FR2969614A1 - New pyrimidinone compounds are akt phosphorylation inhibitors useful for treating e.g. gastric cancer, glioblastomas, thyroid cancer, bladder cancer, breast cancer, melanoma, lymphoid or myeloid hematopoietic tumors, and sarcomas - Google Patents

Abstract

Pyrimidinone compounds (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. Pyrimidinone compounds of formula (I) and their racemic forms, enantiomers, diastereoisomers, and addition salts with mineral and organic acids or bases are new. R1 : H or methyl; R2 : H or F; R3 : H or halo, preferably F; R4 : alkyl, alkoxy, heterocycloalkyl, aryl or heteroaryl (all optionally substituted by halo, OH, oxo, alkyl, heterocycloalkyl, alkoxy, NR1vR1w or SO 2Alk), NR1xR1y, H, halo, or hydroxyl; either R5, R5a : H or an alkyl; or CR5R5a : 3-10-membered cyclic group (spirocycloalkyl) optionally containing one or more heteroatoms (preferably spiroheterocycloalkyl) of O, S, or NH, where the cyclic group is optionally substituted by one or more halo, alkyl, cycloalkyl, hydroxyl, oxo, alkoxy, NH 2, NHalk or N(alk) 2; either R6 : H, alkyl (optionally substituted by halo, deuterium, OH or alkoxy), cycloalkyl or phenyl (optionally substituted by halo or alkoxy); or CR5R6 : 3-10 membered cyclic group (cycloalkyl) optionally containing one or more heteroatoms (heterocycloalkyl) of O, S, or NH (where the cyclic groups are optionally substituted by one or more halo, alkyl, hydroxyl, oxo, alkoxy or NH 2), NHalk or N(alk) 2; either R1x : H or alkyl group; and R1y : H, cycloalkyl group or alkyl optionally substituted by one or more OH, alkoxy, NR1vR1w or heterocycloalkyl; or NR1xR1y : 3-10 membered cyclic group (optionally one or more other heteroatoms of O, S, NH or N-alkyl group), where the cyclic group is optionally substituted by one or more halo, OH, oxo, alkyl, heterocycloalkyl, alkoxy, -NR1vR1w or SO 2Alk; either R1v : H or alkyl group; and R1w : H, cycloalkyl group or alkyl optionally substituted by one or more OH, alkoxy, or heterocycloalkyl; or NR1vR1w : 3-10 membered cyclic group (optionally one or more other heteroatoms of O, S, NH or N-alkyl group), where the cyclic group is optionally substituted by one or more halo, OH, oxo, alkyl, heterocycloalkyl, alkoxy, or NH 2, NHalk, N(alk) 2or SO 2alk; and R : H, alkyl, cycloalkyl, or (hetero)aryl. Independent claims are included for: (1) the preparations of (I); and (2) intermediates comprising (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester (C), (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid ethyl ester compound of formula (E), or (4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetic acid metal salt of formula (D) or (F) and 2,3-dihydro-1H-indole compound of formula (L). Y0 : Na, Li or K. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Akt phosphorylation inhibitor. The ability of (I) to inhibit akt phosphorylation was tested in human prostate carcinoma (PC3) cell line using multi-spot biomarker detection of meso scale technique. The result showed that 2-[2-((+)-2-fluoromethyl-2,3-dihydro-indol-1-yl)2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one exhibited an IC 50value of 2 nM.

Description

NOVEL DERIVATIVES OF PYRIMIDINONES, THEIR PREPARATION AND THEIR PHARMACEUTICAL USE AS INHIBITORS OF PHOSPHORYLATION OF AKT (PKB) The present invention relates to new chemical compounds derived from pyrimidinones, their process of preparation, the new intermediates obtained, their application as medicaments the pharmaceutical compositions containing them and the novel use of such derivatives.

The present invention thus also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans. More particularly, the invention relates to novel pyrimidinone derivatives and their pharmaceutical use for the prevention and treatment of conditions capable of being modulated by inhibition of the P13K / AKT / mTOR pathway. AKT is a key player in this signaling path. A high level of AKT phosphorylation is the marker of pathway activation that is found in many human cancers. The products of the present invention can thus be used in particular for the prevention or the treatment of conditions capable of being modulated by the inhibition of AKT phosphorylation (P-AKT). The inhibition of P-AKT can be obtained in particular by the inhibition of the P13K / 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), P13K phosphoinositide kinase, serine-threonine kinase AKT, mTOR kinase. Inhibition and regulation of the P13K / AKT / mTOR pathway is a novel and powerful mechanism of action for the treatment of a large number of cancerous diseases including solid and liquid tumors.

Such conditions which can be treated by the products of the present application are solid or liquid human tumors. Role of the P13K / AKT / mTOR pathway The P13K / AKT / mTOR signaling pathway is a complex network that regulates multiple cellular functions, such as growth, survival, proliferation and cell motility, which are key processes in tumorigenesis. This signaling pathway is an important target in the treatment of cancer because most of its effectors are altered in human tumors. The main effectors contributing to the activation of the pathway are: i) oncogenes such as ErbB1 (EGFR), ErbB2 (HER2), PIK3CA and AKT activated by mutation, amplification or overexpression; ii) deficiency of tumor suppressor genes such as PTEN, TSC112, LKB and PML that are inactivated as a result of mutations or deletions (Jiang LZ & Liu LZ, Biochim Biophys Acta, 2008, 1784: 150; Vivanco 1 & Sawyers CL, 2002, Nat Rev Cancer, 2: 489, Cu11yM et al., Nature Rev. Cancer, 2006, 6: 184). Activation of oncogenes of this signaling pathway is found in many human cancer diseases. PIK3CA activating mutations are present in 15-300% of colon, breast, endometrial, liver, ovarian and prostate cancers (TL Yuan and LC Cantley, Oncogene, 2008, 27). : 5497; Y. Samuels et al., Science, 2004, 304: 554; KE, Bachman et al., Cancer Biot Ther, 2004, 3: 772; DA Levine et al., Clin Canc Res., 2005, 11: 2875; Hartmann et al., Acta Neuropathol 2005, 109: 639). - the amplifications, activating and overexpressing mutations of RTKs such as EGFR and HER2 in brain, breast and lung cancers (NSCLC) - the amplification and activating overexpression of AKT in cancers of the brain, lung ( NSCLC), breast, kidney, ovary and pancreas (Testa JR and Bellacosa A., Proct Nat1 Acad Sci USA 2001, 98: 10983, Cheng et al., Proct Nat1 Acad Sci USA 1992, 89: 9267, Bellacosa et al., Int J Cancer, 1995, 64: 280, Cheng et al., Proct Natl Acad Sci USA 1996, 93: 3636, Yuan et al. Oncogene, 2000, 19: 2324). The deficiency of the tumor suppressor genes of this signaling pathway is also found in many human cancerous diseases: the deletion of PTEN in 500% 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., Amer J. Pathol., 2002, 161: 439; Endersby R & Baker SJ, Oncogene, 2008, 27: 5416, Li et al., Science, 1997, 275: 1943, Steack PA et al., Nat Genet., 1997, 15: 356), mutations of TSC1 / 2 in more than 500% of tuberous sclerosis o mutations or deletions of LK81 (or STK11) which predispose to cancers of the gastrointestinal tract and pancreatic cancer and which are found especially in 10-380 / 0 adenocarcinomas of lung (Shah U. et al., Cancer Res., 2008, 68: 3562) o PML changes by translocation in human tumors (Gurrieri C et al, J. NAt1 Canc Inst Inst 2004, 96: 269). In addition, this signaling pathway is a major factor in resistance to chemotherapy, radiotherapy and targeted therapies such as EGFR and HER2 inhibitors for example (C. Sawyers et al., Nat Rev 2002). Role of AKT AKT (protein kinase B, PKB) is a serine-threonine kinase that occupies a central place in one of the major cell signaling pathways, the P13K / AKT 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, Ce11, 2007 129: 1261). Activation of AKT promotes the internalisation of nutrients,

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which triggers a process of anabolic metabolism supporting growth and cell proliferation. In particular, AKT controls the initiation of protein synthesis through a cascade of interactions that proceeds via TSC1 / 2 (tuberous sclerosis complex), Rheb, and TOR to achieve two critical targets of the pathway. signaling, p70S6K and 4EBP. AKT also induces inhibitory phosphorylation of the Forkhead transcription factor and inactivation of GSK3 (3 which lead to inhibition of apoptosis and cell cycle progression (Franke TF, Oncogene, 2008, 27: 6473). is therefore a target for anti-cancer therapy and the inhibition of AKT activation by the inhibition of its phosphorylation can induce apoptosis of malignant cells and thereby present a treatment for cancer. with tyrosyne kinase activity such as IGF1 R Abnormally high levels of protein kinase activity have been implicated in many diseases resulting from abnormal cell function This can be caused either directly or indirectly by a malfunction in the mechanisms of activity control related to, for example, mutation, over-expression or inappropriate activation of the enzyme, or over- or under-production of cytokines or growth, also involved in signal transduction upstream or downstream of kinases. In all these cases, a selective inhibition of the kinase action suggests a beneficial effect. The type 1 receptor for insulin-Iike 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 greater 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 5 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 establishment and maintenance of the transformed phenotype in vitro as in vivo [Baserga R, Exp. Cell. Res., 1999, 253, pages 1-6]. The kinase activity of IGF-I-R is essential for the transformation activity of several oncogenes: EGFR, PDGFR, the large antigen of SV40 virus, activated Ras, Raf, and v-Src. Expression of IGF-I-R in normal fibroblasts induces a neoplastic phenotype, which can then lead to tumor formation in vivo. The expression of IGF-I-R plays an important role in the independent growth of the substrate. IGF-I-R has also been shown to be a protector in apoptosis-induced chemotherapy, radiation, and cytokine-induced apoptosis. In addition, inhibition of endogenous IGF-IR by a dominant negative, triple helix formation or expression of antisense causes suppression of the transforming activity in vitro and decrease of tumor growth in the cells. animal models. PDK1 3'-Phosphoinositide-dependent protein kinase-1 (PDK1) is one of the essential components of the P13K-AKT signaling pathway. It is a serine-threonine (Ser / Thr) kinase whose role is to phosphorylate and activate 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), p70S6K (or p70 ribosomal S6 kinase), and various isoforms of protein kinase C ( PKC) (Vanhaesebroeck B. & Alessi DR., Biochem J, 2000, 346: 561). One of the key roles of PDK1 is therefore the activation of AKT: in

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the presence of PIP3, the second messenger generated by P13K, PDK-1 is recruited to the plasma membrane via its PH domain (plekstrin homology) and phosphorylates AKT on threonine 308 located in the activation loop, an essential modification of the activation AKT. PDK1 is ubiquitously expressed and is a constitutively active kinase. PDK1 is a key element in the P13K / AKT signaling pathway for the regulation of key processes in tumorigenesis such as cell proliferation and survival. Since this pathway is activated in more than 500% of human cancers, PDK1 represents a target for anticancer therapy. Inhibition of PDK1 should result in effective inhibition of cancer cell proliferation and survival and thus provide therapeutic benefit for human cancers (Bayascas JR, Eye cycle, 2008, 7: 2978, Peifer C. & Alessi DR ChemMedChem, 2008, 3: 1810). Phosphoinositide-3 kinases (P13Ks) P13K lipid kinase is an important target in this signaling pathway for oncology. P13Ks of class I are divided into class la (P13Ka, 13.8) activated by receptors with tyrosine kinase activity (RTKs), G-protein coupled receptors (GPCRs), GTPases of the Rho family, p21-Ras and in class Ib (P13Ky) activated by the GPCRs and by p21-Ras. P13Ks of class la are heterodimers which consist of a catalytic subunit p110a, R or 8 and a regulatory subunit p85 or p55. Class Ib (p110y) is monomeric. P13Ks in class 1 are lipids / protein kinases that are activated by RTKs, GPCRs or Ras after membrane recruitment. These P13Ks of class 1 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

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cell transformation such as proliferation, growth and cell survival as well as angiogenesis. Class 1 P13Ks are involved in human cancers: somatic mutations of the PIK3CA gene that codes for P13Ka are found in 15-350 / 0 of human tumors including two main oncogenic mutations H1047R (in the kinase domain) and E545K / E542K (in the helical domain) (Y. Samuels et al., Science, 2004, 304: 554, TL Yuan and LC Cantley, Oncogene, 2008, 27: 5497). Inhibitors of P13K are expected to be effective for the treatment of many human cancers with genetic alterations leading to activation of the P13K / AKT / mTOR pathway (Vogt P. et al., Virology, 2006, 344: 131; Vogt PK, Oncogene, 2008, 27: 5486). Morpholino pyrimidinone derivatives which are kinase inhibitors are known to those skilled in the art.

The WO2008 / 148074 application describes products that have mTOR inhibitory activity. These products are pyrido [1,2-a] pyrimidin-4-ones which differ from the products of the present invention because of their wholly aromatic character and their substitutions. The application WO2008 / 064244 describes the application of the P13K 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 of their substitutions

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The WO2003 / 024949 application describes DNAPK inhibitory products useful for the treatment of deficient ATM cancers. These products are pyrido [1,2-a] pyrimidin-4-ones which differ from the products of the present invention because of their wholly aromatic character and their substitutions. Morpholino pyrimidine kinase inhibitor derivatives are also known to humans. art. The applications WO2009 / 007748, WO2009 / 007749, WO2009 / 007750 and WO2009 / 007751 describe products which have an inhibitory activity of mTOR and / or P13K for the treatment of cancers. These products are pyrimidines substituted at 2, 4 and 6 and the products of the present invention differ because of the presence of the carbonyl group on pyrimidinone as well as by the different substituents. The subject of the present invention is the products of formula (1 R3 -'-Di (1) wherein: R represents a hydrogen atom or an alkyl, cycloalkyl, aryl or heteroaryl radical; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a halogen atom;

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R4 represents a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy radicals; heterocycloalkyl, aryl heteroaryl and NRxRy; all these alkyl, alkoxy, heterocycloalkyl, aryl and heteroaryl radicals themselves being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, oxo, alkyl, heterocycloalkyl, alkoxy and NRvRw radicals, and S02AI k; R5 and R5 ', which may be identical or different, represents a hydrogen atom or an alkyl radical or, together with the carbon atom to which they are bonded, form a cyclic radical containing from 3 to 10 members (spirocycloalkyl) optionally containing one or more heteroatoms; (spirohétérocycloalkyle); chosen from O, S, NH, these cyclic radicals being optionally substituted with one or more identical or different radicals chosen from halogen atoms, alkyl, cycloalkyl, hydroxyl, oxo, alkoxy and NH 2 radicals; NHalk and N (alk) 2; R6 represents a hydrogen atom; an alkyl radical which is itself optionally substituted with one or more identical or different radicals chosen from halogen atoms, deuterium atoms and hydroxyl and alkoxy radicals; a cycloalkyl radical or a phenyl radical itself optionally substituted with one or more identical or different radicals chosen from halogen atoms or alkoxy radicals; R 5 and R 6 may optionally form, with the carbon atoms to which they are bonded, a 3 to 10-membered (cycloalkyl) cyclic radical optionally containing one or more heteroatoms (heterocycloalkyl) chosen from O, S, NH, these cyclic radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms, alkyl, hydroxyl, oxo, alkoxy and NH 2 radicals; NHalk and N (alk) 2; 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 optionally being substituted with one or more identical or different radicals selected from halogen atoms and hydroxyl, oxo, alkyl, heterocycloalkyl, alkoxy, NRvRw and -SO2Alk radicals; 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; by one or more identical or different radicals selected from halogen atoms and hydroxyl, oxo, alkyl, heterocycloalkyl, alkoxy, NH 2 radicals; NHalk and N (alk) 2 and - SO2A1 k; said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). The products of formula (1) according to the present invention are such that: - at least one of R2, R3, R4, R5, R5 'and R6 is different from halogen, hydroxyl, alkyl and alkoxy; the other substituents R and R1 of said products of formula (1) having any of the definitions indicated above or below - or R is not a hydrogen atom or an alkyl radical optionally substituted by one or more atoms halogen, the other substituents R1, R2, R3, R4; R5, R5 'and R6 of said products of formula (1) having any of the definitions given above or hereinafter. In the products of formula (1): the term "alkyl radical (or alk)" denotes the linear and branched radicals containing from 1 to 10 carbon atoms, such as 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 radicals are preferred alkyl containing 1 to 4 carbon atoms from the above list; the term "alkoxy radical" denotes linear and branched radicals containing from 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy, as well as their linear or branched positional isomers: alkoxy radicals containing from 1 to 4 carbon atoms of the above list are preferred; the term "alkylthio radical" denotes the linear and, if appropriate, branched, linear, secondary or tertiary methylthio, propylthio, isopropylthio, butylthio, pentylthio or hexylthio radicals, as well as their linear or branched positional isomers: alkylthio radicals containing 1 to 4 carbon atoms from the above list; the term "halogen atom" denotes the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom. the term "cycloalkyl radical" denotes a saturated carbocyclic radical containing 3 to 10 carbon atoms and thus particularly denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, and especially the cyclopropyl, cyclopentyl and cyclohexyl radicals; in the -O-cycloalkyl radical, cycloalkyl is as defined above;

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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) - link, heterocyclic radicals containing one or more identical or different heteroatoms selected from O, N, or S with N, if appropriate, optionally substituted; the term "aryl radical" thus denotes monocyclic or bicyclic radicals containing 6 to 12 members, such as for example the phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly the phenyl and naphthyl radicals and even more particularly the phenyl radical. It may be noted that a carbocyclic radical containing a -C (O) - linkage is, for example, the tetralone radical; the term "heteroaryl radical" thus denotes monocyclic or bicyclic radicals containing 5 to 12 ring members: monocyclic heteroaryl radicals such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3-furyl, 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 (1) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example: - among salification compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N methylglucamine, - among the esterification compounds, the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being substitutable by radicals chosen from, for example, halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl groups; or phenethyl. The addition salts with the inorganic or organic acids of the products of formula (1) may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids. It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or isomeric cistrans. The term stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above. In the products of formula (1) as defined above, NRxRy may for example be such that either Rx represents a hydrogen atom or an alkyl radical and Ry represents a hydrogen atom or an alkyl radical; or Rx and Ry form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 7 members and optionally one or more other heteroatoms chosen from O, S, NH, this cyclic radical being optionally substituted as indicated above or below; and NRvRw may be such that Rv represents a hydrogen atom or an alkyl radical and Rw represents a hydrogen atom or an alkyl radical; or Rv and Rw form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 7 members and optionally one or more other heteroatoms chosen from O, S, NH, this cyclic radical being optionally substituted as indicated above or below; said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1).

In particular, when NRxRy or NRvRw forms a ring respectively with the atom to which they are bonded as defined above, such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl and piperazinyl radicals. or homopiperazinyl, these radicals themselves being optionally substituted as indicated above or hereinafter. The NRxRy or NRvRw ring may more particularly be chosen from pyrrolidinyl radicals, morpholinyl itself optionally substituted by one or two alkyl radicals or piperazinyl radical, itself optionally substituted on the second nitrogen atom by an alkyl, phenyl or -CH 2 radical. -phenyl or -SO2-Alk, all these latter alkyl radicals, Alk and phenyl being themselves optionally substituted by one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals.

The subject of the present invention is thus the products of formula (1) as defined above in which: R represents a hydrogen atom or an alkyl, cycloalkyl or phenyl radical; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom; a halogen atom; or a hydroxyl, alkyl, or alkoxy, heterocycloalkyl, NRxRy, phenyl or heteroaryl radical; the alkyl radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, heterocycloalkyl and NRvRw radicals; the alkoxy radicals being optionally substituted with one or more halogen atoms; R5 and R5 ', which may be identical or different, represent a hydrogen atom or an alkyl radical or, together with the carbon atom to which they are bonded, form a cyclic radical of 3 to 6 ring members optionally containing one or more heteroatoms chosen from O S, NH, optionally substituted with an alkyl or cycloalkyl radical; R6 represents a hydrogen atom; or an alkyl radical (itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms, deuterium atoms and hydroxyl and alkoxy radicals; a cycloalkyl radical or a phenyl radical which is itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms or R5 and R6 alkoxy radicals which may optionally form, with the carbon atoms to which they are bonded, a cyclic radical containing from 3 to 7 members, said products of formula (1) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1) The present invention particularly relates to the products of formula (1) as defined above in which: R2 represents a hydrogen atom or u n fluorine atom; R3 represents a hydrogen atom or a fluorine, chlorine or bromine atom; R4 represents a hydrogen atom; a halogen atom selected from chlorine, fluorine and bromine; and a hydroxyl, alkyl radical; alkoxy; a pyrrolidinyl or piperidyl radical optionally substituted by an alkyl radical; morpholinyl; piperazinyl optionally substituted with alk on N; phenyl optionally substituted with one or more radicals selected from Cl, F or OCH3; and pyridyl; it being understood that the alkyl radicals are optionally substituted with one or more identical or different radicals chosen from fluorine atoms, the hydroxyl radical, and the piperazinyl radical, itself optionally substituted on N by an alkyl or SO 2 -alk radical; it being understood that the alkoxy radicals are optionally substituted by one or more fluorine atoms; R5 and R5 ', which may be identical or different, represents a hydrogen atom or an alkyl radical or, together with the carbon atom to which they are bonded, form a spirocyclopropyl, spirotetrahydropyran or spiropiperidyl radical optionally substituted by an alkyl or cycloalkyl radical over N; R6 represents a hydrogen atom; or an alkyl radical which is itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms; a cyclopropyl radical; or a phenyl radical itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms; R5 and R6 may optionally form with the carbon atoms to which they are attached a cyclopentyl radical; said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). In the products of formula (1) as defined above, when R 4 represents an alkyl or alkoxy radical optionally substituted with one or more halogen atoms, R 4 may in particular represent a radical - CF 3, -OCF 3 or alternatively -OCHF 2 The subject of the present invention is particularly the products of formula (1) as defined above, corresponding to the following formulas: 6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [cyclopropane] 1,3'-indol] -1 '(2'H) -yl) ethyl] pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- [2-oxo-2- -phenyl-2,3-dihydro-1H-indol-1-yl) ethyl] pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2- [4- (Trifluoromethoxy) -2,3-dihydro-1H-indol-1-yl] ethyl) pyrimidin-4 (3H) -one-3-methyl-6- (morpholin-4-yl) -2- (2-oxo) 2- [4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- {2- oxo-2- [4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [4- (2-methoxyphenyl)} 2,3-Dihydro-1H-indol-1-yl] -2-o xylethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2- [4- (1-propylpiperidin-3- yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [4- (difluoromethoxy) -2,3-dihydro-1H-indol) 1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2- [4- (difluoromethoxy) -2,3-d 1H-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- oxo-2- [4- (pyridin-4-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one -2- [2- (1- methylspiro [indole-3,4'-piperidin] -1 (2H) -yi) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4- yl) -2- {2-oxo-2- [4- (pyridin-2-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one-6 - (Morpholin-4-yl) -2- {2-oxo-2- [4- (pyridin-3-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 ( 3H) -one - 2- {2- [4- (2-chlorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidine -4 (3H) -one - 2- [2- (4-chloro-2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -3-cyclopropyl-6- (morphol in-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- [2-oxo-2- (2,3,3a, 8b-tetrahydro-cyclopenta [b] indol-4 (1H) -yl) ethyl] pyrimidin-4 (3H) -one - 2- [2- (4 - {[4- (methylsulfonyl) piperazin-1-yl] methyl} -2,3-dihydro-1H -indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- (2- {4 - [(4-methylpiperazin-1-yl) methyl) ] -2,3-Dihydro-1H-indol-1-yl} -2-oxoethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2- [4- 2-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-3-methyl-2- (2- {4 - [(4-methylpiperazin-1-yl) methyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -6- (morpholin-4-yl) pyrimidine 4- (3H) -one-6- (morphol-4-yl) -2- [2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole-3,4'- pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one-3-methyl-6- (morpholin-4-yl) -2- [2-oxo-2- (2 ', 3') 5 ', 6'-Tetrahydrospiro [indole-3,4'-pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one-3-methyl-6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [indole-3,4'-piperidin] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one - 6 - (Morpholin-4-yl) -2- {2-oxo-2 - [(2R) -2-phenyl-2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one 6- (morpholin-4-yl) -2- {2-oxo-2 - [(2S) -2-phenyl-2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [4- (4-methylpiperazin-1-yl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholine) 4-yl) pyrimidin-4 (3H) -one - 2- {2 - [(2R) -2- (4-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl (6-morpholin-4-yl) pyrimidin-4 (3H) -one-2- {2 - [(2S) -2- (4-fluorophenyl) -2,3-dihydro-1H-indol-1} -yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2 - {(2R) -4- (difluoromethoxy) -2-methyl-2,3 1-Dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one -2- {2 - [(2S) -4- (difluoromethoxy) ) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2- [ (2R) -4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin 4 (3H) -one - 2- {2 - [(2S) -4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethane hyl-3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- {2- [4- (morpholin-4-yl)} -2,3-Dihydro-1H-indol-1-yl] -2-oxoethyl} pyrimidin-4 (3H) -one - 2- {2 - [(2R) -2-cyclopropyl} -2,3-d 1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one -2- {2 - [(2S) -2-cyclopropyl-2} 3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-2- {2 - [(2R) -2-methyl) 4- (Trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one

21

2- {2 - [(2S) -2-methyl-4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) ) pyrimidin-4 (3H) -one - 2- [2 - ((+) - 2-Fluoromethyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholin-4- 1H-3H-pyrimidin-4-one -2- [2- (2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholin-4-yl-3-phenyl-3H pyrimidin-4-one as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (1). The present invention also relates to any process for preparing the products of formula (1) as defined above. The products according to the invention can be prepared from conventional methods of organic chemistry. Preparation of compounds of formula (1) The products of general formula (1) according to the present invention can 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: ## STR5 ## in which the substituents R 2, R 3, R 4, R 5, R 5 'and R 6 have the meanings indicated above. 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 can be obtained by "one-pot" reaction between the morpholine and an excess (for example 3 equivalents) of imino-ether A

23

(or its aminoacrylate tautomer), in a solvent such as ethanol, at a temperature between 20 ° C and the boiling point of the solvent. The carboxylate D may be obtained by hydrolysis of the ester C in the presence of a base such as sodium hydroxide or lithium hydroxide, in a solvent such as tetrahydrofuran or methanol, at a temperature of between 0 ° C. and 30 ° C. The amides (I) -a can be obtained from carboxylate D by condensation of an indoline L in the presence of a peptide coupling agent such as, for example, EDCI (ethyl dimethylaminopropyl carbodiimide), DMT-MM. [4- (4,6-Dimethoxy-1,2,3-triazin-2-yl) 4-methylmorpholinium chloride], BOP [benzotriazol-1-yloxy-tris-dimethylamino phosphonium hexafluorophosphate], PyBOP [hexafluorophosphate benzotriazol-1-yloxytris pyrrolidino phosphonium], PyBROP [bromo tris-pyrrolidino phosphonium hexafluorophosphate], HATU [047-azabenzotriazol-1-yl] -1,1,3,3-tetramethyluronium hexafluorophosphate)] or a mixture thereof HOBT / EDCI [hydroxybenzotriazole / ethyl dimethylaminopropyl carbodiimide], in a solvent such as N, N-dim thylformamide, 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 reacting an indoline L 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) 2185-2189 and by Auzeloux, P et al. in J. Med. Chem. 2000, 43 (2), 190-197. General Scheme 1B: R 1 y N OFY = Na, Li, KN OCRI CD) Saponification L R3 + YE R3 R2, RXX = Cl, Br, I, OTf or X = B (OH) 2 R3 R2 cD in which the substituents R R 2, R 3, R 4, R 5, R 5 'and R 6 have the meanings indicated above. In General Scheme 1B: Esters E can be obtained from ester C by reaction with a compound RX (X = Cl, Br, 1 or triflate), in the presence of a base such as sodium hydroxide, tert-butylate of potassium or cesium carbonate, in a solvent such as methanol, ethanol or dioxane, at a temperature of between 0 ° C. and 50 ° C., for example according to the method described by Noël D.

D'Angelo et al. in J. Med. Chem. 2008, 51, 5766-5779. Esters E can also be obtained from ester C by reaction with a compound R5-X (X = B (OH) 2), in the presence of a base such as DMAP (dimethyl-pyridin-4-yl). -amine) and NaHMDS (1,1,1,3,3,3-hexamethyl-disilazane), a copper (II) salt such as copper acetate (Cu (OAc) 2) in a solvent such as toluene, dioxane or tetrahydrofuran, at a temperature between 0 ° C. and the boiling point of the solvent, according to, for example, the process described by Takayuki Tsuritani et al. (Organic Letters 2008, 10 (8), 1653-1655). 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 indoline L 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 hexafluorophosphate] 1-yloxy tris-pyrrolidino phosphonium], PyBROP [bromo tris pyrrolidino phosphonium hexafluorophosphate], HATU [047-azabenzotriazol-1-yl] -1,1,3,3-tetramethyluronium hexafluorophosphate)] or a HOBT mixture / 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 indoline L, in the presence of an agent such as trimethyl aluminum, in a solvent such as toluene, at a temperature of between 20 ° C. 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: I R, X; X = Cl, Br, 1 or OTf R3 R2 R4 CN DOGX = Cl, Br, I, OTf) = C, Br, I, OTf or B (OH) 2 C ") (Boc) K in which the substituents R, R 1, R 2, R 3, R 4, R 5, R 5 'and R 6 have the meanings indicated above.

In General Scheme 1C: ester G can be obtained from ester C by reaction with (Boc) 20 (tert-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 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 the ester G by reaction with R 1 -X (X = Cl, Br, 1 or OTf and R 1 is an alkyl group), 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. and 100 ° C., for example according to the process described by Noël D. D'Angelo et al. in J. Med. Chem. 2008, 51, 5766-5779. The product H where R 1 = F can be obtained by reacting the product G with N-fluorobenzenesulphonimide, in the presence of a base such as the potassium salt of hexamethyl-disilylazane, in a solvent such as tetrahydrofuran, at a temperature of 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 group R 1 is an alkyl radical 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, tert-butyl ester and potassium 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 the esters H or J by reaction of an indoline L, in the presence of an agent such as trimethyl aluminum, in a solvent such as toluene, at a temperature between ° 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 amides (I) -c by reaction with a compound RX (X = Cl, Br, 1 or triflate), in the presence of a base such as sodium hydroxide, tert-butylate of potassium 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 and al. in J. Med. Chem. 2008, 51, 5766-5779.

Alternatively, the amides (I) -d can be obtained from esters K by reaction of an indoline L, in the presence of an agent such as trimethylaluminium, in a solvent such as toluene, at a temperature of between 20 ° C. 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 RX (X = Cl, Br, I, triflate or boronate B (OH) 2), in the presence of a base such as sodium hydroxide, tert-butylate or potassium or cesium carbonate, in a solvent such as methanol, ethanol or dioxane, at a temperature of between 0 ° C. and 50 ° C., for example according to 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. The indolines of general formula (L), when they are not commercial, can generally be obtained from the corresponding M1 indoles by reduction in the presence of a reducing agent such as a hydride (sodium cyanoborohydride, for example) at room temperature. in a solvent such as acetic acid or trifluoroacetic acid, at a temperature between -5 ° C and 25 ° C, as described, for example, by Kumar, Y. (Synth.Commun., 1983, 13 ( 6), 489). R5 R4 R5 R4 R3 Reduction R6 M1 L wherein the substituents R2, R3, R4, R5, and R6 have the meanings given above.

The enantiomerically enriched indolines can be obtained for example by chemical resolution of the enantiomers with the aid of an enantiomerically pure chiral couplet, as described in General Scheme ID. For example, the resolution of enantiomers of indoline L can be achieved by chromatographic separation of the two diastereoisomers formed by peptide coupling with o-benzyl-D-lactic acid in the presence of a peptide coupling agent such as, for example, EDCI (N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide), DMT-MM [4- (4,6-dimethoxy-1,2,3-triazin-2- yl) 4-methylmorpholinium], BOP [benzotriazol-1-yloxy-tris-dimethylamino phosphonium hexafluorophosphate], PyBOP [benzotriazol-1-yloxy-tris-pyrrolidino phosphonium hexafluorophosphate], PyBROP [bromo trispyrrolidino phosphonium hexafluorophosphate], HATU [047-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate)] or a mixture of HOBT / EDCI [hydroxybenzotriazole / ethyl dimethylaminopropyl carbodiimide], in a solvent such as N, N-dimethylformamide, pyridine, ethanol, water or methanol, at a temperature between ° C and 100 ° C, as for example under the conditions described by Kunishima, M. et al. (Tetrahedron, 2001, 57, 1551). The enantiomers (+) - L and (-) - L can be respectively obtained from the compounds M2: dia A and M2: dia B by reaction in the presence of an acid such as concentrated hydrochloric acid, within a solvent such as an alcohol (eg ethanol), at a temperature between 20 ° C and the boiling point of the solvent, as, for example, under the conditions described by Krasnov, VP et al. (Mendeleev Commun 2002, 12 (1), 27). General scheme ID: EDC I / pyrid i ne L R6 R3 R2 M2: dia A M2: dia B R6 R6 (+) - L

wherein the substituents R2, R3, R4, R5, R5 'and R6 have the meanings given above.

The products of general formula (M1-a) can in particular be prepared as indicated in General Scheme 1E below, from the M3 compounds by Suzuki type coupling with an arylboronic acid or an arylboronate in the presence of a catalyst based on palladium (dichlorobis (tri-o-tolylphosphine) palladium (II) for example), a base such as potassium carbonate in a solvent such as a mixture of dioxane and water at a temperature between ° C and the boiling point of the solvent, or alternatively with an arylboronic acid or an arylboronate in the presence of a catalyst such as [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II), copper chloride (I), a base such as cesium carbonate in a solvent such as N, N-dimethylformamide at a temperature between 20 ° C and the boiling point of the solvent (optionally under irradiation with microwaves) , for example according to the conditions described in US Patent 2007/0072897 A1.

General Scheme 1E: H R 6 M 3 M 1-a in which the substituents R 2, R 3, R 5 and R 6 have the meanings indicated above. Alternatively, the derivatives of general formula (M1-b) can be obtained according to the general scheme 1 F below, from the corresponding commercial indole-2-carboxylic acid M4, by decarboxylation reaction. This reaction is preferably carried out at a temperature between 200 ° C and 240 ° C, in the presence of copper (0) and quinoline according to, for example, the conditions described by Tapia, R.A. et al. (Bioorg Med Chem, 2003, 11, 3407). General Scheme IF: M4 M1-b in which the substituents R2, R3 and R4 have the meanings indicated above.

Alternatively, the derivatives of general formula (M1-c) can be obtained according to the general scheme 1G below, by analogy with the conditions described by Katayama, M. et al. (Biosci Biotechnol Biochem., 2008, 72 (8), 2025). 1G general scheme: R4 R4 R3 R3 OH ## STR3 ## wherein R3 and R2 have the meanings given above. General scheme 1G: The M6 derivatives can be prepared from the corresponding commercial derivatives M5, by reaction with sodium chlorodifluoroacetate, in the presence of a base such as potassium carbonate, in a solvent such as a mixture of N, N-dimethylformamide and water at a temperature between 20 ° C and the boiling point of the solvent, by analogy with the conditions described in the patent WO2009 / 92590. The M7 derivatives can be prepared from the derivatives M6, by reaction with tris (dimethylamino) methane, in a solvent such as N, N-dimethylformamide, at a temperature between 20 ° C and the boiling point of the solvent, by analogy with the conditions described by Hume, W. E. et al (Tetrahedron, 2002, 58, 3605) The M1-c derivatives can be prepared from the M7 derivatives, by reduction and cyclization in the presence of hydrazine hydrate, a catalyst such as nickel Raney, in a solvent such as a mixture of methanol and tetrahydrofuran, at a temperature between 20 ° C and the boiling point of the solvent, by analogy with the conditions described by Hume, WE et al. (Tetrahedron, 2002, 58, 3605).

Alternatively, the derivatives of general formula (M1-d) in which X represents a group SO2Alk or Alk can be obtained according to the general scheme 1H below, from the corresponding commercial aldehydes M8, by reaction of reductive amination in the presence of corresponding commercial piperazines and a reducing agent such as sodium triacetoxyborhydride, in a solvent such as tetrahydrofuran, at a temperature of between 20 ° C. and the boiling point of the solvent, according to, for example, the conditions described in WO2007 / 113249 A2.

General Scheme 1H: wherein R 2, R 3, R 5 and R 6 have the meanings indicated above. Alternatively, the derivatives of general formula (M1-e) can be obtained according to the general scheme 11 below, from the corresponding commercial 4-hydroxy-2-methyl-indole derivatives M9, by reaction with Freon-22, in presence of a phase transfer agent such as tetrabutylammonium bromide and a base such as sodium hydroxide, in a solvent such as dichloromethane, at a temperature of between 0 ° C. and room temperature, according to for example the conditions described in the patent WO2006 / 019831. General Scheme 11: R2 R2 R3 M9 M1-e wherein the substituents R2, R3 and R5 have the meanings indicated above. The products of general formula (M1-f) can in particular be prepared as indicated in General Scheme 1J below.

General Scheme 1J: wherein the substituents R2, R3, R4 and R6 have the meanings indicated above. In general scheme 1J: M11 derivatives can be prepared from M10 compounds by Sonogashira-type coupling with a true alkyne in the presence of a palladium-based catalyst such as bis (triphenylphosphine) palladium (II) dichloride and copper iodide in a solvent such as triethylamine and optionally in the presence of a co-solvent such as N, N-dimethylformamide at a temperature between 0 ° C and the boiling point of the solvent according to for example, the conditions described by Kuyper, F. et al. (J. Med Chem., 1996, 39 (4), 892). The M1-f indoles can be obtained by cyclization of the M11 compounds in the presence of copper iodide in a solvent such as DMF at a temperature between 22 ° C and the boiling point of the solvent according to, for example, conditions described by Kuyper, F. et al. (J. Med Chem., 1996, 39 (4), 892). It is understood by those skilled in the art that, for carrying out the processes according to the invention described above, it may be necessary to introduce protective groups of the functional groups. amino, carboxyl and alcohol 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 (1) thus obtained by the processes indicated above, to obtain other intermediates or other products of formula (1), one or more reactions of transformations 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 (1) thus obtained being in all the possible racemic isomeric forms, enantiomers and diastereoisomers. The reactions a) to g) can be carried out under the usual conditions known to those skilled in the art such as, for example, those indicated below. a) The products described above may, if desired, be subjected, on the possible carboxy functions, to esterification reactions which may be carried out according to the usual methods known to those skilled in the art. b) The possible acid-functional ester function transformations of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in an alcoholic medium such as, for example, in methanol or in hydrochloric or sulfuric acid. The saponification reaction may be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide. c) The optional free or esterified carboxy functions of the products described above may, if desired, be reduced according to the alcohol by the methods known to those skilled in the art: the optional esterified carboxy functions may, if desired, be reduced in function alcohol by the methods known to those skilled in the art and in particular by lithium hydride and aluminum in a solvent such as for example tetrahydrofuran or dioxane or ethyl ether. The optional free carboxy functions of the products described above may, if desired, be reduced in particular alcohol function by boron hydride. d) The optional alkoxy functions, such as in particular methoxy, of the products described above may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as For example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux. e) The elimination of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzene sulfonic acid or para-toluenesulphonic, formic or trifluoroacetic or catalytic hydrogenation.

The phthalimido group can be removed by hydrazine. f) The products described above may, if desired, be the subject of salification reactions, for example by a mineral or organic acid or by a mineral or organic base according to the usual methods known to those skilled in the art: such salification reaction can be carried out for example in the presence of hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol. g) The optional optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art. The products of formula (1) as defined above and their addition salts with acids have interesting 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 object of the invention is particularly to provide, as medicaments, the products of formula (1) as defined above, said products of formula (1) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (1). The invention particularly relates, as medicaments, to the products corresponding to the following formulas: 6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [cyclopropane-1,3 ' -indol] -1 '(2'H) -yl) ethyl] pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- [2-oxo-2- (4-phenyl) -2- 3-Dihydro-1H-indol-1-yl) ethyl] pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2- [4- (trifluoromethoxy)) -2,3-Dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one-3-methyl-6- (morpholin-4-yl) -2- (2-oxo-2- [ 4- (Trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo) -2- [4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [4- (2-methoxyphenyl) -2, 3-Dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- ( 2-Oxo-2- [4- (1-propylpiperidin-3-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [ 4- (difluoromethoxy) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one 2- {2- [4- (difluoromethoxy) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 6- (morpholin-4-yl) -2- (2-oxo-2- [4- (pyridin-4-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- [2- (1'-methylspiro [indole-3,4'-piperidin] -1 (2H) -yl) -2-oxoethyl] -6- (morpholin-4- yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2- [4- (pyridin-2-yl) -2,3-dihydro-1H-indol 1-yl] ethyl} pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2- [4- (pyridin-3-yl) -2,3- 1H-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [4- (2-chlorophenyl) -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] -3-cyclopropyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- [2-oxo-2- (2, allyl)); 3,3a, 8b-tetrahydro-cyclopenta [b] indol-4 (1H) -yl) ethyl] pyrimidin-4 (3H) -one -2- [2- (4 - {[4- (methylsulfonyl) piperazin-1 yl] methyl} -2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-2- (2- {4 - [(4-methylpiperazin-1-yl) methyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -6- (morpholin-4-yl) pyrimidine -4 (3H) -one - 2- {2- [4- (2-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4- yl) pyrimidin-4 (3H) -one-3-methyl-2- (2- {4 - [(4-methylpiperazin-1-yl) methyl] -2,3-dihydro-1H-indol-1-yl 2-oxoethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morphol-4-yl) -2- [2-oxo-2- (2 ', 3 ', 5', 6'-Tetrahydrospiro [indole-3,4'-pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one-3-methyl-6- (morpholin-4-yl) ) -2- [2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole-3,4'-pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) ) -one - 3-methyl-6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [indole-3,4'-piperidin] -1 (2H) -yl) ethyl] pyrimidine -4 (3H) -one - 6- (morpholin-4-yl) -2- {2-oxo-2 - [(2R) -2-phenyl-2,3-dihydro-1H-indol-1-yl} ] ethyl} pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- {2-oxo-2 - [(2S) -2-phenyl-2,3-dihydro-1H-indol] -1-yl] ethyl} pyrimidin-4 (3H) -one -2- {2- [4- (4-methylpiperazin-1-yl) -2,3-dihydro-1H-indol-1-yl] -2 oxoethyl} (Morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2 - [(2R) -2- (4-fluorophenyl) -2,3-dihydro-1H-indol-1-ol yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2 - [(2S) -2- (4-fluorophenyl) -2,3-dihydro- 1 H -indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2 - [(2R) -4- (difluoromethoxy) -2 2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2 - [(2S 4 - (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one -2- {2 - [(2R) -4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholine) 4-yl) pyrimidin-4 (3H) -one - 2- {2 - [(2S) -4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] - 2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one

41

6- (Morpholin-4-yl) -2- {2- [4- (morpholin-4-yl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} pyrimidin-4 (3H) -one - 2- {2 - [(2R) -2-cyclopropyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one -2- {2 - [(2S) -2-cyclopropyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4- yl) pyrimidin-4 (3H) -one - 2- {2 - [(2R) -2-methyl-4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl } (6-morpholin-4-yl) pyrimidin-4 (3H) -one-2- {2 - [(2S) -2-methyl-4- (trifluoromethyl) -2,3-dihydro-1H-indol} 1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- [2 - ((+) - 2-fluoromethyl-2,3-dihydroindol 1-yl) -2-oxo-ethyl] -6-morpholin-4-yl-3H-pyrimidin-4-one - 2 - [2- (2,3-dihydro-indol-1-yl) -2- oxo-ethyl] -6-morpholin-4-yl-3-phenyl-3H-pyrimidin-4-one as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases thereof. Formula 1). The invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (1) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, optionally, a pharmaceutically acceptable carrier. The invention thus extends to pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined above. Such pharmaceutical compositions of the present invention may also, if appropriate, contain active principles of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating agents of DNA and others.

These pharmaceutical compositions 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 for the treatment or prevention of a disease in a mammal. The present invention particularly relates to the use of a product of formula (1) 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 (1) as defined above for the preparation of a medicament for the treatment or prevention of diseases in oncology and in particular for the cancer treatment. Among these cancers, one is interested in the treatment of solid or liquid tumors, in the treatment of cancers resistant to cytotoxic agents. The products of the present invention cited can in particular be used for the treatment of primary tumors and / or metastases in particular in gastric, hepatic, renal, ovarian, colon, prostate, endometrial, lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder, breast cancers, in melanoma , in lymphoid or myeloid hematopoietic tumors, in sarcomas, in cancers of the brain, larynx, lymphatic system, cancers of the bones and pancreas, in hamartomas. The subject of the present invention is also the use of the products of formula (1) as defined above for the preparation of medicaments intended for the chemotherapy of cancers. Such drugs for cancer chemotherapy may be used alone or in combination. The products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or in combination with other therapeutic agents, for example. Such therapeutic agents may be commonly used anti-tumor agents.

As kinase inhibitors, there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomucine. Thus the present application relates in particular to the products of formula (1) as defined above for their use for the treatment of cancers.

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

44

Thus the present application relates in particular to the products of formula (1) as defined above for their use for the treatment of cancers resistant to cytotoxic agents. Thus the present application relates in particular to the products of formula (1) as defined above for their use for the treatment of primary tumors and / or metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain cancers, larynx, lymphatic system, cancers of the bones and pancreas. in hamartomas. Thus, the present application relates in particular to the products of formula (1) as defined above, for their use for the chemotherapy of cancers. Thus the present application relates in particular to the products of formula (1) as defined above, for their use for cancer chemotherapy alone or in combination. The subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas C, D, E, F as well as certain indolines L as defined above and referred to below: C, ED, F in wherein R, R2, R3, R4, R5, R5 'and R6 are as defined in any one of claims 1 to 3, wherein said products are in any of the possible isomeric racemic, enantiomeric and diastereoisomeric forms, R1 C6) NY The following examples, which are products of formula (1), illustrate the invention without, however, limiting it. Experimental part The nomenclature of the compounds of this invention was carried out with ACDLABS software version 12.0. 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 the temperature of 303K, except when another solvent is specified (chloroform-d, referenced at 7.26 ppm).

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: 1 m1 / min; Gradient (2 min): 5 to 50% B in 0.8 min; 1.2 min: 100% B; 1.85 min: 100% B; 1.95: 5% B; Retention time = Tr (min).

Method B: WATERS ZQ Apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: XBridge C18 2.5 μm - 3 x 50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 70 ° C; Flow rate: 0.9 ml / min; Gradient (7 min): from 5 to 100% of Ben5,3min, 5,5min: 100% of B; 6.3min: 50/0 of B; Retention time = Tr (min).

Example 1 Synthesis of 6- (Morpholin-4-yl) -2- [2-oxo-2- (spiro [cyclopropane-1,3'-indol] -1 '(2'H) -yl) ethyl] pyrimidine 4 (3H) -one Step 1: HA a solution of 25 g 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 as a white solid, the characteristics of which are following: 1 H NMR spectrum (400 MHz, 8 ppm, DMSO-d6): 1.19 (t, J = 7.1 Hz, 3H); 3.38 at 3.44 (m, 4H); 3.56 (s, 2H); 3.61 (dd, J = 4.0 and 5.7 Hz, 4H); 4.12 (q, J = 7.1 Hz, 2H); 5.20 (s, 1H); 11.69 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.48; [M + H] +: m / z 268; [MH] -: m / z 266 Step 2: H + OvN ~, O Na 1 NON ~ \ O ~ A solution of 10 g of [4- (morpholin-4-yl) -6-oxo-1,6 -dihydropyrimidin-2-yl] ethyl acetate in 300 mL of tetrahydrofuran is added 18.7 mL of 2M sodium hydroxide. The reaction mixture is stirred for 48 hours at room temperature. The precipitate formed is filtered on sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried on a rotary evaporator to give 8.7 g of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate in the form of a white solid of which the characteristics are as follows: 1H NMR Spectrum (400MHz, 8 ppm, DMSO-d6): 3.08 (s, 2H); 3.38 (t, J = 4.6 Hz, 4H); 3.61 (t, J = 4.6 Hz, 4H); 5.08 (s, 1H); 13.16 (bs, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.29; [M + H] +: m / z 240; [MH] -: m / z 238 HO ~, N 1 N 0 Step 3: To a suspension of 222 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl sodium acetate obtained according to the preceding step (example 1 step 2) in 1 ml of N, N-dimethylformamide are successively added 0.14 ml of pyridine and 216 mg of N- [3- (dimethylamino) propyl] -N ethylcarbodiimide hydrochloride. After stirring at room temperature for 10 minutes, a solution of 136 mg of 1,2-dihydro-3-spiro-1'-cyclopropyl-1H-indole (which can be prepared according to US Pat. No. 7,507,748 B2 (2009)) in 4 ml of N, N-dimethylformamide is added. The reaction mixture is stirred at room temperature for 65 hours, then 13 ml of water and 26 ml of ethyl acetate are added. After stirring for 1 hour, the precipitate formed is filtered and then rinsed successively with water (2 × 8 mL) and diethyl ether (3 × 13 mL). After drying under reduced pressure at 40 ° C., 208 mg of 6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [cyclopropane-1,3'-indol] -1 'are obtained. 2'H) -yl) ethyl] pyrimidin-4 (3H) -one in the form of a pinkish crystalline powder having the following characteristics: 1H NMR spectrum (400MHz): 1.02 to 1.14 (m, 4) H); 3.42 (m, 4H); 3.60 (m, 4H); 3.71 (s, 2H); 4.17 (s, 2H); 5.21 (s, 1H); 6.82 (d, J = 7.8 Hz, 1H); 6.99 (t, J = 7.8 Hz, 1H); 7.13 (t, J = 7.8 Hz, 1H); 8.01 (d, J = 7.8 Hz, 1H); 11.60 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.74; [M + H] +: m / z 367; [MH] -: m / z 365 Melting point (Kofler): greater than 260 ° C Example 2 Synthesis of 6- (morpholin-4-yl) -2- [2-oxo-2- (4-phenyl) -2 , 3-dihydro-1H-indol-1-yl) ethyl] pyrimidin-4 (3H) -one25 To a suspension of 250 mg of [4- (morpholin-4-yl) -6-oxo-1,6- sodium dihydropyrimidin-2-yl] acetate (example 1 step 2) in 5 ml of N, N-dimethylformamide are successively added 0.16 ml of pyridine, 240 mg of N- [3- (dimethylamino) propyl] -N ' ethylcarbodiimide hydrochloride and 210 mg of 4-phenyl-2,3-dihydro-1H-indole (Reference Example 1). The reaction mixture is stirred at ambient temperature for 15 hours and then concentrated to dryness under reduced pressure. The residue is taken up and triturated in 30 ml of water, then the precipitate formed is filtered and then solubilized in a 90/10 dichloromethane / methanol mixture and finally concentrated to dryness under reduced pressure. The residue is purified by chromatography on a column of 30 g of silica 20-45 pm, eluting with a mixture of dichloromethane and methanol (90/10: v / v). The fractions containing the expected product are concentrated to dryness under reduced pressure and the residue is triturated in 20 ml of diisopropyl ether. The solid obtained is filtered and then dried under reduced pressure at 40 ° C. 232 mg of 6- (morpholin-4-yl) -2- [2-oxo-2- (4-phenyl-2,3-dihydro-1H-indol-1-yl) ethyl] pyrimidin-4 are thus obtained ( 3H) -one in the form of a pink solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.22 (t, J = 8.7 Hz, 2H); 3.42 (m, 4H); 3.61 (m, 4H); 3.78 (s, 2H); 4.14 (t, J = 8.7 Hz, 2H); 5.21 (s, 1H); 7.07 (d, J = 7.8 Hz, 1H); 7.28 (t, J = 7.8 Hz, 1H); 7.36 to 7.51 (m, 5H); 8.08 (d, J = 7.8 Hz, 1H); 11.62 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.89; [M + H] +: m / z 417; [MH] -: m / z 415 Melting point (Kofler): 266 ° C Example 3 Synthesis of 6- (morpholin-4-yl) -2- (2-oxo-2- [4- (trifluoromethoxy) -2 , 3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one To a solution of 110 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine 2-yl] sodium acetate (example 1 step 2) in 1 ml of N, N-dimethylformamide are successively added 70 μl of pyridine and 107 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride . After stirring at room temperature for 10 minutes, a solution of 178 mg of 4- (trifluoromethoxy) -indoline (Reference Example 2) in 1 mL of N, N-dimethylformamide is added. The reaction mixture is stirred at room temperature for 23 hours, then 13 ml of water and 6 ml of ethyl acetate are added. After stirring at ambient temperature for 2 hours, the precipitate formed is filtered and then rinsed successively with water (2 × 4 mL) and with diethyl ether (3 × 6 mL). After drying under reduced pressure at 40 ° C., 97 mg of 6- (morpholin-4-yl) -2- {2-oxo-2- [4- (trifluoromethoxy) -2,3-dihydro-1H-indol are obtained. 1-yl] ethyl} pyrimidin-4 (3H) -one in the form of a white crystalline powder, the characteristics of which are as follows: NMR spectrum 1H (400MHz): 3.21 (t, J = 8.6 Hz, 2H); 3.41 (m, 4H); 3.60 (m, 4H); 3.77 (s, 2H); 4.22 (t, J = 8.6 Hz, 2H); 5.21 (s, 1H); 7.02 (d,

51

J = 8.1 Hz, 1H); 7.32 (t, J = 8.1 Hz, 1H); 8.02 (d, J = 8.1 Hz, 1H); 11.62 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.85; [M + H] +: m / z 425; [MH] -: m / z 423 Melting point (Kofler): greater than 260 ° C Example 4 Synthesis of 3-methyl-6- (morpholin-4-yl) -2- {2-oxo-2- [4] - (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one Step 1: O ~ Nyyo NO / N ~ ~ O ~ A solution of 500 mg of Ethyl 4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (prepared in step 1 of Example 1) in 1.5 mL of dioxane, 330 mg. of potassium carbonate and 150 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 then, 90/05/05 V / V / V) . 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: 1H NMR Spectrum (400MHz): 1.21 (t, J = 7.1Hz, 3H); 3.29 (partially masked m, 3H); 3.40 (m, 4H); 3.61 (m, 4H); 3.92 (s, 2H); 4.15 (q, J = 7.1 Hz, 2H); 5.35 (s, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.53; [M + H] +: m / z 282; [M-H] -: m / z 280; Step 2: NO 2 O 2 To a solution of 1.62 g of ethyl [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate, in 20 ml. 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, rinsed with diethyl ether and dried to give 730 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo Sodium 1,6-dihydropyrimidin-2-yl] acetate in the form of a white solid, the characteristics of which are as follows: 1H NMR spectrum (40 MHZ): 3.27 to 3.43 (partially masked m, 9H); 3.61 (m, 4H); 5.23 (s, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.31; [M + H] +: m / z 254; [M-H] -: m / z 252; Step 3: OvN ~~, NO / N ~ \ O ~ A solution of 138 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate in 3 ml of N, N-dimethylformamide are successively added 3 ml of pyridine, 94 mg of 4-trifluoromethyl-2,3-dihydro-1H-indole and 153 mg of N- [3- (dimethylamino) propyl). ] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 16 hours. After addition of 50 ml of water and extraction with ethyl acetate (3 × 15 ml), the organic phases are combined and then washed with water (2 × 15 ml), a solution of water saturated with sodium chloride. (15 mL) then dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure. The solid obtained is washed with diethyl ether (5 mL) and then dried to give 64 mg of 3-methyl-6- (morpholin-4-yl) -2- {2-oxo-2- [4- (trifluoromethyl) ) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one as a pink solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.24 at 3.42 (partially masked m, 9H); 3.57 (m, 4H); 4.14 (s, 2H); 4.26 (t, J = 8.6 Hz, 2H); 5.37 (s, 1H); 7.35 (d, J = 8.1 Hz, 1H); 7.41 (t, J = 8.1 Hz, 1H); 8.30 (d, J = 8.1 Hz, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.87; [M + H] +: m / z 423; Example 5 Synthesis of 6- (morpholin-4-yl) -2- (2-oxo-2- [4- (trifluoromethyl) -2,3-dihydro-1H-indol) 1-yl] ethyl} pyrimidin-4 (3H) -one H OvN-1,

NO ~ \ O ~ A solution of 977 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (obtained in step 2 of the Example 1) in 25 ml of N, N-dimethylformamide and 25 ml of pyridine are added 700 mg of 4-trifluoromethyl-2,3-dihydro-1H-indole and 1.15 g of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 16 hours, then water is added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95: 5: v / v) to give 220 mg of 6- (morpholin-4-yl) -2- {2 -oxo-2- [4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one as a white solid, the characteristics of which are as follows: 1H NMR Spectrum (400MHz): 3.27-3.45 (partially masked m, 6H); 3.60 (m, 4H); 3.79 (s, 2H); 4.22 (t, J = 8.6 Hz, 2H); 5.22 (s, 1H); 7.34 (d, J = 8.1 Hz, 1H); 7.41 (t, J = 8.1 Hz, 1H); 8.30 (d, J = 8.1 Hz, 1H); 11.64 (m, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.82; [M + H] +: m / z 409; [MH] -: m / z 407 Example 6 Synthesis of 2- {2- [4- (2-methoxyphenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one To a solution of 170 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 are successively added 0.105 ml of pyridine and 165 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. After stirring at room temperature for 15 minutes, 140 mg of 4- (2-methoxy-phenyl) -2,3-dihydro-1H-indole (Reference Example 3) are added. The reaction mixture is stirred at ambient temperature for 16 hours, then 20 ml of water and 3 ml of ethyl acetate are added. After stirring at room temperature for 1 hour, the precipitate formed is filtered and then rinsed successively with water and diethyl ether.

After drying under reduced pressure at 40 ° C., 202 mg of 2- {2- [4- (2-methoxyphenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} are obtained. 6- (morpholin-4-yl) pyrimidin-4 (3H) -one in the form of a pale pink solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 2.93 (t, J = 8.7 Hz, 2H); 3.42 (m, 4H); 3.61 (m, 4H); 3.74 (s, 3H); 3.76 (s, 2H); 4.11 (t, J = 8.7 Hz, 2H); 5.21 (s, 1H); 6.91 (d, J = 7.9 Hz, 1H); 7.02 (t, J = 7.9 Hz, 1H); 7.11 (d, J = 7.9 Hz, 1H); 7.15 to 7.26 (m, 2H); 7.38 (broad t, J = 7.9 Hz, 1H); 8.03 (d, J = 7.9 Hz, 1H); 11.63 (bs, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.88; [M + H] +: m / z 447; [MH] -: m / z 445 Melting point (Kofler): greater than 260 ° C Example 7 Synthesis of 6- (morpholin-4-yl) -2- {2-oxo-2- [4- (1- propylpiperidin-3-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one To a solution of 20.5 mg of [4- (morpholin-4-yl) Sodium-6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) in 0.8 ml of N, N-dimethylformamide are successively added 0.2 ml of pyridine, 25.7 mg 4- (1-propyl-piperidin-3-yl) -2,3-dihydro-1H-indole (Reference Example 4) and 17.8 mg of N- [3- (dimethylamino) propyl] -N'- ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 24 hours and then concentrated under reduced pressure. The residue is taken up in 10 mL of water and then extracted with dichloromethane (4x20 mL). The organic phases are combined and then washed with water and concentrated under reduced pressure. After drying in an oven, 16.1 mg of 6- (morpholin-4-yl) -2- (2-oxo-2- [4- (1-propylpiperidin-3-yl) -2,3- dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one in the form of a pink solid, the characteristics of which are as follows: EXAMPLE 8 Synthesis of 2- {2- [4- (difluoromethoxy) 2,3-Dihydro-1H-indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one F] O-A solution 237 mg of sodium [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (obtained in step 2 of Example 4) in 7 ml of N, N-dimethylformamide and 7 ml of pyridine are added 220 mg of 4-difluoromethoxy-2,3-dihydro-1H-indole (Reference Example 5) and 364 mg of N- [3- (dimethylamino)) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 16 hours, then 20 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with 0.1 N hydrochloric acid solution, water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95: 5: v / v) to give 110 mg of 2- [2- (4-difluoromethoxy) -2,3 dihydroindol-1-yl) -2-oxo-ethyl] -3-methyl-6-morpholin-4-yl-3H-pyrimidin-4-one in the form of a pale pink solid whose characteristics are as follows: 1H NMR Spectrum (400MHz): 3.15 (t, J = 8.6Hz, 2H); 3.30 (partially masked, 3H); 3.39 (m, 4H); 3.58 (m, 4H); 4.12 (s, 2H); 4.23 (t, J = 8.6 Hz, 2H); 5.37 (s, 1H); 6.88 (d, J = 8.1 Hz, 1H); 7.24 (t, J = 74.2 Hz, 1H); 7.24 (t, J = 8.1 Hz, 1H); 7.89 (d, J = 8.1 Hz, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.77; / N ~

58 [M + H] +: m / z 421; [MH] -: m / z 419 Example 9 Synthesis of 2- {2- [4- (difluoromethoxy) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholine -4-yl) pyrimidin-4 (3H) -one FH OvN ~ 1 NO ~

To a solution of 327 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (obtained in Step 2 of Example 1) 7 ml of 4-difluoromethoxy-2,3-dihydro-1H-indole (reference example 5) and 364 mg of N- dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 16 hours, then 15 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95: 5: v / v) to give 24 mg of 2- {2- [4- (difluoromethoxy) -2, 3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one having the following characteristics: 1H NMR spectrum (400MHz): 3.15 (t, J = 8.6 Hz, 2H); 3.42 (m, 4H); 3.60 (m, 4H); 3.76 (s, 2H); 4.19 (t, J = 8.6 Hz, 2H); 5.21 (s, 1H); 6.87 (d, J = 8.1 Hz, 1H); 7.24 (t, J = 74.2 Hz, 1H); 7.25 (t, J = 8.1 Hz, 1H); 7.89 (d, J = 8.1 Hz, 1H); 11.63 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.73; [M + H] +: m / z 407; Example 10 Synthesis of 6- (Morpholin-4-yl) -2- (2-oxo-2- [4- (pyridin-4-yl) -5,2,3-dihydro) 1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one HO ~ N ~

1N, N 2 O 2 A solution of 26.7 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2 0.8 ml of pyridine, 25 mg of 4-pyridin-4-yl-2,3-dihydro-1H-indole and 23 mg of N- are added successively in 0.8 ml of N, N-dimethylformamide. [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 24 hours and then concentrated under reduced pressure. The residue is taken up in 10 ml of water and then filtered on sintered glass and the precipitate is washed with water (2 × 1 ml) and oven-dried. 27.6 mg of 6- (morpholin-4-yl) -2- (2-oxo-2- [4- (pyridin-4-yl) -2,3-dihydro-1H-indol-1 are obtained. yl] ethyl} pyrimidin-4 (3H) -one as a pink solid whose characteristics are as follows: Example 11 Synthesis of 2- [2- (1'-methylspiro [3,4'-indole-piperidine] ] - 1 (2H) -yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one The product is prepared following the procedure described in Example 10 starting from 35.5 mg [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 25 mg of 1'-methylspiro [indoline- 3,4'-piperidine in place of 4-pyridin-4-yl-2,3-dihydro-1H-indole. 13.8 mg of 2- [2- (1'-methylspiro [3,4'-indol-3,4'-piperidin] -1 (2H) -yl) -2-oxoethyl] -6- (morpholin-4-yl) are obtained pyrimidin-4 (3H) -one in the form of a pale pink powder whose characteristics are the following: Example 12 Synthesis of 6- (morpholin-4-yl) -2- {2-oxo-2- [4- ( pyridin-2-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one The product is prepared following the procedure described in Example 10 starting from 26.7 mg [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (example 1 step 2) and 25 mg of 4-pyridin-2-yl -2,3-dihydro-1H-indole in place of 4-pyridin-4-yl-2,3-dihydro-1H-indole. 26.8 mg of 6- (morpholin-4-yl) -2- {2-oxo-2- [4- (pyridin-2-yl) -2,3-dihydro-1H-indol-1 are obtained. yl] ethyl} pyrimidin-4 (3H) -one in the form of a purple solid whose characteristics are as follows: Example 13 Synthesis of 6- (morpholin-4-yl) -2- {2-oxo-2- [ 4- (pyridin-3-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one HO ~ N ~

The product is prepared following the procedure described in Example 10 starting from 26.7 mg [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2). -yl] sodium acetate (example 1 step 2) and 25 mg of 4-pyridin-3-yl-2,3-dihydro-1H-indole in place of 4-pyridin-4-yl-2,3 1-dihydro-1H-indole. 30.7 mg of 6- (morpholin-4-yl) -2- (2-oxo-2- [4- (pyridin-3-yl) -2,3-dihydro-1H-indol-1 are obtained. yl] ethyl} pyrimidin-4 (3H) -one in the form of a pink powder, the characteristics of which are as follows: EXAMPLE 14 Synthesis of 2- {2- [4- (2-chlorophenyl) -2,3-dihydro- 1 H -indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one OA solution of 264 mg of 4- (2-chloro-phenyl) -2 , 3-dihydro-1H-indole (Reference Example 6) in 5 ml of pyridine are successively added 300 mg of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl). sodium acetate (example 1 step 2), 330 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 6 mL of pyridine. The reaction mixture is stirred at ambient temperature for 4 days. The reaction medium is diluted with ethyl acetate (60 ml) and then successively washed with a 1M aqueous hydrochloric acid solution, a 1M aqueous sodium hydroxide solution, and a saturated sodium chloride water solution. The organic phase is then dried over magnesium sulfate, filtered on sintered glass. A precipitate appears after a few hours which is then filtered on sintered glass and washed with diethyl ether. 294 mg of 2- {2- [4- (2-chlorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidine are obtained. -4 (3H) -one in the form of a beige solid whose characteristics are as follows: Example 15 Synthesis of 2- [2- (4-chloro-2,3-dihydro-1H-indol-1-yl) - 2-20 oxoethyl] -3-cyclopropyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one Step 1: 62 Y To a solution of 1 g of [4- (morpholin-4-yl) - 6-oxo-1,6-dihydropyrimidin-2-yl] ethyl acetate prepared in step 1 of example 1 in 12 ml of toluene are added 643 mg of cyclopropylboronic acid, 680 mg of copper acetate (II), 1.37 g of dimethylaminopyridine and finally 6.23 ml of a solution of sodium bis (trimethylsilyl) amide (0.6 M in toluene) using a dropping funnel. The reaction mixture is heated at 95 ° C for 16 and then cooled to room temperature. After addition of 20 ml of a 1 N aqueous solution of hydrochloric acid and extraction with dichloromethane (3 × 50 ml), the organic phases are combined and then dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (98/02 then 95/05 V / V). 90 mg of (1-cyclopropyl-4-morpholin-4-yl-6-oxo-1,6-dihydro-pyrimidin-2-yl) -acetate are obtained in the form of a yellow oil which is used as it is in the next step.

Step 2: To a solution of 113 mg of 4-chloroindoline in 4 ml of tetrahydrofuran is successively added 2 ml of toluene, 90 mg of (1-cyclopropyl-4-morpholin-4-yl-6-oxo-1 Ethyl 6-dihydro-pyrimidin-2-yl) acetate and then dropwise 0.55 ml of a solution of 2M trimethylaluminium in toluene. The reaction mixture is heated at 90 ° C for 4 hours, then cooled to room temperature and 5 ml of methanol are added. After adding 10 g of silica, the reaction mixture is concentrated under reduced pressure. After purification by chromatography on a silica column (solid deposit), eluting with a mixture of dichloromethane and methanol (100/0 then 98/02 V / V), 39 mg of 2- [2- (4-chloro) 2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -3-cyclopropyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one in the form of a white solid whose characteristics are the following: Example 16 Synthesis of 6- (morpholin-4-yl) -2- [2-oxo-2- (2,3,3a, 8b) tetrahydro-cyclopenta [b] indol-4 (1H) -yl) ethyl] pyrimidin-4 (3H) -one VCl To a solution of 525 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (obtained in step 2 of Example 1) in 4 ml of N, N-dimethylformamide and 4 ml of pyridine are added 320 mg of 1,2,3,3a, 4,8b-hexahydro-cyclopenta [b] indole [Reference Example 7] and 424 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 72 hours and then concentrated under reduced pressure. The residue is taken up in a mixture of water and ethyl acetate and the organic phase is washed successively with water, 1M hydrochloric acid solution, water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is triturated in methanol, filtered and washed with diisopropyl ether to give 375 mg of 6- (morpholin-4-yl) -2- [2-oxo-2- (2,3,3a, 8b) tetrahydrocyclopenta [b] indol-4 (1H) -yl) ethyl] pyrimidin-4 (3H) -one having the following characteristics: 1H NMR spectrum (400MHz): 1.27 (m, 1H); 1.61 (m, 1H); 1.80 to 2.14 (m, 4H); 3.41 (m, 4H); 3.60 (m, 4H); 3.73 (d, J = 16.0 Hz, 1H); 3.91 (m, 2H); 4.89 (m, 1H); 5.20 (s, 1H); 7.05 (t, J = 7.9 Hz, 1H); 7.16 (t, J = 7.9 Hz, 1H); 7.24 (d, J = 7.9 Hz, 1H); 7.99 (d, J = 7.9 Hz, 1H); 11.67 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.79; [M + H] +: m / z 381; [MH] -: m / z 379 Example 17 Synthesis of 2- [2- (4 - {[4- (methylsulfonyl) piperazin-1-yl] methyl} -2,3-dihydro-1H-indol-1 yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one HO v N ~ 1 / NO / N ~

To a solution of 240 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) in 5 ml of N, N-dimethylformamide are successively added 5 mL of pyridine, 299 mg of 4- (4-methanesulfonyl-piperazin-1-ylmethyl) -2,3-dihydro-1H-indole (Reference Example 8) and 264 mg of N-dimethylformamide. [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in 30 ml of water and then extracted with dichloromethane (3x30 ml). The organic phases are combined and then washed with a solution of water saturated with sodium chloride and then dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure. After purification of the residue by chromatography on a silica column, eluting with a mixture of dichloromethane and 7N ammoniacal methanol (90/10), 190 mg of 2- [2- (4 - {[4- (methylsulfonyl) piperazin) are obtained. 1-yl] methyl] -2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpholin-4-yl) pyrimidin-4 (3H) -one [5-carbamoyl] 2- (morpholin-4-yl) -1,3-thiazol-4-yl] ethyl acetate in the form of a white solid, the characteristics of which are as follows: EXAMPLE 18 Synthesis of 2- (2- {4- [(4-methylpiperazin-1-yl) methyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) - one HO ~ N ~

The product is prepared by following the procedure described in Example 17 starting from 410 mg [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl). ] sodium acetate (example 1 step 2) and 400

mg 4- (4-Methyl-piperazin-1-ylmethyl) -2,3-dihydro-1H-indole (Reference Example 9) in place of 4- (4-methanesulfonylpiperazin-1-ylmethyl) -2,3 dihydro-1H-indole. 120 mg of 2- (2- {4 - [(4-methylpiperazin-1-yl) methyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -6- ( morpholin-4-yl) pyrimidin-4 (3H) -one in the form of a white solid, the characteristics of which are as follows: Example 19 Synthesis of 2- {2- [4- (2-fluorophenyl) -2,3- dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one OA a solution of 211 mg of [4- (morpholin-4-yl) Sodium-6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) in 3 ml of pyridine are successively added 115 mg of 4- (2-fluorophenyl) -2,3-dihydro-1 H-indole (diluted in 3 mL of pyridine) and 125 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 3 days. The reaction medium is diluted with ethyl acetate (100 ml) and then successively washed with a 1N aqueous hydrochloric acid solution, an aqueous solution of 1N sodium hydroxide, a solution of water saturated with sodium chloride. The organic phase is then dried over magnesium sulphate, filtered on sintered glass and concentrated under reduced pressure. 187 mg of 2- {2- [4- (2-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidine are obtained. -4 (3H) -one in the form of a beige solid whose characteristics are the following: Example 20 Synthesis of 3-methyl-2- (2- {4 - [(4-methylpiperazin-1-yl) methyl] - 2,3-Dihydro-1H-indol-1-yl} -2-oxoethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one NO / N

To a solution of 500 mg of sodium [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (Example 4 Step 2) in 5 g. ml of N, N-dimethylformamide are successively added 5 ml of pyridine, 404 mg of 4- (4-methyl-piperazin-1-ylmethyl) -2,3-dihydro-1H-indole (Reference Example 9) and 390 mg N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in 30 mL of water saturated with sodium chloride and then extracted with dichloromethane (3x30 mL). The organic phases are combined and then dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure. After purification of the residue by chromatography on a silica column, eluting with a mixture of dichloromethane and 7N ammoniaal methanol (95/05), 40 mg of 3-methyl-2- (2- {4 - [(4-methylpiperazine) are obtained. 1-yl) methyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one in the form of a white solid whose characteristics are the following: EXAMPLE 21 Synthesis of 6- (morpholin-4-yl) -2- [2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole 3, 4'-pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one HOUN ~ 1 / NO ~ ,, ..--

To a solution of 679 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) in 11.3 ml of N, N -dimethylformamide are successively added 3.8 ml of pyridine, 378 mg of 1,2,2 ', 3', 5 ', 6'-hexahydro-spiro [3H-indole-3,4' - [4H] pyran] and 575 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in 25 ml of water and 20 ml of ethyl acetate and then stirred at room temperature for 1 hour. The precipitate formed is filtered and then rinsed successively with water and diethyl ether. 640 mg of 6- (morpholin-4-yl) -2- [2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole-3,4'-pyran] are thus obtained. 1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one in the form of an off-white powder having the following characteristics: Example 22 Synthesis of 3-methyl-6- (morpholin-4-yl) 2- [2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole-3,4'-pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) A solution of 770 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate of sodium (example 4 step 2) in 11.3 ml of N, N-dimethylformamide are successively added 3.8 ml of pyridine, 378 mg of 1,2,2 ', 3', 5 ', 6'-hexahydro- spiro [3H-indole-3,4 '- [4H] pyran] and 575 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in 15 mL of water and 20 mL of ethyl acetate and then stirred at room temperature for 1 hour. The precipitate formed is filtered and then rinsed successively with water and diethyl ether. There is thus obtained 45 mg of 3-methyl-6- (morpholin-4-yl) -2- [2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole-3,4'] pyranidin-4 (3H) -one in the form of an off-white powder, the characteristics of which are as follows: EXAMPLE 23 Synthesis of 3-methyl-6- (morpholinic acid) -pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one 4-yl) -2- [2-oxo-2-5 (spiro [indole-3,4'-piperidin] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one Step 1: OUN ~ ~ / NO ~ \ O ~ A solution of 308 mg of [1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] sodium acetate (Example 4 step 2) in 4.5 ml of N, N-dimethylformamide are successively added 1.5 ml of pyridine, 231 mg of 1,2-dihydro-1'H-spiro [indole-3,4'-piperidine] -1 2-methylpropan-2-ylcarboxylate (may be prepared according to Tetrahedron (2010), 66, 573-577) and 230 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue is taken up in 15 ml of water and 5 ml of diethyl ether and then stirred at room temperature for 1 hour. The precipitate formed is filtered and then rinsed successively with water and diisopropyl ether. 230 mg of 1 - {[1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetyl} -1,2-dihydro-1 'is thus obtained. 2-methylpropan-2-yl H-spiro [indole-3,4'-piperidine] -1'-carboxylate in the form of a white solid which is used as it is in the following step: Step 2: N ~~ / NO ~ / \ O ~ In a microwave tube, 225 mg of 1 - {[1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidine) are introduced. 2-yl] acetyl} -1,2-dihydro-1'H-spiro [indole-3,4'-piperidine] -1'-carboxylate of 2-methylpropan-2-yl in 10 mL of dioxane and 2 mL of an aqueous solution of 2N hydrochloric acid. The tube is then heated under microwave at 110 ° C. for 10 minutes and then allowed to return to ambient temperature. The reaction mixture is concentrated under reduced pressure. The residue is taken up in 10 ml of a solution of a saturated aqueous solution of sodium hydrogencarbonate. After stirring for 10 minutes, the precipitate formed is filtered and then rinsed successively with water and diisopropyl ether. 140 mg of 3-methyl-6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [indole-3,4'-piperidin] -1 (2H) -yl) are thus obtained. ethyl] pyrimidin-4 (3H) -one in the form of a white powder having the following characteristics: Example 24 and Example 25 Synthesis of (+) - 6- (morpholin-4-yl) -2- {2-Oxo-2 - [(ZR) -2-phenyl-2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one and (-) - 6- (Morpholin-4-yl) -2- {2-oxo-2 - [(2S) -2-phenyl-2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) - (±) -6- (Morpholin-4-yl) -2- {2-oxo-2- [2-phenyl-2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 ( 3H) -one is prepared by following the procedure described in example 1 step 3 from 0.50 g of [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2- yl] sodium acetate, 0.42 g of 2-phenyl-indoline (which can be prepared according to Santangelo, EM et al., J. Org Chem 2008, 5915), 0.48 g of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.31 mL of pyridine and 10 ml of N, N-dimethylformamide. After purification by chromatography on a column of 50 g of silica 20-45 μm, eluting with a 90/10 v / v dichloromethane / methanol mixture, 0.43 g of (±) -6- (morpholin-4-yl) are obtained. ) -2- {2-oxo-2- [2-phenyl-2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one as a cream-colored solid, characteristics are as follows: Mass Spectrometry: Method A Retention Time Tr (min) = 0.85; [M + H] +: m / z 417; [MH] -: m / z 415 The products were obtained by chiral chromatographic separation of 420 mg of (±) -6- (morpholin-4-yl) -2- {2-oxo-2- [2-phenyl- 2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one on a Chiralpak AY column (T304) (1080 mg, 20 μm, 7.7 / 35 cm), eluent: acetonitrile / isopropanol : 90/10; flow rate: 250 5 10 15 2025 mL / min. After purification, 208 mg of (+) - 6- (morpholin-4-yl) -2- {2-oxo-2- [2-phenyl-2,3-dihydro-1H-indol are obtained as the first enantiomer. -1-yl] ethyl} pyrimidin-4 (3H) -one, in the form of a pale pink powder whose characteristics are as follows: NMR spectrum 1H (400MHz): 2.89 (d, J = 16.3 Hz , 1H); 3.13 (d, J = 15.7 Hz, 1H); 3.25 to 3.40 (partially masked m, 4H); 3.57 (m, 4H); 3.81 (dd, J = 9.5 and 16.3 Hz, 1H); 3.86 (d, J = 15.7 Hz, 1H); 5.15 (s, 1H); 5.77 (d, J = 9.5 Hz, 1H); 7.07 (t, J = 7.5 Hz, 1H); 7.16 to 7.40 (m, 7H); 8.12 (d, J = 8.3 Hz, 1H); 11.60 (m spread, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.84; [M + H] +: m / z 417; [M-H] -: m / z 415 Rotatory power: ap = + 170 ° (c = 1.389 mg in 0.5 mL of DMSO)

Then the second enantiomer, that is: 202 mg of (-) - 6- (morpholin-4-yl) -2- {2-oxo-2- [2-phenyl-2,3-dihydro-1H-indol-1] -yl] ethyl} pyrimidin-4 (3H) -one in the form of an off-white powder having the following characteristics: 1H NMR spectrum (400MHz): 2.89 (d, J = 16.3 Hz, 1H) ); 3.13 (d, J = 15.7 Hz, 1H); 3.25 to 3.38 (partially masked m, 4H); 3.57 (m, 4H); 3.81 (dd, J = 9.5 and 16.3 Hz, 1H); 3.86 (d, J = 15.7 Hz, 1H); 5.15 (s, 1H); 5.77 (d, J = 9.5 Hz, 1H); 7.07 (t, J = 7.5 Hz, 1H); 7.17 to 7.40 (m, 7H); 8.12 (d, J = 8.3 Hz, 1H); 11.60 (m spread, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.84; [M + H] +: m / z 417; [MH] -: m / z 415 Rotatory power: α = -172 ° (c = 0.681 mg in 0.5 mL of DMSO) Example 26: Synthesis of 2- {2- [4- (4-methylpiperazin) 1-yl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one / HO ~ N ~

1NO 2 ~ A solution of 288 mg of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (example 1 step 2) in 8 mL of N, N-dimethylformamide are successively added 8 ml of pyridine, 160 mg of 4- (4-methyl-piperazin-1-yl) -2,3-dihydro-1H-indole (Reference Example 10) and 212 mg N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 48 hours. After addition of 50 ml of water and extraction with ethyl acetate, the organic phases are combined and then dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure. After purification of the residue by chromatography on a silica column, eluting with a mixture of dichloromethane and 7N ammoniacal methanol (90/10), 29 mg of 2- {2- [4- (4-methylpiperazin-1-yl) are obtained. -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one as a white-pink powder whose characteristics are the following: Example 27 and Example 28: Synthesis of (+) - 2- {2 - [- 2- (4-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2- oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one and (-) - 2- {2 - [- 2- (4-fluorophenyl) -2,3-dihydro-1H- indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one La (±) -2- {2- [2- (4-fluorophenyl) -2, 3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one is prepared following the procedure described in example 1 step 3 from 0.50 g of sodium [4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate, 0.46 g of 244-fluorophenyl) -indoline , 0.48 g of N- [3- (dim thylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.31 mL of pyridine and 10 ml N, N-dimethylformamide. After purification by chromatography on a column of 50 g of silica 20-45 μm, eluting with a 90/10 v / v dichloromethane / methanol mixture, 0.46 g of (±) -2- {2- [2- (4-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one in the form of a meringue cream color with the following characteristics: Mass Spectrometry: Method A Retention time Tr (min) = 0.86; [M + H] +: m / z 435; [MH] -: m / z 433 The products were obtained by chiral chromatographic separation of 460 mg of (±) -2- {2- [2- (4-fluorophenyl) -2,3-dihydro-1H-indol). 1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one on a Chiralpak AY column (T304) (1080 mg, 20 μm, 7.7 / 35 cm), eluent: acetonitrile / isopropanol: 90/10; flow rate: 250 mL / min. After purification, 190 mg of (+) - 2- {2- [2- (4-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} are obtained as the first enantiomer. (Morpholin-4-yl) pyrimidin-4 (3H) -one, in the form of a white lyophilizate, the characteristics of which are as follows: NMR spectrum 1H (400MHz): 2.88 (d, J = 15, 8 Hz, 1H); 3.15 (d, J = 16.3 Hz, 1H); 3.33 (m, 4H); 3.57 (m, 4H); 3.79 (dd, J = 9.5 and 16.3 Hz, 1H); 3.86 (d, J = 15.8 Hz, 1H); 5.15 (s, 1H); 5.78 (d, J = 9.5 Hz, 1H); 7.04 to 7.29 (m, 7H); 8.11 (d, J = 7.8 Hz, 1H); 11.60 (m spread, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.86; [M + H] +: m / z 435; [MH] -: m / z 433 Rotatory power: ap = + 114.3 ° +/- 1.9 (c = 1.720 mg in 0.5 mL of DMSO) Then the second enantiomer, ie: 225 mg of (-) - 2- {2 2- [2- (4-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one in the form of of a white lyophilizate, the characteristics of which are as follows: NMR spectrum 1H (400MHz): 2.88 (d, J = 16.3 Hz, 1H); 3.15 (d, J = 15.9 Hz, 1H); 3.33 (m, 4H); 3.57 (m, 4H); 3.79 (dd, J = 9.5 and 16.3 Hz, 1H); 3.86 (d, J = 15.9 Hz, 1H); 5.15 (s, 1H); 5.78 (d, J = 9.5 Hz, 1H); 7.03 to 7.29 (m, 7H); 8.11 (d, J = 7.8 Hz, 1H); 11.60 (m spread, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.86; [M + H] +: m / z 435; [M-H] -: m / z 433 Rotatory power: ap = -137.1 ° +/- 2.1 (c = 1.844 mg in 0.5 mL of DMSO)

Example 29 and Example 30: Synthesis of (+) - 2- {2 - [- 4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} (6-morpholin-4-yl) pyrimidin-4 (3H) -one and (-) - 2- {2 - [- 4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H- indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one H 1 NN (NNOHC)) to a solution of 196.8 mg of sodium morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (obtained in step 2 of Example 1) in 6 ml of N, N-dimethylformamide and 6 ml of pyridine are added 125 mg of 4-difluoromethoxy-2-methyl-2,3-dihydro-1H-indole (Reference Example 11) and 192.7 mg of N- [3- (dimethylamino) propyl] -N'- ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 16 hours, then 25 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with a 0.1N hydrochloric acid solution, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (95: 5: v / v) to give 220 mg of 2- {2 - [- 4- (difluoromethoxy) -2 - methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one. The enantiomers are separated by chiral chromatography on a Whelk 01 SS phase column (5 μm, 30 × 250 mm), eluting with a mixture of: heptane / dichloromethane / methanol: 60/30/10; flow rate: 43 mL / min.

97 mg of (+) - 2- {2 - [- 4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} are obtained as the first enantiomer. (6-morpholin-4-yl) pyrimidin-4 (3H) -one, in the form of a white solid, the characteristics of which are as follows: 1 H NMR Spectrum (400 MHz): 1.28 (broad d, J = 6) , 4 Hz, 3H); 2.71 (d, J = 16.3 Hz, 1H); 3.35 (partially masked m, 1H); 3.41 (m, 4H); 3.60 (m, 4H); 3.73 (d, J = 15.9 Hz, 1H); 3.93 (d, J = 15.9 Hz, 1H); 4.78 (m, 1H); 5.20 (s, 1H); 6.90 (d, J = 8.1 Hz, 1H); 7.24 (t, J = 74.2 Hz, 1H); 7.26 (t, J = 8.1 Hz, 1H); 7.84 (d, J = 8.1 Hz, 1H); 11.68 (m spread, 1 h) Mass Spectrometry: Method A Retention Time Tr (min) = 0.78; [M + H] +: m / z 421; [M-H] -: m / z 419; Rotatory power: ap = + 80 ° (c = 0.25%, DMSO) Then the second enantiomer, 97 mg of (-) - 2- {2 - [- 4- (difluoromethoxy) -2-methyl-2,3 1-Dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one in the form of a white solid, the characteristics of which are as follows: Spectrum 1H NMR (400MHz): 1.28 (d, J = 6.4Hz, 3H); 2.71 (d, J = 16.3 Hz, 1H); 3.34 (partially masked m, 1H); 3.41 (m, 4H); 3.59 (m, 4H); 3.74 (d, J = 15.9 Hz, 1H); 3.93 (d, J = 15.9 Hz, 1H); 4.77 (m, 1H); 5.20 (s, 1H); 6.90 (d, J = 8.1 Hz, 1H); 7.24 (t, J = 74.2 Hz, 1H); 7.26 (t, J = 8.1 Hz, 1H); 7.84 (d, J = 8.1 Hz, 1H); 11.69 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.78; [M + H] +: m / z 421; [M-H] -: m / z 419; Rotatory power: ap = -73 ° (c = 0.25%, DMSO)

Example 31 and Example 32 Synthesis of (+) - 2- {2 - [- 4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} Methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one and (-) - 2- {2 - [- 4- (difluoromethoxy) -2-methyl-2,3- 1-Dihydro-1H-indol-1-yl] -2-oxoethyl-3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one) To a solution of 242 mg of [ Sodium 1-methyl-4- (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate (obtained in step 2 of Example 4) in 6 ml of N, N-dimethylformamide and 6 ml of pyridine are added 125 mg of 4-difluoromethoxy-2-methyl-2,3-dihydro-1H-indole [Reference Example 11] and 193 mg of N- [3- (dimethylamino) propyl). ] -N'-ethylcarbodiimide hydrochloride. The reaction mixture is stirred at room temperature for 16 hours, then 25 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with a 0.1N hydrochloric acid solution, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (90/10: v / v) to give 170 mg of 2- {2-4- (difluoromethoxy) -2 - methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one. The enantiomers are separated by chiral chromatography on a Whelk 01 SS column, 5 μm, (5 μm, 30 × 250 mm), eluting with a mixture of: heptane / dichloromethane / methanol: 50/35/15; flow rate: 40 mL / min.

The first enantiomer is obtained, 40 mg of (+) - 2- {2-4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} - 3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one, in the form of a white solid, the characteristics of which are as follows: NMR spectrum 1H (400MHz): 1.30 (d, J) = 6.4 Hz, 3H); 2.72 (d, J = 15.9 Hz, 1H); 3.33 (s, 3H); 3.35 to 3.42 (m, 5H); 3.57 (m, 4H); 4.03 (d, J = 16.4 Hz, 1H); 4.29 (d, J = 16.4 Hz, 1H); 4.78 (m, 1H); 5.36 (s, 1H); 6.91 (d, J = 8.1 Hz, 1H); 7.24 (t, J = 74.0 Hz, 1H); 7.26 (t, J = 8.1 Hz, 1H); 7.83 (d, J = 8.1 Hz, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.82; [M + H] +: m / z 435; [M-H] -: m / z 433; Rotatory power: ap = + 67 ° (c = 0.3%, DMSO) Then the second enantiomer, 61 mg of (-) - 2- {2-4- (difluoromethoxy) -2-methyl-2,3- 1-dihydro-1H-indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one, in the form of a white solid, the characteristics of which are the following: 1H NMR Spectrum (400MHz): 1.30 (d, J = 6.4Hz, 3H); 2.72 (d, J = 15.9 Hz, 1H); 3.33 (s, 3H); 3.35 to 3.42 (m, 5H); 3.53 to 3.60 (m, 4H); 4.03 (d, J = 16.4 Hz, 1H); 4.29 (d, J = 16.4 Hz, 1H); 4.78 (m, 1H); 5.36 (s, 1H); 6.91 (d, J = 8.1 Hz, 1H); 7.24 (t, J = 74.0 Hz, 1H); 7.26 (t, J = 8.1 Hz, 1H); 7.83 (d, J = 8.1 Hz, 1H) Mass Spectrometry: Method A Retention Time Tr (min) = 0.82; [M + H] +: m / z 435; [M-H] -: m / z 433; Rotatory power: ap = -91.2 ° (c = 1.706 mg / 0.5 mL DMSO)

Example 33 Synthesis of 6- (Morpholin-4-yl) -2- {2- [4- (morpholin-4-yl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl } Pyrimidin-4 (3H) -one Example 34 and Example 35: Synthesis of (+) - 2- [2- (2-Cyclopropyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl ] -6-morpholin-4-yl-3H-pyrimidin-4-one and 5 - (-) - 2- [2 - (- 2-cyclopropyl-2,3-dihydro-indol-1-yl) -2 O-N-morpholin-4-yl-3H-pyrimidin-4-one HH OO NONO (±) -2- [2 - (- 2-Cyclopropyl-2,3-dihydro-indol-1 2-oxoethyl] -6-morpholin-4-yl-3H-pyrimidin-4-one is prepared by following the procedure described in Example 1 from 0.90 g of sodium (morpholin-4-yl) -6-oxo-1,6-dihydropyrimidin-2-yl] acetate, 0.60 g of (±) -2-cyclopropylindoline (Reference Example 12), from 86 g of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride in a mixture of 0.56 ml of pyridine and 10 ml of N, N-dimethylformamide. After purification by chromatography on a column of 100 g of silica 20-45 μm, eluting with a 90/10 v / v dichloromethane / methanol mixture, 0.88 g of (±) -2- [2 - (- 2) cyclopropyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl-6-morpholin-4-yl-3H-pyrimidin-4-one in the form of a cream meringue, the characteristics of which are Mass spectrometry: Method A Retention time Tr (min) = 0.79; [M + H] +: m / z 381; [M-H] -: m / z 379

The products were obtained by chiral chromatographic separation of 875 mg of (±) -2- [2 - (- 2-cyclopropyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6- morpholin-4-yl-3H-pyrimidin-4-one on a Whelk 01 SS column (1200 g, 10 μm, 8/35 cm), eluent: heptane / ethanol / methanol: 70/15/15; flow rate: 250 mL / min, 2 injections. After purification, 407 mg of (+) - 2- [2 - (- 2-cyclopropyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholin are obtained as the first enantiomer. 4-yl-3H-pyrimidin-4-one, in the form of a white powder, the characteristics of which are as follows: 1H NMR spectrum (400MHz): 0.20 to 0.59 (m, 4H); 1.06 (m, 1H); 2.80 (d, J = 16.3 Hz, 1H); 3.20 to 3.37 (partially masked m, 1H); 3.40 (m, 4H); 3.60 (m, 4H); 3.78 (d, J = 15.7 Hz, 1H); 3.99 (d, J = 15.7 Hz, 1H); 4.41 (t, J = 7.8 Hz, 1H); 5.20 (s, 1H); 7.04 (t, J = 7.9 Hz, 1H); 7.17 (t, J = 7.9 Hz, 1H); 7.28 (d, J = 7.9 Hz, 1H); 7.94 (spread m, 1H); 11.67 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.78; [M + H] +: m / z 381; [M-H] -: m / z 379 Rotatory power: ap = + 61.3 ° +/- 1.1 (c = 2.4 mg in 0.5 mL of DMSO)

Then the second enantiomer, namely: 361 mg of (-) - 2- [2 - (- 2-cyclopropyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholin-4 Impure 3-ethyl-3H-pyrimidin-4-one in the form of a white powder. After repurification of 330 mg of this product by chiral column chromatography Chiralpak IC (xxg, 5 pm, 2/25 cm), eluent: ethanol; flow rate: 15 mL / min; 16 injections give 223 mg of (-) - 2- [2 - (- 2-cyclopropyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholin-4-yl -3H-pyrimidin-4-one in the form of a white powder whose characteristics are as follows: 1 H NMR Spectrum (400MHz): 0.22 to 0.59 (m, 4H); 1.08 (m, 1H); 2.81 (d, J = 16.3 Hz, 1H); 3.34 (partially masked m, 1H); 3.40 (m, 4H); 3.60 (m, 4H); 3.78 (d, J = 15.9 Hz, 1H); 3.99 (d, J = 15.9 Hz, 1H); 4.42 (t, J = 7.8 Hz, 1H); 5.20 (s, 1H); 7.04 (t, J = 7.9 Hz, 1H); 7.18 (t, J = 7.9 Hz, 1H); 7.29 (d, J = 7.9 Hz, 1H); 7.94 (spread m, 1H); 11.67 (m spread, 1 h) Mass Spectrometry: Method A Retention time Tr (min) = 0.78; [M + H] +: m / z 381; [MH] -: m / z 379 Rotatory power: ap = -84.7 ° +/- 1.4 (c = 2,290 mg in 0.5 mL of DMSO) Example 36 and Example 37: (+) - 2- {2- [ 2-methyl-4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one and (-) - 2- {2 - [- 2-methyl-4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidine-4 (3H) -one HHO ~ N ~ NO ~ N ~ N

N N O

Example 38: 2- [2 - ((+) - 2-Fluoromethyl-2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholin-4-yl-3H-pyrimidin 4-one Step 1: To a solution of 640 mg of sodium (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl) -acetate in 20 mL of DMF and 20 mL of pyridine are added 673 mg of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and 378 mg of (-) - (2,3-dihydro-1H-indol-2-yl) -methanol (Example Reference 13). The reaction medium is stirred at ambient temperature for 18 hours, then a mixture of water and dichloromethane is added and, after decantation, the organic phase is dried over magnesium sulphate, filtered and then concentrated under reduced pressure. silica column, eluent: gradient: dichloromethane / methanol 100/0 to 95/05 to give 456 mg of 2- [2 - ((+) - 2-hydroxymethyl-2,3-dihydro-indol-1-yl) 2-oxo-ethyl] -6-morpholin-4-yl-3H-pyrimidin-4-one having the following characteristics: Mass Spectrometry: Method A Retention time Tr (min) = 0.54; [M + H] +: m / z 371; [MH] -: m / z 369 Rotatory power: ap = + 80.0 + 1-1.4 C = 2.061 mg / 0.5ML DMSO Step 2: OH5 o To a solution of 200 mg of 2- [2 - ((+) - 2-hydroxymethyl-2,3-dihydroindol-1-yl) -2-oxo-ethyl] -6-morpholin-4-yl-3H-pyrimidin-4-one in 7 mL of dichloromethane and 0.16 mL of triethylamine and at 0 ° C is added 0.07 mL of methanesulfonyl chloride The cooling bath is removed to allow the temperature to rise to room temperature. Stirring at the same temperature for 45 minutes. Addition of cold water and dichloromethane. After decantation, the organic phase is washed with a saturated solution of sodium bicarbonate. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. On the residue obtained, addition of 5 ml of a solution of tetrabutylammonium fluoride 1M in THF. The reaction medium is refluxed for one hour. After cooling, the addition of dichloromethane and a saturated solution of sodium bicarbonate.

After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 97/03 dichloromethane / methanol to give 48 mg of 2- [2 - ((+) - 2-fluoromethyl-2,3-dihydro-indol-1-yl) 2-oxoethyl] -6-morpholin-4-yl-3H-pyrimidin-4-one having the following characteristics: 1 H NMR spectrum (300 MHz): 2.91 (d, J = 16.3 Hz, 1 H ); 3.32-3.45 (m, 5H); 3.61 (m, 4H); 3.78 (d, J = 16.5 Hz, 1H); 3.99 (d, J = 16.5 Hz, 1H); 4.35 to 4.68 (m, 2H); 4.97 (m, 1H); 5.18 (s, 1H); 7.04 (t, J = 8.0 Hz, 1H); 7.18 (t, J = 8.0 Hz, 1H); 7.28 (d, J = 8.0 Hz, 1H); 7.83 (d, J = 8.0 Hz, 1H); 11.40 (spread m, 1 H) 5 87

Mass Spectrometry: Method A Retention Time Tr (min) = 0.66; [M + H] +: m / z 373; [M-H] -: m / z 371 Rotatory power: ap = + 75.7 + 1-1.3. C = 2.169mg / 0.5ML DMSO

Example 39: 2- [2- (2,3-Dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholin-4-yl-3-phenyl-3H-pyrimidin-4-one ONON Reference Example 1: Synthesis of 4-phenyl-2,3-dihydro-1H-indole: To a solution of 1.5 g of 4-phenylindole in 20 ml of acid trifluoroacetic acid under argon cooled to a temperature of -5 ° C is added progressively 1.0 g of sodium cyanoborohydride. The reaction mixture is stirred at a temperature in the region of 0 ° C. for 2 hours, then it is thrown into 50 g of ice and made alkaline with 30 ml of concentrated sodium hydroxide solution. After addition of 100 mL of ethyl acetate, the mixture is stirred at room temperature and treated with 10 mL of concentrated sodium hydroxide and decanted. The organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is treated with a mixture of 50 ml of water, 50 ml of ethyl acetate and 10 ml of concentrated sodium hydroxide solution and stirred at ambient temperature for 15 minutes and then decanted. The organic phase is separated and the aqueous phase is extracted with 2x50 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is triturated in 20 ml of diisopropyl ether and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a column of 50 g of silica 20-45 pm, eluting with pure dichloromethane. 0.7 g of 4-phenyl-2,3-dihydro-1H-indole are thus obtained in the form of a cream-colored solid, the characteristics of which are as follows: Mass spectrometry: method A Retention time Tr (min) = 0.55; [M + H] +: m / z 196 Reference Example 2: 4-trifluoromethoxy-2,3-dihydro-1H-indole FF 0 F Step 1: To a solution of 1.0 g of 4- ( trifluoromethoxy) -1H-indole-2-25 carboxylic acid in 4.5 mL of quinoline under argon are added 0.18 g of copper (0). The reaction mixture is heated at 200 ° C for 5 hours and then cooled to room temperature. After dilution with 30 mL of diethyl ether, the mixture is filtered through Clarcer. The filtrate is washed successively with 6 × 10 ml of a 6N hydrochloric acid solution, with 10 ml of a saturated solution of sodium hydrogencarbonate, then with 10 ml of saturated brine. The organic phase is dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a cartridge of 25 g of silica 15-40 pm, eluting with a 95/5 v / v cyclohexane / ethyl acetate mixture, at a flow rate of 20 ml / min. 0.33 g of 4- (trifluoromethoxy) -indole are thus obtained in the form of an amber oil, the characteristics of which are as follows: 1 H NMR spectrum (400 MHz): 6.48 (bs, 1H); 6.96 (d, J = 7.9 Hz, 1H); 7.14 (t, J = 7.9 Hz, 1H); 7.41 to 7.47 (m, 2H); 11.49 (m, 1H) Mass Spectrometry: Method A Retention time Tr (min) = 1.01; [MH] -: m / z 200 Step 2: To a solution of 0.87 g of 4- (trifluoromethoxy) -indole in 12 ml of trifluoroacetic acid under argon cooled to a temperature in the region of -5 ° C., is 0.57 g of sodium cyanoborohydride was added gradually. The reaction mixture was allowed to warm to 0 ° C. for 3 hours, then poured into 30 g of ice and made alkaline with 21 ml of concentrated sodium hydroxide solution. After stirring for 19 hours, the mixture is diluted with 60 mL of ethyl acetate and then stirred at room temperature for 30 minutes. After decantation, the organic phase is separated and the aqueous phase is extracted with 3 × 60 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is diluted with a mixture of 50 ml of water, 50 ml of ethyl acetate and 10 ml of concentrated sodium hydroxide solution and stirred at ambient temperature for 30 minutes and then decanted. The organic phase is separated and the aqueous phase is extracted with 3 × 50 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a cartridge of 25 g of silica 15-40 pm, eluting with 95/5 cyclohexane / ethyl acetate mixtures; 90/10; then 85/15 v / v, at a flow rate of 25 mL / min. There is thus obtained 0.18 g of impure 4- (trifluoromethoxy) -indoline in the form of a yellow oil directly used in the next step.

Reference Example 3: Synthesis of 4- (2-methoxy-phenyl) -2,3-dihydro-1H-indole: OMe Step 1: To a solution of 0.78 g of 4-bromoindole in 15 mL of dioxane and 5 ml of water under argon are successively added 0.73 g of 2-methoxyphenylboronic acid, then 1.66 g of potassium carbonate. The reaction mixture is stirred at room temperature for 15 minutes, then 0.16 g of dichlorobis (tri-o-tolylphosphine) palladium (II) is added. The reaction mixture is stirred at room temperature for 16 hours, then at 60 ° C for 18 hours, and finally at 110 ° C for 3 hours. After returning to ambient temperature, the mixture is concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 15 ml of a 2N sodium hydroxide solution and 30 ml of ethyl acetate. The mixture is filtered on Clarcer, then decanted. The organic phase is separated and the aqueous phase is extracted with 2x30 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is purified on a cartridge of 30 g of silica 15-40 pm, eluting with a cyclohexane / dichloromethane 60/40 v / v, at a flow rate of 30 ml / min. 0.44 g of 4- (2-methoxyphenyl) -indole are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows: Mass spectrometry: method A Retention time Tr (min) = 1 , 01; [M + H] +: m / z 224 Melting point (Kofler): 172 ° C Step 2: To a solution of 0.44 g of 4- (2-methoxy-phenyl) -indole in 5 ml of acid trifluoroacétique under argon cooled to a temperature in the region of -5 ° C., 0.26 g of sodium cyanoborohydride is added progressively. The reaction mixture is stirred at a temperature of -5 ° C for 2 hours, then it is thrown into 15 g of ice and basified with 8 ml of concentrated sodium hydroxide solution. After addition of 30 ml of ethyl acetate, the mixture is stirred at room temperature for 1 hour and then decanted. The organic phase is separated and the aqueous phase is extracted with 15 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is diluted with a mixture of 15 mL of water, 15 mL of ethyl acetate and 3 mL of concentrated sodium hydroxide solution and stirred at room temperature for 15 minutes and then decanted. The organic phase is separated and the aqueous phase is extracted with 2x15 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure.

The residue is purified by chromatography on a cartridge of 25 g of silica 15-40 pm, eluting with pure dichloromethane, at a flow rate of 30 ml / min.

0.14 g of 4- (2-methoxy-phenyl) -2,3-dihydro-1H-indole are thus obtained in the form of an off-white solid, the characteristics of which are as follows: Mass spectrometry: A time method retention Tr (min) = 0.55; [M + H] +: m / z 226 Melting point (Kofler): 82 ° C. Reference Example 4: 4- (1-propyl-piperidin-3-yl) -2,3-dihydro-1H-indole The product can be prepared as described in Reference Example 1 step 2 by reduction of the corresponding indole (which can be prepared according to EP21924 Example 17). Reference Example 5 4-difluoromethoxy-2,3-dihydro-1H-indole Step 1: FA a mixture of 23.4 g of sodium chlorodifluoroacetate and 22 g of potassium carbonate in 30 ml of N, N -dimethylformamide and 6 mL of water, is added a solution of 10 g of 2-methyl-3-nitro-phenol in 20 mL of N, N-dimethylformamide. The reaction mixture is then heated at 110 ° C for 3 hours and left for 16 hours, then treated with a mixture of water and ethyl acetate. The organic phase is washed with 1N sodium hydroxide, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the expected product in the form of a brown oil, used as is in the next step. Step 2: To a solution of 6 g of 1-difluoromethoxy-2-methyl-3-nitrobenzene in 60 ml of N, N-dimethylformamide is added 17 g of tris (dimethylamino) methane and the reaction mixture is heated to 80.degree. 100 ° C for 72 hours. The reaction mixture is then concentrated under reduced pressure to give 7.6 g of a crude oil used as it is in the next step. Step 3:20 FA a solution of 7.6 g of [2- (2-difluoromethoxy-6-nitro-phenyl) -vinyl] -dimethyl-amine in 35 mL of methanol and 35 mL of tetrahydrofuran, under an atmosphere of argon are added 7 g of Raney nickel. The reaction mixture is heated to 60 ° C. and 5.6 ml of hydrazine hydrate are added in 4 portions of 1.4 ml every 30 minutes and the mixture is stirred for 16 hours. Step 4: To a solution of 1 g of 4-difluoromethoxyl-1H-indole in 15 mL of trifluoroacetic acid, cooled to 0 ° C is added 0.722 mg of sodium cyanoborohydride and stirring is continued for 3 hours. The reaction mixture is then concentrated under reduced pressure, treated with concentrated sodium hydroxide solution, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (20/80: v / v) to give 300 mg of 4-Difluoromethoxyl-2,3-dihydro- 1H-indole as a yellow oil having the following characteristics: 9410 Reference Example 6: 4- (2-chloro-phenyl) -2,3-dihydro-1H-indole Cl HA a suspension of 960 mg of 4- (2-chloro-phenyl) -1H-indole, in 11 ml of trifluoroacetic acid cooled to 0 ° C., are added portionwise 558 g of sodium cyanoborohydride. The reaction medium is stirred for 16 hours, allowing it to rise to room temperature and then the pH is brought to neutrality with a sodium hydroxide solution. The reaction mixture is diluted with 300 mL of water and extracted with ethyl acetate (2x250 mL). The organic phases are combined and then concentrated to dryness under reduced pressure. After purification of the residue by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (80/20), 395 mg of 4- (2-chloro-phenyl) -2,3- dihydro-1H-indole in the form of a colorless viscous oil.

Reference Example 7: 1,2,3,3a, 4,8b-hexahydro-cyclopenta [bpindole To a solution of 1.5 g of 1,2,3,4-tetrahydro-cyclopenta [b] indole in 40 ml of acid The acetic acid is cooled to 15 ° C. and 1.9 g of sodium cyanoborohydride are added portionwise. The reaction medium is stirred for 20 hours, allowing it to rise to room temperature, and then the pH is brought to neutrality with a 280/0 ammonia solution. The reaction mixture is diluted with water and then extracted with dichloromethane, the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (95/05), to give 1.3 g of 1,2,3,3a, 4,8b-hexahydro- cyclopenta [b] indole in the form of a colorless oil. Reference Example 8: 4- (4-Methanesulfonyl-piperazin-1-ylmethyl) -5,2,3-dihydro-1H-indole To a solution of 1 g of indole-4-carboxaldehyde in 40 mL of tetrahydrofuran under argon 2.92 g of sodium triacetoxyborohydride, 2.26 of 1-methanesulfonyl-piperazine hydrochloride and 545 mg of pyridine are successively added. The reaction mixture is stirred at room temperature for 15 hours and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid cooled at 15 ° C. and then 1.30 g of sodium cyanoborohydride are added portionwise. The reaction medium is stirred for 2 hours, allowing it to warm to room temperature, poured onto a water / ice mixture, treated with ammonia at 280 ° C. to neutral pH and extracted with dichloromethane (4x30 mL). The organic phases are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue obtained is purified on a silica column (eluent: heptane / ethyl acetate from 0 to 1000/0 of ethyl acetate) to give 890 mg of 444-methanesulfonyl-piperazin-1-ylmethyl) -2, 3-dihydro-1H-indole as a yellow solid.

Reference Example 9: 4- (4-methyl-piperazin-1-ylmethyl) -2,3-dihydro-1H-indole HA a solution of 1 g of indole-4-carboxaldehyde in 40 mL of tetrahydrofuran under argon, 1.38 g of 1-methylpiperazine and 2.92 g of sodium triacetoxyborohydride are successively added. The reaction mixture is stirred at room temperature for 15 hours and then concentrated under reduced pressure. The residue is taken up in 40 ml of acetic acid cooled at 15 ° C. and then 1.30 g of sodium cyanoborohydride are added portionwise. The reaction medium is stirred for 2 hours, allowing it to warm to room temperature, poured into a water / ice mixture, treated with ammonia solution to 280/0 until neutral pH and extracted with dichloromethane (4x50 mL). The organic phases are combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: 7 N 95/05 ammoniaal dichloromethane / methanol to give 1.22 g of 4- (4-methyl-piperazin-1-ylmethyl) -2,3-dihydro-1H- indole as a yellow solid.

Reference Example 10: 4- (4-methyl-piperazin-1-yl) -2,3-dihydro-1H-indole To a solution of 490 mg of 4- (4-methyl-piperazin-1-yl) -1 H-indole, in 17 mL of acetic acid cooled to 14 ° C, is added portionwise 429 mg of sodium cyanoborohydride. The reaction medium is stirred for 2 hours at room temperature and then poured into a water / ice mixture and the pH is brought to neutrality with an ammonia solution. The mixture is then extracted with dichloromethane and the combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica column eluting with a mixture of dichloromethane and methanol (95/05), to give 395 mg of 4- (4-methyl-piperazin-1-yl) -2,3-dihydro -1H-indole in the form of a colorless viscous oil. Reference Example 11: 4-difluoromethoxy-2-methyl-2,3-dihydro-1H-indole FOF Step 1: 4-Difluoromethoxyl-2-methylindole F Freon-22 (HCF2Cl) is bubbled in a solution of 3 g of 4-hydroxy-2-methylindole in 90 ml of dichloromethane at 0 ° C, containing a small amount of tetrabutylammonium bromide (used as a phase transfer agent). 45 ml of a 10M sodium hydroxide solution are added dropwise to this solution. The reaction mixture is then stirred for 2 hours at 0 ° C and then allowed to warm to room temperature. The phases are separated and the organic phase concentrated under reduced pressure. The residue obtained is purified on a silica column, eluting with dichloromethane to give 480 mg of 4-Difluoromethoxyl-2-methylindole in the form of a yellow oil, the characteristics of which are as follows: Step 2: 4-Difluoromethoxyl-2- A solution of 480 mg of 4-difluoromethoxyl-2-methylindole in 15 ml of acetic acid cooled to 10 ° C. is added portionwise to 459 mg of a solution of 4-difluoromethoxyl-2-methyl-indole. 99 2969614 100

sodium cyanoborohydride. The reaction medium is stirred for 16 hours, allowing it to rise to room temperature. The reaction medium is poured into a water / ice mixture and then treated with ammonia at 280/0 and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified on a silica column, eluent: heptane / ethyl acetate 80/20 to give 250 mg of 4-Difluoromethoxyl-2-methyl-2,3-dihydro-1H-indole in the form of an oil whose characteristics are as follows: 1H NMR Spectrum (400MHz): 1.17 (d, J = 6.2Hz, 3H); 2.47 (dd, J = 7.6 and 15.9 Hz, 1H); 3.06 (dd, J = 8.9 and 15.9 Hz, 1H); 3.91 (m, 1H); 5.85 (broad m, 1H); 6.25 to 6.35 (m, 2H); 6.93 (t, J = 7.9 Hz, 1H); 7.09 (t, J = 74.8 Hz, 1H) Reference Example 12: Synthesis of (-) - 2-isopropylindoline and (+) - 2-cyclopropylindoline: Step 1A a solution of 1.0 g of 2-iodoaniline in 5 ml of triethylamine under argon is successively added 0.26 g of copper (I) iodide, 0.30 g of bis (triphenylphosphine) palladium dichloride ( II), followed by 0.78 mL of cyclopropylacetylene. The reaction mixture is stirred at room temperature for 30 minutes, then 1 mL of N, N-dimethylformamide is added. The reaction mixture is stirred at room temperature for 30 minutes, then 1 mL of N, N-dimethylformamide is added. The reaction mixture is stirred at room temperature for 30 minutes.

hours, then it is thrown into 100 mL of water. After addition of 50 mL of ethyl acetate, the mixture is filtered through Celite® and then decanted. The organic phase is separated and the aqueous phase is extracted with 3 × 40 mL of ethyl acetate. The organic phases are combined, washed with 2x40 ml of water, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is purified on a column of 50 g of silica 20-45 pm, eluting with a 80/20 v / v dichloromethane / cyclohexane mixture. 0.42 g of 2-cyclopropylethynyl-phenylamine are thus obtained in the form of a brown oil which is used directly in the next step.

2nd step

To a solution of 0.42 g of 2-cyclopropylethynyl-phenylamine in 20 ml of N, N-dimethylformamide under argon is added 0.54 g of copper (I) iodide. The reaction mixture is refluxed for 2 hours and then concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 200 mL of water and 100 mL of dichloromethane, filtered through Celite®, and decanted. The organic phase is separated and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are combined, washed with 100 ml of water, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is purified on a column of 50 g of silica 20-45 .mu.m, eluting with a 50/50 v / v cyclohexane / dichloromethane mixture. There is thus obtained 0.18 g 2 -cyclopropylindole in the form of a yellow solid whose characteristics are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 0.96; [M + H] +: m / z 158

Step 3

102

To a solution of 1.25 g of 2-cyclopropyl-indole in 80 ml of acetic acid under argon cooled to a temperature of 15 ° C is added gradually 1.0 g of sodium cyanoborohydride. The reaction mixture is stirred at a temperature of 15 ° C for 2 hours, then it is treated with 100 mL of water. It is then cooled to a temperature of 5 ° C and alkalized by gradual addition of 140 mL of a 300/0 sodium hydroxide solution. The reaction mixture is diluted with 200 mL of ethyl acetate and then stirred at room temperature for 15 hours. After decantation, the organic phase is separated and the aqueous phase is extracted with 3 × 200 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. The residue is taken up in a mixture of 60 ml of ethyl acetate, 40 ml of water and 10 ml of concentrated sodium hydroxide, and then the mixture is stirred at room temperature for 10 minutes. After decantation, the organic phase is separated and the aqueous phase is extracted with 2x50 mL of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and then concentrated to dryness under reduced pressure. 1.2 g of (±) -2-cyclopropylindoline are thus obtained in the form of a brown oil which is used as it is.

Reference Example 13: 2-Hydroxymethyl-2,3-dihydro-1H-indole Step 1: 1 - ((R) -2-Benzyloxy-propionyl) -2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester: diastereoisomer A 2969614 103 And 1 - ((R) -2-Benzyloxy-propionyl) -2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester diastereoisomer BA a solution of 12.6 g of acid o-benzyl-D-lactic acid in 30 ml of DMF and 10.6 ml of pyridine are added 16.6 g of N- [3- (dimethylamino) propyl] -N'-ethylcarbodiimide hydrochloride and then 10 g of indoline-2-carboxylate. ethyl. The reaction medium is stirred at room temperature for 18 hours. The reaction medium is concentrated under reduced pressure to 2/3 of the volume of the reaction medium. Addition of ethyl acetate and water. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified on a silica cartridge: eluent: gradient: heptane / ethyl acetate from 100/0 to 80/20, to give 7.24 g of 1 - ((R) -2-benzyloxy-propionyl) -2 , 3-dihydro-1H-indole-2-carboxylic acid ethyl ester: diastereoisomer A whose characteristics are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 1.08; [M + H] +: m / z 354; [M + Na] +: m / z 376 (base peak) and 7.5 g of 1 - ((R) -2-benzyloxy-propionyl) -2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester: diastereoisomer B in the form of a white solid whose characteristics are as follows: Mass spectrometry: Method A Retention time Tr (min) = 1.06; [M + H] +: m / z 354; [M + Na] +: m / z 376; base peak: m / z 282 Step 2: (R) -2-Benzyloxy-1- (2-hydroxymethyl-2,3-dihydro-indol-1-yl) -propan-1-one: diastereoisomer A and 10 (+) - (2,3-Dihydro-1H-indol-2-yl) -methanol To a solution of 3.31 g of 1 - ((R) -2-benzyloxy-propionyl) -2,3-dihydro-1 H-indole-2-carboxylic acid ethyl ester: diastereoisomer A in 7.5 mL of THF and 7.5 mL of ethanol are added 1.04 g of sodium borohydride. The reaction medium is stirred at room temperature for 5 hours. Addition of dichloromethane and water. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified on a silica cartridge: eluent: heptane / ethyl acetate 50/50, to give 0.98 g of (R) -2-benzyloxy-1- (2-hydroxymethyl-2,3-dihydroindol 1-yl) propan-1-one: diastereoisomer A, the characteristics of which are as follows: Mass spectrometry: method A 2969614 105

Retention time Tr (min) = 0.85; [M + H] +: m / z 312 and 1.65 g of (+) - (2,3-dihydro-1H-indol-2-yl) -methanol in the form of a white solid, the characteristics of which are as follows: : Mass Spectrometry: Method A Retention time Tr (min) = 0.19; [M + H] +: m / z 150 Step 3: (+) - (2,3-Dihydro-1H-indol-2-yl) -methanol To a solution of 0.9 g of (R) -2-benzyloxy 1- (2-Hydroxymethyl-2,3-dihydro-indol-1-yl) -propan-1-one: diastereoisomer A in 9 mL of ethanol and 9 mL of 370/0 hydrochloric acid are refluxed. during two hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with water. Addition of 2N sodium hydroxide to pH = 10. The medium is extracted with dichloromethane. After decantation, the organic phase is dried over magnesium sulphate, filtered and then concentrated under reduced pressure to give 0.4 g of (+) - (2,3-dihydro-1H-indol-2-yl) -methanol whose characteristics are: Mass Spectrometry: Method A Retention Time Tr (min) = 0.19; [M + H] +: m / z 150 PR = + 38.5 + 1-0.9. C = 1.974mg / 0.5ML DMSO Step 4: (R) -2-Benzyloxy-1- (2-hydroxymethyl-2,3-dihydro-indol-1-yl) -propan-1-one: diastereoisomer B And (- ) - (2,3-Dihydro-1H-indol-2-yl) -methanol To a solution of 5.75 g of 1 - ((R) -2-benzyloxy-propionyl) -2,3-dihydro-1H- indole-2-carboxylic acid ethyl ester: diastereoisomer B in 20 ml of THF are added 1.36 g of sodium borohydride. The reaction medium is stirred at room temperature for 18 hours. Addition of 10 mL of ethanol and 0.4 g of sodium borohydride. After stirring for two hours at room temperature, the addition of dichloromethane and water. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified on a silica cartridge: eluent: gradient: dichloromethane / methanol from 00/0 to 98/02, to give 0.51 g of (R) -2-benzyloxy-1- (2-hydroxymethyl-2,3- dihydro-indol-1-yl) -propan-1-one: diastereoisomer B whose characteristics are as follows: Mass Spectrometry: Method A Retention time Tr (min) = 0.82; [M + H] +: m / z 312 and 0.96 g of (-) - (2,3-dihydro-1H-indol-2-yl) -methanol in the form of a white solid whose characteristics are: Mass Spectrometry: Method A Retention Time Tr (min) = 0.19; [M + H] +: m / z 150 PR = -38.9 + 1-0.8. C = 2.255mg / 0.5ML DMSO Step 3: (-) - (2,3-Dihydro-1H-indol-2-yl) -methanol To a solution of 117 mg of (R) -2-benzyloxy-1- (2-hydroxymethyl-2,3-dihydroindol-1-yl) propan-1-one: diastereoisomer B in 1.2 mL of ethanol and 1.2 mL of 370/0 hydrochloric acid are refluxed for two hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with water. Addition of 2N sodium hydroxide to pH = 10. The medium is extracted with dichloromethane. After decantation, the organic phase is dried over magnesium sulphate, filtered and then concentrated under reduced pressure to give 50 mg of (-) - (2,3-dihydro-1H-indol-2-yl) -methanol, the characteristics of which are the following: Mass Spectrometry: Method A Retention time Tr (min) = 0.19; [M + H] +: m / z 150 PR = -38.9 + 1-0.8. C = 2.255mg / 0.5ML DMSO Example 40: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 1 0.2 g Excipient for a tablet finished at 1 g 2969614 108

(details of the excipient: lactose, talc, starch, magnesium stearate). 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 AKT phosphorylation is measured by the MSD Multi-spot Biomarker Detection technique of Meso Scale Discovery also described below. Study of the expression of pAKT in PC3 human prostate carcinoma cells measured by MSD Multi-spot Biomarker Detection technique of Meso Scale Discovery (Test A): This test is based on the measurement of AKT protein expression Phosphorylated on serine 473 (P-AKT-S473), in the human prostate carcinoma cell line PC3, by the sandwich-based immunoassay technique using the MSD Multi-spot Biomarker Detection kit from Meso Scale Discovery: phospho kits -Akt (Ser473) whole cell lysate (# K151 CAD) or phospho-Akt (Ser473) / Total Akt whole cell lysate (# K151O0D). The primary antibody specific for P-AKT-S473 (Kit # K151 CAD) is coated on one electrode in each well of the MSD kit 96-well plates: after addition of a protein lysate in each well, the signal is exposed. by the addition of a labeled secondary detection antibody with an electrochemiluminescent compound. The procedure followed is that described in the kit.

On day 1, the PC3 cells are seeded in 96-well plates (TPP, # 92096) at the concentration of 35000 cells / well in 200 μl of DMEM medium (DMEM Gibco # 11960-044) containing 100% fetal calf serum. (Gibco SVF, # 10500-056) and 10/0 Glutamine (L-Glu Gibco # 25030-024), and incubated at 37 ° C, 50/0 CO2, overnight. 2969614 109

On day 2, the cells are incubated in the presence or absence of test products for 1 to 2 hours at 37 ° C. in the presence of 50% CO 2. Molecules diluted in dimethylsulfoxide (DMSO Sigma # D2650) are added from a stock solution concentrated 20-fold, the final percentage of DMSO being 0.10 / 0. The molecules are tested either at a single concentration of less than or equal to 10 μM, or at increasing concentrations in a range that may range from less than 1 nM to 10 μM. After this incubation, the cells are lysed for the preparation of the proteins. For this, after aspiration of the culture medium, 50 μl of lysis buffer Tris Lysis Buffer complete kit MSD containing solutions of protease inhibitors and phosphatases are added in the wells and the cells are lysed for 1H at 4 ° C under 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 of Tris Wash Buffer from the MSD kit. The lysates prepared previously are transferred to the multispot 96 well plates of the MSD kit and incubated for 1 hour at room temperature, with stirring. Four washes are performed with 150 μl 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 ambient temperature, with stirring. Four washes are performed with 150 μl of Tris Wash Buffer from the MSD kit. 150 μl of 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 0.10 / 0 DMSO are considered the 100% signal (max). The calculation of the percentage inhibition is done to

No.

each concentration of product tested according to the following formula: (1- "swarmin) / (max-min))) x100. The activity of the product is translated into C150, obtained from a dose-response curve of different concentrations tested and representing the dose giving 50% specific inhibition (C150 absolute). 2 independent experiments allow to calculate the average of C150s. The results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below: Table of pharmacological results: Example Test A IC50 (nM) Example 1 Example 2 Example 3 Example 5 EXAMPLE 6 EXAMPLE 9 EXAMPLE 9 EXAMPLE 9 EXAMPLE 9 Example 10 EXAMPLE 13 EXAMPLE 13 EXAMPLE 13 EXAMPLE 14 EXAMPLE 17

Claims (18)

CLAIMS1) Products of formula (1): R3 / N ,,, in which: R represents a hydrogen atom or an alkyl, cycloalkyl, aryl or heteroaryl radical; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy radicals; heterocycloalkyl, aryl heteroaryl and NRxRy; all these alkyl, alkoxy, heterocycloalkyl, aryl and heteroaryl radicals themselves being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, oxo, alkyl, heterocycloalkyl, alkoxy and NRvRw radicals, and S02A1 k; R5 and R5 ', which may be identical or different, represents a hydrogen atom or an alkyl radical or, together with the carbon atom to which they are bonded, form a cyclic radical containing from 3 to 10 members (spirocycloalkyl) optionally containing one or more heteroatoms; (spiroheterocycloalkyl) chosen from O, S, NH, these cyclic radicals being optionally substituted by one or more identical or different radicals chosen from halogen atoms, alkyl, cycloalkyl, hydroxyl, oxo and alkoxy radicals; , NH2; NHalk and N (alk) 2; R6 represents a hydrogen atom; an alkyl radical which is itself optionally substituted with one or more identical or different radicals chosen from halogen atoms, deuterium atoms and hydroxyl and alkoxy radicals, a cycloalkyl radical or a phenyl radical itself optionally substituted by one or more identical or different radicals chosen from halogen or alkoxy radicals; R5 and R6 may optionally form with the carbon atoms to which they are bonded a 3- to 10-membered (cycloalkyl) cyclic radical optionally containing one or more heteroatoms (heterocycloalkyl) selected from O, S, NH, these cyclic radicals being optionally substituted by one or more identical or different radicals selected from halogen atoms, alkyl, hydroxyl, oxo, alkoxy, NH 2 radicals; NHalk and N (alk) 2; 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 and alkoxy radicals, NRvRw 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 optionally being substituted with one or more identical or different radicals selected from halogen atoms and hydroxyl, oxo, alkyl, heterocycloalkyl, alkoxy, NRvRw and -SO2Alk radicals; 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 and alkoxy radicals; heterocycloalkyl; 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; by one or more identical or different radicals selected from halogen atoms and hydroxyl, oxo, alkyl, heterocycloalkyl, alkoxy, NH 2 radicals; NHalk and N (alk) 2 and - SO2A1 k; said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). 2) Products of formula (1) as defined in claim 1 wherein: R represents a hydrogen atom or an alkyl, cycloalkyl or phenyl radical; R1 represents a hydrogen atom or a methyl radical; R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a fluorine atom; R4 represents a hydrogen atom; a halogen atom; or a hydroxyl, alkyl, or alkoxy, heterocycloalkyl, NRxRy, phenyl or heteroaryl radical; the alkyl radicals being optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, heterocycloalkyl and NRvRw radicals; the alkoxy radicals being optionally substituted with one or more halogen atoms; R5 and R5 ', which may be identical or different, represent a hydrogen atom or an alkyl radical or form, together with the carbon atom to which they are bonded, a 3- to 6-membered cyclic radical optionally containing one or more heteroatoms chosen from O, S, NH, optionally substituted by an alkyl or cycloalkyl radical; R6 represents a hydrogen atom; an alkyl radical which is itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms, deuterium atoms and hydroxyl and alkoxy radicals; a cycloalkyl radical or a phenyl radical itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms or the alkoxy radicals R 5 and R 6 which may optionally form, with the carbon atoms to which they are bonded, a cyclic radical; containing from 3 to 7 links; said products of formula (1) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (1). 3) Products of formula (1) as defined in claim 1 or 2 wherein: R2 represents a hydrogen atom or a fluorine atom; R3 represents a hydrogen atom or a fluorine, chlorine or bromine atom; R4 represents a hydrogen atom; a halogen atom selected from chlorine, fluorine and bromine; and a hydroxyl, alkyl radical; alkoxy; a pyrrolidinyl or piperidyl radical optionally substituted by an alkyl radical; morpholinyl; piperazinyl optionally substituted with alk on N; phenyl optionally substituted with one or more radicals selected from Cl, F or OCH3; and pyridyl; it being understood that the alkyl radicals are optionally substituted by one or more identical or different radicals chosen from fluorine atoms, the hydroxyl radical, and the piperazinyl radical, itself optionally substituted on N by an alkyl or SO 2 -alk radical; it being understood that the alkoxy radicals are optionally substituted by one or more fluorine atoms; R5 and R5 ', which may be identical or different, represent a hydrogen atom or an alkyl radical or, together with the carbon atom to which they are bonded, form a spirocyclopropyl, spirotetrahydropyran or spiropiperidyl radical optionally substituted by an alkyl or cycloalkyl radical on NOT ; R6 represents a hydrogen atom; an alkyl radical which is itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms; a cyclopropyl radical; or a phenyl radical itself optionally substituted with one or more identical or different radicals chosen from fluorine atoms; R5 and R6 may optionally form with the carbon atoms to which they are attached a cyclopentyl radical; said products of formula (1) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (1). 4) Products of formula (1) as defined in any one of claims 1 to 3, having the following formulas: - 6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [ cyclopropane-1,3'-indol] -1 '(2'H) -yl) ethyl] pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- [2-oxo-2] (4-phenyl-2,3-dihydro-1H-indol-1-yl) ethyl] pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo) -2- [4- (trifluoromethoxy) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one -3-methyl-6- (morpholin-4-yl) -2 - {2-Oxo-2- [4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- {2-oxo-2- [4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one II 7 - 2- {2- [4- (2-methoxyphenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (Morpholin-4-yl) -2- {2-oxo-2- [4- (1-propylpiperidin-3-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one -2- {2- [4- (d-fluoro-methoxy) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4- yl) pyrim idin-4 (3H) -one - 2- {2- [4- (difluoromethoxy) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4- yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2- [4- (pyridin-4-yl) -2,3-dihydro-1H- indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- [2- (1'-methylspiro [indole-3,4'-piperidin] -1 (2H) -yl) -2-oxoethyl] (Morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- {2-oxo-2- [4- (pyridin-2-yl) -2} 3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- {2-oxo-2- [4- (pyridin)} 3-yl) -2,3-dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [4- (2-chlorophenyl) -2,3-dihydro} 1 H -indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- [2- (4-chloro-2,3-dihydro-1 H -indol-1-yl) -2-oxoethyl] -3-cyclopropyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- -oxo-2- (2,3,3a, 8b-tetrahydro-cyclopenta [b] indol-4 (1H) -yl) ethyl] pyrimidin-4 (3H) -one - 2- [2- (4 - {[4] - (Methylsulfonyl) piperazin-1-yl] methyl) -2,3-dihydro-1H-indol-1-yl) -2-oxoethyl] -6- (morpho) -in-4-yl) pyrimidin 4 (3H) -one -2- (2- {4 - [(4-methylpiperazin-1-yl) methyl] -2,3-dihydro-1H-indol-1-yl} -2-oxoethyl) -6 - (Morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2- [4- (2-fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl 8-Methyl-2- (2- {4 - [(4-methylpiperazin-1-yl) methyl] -2,3-morpholin-4-yl) pyrimidin-4 (3H) -one 1-Dihydro-1H-indol-1-yl} -2-oxoethyl) -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morphol-4-yl) -2- 2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole-3,4'-pyran] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one -3 methyl-6- (morpholin-4-yl) -2- [2-oxo-2- (2 ', 3', 5 ', 6'-tetrahydrospiro [indole-3,4'-pyran] -1 (2H) ) -yl) ethyl] pyrimidin-4 (3H) -one-3-methyl-6- (morpholin-4-yl) -2- [2-oxo-2- (spiro [indole-3,4'-piperidin]] -1 (2H) -yl) ethyl] pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2 - [(2R) -2-phenyl-2,3) 1-Dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- (2-oxo-2 - [(2S) -2-phenyl) -2,3-Dihydro-1H-indol-1-yl] ethyl} pyrimidin-4 (3H) -one - 2- {2- [4- (4-methylpiperazin-1-yl) -2,3-dihydro} -1 H-indol 1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one -2- {2 - [(2R) -2- (4-fluorophenyl) -2,3 -dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one-2- {2 - [(2S) -2- (4- fluorophenyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one - 2- {2 - [(2R) 4 - (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) pyrimidin-4 (3H) -one 2- {2 - [(2S) -4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) ) pyrimidin-4 (3H) -one - 2- {2 - [(2R) -4- (difluoromethoxy) -2-methyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl } -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one -2- {2 - [(2S) -4- (difluoromethoxy) -2-methyl-2,3-dihydro- 1H-Indol-1-yl] -2-oxoethyl} -3-methyl-6- (morpholin-4-yl) pyrimidin-4 (3H) -one-6- (morpholin-4-yl) -2- - [4- (Morpholin-4-yl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} pyrimidin-4 (3H) -one 2969614 119 - 2- {2 - [( 2R) -2-cyclopropyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4-yl) py rimidin-4 (3H) -one - 2- {2 - [(2S) -2-cyclopropyl-2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4 yl) pyrimidin-4 (3H) -one 2- {2 - [(2R) -2-methyl-4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl} -6- (morpholin-4- yl) pyrimidin-4 (3H) -one - 2- {2 - [(2S) -2-methyl-4- (trifluoromethyl) -2,3-dihydro-1H-indol-1-yl] -2-oxoethyl (6-morpholin-4-yl) pyrimidin-4 (3H) -one - 2- [2 - ((+) - 2-fluoromethyl-2,3-dihydro-indol-1-yl) -2-oxo ethyl-6-morpholin-4-yl-3H-pyrimidin-4-one - 2- [2- (2,3-dihydro-indol-1-yl) -2-oxo-ethyl] -6-morpholine 4-yl-3-phenyl-3H-pyrimidin-4-one as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (1). 5) Process for preparing the products of formula (1) as defined in any one of claims 1 to 4 according to scheme 1A as defined below. Wherein the substituents R2, R3, R4, R5, R5 'and R6 have the meanings given in any one of claims 1 to 3. Embedded image 6) Process for the preparation of the products of formula (1) as defined in any one of claims 1 to 4 according to scheme 1B as defined below. Scheme 1B: ## STR1 ## wherein R 1 is R 2, R 2, R 2, R 3, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 2 the substituents R, R2, R3, R4, R5, R5 'and R6 have the meanings given in any one of claims 1 to 3. 7) Process for the preparation of the products of formula (1) as defined in any one of claims 1 to 4 according to scheme 1C as defined below. Scheme 1C: 2 I R, X; X = Cl, Br, 1 or OTf R3 R2 R4 CN1 OGX = Cl, Br, I, OTf R1XC) CN1 OJ RX X = Cl, Br, I, OTf or B (OH) 2 Cl- (Boc) Wherein the substituents R, R 1, R 2, R 3, R 4, R 5, R 5 'and R 6 have the meanings given in any one of claims 1 to 3. 8) As medicaments, the products of formula (1) as defined in any one of claims 1 to 4, as well as addition salts with inorganic and organic acids or with inorganic and organic bases pharmaceutically acceptable. said products of formula (1). 9) As medicaments, the products of formula (1) as defined in claim 4, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (1) ). 2969614 123 10) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (1) as defined in any one of claims 1 to 4, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier. 11) Products of formula (1) as defined in any one of claims 1 to 4 for their use for the treatment of cancers. 12) Products of formula (1) as defined in any one of claims 1 to 4 for use in the treatment of solid or liquid tumors. 13) Products of formula (1) as defined in any one of claims 1 to 4 for their use for the treatment of cancers resistant to cytotoxic agents. 14) Products of formula (1) as defined in any one of claims 1 to 4 for their use for the treatment of primary tumors and / or metastases, particularly in gastric, hepatic, renal, ovarian, gastrointestinal tumors. colon, prostate, lung (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, bone and pancreatic cancer, in hamartomas. 25 15) Products of formula (1) as defined in claims 1 to 4, for their use for the chemotherapy of cancers. 54 16) Products of formula (1) as defined in claims 1 to 4, for their use for cancer chemotherapy alone or in combination. 17) Products of formula (1) as defined in any one of claims 1 to 4 as inhibitors of phosphorylation of AKT (PKB) 18) As new industrial products, synthetic intermediates of formulas C, D, E, F and certain indolines L as defined in any one of claims 5 to 7 above and recalled below: NC ~ Wherein R, R2, R3, R4, R5, R5 'and R6 have any of the definitions given in any one of claims 1 to 5, wherein R, R 2, R 3, R 4, R 5, R 5' and R 6 3.