WO2009056693A1 - Nouveaux derives de n, n'- 2, 4-dianilinopyrimidines, leur preparation, a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk - Google Patents

Nouveaux derives de n, n'- 2, 4-dianilinopyrimidines, leur preparation, a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk Download PDF

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WO2009056693A1
WO2009056693A1 PCT/FR2008/001173 FR2008001173W WO2009056693A1 WO 2009056693 A1 WO2009056693 A1 WO 2009056693A1 FR 2008001173 W FR2008001173 W FR 2008001173W WO 2009056693 A1 WO2009056693 A1 WO 2009056693A1
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methyl
products
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phenyl
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Monsif Bouaboula
Bernard Tonnerre
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Sanofi-Aventis
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D401/00—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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/02—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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel N, N '-2,4-dianilinopyrimidine derivatives, process for their preparation, the novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such derivatives of 2 , 4-dianilinopyrimidines.
  • Patent WO200164654-A1 mentions 2, 4-di- (hetero) arylpyrimidines substituted in 5, inhibitors of CDK2 and FAK kinases, as well as other serine-threonine kinase and CDK inhibitory aminopyrimidines are presented in WO2003030909-A1.
  • WO2004046118-A2 discloses 2,4-diphenylaminopyrimidine derivatives as inhibitors of cell proliferation.
  • a series of 5-cyano-2-aminopyrimidines are presented as inhibitors of KDR and FGFR kinases, in WO200078731-A1, other pyrimidines as inhibitors of FAK and IGFR in WO2004080980A-1, and also ZAP-70, FAK and / or Syk tyrosine kinase in WO2003078404A1, and PLK polokinases in WO2004074244-A2, as cytostatic agents.
  • the present invention thus relates to novel 2,4-dianilinopyrimidine derivatives having inhibitory effects vis-à-vis protein kinases.
  • the products of the present invention can thus notably be used for the prevention or control of treatment of conditions capable of being modulated by the inhibition of the activity of protein kinases.
  • protein kinases the protein kinase IKK-alpha (IKKa) and IKK-beta (IKK ⁇ ) are more particularly mentioned.
  • the compounds of the present invention are kinase inhibitors, in particular IKK-alpha and IKK-beta, therefore inhibit NF-KB (nuclear factor kappa B) activity, so they can be used in the treatment of prophylaxis and inflammatory diseases, in cancer and diabetes.
  • kinase inhibitors in particular IKK-alpha and IKK-beta, therefore inhibit NF-KB (nuclear factor kappa B) activity, so they can be used in the treatment of prophylaxis and inflammatory diseases, in cancer and diabetes.
  • NF-kB Nuclear factor kappa B
  • NF-kB belongs to a family of transcription factor complexes consisting of different combinations of Rel / NF-KB polypeptides.
  • Members of this family of NF- ⁇ B-related polypeptides regulate the expression of genes involved in immune and inflammatory responses. ((Bames PJ, Karin M (1997) N Engl J Med 336, 1066-1071) and (Baeuerle PA, Baichwal VR (1997) Adv Immunol 65, 111-137)).
  • NF- ⁇ B dimers are retained in inactive form in the cytoplasm by inhibitory proteins members of the IKB family (Beg et al., Genes Dev., 7: 2064-2070, 1993; Morin, Trends Genet 9: 427-43) 3), 199 '); Haskil and. al., Cell 65: 1281-1289, 1991).
  • the proteins of the IKB family mask the NF-KB nuclear translocation signal.
  • IKB-Kinase complex IKB-Kinase complex
  • IKK IKB-Kinase complex
  • IKB will be subject to ubiquitination leading to its degradation by the proteasome (26S), allowing thus the release and the translocation of NF- ⁇ B in the nucleus or it will bind to specific sequences at the level of the promoters of target genes thus inducing their transcription.
  • IKK IKB-Kinase complex
  • IKKa IKK1
  • IKK2 IKK ⁇
  • IKK2 IKK2 is the dominant kinase (Mercurio et al., Mol., Cell Biol., 19: 1526, 1999-, Zandi et al., Science, 28: 1, 3) 60, 1998; Lee and. al, Proe. Natl. Acad. Sci. USA 95:93) 19, 1998).
  • NF-KB genes regulated by NF-KB encode pro-inflammatory mediators, cytokines, cell adhesion molecules and proteins of the acute phase, which in turn will induce the activation of NF- ⁇ B by autocrine or paracrine mechanisms.
  • NF-KB plays a role in the growth of normal cells but also malignant cells. Proteins produced by expression of NF- ⁇ B regulated genes include cytokines, chemokines, adhesion molecules, cell growth mediators, angiogenesis. In addition, various studies have shown that NF-KB plays an essential role in neoplastic transformations. For example NF- ⁇ B may be associated with cell transformation in vitro and in vivo following overexpression, amplification, rearrangement or translocation events (Mercurio, R, and Manning, AM (1999) Oncogene, 18: 6163- 6171). In some human lymphoid tumor cells, the genes encoding the different NF-KB members are rearranged or amplified. It has been shown that NF- ⁇ B can promote cell growth by inducing transcription of cyclin D, which associated with Rb hyperphosphorylation results in the transition of G1-S phases and the inhibition of apoptosis.
  • NF- ⁇ B constitutive activity of NF- ⁇ B is found following the activation of IKK2.
  • NF- ⁇ B is constitutively activated in Hodgkin's disease and the inhibition of NF- ⁇ B blocks the growth of these lymphomas.
  • I ⁇ B ⁇ repressor induces apoptosis of cells expressing the oncogenic H-Ras allele (Baldwin, J. Clin Invest, 107: 241 (2001), Bargou et al., J.
  • NF-KB The constitutive activity of NF-KB appears to contribute to oncogenesis through the activation of several anti-apoptotic genes such as Al / Bfi-1, IEX-I, MAP, thus resulting in the suppression of the cell death pathway.Through the activation of cyclin D, NF-KB can promote the tumor cell growth The regulation of adhesion molecules and surface proteases suggests a role for NF-KB signaling in metastases.
  • NF-KB is involved in the induction of chemoresistance. NF-KB is activated in response to a number of chemotherapy treatments. Inhibition of NF- ⁇ B by the use of the super-repressor form of I ⁇ B ⁇ in parallel with chemotherapy treatment has been shown to increase the efficacy of chemotherapy in xenograft models.
  • R 2, R 3 and R 4 which are identical or different, are such that one represents a halogen atom or CF 3 and the other two, which are identical or different, represent a hydrogen atom or a halogen atom or an alkyl radical or an alkoxy radical optionally substituted with one or more halogen atoms;
  • R5 represents a hydrogen atom or a halogen atom
  • R1 and R6 represent one of the following 5 alternatives i) to v)
  • R1 represents -X1-R7 with X1 represents - (CH2) m- and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; and R6 represents hydrogen atom or hydroxyl radicals, - (CH2) mOH, -CO-NRaRb, -CH2-NRaRb -CO2H and -
  • R1 represents -X2-R7 with X2 represents:
  • R1 represents -NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms optionally substituted with a radical chosen from -PO (OEt ) 2, -OH, -OaIk, -CF3, -CO-NR8R9 and SO2-alk; and R ⁇ represents hydrogen; it being understood that when W represents a hydrogen atom then z represents
  • R1 represents -CO-N (Rc) -OR 'c and R ⁇ represents hydrogen; with n, n1 and n2, identical or different, represent an integer of 0 to 3; m represents an integer of 1 to 3;
  • Rc and R 'c represent the hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms optionally substituted with one or more halogen atoms, it being understood that the halogen atoms are not not in the vicinal position of the nitrogen atom;
  • NRaRb is such that either Ra and Rb, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or a cycloalkyl radical, these alkyl and cycloalkyl radicals being optionally substituted with one or a plurality of halogen atoms, it being understood that the halogen atoms are not in the vicinal position of the nitrogen atom; a hydroxyl radical or an NH 2, NHalkyl or N (alkyl) 2 radical; either Ra and Rb form with the nitrogen atom to which they are bonded a cyclic amine which may optionally contain one or two other heteroatoms chosen from O, S, N
  • NR8R9 is such that either R8 and R9, which are identical or different, are such that R8 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or a cycloalkyl radical, these alkyl and cycloalkyl radicals being optionally substituted by one or more halogen atoms, a hydroxyl radical or an NH 2, NHalkyl or N (alkyl) 2 radical; and R 9 represents the hydrogen atom and the alkyl, cycloalkyl or heterocycloalkyl radicals themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl, N ( alkyl) 2, the alkyl radicals that represent R 9 being further optionally substituted by a phenyl, heterocycloalkyl or heteroaryl radical, themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkoxy,
  • R 2 R 3, R 4, R 5, Z and the ring (N) have the meanings indicated above or below and R 1 and R6 are such that R1 represents -X1-R7 with X1 represents - (CH2) m- and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; and R ⁇ represents hydrogen atom or hydroxyl radicals, - (CH2) mOH, -CO-NRaRb, -CH2-NRaRb -CO2H, and - CO2alk; with m, n and NRaRb as defined above or below and the heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted with one or more radicals, which are identical or different, as defined above or below, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition
  • R7 is heterocycloalkyl, aryl, or heteroaryl, all optionally substituted, and R6 is hydrogen; with n, nl, n2, Rc and NRaRb as defined above and the heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more radicals, which are identical or different, as defined above or below, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (D.
  • R1 represents -NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms optionally substituted with a radical chosen from -PO (OEt) 2, -OH, -OaIk, -CF3, -CO-NR8R9 and SO2-alk and R ⁇ represents hydrogen, it being understood that when W represents a hydrogen atom, then z represents CO; or R1 represents -CH2-NRC-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms and optionally substituted with a radical chosen from -PO (OEt) 2, -OH, -OEt, -CF3, -CO- N (alk
  • the ring formed can in particular be the 8-aza-bicyclo (3.2.1) octyl cycle or a ring chosen from the following: azabicyclo [ 3.3.1] nonan-3-yl, 6-azabicyclo [3.2.1] octan-3-yl, the "3-azabicyclo [3.2.1] octan-8-yl or 3-azabicyclo [3.3.1] nonan -9-yl.
  • the subject of the present invention is thus the products of formula (I) as defined above in which R 2, R 3, R 4, R 5 and Z have the meanings indicated above or hereafter and the (N) cycle represents one of the rings defined below: an azetidinyl or pyrrolidinyl ring substituted in position 3 by R 1 and R 6 as defined above or hereinafter; a piperidinyl and azepinyl ring substituted in position 3 or 4 by R 1 and R 6 as defined above or hereinafter; an 8-aza bicyclo (3,2,1) octan-3-yl, 6-azabicyclo [3.2.1] octan-3-yl or 3-azabicyclo [3.2.1] octan-8-yl ring; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (I) •
  • the present invention thus relates to the products
  • halogen means fluorine, chlorine, bromine or iodine atoms and preferably fluorine, chlorine or bromine ;
  • alkyl radical denotes a linear or branched radical containing at most 6 carbon atoms and especially the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or isopentyl radicals; pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and their linear or branched positional isomers;
  • hydroxyalkyl radical denotes the alkyl radicals indicated above substituted by one or more hydroxyl radicals
  • alkoxy radical denotes a linear or branched radical containing at most 6 carbon atoms chosen, for example, from methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy, hexoxy and heptoxy radicals, and also their positional isomers; linear or branched;
  • cycloalkyl radical denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 7 ring members and in particular denotes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals;
  • aryl radical refers to unsaturated, monocyclic or fused carbocyclic ring radicals. Examples of such an aryl radical include, in particular, phenyl or naphthyl radicals; the term “heterocyclic radical” denotes a saturated (heterocycloalkyl) or partially or completely unsaturated (heteroaryl) carbocyclic radical consisting of 4 to 10 members interrupted by one to four identical or different heteroatoms chosen from oxygen, nitrogen or sulfur:
  • radicals containing one to four heteroatoms chosen from N optionally oxidized, O and S optionally oxidized such as the radicals, for example thienyl radicals such as 2-thienyl, 3 thienyl, dioxidothienyl, thiazolyl (N, S), furyl (O), 2-furyl, pyrrolyl (NH, NCH 3), isothiazolyl, diazolyl, thiadiazolyl (N, N, S), 1, 3, 4-thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl (N, O), 3-isoxazolyl, 4-isoxazolyl, imidazolyl, pyrazolyl (N, N), triazolyl groups, tetrazolyl and more particularly the oxazolyl, isoxazolyl (N, O) or pyrazolyl radicals; all
  • heterocycloalkyl saturated
  • heterocycloalkyl saturated
  • heterocycloalkyl saturated
  • heterocycloalkyl saturated
  • alkylamino radical or NH (alk) radical and dialkylamino radical or N (alk) 2 denotes NH 2 amino radicals substituted respectively by one or two linear or branched alkyl radicals, which are identical or different in the case of dialkylamino, chosen from alkyl radicals as defined above and optionally substituted as indicated above or below: mention may be made, for example, of methylamino, ethylamino, propylamino or butylamino radicals, and dimethylamino, diethylamino and methylethylamino radicals.
  • cycloalkylamino thus denotes an amino radical substituted in particular by a cycloalkyl radical chosen from the radicals defined above: there may thus be mentioned, for example, the cyclopropylamino, cyclobutylamino or cyclopentylamino radicals; still cyclohexylamino.
  • cyclic amine denotes a monocyclic or bicyclic radical containing from 3 to 10 members in which at least one carbon atom is replaced by a nitrogen atom, this cyclic radical possibly also containing one or more other heteroatoms chosen from O, S, SO 2, N or NR 10 with R 10 as defined above:
  • examples of such cyclic amines include, for example, pyrrolyl, piperidyl, morpholinyl, piperazinyl, pyrrolidinyl and azetidinyl radicals. Mention may more particularly be made of piperidinyl, morpholinyl, piperazinyl or azetidinyl 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). For example, an ester of a product of formula (I) containing a hydroxyl group can be converted by in vivo hydrolysis to its parent molecule.
  • hydroxyl group-containing esters of the formula (I) such as acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bisulfates and the like.
  • 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
  • esters include especially
  • Substituted (aminomethyl) benzoates dialkylamino-methylbenzoates in which the two alkyl groups can be bonded together or can be interrupted by an oxygen atom or by an optionally substituted nitrogen atom or an alkylated nitrogen atom or else morpholino-methyl) benzoates, eg 3- or A- (morpholinomethyl) -benzoates, and (4-alkylpiperazin-1 (yl) benzoates, eg 3- or 4- (4-alkylpiperazin-1-yl) benzoates.
  • the addition salts with the inorganic or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position.
  • stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called isomerism.
  • stereoisomer is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • the subject of the present invention is particularly the products of formula (I) as defined above or below, in which:
  • R 2, R 3 and R 4, which are identical or different, are such that one represents a halogen atom or CF 3 and the other two, which are identical or different, represent a hydrogen atom or a halogen atom or an alkyl radical or an alkoxy radical optionally substituted with one or more halogen atoms;
  • R5 represents a hydrogen atom or a halogen atom;
  • R1 and R ⁇ represent one of the following alternatives i) to v) i) R1 represents - X1-R7 with X1 represents -CH2 and R7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted; and R ⁇ represents a hydrogen atom or hydroxyl radicals, -CH2OH, -CO2H, -CO-NRaRb and -CO2Et;
  • R1 represents -CO-N (Rc) -OR 'c and R ⁇ represents hydrogen; with n, n1 and n2, identical or different, represent an integer of 0 to 2;
  • Rc and R 'c identical or different represent the hydrogen atom or an alkyl radical containing 1 to 2 carbon atoms
  • NRaRb is such that either Ra and Rb, identical or different, represent the hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms optionally substituted by one or more halogen atoms, a hydroxyl radical or an NH 2 radical; , NHalkyl or N (alkyl) 2; or Ra and Rb form with the nitrogen atom to which they are bonded a morpholinyl or pyrrolidinyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and the alkyl radicals themselves optionally substituted with one or several halogen atoms; all the heterocycloalkyl, phenyl and heteroaryl radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms; hydroxyl radicals; cyano; NR8R9; and the alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroary
  • NR8R9 is such that either R8 and R9, which are identical or different, are such that R8 represents a hydrogen atom, a linear or branched alkyl radical containing at most 4 carbon atoms or a cycloalkyl radical containing from 3 to 6 ring members, alkyl and cycloalkyl themselves optionally substituted by one or more halogen atoms or a hydroxyl radical; and R 9 represents the hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl, N (alkyl) 2, phenyl or heterocycloalkyl radicals; or heteroaryl themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl radical radicals, OCH3, CH3, -CH2OH, CN, CF3, OCF3, NH2, NHaIk or N (alk) 2; or R8 and R9 form
  • the subject of the present invention is particularly the products of formula (I) as defined above or below in which R2, R3, R4, R5 and Z have the meanings indicated above or below. and the ring (N) represents a piperidinyl ring substituted at the 3 or 4 position by R 1 and R 6 as defined above or below, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers as well as the addition salts with the mineral and organic acids of said products of formula
  • the subject of the present invention is thus the products of formula (I) as defined above in which Z, the ring (N), R 1 and R 6 have the meanings indicated above or below; R3 and R4, which are identical or different, are such that one represents a halogen atom or CF3 and the other two, which are identical or different, represent a hydrogen atom, a halogen atom or a methyl or methoxy radical, trifluoromethyl or trifluoromethoxy, and R5 represents a hydrogen atom, said products of formula (I) being in all the possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with the mineral and organic acids of said products of formula
  • the subject of the present invention is thus the products of formula (I) as defined above in which Z, the (N) -cycle, R1 and R6 have the meanings indicated above or below and R2, R3 and R4, which are identical or different, are such that one represents a fluorine atom and the other two, which are identical or different, represent a hydrogen atom, a fluorine atom or a methyl radical; R5 represents an atom of hydrogen; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (I).
  • the subject of the present invention is therefore the products of formula (I) as defined above in which R 1, R 2, R 3, R 4, R 5 and R ⁇ and the ring (N) have the meanings indicated above or below. and Z represents SO 2, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula
  • all the heterocycloalkyl, phenyl and heteroaryl radicals that R7 represents may in particular be optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms; NR8R9 radicals; and the alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl radicals, themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, OCF3, CH3, -CH2OH, CN radicals; , CF3, OCF3, NH2, NHaIk, or N (alk) 2, pyrrolidinyl, piperidinyl or morpholinyl optionally substituted with one or more radicals identical or different selected from halogen atoms and alkyl radicals themselves optionally substituted by one or more halogen atoms.
  • radicals which may be identical or different, chosen from halogen atoms; NR8R
  • NR 8 R 9 may especially be such that either R 8 and R 9, which may be identical or different, are such that R 8 represents the hydrogen atom, a linear or branched alkyl radical containing at most 4 carbon atoms or a cycloalkyl radical containing from 3 to 6 members, alkyl and cycloalkyl themselves optionally substituted by one or more halogen atoms or a hydroxyl radical; and R 9 represents the hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl, N (alkyl) 2, phenyl or heterocycloalkyl radicals; or heteroaryl themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl radical radicals, OCH3, CH3, -CH2OH, CN, CF3, OCF3, NH2, NHaIk or N
  • R 2 R 3, R 4, R 5, Z and the ring (N) have the meanings indicated above or below and R 1 and R ⁇ are such that: either R1 is -X1-R7 with X1 is -CH2- and R6 is hydrogen or hydroxyl, CH2-OH; -CO-N (CH3) 2, -CO-NHCH3, -CO-NH- (CH2) 2- N (CH3) 2 and -CO2Et; or R1 represents -X2-R7 with X2 represents:
  • R7 is selected from pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, phenyl, pyridyl, thienyl, thiazolyl, dithiazolyl, pyrazolyl, pyrazinyl, furyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, benzodihydrofuranyl, benzoxodiazolyl, benzothiodiazolyl and benzothienyl, quinolyl, isoquinolyl; all these radicals represented by R7 being optionally substituted with one or more identical
  • the subject of the present invention is particularly the products of formula (I) as defined above with the following names: - ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - [4- (methyl-oxazol-2-ylmethylamino) -piperidin-1-yl] -methanone
  • the subject of the present invention is also the processes for preparing the products of formula (I) as defined above or using the methods known to those skilled in the art.
  • the subject of the present invention is in particular the process for the preparation of the products of formula (I) such that defined above, characterized in that a product of formula (II) is reacted:
  • products of formula (Ia) and (Ib) which may be products of formula (I) in which, respectively, z represents SO2 and z represents CO, and to obtain or of other products of formula (I), one or more of the following transformation reactions can be subjected, if desired and if necessary, in one order.
  • an elimination reaction of the protective groups that the protected reactive functions can carry e) a salification reaction with an inorganic or organic acid to obtain the corresponding salt, f) a reaction of duplication racemic forms in duplicated products, said products of formula (I) thus obtained being in all possible isomeric forms racemic, enantiomers and diastereoisomers.
  • the processes described above can be carried out as follows:
  • the product of formula (II) is subjected to the action of the product of formula (III) as defined above in particular in an alcohol such as for example butanol, propanol, ethanol or dimethylformamide between 80 and 140 0 C, to give a product of formula (IV) as defined above.
  • the product of formula (IV) thus obtained is subjected to the action of the aniline of formula (V) as defined above in particular in an alcohol such as for example butanol or dimethylformamide, in the presence or absence of a strong acid (HCl) in catalytic amount under reflux conditions to give a product of formula (VI) as defined above.
  • the product of formula (VI) is subjected to the action of chlorosulfonic acid, especially first at 0 ° C. and then at ambient temperature to give a product of formula (VII) such as as defined above.
  • the product of formula (VII) thus obtained is subjected to the action of an amine of formula (VIII) as defined above in particular in dichloromethane or a mixture of dichloromethane / THF or dimethylformamide at room temperature, in the presence of an organic base such as triethylamine, diisopropylethylamine or N-methyl morpholine, to give a product of formula (Ia) as defined above.
  • the product of formula ( IV) as defined above is subjected to the action of the methyl ester of 4-amino benzoic acid especially in an alcohol such as butanol at a temperature of 100 to 140 ° C., to give the product of formula (IX) as defined above.
  • This product of formula (IX) is saponified to its corresponding acid of formula (X) using the usual methods known to those skilled in the art such as in particular by the action of sodium hydroxide or potassium hydroxide in water.
  • the products of formulas (Ia) and (Ib) as defined above can therefore constitute products of formula (I) such as as defined above, in which, respectively, z represents SO 2 and z represents CO, or may be converted into products of formula (I) by the usual methods known to those skilled in the art and for example by being subjected to one or more of reactions a) to f) indicated above.
  • hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
  • alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl
  • the amino groups may be protected, for example, by the acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or phthalimido radicals or other radicals known in the peptide chemistry: the amino functions may in particular be protected by a group such as Boc or CH 2 -phenyl and can then be released under the usual conditions known to those skilled in the art.
  • the reactions to which the products of formula (I ') as defined above may be subjected, if desired or necessary, may be carried out, for example, as indicated below.
  • the saponification reactions may be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.
  • the reduction or oxidation reactions may be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as ethyl ether or tetrahydrofuran, in the presence of sodium borohydride or lithium aluminum hydride. ; or for example in a solvent such as acetone or tetrahydrofuran in the presence of potassium permanganate or pyridinium chlorochromate.
  • Obtaining the sulphoxide function can be promoted by an equimolar mixture of the product containing an alkylthio group and the reagent such as in particular a peracid.
  • Obtaining the 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 optional alkoxy functions, such as methoxy in particular, of the products described above may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as For example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux.
  • a solvent such as For example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux.
  • the phthalimido group may in particular be removed by hydrazine.
  • the starting products of formulas (II), (III), (V) and (VIII) can be known, can be obtained commercially or can be prepared according to the usual methods known to those skilled in the art, in particular from products for example by subjecting them to one or more reactions known to those skilled in the art such as, for example, the reactions described above in a) to f).
  • the products of formula (II) which are therefore pyrimidine derivatives and the products of formulas (III) which are derivatives of aniline may be commercially available products such as for example dichloropyrimidine, trichloropyrimidine, 4-fluoroaniline, 3,4-difluoroaniline, 4-fluoro-3-chloroaniline, or aniline.
  • the anilines of formula (III) can in particular be commercial anilines such as, for example, the following trihalogenated anilines: -3,4, 5-trifluoroaniline -2,3,4-trifluoroaniline -2-chloro-4, ⁇ -difluoroaniline -2,4,5-, trifluoroaniline -3-chloro-2,4-difluoroaniline -2,4 dichloro-5-fluoroaniline. 4-Trifluoromethyl-phenylamine
  • the aniline of formula (V) is commercial.
  • the amines of formula (VIII) can in particular be commercial amines such as, for example, the following trihalogenated anilines:
  • Another subject of the present invention is, as new industrial products, compounds of formulas (VII), (IX) and (X).
  • the products of formula (I) as defined above and their addition salts with acids have interesting pharmacological properties.
  • the compounds of the present invention can therefore inhibit the activity of kinases, in particular IKK1 and IKK2 with an IC50 of less than 10 ⁇ M.
  • the compounds of the present invention can thus inhibit the activation of NF- ⁇ B, and the production of cytokines with IC 50 of less than 10 ⁇ M.
  • the compounds of the present invention can thus inhibit the proliferation of a large panel of tumor cells with IC50 values of less than 10 ⁇ M.
  • the compounds of formula (I) may therefore have drug activity in particular as inhibitors of IKK1 and IKK2 and may be used in the prevention or treatment of diseases in which the inhibition of IKK1 or IKK2 is beneficial.
  • diseases such as inflammatory diseases or diseases with an inflammatory component such as inflammatory arthritis including rheumatoid arthritis, spondyl osteoarthritis, Reiters syndrome, psoriatic arthritis, bone resorption diseases; multiple sclerosis, inflammatory diseases of bowel including Crohn's disease; asthma, chronic pulmonary obstruction, emphysema, rhinitis, acquired myasthenia gravis, graft disease, transplant rejection, psoriasis, dermatitis, allergic disorders, immune system diseases, cachexia, severe acute respiratory syndrome, septic shock, heart failure, myocardial infarction, atherosclerosis, reperfusion injury, AIDS, cancer and insulin resistance disorders such as diabetes , hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, polycystic ovarian diseases, hypertension, cardiovascular disorders, Syndrome X, autoimmune diseases such as systemic lupus, lupus erythematosus, induced glomerulone
  • the products of formula (I) according to the present invention as modulators of apoptosis may be useful in the treatment of various human diseases including aberrations in apoptosis such as cancers: such as in particular but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone-dependent tumors of the breast, prostate and ovary, and precancerous lesions such as polyposis familial adenoma, viral infections (such as, but not limited to, but not limited to those caused by Herpes virus, poxvirus, Epstein - Barr virus, Sindbis virus and adenovirus), myelodysplastic syndromes, ischemic disorders associated with myocardial infarction, cerebral congestion, arrhythmia, atherosclerosis, liver disorders induced by toxins or alcohol, haematological disorders such as in particular, but not limited to, chronic anemia and aplastic anemia, degenerative diseases of the musculoskeletal system such as, but not limited to, osteoporosis, cystic fibrosis
  • the compounds according to the invention have an anticancer activity and an activity in the treatment of other proliferative diseases such as psoriasis, restenosis, atherosclerosis, AIDS for example, as well as in diseases caused by proliferation.
  • these compounds are useful in the prevention and treatment of leukemias, both primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer, lung cancer, cancer of the lungs, small bowel, colon and rectal cancer, respiratory tract cancer, oropharynx and hypopharynx, esophageal cancer, liver cancer, stomach cancer, bile duct cancer, cancer of the gall bladder, pancreatic cancer, urinary tract cancers including kidney, urothelium and bladder, cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma; cancers of the male genital tract including prostate cancer, seminal vesicles, testes, germ cell tumors; cancers of the endocrine glands including thyroid, pituitary, adrenal gland cancer; skin cancers including hemangiomas, melanomas, sarcomas, including Kaposi's sarcoma; tumor
  • the compound (s) of formula (I) may be administered in combination with one or more anti-cancer active principle (s), in particular antitumor compounds such as alkylating agents such as alkylsulfonates ( busulfan), dacarbazine, procarbazine, nitrogen mustards (chlormethine, melphalan, chlorambucil), cyclophosphamide, ifosfamide; nitrosoureas such as carmustine, lomustine, semustine, streptozocin; antineoplastic alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel or taxotere; antineoplastic antibiotics such as actinomycin; intercalators, antineoplastic antimetabolites, folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogues such as mercaptopurine, ⁇ -thioguanine; inhibitors of pyrimidine synthesis, aromata
  • the compounds of formula (I) may also be administered in combination with one or more other active ingredients useful in one of the pathologies indicated above, for example an anti-emetic, anti-pain, anti-inflammatory agent, anticachexia.
  • the subject of the present invention is thus, as medicaments, the products of formula (I) as defined above as well as the addition salts with pharmaceutically acceptable inorganic and organic acids of said products of formula (I).
  • the subject of the present invention is, in particular, as medicaments, the products of formula (I) as defined above, corresponding to the following names: - ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino ] - phenyl ⁇ - [4- (methyl-oxazol-2-ylmethylamino) -piperidin-1-yl] -methanone - ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] - phenyl ⁇ - [3- (methyl-1H-pyrrole-2-ylmethyl-amino) - Piperidin-1-yl] -methanone (Racemic)
  • the subject of the present invention is also the pharmaceutical compositions containing, as active principle, at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier.
  • the present invention also relates to pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) whose names are given above or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier.
  • the present invention particularly relates to the use of the products of formula (I) as defined above or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of a disease by inhibition of IKK protein kinase activity.
  • the present invention thus relates to the use as defined above in which the protein kinase is in a mammal.
  • the subject of the present invention is therefore the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease chosen from the diseases mentioned above. above.
  • the subject of the present invention is in particular the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease chosen from the following group: inflammatory diseases, diabetes and cancers.
  • the present invention particularly relates to the use 'of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of inflammatory diseases.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diabetes.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment of cancers.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the treatment of solid or liquid tumors.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the treatment of cancers resistant to cytotoxic agents.
  • the subject of the present invention is in particular the use of a product of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers.
  • the subject of the present invention is in particular the use of a product of formula (I) as defined above for the preparation of medicaments intended for cancer chemotherapy alone or in combination or in combination form as defined herein. -above.
  • the present invention particularly relates to the use of a product of formula (I) as defined above as inhibitors of IKK.
  • the present invention particularly relates to the products of formula (I) as defined above which constitute Examples 1 to 109 of the present invention.
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-fluoro-phenyl) -amine
  • dichloropyrimidine a mixture containing 15 g of dichloropyrimidine in 200 ml of n-butanol, with stirring, 10 ml of 4- fluoroaniline and then 18 ml of di-isopropyl-ethylamine.
  • the reaction mixture is stirred under reflux for 2 hours.
  • the reaction medium is cooled and concentrated to dryness.
  • Step 3 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride
  • Procedure Ib 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride
  • Stage 1 4-Chloro-N- (3,4-difluorophenyl) pyrimidin-2-amine
  • the preparation of this compound is carried out according to the same process as for procedure la from the reaction of 9.21 g of dichloropyrimidine with 8 g 3,4-difluoroaniline: 10.3 g of expected product are thus obtained.
  • Stage 2 N4- (3,4-Difluoro-phenyl) -N2-phenyl-pyrimidine-2,4-diamine
  • the preparation of this compound is carried out according to the same process as for example 1 from the reaction of 7g (2-Chloro-pyrimidin-4-yl) - (3,4-difluoro-phenyl) amine obtained in Step 1 above with 2.72 g of aniline: 8 g of the expected product are thus obtained.
  • Step 3 4- [4- (3,4-Difluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride
  • the preparation of this compound is carried out according to the same procedure as in Example 1 starting from the reaction of 8 g of N-4- (3,4-difluoro-phenyl) -N-2-phenyl-pyrimidine-2,4-diamine obtained in stage 2 above with chlorosulphonic acid gives 9 g expected product.
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-fluoro-3-methylphenyl) -amine
  • Step 2 N-4- (4-Fluoro-3-methyl-phenyl) -N-2-phenylpyrimidine-2,4-diamine
  • Step 3 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride.
  • Stage 1 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzoic acid methyl ester
  • a mixture containing 16 g of chloropyrimidine obtained in Stage 1 of Procedure la and 10.8 g of amino 4-methyl benzoate in n-butanol is heated at 140 0 C overnight. After cooling, the precipitate is filtered. This precipitate is washed with Et2O and recrystallized from a DCM-MeOH-iPr20 mixture. 23.5 g of expected product are thus obtained.
  • Step 2 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2- ylamino] -benzoic acid
  • Step 1 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzoic acid methyl ester
  • Step 2 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzoic acid 2.08 g of the product obtained in Step 1, in the presence of 410 mg of sodium hydroxide in a mixture of MeOH (5 mL), water (5 mL) and dioxane (20 mL) are brought to a temperature of 40 0 C overnight. The reaction medium is concentrated to dryness and taken up in 100 ml of water. The impurities are extracted with two volumes of Et2O and the aqueous phase is then acidified to pH 6 with 1N HCl. The precipitate formed is filtered, rinsed with distilled water and suspended. in DCM and the solvent is evaporated. 1.3 g of expected acid are obtained.
  • Procedure 2c 4- [4- (4-Trifluoromethyl-phenylamino) -pyrimidin-2-ylamino] -benzoic acid.
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-trifluoromethyl-phenyl) -amine
  • Step 2 4- [4- (4-Trifluoromethyl-phenylamino) -pyrimidin-2-ylamino] -benzoic acid methyl ester
  • Step 3 4- [4- (4-Trifluoromethyl-phenylamino) -pyrimidin-2-ylamino] -benzoic acid.
  • Step 3 of Procedure 1 From 6.4 g. A mixture containing 8 g of ester obtained in Stage 2 and 2.26 g of sodium hydroxide. 4.2 g of expected product are thus obtained.
  • Procedure 3 Preparation of the sulfonamide-type reaction intermediates Procedure 3a: N-4- (4-Fluoro-3-methyl-phenyl) -N-2- [4- (4-methylamino-piperidine-1-sulfonyl) -phenyl] -pyrimidine-2,4-diamine
  • Step 1 (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -methyl-carbamic acid tert-butyl ester
  • Step 2 N * 4 - (4-Fluoro-3-methyl-phenyl) -N * 2 - [4- (4-methylamino-piperidine-1-sulfonyl) -phenyl] -pyrimidine-2,4-diamine
  • Step 2 N-2- [4- (3-Aminomethyl-piperidine-1-sulfonyl) -phenyl] -N-4- (4-fluoro-phenyl) -pyrimidine-2,4-diamine (Racemic)
  • Procedure 3c N-2- [4- (3-S-Amino-pyrrolidine-1-sulfonyl) -phenyl] -N-4- (4-fluoro-phenyl) -pyrimidine-2,4-diamine Step 1: ( 1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -pyrrolidin-3-S-yl) -carbamic acid tert-butyl ester
  • Step 2 N-2- [4- (3-S-Aminopyrrolidine-1-sulfonyl) phenyl] -N-4- (4-fluoro-phenyl) -pyrimidine-2,4-diamine
  • Procedure 3d N-2- [4- (3-R-Amino-pyrrolidine-1-sulfonyl) -phenyl] -N-4- (4-fluoro-phenyl) -pyrimidine-2,4-diamine
  • Step 1 ( 1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -pyrrolidin-3-R-yl) -carbamic acid tert-butyl ester
  • Step 1 of procedure 3a from 400 mg of sulfonyl chloride hydrochloride obtained in procedure la and 198 mg of commercial amine pyrrolidin-3-S-yl-carbamic acid tert-butyl ester, 379 mg of expected product.
  • Step 1 6-Benzyl-1-oxa-6-aza-spiro [2.5] octane
  • N-benzyl-4-piperidone 12.8 g of dimethyloxosulfonium methylide and 0.34 g of tetrabutylairanonium bromide in 100 mL of toluene
  • a solution of 3.2 g of sodium hydroxide in 32 ml of water is added dropwise and the reaction medium is left stirring at 80 ° C. for 3 hours. After cooling, washed with water, dried over Na 2 SO 4 and concentrated to dryness. 11.7 g of epoxide are thus obtained.
  • Step 2 4-Aminomethyl-1-benzyl-piperidin-4-ol
  • Step 3 (1-Benzyl-4-hydroxy-piperidin-4-ylmethyl) -carbamic acid tert-butyl ester
  • Step 5 4-Aminomethyl-1- ⁇ 4- [4- (4-fluoro-3-methylphenylamino) -pyrimidin-2-ylamino] benzenesulfonyl ⁇ -piperidin-4-ol
  • step 1 of procedure 3a from 700 mg of sulfonyl chloride hydrochloride obtained in procedure Ic and 420 mg of piperidine obtained in stage 4, 540 mg of a compound which undergoes a decarboxylation reaction to give 150 mg of expected sulfonamide.
  • step 1 of procedure 3a from 2 g of sulfonyl chloride hydrochloride obtained in procedure Ic and 1.38 g of the racemic amine pyrrolidin-3-ylmethyl-carbamic acid benzyl obtained at the stage 4, 1.8 g of a compound which undergoes a hydrogenolysis reaction to give 1.3 g of the expected sulfonamide are obtained.
  • step 1 of procedure 3a from 3.5 g of sulfonyl chloride hydrochloride obtained in procedure la and 2 g of 3-N-boc-3-methylaminopiperidine, 2.65 g of a compound which undergoes a decarboxylation reaction to give 1.9 g of expected sulfonamide.
  • Procedure 4a ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - (4-methylamino-piperidin-1-yl) -methanone
  • Step 1 (1) ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -piperidin-4-yl) -methyl-carbamic acid tert-butyl ester.
  • Step 2 ⁇ 4- [4- (4-Fluorophenylamino) pyrimidin-2-ylamino] -phenyl ⁇ - (3-methylamino-piperidin-1-yl) -methanone
  • Step 1 (1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -piperidin-4-yl) -methyl-carbamic acid tert-butyl ester
  • Stage 2 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2- ylamino] -phenyl ⁇ - (4-methylamino-piperidin-1-yl) -methanone According to the decarboxylation reaction described in stage 2 of procedure 4a, 4.3 g of the compound obtained in stage 1 make it possible to obtain 2.1 g of the expected carboxamide. .
  • Procedure 4d (4-Methylamino-piperidin-1-yl) - ⁇ 4- [4- (4-trifluoromethyl-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ -methanone
  • Step 1 Methyl- (1 - 4- [4- (4-Trifluoromethyl-phenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -piperidin-4-yl) -carbamic acid tert-butyl ester
  • Step 2 (4-Methylamino-piperidin-1-yl) - ⁇ 4- [4- (4-trifluoromethyl-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ -methanone
  • MH + 470.9
  • Melting point 225-226 0 C
  • Example 1 ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - [4- (methyl) -2-
  • Example 3 ⁇ 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - ⁇ 4- [methyl- (1H-pyrazol-3-ylmethyl) -amino] -piperidin-1-yl ⁇ methanone
  • Example 6 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - [4- (methyl-oxazol-2-ylmethylamino) -piperidin-1-yl] -methanone
  • Example 7 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - [3- (methyl-oxazol-2-ylmethylamino) piperidin-1-yl] -methanone (Racemate)
  • Example 8 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2- ylamino] -phenyl ⁇ - [3- (methyl-lH-pyrrole-2-ylmethyl-amino) • piperidin-1-yl] -methanone (Racemic)
  • Example 9 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - [3- (aminothiazol-2-yl-amino-amino) -piperidin-1-yl] -methanone (Racemic )
  • Example 10 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - ⁇ 3- [methyl- (1H-pyrazol-3-ylmethyl) -amino] -piperidin-1 yl ⁇ -methanone (Racemic)
  • Example 11 N * 4 - (4-Fluoro-3-methyl-phenyl) -N * 2 * - (4- ⁇ 4 - [(2-methanesulfonyl-ethyl) -methyl-amino] -piperidine-1-sulfonyl ⁇ -phenyl) -pyrimidine-2,4-diamine
  • Example 12 2- [(1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -methyl-amino] -N , N-dimethyl-acetamide
  • Example 13 3 - [(1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benze-nesulfonyl ⁇ -piperidin-4-yl) methyl-amino] -N, N-dimethyl-propionamide
  • Example 14 1- ⁇ 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -3-pyridin-3-ylmethyl-piperidine-3-carboxylic acid ethyl ester (Racemic)
  • Example 15 1- ⁇ 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -3-pyridin-3-ylmethyl-piperidine-3-carboxylic acid dimethylamine (Racemic)
  • Stage 1 660 mg of KOH is dissolved in 5 ml of water. 3.5 g of ester obtained in Example 14 and 50 ml of MeOH are added to this solution. After a reflux of 3 hours, the reaction medium is concentrated to dryness and taken up with acidified water at a pH of 7. The precipitate formed is filtered off.
  • Example 16 1- ⁇ 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -3-pyridin-3-ylmethyl-piperidine-3-carboxylic acid methylamide (Racemic)
  • Example 17 1- ⁇ 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -3-pyridin-3-ylmethyl-piperidine-3-carboxylic acid (2-dimethylamino-ethyl) -amide (Racemic )
  • Example 18 N * 4 - (4-Fluoro-phenyl) -N * 2 - [4- (3 - ⁇ [(1-methyl-1H-pyrrol-2-ylmethyl) -amino] -methyl ⁇ -piperidine 1-sulfonyl) -phenyl] -pyrimidine-2,4-diamine (Racemic)
  • Example 21 N * 4 - (4-Fluoro-phenyl) -N * 2 - (4- ⁇ 3 - [(2-methanesulfonyl-ethylamino) -methyl] -piperidine-1-sulfonyl ⁇ -phenyl) -pyrimidine -2,4-diamine (Racemic)
  • Example 22 4-Dimethylaminomethyl-1- ⁇ 4- [4- (4-fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-ol
  • Example 23 1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -4-imidazol-1-ylmethyl-piperidin-4-ol
  • Step 1 To a solution containing 290 mg of imidazole in 5 mL of DMSO, 1.2 equivalents of sodium hydride are added. After stirring for 20 minutes at RT, 700 mg of epoxide obtained in stage 1 of procedure 3e are added and the mixture is left stirring for 18 hours at RT. It is taken up with water, extracted with DCM, dried over Na 2 SO 4 and concentrated. 540 mg of expected alcohol are obtained by trituration. Stage 2: Following a hydrogenolysis reaction described in Stage 4 of Procedure 3e, starting from 540 mg of alcohol obtained in Stage 1, 280 mg of expected piperidine is obtained. Step 3: Following the procedure described in Step 1 of Procedure 3a, from 600 mg of sulfonyl chloride hydrochloride and 280 mg of piperidine obtained in Step 2, 330 mg of expected sulfonamide is obtained.
  • Example 24 N * 4 - (4-Fluoro-3-methylphenyl) -N * 2 * - (4- ⁇ 3- (2-methanesulfonyl-ethylamino) -methyl] -pyrrolidine-1-sulfonyl ⁇ -phenyl) -pyrimidine-2,4-diamine (Racemic)
  • Example 25 N * 4 - (4-Fluoro-3-methyl-phenyl) -N * 2 - [4- (3 - ⁇ [(1-methyl-1H-pyrrol-2-ylmethyl) -amino] - methyl ⁇ - pyrrolidine-1-sulfonyl) -phenyl] -pyrimidine-2,4-diamine (Racemic)
  • Example 26 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - [3- (5-methyl-isoxazol-3-ylinethyl-amino) -piperidin-1-yl] -methanone (Racemic)
  • Example 27 N * 4 - (4-Fluoro-phenyl) -N * 2 - (4- ⁇ 3 - [(2-methanesulfonyl-ethyl) -methyl-amino] -piperidine-1-sulfonyl ⁇ -phenyl ) -pyrimidine-2,4-diamine
  • Example 28 N * 4 - (4-Fluoro-phenyl) -N * 2 - ⁇ 4- [4- (2-methanesulfonyl-ethylamino) -piperidine-1-sulfonyl] -phenyl ⁇ -pyrimidine-2,4 diamine
  • Example 29 [3- (1- ⁇ 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ piperidin-4-ylamino-methyl) -ethyl] -phosphonic acid diethyl ester
  • Step 1 [2- (1-Benzylpiperidin-4-ylamino) -ethyl] -phosphonic acid diethyl ester
  • Stage 3 [2- (Methyl-piperidin-4-yl-amino) -ethyl] -phosphonic acid diethyl ester
  • Step 4 [3- (1- ⁇ 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ piperidin-4-ylamino-methyl) -ethyl] -phosphonic acid diethyl ester
  • Example 30 [2- (1- ⁇ 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-ylamino) -ethyl] -phosphonic acid diethyl ester
  • Step 1 ⁇ 2 - [(1-Benzyl-piperidin-4-yl) -tert-butoxycarbonyl-amino] -ethyl ⁇ -phosphonic acid diethyl ester
  • CH3CN a solution of 3.4 g of piperidine obtained in Step 1 of Example 29 in CH3CN (20 mL) was added dropwise 2 g of BOC2O dissolved in CH3CN (16 mL) and stirred 18 hours at RT. It is concentrated to dryness and chromatographed (Al 2 O 3) and eluted with DCM / AcOEt (v / v; 1/1) to give 3 g of expected product.
  • Step 2 [2- (tert-Butoxycarbonyl-piperidin-4-yl-amino) -ethyl] -phosphonic acid diethyl ester
  • Step 3 [2- (1- ⁇ 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-ylamino) -ethyl] -phosphonic acid diethyl ester
  • 800 mg of difluorinated derivative of Procedure 2b and 880 mg of compound obtained in Stage 2 make it possible to obtain 1.3 g of an intermediate compound which undergoes a decarboxylation reaction for given 1 g of the expected compound.
  • Example 31 [2- (1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-ylamino) -ethyl] -phosphonic acid diethyl ester
  • Example 32 (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino)] pyrimidin-2-ylamino] -benzenesulfonyl) -piperidin-4-yl) - (3-fluoro-pyridin-4-yl) -methanol
  • Stage 1 (3-fluoro-pyridin-4-yl) -piperidin-4-yl-methanol
  • a cold solution (-90 ° C.) of 1.82 g of 3- fluoropyridine in 50 ml of THF
  • 12 ml of LDA (I.8 M) are added.
  • the solution is stirred under nitrogen for 30 minutes while maintaining the same temperature.
  • a solution of 2 g of 4-carboxaldehyde-piperidine-1-carboxylic acid tert-butyl ester in 22 mL of THF is added slowly keeping the temperature below -70 ° C.
  • the reaction mixture is stirred at this temperature for 30 minutes. minutes.
  • Step 2 (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) - (3-fluoro-pyridin-4-) yl) -methanol
  • Example 35 1- (1- ⁇ 4- [4- (4-Fluoro-3-methyl-1-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -2- (3-methyl) -2- pyridin-2-yl) ethanol (racemic)
  • Step 1 2- (3-Methyl-pyridin-2-yl) -1-piperidin-4-yl-ethanol
  • Example 36 (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -pyridin-4-yl-methanol (racemic )
  • Step 2 Racemic (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) pyridin-4-yl-methanol
  • Example 37 (1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzen-1-yl) -piperidin-4-yl) - (3-fluoropyridin-4-yl) -methanol (racemic)
  • Example 38 1- (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -2- (4-methyl) -2- pyridin-2-yl) ethanol (racemic)
  • Step 1 2- (4-Methyl-pyridin-2-yl) -1-piperidin-4-yl-ethanol
  • Step 2 1- (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -2- (3-methyl) -2- pyridin-2-yl) ethanol (racemic)
  • Example 39 ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - (piperidin-4-yl) - (3-fluoropyridin-4-yl) -methanol) -methanone (racemic)
  • Example 40 [4-R- (Amino-phenyl-methyl) -piperidin-1-yl] - ⁇ 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ -methanone
  • a solution containing 220 mg of phenylpiperidin-4-R-yl-methylamine commercial amine in 20 ml of a DCM / DMF mixture (v / v; 1/1) is added at room temperature in the order DIPEA (I.5 mL), BOP (360 mg), then, in a small portion over 30 minutes, 300 mg of acid obtained in procedure 2a. Stirred overnight. It is evaporated to dryness, carbonated water (K2CO3) is added and the mixture is extracted with AcOEt. After treatment, chromatography (SiO2) and elution with DCM / MeOH (v / v; 94/6) and recrystallization from DCM / iPr2O.
  • Example 42 N * 4 - (4-Fluoro-3-methyl-phenyl) -N * 2 - ⁇ 4- [3- (pyridin-3-yloxy) -piperidine-1-sulfonyl] -phenyl ⁇ -pyrimidine Racemic -2,4-diamine
  • Example 43 ⁇ 4-R- [Amino- (4-fluoro-phenyl) -methyl] -piperidin-1-yl ⁇ - ⁇ 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] - phenyl ⁇ -methanone
  • Example 45 (1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -3-pyridin-3-ylmethyl-piperidin-3-yl) -methanol (Racemic)
  • Example 46 Racemic ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) - ⁇ -trimyridin-2- ⁇ lamino] -phenyl ⁇ - (3-pyridyl-oxy-piperidin-1-yl) -methanone.
  • Stage 1 To a solution containing 18.23 g of dimethyloxosulfonium in methylide and 0.485 g of tetrabutylammonium in 150 ml of toluene, a solution of 4.5 g of sodium hydroxide in 48 ml of water is added dropwise and the reaction medium is left stirring. at 80 0 C for 3 hours. After cooling, washed with water, dried over Na 2 SO 4 and concentrated to dryness. 13 gd / epoxide is thus obtained.
  • Step 2 In a sealed tube, 1.5 g of the epoxide obtained in Stage 1 are heated at 80 ° C. for 4 hours in the presence of 1 g of pyrrolidine in 25 ml of ethanol. After usual treatment, 1.5 g of aminoalcohol are obtained which undergo a decarboxylation reaction to give the expected piperidine-4-methyl-pyrrolidine
  • Example 48 ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyridin-2-ylamino] -phenyl ⁇ - (4-pyrrolidin-1-ylmethylpiperidin-4-ol) -methanone
  • Example 79 The sulfonyl chloride of Procedure 1a, 330 mg, is suspended in 40 ml of CH 2 Cl 2. 186 mg of commercial amino alcohol (interchim BG206) are added then 0.55 ml of TEA is added and the mixture is stirred at room temperature overnight. The reaction medium is evaporated on the rotavapor and then taken up in H 2 O: 100 cm 3 and extracted with 3 ⁇ 100 cm 3 of AcOEt; the AcOEt phases are combined and evaporated with the rotavapor; Purified by prep C18 HPLC, evaporated on MeCN and freeze-dried. 152 mg of white lyophilisate are obtained.
  • Example 79, 90 and 91 are separated in chiral chromatography as in Example 32, to give respectively the following enantiomers (of undefined absolute configuration): Examples 92 &93; Examples 94 &95; Examples 96 & 97.
  • the rotational powers are measured using DMSO as the solvent. The concentrations are in mg / mL.
  • Example 98 The compound of Example 88 (50 mg) is dissolved in 5 ml of methanol and 10 mg of sodium borohydride are added. After one hour, 3 mg NaBH4 are added and the reaction left at room temperature for 2 hr added water and then evaporated to dryness and purified by HPLC under basic conditions. 38 mg of white powder are obtained, the expected product (example 98).
  • examples 99, 100, 101 are prepared by reducing the corresponding ketones.
  • the ketones can be obtained according to the following synthesis scheme: stage a stage b
  • This intermediate compound is itself an example of the present invention (Example 104).
  • Stage b To the amide of stage a, 2.6 g in 25 ml of methylene chloride, 25 ml of trifluoroacetic acid are added under an inert atmosphere. After 3h at room temperature, the medium is evaporated to dryness and then dissolved in methanol on a Varian Mega Bond Elut SCX cartridge. After elution with pure methanol, the expected product is then eluted with a solution of 7N ammonia in methanol. This gives 1.64 g of yellow oil after evaporation to dryness.
  • Stage E A 2.29g of N-BOC commercial isonipecotic acid in 40 ml methylene chloride is added several times, 1.78 g of imidazole carbonyl and the whole is stirred for 2.5 hours at room temperature. 1.072 g of N, O dimethoxy hydroxylamine hydrochloride is then added and the reaction is stirred at room temperature overnight. The medium is washed with water, then 0.01N HCl, then NaHCO3 and again with water. After drying, evaporation, the crude is purified on a silica cartridge with the eluent mixture of methylene chloride / ethyl acetate 9/1 and 8/2. 2.67 g of the expected product are obtained.
  • Example 105 (1- ⁇ [4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ piperidin-4-yl) (pyridin-3-yl) methanamine
  • the ketone, 290.1 mg, is dissolved in 20 ml of ethanol. 208.3 mg of commercial hydroxylamine hydrochloride are added as well as 409.7 mg of NaAcO. The resulting fine suspension is stirred at RT overnight. The reaction mixture is evaporated under reduced pressure using the rotavapor and then taken up in H 2 O: 30 ml and extracted with 3 ⁇ 20 ml of AcOEt; The AcOEt phases are combined and evaporated on the rotavapor. Purified by flash chromatography eluting the product on a cartridge of 90 g of Merck silica (15-40 microM) by a CH2Cl2 / CH3OH gradient.
  • Stage 2 tert-butyl 4- [amino (pyridin-3-yl) methyl] piperidine-1-carboxylate
  • EtOH a solution in 2 ml of EtOH
  • 2 ml of glacial acetic acid a solution in 2 ml of water
  • 171.3 mg of Zinc powder are added to the solution obtained.
  • the suspension is shaken by ultrasound overnight.
  • the reaction mixture was evaporated on a rotary evaporator, under reduced pressure and then taken up in methanol and the methanolic solution was deposited on a 10 g Varian SCX bonded Bond cartridge previously conditioned with MeOH.
  • elution with a CH 3 OH / NH 3 (2N) solution and then evaporating in a rotavapor, under reduced pressure gives 123 mg of a white powder. corresponding to the expected product.
  • Step 3 1-Piperidin-4-yl-1-pyridin-3-ylmethanamine
  • the compound obtained in Step 2, 234 mg, is dissolved in 5 ml of DCM, 3 ml of CF3CO2H are added.
  • the clear yellow solution obtained is stirred for 2 hours at RT and then evaporated in a rotary evaporator under reduced pressure.
  • Step 4 (1 - ⁇ [4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ piperidin-4-yl) (pyridin-3-yl) methanamine
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-fluoro-phenyl) -amine
  • stirring is added mL of 4-fluoroaniline followed by 18 mL of diisopropylethylamine.
  • the reaction mixture is stirred under reflux for 2 hours.
  • the reaction medium is cooled and concentrated to dryness.
  • a solution of K 2 CO 3 was added to the residue and extracted 3 times with ethyl acetate, washed with saturated NaCl solution and dried (Na 2 SO 4).
  • Step 3 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-fluoro-3-methylphenyl) -amine
  • Step 2 N-4- (4-Fluoro-3-methyl-phenyl) -N-2-phenylpyrimidine-2,4-diamine
  • Example 108 1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -4-pyrrolidin-1-ylmethylpiperidin-4-ol
  • Example 109 1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -4-pyrrolidin-1-ylmethyl-piperidin-4-ol
  • the procedure is as for example 108 from 500 mg of the sulfonyl chloride hydrochloride described in procedure Ib and 359 mg of amine described in procedure 2, 210 mg of expected product is obtained.
  • Example 111 Pharmaceutical Composition
  • Examples 6 and 105 are taken as examples in the pharmaceutical preparations which constitute Examples 110 and 111 above, this pharmaceutical preparation can be carried out differently as indicated above and if desired with other products in examples in this application.
  • IKK1 and IKK2 The compounds are tested for the inhibition of IKK1 and IKK2 using a flash-supported kinase test.
  • the compounds to be tested are dissolved at 10 mM in DMSO and then diluted in kinase buffer (50 mM Tris, pH 7.4 containing 0.1 mM EGTA, 0.1 mM sodium orthovanadate and 0.1% p-mercaptoethanol).
  • Serial 3-to-3 dilutions are made from this solution. 10 .mu.l of each dilution are added to the wells of a 96-well plate in duplicate. 10 ⁇ l of kinase buffer is added to the control wells which will serve as 0% inhibition and 10 ⁇ l of 0.5 mM EDTA is added to the control wells (100% inhibition). 10 ⁇ l of the IKK1 or IKK2 mixture (0.1 ⁇ g / well), 25-55 IKB-biotinylated substrate peptide and BSA (5 ⁇ g) are added to each well.
  • the wells are washed twice with a solution of 50 mM Tris-EDTA pH7.5 and the radioactivity determined on a microbeta counter.
  • the compounds of the invention tested in this test show an IC50 of less than 10 ⁇ M, which shows that they can be used for their therapeutic activity.
  • the compounds according to the invention have been the subject of pharmacological tests for determining their anticancer activity.
  • MDA-MB231 American type culture collection, Rockville, Maryland, USA, ATCC-HTB26
  • MDA-A1 or MDA-ADR known as MDR-resistant multi-drug line, and described by E.Collomb et al. in Cytometry, 12 (1): 15-25, 1991
  • MCF7 ATCC-HTB22
  • prostate cancer DU145 (ATCC-HTB81) and PC3 (ATCC-CRL1435),
  • HCT116 ATCC-CCL247
  • HCT15 ATCC-CCL225
  • H460 (described by Carmichael in Cancer Research 47 (4): 936-942, 1987 and issued by the National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland, USA), - glioblastoma ( SF268 described by Westphal in Biochemical & Biophysical Research Communications 132 (1): 284-289, 1985 and issued by the National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland, USA), Leukemia (CMLT1 described by Kuriyama et al., in Blood, 74: 1989, 1381-1387, by Soda et al in British Journal of Haematology, 59: 1985, 671-679 and by Drexler, in Leukemia Research, 18: 1994, 919-927 and issued by the company DSMZ, Mascheroder Weg Ib, 38124 Braunschweig, Germany).
  • CMLT1 described by Kuriyama et al., in Blood, 74: 1989, 1381-1387, by Soda et al in British Journal of Haematology,

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WO2011107494A1 (de) 2010-03-03 2011-09-09 Sanofi Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2012004269A1 (de) 2010-07-05 2012-01-12 Sanofi ( 2 -aryloxy -acetylamino) - phenyl - propionsäurederivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
WO2012004270A1 (de) 2010-07-05 2012-01-12 Sanofi Spirocyclisch substituierte 1,3-propandioxidderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
WO2012010413A1 (de) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylen-substituierte hydroxy-phenyl-hexinsäuren, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US10227342B2 (en) 2014-06-19 2019-03-12 Ariad Pharmaceuticals, Inc. Heteroaryl compounds for kinase inhibition
CN114621206A (zh) * 2022-03-24 2022-06-14 安徽医科大学 一种5-取代的嘧啶二胺类衍生物及其制备方法与应用
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US12084431B2 (en) 2018-05-14 2024-09-10 Takeda Pharmaceutical Company Limited Pharmaceutical salts of pyrimidine derivatives and method of treating disorders

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KR20130031296A (ko) 2010-05-21 2013-03-28 케밀리아 에이비 신규한 피리미딘 유도체
DK2688883T3 (en) 2011-03-24 2016-09-05 Noviga Res Ab pyrimidine
KR20210043637A (ko) * 2018-08-14 2021-04-21 메이 파마, 아이엔씨. 재발성 여포성 림프종의 치료

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WO2006133426A2 (en) * 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2007006926A2 (fr) * 2005-07-11 2007-01-18 Sanofi-Aventis Nouveaux derives de 2,4-dianilinopyrimidines, leur preparation, a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk

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WO2001064654A1 (en) * 2000-03-01 2001-09-07 Astrazeneca Ab Pyrimidine compounds
WO2006133426A2 (en) * 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2007006926A2 (fr) * 2005-07-11 2007-01-18 Sanofi-Aventis Nouveaux derives de 2,4-dianilinopyrimidines, leur preparation, a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (de) 2010-03-03 2011-09-09 Sanofi Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung
WO2012004269A1 (de) 2010-07-05 2012-01-12 Sanofi ( 2 -aryloxy -acetylamino) - phenyl - propionsäurederivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
WO2012004270A1 (de) 2010-07-05 2012-01-12 Sanofi Spirocyclisch substituierte 1,3-propandioxidderivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
WO2012010413A1 (de) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylen-substituierte hydroxy-phenyl-hexinsäuren, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
US10227342B2 (en) 2014-06-19 2019-03-12 Ariad Pharmaceuticals, Inc. Heteroaryl compounds for kinase inhibition
US11958850B2 (en) 2014-06-19 2024-04-16 Takeda Pharmaceutical Company Limited Heteroaryl compounds for kinase inhibition
US12084431B2 (en) 2018-05-14 2024-09-10 Takeda Pharmaceutical Company Limited Pharmaceutical salts of pyrimidine derivatives and method of treating disorders
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
CN114621206A (zh) * 2022-03-24 2022-06-14 安徽医科大学 一种5-取代的嘧啶二胺类衍生物及其制备方法与应用
CN114621206B (zh) * 2022-03-24 2023-11-24 安徽医科大学 一种5-取代的嘧啶二胺类衍生物及其制备方法与应用

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