MX2008009473A - Sulphur-containing 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 n is 0 or 2;R is pyridyl or pyrimidinyl substituted with an NR1R2 radical, in which one of R1 and R2 is hydrogen or alkyl and the other of R1 and R2 is hydrogen or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl, pyridyl, and CO-R3 with R3 chosen in particular from amino, alkoxy, heterocycloalkyl, aryl, aryloxy and heteroaryl radicals;all these radicals being optionally substituted;and the salts thereof.

Description

DERIVATIVES NEW AZU FRADOS DE U REA CÍCLICA. YOUR PREPARATION AND YOUR PHARMACEUTICAL UTILIZATION AS KINASE INHIBITORS The present invention relates to novel sulfurized cyclic urea derivatives, to their preparation process, to their application as medicaments, to the pharmaceutical compositions containing them and to the pharmaceutical use of said derivatives for the prevention and treatment of conditions that may be modulated by the inhibition of the activity of the protein kinases. The present invention relates to novel cyclic urea derivatives having inhibitory effects of protein kinases. The products of the present invention can thus be used primarily for the prevention or treatment of conditions that can be modulated by the inhibition of protein kinase activity. The inhibition and regulation of protein kinases are mainly a novel mechanism of potent action for the treatment of a large number of solid or liquid tumors. Said conditions that can be treated by the products of the present application are, therefore, very especially solid or fluid tumors. Said protein kinases belong mainly to the following group: EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PLK. PDGFR, tie2, VEG FR, AKT and Raf. The protein kinase IGF 1 -R (Growth Factor Receptor of lnsulin-1) is most especially indicated. 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, mainly I GF-1 R (Receptor Growth Factor I nsulin 1), play an important role in numerous cancers. The inhibition of said 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 novel products that inhibit said 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 kinases 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., 1995, 9, pages 576-596]. Serine / threonine kinases are, for example, the isoforms of protein kinases C [A. C. Newton, J. Biol. Chem., 1 995, 270, pages 28495-28498] and a group of kinase-dependent cyclins, such as cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, pages 1 95-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 elevated levels of protein kinase activity have been implicated in numerous diseases resulting from abnormal cellular functions. This may come either directly or indirectly from a dysfunction in the control mechanisms of the kinase activity bound, for example, to a mutation, an overexpression or an inappropriate activation of the enzyme, or by an over or underproduction of cytokines or 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 receptor-like growth factor receptor 1 (IGF-IR) is a transmembrane receptor with tyrosine kinase activity that binds first to IGF-I but also to IGF-II and insulin with a higher affinity. weak. The binding of IGF1 to its receptor leads to oligomerization of the receptor, activation of tyrosine kinase, intermolecular autophosphorylation and phosphorylation of cellular substrates (main 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 highlight 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 its 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 widely documented that IGF-I-R is necessary to establish 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 essential for the transformation activity of several oncogenes: EGFR, PDGFR, the SV40 virus T antigen, activated 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 substrate independent growth. IGF-I-R has also been shown as a protector of apoptosis induced by chemotherapy, radiotherapy and apoptosis induced by cytokines. In addition, the inhibition of endogenous IGF-I-R by a dominant negative, the formation of a triple helix or the expression of an antisense 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 the integrins, family of heterodimeric receptors of cell adhesion. FAK and integrins are colocalized in perimembrane structures called adhesion plates. It has been shown 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, 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 in tyrosine 925, thus incorporating the Grb2 adapter protein and inducing in certain 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: 13189-131951997]. Activation of FAK can also induce the signaling pathway of the Jun-NH2-terminal kinase (JNK) and produce the progression of cells towards the Q1 phase of the cell cycle [Oktay et al., J. Cell. Biol.145: 1461-1469 1999]. The phosphatidylinositol-3-OH-kinase (PI3-kinase) also binds to 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: 2606-26131996]. 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 have an important role in cell proliferation and / or survival in vitro. For example, in CHO cells, some authors have shown that overexpression of p125FAK results in an acceleration of the G1 to S transition, suggesting that p125FAK promotes cell proliferation [Zhao J.-H et al. J. Cell Biol.143: 1997-2008 1998]. Other authors have shown that tumor cells treated with FAK antisense 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 and deficiencies of cell migration in response to chemotactic signals and these defects are suppressed by a reexpression of FAK [D. J. Sieg et al., J. Cell Science. 112: 2677-91 1999]. 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 in human astrocytoma cells favors the migration of cells. The involvement of FAK in the stimulation of proliferation and the migration of cells in numerous cell types in vitro, suggests the potential role of FAK in neoplastic processes. A recent study has effectively demonstrated the increased proliferation of tumor cells in vivo after the induction of FAK expression in human astrocytoma cells [Cary L. A. et al. J. Cell Sci. 109: 1787-94 1996; Wang D et al. J. Cell Sci. 113: 4221 -4230 2000]. In addition, immunohistochemical studies of human biopsies have shown that FAK was overexpressed in cancers of the prostate, breast, thyroid, colon, melanoma, brain and lung, with FAK expression level directly correlated with tumors presenting the most severe phenotype. aggressive [Weiner T. M. et al. Lancet. 342 (8878): 1024-1025 1993; Owens et al. Cancer Research. 55: 2752-2755 1995; M aung K. et al. Oncogene 18: 6824-6828 1 999; Wang D et al. J. Cell Sci. 1 13: 4221 -4230 2000]. AKT protein kinase (also known by the name of PKB) and phosphoinositide 3-kinase (PI 3K) are involved in a cell signaling pathway that transmits signals from growth factors that activate membrane receptors. This transduction pathway is involved in multiple cell functions: regulation of apoptosis, control of transcription and translation, glucose metabolism, angiogenesis and mitochondrial integrity. First identified as a major player 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 different stimuli in a certain number of cell types and tumor cells. According to these findings, it has been shown that AKT could, by phosphorylation of given serine residues, inactivate BAD, GSK3D, caspase-9, the Forkhead transcription factor and activate IKKalfa and e-NOS. It is interesting to indicate that the BAD protein is hyperphosphorylated in 11 human tumor cell lines of 41 studied. Furthermore, it has been shown that hypoxia modulated the induction of VEGF in cells transformed with Ha-ras by activating the PI3K / AKT pathway and involving the transcription factor binding sequence HIF-1 (hypoxia-inducible factor-1) called HRE by «hypoxy-responsive-element». AKT plays a very important role in cancer pathologies. Amplification and / or overexpression of AKT has been shown in numerous human tumors such as gastric carcinoma (amplification of AKT1), ovarian, breast or pancreatic carcinomas (amplification and overexpression of AKT2) and receptor-deficient breast carcinomas of estrogens as well as prostate carcinomas independent of androgens (overexpression of AKT3). In addition, AKT is constitutively activated in all PTEN (- / -) tumors, PTEN phosphatase being deleted 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. et al., Am J Pathol 1998 Jan; 152 (1): 51-61; Mazure NM et al., Blood 1997, 90, 3322-3331; Zhong H. et al. Cancer Res. 2000, 60, 1541-1545). The subject of the present invention is the products of general formula (I): wherein: n represents the integer 0 or 2 Ra and Rb represent CH3 or form together with the carbon atom to which a cycloaikyl radical is attached, R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1 R2, where N R1 is R2 such that: one of R1 and R2 represents a hydrogen atom or an alkyl radical, and the other of R1 and R2 is selected from the hydrogen atom and alkyl radicals optionally substituted with a radical selected from hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, and piperazinyl itself optionally substituted on its second nitrogen atom with an alkyl radical; optionally substituted cycloaicyl, heterocycloalkyl, aryl and heteroaryl radicals; and the radical CO-R3 with R3 chosen from NR4R5 and the optionally substituted alkoxy, heterocycloalkyl, aryl, aryloxy and heteroaryl radicals; R4 and R5, identical or different from R1 and R2, are such that: either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and the other of R4 and R5 is chosen from the hydrogen atom and the radicals alkyl optionally substituted with a radical selected from the hydroxyl, alkoxy, aziridyl, azetidyl, pyrrolidinyl, piperidyl, morpholinyl, and piperazinyl radicals itself optionally substituted on its second nitrogen atom with an alkyl radical; the radicals are optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl; either R4 and R5 form with the nitrogen atom to which they are attached a cyclic amine optionally containing another heteroatom selected from N and O, optionally substituted, all the above radicals being aryl, phenyl, aryloxy, and heteroaryl as well as the cyclic amine NR4R5 optionally substituted with one to three identical or different radicals chosen from halogen atoms, alkyl, phenyl, NH2, NHAIk, N (Alk) 2, 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 mineral and organic acids or with the mineral and organic bases of said products of formula (I). It can be indicated 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: n represents the integer 0 or 2, Ra and Rb represent CH3, R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1 R2, where NR1 R2 is such that: one of R1 and R2 represents a hydrogen atom or an alkyl radical, and the other of R1 and R2 is selected from the hydrogen atom and alkyl radicals optionally substituted with a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, or piperazinyl radicals itself substituted optionally at its second nitrogen atom with an alkyl radical; the cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals, optionally substituted; and the radical CO-R3 with R3 chosen from NR4R5 and the optionally substituted alkoxy, piperidyl, phenyl and phenoxy radicals; R4 and R5, identical or different from R1 and R2, are such that: either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and the other of R4 and R5 is chosen from the hydrogen atom and the radicals alkyl optionally substituted with a radical selected from the hydroxyl, alkoxy, aziridyl, azetidyl, pyrrolidinyl, piperidyl, morpholinyl, or piperazinyl radicals itself optionally substituted on its second nitrogen atom with an alkyl radical; the cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals, optionally substituted; either R4 and R5 form with the nitrogen atom to which they are attached a cyclic amine optionally containing another heteroatom chosen from N and O, optionally substituted, all the above radicals being phenyl, pyrimidinyl and pyridyl optionally substituted with one to three identical or different chosen among the halogen atoms, the alkyl, phenyl, NH2, NHAIk, N (Alk) 2, CO-NHAIk and CO-N (Alk) 2 radicals; 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 formula (I) and in the text that follows, the terms have the following meanings: - the term 'Hal', 'Halo' or halogen designates the fluorine, chlorine, bromine or iodine atoms and preferably fluorine and chloro - the term "alkyl radical" or "alk" designates a straight or branched radical comprising at most 12 carbon atoms, chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, fer-butyl, pentyl, isopentyl, sec-pentyl, ferc-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, ferc-hexyl and likewise heptyl, octyl, nonyl, decyl, undecyl and dodecyl, as well as their linear or branched positional isomers, Most particularly cited are alkyl radicals having a maximum of 6 carbon atoms, and in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, fer- t-butyl, linear or branched pentyl and straight or branched hexyl radicals. the term "alkoxy radical" denotes a linear or branched radical comprising at most 12 carbon atoms and preferably 6 carbon atoms, chosen for example from the methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy, hexoxy radicals and heptoxy, as well as their linear or branched positional isomers. the term "non-radical cycloalkyl" designates a monocyclic or bicyclic carbocyclic radical comprising from 3 to 10 links 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 being optionally substituted as indicated above: are cited, for example, the formyl, acetyl, propionyl, butyryl or benzoyl radicals, or in addition, valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl. It is indicated that the radical CO-R3 can take primarily the values defined above for -CO-r. - the term aryl radical refers to unsaturated, monocyclic radicals or those formed by condensed and carbocyclic rings. As examples of such a radical aryl, phenyl or naphthyl radicals may be mentioned. The phenyl radical is more especially 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 the oxygen, nitrogen or sulfur atoms: as heterocycloalkyl radicals, the dioxolane radicals may be mentioned in particular. dioxane, dithiolane, thiooxolane, thioxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholyl nyl or further tetrahydrofuryl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolyl nyl, piperidinyl, perhydropyranyl, pyrindolinyl, tetrahydroquinoline, tetrahydroisoquinoline or thioazolidinyl, all of these radicals being optionally substituted. Among the heterocycloalkyl radicals, there may be mentioned more particularly the optionally substituted piperazinyl radicals, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or thioazolidinyl. The term "heteroaryl radical" refers to a partially or fully unsaturated carbocyclic radical consisting of 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, citing furyl radicals, such as 2-furyl, thienyl, such as 2-thienyl and 3-thienyl, pyrrolyl, diazolium, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl oxadiazolyl, 3 or 4-isoxazolyl, imidazolyl, pi razolyl and isoxazolyl . Among the 6-membered heteroaryl radicals, mention may be made, in particular, of the pyridyl radicals, such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyridyl, pyrimidinyl, pi-ridacinyl, pyrazinyl and tetrazolyl. As condensed heteroaryl radicals containing at least one heteroatom selected from sulfur, nitrogen and oxygen, there may be mentioned, for example, benzothienyl, such as 3-benzothienyl, benzofuryl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl, purinyl, qui nolei nilo, isoqui noleinilo and naftiridinilo.

Among the fused heteroaryl radicals, the benzothienyl, benzofuranyl, indolyl or quinoleinyl, benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl radicals can be especially mentioned. , 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) into a product of formula (I). For example, an ester of a product of 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 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 formula (I) products containing a hydroxy group can be prepared from acidic moieties, such as those described by Bundgaard et. al., J. Med. Chem., 1989, 32, pages 2503-2507: these asters include primarily substituted (aminomethyl) -benzoates, dialkylamino-methylbenzoates in which the two alkyl groups may be linked together or may be interrupted by an oxygen atom or by an optionally substituted nitrogen atom or by 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 -i I) benzoates. The carboxy radical (s) of the products of formula (I) can be salified or esterified by different groups known to the person skilled in the art, among which the following compounds may be mentioned as non-limiting examples. - between the salification compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine,? ? -dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine and N-methylglucamine, - among the esterification compounds, the 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, as for example, in the chloromethyl, hydroxy propyl, methoxymethyl, propionyloxy methyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups. Esterified carboxyl means, for example, radicals such as alkyloxycarbonyl radicals, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl. Mention may also be made of radicals formed with easily degradable ester residues, such as methoxymethyl or ethoxymethyl radicals; acyloxyalkyl radicals, such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals, such as methoxycarbonyloxymethyl or ethyl radicals and isopropyloxycarbonyloxymethyl or ethyl radicals. A list of such radicals can be found, for example, in European patent EP 0 034 536. By "amidified carboxy" are understood the radicals of the type: -CONR4R5 in which the radicals R4 and R5 have the meanings indicated above.

By alkylamino radical NHalk, it is meant the methylamino, ethylamino, propylamino or butylamino, pentylamine or hexylamino, linear or branched radicals. Alkyl radicals having a maximum of 4 carbon atoms are preferred, the alkyl radicals can be chosen from the above-mentioned alkyl radicals. By radical dialkylamino N (alk) 2, it is understood the radicals in which alk takes the values defined above: as above, alkyl radicals having at most 4 carbon atoms chosen from the list indicated above are preferred. Mention may be made, for example, of the dimethylamino, diethylamino or methylethylamino radicals. The term "cyclic amine" designates a cycloalkyl radical having from 3 to 8 links in which a carbon atom is replaced by a nitrogen atom, the cycloalkyl radical has the meaning indicated above and may also include one or more different heteroatoms chosen from "O". , S, S02, N or NR3 with R3 as defined above: Examples of said cyclic amines include, for example, the aziridyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, indolinyl, pirindolinyl or tetrahydroquinolei nyl, optionally substituted: pyrrolidi nyl, pi peridinyl and morpholinium radicals are more particularly mentioned. Salified carboxy means the 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, propylamine, trimethylamine, 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 hydrochloric or methanesulfonic acids, for example. The addition salts with the mineral or organic acids of the products of formula (I) can be, for example, the salts formed with the hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic acids , maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, the alkylsulfonic acids such as, for example, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyldisulfonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, aryimonosulfonic acids, such as benzenesulfonic acid, and aryldisulfonic acids. It can 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, such as occurs mainly in monosubstituted cyclohexanes, in those which the substituent may be in axial or equatorial position, and the different possible rotational conformations 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 invention is in particular the products of formula (I) tai as defined above in which: n represents the integer 0 or 2 R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1 R2, where N R1 R2 is such that R 1 represents a hydrogen atom or an alkyl radical and R 2 is selected from the hydrogen atom and alkyl radicals optionally substituted with a hydroxyl, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or piperazinyl radical, itself optionally substituted on its second nitrogen atom with an alkyl radical; comprising cycloalkyl radicals of 3 to 6 links; the phenyl radical optionally substituted; the pyrimidinyl radical; the pyridyl radical optionally substituted with a halogen atom; and the radical CO-R3 with R3 chosen from NR4R5 and the alkoxy, piperidyl and optionally substituted phenyl radicals; R4 and R5, identical or different from R1 and R2, are such that either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and the other of R4 and R5 is selected from the hydrogen atom and the alkyl radicals optionally substituted with a hydroxyl, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, or piperazinyl radical itself optionally substituted on its second nitrogen atom with an alkyl radical; comprising cycloalkyl radicals of 3 to 6 links; the phenyl radical optionally substituted; the pyrimidinyl radical; the pyridyl radical optionally substituted with a halogen atom; either R4 and R5 form with the nitrogen atom to which they are attached an aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or piperazinyl radical itself optionally substituted on its second nitrogen atom with an alkyl radical, all phenyl radicals being optionally substituted with one to three identical or different radicals chosen from the halogen atoms, the alkyl radicals and the radicals CO-N HAIk 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 mineral and organic acids or with the organic and mineral bases of said products of formula (I). The subject of the invention is essentially the products of formula (I) as defined above in which: n represents the integer 0 or 2 R represents a pyridyl or pyrimidinyl radical substituted with a radical NR 1 R2, where NR1 R2 is such that R1 represents a hydrogen atom or an alkyl radical comprising one or two carbon atoms, and R2 is selected from alkyl radicals comprising from 1 to 4 carbon atoms optionally substituted with a hydroxyl radical; the phenyl radical optionally substituted; the pyrimidinyl radical; the pyridyl radical optionally substituted with a halogen atom; and the radical CO-R3 with R3 selected from pi peridyl, phenyl optionally substituted, NH (alk) and N (alk) 2; all phenyl radicals being optionally substituted with one to three identical or different radicals chosen 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 mineral and organic acids or with the mineral and organic bases of said products of formula (I). The subject of the invention is essentially the products of formula (I) as defined above in which: n represents the integer 0 or 2 R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1 R2, in which R 1 represents a hydrogen atom and R2 represents an isopropyl radical substituted with a hydroxyl radical; an optionally substituted phenyl radical; a pyrimidinyl radical; a pyridyl radical optionally substituted with a fluorine atom; or a radical CO-R3 with R3 chosen from piperidyl, phenyl optionally substituted, NHCH3 and N (CH3) 2; all phenyl radicals being optionally substituted with one to three identical or different radicals chosen from the chlorine and fl uor atoms, the methyl radical and the 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 invention has as its main object the products of formula (I) as defined above in which: n. Ra, Rb and R have the meanings indicated in any one of the preceding claims, in which the radicals NR1R2 or NR4R5 or NR1R2 and NR4R5 are chosen from the following radicals referred to as eg 18 to ex 40: ex 18 ex 19 ex20 ex 21 ej22 ej 23 ej24 ej25 ej26 ej27 ej 28 ej 29 ej30 eg 31 ex 32 ex 33 H HN "HN ^?,? ' I I ej34 ej35 ej 36 ej 37 ej 38 ej 39 ej 40 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) belonging to formula (I) as defined above in which the radical N R1 R2 is chosen from the values ex 18 to ex 40: The present invention it has as its main object the products of formula (I) as defined above belonging to formula (la): . { ta} wherein n and N R4R5 have the definitions indicated above and mainly N R4R5 is chosen from the values eg 18 to ej 40 defined above, said products of formula (la) being in all isomeric possible 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, mention may be made, more precisely, of the products of formula (I) as defined above, the names of which are given below: 1 - (. {2 - [(2,5-dichlorophenyl)) ami no] pyridin-4-yl.} methyl) -5,5-di methyl-3. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] -phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} pi peridin- 1 -carboxamide 3,4- dichloro-N-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide - 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) -sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} 3-methylurea 1 - ( {2 - [(2,5-difluorophenyl) amino] pyridin-4-yl}. Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 3,5-dichloro-N-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide 2-chloro-N-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -6-fluoro-3-methylbenzamide 3- (. {4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] -phenyl} imidazolidin- 1 -yl) methyl] pyridin-2-yl.} Amino) -N, N-dimethylbenzamide 1 - [(2- {[[(1 R) -2-hydroxy-1-methylethyl] amino} pyrimidin -4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione 3-. { 4 - [(5, 5-di methyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] -phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1-dimethylurea 5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidine n-2,4-dione 3-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) -sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1 -di met I urea - 5, 5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] -methyl} -3-. { 4- (trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione 5, 5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridi n-4-yl] -methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 5, 5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidi n-4-yl] -methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 5, 5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] -methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione 1 - (. {2 - [(5-fluoropyridin-3-yl) amino] pyridin-4-yl}. rnethyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione having said products of formula (I) in all 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 products of formula (I) according to the present invention can be prepared according to the usual methods known to the person 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 as, for example, those described by R. C. Larock in: Comprehensive Organic Transformations, VCH publishers, 1989. The products according to the present invention can be prepared primarily as indicated in General Scheme 1, General Scheme 2 and General Scheme 3 below. The preparations of the examples of the present invention are provided in the illustrations of the following Schemes. Said synthesis schemes form part of the present invention: thus the present invention has as its object the processes of preparation of the products of formula (I) as defined in General Scheme 1, constituted by General Scheme 1 A and by the General Scheme 1 B, General Scheme 2 and General Scheme 3 above. General Scheme 1 A: In General Scheme 1A: Alcohol B can be obtained by treating aldehyde A with 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 C can be obtained from alcohol B, as in the conditions described by Fucase K. et al. (Tetrahedron Lett, 1991, 32 (32), 4019-4022) by treatment with thionyl chloride in the presence of DM F in a solvent such as dichloromethane at a temperature comprised between 0 ° C and 20 ° C. The isocyanate E can be obtained from the anilines D 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. M ed. Chem. (1991), 34 (1), 281 -90) Hydantoin F can be obtained from isocyanate E by reaction with methyl 2,2-dimethyl glycinate in a solvent such as toluene or α, ? -dimethylformamide at a temperature comprised between 20 ° C and the reflux of the solvent as described for example Brana M. F. (J. Het Chem. (2002), 39 (2), 41 7-420 The product G can be prepared by reaction of the products F and C with sodium hydride in tetrahydrofuran or N, N-dimethylformamide at a temperature between 0 ° C and 60 ° C as described by Johnson TA et al. (J. Am. Chem. Soc. (2002), 124, 1 1689-1 1698).

The product of general formula H can be prepared either by reaction of G with meta-chloro 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, I. H. et al. (Bull Korean Chem Soc (2002), 23 (12), 1823-1826). Well by reaction of F with P (general scheme 1B) in the presence of sodium hydride in tetrahydrofuran or N, N-dimethylformamide at a temperature comprised between 0 ° C and 60 ° C as described for the preparation of compound G The products of general formula I and L can be prepared by reacting H with ammonia in solution in water and / or dioxane or with an amine (RNH2) in solution in dioxane in a sealed tube in a microwave oven or by heating at temperatures between 40 ° C. and 1 50 ° C or as described by Font, D et al. (Synthesis (2002), (13), 1 833-1 842). The products of formula J can be prepared from I by reaction with an aryl or heteroaryl bromide (R2-Br) in the presence of a palladium-based catalyst such as palladium acetate and a ligand such as Xantphos (9, 9-dimethyl-4,5-bis (diphenylphosphino) xanthene) 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 products of general formula K can be obtained by reacting I with an isocyanate (R 4 -N = C = 0) using the usual methods known to the person skilled in the art. General Scheme 1 B: In General Scheme IB: Intermediates H for which n = 2 can be prepared as described in general scheme 1 A and intermediates H for which n = 0 can be prepared as described in general scheme 1B The product M can be obtained by treatment of alcohol B with 3,4-dihydro-2H-pyran in dichloromethane in the presence of para-toluene sulfonic acid at a temperature of 20 ° C as described by Greene TW et al. (protective g roups in organic chemistry, John Wiley &Sons 1991, second edition). The product N can be prepared by oxidation of the sulfur following the conditions described for the product H. The product O can be prepared by deprotection of the product N as described by Greene T. W. et al. (protective groups in organic chemistry, John Wiley &Sons 1991, second edition) The product P can be prepared by halogenation of the alcohol O as described in the preparation of product C. General Scheme 2: In General Scheme 2: R 'represents alkyl or aryl as defined in R3 The product R can be prepared by brominating the product Q in the presence of N-bromosucci nimide in a solvent such as carbon tetrachloride as described by Brown, D. J. et al. (Aust J Chem (1974), 2251). The product S can be prepared from the products R and F as described in the preparation of the product G. The product T can be prepared from S by reaction with a carbamate (NH2COOR ') in the presence of a palladium-based catalyst such as that described in the preparation of J. The product U can be prepared either by reaction of the carbamate T with a 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. (Zh. Prikl. Khim. (1 993), 66 (6), 1319-1327). Well from S by reaction with a urea (NH2CONR4R5) in the presence of a palladium-based catalyst such as that described in the preparation of J. The product J can be prepared from S 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 3: In General Scheme 3: R 'represents alkyl or aryl as defined in R3 The alcohol W can be prepared by reducing the V ester 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. et al. (Synlett (1999), (10), 1636-1638). The product X is prepared by chlorination of the alcohol W as described in the preparation of C. The product Y can be prepared from the products F and X using the conditions described for the preparation of G The product Z can be prepared from of the product Y and the carbamate (NH2COOR ') using the conditions described for the preparation of J The product AA can be prepared either by reaction of the product Z with an amine (NH R4R5) as under the conditions described for the product U Well by reaction of the product Y with a urea (NH2CONR4R5) as in the conditions described for the product "J The product AB can be prepared from the product Y and the amine (NH2R2) as in the conditions described for the preparation of the product J. The product AC can be prepared from the Product Y and the amide (NH2COR3) in the presence of a copper catalyst as described by Buchwald SL et al. (J. Am. Chem. Soc. (2001), 123, 7727-7729) In said preparations of the formula products (I) according to the present invention, the starting materials, the intermediates and the products of formula (I), which may be in protected form, may be subjected, if necessary or desired, to one or more of the transformation reactions following, 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 transformation ion of the ketone function in oxime function, e) a reduction reaction of the free or esterified carboxy function in 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 aldehyde, acid or ketone function, h) a reaction of transformation of the nitrile radical into tetrazolyl, i) a reduction reaction of the nitrated compounds in aminated compounds, j) a reaction of elimination of 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) thus obtained in all possible isomeric, racemic, enantiomeric and di astereoi som forms ages.

It can be noted that such reactions of transformation of substituents in other substituents can also be carried out on the starting materials as well as on the intermediates, as defined above, before continuing 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 amino and monoalkylamino, imino, thio groups, which may therefore be protected with appropriate protective 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, 1991. Mention may be made of the following non-exhaustive list of examples of protection of reactive functions: 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 or other radicals known in peptide chemistry, the acyl groups, such as the formyl group, can be protected, for example, in the form of cyclic or non-cyclic ketals or thioketals, such as dimethyl or diethyl ketal or ethylenedioxyketal or diethylthioketal or ethylendithioketal, the acid functions of the The products described above can, if desired, be amidated with a primary or secondary amine, for example in methylene chloride in the presence, for example, of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride at room temperature, - the functions The acids can be protected, for example, in the form of esters formed with the easily degradable esters, such as the benzylic or fer-butyl esters or esters known in peptide chemistry. These reactions a) to k) indicated above can be carried out, for example, as follows: a) The products described above can be subjected, if desired, to the possible carboxy functions, of esterification reactions that can be carried out according to the usual methods known to the person skilled in the art. b) The optional transformations of the ester functions in acid function of the products described above can be carried out, if desired, under the usual conditions known to the person skilled in the art, mainly by acid or alkaline hydrolysis, for example with soda or potash in an 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, primarily fluorine, can be converted, if desired, into the sulphoxy or sulfone functions corresponding under the usual conditions known to the person skilled in the art, such as for example with peracids, such as for example peracetic acid or metachloroperbenzoic acid, or also with ozone, oxone, sodium periodate in a solvent such as, for example, methylene or dioxane at room temperature. Obtaining the sulfoxide function can be favored with an equimolar mixture of the product comprising an alkylthio group and the reactant, such as mainly 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 conversion reaction of a ketone function into oxime can be carried out under the usual conditions known to the person 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 the methods known to the person skilled in the art: the eventual carboxy esterified functions can be reduced, if desired, depending on alcohol by the methods known to the person skilled in the art and mainly with lithium and aluminum hydride 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 mainly methoxy, of the products described above can be converted, if desired, into hydroxyl function under the usual conditions known to the person skilled in the art, for example, with boron tri-boron in a solvent, such as for example methylene chloride, with hydrobromide or pyridine hydrochloride or also with hydrobromic or hydrochloric acid in water or trifluoroacetic acid at reflux. 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 the person skilled in the art, such as for example by the action of manganese oxide to obtain the aldehydes or 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 the person skilled in the art, such as for example by cycloaddition of a metal azide, such as for example the azi hard 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) KOZI MA S. et al. It can be noted that the conversion reaction of a carbamate in urea and especially of a sulfonylcarbamate in sulfonylurea 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 also, if necessary, according to other usual methods known to the person skilled in the art. i) The elimination of protective groups such as those indicated above can be carried out under the usual conditions known to the person skilled in the art, principally by acid hydrolysis carried out with an acid such as hydrochloric, benzenesulfonic or para-toluenesulfonic acid, formic acid or trifluoroacetic or also by catalytic hydrogenation. The phthalimido group can be removed with hydrazine. A list of the different protective groups which can be used, for example, is found in patent BF 2 499 995. j) The products described above can, if desired, be subjected 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 the person 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 the person skilled in the art. The optional reactive functions that are optionally protected are mainly the hydroxy or amino functions. The usual protective groups are used to protect these functions. Mention may be made, for example, of the following protective groups of the amino radical: tere-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl and benzyloxycarbonyl. As the protecting group of the hydroxy radical, radicals such as formyl may be mentioned, chloroacetyl, tetrahydropyranyl, trimethylsilyl and tert-butyldimethylsilyl or. It is understood that the above list is not limiting and that other protective groups, for example, known in peptide chemistry, can be used. A list of such protective groups is found, for example, in French patent BF 2,499,995, 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 BF 2,499,995. The preferred form of elimination is acid hydrolysis by means of acids chosen from hydrochloric, benzenesulfonyl or paratoluenesulfonic, 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. An example of removal of the terbutyldimethylsilyl group by hydrochloric acid is given below in the examples. - 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 conventional conditions known to the person 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 symmetrical or mixed anhydride. The starting materials used to prepare the products of formula (I) according to the present invention can be known and be commercially available or can be prepared according to methods known to the person skilled in the art. The products object of the present invention are endowed with interesting and pharmacological properties: it has been found that they have mainly inhibitory properties of protein kinases. Among these protein kinases, I GF1 R. is mainly mentioned.

The tests provided in the experimental part below 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 general formula (I) of the present invention to be used as medicaments for the treatment of malignant tumors. The products of formula (I) can also be used in the veterinary field. The object of the invention is therefore to apply, as medicaments, the products of general formula (I) acceptable from a pharmaceutical point of view. The subject of the invention is especially the application, as medicaments, of the products whose names are mentioned below: 1 - ( {2 - [(2,5-dichlorophenyl) amino] pyridin-4-yl.} Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione-N-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] -phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} piperidin-1 -carboxamide 3,4-dichloro-N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide 1 -. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) -sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} 3-methylurea 1 - ( {2 - [(2,5-difluorophenyl) amino] pyridin-4-yl}. Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidi n-2,4-dione 3, 5-dichloro-N-. { 4 - [(5, 5-dimethyl-2,4-d-oxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidi n-1-yl) methyl] pyridin-2- il} benzamide - 2-chloro-N-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -6-fluoro-3-methylbenzamide 3- (. {4 - [(5, 5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin -1 -yl) methyl] pyridin-2-yl.}. Amino) -N, N-dimethylbenzamide 1 - [(2- {[[(1 R) -2-hydroxy-1-methyl ethyl] amino} pyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phen l} imidazolidin-2,4-dione 3-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] -phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1-dimethylurea-5, 5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 3-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) -sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1-dimethylurea 5, 5-dimethyl-1 -. { [2- (pyrimidi n-5-ylamino) pyridin-4-yl] -methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione 5, 5-dimethyl-1 -. { [2- (pyrimidi n-5-ylamino) pyridin-4-yl] -methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 5,5-dimethyl-1 -. { [2- (pyrim i din-5-i lamino) pyrimidin-4-l] -methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione-5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] -methyl} -3-. { 4- [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-clione 1 - (. {2 - [(5-fluoropyridin-3-yl) ami] pyridin-4-yl} methyl) -5,5-di methyl-3. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione being said products of formula (I) in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases acceptable from one point of view pharmaceutical of said products of formula (I). The products can be administered parenterally, buccally, perlingually, rectally or topically. The invention also relates to 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 forms are prepared according to the usual methods. The active ingredient 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.mo. , paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers and preservatives. The usual dose, variable according to the subject treated and the condition to be treated, can be, for example, from 10 mg to 500 mg per day in humans, orally. The present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicaments intended to inhibit the activity of protein kinases and primarily 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), wherein 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 pharmaceutically acceptable salts of said products of formula (I), wherein the protein kinase is chosen from the following group: EGFR, Fak, FLK-1, FGFR 1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IG F-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 IGF 1 R.

The present invention also 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 present. 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 pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended for preventing or treating a disease characterized by 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 of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to prevent treating a disease that belongs to the following group: disorders of blood vessel proliferation, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retnopathies, 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 salt is acceptable from a pharmaceutical point of view of said products of formula (I) for the preparation of a medicament intended to treat diseases in oncology. The present invention relates especially to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to treat the 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 especially relates to the treatment of breast, stomach, colon, lung, ovarian, uterus, brain, kidney, larynx, lymphatic system, thyroid, cancer, Genitourinary, nano-canal apparatus that includes the gallbladder and prostate, cancer of the bones, pancreas and melanomas. The present invention also relates more particularly to the treatment of breast, colon and lung cancer. The present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended for chemotherapy of cancers. As drugs 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. As examples of known inhibitors of chimeric proteins, mention may be made in particular of butyrolactone, flavopi ridol, 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, olomucin, Glivec, as well as Iressa. The products of formula (I) according to the present invention can also be advantageously used in combination with antiproliferative agents: as examples of such it is antiproliferative agents but without however being limited to this listAromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, active agents on microtubules, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, can be cited. , COX-2 inhibitors, MP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that decrease the activity of protein kinases and also antiangiogenic compounds, agonists of the gonadorreli na, antiandrogens, bengamides, bisphosphonates and trastuzumab. Mention may also be made, as examples, of antimicrotubulinic agents such as taxoids, vinca alkaloids, alkylating agents such as cyclophosphamide, DNA intercalating agents such as cis-platinum, agents that act on topoisomerase as 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 mineral and organic bases acceptable from a pharmaceutical point of view of said products of formula (I), as well as their prodrugs. The present invention relates especially to products of formula (I) as defined above as inhibitors of IG F 1 R. The present invention relates more particularly to products of formula (I) as defined above as inhibitors. of IGF 1 R. NMR 1 H spectra are recorded on BRUKE R spectrometers at 400 M Hz (ADVANCE DRX-400) or at 300 MHz (BRUKER AVANCE DPX-300). The chemical shifts are given in ppm (d in ppm) - in the solvent dimethylsulfoxide-d6 (DM SO-d6), referred to 2.50 ppm at the temperature of 30 ° C. The mass spectra were performed, either in electrospray (ES) in Q-Tof-2 (Micromass), ZQ (Micromass) and Quattro Premier (Micromass) equipment, or in electronic impact (I E); 70 eV; Micromass GCTof Premier equipment, either in chemical ionization (IC); ammonia reactant gas; Micromass GCTof equipment. The LCMS is performed in Column Hypersil Gold C1 8 3x50 mm particle diameter: 3pm Initial conditions: Solvent A: Water with 0.05% TFA 95% Solvent B: Acetonitrile with 0.05% TFA 5% Flow rate 0.9 ml Pressure at t0: 145b volume injected: 5 pL GRADI ENTE at 7mn Time% A% B 0 95 5 5 5 95 5, 5 5 95 Detector U .V. DAD: 200 < ? < 400 nm, the masses are determined by electrospray (ES +) in the equipment Q-Tof-2 (icromass) The examples whose preparation follows illustrate the present invention without limiting it. Example 1: 1 - ( {2 - [(2,5-Dichlorophenyl) amino] pyridin-4-yl}. Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione Step e): 1 - ( {2 - [(2,5-dichlorophenyl) amino] pyridin-4-yl}. Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 0.8 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) below, of 80 cm 3 of toluene and of 0,45 g of 2,5-dichloroaniline, under an inert atmosphere of argon at a temperature close to 20 ° C, 0 are added , 17 g of palladium acetate, 0.48 g of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene and 2.4 g of cesium carbonate. The reaction medium is heated to reflux for 1 8 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The rest obtained is purified by flash chromatography (SiO2, dichloromethane as eluent). The fractions containing the product are concentrated under reduced pressure. This gives 0.46 g of 1 - (. {2 - [(2,5-dichlorophenyl) ami no] pi-ridin-4-yl} methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: Spectrum R N 1 H at 400 M Hz: 1.45 (s, 6H); 4.58 (s, 2H); 6.92 (broad d, J = 5, 5 Hz, 1 H); 7, 03 (dd, J = 2.5 and 8.5 Hz, 1 H); 7, 1 3 (broad s, 1 H); 7.47 (d, J = 8.5 Hz, 1 H); 7.69 (d, J = 9.0 Hz, 2H); 7.88 (d, J = 9.0 Hz, 2H); 8, 15 (d, J = 5.5 Hz, 1 H); 8, 36 (d, J = 2.5 Hz, 1 H); 8.46 (s, 1 H) Mass Spectrum (ES): m / z = 555 [M + H] + base peak Phase dj .: 1 - [(2-chloropyridin-4-yl) methyl] -5, 5-dimethyl-3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 5 g of 5, 5-dimethyl-3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step c) below in 220 ml of anhydrous THF, in an inert atmosphere of argon at a temperature close to 20 ° C, 0.9 g of sodium hydride are added, stirring is maintained at this temperature for 30 minutes and a solution of 3 g of 2-chloro-4- (chloromethyl) pyridine obtained in the following phase b) is added in 10 ml of anhydrous THF. The reaction medium is heated at 60 ° C for 48 hours. The reaction medium is poured onto ice and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica 40-60 μm (dichloromethane / ethyl acetate 97/03 by volume). The fractions containing the product are concentrated under reduced pressure. Thus, 1.17 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3- are obtained. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione as a white powder whose characteristics are as follows: MP 1 1 1 ° C M ore spectrum (CI): m / z = 447 M NH 4 \ m / z = 430 [M + H] + base peak Phase c): 5, 5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] -phenyl} imidazolidin-2,4-dione To a solution of 4 g of 4- (trifluoromethyl) thio-phenyl isocyanate in 40 ml of toluene, under an inert atmosphere of argon at a temperature close to 20 ° C, 5.12 ml of triethylamine and 2.8 g of a-aminoisobutyric acid methyl ester hydrochloride. The mixture thus obtained is refluxed for 24 hours and cooled to room temperature. The reaction mixture is concentrated to dryness under reduced pressure, the residue obtained is taken up in ethyl ether and filtered. The solid thus obtained is taken up with dichloromethane and washed with water to give 2.76 g of 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: MR NMR 1 H at 300 MHz: 1.44 (s: 6H); 7.62 (broad d, J = 8.5 Hz: 2H); 7.85 (broad d, J = 8.5 Hz: 2H); 8, 72 (mf: 1 H). Mass Spectrum (CI): m / z = 322 M NH Phase b): 2-chloro-4- (chloromethyl) pyridine To a solution of 1.1 g of (2-chloropyridin-4-yl) methanol obtained in step a) below in 200 ml of dichloromethane are added 6.896 ml_ of thionyl chloride and 2.1 ml of dimethylformamide, the mixture of The reaction is stirred for 3 h and 50 ml of water are added dropwise. The solution is dried over magnesium sulfate, filtered and concentrated in vacuo to provide 12.8 g (100%) of product in the form of an amber liquid used as it is without further purification. RfCCM silica = 0.44 (eluent dichloromethane). Phase a): (2-Chloro-pyridin-4-yl) -methanol To a solution of 14.85 g of 2-chloroisonicotinic acid ethyl ester in 300 ml_ of ethanol, 9.08 g of sodium borohydride in small portions are added under argon at 40 ° C for 45 min. After the addition, the reaction mixture is stirred for 15 minutes and then the temperature is gradually increased to reflux which is maintained for 4 h. After returning to room temperature, 50 mL of a saturated solution of ammonium chloride are added and the solvents are evaporated under reduced pressure. The residue is taken up in 200mL of water and extracted with 3x100mL of ethyl acetate, the organic phase is washed with 2x100mL of saturated sodium chloride solution, dried over sodium sulfate and filtered. After evaporating under a reddish pressure, the product is obtained in the form of a white solid 1 1.4 g. RfCCM silica = 0.38 (dichloromethane / methanol 90/10 eluent). Example 2; N-. { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} piperidin-1 -carboxamide The product is prepared following the mode of operation described in Example 1 from 0.4 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thiojphenyl} imidazolidin-2,4-dione obtained in step d) of example 1 and 0.18 g of 1-piperidinecarboxamide instead of 2,5-dichloroaniline used in example 1. After purification by flash chromatography with packed column (SiO 2, dichloromethane / methanol 98/02 in volumes as eluents), 0.21 g of N- is obtained. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenylimide} imidazolidin-1-yl) methyl] pyridin-2-yl} piperidin-1 -carboxamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: from 1.39 to 1.60 (m, 6H); 1, 41 (s, 6H); 3.42 (m, 4H); 4.59 (s, 2H); 7.01 (dd, J = 1.0 and 5.5 Hz, 1 H); 7.67 (d, J = 8.5 Hz, 2H); 7.82 (broad s, 1 H); 7.86 (d, J = 8.5 Hz, 2H); 8, 16 (d, J = 5.5 Hz, 1 H); 9.05 (s, 1 H). Mass Spectrum (ES): m / z = 522 [M + H] + base peak Example 3: 3,4-dichloro-N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide To a solution of 0.7 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1, of 70 cm 3 of dioxane and of 0,63 g of 3,4-dichlorobenzamide, under an inert atmosphere of argon at a temperature close to 20 ° C, 0.16 g of copper iodide, 0.1 g of bis-methylcyclohexanediamine and 0.665 g of potassium carbonate are added. The reaction medium is heated to reflux for 18 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by flash chromatography (Si02, dichloromethane / ethyl acetate 95/05 by volume as eluents). The fractions containing the product are concentrated under reduced pressure. 0.49 g of 3,4-dichloro-N- are thus obtained. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.45 (s, 6H); 4.69 (s, 2H); 7.25 (dd, J = 1.5 and 5.5 Hz, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.79 (d, J = 8.5 Hz, 1H); 7.87 (d, J = 8.5 Hz, 2H); 7.98 (dd, J = 2.0 and 8.5 Hz, 1H); 8.21 (broad s, 1H); 8.28 (d, J = 2.0 Hz, 1H); 8.36 (d, J = 5.5 Hz, 1H); 11.05 (s, 1H). Mass Spectrum (ES): m / z = 583 [M + H] + base peak Example 4: 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3-methylurea.

Phase cj. 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3-methylurea. To a solution of 0.69 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione obtained in the above phase b) in 20 ml of dioxane are added successively under argon, 0.166 g of methyl urea, 1.85 g of cesium carbonate, 0.104 g of 9,9-dimethyl- 4,5-bis (d-phenylphosphino) xanthene and 0.33 g of palladium acetate. The reaction mixture is refluxed for 2.5 hours, concentrated under reduced pressure and the residue is purified on a silica column with a mixture of cyclohexane and ethyl acetate (20/80 by volume) to provide 0.1. 1 g of 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3-methylurea whose characteristics are the following: Spectrum R N 1 H at 400 MHz: 1.44 (s, 6H); 2.73 (d, J = 5.0 Hz, 3H); 4.60 (s, 2H); 6.97 (dd, J = 2.0 and 5.5 Hz, 1 H); 7.30 (broad s, 1 H); 8.04 (d, J = 9.0 Hz, 2H); 8,12 (d, J = 5.5 Hz, -1 H); 8,17 (broad q, J = 5.0 Hz, 1 H); 8.31 (d, J = 9.0 Hz, 2H); 9, 18 (s, 1 H). Mass Spectrum (ES): m / z = 500 [M + H] + base peak Phase b: 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4- [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2, 4-dione To a solution of 5 g of 3- (4-trifluoromethanesulfonyl-phenyl) -5,5-dimethyl-imidazolidin-2,4-dione obtained in step a) below in 180 ml of tetrahydrofuran are added successively under argon, 0.88. g of 60% sodium hydride and 3.61 g of 2-chloro-4-chloromethyl-pyridine. The solution is refluxed for 24 h. The reaction mixture is poured into distilled water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The remainder is purified by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) to provide 2.29 g of 1 - [(2-chloropyridin-4-yl) methyl] -5 , 5-d imetil-3-. { 4- [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.44 (s, 6H); 4.68 (s, 2H); 7.49 (broad d, J = 5.5 Hz, 1 H); 7.42 (broad s, 1 H); 8.07 (d, J = 9.0 Hz, 2H); 8.31 (d, J = 9.0 Hz, 2H); 8.37 (d, J = 5.5 Hz, 1 H). Mass Spectrum (ES): m / z = 462 [M + H] + base peak Phase a): 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) -sulfonyl] phenyl} imidazolidin-2, 4-dione To a solution of 9.56mL of diphosgene in toluene, 2.4 g of animal black (3S black), 1 6.2 g of 4-trifluorosulfonylaniline in 1 50mL of toluene are added successively under argon at -20 ° C followed by 200mL of toluene. The reaction mixture is refluxed for 2 hours and cooled to room temperature. 13.26 g of methyl 2,2-methyl glycine methyl ester are added in 150 ml of toluene followed by 50.55 ml of triethylamine. The reaction mixture is refluxed for 1 h, cooled again to room temperature and filtered. The organic phase is washed successively with water and 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 provide 14.5 g of 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are the following: Spectrum. 1 H NMR at 400 MHz: 1.44 (s, 6H); 7.99 (d, J = 9.0 Hz, 2H); 8.27 (d, J = 9.0 Hz, 2H); 8.81 (broad s, 1 H). Mass Spectrum (ES): m / z = 337 [M + H] + base peak Example 5: 1 - ( {2 - [(2,5-difluorophenyl) amino] pyridin-4-yl.} Methyl ) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 42.9 mg of 1 - [(2-chloropyridin-4-yl) methyl] 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1 and 19.2 mg of 2,5-difluoroaniline in 5 ml of dioxane, under an inert argon atmosphere, 2.2 mg of palladium acetate are added, 6.9 mg of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene and 123 mg of cesium carbonate. The reaction medium is heated at 120 ° C for 12 hours, cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC chromatography (column C 1 8 reverse phase, elution with a water / acetonitrile gradient containing 0.1% trifluoroacetic acid). After evaporating the solvents under reduced pressure, 26.4 mg of 1 - (. {2 - [(2,5-difluorophenyl) amino] pyridin-4-yl} methyl) -5,5-dimethyl- 3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: LCMS: m / Z = 523.27 [M + H] +; RT: 1.95 min. Example 6: 3,5-dichloro-N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide To a solution of 42.9 mg of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1 and 28.2 mg of 3,5-dichlorobenzamide in 5 ml of dioxane, under an inert argon atmosphere, 2.2 mg of palladium acetate are added , 6.9 mg of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene and 123 mg of cesium carbonate. The reaction medium is heated at 120 ° C for 12 hours, cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC chromatography (column C1 8 reverse phase, elution with a water / acetonitrile gradient containing 0.1% trifluoroacetic acid). After evaporating the solvents under reduced pressure, 22.6 mg of 3,5-dichloro-N- are obtained. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide whose characteristics are the following: LCMS: TR = 2.40 min m / Z = 583.30 [M + H] + Example 7 2-chloro-N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -6-fluoro-3-methylbenzamide To a solution of 42.9 mg of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1, and 27.9 mg of 2-chloro-6-fluoro-3-methyl-benzamide in 5 ml_ of dioxane, under an inert argon atmosphere, add 2, 2 mg of paiadium acetate, 6.9 mg of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene and 123 mg of cesium carbonate. The reaction medium is heated at 120 ° C for 12 hours, cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC chromatography (column C 18 reverse phase, elution with a water / acetonitrile gradient containing 0.1% trifluoroacetic acid). After evaporating the solvents under reduced pressure, 18.2 mg of 2-chloro-N- are obtained. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -6-fluoro-3-methylbenzamide whose characteristics are the following: LCMS: m / Z = 581, 31 [M + H] +; RT: 2.28 min. Example 8: 3- ( { 4 - [(5, 5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] phenyl}. imidazolidin-1-yl) methyl] pyridin-2-yl.}. amino) -N, N-dimethylbenzamide To a solution of 42.9 mg of 1 - [(2-chloropyridin-4-yl) methyl] 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2, 4-dione obtained in step d) of example 1, and 24.4 mg of 3-Amino?,? -dimethyl-benzamide in 5 ml of dioxane, under an inert atmosphere of argon, are added 2, 2 mg of palladium acetate, 6.9 mg of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene and 123 mg of cesium carbonate. The reaction medium is heated at 120 ° C for 12 hours, cooled to room temperature and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC chromatography (column C 1 8 reverse phase, elution with a water / acetonitrile gradient containing 0.1% trifluoroacetic acid). After evaporating the solvents under reduced pressure, 33.2 mg of 3- (. {4 - [(5,5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] are obtained] phenyl.}. imidazolidin-1-yl) methyl] pyridin-2-yl.} amino) -? ,? -dimethylbenzamide whose characteristics are the following: LCMS: m / Z = 558.23 [M + H] +; RT: 1.46 min. Example 9: 1 - [(2- {[[(1 R) -2-hydroxy-1-methylethyl] amino] pyrimidin-4-yl) methyl] -5,5-dimethyl -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione Step d): 1 - [(2-. {[[(1 R) -2-hydroxy-1-methyl-ethyl] amino] -pyrimidin-4-yl) methyl] -5,5-dimethyl-3- . { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione A solution of 100 mg of 5,5-dimethyl-1-. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} -3-. { 4- [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione obtained in step c) below and 44.5 mg of (R) 2-amino-1-propanol in 2 ml of dioxane is poured into a sealed tube with a teflon septum. The tube is placed in a microwave oven (Emrys Optimizer, Personal Chemistry) and the solution is stirred at 120 ° C for 1 hour. After cooling to room temperature, the solvent is evaporated under reduced pressure and the residue is purified by preparative HPLC chromatography (reverse phase C18 column, elution with a water / acetonitrile gradient containing 0.1% trifluoroacetic acid). After lyophilizing the solution a white solid is obtained which is treated with a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and evaporated to yield 49.7 mg of 1 - [(2- {[[(1 R) -2-hydroxy-1-methylethyl] amino} pyrimidin-4. -yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 Hz: d = 8.32 (d, 2H); 8.22 (d, 1H); 8.05 (d, 2H); 6.80 (d, 1H); 6.67 (d, 1H); 4.65 (t, 1H); 4.46 (s, 2H); 3.93 (m, 1H); 3.44 (m, 1H); 1.48 (s, 6H); 1.09 (s, 3H) Mass Spectrum (ES): m / z = 502 [M + H] + Phase c): 5,5-dimethyl-1-. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} -3-. { 4- [(trifluoromethyl] sulfonyl] phenyl} imidazolidin-2,4-dione To a solution of 4.90 g of 5,5-dimethyl-1 -. { [2- (methylthio) pyrimidin-4-yl] methyl} -3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2, 4-dione obtained in the following phase b) in 80 ml of dichloroethane are added 16.37 g of 3-chloroperbenzoic acid (70%). The reaction mixture is stirred for 16 hours at room temperature and 2.73 g of 3-chloroperbenzoic acid (70%) are added again and the reaction mixture is heated at 40 ° C for 2 hours. The solution is washed twice with a saturated solution of sodium hydrogencarbonate. The organic phase is dried over anhydrous sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a gradient of heptane and ethyl acetate to give 4.30 g of 5,5-dimethyl-1 -. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: d = 9.06 (d, 1 H); 8.32 (d, 2H); 8.03 (m, 3H); 4.89 (s, 2H); 3.43 (s, 3H); 1.51 (s, 6H) Mass Spectrum (ES): m / z = 508 [M + H] + Phase b): 5,5-dimethyl-1 -. { [2- (methylthio) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 1.00 g of 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step c) of example 1 in 10 ml of?,? - dimethylformamide were added 0.087 g of sodium hydride at 0 ° C. After stirring for 10 minutes, 2.88 g of a 40% solution of 4-bromomethyl-2-methylthio-pyrimidine in hexane are added and the mixture is stirred for 4 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is purified by preparative HPLC (column C 18 reverse phase, eluting with a water / acetonitrile gradient containing 0.1% trifluoroacetic acid). After lyophilizing the fractions, 1.12 g of 5,5-dimethyl-1 - are obtained. { [2- (methylthio) pyrimidin-4-yl] methyl} -3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 8.59 (d, 1H); 7.86 (d, 2H); 7.65 (d, 2H); 7.32 (d, 1H); 4.65 (s, 2H); 2.55-2.45 (s, 3H); 1.45 (s, 6H) Mass Spectrum (ES): m / z = 443 [M + H] + Examples 10 to 17 whose names and structures are described below, are prepared as indicated above in the Schemes general.

Example 10: 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1 -dimethylurea Phase i: 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1 -dimethylurea To a solution of 90 mg of. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} Phenyl carbamate obtained in the following phase h) in 4 mL of tetrahydrofuran is added 0.85 mL of a 2M solution of dimethylamine in tetrahydrofuran under argon. The reaction mixture is stirred for 1 5 hours at room temperature 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 30 mg of 3-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} -] mdazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1 -dimethylurea whose characteristics are the following: 1 H NMR spectrum at 400 M Hz: 1.45 (s, 6H); 2.90 (s, 6H); 4.57 (s, 2H); 7.09 (d, J = 5.5 Hz, 1 H); 7.67 (d, J = 8.5 Hz, 2H); 7.86 (d, J = 8.5 Hz, 2H); 8.48 (d, J = 5.5 Hz, 1 H); 9.25 (s, 1 H). Mass Spectrum (ES): m / z = 483 [M + H] + Phase hj .:. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} fenium carbamate To a solution of 0.8 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in the following phase g) in 40 mL of tetrahydrofuran are successively added at 0 ° C under argon, 0.257 mL of pyridine and 0.34 mL of fenioformate chloroformate and the solution is stirred for 15 hours at room temperature. The reaction mixture is taken up in ethyl acetate, washed successively with concentrated hydrochloric acid, with water, a saturated solution of sodium hydrogencarbonate, a saturated solution of sodium chloride and dried over magnesium sulfate. After filtration the solution is concentrated under reduced pressure and the residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (65/35 by volume) to provide 0.68 g of. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} fentium carbamate whose characteristics are the following: Spectrum R N 1 H at 400 MHz: 1.46 (s, 6H); 4.67 (s, 2H); 6.75 (m, 3H); from 7.02 to 7.50 (m, 3H); 7.60 (d, J = 8.5 Hz, 2H); 7.82 (d, J = 8.5 Hz, 2H); 8, 61 (d, J = 5.5 Hz, 1 H); 9.30 (s, 1 H). Mass Spectrum (ES): m / z = 532 [M + H] + gi phase: 1 - [(2-aminopyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 0.49 g of 5,5-dimethyl-1 -. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} -3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in the following phase f) in 2.2 mL of dioxane is added 2.2 mL of concentrated ammonia. The reaction mixture is heated with microwaves at 120 ° C for 1 hour, left at room temperature for 15 hours and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (75/25 by volume) to provide 0.31 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -5 , 5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.43 (s, 6H); 4.41 (s, 2H); 6.59 (s, · 2H); 6.66 (d, J = 5.5 Hz, 1H); 7.66 (d, J = 8.5 Hz, 2H); 7.86 (d, J = 8.5 Hz, 2H); 8.19 (d, J = 5.5 Hz, 1H). Mass Spectrum (IE): m / z = 411: [M] + (base peak) m / z = 396: [M] + - CH3 m / z = 303: [M] + - C6H6N3 m / z = 109 : [C5H6N3] + Phase?: 5,5-dimethyl-1-. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 1.32 g of 5,5-dimethyl-3- are added. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step c) of example 1 under argon to a suspension of 0.26 g of sodium hydride in 30 ml_ of dimethylformamide. After stirring at room temperature for 1.5 hours, a solution of 1.35 g of 4- (chloromethyl) -2- (methylsulfonyl) pyrimidine obtained in the following phase e) is added in 5 mL of dimethylformamide. The reaction mixture is stirred for 15 hours at room temperature, poured into distilled water and extracted with ethyl acetate. The aqueous 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 purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (65/35 by volume) to give 0.35 g of 5,5-dimethyl-1 -. { [2- (Methylsulfonyl) pyrimidin-4-yl] methyl} -3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.49 (s, 6H); 3.41 (s, 3H); 4.88 (s, 2H); 7.66 (d, J = 8.5 Hz, 2H); 7.86 (d, J = 8.5 Hz, 2H); 7.99 (d, J = 5.5 Hz, 1H); 9.04 (d, J = 5.5 Hz, 1H). Mass Spectrum (ES): m / z = 475 [M + H] + m / z = 473 [M-H] -phase e): 4- (chloromethyl) -2- (methylsulfonyl) pyrimidine To a solution of 1.2 g of [2- (methylsulfonyl) pyrimidin-4-yl] methanol obtained in the following phase d) in 28 ml_ of dichloromethane, 2.28 ml of dimethylformamide and 0.56 ml of chloride are successively added. of thionyl. The reaction mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure to provide 1.3 g of 4- (chloromethyl) -2- (methylsulfonyl) pyrimidine whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 3.42 (s, 3H); 4.95 (s, 2H); 7.99 (d, J = 5.5 Hz, 1H); 9.12 (d, J = 5.5 Hz, 1H) Mass Spectrum (EI): m / z = 206: [M] + m / z = 191: [M] + - CH3 m / z = 142: [M] + - S02 m / z = 127: [M] + - S02CH3 (base peak) Phase d): [2- (methylsulfonyl) pyrimidin-4-yl] methanol To a solution of 2.66 g of 2- (methylsulfonyl) -4 - [(tetrahydro-2H-pyran-2-yloxy) methyl] pyrimidine obtained in the following phase c) in 244 ml_ of ethanol is added 0.8 ml. of concentrated hydrochloric acid. The reaction mixture is stirred at room temperature for 1 hour and concentrated under reduced pressure to provide 1.2 g of [2- (methylsulfonyl) pyrimidin-4-yl] methanol whose characteristics are as follows: 1 H to 300 nm NMR spectrum MHz: 3.40 (s, 3H); 4.68 (d, J = 5.5 Hz, 2H); 5.87 (t, J = 5.5 Hz, 1 H); 7.85 (d, J = 5.5 Hz, 1 H); 9.02 (d, J = 5.5 Hz, 1 H). Mass Spectrum (I E): m / z = 188: [M] + m / z = 158. [M] + - CH20 m / z = 124: [M] + - S02 m / z = 109: [M] + - S02CH3 (base peak) Phase cjj. 2- (Methylsulfonyl) -4 - [(tetrahydro-2H-pyran-2-loxi) methyl] pyrimidine To a solution of 2.63 g of 2- (methylthio) -4 - [(tetrahydro-2H-pyran-2-yloxy) methyl] pyrimidine obtained in the following phase b) in 79 mL of dichloromethane and, 8 ml_ of methanol is added 8.3 g of meta-chloroperbenzoic acid. The reaction mixture is stirred for 5 hours at room temperature. The organic phase is washed successively with a saturated solution of sodium bisulfite, a saturated solution of sodium bicarbonate, a saturated solution of sodium chloride, dried over magnesium sulfate and filtered. The solvent is distilled under reduced pressure to provide 3.02 g of 2- (methylsulfonyl) -4 - [(tetrahydro-2H-pyran-2-yloxy) methyl] pyrimidine whose characteristics are as follows: 1 H NMR spectrum at 400 MHz : from 1, 40 to 1, 87 (m, 6H); 3.40 (s, 3H); 3.49 (m, 1 H); 3.79 (m, 1 H); 4.74 (d, J = 16.0 Hz, 1 H); 4.80 (t, J = 3.0 Hz, 1 H); 4.83 (d, J = 16.0 Hz, 1 H); 7.86 (d, J = 5.5 Hz, 1 H); 9.05 (d, J = 5.5 Hz, 1 H). Mass Spectrum (ES): m / z = 273 [M + H] + (base peak) m / z = 189 [M + H] + -C5H90 (base peak) Phase b): 2- (methylthio) -4 - [(Tetrahydro-2H-pyran-2-yloxy) methyl] pyrimidine To a solution of 3.4 g of [2- (methylthio) pyrimidin-4-yl] methanol obtained in step a) below in 60 mL of dichloromethane 2.1 g of 3,4-dihydropyran and 0.414 g of para-toluenesulfonic acid are added. The reaction mixture is stirred at room temperature for 15 hours and refluxed for 1 hour and cooled in an ice bath. The organic phase is washed successively with a saturated solution of sodium bicarbonate, with water, with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (10/90 by volume) to give 4.75 g of 2- (methylthio) -4 - [(tetrahydro-2H-pyran 2-yloxy) methyl] pyrimidine whose characteristics are as follows: 1 H NMR spectrum at 300 MHz: from 1.40 to 1.87 (m, 6H); 2.50 (s masked, 3H); 3.48 (m, 1 H); 3.78 (m, 1 H); 4.51 (d, J = 1 5.0 Hz, 1 H); 4.65 (d, J = 15.0 Hz, 1 H); 4.74 (t, J = 3.0 Hz, 1 H); 7.23 (d, J = 5.5 Hz, 1 H); 8.61 (d, J = 5.5 Hz, 1 H). Mass Spectrum (I E): m / z = 240; [M] + m / z = 140: [M] + - C5H902 Mass Spectrum (CI): m / z = 241 [M + H] + Phase a): [2- (methylthio) pyrimidine-4- M] methanol To a solution of 10 g of 4-formyl-2- (methylthio) pyrimidine in 200 mL of methanol are added under argon, in portions, 4.9 g of sodium borohydride. The reaction mixture is stirred for 15 hours at room temperature and concentrated under reduced pressure. The residue is taken up in dichloromethane, washed successively with water, a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is triturated in diisopropyl ether to provide 5.4 g of [2- (methylthio) pyrimidin-4-yl] methanol whose characteristics are as follows: 1 H NMR spectrum at 300 MHz: 2.49 (s, 3H); 4.49 (d, J = 5.5 Hz, 2H); 5.60 (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 (EI): m / z = 156: [M] + m / z = 138: [M] + - H20 Example 11: 5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 0.1 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2, 4-dione obtained in step g) of Example 10 in 10 mL of dioxane, successively added under argon, 0.1 g of 3-bromopyridine, 0.39 g of cesium carbonate, 0.044 g of sodium hydroxide. , 9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos) and 0.01 5 g of palladium acetate. The reaction mixture is heated at 100 ° C for 15 hours and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane, acetonitrile and methanol (98/1/1 by volume) to provide 0.0264 g of 5,5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyrimidin-4-yl] methyl} -3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.45 (s, 6H); 4.61 (s, 2H); 7.00 (d, J = 5.5 Hz, 1 H); 7.21 (dd, J = 5.0 and 8.0 Hz, 1 H); 7.70 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8, 14 (broad d, J = 5.5 Hz, 1 H); 8, 19 (broad d, J = 8.0 Hz, 1 H); 8.48 (d, J = 5.5 Hz, 1 H); 8.92 (broad d, J = 5.0 Hz, 1 H); 9.80 (s, 1 H). Mass Spectrum (ES): m / z = 489 [M + H] + m / z = 487 [MH] "Example 12: 3- { 4 - [(5,5-dimethyl-2,4-dioxo -3- { 4- [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl.} - 1, -dimethylurea Phase: 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) suphonyl] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1-dimethylurea To a solution of 0.12 g of. { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} Phenyl carbamate obtained in the following phase b) in 4 mL of tetrahydrofuran is added 1.06 mL of a 2M solution of dimethylamine in tetrahydrofuran. The reaction mixture is stirred at room temperature under argon for three hours and concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2 by volume) to provide 0.06 g of 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} -1, 1 -dimethylurea whose characteristics are the following: MR spectrum N 1 H at 400 MHz: 1.48 (s, 6H); 2.89 (s, 6H); 4.59 (s, 2H); 7, 11 (d, J = 5.5 Hz, 1 H); 8.03 (d, J = 8.5 Hz, 2H); 8.30 (d, J = 8.5 Hz, 2H); 8.48 (d, J = 5.5 Hz, 1 H); 9.27 (s, 1 H). Mass Spectrum (ES): m / z = 51 5 [M + H] + m / z = 513 [M-H] - Phase bj .:. { 4 - [(5,5-Dimethyl-2,4-dioxo-3- {4- [(trifluoromethyl) sulfonyl] phenyl]} imidazolidin-1-yl) methyl] pyrimidin-2-ylcarbamate phenyl a solution of 0.8 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione obtained in the following phase a) in 40 mL of tetrahydrofuran are successively added at 0 ° C under argon, 0.1 84 mL of pyridine and 0.23 μL of phenyl chloroformate and the solution is added. stir for 15 hours at room temperature. The reaction mixture is taken up in ethyl acetate, washed successively with concentrated hydrochloric acid, with water, a saturated solution of sodium hydrogencarbonate, a saturated solution of sodium chloride and dried over magnesium sulfate. After filtration the solution is concentrated under reduced pressure and the residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (65/35 by volume) to provide 0.68 g of. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyrimidin-2-yl} Phenyl carbamate whose characteristics are the following: MR Spectrum N 1 H at 400 MHz: 1, 43 (s, 6H); 4.55 (s, 2H); 7.01 (d, J = 5.5 Hz, 1 H); 7.08 (d, J = 7.5 Hz, 2H); 7.28 (t partially masked, J = 7.5 Hz, 1 H); 7.31 (t, J = 7.5 Hz, 2H); 7.84 (s, 1 H); 7.86 (d, J = 8.5 Hz, 2H); 7, 97 (d, J = 8.5 Hz, 2H); 8, 50 (d, J = 5, 5 Hz, 1 H). Mass Spectrum (ES): m / z = 563 [M + H] + Phase aj .: 1 - [(2-aminopyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4- [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione To a solution of 0.91 g of 1- (2-methanesulfonyl-pyrimidin-4-ylmethyl) -5,5-dimethyl-3- (4-trifluoromethylsulfonyl-phenyl) -imidazolidin-2,4-dione obtained in the c) of Example 9 in 5 mL of dioxane, 5 mL of concentrated ammonia are added. The reaction mixture is heated with microwaves at 120 ° C for 1 hour, left at room temperature for 1 5 hours and concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (70/30 by volume) to provide 0.54 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -5 , 5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.46 (s, 6H); 4.43 (s, 2H); 6.59 (broad s, 2H); 6.69 (d, J = 5.5 Hz, 1 H); 8.03 (d, J = 8.5 Hz, 2H); 8,19 (d, J = 5.5 Hz, 1 H); 8.30 (d, J = 8.5 Hz, 2H). Mass Spectrum (ES): m / z = 444 [M + H] + Example 13: 5,5-d-methyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione Phase c > : 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione To a solution of 0.36 g of 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione obtained in the following phase b) in 20 ml_ of dioxane are added successively under argon, 0.19 g of 5-bromopyrimidine, 0.056 g of 9,9-dimethyl-4,5-bis (diphenylphosphino) ) Xanthene (Xantphos), 0.027 g of palladium acetate and 1 g of cesium carbonate. The reaction mixture is heated at 90 ° C for 3 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 provide 0.15 g of 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.48 (s, 6H); 4.61 (s, 2H); 6.90 (broad s, 1 H); 6.94 (broad d, J = 5.5 Hz, 1 H); 8.07 (d, J = 8.5 Hz, 2H); 8, 19 (d, J = 5.5 Hz, 1 H); 8.31 (d, J = 8.5 Hz, 2H); 8.70 (s, 1 H); 9, 12 (s, 2H); 9.38 (s, 1 H). Mass Spectrum (ES): m / z = 521 [M + H] + m / z = 519 [MH] - Phase b_li 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl- 3-. { 4- [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione To a solution of 1.5 g of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} Acetamide obtained in the following phase a) in 25 mL of methanol is added 0.62 mL of a 30% sodium hydroxide solution in water. The reaction mixture is heated at 50 ° C for 24 hours and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (85/1 5 by volume) to provide 0.4 g of 1 - [(2-aminopyridin-4-yl) methyl] - 5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.50 (s, 6H); 3.41 (s, 3H); 4.89 (s, 2H); 8.00 (d, J = 7.0 Hz, 1 H); 8.03 (d, J = 8.5 Hz, 2H); 8.30 (d, J = 8.5 Hz, 2H); 9.05 (d, J = 7.0 Hz, 1 H). Mass Spectrum (ES): m / z = 443 [M + H] + Phase ali N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} acetamide To a solution of 3 g of 1- (2-chloro-pyridin-4-ylmethyl) -5, 5-dimethyl-3- (4-trifluoromethanesulfonyl-phenyl) -imidazolidin-2,4-dione obtained in step b) of example 4 in 60 ml of dioxane are added successively under argon, 0.96 g of acetamide, , 45 g of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos), 0. 146 g of palladium acetate and 7.4 g of cesium carbonate. The reaction mixture is refluxed for 5 hours, 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 provide 1.5 g of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} acetamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1, 43 (s, 6H); 2.07 (s, 3H); 4.63 (s, 2H); 7, 15 (dd, J = 1, 5 and 5.5 Hz, 1 H); 8.03 (d, J = 8.5 Hz, 2H); 8,11 (broad s, 1 H); 8.24 (d, J = 5.5 Hz, 1 H); 8.30 (d, J = 8.5 Hz, 2H); 1 0.5 (broad s, 1 H). Mass Spectrum (ES): m / z = 485 [M + H] + m / z = 483 [M-H] 'Example 14: 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione Stage c): 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} -3- . { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 0.2 g of 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in the following phase b) in 5 ml_ of dioxane are added successively under argon, 0.1 g of 5-bromopyrimidine, 0.025 g of 9,9-dimethyl-4,5-bis (diphenylphosphino) ) Xanthene (Xantphos), 0.01 g of palladium acetate and 0.55 g of cesium carbonate. The reaction mixture is refluxed for 15 hours, filtered and concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of dichloromethane, methanol and ammonia (93/6/1 in volumes) to provide 0.02 g of 5,5-dimethyl-1. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 300 MHz: 1.45 (s, 6H); 4.59 (s, 2H); 6.90 (broad s, 1H); 6.92 (broad d, J = 5.5 Hz, 1H); 7.69 (d, J = 8.5 Hz, 2H) 7.87 (d, J = 8.5 Hz, 2H); 8.18 (d, J = 5.5 Hz, 1H); 8.70 (s, 1H); 9.13 (s, 2H); 9.40 (s, 1H). Mass Spectrum (ES): m / z = 489 [M + H] + m / z = 487 [MH] ~ Phase b ^ 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl -3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 1.54 g of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3- {4- [(trifluoromethyl) thio] phenyl} tmidazolidin-1-yl) methyl] pyridin-2-yl} The acetamide obtained in the following phase a) in 25 mL of methanol is added 0.68 mL of a 30% sodium hydroxide solution in water. The reaction mixture is heated at 50 ° C for 8 hours and concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/2 by volume) to provide 0.77 g of 1 - [(2-aminopyridin-4-yl) methyl] -5.5 -dimetil-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.40 (s, 6H); 4.44 (s, 2H); 5.88 (broad s, 2H); 6.42 (broad s, 1 H); 6.50 (dd, J = 1, 5 and 5.5 Hz, 1 H); 7.67 (d, J = 8.5 Hz, 2H); 7.83 (d, J = 5.5 Hz, 1 H); 7.88 (d, J = 8.5 Hz, 2H). Mass Spectrum (ES): m / z = 41 1 [M + H] + Phase li N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) th] phenyl]} - midazolidin-1-yl) methyl] pyridin-2-yl} acetamide To a solution of 3 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1 in 60 ml_ of dioxane are added successively under argon, 1.03 g of acetamide, 0.484 g of 9,9-dimethyl-4,5-bis (diphenylphosphino) Xanthene (Xantphos), 0.156 g of palladium acetate and 7.96 g of cesium carbonate. The reaction mixture is heated at 90 ° C for 5 hours, filtered and concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of ethyl acetate and cyclohexane (50/50 by volume) to give 2.85 g of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} acetamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.41 (s, 6H); 2.09 (s, 3H); 4.63 (s, 2H); 7, 1 3 (cid, J = 1, 5 and 5.5 Hz, 1 H); 7.66 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8,11 (broad s, 1 H); 8.24 (d, J = 5.5 Hz, 1 H); 1 0.5 (broad s, 1 H). Mass Spectrum (ES): m / z = 453 [M + H] + m / z = 451 [M-H] - Example 15: 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl] thio] phenyl} imidazolidin-2, 4-dione To a solution of 0.13 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step g) of example 10 in 10 ml of dioxane are added successively under argon, 0.075 g of 5-bromopyrimidine, 0.02 g of 9,9-dimethyl-4,5- bis (diphenylphosphino) xanthene (Xantphos), 0.007 g of palladium acetate and 0.39 g of cesium carbonate. The reaction mixture is refluxed for 1.5 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 (98/2 by volume) to provide 0.043 g of 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.45 (s, 6H); 4.64 (s, 2H); 7.06 (d, J = 5.5 Hz, 1 H); 7.71 (d, J = 8.5 Hz, 2H); 7.86 (d, J = 8.5 Hz, 2H); 8, 52 (d, J = 5.5 Hz, 1 H); 8.76 (s, 1 H); 9, 18 (s, 2H); 10.0 (s, 1 H). Mass Spectrum (ES): m / z = 490 [M + H] + m / z = 488 [M-H] - Example 16: 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione To a solution of 0.36 g of 1 - [(2-aminopyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step g) of example 10 in 20 ml of dioxane are added successively under argon, 0.19 g of 5-bromopyrimidine, 0.055 g of 9,9-dimethyl-4,5- bis (diphenylphosphino) xanthene (Xantphos), 0.018 g of palladium acetate and 1 g of cesium carbonate. The reaction mixture is refluxed for 15 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 provide 0.16 g of 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.48 (s, 6H); 4.67 (s, 2H); 7, 10 (d, J = 5.5 Hz, 1 H); 8.08 (d, J = 8.5 Hz, 2H); 8.30 (d, J = 8.5 Hz, 2H); 8.52 (d, J = 5.5 Hz, 1 H); 8, 76 (s, 1 H); 9, 19 (s, 2H); 1 0.0 (s, 1 H). Mass Spectrum (ES): m / z = 522 [M + H] + m / z = 520 [MH] "Example 17: 1 - ( { 2 - [(5-fluoropyridin-3-yl) amino] pyridin-4-yl.} methyl) -5,5-dimethyl-3-. {4 - [(trifluoromethyl) thio] phenyl}. imidazolidin-2,4-dione To a solution of 0.2 g of 1 - [(2-aminopyridin-4-yl) methyl] -5,5-d-methyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} Irnidazolidin-2,4-dione obtained in step b) of Example 14 in 5 ml of dioxane are added successively under argon, 0.087 g of 5-bromo-3-fluoropyridine, 0.025 g of 9,9-dimethyl. -4,5-bis (diphenylphosphino) xanthene (Xantphos), 0.010 g of palladium acetate and 0.7 g of cesium carbonate. The reaction mixture is refluxed for 3.5 hours, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica eluting with a gradient of acetone in dichloromethane to provide 0.17 g of 1- (. {2 - [(5-fluoropyridin-3-yl) amino] pyridin-4-yl. .) methyl) -5,5-dimethyl-3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.45 (s, 6H); 4.59 (s, 2H); 6.90 (broad s, 1H); 6.92 (broad d, J = 5.5 Hz, 1H); 7.69 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8.05 (d, J = 2.5 Hz, 1H), 8.20 (d, J = .5 Hz, 1H) 8.38 (td, J = 2.5 and 12.5 Hz, 1H); 8.50 (t, J = 2.5 Hz, 1H) 9.55 (broad m, 1H). Mass Spectrum (ES): m / z = 506 [M + H] + The present invention mainly comprises the products of formula (I) which belong to the following formula: (la) where n and NR4R5 have the meanings indicated above. The products of formula (la) can be prepared mainly as indicated in general scheme 3 in two steps (compounds Z and AA). The products of formula (la) as defined above in which the radical NR4R5 has the values indicated above numbered in Example 1 to 8 respectively correspond to examples 1 to 8 belonging to the present invention: the preparation of the product of example 18 is described below and the products of examples 1 to 43 are prepared as indicated for the product of example 18 by replacing in phase B) 3-pyrrolidin-1-yl-propylamine by the intermediate corresponding appropriate of formula HNR4R5. Examples of the products having different radicals N R 4 R 5 according to the present invention are indicated below: ex 18 ex 19 ex 20 ex 21 Example 18: 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (3-pyrrolidin-1-ylpropyl) urea Phase bj .: 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (3-pyrrolidin-1-ylpropyl) urea To a solution of 0.1 g of. { . { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} ethyl carbamate obtained in step a) below in 2 mL of N-methyl pyrryleidinone is added 0.316 mL of 3-pyrrolidin-1-yl-propylamine. The solution is heated to 1 30 ° C with microwaves for 1 hour. The reaction mixture is diluted with 10 mL of distilled water and extracted 3 times with 30 mL of ethyl acetate. The combined organic phases are concentrated under reduced pressure and the residue is purified by chromatography on a column of silica (eluting with a gradient of dichloromethane and a mixture of methanol and ammonia 85/15 by volume) to provide 0., 072 g of 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (3-pyrrolidin-1-ylpropyl) urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 1.61 (m, 2H); 1.67 (m, 4H); 2.41 (m, 6H); 3.20 (q, J = 6.5 Hz, 2H); 4.56 (s, 2H); 6.94 (broad d, J = 5.5 Hz, 1H); 7.32 (broad s, 1H); 7.67 (d, J = 9.0 Hz, 2H); 7.87 (d, J = 9.0 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.27 (m, 1H); 9.11 (s, 1?). Mass Spectrum (ES): m / z = 565, [M + H] + base peak Phase a):. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} ethyl carbamate To a solution of 4.3 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) th] phenyl} imidazolidine-2,4-dione obtained in step d) of Example 1 in 105 ml_ of dioxane are added successively under argon, 1.36 g of ethyl carbamate, 12.38 g of cesium carbonate, 0.22 g of palladium acetate and 0.58 g of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene. The reaction mixture is refluxed for 2 hours, filtered and concentrated under reduced pressure. The rest is triturated with diethyl ether to provide 3.56 of. { . { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} ethyl carbamate whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.23 (t, J = 7.5 Hz, 3H); 1.42 (s, 6H); 4.14 (q, J = 7.5 Hz, 2H); 4.62 (s, 2H); 7.09 (dd, J = 1.5 and 5.5 Hz, 1H); 7.66 (d, J = 8.5 Hz, 2H); 7.86 (m, 3H); 8.20 (d, J = 5.5 Hz, 1H); 10.1 (broad s, 1H). Mass Spectrum (EI): m / z = 482 M + base peak m / z = 467 (M -CH3) + m / z = 410 (M -C02C2H5) +. Example 19: 1-cyclopentyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea Prepared as in step b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with cyclopentylamine and N-methylpyrrolidinone with tetrahydrofuran, heating for 2 hours at 140 ° C, to provide 97 mg of 1-cyclopentyl -3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.39 (partially masked m, 2 H); 1.42 (s, 6H); from 1.50 to 1.72 (m, 4H); 1.86 (m, 2H); 4.00 (m, 1H); 4.58 (s, 2H) 6.94 (broad d, J = 5.5 Hz, 1H); 7.36 (broad s, 1H); 7.65 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.20 (broad d, J = 7.5 Hz, 1H); 9.02 (s, 1H). Mass Spectrum (ES): m / z = 522 [M + H] + m / z = = 520; [M-H] - Example 20: 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (2-pyrrolidin-1-ylethyl) urea It was prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with N- (2-aminoethyl) pyrrolidine to provide 93 mg of 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (2-pyrrolidin-1-ylethyl) urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6 H) 1.69 (m, 4 H); 2.47 (m, 4H); 2.52 (partially masked t, J = 6.5 Hz, 2H); 3.27 (q, J = 6.5 Hz, 2H); 4.58 (s, 2H); 6.94 (broad d, J = 5.5 Hz, 1H); 7.36 (broad s, 1H); 7.67 (d, J = 9.0 Hz, 2H); 7.87 (d, J = 9.0 Hz, 2H); 8.10 (d, J = 5.5 Hz, 1H) 8.25 (broad m, 1H); 9.17 (s, 1H). Mass Spectrum (ES): m / z = 551 [M + H] + m / z = 411; [MH -C7H12N20] + m / z = 141; C7H13N20 + base peak Example 21 .: 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (4-pyrrolidin-1-ylbutyl) urea was prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with 1- (4-aminobutyl) pyrrolidine to give 100 mg of 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (4-pyrrolidin-1-ylbutyl) urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 1.47 (m, 4H); 1.65 (m, 4H); 2.38 (m, 6H); 3.17 (q, J = 6.5 Hz, 2H); 4.58 (s, 2H); 6.95 (broad d, J = 5.5 Hz, 1H); 7.32 (broad s, 1H); 7.67 (d, J = 9.0 Hz, 2H); 7.87 (d, J = 9.0 Hz, 2H); 8.12 (d, J = 5.5 Hz, 1H); 8.26 (broad m, 1H); 9.12 (s, 1H). Mass Spectrum (ES): m / z = 579 [M + H] + m / z = 290; [M + 2H] 2 + / 2 peak base ej22 ej23 ej 24 ex 25 Example 22: 1-cyclopropyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea Prepared as in step b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with cyclopropylamine and N-methylpyrrolidinone with tetrahydrofuran, heating for 2 hours at 140 ° C, to give 110 mg of 1-cyclopropyl -3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H NMR spectrum 400 Hz: 0.44 (m, 2H); 0.66 (m, 2H); 1.42 (s, 6H); 2.60 (m, 1H); 4.56 (s, 2H); 6.95 (dd, J = 1.5 Hz, 1H); 7.37 (broad s, 1H) 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.23 (broad m, 1H); 9.06 (s, 1H). Mass Spectrum (ES): m / z = 494 [M + H] + m / z = 492; [M-H] - m / z = 538; MH- + HC02H m / z = 409 [M + H] + - C4H6NO Example 23: 1-cyclobutyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) th] phenyl].,] -dazolidin-1-yl) methyl] pyridine 2-il} urea Prepared as in step b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with cyclobutylamine and N-methylpyrrolidinone with methanol, to give 50 mg of 1-cyclobutyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H 400 MHz NMR spectrum: 1.42 (s, 6H); from 1.55 to 1.70 (m, 2H); from 1.81 to 1.94 (m, 2H); from 2.18 to 2.27 (m, 2H); 4.18 (m, 1H); 4.58 (s, 2H); 6.96 (dd, J = 1.5 and 5.5 Hz, 1H); 7.37 (broad s, 1H); 7.66 (d, J = 9.0 Hz, 2H); 7.87 (d, J = 9.0 Hz, 2H); 8.13 (d, J = 5.5 Hz, 1H); 8.36 (broad d, J = 7.5 Hz, 1H); 9.06 (s, 1H). Mass Spectrum (ES): m / z = 508 [M + H] + m / z = 506; [M-H] - Eiomplo 24: 1-cyclopentyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1- methylurea Prepared as in phase b) of example 18 by replacing 3-P'-pyrrolidin-1-yl-propylamine with N-methylcyclopentylamine and N-methylpyrrolidinone with tetrahydrofuran, to give 56 mg of 1-cyclopentyl- 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1-methylurea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.41 (s, 6H); from 1.45 to 1.80 (m, 8H); 2.81 (s, 3H); 4.60 (s, 2H); 4.61 (m, 1H); 7.01 (broad d, J = 5.5 Hz, 1H); 7.68 (d, J = 8.5 Hz, 2H); 7.86 (m, 3H); 8.18 (d, J = 5.5 Hz, 1H); 8.73 (s, 1H). Mass Spectrum (ES): m / z = 536 [M + H] + m / z = 534 [M-H] - Example 25: 1 -cyclohexyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea Prepared as in step b) of example 18 by replacing 3-pyrrolidin-1-tl-propylamine with cyclohexylamine and N-methylpyrrolidinone with tetrahydrofuran, to give 90 mg of 1-cyclohexyl-3-. { 4 - [(5,5-Dimeti! -2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: From 1.16 to 1.39 (m, 5H); 1.42 (s, 6H); 1.53 (m, 1H); 1.65 (m, 2H); 1.82 (m, 2H); 3.56 (m, 1H); 4.58 (s, 2H) 6.94 (broad d, J = 5.5 Hz, 1H); 7.33 (broad s, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.12 (d, J = 5.5 Hz, 1Hj; 8.23 (broad d, J = 7.5 Hz, 1 H); 9.06 (s, 1 H). Mass Spectrum (ES): m / z = 536 [M + H] + m / z = 534; [M-H] - MH- + HC02H = 580- ex 26 ex 27 ex 28 ex 29 ex 30 Example 26: N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl } azridine-1 -carboxamide Example 27: N-. { 4 - [(5,5-Dimethyl-2,4-d-oxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} azetidin-1 -carboxamide Prepared as in step b) of example 1 8 by replacing 3-pyrrolidin-1-yl-propylamine with azetidine and N-methylpyrrolidinone with tetrahydrofuran, to give 65 mg of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} azetidine-1-carboxamide whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 2, 15 (m, 2H); 3.98 (t, J = 7.5 Hz, 4H); 4.59 (s, 2H); 7.01 (broad d, J = 5.5 Hz, 1 H); 7.66 (d, J = 8.5 Hz, 2H); 7.86 (d, J = 8.5 Hz, 2H); 7.95 (broad s, 1 H); 8, 16 (d, J = 5.5 Hz, 1 H); 8.97 (s, 1 H).

Mass Spectrum (ES): m / z = 494 [M + H] + [M-H] - = 492- m / z = 492; [M-H] - Example 28: N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phen'yl} imidazolidin-1-yl) methyl] pyridin-2-yl } pyrrolidin-1 -carboxamide Prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with pyrrolidine to give 40 mg of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} pyrrolidine-1-carboxamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 1.83 (m, 4H); 3.39 (m, 4H); 4.59 (s, 2H); 7.01 (dd, J = 1.5 and 5.0 Hz, 1H); 7.67 (d, J = 9.0 Hz, 2H); 7.86 (d, J = 9.0 Hz, 2H); 7.96 (broad s, 1H); 8.16 (d, J = 5.0 Hz, 1H); 8.60 (s, 1H). Mass Spectrum (ES): m / z = 508 [M + H] + Example 29: N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} morpholine-4-carboxamide Prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with morpholine and N-methylpyrrolidinone with tetrahydrofuran, to give 84 mg of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} morpholine-4-carboxamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 3.45 (m, 4H); 3.58 (m, 4H); 4.60 (s, 2H); 7.03 (broad d, J = 5.5 Hz, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.84 (broad s, 1H); 7.86 (d, J = 8.5 Hz, 2H); 8.18 (d, J = 5.5 Hz, 1H); 9.19 (s, 1H) Mass Spectrum (ES): m / z = 524 [M + H] + m / z = 522; [M-H] - Example 30: N-. { 4 - [(5,5-Dimethyl-2,4-d-oxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl } -4-methylpiperazine-1-carboxamide It was prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with N-methylpiperazine and N-methylpyrrolidinone with tetrahydrofuran, to give 50 mg of N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [[(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -4-methylpiperazine-1-carboxamide whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.41 (s, 6H); 2.18 (s, 3H); 2.29 (m, 4H); 3.45 (m, 4H); 4.59 (s, 2H); 7.02 (broad d, J = 5.5 Hz, 1H); 7.66 (d, J = 8.5 Hz, 2H); 7.82 (broad s, 1H); 7.86 (d, J = 8.5 Hz, 2H) ¡8.17 (d, J = 5.5 Hz, 1H); 9.12 (s, 1H) Mass Spectrum (ES): m / z = 537 [M + H] + m / z = 535¡ [MH] - m / z = 437 [M + H] + - C5H11N2 ex 31 ex 32 ex 33 Example 31_: 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (2-piperidin-1-ylethyl) urea It was prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with 1- (2-aminoethyl) piperidine and N-methylpyrrolidinone by tetrahydrofuran, to provide 88 mg of 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (2-piperidin-1-ylethyl) urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.35 to 1.55 (m, 6H); 1.42 (s, 6H); 2.36 (m, 6H); 3.26 (partially masked m, 2H); 4.58 (s, 2H); 6.94 (dd, J = 1.5 and 5.5 Hz, 1H); 7.30 (broad s, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.42 (broad m, 1H); 9.20 (s, 1H). Mass Spectrum (ES): m / z = 565 [M + H] + m / z = 563; [M-H] - Example 32: 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- [2- (4-Methylpiperazin-1-yl) ethyl] urea Was prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with 1- (2-aminoethyl) -4-methyl piperazine and N-methylpyrrolidinone by tetrahydrofuran, to provide 60 mg of 1 -. { 4 - [(5,5-Dimethyl-2,4-d-oxo-3. {4 - [(trifluoromethyl) thio] phenyl} - midazolidin-1-yl) methyl] pyridin-2- il} -3- [2- (4-methylpiperazin-1-yl) ethyl] urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); from 2.35 to 2.42 (m, 6H) ¡3.27 (partially masked m, 2H); 3.59 (m, 4H); 4.58 (s, 2H); 6.95 (dd, J = 1.5 and 5.5 Hz, 1H); 7.30 (broad s, 1H); 7.66 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.12 (d, J = 5.5 Hz, 1H); 8.44 (broad m, 1H); 9.21 (s, 1H). Mass Spectrum (ES): m / z = 567 [M + H] + Example 33: 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (2-morpholin-4-ylethyl) urea It was prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with 1- (2-aminoethyl) morpholine and N-methylpyrrolidinone by tetrahydrofuran, to provide 110 mg of 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- (2-morpholin-4-ylethyl) urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 2.15 (s, 3H); from 2.25 to 2.44 (m, 10H); 3.26 (partially masked m, 2H); 4.57 (s, 2H); 6.95 (broad d, J = 5.5 Hz, 1H); 7.29 (broad s, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.44 (broad m, 1 H); 9.20 (s, 1 H) Mass Spectrum (ES): m / z = 580 [M + H] + ex 34 ex 35 ex 36 ex 37 Example 34: 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1-ethyl-1-methylurea It was prepared as in phase b) of example 18 by replacing 3-Pyrrolidin-1-yl-propylamine with N-ethyl methylamine and N-methylpyrrolidinone with tetrahydrofuran, to give 101 mg of 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1-ethyl-1-methylurea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1, 06 (t, J = 7.0 Hz, 3H); 1, 42 (s, 6H); 2.94 (s, 3H); 3.36 (d, J = 7.0 Hz, 2H); 4.59 (s, 2H); 7.02 (dd, J = 1.5 and 5.5 Hz, 1 H); 7.67 (d, J = 8.5 Hz, 2H) 7.85 (d, J = 8.5 Hz, 2H); 7.87 (s masked, 1 H); 8,17 (d, J = 5.5 Hz, 1 H); 8.72 (s, 1 H). Mass Spectrum (ES): m / z = 496 [M + H] + m / z = 494; [M-H] - Example 35: 3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1-methyl-1-propylurea Prepared as in step b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with N-methyl-N-propylamine and N-methylpyrrolidinone with tetrahydrofuran, to provide 100 mg of 3-. { 4 - [(5,5-Dimethyl-2,4-d-oxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1-methyl-1-propylurea whose characteristics are the following: Spectrum R N 1 H at 400 MHz: 0.85 (t, J = 7.0 Hz, 3H); 1.41 (s, 6H); 1.51 (m, 2H) 2.95 (s, 3H); 3.28 (masked m, 2H); 4.59 (s, 2H); 7.01 (dd, J = 1.5 Hz and 5.5 Hz. 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.85 (d, J = 8.5 Hz, 2H); 7.87 (s masked, 1H); 8.17 (d, J = 5.5 Hz, 1H); 8.72 (s, 1H). Mass Spectrum (ES): m / z = 510 [M + H] + m / z = 510; [M-H] - Example _36: 1-butyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1-methylurea Prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with N-methyl-N-butylamine to give 40 mg of 1-butyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -1-methylurea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 0.89 (t, J = 7.0 Hz, 3H); 1.27 (m, 2H); 1.42 (s, 6H); 1.47 (m, 2H); 2.94 (s, 3H); 3.30 (masked m, 2H); 4.59 (s, 2H); 7.01 (broad d, J = 5.5 Hz, 1H); 7.69 (d, J = 8.5 Hz, 2H); 7.85 (d, J = 8.5 Hz, 2H); 7.86 (s, 1H); 8.17 (d, J = 5.5 Hz, 1H); 8.72 (broad t, J = 6.5 Hz, 1H). Mass Spectrum (ES): m / z = 524 [M + H] + m / z = 522; [M-H] - Example 37: 1 -butyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methy1] pyridin-2-yl } urea Prepared as in step b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with N-butylamine to give 40 mg of 1-butyl-3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 0.90 (t, J = 7.0 Hz, 3H); 1.31 (m, 2H); 1.42 (s, 6H); 1.44 (m, 2H); 3.17- (q, J = 7.0 Hz, 2H); 4.58 (s, 2H); 6.94 (dd, J = 1.5 and 5.5 Hz, 1H); 7.31 (broad s, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.12 (d, J = 5.5 Hz, 1H); 8.25 (broad t, J = 7.0 Hz, 1H); 9.11 (s, 1H). Mass Spectrum (ES): m / z = 510 [M + H] + m / z = 508; [M-H] - ej 38 ej 39 ej 40 Example 38: 1 - [S-Idimethylamino-J-propylj-SH-SS-dimethyl-2-dioxo-SH-trifluoromethyl-thiojphenyl-jimidazolidin-1-yl) -methyl] mp. Prepared as in phase b) of example 18 by replacing the 3-pyrrolidone- 1-yl-propylamine by?,? - dimethylethylenediamine and N-methylpyrrolidinone by tetrahydrofuran, to provide 54 mg of 1- [3- (dimethylamino) propyl] -3-. { 4 - [(5,5-dimethyl-2,4-d-oxo-3. {4 - [(trifluoromethyl) thio] phen.l.] Imidazolidin-1-l) methyl] pyridin-2- L} urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6 H); 2.17 (s, 6H); 2.34 (t, J = 6.5 Hz, 2H); 3.24 (q, J = 6.5 Hz, 2H); 4.58 (s, 2H); 6.94 (broad d, J = 5.5 Hz, 1H); 7.37 (broad s, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.17 (broad t, J = 6.5 Hz, 1H); 9.17 (s, 1H) Mass Spectrum (ES): m / z = 525 [M + H] + m / z = 523; [M-H] - Example 39: 1- [3- (dimethylamino) propyl] -3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea Prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with N, N-dimethyl-1,3-propanediamine to provide 106 mg of 1- [3- (dimethylamino) propyl] -3-. { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6 H); 1.59 (m, 2H); 2.12 (s, 6H); 2.23 (t, J = 6.5 Hz, 2H); 3.18 (q, J = 6.5 Hz, 2H); 4.58 (s, 2H); 6.95 (broad d, J = 5.5 Hz, 1H); 7.31 (s, broad, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.31 (broad t, J = 6.5 Hz, 1H); 9.13 (s, 1H). Mass Spectrum (ES): m / z = 539 [M + H] + m / z = 537 [? -?] · Example 40: 1- [4- (dimethylarnino) butyl] -3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) th] phenyl]} imidazolidin-1-yl) methyl] pyridin-2 -il} urea Prepared as in phase b) of example 18 by replacing 3-pyrrolidin-1-yl-propylamine with?,? -dimethylaminobutylamine and N-methylpyrrolidinone with tetrahydrofuran, to provide 60 mg of 1- [4- (dimethylamino) butyl] -3-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: From 1.36 to 1.50 (m, 4H); 1.42 (s, 6H); 2.10 (s, 6H); 2.19 (t, J = 6.5 Hz, 2H); 3.17 (q, J = 6.5 Hz, 2H); 4.58 (s, 2H); 6.94 (broad d, J = 5.5 Hz, 1H); 7.31 (broad s, 1H); 7.66 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8.11 (d, J = 5.5 Hz, 1H); 8.26 (broad t, J = 6.5 Hz, 1H); 9.12 (s, 1H) Mass Spectrum (ES): m / z = 553 [M + H] + m / z = 551; [M-H] - Example 40A: 1- ( {2 - [(5-fluoropyridin-3-yl) amino] pyridin-4-yl}. Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione The product was prepared using the general method of Example 18 phase b) above by replacing 3-pyrrolidin-1-yl-propylamine and N-methylpyrrolidinone with a 7N solution of ammonia in methanol. 1 - ( {2 - [(5-fluoropyridin-3-yl) amino] pyridin-4-yl}. Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione is obtained in the form of a solid whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 4.58 (s, 2H); 6.95 (broad d, J = 5.5 Hz, 1 H); 7.07 (very widespread m, 2H); 7.38 (broad s, 1 H); 7.66 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 8, 12 (d, J = 5.5 Hz, 1 H); 9.08 (s, 1 H) Mass Spectrum (ES): m / z = 454 [M + H] + m / z = 452; [M-H] - Example 40B: 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- [3- (pyrrolidin-1-ylmethyl) cyclobutyl] urea Phase 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl] thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- [3- (pyrrolidin-1-ylmethyl) cyclobutyl] urea To a solution of 22 mg methanesulfonate of. { 3 - [( { 4 - [(5,5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] phenyl]., Midazolidin-1-yl) methyl] pyridine -2-yl.}. Carbamoyl) amino] cyclobutyl} The methyl obtained in the following phase b) in 0.8 mL of tetrahydrofuran is added 15 μm of pyrrolidine. The reaction mixture is heated with microwaves at 130 ° C for 1 hour and concentrated under reduced pressure. The residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to provide 7 mg of 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- [3- (pyrrolidin-1-ylmethyl) cyclobutyl] urea whose characteristics are the following: NM 1 H spectrum at 400 MHz (mixture 60% - 40% of Cis and Trans isomers): 1.42 (s, 6H); 1.52 (m, 1H); 1.65 (m, 4H); from 1.95 to 2.57 (partially masked m, 10H); 4.03 (m, 0.6H); 4.22 (m, 0.4H); 4.57 (s, 2H); 6.96 (broad d, J = 5.5 Hz, 1H); 7.37 (broad s, 1H) 7.67 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H) 8.13 (m, 1H) 8.24 (s, 1H); 8.27 (broad m, 0.6H) 8.38 (broad m, 0.4H); 9.02 (s, 0.6H); 9.04 (s, 0.4H). Mass Spectrum: m / z = 591 [M + H] + Phase b): methanesulfonate of. { 3 - [( { 4 - [(5,5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridine- 2-yl.}. Carbamoyl) amino] cyclobutyl} m ethyl.

To a solution of 120 mg of 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- [3- (hydroxymethyl) cyclobutyl] urea obtained in the following phase a) in 1 mL of dichloromethane are added successively, under argon at 0 ° C, 2.7 mg of 4-N, N-dimethylamino pyridine, 46pL of triethylamine and 26μ? of methanesulfonic acid chloride. The reaction mixture is kept under stirring for 1 hour at this temperature, the ice bath is removed, 20 mL of a saturated solution of sodium hydrogencarbonate are added and the aqueous phase is extracted 2 times with 50 mL of ethyl acetate. The combined organic phases are 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 column of silica, eluting with a mixture of ethyl acetate and dichloromethane (90/10 by volume) to give 95 mg of methanesulfonate. { 3 - [( { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl] imidazolidin-1-yl) methyl] pyridin-2-yl.}. carbamoyl) amino] cyclobutyl} methyl whose characteristics are the following: 1 H NMR spectrum at 400 MHz (mixture 60% - 40% of Cis and Trans isomers): 1, 41 (s, 6H); from 1.65 to 2.43 (m, 5H); 3, 18 (s, 1, 8H); 3.20 (s, 1 .2H); 4.12 (m, 0.6H); 4.20 (d, J = 6.0 Hz, 0.4H); 4.29 (d, J = 6.0 Hz, 0.4H); 4.32 (m, 0.4H); 4.59 (s, 2H); 6.98 (broad d, J = 5.5 Hz, 1 H); 7.35 (broad s, 0.4H); 7.38 (broad s, 0.6H); 7.68 (d, J = 8.5 Hz, 2H); 7.89 (d, J = 8.5 Hz, 2H); 8, 14 (m, 1 H), 8.32 (broad d, J = 8.0 Hz, 0.6H); 8.48 (broad d, J = 0.4H); 9.09 (s, 0.6H); 9,11 (s, 0.4H). Mass spectrum:. m / z = 616 [M + H] + m / z = 614 [-H] - Phase ali 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- [3- (hydroxymethyl) cyclobutyl] urea To a solution of 650 mg of. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} Ethyl carbamate obtained in step a) of example 18 in 3 ml_ of tetrahydrofuran is added 409 mg of (3-Amino-cyclobutyl) -methanol obtained according to the literature: aruyama, T. et al. Chem. Pharm. Bull. (1990), 38 (10), p2719-2725. The reaction mixture is heated with microwaves at 130 ° C for 3 hours and concentrated under reduced pressure. The residue is purified by HPLC (C18 reverse phase column, elution with a water / acetonitrile gradient containing 0.1% formic acid) to provide 122 mg of 1-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -3- [3-- (hydroxymethyl) cyclobutyl] urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz (mixture 60% - 40% cis-trans isomers): 1.42 (s, 6H); 1.62 (m, 1H); from 1.85 to 2.32 (m, 4H); from 3.30 to 3.47 (partially masked m, 2H); 4.04 (m, 0.6H); 4.21 (m, 0.4H); 4.49 (t, J = 5.5 Hz, 0.6H); 4.56 (t, J = 5.5 Hz, 0.4H); 4.58 (s, 2H); 6.96 (broad d, J = 5.5 Hz, 1H); 7.35 (broad s, 0.4H); 7.39 (broad s, 0.6H); 7.68 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8.14 (m, 1H); 8.21 (broad d, J = 8.0 Hz, 0.6H); 8.39 (broad d, J = 8.0 Hz, 0.4H); 9.00 (s, 0.6H); 9.04 (s, 0.4H). Mass Spectrum: m / z = 538 [M + H] + m / z = 536 [MH] - Example 40C: 1 - ( { 2 - [(3-fluorophenyl) amino] pyridin-4-yl.} methyl) -5,5- dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 520 mg of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of Example 1 in 15 ml_ of dioxane are added successively under argon, 27 mg of palladium diacetate, 84 mg of (9,9-dimethyl-9H-xanthene-3, 6-diyl) bis (diphenylphosphine) (Xantphos), 1.5 g of cesium carbonate and 269 mg of 3-fluoroaniline. The reaction mixture is heated at 100 ° C for 1.5 hours, filtered and the filtrate is concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of petroleum ether and ethyl acetate (70/30 by volume) to provide 404 mg of 1 - (. {2 - [(3-fluorophenyl) amino]] pyridin-4-yl.} methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} im «dazolidin-2,4-dione whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.44 (s, 6H); 4.57 (s, 2H); 6.66 (m, 1 H); 6.85 (m, 2H); from 7.20 to 7.31 (m, 2H); 7.69 (d, J = 8.5 Hz, 2H); 7.83 (td, J = 1, 5 and 12.0 Hz, 1 H); 7.88 (d, J = 8.5 Hz, 2H); 8, 15 (d, J = 5.5 Hz, 1 H); 9.25 (s, 1 H). Mass Spectrum (ES): m / z = 505 [M + H] + Example 40D: 1 -. { [2- (cyclopropylamino) pyridin-4-yl] methyl} -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) th] phenyl} imidazolidin-2,4-dione 700 mg of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1 and 1.6 ml of cyclopropylamine are heated with microwaves at 150 ° C for 12 hours and 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 65 mg of 1 -. { [2- (cyclopropylamino) pyridin-4-yl] methyl} -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 0.40 (m, 2H); 0.68 (m, 2H); 1, 41 (s, 6H); 2.50 (masked m, 1 H); 4.49 (s, 2H); 6.58 (m, 2H); 6.70 (d, J = 2.0 Hz, 1 H); 7.65 (d, J = 8.5 Hz, 2H); 7.87 (d, J = 8.5 Hz, 2H); 7.92 (d, J = 5.5 Hz, 1 H). Mass spectrum (ES): m / z = 451 [M + H] + Example 40E: 1 - (. {2 - [(2-chloropyridin-3-yl) amino] pyridin-4-yl.} Methyl ) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 600 mg of 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step b) of example 14 in 50 ml of dioxane are added successively under argon, 33 mg of palladium diacetate, 100 mg of (9,9-dimethyl-9H-xanthene-3, 6-diyl) bis (diphenylphosphine) (Xantphos), 1.81 g of cesium carbonate and 0.42 g of 2-chloro-3-iodopyridine. The reaction mixture is heated at 90 ° C for 5 hours, filtered and the filtrate is concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) to give 0.47 g of 1 - (. {2 - [(2-chloropyridin-3-) il) amino] pyridin-4-yl}. methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.46 (s, 6H); 4.58 (s, 2H); 6.90 (broad d, J = 5.5 Hz, 1 H); 7.12 (broad s, 1 H); 7.35 (dd, J = 5.5 and 8.5 Hz, 1 H); 7.69 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8.00 (dd, J = 2.0 and 5.5 Hz, 1 H); 8, 10 (d, J = 5.5 Hz, 1 H); 8.47 (s, 1 H); 8.56 (dd, J = 2.0 and 8.5 Hz, 1 H). Mass spectrum (ES): m / z = 522 [M + H] + m / z = 520 [MH] - Example 40F: 1 - ( { 2 - [(6-chloropyridin-3-yl) amino] pyridin-4-yl.} methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 400 mg of 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step b) of example 14 in 30 ml of dioxane are added successively under argon, 22 mg of palladium diacetate, 67 mg of (9,9-dimethyl-9H-xanthene-3, 6-diyl) bis (diphenylphosphine) (Xantphos), 1.2 g of cesium carbonate and 0.28 g of 2-chloro-5-iodopyridine. The reaction mixture is heated at 90 ° C for 3 hours, it is filtered and the filtrate is concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) to provide 0.38 g of 1 - (. {2 - [(6-chloropyridin-3-) il) amino] pyridin-4-yl}. methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.43 (s, 6H); 4.59 (s, 2H); 6.86 (broad s, 1 H); 6.89 (broad d, J = 5.5 Hz, 1 H); 7.38 (d, J = 8.5 Hz, 1 H); 7.69 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8, 14 (d, J = 5.5 Hz, 1 H); 8.27 (dd, J = 2.5 and 8.5 Hz, 1 H); 8.64 (d, J = 2.5 Hz, 1 H); 9.38 (s, 1 H). Mass spectrum (ES): m / z = 522 [M + H] + Example 40G: 1 - (. {2 - [(6-hydroxypyridin-3-yl) amino] pyridin-4-yl.} Methyl ) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione To a solution of 500 mg of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1 in 15 ml_ of dioxane are added successively under argon, 52 mg of palladium diacetate, 160 mg of (9,9-dimethyl-9H-xanthene-3, 6-diyl) bis (diphenylphosphine) (Xantphos), 1.74 g of cesium carbonate and 320 mg of 5-amino-2-hydroxypyridine. The reaction mixture is refluxed for 5 hours, 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 (98/2 by volume) to give 1 mg of 1- (. {2 - [(6-hydroxypyridin-3-yl) amino] pyridin-4-yl.} methyl) -5,5-dimethyl-3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: Spectrum R N 1 H at 400 Hz: 1.45 (s, 6H); 4.58 (s, 2H); 6.40 (d, J = 10.0 Hz, 1H); 6.80 (m, 2H); 7.48 (broad d, J = 10.0 Hz, 1H); 7.67 (d, J = 8.5 Hz, 2H); 7.88 (m, 3H); 7.99 (d, J = 5.0 Hz, 1H); 9.00 (extended m, 1H). Mass spectrum (ES): m / z = 504 [+ H] + m / z = 502 [MH] "Example 40H: 5,5-dimethyl-1 - [(2- {[5- (pyrrolidin- 1-ylmethyl) pyridin-3-yl] amino.}. Pyridin-4-yl) methyl] -3-. {4 - [(trifluoromethyl) thio] phenyl}. Imidazolidin-2,4-dione Step bj? 5,5-dimethyl-1 - [(2- {[[5- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino} pyridin-4-yl) methyl] -3 -. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidm 2. 4- dione To a solution of 360 mg of 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step b) of example 14 in 25 ml of dioxane are added successively under argon, 29 mg of palladium diacetate, 61 mg of (9,9-dimethyl-9H-xanthene-3, 6-diyl) bis (diphenylphosphine) (Xantphos), 1.1 g of cesium carbonate and 0.25 g of 3-Bromo-5-pyrrolidin-1-methylmethyl-pyridine obtained in step a) below. The reaction mixture is refluxed for 5 hours, filtered and the filtrate is concentrated under reduced pressure. The remainder is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (96/4 by volume) to provide 56 mg of 5,5-dimethyl-1 - [(2- {[5- (pyrrolidine -1-ylmethyl) pyridin-3-yl] amino.}. Pyridin-4-yl) methyl] -3-. { 4- [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1.44 (s, 6H); 1.69 (m, 4H); 2.43 (m, 4H); 3.54 (s, 2H); 4.57 (s, 2H); 6.83 (m, 2H); 7.69 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8.00 (d, J = 2.5 Hz, 1 H); 8.07 (t, J = 2.5 Hz, 1 H); 8, 14 (d, J = 5.5 Hz, 1 H); 8.73 (d, J = 2.5 Hz, 1 H); 9, 15 (s, H). Mass spectrum (ES): m / z = 571 [M + H] + m / z = 569 [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 sequentially 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, washed with a saturated solution of sodium hydrogencarbonate, with 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 in volumes) to provide 1.4 g of 3-Bromo-5-pyrrolidin-1-methylmethyl-pyridine in shape of a light yellow oil.

Mass Spectrum (ES): m / z = 241 [M + H] + m / z = 161 [M + H] + - Br (base peak) Example 401: 5,5-dimethyl-1 - [(2- { [6- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino.}. Pyridin-4-yl) methyl] -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione Step b: 5,5-dimethyl-1 - [(2- {[[6- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino} pyridin-4-yl) methyl] -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin 2,4-dione To a solution of 0.5 g of 1 - [(2-aminopyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step b) of example 14 in 1 5 ml of dioxane are added successively under argon, 0.32 g of 5-Bromo-2-pyrrolidin-1-ylmethyl-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 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 (96/4 by volume) to provide 0.1 g of 5,5-dimethyl-1 - [(2- {[6- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino.}. pyridin-4-yl) methyl] -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione whose characteristics are as follows: 1 H NMR spectrum at 400 MHz: 1.43 (s, 6H); 1.70 (m, 4H); 2.46 (m, 4H); 3.60 (s, 2H); 4.56 (s, 2H); 6.82 (m, 2H); 7.29 (d, J = 8.5 Hz, 1 H); 7.69 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8,11 (d, J = 5.5 Hz, 1 H); 8, 15 (dd, J = 2.5 and 8.5 Hz, 1 H); 8.64 (d, J = 2.5 Hz, 1 H); 9, 12 (s, 1 H). Mass Spectrum (ES): m / z = 571 [M + H] + m / z = 569 [M-H] Phase a): 5-Bromo-2-pyrrolidin-1-methylmethyl-pyridine To a solution of 2 g of 5-bromo-2-formylpyridine in 20 measure 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 1 hour, diluted with dichloromethane and the organic phase is washed with a saturated solution of sodium hydrogencarbonate, with water, a saturated solution of sodium chloride, dried over magnesium sulfate, it is filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column. The reaction mixture is refluxed 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 (98/2 by volume) to give 50 mg of 1- (3- (azetidin-1-methylmethyl) cyclobutyl] -3-. { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-l) methyl] pyridin-2-yl} urea whose characteristics are the following: 1 H NMR spectrum at 400 MHz: 1, 43 (s, 6H); 4.61 (s, 2H); 6.99 (broad s, 1 H); 7.03 (dd, J = 1.5 and 5.5 Hz, 1 H); 7.69 (d, J = 8.5 Hz, 2H); 7.88 (d, J = 8.5 Hz, 2H); 8, 1 2 (dd, J = 2.0 and 6.0 Hz, 1 H); 8.28 (d, J = 5.5 Hz, 1 H); 8.82 (d, J = 6.0 Hz, 1 H); 9.26 (d, J = 2.0 Hz, 1 H); 9.80 (s, 1 H). Mass Spectrum (ES): m / z = 489 [M + H] + m / z = 487 [MH] "Example 40k: 1 - [3- (azetidin-1-ylmethyl) cyclobutylJ-3- { - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl}. Urea To a solution of 22 mg metanosuifonate of. { 3 - [( { 4 - [(5,5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridine- 2-yl.}. Carbamoyl) amino] cyclobutyl} The methyl obtained in step b) of example 40B in 0.8 ml_ of tetrahydrofuran is added with 12 pL of azetidine. The reaction mixture is heated with microwave at 1 30 ° C for 1 hour and concentrated under reduced pressure. The residue is purified by HPLC (water-acetonitrile gradient containing 0.1% formic acid) to provide 4 mg of 1- [3- (azetidin-1-methylmethyl) cyclobutyl] -3-. { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-ii} urea whose characteristics are the following: LCMS: TR = 3.54 min; m / Z = 577 [M + H] +; m / z = 575 [MH] "Example 40L: { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl.}. imidazolidin- 1 -yl) methyl] pyridin-2-yl.} Methyl carbamate To a solution of 0.5 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione obtained in step d) of example 1 in 15 ml of dioxane are successively added under argon, 131 mg of methyl carbamate, 1.44 g of cesium carbonate, 26 mg of palladium acetate and 67 mg of 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene. The reaction mixture is refluxed for 1 hour, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica eluting with a gradient of dichloromethane and ethyl acetate (from 100/0 to 80/20 in volumes) to provide 243 mg of. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} Methyl carbamate whose characteristics are the following: NMR: 1 H NMR spectrum at 400 MHz: 1.42 (s, 6H); 3.67 (s, 3H); 4.62 (s, 2H); 7.09 (dd, J = 1.5 and 5.5 Hz, 1H); 7.66 (d, J = 8.5 Hz, 2H); 7.86 (m, 3H); 8.20 (d, J = 5.5 Hz, 1H); 10.1 (broad s, 1H). Mass Spectrum (EI): m / z = 467 M + peak base In vitro biological assays A) Experimental protocol for the IGF-1R kinase assay: The inhibitory activity of the compounds on IGF1 is determined by measuring the inhibition of enzyme autophosphorylation using a time-resolved fluorescence assay (HTRF). The human cytoplasmic domain of IGF-1R was cloned in fusion with glutathione S-transferase (GST) in the baculovirus expression vector pFastBac-GST. The protein is expressed in SF21 cells and purified to approximately 80% homogeneity. For the enzymatic assay, the 10 mM test compound in DMSO solution is diluted in steps 1/3 in a Hepes 50mM buffer, pH 7.5, 5mM MnCl2, 50mM NaCl, 3% Glycerol, 0.025% Tween 20, For the determination of the inhibition, the successive dilutions of the compound are pre-incubated 30 min and 90 min in the presence of 5 nM enzyme, not exceeding the final DMSO concentration of 1%. The enzymatic reaction starts to have 120 μ? of final ATP and stopped after 5 ml n by the addition of 100 mM Hepes buffer, pH 7.0, containing 0.4 M potassium fluoride, 133 mM EDTA, 0.1% BSA, anti-GST antibody marked with XL665 and anti-phosphotyrosine antibody conjugated with europium cryptate Eu-K (Cis-Bio I nt.). The characteristics of the two fluorophores, XL-665 and Eu-K, are available in G. Mathis et al. , Anticancer Research, 1 997, 17, pages 301 1 -3014. The energy transfer between the excited europium cryptate versus the XL665 acceptor is proportional to the degree of autophosphorylation of IG F-1 R. The specific long-term signal of XL-665 was measured on a GENAN Pro TECAN plate counter. The inhibition of the autophosphorylation of I GF-1 R at 30 min and 90 min times with the tested compounds of the invention were calculated with respect to a control 1% DM SO, whose activity is determined in the absence of compound. A curve is established that represents the% inhibition as a function of the log of the concentration to determine the concentration corresponding to 50% inhibition (Cl50). B) Determination of autophosphorylation of IGF-1 R in M CF7 cells after stimulation with IGF-1 Cell culture and assay performance: The autophosphorylation of IG F 1 R in cells induced with IGF 1 was evaluated by a technique ELI SA (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% CO2 in medium containing 10% serum. After one night in 10% serum, the serum is removed to the cells for 24 hours. The compounds are added to the medium 1 hour before stimulation with IGF1. After 10 minutes of stimulation with I GF1, the cells are lysed with a buffer (50 mM Hepes pH 7.6, Triton X1 00 1%, 2 mM Orthovanadate, mixture of protease inhibitors). The 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. The level of peroxidase activity (determined by DO with a luminescent substrate) reflects the phosphorylation state of the receptor. 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 control: cells stimulated with IG F1 if n compound. (iii) The signal value of the minimum response is calculated from the negative control: cells not stimulated with IGF 1 without compound. (iv) Using these values as maximum (100%) and minimum (0%) respectively, the data was normalized to obtain a percentage of the maximum response. (v) A dose response curve is plotted and IC 50 calculated (concentration at which the compound induces a 50% decrease in the signal) of the compound by non-linear regression analysis. C) Determination of the proliferation / viability of M EF-IGF 1 R Cell culture: the M cells EF-IG F1 R (stable clone of cells transfected with the hl G F-1 R receptor) are placed in culture at 37 ° C under 5% C02 in MS MS containing 1% SVF. Assay procedure: Cells are seeded at 5,000 cells per well in Cytostar 96 well plates (Amersham) with 0.2 μl EM EM culture medium at 37 ° C for 1 8 hours. The cells are washed twice with EM MS medium and left in culture without serum for 24 hours. The compounds are added at different concentrations in the presence of rhIGF I (100ng / mL) and 0.1 pCi of Thymidine [14C] (specific activity ~ 50 mCi / mmol) to provide 0.2 mL volume per well. After incubation for 72 hours in the presence of the compound, at 37 ° C under 5% CO2, the incorporation of [4C] Thymidine is determined by counting the radioactivity in a Microbeta trilux counter (Perkin-elmer). The IC 50 determination is made from 1 0 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. (I) The signal value of the maximum response is calculated from the positive control: cells stimulated with IGF1 without compound. (iii) The value of the minimum response signal is calculated from the negative control: cells not stimulated with IGF 1 without compound. (iv) Using these values as maximum (100%) and minimum (0%) respectively, the data was normalized to obtain a percentage of the maximum response. (v) A dose response curve is plotted and IC 50 calculated (concentration at which the compound induces a 50% decrease in the signal) of the compound 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 IC 50 (nM) are distributed as follows: + > 100nM 1 0nM < ++ < 100 nM +++ < 10 nM The following examples of pharmaceutical compositions form part of the present invention: it can be indicated that pharmaceutical compositions prepared with other products of formula (I), their salt or their prodrugs according to the present invention also form part of the present invention. . EXAMPLE 41: FA-MECHANICAL COMPOSITION: Tablets are prepared that 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 42: PHARMACEUTICAL COMPOSITION: Tablets are prepared which meet the following formula: Product of Example 9 0.2 g Excipient for a tablet c. s. p 1 g (detail of the excipient: lactose, talc, midon, magnesium stearate)

Claims (8)

1. CLAIMS 1. Products of formula (I): wherein: n represents the integer 0 or 2 Ra and Rb represent CH3 or form together with the carbon atom to which a cycloalkyl radical is attached, R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1 R2, being NR1 R2 such that: one of R1 and R2 represents a hydrogen atom or an alkyl radical, and the other of R1 and R2 is selected from the hydrogen atom and the alkyl radicals optionally substituted with a radical selected from the hydroxyl, alkoxy, aziridyl radicals , azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, and piperazinyl itself optionally substituted on its second nitrogen atom with an alkyl radical; the optionally substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals; and the radical CO-R3 with R3 chosen from NR4R5 and the optionally substituted alkoxy, heterocycloalkyl, aryl, aryloxy and heteroaryl radicals;
2. R4 and R5, identical or different from R1 and R2, are such that either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and the other of R4 and R5 is selected from the hydrogen atom and the alkyl radicals optionally substituted with a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidyl or, piperidyl, morpholinyl, and piperazinyl radicals itself optionally substituted on its second nitrogen atom with 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 optionally containing another heteroatom chosen from N and O, optionally substituted, all the above radicals being aryl, phenyl, aryloxy, and heteroaryl as well as the cyclic amine NR4R5 optionally substituted with one to three identical or different radicals chosen from the halogen atoms, the alkyl, phenyl, NH2, NHAIk, N (Alk) 2, CO-NHAIk and CO-N (Alk) 2 radicals; 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) as defined in claim 1: wherein: n represents the integer 0 or 2, Ra and Rb represent CH3, R represents a pyridyl radical or substituted pyrimidinyl radical NR1 R2, where N R1 R2 is such that: one of R1 and R2 represents a hydrogen atom or a alkyl radical, and the other of R1 and R2 is selected from the hydrogen atom and alkyl radicals optionally substituted with a radical selected from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, or piperazinyl radicals itself optionally substituted in its second nitrogen atom with an alkyl radical; the cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals, optionally substituted; and the radical CO-R3 with R3 chosen from NR4R5 and the optionally substituted alkoxy, piperidyl, phenyl and phenoxy radicals; R4 and R5, identical or different from R1 and R2, are such that either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and the other of R4 and R5 is selected from the hydrogen atom and the alkyl radicals optionally substituted with a radical chosen from the hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholine nyl, or piperazinyl radicals itself optionally substituted on its second nitrogen atom with an alkyl radical; the cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals, optionally substituted; either R4 and R5 form with the nitrogen atom to which they are attached a cyclic amine optionally containing another heteroatom chosen from N and O, optionally substituted, all the above radicals being phenyl, pyrimidinyl and pyridyl optionally substituted with one to three identical or different chosen among the halogen atoms, the alkyl, phenyl, NH2, NHAIk, N (Alk) 2, CO-NHAIk and CO-N (Alk) 2 radicals; 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. 3. Products of formula (I) as defined in any of claims 1 or 2 wherein: n represents the integer 0 or 2 R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1 R2, being NR 1 R2 such that R1 represents a hydrogen atom or an alkyl radical and R2 is selected from the hydrogen atom and alkyl radicals optionally substituted with a hydroxyl, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholyl or piperazinyl radical, itself optionally substituted on its second nitrogen atom with an alkyl radical; cycloalkyl radicals comprising 3 to 6 links; the phenyl radical optionally substituted; the pyrimidinyl radical; the pyridyl radical optionally substituted with a halogen atom; and the radical CO-R3 with R3 chosen from NR4R5 and the alkoxy, piperidyl and optionally substituted phenyl radicals; R4 and R5, identical or different from R1 and R2, are such that either one of R4 and R5 represents a hydrogen atom or an alkyl radical, and the other of R4 and R5 is selected from the hydrogen atom and the alkyl radicals optionally substituted with a hydroxyl, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, or piperazinyl radical itself optionally substituted on its second nitrogen atom with an alkyl radical; cycloalkyl radicals comprising 3 to 6 links; the phenyl radical optionally substituted; the pyrimidinyl radical; the pyridyl radical optionally substituted with a halogen atom; either R4 and R5 form with the nitrogen atom to which they are attached an aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or piperazinyl radical itself optionally substituted on its second nitrogen atom with an alkyl radical, all the optionally substituted phenyl radicals being With one to three identical or different radicals selected from the halogen atoms, the alkyl radicals and the radicals CO-N HAIk 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 mineral and organic acids or with the mineral and organic bases of said products of formula (I).
4. 4. Products of formula (I) as defined in any one of the preceding claims wherein: n represents the integer 0 or 2 R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1 R2, where NR1 R2 is such that R 1 represents a hydrogen atom or an alkyl radical comprising one or two carbon atoms, and R 2 is chosen from the radicals to the chyle comprising from 1 to 4 carbon atoms optionally substituted with a hydroxyl radical; the phenyl radical optionally substituted; the pyrimidine nyl radical; the pyridyl radical optionally substituted with a halogen atom; and the radical CO-R3 with R3 selected from piperidyl, optionally substituted phenyl, NH (alk) and N (alk) 2; all phenyl radicals being optionally substituted with one to three identical or different radicals chosen from the halogen atoms, the alkyl radicals and the radicals CO-NHAIk and CO-N (Al k) 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 organic and mineral bases of said products of formula (I).
5. 5. Products of formula (I) as defined in any one of the preceding claims in which: n represents the integer 0 or 2 R represents a pyridyl or pyrimidi nyl radical substituted with a radical NR1 R2, wherein R1 represents a hydrogen atom and R2 represents an isopropyl radical substituted with a hydroxyl radical; an optionally substituted phenyl radical; a pyrimidinyl radical; a pyridyl radical optionally substituted with a fluorine atom; or a radical CO-R3 with R3 chosen from piperidyl, optionally substituted phenyl, N HCH3 and N (CH3) 2; all phenyl radicals being optionally substituted with one to three identical or different radicals chosen from the chlorine and fluorine atoms, the methyl radical and the 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. 6. Products of formula (I) as defined in any one of the preceding claims wherein n, Ra, Rb and R have the meanings indicated in any one of the preceding claims, wherein the radicals NR1R2 or NR4R5 or NR1R2 and NR4R5 are chosen from the following radicals named ex 18 to ex 40: ex 18 ex 19 ex20 ex 21 ej 22 ej23 ej24 ej25 ej26 ej27 ej 28 ej 29 ej30 ex 31 ex 32 ex 33 ex 34 ex 35 ex 36 ex 37 ex 38 ex 39 ex 0 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).
7. 7. Products of formula (I) as defined in any one of the preceding claims pertaining to formula (la): (ta) wherein n and N R4R5 have the definitions indicated in any one of the preceding claims and mainly in claim 6, said products of formula (la) being in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (la). 8. Products of formula (I) as defined in claim 1 (any one of the preceding claims) whose names are as follows: 1 - ( { 2 - [(2,5-dichlorophenyl) amino) pyridin-4-yl.} methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl] thio] phenyl} imidazolidin-2,4-dione N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] -phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} piperidin-1 -carboxamide 3,4-dichloro-N-. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide 1 -. { 4 - [(5,5-Dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) -sulfonyl] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} 3-methylurea-1 - ( {2 - [(2,5-difluorophenyl) amino] pyridin-4-yl}. Methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 3,5-dichloro-N-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} benzamide 2-chloro-N-. { 4 - [(5, 5-dimethyl-2,4-dioxo-3-. {4 - [(trifluoromethyl) ti or] phenyl} imidazolidin-1-yl) methyl] pyridin-2-yl} -6-fluoro-3-methylbenzamide 3- (. {4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) -thio] phenyl} i midazolidin -1-yl) methyl] pyridin-2-yl.}. Amino) -N, N-dimethyl-benzamide-1 - [(2- {[[(1 R) -2-hydroxy-1-methyl-ethyl] -amino} pyrimidin-4-yl) methyl] -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-214-dione 3-. { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) thio] phenyl}. I midazolidin-1-yl) methyl] pyrimidin-2-yl } -1, 1-dimethylurea 5, 5-dimethyl-1 -. { [2- (pyridin-3-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 3-. { 4 - [(5,5-dimethyl-2,4-dioxo-3. {4 - [(trifluoromethyl) -sulfonyl] phenyl} imidazolidin n-1-yl) methyl] pyrimidin-2-yl} -1, 1-dimethyl urea 5, 5-dimeti 1- -. { [2- (pyrimid-5-ylamino) pyridin-4-i] meth} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione-5, 5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyridin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 5,5-dimethyl-1 -. { [2- (pyrimia <Jin-5-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione 5,5-dimethyl-1 -. { [2- (pyrimidin-5-ylamino) pyrimidin-4-yl] methyl} -3-. { 4 - [(trifluoromethyl) sulfonyl] phenyl} imidazolidin-2,4-dione 1 - (. {2 - [(5-fluoropyridin-3-yl) amino] pyridin-4-yl}. methyl) -5,5-dimethyl-3-. { 4 - [(trifluoromethyl) thio] phenyl} imidazolidin-2,4-dione, said products of formula (I) being in all possible racemic, enantiomeric and diastereomeric isomeric 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). 9. As medicaments, the products of formula (I) as defined in any of claims 1 to 8, as well as their prodrugs, said products of formula (I) being in all possible isomeric forms, racemic, enantiomeric and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases acceptable from a pharmaceutical point of view of said products of formula (I). 10. As medicines, the products of formula (I) as defined in claim 7, as well as their prodrugs, said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereomeric forms, as well as the addition salts with the mineral and organic acids or with the mineral and organic bases acceptable from a pharmaceutical point of view of said products of formula (I). eleven . Pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined in claims 9 and 1 0. 12. Pharmaceutical compositions as defined in the preceding claims which also contain principles. assets of other cancer chemotherapy drugs. 13. 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. 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 to inhibit the activity of protein kinases and mainly of a protein kinase. 5. Use of products of formula (I) as defined in the preceding claim or of 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 pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is I GF1 R 17. 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 a medicament intended for prevent or treat a disease that belongs to the following group: disorders of blood vessel proliferation, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathies, psoriasis, rheumatoid arthritis , diabetes, muscle degeneration, oncology diseases and cancers. 1
8. 8. Use of products of formula (I) as has been