.32 (s, 9H); 1.40 (s, 6H); 1.69 (m, 4H) 2.47 (partially masked m, 4H) 2.52 (partially masked t, J = 6.5 Hz, 2H); 3.27 (c partially masked, J = 6.5 Hz, 2H); 4.56 (s, 2H); 6.91 (dd, J = 1.5 and 5.5 Hz, 1H); 7.34 (broad d, J = 9.0 Hz, 2H); 7.35 (broad s, 1H) 7.51 (broad d, J = 9.0 Hz, 2H); 8.10 (d, J = 5.5 Hz, 1H); 8.24 (broad m, 1H); 9.17 (broad s, 1H). Mass spectrum (ES): m / z = 507 [+ H] +; Example 12: 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) -3 - (3-pyrrolidin-1-ylbutyl) urea It can be prepared as in a phase c) of example 9 but from 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2) -thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] -imidazolidine-2,4-dione obtained in step b) of example 9, of 2 ml of dioxane and 40.2 mg of 4-pyrrolidin-1-ylbutan-1-amine. After chromatography on a silica column, eluting with a mixture of dichloromethane / methanol / 28% aqueous ammonia (95/4/1 by volume), 60.2 mg of 1- (4-. {[3- (4 -tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. pyridin-2-yl) -3- (4-pyrrolidin-1-ylbutyl) urea as a powder white whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.32 (s, 9H); 1.40 (s, 6H); 1.48 (m, 4H); 1.65 (m, 4H); 2.38 (m, 6H); 3.17 (q, J = 6.5 Hz, 2H); 4.56 (s, 2H); 6.92 (broad d, J = 5.5 Hz, 1H); 7.31 (broad s, 1H); 7.34 (broad d, J = 8.5 Hz, 2H); 7.51 (broad d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.25 (broad m, 1H); 9.12 (broad s, 1H). Mass spectrum (ES): m / z = 535 [M + H] + (base peak); m / z = 533 [M-H] - e1 13 ej14 ej15 ei16 Example 13 ,: 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} pyridin -2-yl) -3-cyclopropylurea can be prepared as in step c) of example 9 but from 200 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo -2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] -imidazolidine-2,4-dione obtained in step b) of example 9, of 4 ml of ethanol and of 32.3 mg of cyclopropanoamine. After one hour of heating at a temperature of 50 ° C and chromatography on a silica column eluting with a heptane / ethyl acetate mixture (gradient 100/0 to 0/100 by volume), 76.1 mg of sodium chloride are obtained. - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl] pyridin-2-yl) -3-cyclopropylurea in the form of a white powder whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 0.44 (m, 2H); 066 (m, 2H,); 1.31 (s, 9H). 1.40 (s, 6H); 2.60 (m, 1H); 4.56 (s, 2H); 6.92 (dd, J = 1.5 and .5 Hz, 1H); 7.34 (broad d, J = 8.5 Hz, 2H); 7.36 (broad s, 1H); 7.52 (broad d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.24 (broad m, 1H); 9.09 (broad s, 1H). Mass spectrum (ES): m / z = 450 [M + H] + (base peak) Example 14: 1 - (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl -2,4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) -3-cyclobutylurea It can be prepared as in step c) of example 9 but from 200 mg of 3- (4-tert-butyl). butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1,2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] -imidazolidine-2,4 -dione obtained in step b) of example 9, 4 ml of dioxane and 40.2 mg of cyclobutanamine. After chromatography on a silica column eluting with a heptane / ethyl acetate mixture (gradient from 100/0 to 0/100 by volume), 112.6 mg of 1- (4-. {[3- (4 -tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. pyridin-2-yl) -3-cyclobutylurea in the form of a white powder whose characteristics are as follows: 1 H NMR at 400 MHz: 1.31 (s, 9 H); 1.40 (s, 6H); 1.65 (m, 2H); 1.88 (m, 2H); 2.24 (m, 2H); 4.18 (m, 1H); 4.56 (s, 2H); 6.92 (dd, J = 1.5 and 5.5 Hz, 1H); 7.34 (broad d, J = 8.5 Hz, 2H) 7.35 (broad s, 1H); 7.52 (broad d, J = 8.5 Hz, 2H); 8.13 (d, J = 5.5 Hz, 1H); 8.37 (broad d, J = 8.0 Hz, 1H); 9.07 (broad s, 1H). Mass spectrum (ES): m / z = 464 [M + H] + (base peak); m / z = 462 [MH] - (base peak) Example 15: 3- (4-. {[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1- il] methyl.}. pyridin-2-yl) -1-cyclopentyl-1-methylurea Phase bli 3- (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyridin-2 -yl) -1-cyclopentyl-1-methylurea To a solution of 0.16 g of (4- {[[3- (4-tert-butylphenyl) -5,5-d, methyl-2,4-dioxoimidazolidin 1-yl] methyl.}. Pyridin-2-yl) carbamate obtained in step a) then in 2 ml of tetrahydrofuran are successively added 0.368 ml of N-methylcyclopentylamine and 0.512 ml of triethylamine. The reaction mixture is heated in the microwave at 130 ° C for 3 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 0.048 g of 3- (4. {[3- (4-tert-butylphenyl) ) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. Pyrid i n-2-yl) -1-cyclopentyl-1-methylurea whose characteristics are the following: RN 1 H spectrum at 400 MHz : 1.31 (s, 9H); 1.39 (s, 6H); from 1.42 to 1.79 (m, 8H); 2.82 (s, 3H); 4.58 (s, 2H); 4.60 (m, 1H); 6.98 (dd, J = 1.5 and 5.5 Hz, 1H); 7.33 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 7.85 (broad s, 1H); 8.17 (d, J = 5.5 Hz, 1H); 8.72 (s, 1H).

Mass spectrum (ES): m / z = 492 [M + H] +; Step a): (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) carbamate of ethyl To a solution of 3.5 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in phase a ) of example 7 in 90 ml of dioxane are added successively under argon, 406 mg of palladium diacetate, 1.1 g of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) [xantphos ], 1 2.9 g of cesium carbonate and 1.86 g of ethyl carbamate. The reaction mixture is heated at 105 ° C for 7 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (60/40 by volume) to give 1.8 g of (4-. {[3- (4-tert-butylphenyl) Ethyl) -5,5-dimethyl-2,4-d-oxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) carbamate whose characteristics are as follows: 1 H NMR spectrum at 300 MHz: 1 , 23 (t, J = 7.5 Hz, 3H); 1, 31 (s, 9H); 1.40 (s, 6H); 4, 14 (q, J = 7.5 Hz, 2H); 4.60 (broad s, 2H); 7.07 (d width, J = 5.5 Hz, 1H); 7.32 (d, J = 8.5 Hz, 2H) 7.52 (d, J = 8.5 Hz, 2H); 7.86 (broad s, 1H); 8.20 (d, J = 5.5 Hz, 1H); 10.05 (broad s, 1 H). Mass spectrum (ES): m / z = 439 [+ H] +; m / z = 437 [M + H] + Example 16: 1- (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoamidazolidin-1- il] methyl.}. pyridin-2-yl) -3-cyclohexylurea It can be prepared as in step c) of example 9 but from 200 mg of 3- (4-tert-butylphenyl) -5, 5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of Example 9, 4 ml of ethanol and 56 mg of cyclohexanamine. After chromatography on a silica column, eluting with a heptane / ethyl acetate mixture (gradient from 100/0 to 0/100 by volume), 92 mg of 1- (4-. {[3- (4-tert. -butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. pyridin-2-yl) -3-cyclohexylurea in the form of a pale yellow powder whose characteristics are the following: NMR spectrum 1 H at 400 MHz: From 1.14 to 1.44 (m, 5H); 1.31 (s, 9H); 1.40 (s, 6H); 1.53 (m, 1H); 1.66 (m, 2H); 1.82 (m, 2H); 3.56 (m, 1H) 4.56 (s, 2H); 6.91 (dd, J = 1.5 and 5.5 Hz, 1H); 7.33 (broad s, 1H); 7.34 (broad d, J = 8.5 Hz, 2H); 7.51 (broad d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.20 (extended m, 1H); 9.06 (s, 1H) Mass spectrum (ES): m / z = 492 [M + H] + (base peak) m / z = 490 [M-H] "(base peak) Example 17: N- (4- { [3- (4-tert-Butylphenyl) -5,5-dimetN-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) aziridine- 1 -carboxamide Example 18: N- (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl ) azetidine-1-carboxamide It can be prepared as in step c) of example 9 but from 200 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2, 3-a] pyridin-7-yl) methyl] -imidazolidine-2,4-dione obtained in phase b) of example 9, 4 ml of dioxane and 32.3 mg of azetidine. After forty-five minutes of heating at a temperature of 80 ° C and purification by HPLC (water-acetonitrile gradient containing 0.1% formic acid), 29 mg of N- (4-. {[3- ( 4-tert-butylphenyl) -5,5-d, methyl-2,4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) azetidine-1 -carboxamide in the form of a white powder whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.32 (s, 9H); 1.40 (s, 6H); 2, 15 (m, 2H); 3.98 (m, 4H); 4.57 (s, 2H); 6.97 (dd, J = 1.5 and 5.5 Hz, 1 H); 7.33 (broad d, J = 8.5 Hz, 2H); 7.51 (broad d, J = 8.5 Hz, 2H); 7.94 (broad s, 1 H); 8, 16 (d, J = 5.5 Hz, 1 H); 8.95 (s, 1 H) Mass spectrum (ES): m / z = 450 [M + H] + (base peak) Example 19: N- (4- { [3- (4- tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} pyridin-2-yl) pyrrolidine-1-carboxamide It can be prepared as in step c) of example 9 but from 200 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2.4 ] oxadiazolo [2,3-a] pyridin-7-yl) methyl] -imidazolidine-2,4-dione obtained in phase b) of example 9, 4 ml of dioxane and 40.2 mg of pyrrolidine. After chromatography on a silica column, eluting with a heptane / ethyl acetate mixture (gradient from 100/0 to 0/100 by volume), 64.3 mg of N- (4-. {[3- (4 -tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} pyridin-2-yl) pyrrolidine-1-carboxamide in the form of a beige powder whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.40 (s, 6H); 1.84 (m, 4H); 3; 40 (m, 4H); 4.58 (s, 2H); 6.98 (dd, J = 1.5 and 5.5 Hz, 1H) 7.33 (d, J = 9.0 Hz, 2H); 7.51 (d, J = 9.0 Hz, 2H); 7.93 (broad s, 1H); 8.16 (d, J = 5.5 Hz, 1H); 8.59 (s, 1H) Mass spectrum (ES): m / z = 464 [M + H] + (base peak) Example 20: N- (4- { [3- (4-tert- butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} pyridin-2-yl) morpholine-4-carboxamide It can be prepared as in step c) of example 9 but from 150 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl ester ] -imidazolidine-2,4-dione obtained in phase b) of example 9, 3 ml of dioxane and 36.9 mg of morpholine. After chromatography on a silica column eluting with a heptane / ethyl acetate mixture (gradient from 100/0 to 0/100 by volume), 74 mg of N- (4-. {[3- (4-tert. -butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. pyridin-2- L) morpholine-4-carboxamide in the form of a yellow wax whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.32 (s, 9 H); 1.39 (s, 6H); 3.45 (m, 4H); 3.59 (m, 4H) 4.58 (s, 2H); 7.00 (dd, J = 1.5 and 5.5 Hz, 1H); 7.33 (broad d, J = 8.5 Hz, 2H); 7.51 (broad d, J = 8.5 Hz, 2H); 7.84 (broad s, 1H); 8.18 (d, J = 5.5 Hz, 1H); 9.17 (s, 1H) Mass spectrum (ES): m / z = 480 [+ H] + (base peak) Example 21_: N- (4- { [3- (4-tert-butylphenyl) ) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) -4-methylpiperazine-1-carboxamide A solution of 100 mg of 3- (4-tert-butylphenyl) - 5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in the phase b) of example 9 in 2 ml of dioxane and 31 ml? of N-methylpiperazine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 94 mg of N- (4- { [3- (4- tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyridin-2-yl) -4-methylpiperazine-1-carboxamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.30 (s, 9H); 1.40 (s, 6H); 2.19 (s, 3H); 2.29 (m, 4H); 3.46 (m, 4H); 4.58 (s, 2H); 6.99 (broad d, J = 5.5 Hz, 1H); 7.33 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 7.81 (broad s, 1H); 8.18 (d, J = 5.5 Hz, 1H); 9.13 (broad s, 1H). Mass spectrum (ES): m / z = 493 [M + H] +; m / z = 267.6 [M + CH3CN + H] 2+ / 2 peak of m / z = 247 [M + 2H] 2+ / 2 ex 22 ex 23 ex 24 Example 22i 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) -3- (2-piperidin-1-ylethyl) urea A solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2, 4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in phase b) of example 9 in 2 ml of dioxane and 36 ml? of 1- (2-aminoethyl) piperidine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 75 mg of 1 - (4- { [3- (4- tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. pyridin-2-yl) -3- (2-piperidin-1-ylethyl) urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.40 (m, 8H); 1.52 (m, 4H); 2.44 (m, 6H); 3.27 (q, J = 6.0 Hz, 2H); 4.56 (s, 2H); 6.91 (broad d, J = 5.5 Hz, 1 H); 7.29 (broad s, 1 H); 7.33 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 8,11 (d, J = 5.5 Hz, 1 H); 8.43 (broad m, 1 H); 9.23 (broad s, 1 H). Mass spectrum (ES): m / z = 521 [M + H] +; m / z = 281 [M + CH 3 CN + H) 2+ / 2; m / z = 261 [M + 2H) 2+ / 2 base peak Example 23: 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2 il) -3- [2- (4-methylpiperazin-1-yl) ethyl] urea A solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of example 9 in 2 ml of dioxane and of 48 μ? of 1- (2-aminoethyl) -4-methylpiperazine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica eluting with a gradient (100/0 to 75/25 by volume) of dichloromethane and methanol / ammonia (6/1 by volume) to give 75 mg of 1- (4. {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl} pyridin-2-yl) -3- [2- (4-methylpiperazin-1-yl) ethyl] urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.40 (s, 6H); 2.15 (s, 3H); from 2.25 to 2.45 (m, 10H); from 3.35 to 3.45 (masked m, 2H); 4.55 (s, 2H); 6.92 (broad d, J = 5.5 Hz, 1H); 7.28 (broad s, 1H) 7.34 (d, J = 8.5 Hz, 2H); 7.52 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H) 8.47 (broad t, J = 6.0 Hz, 1H); 9.22 (broad s, 1H). Mass spectrum (ES): m / z = 536 [M + H] +; m / z = 480 [M-tBu + 2H] + base peak Example 24: 1- (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin- 1-yl] methyl.}. Pyridin-2-yl) -3- (2-morpholin-4-ylethyl) urea A solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-t 'oxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazoliclin-2,4-dione obtained in step b) of example 9 in 2 ml dioxane and 37 μ? of 1 - (2-aminoethyl) morpholine is heated in the microwave at 1 30 ° C for 1 5 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica eluting with a gradient (1 00/0 to 75/25 by volume) of dichloromethane and methanol / ammonia (6/1 by volume). to give 77 mg of 1- (4- {[[3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl} pyridin-2-yl) -3- (2-morpholin-4-ylethyl) urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.40 (s, 6H); 2.40 (m, 6H); from 3.35 to 3.45 (masked m, 2H); 3.60 (m, 4H); 4.56 (s, 2H); 6.93 (broad d, J = 5.5 Hz, 1 H); 7.29 (broad s, 1 H); 7.34 (d, J = 8.5 Hz, 2H); 7.52 (d, J = 8.5 Hz, 2H); 8, 12 (d, J = 5.5 Hz, 1 H); 8.48 (broad m, 1 H); 9.22 (broad s, 1 H). Mass spectrum (ES) m / z = 523 [M + H] +. m / z = 282.6 [M + CH3CN + H] 2+ / 2 base peak m / z = 262 [M + 2H] 2+ / 2 eg 25 eÍ 26 ex 27 ex 28 Example 25: 3- (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) -1 - ethyl-1-methylurea A solution of 1,00 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of example 9 in 2 ml dioxane and 24 μ? of N-ethyl-N-methylamine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a silica column eluting with a mixture of petroleum ether and ethyl acetate (gradient 40/60 to 0/100 by volume) then by HPLC (water gradient). acetonitrile containing 0.1% formic acid) to give 12 mg of 3- (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1- il] methyl.}. pyridin-2-yl) -1-methylurea whose characteristics are as follows: NMR spectrum 1? at 400 MHz: 1.07 (t, J = 7.0 Hz, 3H); 1.31 (s, 9H); 1.40 (s, 6H); 2.93 (s, 3H); from 3.35 to 3.45 (masked m, 2H); 4.59 (s, 2H); 6.99 (broad d, J = 5.5 Hz, 1H); 7.33 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 7.86 (broad s, 1H); 8.18 (d, J = 5.5 Hz, 1H) 8.71 (broad s, 1H). Mass spectrum (ES): m / z = 452 [M + H] + base peak Example 26: 3- (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2 , 4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) -1-methyl-1-propylurea A solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of example 9 in 2 ml of dioxane and 29 μ? of N-methyl-N-propylamine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on silica column eluting with a mixture of petroleum ether and ethyl acetate (40/60 by volume) to give 61 mg of 3- (4- { [3- (4-tert-butylphenyl) -5,5- dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} pyrimidin-2-yl) -1-methyl-1-propylurea in the form of a white powder whose characteristics are the following: 1 H NMR spectrum at 400 Hz: 0 , 85 (t, J = 7.5 Hz, 3H); 1.31 (s, 9H); 1.39 (s, 6H); 1.52 (m, 2H); 2.94 (s, 3H); from 3.25 to 3.35 (masked m, 2H) 4.58 (s, 2H) 6.98 (dd, J = 1.5 and 5.5 Hz, 1H); 7.33 (d, J = 8.5 Hz, 2H); 7.50 (d, J = 8.5 Hz, 2H); 7.85 (broad s, 1H); 8.18 (d, J = 5.5 Hz, 1H); 8.72 (broad s, 1H). ES m / z = 466 [M + H] + base peak Example 27: 1-butyl-3- (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4 -dioxoimidazolidin-1-yl] methyl.}. pyridin-2-yl) -1-methylurea It can be prepared as in step c) of example 9 but from 150 mg of 3- (4-tert-butylphenyl) -5 , 5-dimethyl-1 - [(2-thioxo-2H- [1,2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] -imidazolidine-2,4-dione obtained in the phase b) of Example 9, 3 ml of dioxane and 36.9 mg of N-methylbutan-1-amine. After chromatography on a silica column eluting with a heptane / ethyl acetate mixture (gradient from 100/0 to 0/100 by volume), 77.8 mg of 1-butyl-3- (4- {[[ 3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) -1-methylurea in the form of a white powder whose characteristics are following: 1 H NMR spectrum at 400 MHz: 0.90 (t, J = 7.5 Hz, 3H); 1.26 (m, 2H); 1.31 (s, 9H); 1.39 (s, 6H); 1.48 (m, 2H); 2.95 (s, 3H); 3.32 (partially masked t, J = 7.5 Hz, 2H); 4.58 (s, 2H); 6.98 (dd, J = 1.5 and 5.5 Hz, 1H); 7.34 (broad d, J = 8.5 Hz, 2H); 7.51 (broad d, J = 8.5 Hz, 2H); 7.85 (broad s, 1H); 8.17 (d, J = 5.5 Hz, 1H); 8.70 (s, 1H) Mass spectrum (ES): m / z = 480 [M + H] + (base peak) Example 28: 1-butyl-3- (4- { [3- ( 4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} - pyridin-2-yl) urea It can be prepared as in step c) of example 9 but from 200 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of example 9, 4 ml of dioxane and 41.3 mg of N-butan-1-amine. After chromatography on a silica column, eluting with a heptane / ethyl acetate mixture (gradient from 100/0 to 0/100 by volume), 150.7 mg of 1-butyl-3- (4- {[[ 3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyridin-2-yl) urea in the form of a white powder whose characteristics are the following: Spectrum 1 H NMR at 400 MHz: 0.90 (t, J = 7.5 Hz, 3H); 1.31 (s, 9H); 1.33 (m, 2H); 1.40 (s, 6H); 1.45 (m, 2H); 3.17 (q, J = 7.0 Hz, 2H); 4.56 (s, 2H); 6.91 (dd, J = 1.5 and 5.5 Hz, 1H); 7.31 (broad s, 1H); 7.34 (broad d, J = 8.5 Hz, 2H); 7.52 (broad d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.24 (broad m, 1H); 9.12 (s, 1H) Mass spectrum (ES): m / z = 466 [M + H] + (base peak) ex 30 ex 31 Example 29: 1- (4-. {[3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-d-oxoimidazolidin-yl] methyl] pyridin-2-yl) -3- [2- (dimethylamino) ethyl] urea A solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2] , 4] oxadiazolo [2,3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of example 9 in 2 ml of dioxane and 35 ml? of N, N-dimethyl-1,3-ethylenediamine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica eluting with a gradient (100/0 to 75/25 by volume) of dichloromethane and methanol / ammonia (6/1 by volume) to give 72 mg of 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} pyridin-2-yl) - 3 - [(2- (dimethylamino) ethyl] urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 40 (s, 6H); 2, 19 (s, 6H), 2.38 (m, 2H), 3.35 (q, J = 6.0 Hz, 2H), 4.56 (s, 2H), 6.91 (dd, J = 1, 5 and 5). , 5 Hz, 1 H), 7.34 (m, 3 H), 7.51 (d, J = 8.5 Hz, 2 H), 8, 1 1 (d, J = 5, 5 Hz, 1 H); 8, 19 (broad m, 1 H); 9, 1 9 (broad s, 1 H) Mass spectrum (ES): m / z = 481 [M + H] + base peak Example 30: 1 - (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-yl] methyl.}. Pyridin-2-yl) -3- [3- (dimethylamino) propyl] urea A solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridin-7) -yl) methyl] imidazolidine-2,4-dione obtained in phase b) of example 9 in 2 ml of dioxane and 35 ml. of N, N-dimethyl-1,3-propanediamine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue purified by chromatography on a column of silica eluting with a mixture of dichloromethane / methanol / ammonia (75/23/2 by volume) to give 72 mg of 1- (4-. { . [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl] pyridin-2-yl) -3- [3- (dimethylamino) propyl] urea whose characteristics are the following: 1 H NMR spectrum at 400 Hz: 1.31 (s, 9 H); 1.40 (s, 6H); 1.60 (m, 2H); 2.16 (s, 6H); 2.29 (m, 2H); 3.19 (q, J = 6.0 Hz, 2H); 4.57 (s, 2H); 6.91 (broad d, J = 5.5 Hz, 1H); 7.29 (broad s, 1H) 7.33 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.33 (broad m, 1H); 9.17 (broad s, 1H). Mass spectrum (ES): miz = 495 [M + H] + base peak Example 31_: 1- (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4 -dioxoimidazolidin-yl] methyl.}. pyridin-2-yl) -3- [4- (dimethylamino) butyl] urea A solution of 100 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2) 3-a] pyridin-7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of example 9 in 2 my dioxane and 35 μ? of N, N-dimethyl-1,3-propanediamine is heated in the microwave at 130 ° C for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue purified by chromatography on a column of silica eluting with a mixture of dichloromethane / methanol / ammonia (75/23/2 by volume) to give 77 mg of 1- (4- { [3- (4-tert-butylphenyl) -5, 5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) -3- [4- (dimethylamino) butyl] urea whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1, 31 (s, 9H); 1.40 (s, 6H); 1.45 (m, 4H); 2, 13 (s, 6H); 2.25 (m, 2H); 3, 17 (q, J = 6.0 Hz, 2H); 4.56 (s, 2H); 6.91 (dd, J = 1.5 and 5.5 Hz, 1 H); 7.30 (broad s, 1 H); 7.34 (d, J = 8.5 Hz, 2H); 7.52 (d, J = 8.5 Hz, 2H); 8,11 (d, J = 5.5 Hz, 1 H); 8.28 (broad t, J = 6.0 Hz, 1 H); 9, 14 (broad s, 1 H). Mass spectrum (ES): m / z = 509 [M + H] + base peak Example 31 A: 3- (4-tert-butylphenyl) -1 - (. {2 - [(5-fluoropyridin-3 -yl) amino] pyridin-4-yl.} methyl) -5,5-dimethylimidazolidine-2,4-dione To a solution of 200 mg of 1 - [(2-aminopyridin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione hydrochloride obtained in step c ) of example 7 in 5 ml of dioxane are added successively under argon 1.1, palladium diacetate 1 mg, 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (xantphos ), 777 mg of cesium carbonate and 96 mg of 5-bromo-3-fluoropyrimidine. The reaction mixture is heat at reflux for 1 h, then filter and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and acetone (70/30 by volume) to give 210 mg of 3- (4-tert-butylphenyl) -1 - (. {2- [2- (5-fluoropyridin-3-yl) amino] pyridin-4-yl}. Methyl) -5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1, 31 (s, 9H); 1, 42 (s, 6H); 4.59 (s, 2H); 6.90 (m, 2H); 7.36 (d, J = 8.5 Hz, 2H); 7.52 (d, J = 8.5 Hz, 2H); 8.04 (d, J = 2.5 Hz, 1 H); 8.20 (d, J = 5.5 Hz, 1 H); 8.40 (td, J = 2.5 and 12.0 Hz, 1 H); 8.50 (t, J = 2.5 Hz, 1 H); 9.60 (s, 1 H). Mass spectrum (ES): m / z = 462 [M + H] +; Example 31 B: 3- [1 - (N, N-dimethylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione Step b): 3- [1 - (N, N-dimethylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione To a solution of 242 mg of 1 - [(2-chloropyridin-4-yl) methyl] -3 [1- (N, N-dimethylglycyl) -3,3-dimethyl-2,3-dihydro-1H-indol-6-yl] -5,5-dimethylimidazolidine-2, 4-dione obtained in step a) then in 2 ml of N-methylpyrrolidinone are added successively under argon, 70 mg of 3-aminopyridine, 29 mg of (9,9-dimethyl-9H-xanthene-3,6- diyl) bis (diphenylphosphine) (Xantphos), 11 mg of palladium acetate and 652 mg of cesium carbonate. The reaction mixture is heated at 140 ° C for 1 h in the microwave, cooled to room temperature, diluted with 10 ml of dichloromethane, filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 30 ml of water and the precipitate formed is filtered and purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (93/7 by volume) to give 75 mg of 3- [1- ( N, N-dimethylglycyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl-1-. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 6H); 1.42 (s, 6H); 2.28 (s, 6H); 3.23 (s, 2H); 3.99 (s, 2H); 4.55 (s, 2H); 6.82 (m, 2H); 7.08 (dd, J = 2.0 and 8.0 Hz, 1H); 7.27 (dd, J = 5.0 and 8.5 Hz, 1H); 7.37 (d, J = 8.0 Hz, 1H); 8.06 (broad s, 1H); 8.08 (dd, J = 1.5 and 5.0 Hz, 1H); 8.13 (d, J = 5.5 Hz, 1H); 8.21 (broad d, J = 8.5 Hz, 1H) 8.78 (d, J = 3.0 Hz, 1H); 9.21 (s, 1H). Mass spectrum (ES) m / z 542 [M + H] +. m / z = 457 [M + H] + - Tbu (base peak); m / z = 540 [M-H] "Phase a): 1 - [(2-chloropyridin-4-yl) methyl] -3- [1- (N, N-dimethylglycyl) -3.3- dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethylimidazolidine-2,4-dione A solution of 0.951 g of 3- [1 - (chloroacetyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -1 - [(2-chloropyridin-4-yl) ) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step j) of Example 3 in 80 ml of a 2 M solution of dimethylamine in tetrahydrofuran is heated at 60 ° C for 4 h. The reaction mixture is then concentrated under reduced pressure and the residue is disintegrated in 30 ml of water. A solid is formed which is filtered, washed twice with 5 ml of diisopropyl ether and dried to give 3.5 g of 1 - [(2-chloropyridin-4-yl) methyl] -3- [1 - (N , N-dimethylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethylimidazolidine-2,4-dione, whose characteristics are as follows: Spectrum RM N 1 H at 400 MHz: 1.31 (s, 6H); 1.40 (s, 6H); 2, 28 (s, 6H); 3.23 (s, 2H); 3.99 (s, 2H); 4.63 (s, 2H); 7.09 (broad d, J = 8.0 Hz, 1 H); 7.35 (d, J = 8.0 Hz, 1 H); 7.44 (broad d, J = 5.5 Hz, 1 H); 7.58 (broad s, 1 H); 8.08 (broad s, 1 H); 8.38 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 484 [M + H] +; Example 31 C: 3- [4- ( { 3- [1 - (N, N-dimethylglycyl) -3,3-dimethyl-2,3-dihydro- 1 H-indol-6-yl] -5,5-dimethyl-2,4-d-oxoimidazolidin-1-yl} methyl) pyridin-2-yl] -1, 1 -dimethylurea To a solution of 242 mg of 1- (2-chloro-pyridin-4-ylmethyl) -3- [1- (2-dimethylamino-acetyl) -3,3-dimethyl-2,3-dihydro-1H-indole -6-yl] -5,5-dimethyl-imidazolidine-2,4-dione obtained in step a) of Example 31 B in 10 ml of dioxane are added successively under argon, 33 mg of NN-dimethylurea, 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 22 mg of palladium acetate and 652 mg of cesium carbonate. The reaction mixture is refluxed for 6 h, cooled to room temperature, filtered, washed 3 times with 10 ml of dichloromethane and the filtrate is concentrated under reduced pressure. The residue is dissolved in 20 ml of water and the precipitate formed is filtered twice and purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (93/7 by volume) to give 40 mg of 3- [4]. - ( { 3- [1 - (N, N-dimethylglycyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl-2,4- dioxoimidazolidin-1-yl] methyl) pyrid i n-2-yl] -1,1-dimethylurea having the following characteristics: 1 H NMR spectrum at 400 MHz: 1.37 (s, 6H); 1.49 (s, 6H); 2.89 (s, 6H); 3.07 (s, 6H); 4.39 (broad s, 2H); 4.76 (s, 2H); 7.30 (dd, J = 1, 5 and 8.0 Hz, 1 H); 7.37 (broad d, J = 5.5 Hz, 1 H); 7.43 (d, J = 8.0 Hz, 1 H); 8.08 (d, J = 1.5 Hz, 1 H); 8, 17 (broad s, 1 H); 8.29 (d, J = 5.5 Hz, 1 H); 10, 1 (extended m, 1 H). Mass spectrum (ES): m / z = 536 [M + H] +; m / z = 406 [+ H] + -COCHzN (CH 3) 2 -N (CH 3) 2 (base peak) Example 31 D: 3- [1 - (N-isopropylglycyl) -3,3-dimethyl-2, 3-dihydro-1 H-indol-6-yl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione Step b): 3- [1 - (N-isopropylglycyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione To a solution of 249 mg of 1 - [(2-chloropyridin-4-yl) methyl] -3- [1- (N-isopropylglycyl) -3,3-dimethyl-2,3- dihydro-1 H-indol-6-yl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a) then in 3 ml of N-methylpyrrolidinone are added successively under argon, 94 mg of 3-aminopyridine , 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 22 mg of palladium acetate and 652 mg of cesium carbonate. The The reaction mixture is heated at 140 ° C for 1 h in the microwave, cooled to room temperature, diluted with 20 ml of dichloromethane, filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in 40 ml of water and the precipitate formed is filtered and purified by chromatography on a silica column using a mixture of dichloromethane and methanol (93/7 by volume) to give 35 mg of 3- [1 - ( N-isopropylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) -pyridin-4-yl] methyl} imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 Hz: 1, 00 (d, J = 6.5 Hz, 6H); 1.33 (s, 6H); 1, 43 (s, 6H); 2.00 (very widespread m, 1 H); 2.75 (m, 1 H); 3.49 (broad s, 2H); 3.91 (s, 2H); 4.54 (s, 2H); 6.82 (m, 2H); 7.09 (dd, J = 1, 5 and 8.0 Hz, 1 H); 7.27 (dd, J = 5.0 and 8.0 Hz, 1 H); 7.38 (d, J = 8.0 Hz, 1 H); 8.08 (m, 2H); 8, 12 (d, J = 5.5 Hz, 1 H); 8.21 (broad d, J = 8.0 Hz, 1 H); 8.78 (d, J = 2.5 Hz, 1 H); 9.21 (s, 1 H). Mass spectrum (ES): m / z = 55 [M + H] +; m / z = 279 [M + 2H] ++ Step a): 1 - [(2-chloropyridin-4-yl) methyl] -3- [1 - (N-isopropylglycyl) -3,3-dimethyl-2, 3-dihydro-1 H-indol-6-yl] -5,5-dimethylimidazolidine-2,4-dione A solution of 1,426 g of 3- [1- (chloroacetyl) -3,3-dimethyl-2,3-dihydro-1H-indol-6-yl] -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step j) of Example 3 in 25 ml of isopropylamine is heated at reflux for 4 h. The reaction mixture is then concentrated under reduced pressure and the residue is taken up in 30 ml of water and partitioned in 2 ml of diethyl ether. A solid is formed which is filtered, washed twice with 5 ml of diisopropyl ether and dried to give 1.2 g of 1 - [(2-chloropyridin-4-yl) methyl] -3- [1- (N -isopropylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.00 (d, J = 6.5 Hz, 6H); 1.32 (s, 6H); 1.40 (s, 6H); 1.95 (extended m, 1H); 2.75 (m, 1H); 3.48 (broad s, 2H); 3.91 (s, 2H); 4.63 (s, 2H); 7.10 (dd, J = 2.0 and 8.0 Hz, 1H); 7.36 (d, J = 8.0 Hz, 1H); 7.45 (broad d, J = 5.5 Hz, 1H); 7.57 (broad s, 1H); 8.09 (broad s, 1H); 8.38 (d, J = 5.5 Hz, 1H). Mass spectrum (ES): m / z = 498 [+ H] +; Example 31E: 3- [4- ( { 3- [1 - (N-isopropylglycyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl -2,4-dioxoimidazolidin-1-yl.} Methyl) pyridin-2-yl] -1,1-dimethylurea Step b): 3- [4- ( { 3- [1 - (N-isopropylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5, 5- dimethyl-2,4-dioxoimidazolidin-1-yl.] methyl) pyridin-2-yl] -1,1-di-methylurea To a solution of 400 mg of [2- (6-. {3- [(2-chloropyrid-di-4-yl) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl] -3,3-dimethyl-2,3-dihydro-1 H-indole Tere-butyl-1-yl) -2-oxoethyl] isopropylcarbamate obtained in step a) then in 15 ml of dioxane are added successively under argon, 88 mg of N, N-dimethylolurea, 39 mg of sodium hydroxide. , 9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos), 30 mg of palladium acetate and 872 mg of cesium carbonate. The reaction mixture is refluxed for 4 h, filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 30 ml of ethyl acetate, washed 3 times with 15 ml of water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 280 mg of a yellow lake which is taken up in 10 ml of a solution of 4 N hydrochloric acid in dioxane. and it is stirred for 17 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 20 ml of ethyl ether and the solid formed is filtered and dried to give 200 mg of 3- [4- (. {3- [1 - (N-isopropylglycyl) -3,3-dimethyl-2,3-dihydro-1 H -indol-6-yl] -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl.] Methyl) pyridi n-2-yl] -1, 1 -dimethylurea in the form of hydrochloride whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.29 (d, J = 6.5 Hz, 6H); 1.38 (s, 6H); 1.47 (s, 6H); 3.04 (s, 6H); from 3.30 to 3.60 (masked m, 1 H); 4.00 (s, 2H); 4, 16 (t, J = 6.0 Hz, 2H); 4.72 (s, 2H); 7.27 (dd, J = 2.0 and 8.0 Hz, 1 H); 7.30 (broad d, J = 5.5 Hz, 1 H); 7.43 (d, J = 8.0 Hz, 1 H); 8.05 (broad s, 1 H); 8.09 (d, J = 2.0 Hz, 1 H); 8.28 (d, J = 5.5 Hz, 1 H); 8.96 (broad m, 2H); 10.6 (extended m, 1 H). Mass spectrum (ES): m / z = 550 [M + H] +; m / z = 406 [M + H] + -COCH2N (CH3) 2 - (CH3) 2 (base peak) Phase a): [2- (6- { 3 - [(2-chloropyridin-4- il) methyl] -4,4-dimethyl-2,5-dioxoimidazolidin-1-yl.} - 3,3-dimethyl-2,3-dihydro-1 H-indol-1-yl) -2-oxoethyl-isopropylcarbamate tere-butyl To a solution of 498 mg of 3- [1 - (chloroacetyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a) of Example 31 D in 10 ml of dichloromethane are added successively 0.28 ml of triethylamine and 0.24 g of di-tert-dicarbamate. Butyl drop by drop in solution in 4 ml of dichloromethane. The reaction mixture is stirred at room temperature for 15 hours then washed 3 times with 20 ml of water. Dry over magnesium sulfate, it is filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95/5 by volume), then crystallized from 10 ml of diethyl ether, filtered and dried to give 0.41 g of [2]. - (6- { 3 - [(2-chloropyridin-4-yl) methyl] -4,4-d, methyl-2,5-dioxoimidazolidin-1-yl.} - 3, 3-dimethyl-2 , Tere-butyl 3-dihydro-1H-indol-1-yl) -2-oxoethyl tetrashropylcarbamate whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: from 1.02 to 1.47 (m, 27H); from 3.91 to 4.32 (m, 5H); 4.63 (s, 2H); 7.09 (broad d, J = 8.0 Hz, 1 H); 7.38 (d, J = 8.0 Hz, 1 H); 7.45 (broad d, J = 5.5 Hz, 1 H); 7.57 (broad s, 1 H); 8.08 (broad s, 1 H), 8.38 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 598 [M + H] +; m / z = 498 [M + H] + - COOTBu; m / z = 642 [M-H] - + HCOOH Example 31 F; 3- (4-tert-Butylphenyl) -5,5-dimethyl-1 - [(2- {[[4- (pyrrolidin-1-ylmethyl) phenyl] amino} pyridin-4-yl) methyl] imidazolidine -2,4-dione Step d: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[[4- (pyrrolidin-1-methylmethyl) phenyl] amino} pyridin -4-yl) methyl] imidazolidine-2,4-dione To a solution of 1.15 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5, 5-Dimethylimidazolidine-2,4-dione obtained in step a) of Example 7 in 50 ml of dioxane are added successively under argon, 520 mg of 4- (pyrrolidin-1-ylmethyl) aniline obtained in step c) below , 3.4 g of cesium carbonate, 207 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) [xantphos] and 67 mg of palladium diacetate. The reaction mixture is heated at 90 ° C for 6 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 88 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1- [ 2-. { [4- (pyrrolidin-1-ylmethyl] imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.41 (s, 6H) ¡1, 78 (m, 4H), 2.40 (m, 4H), 3.49 (s, 2H), 4.51 (s, 2H), 6.73 (broad d, J = 5.5 Hz, 1H) 6.79 (broad s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 2H), 7.52 (d, J = 8.5 Hz , 2H), 7.58 (d, J = 8.5 Hz, 2H), 8.09 (d, J = 5.5 Hz, 1H), 8.92 (s, 1H). ): m / z = 526 [M + H] +, m / z = 455 [M + H] + -NH (CH2) 4 Phase c: 4- (pyrrolidin-1-ylmethyl) aniline To a solution of 1.28 g of 4- (pyrrolidin-1-ylcarbonyl) aniline obtained in step b) then in 100 ml of tetrahydrofuran, 1.28 g of lithium aluminum hydride are added under argon. The reaction mixture is stirred one hour at room temperature, then cooled to 0 ° C and treated successively with 1.28 ml of water, 1.28 ml of a 15% sodium hydroxide solution (by weight) and 3.85 mi of water. The solid formed is filtered, washed with ethyl acetate and the filtrate is concentrated under reduced pressure to give 1.1 g of 4- (pyrrolidin-1-ylmethyl) aniline in the form of a dark yellow oil whose characteristics are following: 1 H NMR spectrum at 400 MHz: 1.64 (m, 4H); 2.34 (m, 4H); 3.37 (s, 2H); 4.88 (broad s, 2H); 6.49 (d, J = 8.5 Hz, 2H); 6.91 (d, J = 8.5 Hz, 2H). Mass spectrum (IE): m / z = 176: [M] + m / z = 106: [M] + - N (CH2) 4 Phase b: 4- (pyrrolidin-1-ylcarbonyl) aniline To a solution of 1.28 g of 1- (4-nitrobenzoyl) pyrrolidine obtained in step a) in 50 ml of methanol are then added under argon 4.26 g of ammonium formate and 9 mg of palladium on carbon at 10%. The reaction mixture is stirred at room temperature for 5 hours then filtered over celite and concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.28 g of 4- (pyrrolidin-1-ylcarbonyl) aniline whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.80 (m, 4H); 3.43 (m, 4H); 5.45 (s, 2H); 6.52 (d, J = 8.5 Hz, 2H); 7.28 (d, J = 8.5 Hz, 2H). Mass spectrum (IE): m / z = 190 [M] + m / z = 120 [M] + - N (CH2) 4 m / z = 92 [120] + - CO Phase a: 1 - (4- nitrobenzoyl) pyrrolidone To a solution of 1.98 g of para-nitrobenzoic acid in 50 ml of dichloromethane are successively added under argon at 0 ° C, 0.781 ml of pyrrolidine, 0.13 g of hydroxy-benzotriazole, 2.3 g of 1.3 -dimethylaminopropyl-3-ethylcarbodiimide and 3.43 ml of diisopropylamine. The reaction mixture is stirred at room temperature for 15 hours, then washed with water. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and it is concentrated under reduced pressure. The obtained residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.9 mg of (4-nitro-phenyl) -pyrrolidin-1-yl-methanone whose characteristics are the following: 1 H NMR spectrum at 400 MHz: From 1.78 to 1.93 (m, 4H); 3.33 (t, J = 4.5 Hz, 2H); 3.50 (t, J = 4.5 Hz, 2H); 7.78 (d, J = 8.5 Hz, 2H); 8.28 (d, J = 8.5 Hz, 2H). Mass spectrum (ES): m / z = 221 [M + H] +; Example 31 G: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[[3- (pyrrolidin-1-methylmethyl) phenyl] amino} pyridin-4-yl. ) methyl] imidazolidine-2,4-dione Step d: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[[3- (pyrrolidin-1-ylmethyl) phenyl] amino} pyridin-4-yl) methyl] imidazolidine-2,4-dione To a solution of 1.15 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2 , 4-dione obtained in step a) of Example 7 in 50 ml of dioxane are added successively under argon, 520 mg of 3- (pyrrolidin-1-ylmethyl) aniline obtained in step c) below, 3.4 g of cesium carbonate, 207 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) [xantphos] and 67 mg of diacetate of palladium. The reaction mixture is heated at 90 ° C for 6 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 59 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [ 2-. { [3- (pyrrolidin-1-ylmethyl) phenyl] amino} pyridin-4-yl) methyl] imidazolidine-2,4-dione whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 41 (s, 6H); 1.69 (m, 4H); 2.41 (m, 4H); 3.51 (s, 2H); 4, 52 (s, 2H); 6.73 (broad d, J = 5.5 Hz, 1 H); 6.80 (m, 2H); 7, 18 (t, J = 7.5 Hz, 1 H); 7.34 (d, J = 8.5 Hz, 2H); 7.49 (broad s, 1 H); 7.52 (d, J = 8.5 Hz, 2H); 7.66 (broad d, J = 7.5 Hz, 1 H); 8, 10 (d, J = 5.5 Hz, 1 H); 8.94 (s, 1 H). Mass spectrum (ES): m / z = 526 [M + H] +; m / z = 570 [M-H] "+ HCOOH Phase c: 3- (pyrrolidin-1-ylmethyl) aniline To a solution of 1.12 g of 3- (pyrrolidin-1-ylcarbonyl) aniline obtained in step b) then in 100 ml of tetrahydrofuran are added under argon 0.89 g of lithium aluminum hydride. The reaction mixture is stirred one hour at room temperature, it is then cooled to 0 ° C and treated successively with 0.89 ml of water, 0.89 ml of a 15% sodium hydroxide solution (by weight) and 2.67 ml of water. The solid formed is filtered, washed with ethyl acetate and the filtrate is concentrated under reduced pressure to give 1.02 g of 3- (pyrrolidin-1-ylmethyl) aniline having the following characteristics: 1 H NMR spectrum at 400 MHz : 1.78 (m, 4H); 2.39 (m, 4H); 3.39 (s, 2H); 4.92 (broad s, 2H); 6.41 (m, 2H); 6.52 (broad s, 1 H); 6.91 (t, J = 7.5 Hz, 1 H). Mass spectrum (IE) m / z = 176 [M] + m / z = 1 06 [M] + - N (CH2) 4 Phase b: 3- (pyrrolidin-1-ylcarbonyl) aniline To a solution of 1.91 g of 1- (3-nitrobenzoyl) pyrrolidine obtained in step a), then in 50 ml of methanol, 4.38 g of ammonium formate and 9 mg of palladium on carbon are added under argon. 10% The reaction mixture is stirred at room temperature for 1 hour, then filtered over celite and concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under pressure. reduced to give 1.12 g of 3- (pyrrolidin-1-ylcarbonyl) aniline whose characteristics are as follows: NM 1 H spectrum at 400 MHz: From 1.71 to 1.91 (m, 4H); from 3.25 to 3.48 (m, 4H); 5, 1 5 (broad s, 2H); 6.59 (m, 2H); 6.64 (broad s, 1 H); 7.02 (t, J = 7.5 Hz, 1 H). Mass spectrum (IE): m / z = 190 [M] + m / z = 120 [M] + - N (CH2) 4 m / z = 92 [120] + - CO Phase a: 1 - (3- nitrobenzoyl) pyrrolidine To a solution of 1.98 g of meta-nitrobenzoic acid in 50 ml of dichloromethane are added successively under argon at 0 ° C, 0.81 ml of pyrrolidine, 0.13 g of hydroxy-benzotriazole, 2.3 g of 1 , 3-dimethylaminopropyl-3-ethyl carbodiimide and 3.43 ml of diisopropylamine. The reaction mixture is stirred at room temperature for 15 hours, then washed with water. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica gel eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.92 mg of 1- (3-nitrobenzoyl) -pyrrolidine whose characteristics are the following: 1 H NMR spectrum at 400 MHz: From 1.77 to 1.94 (m, 4H); 3.39 (t, J = 5.0 Hz, 2H); 3.50 (t, J = 5.0 Hz, 2H); 7.73 (t, J = 7.5 Hz, 1 H); 7.98 (broad d, J = 7.5 Hz, 1 H); from 8.24 to 8.33 (m, 2H). Mass spectrum (ES): m / z = 221 [M + H] +; m / z = 265 [MH] "+ HCOOH Example 31 H: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2 { [3- (2-pyrrolidin-1 - Lethyl) phenyl] amino.}. Pyridin-4-yl) methyl] imidazolidine-2,4-dione Step d: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[[(3- (2-pyrrolidin-1-ylethyl) phenyl] amino} pyridine 4-yl) methyl] imidazolidine-2,4-dione To a solution of 1.15 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] - 5,5-dimethylimidazolidine-2,4-dione obtained in step a) of Example 7 in 50 ml of dioxane are added successively under argon, 567 mg of 3- (2-pyrrolidin-1-ethylthyl) aniline obtained in step c) then 3.4 g of cesium carbonate, 207 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) [xantphos] and 67 mg of palladium diacetate . The reaction mixture is heated at 90 ° C for 3 hours, filtered and concentrated reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (90/10 by volume) to give 65 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [ 2-. { [3- (2-pyrrolidin-1-ethylthyl) phenyl] amino} pyridin-4-yl) methyl] imidazolidine-2,4-dione whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 41 (s, 6H); 1.68 (m, 4H); 2.46 (m, 4H); from 2.55 to 2.71 (m, 4H); 4.52 (s, 2H); 6.74 (m, 2H); 6.80 (broad s, 1 H); 7, 1 3 (t, J = 7.5 Hz, 1 H); 7.33 (d, J = 8.5 Hz, 2H); 7.41 (broad s, 1 H); 7.51 (d, J = 8.5 Hz, 2H); 7.54 (broad d, J = 7.5 Hz, 1 H); 8, 10 (d, J = 5.5 Hz, 1 H); 8.90 (s, 1 H). Mass spectrum (ES): m / z = 540 [M + H] +; m / z = 442 [? +? - (CH2) 2N (CH2) 4 Phase c: 3- (2-pyrrolidin-1-ethyl) aniline To a solution of 1.46 g of 3- (2-oxo-2-pyrrolidin-1-ylethyl) aniline obtained in step b) then in 1000 ml of tetrahydrofuran are added under argon 1.08 g of hydride. lithium and aluminum. The reaction mixture is stirred one hour at room temperature, then cooled to 0 ° C and treated successively with 1.08 ml of water, 1.08 ml of a 15% sodium hydroxide solution (by weight) and 3.24 ml of water. The solid formed is filtered, washed with ethyl acetate and the filtrate is concentrated under pressure reduced to give 0.568 g of 3- (2-pyrrolidin-1-ylethyl) aniline whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.65 (m, 4H); 2.42 (m, 4H); 2.54 (m, 4H); 4.89 (broad s, 2H); from 6.30 to 6.42 (m, 3H); 6.89 (t, J = 7.5 Hz, 1 H). Mass spectrum (ES): m / z = 1 91 [M + H] +; Phase b: 3- (2-oxo-2-pyrrolidin-1-ethyl) aniline To a solution of 2.12 g of 1 - [(3-nitrophenyl) acetyl] pyrrolidine obtained in step a) in 50 ml of methanol are then added under argon, 4.56 g of ammonium formate and 96 mg of palladium on carbon at 10%. The reaction mixture is stirred at room temperature for 1 hour, then filtered over celite and concentrated under reduced pressure. The residue is taken up in water and extracted with dichloromethane. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.46 g of 3- (2-oxo-2-pyrrolidin-1). -ilethyl) aniline whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: From 1.69 to 1.90 (m, 4H); 3.39 (partially masked m, 2H); from 3.35 to 3.45 (m, 4H); 4.95 (broad s, 2H); 6.36 (broad d, J = 7.5 Hz, 1 H); 6.40 (broad d, J = 7.5 Hz, 1 H); 6.44 (broad s, 1 H); 6.91 (t, J = 7.5 Hz, 1 H).

Mass spectrum (ES): m / z = 205 [M + H] +; Phase a: 1 - [(3-nitrophenyl) acetyl] pyrrolidone To a solution of 1.98 g of meta-nitrobenzoic acid in 50 ml of dichloromethane are added successively under argon at 0 ° C, 0.81 ml of pyrrolidine, 0.13 g of hydroxy benzotriazole, 2.3 g of 1, 3-dimethylaminopropyl-3-ethyl carbodiimide and 3, 43 ml of diisopropylamine. The reaction mixture is stirred at room temperature for 15 hours, then washed with water. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.92 mg of 1 - [(3-nitrophenyl) acetyl] pyrrolidine whose characteristics are as follows : 1 H NMR spectrum at 400 MHz: 1.79 (m, 2H); 1.90 (m, 2H); 3.41 (partially masked t, J = 5.0 Hz, 2H); 3.52 (t, J = 5.0 Hz, 2H); 3.82 (s, 2H); 7.60 (t, J = 7.5 Hz, 1H); 7.70 (broad d, J = 7.5 Hz, 1H); 8.10 (broad d, J = 7.5 Hz, 1H); 8.12 (broad s, 1H). Mass spectrum (ES): m / z = 235 [M + H] +; Example 311: 3- (4-tert-butylphenyl) -1 - (. {2 - [(3-fluorophenyl) amino] pyridin-4-yl}. Methyl) -5,5-dimethylimidazolidine-2,4- diona To a solution of 0.5 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a ) of example 7 in 15 ml of dioxane are added successively in argon, 250 μ? of 3-fluoroaniline, 1.6 g of cesium carbonate, 90 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bts (diphenylphosphine) [xantphos] and 29 mg of palladium diacetate. The reaction mixture is heated at 95 ° C for 2 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column using a mixture of cyclohexane and ethyl acetate (60/40 by volume) to give 451 mg of 3- (4-tert-butylphenyl) -1 - (. - [(3-fluorophenyl) amino] pyridin-4-yl.} Methyl) -5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: NMR spectrum 1 H at 400 MHz: 1.31 ( s, 9H); 1, 41 (s, 6H); 4.54 (s, 2H); 6.66 (tt, J = 2.0 and 8.5 Hz, 1 H); 6.82 (m, 2H); from 7.20 to 7.32 (m, 2H); 7.37 (d, J = 8.5 Hz, 2H); 7.52 (d, J = 8.5 Hz, 2H); 7.83 (td, J = 2.0 and 8.5 Hz, 1 H); 8, 16 (d, J = 5.5 Hz, 1 H); 9.28 (s, 1 H).

Mass spectrum (ES): m / z = 461 [M + H] +; m / z = 459 [M-H] - Example 31 J: 3- (4-tert-butylphenyl) -1 -. { [2- (cyclopropylamino) pyridin-4-yl] methyl} -5,5-dimethylimidazoiidine-2,4-dione A suspension of 0.6 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a) of Example 7 in 1.1 mL of cyclopropylamine is heated in a microwave at 50 ° C for 6 hours then concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of petroleum ether and ethyl acetate (50/50 by volume) to give 48 mg of 3- (4-tert-butylphenyl) -1-. { [2- (cyclopropylamino) pyridin-4-yl] methyl} -5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 0.40 (m, 2H); 0.67 (m, 2H); 1, 31 (s, 9H); 1.40 (s, 6H); 2.50 (masked m, 1 H); 4.48 (s, 2H); 6.55 (m, 2H); 6.71 (broad m, 1 H); 7.32 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 7.93 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 407: [M + H] + Example 31 K: 3- (4-tert-butylphenyl) -1 - (. {2 - [(2-chloropyridin-3-yl) ) amino] pyridin-4-yl.} methyl) -5,5-dimethylimidazolidine-2,4-dione To a solution of 0.8 g of 1 - [(2-aminopyridin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione hydrochloride obtained in the step c) of Example 7 in 50 ml of dioxane are added successively under argon 0.628 g of 2-chloro-3-iodopyridine, 2.8 g of cesium carbonate, 150 mg of (9,9-dimethyl-9H-xantheno- 3,6-diyl) bis (diphenylphosphine) (xantphos) and 49 mg of palladium diacetate. The reaction mixture is heated at 90 ° C for 3 h, then filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) to give 0.51 g of 3- (4-tert-butylphenyl) -1 - (. { 2 - [(2-chloropyridin-3-yl) amino] pyridin-4-yl.} Methyl) -5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 43 (s, 6H); 4.57 (s, 2H); 6.89 (dd, J = 1, 5 and 5.5 Hz, 1 H); 7, 11 (broad s, 1 H); 7.39 (m, 3H); 7.52 (d, J = 8.5 Hz, 2H); 8.00 (dd, J = 2.0 and 5.0 Hz, 1 H); 8, 10 (d, J = 5.5 Hz, 1 H); 8, 55 (m, 2H). Mass spectrum (ES): m / z = 478 [M + H] +; m / z = 476 [MH] "Example 31 L: 3- (4-tert-butylphenyl) -1 - (. {2 - [(6-chloropyridin-3-yl) amino] pyridin-4-yl}. methyl) -5,5-dimethylimidazolidine-2,4-dione To a solution of 0.5 g of 1 - [(2-aminopyridin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-d-methylimidazolidine hydrochloride , 4-dione obtained in step c) of Example 7 in 35 ml of dioxane are added successively under argon 0.39 g of 2-chloro-5-iodopyridine, 1.8 g of cesium carbonate, 947 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (xantphos) and 30 mg of palladium diacetate. The reaction mixture is heated at 90 ° C for 3 h, then filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (62/38 by volume) to give 0.368 g of 3- (4-tert-butylphenyl) -1 - (. - [(6-chloropyridin-3-yl) amino] pyridin-4-yl} methyl) -5,5-dimetiimidazoljdin-2,4-dione whose characteristics are the following: NMR spectrum 1 H at 400 MHz: 1.31 (s, 9H); 1, 41 (s, 6H); 4.57 (s, 2H); 6.85 (m, 2H); 7.35 (d, J = 8.5 Hz, 2H); 7.39 (d, J = 8.5 Hz, 1 H); 7.52 (d, J = 8.5 Hz, 2H); 8, 16 (d, J = 5.5 Hz, 1 H); 8.27 (dd, J = 2.5 and 8.5 Hz, 1 H); 8.65 (d, J = 2.5 Hz, 1 H); 9.40 (s, 1 H). Mass spectrum (ES): m / z = 478 [M + H] +; m / z = 476 [MH] "Example 31: 3- (4-tert-butylphenyl) -1 - (. {2 - [(6-hydroxypyridin-3-yl) amino] pyridin-4-yl}. methyl) -5,5-dimethylimidazolidine-2,4-dione To a solution of 0.5 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a ) of example 7 in 15 ml of dioxane are added successively under argon, 285 mg of 5-amino-2-hydroxypyridine, 6 g of cesium carbonate, 90 mg of (9,9-dimethyl-9H-xanthene-3, 6-diyl) bis (diphenylphosphine) [xantphos] and 29 mg of palladium diacetate. The reaction mixture is heated at 1 00 ° C for 1 hour, filtered and concentrated at reduced pressure. The residue is successively purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/5 by volume) then by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 35 mg of 3%. - (4-tert-Butylphenyl) -1 - (. {2 - [(6-hydroxypyridin-3-yl) amino] pyridin-4-yl}. Methyl-5,5-dimethylimidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1, 32 (s, 9H), 1, 42 (s, 6H), 4.58 (s, 2H), 6.41 (d, J = 9 , 5 Hz, 1 H), 6.80 (m, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.48 (broad d, J = 9.5 Hz, 1 H); 7.52 (d, J = 8.5 Hz, 2H), 7.78 (s broad, 1 H), 7.98 (d, J = 5.5 Hz, 1 H), 9.07 (m) extended, 1 H) Mass spectrum (ES): m / z = 460 [M + H] +, m / z = 458 [-H] - Example 31 N: 3-í4- (2-hydroxy-1) , 1-dimethylethyl) phenyl] -5,5-dimethyl-1 - { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. Imidazolidine-2,4-dione Phase q): 3- [4- (2-hydroxy-1,1-dimethylethyl) phenyl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione To a solution of 0.29 ml of diborane dimethyl sulfide (2 M in tetrahydrofuran) in 5 ml of tetrahydrofuran, under argon, at room temperature, 0.11 g of 2- (4-. {4, 4-dimethyl-2 > 5-dioxo-3- [2- (pyridin-3-ylamino) -pyridin-4-ylmethyl] -imidazolidin-1-yl.} - phenyl) -2-methyl-propionic obtained in Phase f) below. The reaction medium is stirred at this same temperature for one hour and concentrated under reduced pressure. The residue obtained is taken up in 10 ml of methanol and 2 ml of 1N hydrochloric acid. The obtained solution is concentrated under reduced pressure. The residue obtained is purified by LC / MS preparation (Gradient acetonitrile / water / TFA 0.07%). The product obtained is taken up in 10 ml of ethyl acetate, 2 ml of water and 1 ml of 1N sodium hydroxide. The organic phase is dried over magnesium sulphate, filtered and then concentrated under reduced pressure to give 0.048 g of 3% strength. - [4- (2-hydroxy-1,1-dimethylethyl) phenyl] -5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 Hz: 1.25 (s, 6H); 1.42 (s, 6H); 3.45 (d, J = 5.5 Hz, 2H); 4.55 (s, 2H); 4.71 (t, J = 5.5 Hz, 1H); 6.82 (broad d, J = 5.5 Hz, 1H); 6.84 (broad s, 1H); 7.27 (dd, J = 5.0 and 8.5 Hz, 1H); 7.34 (d, J = 8.5 Hz, 2H); 7.50 (d, J = 8.5 Hz, 2H); 8.08 (dd, J = 1.5 and 5.0 Hz, 1H); 8.12 (d, J = 5.5 Hz, 1H); 8.21 (ddd, J = 1.5 -2.5 and 8.5 Hz, 1H); 8.79 (d, J = 2.5 Hz, 1H); 9.21 (s, 1H). Mass spectrum (ES): m / z = 460 [M + H] + base peak Phase f): 2- [4- (4,4-dimethyl-2,5-dioxo-3- { [ 2- (pyridin-3- ilamino) pyridin-4-yl] methyl} imidazolidin-1-yl) phenyl] -2-methylpropanoic acid To a solution of 0.34 g of 2- [4- (4,4-dimethyl-2,5-dioxo-3 { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl. methyl imidazolidin-1-yl) phenyl] -2-methylpropanoate obtained in step e) then in 20 ml of methanol, at room temperature, add 7 ml of 1 N potassium hydroxide. reflux for two hours and concentrate under reduced pressure. The residue obtained is taken up in 10 ml of water, then acidified with 2 N HCl until pH = 5. The white solid formed is filtered, then dried to give 0.225 g of 2- [4- (4,4-dimethyl-2,5-dioxo-3. {[2- (pyridin-3-ylamino) pyridin. -4-yl] methyl.}. Imidazolidin-1-yl) phenyl] -2-methylpropanoic whose characteristics are as follows: RN 1 H spectrum at 400 MHz: 1.41 (s, 6H); 1.50 (s, 6H); 4.55 (s, 2H); 6.83 (m, 2H); 7.27 (dd, J = 5.0 and 8.5 Hz, 1 H); 7.40 (d, J = 8.5 Hz, 2H); 7.48 (d, J = 8.5 Hz, 2H); 8, 08 (broad d, J = 5.0 Hz, 1 H); 8, 12 (d, J = 5.5 Hz, 1 H); 8, 21 (broad d, J = 8.5 Hz, 1 H); 8.78 (d, J = 2.5 Hz, 1 H); 9.20 (s, 1 H); 12.4 (extended m, 1 H). Mass spectrum (ES): m / z = 474 [M + H] + base peak Phase e): 2- [4- (4,4-dimethyl-2,5-dioxo-3. [Methyl 2- (pyridin-3-ylamino) pyridin-4-yl] methyl]} imidazolidin-1-yl) phenyl] -2-methylpropanoate To a solution of 1.23 g of the methyl ester of 2- acid. { 4- [3- (2-chloro-pyridin-4-ylmethyl) -4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl] -phenyl} -2-Methyl-propionic obtained in the following phase in 40 ml of dioxane, 0.4 g of 3-aminopyridine, 0.16 g (9.9-dimethyl-9H-xanthene-3,6-) are successively added under argon. diyl) bis (diphenylphosphine) (xantphos), 0.065 g of palladium acetate and 3.65 g of cesium carbonate.The reaction mixture is refluxed for 4 h and then concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/02 by volume) to give 0.96 g of 2- [4 (4,4-dimethyl-2,5-dioxo-3 - methyl {- [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidin-1-yl) phenyl] -2-methylpropanoate whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 1.54 (s, 6H); 3.61 (s, 3H); 4.56 (s, 2H); 6.82 (broad d, J = 5.5 Hz, 1H); 6.84 (broad s, 1H); 7.26 (dd, J = 5.0 and 8.5 Hz, 1H); 7.41 (d, J = 8.5 Hz, 2H); 7.45 (d, J = 8.5 Hz, 2H); 8.08 (dd, J = 1.5 and 5.0 Hz, 1H); 8.12 (d, J = 5.5 Hz, 1H); 8.20 (ddd, J = 1.5-2.5 and 8.5 Hz, 1H); 8.78 (d, J = 2.5 Hz, 1H); 9.19 (s, 1H). Mass spectrum (ES): m / z = 488 [M + H] + base peak Phase d: 2- methyl acid ester. { 4- [3- (2-chloro-pyridin-4-ylmethyl) -4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl] -phenyl} -2-methyl-propionic To a solution of 5 g of 2- [4- (4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl] -phenyl] -2-methyl-propionic acid methyl ester obtained in the phase c) then in 30 ml of anhydrous dimethylformamide, under argon at room temperature, 0.19 g of 60% sodium hydride in oil are added. Stirring is maintained at this temperature for 20 minutes, then a solution of 0.63 g of 2-chloro-4- (chloromethyl) pyridine in 10 ml of anhydrous dimethylformamide is added. The reaction medium is heated to 60 ° C for 5 hours, then poured into ice and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/02 by volume) to give 1.23 g of the methyl ester of 2- acid. { 4- [3- (2-chloro-pyridin-4-ylmethyl) -4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl] -phenyl} -2-methyl-propionic whose characteristics are the following: Mass spectrum (ES): m / z = 430 [M + H] + base peak Phase c): 2- [4- (4,4-dimethyl-2 Methyl, 5-dioxoimidazolidin-1-yl) phenyl] -2-methylpropanoate To a solution of 3.7 ml of trichloromethyl chloroformate (diphosgene) in 1 ml of toluene, under argon, 1 g of 3S black is added. To this suspension cooled to -20 ° C is added 4.3 g of methyl 2- (4-aminophenyl) -2-methylpropanoate obtained in step b) then in solution in 1 ml of toluene. The reaction mixture is heated progressively to room temperature, then brought to reflux for 4 hours. After cooling to room temperature, 16.6 ml of triethylamine and 4.25 g are added. of dimethylglycine methyl ester hydrochloride and the mixture is refluxed for 24 hours, then concentrated under reduced pressure. The residue obtained is taken up with ethyl ether and water, the phases are separated and the organic phase is dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give 1.23 g of 2- [4- (4, Methyl 4-dimethyl-2,5-dioxoimidazolidin-1-yl) phenyl] -2-methylpropanoate whose characteristics are the following: Mass spectrum (ES): m / z = 305 [M + H] + base peak Stage b): methyl 2- (4-aminophenyl) -2-methylpropanoate To a solution of 4.68 g of methyl 2-methyl-2- (4-nitrophenyl) propanoate in 200 ml of ethanol, under argon, 0 is added, 5 g of palladium on carbon (10%). The suspension is heated to 55 ° C, then 28 ml of hydrazine are added dropwise at this same temperature and the heating is continued for 3 hours at 55 ° C. After cooling, the reaction medium is filtered over celite and the filtrate is concentrated under reduced pressure to give 4 g of 2- (4-amino-phenyl) -2-methyl-propionic acid methyl ester as a colorless oil. whose characteristics are the following: Mass spectrum (ES): m / z = 194 [M + H] + base peak Phase a): methyl 2-methyl-2- (4-nitrophenyl) propanoate To a solution of 5 g of 2- (4-nitro-phenyl) -2-methyl-propionic acid in 40 ml of methanol, under argon, add 4 ml of sulfuric acid. The reaction medium is refluxed for 3 hours and concentrated under reduced pressure. The residue is taken up in a mixture of ice water and dichloromethane, the phases are separated and the organic phase is dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to give 5.18 g of methyl 2-methyl-2- (4-nitrophenyl) propanoate as a pale yellow solid, the characteristics of which are as follows: Mass spectrum (ES): m / z = 224 [M + H] +; m / z = 194 [M -NO + H] + base peak Example 31 Q: 1 - (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin -1 -yl] methyl.}. Pyridin-2-yl) -3-pyridin-3-ylurea To a solution of 200 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridine- 7-yl) methyl] imidazolidine-2,4-dione obtained in step b) of example 9 in 4 ml of dioxanose are added 53 mg of 3-aminopyridine. The reaction mixture is heated in the microwave at 130 ° C for 20 minutes and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 129 mg of 1- (4- {[3-4 (tert-butylphenyl) -5, 5-dimethyl-2,4-dioxoimidazolin-1-yl] methyl.}. Pyridin-2-yl) -3-pyridin-3-ylurea whose characteristics are the following: NMR spectrum 1 H at 400 MHz: 1, 31 (s, 9H); 1, 41 (s, 6H); 4.61 (s, 2H); 7.03 (dd J = 1, 5 and 5.5 Hz, 1 H); 7.33 (partially masked m, 1 H); 7.36 (d, J = 8.5 Hz, 2H); 7.52 (m, 3H); 8.03 (broad d, J = 8.0 Hz, 1 H); from 8.21 to 8.28 (m, 2H); 8.70 (d, J = 2.5 Hz, 1 H); 9.70 (broad s, 1 H). Mass spectrum (ES): m / z = 487 [M + H] +; m / z = 485 [MH] "Example 31 P: 1 - (4- { [3- (4-tert-butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolin-1 -yl] methyl.}. pyridin-2-yl) urea To a solution of 250 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2-thioxo-2H- [1, 2,4] oxadiazolo [2,3-a] pyridine- 7-yl) methyl] imidazolidine-2,4-dione obtained in phase b) of Example 9 in 5 ml of dioxane, 6.5 ml of a 7 N solution of ammonia in methanol are added. The reaction mixture is heated in the microwave at 130 ° C for 3 hours and concentrated under reduced pressure. The residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to give 54 mg of 1- (4- {[3- (4-tert-butylphenyl) -5,5-dimethyl) -2,4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) urea whose characteristics are the following: 1 H NMR spectrum at 300 MHz: 1.31 (s, 9H); 1, 41 (s, 6H); 4.61 (broad s, 2H); 7.02 (broad d, J = 5.5 Hz, 1 H); 7, 10 (m very spread, 2H); 7.34 (m, 3H), 7.52 (d, J = 8.5 Hz, 2H); 8, 16 (d, J = 5.5 Hz, 1 H); 9.46 (extended m, 1 H). Mass spectrum (ES): m / z = 410 [M + H] +; m / z = 408 [-H] "Example 31 Q: (4- { [3- (4-tert-Butylphenyl) -5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl. methyl pyridin-2-yl) carbamate To a solution 0.5 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in phase a of Example 7 in 15 ml of dioxane are added successively under argon, 146 mg of methyl carbamate, 1.6 g of cesium carbonate, 75 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) [xantphos] and 29 mg of palladium diacetate. The reaction mixture is heated at 1 10 ° C for 1 hour, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and ethyl acetate (80/20 by volume) to give 450 mg of (4-. {[3- (4-tert-butylphenyl) - Methyl 5,5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.}. Pyridin-2-yl) carbamate whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.40 (s, 6H); 3.68 (s, 3H); 4.61 (broad s, 2H); 7.07 (broad d, J = 5.5 Hz, 1 H); 7.33 (d, J = 8.5 Hz, 2H); 7.51 (d, J = 8.5 Hz, 2H); 7.87 (broad s, 1 H); 8.21 (d, J = 5.5 Hz, 1 H); 10, 15 (broad s, 1 H). Mass spectrum (ES): m / z = 425 [M + H] +; m / z = 423 [MH] "Example 31 R: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - { [2- (pyridazin-4-ylamino) pyridine-4- il] methyl.}. imidazolidine-2,4-dione To a solution of 0.872 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a) of Example 7 in 25 ml of dioxane are added successively under argon, 430 mg of 4-aminopyridazine, 2.8 g of cesium carbonate, 156 mg of (9,9-dimethyl-9H-xanthene-3 , 6-diyl) bis (diphenylphosphine) [xantphos] and 50 mg of paiadium diacetate. The reaction mixture is heated at 90 ° C for 6 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 55 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 -. { [2-pyridazin-4-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.32 (s, 9H); 1, 42 (s, 6H); 4.60 (s, 2H); 6.98 (broad s, 1 H); 7.01 (broad d, J = 5.5 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 2H); 7.53 (d, J = 8.5 Hz, 2H); 8, 13 (dd, J = 3.0 and 6.5 Hz, 1 H); 8.29 (d, J = 5.5 Hz, 1 H); 8.83 (d, J = 6.5 Hz, 1 H); 9.26 (d, J = 3.0 Hz, 1 H); 9.81 (s, 1 H). Mass spectrum (ES): m / z = 443 [MH] "; m / z = 445 [M + H] +; Example 40S: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[[6- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino} pyridin-4-yl) methyl] imidazolidine-2,4-dione Step b): 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[[6- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino} pyridin-4-yl) methyl] imidazolidine-2,4-dione To a solution of 0.5 g of 1 - [(2-aminopyridin-4-yl) methyl] -3- (4-tert-butylphenyl) - 5,5-Dimethylimidazolidine-2,4-dione obtained in step c) of Example 7 in 15 ml of dioxane are added successively under argon, 0.32 g of 5-bromo-2- (pyrrolidin-1-methylmethyl) pyridine. obtained in step a) below, 77 mg of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (xantphos), 38 mg of palladium acetate and 1.75 g of cesium carbonate. The reaction mixture is refluxed for 7 hours, then filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (87/13 by volume) to give 62 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1- [ 2-. { [6- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino} pyridin-4-yl) methyl] imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1.41 (s, 6H); 1.69 (m, 4H); 2.46 (m, 4H); 3.60 (s, 2H); 4.54 (broad s, 2H); 6.80 (broad d, J = 5.5 Hz, 1H); 6.82 (broad s, 1H); 7.29 (d, J = 8.5 Hz, 1H); 7.35 (d, J = 8.5 Hz, 2H) ¡7.52 (d, J = 8.5 Hz, 2H) ¡8.11 (d, J = 5.5 Hz, 1H); 8.16 (dd, J = 2.5 and 8.5 Hz, 1H); 8.65 (d, J = 2.5 Hz, 1H); 9.14 (s, 1H). Mass spectrum (ES): m / z = 527 [+ H] +; m / z = 264 [M + 2H] ++ Step a): 5-bromo-2- (pyrrolidin-1-yl methyl) iri di na To a solution of 2 g of 5-bromo-2-formylpyridine in 20 ml of dichloro-1,2-ethane are added successively under argon, 4.55 g of sodium triacetoxyboroide and 0.94 ml of pyrrolidine. The reaction mixture is stirred at room temperature for 1 hour then diluted with dichloromethane and the organic phase is washed with saturated sodium bicarbonate solution, water, a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2 by volume) to give 0.93 mg of 5-bromo-2-pyrrolidin-1-methylmethyl-pyridine, the characteristics of which are following: RN spectrum 1 H at 400 Hz: 1.70 (m, 4H); 2.48 (m, 4H); 3.69 (s, 2H); 7.40 (d, J = 8.5 Hz, 1 H); 7, 99 (dd, J = 2.5 and 8.5 Hz, 1 H); 8.59 (d, J = 2.5 Hz, 1 H). LCMS mass spectrum: m / z = 241: [M + H] + Example 40T: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [2- (5-pyrrolidin-1-methylmethyl) pyridin-3-ylamino) -pyridin-4-ylmethyl] imidazolidine-2,4-dione Step b): 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [2- (5-pyrrolidin-1-ylmethyl-pyridin-3-ylamino) -pyridin-4-ylmethyl] midazolidine- 2, 4-dione To a solution of 500 mg of 1 - [(2-aminopyridin-4-yl) methyl] -3- (4-tert-butylphenyl) -5,5-dimethylimidazolidine-2,4-dione obtained in the step c) of Example 7 in 15 ml of dioxane are added successively under argon, 46 mg of paladip diacetate, 95 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) (Xantphos ), 1. 8 g of cesium carbonate, and 0.39 g of 3-bromo-5-pyrrolidin-1 -methyl-pyridine obtained in step a) below. The reaction mixture is refluxed for 4 hours, then filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (96/4 by volume) to give 90 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [ 2- (5- (pyrrolidin-1-ylmethyl) pyridin-3-ylamino) pyridin-4-ylmethyl] imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.31 (s, 9H); 1, 42 (s, 6H); 1.70 (m, 4H); 2.43 (m, 4H); 3.54 (s, 2H); 4.54 (s, 2H); 6.81 (m, 2H); 7.35 (d, J = 8.5 Hz, 2H); 7.52 (d, J = 8.5 Hz, 2H); 8.00, (d, J = 2.0 Hz, 1 H); 8.07 (d, J = 2.0 Hz, 1 H); 8, 14 (d, J = 5.5 Hz, 1 H); 8.73 (d, J = 2.0 Hz, 1 H); 9.18 (s, 1 H). Mass spectrum (ES): m / z = 527 [M + H] +; m / z = 525 [M-H] "Phase a): 3-bromo-5-pyrrolidin-1-methylmethyl-pyridine To a solution of 5-bromo-3-pyridine carboxaldehyde in 20 ml of dichloro-1,2-ethane are added successively under argon, 4.55 g of sodium triacetoxyborohydride and 0.94 ml of pyrrolidine. The reaction mixture is stirred at room temperature for 3 hours then washed with a saturated solution of sodium bicarbonate, water, a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (80/20 by volume) to give 1.4 g of 3-bromo-5-pyrrolidin-1-methylmethyl-pyridine in the form of a pale yellow oil. Mass spectrum (ES): m / z = 241 [M + H] +; m / z = 161 [M + H] + - Br (base peak) Example 31 U: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[4- (2-pyrrolidin-1-ylethyl) phenyl] amino.}. Pyridin-4-yl) methyl] imidazolidine-2,4-dione Step d: 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [(2- {[[4- (2-pyrrolidin-1-ylethyl) phenyl] amino} pyri din-4-yl) methyl] imidazolidine-2,4-dione To a solution of 1.16 g of 3- (4-tert-butylphenyl) -1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethylimidazolidine-2,4-dione obtained in step a) of Example 7 in 50 ml of dioxane are added successively under argon, 570 mg of 43- (2-pyrrolidin-1-ethylthyl) aniline obtained in step c) below, 3.34 g of cesium carbonate, 210 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl) bis (diphenylphosphine) [xantphos] and 67 mg of diacetate of palladium. The reaction mixture is heated at 90 ° C for 5 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/5 by volume) to give 99 mg of 3- (4-tert-butylphenyl) -5,5-dimethyl-1 - [ 2-. { [4- (2-pyrrolidin-1-ethylthyl) phenyl] amino} pyridin-4-yl) methyl] imidazolidine-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 M Hz: 1.31 (s, 9H); 1, 41 (s, 6H); 1, 68 (m, 4H); 2.46 (m, 4H) from 2.55 to 2.71 (m, 4H); 4.52 (s, 2H); 6.74 (d, J = 5.5 Hz, 1H); 6.80 (s, 1H); 7.09 (d, J = 8.5 Hz, 2H); 7.33 (d, J = 8.5 Hz, 2H); 7.50 (m, 4H); 8.10 (d, J = 5.5 Hz, 1H); 8.90 (s, 1H). Mass spectrum (ES): m / z = 540 [M + H] +; Phase c: 4- (2-pyrrolidin-1-ylethyl) aniline To a solution of 1.22 g of 4- (2-oxo-2-pyrrolidin-1-ylethyl) -annin obtained in step b) then in 100 ml of tetrahydrofuran, 1.1 g of sodium hydride are added under argon. lithium and aluminum. The reaction mixture is stirred one hour at room temperature, then cooled to 0 ° C and treated successively with 1.1 ml of water, 1.1 ml of a 15% sodium hydroxide solution (by weight) and 3.4 ml of water. The solid formed is filtered, washed with ethyl acetate and the filtrate is concentrated under reduced pressure to give 1.15 g of 4- (2-pyrrolidin-1-ylethyl) aniline having the following characteristics: Mass spectrum (ES) ): m / z = 191 [+ H] +; Phase b: 3- (2-oxo-2-pyrrolidin-1-ylethyl) aniline To a solution of 0.8 g of 1 - [(4-nitrophenyl) acetyl] pyrrolidine obtained in step a) then in 20 ml of methanol are added under argon, 1.72 g of ammonium formate and 36 mg of palladium on carbon at 10%. The reaction mixture is stirred at room temperature for 1 hour, then filtered over celite and concentrated under reduced pressure. The residue is taken up in water and extracted with dichloromethane. The organic phase is then washed with water, a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.49 g of 4- (2-oxo-2-pyrrolidine. -1-ethyl) aniline whose characteristics are the following: Mass spectrum (ES): m / z = 205 [M + H] +; Phase a: 1 - [(4-nitrophenyl) acetyl] pyrrolidone To a solution of 3 g of para-nitrobenzoic acid in 50 ml of dichloromethane are added successively under argon at 0 ° C, 1.1 ml of pyrrolidine, 0.199 g of hydroxy benzotriazole, 2.3 g of 1.3 -dimethylaminopropyl-3-ethyl carbodiimide and 4.98 ml of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours, then washed with water. The organic phase is then washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (55/45 by volume) to give 2.98 mg of 1 - [(4-nitrophenyl) acetyl] pyrrolidine whose characteristics are as follows: Mass spectrum (ES): m / z = 235 [+ H] +; Biological assays in vi tro A) Experimental protocol for the IGF-1R kinase assay: The inhibitory activity of the compounds on IGF1R is determined by measuring the inhibition of the autophosphorylation of the enzyme using a temporary redissolution fluorescence assay (HTRF). The human cytoplasmic domain of IGF-1R has been cloned in fusion with glutathione S-transferase (GST) in the baculovirus expression vector pFastBac-GST. The protein is expressed in SF21 cells and approximately 80% homogeneity is purified. For the enzyme assay, the compound to be tested in 10 mM solution in DMSO is diluted stepwise to 1/3 in a 50 mM Hepes buffer, pH 7.5, 25 mM MnCl, 50 mM NaCl, 3% glycerol, Tween 20 al 0.025%. For the measurement of the inhibition, the successive dilutions of the compound are pre-incubated 30 min and 90 min in the presence of 5 nM enzyme, the final concentration of DMSO not exceeding 1%. The enzymatic reaction starts to have 120 μ? of final ATP and is interrupted after 5 min by the addition of Hepes buffer 100 mM, pH 7.0, containing 0.4 M potassium fluoride, 133 mM EDTA, 0.1% BSA, anti-GST antibody labeled with XL665 and antiphosphotyrosine antibody conjugate with europium cryptate Eu-K (Cis-Bio Int.). The characteristics of two fluorophores, XL-665 and Eu-K, are available from G. Mathis et al., Anticancer Research, 1997, 17, pages 3011-3014. The energy transfer between the excited europium cryptate and the XL665 acceptor is proportional to the degree of autophosphorylation of IGF-1R. The XL-665 specific long-term signal was measured in a GENAN Pro TECAN colony counter. Inhibition of IGF-1R autophosphorylation at 30 min and 90 min periods with the tested compounds of the invention is calculated in relation to a reference of 1% DMSO, whose activity is measured in the absence of the compound. A curve is created that represents the% inhibition as a function of the log of the concentration to determine the concentration corresponding to 50% inhibition (IC50). B) Measurement of autophosphorylation of IGF-1R in MCF7 cells after stimulation with IGF-1 Cell culture and assay performance: The autophosphorylation of IGF1R in cells induced by IGF1 is evaluated by an ELISA technique (Enzyme Linked ImmunoSorbent Assay ). The MCF-7 cells are seeded at 60,000 cells per well in 6-well plates and incubated at 37 ° C, 5% C02 in medium containing 10% serum. After one night in 10% serum, serum is removed from the cells for 24 hours. The compounds are added to the medium 1 hour before stimulation with IGF1. After 10 minutes of Stimulation with IGF1, the cells are used with a buffer (50 mM Hepes pH 7.6, 1% Triton X100, 2 mM orthovanadate, mixture of protease inhibitors). Cell lysates are incubated in a 96-well plate precoated with an anti-IGF1 R antibody, followed by incubation with an anti-phosphotyrosine antibody coupled to the enzyme peroxidase. Peroxidase activity level (measured by OD with luminescent substrate) reflects the state of phosphorylation of the receptor. Calculation of the results: (i) The tests are carried out in duplicate and the average of the two tests is calculated. The signal value of the maximum response is calculated from the positive reference: cells stimulated by IGF 1 without compound. (iii) The value of the minimum response signal is calculated from the negative reference: cells not stimulated by IG F 1 without compound. (iv) Using these values as maximum (100%) and minimum (0%) respectively, the data have been normalized so that they give a percentage of the maximum response. (v) A dose response curve is plotted and the IC50 calculated (concentration at which the compound induces a 50% signal decrease) of the compound by non-linear regression analysis. C) M proliferation / visibility of M EF-IGF1 R Cell culture: MEF-IGF1 R cells (stable clone of cells transfected by the hl GF-1 R receptor) are placed in culture at 37 ° C under 5% C02 in EME medium containing 10% SVF. Test procedure: The MCF cells are seeded at 5,000 cells per well in 96-well Cytostar plates (Amersham) with 0.2 ml EM EM culture medium at 37 ° C, for 1 8 hours. The cells are then washed twice with ME MS medium and left in culture without serum for 24 hours, then the compounds are added at different concentrations in the presence of rhIGFI (100 ng / ml) and 0.1 pCi of thymidine [ 14C] (specific activity ~ 50 mCi / mmol) to give 0.2 ml volume per well. After incubation for 72 hours in the presence of the compound, at 37 ° C in 5% C02, the incorporation of [14 C] thymidine is measured by counting the radioactivity in a Microbeta trilux counter (Perkin-Elmer). The IC50 determination is made from 10 increasing concentrations of the compound. Calculation of the results: (i) The tests are carried out in duplicate and the average of the two tests is calculated. (ii) The signal value of the maximum response is calculated from the positive reference: cells stimulated by IGF 1 without compound. (iii) The signal value of the minimum response is calculated from the negative reference: cells not stimulated by I GF1 without compound. (iv) Using these values as maximum (100%) and minimum (0%) respectively, the data has been normalized so that they give a percentage of the maximum response. (v) A dose response curve is plotted and the IC50 (concentration at which the compound induces a 50% signal decrease) of the compound is calculated by non-linear regression analysis.

The following table provides the activities of certain examples of the present invention in the 3 tests A, B and C described above: * For tests A, B and C IC50 (nM) are distributed as follows: + > 100 nM 10 nM < ++ < 100 nM +++ < 10 nM The products of formula (la) as defined above in which the radical NR4R5 has the values indicated above numbered from ex 9 to ex 31 corresponds respectively to examples 9 to 31 belonging to the present invention: the products of Examples 9 to 31 are prepared as indicated in the general synthetic schemes described above. A general method of preparation of ureas (as principally for the preparation of products of Examples 9 to 31) is as follows: 0.3 mmol of. { 4- [3- (4-tert-Butyl-phenyl) -5,5-dimethyl-2, 4-dioxo-imidazolidin-1-ylmethyl-pyridin-2-yl} ethyl carbamate and 3 mmoles of the appropriate amine and heated in 3 ml of N-methyl pyrrolidinone for 2 hours in the microwave at 130 ° C and thus the expected corresponding urea is obtained. He . { 4- [3- (4-tert-Butyl-phenyl) -5,5-dimethyl-2,4-dioxo-imidazolidin-1-ylmethyl] -pyridi n-2-yl} ethyl carbamate can be prepared from 3- (4-tert-butyl-phenyl) -1 - (2-chloro-pyridin-4-ylmethyl) -5,5-dimethyl-imidazolidine-2,4-dione and from ethyl carbamate by palladium coupling as described above in the General Scheme ?? 3- (4-tert-Butyl-phenyl) -1 - (2-chloro-pyridin-4-ylmethyl) -5,5-dimethyl-imidazolidine-2,4-dione can be prepared as indicated in the Schemes Generals above. Example 32: PHARMACEUTICAL COMPOSITION: Tablets are prepared which meet the following formula: Product of example 1 0.2 g Excipient for a tablet c. s. p 1 g (detail of the excipient: lactose, talc, starch, magnesium stearate). Example 33: PHARMACEUTICAL COMPOSITION: Tablets are prepared which meet the following formula: Product of example 8 0.2 g Excipient for a tablet c. s. p 1 g (detail of the excipient: lactose, talc, starch, magnesium stearate).

Claims (6)

CLAIMS 1. Products of formula (I): wherein: Ra and Rb represent CH3 or form together with the carbon atom to which a cycloalkyl radical is attached, Xi and X2 are such that: either one represents hydrogen and the other represents alkyl, either one represents -OCF3 or - SCF3 and the other represents the radical NH-CO-R6, either X1 and X2 form with the phenyl radical to which they are attached a dihydroindole radical occasionally substituted by one or more alkyl radicals and at its nitrogen atom by a radical CO-alkyl -R3, R represents a pyridyl or pyrimidinyl radical substituted by a radical NR, R2, where NRi R2 is such that: one of R1 and R2 represents a hydrogen atom or an alkyl radical, and another of R1 and R2 is selected from the hydrogen atom and the alkyl radicals optionally substituted by a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radicals and the piperazinyl itself occasionally substituted on its second nitrogen atom by an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals; and the radical CO-R3 with R3 selected from NR4R5 and the alkoxy, heterocycloalkyl, aryl, aryloxy and heteroaryl radicals, occasionally substituted; R4 and R5, identical or different from R1 and R2, are such as: either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and another of R4 and R5 is selected from the hydrogen atom and the alkyl radicals optionally substituted by a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radicals and the piperazinyl itself occasionally substituted on its second nitrogen atom by an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals; either R4 and R5 form, with the nitrogen atom to which they are attached, a cyclic amine containing occasionally another heteroatom selected from N and O, occasionally substituted, all the above aryl, phenyl, aryloxy and heteroaryl radicals as well as the cyclic amine NR4R5 , which are optionally substituted by one to three identical or different radicals selected from the halogen atoms, the alkyl, phenyl, N H2, N HAIk, N (Alk) 2, CO-NHAIk and CO-N (Alk) 2; Re represents alkyl optionally substituted by one or more identical or different radicals selected from the values of said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). 2. Products of formula (I) such as those defined in claim 1: wherein: Ra and Rb represent CH3) i and X2 have the meaning indicated in claim 1, R represents a pyridyl or pyrimidinyl radical substituted by a radical NR-, R2 being such that: one of R and R2 represents a hydrogen atom or an alkyl radical, and another of R1 and R2 is selected from the hydrogen atom and the alkyl radicals optionally substituted by a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radicals or the piperazinyl itself occasionally substituted at its second nitrogen atom by an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals; and the radical CO-R3 with R3 selected from NR4R5 and the alkoxy, piperidyl, phenyl and phenoxy radicals occasionally substituted; R4 and R5, identical or different from R1 and R2, are such that: either one of R and R5 represents a hydrogen atom or an alkyl radical, and another of R4 and R5 is selected from the hydrogen atom and the radicals alkyl optionally substituted by a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radicals and the piperazinyl itself occasionally substituted on its second nitrogen atom by an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals; either R4 and R5 form, with the nitrogen atom to which they are attached, a cyclic amine that occasionally contains another heteroatom selected from N and O, occasionally substituted, all the above radicals phenyl, pyrimidinyl and pyridyl, which are optionally substituted by each other three identical or different radicals selected from halogen atoms, alkyl, phenyl, NH2, NHAIk, N (Alk) 2, CO-NHAIk et CO- radicals N (Alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). 3. Products of formula (I) as defined in claim 1 or 2, wherein: Xi and X2 are such that either one represents hydrogen and the other represents an alkyl radical, either one represents -OCF3 or -SCF3 and the other represents the radical NH -CO-R6, either Xi and X2 form with the phenyl radical to which a dihydro-nol radical is attached, occasionally substituted by one or several alkyl radicals and at its nitrogen atom by the radical CO- CH2-NH-cycloalkyl, R represents a pyridyl or pyrimidinyl radical substituted by a radical NR ^, where N RT R2 is such that it represents a hydrogen atom or an alkyl radical, and R2 is selected from the hydrogen atom and optionally substituted alkyl radicals by a hydroxyl radical, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or the piperazinyl itself occasionally substituted on its second nitrogen atom by an alkyl radical; the cycloalkyl radicals that they have 3 to 6 links; the optionally substituted phenyl radical; the pyrimidinyl radical; the pyridyl radical optionally substituted by a halogen atom; and the radical CO-R3 with R3 selected from NR4R5 and the alkoxy, piperidyl and phenyl radicals occasionally substituted; R4 and R5, identical or different from Rn and R2, are such that: either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and another of R4 and R5 is selected from the hydrogen atom and the radicals alkyl optionally substituted by a hydroxyl, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl radical or the piperazine itself occasionally substituted on its second nitrogen atom by an alkyl radical; the cycloalkyl radicals having 3 to 6 links; the optionally substituted phenyl radical; the pyrimidinyl radical; the pyridyl radical optionally substituted by a halogen atom; either R4 and R5 form with the nitrogen atom to which they are attached an aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholyl nyl radical or the piperazinyl itself optionally substituted on its second nitrogen atom by an alkyl radical, all phenyl radicals being optionally substituted by one to three identical or different radicals selected from the halogen atoms, the alkyl radicals and the radicals CO-NHAIk and CO-N (Alk) 2; R6 represents optionally substituted alkyl by one or more identical or different radicals selected from the values of Ra, said products of formula (I) in all isomeric forms, racemic, enantiomeric and diastereoisomeric, as well as the addition salts with the organic and organic acids or with the mineral and organic bases of said formula products (I) 4. Products of formula (I) as defined in any one of the preceding claims wherein and X2 are such that: either one represents hydrogen and the other represents a tere-butyl radical, either one represents -OCF3 or - SCF3 and the other represents the radical NH-CO-CH (NH2) -phenyl, well and X2 form with the phenyl radical to which a dihydroindol radical substituted by two methyl radicals and at its nitrogen atom by the radical CO- are attached. CH2-NH-cyclopentyl, R represents a pyridyl or pyrimidinyl radical substituted by a radical NR1 R2, where N Rt R2 is such that R1 represents a hydrogen atom or an alkyl radical having one or two carbon atoms, and R2 is selects from alkyl radicals having 1 to 4 carbon atoms optionally substituted by a hydroxyl radical; the optionally substituted phenyl radical; the radical piri mi di nil o; the pyridyl radical optionally substituted by a halogen atom; and the radical CO-R3 with R3 selected from piperidyl, optionally substituted phenyl, NH-cycloalkyl, NH2, NH (alk) and N (alk) 2; all phenyl radicals being optionally substituted by one to three identical or different radicals selected from the halogen atoms, the alkyl radicals and the radicals CO-NHAIk and CO-N (Alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the organic and mineral acids or with the mineral and organic bases of said products of formula (I). 5. Products of formula (I) as defined in any one of the preceding claims wherein ? ? and X2 have the meanings indicated in any one of the preceding claims R represents a pyridyl or pyrimidinyl radical substituted by a radical NR 1 R 2 in which R represents a hydrogen atom and R 2 represents a pyrimidinyl or pyridyl radical; CO-N (CH3) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). 6. Products of formula (I) as defined in any one of the preceding claims wherein ?, X2. Ra, Rb and R have the meanings indicated in any one of the preceding claims, and the radicals R! R2 or NR4R5 or NRTR2 and NR4R5 are selected from the following radicals designated ex 9 to ex 31: ej13 ej14 ej15 ej 16 ej22 ej23 ej24 ej25 ej28 ej27 ej29 ej30 ej31 said products of formula (I) being in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (I). 7. Products of formula (I) as defined in any one of the preceding claims pertaining to formula (la): wherein n and NR R5 have the definitions indicated for any one of the preceding claims and especially in claim 6, said products of formula (la) being in all possible racemic, enantiomeric and diastereomeric isomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said formula products (la). 8. Products of formula (I) as defined in any one of the preceding claims, the names of which are the following: 3- (4-tert-butyl-phenyl) -5,5-dimethyl-

1 - [

2- (pyridine -3-ylamino) -pyrimidin-4-ylmethyl] -imidazolidine-2,4-dione

3- (

4- { [3- (4-tert-Butylphenyl) -5,

5-dimethyl-2,4-dioxoimidazolidin-1-yl] methyl.} Pyrimidin-2-yl) -1, 1- dimethylurea 3- [4- (. {3- [1- (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1H-indol-

6-M] -5,5-dimethyl-2 , 4-dioxoimidazolidin-1-yl.} MetM) pyridin-2-yl] -1, 1-dimethylurea-3- [1- (N-cyclopentylglycyl) -3,3-dimethyl-2,3-dihydro-1 H-indol-6-yl] -5,5-dimethyl-1-. { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione (2R) -2-amino-N- [5- (4,4-dimethyl-2,5-dioxo-3 { [2- (pyridin-3-ylamino) pyridine- 4-yl] methyl.}. Imidazolidin-1-yl) -2- (trifluoromethoxy) phenyl] -2-phenylacetamide (2R) -2-amino-N-. { 5- (4,4-DimetM-2,5-dioxo-3 { [2- (pyridin-3-ylamino) pyridin-4-yl] methyl.}. Imidazolidin-1-yl) -2- ( trifluoromethyl) thio] phenyl] -2-phenylacetamide - (2R) -2-amino-N-. { 5- [3- (2 - [(Dimethylcarbamoyl) amino] pyridin-4-yl.} Methyl) -4,4-dimethyl-2,5-dioxoimidazolin-1-yl] -2- (trifluoromethoxy) phenyl} -2-phenylacetamide (2R) -2-amino-N-. { 5- [3- (2 - [(dimethylcarbamoyl) amino] pyridin-4-yl] methyl) -4,4-dimethyl-2,5-dioxoimidazolin-1-yl] -2 - [(trifluoromethyl) thio] phenyl } -2-phenylacetamide-3- (4-tert-butylphenyl) -5,5-dimethyl-1-. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} imidazolidine-2,4-dione-3- (4-tert-butylphenyl) -5,5-dimethyl-1-. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] metM} imidazolidine-2,4-dione being said products of formula (I) in all forms possible racemic, enantiomeric and diastereomeric isomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases of said products of formula (I). 9. As medicaments, the products of the formula (I) as defined in claims 1 to 8, as well as their prodrugs, said products of the formula (I) being in all possible forms of isomers, racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of said products of the formula IO- I O. As medicaments, the products of formula (I) as defined in claim 8, as well as their prodrugs, said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereomeric forms, as well as as the addition salts with the mineral and organic acids or with the pharmaceutically acceptable organic and mineral bases of said products of formula (I). eleven . Pharmaceutical compositions containing, as an active ingredient, at least one of the medicaments as defined in claims 9 and 10. 12. The pharmaceutical compositions as defined in the preceding claims, which additionally contain active ingredients of other medicaments. chemotherapy against cancer. 13. The pharmaceutical compositions according to any one of the preceding claims, characterized in that they are used as medicaments, in particular for the chemotherapy of cancers. 14. Use of products of formula (I) as defined in any one of the preceding claims or of the pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicaments intended to inhibit the activity of protein kinases and mainly of a protein kinase. 15. Use of products of formula (I) as defined in the preceding claim or of the pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is a protein tyrosine kinase. 16. Use of products of formula (I) as defined in any one of the preceding claims or of the pharmaceutically acceptable salts of said products of formula (I), wherein the protein kinase is IGF 1 R. 1 7. The use of the products of the formula (I) as defined in any one of the preceding claims, or of the pharmaceutically acceptable salts of said products of the formula (I) for the preparation of a medicament intended to prevent or treat a disease that belongs to the following group: disorders of the proliferation of vessels blood disorders, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retnopathies, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, oncology diseases and cancers. 18. Use of the products of the formula (I) as defined in any one of the preceding claims, or of the pharmaceutically acceptable salts of said products of the formula (I) for the preparation of a medicament intended to treat cancers. 19. Use of products of formula (I) according to the preceding claim, in which the disease to be treated is a cancer of solid or liquid tumors. 20. Use of products of formula (I) according to the preceding claim, in which the disease to be treated is a cancer resistant to cytotoxic agents. twenty-one . Use of products of formula (I) according to any one of the preceding claims or of the pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to treat cancers, including breast, stomach cancers , colon, lung, ovary, uterus, brain, kidney, larynx, lymphatic system, thyroid, genitourinary system, duct that includes the gallbladder and prostate, bone cancer, pancreas and melanomas. 22. Use of products of formula (I) according to the preceding claim, wherein the disease to be treated is a breast, colon or lung cancer. 23. Use of the products of the formula (I) as defined in any one of the preceding claims, or of the pharmaceutically acceptable salts of said products of the formula (I) for the preparation of a medicament for chemotherapy of cancers. 24. Use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of drugs destined for the chemotherapy of cancers used alone or associated to others. 25. Use of products of formula (I) as defined in any one of the preceding claims or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicaments intended for use alone or in association with others with chemotherapy or radiotherapy or alternatively associated with other therapeutic agents. 26. Use of the products of the formula (I) according to the preceding claim, in which the therapeutic agents may be the antitumor agents commonly used. 27. Products of formula (I) as defined in any one of the other preceding claims, as IGF1R inhibitors, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the pharmaceutically acceptable mineral and organic bases of said formula products (I), as well as their prodrugs.