EP2118092A1 - NEUE N,Ný-2,4-DIANILINPYRIMIDIN-DERIVATE, IHRE HERSTELLUNG ALS ARZNEIMITTEL, PHARMAZEUTISCHE ZUSAMMENSETZUNGEN DARAUS UND IHRE VERWENDUNG ALS IKK-HEMMER - Google Patents

NEUE N,Ný-2,4-DIANILINPYRIMIDIN-DERIVATE, IHRE HERSTELLUNG ALS ARZNEIMITTEL, PHARMAZEUTISCHE ZUSAMMENSETZUNGEN DARAUS UND IHRE VERWENDUNG ALS IKK-HEMMER

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Publication number
EP2118092A1
EP2118092A1 EP08750461A EP08750461A EP2118092A1 EP 2118092 A1 EP2118092 A1 EP 2118092A1 EP 08750461 A EP08750461 A EP 08750461A EP 08750461 A EP08750461 A EP 08750461A EP 2118092 A1 EP2118092 A1 EP 2118092A1
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EP
European Patent Office
Prior art keywords
formula
products
radicals
optionally substituted
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP08750461A
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English (en)
French (fr)
Inventor
Didier Babin
Monsif Bouaboula
Pierre Casellas
Maria Mendez-Perez
Serge Mignani
Jean-Flaubert Nguefack
Jacob-Alsboek Olsen
Bernard Tonnerre
Jean Wagnon
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Sanofi Aventis France
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Sanofi Aventis France
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Publication of EP2118092A1 publication Critical patent/EP2118092A1/de
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 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

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 represents a hydrogen or halogen atom
  • 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 6 - ⁇ following alternatives i) to vi): i) R1 represents -X1-R7 with X1 represents - (CH2) m- and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; and R6 is hydrogen, or hydroxyl, methyl, methoxy, - (CH2) mOH, -CO-NRaRb, -CH2-NraRb, -CO2H, and -CO2alk;
  • 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 R6 represents hydrogen; it being understood that when W represents a hydrogen atom then z represents CO;
  • 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 by a radical chosen from - PO (OEt) 2, -OH, -OEt, -CF3, -CO- N (alk) 2 and SO2-alk; and R6 represents hydrogen;
  • R1 represents -CO-N (Rc) -OR 'c and R6 represents hydrogen
  • R1 represents X3-R7 with X3 represents -CH (OH) -
  • R7 represents a heterocycloalkyl, aryl, or heteroaryl ring, all optionally substituted; and R6 represents hydrogen atom or hydroxyl, methyl, methoxy, - (CH2) mOH, -CO-NRaRb, -CH2-
  • NRaRb and -C02alk 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, identical or different, represent the hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms optionally substituted with one or more halogen atoms;
  • 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 by one or more atoms halogen, 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 or NR10, the
  • 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 represented by R 9 being furthermore optionally substituted by a phenyl, heterocycloalkyl or heteroaryl radical, themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy
  • the subject of the present invention is in particular the products of formula (I) as defined above in which R 2, R 3, R 4, R 5, Z and the ring (N) as well as R 1 and R 6 have the meanings indicated above or hereinafter and R represents a halogen atom; 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).
  • R has the definition indicated above or below, R2, R3 and R4, which are identical or different, are such that one represents a halogen atom or CF3 and the other two, 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;
  • Z represents CO or SO2; cycle (N) is being substituted on the same carbon atom by R1 and R6, containing 4 to 7 members, being saturated and may additionally contain a carbon bridge consisting of 1 to 3 carbons, it being understood that 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 - CO2alk;
  • 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 R6 represents hydrogen; it being understood that when W represents a hydrogen atom then z represents CO;
  • 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 by a radical chosen from - PO (OEt) 2, -OH, -OEt, -CF3, -CO- N (alk) 2 and SO2-alk; and R6 represents hydrogen;
  • R1 represents -CO-N (Rc) -OR 'c and R6 represents hydrogen
  • 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 by one or more atoms of halogen, 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 or NR
  • heterocycloalkyl, aryl 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 heteroaryl radicals, themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, radicals, CF3, OCF3, or NRaRb;
  • 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 represented by R 9 being furthermore optionally substituted by a phenyl, heterocycloalkyl or heteroaryl radical, themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy
  • the present invention thus relates to the products of formula (I) as defined above in which R, R2, R3, R4, R5, Z and the ring (N) have the meanings indicated above or below.
  • R 1 and R 6 are such that R 1 represents -X 1 -R 7 with X 1 represents - (CH 2) m - and R 7 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 - 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
  • R1 and R6 are such that: either 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 by a a radical chosen from -PO (OEt) 2, -OH, -OaIk, -CF3, -CO-NR8R9 and SO2-alk and R6 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-
  • the ring formed can in particular be the 8-aza bicyclo (3,2,1) octyl cycle) or else a ring chosen from the following: azabicyclo [3.3.1] nonan-3-yl, 6 azabicyclo [3.2.1] octan-3-yl, 3-azabicyclo [3.2.1] octan-8yl or else 3-azabicyclo [3.3.1] nonan-9-yl.
  • the present invention thus relates to the products of formula (I) as defined above in which R, R2, R3, R4, R5 and Z have the meanings indicated above or below and the cycle (N). represents a pyrrolidinyl ring substituted at 3 by R1 and R6 as defined above or hereinafter or a piperidinyl ring substituted in position 3 or 4 by R1 and R6 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 (I).
  • halogen denotes 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, neo-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and that their linear or branched position 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 from 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
  • pyridyl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyridyl N-oxide, pyrimidinyl, pyridazinyl and pyrazinyl radicals; among the fused heteroaryl radicals containing at least one heteroatom selected from sulfur, nitrogen and oxygen, mention may be made, for example, of benzothienyl, benzofuryl, benzofuranyl, benzoxazolyl, indazolyl, indolyl, indolinyl, indolinonyl, quinolyl and isoquinolyl radicals, azaindolyl, benzimidazolyl, benzothiazolyl, naphthyridinyl such as [1, 8] naphthyridinyl; imidazo (4,5) pyridinyl; indolizinyl; quinazoliny
  • heterocycloalkyl saturated for example, oxiranyl, oxetanyl, tetrahydrofuranyl, dioxolanyl, dithiolanyl, tetrahydropyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, diazepinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxydothiomorpholinyl and imidazolidinyl radicals may be mentioned; more particularly the pyrrolidinyl, piperidinyl, azepinyl, piperazinyl or morpholinyl radicals; all the cyclic radicals being optionally substituted as indicated above or hereinafter.
  • 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 radical 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, cyclopentylamino or cyclohexylamino radicals.
  • 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.
  • 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 2503-2507: these esters include, in particular, substituted (aminomethyl) -benzoates, dialkylamino-methylbenzoates in which the two alkyl groups can be bonded together or can be interrupted by an oxygen atom or a hydrogen atom.
  • optionally substituted nitrogen is an alkylated nitrogen atom or else morpholino-methyl) benzoates, eg 3- or 4- (morpholinomethyl) -benzoates, and (4-alkylpiperazin-1-yl) benzoates, eg 3- or 4- (4-alkylpiperazin-1-yl) benzoates.
  • morpholino-methyl eg 3- or 4- (morpholinomethyl) -benzoates
  • (4-alkylpiperazin-1-yl) benzoates eg 3- or 4- (4-alkylpiperazin-1-yl) benzoates.
  • these acid salts are also part of the invention. There may be mentioned, for example, the salts provided with hydrochloric or methanesulphonic acids.
  • the addition salts with the mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric acids, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulphonic acid, alpha, beta-ethanedisulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid and aryldisulphonic acids.
  • hydrochloric acids hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic,
  • 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 attached substituents, either on double bonds or on rings, often referred to as E / Z geometrical isomerism or cis-trans or diastereoisomeric isomerism.
  • the term stereoisomer is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • the present invention particularly relates to the products of formula (I) as defined above or below in which: R has the definition indicated above or below,
  • 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;
  • R 1 and R 6 represent one of the following alternatives: i) to v) i) R 1 represents -X 1 -R 7 with X 1 represents -CH 2 and R 7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted; and R6 represents hydrogen atom or hydroxyl radicals, -CH2OH, -CO2H, -CO-NRaRb and -CO2Et;
  • R7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted, and R6 represents hydrogen;
  • R1 represents -NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms optionally substituted with a radical chosen from -PO (OEt) 2, -OH, - Et3, -CF3, -CO-NR8R9 and SO2-alk; and R6 represents hydrogen; it being understood that when W represents a hydrogen atom then z represents CO;
  • R1 represents -CH2-NRc-W with W represents the atom hydrogen or an alkyl radical containing 1 to 4 carbon atoms linear or branched from 3 carbon atoms and optionally substituted with a radical SO2-alk; and R6 represents hydrogen;
  • R1 represents -CO-N (Rc) -OR 'c and R6 represents hydrogen
  • 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
  • NR8R9 is such that either R8 and R9, identical or different, are such that R8 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 (alk) 2; or R8 and R9 form with the nitrogen atom
  • the subject of the present invention is particularly the products of formula (I) as defined above or below in which R, R2, R3, R4, R5 and Z have the meanings indicated above or below.
  • 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 inorganic and organic acids of said formula products
  • the present invention thus relates to the products of formula (I) as defined above in which R, Z, the ring (N), R1 and R ⁇ have the meanings indicated above or below; R2, 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 radical, methoxy, trifluoromethyl or trifluoromethoxy; and R5 represents a hydrogen atom; 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
  • the subject of the present invention is thus the products of formula (I) as defined above in which R, 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 a hydrogen atom; 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, R1, R2, R3, R4, R5, R6 and the ring (N) have the meanings indicated above or below. after Z and Z represents SO 2, said products of formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral 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, R1, R2, R3, R4, R5, R6 and the ring (N) have the meanings indicated above or below. after Z represents CO, 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 (I).
  • 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 by one or more identical or different radicals chosen from halogen atoms and the alkyl radicals themselves optionally substituted with one or several halogen atoms.
  • radicals which may be identical or different, chosen from halogen atoms; NR8
  • NR 8 R 9 may in particular be such that either R 8 and R 9, which are identical or different, are such that R 8 represents the hydrogen atom, a linear or branched alkyl radical containing at least plus 4 carbon atoms or a cycloalkyl radical containing 3 to 6 members, alkyl and cycloalkyl themselves optionally substituted by a or more than one halogen atom 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 (
  • R1, R2, R3, R4, R5, Z and the ring (N) have the meanings indicated above or below.
  • R1 and R6 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:
  • R6 represents hydrogen
  • 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 by one or more identical
  • 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) as 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 that, to obtain or of other products of formula (I), it is possible to subject, if desired and if necessary, to one of or several of the following transformation reactions, in any order: a) an alkylthio group oxidation reaction to the corresponding sulfoxide or sulfone, b) an alkoxy function conversion reaction to a hydroxyl function, or a hydroxyl function in alkoxy function, c) an oxidation reaction of alcohol function as an aldehyde or ketone function, d) an elimination reaction of the protective groups that can carry the protected reactive functions, e) a salification reaction with a mineral or organic acid for to obtain the corresponding salt, f) a resolving reaction of the racemic
  • 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.
  • an alcohol such as for example butanol, propanol, ethanol or dimethylformamide between 80 and 140 0 C
  • 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 of formula in particular 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 SO2 and z represents CO, or can 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.
  • reactions of transformation a) to f) of substituents in other substituents can also be carried out on the starting materials as well as on the intermediates as defined above before continuing the synthesis according to the reactions indicated in the processes above.
  • the hydroxyl groups may be protected, for example, by 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, phthalimido radicals or other radicals known in the peptide chemistry: the amino functions may in particular be protected by a group such as than Boc or CH 2 -phenyl and can then be released under the usual conditions known to man of career .
  • the saponification reactions can 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.
  • the optional alkylthio groups of the products described above may, if desired, be converted into the corresponding sulfoxide or sulfone functions under the usual conditions known to those skilled in the art, such as, for example, peracids, such as, for example, peracetic or metachloroperbenzoic acid or alternatively by oxone, sodium periodate in a solvent such as for example methylene chloride or dioxane at room temperature.
  • peracids such as, for example, peracetic or metachloroperbenzoic acid or alternatively by oxone, sodium periodate in a solvent such as for example methylene chloride or dioxane at room temperature.
  • Obtaining the 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 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 methylene chloride, for example, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or refluxing trifluoroacetic acid.
  • (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 commercial products for example by subjecting them to one or more reactions known to the human being. 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) may in particular be commercial anilines such as, for example, the following trihalogenated anilines: -3,4,5-trifluoroaniline -2,3,4-trifluoroaniline -2-chloro-4,6-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:
  • aldehydes or ketones of formula (X) are given in the experimental part by way of non-limiting examples.
  • 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 bowel disease 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, ovarian diseases polycystic diseases, hypertension, cardiovascular disorders, Syndrome X, autoimmune diseases such as in particular systemic lupus, lupus erythematosus, 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, but not limited to, chronic anemia and aplastic anemia, degenerative diseases of the musculoskeletal system such as, but not limited to, osteoporosis, cystic fibrosis, kidney
  • 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.
  • vascular smooth muscle cells angiogenesis and in rheumatoid arthritis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, restenosis following angioplasty or vascular surgery, formation of hypertrophic scars, angiogenesis and endotoxic shock.
  • these drugs find their therapeutic use, especially in the treatment or prevention of diseases caused or exacerbated by the proliferation of cells and in particular tumor cells.
  • 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, the small intestine, colon and rectal cancer, cancer of the respiratory tract, 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
  • 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, 6-thioguanine; inhibitors of pyrimidine synthesis, aromatase
  • 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, anti-cachexia.
  • 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
  • the present invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier.
  • the subject of the present invention is also the pharmaceutical compositions containing as active principle 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 thereof . 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 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 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 relates particularly to the products of formula (I) as defined above which are examples 1 to 260 of the present invention.
  • Procedure 1 Preparation of the sulfonyl chloride hydrochlorides
  • Procedure la 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-fluoro-phenyl) -amine
  • Step 2 N-4- (4-Fluoro-phenyl) -N-2-phenyl-pyrimidine-2,4-diamine
  • 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
  • Step 1 4-Chloro-N- (3,4-difluorophenyl) pyrimidin-2- Amine
  • Step 2 N4- (3,4-Difluoro-phenyl) -N2-phenyl-pyrimidine-2,4-diamine
  • 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 the above stage with chlorosulphonic acid gives 9 g of 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 2 (5-Fluoro-N * 4 - (4-fluoro-phenyl) -N * -2-phenylpyrimidine-2,4-diamine
  • Step 3 4- [5-Fluoro-4- (4-fluoro-3-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl hydrochloride
  • Procedure 1 4- [5-Fluoro- 4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride
  • the preparation of this compound is carried out according to the same procedures as in the Procedure Ib replacing 4-fluorophenylamine with 4-fluoro-3-methylphenylamine.
  • 4-fluoro-3-methyl-phenylamine and 6 g of 2,4-dichloro-5-fluoropyrimidine 11 g of the expected hydrochloride are obtained.
  • Procedure 2a 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzoic acid
  • Step 1 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzoic acid methyl ester
  • Procedure 2b 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzoic acid
  • Step 1 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidine -
  • 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
  • stage 2 of procedure 1 starting from 4.6 g.
  • Step 3 4- [4- (4-Trifluoromethyl-phenylamino) -pyrimidin
  • 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 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
  • the compound obtained in Stage 1 is dissolved in MeOH and then treated with 35 mL Et2O / 2N HCl overnight.
  • the hydrochloride is filtered off, redissolved in water, basified with solid K2CO3 and extracted with AcOEt. After washing with water and drying on Na 2 SO 4 of the organic phase, 2.25 g of a powder is obtained by evaporation of the solvent.
  • MH + 471.3
  • Step 1 1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-3-ylmethyl) carbamicacidtert-butyl ester (Racemic;
  • step 1 of procedure 3a from 4 g of sulfonyl chloride hydrochloride obtained in procedure la and 3.43 g of the racemic commercial amine piperidin-3-ylmethyl-carbamic acid tert- butyl ester, 2.7 g of expected product are obtained.
  • stage 2 of procedure 3a According to the decarboxylation reaction described in stage 2 of procedure 3a, from 2.7 g of the product obtained in stage 1, 2.3 g of expected product are obtained.
  • 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-Amino-pyrrolidine-1-sulfonyl) phenyl] -N-4- (4-fluoro-phenyl) -pyrimidine-2,4-diamine
  • 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 tetrabutylammonium 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 6 g of epoxide obtained in Step 1 are put in a solution of ammonia-saturated MeOH. And heated for 72 hours in sealed tube. It is concentrated under vacuum and purified on an alumina column (gradient DCM-MeOH: v / v, 9/1). 5.3 g of aminoalcohol is obtained.
  • Stage 3 (1-Benzyl-4-hydroxy-piperidin-4-ylmethyl) -carbamic acid tert-butyl ester 5.3 g of aminoalcohol obtained in stage 2 in solution in DCM is treated with 5.2 g of BOC2O dissolved in DCM and stirred for 15 minutes at RT.
  • 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 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 3h N-2- [4- (4-Amino-piperidine-1-sulfonyl) -phenyl] -N-4- (3,4-difluoro-phenyl) -pyrimidine-2,4-diamine (Racemic)
  • step 1 of procedure 3a from 5 g of sulfonyl chloride hydrochloride obtained in procedure Ib and 2.41 g of 4-N-boc -4-aminopiperidine, 2.9 g of a compound which undergoes a decarboxylation reaction to give 2.9 g of the expected sulfonamide.
  • step 1 of procedure 3a from 5.8 g of sulfonyl chloride hydrochloride obtained in procedure Ic and 2,996 g of 3-boc-aminomethyl-piperidine, 4.1 g of a compound are obtained. which undergoes a decarboxylation reaction to give 2.2 g of expected sulfonamide.
  • Step 1 (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzoyl ⁇ -piperidin-4-yl) -methyl-carbamic acid tert-butyl ester.
  • stage 1 The product obtained in stage 1 is dissolved in 40 ml of MeOH. 40 ml of Et2O 2 N are added at ambient temperature and the mixture is left stirring for 6 hours. After evaporation to dryness, the residue is triturated in Et 2 O and filtration of the suspension generates 3.3 g of the expected product hydrochloride.
  • the hydrochloride is dissolved in water and basified with solid potassium carbonate. The extraction of this aqueous phase is done with ethyl acetate containing a little THF. After washing and drying, the organic phase over Na 2 SO 4 is evaporated to dryness and recrystallized from a DCM-iPr 2 O mixture to obtain 2.25 g of the expected product.
  • MH + 435.2
  • Step 1 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - (3-methylamino-piperidin-1-yl) -methanone (Racemic)
  • 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
  • Step 2 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - (4-methylamino-piperidin-1-yl) -methanone
  • 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
  • Step 2 4-Hydroxy-4-pyrrolidin-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester
  • Procedure 5b 4- (2-methyl-Pyrrolidin) -1-ylmethylpiperidin-4-ol
  • the synthesis of this compound is carried out according to the scheme described in Procedure 5a by replacing pyrrolidine with 2-methylpyrrolidine in step 2.
  • Procedure 5c 4- (3-methyl-Pyrrolidin) -1-ylmethylpiperidin-4-ol The synthesis of this compound is carried out according to the scheme described in Procedure 5a by replacing pyrrolidine with 3-methylpyrrolidine in step 2.
  • Procedure 5d 4- (2-iR-methyl-Pyrrolidin) -1-ylmethylpiperidin-4-ol
  • the synthesis of this compound is carried out according to the scheme described in procedure 5a by replacing pyrrolidine with 2- methylpyrrolidine in the stage
  • Example 1 ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-yl-amino] -phenyl ⁇ - [4- (methyl- [1,2,3] thiadiazol-4-ylmethyl) amino) -piperidin-1-yl] - methanone
  • Example 2 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - ⁇ 4- [methyl- (1H-pyrazol-4-ylmethyl) -amino] -p-peridin-1 yl ⁇ methanone
  • 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 9 ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - [3- (aminothiazol-2-ylmethylamino) -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) -methylamino] - 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 dimethylamide (Racemic)
  • Stage 1 660 mg of KOH are 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- Fluoro-phenylamino) -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-methylamino-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 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 and stirring is continued 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-ylmethyl) - 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
  • Step 2 ⁇ 2 - [(1-Benzylpiperidin-4-yl) -methylamino] -ethyl ⁇ -phosphonic acid diethyl ester
  • NaBH (OAC) 3 1.6 g
  • Step 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
  • Step 2 [2- (tert-Butoxycarbonyl-piperidin-4-yl-amino) -ethyl] -phosphonic acid diethyl ester Refluxed in EtOH (25 mL), a mixture of compound obtained in Step 1 (3 g) and palladium hydroxide on charcoal. After 2h30 reflux, filtered and concentrated to obtain 2.2 g of expected compound.
  • 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 reaction of decarboxylation to give 1 g of the expected compound.
  • Example 31 [2- (1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-ylamino) -ethyl] -phosphoic 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
  • 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-phenylamino) -pyriitidin-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
  • Step 2 1- (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -2-
  • Example 36 (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -pyridin-4-yl-methanol (racemic)
  • Example 37 (1- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -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 According to the procedure described in Step 1 of the Example
  • Step 2 1- (1- ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl) -2-
  • 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. Evaporate to dryness, add carbonated water (K2CO3) and extract by 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 44 ⁇ 4-S- [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
  • Example 46 Racemic ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino] -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 g of epoxide are thus obtained
  • Stage 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
  • Stage 3 Following the procedure described in Step 1 of Procedure 3a, from 500 mg of sulfonyl chloride hydrochloride of Procedure la and 370 mg of piperidine obtained in stage 2, 140 mg of expected sulfonamide are obtained.
  • Example 48 ⁇ 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -phenyl ⁇ - (4-pyrrolidin-1-ylmethylpiperidin-4-ol) -methanone
  • reaction of the acid of procedure 4a with the commercial aldehydes (or ketones) the following products (30 examples in the table below which are Examples 50 to 78 of US Pat. present invention) are obtained by adapting the procedure according to the procedure below.
  • a solution of 0.12 mmol of adheyde in 1.0 mL of THF and 0.3 mL of AcOH is added.
  • 128 mg of polymer bearing CNBH3 are added and the mixture is stirred under argon atmosphere overnight at RT.
  • the reaction mixture is filtered, the filtrate is washed with 5 ml of THF and concentrated in vacuo.
  • the reaction crude is dissolved in 2 ml of DMF and purified by preparative HPLC to give the expected product described as trifluoroacetic acid salt.
  • 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.
  • Rotatory 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.
  • ketones can be obtained according to the following synthesis scheme:
  • Stage c To 2.06 g of amide compound of stage b in 46 ml of methylene chloride and 3.3 ml of triethylamine are added several times 1.21 g of sulfonyl chloride of procedure Ib. After 2 hours at room temperature, the reaction medium is evaporated to dryness and the white solid obtained is rinsed twice with 30 ml of methylene chloride to give after drying 2.08 g of expected white solid.
  • This intermediate compound is itself an example of the present invention (Example 104).
  • stage a To the amide of stage a, 2.6 g in 25 ml of methylene chloride are added 25 ml of trifluoroacetic acid 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.
  • Example 105 (1 - ⁇ [4- ( ⁇ 4- [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ piperidin-4-yl) (pyridin-3-yl) methanamine
  • Stade 1 tert-butyl 4- [(hydroxyimino) (pyridin-3-yl) methyl] piperidine-1-carboxylate
  • 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 rotary evaporator and then taken up in H 2 O: 30 ml and extracted by 3 x 20 ml of AcOEt; The AcOEt phases are combined and evaporated on the rotavapor.
  • Step 2 tert-butyl 4- [amino (pyridin-3-yl) methyl] piperidine-1-carboxylate
  • 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
  • the products of Examples 106 and 107 are obtained from the compound of Procedure la and the commercial amines (R) -Phenyl-1-piperidin-4 respectively. methanamine and (S) -Phenyl-1-piperidin-4-methanamine.
  • Examples 181 to 260 are synthesized from the corresponding sulfonyl chloride chlorides la-d with the amines described in procedures 5a-f.
  • Tablets having the following formula were prepared: Product of Example 6 0.2 g Excipient for a tablet finished at I g
  • Examples 6 and 105 are taken as examples in the pharmaceutical preparations which constitute Examples 108 and 109 above, this pharmaceutical preparation being able to be carried out differently as indicated above and if desired with other products in examples in this application.
  • IKK2 using a kinase test on flash-plate support.
  • 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).
  • 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.
  • the compounds of formula (I) according to the present invention have been tested in vitro on a panel of tumor lines of human origin originating from:
  • MDA-MB231 American type culture collection, Rockville, Maryland, USA, ATCC-HTB26
  • MDA-A1 or MDA-ADR referred to as MDR-resistant multi-drug line, and described by E.Collomb et al. in Cytometry, 12 (1): 15-25, 1991
  • MCF7 ATCC-HTB22
  • DU145 ATCC-HTB81
  • 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),
  • CLT1 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).

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EP08750461A 2007-01-05 2008-01-02 NEUE N,Ný-2,4-DIANILINPYRIMIDIN-DERIVATE, IHRE HERSTELLUNG ALS ARZNEIMITTEL, PHARMAZEUTISCHE ZUSAMMENSETZUNGEN DARAUS UND IHRE VERWENDUNG ALS IKK-HEMMER Withdrawn EP2118092A1 (de)

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FR2911138B1 (fr) 2009-02-20
CL2008000020A1 (es) 2009-01-23
WO2008099073A1 (fr) 2008-08-21
US20100093668A1 (en) 2010-04-15
AR064730A1 (es) 2009-04-22
CN101605783A (zh) 2009-12-16
FR2911138A1 (fr) 2008-07-11
UY30857A1 (es) 2008-09-02
CA2672959A1 (fr) 2008-08-21
JP2010514821A (ja) 2010-05-06

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