FR2969607A1 - New substituted morpholinyl-3H-pyrimidin-4-one compounds are akt phosphorylation inhibitors useful for treating gastric cancer, ovarian cancer, glioblastomas, melanoma, sarcomas, brain cancer, bone cancer and hamartomas - Google Patents

Abstract

Substituted morpholinyl-3H-pyrimidin-4-one compounds (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. Substituted morpholinyl-3H-pyrimidin-4-one compounds of formula (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. X : O or S; Y1 : S; R : H; R1 : H or methyl; R2 : H or F; R3 : H or halo; R4 : H, halo or hydroxyl, alkyl (optionally substituted by halo or OH), or alkoxy (optionally substituted by one or more halo); R5, R5a : H or alkyl group; R6 : H, or alkyl (optionally substituted by halo or OH); and R7 : H. Independent claims are included for: (1) the preparation of (I); and (2) intermediates comprising (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (C) and (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid metal salt of formula (D). Y0 : Na, Li or K. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Akt phosphorylation inhibitor. The ability of (I) to inhibit akt phosphorylation was tested in human prostate carcinoma (PC3) cell line using multi-spot biomarker detection of meso scale technique. The result showed that 2-[2-((S)-2-methyl-2,3-dihydro-indol-1-yl)-2-thioxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-thione exhibited an IC 5 0value of 4 nM.

Description

NOVEL THIOPYRIMIDINONE DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS INHIBITORS OF PHOSPHORYLATION OF AKT (PKB) The present invention relates to novel chemical compounds which are derivatives of thiopyrimidinones, their process of preparation, the novel intermediates obtained, their application as drugs, 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 thiopyrimidinone derivatives and their pharmaceutical use for the prevention and treatment of conditions capable of being modulated by inhibition of the P13K / 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 P13K / AKT / mTOR pathway, and in particular by the inhibition of kinases belonging to this pathway such as receptors with tyrosine kinase activity such EGFR, IGFR, ErbB2 , 3'-phosphoinositide-dependent protein kinase-1 (PDK1), P13K phosphoinositide kinase, serine-threonine kinase AKT, mTOR kinase. Inhibition and regulation of the P13K / AKT / mTOR pathway is a novel and powerful mechanism of action for the treatment of a large number of cancerous diseases including solid and liquid tumors.

Such conditions which can be treated by the products of the present application are solid or liquid human tumors. Role of the P13K / AKT / mTOR pathway The P13K / 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 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) deficiency of tumor suppressor genes such as PTEN, TSC112, LKB and PML that are inactivated as a result of mutations or deletions (Jiang LZ & Liu LZ, Biochim Biophys Acta, 2008, 1784: 150; Vivanco 1 & Sawyers CL, 2002, Nat Rev Cancer, 2: 489, Cu11yM 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 15-300% 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; Hartmann et al., Acta Neuropathol 2005, 109: 639). - the amplifications, activating and overexpressing mutations of RTKs such as EGFR and HER2 in brain, breast and lung cancers (NSCLC) - the amplification and activating overexpression of AKT in cancers of the brain, lung ( 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 500% of lung cancers (NSCLC), liver, kidney, prostate, 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; R & 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 than 500% of tuberous scleroses 0 mutations or deletions of LK81 (or STK11) which predispose to cancers of the gastrointestinal tract and to pancreatic cancer and which are found in particular in 10-380 / 0 of lung adenocarcinomas ( U.S. Shah et al., Cancer Res., 2008, 68: 3562), PML modification by translocation in human tumors (Gurrieri C et al, J. NAt1 Cancer Inst. 2004, 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 signaling pathways, the P13K / 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

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(2) by phosphorylation of serine 473 (P-S473) by mTORC2 (or mTOR-Rictor complex), resulting in complete activation. AKT in turn regulates a large number of proteins including mTOR (mammalian target of Rapamycin), BAD, GSK3, p21, p27, FOXO or FKHRL1 (BD Manning & 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 of 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 pathway. signaling, p70S6K and 4EBP. AKT also induces inhibitory phosphorylation of the Forkhead transcription factor and inactivation of GSK3 that lead to inhibition of apoptosis and cell cycle progression (Franke TF, Oncogene, 2008, 27: 6473). AKT is therefore a target for anti-cancer therapy and inhibition of AKT activation by inhibition of its phosphorylation can induce apoptosis of malignant cells and thus, present a treatment for cancer. Receptors with tyrosyne kinase activity such as IGF1 R Abnormally high levels of protein kinase activity have been implicated in many diseases resulting from abnormal cell functions. This can come either directly or indirectly, from a dysfunction in the mechanisms of kinase activity control, linked for example to a mutation, an over-expression or an inappropriate activation of the enzyme, or by an over- or under- -production of cytokines or growth factors, 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-I 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, the large antigen of SV40 virus, 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 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 P13K-AKT signaling pathway. It is a serine-threonine (Ser / Thr) kinase whose role is to phosphorylate and activate

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other Ser / Thr kinases of the AGC family involved in the control of growth, proliferation, cell survival and metabolic regulation. These kinases include protein kinase B (PKB or AKT), SGK (or serum and glucocorticoid regulated kinase), RSK (or p90 ribosomal S6 kinase), p70S6K (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 messenger generated by P13K, 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 P13K / 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 500% of human cancers, PDK1 represents a target for anticancer 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, Eye cycle, 2008, 7: 2978, Peifer C. & Alessi DR ChemMedChem, 2008, 3: 1810). Phosphoinositide-3 kinases (P13Ks) P13K lipid kinase is an important target in this signaling pathway for oncology. P13Ks in class 1 are divided into the (P13K) class activated by tyrosine kinase receptors (RTKs), G-protein coupled receptors (GPCRs), Rho GTPases, p21-Ras and class Ib (P13K) enabled by GPCRs and p21-Ras. P13Ks of class la are heterodimers which consist of a catalytic subunit p110. or and a p85 or p55 regulatory subunit Class lb (p110) is monomeric. P13Ks in class 1 are lipids / protein kinases that are activated by RTKs, GPCRs or Ras after membrane recruitment. These P13Ks of Class 1

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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.

Class 1 P13Ks are involved in human cancers: somatic mutations of the PIK3CA gene that codes for P13K are found in 15-350 / 0 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). Inhibitors of P13K are expected to be effective for the treatment of many human cancers with genetic alterations leading to activation of the P13K / 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 TGX-221 and TGX-155 inhibitors of P13K 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 the applications WO2004 / 016607 and WO2001 / 053266 which differ from the products of the present invention.

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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. Application WO2003 / 024949 discloses DNAPK inhibiting 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 have an inhibitory activity of mTOR and / or P13K 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 thiocarbonyl group on pyrimidinone as well as by the various substituents. The subject of the present invention is the products of formula (1 ): R3 (I) wherein: X and Y, which are identical or different, are such that: X represents O or S and Y represents S, R represents a hydrogen atom; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom, a halogen atom or a hydroxyl, alkyl or alkoxy radical, the alkyl radicals being optionally substituted with one or more identical or different radicals chosen from halogen atoms and the hydroxyl radical, radicals; alkoxy being optionally substituted with one or more halogen atoms; R5 and R5 ', which may be identical or different, represents a hydrogen atom or an alkyl radical; R6 represents a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl radical; R7 represents a hydrogen atom; Said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (1).

In the products of formula (1): the term "alkyl radical (or alk)" denotes the radicals, linear and branched, containing from 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dry butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl as well as their linear or branched positional isomers: alkyl radicals containing from 1 to 6 carbon atoms and more particularly alkyl radicals containing 1 to 4 carbon atoms from the above list; the term "alkoxy radical" denotes linear and branched radicals, containing from 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy, as well as their linear or branched positional isomers; alkoxy radicals containing from 1 to 4 carbon atoms of the above list are preferred; 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; 2969607 He

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 be made in particular of the 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 members. , optionally containing a -C (O) - chain, 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 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 salified tetrazolyl, all these

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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 and 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 carboxyl group (s) of the products of formula (1) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example: - among 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 able to be substituted by radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for example in the chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl and benzyl groups; or phenethyl. The addition salts with the inorganic or organic acids of the products of formula (1) may 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 thus the products of formula (1) as defined above in which: X and Y, which are identical or different, are such that: X represents O or S and Y represents S, R represents an atom of 'hydrogen; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom, a halogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms; R5 and R5 'represent a hydrogen atom; R6 represents a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from fluorine atoms and the hydroxyl radical; R7 represents a hydrogen atom; said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). In the products of formula (1) as defined above, R 4 represents, for example, a hydrogen atom or a halogen atom such as fluorine, chlorine or bromine or else the radical CF 3, the other substituents R, R 1, R2, R3, R5, R5 'and R6 having any of their meanings indicated above for said products of formula (1). In the products of formula (1), R6 represents, for example, a hydrogen atom or a methyl radical optionally substituted by a fluorine atom or the hydroxyl radical. the other substituents R, R1, R2, R3, R4, R5 and R5 'having any of their meanings indicated above for said products of formula (1). The subject of the present invention is particularly the products of formula (1) as defined above, corresponding to the following formulas: -1 - ((S) -2-Methyl-2,3-dihydro-indol-1-yl) 2- (4-Morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone -1 - ((R) -2-Methyl-2,3-dihydro-indol- 1-yl) -2- (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone - 2- [2 - ((S) -2-Methyl-2 , 3-dihydro-indol-1-yl) -2-thioxo-ethyl] -6-morpholin-4-yl-3H-pyrimidine-4-thione, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (1). The present invention also relates to any process for preparing the products of formula (1) as defined above.

The products according to the invention can be prepared from conventional methods of organic chemistry. Preparation of compounds of formula (1) The products of general formula (1) according to the present invention may in particular be prepared as indicated in General Schemes 1A-1 B below. As such, 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 present invention thus also relates to the processes for preparing the products of formula B to (1) as defined in General Schemes 1 A-1 B below.

Schemes 1A and 1B below are illustrative of the methods used for the preparation of the products of formula (1). As such, they can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds.

The products of formula (1) as defined above according to the present invention can thus in particular be prepared according to the processes described in scheme 1A and I B. The subject of the present invention is thus also the process for the preparation of products of formula (1) according to Scheme 1A as defined below.

The present invention thus also relates to the process for preparing products of formula (1) according to Scheme 1B as defined below. General Scheme 1A: RRI OUN ~ OSN \ ^ / O ~ and NO Reagent Lawesson NO R7 C`) C Hnn R7 N ~ BR SANI ONa R7 NoOH / THF EDCI / pyridine / DMF C7 DC ") R6 in which the substituents R, R2, R3, R4, R5, R6 and R7 have the meanings indicated above.The ester B 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 Thiopyrimidones C can be obtained from pyrimidones B by reaction with a sulfurization reagent such as Lawesson's reagent, in a solvent such as toluene at a temperature between 22 ° C and the boiling point of the solvent, as, for example, under the conditions described by Jones G (Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (1983), 11, 2645 - 2648. The carboxylates D can be obtained by hydrolysis of the esters 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. The amides (1) can be obtained from carboxylates D by condensation of an indoline G in the presence of a peptide coupling agent such as, for example, EDCI (ethyl dimethylaminopropyl carbodiimide), DMT-MM. [4- (4,6-dimethoxy-1,2,3-triazin-2-yl) -4-methylmorpholinium chloride], BOP [benzotriazol-1-yloxy-tris-dimethylamino phosphonium hexafluorophosphate], PyBOP [hexafluorophosphate benzotriazol-1-yloxy tris-pyrrolidino phosphonium], PyBROP [bromo tris pyrrolidino phosphonium hexafluorophosphate], HATU [047-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate)] or a mixture thereof HOBT / EDCI [hydroxybenzotriazole / ethyl dimethylaminopropyl carbodiimide], in a solvent such as N, N-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). Alternatively, the compounds (1) can be obtained according to the general scheme I B. wherein the substituents R, R2, R3, R4, R5, R6 and R7 have the meanings indicated above. The carboxylates E may be obtained by hydrolysis of the esters B, 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 the carboxylates E by condensation of an indoline G in the presence of a peptide coupling agent such as, for example, EDCI (ethyl dimethylaminopropyl carbodiimide), DMT-MM [chloride of 4- (4,6-dimethoxy-1,2,3-triazin-2-yl) 4-methylmorpholinium], BOP [benzotriazol-1-yloxy-tris-dimethylamino phosphonium hexafluorophosphate], PyBOP [benzotriazol-1-yloxy hexafluorophosphate] tris-pyrrolidino phosphonium], PyBROP [bromo tris pyrrolidino phosphonium hexafluorophosphate], HATU [047-azabenzotriazol-1-yl] -1,1,3,3-tetramethyluronium hexafluorophosphate)] or a mixture HOBT / EDCI [hydroxybenzotriazole] / ethyl dimethylaminopropyl carbodiimide], in a solvent such as N, Nd imethylformamide, 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). Thiopyrimidones (Ia) and thiopyrimidones-thioamides (Pb) can be obtained from compounds F by reaction with a sulfurization reagent such as Lawesson's reagent, in a solvent such as toluene at a temperature of between 22 ° C. and the boiling temperature of the solvent, as, for example, under the conditions described by Jones G. (Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), (1983), 11 , 2645-2648 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 in particular alcohol function by 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 For example, methylene chloride, 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, benzene sulfonic acid or para-toluenesulphonic, formic or trifluoroacetic or catalytic hydrogenation. The phthalimido group can be removed by hydrazine. f) The products described above may, if desired, be the subject of salification reactions, for example by a mineral or organic acid or by 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 (1) as defined above and their addition salts with acids have interesting properties

21

particularly because of their kinase inhibitory 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 object of the invention is particularly to provide, as medicaments, the products of formula (1) as defined above, said products of formula (1) 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 (1). The subject of the invention is particularly suitable, as medicaments, the products corresponding to the following formulas: - 1 - ((S) -2-Methyl-2,3-dihydro-indol-1-yl) -2- (4) -morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone - 1 - ((R) -2-Methyl-2,3-dihydro-indol-1-yl) 2- (4-Morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone - 2- [2 - ((S) -2-Methyl-2,3-dihydro- indol-1-yl) -2-thioxo-ethyl] -6-morpholin-4-yl-3H-pyrimidine-4-thione as well as addition salts with mineral and organic acids or with inorganic and organic pharmaceutically acceptable bases acceptable of said products of formula (1).

The invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (1) 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 drugs 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 may 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, simple or coated tablets, pills, lozenges, capsules, drops, granules, injectable preparations, 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, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, 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 subject of the present invention is in particular the use of a product of formula (1) as defined above for the preparation of a medicament

23

intended 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 (1) 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 (1) 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. As kinase inhibitors, there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomucine.

Thus the present application relates in particular to the products of formula (1) as defined above for their use for the treatment of cancers. Thus the present application relates in particular to the products of formula (1) as defined above for their use for the treatment of solid or liquid tumors. Thus the present application relates in particular to the products of formula (1) as defined above for their use for the treatment of cancers resistant to cytotoxic agents.

Thus the present application relates in particular to the products of formula (1) as defined above for their use for the treatment of primary tumors and / or metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain cancers, larynx, lymphatic system, cancers of the bones and pancreas. in hamartomas. Thus, the present application relates in particular to the products of formula (1) as defined above, for their use for the chemotherapy of cancers. Thus the present application relates in particular to the products of formula (1) as defined above, for their use for cancer chemotherapy alone or in combination.

The subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas C and D as defined above and referred to below: in which R represents a hydrogen atom in the products of formula C and D. The following examples which are products of formula (1) illustrate the invention without however limiting it. Experimental part The nomenclature of the compounds of this invention was carried out with ACDLABS software version 10.0. The microwave oven used is a Biotage device, Initiator Tm 2.0, 10 400W max, 2450 MHz. 1H NMR spectra at 400 MHz and 1H at 500 MHz were carried out on BRUKER AVANCE DRX-400 or BRUKER AVANCE DPX-500 spectrometer with the chemical shifts (8 in ppm) in the solvent dimethylsulfoxide-d6 (DMSO-d6) referenced at 2.5 ppm at the temperature of 303K. Mass spectra (MS) were obtained either by method A or by method B. Method A: WATERS UPLC-SQD apparatus; Ionisation: electrospray in positive and / or negative (ES +/-) mode; Chromatographic Conditions: Column: ACQUITY BEH C1 $ 1.7 pm - 2.1 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 50 ° C; Flow: 1 m1 / 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). R I N Y = Na, Li, K C ~ 0 D 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 Ben5,3min, 5,5min: 100% of B; 6.3min: 5% B; Retention time = Tr (min). The rotational powers (PR) were performed on a model 341 polarimeter from Perkin Elmer. wavelength: sodium line (589 nanometers) Example 1: Synthesis of 1 - ((S) -2-Methyl-2,3-dihydro-indol-1-yl) -2- (4-morpholin-4) 1H-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone Step 1: [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate 25 ml of ethyl morpholine in a solution of 25 g of morpholine in 400 ml of ethanol heated to 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 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 whose characteristics are the following: 1H NMR spectrum (400MHz): 1.19 (t, J = 7.1 Hz, 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 Step 2: (4-Morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -acetic acid ethyl ester In a flask, the mixture of 1 g of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] ethyl acetate obtained in the preceding step with X g of 2,4-disulphide of 2, 4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane (Lawesson's reagent) in 20 mL of toluene is heated at 60 ° C for 18 hours. After cooling, the solid formed is filtered. The filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column (eluent: dichloromethane / ethyl acetate 85/15) to give 0.86 g of (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidine). 2-yl) -acetic acid ethyl ester in the form of a beige solid whose characteristics are as follows: Mass spectrometry: AN method Retention time Tr (min) = 0.51; [M + H] +: m / z 284; [M-H] -: m / z 282; base peak: m / z 236 Step 3: (4-Morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -acetate sodium NH 2 0 ~ ONa To a solution of 865 mg of (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl) acetic acid ethyl ester in 15 mL of THF is added 3.05 mL of 2N sodium hydroxide. The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is dried in a vacuum oven in the presence of P2O5 to give 0.8 g of sodium (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl) -acetate, the characteristics of which are as follows: are: Mass Spectrometry: Method A Retention Time Tr (min) = 0.31; [M + H] +: m / z 256; [M-H] -: m / z 254; base peak: m / z 210 Step 4: Synthesis of 1 - ((S) -2-Methyl-2,3-dihydro-indol-1-yl) -2- (4-morpholin-4-yl) -6- thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone OA solution of 200 mg of sodium (4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl) -acetate in 5 ml of DMF and 5 ml of pyridine are added 432 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 106 mg of (S) -2-methyl-2,3-dihydro-1 H-indole (which may be prepared according to Krasnov, VP et al (Mendeleev Commun 2002, 12 (1), 27-28) The reaction medium is stirred at room temperature for 18 hours.

Add 50 mL of dichloromethane and 20 mL of water. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column (eluent: 99/1 and 98/02 dichloromethane / methanol) to give 57 mg of 1 - ((S) -2-methyl-2,3-dihydro-indol-1 yl) -2- (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone as a beige solid whose characteristics are as follows: 1H NMR spectrum ( 400 MHz) for this lot all signals are broad with: 1.26 (m, 3 H); 2.69 (d, J = 15.2 Hz, 1H); 3.38 (dd, J = 9.4 and 15.2 Hz, 1H); 3.50 to 3.66 (m, 8H); 3.87 (d, J = 15.4 Hz, 1H); 4.06 (d, J = 15.4 Hz, 1H); 4.70 (m, 1H); 6.37 (s, 1H); 7.05 (t, J = 8.0 Hz, 1H); 7.18 (t, J = 8.0 Hz, 1H); 7.29 (d, J = 8.0 Hz, 1H); 7.95 (d, J = 8.0 Hz, 1H); 12.79 (m spread, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.75; [M + H] +: m / z 371; [M-H] -: m / z 369 Rotatory power: ap = + 86.0 +/- 1.6. C = 1.606mg / 0.5ML DMSO Step 4 ': Alternatively, the compound 1 - ((S) -2-Methyl-2,3-dihydro-indol-1-yl) -2- (4-morpholin-4-yl) 6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone can also be obtained in three steps: Step 4'a: H + Na 1 NON ~ \ O ~ A solution of 10 g of [4 - (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] ethyl 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 (400 MHz): 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 Step 4'b: Preparation of 2- {2 - [(2S) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} (Morpholin-4-yl) pyrimidin-4 (3H) -one and 2- {2 - [(2R) -2-methyl-2,3-dihydro-1H-indol-1-yl] 2- [2- (2-methyl-2,3-dihydro-1H) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one is prepared by following the procedure described in Example 1 (step 4) from 500 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate and 510 mg of 2-methyl-2,3-dihydro-1H-indole. 400 mg of 2- [2- (2-methyl-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) are obtained -one in the form of a white powder whose characteristics are as follows: 1H NMR spectrum (400MHz): 1.26 (d, J = 6.1 Hz, 3H); 2.65 to 2.72 (m, 1H); 3.18 to 3.44 (partially masked m, 5H); 3.54 to 3.63 (m, 4H); 3.72 (d, J = 15.7 Hz, 1H); 3.92 (d, J = 15.7 Hz, 1H); 4.71 (m, 1H); 5.20 (s, 1H); 7.04 (t, J = 7.8 Hz, 1H); 7.18 (t, J = 7.8 Hz, 1H); 7.29 (d, J = 7.8 Hz, 1H); 7.96 (d, J = 7.8 Hz, 1H); 11.69 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.70; [M + H] +: m / z 355; [MH] -: m / z 353 Melting point (Kofler): 172 ° C. The enantiomers are separated by chiral chromatography on a column: Chiralpak T304 chiral column 20 μm (1080 g, 20 μm, 8/35 cm), eluent: Acetonitrile / Isopropanol: 90/10; flow rate: 185 mL / min. After purification, 160 mg of (R) -2- {2 - [(2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- are obtained as the first enantiomer. (morpholin-4-yl) pyrimidin-4 (3H) -one, in the form of a pink amorphous solid whose characteristics are as follows: 1H NMR spectrum (400MHz): for this batch, the signals are broad with: 1, 26 (d, J = 6.8 Hz, 3H), 2.44 (partially masked m, 1H), 2.69 (d, J = 15.2 Hz, 1H), 3.42 (m, 4H), 3.60 (m, 4H), 3.72 (d, J = 15.7Hz, 1H), 3.92 (d, J = 15.7Hz, 1H), 4.72 (d, J = 15.7Hz, 1H); (m, 1 H), 5.20 (s, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H); 7.28 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 11.67 (extended m, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.70; [M + H] +: m / z 355; [MH] -: m / z 353; Rotatory power: ap = + 65.0 ° + 1-1.3 (c = 1.736 mg in 0.5 mL of methanol) Then the second enantiomer, ie: 143 mg of (S) -2- {2 - [(2-methyl-2,3-dihydro-1H-indol-1) -yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one It forms a white amorphous solid whose characteristics are as follows: 1 H NMR spectrum (400 MHz): for this batch, the signals are broad with: 1.26 (d, J = 6.8 Hz, 3 H); 2.45 (partially masked m, 1H); 2.69 (m, 1H); 3.41 (m, 4H); 3.61 (m, 4H); 3.72 (d, J = 15.7 Hz, 1H); 3.92 (d, J = 15.7 Hz, 1H); 4.70 (m, 1H); 5.20 (s, 1H); 7.04 (t, J = 7.8 Hz, 1H); 7.18 (t, J = 7.8 Hz, 1H); 7.28 (d, J = 7.8 Hz, 1H); 7.96 (d, J = 7.8 Hz, 1H); 11.64 (spread m, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.70; [M + H] +: m / z 355; [M-H] -: m / z 353; Rotation: ap = -72.8 ° + 1-1.2 (c = 2,338 mg in 0.5 mL of methanol) Step 4'c: Example 1: 1 - ((S) -2-Methyl-2, 3-dihydro-indol-1-yl) -2- (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone and Example 2: Synthesis of 2- 2 - ((S) -2-Methyl-2,3-dihydro-indol-1-yl) -2-thioxo-ethyl] -6-morpholin-4-yl-3H-pyrimidine-4-thione The product is prepared by following the procedure described in Example 1 (Step 2) starting from 354 mg of 2- {2 - [(2S) -2-methyl-2,3-dihydro-1H-indol-1-yl) ] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one obtained in Example 1 (Step 4'b) and 0.8 g of 2,4-disulphide of 2,4 bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane (Lawesson's reagent). After purification by chromatography on a silica column (eluent: dichloromethane / methanol 99/01 then 98/02), 135 mg of 2- [2- 1 NH N 1 NH N 10 ((S) -2-methyl-2 are obtained, 3-dihydro-indol-1-yl) -2-thioxo-ethyl] -6-morpholin-4-yl-3H-pyrimidine-4-thione as a light yellow solid, the characteristics of which are as follows: NMR spectrum 1H (400 MHz) for this batch we observe a doubling of 2/3 - 1/3 conformers with: 1.25 (d, J = 6.6 Hz, 2 H); 1.29 (d, J = 6.6 Hz, 1H); 2.65 (d, J = 16.3 Hz, 0.65H); 2.73 (d, J = 16.3 Hz, 0.35 H); 3.34 to 3.42 (m, 1H); 3.45 to 3.66 (m, 8H); 4.15 to 4.55 (m, 2H); 5.18 (m, 0.35H); 5.50 (m, 0.65H); 6.33 (s, 0.65H); 6.36 (s, 0.35H); 7.15 to 7.45 (m, 3H); 7.52 (d, J = 8.0 Hz, 0.65 H); 9.14 (d, J = 8.0 Hz, 0.35 H); 12.68 (s, 0.65H); 12.79 (s, 0.35 H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.85; [M + H] +: m / z 387; [MH] -: m / z 385 and 134 mg of 1 - ((S) -2-methyl-2,3-dihydro-indol-1-yl) -2- (4-morpholin-4-yl) thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone as a light yellow solid whose characteristics are as follows: 1 H NMR spectrum (400 MHz) for this batch all the signals are broad with: 1, 26 (m, 3H); 2.69 (d, J = 15.2 Hz, 1H); 3.38 (dd, J = 9.4 and 15.2 Hz, 1H); 3.50 to 3.66 (m, 8H); 3.87 (d, J = 15.4 Hz, 1H); 4.06 (d, J = 15.4 Hz, 1H); 4.70 (m, 1H); 6.37 (s, 1H); 7.05 (t, J = 8.0 Hz, 1H); 7.18 (t, J = 8.0 Hz, 1H); 7.29 (d, J = 8.0 Hz, 1H); 7.95 (d, J = 8.0 Hz, 1H); 12.79 (m spread, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.75; [M + H] +: m / z 371; Example 3 Synthesis of 1 - ((R) -2-Methyl-2,3-dihydro-indol-1-yl) -2- (4-morpholin-4-yl) -6 The product is prepared by following the procedure described in Example 1 (Step 4) starting from 200 mg of (4-morpholinic acid). Sodium 4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -acetate obtained in Example 1 (Step 2) and 106 mg of (R) -2-methyl-2, 3-dihydro-1H-indole (which can be prepared according to Krasnov, VP et al (Mendeleev Commun 2002, 12 (1), 27-28) After purification by silica column chromatography (eluent: dichloromethane / dichloromethane 98/02), 71 mg of 1 - ((R) -2-methyl-2,3-dihydro-indol-1-yl) -2- (4-morpholin-4-yl) -6- are obtained. thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone as a white powder having the following characteristics: 1 H NMR spectrum (400 MHz): 1.27 (broad d, J = 6.4 Hz, 3H), 2.69 (d, J = 16.3 Hz, 1H), 3.33 to 3.42 (partially masked m, 1H), 3.53 to 3.65 ( m, 8H), 3.87 (d, J = 15.7 Hz, 1H); 4.06 (d, J = 15.7 Hz, 1H); 4.70 (m, 1H); 6.37 (s, 1H); 7.05 (t, J = 7.8 Hz, 1H); 7.18 (t, J = 7.8 Hz, 1H); 7.29 (d, J = 7.8 Hz, 1H); 7.95 (broad d, J = 7.8 Hz, 1H); 12.79 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.75; [M + H] +: m / z 371; [MH] -: m / z 369 Example 4: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 1 0.2 g 3520 Excipient for a tablet finished at 1 g (detail of the 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 exemplary products in the present application. Pharmacological Part: Experimental Protocols In Vitro Experimental Procedures The inhibitory activity of the molecules on AKT phosphorylation is measured by the MSD Multi-spot Biomarker Detection technique of Meso Scale Discovery also described below. Study of the expression of pAKT in human PC3 prostate carcinoma cells measured by the MSD Multi-spot Biomarker Detection technique of Meso Scale Discovery (Test A): This test is based on the measurement of protein expression AKT phosphorylated on serine 473 (P-AKT-S473), in the PC3 human prostate carcinoma cell line, 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 MSD kit 96-well plates: after addition of a protein lysate in each well, the signal is exposed. by the addition of a labeled secondary detection antibody 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 the concentration of 35000 cells / well in 200 μl of DMEM medium (DMEM Gibco # 11960-044) containing 100% fetal calf serum. (Gibco SVF, # 10500-056) and 10/0 Glutamine (L-Glu Gibco # 25030-024), and incubated at 37 ° C, 50/0 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 50% 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 0.10 / 0. 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 lysis buffer Tris Lysis Buffer complete MSD kit containing solutions of protease inhibitors and phosphatases are added to the wells and the cells are lysed for 1 hour at 4 ° C. with stirring. . 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 hour at room temperature with the blocking solution of the MSD kit. Four washes are performed with 150 μl of Tris Wash Buffer from the MSD kit. The lysates previously prepared are transferred into the 96-well Mufti- 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 ambient 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 background that will be subtracted from all measurements (min). Wells containing cells in the absence of product and in the presence of 0.10 / 0 DMSO are considered the 100% signal (max). The percent inhibition calculation is made for each test product concentration according to the following formula: (1- "test-min) / (max-min))) x100. The activity of the product is translated into C150, obtained from a dose-response curve of different concentrations tested and representing the dose giving 50% specific inhibition (C150 absolute). 2 independent experiments allow to calculate the average of C150s.

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 IC50 (nM) Example 1 Example 2 Example 3

Claims (11)

CLAIMS 1) Products of formula (1): R3 (I) ~ O ~ wherein: X and Y, identical or different, are such that: X represents O or S and Y represents S, R represents a hydrogen atom; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom, a halogen atom or a hydroxyl, alkyl or alkoxy radical, the alkyl radicals being optionally substituted with one or more identical or different radicals chosen from halogen atoms and the hydroxyl radical, radicals; alkoxy being optionally substituted with one or more halogen atoms; R5 and R5 ', which may be identical or different, represents a hydrogen atom or an alkyl radical; R6 represents a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl radical; R7 represents a hydrogen atom; said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). 2) Products of formula (1) as defined in claim 1 wherein: X and Y, identical or different, are such that: X represents O or S and Y represents S, R represents a hydrogen atom; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom, a halogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms; R5 and R5 'represent a hydrogen atom; R6 represents a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from fluorine atoms and the hydroxyl radical; R7 represents a hydrogen atom; Said products of formula (1) being in all possible isomeric forms racemic, enantiomeric and diastereoisomeric, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). 41 3) Products of formula (1) as defined in any one of claims 1 or 2, corresponding to the following formulas: - 1 - ((S) -2-Methyl-2,3-dihydro-indol-1-yl ) -2- (4-Morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone - 1 - ((R) -2-Methyl-2,3-dihydroindol -1-yl) -2- (4-morpholin-4-yl-6-thioxo-1,6-dihydro-pyrimidin-2-yl) -ethanone-2- [2 - ((S) -2-Methyl) 2,3-dihydro-indol-1-yl) -2-thioxo-ethyl] -6-morpholin-4-yl-3H-pyrimidine-4-thione, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). 4) Process for the preparation of the products of formula (1) as defined in any one of claims 1 to 3 according to scheme 1A as defined below. Scheme 1A: General Scheme 1A: H CoN R7 N ~ BR 1 SN ONa II I R7 NO EDCI / pyridine / DMF)) DC`) R 1 S ~ / N / / / O ~ 17 TT and R7 Reagent from Lawesson G NaOH / THF wherein the substituents R, R2, R3, R4, R5, R6 and R7 have the meanings given in any one of claims 1 or 2. 5) Process for the preparation of the products of formula (1) as defined in any one of claims 1 to 3 according to scheme 1B as defined below. Embedded image A Lawesson reagent in which the substituents R 1, R 2, R 3, R 4, R 5, R 6 and R 7 have the meanings indicated in FIG. 1B: R II II NaOH / THF R R2 v N 0 N ~ ONa G II II in any one of claims 1 or 2. 6) As medicaments, the products of formula (1) as defined in any one of claims 1 to 3, as well as the addition salts with inorganic and organic acids or with the mineral and organic bases pharmaceutically acceptable said products of formula (1). 7) As medicaments, the products of formula (1) 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 (1) ). 8) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (1) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt of this product and a pharmaceutically acceptable carrier. 9) Products of formula (1) as defined in any one of claims 1 to 3 for their use for the treatment of cancers. 10) Products of formula (1) as defined in any one of claims 1 to 3 for their use for the treatment of solid or liquid tumors. 11) Products of formula (1) as defined in any one of claims 1 to 3 for their use for the treatment of cancers resistant to cytotoxic agents. 1) Products of formula (1) as defined in any one of claims 1 to 3 for their use for the treatment of primary tumors and / or metastases, particularly in gastric, hepatic, renal, ovarian, colon cancers. , prostate, lung (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain cancers , larynx, lymphatic system, bone and pancreatic cancers, in hamartomas. 13) Products of formula (1) as defined in claims 1 to 3, for their use for the chemotherapy of cancers. 14) Products of formula (1) as defined in claims 1 to 3, for their use for cancer chemotherapy alone or in combination. 1) Products of formula (1) as defined in any one of claims 1 to 3 as inhibitors of phosphorylation of AKT (PKB) 16) As new industrial products, synthetic intermediates of formulas C and D such as defined in claim 4 above and recalled below: RINNY = Na, Li, KC ~ 0 D in which R represents a hydrogen atom in the products of formula C and D, and R7 has the definition indicated in any one of claims 1 to 2.