WO2014053568A1 - Dérivés d'indolyldihydroimidazopyrimidinone, leur préparation et utilisation thérapeutique - Google Patents

Dérivés d'indolyldihydroimidazopyrimidinone, leur préparation et utilisation thérapeutique Download PDF

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Publication number
WO2014053568A1
WO2014053568A1 PCT/EP2013/070581 EP2013070581W WO2014053568A1 WO 2014053568 A1 WO2014053568 A1 WO 2014053568A1 EP 2013070581 W EP2013070581 W EP 2013070581W WO 2014053568 A1 WO2014053568 A1 WO 2014053568A1
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indol
dimethyl
dihydro
imidazo
pyrinnidin
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PCT/EP2013/070581
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English (en)
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Michel Tabart
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Sanofi
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel chemical compounds, indolyldihydroimidazopyrimidinone derivatives, to the process for preparing same, to the novel intermediates obtained, to the use thereof as medicaments, to the pharmaceutical compositions containing same and to the novel use of such derivatives.
  • the present invention thus also relates to the use of said derivatives for preparing a medicament intended for treating humans.
  • the present invention is directed towards compounds which act on protein kinases, these kinases being involved in the development of cancers. More particularly, the present invention is directed towards compounds which act on a target called Pirn which is involved in the development of cancers.
  • Pirn kinases which encompass Pim-1 , Pim-2 and Pim-3, form a distinct family of serine/threonine kinases and play a functional role in cell growth, differentiation and apoptosis.
  • One of the mechanisms via which Pirn kinases can increase the survival of cancer cells and promote progression of the cancer involves modulation of the activity of BAD, a key regulator of apoptosis. Pirn kinases are strongly homologous to one another and show a similar oncogenic behaviour.
  • Pirn kinases in particular Pim-1 and Pim-2, have proven to be abnormally expressed in a large number of malignant hematological diseases.
  • Amson et al. point out the overexpression of Pim-1 in acute myeloid leukemia and acute lymphoid leukemia, and that the overexpression of Pim-1 appears to result from an inappropriate activation in various leukemias (Proc. Natl. Acad. Sci., Vol. 86., 8857- 8861 (1989)).
  • Studies have demonstrated the overexpression of Pim-1 in primary and metastatic CNS lymphoma, an aggressive form of non-Hodgkin's lymphoma (Rubenstein et al., Blood, Vol. 107, no. 9, 3716-3723 (2006)).
  • Huttmann et al. have also discovered an overexpression of Pim-2 in B-cell chronic lymphocytic leukemia and suggest that an up-regulation of Pim-2 may be associated with a more aggressive progression of the disease (Leukemia, 20, 1774-1782 (2006)).
  • An abnormal expression of Pim-1 and of Pim-2 has been linked to multiple myeloma (Claudio et al., Blood, v. 100, no. 6, 2175-2186 (2002)).
  • Pim-1 hypermutations have been identified in diffuse large cell lymphomas (Pasqualucci et al., Nature, Vol. 412, 2001 , p. 341 -346 (2001 )) and in conventional and nodular lymphocyte predominant Hodgkin's lymphoma (Liso et al., Blood, Vol. 108, no. 3, 1013-1020 (2006)).
  • Pim-2 is linked to perineural invasion (PIN), during which the cancer cells wrap themselves around the nerves, which is often found in certain cancers such as prostate cancer, pancreatic cancer, bile duct cancer and head and neck cancer (Ayala et al., Cancer Research, 64, 6082 - 6090 (2004)).
  • PIN perineural invasion
  • Pim- 3 is expressed aberrantly in human and mouse hepatocarcinomas and human pancreatic cancer tissues (Caner Res. 66 (13), 6741 -6747 (2006)).
  • An aberrant expression of Pim-3 has also been observed in gastric adenoma and the metastatic sites of gastric carcinoma (Zheng et al., J Cancer Res Clin Oncol, 134:481 -488 (2008)).
  • Pirn kinase inhibitors are of use for treating cancer, in particular leukemias, lymphomas, myelomas and various solid tumors, in particular head and neck cancers, colon cancer, prostate cancer, pancreatic cancer, liver cancer and oral cancer, for example. Since cancer remains a disease for which the existing treatments are insufficient, it is clearly necessary to identify new Pirn kinase inhibitors which are effective for treating cancer.
  • R1 represents a hydrogen atom or an alkyl or cycloalkyl radical optionally substituted with one or more halogens and optionally containing one or more deuterium atoms
  • R2 represents a hydrogen atom or a halogen atom
  • R3 represents a hydrogen atom; a halogen atom; a hydroxyl radical; a nitro radical; or a C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; -Y-alkyl; R; OR; CO 2 H; -CO 2 R; -NRxRy or -CONRxRy radical, all optionally substituted;
  • Y represents S, SO or SO 2 ;
  • NRxRy being such that either Rx represents a hydrogen atom or an alkyl or cycloalkyl radical and Ry represents a hydrogen atom, or an alkyl, cycloalkyl, heterocydoalkyi, aryl, heteroaryl, COR or SO 2 R radical, all optionally substituted; or Rx and Ry 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 itself optionally substituted;
  • R represents a C1-C10 alkyl, a cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl radical, all optionally substituted;
  • alkoxy, phenoxy, alkylthio, alkyl, alkenyl, alkynyl, heterocycloalkyl, aryl and heteroaryl radicals being themselves optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms; hydroxyl, NH 2 , NHalk and N(alk) 2 radicals; and alkyl, alkoxy, piperidyl, pyrrolidinyl, pyridyl or phenyl radicals, themselves optionally substituted with one or more halogen atoms;
  • heterocycloalkyl and heteroaryl radicals it being possible for the heterocycloalkyl and heteroaryl radicals to also contain an oxo radical
  • NRvRw being such that either Rv represents a hydrogen atom or an alkyl radical optionally substituted with a cycloalkyl radical and Rw represents a hydrogen atom, a cycloalkyl or heterocycloalkyl radical or an alkyl radical itself optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and hydroxyl, alkoxy, NH 2 , NHalk and N(alk) 2 and NHcycloalkyl radicals; or Rv and Rw form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 ring members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being optionally substituted; the cyclic radicals that Rx and Ry or Rv and Rw, respectively, can form with the nitrogen atom to which they are bonded being optionally substituted with one or more radicals, which may be identical or different
  • Rz represents the values of Ry with the exception of hydrogen; Rx, Ry, Rv, Rw and Rz in the CO 2 NRxRy , -CO-NRxRy, -CO2NRvRw-, -CONRvRw, -NRvCORw, -CORw and -NRVCO 2 RZ radicals being chosen among the meanings indicated above respectively for Rx, Ry, Rv, Rw and Rz;
  • alkyl alk
  • alkenyl alkynyl
  • alkoxy alkylthio radicals
  • one or more of the hydrogen atoms of said products of formula (I) can represent a deuterium atom
  • said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • the compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and also mixtures thereof, including racemic mixtures, are part of the invention.
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same structural formula, but the various groups of which are arranged differently in space, such as, in particular, in monosubstituted cyclohexanes, the substituent of which can be in the axial or equatorial position, and the various possible rotational conformations of ethane derivatives.
  • stereoisomerism owing to the different spatial arrangements of substituents attached either on double bonds or on rings, which is often referred to as geometric isomerism or cis-trans isomerism.
  • stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • the compounds of formula (I) can comprise one or more stereochemistries of the type E/Z on double bonds or cis/trans on nonaromatic rings. These various stereoisomers and also mixtures thereof are part of the invention.
  • the compounds of formula (I) can exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts can be prepared with pharmaceutically acceptable acids (P. Stahl, C. Wermuth; Handbook of Pharmaceutical Salts; Wiley Ed.), but salts of other acids that are of use, for example, for purifying or isolating the compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) can comprise one or more isotopes of the atoms described above, in particular deuterium D, tritium T, 1 1 C, 13C, 14C, 150, 15N, 18F, 1231, 1241 and 1351. These compounds, whatever their isotope compositions, are part of the invention.
  • the present invention relates in particular to the products of formula (I) as defined above, in which R1 and R2 have the meanings indicated above and R3 represents a halogen atom or a C2-C6 alkenyl; C2-C6 alkynyl; R; O-alkyl; O-heterocycloalkyl; - CO 2 alkyl; -NRxRy or -CONRxRy radical, all optionally substituted;
  • NRxRy being such that either Rx represents a hydrogen atom or an alkyl or cycloalkyi radical and Ry represents a hydrogen atom, or an alkyl, cycloalkyi or heterocycloalkyi radical, all optionally substituted; or Rx and Ry 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 itself optionally substituted;
  • R represents a C1-C10 alkyl, a cycloalkyi, a heterocycloalkyi, a phenyl or a heteroaryl radical, all optionally substituted;
  • alkoxy, alkyl, alkenyl, alkynyl, heterocycloalkyi, aryl and heteroaryl radicals being themselves optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms; hydroxyl, NH 2 , NHalk and N(alk) 2 radicals; and alkyl, alkoxy, piperidyl, pyrrolidinyl, pyridyl or phenyl radicals, themselves optionally substituted with one or more halogen atoms;
  • heterocycloalkyi and heteroaryl radicals may also contain an oxo radical, NRvRw being such that either Rv represents a hydrogen atom or an alkyl radical optionally substituted with a cycloalkyi radical and Rw represents a hydrogen atom or an alkyl radical itself optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and hydroxyl, alkoxy, NH 2 , NHalk, N(alk) 2 and NHcycloalkyl radicals; or Rv and Rw form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 ring members and optionally one or more other heteroatoms chosen from O, S, NH and N-alkyl, this cyclic radical being optionally substituted;
  • the cyclic radicals that Rx and Ry or Rv and Rw, respectively, can form with the nitrogen atom to which they are bonded being optionally substituted with one or more radicals, which may be identical or different, chosen from alkyl, hydroxyl, NH 2 , NHalk, N(alk) 2 , phenyl and -CH 2 -phenyl radicals;
  • alkyl (alk), alkenyl, alkynyl and alkoxy radicals above being linear or branched and containing at most 6 carbon atoms,
  • one or more of the hydrogen atoms of said products of formula (I) can represent a deuterium atom
  • products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • the subject of the present invention is in particular the products of formula (I) as defined above, in which R1 and R3 have the meanings indicated above and R2 represents H,
  • said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • the present invention relates in particular to the products of formula (I) as defined above, in which R1 and R3 have the meanings indicated above and R2 represents F, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).
  • R1 represents a hydrogen atom or an alkyl radical.
  • the present invention relates in particular to the products of formula (I) as defined above, in which R2 and R3 have the meanings indicated above and R1 represents a hydrogen atom or the CH 3 radical,
  • alkyl (or alk) radical denotes 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 also the linear or branched positional isomers thereof: preference is given to the alkyl radicals containing from 1 to 6 carbon atoms and more particularly the alkyl radicals containing from 1 to 4 carbon atoms of the list above;
  • alkenyl radical denotes linear and branched radicals containing from 2 to 10 carbon atoms, chosen from the alkyl radicals defined above containing one or more double bonds, such as allyl, but-3-enyl or pent-4-enyl, and also the linear or branched positional isomers thereof: preference is given to the allyl and but-3-enyl radicals;
  • alkoxy radical denotes the linear and branched radicals, containing from 1 to 10 carbon atoms, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy or hexoxy, and also the linear or branched positional isomers thereof: preference is given to the alkoxy radicals containing from 1 to 4 carbon atoms of the list above;
  • alkythio or -S(O)x alkyl denotes the linear, and where appropriate branched, radicals in which the alkyl residue has the definition indicated above for the alkyl radical; -S(O)x alkyl thus in particular represents -S(O)x methyl, -S(O)x ethyl, -S(O)x propyl, -S(O)x isopropyl, linear, secondary or tertiary -S(O)x butyl, - S(O)x pentyl or -S(O)x hexyl and also the linear or branched positional isomers thereof: preference is given to the -S(O)x alkyl radicals containing from 1 to 4 carbon atoms of the list above;
  • halogen atom denotes chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom
  • cycloalkyl radical denotes a saturated carbocyclic radical containing from 3 to 10 carbon atoms, and thus denotes in particular the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals and quite particularly the cyclopropyl, cyclopentyl and cyclohexyl radicals;
  • the cycloalkyl residue is as defined above;
  • heterocycloalkyl radical thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 ring members, interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms: mention may, for example, be made of morpholinyl, thiomorpholinyl, homomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyran, oxodihydropyridazinyl, or else oxetanyl radicals, all these radicals being optionally substituted; mention may in particular be made of morpholinyl, thiomorpholinyl, homomorpholinyl, piperazinyl, piperidyl
  • aryl and heteroaryl denote monocyclic or bicyclic, respectively, carbocyclic and heterocyclic, unsaturated or partially unsaturated radicals containing at most 12 ring members, which can optionally contain a -C(O) ring member, the heterocyclic radicals containing one or more heteroatoms, which may be identical or different, chosen from O, N or S with N, where appropriate, optionally substituted;
  • aryl radical thus denotes monocyclic or bicyclic radicals containing from 6 to 12 ring members, such as, for example, phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly phenyl and naphthyl radicals and even more particularly the phenyl radical.
  • a carbocyclic radical containing a -C(O) ring member is, for example, the tetralone radical;
  • heteroaryl radical thus denotes monocyclic or bicyclic radicals containing from 5 to 12 ring members: monocyclic heteroaryl radicals such as, for example, the radicals: thienyl such as 2-thienyl and 3-thienyl, furyl such as 2-furyl or 3-furyl, pyrannyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, triazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such as 3- or 4-isoxazolyl, furazanyl, free or salified t
  • heteroaryl or bicyclic radicals mention may be made more particularly of pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl, benzothiazolyl or benzimidazolyl radicals optionally substituted with one or more substituents, which may be identical or different, as indicated above.
  • the carboxy radical(s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which mention may be made, for example, of:
  • inorganic bases such as, for example, an equivalent of sodium, of potassium, of lithium, of calcium, of magnesium or of ammonium
  • organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methylglucamine,
  • the alkyl radicals for forming alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, it being possible for these alkyl radicals to be substituted with radicals chosen, for example, from halogen atoms, and hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for instance in the chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
  • NRxRy or NRvRw forms a ring as defined above
  • such an aminated ring can be chosen in particular from piperidyl, morpholinyl, homomorpholinyl, azetidine, oxaazaspiro[3.3]heptane, isoxazolidine, 1 ,2-oxazinane, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, azepinyl, piperazinyl and homopiperazinyl radicals, these radicals being themselves optionally substituted as indicated above or hereinafter.
  • NRxRy or NRvRw forms a ring as defined above
  • such an aminated ring can be chosen in particular from piperidyl, morpholinyl, azetidine, oxaazaspiro[3.3]heptane, isoxazolidine, pyrrolidinyl, piperazinyl, homopiperazinyl or 1 ,2-oxazinane radicals, which are optionally substituted as indicated above.
  • the subject of the present invention is also any process for preparing the products of formula (I) as defined above.
  • the subject of the present invention is thus in particular a process for synthesis of the products of formula (I) as defined above, described in scheme 1 or 2a or 2b or 3 as defined hereinafter.
  • alk represents an alkyl radical and PG represents a protective group for nitrogen, or a hydrogen atom. It may be noted that, in the boron derivative B(Oalk) 2 , the two alk radicals can be linked.
  • alk represents an alkyl radical and PG represents a protective group for nitrogen,or a hydrogen atom. It may be noted that, in the boron derivative B(Oalk) 2 , the two alk radicals can be linked.
  • Alk above may be identical or different.
  • alk represents an alkyl radical and PG represents a protective group for nitrogen, or a hydrogen atom. It may be noted that, in the boron derivative B(Oalk) 2 , the two alk radicals can be linked.
  • the amine group protected by PG may be, for example, a benzylamine, para- methoxybenzylamine, 2,4-dimethoxybenzylamine or 4-methoxyphenylethylamine.
  • R, R1 , R2 and R3 as defined above may be in protected form, the deprotection thereof being subsequently carried out if necessary according to the usual methods known to those skilled in the art.
  • the products of the present invention are in particular of use for antitumor therapies.
  • the products of the invention can thus also increase the therapeutic effects of commonly used antitumor agents.
  • the products of the invention can thus also increase the therapeutic effects of commonly used radiotherapies.
  • the subject of the invention is quite particularly, as medicaments, the products corresponding to the following formulae: 7- ⁇ 5-[3-(2-Diethylaminoethoxy)phenyl]-1 H-indol-3-yl ⁇ -1 -isopropyl-2,2-dimethyl- 2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one lsopropyl-2,2-dimethyl-7-[5-(4-piperazin-1 -ylphenyl)-1 H-indol-3-yl]-2,3-dihydro- 1 H-imidazo[1 ,2-a]pyrimidin-5-one 7-(5-Bromo-1 H-indol-3-yl)-1 -isopropyl-2,2-dimethyl-2,3-dihydro-1 H- imidazo[1 ,2-a]pyrimidin-5-one lsopropyl-7- ⁇ 5-[4-(4-iso
  • the invention also relates to pharmaceutical compositions containing, by way of active ingredient, at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, a pharmaceutically acceptable carrier.
  • the invention thus extends to the pharmaceutical compositions containing, as active ingredient, at least one of the medicaments as defined above.
  • the present invention relates to pharmaceutical compositions comprising, as active ingredient, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, and also at least one pharmaceutically acceptable excipient.
  • excipients are chosen, according to the pharmaceutical form and the mode of administration desired, from the usual excipients which are known to those skilled in the art.
  • the active ingredient of formula (I) above, or its salt can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals or to human beings for the treatment of the above disorders or diseases.
  • compositions of the present invention can also, where appropriate, contain active ingredients of other antimitotic medicaments, such as, in particular, those based on taxol, cisplatin, DNA-intercalating agents, and the like.
  • the appropriate unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, and sublingual, buccal, subcutaneous, intramuscular or intravenous administration forms.
  • These medicaments are of use in therapy, in particular in the treatment of cancers sensitive to Pim kinase dysregulation.
  • the Pim kinase inhibitors which are subjects of the present invention are of use for treating cancer. Since cancer remains a disease for which the existing treatments are insufficient, it is clearly necessary to identify new Pim kinase inhibitors which are effective for treating cancer.
  • the present invention also relates to a method for treating the pathological conditions indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt thereof.
  • the usual dosage which is variable according to the product used, the individual treated and the condition in question, can be, for example, from 0.05 to 5 g per day in adults, or preferably from 0.1 to 2 g per day.
  • the subject of the present invention is also the use of products of formula (I) as defined above, for preparing a medicament intended for the treatment or prevention of a disease characterized by the dysregulation of the activity of a protein kinase or lipid kinase.
  • Such a medicament can in particular be intended for the treatment or prevention of a disease in a mammal.
  • the subject of the present invention is in particular the use of a product of formula (I) as defined above, for preparing a medicament intended for the prevention or treatment of diseases associated with an uncontrolled proliferation.
  • the subject of the present invention is thus quite particularly the use of a product of formula (I) as defined above, for preparing a medicament intended for the treatment or prevention of diseases in oncology, and in particular intended for the treatment of cancers.
  • the subject of the present invention is the products of formula (I) as defined above, for use thereof in the treatment of solid or liquid tumors.
  • the cited products of the present invention can in particular be used for the treatment of primary tumors and/or of metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate, endometrial and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid hematopoietic tumors, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic cancers, and in hamartomas.
  • gastric gastric, hepatic, renal, ovarian, colon, prostate, endometrial and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid hematopoietic tumors, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic cancers
  • the subject of the present invention is therefore the products of formula (I) as defined above, for use thereof in cancer chemotherapy, alone or in combination.
  • the products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or else in combination, for example, with other therapeutic agents.
  • Such therapeutic agents may be commonly used antitumor agents.
  • a therapeutic benefit can in particular be expected by administering the products of the present application in combinations with varied targeted therapies, for example and in a nonlimiting manner: targeted therapies which inhibit the kinases or pseudo-kinases implicated in the cancer field.
  • the present invention relates in particular to the products of formula (I) as defined above, for use thereof in the treatment or prevention of a disease chosen from the following group: blood vessel proliferation disorders, fibrotic disorders, "mesangial" cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.
  • a disease chosen from the following group: blood vessel proliferation disorders, fibrotic disorders, "mesangial" cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.
  • a disease chosen from the following group: blood vessel proliferation disorders, fibrotic disorders, "mesangial" cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoi
  • the products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or else in combination, for example, with other therapeutic agents.
  • Such therapeutic agents may be commonly used antitumor agents.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of cancers.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of solid or liquid tumors.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of cancers resistant to cytotoxic agents.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in the treatment of primary tumors and/or of metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid hematopoietic tumors, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic cancers, and in hamartomas.
  • gastric, hepatic, renal, ovarian, colon, prostate and lung (NSCLC and SCLC) cancers glioblastomas, thyroid, bladder and breast cancers
  • melanoma in lymphoid or myeloid hematopoietic tumors
  • sarcomas in brain, larynx and lymphatic system cancers, bone and pancreatic cancers, and in hamart
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in cancer chemotherapy.
  • the present application relates in particular to the products of formula (I) as defined above, for use thereof in cancer chemotherapy, alone or in combination.
  • the subject of the present invention is also, as novel industrial products, certain starting products or synthesis intermediates as defined above or hereinafter.
  • the subject of the present invention is thus in particular, as novel industrial products, the starting products or synthesis intermediates of formulae B, C, D, H, L M, M1 , N, N1 , O and Q as defined above and hereinafter, in which the substituents have the definitions indicated for the products of formula (I):
  • DAD wavelength-scanning detector
  • HATU 0-(7-Azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the 1 H NMR spectra at 400 MHz and 1 H NMR spectra at 500 MHz were carried out on a Bruker Avance DRX-400 or Bruker Avance DPX-500 spectrometer with the chemical shifts ( ⁇ in ppm) in the solvent dimethyl sulfoxide-d6 (DMSO-d6) referenced at 2.5 ppm at the temperature of 303K.
  • DMSO-d6 solvent dimethyl sulfoxide-d6
  • stage 2 In a round-bottomed flask, with stirring under argon and equipped with a condenser, 1 .125 g of 7-chloro-2,2-dimethyl-2,3,6,7-tetrahydroimidazo[1 ,2-a]pyrimidin-5(1 H)-one (stage 2) are solubilised in 15 ml of dimethylformamide and 487 mg of sodium hydride at 60% in oil, then 0.913 ml of 2-iodopropane, are added. The mixture is stirred at a temperature of 60°C for one hour. After a return to a temperature of about 20°C, the reaction medium is poured into 30 ml of water.
  • Stage 4 Synthesis of 2-(3-bromophenoxy)-N,N-diethylethanamine 1 .79 g of 2-chloro-N,N-diethylethanannine and 4.8 g of potassium carbonate are added to a solution of 1 .5 g of 3-bromophenol in 20 ml of dimethylformamide under argon and with stirring. After 5 hours at a temperature of 60°C, and a return to a temperature of about 20°C, the reaction medium is diluted with 100 ml of water, and extracted twice with ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • dichloropalladiunn (II) complexed with methylene chloride (1 :1 ) are introduced into 12 ml of dioxane and 4 ml of water.
  • the reaction medium is placed at 140°C for 15 min under microwave irradiation.
  • the reaction medium is poured onto a water/ethyl acetate mixture, filtered through Clarcel, and separated by settling out, and then the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. After flash
  • reaction medium is poured into 250 ml of ice-cold water, extracted with three times 100 ml of ethyl acetate, and the combined organic phases are washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • the oily residue is poured dropwise into 250 ml of ice-cold water and left to stir for 30 min.
  • the solid form is dried by suction and then dried under vacuum. 726 mg of 2-[3-(3-bromo-1 H-indol-5- yl)phenoxy]-N,N-diethylethanamine are obtained in the form of a brown oil, the characteristics of which are the following:
  • dichloropalladium (II) complexed with methylene chloride (1 :1 ) and 431 mg of potassium acetate are introduced into 5 ml of dioxane.
  • the mixture is brought to the reflux of dioxane for 4 hours.
  • the reaction medium is poured into a water/ethyl acetate mixture, filtered through Clarcel, and separated by settling out, and the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Stage 9 7-(5- ⁇ 3-[2-(diethylamino)ethoxy]phenyl ⁇ -[(4-methylphenyl)sulfonyl]- 1 H-indol-3-yl)-2,2-dimethyl-1 -(propan-2-yl)-2,3-dihydroimidazo[1 ,2-a]pyrimidin- 5(1 H)-one
  • reaction medium is poured onto a water/ethyl acetate mixture, filtered through Clarcel, and separated by settling out, and then the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • the methanol is concentrated and then the residue is taken up in a water/ethyl acetate mixture.
  • the aqueous phase is extracted twice with ethyl acetate and then twice with dichloromethane.
  • the combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Stage 1 Synthesis of 2-methylpropan-2-yl 4-(4-bromophenyl)piperazine-1- carboxylate 19.2 ml of triethylamine, 563 mg of 4-dimethylaminopyridine and 1 1 .9 g of bis(2- methylpropan-2-yl) dibicarbonate are added, with stirring, to a suspension of 14.7 g of 1 -(4-bromophenyl)piperazine hydrochloride in 1 10 ml of acetonitrile. After 16 hours with stirring at a temperature of about 20°C, 120 ml of water are added to the mixture, and the solid formed is dried by suction and dried under vacuum. 17.2 g of 2-methylpropan-2-yl (4-bromophenyl)piperazine-1 -carboxylate are obtained in the form of a white solid, the characteristics of which are the following:
  • the 2-methylpropan-2-yl 4-[4-(1 H-indol-5-yl)-phenyl]piperazine-1 -carboxylate can be prepared in the following way: In a round-bottomed flask, 2.6 g of [4-(4- ⁇ [(2-methylpropan-2- yl)oxy]carbonyl ⁇ piperazin-1 -yl)phenyl]boronic acid, 1 .5 g of 5-bromoindole, 7.5 g of cesium carbonate, and 336 mg of [1 ,1 '-bis(diphenylphosphino)ferrocene]
  • dichloropalladium (II) complexed with methylene chloride (1 :1 ) are introduced into a mixture of 23 ml of dioxane and 8 ml of water.
  • the mixture is heated to a temperature of 100°C. After 16 hours at this temperature, the mixture is placed at a temperature of about 20°C, diluted with 30 ml of water, and extracted with twice 40 ml of ethyl acetate.
  • the combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. After flash
  • Stage 4 Synthesis of 2-methylpropan-2-yl 4-(4- ⁇ 3-bromo-1 -[(4- methylphenyl)sulfonyl]-1 H-indol-5-yl ⁇ phenyl)piperazine-1 -carboxylate
  • Step 1 In a round-bottomed flask, under argon and with stirring, at a temperature of about 0°C, 755 mg of 2-methylpropan-2-yl 4-[4-(1 H-indol-5-yl)phenyl]piperazine-1 - carboxylate are placed in 5 ml of pyridine. A solution of 704 mg of pyridinium bromide in 3 ml of pyridine is slowly added at this temperature.
  • Step 2 In a round-bottomed flask, with stirring and under argon, 910 mg of 2- methylpropan-2-yl 4-[4-(3-bromo-1 H-indol-5-yl)phenyl]piperazine-1 -carboxylate are solubilised in 10 ml of tetrahydrofuran. At a temperature of 0°C, 120 mg of sodium hydride at 60% in oil are slowly added, followed, after 5 min, still at 0°C, by 418 mg of 4-methylbenzenesulfonyl chloride, and then the reaction medium is stirred at a temperature of about 20°C.
  • reaction medium is diluted with 30 ml of water and extracted with twice 30 ml of ethyl acetate.
  • the combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • flash chromatography on a silica column [eluent: heptane/ ethyl acetate (gradient of 100/0 to 60/40 by volume)], 657 mg of 2-methylpropan-2-yl 4-(4- ⁇ 3-bromo-1 -[(4-methylphenyl)sulfonyl]-1 H-indol-5-yl ⁇ pheny)piperazine-1 - carboxylate are obtained in the form of a beige solid, the characteristics of which are the following:
  • reaction medium After 15 min at 160°C under microwave irradiation, the reaction medium is diluted in 30 ml of water and then extracted with twice 30 ml of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and
  • reaction medium After the reactor has been closed, the reaction medium is placed at 140°C for 15 min under microwave irradiation. The reaction medium is subsequently poured onto a water/ethyl acetate mixture, filtered through Clarcel, and separated by settling out, and then the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Stage 7 Synthesis of 2-methylpropan-2-yl 4-(4- ⁇ 3-[2,2-dimethyl-5-oxo-1 - (propan-2-yl)-1 ,2,3,5-tetrahydroimidazo[1 ,2-a]pyrimidin-7-yl]-1 H-indol-5- yl ⁇ phenyl)piperazine-1 -carboxylate
  • reaction mixture is then poured into 240 ml of aqueous ammonium chloride solution at 0°C, the resulting mixture is separated by settling out and then extraction is carried out with three times 100 ml of diethyl ether, the organic phase is washed with a saturated solution of sodium chloride, then drying over sodium sulfate, filtration and
  • Stage 3 synthesis of 7-[5-bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]- 2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • Stage 4 synthesis of 7-[5-bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-1 - isopropyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • the solid obtained is taken up in a small amount of ether, filtered, dried by suction and then dried under a vacuum bell so as to obtain 2.98 g of 7-[5- bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-1 -isopropyl-2,2-dimethyl-2,3- dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one in the form of a white solid, the
  • Stage 5 Synthesis of 7-(5-bromo-1 H-indol-3-yl)-1 -isopropyl-2,2-dimethyl-2,3- dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one 400 mg of 7-[5-bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-1 -isopropyl- 2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one, 0.23 g of
  • dichloropalladium (II) complexed with methylene chloride (1 :1 ) are added and then irradiated again for 1 h at 120°C and then 1 h at 130°C.
  • the reaction medium is diluted in 10 ml of water and then extracted with three times 15 ml of ethyl acetate.
  • the combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Stepl synthesis of 1 -isopropyl-2,2-dimethyl-7-[5-(4,4,5,5-tetrannethyl-1 ,3,2- dioxaborolan-2-yl)-1 -(2-thmethylsilanylethoxynnethyl)-1 H-indol-3-yl]-2,3-dihydro-1 H- imidazo[1 ,2-a]pyhmidin-5-one
  • Stage 2 synthesis of 1 -isopropyl-2,2-dimethyl-7-[5-[(S)-4-(5,6,7,7a-tetrahydro-1 H- pyrrolo[1 ,2-c]imidazol-3-yl)phenyl]-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]- 2,3-dihydro-1 H-imidazo[1 ,2-a]pyrinnidin-5-one
  • reaction medium is diluted in 30 ml of water and then extracted three times with 30 ml of ethyl acetate.
  • the combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Stage 3 synthesis of 1 -isopropyl-2,2-dimethyl-7- ⁇ 5-[(S)-4-(5,6,7,7a-tetrahydro-1 H- pyrrolo[1 ,2-c]imidazol-3-yl)phenyl]-1 H-indol-3-yl ⁇ -2,3-dihydro-1 H-imidazo[1 ,2- a]pyrimidin-5-one
  • reaction medium is placed at 185°C for 15 min under microwave irradiation.
  • the reaction medium is poured into water, extracted three times with ethyl acetate, washed with distilled water, dried over magnesium sulfate, filtered and then evaporated to dryness under reduced pressure.
  • Stage 1 synthesis of 7-[5-bromo-1 -(toluene-4-sulfonyl)-1 H-indol-3-yl]-1 -isopropyl-2,2- dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyhnnidin-5-one
  • Stage 2 synthesis of 1 -isopropyl-2,2-dimethyl-7-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 -tosyl-1 H-indol-3-yl)-2,3-dihydroimidazo[1 ,2-a]pyhmidin-5(1 H)- one
  • Stage 3 synthesis of 1 -isopropyl-2,2-dimethyl-7-(5-(2-methyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1 -tosyl-1 H-indol-3-yl)-2,3-dihydroimidazo[1 ,2-a]pyrimidin- 5(1 H)-one
  • Stage 4 synthesis of 1 -isopropyl-2,2-dimethyl-7-[5-(2-methyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1 H-indol-3-yl]-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5- one
  • 216 mg of 1 -isopropyl-2,2-dimethyl-7-(5-(2-methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)- 1 -tosyl-1 H-indol-3-yl)-2,3-dihydroimidazo[1 ,2-a]pyrimidin-5(1 H)-one and 164.1 mg of potassium hydroxide are introduced into 15 ml of methanol.
  • the reaction mixture is heated at 70°C for 45 min, and then evaporated to dryness under reduced pressure.
  • the residue is taken up in dichloromethane, and the solution obtained is poured into water. Extraction is carried out with dichloromethane, the organic phase is dried over magnesium sulfate, and then filtration and concentration to dryness are carried out.
  • Stage 1 synthesis of 1 -isopropyl-2,2-dimethyl-7-(5-(2-ethyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1 -tosyl-1 H-indol-3-yl)-2,3-dihydroimidazo[1 ,2-a]pyrimidin- 5(1 H)-one
  • Stage 4 synthesis of 1 -isopropyl-2,2-dimethyl-7-[5-(2-ethyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1 H-indol-3-yl]-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5- one
  • Stage 1 synthesis of 7-[5-Bromo-1 -(toluene-4-sulfonyl)-1 H-indol-3-yl]-6-fluoro-1 - isopropyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyhmidin-5-one
  • reaction medium is placed at 100°C for 2h under microwave irradiation.
  • the reaction medium is concentrated to dryness under reduced pressure, taken up with ethyl acetate, washed with water, then concentrated to dryness under reduced pressure.
  • Stage 2 synthesis of 6-fluoro-1 -isopropyl-2,2-dinnethyl-7-(5-(4,4,5,5-tetrannethyl- 1 ,3,2-dioxaborolan-2-yl)-1 -tosyl-1 H-indol-3-yl)-2,3-dihydroimidazo[1 ,2-a]pyrimidin- 5(1 H)-one
  • Stage 3 synthesis of 7-[5-(2-ethyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)-1 -(toluene-4- sulfonyl)-1 H-indol-3-yl]-6-fluoro-1 -isopropyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2- a]pyrimidin-5-one
  • Stage 4 synthesis of 7-[5-(2-ethyl-1 ,2,3,4-tetrahydroisoquinolin-6-yl)-1 H-indol-3-yl]-6- fluoro-1 -isopropyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • Stage 1 synthesis of 1 -isopropyl-7-(5-(2-isopropylisoindolin-5-yl)-1 -tosyl-1
  • Stage 2 synthesis of 1 -isopropyl-7-[5-(2-isopropyl-2,3-dihydro-1 H-isoindol- indol-3-yl]-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • Stage 1 synthesis of racemic 7-(5-((RS)-2-ethyl-3-methyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1 -tosyl-1 H-indol-3-yl)-1 -isopropyl-2,2-dimethyl-2,3- dihydroimidazo[1 ,2-a]pyhmidin-5(1 H)-one
  • the separation is carried out by injections of amounts of 15 mg of racemic mixture with enrichment of the first enantiomer, and a first intermediate batch is withdrawn in order to enrich in a second enantiomer.
  • enantiomer 1 arbitrarily named (absolute configuration not determined) 7-[5-((R)-2-ethyl-3-methyl-1 ,2,3,4- tetrahydroisoquinolin-7-yl)-1 H-indol-3-yl]-1 -isopropyl-2,2-dimethyl-2,3-dihydro-1 H- imidazo[1 ,2-a]pyrimidin-5-one
  • enantiomer 2 named 7-[5-((S)-2-ethyl-3- methyl-1 ,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-indol-3-yl]-1 -isopropyl-2,2-dimethyl-2,3- dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one are obtained, the characteristics of which are respectively the following:
  • Stage 1 synthesis of N1 -benzyl-N-2-tert-butyl-2-methylpropane-1 ,2-diamine
  • 1 1 .18 g of N-benzyl-2-tert-butylamino-2-methylpropionamide (prepared according to the procedure described by J.T.Lai et al., in Tetrahedron Letters, 1982, 23 (6), p. 595-598) are introduced into 350 ml of anhydrous diethyl ether at 20°C, and then 17.08 g of lithium aluminum hydride are added in small portions.
  • reaction mixture is stirred at 20°C for 18 hours, and then 37 g of sodium carbonate decahydrate are added in small portions while maintaining the temperature below 10°C using a bath of water and ice.
  • the reaction mixture is subsequently filtered and then dried over anhydrous sodium sulfate, filtered again, and then evaporated to dryness under reduced pressure.
  • 9.43 g of N1 -benzyl-N-2-tert-butyl-2-methylpropane-1 ,2-diamine are obtained, the characteristics of which are the following:
  • Stage 4 synthesis of 7-[5-bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-1 - tert-butyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one 850 mg of methyl 3-[5-bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-3- oxopropionate (prepared in Example 3), 801 mg of 1 -tert-butyl-5,5- dimethylimidazolin-2-ylideneamine hydrobromide, 1 .38 g of potassium carbonate then 15 ml of acetonitrile are introduced into a reactor for a microwave oven.
  • reaction medium After the reactor has been closed, the reaction medium is placed at 140°C for 1 h min under microwave irradiation. The reaction medium is filtered through sintered glass No. 3, and the filtrate is evaporated to dryness under reduced pressure. After flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate 30/70 by volume], 510 mg of 7-[5-bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-1 - tert-butyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one are obtained, the characteristics of which are the following:
  • Stage 5 synthesis of 7-(5-bromo-1 H-indol-3-yl)-1 -tert-butyl-2,2-dimethyl-2,3-dihydro- 1 H-imidazo[1 ,2-a]pyrimidin-5-one 120 mg of 7-[5-bromo-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-1 -tert-butyl- 2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one, 26.5 mg of
  • ethylenediamine, 167 mg of cesium fluoride, then 4 ml of dimethylformamide are introduced into a reactor for a microwave oven. After the reactor has been closed, the reaction medium is placed at 185°C for 20 min under microwave irradiation. The reaction medium is then poured onto 40 ml of water. Extraction is carried out with a mixture of methylene chloride and methanol (90/10), the organic phase is washed with a saturated solution of sodium chloride, and then the resulting product is dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The solid obtained is triturated from 3 ml of diisopropyl ether, filtered and oven-dried at 40°C under reduced pressure.
  • Stage 1 Synthesis of 2-methylpropan-2-yl 4-(4- ⁇ 3-(1 -tert-butyl-2,2-dimethyl-5-oxo- 1 ,2,3,5-tetrahydroinnidazo[1 ,2-a]pyrimidin-7-yl]-1 H-indol-5-yl ⁇ phenyl)piperazine-1 - carboxylate
  • the emulsion is separated by settling out and the aqueous phase is washed with 2x200 ml of ethyl acetate.
  • the organic phases are combined and then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, so as to give 54.1 g of 5-bromo-1 -(toluene-4-sulfonyl)-1 H-indole in the form of a pale yellow powder, the characteristics of which are the following:
  • reaction medium is placed at 125°C for 1 h 50 min under microwave irradiation. This operation is repeated four times.
  • the reaction media are combined and then poured into 100 ml of water and stirred for 3 hours.
  • the suspension is filtered through sintered glass number 4 and rinsed with 2 times 100 ml of ethyl acetate.
  • the filtrate is separated by settling out and then the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure.
  • Stage 6 1 -lsopropyl-2,2-dimethyl-7-r5-(1 -methyl-1 H-pyrazol-4-yl)-1 -(toluene- 4-sulfonyl)-1 H-indol-3-yl1-2,3-dihydro-1 H-imidazoM ,2-alpyrimidin-5-one
  • reaction medium After the reactor has been closed, the reaction medium is placed at 150°C for 2h 50 min under microwave irradiation. The reaction medium is concentrated under reduced pressure. The residue obtained is stirred into 50 ml of water and then extracted with 3 times 40 ml of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • Stage 7 1 -lsopropyl-2,2-dimethyl-7-r5-(1-methyl-1 H-pyrazol-4-yl)-1 H-indol-3-vn- 2,3-dihydro-1 H-imidazoM ,2-alpyrimidin-5-one
  • Stage 1 Synthesis of 1 -isopropyl-2,2-dimethyl-7-[5-(4-methylpiperazin-1 -yl)-1- (2-trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-2,3-dihydro-1 H-imidazo[1 ,2- a]pyrimidin-5-one
  • Stage 1 Synthesis of 1 -isopropyl-2,2-dimethyl-7-[1 -(2- trimethylsilanylethoxymethyl)-5-trimethylsilanylethynyl-1 H-indol-3-yl]-2,3- dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • reaction medium is subsequently diluted in dichloromethane, and washed with water, and the organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. After flash chromatography on a silica column [eluent:
  • Stage 2 synthesis of 7-[5-ethynyl-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol- 3-yl]-1 -isopropyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • Stage 3 Synthesis of 1 -isopropyl-2,2-dimethyl-7-[5-(1 H-1 ,2,3-triazol-4-yl)-1 -(2- trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-2,3-dihydro-1 H-imidazo[1 ,2- a]pyrimidin-5-one
  • a reactor for a microwave oven 166 mg of 7-[5-ethynyl-1 -(2- trimethylsilanylethoxymethyl)-1 H-indol-3-yl]-1 -isopropyl-2,2-dimethyl-2,3-dihydro-1 H- imidazo[1 ,2-a]pyrimidin-5-one, 120.3 mg of trimethylsilylazide and 3.3 mg of cuprous iodide are introduced into a mixture of 1 1 .5 ml of dimethylformamide and 1 .28 ml of methanol, and then the mixture is ir
  • a further 120.3 mg of trimethylsilylazide are subsequently added and irradiation is again carried out for one hour at 140°C.
  • the reaction medium is subsequently poured into a mixture of ethyl acetate, sodium bicarbonate and water, and the organic phase is separated by settling out, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. After flash chromatography on a silica column
  • Stage 4 Synthesis of 1-isopropyl-2,2-dimethyl-7-[5-(1 H-[1,2,3]triazol-4-yl)-1 H- indol-3-yl]-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • stage 3 but using 1 15 mg of 1 - isopropyl-2,2-dimethyl-7-[5-(1 H-1 ,2,3-triazol-4-yl)-1 -(2-trimethylsilanylethoxymethyl)- 1 H-indol-3-yl]-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one, 26.6 mg of ethylenediamine, 168.2 mg of cesium fluoride and 2 ml of dimethylformamide, 10 mg of 1 -isopropyl-2,2-dimethyl-7-[5-(1 H-[1 ,2,3]triazol-4
  • Stage 1 synthesis of 7-[5-hydroxy-1 -(2-trimethylsilanylethoxymethyl)-1 H-indol- 3-yl]-1 -isopropyl-2,2-dimethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • Stage 4 synthesis of 1 -isopropyl-2,2-dimethyl-7-[5-(pyrrolidin-3-ylmethoxy)-1 H- indol-3-yl]-2,3-dihydro-1 H-imidazo[1 ,2-a]pyrimidin-5-one
  • Stage 1 Synthesis of methyl 3-(1 -isopropyl-2,2-dimethyl-5-oxo-1 ,2,3,5- tetrahydroimidazo[1 ,2-a]pyrimidin-7-yl)-1 -(2-trimethylsilanylethoxymethyl)-1 H- indole-5-carboxylate
  • 1 g of 7-[5-bromo-1 -(2-trimethylsilanylethoxym 3-yl]-1 -isopropyl-2,2-dinnethyl-2,3-dihydro-1 H-imidazo[1 ,2-a]pyhnnidin-5-one, 84 mg of palladium acetate, 208 mg of 1 ,1 '-bis(diphenylphosphino)ferrocene and 190.3 mg of triethylamine are introduced into a mixture of 8.9 ml of dimethylformamide and 4.2 ml of methanol.
  • the reaction medium is heated at 120°C under a pressure of 8 bar of carbon monoxide for 6 hours and then concentrated to dryness under reduced pressure.
  • the solid residue obtained is chromatographed on a silica column, elution being carried out with ethyl acetate. 786.4 mg of methyl 3-(1 -isopropyl-2,2-dimethyl- 5-OXO-1 ,2,3,5-tetrahydroimidazo[1 ,2-a]pyrimidin-7-yl)-1 -(2- trimethylsilanylethoxymethyl)-1 H-indole-5-carboxylate are obtained in the form of a beige powder, the characteristics of which are the following:
  • Stage 2 Synthesis of 3-(1 -isopropyl-2,2-dimethyl-5-oxo-1 ,2,3,5- tetrahydroimidazo[1 ,2-a]pyrimidin-7-yl)-1 -(2-trimethylsilanylethoxymethyl)-1 H- indole-5-carboxylic acid (2-hydroxyethyl)amide
  • Examples 21 to 204 thus form part of the present invention without, however, limiting it.
  • Such a table indicates, for each of examples 21 to 204, the structure, the name, the general synthesis process used and also the standard example which describes this process, plus the LC/MS method used to characterize these products and the characteristics of the products, namely the retention time and also the mass observed in this technique.
  • Example 205 Pharmaceutical composition
  • Examples 8 and 4 are taken as pharmaceutical preparation examples, it being possible for this preparation to be carried out, if desired, with other products in examples in the present application.
  • the preparations of the pharmaceutical compositions as defined above could thus be carried out with any one of the products of formula (I) according to the present invention: such pharmaceutical compositions form part of the present invention.
  • Test 1 TR-FRET Assay In order to determine the inhibition of the Pirn kinase activity, the compounds of the invention are tested in accordance with a routinely used in vitro TR-FRET (Time Resolved-Fluorescence Resonance Energy Transfer) assay.
  • TR-FRET Time Resolved-Fluorescence Resonance Energy Transfer
  • the TR-FRET assay is based on the detection of the phosphorylation of the specific Ser1 12 residue in the Bad protein, which has proved to be a natural substrate for Pirn kinases in cells. The following reagents are used for the assay:
  • Pirn kinase - His6-tagged, recombinant, full-length human Pim-1 , Pim-2 or Pim-3 protein prepared by the Sanofi "protein production" group;
  • a-P ⁇ Bad-Eu - mouse monoclonal antibody (Cell Signaling Technology #9296B, Danvers, Massachusetts, United States) directed against phosphoBad (Ser1 12) (7E1 1 ) labeled on request by PerkinElmer with the reagent LanceTM Eu-W1024.
  • the assay is based on the PerkinElmer LanceTM technology: the Eu-labeled antibody binds to phospho-Serl 12 and generates a TR-FRET signal by interaction with the APC-labeled antibody directed against His6, bound to the His6 tag of Bad.
  • the ratio of the fluorescence signal at 665 nm to the fluorescence signal at 615 nm is used as reading signal for the IC50 (calculations based on the 4-parameter logistic model).
  • the assay is carried out in a 384-well format; the liquids are handled using a Beckman NX liquid-handling workstation.
  • the compounds being assayed are tested at 10 concentration points in duplicate; the highest concentration of compound is typically equal to 30 ⁇ .
  • the concentration of ATP is equal to 40 ⁇ .
  • Test 2 Cell viability test
  • KG1 cells are incubated in wells (96-well format) for 72 hours, with a compound of the invention at three successive dilutions, with generally nine doses in total, with a maximum dose of 10 ⁇ .
  • the cell viability is evaluated by adding CellTiter-Glo ® (Promega, Madison, Wisconsin, USA) for 10 minutes, and the readings are carried out using a SpectraMax Pro V5 plate reader (Molecular Devices, Sunnyvale, CA, USA).
  • the strength of the luminescence signal is directly proportional to the number of live cells.
  • the EC50 represents the concentration of the compound which results in a 50% reduction in cell viability / proliferative expansion.

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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne de nouveaux produits de formule (I) : Dans la formule, R1 représente H, Alk ou un cycloalkyle éventuellement substitué par un ou plusieurs Hal ; R2 représente H ou Hal ; et R3 représente H ; Hal, OH ; NO2 ; un alcényle C2-C6 ; alcynyle C2-C6 ; -Y-alkyle ; R ; OR ; -CO2H ; -CO2R ; -NRxRy, -CONRxRy ou -CO2NRxRy, tous éventuellement substitués ; où Y représente S, SO ou SO2 ; NRxRy est tel que soit Rx représente H, alk or un cycloalkyle et Ry représente H, alk, un cycloalkyle, hétérocycloalkyle, aryle, hétéroaryle, COR ou SO2R, tous éventuellement substitués ; soit Rx et Ry forment, avec N, un radical cyclique éventuellement substitué ; R représente alk, un cycloalkyle, hétérocycloalkyle, aryle ou hétéroaryle, tous éventuellement substitués ; un ou plusieurs des H représentant un atome de deutérium. Les produits selon l'invention, sous une forme isomère quelconque, et leurs sels, sont utilisés à titre de médicaments, en particulier à titre d'agents anticancéreux.
PCT/EP2013/070581 2012-10-02 2013-10-02 Dérivés d'indolyldihydroimidazopyrimidinone, leur préparation et utilisation thérapeutique WO2014053568A1 (fr)

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