FR2947548A1 - New 6-morpholin-4-yl-pyrimidin-4-(3H)-one derivatives are protein kinase B inhibitors useful for treating e.g. gastric cancers, glioblastoma, thyroid cancers, bladder cancers, breast cancers, melanoma, sarcomas and larynx cancer - Google Patents

Abstract

6-Morpholin-4-yl-pyrimidin-4-(3H)-one derivatives (I) and their all possible isomeric and racemic forms, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. 6-Morpholin-4-yl-pyrimidin-4-(3H)-one derivatives of formula (I) and their all possible isomeric and racemic forms, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. Z : Nalk or N-phenyl (both optionally substituted by one or more halo, alkyl, alkoxy, hydroxyl, cyano or phenyl optionally substituted by one or more halo, OH, alkoxy or alkyl), -O-,-NH, or Ncycloalkyl; n : 0-4; R 1> : alkyl or alkoxy (both optionally substituted by NR1xR1y or one or more halo), H, halo or OH, provided that R 1>fused with phenyl to form a naphthyl group; R 2>, R 3> : H, halo, alkyl optionally substituted by one or more halo; R 4> : H; alk : alkyl; either R1x : H or alkyl; and R1y : H or alkyl; or NR1xR1y : 3-10 membered cyclic group optionally containing heteroatoms of O, S, NH or N-alkyl and optionally substituted by one or more halo, alkyl, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2, where all the alkyl and alkoxy is 1-6C alkyl and 1-6C alkoxy. Independent claims are included for: (1) the preparations of (I); and (2) intermediates comprising (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester (C), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-sodium acetate (D1), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-lithium acetate (D2), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-potassium acetate (D3), 2-(4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-N-phenyl-acetamide compound of formula (F), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (J), and substituted 2-(4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-N-phenyl-acetamide compound of formula (K) (where Z is NH or O). [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Akt Phosphorylation inhibitor; Protein kinase B (PKB) inhibitor. The ability of (I) to inhibit AKT phosphorylation was tested in human prostate carcinoma cells using sandwich immunoassay. The result showed that 2-[(6-methyl-1,3-benzoxazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one exhibited an IC 5 0value of 8 nM.

Description

The present invention relates to novel 1H-pyrimidin-2-one chemical compounds, derived the novel intermediates obtained, their application as medicaments, the pharmaceutical compositions containing them and the new use of such derivatives.

The present invention thus also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans. More particularly, the invention relates to novel pyrimidinone derivatives and their pharmaceutical use for the prevention and treatment of conditions capable of being modulated by inhibition of the PI3K / AKT / mTOR pathway. AKT is a key player in this signaling path. A high level of AKT phosphorylation is the marker of pathway activation that is found in many human cancers. The products of the present invention can thus be used in particular for the prevention or treatment of conditions capable of being modulated by the inhibition of AKT phosphorylation (P-AKT). The inhibition of P-AKT can be obtained in particular by the inhibition of the PI3K / AKT / mTOR pathway, and in particular by the inhibition of kinases belonging to this pathway such as receptors with tyrosine kinase activity such as EGFR, IGFR, ErbB2 , 3'-phosphoinositide-dependent protein kinase-1 (PDK1), phosphoinositide kinase PI3K, serine threonine kinase AKT, mTOR kinase. The inhibition and regulation of the PI3K / AKT / mTOR pathway is a novel and powerful mechanism of action for the treatment of a large number of cancerous diseases including solid and fluid tumors. Such conditions which can be treated by the products of the present application are solid or liquid human tumors. Role of the PI3K / AKT / mTOR pathway The PI3K / AKT / mTOR signaling pathway is a complex network that regulates multiple cellular functions, such as growth, survival, proliferation and cell motility, which are key processes in the pathway. tumorigenesis.

This signaling pathway is an important target in the treatment of cancer because most of its effectors are altered in human tumors. The main effectors contributing to the activation of the pathway are: i) oncogenes such as ErbB1 (EGFR), ErbB2 (HER2), PIK3CA and AKT activated by mutation, amplification or overexpression; ii) the deficiency of tumor suppressor genes such as PTEN, TSC1 / 2, LKB and PML that are inactivated by mutations or deletions (Jiang LZ & Liu LZ, Biochim Biophys Acta, 2008, 1784: 150; & Sawyers CL, 2002, Nat Rev Cancer, 2: 489, Cully M et al., Nature Rev. Cancer, 2006, 6: 184). Activation of oncogenes of this signaling pathway is found in many human cancer diseases. PIK3CA activating mutations are present in 15-30% of colon, breast, endometrial, liver, ovarian and prostate cancers (TL Yuan and LC Cantley, Oncogene, 2008, 27: 5497). Y. Samuels et al., Science, 2004, 304: 554, KE Bachman et al.

Cancer Biol Ther, 2004, 3: 772; DA Levine et al. Clin Canc Res. 2005, 11: 2875; C. Hartmann et al. Acta Neuropathol. 2005, 109: 639). amplifications, activating and overexpressing mutations of RTKs such as EGFR and HER2 in brain, breast and lung cancers (NSCLC) - amplification and activating overexpression of AKT in brain, lung and lung cancers (NSCLC) ), breast, kidney, ovary and pancreas (Testa JR and Bellacosa A., Proct Natl Acad Sci USA 2001, 98: 10983, Cheng et al., Proc Natl Acad. Sci USA 1992, 89: 9267, Bellacosa et al, J. Cancer, 1995, 64: 280, Cheng et al., Proct Natl Acad Sci USA 1996, 93: 3636, Yuan et al. Oncogene, 2000, 19: 2324).

The deficiency of the tumor suppressor genes of this signaling pathway is also found in many human cancer diseases: o the deletion of PTEN in 50% of lung cancers (NSCLC), liver, kidney, prostate, breast , brain, pancreas, endometrium and colon (Maxwell GL et al., Res Res 1998, 58: 2500, Zhou XP et al., J. Pathol., 2002, 161: 439; & Baker SJ, Oncogene, 2008, 27: 5416, Li et al., Science, 1997, 275: 1943, Steack PA et al., Nat Genet., 1997, 15: 356), the mutations of TSC1 / 2 in more 50% of tuberous sclerosis o mutations or deletions of LKB1 (or STK11) which predispose to cancers of the gastrointestinal tract and pancreatic cancer and which are found in particular in 10-38% of lung adenocarcinomas (Shah U. et al., Cancer Res., 2008, 68: 3562), the PML modification by translocation in human tumors (Gurrieri C et al., J. NAtI Cancer Inc. 2004, et al. 96: 269). In addition, this signaling pathway is a major factor of resistance to chemotherapy, radiotherapy and targeted therapies such as EGFR and HER2 inhibitors for example (C. Sawyers et al., Nat Rev 2002). Role of AKT AKT (protein kinase B, PKB) is a serine-threonine kinase that occupies a central place in one of the major cell signaling pathways, the PI3K / AKT pathway. AKT is particularly involved in the growth, proliferation and survival of tumor cells. Activation of AKT is done in two steps (i) by phosphorylation of Threonine 308 (P-T308) by PDK1 and (2) by phosphorylation of Serine 473 (P-S473) by mTORC2 (or mTORC2 complex). Rictor), resulting in total activation. AKT in turn regulates a large number of proteins including mTOR (mammalian target of Rapamycin), BAD, GSK3, p21, p27, FOXO or FKHRLI (Manning BD & Cantley LC, Cell, 2007 129: 1261). Activation of AKT promotes the internalization of nutrients, which triggers anabolic metabolism process supporting cell growth and proliferation. In particular, AKT controls the initiation

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protein synthesis through a cascade of interactions that proceeds via TSC1 / 2 (tuberous sclerosis complex), Rheb, and TOR to achieve two critical targets of the signaling pathway, p70S6K and 4EBP. AKT also induces inhibitory phosphorylation of the Forkhead transcription factor and inactivation of GSK3 (3 which lead to inhibition of apoptosis and cell cycle progression (Franke TF, Oncogene, 2008, 27: 6473). is therefore a target for anti-cancer therapy and the inhibition of AKT activation by the inhibition of its phosphorylation can induce apoptosis of malignant cells and thereby present a treatment for cancer. with tyrosyne kinase activity as IGFI R Abnormally high levels of protein kinase activity have been implicated in many diseases resulting from abnormal cell function This can be caused either directly or indirectly by a malfunction in the mechanisms of activity control related to, for example, mutation, over-expression or inappropriate activation of the enzyme, or over- or under-production of cytokines or growth, also involved in signal transduction upstream or downstream of kinases. In all these cases, a selective inhibition of the kinase action suggests a beneficial effect. The type 1 receptor for insulin-like growth factor (IGF-IR) is a transmembrane receptor with tyrosine kinase activity that binds primarily to IGFI but also to IGFII and insulin with a higher low affinity. The binding of IGF1 to its receptor results in oligomerization of the receptor, activation of tyrosine kinase, intermolecular autophosphorylation and phosphorylation of cellular substrates (major substrates: IRS1 and Shc). The ligand-activated receptor induces mitogenic activity in normal cells. However, IGF-I-R plays an important role in so-called abnormal growth.

Several clinical reports highlight the important role of the IGF-1 pathway in the development of human cancers: IGF-IR is often found to be over-expressed in many tumor types (breast, colon, lung, sarcoma, prostate, multiple myeloma) and its presence is often associated with a more aggressive phenotype. High circulating IGF1 concentrations are strongly correlated with a risk of prostate, lung and breast cancer. In addition, it has been widely documented that IGF-I-R is required for the establishment and maintenance of the transformed phenotype in vitro as 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, SV40 large-virus antigen, activated Ras, Raf, and v-Src. Expression of IGF-I-R in normal fibroblasts induces a neoplastic phenotype, which can then lead to tumor formation in vivo. The expression of IGF-I-R plays an important role in the independent growth of the substrate. IGF-I-R has also been shown to be a protector in apoptosis induced by chemotherapy, radiation, and cytokine-induced apoptosis. In addition, inhibition of endogenous IGF-IR by a dominant negative, triple helix formation or expression of antisense causes suppression of the transforming activity in vitro and decrease of tumor growth in the cells. animal models. PDK1 3'-Phosphoinositide-dependent protein kinase-1 (PDK1) is one of the essential components of the PI3K-AKT signaling pathway. It is a serine-threonine (Ser / Thr) kinase whose role is to phosphorylate and activate other Ser / Thr kinases of the AGC family involved in the control of growth, proliferation, cell survival and in the regulation of metabolism. These kinases include protein kinase B (PKB or AKT), SGK (or serum and glucocorticoid regulated kinase), RSK (or p90 ribosomal S6 kinase), p7OS6K (or p70 ribosomal S6 kinase), and various isoforms of protein kinase C ( PKC) (Vanhaesebroeck B. & Alessi DR., Biochem J, 2000, 346: 561). One of the key roles of PDK1 is the activation of AKT: in the presence of PIP3, the second PI3K-generated messenger, PDK-1 is recruited to the plasma membrane via its PH domain (plekstrin homology) and phosphorylates AKT on threonine. 308 located in the activation loop, an essential modification of AKT activation. PDK1 is ubiquitously expressed and is a constitutively active kinase. PDK1 is a key element in the PI3K / AKT signaling pathway for the regulation of key processes in tumorigenesis such as cell proliferation and survival. Since this pathway is activated in more than 50% of human cancers, PDK1 represents a target for cancer therapy. Inhibition of PDK1 should result in effective inhibition of cancer cell proliferation and survival and thus provide therapeutic benefit for human cancers (Bayascas JR, Cell Cycle, 2008, 7: 2978, Peifer C. & Alessi DR ChemMedChem, 2008, 3: 1810). Phosphoinositide-3 kinases (PI3Ks) PI3K lipid kinase is an important target in this signaling pathway for oncology. PI3Ks of class I are divided into class la (PI3Ka, [3, S) activated by tyrosine kinase receptors (RTKs), G-protein coupled receptors (GPCRs), Rho GTPases, p21- Ras and class Ib (PI3Ky) activated by GPCRs and p21-Ras. PI3Ks of class la are heterodimers which consist of a p10a, 3 or S catalytic subunit and a p85 or p55 regulatory subunit. Class Ib (pl 10y) is monomeric. PI3Ks of class I are lipids / protein kinases that are activated by RTKs, GPCRs or Ras after membrane recruitment. These PI3Ks of class I phosphorylate phosphatidylinositol 4,5 diphosphate (PIP2) at position 3 of inositol to give phosphatidylinositol 3,4,5 triphosphate (PIP3), the key secondary messenger of this signaling pathway. In turn, PIP3 recruits AKT and PDK1 to the membrane where they bind to their domain homologous to the pleckstrin (PH domain), leading to the activation of AKT by phosphorylation of PDK1 on threonine 308. AKT phosphorylates many substrates , thus playing a key role in many processes leading to cellular transformation such as proliferation, growth and cell survival as well as angiogenesis.

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Class I PI3Ks are involved in human cancers: Somatic mutations of the PIK3CA gene that codes for PI3Ka are found in 15-35% of human tumors including two main oncogenic mutations H1047R (in the kinase domain) and E545K / E542K ( in the helical domain) (Y. Samuels et al., Science, 2004, 304: 554, TL Yuan and LC Cantley, Oncogene, 2008, 27: 5497). PI3K inhibitors are expected to be effective for the treatment of many human cancers with genetic alterations resulting in activation of the PI3K / AKT / mTOR pathway (Vogt P. et al., Virology, 2006, 344: 131; Vogt PK, Oncogene, 2008, 27: 5486). Morpholino pyrimidinone derivatives which are kinase inhibitors are known to those skilled in the art. The WO2008 / 148074 application describes products that have mTOR inhibitory activity. These products are pyrido [1,2-a] pyrimidin-4-ones which differ from the products of the present invention because of their wholly aromatic character and their substitutions. The application WO2008 / 064244 describes the application of PI3K [1] TGX-221 and TGX-155 inhibitory products useful in the treatment of cancer and in particular in breast cancer. These products are pyrido [1,2-a] pyrimidin-4-ones previously described in applications WO2004 / 016607 and WO2001 / 053266 which differ from the products of the present invention because of their wholly aromatic character and their substitutions. Applications WO2006 / 109081, WO2006 / 109084 and WO2006 / 126010 disclose DNA-PK inhibitory products useful for the treatment of deficient ATM cancers. These products are pyrido [1,2-a] pyrimidin-4-ones which differ from the products of the present invention because of their wholly aromatic character and their substitutions. The application WO2003 / 024949 discloses DNA-PK inhibitory products. useful for the treatment of deficient ATM cancers. These products are pyrido [1,2-a] pyrimidin-4-ones which differ from the products of the present invention because of their wholly aromatic character and their substitutions. Morpholino pyrimidine kinase inhibitor derivatives are also known to humans. art.

The applications WO2009 / 007748, WO2009 / 007749, WO2009 / 007750 and WO2009 / 007751 describe products which possess an inhibitory activity of mTOR and / or PI3K for the treatment of cancers. These products are pyrimidines substituted at 2, 4 and 6 and the products of the present invention are different because of the presence of the carbonyl group on pyrimidinone as well as by the various substituents. The subject of the present invention is the products of formula (I ): R2 R3 wherein: Z is -O-, -NH or Nalk; N represents an integer of 0 to 4; RI represents a halogen atom or a hydroxyl, alkyl or alkoxy radical; the alkyl and alkoxy radicals being optionally substituted with an NRxRy group; R 2 and R 3, which may be identical or different, represent a hydrogen atom, a halogen atom or an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom or an alkyl radical; or Rx and Ry form with the nitrogen atom to which they are bound a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this radical cyclic ring being optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl, oxo, alkoxy, NH 2 radicals; NHalk and N (alk) 2; said products of formula (1) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

In the products of formula (I): the term "alkyl radical (or alk)" denotes the radicals, linear and, if appropriate, branched, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl; , isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl and their linear or branched positional isomers: alkyl radicals containing from 1 to 6 carbon atoms and more particularly alkyl radicals containing from 1 to 4 atoms are preferred. carbon from the list above; the term "alkoxy radical" denotes the linear and, if appropriate, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy radicals, as well as their linear or branched positional isomers: alkoxy radicals containing 1 to 4 carbon atoms from the above list; the term "alkylthio radical" denotes the linear and, if appropriate, branched, linear, secondary or tertiary methylthio, propylthio, isopropylthio, butylthio, pentylthio or hexylthio radicals, as well as their linear or branched positional isomers: alkylthio radicals containing 1 to 4 carbon atoms from the above list; the term "halogen atom" denotes the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom. the term "cycloalkyl radical" denotes a saturated carbocyclic radical containing 3 to 10 carbon atoms and thus particularly denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals and especially the cyclopropyl, cyclopentyl and cyclohexyl radicals; in the -O-cycloalkyl radical, cycloalkyl is as defined above; the term "heterocycloalkyl radical" thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms; for example morpholinyl, thiomorpholinyl, homomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyran, oxodihydropyridazinyl or oxetanyl radicals being optionally substituted; mention may in particular be made of morpholinyl, thiomorpholinyl, homomorpholinyl, piperazinyl, piperidyl, homopiperazinyl or pyrrolidinyl radicals, the terms aryl and heteroaryl denote unsaturated or partially unsaturated, respectively carbocyclic and heterocyclic, monocyclic or bicyclic radicals, containing at most 12 links, optionally containing a -C (O) linkage, heterocyclic radicals containing one or more identical or different heteroatoms selected from O, N, or S with N, optionally substituted; the term "aryl radical" thus denotes monocyclic or bicyclic radicals containing 6 to 12 members, such as, for example, the phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly the phenyl and naphthyl radicals and even more particularly the phenyl radical. It may be noted that a carbocyclic radical containing a C - (O) - linkage is, for example, the tetralone radical; the term "heteroaryl radical" thus denotes monocyclic or bicyclic radicals containing 5 to 12 ring members: monocyclic heteroaryl radicals such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3-furyl, pyrannyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazolyl, all these radicals being optionally substituted, among which more particularly the thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals such as, for example, benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl; azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or oxodihydropyridino pyrazolyl, all of these radicals being optionally substituted; As examples of heteroaryl or bicyclic radicals, there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl, benzothiazolyl or benzimidazolyl radicals optionally substituted by one or more identical or different substituents as indicated above. The carboxy radical (s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example: among 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, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, 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 being substitutable; selected from, for example, halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for example, chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl. or phenethyl. The addition salts with the inorganic or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids. It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can 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 arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or isomeric cistrans. The term stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above. The subject of the present invention is the products of formula (I) as defined above in which: Z represents -O-, -NH or Nalk; n represents an integer of 0 to 4; RI represents a halogen atom or an alkyl or alkoxy radical; R2 and R3 represent a hydrogen atom; R4 represents a hydrogen atom; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom or an alkyl radical; or either R 1 and R 4 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, NH and N-alkyl, cyclic radical being optionally substituted; all the above alkyl (alk) and alkoxy radicals being linear or branched and having from 1 to 6 carbon atoms, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). In particular, when NRxRy forms a ring as defined above, such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl, piperazinyl or homopiperazinyl radicals, these radicals themselves being optionally substituted. as indicated above or below. The NRxRy ring may more particularly be chosen from pyrrolidinyl and morpholinyl radicals optionally substituted by one or two alkyl or piperazinyl radicals optionally substituted on the second nitrogen atom by an alkyl, phenyl or CH 2 -phenyl radical, themselves optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals. The subject of the present invention is particularly the products of formula (I) as defined above, corresponding to the following formulas: 2 - [(5-fluoro-1H-benzimidazol-2-yl) methyl] -6- ( morpholin-4-yl) pyrimidin-4 (3H) -one - 2- (1,3-benzoxazol-2-ylmethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- [ (6-Bromo-1H-benzimidazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(6-methoxy-1H-benzimidazol-2-) yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(5,6-difluoro-1H-benzimidazol-2-yl) methyl] -6- (morpholine) 4-yl) pyrimidin-4 (3H) -one - 2 - [(6-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(5-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -25 one as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is in particular the products of formula (I) as defined above having the following formulas: 2 - [(1-methyl-1H-benzimidazol-2-yl) methyl] -6- (morpholinic acid) 4-yl) pyrimid-in-4 (3H) -one as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The present invention also relates to any process for preparing the products of formula (I) as defined above. The products according to the invention can be prepared from conventional methods of organic chemistry. Preparation of Compounds of Formula (I) The products of general formula (I) according to the present invention may in particular be prepared as indicated in General Schemes 1A-1 B below. In this respect, the methods described can not constitute a limitation of the scope of the invention as regards the methods of preparation of the claimed compounds. The preparations of the examples of the present invention give illustrations of the schemes below. Such synthetic schemes are part of the present invention: the object of the present invention is also the processes for the preparation of the products of formula C to (I) -b, as defined in General Schemes 1A-1B below. . General Scheme 1A: CIH A B C XH XH "" ry f (R1) ,,. NOY = Na, Li, K In General Scheme 1A: Ketene amine B can be obtained from imino-ether A or its commercial amino-acrylate tautomer, by reaction with morpholine in a solvent such as ethanol, at a temperature between 0 ° C. and the boiling point of the solvent according to the method described by Landwehr J. et al. in J. Med. Chem. 2006, 49, 4327-4332. The ester C can be obtained by reaction of the ketene amine B with the imino ether 10 A, or its tautomer amino-acrylate, in a solvent such as ethanol, at a temperature between 20 ° C and the point d boiling of the solvent. Alternatively, the ester C can be obtained by one-pot reaction between morpholine and an excess (for example 3 equivalents) of imino ether A (or its aminoacrylate tautomer), in a solvent such as ethanol. at a temperature between 20 ° C and the boiling point of the solvent. The carboxylate D may be obtained by hydrolysis of the ester C in the presence of a base such as sodium hydroxide or lithium hydroxide, in a solvent such as tetrahydrofuran or methanol, at a temperature of between 0 ° C. and 30 ° C. .

Amides F can be obtained from carboxylate D by condensation of an aniline E in the presence of a peptide coupling agent such as ethyl dimethylaminopropyl carbodiimide (EDCI), 4- (4,6-dimethoxy) chloride. 1,2,3-triazin-2-yl) 4-methylmorpholinium (DMT-MM), benzotriazol-1-yloxy-tris-dimethylamino phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytrispyrrolidino phosphonium hexafluorophosphate ( PyBOP), bromo trispyrrolidino phosphonium hexafluorophosphate (PyBROP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), or a mixture of hydroxybenzotriazole / ethyl dimethylaminopropyl carbodiimide HOBT / EDCI in a solvent such as dimethylformamide, pyridine, ethanol, water or methanol at a temperature between 20 ° C and 50 ° C as for example under the conditions described by Kunishima M. et al. in Tetrahedron 2001, 57, 1551-1558.

The products (I) -a can be obtained from the amides F by cyclodehydration in a solvent such as acetic acid, or in the presence of an acid such as para-toluenesulphonic acid, in a solvent such as toluene, xylene or n-butanol, at the boiling point of the solvent, according to, for example, the method described by Arakawa.K et al. In Chemical and Pharmaceutical Bulletin, 45 (12), 1984-1993, 1997. General Scheme 1B: H • Off / / 0 0 VO (Boc) NO / R2 X then R3X iy XO ~~ C7 NOX = CI, Br , I or OTf C0) H or (PhSOZ) ZN-F Cn C C G R2 -X and then R3X X = CI, Br, I or OTf (R1) n H = N (R1) n Côn In General Scheme 1B: ## STR5 ## ester G can be obtained from ester C by reaction with (Boc) 2 O (tert-butyl dicarbonate), in a solvent such as dimethylformamide or dioxane. acetonitrile or dichloromethane, in the presence of a base such as, for example, sodium hydride, triethylamine, N, N-diisopropylethylamine or pyridine, at a temperature between 0 ° C and 60 ° C, according to for example the method described by Hioki K. et al. Synthesis 2006, 12, 1931-1933.

The products H can be obtained from ester G by reaction with R2-X and optionally with R3-X (X = Cl, Br, I or OTf and R2 and R3 are alkyl groups), in the presence of base such as sodium hydroxide, potassium tert-butoxide or cesium carbonate, in a solvent such as methanol, ethanol or dioxane, at a temperature of between 0 ° C. and 100 ° C., for example according to the process described by Noël D. D'Angelo et al. in J. Med. Chem. 2008, 51, 5766-5779. The product H where R 2 = R 3 = F can be obtained by reaction of the product G with N-fluorobenzenesulfonimide, in the presence of a base such as the potassium salt of hexamethyl-disilylazane, in a solvent such as tetrahydrofuran, at a temperature between -78 ° C and 20 ° C, according to for example the method described by Christopher S. Burgey et al. in J. Med. Chem. 2003, 46, 461-473. The esters J where the R2 and R3 groups are alkyl radicals can be obtained from the ester C in the same way as the products H, in the presence of a base such as butyl lithium, sodium hydride, potassium tertiobutylate or cesium carbonate in a solvent such as methanol, ethanol, tetrahydrofuran, dimethylformamide or dioxane at a temperature between 0 ° C and 100 ° C.

The amides K can be obtained from esters H or J, by reaction of an aniline E, in the presence of an agent such as trimethylaluminium, in a solvent such as toluene, at a temperature of between 20 ° C. and 20 ° C. boiling point of the solvent, as for example under the conditions described by Auzeloux, P et al. in J. Med. Chem. 2000, 43 (2), 190-197.

Products (I) -b can be obtained from amides K by cyclodehydration, in the presence of an acid such as para-toluenesulphonic acid, in a solvent such as acetic acid, toluene, xylene or n-butanol, at the boiling point of the solvent according to, for example, the method described by Arakawa K. et al. In Chemical and Pharmaceutical Bulletin (1997) 45 (12), 1984-1993. Among the starting materials of formula A or B, some are known and can be obtained either commercially or according to the usual methods known to those skilled in the art, for example from commercial products. It is understood by those skilled in the art that for the implementation of the methods according to the invention described above, it may be necessary to introduce protective groups of amino, carboxyl and alcohol functions in order to avoid side reactions.

The following non-exhaustive list of examples of protection of reactive functions may be mentioned: the hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl, - the amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, BOC, benzyloxycarbonyl, phthalimido or other radicals known in the peptide chemistry, the acid functions may be protected for example in the form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry. A list of different protecting groups for use in the manuals known to those skilled in the art and for example in the patent BF 2 499 995 can be found. It can be noted that it is possible to subject, if desired and if necessary, intermediate products. or products of formula (I) thus obtained by the processes indicated above, to obtain other intermediates or other products of formula (I), one or more reactions of transformations known to those skilled in the art such for example: a) an acid function esterification reaction, b) an acid functional ester saponification reaction, c) a free or esterified carboxy function reduction reaction, d) a reaction conversion of alkoxy function to hydroxyl function, or hydroxyl function in alkoxy function, e) elimination reaction of the protective groups that can carry the reactive functions protected s

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f) a salification reaction with a mineral or organic acid or a base to obtain the corresponding salt, g) a resolving reaction of the racemic forms into split products, said products of formula (I) thus obtained being in all isomeric forms possible racemic, enantiomeric and diastereoisomeric. The reactions a) to g) can be carried out under the usual conditions known to those skilled in the art such as, for example, those indicated below. a) The products described above may, if desired, be subjected, on the possible carboxy functions, to esterification reactions which may be carried out according to the usual methods known to those skilled in the art. b) The possible acid-functional ester function transformations of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in an alcoholic medium such as, for example, in methanol or in hydrochloric or sulfuric acid. The saponification reaction may be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide. c) The optional free or esterified carboxy functions of the products described above may, if desired, be reduced according to the alcohol by the methods known to those skilled in the art: the optional esterified carboxy functions may, if desired, be reduced in function alcohol by the methods known to those skilled in the art and in particular by lithium hydride and aluminum in a solvent such as for example tetrahydrofuran or dioxane or ethyl ether. The optional free carboxy functions of the products described above may, if desired, be reduced depending on the alcohol, especially with boron hydride. d) The optional alkoxy functions, such as in particular methoxy, of the products described above may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as methylene chloride, for example, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux. e) The elimination of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid or benzene sulfonic acid. or para-toluene sulfonic, formic or trifluoroacetic or by catalytic hydrogenation. The phthalimido group can be removed by hydrazine. F) The products described above may, if desired, be subjected to salification reactions, for example by an inorganic or organic acid or a mineral or organic base according to the usual methods known to those skilled in the art: such salification reaction can be carried out for example in the presence of hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol. g) The optional optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art. The products of formula (I) as defined above, as well as their addition salts with acids, have interesting pharmacological properties, in particular because of their kinase inhibiting properties as indicated above. The products of the present invention are especially useful for tumor therapy.

The products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents. These properties justify their application in therapeutics and the subject of the invention is particularly useful as medicaments, the products of formula (I) as defined above, said products of formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). The subject of the invention is particularly suitable, as medicaments, the products corresponding to the following formulas: 2 - [(5-fluoro-1H-benzimidazol-2-yl) methyl] -6- (morpholin-4- yl) pyrimidin-4 (3H) -one - 2- (1,3-benzoxazol-2-ylmethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(6-bromo) 1H-benzimidazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(6-methoxy-1H-benzimidazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(5,6-difluoro-1H-benzimidazol-2-yl) methyl] -6- (morpholin-4- yl) pyrimid in-4 (3H) -one - 2 - [(6-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one 2 - [(5-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one and addition salts with mineral acids and organic or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). The invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, optionally, a pharmaceutically acceptable carrier. The invention thus extends to pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above. Such pharmaceutical compositions of the present invention may also, if appropriate, contain active principles of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating agents of DNA and others. These pharmaceutical compositions can be administered orally, parenterally or locally by topical application to the skin and mucous membranes or by intravenous or intramuscular injection. These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine such as, for example, single or coated tablets, pills, lozenges, capsules, drops, granules, injectables , ointments, creams or gels; they are prepared according to the usual methods. The active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 0.05 to 5 g per day in the adult, or preferably from 0.1 to 2 g. per day. Such a medicament may especially be intended for the treatment or prevention of a disease in a mammal.

The present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the prevention or treatment of diseases related to uncontrolled proliferation. The present invention thus particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diseases in oncology and in particular for treatment of cancers. Among these cancers, one is interested in the treatment of solid or liquid tumors, in the treatment of cancers resistant to cytotoxic agents. The products of the present invention cited can in particular be used for the treatment of primary tumors and / or metastases, particularly in gastric, hepatic, renal, ovarian, colon, prostate, endometrial, lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder, breast cancers, in melanoma, in lymphoid or myeloid hematopoietic tumors, in sarcomas, in cancers of the brain, larynx, lymphatic system, cancers of the bones and pancreas, in hamartomas. The subject of the present invention is also the use of the products of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers.

Such drugs for cancer chemotherapy may be used alone or in combination. The products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or in combination with other therapeutic agents, for example. Such therapeutic agents may be commonly used anti-tumor agents. The subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas C, D, F, J and K as defined above and recalled hereinafter: X H H CN Y = Na, Li Wherein R1, R2 and R3 are as defined in any one of claims 1 to 2. The following examples which are products of formula (I): ## STR5 ## wherein R 1, R 2 and R 3 are as defined in any one of claims 1 to 2. The present invention has the following nomenclature of the compounds of this invention: ACDLABS version 10.0.

The microwave oven used is a Biotage device, Initiator TM 2.0, 400W max, 2450 MHz. 400 MHz and 500 MHz MHz NMR spectra were carried out on BRUKER AVANCE DRX-400 or BRUKER AVANCE DPX-500 spectrometer with chemical shifts (5 ppm) in dimethylsulfoxide-d6 solvent (DMSO-d6). ) referenced at 2.5 ppm at the temperature of 303K. Mass spectra (SM) were obtained either by Method A or Method B: Method A: WATERS UPLC-SQD Apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: ACQUITY BEH C18 1.7 μm - 2.1 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 50 ° C; Flow rate: 1 ml / min; Gradient (2 min): 5 to 50% B in 0.8 min; 1.2 min: 100% B; 1.85 min: 100% B; 1.95: 5% B; Retention time = Tr (min). Method B: WATERS ZQ Apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: XBridge C18 2.5 μm - 3 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 70 ° C; Flow rate: 0.9 ml / min; Gradient (7 min): from 5 to 100% of Ben5,3 min; 5.5 min: 100% B, 6.3min: 5% B; Retention time = Tr (min). Example 1 Synthesis of 2- [4- (Morpholin-4-yl) -6-oxo-1,6-25-dihydropyrimidin-2-yl] -N-phenylacetamide Step 1: H 2 O ~ NyyO. O, N ,, O

To a solution of 25 g of morpholine in 400 ml of ethanol heated at 95 ° C. are added 168.5 ml of ethyl 3-ethoxy-3-iminopropanoate hydrochloride, then 155 ml of N, N-diisopropylethylamine in 200 ml of ethyl acetate. ethanol. The reaction mixture is heated at 95 ° C for 30 hours and then allowed to warm to room temperature. The precipitate formed is filtered on sintered glass and then washed with 100 ml of ethanol, 2 times 500 ml of water and finally 500 ml of ethyl ether. The solid is dried under vacuum to give 35 g of ethyl [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate as a white solid, the characteristics of which are following: 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 1.19 (t, J = 7.1Hz, 3H); 3.38 at 3.44 (m, 4H); 3.56 (s, 2H); 3.61 (dd, J = 4.0 and 5.7 Hz, 4H); 4.12 (q, J = 7.1 Hz, 2H); 5.20 (s, 1H); 11.69 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.48; [M + H] +: m / z 268; [MH] -: m / z 266 Purity: 98% Step 2: H 2 O / N / NOA solution of 10 g of [4- (morpholin-4-yl) -6-oxo-1,6) ethyl dihydropyrimidin-2-yl] acetate in 300 ml of tetrahydrofuran is added 18.7 ml of 2M sodium hydroxide. The reaction mixture is stirred for 48 hours at room temperature. The precipitate formed is filtered on sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried on a rotary evaporator to give 8.7 g of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate in the form of a white solid of which the characteristics are as follows: 1H NMR Spectrum (400MHz, d in ppm, DMSO-d6): 3.08 (s, 2H); 3.38 (t, J = 4.6 Hz, 4H); 3.61 (t, J = 4.6 Hz, 4H); 5.08 (s, 1H); 13.16 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.29; [M + H] +: m / z 240; [MH] -: m / z 238 Purity: 98% Step 3: To a solution of 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] sodium acetate in 8 ml of methanol are added 151 mg of 1,2-diamino-4-fluorobenzene. The mixture is stirred at ambient temperature for 5 minutes and then 354 mg of 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholin-4-hydrate chloride is added. This is stirred for 30 minutes at room temperature. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is taken up in 30 ml of acetic acid. The reaction mixture is refluxed for 1 hour and then concentrated under reduced pressure. 30 ml of water and a saturated aqueous solution of sodium bicarbonate are then added until a pH in the region of 7 is reached. 20 ml of ethyl acetate are then added and the mixture is stirred for 1 hour. The precipitate formed is filtered off and then purified by chromatography on a column of silica gel, eluting with a gradient of the eluent CH 2 Cl 2 / MeOH: 80/20 in dichloromethane from 0% to 100% in 25 minutes. 140 mg of 2 - [(5-fluoro-1H-benzimidazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimid-4 (3H) -one are obtained in the form of an off-white solid with the characteristics are as follows: 1H NMR Spectrum (400MHz, d in ppm, DMSO-d6): 3.37 (t, J = 4.9 Hz, 4H); 3.58 (t, J = 4.9 Hz, 4H); 4.08 (s, 2H); 5.22 (s, 1H); 7.00 (t, J = 8.2 Hz, 1H); 7.31 (dd, J = 0.7 and 9.8 Hz, 1H); 7.49 (bs, 1H); 12.15 (bs, 2 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.41; [M + H] +: m / z 330; [MH] -: m / z 328 Purity: 98% Example 2: Synthesis of 2- (1,3-benzoxazol-2-ylmethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one H Step 1: To a solution of 500 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate in 4 mL of dimethylformamide is added 4 mL of pyridine, 550 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 700 mg of 2-aminophenol. It is stirred at ambient temperature for 1 night, and then the reaction mixture is concentrated under reduced pressure. Water and ethyl acetate are added and the mixture is stirred for 30 minutes. The precipitate formed is filtered, rinsed with water, with ethyl ether and with petroleum ether. The solid obtained is dried under vacuum. 370 mg of N- (2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are thus obtained in the form of a beige solid. whose characteristics are as follows: Mass Spectrometry: Method B Retention time Tr (min) = 2.58; [M + H] +: m / z 331; [MH] -: m / z 329 Purity: 98% Step 2: To a solution of 200 mg of N- (2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-yl] acetamide in 40 mL of toluene is added 20 mg of 4-methylbenzenesulfonic acid hydrate. The reaction mixture is refluxed for 1 night. After cooling to 0 ° C, the insoluble material is filtered. The filtrate is concentrated to dryness under reduced pressure and then the residue is chromatographed on a column of silica gel, eluent: CH 2 Cl 2 / MeOH: 98/02 then 90/10. 16 mg of 2- (1,3-benzoxazol-2-ylmethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one are thus obtained in the form of a white solid, the characteristics of which are as follows: 1H NMR Spectrum (400MHz, d in ppm, DMSO-d6): 3.35 (t, J = 5.0Hz, 4H); 3.56 (t, J = 4.9 Hz, 4H); 4.25 (s, 2H); 5.25 (brs, 1H); 7.31 to 7.40 (m, 2H); 7.62 to 7.74 (m, 2H); 11.92 (bs, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.60; [M + H] +: m / z 313; [MH] -: m / z 311 Purity: 98% Melting point (Kofler) = 224 ° C Example 3: Synthesis of 2 - [(5-bromo-1H-benzimidazol-2-yl) methyl] -6- (4-morpholin-4-yl) pyrimidin-4 (3H) -one 1.3 g of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate are introduced into a flask of sodium in 10 mL of dimethylformamide and then 10 mL of pyridine, 1.44 g of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 1.87 g of 4-bromobenzene-1,2-diamine were added. The mixture is stirred at room temperature for 1 night and then the reaction mixture is concentrated to dryness under reduced pressure. The residue is taken up in 40 ml of acetic acid and refluxed for 4 hours and then concentrated under reduced pressure. 100 ml of water and a saturated aqueous sodium bicarbonate solution are then added until a pH in the region of 7 is obtained. 200 ml of ethyl acetate are then added and the mixture is stirred for 1 hour. The precipitate formed is filtered and then purified by chromatography on a column of silica gel, eluting with a gradient of the eluent CH 2 Cl 2 / MeOH: 80/20 in dichloromethane from 0% to 100% in 25 minutes. 560 mg of 24 (5-bromo-1H-benzimidazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one are obtained in the form of an off-white solid whose characteristics are the following: 1H NMR Spectrum (400 MHz, d in ppm, DMSO-d6): 3.34 to 3.39 (m, 4H); 3.55 to 3.59 (m, 4H); 4.09 (s, 2H); 5.21 (s, 1H); 7.28 (dd, J = 2.0 and 8.6 Hz, 1H); 7.47 (d, J = 8.6 Hz, 1H); 7.71 (d, J = 2.0 Hz, 1H), 12.20 (spread m, 2H) Mass Spectrometry: Method B Retention Time Tr (min) = 2.71; [M + H] +: m / z 390; [MH] -: m / z 388 Purity: 98 Example 4: Synthesis of 2 - [(6-methoxy-1H-benzimidazol-2-yl) methyl] -6-25 (morpholin-4-yl) pyrimidin-4 (3H) -one O The product is prepared following the procedure described in step 3 of Example 1 starting from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6 sodium dihydropyrimidin-2-yl] acetate and 166 mg of 1,2-diamino-4-methoxybenzene instead of 1,2-diamino-4-fluorobenzene. After purification by column chromatography on silica gel, eluting with a gradient of pure CH 2 Cl 2 to CH 2 Cl 2 / MeOH: 85/15, 8 mg of 2 - [(6-methoxy-1H-benzimidazol-2-yl) methyl are obtained. ] (6-morpholin-4-yl) pyrimidin-4 (3H) -one as an off-white solid whose characteristics are as follows: 1H NMR Spectrum (400 MHz, d in ppm, DMSO-d6): 3, 38 (m, 4H); 3.58 (m, 4H); 3.76 (s, 3H); 4.04 (s, 2H); 5.21 (s, 1H); 6.72 to 6.82 (m, 1H); 6.89 to 7.15 (m spread, 1H); 7.27 to 7.52 (metal, 1H); 11.82 (metal, 1H); 12.11 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.40; [M + H] +: m / z 342 Purity: 90% Example 5: Synthesis of 2 - [(5,6-difluoro-1H-benzimidazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one H The product is prepared following the procedure described in step 3 of Example 1 from 261 mg of [4- (morpholin-4-yl) -6-oxo). -1.6- or 20

34

sodium dihydropyrimidin-2-yl] acetate and 173 mg of 1,2-diamino-4,5-difluorobenzene instead of 1,2-diamino-4-fluorobenzene. After purification by column chromatography on silica gel, eluting with a gradient of pure CH 2 Cl 2 to CH 2 Cl 2 / MeOH: 85/15, 150 mg of 2 - [(5,6-difluoro-1H-benzimidazol-2-yl) are obtained. ) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one as a light pink solid whose characteristics are as follows: 1H NMR Spectrum (400 MHz, d in ppm, DMSO-d6): 3.34-3.39 (m, 4H); 3.55 to 3.60 (m, 4H); 4.08 (s, 2H); 5.21 (s, 1H); 7.57 (dd, J = 7.8 and 10.8 Hz, 2H); 12.16 (bs, 2 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.51; [M + H] +: m / z 348; [MH] -: m / z 346 Purity: 98% Example 6: Synthesis of 2 - [(6-fluoro-1,3-benzoxazol-2-yl) methyl] -6-15 (morpholin-4-yl) pyrimidine The product is prepared following the procedure described in step 1 of Example 2 from 550 mg of [4- (morpholin-4-yl) -6- sodium oxo-1,6-dihydropyrimidin-2-yl] acetate and 815 mg of 2-amino-5-fluorophenol instead of 2-aminophenol. After purification by chromatography on a column of silica gel, eluting with pure CH2Cl2 and then CH2Cl2 / MeOH: 95/05, 149 mg of N- (4-fluoro-2-hydroxyphenyl) -2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a gray solid whose characteristics are as follows.

Step 2: The product is prepared following the procedure described in step 2 of Example 2 starting from 120 mg N- (4-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4- yl) -6-oxo-1,6-dihydropyrimid-2-yl] acetamide, 11 mg of 4-methylbenzenesulfonic acid hydrates and replacing toluene with xylene. After purification by column chromatography on silica gel, eluent: CH 2 Cl 2 / MeOH 98/2, 15 mg of 2 - [(6-fluoro-1,3-benzoxazol-2-yl) methyl] -6- ( morpholin-4-yl) pyrimidin-4 (3H) -one as a white solid whose characteristics are as follows.

Example 7 Synthesis of 2 - [(5-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one H Step 1: The product is prepared by following the procedure described in step 1 of Example 2 from 1 g of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. sodium and 466 mg of 2-amino-4-fluorophenol instead of 2,4-difluoroaniline. 795 mg of 2 N- (5-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a solid. brown whose characteristics are as follows. Step 2: The product is prepared following the procedure described in step 2 of Example 2 starting from 700 mg N- (5-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4- yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide, 292 mg of 4-methylbenzenesulfonic acid hydrate and replace the toluene with xylene. After purification by chromatography on a column of silica gel, eluting with a CH 2 Cl 2 / MeOH: 98/02 mixture then CH 2 Cl 2 / MeOH: 95/05, followed by recrystallization from methanol, 188 mg of 2- [ (5-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one as a brown solid, the characteristics of which are as follows. Example 8: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 1 0.2 g Excipient for a tablet finished at 1 g (detail of excipient: lactose, talc, starch, magnesium stearate ). Example 1 is taken as an example of a pharmaceutical preparation, which preparation can be carried out if desired with other products as examples in the present application. Pharmacological Part: Experimental Protocols In Vitro Experimental Procedures The inhibitory activity of the molecules on AKT phosphorylation is measured either by western blotting by the technique described below, or by the MSD Multi-spot Biomarker detection technique of Meso Scale Discovery. also described below. It has been demonstrated on a set of molecules that the two techniques give compatible results. Study of the expression of pAKT in human PC3 prostate carcinoma cells measured by western blotting (Test A): This test is based on the measurement of the expression of the phosphorylated AKT protein on serine 473. AKT (pAKT) is measured by western blotting in the PC3 human prostate carcinoma line (ATCC CRL-1435), using an antibody specifically recognizing pAKT-S473. On day 1, the PC3 cells are seeded in 6-well plates (TPP, # 92006) at a concentration of 0.8 × 10 6 cells / well in 1800 μl of DMEM medium (DMEM Gibco # 11960-044) containing 10% fetal calf serum. (Gibco SVF, # 10500-056) and 1% Glutamine (Gibco L-Glu # 25030-024), and incubated at 37 ° C, 5% CO2, overnight. On day 2, the cells are incubated in the presence or absence of test products for 1 to 2 hours at 37 ° C. in the presence of 5% CO 2. The molecules diluted in dimethylsulfoxide (DMSO Sigma # D2650) are added from a stock solution concentrated 10 times, the final percentage of DMSO being 0.1%. The molecules are tested either at a single concentration of less than or equal to 10 μM, or at increasing concentrations in a range that may range from less than 1 nM to 10 μM.

After this incubation, the cells are lysed for the preparation of the proteins. After aspiration of the culture medium, the cells are rinsed with 1 ml of PBS (Gibco DPBS, # 14190-094), recovered by scraping into 200 μl of complete HNTG buffer and transfer to a 96-well plate (Greiner # 651201), and lysed for 1H on ice. The HNTG buffer is composed of the following mixture: 50 mM Hepes, 150 mM NaCl, 1% Triton, 10% Glycerol, with extemporaneous additive of a Protease Inhibitor Cocktail Mini pellet (Roche 1836153) and a Phosphatase Inhibitor Cocktail pellet (Roche104906837001) for 10m1 of buffer. The lysate is centrifuged for 10 min at 6000 rpm. 155 μl of supernatant are recovered. 150 μl were incubated for denaturation for 5min at 95 ° C in the presence of 4X NuPAGE LDS Sample Buffer buffer diluted 4-fold (Ref InVitrogen NP0007) and NuPAGE 10X Sample Reducing Agent diluted 10-fold (Ref InVitrogen NP0009). These samples are then frozen at -20 ° C. 5 μl are assayed by the microBCA technique according to the MicroBCA Protein Assay Kit (Pierce # 23235). For the separation of the proteins, 20 μg of proteins are deposited on NU-PAGE gel 4-12% Bis Tris Gel 12 wells (Ref InVitrogen NP0322BOX) and the migration is carried out for 1 h 30 in migration buffer NU-PAGE MOPS SDS Running Buffer 20X diluted 20 times (Ref InVitrogen NP0001), at 150 volts.

The gel is then transferred to an Invitrolon PVDF membrane (Invitrogen # LC2007) previously permeabilized for a few seconds in ethanol (Ethanol Fischer Scientific # E / 0600DF / 15). The transfer is carried out in a Biorad vat at 30 volts overnight or at 60 volts for 3 hours, in the presence of transfer buffer NUPAGE Transfer Buffer 20X diluted 20 times (Ref InVitrogen NP0006). The membrane is then saturated in saturation solution composed of TBS (Tris Buffer Saline 10x, Sigma # T5912 Sigma, diluted 10 times), Tween 20 0.1% (# P5927 Sigma) and BSA 3% (Bovine Albumin Serum Fraction V, Sigma # A4503) during 6 hours after a transfer of a duration of one night or during lh after a transfer of a duration of 3h. The primary antibodies are diluted 1/1000 for the antiphospho antibody AKT-Ser473 (193H2, rabbit monoclonal, cat # 4058 from Cell Signaling Technology) Abcam), in saturation solution composed of PBS, 0.1% Tween 20, BSA 3%, then stirred overnight at 4 ° C. Two rinses of 5 minutes in washing solution composed of TBS, 0.1% Tween 20 are carried out before the hybridization of the secondary antibodies. The secondary antibodies are diluted to 1 / 10,000th for Rabbit Anti-Mouse IgG HRP antibody (W402 Promega) and 1 / 10,000th for the 20 Goat Anti-Rabbit IgG HRP antibody (W401 Promega) in saturation solution then put under stirring for 1h at room temperature. Two rinses of 30 minutes in washing solution are carried out then a rinsing of 5 minutes with H2O is carried out to eliminate the remaining Tween 20. The visualization solution is volume-to-volume prepared according to the Western Lightning Chemiluminescence Reagent Plus technical data sheet (Western Lightning Chemiluminescence Reagent Plus Perkin Elmer # NEL104). The membrane is placed for 1 min in the developer solution, drained, inserted between two transparencies and placed in the meter for reading the luminescence and quantizing the signal. Luminescence is read with FujiFilm (Ray Test). The FUJI device measures the total luminescence signal obtained (AU) for each selected band. Then it subtracts the background noise (BG) proportional to the size of the selected band (Area), background noise calculated from a specific background noise band, in order to obtain the specific signal (AU-BG ) for each band. The band obtained in the absence of product and in the presence of 0.1% DMSO is considered as the 100% signal. The software calculates the% specific activity (Ratio) obtained for each selected band based on this 100% signal. The percent inhibition calculation is done for each concentration according to the formula (100% - Ratio). 2 independent experiments make it possible to calculate the average of the percentages of inhibition obtained at a given concentration for the products tested only at a concentration. Where appropriate, the activity of the products is translated into approximate IC50, obtained from a dose-response curve of different concentrations tested and representing the dose giving 50% specific inhibition (absolute IC 50). 2 independent experiments make it possible to calculate the average IC50s. Study of the expression of pAKT in PC3 human prostate carcinoma cells measured by the MSD Multi-spot Biomarker Detection technique of Meso Scale Discovery (Test B): This test is based on the measurement of AKT protein expression Phosphorylated on serine 473 (P-AKT-S473), in the human prostate carcinoma cell line PC3, by the sandwich-based immunoassay technique using the MSD Multi-spot Biomarker Detection kit from Meso Scale Discovery: phospho kits -Akt (Ser473) whole cell lysate (# K151 CAD) or phospho-Akt (Ser473) / Total Akt whole cell lysate (# K151OOD). The primary antibody specific for P-AKT-S473 (Kit # K151 CAD) is coated on one electrode in each well of the 96 well plates of the MSD kit: after addition of a protein lysate in each well, the revelation of the signal is done by the addition of a secondary detection antibody labeled with an electrochemiluminescent compound. The procedure followed is that described in the kit.

On day 1, the PC3 cells are seeded in 96-well plates (TPP, # 92096) at a concentration of 35,000 cells / well in 200 μl of DMEM medium (DMEM Gibco # 11960-044) containing 10% fetal calf serum ( SVF Gibco, # 10500-056) and 1% Glutamine (L-Glu Gibco # 25030-024), and incubated at 37 ° C, 5% CO2, overnight.

On day 2, the cells are incubated in the presence or absence of test products for 1 to 2 hours at 37 ° C. in the presence of 5% CO 2. The molecules diluted in dimethylsulfoxide (DMSO Sigma # D2650), are added from a stock solution concentrated 20 times, the final percentage of DMSO being 0.1%. The molecules are tested either at a single concentration of less than or equal to 10 μM, or at increasing concentrations in a range that may range from less than 1 nM to 10 μM. After this incubation, the cells are lysed for the preparation of the proteins. For this, after aspiration of the culture medium, 50 μl of Tris Lysis Buffer complete lysis buffer of the MSD kit containing the protease inhibitor and phosphatase solutions are added to the wells and the cells are lysed for 1 h at 4 ° C. with shaking. . At this stage the plates containing the lysates can be frozen at -20 ° C or -80 ° C. The wells of the 96-well plates of the MSD kit are saturated for 1 h at room temperature with the blocking solution of the MSD kit. Four washes are performed with 150 μl Tris Wash Buffer Wash Solution from the MSD kit. The lysates prepared above are transferred into the 96-well multi-spot plates of the MSD kit and incubated for 1 hour at room temperature, with stirring. Four washes are performed with 150 μl of Tris Wash Buffer from the MSD kit. 25 μl of the MSD sulfo-tag detection antibody solution are added to the wells and incubated for 1 hour at

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room temperature, with stirring. Four washes are performed with 150 μl of Tris Wash Buffer from the MSD kit. 150p1 Read Buffer revelation buffer from the MSD kit is added to the wells and the plates are read immediately on the S12400 Meso Scale Discovery Instrument. The device measures a signal for each well. Cell-free wells containing the lysis buffer are used to determine the background noise that will be subtracted from all measurements (min). Wells containing cells in the absence of product and in the presence of 0.1% DMSO are considered the 100% signal (max). The percentage inhibition is calculated for each concentration of product tested according to the following formula: (1- ((swarmin) / (max-min))) xl 00. The activity of the product is translated to IC 50, obtained at from a dose-response curve of different concentrations tested and representing the dose giving 50% specific inhibition (C150 absolute). 2 independent experiments make it possible to calculate the average of Cl50. The results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below: Table of pharmacological results: example Test A * Test B * Example 1 +++ Example 2 ++ Example 3 Example 4 Example Example 6 Example 7 * For tests A and B IC50 (nM) are distributed as follows: +> 5pM; 500nM <++ <5pM; +++ <500nM

Claims (16)

CLAIMS1) Products of formula (I): in which: Z represents -O-, -NH or Nalk; n represents an integer of 0 to 4; RI represents a halogen atom or a hydroxyl, alkyl or alkoxy radical; the alkyl and alkoxy radicals being optionally substituted with an NRxRy group; R 2 and R 3, which may be identical or different, represent a hydrogen atom, a halogen atom or an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom or an alkyl radical; either Rx and Ry form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical optionally substituted by one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl, oxo, alkoxy, NH2 radicals; NHalk and N (alk) 2; all the above alkyl (alk) and alkoxy radicals being linear or branched and having from 1 to 6 carbon atoms, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). 2) Products of formula (I) as defined in claim 1 wherein: Z represents -O-, -NH or Nalk; n represents an integer of 0 to 4; R1 represents a halogen atom or an alkyl or alkoxy radical; R2 and R3 represent a hydrogen atom; R4 represents a hydrogen atom; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom or an alkyl radical; either Rx and Ry form with the nitrogen atom to which they are bound a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this radical cyclic being optionally substituted; all the above alkyl (alk) and alkoxy radicals being linear or branched and containing from 1 to 6 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 3) Products of formula (I) as defined in any one of claims 1 or 2, having the following formulas: 25 - 2 - [(5-fluoro-1H-benzimidazol-2-yl) methyl] -6 - (Morpholin-4-yl) pyrimidin-4 (3H) -one - 2- (1,3-benzoxazol-2-ylmethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-2 - [(6-Bromo-1 H -benzimidazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(6-methoxy-1H-benzimidazole)] 2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(5,6-difluoro-1H-benzimidazol-2-yl) methyl] -6- (Morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(6-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - [(5-fluoro-1,3-benzoxazol-2-yl) methyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -10-one as well as the salts of addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 4) Process for the preparation of the products of formula (I) as defined in any one of claims 1 to 3 according to scheme 1A as defined below. Scheme 1A: HCl: ## STR1 ## wherein R 1 has the meanings indicated in any one of claims 1 or 2. 5) Process for the preparation of the products of formula (I) as defined in any one of claims 1 to 3 according to scheme 1B as defined below. Scheme 1B: CNR OC-? / CNR OJR, -X then R3X X = Cl, Br, I or OTf (Boc) ZO KNC) OGC;) or (PhSO2) ZN-F C :) EX = NH2O wherein the substituents R1, R2 and R3 have the meanings indicated in any one of claims 1 or 2. 6) As medicaments, the products of formula (I) as defined in any one of claims 1 to 3, and the addition salts with inorganic and organic acids or with inorganic and organic bases pharmaceutically acceptable. said products of formula (I). 7) As medicaments, the products of formula (I) as defined in claim 3, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I ). 8) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier. 9) Use of a product of formula (I) as defined in any one of claims 1 to 3 for the preparation of a medicament for the treatment of cancers. 10) Use according to claim 9 for the treatment of solid or liquid tumors. 11) Use according to claim 9 and 10 for the treatment of cancers resistant to cytotoxic agents. 12) Use according to one or more of claims 9 to 11 for the treatment of primary tumors and / or metastases especially in gastric, hepatic, renal, ovarian, colon, prostate, endometrial cancers, lung cancer (NSCLC and SCLC), glioblastoma, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, cancers of the bones and pancreas, in hamartomas. 13) Use of the products of formula (I) as defined in claims 1 to 3, for the preparation of medicaments for the chemotherapy of cancers. 14) Use of the products of formula (I) as defined in claims 1 to 3, for the preparation of medicaments for cancer chemotherapy alone or in combination. 15) Products of formula (I) as defined in any one of claims 1 to 3 as inhibitors of phosphorylation of AKT (PKB) 16) As novel industrial products, the synthetic intermediates of formulas C, D, F, J and K as defined in claim 4 or 5 above and recalled below: XH H R3 R2 HN, XN ( R1) ~ X = NH2O NR Y = Na, Li, KC 0 D CNR 0 F wherein R1, R2 and R3 have the definition given in any one of claims 1 to 2.