FR2951169A1 - New (6-oxo-1,6-dihydro-pyrimidin-2-yl)-amide derivatives are akt phosphorylation inhibitors useful for treating e.g. gastric cancers, glioblastoma, thyroid cancers, bladder cancers, breast cancers, melanoma, sarcoma and hamartoma - Google Patents

Abstract

(6-Oxo-1,6-dihydro-pyrimidin-2-yl)-amide 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. (6-Oxo-1,6-dihydro-pyrimidin-2-yl)-amide 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> : aryl or heteroaryl group (both optionally substituted by one or more groups of alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocycloalkyl (all optionally substituted by one or more halo, OH, alkoxy, NR1vR1w, heterocycloalkyl or heteroaryl), halo, OH, CN, nitro, -COOH, cycloalkyl, -O-cycloalkyl, -COOalk, NR1xR1y-, -CONR1xR1y, NR1xCOR1y-, -NR1xCO2R1z, or -COR1y, where aryl and heteroaryl is optionally substituted by one or more alkyl or alkoxy (both optionally substituted by one or more halo and the heterocycloalkyl and heteroaryl are optionally contains one or more oxo)); either R : H; or RR 1> : 5 or 6 membered ring (saturated or partially or completely unsaturated fused with aryl or heteroaryl and optionally containing one or more other heteroatoms of O, S, N, NH or N-alk), bicyclic group optionally substituted by one or more halo, CO-NH 2, OH, alkyl (optionally substituted by OH, alkoxy, NH 2, NH-Alk or N(alk) 2) or alkoxy; R 2>, R 3> : H, halo or alkyl optionally substituted by one or more halo; R 4> : H; R 5> : H or alkyl optionally substituted by one or more 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 one or more other 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; either R1v : H or alkyl; and R1w : H, cycloalkyl, CO 2alk 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 alk, alkoxy and alkylthio are linear or branched 1-6C alkyl, 1-6C alkoxy and 1-6C alkylthio. Independent claims are included for: (1) preparations of (I); and (2) intermediates comprising (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester (C), (4- morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-sodium acetate (D1), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-lithium acetate (D2), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-potassium acetate (D3), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (E) and (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-metal acetate compound of formula (F). Y1 +> : Na, Li or K. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Akt Phosphorylation inhibitor; Protein kinase B (PKB) inhibitor. The ability of (I) to inhibit akt phosphorylation was tested in human prostate carcinoma cells using western blotting technique. The result showed that N-(3-bromophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide exhibited an IC 5 0value of 23 nM.

Description

NOVEL (6-OXO-1,6-DIHYDRO-PYRIMIDIN-2-YL) -AMIDE DERIVATIVES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS PHOSPHORYLATION INHIBITORS OF AKT (PKB) The present invention relates to novel chemical compounds (6- oxo-1,6-dihydro-pyrimidin-2-yl) -amide), pyrimidinone derivatives, process for their preparation, the novel intermediates obtained, their use 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 treatment of conditions capable of being modulated by the inhibition of AKT phosphorylation (P-AKT). The inhibition of P-AKT can be obtained in particular by the inhibition of the PI3K / AKT / mTOR pathway, and in particular by the inhibition of kinases belonging to this pathway such as receptors with tyrosine kinase activity such as EGFR, IGFR, ErbB2 , 3'-phosphoinositide-dependent protein kinase-1 (PDK1), phosphoinositide kinase PI3K, serine threonine kinase AKT, mTOR kinase. The inhibition and regulation of the PI3K / AKT / mTOR pathway is a novel and powerful mechanism of action for the treatment of a large number of cancerous diseases including solid and fluid tumors.

Such conditions which can be treated by the products of the present application are solid or liquid human tumors.

Role of the PI3K / AKT / mTOR pathway The PI3K / AKT / mTOR signaling pathway is a complex network that regulates multiple cellular functions, such as growth, survival, proliferation and cell motility, which are key processes in the pathway. tumorigenesis. This signaling pathway is an important target in the treatment of cancer because most of its effectors are altered in human tumors. The main effectors contributing to the activation of the pathway are: i) oncogenes such as ErbB1 (EGFR), ErbB2 (HER2), PIK3CA and AKT activated by mutation, amplification or overexpression; ii) the deficiency of tumor suppressor genes such as PTEN, TSC112, LKB and PML that are inactivated as a result of mutations or deletions (Jiang LZ & Liu LZ, Biochim Biophys Acta, 2008, 1784: 150; Vivanco 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 cancer diseases: o the deletion of PTEN in 50% of lung cancers (NSCLC), liver, kidney, prostate, breast , brain, pancreas, endometrium and colon (Maxwell GL et al., Res Res 1998, 58: 2500, Zhou XP et al., J. Pathol., 2002, 161: 439; & Baker SJ, Oncogene, 2008, 27: 5416, Li et al., Science, 1997, 275: 1943, Steack PA et al., Nat Genet., 1997, 15: 356), the mutations of TSC1 / 2 in more 50% of tuberous sclerosis o mutations or deletions of LKB1 (or STK11) which predispose to cancers of the gastrointestinal tract and pancreatic cancer and which are found in particular in 10-38% of lung adenocarcinomas (Shah U. et al., Cancer Res., 2008, 68: 3562), the PML modification by translocation in human tumors (Gurrieri C et al., J. NAtI Cancer Inst. 96: 269). In addition, this signaling pathway is a major factor of resistance to chemotherapy, radiotherapy and targeted therapies such as EGFR and HER2 inhibitors for example (C. Sawyers et al., Nat Rev 2002).

Role of AKT AKT (Protein Kinase B, PKB) is a serine-threonine kinase that occupies a central place in one of the major signaling pathways, the PI3KIAKT pathway. AKT is particularly involved in the growth, proliferation and survival of tumor cells. Activation of AKT is carried out in two steps (i) by phosphorylation of threonine 308 (P-T308) by PDK1 and (2) by phosphorylation of serine 473 (P-S473) by mTORC2 (or mTOR-Rictor complex). ), resulting in total activation. AKT in turn regulates a large number of proteins including mTOR (mammalian target of Rapamycin), BAD, GSK3, p21, p27, FOXO or FKHRL1 (BD Manning & Cantley LC, CelI, 2007 129: 1261). Activation of AKT promotes the internalization of nutrients, which triggers anabolic metabolism process supporting cell growth and proliferation. In particular, AKT controls the initiation

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protein synthesis through a cascade of interactions that proceeds via TSC1 / 2 (tuberous sclerosis complex), Rheb, and TOR to result in two critical targets of the signaling pathway, p7OS6K and 4EBP. AKT also induces inhibitory phosphorylation of the Forkhead transcription factor and inactivation of GSK3I3 that lead to inhibition of apoptosis and cell cycle progression (Franke TF, Oncogene, 2008, 27: 6473). AKT is therefore a target for anti-cancer therapy and inhibition of AKT activation by inhibition of its phosphorylation can induce apoptosis of malignant cells and thus, present a treatment for cancer. Receptors with tyrosyne kinase activity such as IGF1 R Abnormally high levels of protein kinase activity have been implicated in many diseases resulting from abnormal cell functions. This can come either directly or indirectly, from a dysfunction in the mechanisms of kinase activity control, linked for example to a mutation, an over-expression or an inappropriate activation of the enzyme, or by an over- or under- -production of cytokines or growth factors, also involved in signal transduction upstream or downstream of kinases. In all these cases, a selective inhibition of the kinase action suggests a beneficial effect. The type 1 receptor for insulin-like growth factor (IGF-IR) is a transmembrane receptor with tyrosine kinase activity that binds primarily to IGFI but also to IGFII and insulin with a higher low affinity. The binding of IGF1 to its receptor results in oligomerization of the receptor, activation of tyrosine kinase, intermolecular autophosphorylation and phosphorylation of cellular substrates (major substrates: IRS1 and Shc). The ligand-activated receptor induces mitogenic activity in normal cells. However, IGF-I-R plays an important role in so-called abnormal growth.

Several clinical reports highlight the important role of the IGF-I pathway in the development of human cancers: IGF-IR is often found to be over-expressed in many tumor types (breast, colon, lung, sarcoma, prostate, multiple myeloma) and its presence is often associated with a more aggressive phenotype. High circulating IGF1 concentrations are strongly correlated with a risk of prostate, lung and breast cancer. In addition, it has been widely documented that IGF-I-R is required for the establishment and maintenance of the transformed phenotype in vitro as in vivo [Baserga R, Exp. Cell. Res., 1999, 253, pages 1-6]. The kinase activity of IGF-I-R is essential for the transformation activity of several oncogenes: EGFR, PDGFR, the large antigen of SV40 virus, activated Ras, Raf, and v-Src. Expression of IGF-I-R in normal fibroblasts induces a neoplastic phenotype, which can then lead to tumor formation in vivo. The expression of IGF-I-R plays an important role in the independent growth of the substrate. IGF-I-R has also been shown to be a protector in apoptosis-induced chemotherapy, radiation, and cytokine-induced apoptosis. In addition, inhibition of endogenous IGF-IR by a dominant negative, triple helix formation or expression of antisense causes suppression of the transforming activity in vitro and decrease of tumor growth in the cells. animal models.

PDK1 3'-Phosphoinositide-dependent protein kinase-1 (PDK1) is one of the essential components of the 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

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phosphorylated 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. Class I PI3Ks are divided into class Ia (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, 13 or 8 and a p85 or p55 regulatory subunit. 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.

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Class I PI3Ks are involved in human cancers: Somatic mutations of the PIK3CA gene that codes for PI3Ka are found in 15-35% of human tumors including two main oncogenic mutations H1047R (in the kinase domain) and E545K / E542K ( in the helical domain) (Y. Samuels et al., Science, 2004, 304: 554, TL Yuan and LC Cantley, Oncogene, 2008, 27: 5497). PI3K inhibitors are expected to be effective for the treatment of many human cancers with genetic alterations resulting in activation of the PI3K / AKT / mTOR pathway (Vogt P. et al., Virology, 2006, 344: 131; Vogt PK, Oncogene, 2008, 27: 5486). Morpholino pyrimidinone derivatives which are kinase inhibitors are known to those skilled in the art. The WO2008 / 148074 application describes products that have mTOR inhibitory activity. These products are pyrido [1,2-a] pyrimidin-4-ones which differ from the products of the present invention because of their wholly aromatic character and their substitutions. The application WO2008 / 064244 describes the application of the PI3K inhibitor products TGX-221 and TGX-155 (3 which are useful in the treatment of cancer and in particular in breast cancer .These products are pyrido [1,2-a] pyrimidin-4-ones previously described in the applications WO2004 / 016607 and WO2001 / 053266 which differ from the products of the present invention because of their wholly aromatic character and their substitutions WO2006 / 109081, WO2006 / 109084 and WO2006 / 126010 describe DNA-PK inhibitory products useful for the treatment of deficient ATM malignancies 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 WO2003 / 024949 describes DNA-PK inhibitor products useful for the treatment of deficient ATM cancers, which are pyrido [1,2-a] pyrimidin-4-ones which differ from the products of the present invention. the current

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Because of their wholly aromatic nature and their substitutions, morphine pyrimidine kinase inhibitor derivatives are also known to those skilled in the art.

The applications WO2009 / 007748, WO2009 / 007749, WO2009 / 007750 and WO2009 / 007751 describe products which possess an inhibitory activity of mTOR and / or PI3K for the treatment of cancers. These products are pyrimidines substituted at 2, 4 and 6 and the products of the present invention are different because of the presence of the carbonyl group on pyrimidinone as well as by the various substituents. The subject of the present invention is the products of formula (I In which: R 1 represents an aryl or heteroaryl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl radicals, CN, nitro, -COOH, -alkyl, -NRxRy, - CONRxRy, -NRxCORy, -CORy, -NRxCO2Rz, alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, cycloalkyl, O-cycloalkyl, heterocycloalkyl; aryl and heteroaryl; these latter alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, heterocycloalkyl, aryl and heteroaryl radicals being themselves optionally substituted by one or more identical or different radicals selected from halogen atoms and hydroxyl, alkoxy and NRvRw radicals; 75 R2 R3 R N x N N • R1

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the aryl and heteroaryl radicals being furthermore optionally substituted with one or more alkyl and alkoxy radicals themselves optionally substituted with one or more halogen atoms; the heterocycloalkyl and heteroaryl radicals may additionally contain an oxo radical, R represents a hydrogen atom or forms with R1 a saturated or partially or completely unsaturated 5- or 6-membered ring fused to an aryl or heteroaryl radical and optionally containing one or a plurality of other heteroatoms chosen from O, S, N, NH and Nalk, this bicyclic radical being optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals; R2, R3, which may be identical or different, independently represent a hydrogen atom, a halogen atom or an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom; R5 represents a hydrogen atom or an alkyl radical optionally substituted with one or more halogen atoms; 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; 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, where 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;

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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, pyranyl; , 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 such as 3 or 4-isoxazolyl, furazannyl, free or salified 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 by radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for example in the chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl and benzyl groups; or phenethyl.

The addition salts with the inorganic or organic acids of the products of formula (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 phenyl, pyridine, thienyl, benzoxazol-4-yl and indazol-6-yl radical, optionally substituted with one or more identical or different radicals chosen from halogen atoms and CN, nitro, -OOOH, -COOalk, -NRxRy, alkoxy, alkyl, alkynyl and cycloalkyl radicals; these latter alkoxy, alkyl and alkynyl radicals, themselves being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy and NRvRw radicals; the phenyl and heteroaryl radicals being additionally optionally substituted by one or more alkyl and alkoxy radicals; R represents a hydrogen atom or forms with R1 a 1,4-benzoxazin-4-yl or 2,3-dihydro- indol-1-yl, these rings being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals; R2, R3, which may be identical or different, independently represent a hydrogen atom, a fluorine atom or an alkyl radical; R4 represents a hydrogen atom; R5 represents a hydrogen atom or an alkyl radical; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom or an alkyl radical; either Rx and Ry form with the nitrogen atom to which they are bound a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this radical cyclic being optionally substituted; NRvRw being such that Rv represents a hydrogen atom or an alkyl radical and Rw represents a hydrogen atom or an alkyl radical; all the above alkyl (alk) and alkoxy radicals being linear or branched and containing from 1 to 6 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). In particular, when NRxRy or NRvRw forms a ring as defined above, such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl, piperazinyl or homopiperazinyl radicals, these radicals 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 by an alkyl, phenyl 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, corresponding to the following formulas: 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin 2-yl] -N-phenylacetamide-N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-yl) -N-phenylacetamide 2-chlorophenyl) [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (dimethylamino) phenyl] -2- [4- ( morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo] 1,6-Dihydropyrimidin-2-yl] acetamide-N- (3,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (thiophen-3-yl) acetamide - N- (4-fluoro-3-methoxyphenyl) 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-fluorophenyl) -2- [4- (morpholin-4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide; ) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-methylphenyl) -2- [4- (morpholin-4) -yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine -2-yl] acetamide - N- (2,3-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-yl) acetamide 5-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-fluorophenyl) -2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6) Dihydropyrimidin-2-yl] acetamide-N- (3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4 - (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (trifluoromethyl) phenyl] acetam ide - N- (3-bromophenyl) -2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (2-methylpropan-2-yl) phenyl] -2- [4- (morpholin-4) -yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-20-yl] methyl acetyl} amino) benzoate - 3 - ({[4- (morphol In-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoic acid - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin) 2-yl] -N- [3- (propan-2-yl) phenyl] acetamido-N- (3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-Dihydropyrimidin-2-yl] acetamide-N- (3-cyano-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide N- (1 H -indazol-6-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-cyanophenyl) 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (5-fluoropyridin-2-yl) -2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (4-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo} 1,6-Dihydropyrimidin-2-yl] acetamide-N- (3-chloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl) ] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (pyridin-3-yl) acetamide - N- (4-fluoro-2) Methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide N- (3-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamido-N- (3-bromo-4-fluorophenyl) - 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6- dihydropyrimidin-2-yl] -N- (3,4,5-trifluorophenyl) acetamide-N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6- oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-cyclopropylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide N- (2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (difluoromethoxy) phenyl] -2 - [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-fluoro-3-methoxyphenyl) -2- [4- (morpholin-4- yl) -6-oxo-1,6-dihydropyrimidin-2-yl] propanamide-N- (2,3-dimethylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6) dihydropyrimidin-2-yl] acetamide-N- (2-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide -N - (1,3-benzoxazol-4-yl) -2- [4- (morpholi N-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] N- [3- (trifluoromethoxy) phenyl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propan-2 -yloxy) phenyl] acetamido-N- (4-fluoro-2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - { 2- [3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) phenyl] ethyl} carbamate of 2-methylpropan-2-yl N- [4-fluoro-3- (trifluoromethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-ethynyl) phenyl ) -2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (cyclopentyloxy) phenyl] -2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (4-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo} 1, 6-Dihydropyrimidin-2-yl] acetamide - 2- [2- (2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin 4 (3H) -one - N- (3-cyclopropyl-4-fluorophenyl) -2- [ 4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 N- (2,3,4-trifluorophenyl) acetamido-N- [4-fluoro-3- (trifluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo] -N 1,6-Dihydropyrimidin-2-yl] acetamide-N- [3- (2-hydroxyethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] acetamide - N- (3-iodophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-2-fluoro-5 - ([[ Methyl 4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoate - N- (3-ethoxyphenyl) -2- [4- (morpholin-4- yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2,4-difluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo} 1, 6-Dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (2,4,5-trifluorophenyl) acetam ide - N- (3,5-dichloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [ 2- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-oxoéth yl] -6- (Morpholin-4-yl) pyrimidin-4 (3H) -one - N- (4-fluoro-3-nitrophenyl) -2- [4- (morpholin-4-yl) -6-oxo} 1,6-Dihydropyrimidin-2-yl] acetamide-2-fluoro-5 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoic acid - N- (5-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-bromo) 4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide

21

N- (4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-yl] acetamide - N- (3-chloro-4) -fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-bromophenyl) -2- [1- methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [1-ethyl-4- (morpholin-4-yl) -6-oxo-1 6-Dihydropyrimidin-2-yl] -N- (4-fluorophenyl) acetamido-N- (1H-indol-4-yl) -2- [4- (morpholin-4-yl) -6-oxo} 1,6-Dihydropyrimidin-2-yl] acetamide-N- (4-fluorophenyl) -3-methyl-2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl ] butanamide - N- [4-fluoro-3- (methoxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- ( 4-fluoro-3-iodophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide -2- [4- (morpholin-4-yl)) 6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] acetamido-N- [3- (difluoromethyl) -4-fluorophenyl] 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acet amide - 2,2-difluoro-N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3, 4-difluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [2- (2,3-dihydrogen) 1 H -indol-1-yl) -2-oxoethyl] -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one - N- (3-bromo-4-fluorophenyl) -2 - [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [ 1-Methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-cyclopropylphenyl) -2- [1-methyl-4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (4-fluoro-3-methoxyphenyl) -2- [1-methyl-4- (morpholin-4-yl) - 6-Oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (1-benzofur-4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine -2-yl] acetamide - 2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N-phenylacetamide - N- (3-cyclopropyl) -2-yl] acetamide 4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihy dropyrimidin-2-yl] acetamide - N- (3-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2 - [2- (4-Fluoro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-2- [2- (4-Chloro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-N- ( 3-ethynyl-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] -acetamide-2- [2- (4-hydroxy) -2- 2,3-Dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-2- [2- (4,6-difluoro) 2,3-dihydro-1H-indol-1-yl) -2-oxoethyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one and addition salts with mineral acids and organic or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is in particular the products of formula (I) as defined above, corresponding to the following formulas: N- (1H-indol-4-yl) -2- [4- (morpholin-4-yl) ) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [4-fluoro-3- (methoxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo} 1,6-dihydropyrimidin-2-yl] acetamide

23

N- (4-fluorophenyl) -3-methyl-2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] butanamide, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

The present invention also relates to any process for preparing the products of formula (I) as defined above. The products according to the invention can be prepared from conventional methods of organic chemistry. Preparation of compounds of formula (I) The products of general formula (I) according to the present invention may in particular be prepared as indicated in General Schemes 1A-1C below. As such, the methods described can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds.

The preparations of the examples of the present invention give illustrations of the schemes below. Such synthetic schemes are part of the present invention: the subject of the present invention is also the processes for the preparation of the products of formula C to (I) -d as defined in General Schemes 1A-1C below. General Scheme 1A: Saponification + Y Ç) Y = Na, Li, K In General Scheme 1A: Ketene amine B can be obtained from imino-ether A or its commercial amino-acrylate tautomer, by reaction with morpholine in a solvent such as ethanol, at a temperature between 0 ° C. and the boiling point of the solvent, according to the method described by Landwehr J. et al. in J. Med. Chem. 2006, 49, 4327-4332. The ester C may be obtained by reaction of the ketene amine B with the imino ether A, or its tautomer amino-acrylate, in a solvent such as ethanol, at a temperature between 20 ° C and the point d boiling of the solvent. Alternatively, the ester C may be obtained by "one-pot" reaction between the morpholine and an excess (for example 3 equivalents) of imino-ether A (or its amino-acrylate tautomer), in a solvent such as ethanol at a temperature between 20 ° C and the boiling point of the solvent.

The carboxylate D may be obtained by hydrolysis of the ester C in the presence of a base such as sodium hydroxide or lithium hydroxide, in a solvent such as tetrahydrofuran or methanol, at a temperature of between 0 ° C. and 30 ° C. The amides (I) -a can be obtained from the carboxylate D by condensation of an amine R1-NH2 in the presence of a peptide coupling agent such as, for example, EDCI (ethyl dimethylaminopropyl carbodiimide), DMT -MM [4- (4,6-dimethoxy-1,2,3-triazin-2-yl) -4-methylmorpholinium chloride], BOP [benzotriazol-1-yloxy-tris-dimethylamino phosphonium hexafluorophosphate], PyBOP [ benzotriazol-1-yloxy-tris-pyrrolidino phosphonium hexafluorophosphate], PyBROP [bromo tris-pyrrolidino phosphonium hexafluorophosphate], HATU [O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate )] or a mixture HOBT / EDCI [hydroxybenzotriazole / ethyl dimethylaminopropyl carbodiimide], in a solvent such as N, N-di methylformamide, pyridine, ethanol, water or methanol, at a temperature between 20 ° C and 50 ° C, as for example under the conditions described by Kunishima M. et al. in Tetrahedron 2001, 57, 1551-1558.

The amides (I) -a can also be obtained from ester C by reaction of an amine R1-NH2 in the presence of an agent such as trimethyl aluminum or potassium tert-butoxide, in a solvent such as toluene, tetrahydrofuran or N, N-dimethylformamide, at a temperature between 20 ° C and 150 ° C, as for example under the conditions described by Perreux L. et al. In Tetrahedron 2003 (59) 2185-21989 and by Auzeloux, Pet coll. in J. Med. Chem. 2000, 43 (2), 190-197. General Scheme 1B: R5 N Saponification N CD 0 FY = Na, Li, K R5 In General Scheme 1B: Esters E can be obtained from ester C by reaction with a compound R5-X (X = Cl, Br, I or triflate), in the presence of a base such as sodium hydroxide, potassium tert-butoxide or cesium carbonate, in a solvent such as methanol, ethanol or dioxane, at a temperature of between 0 ° C. C and 50 ° C, according to for example the process described by Noël D. D'Angelo et al. in J. Med. Chem. 2008, 51, 5766-5779. The carboxylates F may be obtained by hydrolysis of the esters E, in the presence of a base such as sodium hydroxide or lithium hydroxide, in a solvent such as tetrahydrofuran or methanol, at a temperature of between 0 ° C. and 30 ° C. amides (I) -b can be obtained from carboxylates F by condensation of an amine R1-NH2 in the presence of a peptide coupling agent such as, for example, EDCI (ethyl dimethylaminopropyl carbodiimide), DMT- MM [4- (4,6-dimethoxy-1,2,3-triazin-2-yl) -4-methylmorpholinium chloride], BOP [benzotriazol-1-yloxy-tris-dimethylamino phosphonium hexafluorophosphate], PyBOP [hexafluorophosphate] of benzotriazol-1-yloxytris-pyrrolidino phosphonium], PyBROP [bromo tris pyrrolidino phosphonium hexafluorophosphate], HATU [O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) ] or a mixture HOBT / EDCI [hydroxybenzotriazole / ethyl dimethylaminopropyl carbodiimide], in a solvent such as N, N-dimethylformamide, pyridine, ethanol, water or methanol, at a temperature between 20 ° C and 50 ° C, as for example under the conditions described by Kunishima M. et al. in Tetrahedron 2001, 57, 1551-1558. Amides (I) -b can also be obtained from esters E by reaction of an amine R1-NH2, in the presence of an agent such as trimethyl aluminum, in a solvent such as toluene, at a temperature between 20 ° C and the boiling point of the solvent, as for example under the conditions described by Auzeloux, P et al. in J. Med. Chem. 2000, 43 (2), 190-197. General Scheme 1C: CN D O C R2X then R3X; X = Cl, Br, I or OTf (Boc) 2 R1 R1 RSX X = Cl, Br, I, OTf CN DOJ CN OD (I) -c R2X then R3X X = Cl, Br, I, OTf or (PhSO2 In General Scheme 1C: ester G can be obtained from ester C by reaction with (Boc) 20 (tertiary butyl dicarbonate), in a solvent such as N, N dimethylformamide, dioxane, acetonitrile or dichloromethane, in the presence of a base such as, for example, sodium hydride, triethylamine, N, N-diisopropylethylamine or pyridine, at a temperature of between 0 ° C. and 60 ° C, according to for example the method described by Hioki K. et al. Synthesis 2006, 12, 1931-1933 The products H can be obtained from ester G by reaction with R2-X and optionally with R3-X (X = Cl, Br, I or OTf and R2 and R3 are alkyl groups) in the presence of a base such as sodium hydroxide, potassium tert-butoxide or cesium carbonate, in a solvent such as methanol, ethanol or dioxane, at a temperature between 0 ° C and 100 ° C, according to for example the process described by Noël D. D'Angelo et al. in J. Med. Chem. 2008, 51, 5766-5779. The product H where R 2 = R 3 = F can be obtained by reaction of the product G with N-fluorobenzenesulfonimide, in the presence of a base such as the potassium salt of hexamethyl-disilylazane, in a solvent such as tetrahydrofuran, at a temperature between -78 ° C and 20 ° C, according to for example the method described by Christopher S. Burgey et al. In J. Med. Chem. 2003, 46, 461-473.

The esters J where the groups R 2 and R 3 are alkyl radicals can be obtained from the ester C in the same way as the products H, in the presence of a base such as butyllithium, sodium hydride, potassium tertiobutylate or cesium carbonate in a solvent such as methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide or dioxane at a temperature between 0 ° C and 50 ° C. The amides (I) -c can be obtained from esters H or J by reaction of an amine R1-NH2, in the presence of an agent such as trimethyl aluminum, in a solvent such as toluene, at a temperature of between 20 ° C and the boiling point of the solvent, as for example under the conditions described by Auzeloux, P et al. in J. Med. Chem. 2000, 43 (2), 190-197. The amides (I) -d can be obtained from the amides (I) -c by reaction with a compound R5-X (X = Cl, Br, I or triflate), in the presence of a base such as sodium hydroxide, potassium tertiobutylate or cesium carbonate, in a solvent such as methanol, ethanol or dioxane, at a temperature of between 0 ° C. and 50 ° C., according to, for example, the process described by Noel D. D ' Angelo et al. in J. Med. Chem. 2008, 51, 5766-5779. Alternatively, the amides (I) -d can be obtained from the esters K by reaction of an amine R1-NH2, in the presence of an agent such as trimethylaluminium, in a solvent such as toluene, at a temperature between 20 ° C and the boiling point of the solvent, as for example under the conditions described by Auzeloux, P et al. in J. Med. Chem. 2000, 43 (2), 190-197. The esters K can be obtained from esters J by reaction with a compound R5-X (X = Cl, Br, I or triflate), in the presence of a base such as sodium hydroxide, potassium tert-butoxide or sodium carbonate. cesium, in a solvent such as methanol, ethanol or dioxane, at a temperature of between 0 ° C. and 50 ° C., according to, for example, the process described by Noël D. D'Angelo et al. in J. Med. Chem. 2008, 51, 5766-5779.

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 protective groups used 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 transformation reactions known to those skilled in the art such as for example: a) an esterification reaction of an acid function, b) an ester functional saponification reaction in the acid function, c) a reduction reaction of the free or esterified carboxy function as an alcohol function, d) a transformation reaction with hydroxyl function, or with hydroxyl function with alkoxy function, e) an elimination reaction of the protective groups which the protected reactive functions can carry, 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 racemic isomeric possible form , 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) The optional optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art. The products of formula (I) as defined above, as well as their addition salts with acids, have interesting pharmacological properties, in particular because of their kinase inhibiting properties as indicated above.

The products of the present invention are especially useful for tumor therapy. The products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents. These properties justify their application in therapeutics and the subject of the invention is particularly useful as medicaments, the products of formula (I) as defined above, said products of formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). The subject of the invention is particularly suitable, as medicaments, the products corresponding to the following formulas: 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] N-phenylacetamide - N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-chlorophenyl) -2 - [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (dimethylamino) phenyl] -2- [4- (morpholin-4-yl) ) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine) -2-yl] acetamide - N- (3,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4 - (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (thiophen-3-yl) acetamide - N- (4-fluoro-3-methoxyphenyl) -2- [ 4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo 1, 6-Dihydropyrimidin-2-yl] acetamide - N- (2-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrim] idin-2-yl] acetamide - N- (2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2, 3-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3,5-difluorophenyl) -2- [4- ( morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-Dihydropyrimidin-2-yl] acetamide-N- (4-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- ( 3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo 1, 6-Dihydropyrimidin-2-yl] -N- [3- (trifluoromethyl) phenyl] acetamide-N- (3-bromophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1 6-Dihydropyrimidin-2-yl] acetamide - N- [3- (2-methylpropan-2-yl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine Methyl 2-yl] acetamide - 3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoate - acid 3 - ({[ 4- (morpholin-4-yl) -6-oxo-1,6-dihydropyri midin-2-yl] acetyl} amino) benzoic acid - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propan-2- yl) phenyl] acetamide - N- (3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-cyano) 4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (1H-indazol-6-yl) -2- [ 4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-cyanophenyl) -2- [4- (morpholin-4-yl) -6-oxo 1, 6-Dihydropyrimidin-2-yl] acetamide-N- (5-fluoropyridin-2-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] acetamide - N- (4-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3- chloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6) -oxo-1,6-dihydropyrimidin-2-yl] -N- (pyridin-3-yl) acetamide-N- (4-fluoro-2-methylphenyl) -2- [4- (morpholin-4-yl)} 6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-hydroxyphenyl) -2- [4- (morphol) In-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-bromo-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6- oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (3,4,5-dihydropyrimidin-2-yl) acetamide; -trifluorophenyl) acetamido-N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-cyclopropylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-hydroxyphenyl) -2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (difluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6- oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (4-fluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 -yl] propanamide - N- (2,3-dimethylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-fluoro) 3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (1,3-benzoxazol-4-yl) -2 - [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidi n-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (trifluoromethoxy) phenyl] acetam ide - 2 - [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propan-2-yloxy) phenyl] acetam ide - N- (4-fluoro) 2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - {2- [3 - ({[4- (morpholin-4 2-methylpropan-2-yl-N- [4-fluoro-3- (trifluoromethyl) phenyl] -yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) phenyl] ethyl] carbamate] 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-ethynylphenyl) -2- [4- (morpholin-4-yl)) 6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (cyclopentyloxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine -2-yl] acetamide - N- (4-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide -2- [2- (2,3-Dihydro-1 H -indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - N- (3-cyclopropyl) 4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-diol ydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (2,3,4-trifluorophenyl) acetam ide - N- [4-fluoro-3- (trifluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- ( 2-hydroxyethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-iodophenyl) -2- [4- morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetam ide-2-fluoro-5 - ({[4- (morpholin-4-yl) -6-oxo-1,6) Methyl (N-dihydropyrimidin-2-yl) acetyl) amino) benzoate N- (3-ethoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetam ide - N- (2,4-difluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4 - (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (2,4,5-trifluorophenyl) acetam ide - N- (3,5-dichloro-4-fluorophenyl) 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [2- (2,3-dihydro-4H-1,4-benzoxazin) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide; 4-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidi n-4 (3H) -one - N- (4-fluoro-3-nitrophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 2-Fluoro-5 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoic acid - N- (5-fluoro-2-) hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-bromo-4-fluorophenyl) -2- [4- ( morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6- oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-chloro-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6) Dihydropyrimidin-2-yl] acetamide-N- (3-bromophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 2- [1-ethyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (4-fluorophenyl) acetam ide-N- (1H-indol); 4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-fluorophenyl) -3-methyl-2- [4-yl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] butanamide - N- [4-fluoro 3- (Methoxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-fluoro-3-iodophenyl) - 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide -2- [4- (morpholin-4-yl) -6-oxo-1,6- dihydropyrimidin-2-yl] -N- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] acetamido-N- [3- (difluoromethyl) -4-fluorophenyl] -2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-2,2-difluoro-N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6- oxo-1, 6-dihydropyrimidin-2-yl] acetamide - N- (3,4-difluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine -2-yl] acetamide - 2- [2- (2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one - N- (3-bromo-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N - (3-Cyclopropylphenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6) Dihydropyrimidin-2-yl] acetamide-N- (4-fluoro-3-methoxyphenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] acetamide - N- (1-benzofur-4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [1- methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N-phenylacetamide - N- (3-cyclopropyl-4-fluorophenyl) -2- [1-methyl] 4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl)) 6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [2- (4-fluoro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (Morpholin-4-yl) pyrimidin-4 (3H) -one - 2- [2- (4-chloro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- ( morpholin-4-yl) pyrimidin-4 (3H) -one - N- (3-ethynyl-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin) 2-yl] acetamide - 2- [2- (4-hydroxy-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 ( 3H) -one - 2- [2- (4,6-difluoro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) py rimidin-4 (3H) -one 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).

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, where appropriate, contain active ingredients of other

41

antimitotic drugs such as in particular those based on taxol, cisplatin, intercalators 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.

42

Among these cancers, one is interested in the treatment of solid or liquid tumors, 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 F as defined above and recalled below: R 5 N. ONY = Na, Li, KO R 5 C, ED, F in which R5 has the definition given in any one 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; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: ACQUITY BEH C18 1.7 μm - 2.1 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 50 ° C; Flow rate: 1 ml / min; Gradient (2 min): 5 to 50% B in 0.8 min; 1.2 min: 100% B; 1.85 min: 100% B; 1.95: 5% B; Retention time = Tr (min).

Method B: WATERS ZQ Apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: XBridge C18 2.5 μm - 3 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 70 ° C; Flow rate: 0.9 ml / min; Gradient (7 min): de5 to 100% deBen5,3min, 5.5min: 100% deB, 6.3min: 5% of B; Retention time = Tr (min). Example 1 Synthesis of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] -N-phenylacetamide Step 1: HA 25 g solution of morpholine in 400 ml of ethanol heated to 95 ° C. is added 168.5 ml of ethyl 3-ethoxy-3-iminopropanoate hydrochloride, then 155 ml of N, N-diisopropylethylamine in 200 ml of ethanol. The reaction mixture is heated at 95 ° C for 30 hours and then allowed to warm to room temperature. The precipitate formed is filtered on sintered glass and then washed with 100 ml of ethanol, 2 times 500 ml of water and finally 500 ml of ethyl ether. The solid is dried under vacuum to give 35 g of ethyl [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate in the form of a white solid whose characteristics are the following: following: 1H NMR Spectrum (400MHz, ppm, DMSO-d6): 1.19 (t, J = 7.1Hz, 3H); 3.38 at 3.44 (m, 4H); 3.56 (s, 2H); 3.61 (dd, J = 4.0 and 5.7 Hz, 4H); 4.12 (q, J = 7.1 Hz, 2H); 5.20 (s, 1H); 11.69 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.48; [M + H] +: m / z 268; [MH] -: m / z 266 Step 2: H + OvN ~, O Na 1 NON ~ OA a solution of 10 g of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine) 2-yl] ethyl acetate in 300 mL of tetrahydrofuran is added 18.7 mL of 2M sodium hydroxide. The reaction mixture is stirred for 48 hours at room temperature. The precipitate formed is filtered on sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried on a rotary evaporator to give 8.7 g of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2). in the form of a white solid whose characteristics are as follows: 1H NMR Spectrum: 3.08 (s, 2H); 3.38 (t, J = 4.6 Hz, 4H); 3.61 (t, J = 4.6 Hz, 4H); 5.08 (s, 1H); 13.16 (bs, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.29; [M + H] +: m / z 240; [MH] -: m / z 238 Step 2 ': H + OvN ~, O Li A solution of 2 g of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] ethyl acetate in 75 ml of methanol is added 7.5 ml of water and 197 mg of lithium hydroxide. After stirring for 48 hours at room temperature, the reaction mixture is concentrated under reduced pressure. 50 ml of water are added. The aqueous phase is then washed with ethyl acetate and then lyophilized. 1.73 g of lithium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate are obtained in the form of a white solid, the characteristics of which are similar to the product of the stage. 2.

Step 3: To a solution of 200 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (Example 1 Step 2) in 3 mL of N, N-dimethylformamide is added 370 mg of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 113 mg of 1-hydroxybenzotriazole and 0.140 ml of aniline. The reaction mixture is stirred at ambient temperature for 3 hours and then concentrated under reduced pressure. Water and ethyl acetate are added and the mixture is stirred for 30 minutes. The precipitate formed is filtered and dried on a rotary evaporator. After purification by chromatography on a silica column, eluent: 90/10 dichloromethane / methanol, 161 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] are obtained. N-phenylacetamide in the form of a white solid, the characteristics of which are as follows: 1H NMR spectrum: 3.38 to 3.44 (m, 4H); 3.56 to 3.63 (m, 6H); 5.20 (s, 1H); 7.06 (t, J = 7.8 Hz, 1H); 7.31 (t, J = 8.6 Hz, 2H); 7.56 (d, J = 8.6 Hz, 2H); 10.14 (s, 1H); 11.64 (s wide, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.55; [M + H] +: m / z 315; [MH] -: m / z 313 Example 2: Synthesis of N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] The product is prepared by following the procedure described in step 3 of Example 1 from 300 mg of [4- (morpholin-4-yl) -6-oxoacetamide). Sodium 1,6-dihydropyrimidin-2-yl] acetate, 595 mg of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, 182 mg of 1-hydroxybenzotriazole and 0.235 mL of 4-fluoroaniline instead of aniline. 110 mg of N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of an off-white solid whose characteristics are as follows: 1H NMR Spectrum: 3.41 (t, J = 4.9 Hz, 4H); 3.55 to 3.64 (m, 6H); 5.20 (s, 1H); 7.15 (t, J = 8.9 Hz, 2H); 7.58 (dd, J = 5.6 and 9.0 Hz, 2H); 10.20 (s, 1H); 11.65 (slarge, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 2.86; [M + H] +: m / z 333; [MH] -: m / z 331 Example 3: Synthesis of N- (3-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] The product is prepared by following the procedure described in step 3 of the example starting from 300 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin). 2-yl] lithium acetate obtained in Step 2 'of Example 1 and 0.235 ml of 3-chlororoaniline instead of aniline. After purification by chromatography on a column of silica, eluent: 90/5/5 dichloromethane / methanol / acetonitrile, 71 mg of N- (3-chlorophenyl) -2- [4- (morpholin-4-yl) -6 are obtained. -oxo-1,6-dihydropyrimidin-2-yl] acetamide having the following characteristics: 1H NMR spectrum: 3.42 (d, J = 5.1 Hz, 4H); 3.53 to 3.69 (m, 6H); 5.20 (s, 1H); 7.12 (d, J = 9.0 Hz, 1H); 7.34 (t, J = 8.1 Hz, 1H); 7.42 (dt, J = 1.3 and 7.8 Hz, 1H), 7.77 (t, J = 2.1 Hz, 1H); 10.34 (brs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 0.68; [M + H] +: m / z 349; Example 4: Synthesis of N- [3- (dimethylamino) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-one, m.p. yl] acetamide OvN-NNO / N 2 O To a solution of 250 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) in 4 ml of N, N-dimethylformamide are added 0.160 ml of pyridine, 240 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 400 mg of N, N-dimethyl-m phenylenediamine. It is stirred at room temperature for 1 night and then the reaction mixture is concentrated under reduced pressure. Water and ethyl acetate are added and the mixture is stirred for 30 minutes. The precipitate formed is filtered, rinsed with ethyl ether and dried on a rotary evaporator. After purification by chromatography on a column of silica in a solid deposit, eluent: 95/5 dichloromethane / methanol, a solid is obtained which is taken up in a mixture of dichloromethane, methanol and ethyl ether. The solid is filtered and dried. N- [3- (dimethylamino) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide (30 mg) is obtained in the form of a yellow solid, the characteristics are as follows: 1H NMR Spectrum: 2.86 (s, 6H); 3.41 (t, J = 5.0 Hz, 4H); 3.57 (s, 2H); 3.60 (t, J = 4.9 Hz, 4H); 5.19 (s, 1H); 6.44 (d, J = 9.3 Hz, 1H); 6.86 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H); 7.09 (t, J = 8.3 Hz, 1H); 9.98 (brs, 1H); 11.61 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 0.40; [M + H] +: m / z 358; Example 5: Synthesis of N- (2,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-one. yl] acetamide FN 0 To a solution of 260 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) in 2 ml of N, N-dimethylformamide are added 2.5 mL of pyridine, 233 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 400 mg of 2,4-difluoroaniline. The reaction mixture is stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. Water and ethyl acetate are added and the mixture is stirred for 30 minutes. The precipitate formed is filtered, rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 205 mg of N- (2,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a pink solid whose characteristics are as follows: 1H NMR Spectrum: 3.43 (t, J = 5.0 Hz, 4H); 3.61 (t, J = 5.0 Hz, 4H); 3.66 (s, 2H); 5.20 (s, 1H); 7.01 to 7.13 (m, 1H); 7.25 to 7.40 (m, 1H); 7.83 (q, J = 7.1Hz, 1H); 9.97 (brs, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 0.59; [M + H] +: m / z 351; [MH] -: m / z 349 Example 6: Synthesis of N- (3,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl The product is prepared by following the procedure described in Example 5 from 260 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. sodium (example 1 step 2) and 400 mg of 3,4-difluoroaniline instead of 2,4-difluoroaniline. 210 mg of N- (3,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the Characteristics are as follows: 1H NMR Spectrum (400MHz, ppm, DMSO-d6): 3.41 (t, J = 4.9Hz, 4H); 3.54 to 3.64 (m, 6H); 5.20 (s, 1H); 7.27 (d, J = 8.8 Hz, 1H); 7.39 (dt, J = 9.0 and 10.6 Hz, 1H); 7.64-7.79 (m, 1H), 10.38 (s, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.64; [M + H] +: m / z 351; Example 7 Synthesis of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] -N- (thiophen-3) [MH] -: m / z 349 yl) acetamide OvN / N ', - / - S

The product is prepared following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 400 mg of 3-aminothiophene hydrochloride instead of 2,4-difluoroaniline. 252 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (thiophen-3-yl) acetamide are obtained in the form of a beige solid whose characteristics are as follows: 1H NMR Spectrum: 3.41 (t, J = 5.0 Hz, 4H); 3.51 to 3.64 (m, 6H); 5.20 (s, 1H); 7.08 (d, J = 5.6 Hz, 1H); 7.35 to 7.56 (m, 2H); 10.55 (bs, 1H); 11.64 (bs, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.52; [M + H] +: m / z 321; [MH] -: m / z 319 Example 8: Synthesis of N- (4-fluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2 The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 520 mg of 4-fluoro-3-methoxyaniline instead of 2,4-difluoroaniline. 262 mg of N- (4-fluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid. whose characteristics are as follows: 1H NMR Spectrum (400MHz, ppm, DMSO-d6): 3.41 (t, J = 4.9 Hz, 4H); 3.56 to 3.62 (m, 6H); 3.79 (s, 3H); 5.20 (s, 1H); 7.02 to 7.09 (m, 1H); 7.10 to 7.17 (m, 1H); 7.47 (dd, J = 2.4 and 8.1 Hz, 1H); 10.20 (s, 1H); 11.64 (bs, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.60; [M + H] +: m / z 363; [MH] -: m / z 361 Example 9: Synthesis of N- (2-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] Acetamide No. 15 300 mg of ethyl [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate in 1 ml of N are introduced into a microwavable tube. N-dimethylformamide, 623 mg of 2-fluoroaniline and 378 mg of potassium tert-butoxide. 2 ml of N, N-dimethylformamide are then added. The tube is then heated under microwaves at 150 ° C for 20 minutes. The reaction mixture is concentrated under reduced pressure. 30 ml of water and 10 ml of ethyl acetate are added and the mixture is stirred for 1 hour 30 minutes. The precipitate formed is filtered and rinsed with ethyl acetate, ethyl ether and then petroleum ether. The solid obtained is dried on a rotary evaporator to give 93 mg of N- (2-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine. 2-yl] acetamide in the form of a white solid, the characteristics of which are as follows: 1H NMR spectrum: 3.42 (t, J = 4.9 Hz, 4H); 3.61 (t, J = 4.6 Hz, 4H); 3.67 (s, 2H); 5.19 (s, 1H); 7.12 to 7.20 (m, 2H); 7.21 to 7.32 (m, 1H); 7.81 to 7.98 (m, J = 8.3 and 8.3 Hz, 1H), 10.00 (bs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.56; [M + H] +: m / z 333; [MH] -: m / z 331 Purity: 94% Melting point (Kofler): 279 ° C Example 10: Synthesis of N- (2-methylphenyl) -2- [4- (morpholin-4-yl) -6 The product is prepared by following the procedure described in Example 9 starting with 300 mg of [4- (morpholin-4-yl) -6-hydroxy-2-yl] -acetamide. oxo-1,6-dihydropyrimidin-2-yl] ethyl acetate and 582 mg of 2-methylaniline instead of 2-fluoroaniline. 76 mg of N- (2-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics are the following: 1H NMR Spectrum: 2.21 (s, 3H); 3.43 (t, J = 5.0 Hz, 4H); 3.55 to 3.67 (m, 6H); 5.18 (s, 1H); 7.08 (t, J = 7.8 Hz, 1H); 7.16 (t, J = 7.8 Hz, 1H); 7.21 (d, J = 7.8 Hz, 1H); 7.42 (d, J = 7.8 Hz, 1H); 9.65 (brs, 1H); 11.70 (s, 1 H) H H OvN ~~ / N Mass Spectrometry: Method B Retention Time Tr (min) = 2.81; [M + H] +: m / z 329; [MH] -: m / z 327 Melting point (Kofler): 194 ° C Example 11: Synthesis of N- (2-methoxyphenyl) -2- [4- (morpholin-4-5 yl) -6-oxo The product is prepared following the procedure described in Example 9 starting from 300 mg of [4- (morpholin-4-yl) -6-oxo). Ethyl 1,6-dihydropyrimidin-2-yl] acetate in 2 mL of N, N-dimethylformamide, 637 mg of 2-methoxyaniline instead of 2-fluoroaniline and 300 mg of potassium tert-butoxide. 3 ml of N, N-dimethylformamide are added and the tube is heated under microwaves at 150 ° C. for 20 minutes. The reaction mixture is concentrated under reduced pressure. 15 ml of water and 5 ml of ethyl acetate are added and the mixture is stirred for 2 hours. The aqueous phase is extracted with 5 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. After purification of the solid obtained on a preparative plate (thickness: 2 mm), eluting with a mixture of dichloromethane and methanol (90/10 by volume), 7 mg of N- (2-methoxyphenyl) -2 are thus obtained. [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a pink solid whose characteristics are as follows: 1H NMR Spectrum: 3.43 (t, J = 4.9 Hz, 4H); 3.59 to 3.65 (m, 4H); 3.69 (s, 2H); 3.83 (s, 3H); 5.20 (s, 1H); 6.90 (ddd, J = 2.2 and 6.5 and 8.25 Hz, 1H); 6.99 to 7.13 (m, 2H); 7.97 (d, J = 8.6 Hz, 1H); 9.44 (brs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.59; [M + H] +: m / z 345; Example 12: Synthesis of N- (2,3-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-yl) [MH] -: m / z 343 The product is prepared by following the procedure described in Example 9 from 300 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] ethyl acetate and 840 mg of 2,3-difluoroaniline instead of 2-fluoroaniline. 83 mg of N- (2,3-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose Characteristics are as follows: 1 H NMR Spectrum: 3.42 (t, J = 5.1 Hz, 4H); 3.61 (t, J = 5.1 Hz, 4H); 3.69 (s, 2H); 5.20 (s, 1H); 7.18 (t, J = 7.0 Hz, 2H); 7.69 (bs, 1H); 10.24 (bs, 1H) 11.63 (bs, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.61; [M + H] +: m / z 351; [MH] -: m / z 349 Melting point (Kofler): 248 ° C. EXAMPLE 13 Synthesis of N- (3,5-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo -1,6-Dihydropyrimidin-2-yl] acetamide The product is prepared following the procedure described in Example 9 starting from 300 mg of [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-yl] ethyl acetate and 780 mg of 3,5-difluoroaniline instead of 2-fluoroaniline. 133 mg of N- (3,5-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the characteristics are as follows: 1H NMR Spectrum: 3.41 (t, J = 4.9 Hz, 4H); 3.56 to 3.65 (m, 6H); 5.20 (s, 1H); 6.92 (t, J = 9.3 Hz, 1H); 7.28 (dd, J = 2.2 and 9.5 Hz, 2H); 10.55 (bs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.66; [M + H] +: m / z 351; [MH] -: m / z 349 Melting point (Kofler)> 260 ° C Example 14: Synthesis of N- (3-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1 The product is prepared following the procedure described in Example 9 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dichloroacetamide). ethyl dihydropyrimidin-2-yl] acetate and 0.90 mL of 3-fluoroaniline instead of 2-fluoroaniline. 160 mg of N- (3-fluorophenyl) -2- [4- H H 0 N are obtained

57

(morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a white solid having the following characteristics: 1 H NMR Spectrum (400MHz, ppm, DMSO-d6): 3 , 42 (d, J = 5.0 Hz, 4H); 3.57 to 3.62 (m, 6H); 5.20 (s, 1H); 6.89 (t, J = 9.0 Hz, 1H); 7.27 (d, J = 7.5 Hz, 1H); 7.31 to 7.40 (m, 1H); 7.55 (d, J = 12.1 Hz, 1H); 10.38 (brs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 2.93; [M + H] +: m / z 333; Example 15: Synthesis of N- (4-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide [MH] -: m / z The product is prepared following the procedure described in Example 9 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. ethyl and 1.193 g of 4-chloroaniline instead of 2-fluoroaniline. 140 mg of N- (4-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the characteristics of which are the following: 1 H NMR spectrum: 3.37 to 3.46 (m, J = 4.9 Hz, 4H); 3.51 to 3.66 (m, 6H); 5.21 (s, 1H); 7.38 (d, J = 8.8 Hz, 2H); 7.60 (d, J = 8.8 Hz, 2H); 10.34 (brs, 1H); 11.71 (s wide, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.68; [M + H] +: m / z 349; Example 16: Synthesis of N- (3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] [MH] -: m / z 347 Acetamide N The product is prepared following the procedure described in Example 9 from 300 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. ethyl and 1,254 mL of 3-methoxyaniline instead of 2-fluoroaniline. 56 mg of N- (3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics are the following: 1H NMR Spectrum: 3.41 (t, J = 5.0 Hz, 4H); 3.55 to 3.63 (m, 6H); 3.72 (s, 3H); 5.20 (s, 1H); 6.64 (dd, J = 2.4 and 8.1 Hz, 1H); 7.08 (ddd, J = 0.9 and 1.0 and 8.1 Hz, 1H); 7.21 (t, J = 8.3 Hz, 1H); 7.27 (s, 1H); 10.14 (bs, 1H); 11.63 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.58; [M + H] +: m / z 345; Example 17: Synthesis of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (trifluoromethyl)] [MH] -: m / z 343 The product is prepared by following the procedure described in Example 9 starting from 300 mg of [4- (morpholin-4-yl)). Ethyl 6-oxo-1,6-dihydropyrimidin-2-yl] acetate and 0.705 mL of 3- (trifluoromethyl) aniline instead of 2-fluoroaniline. 228 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (trifluoromethyl) phenyl] acetamide are obtained in the form of a white solid, the characteristics are as follows: 1H NMR Spectrum: 3.37 to 3.46 (m, 4H); 3.54 to 3.66 (m, 6H); 5.21 (slarge, 1H); 7.42 (d, J = 8.1 Hz, 1H); 7.57 (t, J = 8.1Hz, 1H); 7.75 (d, J = 8.3 Hz, 1H); 8.05 (brs, 1H); 10.50 (bs, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 3.39; [M + H] +: m / z 383; Example 18: Synthesis of N- (3-bromophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] [MH] -: m / z 381 The product is prepared by following the procedure described in Example 9 from 300 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). 2-yl] ethyl acetate in and 0.61 mL of 3-bromoaniline instead of 2-fluoroaniline. 105 mg of N- (3-bromophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics as follows: 1H NMR Spectrum (400MHz, ppm, DMSO-d6): 3.37-3.46 (m, 4H); 3.54 to 3.66 (m, 6H); 5.20 (slarge, 1H); 7.15 to 7.34 (m, 2H); 7.47 (d, J = 8.1 Hz, 1H); 7.91 (brs, 1H); 10.33 (bs, 1H); 11.66 (slarge, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.70; [M + H] +: m / z 395; Example 19: Synthesis of N- [3- (2-methylpropan-2-yl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1, m.p. 6-Dihydropyrimidin-2-yl] acetamide To a solution of 261 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (Example 1 Step 2) in 10 ml of methanol are added 224 mg of 3- (tert-butyl) aniline. The reaction mixture is stirred at room temperature for 5 minutes then 442 mg of 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholin-4-hydrate chloride is added. This is stirred for 30 minutes at room temperature. The reaction mixture is concentrated under reduced pressure. The evaporation residue is taken up in 10 ml of water and 10 ml of ethyl acetate. It is then stirred for 15 minutes. The precipitate formed is filtered. There is thus obtained 235 mg of N- [3- (2-methylpropan-2-yl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide in the form of a white solid, the characteristics of which are as follows: 1H NMR spectrum: 1.26 (s, 9H); 3.42 (t, J = 4.8 Hz, 4H); 3.53 to 3.64 (m, 6H); 5.20 (s, 1H); 7.10 (d, J = 8.1 Hz, 1H); 7.23 (t, J = 8.1Hz, 1H); 7.41 (d, J = 8.1Hz, 1H); 7.58 (brs, 1H); 10.09 (bs, 1H); 11.65 (s wide, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.83; [M + H] +: m / z 371; Example 20: Synthesis of methyl 3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoate [MH] -: m / z 3695 H ON Il I \\ / NO

NIN The product is prepared following the procedure described in Example 19 starting from 653 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. (Example 1 step 2) and 567 mg of methyl 3-aminobenzoate instead of 3- (tert-butyl) aniline. 400 mg of methyl 3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoate are obtained in the form of a white solid whose characteristics are the following: 1H NMR spectrum: 3.41 (dd, J = 4.8 and 5.3 Hz, 4H); 3.53 to 3.68 (m, 6H), 3.85 (bs, 3H); 5.21 (brs, 1H); 7.47 (t, J = 8.1 Hz, 1H); 7.66 (d, J = 8.1 Hz, 1H); 7.80 (d, J = 8.3 Hz, 1H); 8.24 (s, 1H); 10.00 to 10.64 (m, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.59; [M + H] +: m / z 373; [MH] -: m / z 371 Purity: 95% Example 21: Synthesis of 3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoic acid HO ~ / N OH C`) To a solution of 335 mg of 3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino ) Methyl benzoate in 25 mL of methanol, 1.8 mL of 2M sodium hydroxide solution is added. The reaction mixture is heated at 60 ° C for 2 h 30, then it is concentrated under reduced pressure. The evaporation residue is taken up in 50 ml of water. The aqueous phase is extracted with ethyl acetate and then acidified (pH = 6) by addition of a 1N hydrochloric acid solution. The precipitate formed is filtered and then washed with 20 ml of water, 5 ml of ethyl acetate and finally 20 mL of ethyl ether. The solid is dried under vacuum and 175 mg of 3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoic acid are thus obtained. white solid form whose characteristics are as follows: 1 H NMR Spectrum (400 MHz, d in ppm, DMSO-d6): 3.42 (t, J = 4.9 Hz, 4 H); 3.52 to 3.72 (m, 6H); 5.21 (s, 1H); 7.43 (t, J = 7.9 Hz, 1H); 7.64 (d, J = 7.8 Hz, 1H); 7.79 (ddd, J = 1.5 and 1.6 and 8.2 Hz, 1H); 8.19 (s, 1H), 10.36 (s, 1H); 11.77 (brs, 1H); 12.94 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.46; [M + H] +: m / z 359; [MH] -: m / z 357 Example 22: Synthesis of 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] -N- [3- (propan) -2-yl) phenyl] acetamide The product is prepared by following the procedure described in Example 19 starting from 653 mg of [4- (morpholin-4-yl) -6-oxo Sodium 1,6,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) using a mixture of 10 ml of water and 2 ml of tetrahydrofuran instead of methanol and 270 mg of isopropylaniline instead of 3- (tertbutyl) aniline. 235 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propan-2-yl) phenyl] acetamide are obtained in the form of of white solid whose characteristics are as follows: 1H NMR spectrum: 1.18 (d, J = 6.8 Hz, 6H); 2.84 (quin, J = 6.9 Hz, 1H); 3.42 (t, J = 4.9 Hz, 4H); 3.54 to 3.65 (m, 6H); 5.20 (s, 1H); 6.94 (d, J = 7.6 Hz, 1H); 7.22 (t, J = 7.8 Hz, 1H); 7.38 (d, J = 8.8 Hz, 1H); 7.45 (s, 1H); 10.09 (s, 1H); 11.64 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.78; [M + H] +: m / z 357; Example 23: Synthesis of N- (3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] [MH] -: m / z Acetamide N The product is prepared following the procedure described in Example 19 from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. of sodium (example 1 step 2) using a mixture of 1 mL of water and 9 mL of ethanol instead of methanol and 214 mg of 3-methyl-aniline instead of 3- (tert-butyl) aniline. 196 mg of N- (3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics are the following: 1H NMR Spectrum: 2.27 (s, 3H); 3.38 at 3.45 (m, 4H); 3.54 to 3.64 (m, 6H); 5.20 (s, 1H); 6.88 (d, J = 7.8 Hz, 1H); 7.19 (t, J = 7.8 Hz, 1H); 7.35 (d, J = 8.8 Hz, 1H); 7.39 (s, 1H); 10.07 (s, 1H); 11.65 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.63; [M + H] +: m / z 329; Example 24: Synthesis of N- (3-cyano-4-fluorophenyl) -2- [4-5 (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine) The product is prepared by following the procedure described in Example 19 from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). -2-yl] sodium acetate (example 1 step 2) and 163 mg of 5-amino-2-fluorobenzonitrile instead of 3- (tert-butyl) aniline. The reaction mixture is concentrated to dryness under reduced pressure and the residue is then purified by chromatography on a silica column, eluting with a gradient of the eluent CH 2 Cl 2 / MeOH: 90/10 in dichloromethane from 0% to 100%. 81 mg of N- (3-cyano-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a solid. amber whose characteristics are as follows: 1 H NMR Spectrum: 3.34 to 3.47 (m, 4H); 3.53 to 3.67 (m, 6H); 5.21 (s, 1H); 7.51 (t, J = 9.2 Hz, 1H); 7.73 to 7.89 (m, 1H); 8.07 (dd, J = 2.8 and 5.7 Hz, 1H); 10.53 (s, 1H); 11.68 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.60; [M + H] +: m / z 358; [MH] -: m / z 356 Purity: 95 Example 25: Synthesis of N- (1H-indazol-6-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6) -d ihydropyrimidin-2-yl] acetamide HHH

The product is prepared by following the procedure described in Example 19 from 261 mg of [4- (morpholin-4-yl) -6-oxo-1). Sodium 6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 280 mg of 1-Boc-6-aminoindazole instead of 3- (tert-butyl) aniline. The reaction mixture is concentrated under reduced pressure and taken up in 13 ml of 1,4-dioxane and 3 ml of 1N hydrochloric acid, and then it is heated under microwaves for 10 minutes at 100 ° C. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure and taken up in 30 ml of water and then a saturated aqueous solution of sodium bicarbonate is added in order to obtain a pH close to 8. The precipitate formed is filtered and washed. with water, ethyl acetate and ethyl ether. After purification by chromatography on a silica column, eluting with a gradient of CH 2 Cl 2 / MeOH: 70/30 eluent in dichloromethane from 0% to 100%, 20 mg of N- (1H-indazol-6-yl) are obtained. 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a white solid, which has the following characteristics: 1H NMR spectrum: 3.42 ( t, J = 4.9 Hz, 4H); 3.60 (dd, J = 4.0 and 5.7 Hz, 4H); 3.64 (s, 2H); 5.20 (s, 1H); 7.08 (dd, J = 1.8 and 8.6 Hz, 1H); 7.67 (d, J = 8.6 Hz, 1H); 7.96 (s, 1H); 8.09 (s, 1H); 10.32 (brs, 1H); 11.67 (bs, 1H); 12.88 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.45; [M + H] +: m / z 355; Example 26 Synthesis of N- (3-cyanophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] [MH] -: m / z Acetamide HHNON The product is prepared following the procedure described in Example 19 from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. sodium (example 1 step 2) using a mixture of 6 mL of water and 1 mL of ethyl acetate instead of methanol and, 118 mg of 3-aminobenzonitrile instead of 3- (tertbutyl) aniline. 120 mg of N- (3-cyanophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of an off-white solid whose characteristics are as follows: 1H NMR Spectrum: 3.41 (t, J = 4.8 Hz, 4H); 3.60 (dd, J = 4.8 and 5.3 Hz, 4H); 3.63 (s, 2H); 5.21 (s, 1H); 7.49 to 7.59 (m, 2H); 7.78 (dt, J = 2.3 and 6.8 Hz, 1H); 8.04 (s, 1H); 10.51 (brs, 1H); 11.69 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.55; [M + H] +: m / z 340; Example 27: Synthesis of N- (5-fluoropyridin-2-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2] [MH] -: m / z 338 The product is prepared by following the procedure described in Example 19 from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl). sodium acetate (example 1 step 2) using a mixture of 7 mL of water and 1.5 mL of tetrahydrofuran instead of methanol and 134 mg of 2-amino-5-fluoropyridine instead of 3- (tert-butyl) )aniline. After stirring for 1 h 30 at room temperature, a precipitate is formed. The reaction mixture is filtered on a sintered glass. The solid obtained is washed with water, ethyl acetate and ethyl ether. 130 mg of N- (5-fluoropyridin-2-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid. broken, the characteristics of which are as follows: 1H NMR Spectrum: 3.36 to 3.46 (m, 4H); 3.60 (t, J = 5.0 Hz, 4H); 3.67 (s, 2H); 5.20 (s, 1H); 7.75 (td, J = 2.7 and 6.1 Hz, 1H); 8.07 (dd, J = 9.4 and 4 Hz, 1H); 8.33 (d, J = 2.7 Hz, 1H), 10.80 (s, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 2.67; [M + H] +: m / z 334; Example 28: Synthesis of N- (4-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2) [MH] -: m / z 332 The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). 2-yl] sodium acetate (example 1 step 2) and 240 mg of 4-fluoro-3-methylaniline instead of 2,4-difluoroaniline. 204 mg of N- (4-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a solid. white, whose characteristics are as follows: 1H NMR Spectrum: 2.20 (d, J = 1.2 Hz, 3H); 3.41 (t, J = 4.9 Hz, 4H); 3.55 to 3.63 (m, 6H); 5.20 (s, 1H); 7.07 (t, J = 9.2 Hz, 1H); 7.33 to 7.41 (m, 1H); 7.46 (dd, J = 2.7 and 6.8 Hz, 1H); 10.13 (s, 1H); 11.63 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.66; [M + H] +: m / z 347; Example 29: Synthesis of N - (3-chloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2] [MH] -: m / z 345 The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). 2-yl] sodium acetate (example 1 step 2) and 278 mg of 3-chloro-4-fluoroaniline instead of 2,4-difluoroaniline. 218 mg of N- (3-chloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a solid are obtained. white, the characteristics of which are as follows: NMR spectrum 1H: 3.41 (t, J = 5.0 Hz, 4H); 3.56 to 3.63 (m, 6H); 5.20 (s, 1H); 7.38 (t, J = 8.8 Hz, 1H); 7.41 to 7.50 (m, 1H); 7.88 (dd, J = 2.7 and 6.8 Hz, 1H), 10.38 (s, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.70; [M + H] +: m / z 367; Example 30: Synthesis of 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (pyridin-3-) [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo). Sodium 1,2,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 427 mg of 3-aminopyridine instead of 2,4-difluoroaniline. 168 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (pyridin-3-yl) acetamide are obtained in the form of a white solid whose characteristics are as follows: 1H NMR Spectrum: 3.39 to 3.46 (m, 4H); 3.56 to 3.66 (m, 6H); 5.20 (slarge, 1H); 7.35 (brs, 1H); 8.00 (d, J = 8.6 Hz, 1H); 8.28 (brs, 1H); 8.71 (brs, 1H); 10.37 (slarge, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.25; [M + H] +: m / z 316; Example 31: Synthesis of N- (4-fluoro-2-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2] [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 200 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 -yl] sodium acetate (example 1 step 2) and 278 mg of 4-fluoro-2-methylaniline instead of 2,4-difluoroaniline. 92 mg of N- (4-fluoro-2-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a pink solid. whose characteristics are as follows: 1H NMR Spectrum: 2.21 (s, 3H); 3.44 (t, J = 4.9 Hz, 4H); 3.57 to 3.66 (m, 6H); 5.19 (s, 1H); 6.99 (td, J = 3.2 and 8.6 Hz, 1H); 7.08 (dd, J = 3.1 and 9.7 Hz, 1H); 7.36 (dd, J = 5.6 and 8.6 Hz, 1H); 9.56 (bs, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.59; [M + H] +: m / z 347; Example 32: Synthesis of N- (3-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] [MH] -: m / z 345 The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl). sodium acetate (example 1 step 2) and 418 mg of 3-aminophenol instead of 2,4-difluoroaniline. 210 mg of N- (3-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a pink solid whose characteristics are the following: 1H NMR spectrum: 3.37 at 3.47 (m, 4H); 3.51 to 3.63 (m, 6H); 5.20 (s, 1H); 6.45 (d, J = 8.6 Hz, 1H); 6.93 (d, J = 8.6 Hz, 1H); 7.07 (t, J = 8.6 Hz, 1H); 7.12 (bs, 1H); 9.36 (bs, 1H); 10.00 (s wide, 1H); 11.63 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.43; [M + H] +: m / z 331; Example 33: Synthesis of N- (3-bromo-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2) [MH] -: m / z The product is prepared by following the procedure described in Example 19 from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl). sodium acetate (example 1 step 2) using a mixture of 7 mL of water and 1.5 mL of tetrahydrofuran instead of methanol and 190 mg of 3-bromo-4-fluoroaniline instead of 3- (tert-butyl) )aniline. 266 mg of N- (3-bromo-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid. whose characteristics are as follows: 1H NMR Spectrum: 3.41 (t, J = 4.9 Hz, 4H); 3.55 to 3.65 (m, 6H); 5.20 (s, 1H); 7.34 (t, J = 8.8 Hz, 1H); 7.44 to 7.53 (m, 1H); 8.00 (dd, J = 2.2 and 6.1 Hz, 1H); 10.35 (brs, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 3.30 [M + H] +: m / z 411; [MH] -: m / z 409 Example 34: Synthesis of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (3,4,5 The product is prepared by following the procedure described in Example 5 from 200 mg of [4- (morpholin-4-yl) -6-oxo-1,6-ONO-N dihydropyrimidine). 2-yl] sodium acetate (example 1 step 2) and 113 mg of 3,4,5-trifluoroaniline instead of 2,4-difluoroaniline. 33 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (3,4,5-trifluorophenyl) acetamide are obtained, the characteristics of which are following: 1H NMR spectrum: 3.41 (dd, J = 4.8 and 5.3 Hz, 4H); 3.54 to 3.66 (m, 6H); 5.20 (s, 1H); 7.46 (dd, J = 6.5 and 10.1 Hz, 2H); 10.55 (s, 1H); 11.64 (s, 1H) Example 35: Synthesis of N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6- The product is prepared by following the procedure described in Example 5 from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). 2-yl] sodium acetate (example 1 step 2) and 525 mg of (5-amino-2-fluorophenyl) methanol instead of 2,4-difluoroaniline. 218 mg of N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of of beige solid whose characteristics are as follows: 1 H NMR spectrum: 3.42 (d, J = 4.9 Hz, 4 H); 3.55 to 3.64 (m, 6H); 4.51 (d, J = 6.1 Hz, 2H); 5.20 (brs, 1H); 5.27 (t, J = 6.0 Hz, 1H); 7.08 (t, J = 9.4 Hz, 1H); 7.46 at 7.54 (m, 1H), 7.63 (d, J = 7.3 Hz, 1H); 10.18 (brs, 1H); 11.64 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.46 [M + H] +: m / z 363; [M-H] -: m / z 361 II II / N O HO 25

73

Melting point (Kofler)> 260 ° C Example 36: Synthesis of N- (3-cyclopropylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] Acetamide The product is prepared following the procedure described in Example 5 starting from 250 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. (Example 1 Step 2) and 395 mg of 3-cyclopropyleaniline (prepared according to Wallace et al in Tetrahedron Lett., 2002, 43, 6987) instead of 2,4-difluoroaniline. 225 mg of N- (3-cyclopropylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics are the following: 1H NMR spectrum: 0.50 to 0.68 (m, J = 2.0 and 4.9 Hz, 2H); 0.88 to 1.02 (m, 2H); 1.79 to 1.94 (m, J = 4.4 and 4.4 Hz, 1H); 3.42 (t, J = 5.1 Hz, 4H); 3.51 to 3.68 (m, 6H); 5.20 (s, 1H); 6.80 (d, J = 8.3 Hz, 1H); 7.17 (t, J = 7.8 Hz, 1H); 7.26-7.36 (m, 2H); 10.06 (bs, 1H); 11.63 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.72 [M + H] +: m / z 353; [MH] -: m / z 355 Melting point (Kofler) = 246 ° C Example 37: Synthesis of N- (2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1 The product is prepared following the procedure described in Example 5 starting from 500 mg of [4- (morpholin-4-yl) -6-oxo-1, Sodium 6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 278 mg of 2-aminophenol instead of 2,4-difluoroaniline. 370 mg of N- (2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics are the following: 1H NMR spectrum: 3.45 (t, J = 5.0 Hz, 4H); 3.59 to 3.65 (m, 4H); 3.69 (s, 2H); 5.21 (s, 1H); 6.76 (t, J = 7.8 Hz, 1H); 6.87 (d, J = 7.8 Hz, 1H); 6.92 (t, J = 8.5 Hz, 1H); 7.86 (d, J = 7.3 Hz, 1H); 9.46 (bs, 1H); 9.82 (brs, 1H); 11.63 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 2.58; [M + H] +: m / z 331; [MH] -: m / z 329 Melting point (Kofler)> 260 ° C Example 38: Synthesis of N- [3- (difluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6- oxo-1, 6-dihydropyrimidin-2-yl] acetamide The product is prepared following the procedure described in Example 5 starting from 200 mg of [4- (morpholin-4-yl) -6-oxo-1 Sodium 6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 520 mg of 3- (difluoromethoxy) aniline instead of 2,4-difluoroaniline. 135 mg of N- [3- (difluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the characteristics are as follows: 1H NMR Spectrum (400MHz, ppm, DMSO-d6): 3.36 to 3.48 (m, 4H); 3.54 to 3.65 (m, 6H); 5.20 (slarge, 1H); 6.88 (bs, 2H); 7.17 (t, J = 69.0 Hz, 1H); 7.36 (s, 1H); 7.48 to 7.57 (m, 1H); 10.34 (brs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.67; [M + H] +: m / z 381; Example 39 Synthesis of N- (4-fluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2] [MH] -: m / z Example 1: oxo To a solution of 535 mg of ethyl [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -acetate in 9 ml of N, N-dimethylformamide under argon are added 88 mg of sodium hydride. The reaction mixture is then stirred for 5 minutes at room temperature, then a solution of 655 mg of di-tert-butyldicarbonate in 2 ml of N, N-dimethylformamide is added. After stirring overnight at room temperature, the reaction mixture is concentrated under reduced pressure. 10 ml of water are added, followed by a solution of 1 N hydrochloric acid until the pH is close to 6. The mixture is extracted with ethyl acetate and the organic phase is dried over magnesium sulphate and then concentrated to dry under reduced pressure. 735 mg of ethyl [4 - ({[((2-methylpropan-2-yl) oxy] carbonyl} oxy) -6- (morpholin-4-yl) pyrimidin-2-yl] acetate are obtained in the form of a yellow oil. Step 2: To a solution of 700 mg of [4 - ({[(2-methylpropan-2-yl) oxy] carbonyl} oxy) -6- (morpholin-4-yl) pyrimidin-2-yl] ethyl acetate in 8 ml of N, N-dimethylformamide under argon are added 84 mg of sodium hydride. The reaction mixture is then stirred for 15 minutes at 0 ° C. 0.130 ml of methane iodide are then added and the mixture is stirred at ambient temperature for 1 night. 0.5 ml of water is added and the reaction mixture is concentrated to dryness under reduced pressure. After purification by chromatography on a silica column eluting with a heptane / ethyl acetate eluent gradient of 0% to 50% and then with 100% ethyl acetate. 150 mg of ethyl 2- [4 - ({[(2-methylpropan-2-yl) oxy] carbonyl} oxy) -6- (morpholin-4-yl) pyrimidin-2-yl] propanoate are obtained in the form of a colorless oil. Step 3: To a solution of 145 mg of 2- [4 - ({[(2-methylpropan-2-yl) oxy] carbonyl} oxy) -6- (morpholin-4) ethyl) pyrimidin-2-yl] propanoate in 5 mL of tetrahydrofuran is added 0.190 mL of 1M sodium hydroxide. After stirring overnight at room temperature, the reaction mixture is concentrated to dryness under reduced pressure. 100 mg of sodium 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] propanoate are obtained in the form of a solid which is used as it is in the following step.

Step 4: The product is prepared following the procedure described in Example 5 starting from 100 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl sodium propanoate and 195 mg of 4-fluoro-3-methoxyaniline instead of 2,4-difluoroaniline. 30 mg of N- (4-fluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] propanamide are obtained in the form of a white solid. whose characteristics are as follows: 1H NMR Spectrum (400MHz, ppm, DMSO-d6): 1.44 (d, J = 7.1Hz, 3H); 3.36 at 3.47 (m, 4H); 3.50 to 3.65 (m, 4H); 3.71 (q, J = 6.8 Hz, 1H); 3.79 (s, 3H); 5.19 (brs, 1H); 7.01 to 7.18 (m, 2H); 7.47 (dd, J = 2.0 and 7.8 Hz, 1H); 10.00 (s, 1H); 11.55 (bs, 1 h) Mass Spectrometry: Method A H ON H ON o Retention time Tr (min) = 0.65 [M + H] +: m / z 377; Example 40: Synthesis of N- (2,3-dimethylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl) [MH] -: m / z 375 The product is prepared by following the procedure described in Example 5 from 260 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. sodium (example 1 step 2) and 242 mg of 2,3-dimethylaniline instead of 2,4-difluoroaniline. 190 mg of N- (2,3-dimethylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the characteristics are as follows: 1H NMR Spectrum: 2.08 (s, 3H); 2.24 (s, 3H); 3.41 to 3.47 (m, 4H); 3.58 to 3.65 (m, 6H); 5.20 (s, 1H); 6.99 to 7.08 (m, 2H); 7.13 (d, J = 7.6 Hz, 1H); 9.57 (s, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.62 [M + H] +: m / z 343; Example 41: Synthesis of N- (2-fluoro-3-methylphenyl) -2- [4-20 (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin), m.p. 2-yl] acetamide C ~) The product is prepared following the procedure described in Example 5 from 260 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine -2-yl] sodium acetate (example 1 step 2) and 250 mg of 2-fluoro-3-methylaniline instead of 2,4-difluoroaniline. 208 mg of N- (2-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid. whose characteristics are as follows: 1 H NMR spectrum: 2.24 (bs, 3H); 3.37 at 3.48 (m, 4H); 3.56 to 3.72 (m, 6H); 5.20 (brs, 1H); 6.97 to 7.08 (m, 2H); 7.71 (brs, 1H); 9.89 (brs, 1H); 11.66 (bs, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.65 [M + H] +: m / z 347; Example 42: Synthesis of N- (1,3-benzoxazol-4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine] [MH] -: m / z 345 The product is prepared by following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl) -6-oxohexyl) -2-yl] acetamide. Sodium 1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 268 mg of 1,3-benzoxazol-4-amine instead of 2,4-difluoroaniline. 193 mg of N- (1,3-benzoxazol-4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of solid green whose characteristics are as follows: 1H NMR Spectrum (400MHz, d in ppm, DMSO-d6): 3.43 to 3.48 (m, 4H); 3.62 (t, J = 4.9 Hz, 4H); 3.80 (s, 2H); 5.21 (s, 1H); 7.36-7.42 (m, 1H); 7.49 (d, J = 8.3 Hz, 1H); 8.08 (d, J = 7.8 Hz, 1H); 8.78 (s, 1H); 10.44 (brs, 1H); 11.73 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.55 5 [M + H] +: m / z 356; Example 43: Synthesis of 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] -N- [3- (trifluoromethoxy)] [MH] -: m / z ) phenyl] acetamide

HHF ON The product is prepared following the procedure described in Example 5 from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. of sodium (example 1 step 2) and 270 mg of 3- (trifluoromethoxy) aniline instead of 2,4-difluoroaniline. 230 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (trifluoromethoxy) phenyl] acetamide are obtained in the form of a white solid. whose characteristics are as follows: 1H NMR Spectrum: 3.37 to 3.44 (m, 4H); 3.54 to 3.64 (m, 6H); 5.20 (s, 1H); 7.05 (d, J = 6.6 Hz, 1H); 7.41 to 7.48 (m, 2H); 7.74 (s, 1H); 10.45 (brs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.78; [M + H] +: m / z 399; Example 44: Synthesis of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propanediol)] 2-yloxy) phenyl] acetamide The product is prepared following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 -yl] sodium acetate (example 1 step 2) and 572 mg of 3-isopropoxyaniline instead of 2,4-difluoroaniline. 228 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propan-2-yloxy) phenyl] acetamide are obtained in the form of of white solid whose characteristics are as follows: 1H NMR Spectrum: 3.35 (t, J = 5.0 Hz, 4H); 3.56 (t, J = 4.9 Hz, 4H); 4.25 (s, 2H); 5.25 (brs, 1H); 7.31 to 7.40 (m, 2H); 7.62 to 7.74 (m, 2H); 11.92 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.60; [M + H] +: m / z 313; Example 45: Synthesis of N- (4-fluoro-2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2] [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 460 mg of 4-fluoro-2-methoxyaniline instead of 2,4-difluoroaniline. 245 mg of N- (4-fluoro-2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a pink solid. whose characteristics are as follows: 1H NMR Spectrum: 3.43 (m, 4H); 3.62 (m, 4H); 3.67 (s, 2H); 3.85 (s, 3H); 5.20 (s, 1H); 6.74 (dt, J = 2.8 and 8.6 Hz, 1H); 6.98 (dd, J = 2.8 and 10.9 Hz, 1H), 7.88 (dd, J = 6.7 and 8.6 Hz, 1H); 9.44 (s, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.62; [M + H] +: m / z 363; Example 46 Synthesis of {2- [3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino [MH] -: m / z 2-Methylpropan-2-yl phenyl] ethyl] carbamate The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6- sodium oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 930 mg of 2-methylpropan-2-yl [2- (3-aminophenyl) ethyl] carbamate instead of 2, 4-difluoroaniline. 285 mg of {2- [3 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) phenyl] ethyl} carbamate are obtained. methylpropan-2-yl as a pink solid whose characteristics are as follows: 1H NMR spectrum: 1.36 (s, 9H); 2.61 to 2.68 (m, 2H); 3.04 to 3.14 (m, 2H); 3.41 m, 4H); 3.56 to 3.63 (m, 6H); 5.20 (s, 1H); 6.84 (broad t, J = 6.7 Hz, 1H); 6.89 (d, J = 8.1Hz, 1H); 7.22 (t, J = 8.1 Hz, 1H); 7.36 to 7.44 (m, 2H); 10.09 (bs, 1H); 11.63 (bs, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.75; [M + H] +: m / z 458; [MH] -: m / z 456 Melting point = 194 ° C Example 47: Synthesis of N- [4-fluoro-3- (trifluoromethyl) phenyl] -2-5 [4- (morpholin-4-yl)] 6-Oxo-1,6-dihydropyrimidin-2-yl] acetamide The product is prepared following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl) Sodium 6-oxo-1,6-dihydropyrimidin-2-yl] acetate (Example 1 Step 2) and 358 mg of 4-fluoro-3- (trifluoromethylaniline) instead of 2,4-difluoroaniline. mg N- [4-fluoro-3- (trifluoromethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a white solid whose characteristics are as follows: 1H NMR Spectrum: 3.39 to 3.42 (m, 4H), 3.57 to 3.61 (m, 4H), 3.62 (s, 2H); 5.21 (s, 1H), 7.49 (t, J = 9.8 Hz, 1H), 7.75-7.83 (m, 1H), 8.06 (dd, J = 2); , 4 and 6.4 Hz, 1H), 10.53 (bs, 1H), 11.68 (bs, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.77; [M + H] +: m / z 401; [MH] -: m / z 399 Example 48: Synthesis of N- (3-ethynylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydrohydroimidin-2-yl] acetamide H OvN II yN The product is prepared following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2). -yl] sodium acetate (example 1 step 2) and 201 mg of 3-aminophenylacetylene instead of 2,4-difluoroaniline. 190 mg of N- (3-ethynylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the characteristics of which are the following: 1 H NMR spectrum: 3.39 to 3.44 (m, 4H); 3.58 to 3.64 (m, 6H); 4.16 (s, 1H); 5.20 (s, 1H); 7.17 (d, J = 7.8 Hz, 1H); 7.33 (t, J = 7.8 Hz, 1H); 7.54 (d, J = 7.8 Hz, 1H); 7.75 (s, 1H); 10.27 (s, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.64; [M + H] +: m / z 339; The product is prepared following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl) -6- Example 49: Synthesis of N- [3- (cyclopentyloxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide HH ON dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 354 mg of 3- (cyclopentyloxy) aniline instead of 2,4-difluoroaniline. 269 mg of N- [3- (cyclopentyloxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the characteristics are as follows: 1H NMR Spectrum: 1.50 to 1.75 (m, 6H); 1.83 to 1.96 (m, 2H); 3.39 to 3.44 (m, 4H); 3.54 to 3.63 (m, 6H); 4.73 (m, 1H); 5.20 (s, 1H); 6.60 (dd, J = 2.0 and 8.3 Hz, 1H); 7.03 (broad, J = 8.3 Hz, 1H); 7.18 (t, J = 8.3 Hz, 1H); 7.26 (t, J = 2.2 Hz, 1H); 10.10 (s, 1H); 11.64 (bs, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.84; [M + H] +: m / z 399; Example 50: Synthesis of N- (4-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2) [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 500 mg of [4- (morpholin-4-yl) -6-oxoethyl) -acetamide (VAC, SON4.056.1). Sodium 1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 815 mg of 2-amino-5-fluorophenol instead of 2,4-difluoroaniline. After purification by chromatography on a silica column, eluent: CH 2 Cl 2 / MeOH 95/5, 149 mg of N- (4-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6- are obtained. oxo-1,6-dihydropyrimidin-2-yl] acetamide as a gray solid whose characteristics are as follows: 1H NMR spectrum: 3.41 to 3.47 (m, 4H); 3.59 to 3.64 (m, 4H); 3.67 (s, 2H); 5.20 (s, 1H); 6.58 (dt, J = 2.8 and 8.8 Hz, 1H); 6.66 (dd, J = 2.8 and 10.4 Hz, 1H); 7.80 (dd, J = 6.4 and 8.8 Hz, 1H); 8.66 to 12.13 (m spread, 3 h) Mass Spectrometry: Method B Retention time Tr (min) = 2.74 [M + H] +: m / z 349; Example 51: Synthesis of 2- [2- (2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin [MH] -: m / z 347 The product is prepared by following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl) -6- (4H) -one (VAC, PSB2.078.6). sodium oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 238 mg of indoline instead of 2,4-difluoroaniline. 230 mg of

2- [2- (2,3-Dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one as a pink solid pale whose characteristics are as follows: 1 H NMR Spectrum: 3.17 (t, J = 8.3 Hz, 2 H); 3.41 (m, 4H); 3.60 (m, 4H); 3.75 (s, 2H); 4.14 (t, J = 8.3 Hz, 2H); 5.21 (s, 1H); 7.01 (t, J = 7.6 Hz, 1H); 7.16 (t, J = 7.6 Hz, 1H); 7.25 (d, J = 7.6 Hz, 1H); 8.02 (d, J = 7.6 Hz, 1H); 11.61 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.64 [M + H] +: m / z 341; Example 52: Synthesis of N- (3-Cyclopropyl-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2) [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl)] -methyl-acetamide (VAC, PSB2.078.11). Sodium 6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 302 mg of 3-cyclopropyl-4-fluoroaniline (prepared according to patent application US 2007/0185058.) Instead 2,4-difluoroaniline. 225 mg of N- (3-cyclopropyl-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a yellow solid. The characteristics of which are as follows: NMR spectrum 1H: 0.62 (m, 2H); 0.99 (m, 2H); 1.97 to 2.09 (m, 1H); 3.41 (m, 4H); 3.56 (s, 2H); 3.58 to 3.63 (m, 4H); 5.20 (s, 1H); 7.07 (t, J = 9.5 Hz, 1H); 7.18 (dd, J = 2.3 and 7.0 Hz, 1H); 7.30 to 7.37 (m, 1H); 10.11 (s, 1H); 11.63 (bs, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.75 88 [M + H] +: m / z 373; Example 53: Synthesis of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (2,3,4) [MH] -: m / z 371 trifluorophenyl) acetamide (VAC, PSB2.078.12) The product is prepared by following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4- sodium (yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 294 mg of 2,3,4-trifluoroaniline instead of 2,4-difluoroaniline. 195 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (2,3,4-trifluorophenyl) acetamide are obtained in the form of a white solid. whose characteristics are as follows: 1H NMR Spectrum: 3.43 (m, 4H); 3.61 (m, 4H); 3.67 (s, 2H); 5.20 (s, 1H); 7.24-7.35 (m, 1H); 7.56 to 7.67 (m, 1H); 10.18 (brs, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.65 [M + H] +: m / z 369; Example 54: Synthesis of N- [4-fluoro-3- (trifluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1, 6- [MH] -: m / z dihydropyrimidin-2-yl] acetamide C) The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1, Sodium 6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 270 mg of 4-fluoro-3- (trifluoromethoxy) aniline instead of 2,4-difluoroaniline. 270 mg of N- [4-fluoro-3- (trifluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of of white solid whose characteristics are as follows: 1H NMR spectrum (400MHz): 3.37 to 3.44 (m, 4H); 3.55 to 3.65 (m, 6H); 5.20 (s, 1H); 7.40 to 7.59 (m, 2H); 7.90 (d, J = 6.8 Hz, 1H); 10.48 (brs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.80 [M + H] +: m / z 417; Example 55: Synthesis of N- [3- (2-Hydroxyethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin] [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl) -6-oxo-1). Sodium 6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 294 mg of 2- (3-aminophenoxy) ethanol instead of 2,4-difluoroaniline. 180 mg of N- [3- (2-hydroxyethoxy) phenyl] -2- [4- (morpholin-4-yl) - are obtained.

6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a pink solid whose characteristics are as follows: 1H NMR spectrum (400MHz): For this batch, we observe broad signals with: 3.42 (m , 4H); 3.59 (m, 6H); 3.70 (m, 2H); 3.93 (m, 2H); 4.82 (m, 1H); 5.20 (s, 1H); 6.64 (d, J = 8.1 Hz, 1H); 7.07 (d, J = 8.1 Hz, 1H); 7.15 to 7.23 (t, J = 8.1 Hz, 1H); 7.28 (s, 1H); 10.12 (s, 1H); 11.65 (s, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.46 [M + H] +: m / z 375; [M-H] -: m / z 373

Example 56: Synthesis of N- (3-iodophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] acetamide H ON Il I \\ / NO C) The product is prepared following the procedure described in Example 5 starting from 268 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. sodium (example 1 step 2) and 324 mg of 3-iodoaniline instead of 2,4-difluoroaniline. 345 mg of N- (3-iodophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid, the characteristics of which are the following: 1H NMR Spectrum (400MHz): 3.41 (m, 4H); 3.58 to 3.64 (m, 6H); 5.20 (s, 1H); 7.12 (t, J = 8.1 Hz, 1H); 7.42 (d, J = 8.1 Hz, 1H); 7.50 (d, J = 8.1 Hz, 1H); 8.06 (s, 1H); 10.26 (bs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 3.41 [M + H] +: m / z 441; Example 57: Synthesis of 2-fluoro-5 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 500 mg of [4- (morpholin-4-yl) -6-oxo). Sodium 1,6,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 466 mg of methyl 5-amino-2-fluorobenzoate instead of 2,4-difluoroaniline. 625 mg of methyl 2-fluoro-5 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoate are obtained in the form of a pink solid. whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.41 (m, 4H); 3.57 to 3.62 (m, 6H); 3.85 (s, 3H); 5.20 (s, 1H); 7.32 (dd, J = 9.0 and 10.6 Hz, 1H); 7.79 (ddd, J = 2.9 and 4.1 and 9.0 Hz, 1H); 8.15 (dd, J = 2.9 and 6.4 Hz, 1H); 10.40 (s, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.59 [M + H] +: m / z 391; Example 58: Synthesis of N- (3-ethoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] [MH] -: m / z Acetamide C ~) The product is prepared following the procedure described in Example 5 from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 540 mg of 3-ethoxyaniline instead of 2,4-difluoroaniline. 235 mg of N- (3-ethoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics are the following: 1H NMR Spectrum (400MHz): 1.31 (t, J = 7.0Hz, 3H); 3.41 (m, 4H); 3.55 to 3.64 (m, 6H); 3.98 (q, J = 7.0 Hz, 2H); 5.20 (s, 1H); 6.62 (d, J = 8.0 Hz, 1H); 7.06 (d, J = 8.0 Hz, 1H); 7.19 (t, J = 8.0 Hz, 1H); 7.26 (bs, 1H); 10.12 (bs, 1H); 11.64 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.66 [M + H] +: m / z 359; EXAMPLE 59 Synthesis of N- (2,4-difluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine] [MH] -: m / z The product is prepared by following the procedure described in Example 5 from 260 mg of [4- (morpholin-4-yl) -6-oxo). Sodium 1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 318 mg of 2,4-difluoro-3-methoxyaniline instead of 2,4-difluoroaniline. 255 mg of N- (2,4-difluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.43 (m, 4H); 3.61 (m, 4H); 3.66 (s, 2H); 3.93 (s, 3H); 5.20 (s, 1H); 7.11 (ddd, J = 2.1 and 9.0 and 10.9 Hz, 1H); 7.50 (dt, J = 5.5 and 9.0 Hz, 1H); 10.00 (s, 1H); 11.65 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 3.01 [M + H] +: m / z 381; Example 60: Synthesis of 2- [4- (Morpholin-4-yl) -6-oxo-1,6-5-dihydropyrimidin-2-yl] -N- (2,4), m.p. 5-trifluorophenyl) acetamide The product is prepared following the procedure described in Example 5 starting from 260 mg of [4- (morpholin-4-yl) -6- sodium oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 294 mg of 2,4,5-trifluoroaniline instead of 2,4-difluoroaniline. [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (2,4,5-trifluorophenyl) acetamide as a white solid, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 3.42 (m, 4H), 3.61 (m, 4H), 3.69 (s, 2H), 5.20 (s, 1H); 65 (dt, J = 7.6 and 10.8 Hz, 1H), 8.01 (td, J = 8.0 and 12.3 Hz, 1H), 10.18 (bs, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 3.10 20 [M + H] +: m / z 369; [MH] -: m / z 367 Example 61 Synthesis of N- (3,5-dichloro-4-fluorophenyl) -2- [4- (morp) holin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide The product is prepared following the procedure described in Example 5 starting from 260. mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 360 mg of 3,5-dichloro-4-fluoroaniline at instead of 2,4-difluoroaniline. 259 mg of N- (3,5-dichloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.41 (m, 4H); 3.56 to 3.64 (m, 6H); 5.21 (s, 1H); 7.74 (d, J = 6.1 Hz, 2H); 10.50 (bs, 1H); 11.66 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.82 [M + H] +: m / z 401; Example 62: Synthesis of 2- [2- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-oxoethyl] -6- (morpholin-4) [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting from 260 mg of [4- (morpholinic acid) -benzylamine). 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 270 mg of 3,4-dihydro-2H-1,4-benzoxazine instead of 2 , 4-difluoroaniline. After purification by chromatography on a silica column, eluent CH 2 Cl 2 / MeOH 95/05, 150 mg of 2- [2- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-oxoethyl are obtained. ] (6-morpholin-4-yl) pyrimidin-4 (3H) -one as a white solid whose characteristics are as follows:

1H NMR Spectrum (400MHz): 3.36-3.45 (m, 4H); 3.52 at 3.70 (m, 4H); 3.81 to 3.95 (m, 4H); 4.30 (m, 2H); 5.18 (s, 1H); 6.81 to 6.95 (m, 2H); 6.99 to 7.16 (m, 1H); 7.22 to 8.18 (m, 1H); 11.59 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.62 [M + H] +: m / z 357; Example 63: Synthesis of N- (4-fluoro-3-nitrophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2) [MH] -: m / z The product is prepared by following the procedure described in Example 5 starting with 500 mg of [4- (morpholin-4-yl) -6-oxo]. Sodium 1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 510 mg of 4-fluoro-3-nitroaniline instead of 2,4-difluoroaniline. 339 mg of N- (4-fluoro-3-nitrophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a solid. white, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 3.41 (m, 4H); 3.58 to 3.62 (m, 4H); 3.64 (s, 2H); 5.21 (s, 1H); 7.56 (dd, J = 9.0 and 11.2 Hz, 1H); 7.83 to 7.88 (ddd, J = 2.9 and 4.0 and 9.0 Hz, 1H); 8.47 (dd, J = 2.9 and 6.8 Hz, 1H); 10.63 (brs, 1H); 11.69 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.63 [M + H] +: m / z 378; Example 64: Synthesis of 2-fluoro-5 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] [MH] -: m / z ] acetyl} amino) benzoic acid (C) To a solution of 310 mg of 2-fluoro-5- ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] Methyl acetyl} amino) benzoate prepared in Example 57 in 7 mL of methanol are added 0.4 mL of 2M sodium hydroxide. After stirring overnight at room temperature, again 0.4 ml of 2M sodium hydroxide and refluxed for 3 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The evaporation residue is taken up in water. The aqueous phase is extracted with ethyl acetate and then acidified with a 1N aqueous hydrochloric acid solution (pH = 5). The insoluble material is filtered. The filtrate is concentrated under reduced pressure and then taken up in water and a few drops of a 1N aqueous hydrochloric acid solution. The precipitate formed is filtered off, rinsed with petroleum ether and concentrated to dryness under reduced pressure. . 52 mg of 2-fluoro-5- ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoic acid are obtained in the form of a solid. pale pink whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.41 (m, 4H); 3.60 (t, J = 4.9 Hz, 6H); 5.20 (s, 1H); 7.24 (t, J = 9.8 Hz, 1H); 7.75 (m, 1H); 8.06 (m, 1H); 10.34 (brs, 1H); 11.67 (bs, 1 h) Mass Spectrometry: Method A OH Retention time Tr (min) = 0.46 [M + H] +: m / z 377; Example 65: Synthesis of N- (5-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2) [MH] -: m / z 375 The product is prepared by following the procedure described in Example 5 starting with 1 g of [4- (morpholin-4-yl) -6-oxo-1). Sodium 6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 466 mg of 2-amino-4-fluorophenol instead of 2,4-difluoroaniline. 795 mg of 2 N- (5-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a solid. brown whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.44 (m, 4H); 3.59 to 3.65 (m, 4H); 3.72 (s, 2H); 5.21 (s, 1H); 6.70 to 6.78 (m, 1H); 6.81 to 6.87 (m, 1H); 7.85 (dd, J = 3.0 and 10.8 Hz, 1H); 9.10 to 10.09 (m spread, 1H); 10.64 to 11.96 (m spread, 1 H) Mass Spectrometry: Method A Retention time Tr (min) = 0.55 [M + H] +: m / z 349; Example 66: Synthesis of N- (2-bromo-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2) [MH] -: m / z 347 The product is prepared by following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1, Sodium 6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 260 mg of 2-bromo-4-fluoroaniline instead of 2,4-difluoroaniline. 310 mg of N- (2-bromo-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a brown solid. whose characteristics are as follows: 1H NMR Spectrum (400MHz): For this batch, all the signals are broad with: 3.44 (m, 4H); 3.62 (m, 4H); 3.65 (s, 2H); 5.20 (s, 1H); 7.22-7.32 (m, 1H); 7.58 to 7.67 (m, 2H); 9.73 (s, 1H); 11.68 (s, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.65 [M + H] +: m / z 411; Example 67: Synthesis of N- (4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2) [MH] -: m / z 409 Step 1: O-Nyyo To a solution of 500 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] ethyl acetate prepared Step 1 of Example 1 in 1.5 mL of dioxane, 330 mg of potassium carbonate and 15020 mL of methyl iodide. The reaction mixture is heated at 40 ° C for 16 and then cooled to room temperature. The suspension is filtered on sintered glass and then rinsed with dioxane and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane, acetonitrile and methanol (98/01/01, 96/02/02 and then 90/05/05 VNN). 200 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] ethyl acetate are obtained in the form of a white solid, the characteristics of which are as follows: Mass Spectrometry: Method A Retention Time Tr (min) = 0.53 [M + H] +: m / z 282; [MH] -: m / z 280 Step 2: There is a soliton of 190 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 ethyl acetate in 10 ml of toluene are added 0.135 ml of 4-fluoroaniline and 0.670 ml of a solution of trimethylaluminum 2M dropwise. After stirring for 30 minutes at room temperature, 10 ml of toluene are added. After stirring for 4 hours at room temperature, the reaction mixture is poured into water and a solution of 1M potassium phosphate is added. The precipitate is filtered on sintered glass and then rinsed with ethyl acetate. The filtrate is then washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase is extracted and then dried over magnesium sulphate, filtered on sintered glass and concentrated under reduced pressure. After purification of the residue by chromatography on a silica column eluting with a melange 2951169 100

dichloromethane and methanol (95/05, VN) gives 20 mg of N- (4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1, 6- dihydropyrimidin-2-yl] acetamide as a white solid whose characteristics are as follows: 1 H NMR Spectrum (400 MHz): 3.34 (s, 3H); 3.40 (m, 4H); 3.58 (m, 4H); 3.90 (s, 2H); 5.35 (s, 1H); 7.15 (t, J = 9.0 Hz, 2H); 7.57 (dd, J = 5.1 and 9.0 Hz, 2H); 10.25 (s, 1 H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.62 [M + H] +: m / z 347; Example 68: Synthesis of N- (3-chloro-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1, 6-allyl) 2-Dihydropyrimidin-2-yl] acetamide Step 1: A solution of 1.62 g of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 ethyl acetate prepared in step 2 of Example 67, in 20 mL of tetrahydrofuran are added 2.88 mL of 2M sodium hydroxide. The reaction mixture is stirred for 48 hours at room temperature. The precipitate formed is filtered on sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried on a rotary evaporator. 730 mg of sodium [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate are obtained in the form of a white solid, the characteristics of which are as follows: 10 20 25 2951169 101

Mass Spectrometry: Method B Retention time Tr (min) = 1.67 [M + H] +: m / z 254; [MH] -: m / z 252 Step 2: To a solution of 200 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate 2.5 ml of pyridine, 182 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 210 mg of 3-chloro-4-fluoroaniline are added to 2.5 ml of N, N-dimethylformamide. It is stirred at ambient temperature for 1 night, and then the reaction mixture is concentrated under reduced pressure. Water is added, then extracted with ethyl acetate, washed again with water and concentrated under reduced pressure. The residue obtained is washed with ethyl acetate and then rinsed with ethyl ether. 76 mg of N- (3-chloro-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained. in the form of a Parma solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.34 (s, 3H); 3.37 at 3.42 (m, 4H); 3.55 to 3.60 (m, 4H); 3.91 (s, 2H); 5.36 (s, 1H); 7.38 (t, J = 9.0 Hz, 1H); 7.41 to 7.47 (m, 1H); 7.87 (dd, J = 2.4 and 6.8 Hz, 1H); 10.42 (s, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.75 [M + H] +: m / z 381; [MH] -: m / z 379 Melting point (Kofler): 248 ° C Example 69: Synthesis of N- (3-bromophenyl) -2- [1-methyl-4- (morpholin-4-) Yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide The product is prepared following the procedure described in Example 68 from 200 mg of [1]. sodium methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate and 257 mg of 3-bromoaniline. 51 mg of N- (3-bromophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid. whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.34 (s, 3H); 3.37 at 3.42 (m, 4H); 3.58 (m, 4H); 3.92 (s, 2H); 5.36 (s, 1H); 7.19-7.33 (m, 2H); 7.45 (m, 1H); 7.91 (brs, 1H); 10.37 (bs, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.75 [M + H] +: m / z 407; [M-H] -: m / z 405 Melting point (Kofler): 266 ° C

Example 70: Synthesis of 2- [1-ethyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (4-fluorophenyl) acetamide Step 1: 2951169 The product is prepared following the procedure described in Example 67 starting from 600 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. ethyl, prepared in step 1 of Example 1 and 0.23 ml of ethyl iodide instead of methyl iodide, and replacing the potassium carbonate with cesium carbonate. After purification by chromatography on a column of silica, eluent: CH2Cl2 / CH3CN / MeOH, 96/02/02, 190 mg of [1-ethyl-4- (morpholin-4-yl) -6-oxo-1,6 are obtained. ethyl dihydropyrimidin-2-yl] acetate in the form of a white solid, the characteristics of which are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 0.59; [M + H] +: m / z 296; [MH] -: m / z 294 Purity: 86% Step 2: To a solution of 0.13 mL of 4-fluoroaniline in 4 mL of toluene is successively added dropwise 0.640 mL of a solution of 2M trimethylaluminium in toluene then, after stirring for 40 minutes at room temperature, a solution of 190 mg of [1-ethyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. ethyl in 6 mL of toluene. The reaction mixture is heated to

104

80 ° C for 4 hours, cooled with an ice bath and poured over water. A 1M solution of potassium phosphate and ethyl acetate are then added, the organic phase is extracted, washed again with a 1M solution of potassium phosphate and then dried over magnesium sulfate, filtered and finally concentrated under reduced pressure. . After purification by chromatography on a silica column, eluent: CH 2 Cl 2 / CH 3 CN / MeOH, 98/01/01 then, 96/02/02, 60 mg of 2- [1-ethyl-4- (morpholin-4-yl) is obtained ) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (4-fluorophenyl) acetamide as a white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 1.16 (t, J = 7.1 Hz, 3H); 3.39 (m, 4H); 3.57 (m, 4H); 3.88 (s, 2H); 3.91 (q, J = 7.1 Hz, 2H); 5.33 (s, 1H); 7.15 (t, J = 8.9 Hz, 2H); 7.57 (dd, J = 5.0 and 8.9 Hz, 2H); 10.26 (s, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.66 [M + H] +: m / z 361; [MH] -: m / z 359 Melting point (Kofler): 238 ° C Example 71: Synthesis of N- (1H-indol-4-yl) -2- [4- (morpholin-4-yl) - 6-oxo-1,6-dihydropyrimidin-2-yl] acetamide Step 1: The product is prepared following the procedure described in Example 5 starting from 500 mg of [4- (morpholin-4-yl) Sodium 6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) and 445 mg of 2-methylpropan-2-yl 4-amino-1H-indole-1-carboxylate instead 2,4-difluoroaniline. 500 mg of 4 - ({[4- (morpholin-4-yl) -6-oxo-2951169 are obtained.

2-methylpropan-2-yl 1,6-dihydropyrimidin-2-yl] acetyl} amino) -1H-indole-1-carboxylate as a brown solid, the characteristics of which are as follows: Mass Spectrometry: A Time Method retention Tr (min) = 0.88 [M + H] +: m / z 454; [MH] -: m / z 452 Step 2: On a solution of 200 mg of 4 - ({[4- (morpholin-4-yl) -6-oxo-1,6- 2-methylpropan-2-yl dihydropyrimidin-2-yl] acetyl} amino) -1H-indol-1-carboxylate in 8 ml of dichloromethane are added dropwise 0.940 ml of trifluoroacetic acid. After stirring for 3 days at room temperature, the reaction medium is concentrated under reduced pressure, taken up in toluene and concentrated under reduced pressure. After purification by chromatography on a silica column, eluent: CH 2 Cl 2 / MeOH, 90/10, 48 mg of N- (1H-indol-4-yl) -2- [4- (morpholin-4-yl) - are obtained. 6-oxo-1,6-dihydropyrimidin-2-yl] acetamide having the following characteristics: 1H NMR Spectrum (400MHz): 3.43 (m, 4H); 3.60 (m, 4H); 3.73 (s, 2H); 5.21 (s, 1H); 6.68 (bs, 1H); 7.01 (t, J = 7.9 Hz, 1H); 7.16 (d, J = 7.9 Hz, 1H); 7.30 (t, J = 2.4 Hz, 1H); 7.55 (d, J = 7.9 Hz, 1H); 9.80 (bs, 1H); 11.11 (bs, 1H); 11.67 (m spread, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.48 [M + H] +: m / z 354; [M-H] -: m / z 352 2951169 106

Example 72: Synthesis of N- (4-fluorophenyl) -3-methyl-2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] butanamide Step 1: The product is prepared following the procedure described in Example 67 from 600 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. ethyl prepared in step 1 of Example 1 and 0.29 ml 2-iodopropane instead of methyl iodide and replacing the potassium carbonate with cesium carbonate. After purification by chromatography on a column of silica, eluent: CH 2 Cl 2 / CH 3 CN / MeOH, 90/05/05, 20 mg of 3-methyl-2- [4- (morpholin-4-yl) -6-oxo are obtained. Ethyl 1,6-dihydropyrimidin-2-yl] butanoate as a white solid whose characteristics are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 0.70 [M + H] + : m / z 310; The product is prepared by following the procedure described in Example 70 starting from 0.023 mL of 4-fluoroaniline and 36 mg of 3-chloroaniline. ethyl-2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] butanoate instead of [1-ethyl-4- (morpholin-4-yl) 6-Oxo-1,6-dihydropyrimidin-2-yl] ethyl acetate. After purification by chromatography on a column of silica, eluent: CH 2 Cl 2 / CH 3 CN / MeOH, 94/03/03, 15 mg of N- (4-fluorophenyl) -3-methyl-2- [4-

(morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] butanamide under

5 form of white solid whose characteristics are as follows:

1H NMR Spectrum (400MHz):

0.87 (d, J = 6.6 Hz, 3H); 0.97 (d, J = 6.6 Hz, 3H), 2.53 to 2.57 (m, 1H); 3.24 (d, J = 10.3 Hz, 1H); 3.42 to 3.47 (m, 4H); 3.59 to 3.65 (m, 4H); 5.21 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H); 7.59 (dd, J = 5.1 and 8.8 Hz, 2

H); 10.09 (bs, 1H); 11.30 (s large, 1 H)

Mass spectrometry: method A

Retention time Tr (min) = 0.76

[M + H] +: m / z 375; [M-H] -: m / z 373

Melting point (Kofler): 266 ° C

15

Example 73: Synthesis of N- [4-fluoro-3- (methoxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide

N O Step 1:

374 mg of 60% sodium hydride in 10 ml of tetrahydrofuran, 1 g of (5-amino-2-fluorophenyl) methanol and 0.441 ml of methyl iodide are introduced into a flask. After stirring for one hour at room temperature, a solution of sodium chloride and diethyl ether are added. The organic phase is

Extracted and then washed with water to pH = 7. It is then dried over magnesium sulphate, filtered and concentrated under reduced pressure. 900 mg of 4-fluoro-3- (methoxymethyl) aniline are obtained in the form of a black oil which is used as it is in the following stage.

Step 2: 2951169 The product is prepared following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl sodium acetate (example 1 step 2) and 900 mg of 4-fluoro-3- (methoxymethyl) aniline previously prepared instead of 2,4-difluoroaniline. 168 mg of N- [4-fluoro-3- (methoxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-yl] acetamide are obtained in the form of white solid whose characteristics are as follows:

1H NMR Spectrum (400MHz): 3.31 (partially masked, 3H); 3.41 (m, 4H); 3.59 (m, 6H); 4.43 (s, 2H); 5.20 (s, 1H); 7.14 (t, J = 9.3 Hz, 1H); 7.51 (m, 1H); 7.63 (m, 1H); 10.21 (brs, 1H); 11.63 (s wide, 1H) Mass Spectrometry: Method A

Retention time Tr (min) = 0.60

[M + H] +: m / z 377; [MH] -: m / z 375 Melting point (Kofler): 220 ° C Example 74: Synthesis of N- (4-fluoro-3-iodophenyl) -2- [4- (morpholin-4-yl) - Step 1: To a suspension of 1 g of iron filings in 10 ml of ethanol, 5 ml of water and 250.4 mg of ammonium chloride, m.p. brought to H ON Il I 2951169 109

reflux is added 1 g of 4-fluoro-3-nitrobenzene solubilized in 5 mL of ethanol. After 1 hour of refluxing, the reaction mixture is filtered and the organic extracts are evaporated. The evaporation residue is taken up in a mixture of water and dichloromethane. The aqueous phase is extracted with 3 times dichloromethane. The organic extracts are combined, dried over magnesium sulphate and concentrated under reduced pressure. 840 mg of 4-fluoro-3-iodoaniline are obtained, the characteristics of which are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 0.60 [M + H] +: m / z 238 Step 2 The product is prepared by following the procedure described in Example 5 from 300 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. sodium (example 1 step 2) and 272 mg of 4-fluoro-3-iodoaniline. 309 mg of N- (4-fluoro-3-iodophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained, the characteristics of which are following: 1H NMR Spectrum (400MHz): 3.42 (m, 4H); 3.57 to 3.63 (m, 6H); 5.21 (s, 1H); 7.23 (t, J = 8.6 Hz, 1H); 7.52 (ddd, J = 2.5 and 4.4 and 8.6 Hz, 1H); 8.12 (dd, J = 2.5 and 5.4 Hz, 1H); 10.29 (bs, 1H); 11.65 (bs, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.74 [M + H] +: m / z 459; [M-H] -: m / z 457

Example 75: Synthesis of 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] The product is prepared following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1, Sodium 6-dihydropyrimidin-2-yl] acetate, 300 mg of 3- (1,1,2,2-

Tetrafluoroethoxy) aniline, 300 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 2 mL of pyridine and 2 mL of dimethylformamide. 300 mg of 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (1,1,2,2-) are obtained.

tetrafluoroethoxy) phenyl] acetamide in the form of a white solid

10 the characteristics are as follows:

1H NMR Spectrum (400MHz):

all signals are wide with: 3.41 (m, 4 H); 3.60 (m, 6H); 5.20 (s, 1H); 6.79 (t, J = 52.5 Hz, 1H); 6.94 to 7.01 (m, 1H); 7.35 to 7.50 (m, 2H); 7.69 (s, 1H); 10.40 (s, 1H); 11.66 (s, 1 H)

Mass Spectrometry: Method A

Retention time Tr (min) = 0.77

[M + H] +: m / z 431; [M-H] -: m / z 429

Melting point (Kofler): 229 ° C Example 76: Synthesis of N- [3- (difluoromethyl) -4-fluorophenyl] -2- [4- (morpholin-4-yl) -6-oxo-1, 6 Step 1: O, + NIIOA a solution of 3.36 g of 2-fluoro-5-nitrobenzaldehyde in a solution of 3-dihydropyrimidin-2-yl] acetamide

100 ml of dichloromethane are added, at a temperature in the region of 20 ° C. and under argon, 4.48 g (3.5 ml) of N-ethyl-N- (trifluorolambda-4-sulphanyl) ethanamine. After stirring for 3 hours at a temperature in the region of 20 ° C., 300 ml of a saturated aqueous solution of sodium hydrogencarbonate are slowly added. After

After stirring for one hour, the organic phase is washed with 40 ml of water and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 3.6 g of 2- (difluoromethyl) -1-fluoro-4-nitrobenzene are obtained in the form of a yellow liquid, the characteristics of which are as follows:

Mass spectrometry: The spectra were carried out by direct introduction on a WATERS GCTof apparatus (direct introduction without LC): E1: [M] +. m / z = 191

Step 2: 2 H 2N A solution of 2 g of 2- (difluoromethyl) -1-fluoro-4-nitrobenzene in a suspension of 7 g of iron in 30 ml of refluxing acetic acid under argon is added slowly to 10 mL of acetic acid.

The reaction mixture is stirred for 1 hour under reflux and then cooled to room temperature. 20 ml of ethyl acetate are then added and the reaction mixture is filtered through Clarcel, rinsed with ethyl acetate and then concentrated to dryness under reduced pressure. The residue is taken up in 100 mL of ethyl acetate and filtered again on Clarcel and concentrated to dryness under reduced pressure. After purification on a silica column of the oily residue, eluent: CH 2 Cl 2 / MeOH 95/05, 1.1 g of a mixture containing 3- (difluoromethyl) -4-fluoroaniline in the form of a brown liquid used, such as in the next step.

Step 3: The product is prepared following the procedure described in Example 5 starting from 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. sodium, 1.1 g of 3- (difluoromethyl) -4-fluoroaniline (step 2), and 300 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 2 mL of pyridine and 2 mL of dimethylformamide. 260 mg of N- [3- (difluoromethyl) -4-fluorophenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.41 (m, 4H); 3.52 to 3.67 (m, 6H); 5.21 (s, 1H); 7.20 (t, J = 54.3 Hz, 1H); 7.34 (t, J = 8.9 Hz, 1H); 7.68 (m, 1H); 7.90 (m, 1H); 10.41 (s, 1H); 11.67 (bs, 1H) 5 2951169 113

Mass Spectrometry: Method A Retention Time Tr (min) = 0.67 [M + H] +: m / z 383; [M-H] -: m / z 381 Melting point (Kofler): greater than 260 ° C

Example 77: Synthesis of 2,2-difluoro-N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-dihydropyrimidin-2-yl] acetamide F Step 1 : X oo ON 10 15 NO

To a solution of 570 mg of potassium 1,1,1,3,3,3-hexamethyldisilazan-2-ide in 9 ml of tetrahydrofuran at a temperature of 78 ° C and under argon is added 350 mg of 4 - ({[(2-methylpropan-2-yl) oxy] carbonyl} oxy) -6- (morpholin-4-yl) pyrimidin-2-yl] ethyl acetate dissolved beforehand in 6 ml of tetrahydrofuran. After stirring for 45 minutes at this temperature, 409 mg of manganese dibromide (2+) are added. After thirty minutes of agitation of the suspension obtained, still at a

114

at a temperature of 78 ° C., 847 mg of N-fluoro-N- (phenylsulfonyl) benzenesulphonamide are added. After returning to a temperature of 20 ° C, the suspension is stirred overnight. The medium is poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness. under reduced pressure. The residue is taken up in 10 ml of methylene chloride and the insoluble matter is then filtered and washed with 5 times 5 ml of methylene chloride. The filtrate is concentrated to dryness under reduced pressure and after purification on a silica column of the oily residue, eluent: CH2Cl2 / AcOEt, 95/05, 278 mg of difluoro [4 - ({[(2-methylpropan-2-yl) are obtained. ) Oxycarbonyl) oxy) -6- (morpholin-4-yl) pyrimidin-2-yl] ethyl acetate in the form of a colorless oil, the characteristics of which are as follows: Mass spectrometry: method A Retention time Tr (min) = 1.06 [M + Na] +: m / z 426; base peak: m / z 304 Step 2: To a solution of 0.136 ml of 4-fluoroaniline in 5 ml of toluene at a temperature of between 0 ° C. and 10 ° C., 0.756 ml of a solution of trichloride of aluminum (2N) in toluene. After stirring for 40 minutes at a temperature in the region of 20 ° C., 271 mg of difluoro [4 - ({[(2-methylpropan-2-yl) oxy] carbonyl} oxy) -6- (morpholin-4-) are added slowly. yl) pyrimidin-2-yl] ethyl acetate solubilized in 6 mL of toluene. After 2h30 reflux, it returns to a temperature of 20 ° C and then at 0 ° C added 26 mL of water and 26 mL of a molar solution of potassium dihydrogen phosphate and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. After purification on a silica column of the residue, eluent: 2951169 115 CH2Cl2 / MeOH, 95/05, the solid is taken up in 5 mL of dichloromethane, the mixture is heated at 40 ° C. for 5 minutes and then it is returned to a temperature of 20 ° C. The insoluble material is filtered off and the residue is washed with three pastes in 1 ml of dichloromethane.

5 then dried under a vacuum bell. We obtain 28 mg of 2,2-difluoro-N- (4-

fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-

acetamide in the form of a white powder whose

characteristics are as follows:

1H NMR Spectrum (400MHz):

3.51 (m, 4H); 3.58 to 3.64 (m, 4H); 5.92 (brs, 1H); 7.20 (t, J = 9.0 Hz, 2H); 7.70 (dd, J = 5.2 and 9.0 Hz, 2H); 10.70 (brs, 1H); 11.82 (spread m, 1 H)

Mass spectrometry: method A

Retention time Tr (min) = 0.69

[M + H] +: m / z 369; [M-H] -: m / z 367

Example 78: Synthesis of N- (3,4-difluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide

H ON

NONO The product is prepared following the procedure described in Example 5 starting from 250 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] sodium acetate (example 68 step 1), 169 mg 3,4-difluoroaniline, and 285 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 2 mL of pyridine and 2 mL of dimethylformamide. 180 mg of N- (3,4-difluorophenyl) -2- [1-methyl-4- (morpholin-4-allyl) are obtained.

yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.33 (s, 3H); 3.39 (m, 4H); 3.58 (m, 4H); 3.91 (s, 2H); 5.36 (s, 1H); 7.26 (m, 1H); 7.39 (q, J = 9.5 Hz, 1H); 7.73 (ddd, J = 2.2 and 7.5 and 13.0 Hz, 1H); 10.43 (s, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.69 [M + H] +: m / z 365; [M-H] -: m / z 363 10 Melting point (Kofler): greater than 260 ° C.

Example 79: Synthesis of 2- [2- (2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one ON

The product is prepared following the procedure described in Example 5 starting from 200 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). 2-yl] sodium acetate (example 68 step 1), 174 mg of 2,3-dihydro-1H-indole, and 185 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.12 mL of pyridine and 3 mL of dimethylformamide. After purification on a silica column, eluent: CH 2 Cl 2 / MeOH, 93/07, the solid is taken up in 4 ml of methanol and a few drops of acetone. The suspension is heated to a temperature of 80 ° C, filtered hot and then recrystallized at a temperature of 20 ° C and then 25 ° C. The solid is filtered, rinsed with diethyl ether and then dried under vacuum. 52 mg of 2- [2- (2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) are obtained ) -one in the form of white crystals whose characteristics are as follows:

1H NMR Spectrum (400MHz):

3.17 (t, J = 8.4 Hz, 2H); 3.32 (s, 3H); 3.39 (m, 4H); 3.58 (m, 4H); 4.11 (s, 2H); 4.17 (t, J = 8.4 Hz, 2H); 5.36 (s, 1H); 7.02 (t, J = 7.5 Hz, 1H); 7.16 (t, J = 7.5 Hz, 1H); 7.26 (d, J = 7.5 Hz, 1H); 8.01 (d, J = 7.5 Hz, 1H)

Mass spectrometry: method A

Retention time Tr (min) = 0.68 [M + H] +: m / z 355; [M-H] -: m / z 353

Melting point (Kofler): greater than 250 ° C Example 80: Synthesis of N- (3-bromo-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo 1,6-dihydropyrimidin-2-yl] acetamide

The product is prepared following the procedure described in Example 5 starting from 200 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6). sodium dihydropyrimidin-2-yl] acetate (example 68 step 1), 199 mg of 3-bromo-4-fluoroaniline, and 228 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 1.5 mL of pyridine and 1.5 mL of dimethylformamide. 185 mg of N- (3-bromo-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained. white solid form whose characteristics are as follows: 1H NMR Spectrum (400MHz): 2951169 118

3.34 (s, 3H); 3.39 (m, 4H); 3.58 (m, 4H); 3.91 (s, 2H); 5.36 (s, 1H); 7.30-7.38 (t, J = 8.9 Hz, 1H); 7.48 (ddd, J = 2.7 and 4.4 and 8.9 Hz, 1H); 7.99 (dd, J = 2.7 and 6.4 Hz, 1H); 10.40 (s, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.76 [M + H] +: m / z 425; [M-H] -: m / z 423 Melting point (Kofler): greater than 262 ° C

Example 81: Synthesis of N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- The product is prepared by following the procedure described in Example 5 starting from 250 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo] Sodium 6-dihydropyrimidin-2-yl] acetate (example 68 step 1), 184 mg of (5-amino-2-fluorophenyl) methanol, and 285 mg of N- [3- (dimethylamino) propyl] - N'-ethylcarbodiimide hydrochloride in a mixture of 2 mL of pyridine and 2 mL of dimethylformamide. 157 mg of N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-en) are obtained. yl] acetamide as a gray solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.34 (s, 3H); 3.40 (m, 4H); 3.59 (m, 4H); 3.90 (s, 2H); 4.52 (d, J = 5.6 Hz, 2H); 5.27 (t, J = 5.6 Hz, 1H); 5.35 (s, 1H); 7.08 (t, J = 9.3 Hz, 1H); 7.43 to 7.53 (m, 1H); 7.64 (dd, J = 2.7 and 6.6 Hz, 1H); 10.23 (s, 1H) OH 2951169 119

Mass Spectrometry: Method A Retention time Tr (min) = 0.49 [M + H] +: m / z 377; [MH] -: m / z 375 Melting point (Kofler): greater than 224 ° C Example 82: Synthesis of N- (3-cyclopropylphenyl) -2- [1-methyl-4- (morpholin-4-yl) 6-Oxo-1,6-dihydropyrimidin-2-yl] acetamide NO The product is prepared following the procedure described in Example 5 starting from 200 mg of [1-methyl-4- (morpholin-4) sodium (-yl-6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 68, step 1), 194 mg of 3-cyclopropyleaniline (prepared according to Wallace et al., Tetrahedron Lett. 6987), and 185 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 4 ml of dimethylformamide. After extraction with ethyl acetate and purification on a silica column of the residue obtained, eluent: CH2Cl2 / MeOH, 95/05, 129 mg of N- (3-cyclopropylphenyl) -2- [1-methyl-4 are obtained. (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide in the form of a white solid, the characteristics of which are as follows: 1H NMR spectrum (400MHz): 0.57 to 0.64 (m, 2H); 0.90 to 0.98 (m, 2H); 1.82 at 91 (m, 1H); 3.33 (s, 3H); 3.38 at 3.43 (m, 4H); 3.57 to 3.62 (m, 4H); 3.89 (s, 2H); 5.35 (s, 1H); 6.79 (broad d, J = 7.8 Hz, 1H); 7.17 (t, J = 7.8 Hz, 1H) 25; 7.28 (t, J = 1.5 Hz, 1H); 7.31 (d, J = 7.8 Hz, 1H); 10.11 (s, 1 H) Mass Spectrometry: method A 5

120

Retention time Tr (min) = 0.76 [M + H] +: m / z 369; [MH] -: m / z 367 Melting point (Kofler): 216 ° C Example 83: Synthesis of N- (4-fluoro-3-methoxyphenyl) -2- [1-methyl-4- (morpholin-4- yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide NO The product is prepared following the procedure described in Example 5 starting from 200 mg of [1-methyl-4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (example 68 step 1), 205 mg of 4-fluoro-3-methoxyaniline, and 185 mg of N- [3 - (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of dimethylformamide.

After extraction with ethyl acetate and purification on a silica column of the residue obtained, eluent: CH 2 Cl 2 / MeOH, 95/05 and then 90/10, 42 mg of N- (4-fluoro-3-methoxyphenyl) are obtained. 2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a white solid, which has the following characteristics: 1H NMR spectrum ( 400MHz): 3.34 (s, 3H); 3.38 at 3.42 (m, 4H); 3.55 to 3.62 (m, 4H); 3.79 (s, 3H); 3.90 (s, 2H); 5.35 (s, 1H); 7.05 (ddd, J = 2.4 and 4.0 and 8.8 Hz, 1H); 7.14 (dd, J = 8.8 and 11.2 Hz, 1H); 7.47 (dd, J = 2.4 and 8.1 Hz, 1H); 10.26 (s, 1 H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.64 121

[M + H] +: m / z 377; [M-H] -: m / z 375 Melting point (Kofler): greater than 260 ° C

Example 84: Synthesis of N- (1-benzofur-4-yl) -2- [4- (morpholin-4-5 yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] acetamide NO The product is prepared by following the procedure described in Example 5 starting from 250 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate, 178 mg of 1-benzofuran-4-amine, 300 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 2 mL of pyridine and 3 mL of dimethylformamide. 275 mg of 2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N-phenylacetamide are obtained in the form of an off-white solid whose The characteristics are as follows: 1H NMR Spectrum (400MHz): 3.43 (m, 4H); 3.60 (m, 4H); 3.73 (s, 2H); 5.21 (s, 1H); 7.12 (broad, J = 2.2 Hz, 1H); 7.25 (t, J = 8.1 Hz, 1H); 7.35 (d, J = 8.1 Hz, 1H); 7.71 (d, J = 8.1 Hz, 1H); 7.94 (d, J = 2.2 Hz, 1H); 10.12 (s, 1H); 11.70 (spread m, 1H) Mass Spectrometry: Method B Retention time Tr (min) = 2.96 [M + H] +: m / z 355; [M-H] -: m / z 353 Melting point (Kofler): greater than 260 ° C 25

122

Example 85: Synthesis of 2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N-phenylacetamide The product is prepared according to the procedure described in Example 5 starting from 200 mg of sodium [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 68 step 1) , 134 mg of aniline, and 180 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of dimethylformamide. 95 mg of 2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N-phenylacetamide are obtained in the form of a violet solid whose characteristics are the following: 1H NMR Spectrum (400MHz): 3.35 (s, 3H); 3.41 (m, 4H); 3.58 (m, 4H); 3.91 (s, 2H); 5.35 (s, 1H); 7.06 (t, J = 7.8 Hz, 1H); 7.31 (t, J = 7.8 Hz, 2H); 7.55 (d, J = 7.8 Hz, 2H); 10.19 (s, 1 H) Mass Spectrometry: Method B Retention Time Tr (min) = 2.87 [M + H] +: m / z 329; [M-H] -: m / z 327 Melting point (Kofler): 212 ° C

Example 86: Synthesis of N- (3-Cyclopropyl-4-fluorophenyl) -2- [I-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 3 Step 1 To a solution of 950 mg of 3-bromo-4-fluoroaniline in 20 ml of toluene under stirring and under argon are added 558 mg of cyclopropylboronic acid, 3.7 g of tribasic potassium phosphonate, 70 mg of tricyclohexylphosphane and mg of palladium diacetate (2+) in 1.5 mL of water. The mixture is degassed and then heated to a temperature of 100 ° C. After 15 hours, the reaction medium is cooled to a temperature of 20 ° C, poured into 100 mL of water, and then extracted with four times 60 mL of diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified on a silica column, eluent: cyclohexane / ethyl acetate 70/30, 494 mg of 3-cyclopropyl-4-fluoroaniline is obtained in the form of a brown oil, the characteristics of which are as follows: Mass spectrometry : Method A Retention time Tr (min) = 0.40 [M + H] +: m / z 152; Step 2 The product is prepared following the procedure described in Example 5 starting from 200 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). 2-yl] sodium acetate (example 68 step 1), 220 mg of 3-cyclopropyl-4-fluoroaniline, and 180 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture 0.12 mL of pyridine and 2.5 mL of dimethylformamide. After extraction with ethyl acetate and purification on an eluent silica column: CH 2 Cl 2 / MeOH, 90/10, the residue is taken up in 10 ml of diisopropyl ether, the precipitate is filtered off and dried under vacuum to obtain 69 mg N- (3-Cyclopropyl-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide as a yellow solid whose characteristics are as follows: 1H NMR spectrum (400MHz): 0.57 to 0.66 (m, 2H); 0.94 to 1.03 (m, 2H); 1.93 to 2.08 (m, 1H); 3.33 (s, 3H); 3.37 at 3.42 (m, 4H); 3.55 to 3.62 (m, 4H); 3.87 (s, 2H); 5.35 (s, 1H); 7.07 (dd, J = 8.8 and 10.3 Hz, 1H); 7.16 (dd, J = 2.6 and 7.0 Hz, 1H); 7.29-7.38 (m, 1H); 10.16 (s, 1 H) Mass Spectrometry: Method B Retention time Tr (min) = 3.53 [M + H] +: m / z 387; [MH] -: m / z 385 Melting point (Kofler): 245 ° C Example 87: Synthesis of N- (3-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6 -oxo-1, 6-dihydropyrimidin-2-yl] acetamide H ON

The product is prepared by following the procedure described in Example 5 starting from 500 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate. , 357 mg of 2-amino-6-fluorophenol, 600 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 4 mL of pyridine and 4 mL of dimethylformamide. 335 mg of N- (3-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- are obtained.

yl] acetamide in the form of a beige solid whose characteristics are as follows:

1H NMR Spectrum (400MHz):

3.44 (m, 4H); 3.62 (m, 4H); 3.71 (s, 2H); 5.21 (s, 1H); 6.78 (dt, J = 6.0 and 8.1 Hz, 1H); 6.94 (broad t, J = 8.1 Hz, 1H); 7.64 (d, J = 8.1 Hz, 1H); 9.55 to 10.10 (m spread, 2H); 11.69 (spread m, 1H) Mass Spectrometry: Method B

Retention time Tr (min) = 2.66

[M + H] +: m / z 349; [M-H] -: m / z 347

Melting point (Kofler): greater than 260 ° C Example 88: Synthesis of 2- [2- (4-fluoro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- ( morpholin-4-yl) pyrimidin-4 (3H) -one The product is prepared by following the procedure described in Example 5 from 261 mg of [4- (morpholin-4-yl) -6 sodium oxo-1,6-dihydropyrimidin-2-yl] acetate, 274 mg of 4-fluoro-2,3-dihydro-1H-indole, 254 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.16 mL of pyridine and 4 mL of dimethylformamide. 249 mg of 2- [2- (4-fluoro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) are obtained. ) -one in the form of a white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.20 (t, J = 8.4 Hz, 2H); 3.41 (m, 4H); 3.61 (m, 4H); 3.76 (s, 2H); 4.21 (t, J = 8.4 Hz, 2H); 5.21 (s, 1H); 6.86 (t, J = 8.6 Hz, 1H); 7.12 to 7.31 (m, 1H); 7.84 (d, J = 8.1 Hz, 1H); 11.61 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 3.20 [M + H] +: m / z 359; [MH] -: m / z 357 Melting point (Kofler): greater than 260 ° C Example 89: Synthesis of 2- [2- (4-chloro-2,3-dihydro-1H-indol-1-yl) 2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one 7, N ,,, O The product is prepared following the procedure described in Example 5 from 261 mg sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate, 307 mg of 4-chloro-2,3-dihydro-1H-indole, 254 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 247 mg of 2- [2- (4-chloro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) are obtained. ) -one in the form of a white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.18 (t, J = 8.4 Hz, 2H); 3.41 (m, 4H); 3.60 (m, 4H); 3.76 (s, 2H); 4.20 (t, J = 8.4 Hz, 2H); 5.21 (s, 1H); 7.09 (d, J = 8.1 Hz, 1H); 7.22 (t, J = 8.1 Hz, 1H); 7.97 (d, J = 8.1 Hz, 1H); 11.62 (bs, 1 h) Mass Spectrometry: Method B Retention time Tr (min) = 3.46; [M + H] +: m / z 375; [MH] -: m / z 373 Melting point (Kofler): greater than 260 ° C Example 90: Synthesis of N- (3-ethynyl-4-fluorophenyl) -2- [4- (morpholin-4-yl) Step 1: To a solution of 1.169 g of 2-bromo-1-fluoro-4-nitrobenzene in 13 mL of triethylamine with stirring under argon, 1.126 ml of ethynyl (trimethyl) silane, 55 mg of triphenylphosphine and 24 mg of palladium acetate (2+) are added. After 4 hours and thirty minutes at a temperature of 100 ° C., the reaction medium is cooled and the insoluble material is filtered on sintered glass. The filtrate is concentrated to dryness under reduced pressure. After two purifications on an eluent silica column: Heptane / AcOEt, 90/10 and Heptane / AcOEt, 95/5, 460 mg of [(2-fluoro-5-nitrophenyl) ethynyl] (trimethyl) silane in the form of a yellow solid whose characteristics are as follows: Mass Spectrometry: The spectra were made by direct introduction on a WATERS GCTof apparatus (direct introduction without LC): El: [M] +. m / z 237; base peak: m / z 222 Step 2 2951169 129 FA a solution of 460 mg of [(2-fluoro-5-nitrophenyl) ethynyl] (trimethyl) silane in 10 mL of methanol is added 460 mg of iron and the medium is adjusted to pH 4-5 with concentrated hydrochloric acid. After reflux for three hours thirty, the medium is cooled and then filtered through silica, concentrated to dryness under reduced pressure. The residue is taken up in diethyl ether, the insoluble material is filtered off and the filtrate is concentrated to dryness under reduced pressure. 370 mg of 4-fluoro-3 - [(trimethylsilyl) ethynyl] aniline are obtained in the form of an orange oil, the characteristics of which are as follows: Mass spectrometry: method A Retention time Tr (min) = 1.11 [M + H] +: m / z 208; base peak: m / z 249 Step 3 To a solution of 360 mg of 4-fluoro-3 - [(trimethylsilyl) ethynyl] aniline in 5 mL of methanol was added 16 mg of potassium carbonate. After stirring overnight under argon and at a temperature in the region of 20 ° C., the mixture is concentrated to dryness under reduced pressure and then taken up in 8 ml of water, neutralized with a few drops of hydrochloric acid (1 N) and then extracted. three times with diethyl ether. The combined organic phases are dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 225 mg of 3-ethynyl-4-fluoroaniline are obtained in the form of a brown oil, the characteristics of which are as follows: Mass spectrometry: method A 2951169 130

Retention time Tr (min) = 0.49 [M + H] +: m / z 136; Step 4 NO The product is prepared following the procedure described in Example 5 from 204 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate, 211 mg of 3-ethynyl-4-fluoroaniline, 195 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.126 mL of pyridine and 3 mL of dimethylformamide. 200 mg of N- (3-ethynyl-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide are obtained in the form of a white solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.41 (m, 4H); 3.60 (m, 6H); 4.48 (s, 1H); 5.20 (s, 1H); 7.27 (t, J = 9.0 Hz, 1H); 7.56 (m, 1H); 7.78 (dd, J = 1.5 and 5.9 Hz, 1H); 10.31 (m spread, 1H); 11.66 (m spread, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.75 [M + H] +: m / z 357; [M-H] -: m / z 355 Melting point (Kofler): greater than 260 ° C

Example 91: Synthesis of 2- [2- (4-hydroxy-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) The product is prepared following the procedure described in Example 5 starting from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine). 2-yl] sodium acetate, 270 mg of 2,3-dihydro-1H-indol-4-ol, 254 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.16 mL of pyridine and 4 mL of dimethylformamide. 205 mg of 2- [2- (4-hydroxy-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) are obtained ) as a pink solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.01 (t, J = 8.1 Hz, 2H); 3.41 (m, 4H); 3.61 (m, 4H); 3.71 (s, 2H); 4.12 (t, J = 8.1 Hz, 2H); 5.20 (s, 1H); 6.49 (d, J = 8.1 Hz, 1H); 6.97 (t, J = 8.1 Hz, 1H); 7.50 (d, J = 8.1 Hz, 1H); 9.44 (brs, 1H); 11.60 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.57 [M + H] +: m / z 357; [MH] -: m / z 355 Melting point (Kofler): greater than 260 ° C Example 92: Synthesis of 2- [2- (4,6-difluoro-2,3-dihydro-1H-indol-1) 2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one OH 2 NO The product is prepared following the procedure described in Example 5 starting from 261 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate, 310 mg of 4,6-difluoro-2,3-dihydro-1H-indole, 254 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 225 mg of 2- [2- (4,6-difluoro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 are obtained (3H) -one in the form of a white solid whose characteristics are as follows: 1 H NMR spectrum (400 MHz): 3.17 (t, J = 8.4 Hz, 2 H); 3.41 (m, 4H); 3.61 (m, 4H); 3.78 (s, 2H); 4.24 (t, J = 8.4 Hz, 2H); 5.21 (s, 1H); 6.89 (broad t, J = 8.9 Hz, 1H); 7.64 (broad d, J = 8.9 Hz, 1H); 11.62 (m spread, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 0.73 [M + H] +: m / z 377; [MH] -: m / z 375 Melting point (Kofler): greater than 260 ° C Example 93 70: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 1 0.2 g Excipient for a tablet finished at 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

133

Example 1 is taken as an example of a pharmaceutical preparation, this preparation can be carried out if desired with other products examples in the present application. Pharmacological part: Experimental protocols In vitro experimental procedures The inhibitory activity of the molecules on the phosphorylation of AKT is measured either by western blotting by the technique described below, or by the MSD Multi-spot Biomarker detection technique of Meso Scale Discovery also described below. It has been demonstrated on a set of molecules that the two techniques give compatible results. Study of the expression of pAKT in human PC3 prostate carcinoma cells measured by western 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.

134

After this incubation, the cells are lysed for the preparation of the proteins. After aspiration of the culture medium, the cells are rinsed with 1 ml of PBS (Gibco DPBS, # 14190-094), recovered by scraping into 200 μl of complete HNTG buffer and transfer to a 96-well plate (Greiner # 651201), and lysed for 1H on ice. The HNTG buffer is composed of the following mixture: 50 mM Hepes, 150 mM NaCl, 1% Triton, 10% Glycerol, with extemporaneous additive of a Protease Inhibitor Cocktail Mini pellet (Roche 1836153) and a Phosphatase Inhibitor Cocktail pellet (Roche104906837001) for 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 NP0322BOX) and the migration is carried out for 1 h 30 in migration buffer NU-PAGE MOPS SDS Running Buffer 20X diluted 20 times (Ref InVitrogen NP0001), at 150 volts. The gel is then transferred to an Invitrolon PVDF membrane (Invitrogen # LC2007) previously permeabilized for a few seconds in ethanol (Ethanol Fischer Scientific # E / 0600DF / 15).

The transfer is carried out in a Biorad tank 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), 0.1% Tween 20 (# P5927 Sigma) and 3% BSA (Bovine Albumin Serum Fraction V, 2951169 135

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 5 Signaling Technology) Abcam), in saturation solution composed of PBS, Tween 20 0.1%, 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 1 / 10,000th for Rabbit anti-mouse IgG HRP antibody (W402 Promega) and 1 / 10,000th for Goat anti-Rabbit IgG HRP antibody (W401 Promega) in saturation solution then put under control. 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 developing solution is volume-to-volume prepared according to the data sheet of the Western Lightning Chemiluminescence Reagent Plus (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), calculated background noise 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 calculation of 2951169 136

Percent inhibition is done for each concentration according to the formula (100% - Ratio). 2 independent experiments make it possible to calculate the average of the inhibition percentages 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 the MSD Multi-spot Biomarker Detection kit from Meso Scale Discovery: phospho 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 96 well plates of the MSD kit: after addition of a protein lysate in each well, the revelation of the signal is by the addition of a labeled secondary detection antibody with an electrochemiluminescent compound. The procedure followed is that described in the kit. On day 1, the PC3 cells are seeded in 96-well plates (TPP, # 92096) at the concentration of 35000 cells / well in 200 μl of DMEM medium (Gibco DMEM # 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. 2951169 137

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. 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. agitation. 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 made with 150 μl of 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 room temperature, with stirring. Four washes are performed with 150 μl Tris Wash Buffer Wash Solution from the MSD kit. 150 μl Read Buffer revelation buffer from the MSD kit are added to the wells and the plates 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 percent inhibition calculation is done for 2951169 138

each concentration of product tested according to the following formula: (1- ((swarmin) / (max-min))) xl 00. The activity of the product is translated into IC50, obtained 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 Example 3 Example 4 EXAMPLE 6 EXAMPLE 7 EXAMPLE 8 EXAMPLE 9 EXAMPLE 10 3498 EXAMPLE 11 632 Example 12 737 Example 13 Example 14 570 74 Example 15 1420 Example 16 850 Example 17 1481 Example 18 23 Example 19 42 Example 20 1314 Example 21 10000 9 EXAMPLE 23 EXAMPLE 23 EXAMPLE 24 EXAMPLE 25 EXAMPLE 26 2287 EXAMPLE 27 EXAMPLE 28 EXAMPLE 29 EXAMPLE 30 Example 31 Example 32 3635 Example 33 93 Example 34 609 Example 35 10000 Example 36 200 Example 37 10000 Example 38 480 EXAMPLE 39 EXAMPLE 39 EXAMPLE 40 EXAMPLE 43 EXAMPLE 43 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 44 EXAMPLE 53 EXAMPLE 54 EXAMPLE 54 Example 55 5865 Example 58 760 71 Example 59 417 50 Example 60 Example 61 Example 62 Example 530 Example 63 Example 6 Example Example Example Example Example Example 6 EXAMPLE 68 EXAMPLE 69 EXAMPLE 69 EXAMPLE 70 EXAMPLE 71 5375 EXAMPLE 72 EXAMPLE 73 650 EXAMPLE 74 EXAMPLE 75 EXAMPLE 76 EXAMPLE 77 698 EXAMPLE 78 129 EXAMPLE 79 Example 80 Example 81 Example 82 Example 83 Example 84 Example Example 86 Example 87 Example 88 Example 89 1 Example 90 Example 91 Example 92 Tests A and B: IC 50 (nM) 10 15 20

Claims (17)

CLAIMS 1) Products of formula (I): wherein R1 represents an aryl or heteroaryl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, CN, nitro, -COOH radicals, -000alk, -NRxRy, -CONRxRy, -NRxCORy, -CORy, -NRxCO2Rz, alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, cycloalkyl, O-cycloalkyl, heterocycloalkyl; aryl and heteroaryl; these latter alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, heterocycloalkyl, aryl and heteroaryl radicals being themselves optionally substituted by one or more identical or different radicals selected from halogen atoms and hydroxyl, alkoxy and NRvRw radicals; the aryl and heteroaryl radicals being furthermore optionally substituted with one or more alkyl and alkoxy radicals themselves optionally substituted with one or more halogen atoms; the heterocycloalkyl and heteroaryl radicals may additionally contain an oxo radical, R represents a hydrogen atom or forms with R1 a saturated or partially or completely unsaturated 5- or 6-membered ring fused to an aryl or heteroaryl radical and optionally containing one or several other heteroatoms chosen from O, S, N, NH and Nalk, this bicyclic radical being optionally substituted by one or more identical radicals or different radicals chosen from halogen atoms; and hydroxyl, alkyl and alkoxy radicals; R2, R3, which may be identical or different, independently represent a hydrogen atom, a halogen atom or an alkyl radical optionally substituted with one or more halogen atoms; R4 represents a hydrogen atom; R5 represents a hydrogen atom or an alkyl radical optionally substituted with one or more halogen atoms; 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 meaning 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 the possible isomeric forms racemic, enantiomers and diastereoisomers, 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). 2) Products of formula (I) as defined in claim 1 in which: R 1 represents a phenyl, pyridine, thienyl, benzoxazol-4-yl and indazol-6-yl radical, optionally substituted with one or more identical or different radicals; selected from halogen atoms and CN, nitro, -COOH, -alkyl, -NRxRy, alkoxy, alkyl, alkynyl and cycloalkyl radicals; these latter alkoxy, alkyl and alkynyl radicals, themselves being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl radicals alkoxy and NRvRw; the phenyl and heteroaryl radicals being further optionally substituted with one or more alkyl and alkoxy radicals; R represents a hydrogen atom or forms with R1 a 1,4-benzoxazin-4-yl or 2,3-dihydroindol-1-yl ring, these rings being optionally substituted by one or more identical or different radicals chosen; among the halogen atoms and the hydroxyl, alkyl and alkoxy radicals; R2, R3, which may be identical or different, independently represent a hydrogen atom, a fluorine atom or an alkyl radical; R4 represents a hydrogen atom; R5 represents a hydrogen atom or an alkyl radical; NRxRy being such that Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom or an alkyl radical; either Rx and Ry form with the nitrogen atom to which they are bound a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this radical cyclic being optionally substituted; NRvRw being such that Rv represents a hydrogen atom or an alkyl radical and Rw represents a hydrogen atom or an alkyl radical; all the above alkyl (alk) and alkoxy radicals being linear or branched and containing from 1 to 6 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 3) Products of formula (I) as defined in any one of claims 1 or 2, corresponding to the following formulas: - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine -2-yl] -N-phenylacetamide-N- (4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- ( 3-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (dimethylamino) phenyl] -2- [4- (3-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2,4-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo] 146 - N- (3,4-Difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl -1,6-dihydropyrimidin-2-yl] acetamide ] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (thiophen-3-yl) acetamide - N- (4-fluoro-3) methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-fluorophenyl) -2- [4- (morpholin-4) 1-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydroxy dropyrimidin-2-yl] acetamide - N- (2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2, 3-difluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3,5-difluorophenyl) -2- [4- ( morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-Dihydropyrimidin-2-yl] acetamide-N- (4-chlorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- ( 3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo 1, 6-Dihydropyrimidin-2-yl] -N- [3- (trifluoromethyl) phenyl] acetam ide-N- (3-bromophenyl) -2- [4- (morpholin-4-yl) -6-oxo} 1,6-Dihydropyrimidin-2-yl] acetamide - N- [3- (2-methylpropan-2-yl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6) Methyl 3- (3- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl) amino) benzoate, dihydropyrimidin-2-yl] acetamide {[4- (morpholin-4-yl) -6-oxo-1, 6-Dihydropyrimidin-2-yl] acetyl} amino) benzoic acid - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propanediol) 2-yl) phenyl] acetamido-N- (3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-yl) -cyano-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (1H-indazol-6-yl) - 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-cyanophenyl) -2- [4- (morpholin-4-yl) - 6-Oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (5-fluoropyridin-2-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine -2-yl] acetamide - N- (4-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-Chloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) ) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (pyridin-3-yl) acetamide-N- (4-fluoro-2-methylphenyl) -2- [4- (morpholin-4- yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (3-hydroxyphenyl) 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-bromo-4-fluorophenyl) -2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 148 - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] N- (3,4,5-trifluorophenyl) acetamido-N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1, 6- dihydropyrimidin-2-yl] acetamide-N- (3-cyclopropylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (2- hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (difluoromethoxy) phenyl] -2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-fluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo] -1,6-Dihydropyrimidin-2-yl] propanamide-N- (2,3-dimethylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-fluoro-3-methylphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- benzoxazol-4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1, 6-Dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (trifluoromethoxy) phenyl] acetamide - 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (propan-2-yloxy) phenyl] acetam ide - N- (4- fluoro-2-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - {2- [3 - ({[4- (morpholine)} 2-Methylpropan-2-yl-N- [4-fluoro-3- (trifluoromethyl) phenyl 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) phenyl] ethyl] carbamate ] -2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide9-N- (3-ethynylphenyl) -2- [4- (morpholin-4-yl) ) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- [3- (cyclopentyloxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6) dihydropyrimidin-2-yl] acetamide - N- (4-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2 - [2- (2,3-Dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - N- (3-cyclopropyl) -4-fluorophenyl) -2- [4- (morpholin-4- yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- ( 2,3,4-trifluorophenyl) acetamido-N- [4-fluoro-3- (trifluoromethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 N- [3- (2-hydroxyethoxy) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (acetyl) -acetamide 3-iodophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-2-fluoro-5 - ([4- (morpholin-4- Methyl (N- (3-ethoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino) benzoate 1, 6-Dihydropyrimidin-2-yl] acetamide-N- (2,4-difluoro-3-methoxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine) 2-yl] acetamide 25 - 2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- (2,4,5-trifluorophenyl) acetam ide - N - (3,5-dichloro-4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydro-pyrimidin-2-yl] acetamide 2951169 150 - 2- [ 2- (2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-oxo ethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - N- (4-fluoro-3-nitrophenyl) -2- [4- (morpholin-4-yl) -6-oxo] 1, 6-Dihydropyrimidin-2-yl] acetamide 5-2-fluoro-5 - ({[4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} amino acid ) benzoic acid - N- (5-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (2-bromo) 4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-fluorophenyl) -2- [1-methyl] 4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-chloro-4-fluorophenyl) -2- [1-methyl-4- (morpholine 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 15-N- (3-bromophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6- 2- [1-ethyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N-oxo-1, 6-dihydropyrimidin-2-yl] acetamide; -fluorophenyl) acetamido-N- (1H-indol-4-yl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-fluorophenyl) -3-methyl-2- [4- (morpholin-4-yl) -6-oxo-1,6-diol ydropyrimidin-2-yl] butanamide - N- [4-fluoro-3- (methoxymethyl) phenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (4-fluoro-3-iodophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [4- (morpholine) 4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] -N- [3- (1,1,2,2-tetrafluoroethoxy) phenyl] acetamido-N- [3- (difluoromethyl)) 4-fluorophenyl] -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 2951169 151-2,2-difluoro-N- (4-fluorophenyl) 2- [4- (Morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3,4-difluorophenyl) -2- [1-methyl-4- ( morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 5 - 2- [2- (2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] 3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one - N- (3-bromo-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) 6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- [4-fluoro-3- (hydroxymethyl) phenyl] -2- [1-methyl-4- (morpholin-4-yl)] - 6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - N- (3-c) 1-methylpropylphenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide-N- (4-fluoro-3-methoxyphenyl) -2- [1-Methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide 15-N- (1-benzofur-4-yl) -2- [4- morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin) 2-yl] -N-phenylacetamide-N- (3-cyclopropyl-4-fluorophenyl) -2- [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2 -yl] acetamide - N- (3-fluoro-2-hydroxyphenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [2] - (4-Fluoro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one 25 - 2- [2 - (4-Chloro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one N- (3-ethynyl) 4-fluorophenyl) -2- [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetamide - 2- [2- (4-hydroxy-2,3-dihydro 1H-Indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-2- [2- 2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one152 as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). 4) Process for the preparation of the products of formula (I) as defined in any one of claims 1 to 3 according to scheme 1A as defined below. Scheme 1A: wherein the substituent R 1 has the meanings indicated in any one of claims 1 or 2. 5) Process for the preparation of the products of formula (I) as defined in any one of claims 1 to 3 according to scheme 1B as defined below. Scheme 1 B: CN O1 CIH BA Saponification Ç) CN DODY = Na, Li, K3 R5 H 'OX ^ R5 O NI NONOX = CI, Br, I or OTf CN 0 C Saponification CN 0 FY = Na, Li, K CN 0 (I) -b wherein the substituents R1 and R5 have the meanings given in any one of claims 1 or 2. 6) Process for the preparation of the products of formula (I) as defined in any one of claims 1 to 3 according to scheme 1C as defined below. Scheme 1C: 4 CN O C R2X then R3X; X = Cl, Br, I or OTf (Boc) R1 R1 RSX X = Cl, Br, I, OTf CN OJ CN O (I) -c R2X then R3X X = Cl, Br, I, OTf or (PhSO2 ) 2N-F wherein the substituents R1, R2, R3 and R5 have the meanings given in any one of claims 1 or 2. 7) As medicaments, the products of formula (I) as defined in any one of claims 1 to 3, as well as addition salts with inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases. said products of formula (I). 8) 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 ). 2951169 155 9) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier. 10) 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. 11) Use according to claim 10 for the treatment of solid or liquid tumors. 12) Use according to claim 10 or 11 for the treatment of cancers resistant to cytotoxic agents. 13) Use according to one or more of claims 10 to 12 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, larynx, lymphatic system, cancers of the bones and pancreas, in hamartomas. 14) Use of the products of formula (I) as defined in claims 1 to 3 for the preparation of medicaments for the chemotherapy of cancers. 15) 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. 16) Products of formula (I) as defined in any one of claims 1 to 3 as inhibitors of phosphorylation of AKT (PKB) 2951169 156 17) As new industrial products, the synthetic intermediates of formulas C, D, E and F as defined in claim 4 above and recalled below: C, ED, F 5 in which R5 has the definition as defined in any one of claims 1 to 2. R5 NY NY = Na, Li, K o