FR2951174A1 - New tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives are akt phosphorylation inhibitors useful for treating e.g. liver cancers, glioblastoma, thyroid cancers, bladder cancers, breast cancers, melanoma, Pompe disease and malaria - Google Patents

Abstract

Tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives (I) and their all possible isomeric forms, racemates, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases are new. Tetrahydro-pyrimido(1,2-a)pyrimidin-6-one derivatives of formula (I) and their all possible isomeric forms, racemates, enantiomers, diastereoisomers, or addition salts with mineral and organic acids or bases, are new. R 1> : -L-aryl or -L-heteroaryl group (both optionally substituted by one or more groups of alkoxy, phenoxy, alkylthio, alkyl or heterocycloalkyl (all optionally substituted by one or more halo or NR1vR1w), halo, OH, CN, nitro, -COOH, cycloalkyl, -COOalk, NR1xR1y-, -CONR1xR1y, NR1xCOR1y-, -NR1xCO2R1z, or -COR1y, where the heterocycloalkyl and heteroaryl optionally contains one or more oxo); L : single, bond, 1-6C alkyl (optionally substituted by OH), CO, COalk or L1a-X; L1a : 1-6C alkyl; X : O or S; R 2> : H or alkyl; R 3> : alkyl optionally substituted by one or more halo; R 4> : H or halo; either R1x : H or alkyl; and R1y : H, cycloalkyl or alkyl (optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl); 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), preferably morpholino group; either R1v : H or alkyl; and R1w : H, cycloalkyl or alkyl (optionally substituted by one or more OH, alkoxy, or heterocycloalkyl); or NR1vR1w : 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; alk : alkyl; and R1z : cycloalkyl or alkyl (optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl), where all the alkyl (alk), alkoxy and alkylthio are linear or branched 1-6C alkyl, 1-6C alkoxy and 1-6C alkylthio. Independent claims are included for: (1) the preparations of (I); and (2) intermediates comprising substituted 2-hydroxy-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (C), 2-chloro-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (D), 2-morpholin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (E), and 2-chloro-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one compound of formula (J). [Image] [Image] ACTIVITY : Cytostatic; Metabolic; Antimalarial; Hypnotic; Protozoacide; Antiparasitic. 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 western blotting technique. The result showed that (S)-9-[2-(4-methoxyphenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one exhibited an IC 5 0value of 15 nM.

Description

NOVEL 1,2,3,4-TETRAHYDRO-PYRIMIDO {1,2-a} PYRIMIDIN-6-ONE DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS PHOSPHORYLATION INHIBITORS OF AKT (PKB) The present invention relates to novel chemical compounds (1,2,3,4-tetrahydro-pyrimido {1,2-a} pyrimidin-6-one), pyrimidinone derivatives, process for their preparation, the novel intermediates obtained, their application as medicaments, the pharmaceutical compositions containing them and the novel 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 the 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), PI3K phosphoinositide kinase, serine-threonine kinase AKT, mTOR kinase.

Inhibition and regulation of the PI3K / AKT / mTOR pathway is a novel and potent 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, TSC112, LKB and PML which are inactivated as a result of mutations or deletions (Jiang LZ & Liu LZ, Biochim Biophys Acta, 2008, 1784: 150; Vivanco I & 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 cancers of the colon, breast, endometrium, liver, ovary and prostate (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; 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 cancerous diseases: the deletion of PTEN in 50% 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), mutations of TSC1 / 2. in more than 50% of tuberous scleroses o mutations or deletions of LKB1 (or STK11) which predispose to cancers of the gastrointestinal tract and to pancreatic cancer and which are found in particular in 10-38% 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. NAtI Cancer Ins. 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 cell signaling pathways, the PI3KIAKT 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, p7OS6K and 4EBP. AKT also induces inhibitory phosphorylation of the Forkhead transcription factor and inactivation of GSK313 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 IGFI pathway in the development of human cancers:

IGF-I-R is often found 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

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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, Eye 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, 13.8) activated by tyrosine kinase receptors (RTKs), G-protein coupled receptors (GPCRs), Rho GTPases, p21-Ras and in class Ib (PI3Ky) activated by the GPCRs and by p21-Ras. PI3Ks of class la are heterodimers which consist of a catalytic subunit p10a, p13 or p8 and a regulatory subunit p85 or

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p55. Class Ib (p110y) 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. 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 the products TGX-221 and TGX-155 PI3K13 inhibitors useful in the treatment of cancer and in particular in breast cancer. These products are pyrido [1,2-

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a] pyrimidin-4-ones previously described in the 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. 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. The subject of the present invention is the products of formula (I): in which: R 1 represents a -L-aryl or -L-heteroaryl radical, such that L represents: either a single bond or a linear or branched alkyl radical containing from 1 to 6 carbon atoms and optionally substituted by a hydroxyl radical, either a CO group or ûCO-Al k-;

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or a group L'-X where L 'represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms and X an oxygen or sulfur atom; the aryl and heteroaryl radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, CN, nitro, -COOH, -alkyl, -NRxRy, -CONRxRy, -NRxCORy, -NRxCO2Rz radicals, -COR y, alkoxy, phenoxy, alkylthio, alkyl, cycloalkyl and heterocycloalkyl; these latter alkoxy, phenoxy, alkylthio, alkyl and heterocycloalkyl radicals, themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and NRvRw; heterocycloalkyl and heteroaryl radicals additionally capable of containing an oxo radical; R2 represents a hydrogen atom or an alkyl radical; R3 represents an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom or a halogen atom; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and NRvRw radicals; and heterocycloalkyl; 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 being optionally substituted; NRvRw being such that Rv represents a hydrogen atom or an alkyl radical and Rw represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and heterocycloalkyl radicals; ; either Rv and Rw 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 being optionally substituted; the cyclic radicals that can be formed by Rx and Ry or Rv and Rw respectively with the nitrogen atom to which they are attached, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, alkyl radicals, hydroxyl radicals, oxo, alkoxy, NH2; NHalk and N (alk) 2; Rz represents the values of Ry with the exception of hydrogen; Rx, Ry and Rz in the radicals -NRxCORy, -CORy and NRxCO2Rz being selected from the meanings indicated above for Rx, Ry, and Rz; said products of formula (I) 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 (I). The subject of the present invention is therefore the products of formula (I) as defined above in which: R 1 represents a -L-aryl or -L-heteroaryl radical, such that L represents: either a single bond or a a linear or branched alkyl radical containing from 1 to 6 carbon atoms and optionally substituted with a hydroxyl radical, either a CO group or an L'-X group where L 'represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms; carbon and X an oxygen or sulfur atom; the aryl and heteroaryl radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, CN, nitro, -COOH, -alkyl, -NRxRy, -CONRxRy, -NRxCORy, -NRxCO2Rz radicals, -COR y, alkoxy, phenoxy, alkylthio, alkyl, cycloalkyl and heterocycloalkyl; these latter alkoxy, phenoxy, alkylthio, alkyl and heterocycloalkyl radicals, themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and NRvRw; heterocycloalkyl and heteroaryl radicals additionally capable of containing an oxo radical; R2 represents a hydrogen atom or an alkyl radical; R3 represents an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom or a halogen atom; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and NRvRw radicals; and heterocycloalkyl; 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 being optionally substituted; NRvRw being such that Rv represents a hydrogen atom or an alkyl radical and Rw represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and heterocycloalkyl radicals; ; either Rv and Rw form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 ring members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being optionally substituted;

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the cyclic radicals that can be formed by Rx and Ry or Rv and Rw respectively with the nitrogen atom to which they are attached, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, alkyl radicals, hydroxyl radicals, oxo, alkoxy, NH2; NHalk and N (alk) 2; Rz represents the values of Ry with the exception of hydrogen; Rx, Ry and Rz in the radicals -NRxCORy, -CORy and NRxCO2Rz being selected from the meanings indicated above for Rx, Ry, and Rz; said products of formula (I) 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 (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, if appropriate, 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 carboxyl group (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 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 selected from, for example, halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl groups such as, for example, chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl groups; 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 cis-trans isomerism. 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: R 1 represents a -L-phenyl or -L-heteroaryl radical, such that L represents: either a single bond or an alkyl radical linear or branched containing from 1 to 6 carbon atoms and optionally substituted by a hydroxyl radical, a CO group or ûCO-Al k-; or a group L'-X where L 'represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms and X an oxygen or sulfur atom; the phenyl and heteroaryl radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms and -NRxRy, alkoxy and alkyl radicals; these latter alkoxy and alkyl radicals themselves being optionally substituted by one or more radicals chosen from halogen atoms; R2 represents an alkyl radical; R3 represents an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom or a fluorine 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 morpholino radical; all the above alkyl (alk) or 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). In particular, when NRxRy or NRvRw forms a ring as defined above, such an amine ring may be chosen especially from the pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl, piperazinyl or homopiperazinyl radicals, these radicals being themselves optionally substituted as indicated above or hereinafter. The NRxRy or NRvRw ring may more particularly be chosen from pyrrolidinyl, morpholinyl radicals optionally substituted by one or two alkyl or piperazinyl radicals optionally substituted on the second nitrogen atom with an alkyl, phenyl or or CH 2 -phenyl radical, themselves same 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 having the following formulas: - (8S) -9- [2- (4-methoxyphenyl) ethyl] -2- (morpholin-4 -yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one-9- [2- (4-methoxyphenyl) ethyl] -2 - (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholinic acid) 4-yl) -9- (2-phenylethyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 benzyl-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(2S) -2-hydroxy-2-phenylethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] ] pyrimidin-4-one - (8S) -9 - [(2R) -2-hydroxy-2-phenylethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) - 6,7,8,9 4-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(2S) -2-hydroxy-2- (4-methoxyphenyl) ethyl] -2- (morpholin-4) -yl) -8- ( trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9 - [(1 R)) 1-phenylethyl] -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [1- (4- methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4- one - (8S) -9 - [(1S) -1- (4-bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro- 4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R) -1- (4-bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (Trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9-phenyl-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (4-fluorophenyl) -2- (morpholin-4-yl) 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-fluorophenyl) -2- (morpholine) 4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2-fluorophenyl) - 2- ( morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1 R) 1- (3-Fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4 -one - (8S) -9- (4-fluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] ] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (phenylcarbonyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2] -a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (pyridin-3-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (pyridin-4-yl) -8- (trifluoromethyl) -6,7,8 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (4-methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 7,8,9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2-chlorobenzyl) -2- (morpholin-4-yl) -8- ( trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-fluorobenzyl) -2- (morpholin-4-yl) - 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [2- (2-methoxyphenyl) ethyl] -2 - (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [2- (3-Methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-Methoxybenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin 4-one - (8S) -9- (4-methoxyphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2- a] Pyrimidin-4-one - (8S) -9 - [(2-fluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3,5-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2,4-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) 6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (2,3,4-trifluorobenzyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(( 5-chloro-1-benzothiophen-3-yl) methyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] ] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6, 7,8,9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1 R or 1S) -1- (4-fluorophenyl) ethyl] -2 - (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3- methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 (4-Chlorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - ( 8S) -2- (Morpholin-4-yl) -8- (trifluoromethyl) -9- [4- (trifluoromethyl) phenyl] -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethane) hyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1- (2-fluorophenyl) ) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) - 9- [2- (3-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidine -4-one - (8S) -9-benzyl-3-fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-tetrahydro-4H-pyrimido] -a] pyrimidin-4-one - (8S) -9- (3,5-difluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(2,6-difluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 , 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one

21

- (8S) -9 - [(2,4-difluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (phenylacetyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [ 1,2-a] pyrimidin-4-one - (8S) -9- [2- (3-chlorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-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 general schemes 1 and 2 below are illustrative of the methods used for the preparation of the products of formula (I). 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 (I) as defined above according to the present invention can thus be prepared in particular according to the methods described in Schemes 1 and 2. The subject of the present invention is therefore also the process for the preparation of products of formula (I) according to scheme 1 as defined below. The present invention thus also relates to the process for preparing products of formula (I) according to general scheme 2 as defined below. General Scheme 1: A OR OR OB R4 base 22 R3 R3 R1 R2 R1 R2 ON NH Chlorination O_N NH Y R4 ~ N OH CY R4 ~ N Cl D CD o (I) -1 F Morpholine R3 r (ùR2 O ~ N NH Y R4N ## STR1 ## In general scheme 1: The guanidines A are either commercially available or are prepared according to the methods described in Lochead, US Pat. No. 4,175,191. AW et al (EP1460076 2002), Lochead, AW et al (EP1340761 2003), Lochead, AW et al (EP1454909 2004) and Lochead, AW et al (WO2005058908 2005) .Compounds C can be obtained by condensation. a guanidine A with a dialkyl (preferably diethyl) malonate B, in the presence of a base such as sodium methoxide, at a temperature between 60 ° C and 100 ° C, according to the conditions described for example by Badawey E.-SAM et al (Eur J Med Chem, 1998, 33 (5), 349-361) Compounds D can be obtained from a compound C by treatment with a chlorine agent such as phosphorus oxychloride, in the absence of a solvent, at a temperature of between 20 ° C. and 120 ° C., or in the presence of a solvent such as dichloroethane, at a temperature of between 20 ° C. and the boiling temperature of the solvent, as per

23

for example under the conditions described by Yamashita, A. et al (Syn.Commun (2004), 34 (5), 795-803). The compounds E can be obtained from a compound D by reaction with morpholine, in the absence of a solvent, at a temperature of between 20 ° C. and 120 ° C., or in the presence of a solvent such as acetonitrile, at a temperature between 20 ° C and the reflux temperature of the solvent, as described for example by Aliabiev SB (Lett Org Chem (2007), 4 (4), 273-280. -1 can be obtained by an alkylation or acylation reaction, by addition of a compound F (R1-X with R1 = L-Aryl or heteroaryl as defined above and X = Cl, Br, I or OTf in the case of an alkylation and X = Cl in the case of an acylation) on a mixture of a compound E and a base such as sodium hydride or cesium carbonate in excess, in a solvent such as tetrahydrofuran, N, N-dimethylformamide or acetonitrile, at a temperature between 0 ° C and 80 ° C, as described for example by Ting PC et al (J. Med Chem (1990)). ), 33 (10), 2697-2706) in the case of the alkylation reaction. The compounds (1) -2 can be obtained by reaction of a compound E with a halide (X = Cl, Br or I) or aryl or heteroaryl triflate G, in the presence of a coupling agent such as copper iodide, in the presence or absence of a copper ligand such as (+/-) - trans-1,2-diaminocyclohexane or 4,7-dimethoxy-1,10-phenanthroline, in the presence of a base such as potassium phosphate, in a solvent such as N-methyl pyrrolidone or N, N-dimethylformamide, under microwave irradiation, at a temperature between 100 ° C and 200 ° C, as described for example by Lianbo Z. et al. (J. Org Chem (2009), 74 (5), 2200-2202). Alternatively, the compounds (I) -1 can be obtained according to the general scheme 2. General Scheme 2: R3 R11 R2 ON N • R1 Morpholine a R4 ~ N CoD The compounds (I) -1 can be obtained from a compound By reaction with morpholine, in the absence of solvent at a temperature between 20 ° C and 120 ° C, or in the presence of a solvent such as acetonitrile, at a temperature between 20 ° C and the temperature solvent reflux, as described for example by Aliabiev SB (Lett Org Chem (2007), 4 (4), 273-280) The compounds J can be obtained by an alkylation or acylation reaction, by addition of a compound F (R1-X with R1 = L-Aryl or heteroaryl as defined above and X = Cl, Br, I or OTf in the case of an alkylation and X = Cl in the case of acylation) on a mixture of a compound E and a base such as sodium hydride or cesium carbonate in excess, in a solvent such as tetrahydrofuran, N, N-dimethyl formamide or acetonitrile, at a temperature between 0 ° C and 80 ° C, as described for example by Ting P.C. et al. (J. Med Chem (1990), 33 (10), 2697-2706) in the case of the alkylation reaction. Alternatively, the compounds J can be obtained by Mitsunobu reaction between a compound D and an alcohol H, in the presence of diethyl azodicarboxylate and triphenylphosphine (optionally supported on resin), in a solvent such as tetrahydrofuran, at a temperature of between 0 ° C and 65 ° C, as described for example by Mitsunobu O. et al. (Synthesis (1981), 1-28). In cases where R2 is different from R3 and if the synthesis is not stereoselective, the enantiomers or the possible diastereoisomers of the synthesis intermediates or the compounds (H) can be separated by chromatography on chiral support. R3

R 1 R 2 O N NH Alkylation or Acylation O, N N, R 1 Y R 4 -N CI

The following examples of products of formula (I) illustrate the invention without however limiting it. Some of the starter products of formula A or B 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 the 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 groups, 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 under 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 can be found in the manuals known to those skilled in the art and for example in the patent FR 2,499,995. It may 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 esterification reaction of acid function, b) an ester function saponification reaction in acid function, c) a reduction reaction of the carboxy function free or esterified alcohol function, d) a reaction of conversion of alkoxy function to hydroxyl function, or of hydroxyl function to alkoxy function, e) elimination reaction of the protective groups that can be carried by the protected reactive functions, f) a salification reaction with a mineral or organic acid or with 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 any isomeric possible racemic forms , enantiomers and diastereoisomers. 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 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) Any 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 particularly useful for the therapy of tumors. 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 invention has particularly as object as medicaments, the products of formula (I) as defined above, said products of formula (I) being in all isomeric forms possible racemic , 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, as medicaments, the products corresponding to the following formulas: - (8S) -9- [2- (4-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8 - (Trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - 9- [2- (4-methoxyphenyl) ethyl] -2- (morpholin-4 -yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) - 9- (2-phenylethyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9-benzyl-2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(2S) 2-hydroxy-2-phenylethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4- one - (8S) -9 - [(2R) -2-hydroxy-2-phenylethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H- pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(2S) -2-hydroxy-2- (4-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8 - (trifluoromethyl) -6,7,8,9-t Erythrhydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9 - [(1R) -1-phenylethyl] -8- (trifluoromethyl) 6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [1- (4-methoxyphenyl) ethyl] -2- (morpholin-4) -yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1 S) -1- (4-Bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R) -1- (4-bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9-phenyl-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (4-fluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro 4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-fluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2-fluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) yl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R) -1- (3-fluorophenyl) ethyl] 2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- ( 4-fluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) 2- (Morpholin-4-yl) -9- (phenylcarbonyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - ( 8S) -2- (Morpholin-4-yl) -9- (pyridin-3-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidine -4-one - (8S) -2- (morpholin-4-yl) -9- (pyridin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1] 2-a] pyrimidin-4-one - (8S) -9- (4-methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2-chlorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9 4-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-fluorobenzyl) -2- (morphol-4-yl) -8- (trifluoromethyl) -6, 7,8,9-te Trahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [2- (2-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) 6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [2- (3-methoxyphenyl) ethyl] -2- (morpholin-4) -yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-methoxybenzyl) -2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (4-methoxyphenyl) 2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [(2-fluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one (8S) -9- (3,5-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] ] pyrimidin-4-one - (8S) -9- (2,4-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (2,3,4-trifluorobenzyl) -8- (trifluoric acid) luoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(5-chloro-1-benzothiophen-3-yl) methyl) 2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [(1 R or 1 S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1] 2-a] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) ) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-methylphenyl) -2- (morpholin-4-yl) - 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (4-chlorophenyl) -2- (morpholin-4) -yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) - 8- (trifluoromethyl) -9- [4- (trifluoromethyl) phenyl] -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [ (1 R or 1 S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-py rimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1- (2-fluorophenyl) ethyl] -2- (morphol-4-yl) - 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [2- (3-fluorophenyl) ethyl] -2 - (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9-benzyl-3 2-Fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 (3,5-difluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one (8S) -9 - [(2,6-difluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1] 2-a] pyrimidin-4-one - (8S) -9 - [(2,4-difluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8, 9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (phenylacetyl) -8- (trifluoromethyl) -6.7, 8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [2- (3-chlorophenyl) ethyl] -2- (morpholin-4-y) 1) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, as well as the addition salts with the mineral and organic acids 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 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 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, E and J as defined above and recalled below: R3 R3 R3-R2 R1-R2 R1-R2 In which R1, R2, R3 and R4 have the meanings given in R3, R4, R4 and R4 are as defined in R4 and R4. any of claims 1 to 2. The following examples which are products of formula (I) 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, InitiatorTM 2.0, 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 a temperature of 303K. Mass spectra (SM) were obtained either by Method A or Method B: Method A: WATERS UPLC-SQD Apparatus; Ionization: electrospray in positive and / or negative (ES +/-) mode; 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): de5 to 100% deBen5,3min, 5.5min: 100% deB, 6.3min: 5% of B; Retention time = Tr (min). The rotational powers (PR) were measured on a model 341 polarimeter from Perkin Elmer. Wavelength: A line of sodium (589 25 nanometers). Preparative HPLC / MS Purifications: Method C SunFire C18 Reverse Phase Column (Waters) 30x100, 5 p. Gradient of acetonitrile (+ 0.07% TFA) in water (+ 0.07% TFA)

TO: 20% acetonitrile (+ 0.07% TFA) Ti: 20% acetonitrile (+ 0.07% TFA) T11.5: 95% acetonitrile (+ 0.07% TFA) T15: 95% acetonitrile (+ 0.07% TFA) T15.5: 20% acetonitrile (+ 0.07% TFA)

Flow rate: 30 ml / min Mass: 130-800 AMU =; ESP +, ESP ^ Method D SunFire C18 reverse phase column (Waters) 30 x 100, 5 p. Gradient of acetonitrile (+ 0.07% TFA) in water (+ 0.07% TFA)

TO: 40% acetonitrile (+ 0.07% TFA) Ti: 40% acetonitrile (+ 0.07% TFA) Tl 1: 95% acetonitrile (+ 0.07% TFA) T14.5: 95% acetonitrile (+ 0.07% TFA) T15: 10% acetonitrile (+ 0.07% TFA) Flow: 30 ml / min Mass: 130-800 UMA =; ESP +, ESP Example 1: (S) -9- [2- (4-methoxy-phenyl) -ethyl] -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [ 1,2-a] pyrimidin-4-one ## STR2 ## Step f: (S) -9- [2- (4-methoxy-phenyl) -ethyl] -2-morpholin-4-yl Trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one to a solution of 150 mg of (S) -2-morpholin-4-yl-8- trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one in 5 ml of anhydrous dimethylformamide are added, at room temperature and under argon, 0.5 g of cesium carbonate. 0.23 g of 4-methoxyphenethyl bromide and 5 mg of benzyl triethylammonium chloride (BTEAC). The reaction mixture is heated at 80 ° C for 18 hours. After cooling, 10 ml of cold water and 50 ml of ethyl acetate are added to the mixture obtained. The organic phase is separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica (gradient from 0% to 20% of the eluent CH 2 Cl 2 / MeOH / NH 4 OH 28% 38/17/2 in dichloromethane), to give 160 mg of the (S) -9- [2- (4-methoxy-phenyl) -ethyl] -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one with the characteristics are as follows: 1H NMR Spectrum: 1.82 to 2.05 (m, 1H); 2.25 to 2.39 (m, 1H); 2.73 to 2.83 (m, 1H); 2.88 to 2.99 (m, 1H); 3.10 to 3.21 (m, 1H); 3.34 to 3.41 (m, 1H); 3.43 to 3.46 (m, 4H); 3.65 (m, 4H); 3.72 (s, 3H); 4.03 to 4.23 (m, 2H); 4.47 at 4.60 (m, 1H); 4.99 (s, 1H); 6.87 (d, J = 8.6 Hz, 2H); 7.12 (d, J = 8.6 Hz, 2H) Mass Spectrometry: Method A

38

Retention time Tr (min) = 0.93 [M + H] +: m / z 439 Rotatory power: PR = +91; C = 2.426mg / 0.5ML MeOH.

Step e: (S) -2-Morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one o, H / NnNN CF H 3

A mixture of 1 g of (S) -2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one and 15 ml of morpholine is heated at 80 ° C. After one hour and a half of heating and after control by LC / MS, the reaction is complete. After cooling, the reaction mixture is concentrated under reduced pressure. On the residue obtained, 10 ml of cold water and 100 ml of ethyl acetate are added. The resulting organic phase is separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.2 g of (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: Mass Spectrometry: Method A Retention time Tr (min) = 0.49 [M + H] +: m / z 305; [M-H] -: m / z 303 Rotatory power: PR = +14.2 +/- 0.6; C = 2.25mg / 0.5ML MeOH.

Step d: (S) - 2-Chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one O.O.O. N ~ CF3 CF3 CINNH CI ~ The separation of the two enantiomers of (R, S) -2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (17 g) is performed by chiral chromatography: stationary phase: Chiralpak AD; mobile phase: EtOH (20%) / heptane (80%). The levogyre enantiomer is concentrated to give 8.52 g of (R) -2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one, in the form of a white powder. The dextrorotatory enantiomer is concentrated to obtain 8.21 g of (S) -2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one, in the form of a white powder, the characteristics of which are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 0.51 [M + H] +: m / z 254; [M-H] -: m / z 252 Rotatory power: PR = + 21.3 + 1-0.5. MeOH. Step c: (R, S) -2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one # CINLN CF3 To a suspension of 34 g of R, S) -2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one in 500 ml of 1,2-dichloroethane are added, room temperature and under argon atmosphere, 60 mL of phosphorus oxychloride. The resulting mixture is then heated to 65 ° C. After stirring for 3 hours at 65 ° C, the reaction is complete by LC / MS control. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 100 ml of cold water and 400 ml of ethyl acetate. 32% sodium hydroxide solution is added to the pH of 6 on the mixture obtained. The resulting organic phase is separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange residue. This residue is purified by chromatography on silica (eluent: CH 2 Cl 2 / MeOH: 97/03) to give 20 g of (R, S) -2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one, in the form of a white solid, the characteristics of which are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 0.51 [M + H] +: m / z 254; [M-H] -: m / z 252 Step b: (R, S) -2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one o

On a mixture of 50 ml of diethyl malonate are added 10 g of 6-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride and 10 g of sodium methoxide. The mixture obtained is heated at 100 ° C. for 75 minutes. The heterogeneous mixture thickens and turns yellow with a slight gassing. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is triturated with ethyl ether. The solid formed is sintered and then taken up in 20 ml of cold water. On the slurry obtained, 12N hydrochloric acid is added until pH = 5-6. The suspension obtained is filtered on sintered glass and the insoluble material is rinsed with ethyl ether to give 11.5 g of (R, S) -2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydro- pyrimido [1,2-a] pyrimidin-4-one, in the form of a white solid, the characteristics of which are as follows Mass spectrometry: Method A Retention time Tr (min) = 0.26 [M + H] +: m / z 236; [MH] -: m / z 234 Step a: (R, S) -6-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride NH2HCl HN N CF3 In an autoclave, under 3 bar, at 22 ° C., for 24 hours, a mixture of 1.1 g of 10% Pd / C, 22 g of 2-amino-4- (trifluoromethyl) pyrimidine dissolved in 200 ml of water, 50 ml The resulting mixture is then filtered and the filtrate is concentrated under reduced pressure. The residue obtained is dried in an oven, in the presence of P2O5, to give 27 g of (R, S) -6-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride, in the form of a solid gray, the characteristics of which are as follows: Mass spectrometry: Method A Retention time Tr (min) = 0.17 [M + H] +: m / z 168 Example 2: (R, S) -9- [ 2- (4-Methoxy-phenyl) -ethyl] -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one O) ## STR1 ## Step b: (R, S) -9- [2- (4-methoxy-phenyl) -ethyl] -2-morpholin-4-yl-8-trifluoromethyl-6, 7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one To a solution of 120 mg of (R, S) -2-morpholin-4-yl-8-trifluoromethyl-6,7 8.9-Tetrahydropyrimido [1,2-a] pyrimidin-4-one in 5 ml of anhydrous dimethylformamide are added, at room temperature and under argon, 0.5 g of cesium carbonate, 0.23 g of the bromide. of 4-methoxyphenethyl and 10 mg of benzyl triethylammonium chloride (BTEAC) . The resulting mixture is heated at 80 ° C for 18 hours.

After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is taken up in 50 mL of ethyl acetate and the resulting solution is washed with 3 mL of water. The organic phase is separated and then dried over magnesium sulfate, filtered and evaporated under reduced pressure. After purification by chromatography on silica (gradient from 0% to 20% of the eluent CH 2 Cl 2 / MeOH / NH 4 OH 28% 38/17/2 in dichloromethane), 80 mg of the (R, S) - (9- [2- (4-methoxy-phenyl) -ethyl] -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one having the characteristics are as follows: 1H NMR Spectrum: 1.85 to 2.02 (m, 1H) 2.27 to 2.35 (m, 1H) 2.72 to 2.84 (m, 1H) 2.88 to 2.98 (m, 1H); 3.09 to 3.20 (m, 1H); 3.37 to 3.42 (m, 1H); 4H), 3.63 to 3.67 (m, 4H), 3.72 (s, 3H), 4.08 (m, 1H), 4.14 to 4.21 (m, 1H); 4.51 to 4.63 (m, 1H); 5.00 (s, 1H); 6.88 (d, J = 8.6 Hz, 2H); 7.13 (d, J); = 8.6 Hz, 2 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.93 [M + H] +: m / z 439 Step a: (R, S) -2-morpholin- 4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one o-N NN CF 3 A mixture of 220 mg of (R, S) ) -2-chloro-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2- -a] pyrimidin-4-one in 5 mL of morpholine is heated to 80 ° C. After one and a half hours of heating, the reaction is complete according to LC / MS control. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica (gradient from 5% to 20% of the eluent CH 2 Cl 2 / MeOH / NH 4 OH 28% 38/17/2 in dichloromethane) to give 270 mg of the (R, S) -2 -morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one having the following characteristics: Mass Spectrometry: Method B Retention time Tr (min) = 2.53 [M + H] +: m / z 305; [MH] -: m / z 303 Example 3: (S) -2-Morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one o F ~ \ N ^ NN <F Omo / F Step a: (R, S) -2-Morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9 Tetrahydropyrimido [1,2-a] pyrimidin-4-one is prepared by following the procedure described in Example 2 starting from 80 mg of (R, S) -2-morpholin-4-yl- 8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one and 240 mg of (2-bromoethyl) benzene. After purification by chromatography on silica (eluent: a gradient of 5% to 20% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 75 mg of the (R, S) - 2-morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1H NMR spectrum: 1.85 to 2.01 (m, 1H); 2.27 to 2.35 (m, 1H); 2.86 (m, 1H); 2.95 to 3.05 (m, 1H); 3.11 to 3.21 (m, 1H); 3.39 to 3.49 (m, 5H); 3.63 to 3.68 (m, 4H); 4.08 to 4.23 (m, 2H); 4.53 to 4.62 (m, 1H); 5.00 (s, 1H); 7.18 to 7.25 (m, 3H); 7.29 to 7.34 (m, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.95 [M + H] +: m / z 409 Step b: The separation of the two enantiomers of (R, S) -2-Morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one is produced by chromatography chiral: Chiralpak column IC 20 pm; Elution 75% Heptane 20% EtOH 5% MeOH The dextrorotatory enantiomer is concentrated to obtain 27 mg of (S) -2-morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidine. 4-one having the following characteristics: 1H NMR spectrum: 1.94 (m, 1H); 2.23 - 2.35 (m, 1H); 2.83 to 2.91 (m, 1H); 2.96 to 3.04 (m, 1H); 3.16 (m, 1H); 3.40 to 3.52 (m, 5H); 3.65 (m, 4H); 4.07 to 4.21 (m, 2H); 4.50 to 4.62 (m, 1H); 5.00 (s, 1H); 7.18 to 7.25 (m, 3H); 7.29 to 7.35 (m, 2H) Mass Spectrometry: Method A Retention time Tr (min) = 0.95 [M + H] +: m / z 409 Rotatory power: PR = positive sign (+ 40); C = 1.093mg / 0.5ML DMSO. Chromatographic purification also leads to 30 mg of the levorotatory enantiomer, (R) -2-morpholin-4-yl-9-phenethyl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2] -a] pyrimidin-4-one.

Example 4: (S) -9-Benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one 0 Stage b:

The separation of the two enantiomers of (R, S) -9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4- one is performed by chiral chromatography: column 6x35cm; mobile phase: EtOH 60% Heptane 40%. The dextrorotatory enantiomer is concentrated to give 36 mg of (S) -9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1H NMR spectrum: 2.10 to 2.25 (m, 1H); 2.35 to 2.43 (m, 1H); 3.19 to 3.27 (m, 5H); 3.39-3.53 (m, 4H); 4.16 to 4.27 (m, 1H); 4.51 (d, J = 15.9 Hz, 1H); 4.57 to 4.72 (m, 1H); 4.96 (s, 1H); 5.23 (d, J = 15.9 Hz, 1H); 7.20 to 7.27 (m, 3H); 7.28 to 7.34 (m, 2H) Mass Spectrometry: Method A Retention time Tr (min) = 0.88 [M + H] +: m / z 395 Rotatory power: PR = + 16.3 + / -0.7. C = 1.960mg / 0.5ML DMSO. The above chromatographic purification also leads to 38 mg of the laevorotatory enantiomer, ((R) -9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one Step a: (R, S) -9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [ 1,2-a] pyrimidin-4-one The product is prepared following the procedure described in Example 2, starting from 140 mg of (R, S) -2-morpholin-4-yl- 8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one and 0.270 ml of benzyl bromide After purification by chromatography on silica (gradient from 5% to 20% from eluent CH2Cl2 / MeOH / 28% NH4OH 38/17/2 in dichloromethane), 32 mg of (R, S) -9-benzyl-2-morpholin-4-yl-8-trifluoromethyl-6 are obtained. 7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1 H NMR Spectrum: 2.11 to 2.25 (m, 1H); at 2.44 (m, 1H), 3.17 to 3.27 (m, 5H), 3.40 to 3.53 (m, 4H), 4.18 to 4.2 9 (m, 1H); 4.51 (d, J = 15.9 Hz, 1H); 4.58 to 4.7210 (m, 1H); 4.96 (s, 1H); 5.22 (d, J = 15.9 Hz, 1H); 7.20 to 7.27 (m, 3H); 7.28-7.36 (m, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.88 [M + H] +: m / z 395 Example 5: 9 - ((S) 2-hydroxy-2-phenylethyl) -2-morpholin-4-yl-8- (S) -trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4- The product is prepared following the procedure described in Example 2 starting from 135 mg of (R, S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9- tetrahydropyrimido [1,2-a] pyrimidin-4-one and 342 mg of (S) -2-chloro-1-phenylethanol. After purification by chromatography on silica (gradient from 5% to 20% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 26 mg of the 9 - ((S) -2- hydroxy-2-phenylethyl) -2-morpholin-4-yl-8- (R) -trifluoromethyl-6,8,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one and 18 mg of (S) -9 - ((S) -2-hydroxy-2-phenyl-ethyl) -2-morpholin-4-yl-8-trifluoromethyl-6,8,8,9-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one whose characteristics are as follows: NMR spectrum 1H 2.24 (m, 1H); 2.36 to 2.46 (m, 1H); 3.08 (dd, J = 10.0 and 14.2 Hz, 1H); 3.17 to 3.27 (m, 1H); 3.40 to 3.48 (m, 4H); 3.63 to 3.69 (m, 4H); 4.17 to 4.32 (m, 2H); 4.74 to 4.85 (m, 1H); 4.99 (m H); 5.02 (s, 1H); 5.67 (d, J = 5.1Hz, 1H); 7.22 to 7.44 (m, 5H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.85 [M + H] +: m / z 425; [M-H + HCO2H] -: m / z 469 Rotatory power: PR = + 7.4 + 1-0.6; C = 1.959mg / 0.5ML CH3OH.

Example 6: 9 - ((R) -2-Hydroxy-2-phenyl-ethyl) -2-morpholin-4-yl-8- (S) -trifluoromethyl-6,8,8,9-tetrahydro-pyrimido [1] , 2-a] pyrimidin-4-one

The product is prepared following the procedure described in Example 2 starting from 135 mg of (R, S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8 9-Tetrahydropyrimido [1,2-a] pyrimidin-4-one and 342 mg (R) -2-chloro-1-phenylethanol. After purification by chromatography on silica (gradient from 5% to 20% of the eluent CH 2 Cl 2 / MeOH / NH 4 OH 28% 38/17/2 in dichloromethane), 25 mg of 9 - ((R) -2-hydroxy- 2-phenylethyl) -2-morpholin-4-yl-8- (S) -trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one, the characteristics of which are the following: 1H NMR spectrum 1.40 to 1.56 (m, 1H); 2.05 to 2.17 (m, 1H); 3.05 to 3.20 (m, 2H); 3.36 at 3.47 (m, 4H); 3.62 to 3.67 (m, 4H); 3.84-3.94 (m, 1H); 3.96 to 4.03 (m, 1H); 4.54 (dd, J = 6.0 and 13.8 Hz, 1H); 4.96 (s, 1H); 4.99 to 5.04 (m, 1H); 5.56 (bs, 1H); 7.18 to 7.37 (m, 5H) Mass Spectrometry: Method A Retention time Tr (min) = 0.73 [M + H] +: m / z 425; [M-H + HCO2H] -: m / z 469 Rotatory power: PR = + 63.3 +/- 1.4 in MeOH In the purification above, 20 mg of 9 - ((R) -2-hydroxy are also obtained. 2-phenylethyl) -2-morpholin-4-yl-8- (R) -trifluoromethyl-6,8,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one.

Example 7: (8S) -9 - [(2S) -2-hydroxy-2- (4-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8, 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product is prepared following the procedure described in Example 2 starting from 135 mg of (R, S) -2-morpholine 4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one and 760 mg of (S) -2-chloro-1- (4- methoxy-phenyl) -ethanol. After purification by chromatography on silica (gradient from 5% to 20% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 66 mg of (8S) -9 - [(2S 2-hydroxy-2- (4-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2- a] pyrimidin-4-one whose characteristics are as follows: 1H NMR spectrum: 2.14 to 2.29 (m, 1H); 2.35 to 2.44 (m, 1H); 3.06 (dd, J = 9.8 and 13.9 Hz, 1H); 3.14 to 3.27 (m, 1H); 3.37 at 3.50 (m, 4H); 3.62 to 3.69 (m, 4H); 3.74 (s, 3H); 4.14 to 4.28 (m, 2H); 4.79 (m, 1H); 4.90 to 4.98 (m, 1H); 5.01 (s, 1H); 5.57 (d, J = 4.9 Hz, 1H); 6.93 (d, J = 8.6 Hz, 2H); 7.25 (d, J = 8.6 Hz, 2H). Mass spectrometry: method A Retention time Tr (min) = 0.84 [M + H] +: m / z 499 Rotatory power: PR = +4; C = 1.397mg / 0.5m1 in CH3OH. 36 mg of (8R) -9 - [(2S) -2-hydroxy-2- (4-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 are also obtained, 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one. Example 8: (8S) -2- (morpholin-4-yl) -9 - [(1R or 1S) -1-phenylethyl] -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H The product is prepared following the procedure described in Example 1f, starting from 135 mg of (S) -2-morpholin-4-yl. 8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1d) in 5 mL of acetonitrile and 520 mg (1-bromoethyl) benzene. After purification by chromatography on silica (gradient from 5% to 20% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 23 mg of (8S) -2- (morpholin-4) are obtained. N -yl) -9- [1-phenylethyl] -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in the form of a single diastereoisomer of indefinite configuration on the phenethyl chain, the characteristics of which are as follows: 1H NMR spectrum: 1.65 (d, J = 7.0 Hz, 3H); 1.72 to 1.84 (m, 1H); 2.29 to 2.38 (m, 1H); 3.15 to 3.26 (m, 5H); 3.43 to 3.55 (m, 4H); 4.08 (m, 1H); 4.31 to 4.44 (m, 1H); 4.96 (s, 1H); 5.67 (q, J = 7.0 Hz, 1H); 7.23 to 7.40 (m, 5H).

Mass spectrometry: method A Retention time Tr (min) = 4.07 [M + H] +: m / z 409 Rotatory power: PR = +54.5 +/- 0.6; C = 1.594mg / 0.5ML CH3OH.

Example 9: (8S) -9 - [(1R and 1S) -1- (4-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9 4-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one 130 mg of (S) -2-chloro-8-trifluoromethyl-6,7,8,9 are introduced into a flask tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1d) in 3 mL of tetrahydrofuran, 250 mg of resin-supported triphenylphosphine (3 mmol / g) and 116 mg of 1- (4-methoxyphenyl) ethanol . 0.12 ml of diethyl azodicarboxylate are then added dropwise. After addition, the reaction mixture is stirred for 18 hours at room temperature. 250 mg of resin-supported triphenylphosphine (3 mmol / g) are then added to the reaction mixture. After stirring for another 18 hours at room temperature, the resulting mixture is filtered through Millex and the filtrate obtained is then concentrated under reduced pressure. The residue is dissolved in 5 mL of morpholine and the resulting mixture is heated at 80 ° C for 2 hours. The reaction mixture is concentrated under reduced pressure. After purification by chromatography on silica (gradient from 0% to 20% of the eluent CH 2 Cl 2 / MeOH / NH 4 OH 28% 38/17/2 in dichloromethane), 40 mg of (8S) -9- [1- (4-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of a 60/40 mixture of the two diastereoisomers, whose characteristics are as follows: 1H NMR spectrum: 1.61 (d, J = 7.1 Hz, 1.8 H); 1.68 (d, J = 7.1Hz, 1.2H); 2.09 to 2.47 (m, 2H); 3.10-3.65 (partially masked m, 9H); 3.72 (s, 1.2H); 3.74 (s, 1.8H); 3.85 to 4.34 (m, 1.6 H); 4.68 to 4.87 (m, 0.4 H); 4.93 (s, 0.4H); 4.98 (s, 0.6 H); 5.47 (q, J = 7.1Hz, 0.4H); 5.79 (q, J = 7.1Hz, 0.6H); 6.86 (d, J = 8.6 Hz, 0.8H); 6.92 (d, J = 8.6 Hz, 1.2H); 7.26 (d, J = 8.6 Hz, 2H) Mass Spectrometry: Method A Retention time Tr (min) = 0.94 and 0.89 (60/40 mixture of the two diastereoisomers) [M + H ] +: m / z 439

Example 10: (8S) -9 - [(1R or 1S) -1- (4-bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9- tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product is prepared following the procedure described in Example 9 starting from 300 mg of (S) -2-chloro-8- trifluoromethyl-6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one in 6 mL tetrahydrofuran, 600 mg resin-supported triphenylphosphine (3 mmol / g) and 354 mg 1- ( 4-bromophenyl) ethanol. 0.28 ml of diethyl azodicarboxylate are then added dropwise. After addition, the reaction mixture is stirred for 18 hours at room temperature. 600 mg of resin-supported triphenylphosphine (3 mmol / g) are then added to the reaction mixture. After stirring for an additional 18 hours at room temperature, the resulting mixture is filtered through Millex and the resulting filtrate is then concentrated under reduced pressure. The evaporation residue is dissolved in 5 ml of morpholine and the mixture obtained is stirred at ambient temperature for 4 days. The reaction mixture is then concentrated under reduced pressure. After purification by chromatography on silica (gradient from 0 to 20% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 15 mg of one of the (8S) -9 diastereoisomers is obtained. - [1- (4-Bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin 4-one (indeterminate configuration on the phenethyl chain), the characteristics of which are as follows: 1H NMR spectrum: 1.73 (d, J = 7.1 Hz, 3H); 2.16 to 2.31 (m, 1H); 2.39 to 2.47 (m, 1H); 3.12 to 3.25 (m, 5H); 3.35-3.51 (m, 4H); 4.15 (m, 1H); 4.82 to 4.90 (m, 1H); 4.92 (s, 1H); 5.33 (q, J = 7.1Hz, 1H); 7.27 (d, J = 8.6 Hz, 2H); 7.49 (d, J = 8.6 Hz, 2H).

Mass Spectrometry: Method B Retention time Tr (min) = 4.26 [M + H] +: m / z 487

Example 11: (8S) -9 - [(1S or 1R) -1- (4-bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9 4-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one In addition to the above purification, 60 mg of the second diastereoisomer of (85) -9- [1- (4-bromophenyl) ) ethyl] -2- (morpholin-25-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one

54

(unspecified configuration on the phenethyl chain) whose characteristics are as follows: 1 H NMR spectrum: 1.64 (d, J = 7.1 Hz, 3 H); 1.78 to 1.94 (m, 1H); 2.30 to 2.40 (m, 1H); 3.08 to 3.26 (m, 5H); 3.39 to 3.52 (m, 4H); 4.11 (m, 1H); 4.52 (m, 1H); 4.95 (s, 1H); 5.50 (q, = 7.1 Hz, 1H); 7.25 (d, J = 8.6 Hz, 2H); 7.53 (d, J = 8.6 Hz, 2H) Mass Spectrometry: Method B Retention time Tr (min) = 4.37 [M + H] +: m / z 487

Example 12: (8S) -2- (Morpholin-4-yl) -9-phenyl-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4 In a microwave tube, 425 mg of (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one (Example 1 e) in 1 mL of dimethylformamide, 422 mg of tripotassium phosphate, 380 mg of copper iodide and 2 mL of iodo benzene. The resulting mixture is heated in a microwave oven for 30 minutes at 150 ° C.

The reaction mixture is then centrifuged. The separated supernatant is then rinsed with ethyl acetate and then evaporated to dryness. The residue is taken up in ethyl acetate and the resulting solution is washed with water. The organic phase is separated and then dried over magnesium sulfate, filtered and concentrated in vacuo. After purification by chromatography on silica (gradient of 5 to 15% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 150 mg of (8S) -2- (morpholin-4) are obtained. N-phenyl-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1H NMR spectrum: 2.40 to 2.48 (m, 2H); 3.00 to 3.13 (m, 4H); 3.31 to 3.37 (m, 1H); 3.38 at 3.48 (m, 4H); 4.33 to 4.40 (m, 1H); 4.93 (m, 1H); 4.99 (s, 1H); 7.28-7.37 (m, 3H); 7.43 (t, J = 7.7 Hz, 2H). Mass Spectrometry: Method A Retention time Tr (min) = 0.83 [M + H] +: m / z 381 Example 13: (8S) -9- (4-fluorophenyl) -2- (morpholin-4- yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product is prepared by following the procedure described in Example 15. 12, from 140 mg of (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (example 1e) and 0.66 mL of 1-fluoro-4-iodobenzene. After purification by chromatography on silica (gradient from 5% to 15% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 125 mg of the (85) -9- (4- fluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, the characteristics of which are following: 1H NMR spectrum: 2.41 to 2.48 (m, 2H); 3.01 to 3.15 (m, 4H); 3.33 to 3.37 (m, 1H); 3.40 to 3.50 (m, 4H); 4.35 (m, 1H); 4.82 to 4.94 (m, 1H); 5.00 (s, 1H); 7.25 (t, J = 8.8 Hz, 2H); 7.40 (dd, J = 5.6 and 8.8 Hz, 2H). Mass Spectrometry: Method A Retention time Tr (min) = 0.86 [M + H] +: m / z 399 Example 14: (8S) -9- (3-fluorophenyl) -2- (morpholin-4 -yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product is prepared by following the procedure described in the example 12 from 140 mg of (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (example 1e ) and 0.66 mL of 1-fluoro-3-iodobenzene. After purification by chromatography on silica (gradient from 5% to 15% of the eluent CH 2 Cl 2 / MeOH / 28% NH 4 OH 38/17/2 in dichloromethane), 60 mg of the (85) -9- (3- fluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1 H NMR spectrum: 2.41 to 2.48 (m, 2H); 3.03 to 3.15 (m, 4H); 3.25 to 3.27 (m, 1H); 3.42 to 3.49 (m, 4H); 4.32 to 4.41 (m, 1H); 4.93 to 5.00 (m, 1H); 5.02 (s, 1H); 7.14 to 7.24 (m, 2H); 7.30 (td, J = 2.2 and 10.5 Hz, 1H); 7.46 (dt, J = 6.7 and 8.1 Hz, 1H). Mass Spectrometry: Method A Retention time Tr (min) = 0.86 [M + H] +: m / z 399 Example 15: (8S) -9- (2-fluorophenyl) -2- (morpholin-4- yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product is prepared following the procedure described in Example 12 from 140 mg of (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (example 1e ) and 0.66 mL of 1-fluoro-2-iodobenzene. After purification by chromatography on silica (gradient from 5% to 15% of the eluent CH 2 Cl 2 / MeOH / NH 4 OH 28% 38/17/2 in dichloromethane), 12 mg of (8S) -9- (2- fluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1H NMR Spectrum: 2.37-2.47 (m, 2H); 3.05 to 3.09 (m, 5H); 3.41 to 3.47 (m, 4H); 4.35 to 4.44 (m, 1H); 4.89 (m, 1H); 5.02 (s, 1H); 7.24-7.33 (m, 2H); 7.36-7.45 (m, 1H); 7.51 (m, 1H). Mass Spectrometry: Method A Retention time Tr (min) = 0.83 [M + H] +: m / z 399 Example 16: (8S) -9 - [(IR or 1 S) -1- (3- Fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one o Stage b: In a flask, a mixture of 300 mg of (S) -2-chloro-1- [1- (3-fluoro-phenyl) -ethyl] -8-trifluoromethyl-1, is heated at 80 ° C. for 30 minutes. 6,7,8-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one and 3 mL of morpholine. After cooling, the reaction mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and water. The organic phase is separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. After purification by chromatography on silica (eluent: CH 2 Cl 2 / MeOH 97.5 / 2.5), 152 mg of (8S) -9 - [(1- (3-fluorophenyl) ethyl] -2- (morpholin-4-yl) are obtained 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, as a single diastereoisomer (unspecified configuration at the phenethyl chain) having the following characteristics: 1 H NMR spectrum: 1.66 (d, J = 7.0 Hz, 3H), 1.80 to 1.95 (m, 1H), 2.33 to 2.41 (m, 1H), 3.09 to 3.28 (m, 5H), 3.40 to 3.52 (m, 4H), 4.06 to 4.16 (m, 1H); , 56 (m, 1H), 4.95 (s, 1H), 5.51 (q, J = 7.0 Hz, 1H), 7.00 to 7.17 (m, 3H); 7.33 to 7.42 (m, 1H).

Mass Spectrometry: Method A Retention time Tr (min) = 0.94 [M + H] +: m / z 427 Step a: In a flask, 400 mg of (S) -2-chloro-8 are introduced trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1d) 58 in 20 ml of tetrahydrofuran, 1.6 g of resin-supported triphenylphosphine (3 mmol / g) and 663 mg 1- (3-fluorophenyl) ethanol. The reaction mixture is then stirred at room temperature for 5 minutes before addition of 0.790 ml of diethyl azodicarboxylate. After stirring for 1 hour at ambient temperature, the reaction mixture is filtered and the filtrate concentrated under reduced pressure. The residue is taken up in ethyl acetate and water. The organic phase is separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. After purification by chromatography on silica (eluent CH2Cl2 / AcOEt 96/04), 150 mg of (S) -2-chloro-1- [1- (3-fluoro-phenyl) -ethyl] -8-trifluoromethyl are obtained. 1,6,7,8-tetrahydropyrimido [1,2-a] pyrimidin-4-one, in the form of a single diastereoisomer (indeterminate configuration at the phenethyl chain), the characteristics of which are as follows: Mass: Method A Retention time Tr (min) = 1.11 [M + H] +: m / z 376; [M-H] -: m / z 253 (base peak)

Example 17: (8S) -9- (4-fluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] ] pyrimidin-4-one o FA 300 mg solution of 2 (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (example 1e) in 3 mL of acetonitrile are added, under an argon atmosphere, 0.536 g of cesium carbonate and 0.44 mL of 1- (bromomethyl) -4-fluorobenzene. The resulting mixture is then heated at 80 ° C for two hours. The reaction mixture is then evaporated under reduced pressure and the residue obtained is then purified by chromatography on silica (eluent: CH 2 Cl 2 / MeOH 98/02) to give 61 mg of (8S) -9- (4-fluorobenzyl) -2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, as a white solid, Characteristics are as follows: 1H NMR Spectrum: 2.09 to 2.25 (m, 1H); 2.34 to 2.44 (m, 1H); 3.18 to 3.32 (m, 5H); 3.41 to 3.53 (m, 4H); 4.21 (m, 1H); 4.51 (d, J = 15.2 Hz, 1H); 4.60 to 4.72 (m, 1H); 4.96 (s, 1H); 5.17 (d, J = 15.2 Hz, 1H); 7.13 (t, J = 8.7 Hz, 2H); 7.30 (dd, J = 5.4 and 8.7 Hz, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.89 [M + H] +: m / z 413 Example 18 (S) -9-Benzoyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one o F ~ \ N ^ NN <FFA 300 mg solution of 2 (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1e) in 3 mL of tetrahydrofuran are added, under argon atmosphere, 35.7 mg of sodium hydride and then, after 10 minutes of stirring, 0.135 mL of benzoyl chloride. After stirring for six hours at room temperature, a saturated solution of sodium bicarbonate and ethyl acetate is added to the reaction mixture. The organic phase is separated then successively washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica (eluent: CH 2 Cl 2) to give 74 mg of (S) -9-benzoyl-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido [ 1,2-a] pyrimidin-4-one, in the form of a white solid, the characteristics of which are as follows: 1 H NMR spectrum: 2.20 to 2.31 (m, 1H); 2.68 to 2.82 (m, 3H); 2.86 to 2.96 (m, 2H); 3.15 to 3.44 (partially masked m, 4H); 3.75 to 3.87 (m, 1H); 4.17 to 4.30 (m, 1H); 5.15 (s, 1H); 5.38 to 5.53 (m, 1H); 7.37 to 7.43 (m, 2H); 7.45 to 7.53 (m, 3H).

Mass Spectrometry: Method B Retention time Tr (min) = 3.59 [M + H] +: m / z 409 Rotatory power: PR = -15.8 + 1-0.8; C = 1.650mg / 0.5ML DMSO. Example 19: (S) -2-Morpholin-4-yl-9-pyridin-3-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one The product is prepared following the procedure described in Example 12, starting from 200 mg of (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8. 9-Tetrahydropyrimido [1,2-a] pyrimidin-4-one (Example 1c) and 380 mg of 3-iodopyridine. After purification by chromatography on silica (gradient of elution of CH2Cl2 to CH2Cl2 / MeOH 96/04), 48 mg of (S) -2-morpholin-4-yl-9-pyridin-3-yl-8- are obtained. trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one, in the form of a yellow solid, the characteristics of which are as follows: 1H NMR spectrum: 2.44 to 2.48 (m, 2H); 3.00 to 3.13 (m, 4H); 3.31 to 3.37 (m, 1H); 3.41 to 3.47 (m, 4H); 4.37 (d, J = 16.1 Hz, 1H); 4.97 to 5.09 (m, 2H); 7.48 (dd, J = 4.9 and 8.3 Hz, 1H); 7.80 to 7.85 (m, 1H); 8.50 (dd, J = 1.4 and 4.9 Hz, 1H); 8.57 (d, J = 2.2 Hz, 1H).

Mass spectrometry: method A Retention time Tr (min) = 0.55 [M + H] +: m / z 382 Rotatory power: PR = -40 +/- 1.6, C = 0.2% in DMSO.

Example 20: (S) -2-Morpholin-4-yl-9-pyridin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one SAR236152 The product is prepared following the procedure described in Example 12, starting from 200 mg of (S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro- pyrimido [1,2-a] pyrimidin-4-one (Example 1c) and 380 mg of 4-iodopyridine. After purification by chromatography on silica (elution gradient from CH 2 Cl 2 to CH 2 Cl 2 / MeOH 96/04), 26 mg of (S) -2-morphol-4-yl-9-pyridin-4-yl are obtained. 8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one, as a yellow solid, the characteristics of which are as follows: 1H NMR spectrum: 2.43 to 2 , 48 (m, 2H); 3.07 to 3.19 (m, 4H); 3.33 to 3.39 (m, 1H); 3.45 to 3.50 (m, 4H); 4.30 to 4.38 (m, 1H); 5.06 (s, 1H); 5.09 to 5.17 (m, 1H); 7.45 (d, J = 6.1 Hz, 2H); 8.62 (d, J = 6.1 Hz, 2H).

Mass spectrometry: method A [M + H] +: m / z 382; [M-H] -: m / z 380 Retention time Tr (min) = 0.42 Rotatory power: PR = -31 +/- 1.3, C = 0.2% in DMSO. Example 21: (8S) -9- (4-methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] The product is prepared by following the procedure described in Example 12, starting from 100 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl. 6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1c) and 100 mg of 1-iodo-4-methylbenzene. After purification by chromatography on silica (eluent: CH 2 Cl 2 / MeOH 98/2), 23 mg of (8S) -9- (4-methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) is obtained. 6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, as a cream solid, the characteristics of which are as follows: 1H NMR Spectrum: 2.32 (s) , 3H); 2.44 (m, 2H); 2.97 to 3.15 (m, 4H); 3.33 - 3.50 (partially masked m, 5H); 4.34 (m, 1H); 4.86 (m, 1H); 4.98 (s, 1H); 7.22 (s, 4H). Mass Spectrometry: Method A Retention time Tr (min) = 0.90 [M + H] +: m / z 3955 Example 22: (8S) -9- (2-chlorobenzyl) -2- (morpholin-4- yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one ON

F / NNNYFF Omo / A solution of 100 mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one (Example 1 e) in 2 ml of dimethylformamide are added 214 mg of cesium carbonate and 74 mg of 1- (bromomethyl) -2-chlorobenzene. After 16 hours at a temperature of 20 ° C, the reaction medium is poured into water. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC / MS (Method C). After evaporation of the acetonitrile and lyophilization, 94 mg of (85) -9- (2-chlorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9- tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of an oil, the characteristics of which are as follows: 1H NMR spectrum: 2.29 to 2.66 (m, 2H); 3.09 to 3.18 (m, 4H); 3.23 to 3.50 (partially masked m, 5H); 4.27 (m, 1H); 4.68 (d, J = 16.6 Hz, 1H); 4.74 (m, 1H); 4.96 (s, 1H); 5.12 (d, J = 16.6 Hz, 1H); 7.16 to 7.22 (m, 1H); 7.24-7.32 (m, 2H); 7.41 to 7.48 (m, 1H). Mass Spectrometry: Method A Retention time Tr (min) = 0.96 [M + H] +: m / z 429 Example 23: (8S) -9- (3-fluorobenzyl) -2- (morpholin-4- yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one ON

FNFF Omo / The product is prepared following the procedure described in Example 22, starting from 100 mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6.7, 8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, 214 mg of cesium carbonate and 68 mg of 1- (bromomethyl) -3-fluorobenzene. After purification by preparative HPLC / MS (Method C), 102 mg of (85) -9- (3-fluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6.7 are obtained, 8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in the form of an oil having the following characteristics: 1 H NMR spectrum: 2.17 to 2.45 (m.p. , 2H); 3.15 to 3.31 (m, 5H); 3.39 to 3.49 (m, 4H); 4.23 (m, 1H); 4.58 (d, J = 16.1 Hz, 1H); 4.66 to 4.78 (m, 1H); 4.97 (s, 1H); 5.13 (d, J = 16.1 Hz, 1H); 6.98 to 7.15 (m, 3H); 7.35 (dt, J = 6.0 and 8.1 Hz, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.89 [M + H] +: m / z 413 Example 24 (8S) -9- [2- (2-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one 20 o FFF Omo / A solution of 100 mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro 4H-pyrimido [1,2-a] pyrimidin-4-one (Example 1 e) in 2 mL of dimethylformamide are added 214 mg of cesium carbonate and 78 mg of 1- (2-bromoethyl) -3-methoxybenzene. After 18 hours at a temperature of 60 ° C., 78 mg of 1- (2-bromoethyl) -3-fluorobenzene are added. After 2 days at a temperature of 60 ° C, the resulting reaction mixture is poured into water. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure. The residue is purified by preparative HPLC / MS (Method C). After evaporation of the acetonitrile and lyophilization, 25 mg of (8S) -9- [2- (2-methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 are obtained, 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of an oil, the characteristics of which are as follows: 1H NMR spectrum: 1.84 to 2.00 ( m, 1H); 2.25 to 2.35 (m, 1H); 2.83 to 3.03 (m, 2H); 3.06 to 3.30 (m, 2H); 3.44 (m, 4H); 3.61 to 3.67 (m, 4H); 3.76 (s, 3H); 4.08 to 4.24 (m, 2H); 4.37 to 4.52 (m, 1H); 4.99 (s, 1H); 6.88 (dt, J = 0.9 and 7.6 Hz, 1H); 6.96 (broad d, J = 7.9 Hz, 1H); 7.14 (dd, J = 1.5 and 7.6 Hz, 1H); 7.18 to 7.26 (m, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.98 [M + H] +: m / z 439 Example 25: (8S) -9- [2- (3-Methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4 -one ON

FFF Omo / The product is prepared following the procedure described in Example 24, but starting from 100 mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6.7 , 8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, 78 mg of 1- (2-bromoethyl) -3-methoxybenzene and 214 mg of cesium carbonate in 2 mL of dimethylformamide. After 3 days of reaction at a temperature of 60 ° C., treatment as described in Example 24 and purification by preparative HPLC / MS (Method C), 20 mg of (8S) -9- [2- (3) methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, under the form of an oil, the characteristics of which are as follows: 1H NMR spectrum: 1.88 to 2.01 (m, 1H); 2.32 (m, 1H); 2.74 to 2.90 (m, 1H); 2.96 (m, 1H); 3.10 to 3.22 (m, 1H); 3.26 to 3.39 (partially masked m, 1H); 3.43 to 3.48 (m, 4H); 3.62 to 3.68 (m, 4H); 3.73 (s, 3H); 4.02 to 4.23 (m, 2H); 4.49 to 4.65 (m, 1H); 5.00 (s, 1H); 6.70 to 6.88 (m, 3H); 7.14 to 7.26 (m, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.94 [M + H] +: m / z 439 Example 26: (8S) -9- (3-Methoxybenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one ON

F

NY FF Omo / The product is prepared following the procedure described in Example 22, but starting with 100 mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6, 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, 57 mg of 1- (chloromethyl) -3-methoxybenzene and 214 mg of cesium carbonate in 2 mL of dimethylformamide . After treatment, the residue is stirred in acetonitrile. The solid is drained, rinsed with diethyl ether and then dried under vacuum. 111 mg of (8S) -9- (3-methoxybenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1 are thus obtained. 2-a] pyrimidin-4-one, in the form of a white solid, the characteristics of which are as follows: 1 H NMR spectrum: 2.07 to 2.23 (m, 1H); 2.35 to 2.44 (m, 1H); 3.19 to 3.28 (m, 5H); 3.40 to 3.55 (m, 4H); 3.72 (s, 3H); 4.22 (m, 1H); 4.45 (d, J = 15.9 Hz, 1H); 4.56 to 4.70 (m, 1H); 4.96 (s, 1H); 5.21 (d, J = 15.9 Hz, 1H); 6.75 to 6.88 (m, 3H); 7.19 to 7.27 (m, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.88 [M + H] +: m / z 425 Example 27: (8S) -9- (4-Methoxyphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one

Chiral O NNF Omo / FF The product is prepared following the procedure described in Example 12, starting from 100 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8 9-Tetrahydropyrimido [1,2-a] pyrimidin-4-one (Example 1a), 108 mg of 1-iodo-4-methoxybenzene and 79 mg of 4,7-dimethoxy-1,10-phenanthroline . After purification by chromatography on silica (eluent: CH 2 Cl 2 / MeOH 98/2), 31 mg of (8S) -9- (4-methoxyphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) are obtained. 6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of a cream meringue, the characteristics of which are as follows: 1H NMR spectrum: 2.38 to 2 46 (m, 2H); 3.04 to 3.15 (m, 4H); 3.20 to 3.35 (partially masked m, 1H); 3.45 (m, 4H); 3.77 (s, 3H); 4.34 (m, 1H); 4.83 (m, 1H); 4.98 (s, 1H); 6.95 (d, J = 8.8 Hz, 2H); 7.25 (d, J = 8.8 Hz, 2H) Mass Spectrometry: Method A Retention time Tr (min) = 0.83 [M + H] +: m / z 41120

Example 28: (8S) -9 - [(2-fluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, The product is prepared by following the procedure described in Example 18, starting from 300 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-2-pyrimidin-4-one. 6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 156 mg of 2-fluorobenzoyl chloride in 5 ml of tetrahydrofuran. After purification by chromatography on silica (eluent: CH2Cl2 / MeOH 98/02), 35 mg of (85) -9 - [(2-fluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- ( trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of a white meringue, the characteristics of which are as follows: NMR spectrum 1H: 2, 13 to 2.26 (m, 1H); 2.65 to 2.85 (m, 3H); 2.94 to 3.02 (m, 2H); 3.20 to 3.40 (partially masked m, 4H); 3.43 to 3.55 (m, 1H); 4.42 (m, 1H); 5.19 (s, 1H); 5.55 to 5.69 (m, 1H); 7.18 to 7.31 (m, 2H); 7.49 to 7.64 (m, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.79 [M + H] +: m / z 427 Example 29: (8S) -9- (3,5-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one-2 OFFF The product is prepared following the procedure described in Example 22, starting from 100 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1c), 214 mg of cesium carbonate and 75 mg of 1- (bromomethyl) -3,5-difluorobenzene in 2 ml of dimethylformamide. After purification by preparative HPLC / MS (Method C), 85 mg of (85) -9- (3,5-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 are obtained, 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of an oil, the characteristics of which are as follows: 1H NMR spectrum: 2.21 to 2.44 ( m, 2H); 3.14 to 3.33 (m, 5H); 3.36-3.52 (m, 4H); 4.23 (m, 1H); 4.61 (d, J = 16.4 Hz, 1H); 4.68 to 4.81 (m, 1H); 4.98 (s, 1H); 5.07 (d, J = 16.4 Hz, 1H); 6.90 to 7.02 (m, 2H); 7.07 (tt, J = 2.3 and 9.3 Hz, 1H) Mass Spectrometry: Method B Retention time Tr (min) = 3.93 [M + H] +: m / z 431 Example 30 (8S) -9- (2,4-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] The product is prepared by following the procedure described in Example 22, starting from 100 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7 , 8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1c), 214 mg of cesium carbonate and 75 mg of 1- (bromomethyl) -2,4-difluorobenzene in 2 mL of dimethylformamide. After purification by preparative HPLC / MS (Method C), 86 mg of (85) -9- (2,4-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 are obtained, 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of an oil, the characteristics of which are as follows: 1H NMR spectrum: 2.16 to 2.30 ( m, 1H); 2.35 to 2.45 (m, 1H); 3.17 to 3.32 (m, 5H); 3.41 to 3.49 (m, 4H); 4.22 (dd, J = 5.9 and 14.2 Hz, 1H); 4.60 (d, J = 16.1 Hz, 1H); 4.66 to 4.76 (m, 1H); 4.97 (s, 1H); 5.11 (d, J = 16.1 Hz, 1H); 7.03 (ddt, J = 1.1-2.6 and 9.0 Hz, 1H); 7.22 (ddd, J = 2.6 - 9.0 and 10.9 Hz, 1H); 7.30 (dt, J = 6.7 and 9.0 Hz, 1H) Mass Spectrometry: Method B Retention time Tr (min) = 3.96 [M + H] +: m / z 431 Example 31 (8S) -2- (morpholin-4-yl) -9- (2,3,4-trifluorobenzyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-tetrahydro-4H-pyrimido] -a] pyrimidin-4-one N

FFF Omo / The product is prepared following the procedure described in Example 22, starting from 100 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9 tetrahydropyrimido [1,2-a] pyrimidin-4-one (example 1c), 214 mg of cesium carbonate and 82 mg of 1- (bromomethyl) -2,3,4-trifluorobenzene in 2 ml of dimethylformamide. After purification by preparative HPLC / MS (Method C), 76 mg of (8S) -2- (morpholin-4-yl) -9- (2,3,4-trifluorobenzyl) -8- (trifluoromethyl) are obtained. 6.7, 8.9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of an oil, the characteristics of which are as follows: 1H NMR spectrum: 2.15 to 2, 31 (m, 1H); 2.35 to 2.44 (m, 1H); 3.18 to 3.32 (m, 5H); 3.42 to 3.54 (m, 4H); 4.22 (dd, J = 5.5 and 14.3 Hz, 1H); 4.65 (d, J = 16.1 Hz, 1H); 4.73 (m, 1H); 4.98 (s, 1H); 5.16 (d, J = 16.1 Hz, 1H); 7.05 to 7.17 (m, 1H); 7.20 to 7.32 (m, 1H) Mass Spectrometry: Method B Retention time Tr (min) = 4.08 [M + H] +: m / z 449 Example 32: (8S) -9- [(5-Chloro-1-benzothiophen-3-yl) methyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2 The product is prepared by following the procedure described in Example 22, starting from 100 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-. 6,7,8,9-tetrahydropyrimido [1,2-a] pyrimidin-4-one (Example 1c), 214 mg of cesium carbonate and 95 mg of 3- (bromomethyl) -5-chloro 1 - benzothiophene in 2 mL of dimethylformamide. After purification by preparative HPLC / MS (Method C), 72 mg of (85) -9 - [(5-chloro-1-benzothiophen-3-yl) methyl] -2- (morpholin-4-yl) is obtained 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of an oil, the characteristics of which are as follows: 1H NMR Spectrum 2.13 to 2.25 (m, 1H); 2.34 to 2.43 (m, 1H); 3.16 to 3.32 (m, 5H); 3.35 at 3.48 (m, 4H); 4.21 (dd, J = 6.0 and 14.3 Hz, 1H); 4.62 to 4.74 (m, 2H); 5.00 (s, 1H); 5.52 (d, J = 16.1Hz, 1H); 7.42 (dd, J = 2.0 and 8.6 Hz, 1H); 7.67 (s, 1H); 8.01 (d, J = 2.0 Hz, 1H); 8.03 (d, J = 8.6 Hz, 1H) Mass Spectrometry: Method B Retention time Tr (min) = 4.42 [M + H] +: m / z 48520 Example 33: (8S) [(1R or 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H- pyrimido [1,2-a] pyrimidin-4-one OF NN F F F- Step a: The separation of the two diastereoisomers of (8S) -9 - [(1 R and 1 S) -1- (4- fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one is carried out by chromatography chiral: Chiralpak column IC 20 pm; Elution 70% Heptane 30% EtOH, from 130 mg of a 70/30 mixture of the two diastereoisomers. The first diastereoisomer is concentrated to obtain 42 mg of (8S) -9 - [(1R or 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) ) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of a colorless solid, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 1.72 (d, J = 6.8 Hz, 3H); 2.22 (m, 1H); 2.43 (m, 1H); 3.14 to 3.27 (m, 5H); 3.39-3.54 (m, 4H); 4.13 (dd, J = 5.6 and 14.4 Hz, 1H); 4.80 to 4.88 (m, 1H); 4.93 (s, 1H); 5.43 (q, J = 6.8 Hz, 1H); 7.12 (t, J = 8.8 Hz, 2H); 7.36 (dd, J = 5.6 and 8.8 Hz, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.95 [M + H] +: m / z 427 Stage b (8S) -9 - [(1R and 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9- tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one ONF N'NN / F Omo / FF The mixture of (8S) -9 - [(1 R and 1S) -1 - (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one is prepared according to the procedure described in Example 24 from 500 mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one, 1 g of cesium carbonate and 391 mg of 1- (1-chloroethyl) -4-fluorobenzene in 20 ml of acetonitrile. After purification by chromatography on silica (eluent: CH2Cl2 / MeOH 97/3), 130 mg of (8S) -9 - [(1R and 1S) -1- (4-fluorophenyl) ethyl] -2- ( morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in the form of a 70/30 mixture of two diastereoisomers, whose characteristics are as follows: 1 H NMR spectrum: This is a 70-30 mixture of two isomers with: 1.65 (d, J = 7.0 Hz, 2.1 H); 1.72 (d, J = 7.0 Hz, 0.9 H); 1.75 to 1.86 (m, 0.7 H); 2.25 to 2.48 (m, 1.3 H); 3.12 to 3.27 (m, 5H); 3.40 to 3.56 (m, 4H); 4.00 to 4.22 (m, 1H); 4.42 (m, 0.7 H); 4.80 to 4.87 (m, 0.3 H); 4.93 (s, 0.3H); 4.96 (s, 0.7H); 5.44 (q, J = 7.0Hz, 0.3H); 5.65 (q, J = 7.0Hz, 0.7H); 7.06 to 7.21 (m, 2H); 7.32 to 7.40 (m, 2H) Example 34: (8S) -9 - [(1R or 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) ) 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The above purification (Example 33, Step a) also leads to 85 mg of (8S) -9 - [(1R or 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro 4H-pyrimido [1,2-a] pyrimidin-4-one, as a colorless solid, the characteristics of which are as follows: 1 H NMR Spectrum: 1.65 (d, J = 7.0 Hz, 3 H); 1.69 to 1.86 (m, 1H); 2.29 to 2.37 (m, 1H); 3.14 to 3.28 (m, 5H); 3.44 to 3.58 (m, 4H); 4.08 (dd, J = 5.9 and 14.7 Hz, 1H); 4.42 (m, 1H); 4.96 (s, 1H); 5.64 (q, J = 7.0Hz, 1H); 7.17 (t, J = 8.8 Hz, 2H); 7.35 (dd, J = 5.6 and 8.8 Hz, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.95 [M + H] +: m / z 427 Example 35 (8S) -9- (3-methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidine The product is prepared by following the procedure described in Example 12, but starting from 250 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7, 8.9-Tetrahydropyrimido [1,2-a] pyrimidin-4-one (Example 1e) in 4 ml of dimethylformamide, 251 mg of 1-iodo-3-methylbenzene, 349 mg of tripotassium phosphate, 156 mg of copper iodide and 93 mg of (1S, 2S) -cyclohexane-1,2-diamine. After 1 hour at 150 ° C. under microwave irradiation and purification on a silica column of the resulting reaction mixture (elution gradient from CH 2 Cl 2 to CH 2 Cl 2 / MeOH 98/2), 195 mg of (8S) -9- (3-Methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of a green solid, whose characteristics are as follows: 1H NMR Spectrum: 2.31 (s, 3H); 2.37 to 2.47 (m, 2H); 3.02 to 3.16 (m, 4H); 3.19 to 3.39 (partially masked m, 1H); 3.40 to 3.53 (m, 4H); 4.28 to 4.40 (m, 1H); 4.93 (m, 1H); 4.99 (s, 1H); 7.13 (m, 2H); 7.19 (brs, 1H); 7.29 (t, J = 7.5 Hz, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.90 [M + H] +: m / z 395 Example 36: (8S) (4- (4-Chlorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one) Chiral Omo / Cl The product is prepared following the procedure described in Example 12, but starting from 250 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8, 9-Tetrahydropyrimido [1,2-a] pyrimidin-4-one (Example 1 e), 274 mg of 1-chloro-4-iodobenzene, 349 mg of tripotassium phosphate, 156 mg of sodium iodide, copper and 93 mg of (1S, 2S) -cyclohexane-1,2-diamine. After 1 hour at 150 ° C. under microwave irradiation and purification of the resulting reaction mixture on a silica column (elution gradient from CH 2 Cl 2 to CH 2 Cl 2 / MeOH 98/2 O), 145 mg of (8S) -9- (4-Chlorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in the form of of a green meringue, the characteristics of which are as follows: NMR spectrum 1H: 2.41 to 2.47 (m, 2H); 3.07 to 3.12 (m, 4H); 3.20 to 3.43 (partially masked m, 1H); 3.46 (m, 4H); 4.35 (m, 1H); 4.94 (m, 1H); 5.01 (s, 1H); 7.39 (d, J = 8.8 Hz, 2H); 7.49 (d, J = 8.8 Hz, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.94; [M + H] +: m / z 41520 Example 37: (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -9- [4- (trifluoromethyl) phenyl] -6.7.8 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one OF NN

Omo / F F The product is prepared following the procedure described in Example 12 but from 250 mg of (8S) -2-morpholin-4-yl-8-

trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1 e), 313 mg of 1-iodo-4- (trifluoromethyl) benzene, 349 mg of tripotassium phosphate, 156 mg of copper iodide and 93 mg of (1S, 2S) -cyclohexane-1,2-diamine. After 1 hour at 150 ° C. under microwave irradiation and purification of the resulting reaction mixture on a silica column (elution gradient from CH 2 Cl 2 to CH 2 Cl 2 / MeOH 98/2 O), 120

mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -9- [4- (trifluoromethyl) phenyl] -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one in the form of a greenish solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 2.42 to 2.53 (partially masked m, 2H); 3.01 to 3.13 (m, 4H); 3.22 to 3.39 (partially masked m, 1H); 3.41 to 3.46 (m, 4H); 4.37 (m, 1H); 5.03 (s, 1H); 5.05 (m, 1H); 7.62 (d, J = 8.6 Hz, 2H); 7.81 (d, J = 8.6 Hz, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.98 [M + H] +: m / z 449 Example 38: (8S) 1 - [(1R or 1S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one Step c: O

The separation of the two (8S) -9 - [(1 R and 1 S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8 diastereoisomers - (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one is carried out by chiral chromatography (Chiralpak AD column 20 μm, elution 80% heptane 10% EtOH 10 0/0 MeOH) from 70 mg of a 70/30 mixture of the two diastereoisomers. 41.5 mg of (8S) -9 - [(1R or 1S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 are thus obtained, 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1 H NMR spectrum (400 MHz): 1.62 (d, J = 7.2 Hz, 3) H); 1.68 to 1.85 (m, 1H); 2.30 to 2.39 (m, 1H); 3.20 to 3.42 (m, 5H); 3.50 to 3.65 (m, 4H); 4.03 (m, 1H); 4.22 to 4.36 (m, 1H); 4.99 (s, 1H); 6.05 (q, J = 7.2 Hz, 1H); 7.14 to 7.29 (m, 2H); 7.35 to 7.43 (m, 1H); 7.47 (m, 1 H) Mass spectrometry: method B Retention time Tr (min) = 4.02 [M + H] +: m / z 427

82

Rotatory power: PR = +33; C = 2.543mg / 1ML DMSO. Step b: (8S) -9 - [(1R and 1S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8, 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product can be prepared following the procedure described in Example 17, but from 500 mg of (8S) -2- (4-morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, 1 g of cesium carbonate, mg of 1- (1-chloroethyl) -2-fluorobenzene (see Step a below) in 22 mL of acetonitrile. After purification on a silica column (eluent: CH 2 Cl 2 / MeOH 97/03), 70 mg of a 70/30 mixture of the two diastereoisomers of (8S) -9 - [(1 R and 1 S) -1- are obtained. (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of a pale yellow powder, the characteristics of which are as follows: Retention time Tr (min) = 0.93 and 0.90: mixture 70% - 30% of isomers; [M + H] +: m / z 427 O

Step a: 1- (1-chloroethyl) -2-fluorobenzene Cl To a solution of 1 g of commercial 1- (2-fluorophenyl) ethanol in 20 ml of chloroform is added 767 mg of thionyl chloride. After stirring overnight at a temperature in the region of 20 ° C., the reaction mixture is washed with saturated aqueous sodium bicarbonate solution and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 780 mg of 1- (1-chloroethyl) -2-fluorobenzene are thus obtained, which is used as in the following step.

Example 39: (8S) -9 - [(1R or 1S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8, 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one OFNFFF The above purification (example 38, stage c) also leads to 17.9 mg of (8S) -9 - [(1 R or 1) S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidine -4-one, in the form of an amber solid, the characteristics of which are as follows: 1H NMR spectrum (400MHz): 1.69 (d, J = 7.0 Hz, 3H); 1.97 to 2.12 (m, 1H); 2.36 to 2.46 (m, 1H); 3.15 to 3.35 (partially masked m, 5H); 3.43 to 3.59 (m, 4H); 4.09 (m, 1H); 4.72 (m, 1H); 4.93 (s, 1H); 5.73 (q, J = 7.0Hz, 1H); 7.07 to 7.25 (m, 2H); 7.28 to 7.40 (m, 1H); 7.51 (m, 1 H) Mass spectrometry: method B Retention time Tr (min) = 3.93 [M + H] +: m / z 427 Rotating power: PR = -96.3 + 1-1.4; C = 2.812mg / 0.5ML DMSO. Example 40: (8S) -9- [2- (3-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [ 1,2-a] pyrimidin-4-one ON

NN Ney OFFA a solution of 150 mg of (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in 2.5 mL of toluene are added 296 mg of sodium hydroxide in 2.5 mL of water, 33 mg of tetrabutylammonium hydrogen sulfate and 200 mg of 1- (2-bromoethyl) -3-fluorobenzene. After one hour under microwave irradiation (power 100 Watts on CEM discover device) at 60 ° C then one hour again at 60 ° C and twice six hours at 70 ° C. the reaction mixture is diluted with ethyl acetate. The resulting mixture is washed with water. The organic phase is separated and then concentrated to dryness under reduced pressure.

After purification by preparative HPLCIMS of the residue obtained (Method D), 43 mg of (8S) -9- [2- (3-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) are obtained. ) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1H NMR spectrum (400MHz): 1.87 to 2.05 (m) , 1H); 2.29 to 2.38 (m, 1H); 2.82-3.24 (m, 3H); 3.38 to 3.50 (m, 5H); 3.60 to 3.66 (m, 4H); 4.11 to 4.25 (m, 2H); 4.50 to 4.69 (m, 1H); 4.99 (s, 1H); 6.96 to 7.15 (m, 3H); 7.28 to 7.41 (m, 1H) Mass spectrometry: method B Retention time Tr (min) = 4.10 [M + H] +: m / z 427 Example 41: (8S) -9- benzyl-3-fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one Chiral OFN NN N 1 / FFOF Step e: 15 To a suspension of 1 g of (8S) -3-fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro- 4H-pyrimido [1,2-a] pyrimidin-4-one in 11.8 mL of acetonitrile are added 4 g of cesium carbonate and 796 mg of benzyl bromide. After stirring overnight at a temperature in the region of 20 ° C., the suspension obtained is filtered and the resulting filtrate is concentrated to dryness under reduced pressure. The yellow oily residue is purified on a silica column (eluent: CH 2 Cl 2 / MeOH 98/02). The fractions of interest are combined and concentrated to dryness under reduced pressure. The residue is taken up in diethyl ether, drained and dried under vacuum. 600 mg of (8S) -9-benzyl-3-fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1] are thus obtained. , 2-a] pyrimidin-4-one, in the form of a white powder, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 2.17 to 2.30 (m, 1H); 2.39 to 2.46 (m, 1H); 3.31 to 3.52 (m, 9H); 4.23 (m, 1H); 4.55 (d, J = 16.1Hz, 1H); 4.61 to 4.73 (m, 1H); 5.13 (d, J = 16.1 Hz, 1H); 7.20 to 7.26 (m, 3H); 7.28-7.36 (m, 2H) Mass Spectrometry: Method B Retention Time Tr (min) = 4.01 [M + H] +: m / z 413 Stage d: (8S) -3- fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one O

NN ~ 7 Omo / HFF The product can be prepared following the procedure described in Example 16, stage b, but starting with 1 g of (8S) -2-chloro-3-fluoro-8- (trifluoromethyl) ) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in 5 mL of acetonitrile and 1.6 mL of morpholine. After one night at 65 ° C., 1.1 g of (8S) -3-fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H- are obtained. pyrimido [1,2-a] pyrimidin-4-one, in the form of a beige powder, the characteristics of which are as follows: Mass spectrometry: Method A Retention time Tr (min) = 0.56 [M + H] ] +: m / z 323; [MH] -: m / z 321 Step c: (8S) -3-fluoro-2-chloro-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] Pyrimidin-4-one O CIE FFF The separation of enantiomers of (8R, 8S) -2-chloro-3-fluoro-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [ 1,2-a] pyrimidin-4-one is performed by chiral chromatography (Chiralpak AD 20pm 80X350mm 250m1 / min 254nm, 5% EtOH 5% MeOH 90% Heptane + 0.1% TEA), from 6.8 g of a racemic mixture. The dextrorotatory enantiomer is concentrated to obtain 3.13 g of (8S) -2-chloro-3-fluoro-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, in the form of a white solid, the characteristics of which are as follows: Mass spectrometry: Method A Retention time Tr (min) = 0.62 [M + H] +: m / z 272; [M-H] -: m / z 270 Rotatory power: PR = +19.6 +/- 0.6; C = 2.488mg / 0.5ML CH3OH. Step b: (8R, 8S) -2-Chloro-3-fluoro-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one O CINON FFFA a solution of 6.5 g of (8R, 8S) -3-fluoro-2-hydroxy-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidine 4-one in 20 ml of 1,2-dichloroethane are added 8 ml of phosphorus trichloride.

After stirring for 4 hours at a temperature of 65 ° C. and returning to a temperature in the region of 20 ° C., the reaction mixture is concentrated to dryness under reduced pressure. The residue is diluted in 150 mL of ethyl acetate and 10 mL of ice water. At a temperature of between 0 ° C. and 10 ° C., a solution of concentrated sodium hydroxide is added until a pH of between 6 and 7 is obtained. The solid formed is filtered to give 3.5 g of a solid. beige S1. The filtrate is decanted, and the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. After purification of the residue on a silica column (eluent: CH 2 Cl 2 / MeOH 97/03), 3.3 g of a pale yellow solid S 2 are obtained. The two solids S1 and S2 are combined to give 6.8 g of (8R, 8S) -2-chloro-3-fluoro-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one, in the form of a pale yellow powder, the characteristics of which are as follows: Mass spectrometry: Method B Retention time Tr (min) = 2.90 [M + H] + m / z 272; [MH] -: m / z 270 Step a: (8R, 8S) -3-fluoro-2-hydroxy-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2- a] pyrimidin-4-one 88 A suspension of 7 g of 6- (trifluoromethyl) -1,4,5,6-tetrahydropyrimidin-2-amine hydrochloride (example 1, step a) in 35 ml of dimethyl fluoro propanedioate 5.6 g of sodium methoxide are added. After stirring for 3 hours at a temperature of 100 ° C., the medium obtained is concentrated to dryness under reduced pressure. The residue is taken up in diethyl ether and then filtered under vacuum. The solid obtained is taken up in 14 ml of water and the resulting mixture is cooled in ice before acidification to pH 5-6 by addition of concentrated hydrochloric acid (25%). After stirring for 2 hours at a temperature of 0 ° C. and then overnight at a temperature in the region of 20 ° C., the suspension is filtered and the solid is drained and dried under vacuum over P2O5. 6.5 g of (8R, 8S) -3-fluoro-2-hydroxy-8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one are obtained in the form of a yellow powder, the characteristics of which are as follows: Mass spectrometry: Method A Retention time Tr (min) = 0.28 [M + H] +: m / z 254; [MH] -: m / z 252 Example 42: (8S) -9- (3,5-difluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9- Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one Chiral ON Omo / FF The product is prepared following the procedure described in Example 12, but from 250 mg of (8S) 2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1 e), of 276 mg of 1,3- difluoro-5-iodobenzene, 349 mg of tripotassium phosphate, 156 mg of copper iodide and 93 mg of (1S, 2S) -cyclohexane-1,2-diamine. After 1 hour at 150 ° C. under microwave irradiation and purification on a silica column of the reaction mixture (elution gradient from CH 2 Cl 2 to CH 2 Cl 2 / MeOH 98/2), 91 mg of (8S) -9- (3 5-difluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in the form of an ocher meringue, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 2.45 (m, 2H); 3.07 to 3.16 (m, 4H); 3.32-3.37 (m, 1H); 3.45 to 3.55 (m, 4H); 4.36 (m, 1H); 5.01 (m, 1H); 5.04 (s, 1H); 7.18 to 7.34 (m, 3H) Mass spectrometry: Method A Retention time Tr (min) = 0.95 [M + H] +: m / z 417; Example 43: (8S) -9 - [(2,6-difluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6- [M-H + HCO2H] -: m / z 461 7,8,9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one 90 Omo / F F The product is prepared following the procedure described in Example 18, starting from 300. mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (Example 1e), of 47 mg of sodium hydride and 174 mg of 2,6-difluorobenzoyl chloride in 4 mL of tetrahydrofuran. After three successive purifications by chromatography on silica (eluent: CH 2 Cl 2 / MeOH, gradient from 100/0 to 98/2 and then 98/1 and 98/2), 22 mg of (8S) -9 - [(2, 6-difluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, under form of a white solid, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 2.06 to 2.23 (m, 1H); 2.69 to 2.79 (m, 1H); 2.91 (m, 2H); 3.06 (m, 2H); 3.18 to 3.34 (partially masked m, 1H); 3.37 at 3.50 (m, 4H); 4.52 to 4.61 (m, 1H); 5.23 (s, 1H); 5.62 to 5.86 (m, 1H); 7.04 to 7.35 (m, 2H); 7.50 to 7.67 (m, 1H) Mass spectrometry: method A Retention time Tr (min) = 0.93 [M + H] +: m / z 445 Example 44: (8S) -9- [(2,4-Difluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4 -one O

The product is prepared by following the procedure described in Example 18, starting from 300 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8, 9-Tetrahydropyrimido [1,2-a] pyrimidin-4-one (Example 1e), 47 mg of sodium hydride and 174 mg of 2,4-difluorobenzoyl chloride in 4 mL of tetrahydrofuran. After two successive purifications by chromatography on silica (eluent: CH2Cl2 / MeOH gradient from 100/0 to 98/02 and then 99/01), 24 mg of (8S) -9 - [(2,4-difluorophenyl) carbonyl are obtained. 2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in the form of a lacquer colorless, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 2.20 (m, 1H); 2.67 to 2.77 (m, 1H); 2.81 to 2.91 (m, 2H); 3.03 (m, 2H); 3.24 to 3.45 (partially masked m, 2H); 3.37 at 3.46 (m, 2H); 3.52 (m, 1H); 4.30 to 4.48 (m, 1H); 5.21 (s, 1H); 5.53 to 5.67 (m, 1H); 7.18 (dt, J = 2.5 and 8.6 Hz, 1H); 7.35 (ddd, J = 2.5 and 9.3 and 11.2 Hz, 1H); 7.61 to 7.71 (m, 1H) Mass spectrometry: method A Retention time Tr (min) = 0.94 [M + H] +: m / z 445 Example 45: (8S) -2- (Morpholin-4-yl) -9- (phenylacetyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product is prepared in according to the procedure described in Example 18, starting from 300 mg of (8S) -2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one (example 1c), 47 mg of sodium hydride and 152 mg of phenylacetyl chloride in 4 mL of tetrahydrofuran. After two successive purifications by chromatography on silica (eluent: CH2Cl2 / MeOH gradient from 100/0 to 98/02 and then CH2Cl2 / AcOEt 95/05), 12 mg of (8S) -2- (morpholin-4-yl) are obtained. ) (9-phenylacetyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one, as a colorless lacquer, The characteristics are as follows: 1H NMR Spectrum (400MHz): 1.91 (m, 1H); 2.59 to 2.69 (m, 1H); 2.88 (m, 1H); 3.33 at 3.45 (m, 4H); 3.60 (m, 4H); 4.07 (d, J = 16.0 Hz, 1H); 4.16 (d, J = 16.0 Hz, 1H); 4.43 to 4.52 (m, 1H); 5.30 (s, 1H); 5.48 to 5.61 (m, 1H); 7.11 (d, J = 7.7 Hz, 2H); 7.17 to 7.23 (t, J = 7.7 Hz, 1H); 7.28 (t, J = 7.7 Hz, 2H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.99; [M + H] +: m / z 423; [M-H] -: m / z 421; base peak: m / z 303 Example 46: (8S) -9- [2- (3-chlorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6.7,8, 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one The product is prepared following the procedure described in Example 40, starting from 150 mg of (8S) -2- (morpholine 4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one in 2.5 mL of toluene are added 296 mg of sodium in 2.5 mL of water, 33 mg of tetrabutylammonium hydrogen sulfate and 216 mg of 1- (2-bromoethyl) -3-chlorobenzene. After 44 hours at 60 ° C. After cooling, the reaction mixture is diluted with ethyl acetate. The organic phase is separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated to dryness under reduced pressure and the residue is purified by preparative HPLC / MS (Method D). There is thus obtained 42 mg of (85) -9- [2- (3-chlorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro- 4H-pyrimido [1,2-a] pyrimidin-4-one having the following characteristics: 1H NMR spectrum (400MHz): 1.91 to 2.05 (m, 1H); 2.34 (m, 1H); 2.81 to 2.92 (m, 1H); 2.94 to 3.04 (m, 1H); 3.17 (m, 1H); 3.38 at 3.50 (m, 5H); 3.65 (m, 4H); 4.09 to 4.22 (m, 2H); 4.57 to 4.71 (m, 1H); 4.99 (s, 1H); 7.17 (d, J = 7.8 Hz, 1H); 7.25-7.38 (m, 3H) Mass Spectrometry: Method A Retention Time Tr (min) = 1.03 [M + H] +: m / z 443; EXAMPLE 47 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 Example 1) 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 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 prostate cancer carcinoma PC3 human cells measured by western blottinq (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 (Rochet 04906837001) for 10mI 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 NPO322BOX) 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 / 0600DF115). 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 1h 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 Oeil 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 of 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 MSD Multi-spot Biomarker Detection Kit from Meso Scale Discovery: phosphor kits Akt (Ser473) whole cell lysate (# K151CAD) or phospho-Akt (Ser473) / Total Akt whole cell lysate (# K151OOD). The primary antibody specific for P-AKT-S473 (Kit # K151CAD) 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 revealed. 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 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 hour 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 previously are transferred to the multispot 96 well plates of the MSD kit and incubated for 1 hour at room temperature, with stirring. Four washes are performed with 150 μl Tris Wash Buffer Wash Solution 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

100

room temperature, with stirring. Four washes are performed with 150 μl Tris Wash Buffer Wash Solution from the MSD kit. 150pl Read Buffer revelation buffer from the MSD kit is added to the wells and the plates are read immediately on the S12400 instrument of Meso Scale Discovery. 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 (IC50 absolute). 2 independent experiments make it possible to calculate the average of IC50s. 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 2 315 Example 3 Example 4 265 Example 5 EXAMPLE 7 EXAMPLE 7 EXAMPLE 9 EXAMPLE 9 EXAMPLE 10 EXAMPLE 10 EXAMPLE 13 EXAMPLE 14 EXAMPLE 14 EXAMPLE 17 Example 17 EXAMPLE 17 EXAMPLE 17 Example 22 Example 23 Example 23 Example 27 Example 26 Example 27 Example 28 33 Example 29 Example 30 Example 31 Example 32 33 Example 33 Example 34 Example 35 Example 36 Example 37 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 Example 44 2 Example 45 Example 46 * Tests A and B: IC50 (nM) 10 15 20

Claims (16)

CLAIMS 1) Products of formula (I): wherein: R 1 represents a -L-aryl or -L-heteroaryl radical, such that L represents: either a single bond, or a linear or branched alkyl radical containing from 1 to 6 carbon atoms; carbon and optionally substituted with a hydroxyl radical, either a CO or OCO-Al k- group, or a group L'-X where L 'represents a linear or branched alkyl radical containing from 1 to 6 carbon atoms and X a hydrogen atom. oxygen or sulfur; the aryl and heteroaryl radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, CN, nitro, -COOH, -alkyl, -NRxRy, -CONRxRy, -NRxCORy, -NRxCO2Rz radicals, -COR y, alkoxy, phenoxy, alkylthio, alkyl, cycloalkyl and heterocycloalkyl; these latter alkoxy, phenoxy, alkylthio, alkyl and heterocycloalkyl radicals, themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and NRvRw; heterocycloalkyl and heteroaryl radicals additionally capable of containing an oxo radical; R2 represents a hydrogen atom or an alkyl radical; R 3 represents an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom or a halogen atom; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and NRvRw radicals; and heterocycloalkyl; 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 being optionally substituted; NRvRw being such that Rv represents a hydrogen atom or an alkyl radical and Rw represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and heterocycloalkyl radicals; ; either Rv and Rw form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 ring members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being optionally substituted; the cyclic radicals that can be formed by Rx and Ry or Rv and Rw respectively with the nitrogen atom to which they are attached, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, alkyl radicals, hydroxyl radicals, oxo, alkoxy, NH2; NHalk and N (alk) 2; Rz represents the values of Ry with the exception of hydrogen; Rx, Ry and Rz in the radicals -NRxCORy, -CORy and NRxCO2Rz being selected from the meanings indicated above for Rx, Ry, and Rz; all the above alkyl (alk), alkoxy and alkylthio radicals being linear or branched and containing from 1 to 6 carbon atoms, said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, the addition salts with the mineral 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 in which: R1 represents a -L-phenyl or -L-heteroaryl radical, such that L represents: either a single bond or a linear or branched alkyl radical containing from 1 to 6 carbon atoms and optionally substituted with a hydroxyl radical, either a CO group or a CO-Al k- group, or a group L'-X where L 'represents a linear or branched alkyl radical containing from 1 to 6 atoms carbon and X an oxygen or sulfur atom; The phenyl and heteroaryl radicals being optionally substituted with one or more identical or different radicals selected from halogen atoms and -NRxRy, alkoxy and alkyl radicals; these latter alkoxy and alkyl radicals themselves being optionally substituted by one or more radicals chosen from halogen atoms; R2 represents an alkyl radical; R3 represents an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom or a fluorine 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 morpholino radical; all the above alkyl (alk) or alkoxy radicals being linear or branched and containing from 1 to 6 carbon atoms, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, 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). 3) Products of formula (I) as defined in any one of claims 1 or 2, having the following formulas: - (8S) -9- [2- (4-methoxyphenyl) ethyl] -2- (morpholinic acid) 4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one-9- [2- (4-methoxyphenyl) ethyl] - 2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholine 4-yl) -9- (2-phenylethyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) - 9-Benzyl-2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) [(2S) -2-Hydroxy-2-phenylethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-] -a] pyrimidin-4-one - (8S) -9 - [(2R) -2-hydroxy-2-phenylethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one 20 - (8S) -9 - [(2S) -2-hydroxy-2- (4-methoxyphenyl) ethyl] -2- ( morpholin-4-yl) -8- (trifluoromethyl) -6 7,8,9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9 - [(1R) -1-phenylethyl) 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [1- (4-methoxyphenyl) ethyl] 2- (Morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [(1S) -1- (4-bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-tetrahydro-4H-pyrimido] a] pyrimidin-4-one 5 - (8S) -9 - [(1 R) -1- (4-bromophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6 7,8,9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9-phenyl-8- (trifluoromethyl) -6 7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one 5 - (8S) -9- (4-fluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-fluorophenyl) -2- (morpholin-4-yl) 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2-fluorophenyl) -2- (morphine) Lin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1 R) ) -1- (3-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin 4-one - (8S) -9- (4-fluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2- a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (phenylcarbonyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (pyridin-3-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro- 4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -9- (pyridin-4-yl) -8- (trifluoromethyl) -6.7, 8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (4-methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) - 6,7,8,9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2-chlorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-fluorobenzyl) -2- (morpholin-4-yl) ) -8 (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- [2- (2-methoxyphenyl) ethyl] -2- ( morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one 298 - (8S) -9- [2- (3-Methoxyphenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3-Methoxybenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin 4-one 5 - (8S) -9- (4-methoxyphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-tetrahydro-4H-pyrimido] -a] pyrimidin-4-one - (8S) -9 - [(2-fluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro- 4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3,5-difluorobenzyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6.7, 8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (2,4-difluorobenzyl) -2- (morpholin-4-yl) -8- ( trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -2- (m.p. orphan-4-yl) -9- (2,3,4-trifluorobenzyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one 15 - (8S) -9 - [(5-chloro-1-benzothiophen-3-yl) methyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro 4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1- (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) 8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1) (4-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4- one - (8S) -9- (3-methylphenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (4-chlorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one - (8S) -2- (morpholin-4-yl) -8- (trifluoromethyl) -9- [4- (trifluoromethyl) phenyl] -6,7,8,9- tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(1R or 1S) -1- (2-fluorophenyl) ethyl] -2- (morphine Lin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one 295 - (8S) -9 - [(1 R or 1 S) -1- (2-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-tetrahydro-4H-pyrimido] a] pyrimidin-4-one - (8S) -9- [2- (3-fluorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro 4H-pyrimido [1,2-a] pyrimidin-4-one 5- (8S) -9-benzyl-3-fluoro-2- (morpholin-4-yl) -8- (trifluoromethyl) -6.7, 8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9- (3,5-difluorophenyl) -2- (morpholin-4-yl) -8- (trifluoromethyl) ) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(2,6-difluorophenyl) carbonyl] -2- (morpholine) 4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - (8S) -9 - [(2,4 1-Fluorophenyl) carbonyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one - ( 8S) -2- (morpholin-4-yl) -9- (phenylacetyl) -8- (trifluoromethyl) -6,7,8,9-tetrahydro-4H-pyrimido [1, 2-a] pyrimidin-4-one 15- (8S) -9- [2- (3-chlorophenyl) ethyl] -2- (morpholin-4-yl) -8- (trifluoromethyl) -6,7,8, 9-Tetrahydro-4H-pyrimido [1,2-a] pyrimidin-4-one as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 20 4) Process for the preparation of the products of formula (I) as defined in any one of claims 1 to 3 according to scheme 1 as defined below. Embedded image wherein R 1, R 2, R 3 and R 4 have the following meanings: ## STR2 ## wherein R 1, R 2, R 3 and R 4 are the same; The meaning of any one of claims 1 or 2 wherein R is alkyl, X is chloro, bromo or iodo or a sulfonyloxy group such as trifluoromethylsulphonyloxy. 5) Process for the preparation of the products of formula (I) as defined in any one of claims 1 to 3 according to scheme 2 as defined below. Scheme 2: R 3 (R 2 ON N.R 1 Y 3 R 4) / N CD 3 R 3 R 1 R 2 ON NH Alkylation or Acylation O, NN, R 1 Y R 4 - 1, N CI J Morpholine R 1 -XF base or R 1 -OH H DEAD / PPh3 111 wherein the substituents R1, R2, R3 and R4 have the meanings given in any of claims 1 or 2. X represents a chlorine, bromine or iodine atom or a sulfonyloxy group such as trifluoromethylsulfonyloxy. 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). 10 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 thereof. 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), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain cancers, larynx, of the 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 new industrial products, the synthetic intermediates of formulas C, D, E and J as defined in claims 4 and 5 above and recalled below: R3 R3 (1- R2 R1-R2 O_N NH Wherein R 1, R 2, R 3 and R 4 are as defined in any one of claims 1 to 2, wherein R 1, R 2, R 3 and R 4 are as defined in any one of claims 1 to 2.