EP2035408A1 - Derives soufres d ' uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases - Google Patents

Derives soufres d ' uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases

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Publication number
EP2035408A1
EP2035408A1 EP07730827A EP07730827A EP2035408A1 EP 2035408 A1 EP2035408 A1 EP 2035408A1 EP 07730827 A EP07730827 A EP 07730827A EP 07730827 A EP07730827 A EP 07730827A EP 2035408 A1 EP2035408 A1 EP 2035408A1
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Prior art keywords
products
formula
phenyl
radical
dimethyl
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EP07730827A
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German (de)
English (en)
French (fr)
Inventor
Frank Halley
Youssef El-Ahmad
Victor Certal
Hartmut Strobel
Kurt Ritter
Sven Ruf
Anne Dagallier
Corinne Venot
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
Aventis Pharma SA
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Publication of EP2035408A1 publication Critical patent/EP2035408A1/fr
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel sulfur derivatives of cyclic urea, their process of preparation, their use as medicaments, the pharmaceutical compositions containing them and the pharmaceutical use of such derivatives for the prevention and treatment of conditions capable of being modulated. by inhibiting the activity of protein kinases.
  • the present invention relates to novel cyclic urea derivatives having inhibitory effects for protein kinases.
  • the products of the present invention can thus be used in particular for the prevention or treatment of conditions capable of being modulated by the inhibition of the activity of protein kinases.
  • Such conditions which can be treated by the products of the present application are therefore particularly solid or liquid tumors.
  • protein kinases belong especially to the following group: EGFR, Fak, FLK-I, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fit-I 1 IGF-IR, KDR, PLK, PDGFR, tie2, VEGFR, AKT, Raf.
  • the protein kinase IGF1-R (Insulin Growth Factor-1 Receptor) is particularly indicated.
  • the present invention thus particularly relates to novel inhibitors of the receptor
  • IGF-IR that can be used for oncology treatments. Cancer remains a disease for which _ .
  • protein kinases including IGP-IR (Insulin Growth Factor 1 Receptor) play an important role in many cancers.
  • IGP-IR Insulin Growth Factor 1 Receptor
  • the inhibition of such protein kinases is potentially important in the chemotherapy of cancers, in particular to suppress the growth or survival of tumors.
  • the present invention thus relates to the identification of novel products that inhibit such protein kinases.
  • Protein kinases participate in signaling events that control activation, growth, and differentiation of cells in response to either extracellular mediators or environmental changes. In general, these kinases belong to two groups: those which preferentially phosphorylate the serine and / or threonine residues and those which preferentially phosphorylate the tyrosine residues
  • Serine / threonine kinases are, for example, isoforms of protein kinases C [A. C.Newton, J. Biol. Chem. , 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases, such as cdc2 [J.Pines, Trends in Biochemical Sciences, 1995, 18, pp. 195-197].
  • Tyrosine kinases include growth factor receptors such as Epidermal Growth Factor Receptor (EGF) [S.Iwashita and M.Kobayashi, Cellular Signaling, 1992, 4, pages 123-132], and cytosolic kinases such as p56tck, p59fYn, ZAP-70 and csk kinases [C. Chan and. al., Ann. Rev. Immunol., 1994, 12, pages 555-592].
  • EGF Epidermal Growth Factor Receptor
  • the type 1 receptor for insulin-like growth factor is a transmembrane receptor with tyrosine kinase activity that binds primarily to IGFI but also to IGFII and insulin with a more low affinity.
  • the binding of IGFI to its receptor results in oligomerization of the receptor, tyrosine kinase activation, intermolecular autophosphorylation and phosphorylation of cellular substrates (major substrates: IRS1 and Shc).
  • IRS1 and Shc major substrates
  • the ligand-activated receptor induces mitogenic activity in normal cells.
  • IGF-I-R plays an important role in so-called abnormal growth.
  • IGF-I-R is often found over-expressed in many tumor types (breast, colon, lung, sarcoma, prostate, multiple myeloma) and its presence is often associated with a more aggressive phenotype.
  • IGF-IR is required to establish and maintain the in vitro transformed phenotype as in vivo [Baserga R, Exp. Ceil. Res., 1999, 253, pages 1-6].
  • the kinase activity of IGF-IR is essential for the transformation activity of several oncogenes: EGFR, PDGFR, the large antigen of SV40 virus, activated Ras, Raf, and v-Src.
  • Expression IGF-IR in normal fibroblasts induces a neoplastic phenotype, which can then lead to tumor formation in vivo.
  • IGF-IR The expression of IGF-IR plays an important role in the independent growth of the substrate. IGF-IR has also been shown to be a protector in chemotherapy-induced apoptosis, 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.
  • FAK Fecal Adhesion Kinase
  • FAK is a cytoplasmic tyrosine kinase that plays an important role in the transduction of the signal transmitted by integrins, a family of heterodimeric receptors for cell adhesion.
  • FAK and the integrins are colocalized in perimembrane structures called adhesion plates. It has been shown in many cell types that the activation of FAK and its phosphorylation on tyrosine residues and in particular its autophosphorylation on tyrosine 397 were dependent on the binding of integrins to their extracellular ligands and therefore induced during the cell adhesion [Kornberg L, et al. J. Biol. Chem. 267 (33): 23439-442 (1992)].
  • Activation of FAK can also induce the Jun NH2-terminal kinase (JNK) signaling pathway and result in cell progression to the G1 phase of the cell cycle [Oktay et al., J. CeIl. Biol. 145: 1461-1469 1999].
  • Phosphatidylinositol-3-OH kinase (PI3 -kinase) also binds to FAK on tyrosine 397 and this interaction may be required for PI3-kinase activation [Chen and Guan, Proc. Nat. Acad. Sci. USA. 91: 10148-10152 1994; Ling et al. J. CeIl. Biochem. 73: 533-544 1999].
  • the FAK / Src complex phosphorylates various substrates such as paxillin and p130CAS in fibroblasts [Vuori et al. Mol. Ceil. Biol. 16: 2606-2613 1996].
  • FAK inhibitors may be useful in the treatment of cancer.
  • overexpression of p125FAK leads to an acceleration of the G1-S transition, suggesting that p125FAK promotes cell proliferation [Zhao J. -H et al. J. CeIl Biol. 143: 1997-2008 1998].
  • FAK has also been shown to promote cell migration in vitro.
  • fibroblasts deficient for the expression of FAK have a rounded morphology, migration deficiencies in response to chemotactic signals and these defects are suppressed by FAK re-expression
  • AKT protein kinase also known as PKB
  • PI3K phosphoinositide 3 -kinase
  • This transduction pathway is involved in multiple cellular functions: regulation of apoptosis, control of transcription and translation, glucose metabolism, angiogenesis, and mitochondrial integrity.
  • AKT serine / threonine kinase AKT was subsequently identified as a mediator playing a key role in growth factor-induced survival.
  • AKT has been shown to inhibit apoptotic death induced by a variety of stimuli in a number of cell types and tumor cells. Consistent with these findings, it was shown that AKT could, by phosphorylation of given serine residues, inactivate BAD, GSK3 ⁇ , caspase-9, the Forkhead transcription factor and activate iKKalpha and e-NOS.
  • the BAD protein is found to be hyper-phosphorylated in 11 out of 41 human tumor cell lines studied.
  • hypoxia modulated VEGF induction in Ha-ras transformed cells by activating the PI3K / AKT pathway and by implicating the HIF-I transcription factor binding sequence (hypoxia inducible factor). -1) called HRE for "hypoxy-responsive-e1ement".
  • AKT plays a very important role in cancer pathologies.
  • the amplification and / or overexpression of AKT has been reported in many human tumors such as gastric carcinoma (AKT1 amplification), carcinomas of the ovary, breast or pancreas (amplification and overexpression of AKT2) and breast carcinomas deficient in estrogen receptors as well as androgen-independent prostate carcinomas (overexpression of AKT3).
  • AKT is constitutively activated in all PTEN (- / -) tumors, PTEN phosphatase being deleterious or inactivated by mutations in many types of tumors such as ovarian, prostate, endometrial carcinomas. , glioblastomas and melanomas.
  • AKT is also involved in the oncogenic activation of bcr-abl (References: Khawaja A., Nature 1999, 401, 33-34, Cardone et al., Nature 1998, 282, 1318-1321, Kitada S. et al., Am J Pathol 1998 Jan, 152 (1): 51-61, Mazure NM et al., Blood, 1997, 90, 3322-3331, Zhong H. et al., Cancer Res 2000, 60, 1541-1545).
  • n represents the integer 0 or 2
  • Ra and Rb represent CH3 or form together with the carbon atom to which they are bonded a cycloalkyl radical
  • R represents a pyridyl or pyrimidinyl radical substituted by a radical NR1R2, NR1R2 being such that: one of R1 and R2 represents an atom of hydrogen or an alkyl radical, and the other of R1 and R2 is chosen from hydrogen and alkyl radicals optionally substituted with a radical chosen from hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl and piperidyl radicals, morpholinyl, and piperazinyl itself optionally substituted on its second nitrogen atom with an alkyl radical; cycloalkyl, heterocycloalkyl, aryl and optionally heteroaryl radicals substituted; and the radical CO-R3 with R3 selected from ISTR4R5 and the optionally substituted alkoxy, heterocycloalkyl, aryl, ary
  • n represents the integer 0 or 2
  • Ra and Rb represent CH3
  • R represents a pyridyl or pyrimidinyl radical substituted by a radical NR1R2, NR1R2 being such that: one of R1 and R2 represents a hydrogen atom or an alkyl radical, and the other of R1 and R2 is chosen from the atom hydrogen and alkyl radicals optionally substituted by a radical chosen from hydroxyl, alkoxy, aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl or piperazinyl radicals, itself optionally substituted on its second nitrogen atom with an alkyl radical; optionally substituted cycloalkyl, heterocycloalkyl, phenyl, pyrimidinyl and pyridyl radicals; and the radical CO-R3 with R3 selected from NR4R5 and optionally substituted alkoxy, piperidyl, phenyl, and phenoxy radicals; R4 and R5, which are identical to or different from R1 and
  • Halo or halogen denotes fluorine, chlorine, bromine or iodine and preferably fluorine and chlorine
  • alkyl or alk radical denotes a linear or branched radical containing at most 12 carbon atoms chosen from the radicals methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec- pentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and also heptyl, octyl, nonyl, decyl, undecyl and dodecyl, as well as their linear or branched positional isomers,
  • alkyl radicals having at most 6 carbon atoms and in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, linear or branched pentyl and hexyl radicals.
  • alkoxy radical denotes a linear or branched radical containing at most 12 carbon atoms and preferably 6 carbon atoms chosen, for example, from methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy, hexoxy and heptoxy, and than their linear or branched position isomers.
  • cycloalkyl radical denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 ring members and in particular denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals,
  • acyl radical or -CO-r denotes a linear or branched radical containing at most 12 carbon atoms in which the radical r represents an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical, these radicals having the values indicated above; and being optionally substituted as indicated above, mention is made, for example, of the formyl, acetyl, propionyl, butyryl or benzoyl radicals, or else valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radicals. It is noted that the radical CO-R3 can in particular take the values defined above for -CO-r.
  • aryl radical refers to unsaturated, monocyclic or fused carbocyclic rings. Examples of such an aryl radical include phenyl or naphthyl radicals. More particularly, the phenyl radical is mentioned.
  • the aryloxy radical denotes an O-aryl radical in which the aryl radical has the meaning indicated above.
  • heterocycloalkyl radical denotes a saturated carbocyclic radical consisting of at most 7 members interrupted by one or more heteroatoms, identical or different, chosen from oxygen, nitrogen or sulfur atoms: as radicals heterocycloalkyls that may be mentioned in particular include the dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or tetrahydrofuryl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolinyl, piperidinyl and perhydropyranyl radicals. , pyrindolinyl, tetrahydroquinolinyl, tetrahydrois
  • heterocycloalkyl radicals there may be mentioned more particularly the optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl or thioazolidinyl radicals.
  • heteroaryl radical denotes a partially or fully unsaturated carbocyclic radical consisting of at most 7 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms: among the 5-membered heteroaryl radicals; furyl radicals such as 2-furyl, thienyl such as 2-thienyl and 3-thienyl, pyrrolyl, diazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl oxadiazolyl, 3- or 4-isoxazolyl, imidazolyl, pyrazolyl, isoxazolyl.
  • 6-membered heteroaryl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrazolyl.
  • heteroaryl radicals containing at least one heteroatom chosen from sulfur, nitrogen and oxygen mention may be made, for example, of benzothienyl such as 3-benzothienyl, benzofuryl, benzofuranyl, benzopyrrolyl, benzimidazolyl or benzoxazolyl, thionaphthyl, indolyl, purinyl, quinolinyl, isoquinolinyl and naphthyridinyl.
  • fused heteroaryl radicals mention may be made more particularly of benzothienyl, benzofuranyl, indolyl or quinolinyl, benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl and pyrrolyl radicals. , quinazolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, these radicals being optionally substituted as indicated for the heteroaryl radicals.
  • the term patient refers to humans but also other mammals.
  • Prodrug refers to a product that can be converted in vivo by metabolic mechanisms (such as hydrolysis) into a product of formula (I).
  • an ester of a product of formula (I) containing a hydroxyl group can be converted by in vivo hydrolysis to its parent molecule.
  • an ester of a product of formula (I) containing a carboxy group can be converted by hydrolysis in vivo into its parent molecule.
  • esters of products of formula (I) containing a hydroxyl group such as acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleas, methylenebis b- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
  • a hydroxyl group such as acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleas, methylenebis b- hydroxynaphthoates, gentisates
  • Particularly useful hydroxyl-containing products of the formula (I) can be prepared from acidic residues such as those described by Bundgaard et al. al., J. Med. Chem. , 1989, 32, page 2503-2507: these esters include especially (Aminomethyl) -benzoates substituted, dialkylamino-methylbenzoates in which the two alkyl groups may be bonded together or may be interrupted by an oxygen atom or an optionally substituted nitrogen atom or an alkylated nitrogen atom or morpholino methyl) benzoates, eg 3- or 4-
  • mineral bases such as, for example, one 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, procalne, lysine arginine, histidine, N-methylglucamine,
  • mineral bases such as, for example, one 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, procaln
  • the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals which may be substituted by radicals chosen, for example, from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for example in the chloromethyl, hydroxypropyl, methoxy-methyl or propionyloxymethyl groups; methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl.
  • alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl
  • these alkyl radicals which may be substituted by radicals chosen, for example, from halogen atoms, hydroxyl, alkoxy,
  • Esterified carboxy is understood to mean, for example, radicals such as alkyloxycarbonyl radicals, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl radicals.
  • radicals such as alkyloxycarbonyl radicals, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl radicals.
  • radicals formed with easily cleavable ester residues such as methoxymethyl, ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.
  • ester radicals can be found, for example, in European Patent EP 0 034 536.
  • alkylamino radical NHaIk is meant the linear or branched methylamino, ethylamino, propylamino or butylamino, pentylamino or hexylamino radicals.
  • Alkyl radicals having at most 4 carbon atoms are preferred, the alkyl radicals may be chosen from the alkyl radicals mentioned above.
  • dialkylamino radical N (alk) 2 is meant the radicals in which alk takes the values defined above: as previously, alkyl radicals having at most 4 carbon atoms chosen from the list indicated above are preferred. Examples that may be mentioned include dimethylamino, diethylamino and methylethylamino radicals.
  • cyclic amine refers to a 3- to 8-membered cycloalkyl radical in which a carbon atom is replaced by a nitrogen atom, the cycloalkyl radical having the meaning indicated above and which may also contain one or more other heteroatoms chosen from O, S, SO 2, N or NR 3 with R 3 as defined above:
  • examples of such cyclic amines include, for example, aziridyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, indolinyl and pyrindolinyl radicals; or tetrahydroquinolinyl, optionally substituted: more particularly pyrrolidinyl, piperidinyl and morpholinyl are mentioned.
  • Salified carboxy means salts formed for example with an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine and triethylamine. The sodium salt is preferred.
  • the addition salts with the mineral or organic acids of the products of formula (I) may be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic or trifluoroacetic acids, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkyl-disulphonic acids, such as methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.
  • stereoisomery 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 may be in axial or equatorial position, and the different possible rotational conformations of ethane derivatives.
  • stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomers or cis - trans isomers.
  • stereoisomeric is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • the subject of the invention is in particular the products of formula (I) as defined above in which: n represents the integer 0 or 2
  • R represents a pyridyl or pyrimidinyl radical substituted with a radical NR1R2, NR1R2 being such that R1 represents a hydrogen atom or an alkyl radical, and R2 is chosen from hydrogen and alkyl radicals optionally substituted with a hydroxyl radical; , aziridyl, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, or piperazinyl itself optionally substituted on its second nitrogen atom by an alkyl radical; cycloalkyl radicals containing 3 to 6 members; the optionally substituted phenyl radical; the pyrimidinyl radical; the pyridyl radical optionally substituted by a halogen atom, and the radical CO-R3 with R3 chosen from NR4R5 and the alkoxy, piperidyl and optionally substituted phenyl radicals; R4 and R5, which are identical or different from R1 and R2, are such that: either one of
  • R represents a pyridyl or pyrimidinyl radical substituted by a radical NR1R2, NR1R2 being such that R1 represents a hydrogen atom or an alkyl radical containing one or two carbon atoms, and R2 is chosen from alkyl radicals containing 1 to 4 carbon atoms; carbon optionally substituted with a hydroxyl radical; the optionally substituted phenyl radical; the pyrimidinyl radical; the pyridyl radical optionally substituted with a halogen atom; and the radical CO-R3 with R3 chosen from piperidyl, optionally substituted phenyl, NH (alk) and N (alk) 2; all the phenyl radicals being optionally substituted with one to three identical or different radicals chosen from halogen atoms, alkyl radicals and CO-NHAlk and CO-N (Alk) 2 radicals; said products of formula (I) being in all isomeric forms possible racemic, enantio
  • R represents a pyridyl or pyrimidinyl radical substituted by a radical NR1R2, in which R1 represents an atom hydrogen and R2 represents an isopropyl radical substituted with a hydroxyl radical; an optionally substituted phenyl radical; a pyrimidinyl radical; a pyridyl radical optionally substituted with a fluorine atom, or a radical CO-R3 with R3 chosen from piperidyl, optionally substituted phenyl, NHCH3 and N (CH3) 2; all the phenyl radicals being optionally substituted with one to three identical or different radicals chosen from chlorine and fluorine atoms, the methyl radical and the CO-N (CH 3) 2 radical; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition
  • n and NR 4 R 5 are as defined above and in particular NR 4 R 5 is chosen from the ex 18 to ex 40 values defined above, said products of formula (Ia) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers; isomers, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (Ia).
  • the products of formula (I) according to the present invention can be prepared by the application or the adaptation of known methods and in particular the methods described in the literature such as those described by RCLarock in: Comprehensive Organic Transformations, VCH Publishers,
  • the products according to the present invention can in particular be prepared as indicated in General Scheme 1, General Scheme 2 and General Scheme 3 below.
  • Alcohol B can be obtained by treating aldehyde A with a reducing agent such as sodium borohydride, in a solvent such as methanol at a temperature of between 0 ° C. and 60 ° C., for example in the conditions described by Wang, E. et al. (Heterocycles 2002, 57 (11), 2021-2033.).
  • a reducing agent such as sodium borohydride
  • Chlorinated product C can be obtained from Alcohol B, as under the conditions described by Fucase K. et al. (Tetrahedron Lett, 1991, 32 (32), 4019-4022) by treatment with thionyl chloride in the presence of DMF in a solvent such as dichloromethane at a temperature between 0 ° C. and 2O 0 C.
  • the isocyanate E can be obtained from the anilines D by treatment with diphosgene in a solvent such as dioxane or toluene as for example under the conditions described by Francis, J. E et al. (J. Med Chem (1991), 34 (1), 281-90)
  • Hydantoin F can be obtained from isocyanate E by reaction with methyl 2,2-dimethyl glycinate in a solvent such as toluene or N, N-dimethylformamide at a temperature of between 20 ° C. and reflux. of the solvent as described, for example, by Brana MF (J. Het Chem (2002), 39 (2), 417-420.)
  • Product G can be prepared by reaction of products F and C with sodium hydride in terahydrofuran or N, N-dimethylformamide at a temperature between 0 ° C. and 60 ° C. as described by Johnson TA et al (J. Am Chem Soc. (2002), 124, 11689-11698)
  • the product of general formula H can be prepared either by reaction of G with metachloro perbenzoic acid in solvents such as a mixture of dichloromethane methanol (90:10 v / v) or 1,2-dichloroethane to temperatures between 0 0 C and 60 ° C as described by Jeong, IH et al. (Bull Korean Chem Soc (2002), 23 (12), 1823-1826).
  • solvents such as a mixture of dichloromethane methanol (90:10 v / v) or 1,2-dichloroethane to temperatures between 0 0 C and 60 ° C as described by Jeong, IH et al. (Bull Korean Chem Soc (2002), 23 (12), 1823-1826).
  • the products of general formula I and L can be prepared by reaction of H with ammonia in solution in water and / or dioxane or with an amine (RNH 2) in dioxane solution in a tube sealed in the microwave or by heating at temperatures between 40 0 C and 150 0 C or as described by Font, Det coll. (Synthesis (2002), (13), 1833-1842).
  • the products of formula J can be prepared from I by reaction with an aryl or heteroaryl bromide (R2-Br) in the presence of a palladium catalyst such as palladium acetate and a ligand such as Xantphos (9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene) in a solvent such as toluene, dioxane or tert-butanol, for example under the conditions described by BUCHWALD, SL et al. . (J. Org Chem 2001, 66 (8), 2560-2565).
  • the product M can be obtained by treatment of the alcohol B with 3,4-dihydro-2H-pyran in dichloromethane in the presence of para-toluenesulphonic acid at a temperature of 20 ° C. as described by Greene TW et al. (protective groups in organic chemistry, John Wiley & sounds 1991, second edition).
  • the product N can be prepared by oxidation of the sulfur according to the conditions described for the product H.
  • Product O can be prepared by deprotection of product N as described by Greene TW et al. (protective groups in organic chemistry, John Wiley & sounds 1991, second edition)
  • the product P can be prepared by halogenation of the alcohol O as described in the preparation of the product C.
  • R ' is alkyl or aryl as defined in R3.
  • the product R can be prepared by bromination of the product Q in the presence of N-bromosuccinimide in a solvent such as carbon tetrachloride as described by Brown, D. J. et al. (Aust J Chem (1974), 2251).
  • the product S can be prepared from the products R and F as described in the preparation of the product G.
  • the product T can be prepared from S by reaction with a carbamate (NH 2 COOR ') in the presence of a catalyst based on palladium as described in the preparation of J.
  • the product U can be prepared either by reaction of the carbamate T with an amine in a solvent such as N-methylpyrrolidinone or toluene at a temperature of between 50 ° C. and the reflux temperature of the solvent or in the microwave as described. by Manov-Yuvenskii V. I et al. (Zh Prikl, Khim (1993), 66 (6), 1319-1327). Either from S by reaction with a urea (NH 2 CONR 4 R 5) in the presence of a palladium catalyst as described in the preparation of J.
  • a solvent such as N-methylpyrrolidinone or toluene
  • the product can be prepared from S by reaction with an amine (R 2 NH 2) in the presence of a palladium catalyst such as palladium acetate and a ligand such as Xantphos in a solvent such as toluene, dioxane or tert-butanol as for example under the conditions described by BUCHWALD, SL et al. (J. Org Chem 2001, 66 (8), 2560-2565).
  • a palladium catalyst such as palladium acetate and a ligand such as Xantphos
  • solvent such as toluene, dioxane or tert-butanol
  • R ' is alkyl or aryl as defined in R3.
  • the alcohol W can be prepared by reducing the ester V with a reducing agent such as sodium borohydride in a solvent such as ethanol at a temperature of between 20 ° C and 20 ° C. 0 ° C. and the reflux temperature of the solvent as described by Zanka, A. et al. (Synlett (1999), (10), 1636-1638).
  • Product X is prepared by chlorination of the alcohol W as described in the preparation of C.
  • Product Y can be prepared from products F and X using the conditions described for the preparation of G
  • Product Z can be prepared from product y and carbamate (NH 2 COOR ') using the conditions described for the preparation of
  • the product AA can be prepared either by reaction of the product Z with an amine (NHR4R5) as under the conditions described for the product U
  • the product AB can be prepared from the product Y and the amine (NH 2 R 2) as under the conditions described for the preparation of the product J.
  • the product AC can be prepared from product Y and amide (NH 2 COR 3) in the presence of a copper catalyst as described by Buchwald S.L. et al. (J. Am Chem., SOC (2001), 123, 7727-7729)
  • starting materials, intermediates and products of formula (I), which may be in protected form may be subjected, if necessary or desired, to one or more of the following transformation reactions, in any order: a) an esterification reaction of acid function, b) an ester function saponification reaction in acid function, c) an alkylthio group oxidation reaction corresponding sulphoxide or sulfone, d) a reaction of ketone function conversion to oxime function, e) a reduction reaction of the free or esterified carboxy function in alcohol function, f) an alkoxy function conversion reaction to hydroxyl function, or still hydroxyl function in the alkoxy function, g) an oxidation reaction of alcohol function according to aldehyde, acid or ketone, h) a nitrile radical conversion reaction to tetrazolyl, i) a reduction reaction of the nitro compounds to amino compounds, j) a removal reaction
  • the hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, trimethylsilyl or tert-butyldimethylsilyl, methoxymethyl, tetrahydro-pyranyl, benzyl or acetyl,
  • amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, phthalimido or other radicals known in the peptide chemistry,
  • acyl groups such as the formyl group may be protected for example in the form of cyclic or non-cyclic ketals or thiocetals such as dimethyl or diethylketal or ethylene dioxycetal, or diethylthioketal or ethylenedithioketal,
  • the acidic functions of the products described above may, if desired, be amidated by a primary or secondary amine, for example in methylene chloride in the presence, for example, of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride, Room temperature:
  • the acid functions may be protected, for example, in the form of esters formed with easily cleavable esters such as benzyl or terbutyl esters or esters known in peptide chemistry.
  • reactions a) to k) indicated above can be carried out, for example, as indicated below.
  • 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.
  • 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.
  • sulfoxide function can be promoted by an equimolar mixture of the product containing an alkylthio group and the reagent such as in particular a peracid.
  • sulphone function can be promoted by a mixture of the product containing an alkylthio group with an excess of the reagent such as in particular a peracid.
  • the conversion reaction of a ketone function into oxime can be carried out under the usual conditions known to those skilled in the art, such as in particular an action in the presence of an optionally O-substituted hydroxylamine in an alcohol such as, for example ethanol at room temperature or by heating.
  • 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 according to 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 possible free carboxy functions of the products described above can be, if desired, reduced in alcohol function in particular with boron hydride.
  • 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 methylene chloride, for example, with hydrobromide or pyridine hydrochloride or with hydrobromic acid or hydrochloric acid in water or refluxing trifluoroacetic acid.
  • a solvent such as methylene chloride
  • hydrobromide or pyridine hydrochloride hydrobromic acid or hydrochloric acid in water or refluxing trifluoroacetic acid.
  • the possible alcohol functions of the products described above may, if desired, be converted to an aldehyde or acid function by oxidation under the usual conditions known to those skilled in the art, such as, for example, by the action of manganese oxide for obtain the aldehydes or Jones reagent to access the acids.
  • nitrile functions of the products described above may, if desired, be converted into tetrazolyl under the usual conditions known to those skilled in the art, such as, for example, by cycloaddition of a metal azide such as, for example, azide of sodium or a trialkyltin azide on the nitrile function as indicated in the method described in the article referenced as follows:
  • the conversion reaction of a carbamate urea and in particular a sulfonylcarbamate sulfonylurea can be carried out for example at the reflux of a solvent such as toluene in the presence of the appropriate amine.
  • the phthalimido group can be removed by hydrazine.
  • a list of different protecting groups that can be used, for example, in the patent FR 2,499,995 can be found.
  • J) The products described above can, if desired, be subjected to salification reactions, for example by an inorganic or organic acid. or by a mineral or organic base according to the usual methods known to those skilled in the art.
  • k) The possible optically active forms of the products described above may be prepared by splitting the racemics according to the usual methods known to those skilled in the art.
  • Any reactive functions that are optionally protected include the hydroxy or amino functions.
  • Protective groups are used to protect these functions. Examples that may be mentioned include the following protective groups of the amino radical: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl, benzyloxycarbonyl.
  • Protective groups of the hydroxyl radical include radicals such as formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl, tert-butyl dimethylsilyl.
  • the possible reactions of elimination of the protective groups are carried out as indicated in said patent BF 2,499,995.
  • the preferred mode of removal is acid hydrolysis using acids selected from hydrochloric acid, benzene sulfonic acid or para toluene sulfonic acid, formic or trifluoroacetic acid. Hydrochloric acid is preferred.
  • an acid such as aqueous hydrochloric acid, for example at reflux.
  • the optional esterification of a free OH radical is carried out under standard conditions.
  • an acid or a functional derivative can be used, for example an anhydride such as acetic anhydride in the presence of a base such as pyridine.
  • the esterification or the optional salification of a COOH group is carried out under the standard conditions known to those skilled in the art.
  • the optional amidification of a COOH radical is carried out under standard conditions. It is possible to use a primary or secondary amine on a functional derivative of the acid, for example a symmetrical or mixed anhydride.
  • the starting materials used to prepare the products of formula (I) according to the present invention may be known and commercially available or may be prepared according to methods known to those skilled in the art.
  • the products object of the present invention are endowed with interesting pharmacological properties: they have been found to possess, in particular, inhibitory properties of protein kinases.
  • IGF1R insulin growth factor receptor
  • Tests given in the experimental part below illustrate the inhibitory activity of products of the present invention with respect to such protein kinases. These properties therefore make the products of general formula (I) of the present invention usable as medicaments for the treatment of malignant tumors.
  • the products of formula (I) can also be used in the veterinary field.
  • the invention therefore relates to the application, as medicaments, pharmaceutically acceptable products of general formula (I).
  • the subject of the invention is particularly the use, as medicaments, of the products whose names follow: 1- (2 - [(2,5-dichlorophenyl) amino] pyridin-4-yl ⁇ methyl) -5 5-Dimethyl-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidine-2,4-dione N- ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4- [(Trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇ piperidine-1-carboxamide 3,4-dichloro-N- ⁇ 4- [(5,5-dimethyl-2,4-dichloro) ⁇ 3-Dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇
  • the products can be administered parenterally, orally, perlingually, rectally or topically.
  • the invention also relates to pharmaceutical compositions, characterized in that they contain, as active ingredient, at least one of the drugs of general formula (I).
  • compositions may be presented in the form of injectable solutions or suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions.
  • These pharmaceutical forms are prepared according to the usual methods.
  • the active ingredient can be incorporated into excipients usually used in these compositions, such as aqueous vehicles or not, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fats of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives.
  • the usual dose variable depending on the subject treated and the condition in question, can be, for example, from 10 mg to 500 mg per day in humans, orally.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicaments intended to inhibit the activity of protein kinases and especially of a protein kinase.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is chosen from the following group: EGFR, Fak, FLK -I, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-IR, KDR, PDGFR, tie2, VEGFR, AKT, Raf.
  • the present invention thus relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is IGF1R.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is in a cell culture and also this use in a mammal .
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to prevent or treat a disease characterized by the disruption of the activity of a protein kinase and in particular such a disease in a mammal.
  • the present invention relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended to prevent or treat a disease belonging to the following group : disorders of the proliferation of blood vessels, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thromboses, nervous system, retinopathies, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, diseases in oncology, cancers.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for treating diseases in oncology.
  • the present invention particularly relates to the use of products of formula (I) as defined above or pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament for treating cancers.
  • the present invention is particularly interested in the treatment of solid tumors and in the treatment of cancers resistant to cytotoxic agents.
  • the present invention relates particularly to the treatment of breast, stomach, colon, lung, ovarian, uterine, brain, kidney, larynx, lymphatic system, breast cancer, thyroid, uro-genital tract, vesicle and prostate tract, bone cancer, pancreas, melanoma.
  • the present invention is more particularly concerned with the treatment of breast, colon and lung cancer.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicament intended for the chemotherapy of cancers.
  • the products of formula (I) according to the present invention can be used alone or in combination with chemotherapy or radiotherapy or alternatively in combination with other therapeutic agents.
  • the present invention thus relates in particular to pharmaceutical compositions as defined above additionally containing active principles of other cancer chemotherapy drugs.
  • Such therapeutic agents may be anti-tumor agents commonly used.
  • inhibitors of protein kinases include butyrolactone, flavopiridol, 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, olomucine, Glivec and Iressa.
  • the products of formula (I) according to the present invention can thus also advantageously be used in combination with anti-proliferative agents: by way of examples of such antiproliferative agents but without however being limited to this list, mention may be made of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX inhibitors -2, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds decreasing the activity of protein kinases and also anti-angiogenic compounds, gonadorelin agonists, antiandrogens , bengamides, biphophonates and trastuzumab.
  • antiproliferative agents by way of examples of such antiproliferative agents but without however being limited to this list, mention may be made of aromatase inhibitors, antiestrogens, topo
  • anti-microtubule agents such as taxoids, vinka-alkaloids, alkylation agents such as cyclophosphamide, DNA-intercalating agents such as cis-platinum, interactive agents on topoisomerase such as camptothecin and derivatives, anthracyclines such as adriamycin, antimetabolites such as 5-fluorouracil and derivatives and the like.
  • the present invention therefore relates to products of formula (I) as inhibitors of protein kinases, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with acids inorganic and organic or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I) and their prodrugs.
  • the present invention particularly relates to products of formula (I) as defined above as IGF1R inhibitors.
  • the present invention relates more particularly to the products of formula (I) as defined above as IGF1R inhibitors.
  • the 1 H NMR spectra are recorded on BRUKER spectrometers at 400 MHz (AVANCE DRX-400) or 300 MHz spectrometers (BRUKER AVANCE DPX-300).
  • the chemical shifts are given in ppm ( ⁇ in ppm) - in the solvent dimethylsulfoxide - d6 (DMSO-d6) referenced at 2.50 ppm at the temperature of 303K.
  • Mass spectra were made either in electrospray (ES) on Q-Tof-2 (Micromass), ZQ (Micromass) and Quattro Premier (Micromass), or in electronic impact (IE); 7OeV, - Micromass GCTof Premier device, ie in chemical ionization (IC); ammonia reactant gas; Micromass GCTof device.
  • the LCMS is made on Hypersil GoId C18 column 3x50 mm diameter particles: 3 ⁇ m
  • Solvent A 0.05% water
  • Solvent B 0.05% acetonitrile TFA 5%
  • Example 1 1- ( ⁇ 2- [(2,5-dichlorophenyl) amino] pyridin-4-yl ⁇ methyl) -5,5-dimethyl-3- ⁇ 4-
  • Example 2 The product is prepared following the procedure described in Example 1 starting from 0.4 g of 1 - [(2-chloropyridin-4-yl) methyl] -5,5-dimethyl-3 - ⁇ 4- [ (trifluoromethyl) thio] phenyl ⁇ imidazolidine-2,4-dione obtained in step d) of Example 1 and 0.18 g of 1-piperidinecarboxamide instead of 2,5-dichloroaniline used in Example 1. After purification by flash-chromatography (SiO2, dichloromethane / methanol 98/02 by volume as eluents), 0.21 g of N- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3-) 4-
  • Step b 1 - [(2-Chloropyridin-4-yl) methyl] -5,5-dimethyl-3- ⁇ 4- [(trifluoromethyl) sulfonyl] phenyl ⁇ imidazolidine-2,4-dione
  • Example 5 1- (2 - [(2,5-difluorophenyl) amino] pyridin-1-yl] methyl) -5,5-dimethyl-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidine-2,4 -dione
  • Example 8 3- ( ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-ylmethyl] pyridin-2-yl ⁇ amino) -N, N-dimethylbenzamide
  • Example 9 1 - [(2- ⁇ [(1R) -2-Hydroxy-1-methylethyl] amino ⁇ pyrimidin-4-yl) methyl] -5,5-dimethyl-3 - ⁇ 4 - [(trifluoromethyl)) sulphonyl] phenyl-imidazolidine-2,4-dione
  • reaction mixture is taken up in ethyl acetate and washed successively with concentrated hydrochloric acid, water, saturated sodium hydrogencarbonate solution, saturated sodium chloride solution and dried over sodium sulfate. magnesium. After filtration, the solution is concentrated under reduced pressure and the residue purified by chromatography on a silica column, eluting with a mixture of ethyl acetate and cyclohexane (65/35 by volume) to give 0.68 g of [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4-
  • Example 17 1- (2 - [(5-Fluoropyridin-3-yl) amino] pyridin-4-yl] methyl) -5,5-dimethyl-3 - ⁇ 4 - [(trifluoromethyl) thio] phenyl] imidazolidin-2 , 4-dione
  • the residue is purified by chromatography on a silica column eluting with a gradient of acetone in dichloromethane to give 0.17 g of 1 - ( ⁇ 2 - [(5-fluoropyridin-3-yl) amino] pyridin-4-yl ⁇ methyl ) -5,5-dimethyl-3- ⁇ 4-
  • the present invention notably comprises the products of formula (I) belonging to the following formula (Ia):
  • n and NR4R5 have the meanings given above.
  • the formula products (Ia) can in particular be prepared as indicated in the general scheme 3 in two stages (compounds Z and AA).
  • Step b) 1- [4- [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇ -3- (3-pyrrolidin-1-ylpropyl) urea
  • Example 19 1-Cyclopentyl-3- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2 yl ⁇ urea
  • Example 21 1- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇ - 3- (4-pyrrolidin-1-ylbutyl) urea was prepared as in step b) of Example 18, replacing 3-pyrrolidin-1-ylpropylamine with 1- (4aminobutyl) pyrrolidine to give 100 mg of 1- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇ -3- ( 4-pyrrolidin-1-ylbutyl) urea having the following characteristics: 1H NMR spectrum at 400 MHz: 1.42 (s, 6H); 1.47 (m, 4H
  • Example 24 1-Cyclopentyl-3- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-ylmethyl] pyridin-2-yl ⁇ -1-methylurea
  • Example 25 1-Cyclohexyl-3- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2 -yl ⁇ urea was prepared as in step b) of Example 18 by replacing 3-pyrrolidin-1-yl-propylamine by cycloxexylamine and N-methylpyrrolidinone by tetrahydrofuran, to give 90 mg of 1-cyclohexyl-3- ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇ urea whose characteristics are as follows:
  • Example 3 1- ⁇ 4- [4,5-Dimethyl-2,4-dioxo-3- (4- [4- (5-dimethyl-2,4-dioxo) ⁇ -3-
  • Example 33 1- ⁇ 4- [(5,5-Dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇ - 3- (2-morpholin-4-ylethyl) urea was prepared as in step b) of Example 18, replacing 3-pyrrolidin-1-yl-propylamine with 1- (2-aminoethyl) morpholine and N -methylpyrrolidinone with tetrahydrofuran, to give 110 mg of 1- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4-
  • Example 36 1-Butyl-3- ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2 -yl ⁇ -1-methylurea
  • Example 37 1-Butyl-3- ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2 yl ⁇ urea
  • Example 40 1- [4- (Dimethylamino) butyl] -3- ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4-
  • Example 40A 1- (2 - [(5-Fluoropyridin-3-yl) amino] pyridin-4-yl] methyl) -5,5-dimethyl-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidine -2, 4-dione
  • Example 40B 1- ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3- (4-
  • reaction mixture is stirred for 1 hour at this temperature, then the ice bath is removed and 20 ml of a saturated solution of sodium hydrogencarbonate are added and the aqueous phase extracted with 2 times 50 ml of sodium acetate. 'ethyl.
  • the combined organic phases are washed with a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • Example 4OC 1- (2 - [(3-fluorophenyl) amino] pyridin-4-yl] methyl) -5,5-dimethyl-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidine-2,4 -dione
  • Example 4OE 1- ( ⁇ 2- [(2-Chloropyridin-3-yl) amino] pyridin-4-yl ⁇ methyl) -5,5-dimethyl-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidine -2, 4-dione
  • Example 40F 1- ( ⁇ 2- [(6-Chloropyridin-3-yl) amino] pyridin-4-yl ⁇ methyl) -5,5-dimethyl-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidine -2, 4-dione
  • Example 40 1- ( ⁇ 2- [(6-Hydroxypyridin-3-yl) amino] pyridin-4-yl ⁇ methyl) -5,5-dimethyl-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidine -2, 4-dione
  • Example 40H 5,5-Dimethyl-1 - [(2- ⁇ [5- (pyrrolidin-1-ylmethyl) pyridin-3-yl] amino ⁇ pyridin-4-yl) methyl] -3- ⁇ 4- [(( trifluoromethyl) thio] phenyl ⁇ imidazolidine-2,4-dione
  • 1- [(2-aminopyridin-4-ylmethyl) -5,5-dimethyl-3- (4-
  • Example 40 1- [3- (azetidin-1-ylmethyl) cyclobutyl] -3- ⁇ 4- [(5,5-dimethyl-2,4-dioxo-3-yl) [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1-yl) methyl] pyridin-2-yl ⁇ urea
  • Example 40k 1- [3- (Azetidin-1-ylmethyl) cyclobutyl] -3- ⁇ 4 - [(5,5-dimethyl-2,4-dioxo-3- ⁇ 4 - [(trifluoromethyl) thio] phenyl ⁇ imidazolidin-1 - yl) methyl] pyridin-2-yl ⁇ urea
  • Step d) of Example 1 To a solution of 0.5 g of 1 - [(2-chloropyridin-4-ylmethyl) -5,5-dimethyl-3- ⁇ 4- [(trifluoromethyl) thio] phenyl ⁇ imidazolidine-2,4-dione obtained Step d) of Example 1 in 15 ml of dioxane are successively added under argon, 131 mg of methyl carbamate, 1.44 g of cesium carbonate, 26 mg of palladium acetate and 67 mg of 9.9 g. dimethyl-4,5-bis (diphenylphosphino) xanthene. The reaction mixture is refluxed for 1 hour, filtered and concentrated under reduced pressure.
  • IGF-IR Kinase Assay The inhibitory activity of the compounds on IGF1R is determined by measuring the inhibition of autophosphorylation of the enzyme using a time resolved fluorescence assay (HTRF) .
  • HTRF time resolved fluorescence assay
  • the human cytoplasmic domain of IGF-IR was cloned in fusion with glutathione S-transferase (GST) in the baculovirus expression vector pFastBac-GST.
  • GST glutathione S-transferase
  • the protein is expressed in SF21 cells and purified to about 80% homogeneity.
  • test compound 10 inM in solution in DMSO is diluted in 1/3 steps in a 50mM Hepes buffer, pH 7.5, 5mM MnCl 2, 50mM NaCl, 3% Glycerol, 0.025% Tween 20,
  • the successive dilutions of the compound are preincubated for 30 min and 90 min in the presence of 5 nM of enzyme, the final concentration of DMSO not exceeding 1%.
  • the enzymatic reaction is initiated to have 120 ⁇ M final ATP and stopped after 5 min by addition of 100 mM Hepes buffer, pH 7.0, containing 0.4 M potassium fluoride, 133 mM EDTA, 0.1% BSA, the anti- GST labeled with XL665 and anti-phosphotyrosine antibody conjugated with europium Eu-K cryptate (Cis-Bio Int.).
  • the characteristics of the two fluorophores, XL-665 and Eu-K are available in G. Mathis et al., Anticancer Research, 1997, 17, pages 3011-3014.
  • the energy transfer between the excited europium cryptate to the acceptor XL665 is proportional to the degree of autophosphorylation of IGP-IR.
  • the long-term specific signal of XL-665 is measured in a GENios Pro TECAN plate counter. Inhibition of autophosphorylation of IGF-IR at 30 min and 90 min with the tested compounds of the invention is calculated relative to 1% DMSO control, the activity of which is measured in the absence of compound. A curve representing the% inhibition as a function of the log of the concentration is established to determine the concentration corresponding to 50% inhibition (ICso) •
  • the cells are lysed with buffer (50 mM Hepes pH 7.6, 1% Triton X100, 2 mM Orthovanadate, protease inhibitor cocktail).
  • buffer 50 mM Hepes pH 7.6, 1% Triton X100, 2 mM Orthovanadate, protease inhibitor cocktail.
  • the cell lysates are incubated on a 96-well plate pre-coated with an anti-IGFIR antibody, followed by incubation with an anti-phosphotyrosine antibody coupled to the peroxidase enzyme.
  • the level of peroxidase activity (measured by OD with a luminescent substrate) reflects the phosphorylation status of the receptor. Calculation of the results: (i) The tests are performed in duplicate and the average of the two tests is calculated.
  • MEF-IGF1R cells stable clone of cells transfected with the hIGF-1R receptor are cultured at 37 ° C. under 5% CO 2 in EMEM medium containing 10% FCS.
  • Test procedure The cells are seeded at 5,000 cells per well in 96-well Cytostar plates (Amersham) with 0.2 ml of EMEM culture medium at 37 ° C. for 18 hours. The cells are then washed twice with EMEM medium and left in culture without serum for 24 hours. The compounds are then added at different concentrations in the presence of rhIGF1 (100 ng / mL) and 0.1 ⁇ Ci Thymidine [ 14 C] (specific activity ⁇ 50 mCi / mmol) to give 0.2 mL of volume per well. After incubation for 72 hours in the presence of the compound, at 37 ° C.
  • compositions form part of the present invention: it may be noted that also part of the present invention are the pharmaceutical compositions prepared with the other products of formula (I), their salts or their prodrugs according to the present invention.

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WO2013106614A1 (en) 2012-01-13 2013-07-18 Bristol-Myers Squibb Company Triazolyl-substituted pyridyl compounds useful as kinase inhibitors
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US9242975B2 (en) 2012-01-13 2016-01-26 Bristol-Myers Squibb Company Heterocyclic-substituted pyridyl compounds useful as kinase inhibitors
BR112015009850A2 (pt) 2012-11-08 2017-07-11 Bristol Myers Squibb Co compostos de piridila substituídos por heteroarila úteis como moduladores de quinase
TW201422606A (zh) 2012-11-08 2014-06-16 必治妥美雅史谷比公司 可作爲激酶調節劑之經雙環雜環取代之吡啶化合物
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WO2016036796A1 (en) * 2014-09-03 2016-03-10 Genzyme Corporation Cyclic urea compounds as tropomyosin-related kinase (trk) inhibitors
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JP6843775B2 (ja) 2015-06-24 2021-03-17 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ ヘテロアリール置換のアミノピリジン化合物
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US20220143049A1 (en) 2019-03-21 2022-05-12 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
JP2023500906A (ja) 2019-11-08 2023-01-11 インサーム（インスティテュ ナシオナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシェ メディカル） キナーゼ阻害剤に対する獲得抵抗性を有するがんの処置方法
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