FR2888239A1 - New 2,4-dianilinopyrimidine derivatives are kappa B kinase inhibitors, useful to treat or prevent e.g. inflammatory diseases, diabetes, cancer resistant to cytotoxic agents, solid or liquid tumors and in cancer chemotherapy - Google Patents

Abstract

2,4-Dianilinopyrimidine derivatives (I) and their isomers, enantiomers, diastereomers and addition salts with mineral and organic acids, are new. 2,4-Dianilinopyrimidine derivatives of formula (I) and their isomers, enantiomers, diastereomers and addition salts with mineral and organic acids, are new. R2-R4 : halo, H, alkyl or alkoxy; R5 : H or halo; R1 : alkyl (optionally substituted by 5 membered heterocyclic radical (optionally substituted by halo, alkyl or alkoxy) or T), cycloalkyl, alkenyl, alkynyl (all optionally substituted by T) or H; T : halo, OR8 or NR8R9; A : single bond, -CH 2-CO- or NR6; R6 : R1; ring Y1 : 4-8 membered ring containing Y1; Y1 : O or S (optionally oxidized by 2O, N-R7, C=O or dioxolane as protective group of carbonyl, CF 2, CH-OR8 or CH-NR8R9); R7 : alkyl (optionally substituted by phosphonate, alkylthio (optionally oxidized by sulfone or by optionally substituted heterocycloalkyl)), cycloalkyl, CH 2-alkenyl, CH 2-alkynyl (all optionally substituted by naphthyl, halo, OH, alkoxy, phenyl or heteroaryl) or H; either R8 : alkyl (optionally substituted by alkylthio, phenyl or heterocyclic group), (hetero)cycloalkyl (all optionally substituted by halo, OH, alkoxy, NH 2, NHalkyl or N(alkyl) 2); NR8R9 : cyclic amine (containing 1-2 heteroatoms e.g. O, S, N or NR10, optionally substituted by alkyl); and R10 : H or alkyl. The heterocyclic, heterocycloalkyl and heteroaryl radicals contain 4-10 membered ring and 1-3 heteroatoms e.g. O, S, N and NR10. The radicals of naphthyl, phenyl, heterocyclic, heterocycloalkyl and heteroaryl are optionally substituted by halo, OH, alkoxy, alkyl, OH-alkyl, CN, CF 3, NH 2, NHalkyl or N(alk) 2. Provided that at least one of R2-R4 is halo. Provided that when Y1 is NR7, the ring can contain a 1-3C bridging group. An independent claim is also included for the preparation of (I). [Image] ACTIVITY : Antiinflammatory; Antidiabetic; Cytostatic; Antiarthritic; Antirheumatic; Osteopathic; Ophthalmological; Uropathic; Antipsoriatic; Neuroprotective; Antiasthmatic; Respiratory-Gen.; Antiallergic; Muscular-Gen.; Immunosuppressive; Dermatological; Immunomodulator; Antibacterial; Cardiant; Antiarteriosclerotic; Anti-HIV; Anorectic; Gynecological; Hypotensive; Cardiovascular-Gen.; Analgesic; Antianginal; Nephrotropic; Virucide; Vasotropic; Cerebroprotective; Antiarrhythmic; Hepatotropic; Antianemic; Antiangiogenic. MECHANISM OF ACTION : Kappa B kinase inhibitor; Apoptosis modulator; Tumor cell proliferation inhibitor. The ability of (I) to inhibit kappa B kinase was tested using biological assays. The results showed that the IC 50 value of (I) was less than 10 mu M.

Description

R1

S "A Il o 0 ((I)

H

  NOVEL 2,4-DIANILINOPYRIMIDINE DERIVATIVES, THEIR PREPARATION AS MEDICAMENTS, COMPOSITIONS

  PHARMACEUTICALS AND IN PARTICULAR AS INHIBITORS OF IKK

  The present invention relates to novel 2,4-dianilinopyrimidine derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such 2,4-dianilinopyrimidine derivatives.

  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. . Patent 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.

  Similarly, other patents describe reverse transcriptase inhibitory pyrimidines for the treatment of HIV-related infections (WO200185700-A2; WO200185699-A2; WO200027825A1 and WO2003094920A1).

  The present invention thus relates to novel 2,4-dianilinopyrimidine derivatives having inhibitory effects on protein kinases.

  The products of the present invention can thus be used in particular for the prevention or treatment of conditions capable of being modulated by the inhibition of the activity of protein kinases. Among these protein kinases, the protein kinase IKKalpha (IKKa) and IKK-beta (IKK0) 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.

  NF-kB (Nuclear factor kappa B) belongs to a family of transcription factor complexes consisting of different combinations of Rel / NF-KB polypeptides. Members of this family of NF-κB-related polypeptides regulate the expression of genes involved in immune and inflammatory responses. Barries PJ, Karin M (1997) N Engl J Med 336, 1066-1071) and (Baeuerle PA, Baichwal VR (1997) Adv Immunol 65, 111-137)). Under basal conditions, NF-κB dimers are retained in the cytoplasmic form 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: 12811289, 1991). The proteins of the IKB family mask the NF-KB nuclear translocation signal. Stimulation of the cell by different types of ligands such as cytokines, anti-CD40 ligand, lipopolysaccharide (LPS), oxidants, mitogens such as phorbol ester, viruses as well as many other stimulants, leads to activation of the IKB-Kinase complex (IKK) which in turn will phosphorylate IKB at the serine residues 32 and 34. Once phosphorylated, IKB will be subject to ubiquitination leading to its degradation by the proteasome (26S), thus allowing the release and the translocation of NF-κB in the nucleus where it will bind to specific sequences at the level of the target gene promoters thereby inducing their transcription.

  In the IKB-Kinase complex (IKK), the main kinases are IKK1 (IKKa) and IKK2 (IKKR) which are able to directly phosphorylate the different classes of IKB. In this IKK complex, 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).

  Many of the genes regulated by NF-KB encode pro-inflammatory mediators, cytokines, cell adhesion molecules, and acute phase proteins, which in turn will induce the activation of NF-κB by autocrine or paracrine mechanisms.

  Inhibition of NF-κB activation appears to be very important in the treatment of inflammatory diseases.

  In addition NF-KB, plays a role in the growth of normal cells but also malignant cells. Proteins produced by expression of NF-κB 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-κB 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: 61636171) . In some human lymphoid tumor cells, the genes encoding the different NF-KB members are rearranged or amplified. It has been shown that NF-κB can promote cell growth by inducing transcription of cyclin D, which associated with Rb hyperphosphorylation leads to the transition of G1 to s phases and inhibition of apoptosis.

  It has been shown that in a large number of tumor cell lines, constitutive activity of NF-κB is found following the activation of IKK2. NF-κB is constitutively activated in Hodgkin's disease and the inhibition of NF-κB blocks the growth of these lymphomas. On the other hand, inhibition of NF-κB by expression of the IκBα repressor induces apoptosis of cells expressing the oncogenic H-Ras allele (Baldwin, J. Clin Invest, 107: 241 (2001), Bargou et al., J. Clin Invest, 100: 2961 (1997), Mayo et al., Science 178: 1812 (1997).

  The constitutive activity of NF-KB seems to contribute to oncogenesis through the activation of several anti-apoptotic genes such as Al / Bfi1, IEX-1, MAP, thus resulting in the suppression of the cell death pathway. Through the activation of cyclin D, NF-KB can promote the growth of tumor cells. 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-κB by the use of the super-repressor form of IκBα in parallel with chemotherapy treatment has been shown to increase the efficacy of chemotherapy in xenograft models.

  The present invention thus relates to the products of formula (I). Wherein R 2, R 3 and R 4, which may be identical or different, are such that one represents a halogen atom and the other two, which may be identical or different, represent a hydrogen atom or a hydrogen atom; halogen; R5 represents a hydrogen atom or a halogen atom; R1 represents a hydrogen atom, a cycloalkyl radical or an alkyl, alkenyl or alkynyl radical, all optionally substituted by one or more radicals, which may be identical or different, chosen among the halogen atoms, OR8 and NR8R9, A represents a single bond or a radical -CH2-CONR6-, and R6, which is the same as or different from R1, is selected from among the values of R1, the ring containing Y consisting of 4 to 8 members and being saturated or partially saturated with Y representing an oxygen atom O, a sulfur atom S optionally oxidized by or two oxygen atoms or a radical selected from N-R7, C = O, CF2, CH -OR8 or CH-NR8R9;

H

  R7 represents a hydrogen atom or an alkyl, CH2-alkenyl or CH2-alkynyl radical, all optionally substituted with a naphthyl radical or with one or more identical or different radicals chosen from halogen atoms and phenyl and heteroaryl radicals, all these naphthyl, phenyl and heteroaryl radicals being themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF 3, NH 2, NHalk or N radicals ( alk) 2; the heteroaryl radicals consisting of 5 to 10 members and containing 1 to 3 heteroatoms chosen from O, S, N and NR10; R8 represents the hydrogen atom or the alkyl, cycloalkyl or heterocycloalkyl radicals themselves optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NH 2, Nalkyl or N (alkyl) 2 radicals; NR8R9 is such that either R8 and R9, which are identical or different, are chosen from the values of R8, ie R8 and R9 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; R10 represents a hydrogen atom or an alkyl radical; said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (1).

  In the products of formula (I) and in what follows, the terms indicated have the following meanings: the term halogen denotes the fluorine, chlorine, bromine or iodine atoms and preferably fluorine, chlorine or bromine.

  the term "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.

  the term "hydroxyalkyl radical" denotes the alkyl radicals indicated above substituted with at least one hydroxyl radical; the term "alkenyl radical" denotes a linear or branched radical containing at most 6 carbon atoms and preferably 4 carbon atoms chosen for example from the following values: ethenyl or vinyl, propenyl or allyl, 1-propenyl, n-butenyl, i-propenyl, butenyl, 3-methylbut-2-enyl, npentenyl and hexenyl, as well as their linear or branched positional isomers: among the alkenyl values, the allyl or butenyl values are more particularly mentioned.

  the term "alkynyl radical" denotes a linear or branched radical containing at most 6 carbon atoms and preferably 4 carbon atoms chosen, for example, from the following values: ethynyl, propynyl or propargyl, butynyl, n-butynyl, i-butynyl, 3- 2-methylbutynyl, pentynyl or hexynyl and their linear or branched positional isomers: among the alkynyl values, the propargyl value is more particularly mentioned.

  the term "alkylene radical" denotes a linear or branched divalent radical containing at most 12 carbon atoms, derived from the alkyl radical above and thus chosen for example from the methylene, ethylene, propylene, isopropylene, butylene or isobutylene radicals, butylene, pentylene; the term "alkoxy radical" denotes a linear or branched radical containing at most 12 carbon atoms and preferably 6 carbon atoms chosen, for example, from methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy, hexoxy and heptoxy radicals; as well as their linear or branched position isomers, the term "cycloalkyl radical" denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 7 ring members and denotes in particular the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals, the radical term -O- cycloalkyl denotes a radical in which the cycloalkyl radical has the meaning indicated above - the term "aryl radical" refers to unsaturated, monocyclic or carbocyclic fused rings. Examples of such an aryl radical include phenyl or naphthyl radicals.

  the term "heterocyclic radical" denotes a saturated (heterocycloalkyl) or partially or totally unsaturated (heteroaryl) carbocyclic radical consisting of 4 to 10 members interrupted by one or three heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or of sulfur.

  among the 5-membered heteroaryl radicals, mention may be made of furyl, 2-furyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, 1,3,4-thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, 3-isoxazolyl and 4-isoxazolyl radicals, imidazolyl, pyrazolyl, thienyl, 2-thienyl, 3-thienyl, triazolyl groups. Among the heteroaryl radicals containing 6-membered radicals, mention may be made especially of pyridyl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyrazinyl radicals. pyridazinyl, pyridyl, pyrimidinyl, fused heteroaryl radicals containing at least one heteroatom selected from sulfur, nitrogen and oxygen, there may be mentioned for example benzothienyl such as 3-benzothienyl, benzofuryl, benzofuranyl, benzimidazolyl, benzoxazolyl, indolyl , quinolyl, isoquinolyl, azaindolyl and naphthyridinyl.

  Among the fused heteroaryl radicals, there may be mentioned more particularly the benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzothiazolyl, naphthyridinyl, indazolyl, quinolyl radicals such as 4-quinolyl, 5-quinolyl, isoquinolyl, azaindolyl such as 4-azaindolyl, 3-azaindolyl, imidazo ( 4,5) pyridine, indolizinyl, quinazolinyl.

  the amino radical NH 2 may be substituted by one or two identical or different radicals chosen in particular from alkyl radicals, and cycloalkyl and heterocycloalkyl radicals as defined above to give in particular alkylamino radicals NHalk, dialkylamino N (alk) 2 , cycloalkylamino, alkylcycloalkylamino, heterocycloalkylamino or alkylheterocycloalkylamino wherein the alkyl, cycloalkyl or heterocycloalkyl radicals are optionally substituted, in particular with one or more identical or different radicals selected from hydroxyl, alkoxy, NH 2, Nalkyl, N (alkyl) 2; the terms alkylamino radical or NH (alk) radical and dialkylamino or N (alk) 2 radical thus denotes amino groups substituted respectively by one or two linear or branched alkyl radicals, which are identical or different in the case of dialkylamino, chosen from radicals; alkyls as defined above: there may be mentioned, for example, the methylamino, ethylamino, propylamino or butylamino radicals, the dimethylamino, diethylamino and methylethylamino radicals.

  the term 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.

  the term "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.

  The term "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.

  By way of examples, mention may be made of 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. b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

  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, dialkylaminomethylbenzoates 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 morpholino-methyl) benzoates, e. boy Wut. 3- or 4- (morpholinomethyl) benzoates, and (4-alkylpiperazin-1-yl) benzoates, e.g. 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

  When the products of formula (I) contain an amino salifiable by an acid, it is understood that 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 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 or trifluoroacetic acids, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as, for example, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyl-disulfonic acids such as methanedisulfonic acid, alpha, betaethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.

  It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position. However, there is another type of 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 subject of the present invention is in particular the products of formula (I) above in which: R2, R3 and R4, which are identical or different, are such that one represents a fluorine or chlorine atom and the other two, which are identical, or different, represent a hydrogen atom or a fluorine or chlorine atom; R5 represents a hydrogen atom or a fluorine or chlorine atom; R1 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atom, OR8 and NR8R9; A represents a single bond or a radical -CH2CO-NR6-, and R6 represents a hydrogen atom or a linear or branched alkyl radical containing at most 4 carbon atoms; the ring containing Y being composed of 4 to 7 members and being saturated or partially saturated with Y representing an oxygen atom O, a sulfur atom S optionally oxidized by or two oxygen atoms or a radical chosen from N-R7, C = O, CF2, CH-OR8 or CH-NR8R9; R7 represents a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and phenyl and heteroaryl radicals, the phenyl and heteroaryl radicals themselves being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NHalk or N (alk) 2 radicals; the heteroaryl radicals being 5 to 7 membered and containing 1 to 3 heteroatoms selected from O, S, N and NR10; R8 represents the hydrogen atom, linear or branched alkyl radicals containing at most 4 carbon atoms or cycloalkyl radicals containing from 3 to 6 members, alkyl and cycloalkyl themselves optionally substituted with a hydroxyl radical; NR8R9 is such that either R8 and R9, which are identical or different, are chosen from the values of R8, ie R8 and R9 form, with the nitrogen atom to which they are bonded, a cyclic amine chosen from the radicals pyrrolyl, piperidyl and morpholinyl radicals; pyrrolidinyl, azetidinyl and piperazinyl optionally substituted on its second atom by an alkyl radical; 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 in particular the products of formula (I) as defined above in which R 2, R 3 and R 4, which are identical or different, are such that one represents a fluorine atom and the other two, which are identical or different, different, represent a hydrogen atom or a fluorine or chlorine atom; R5 represents a hydrogen atom or a chlorine atom; R 1 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by one or more radicals chosen from the fluorine atom and the hydroxyl, amino, methylamino, dimethylamino, piperidinyl, morpholinyl, azetidinyl or piperazinyl radicals; A represents a single bond or a radical -CH2-CONR6-, and R6 represents a hydrogen atom or an alkyl radical containing at most 1 or 2 carbon atoms; the ring containing Y being composed of 4 to 7 members being saturated with Y representing an oxygen atom O, a sulfur atom S optionally oxidized by or two oxygen atoms or a radical selected from N-R7, CH-NH2, CHNHalk or CH-N (alk) 2; R7 represents a hydrogen atom or an alkyl radical optionally substituted by a phenyl, pyridyl, thienyl, thiazolyl, pyrazinyl, furyl or imidazolyl radical, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals; methoxy, methyl, hydroxymethyl, methoxymethyl, trifluoromethyl, amino, methylamino and dimethylamino; said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (1).

  The subject of the present invention is in particular the products of formula (I) above in which R2, R3 and R4, which are identical or different, are such that one represents a fluorine atom and the two others represent one, one hydrogen atom and the other a fluorine or chlorine atom; R5 represents a hydrogen atom or a chlorine atom; R1 represents a hydrogen atom; a cyclopropyl radical; a methyl radical; or an ethyl, propyl or butyl radical optionally substituted by the fluorine atom or a hydroxyl radical or a dialkylamino radical; A represents a single bond, -CH 2 -CO-NH- or -CH 2 -CO-NCH 3 - and the ring containing Y is chosen from tetrahydropyran, dioxidothienyl and pyrrolidinyl, piperidyl and azepinyl radicals optionally substituted on their nitrogen atom. by a methyl or ethyl radical, themselves optionally substituted with a phenyl, pyridyl, thienyl, thiazolyl, pyrazinyl, furyl or imidazolyl radical; said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (1).

  In the products of formula (I) according to the present invention, when R1 represents hydrogen, then A preferably represents the -CH2-CONR6 radical as defined above.

  The present invention more particularly relates to the products of formula (I) above having the following names: - 2- {4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonylamino} N (tetrahydro-pyran-4-yl) -acetamide - 4- [4- (4-Fluoro-phenylamino) pyrimidin-2-ylamino] -N-methyl-N- (1-pyridin-2-ylmethyl) piperidin-4 benzenesulfonamide - N- (2-Dimethylamino-ethyl) -4- [4- (4-fluorophenylamino) -pyrimidin-2-ylamino] -N- (1-methylpiperidin-4-yl) benzenesulfonamide - 4-benzenesulfonamide [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-25 (2-hydroxy-ethyl) -N- (1-methyl-piperidin-4-yl) -benzenesulfonamide - 4- [4 - (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridyl-3-ylmethyl-piperidin-4-yl) -benzenesulfonamide, said products of formula (I) being in any racemic isomeric possible form , enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (I). The present invention also relates to the processes for preparing the products of formula (I) as defined above.

  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): ## STR2 ## wherein R 5 the meaning indicated above, which is reacted with a product of formula (III). R 2 NH 2 (III) wherein R 2, R 3 and R 4 have the meanings indicated above, to obtain a product of formula (IV), R 3 R 2 R 4 in which R 2, R 3, R 4 and R 5 have the meanings indicated above product of formula (IV) which is reacted with the aniline of formula (V). NH2 (V) to obtain a product of formula (VI): R3 R2

NH R4

H

  in which R2, R3, R4 and R5 have the meanings indicated above, product of formula (VI) which is reacted with chlorosulfonic acid SO2 (OH) Cl to obtain the corresponding product of formula (VII) R3 R2

NH R4

  in which R 2, R 3, R 4 and R 5 have the meanings indicated above, a product of formula (VII) which is reacted with an amine of formula (VIII): HNAJ (VIII) in which R 1 'has the meaning indicated ci above for R 1, in which the optional reactive functional groups are optionally protected by protective groups, to obtain a product of formula (II): R 3 R 2 R 4 in which R 1, R 2, R 3, R 4 and R 5 have the meanings indicated below above, products of formula (II) which can be products of formula (I) and that, to obtain or of other products of formula (I), it is possible to subject, if desired and if necessary, to the one or more of the following transformation reactions, in any order: a) an alkylthio group oxidation reaction to the corresponding sulfoxide or sulfone, b) an alkoxy function-to-hydroxyl function conversion reaction, or a hydroxyl function-based alkoxy, c) a reaction oxidation of alcohol function according to aldehyde or ketone, d) a reaction of removal of protective groups that can carry the protected reactive functions, e) a salification reaction with a mineral or organic acid to obtain the corresponding salt, f ) a resolving reaction of the racemic forms into split products, said products of formula (I) thus obtained being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms.

  The subject of the present invention is also a process for preparing the products of formula (I) as defined above in which Y represents the radical NR7 as defined above with R7 represents CH2RZ and RZ represents an alkyl, alkenyl or alkynyl, all optionally substituted with a naphthyl radical or with one or more identical or different radicals chosen from halogen atoms and phenyl and heteroaryl radicals, all these naphthyl, phenyl and heteroaryl radicals being themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF 3, NH 2, NHalk or N (alk) 2 radicals.

  Such a process is characterized in that the compound of formula (A) is subjected to:

I I O

H O

  in which R1 ', R2, R3, R4 and R5 have the meanings indicated above, to a deprotection reaction of the carbamate function to obtain a product of formula (IX): ## STR2 ## in which wherein R 1 ', R 2, R 3, R 4 and R 5 have the meanings indicated above, product of formula (IX) which is subjected to reductive amination conditions R 4

H

  in the presence of the aldehyde of formula (X): RZ'-CHO (X) in which RZ 'has the meaning indicated above for RZ, in which the optional reactive functional groups are optionally protected by protecting groups, for obtain a product of formula (I2): R3 R2 N-CH2-RZ '

I I O R4

H

  in which R1 ', R2, R3, R4, R5 and RZ' have the meanings indicated above, products of formula (I2) which can be products of formula (I) and that, for obtaining or other products of formula (I), it is possible to subject, if desired and if necessary, in any order, to one or more reactions of transformations a) to f) as defined above, said products of Formula (I2) thus obtained being in all possible isomeric forms racemic, enantiomers and diastereoisomers.

  Under preferred conditions of implementation of the invention, the processes described above can be carried out in the following way: The product of formula (II) is subjected to the action of the product of formula (III) such that defined above in particular in an alcohol such as butanol, propanol, ethanol or dimethylformamide between 80 and 140 ° 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 (HC1) in a catalytic amount under reflux conditions to give a product of formula (VI) as defined above.

  The product of formula (VI) thus obtained is subjected to the action of chlorosulfonic acid, in particular first at 0 ° C. and then at room temperature, to give a product of formula (VI) 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 to give a product of formula (I ') as defined above.

  The deprotection reaction of the carbamate function of the compound of formula (A) to obtain a product of formula (IX) may be carried out using, for example, an acidic agent such as pure trifluoroacetic acid at a temperature close to 0.degree. a mixture of this acid with a suitable solvent such as methylene chloride at about 0 ° C. or else using hydrochloric acid in solution in ether or dioxane at a temperature between 0 ° C. and room temperature.

  The product of formula (IX) is subjected to reductive amination conditions in the presence of the aldehyde of formula (X) to give a product of formula (I2) as defined above, for example in sodium borocyanide or sodium triacetoxyborohydride in a solvent such as methanol, tetrahydrofuran (THF) or their mixture in a pH medium of between 4 and 7.

  According to the values of R1 ', R2, R3, R4 and R5, and RZ', the products of formulas (II) and (I2) as defined above can therefore constitute products of formula (I) as defined herein. above 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.

  Furthermore, it may be noted that such 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 various reactive functions which certain compounds of the above-defined reactions may carry may, if necessary, be protected: for example, they are hydroxyl, acyl or amino and monoalkylamino radicals which may be protected by the appropriate protective groups.

  The following non-exhaustive list of examples of protec-tion of reactive functions can be cited: the hydroxyl groups can 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, tertbutoxycarbonyl, benzyloxycarbonyl, phthalimido or other radicals known in the peptide chemistry: the amine 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 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.

  a) 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, for example acid 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.

  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.

  b) 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.

  c) The possible alcohol functions of the products described above can be, if desired, converted to an aldehyde or ketone function by oxidation under the usual conditions known to those skilled in the art, such as, for example, by the action of manganese oxide for obtain aldehydes or by action of potassium permanganate or pyridinium chlorochromate to access ketones to access ketones.

  d) The elimination of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzene sulfonic acid or paratoluenesulphonic, formic or trifluoroacetic acid or by a catalytic hydrogenation.

  The phthalimido group may in particular be removed with hydrazine.

  A list of different protective groups that can be used, for example, can be found in patent FR 2,499,995.

  e) The products described above may, if desired, be the subject of salification reactions for example by a mineral or organic acid according to the usual methods known to those skilled in the art.

  f) Any optically active forms of the above-described products may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art.

  Illustrations of such reactions defined above are given in the preparation of the examples described hereinafter.

  The starting products of formulas (II), (III), (V), (VIII) and (IX) may be known, may be obtained commercially or may 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 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-fluoro3-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-4,6-difluoroaniline-2,4 5- (trifluoroaniline) -3-chloro-2,4-difluoroaniline 2,4-dichloro-5-fluoroaniline.

  The aniline of formula (V) is commercial.

  The amines of formula (VIII) may also be commercial, for example methyl (1-methylpiperidin-4-yl) -amine.

  The amines of formula (VIII) used in Step 4 of Examples 1, 4 to 8, 11, 12, 14 and 18 to 20 are commercial.

  The preparations of non-commercial amines of formula (VIII) can be carried out according to methods known to those skilled in the art and in particular by the three procedures 1, 2 and 3 indicated hereinafter in the experimental part.

  Examples of aldehydes of formula (X) are given in the experimental part as non-limiting examples.

  The experimental part below gives non-limiting examples of preparation of products of formula (I) according to the present invention and also examples of non-limiting starting materials used in these preparations.

  Another subject of the present invention is, as new industrial products, certain compounds of formulas (VII) and (IX).

  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 10M.

  The compounds of the present invention can thus inhibit the activation of NF-κB, and the production of cytokines with IC50's less than 10 M.

  The compounds of the present invention can thus inhibit the proliferation of a large panel of tumor cells with IC 50's less than 10M.

  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. For example the prevention or treatment of 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, polycystic ovarian diseases, hypertension, cardiovascular disorders, Syndrome X, autoimmune diseases such as systemic lupus, lupus erythematosus, induced glomerulonephritis by deficiencies of the immune system, insulin-dependent autoimmune diabetes, retinitis pigmentosa, rhinosinusitis sensitive to aspirin.

  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 breast, prostate and ovarian tumors, and precancerous lesions such as polyposis familial adenoma, viral infections (such as, 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, hepatic 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 diseases and cancers.

  It therefore appears that 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 of 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.

  As inhibitors of tumor cell 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, cancer of the respiratory tract, oropharynx and hypopharynx, cancer of the esophagus, liver cancer, stomach cancer, bile duct cancer, gallbladder cancer, 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; tumors of the brain, nerves, eyes, meninges, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, schwannomas, meningiomas; hematopoietic malignancies; leukemia such as acute lymphoid leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, chloroma, plasmocytoma, T or B cell leukemia, non-Hodgkin's or Hodgkin's lymphoma, myeloma, various hematological malignancies.

  The present invention particularly relates to combinations defined as follows.

  According to the present invention, 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 inhibitors, capecitabine, pyrimidine analogs such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside; bréquinar; topoisomerase inhibitors such as camptothecin or etoposide; anticancer hormone agonists and antagonists including tamoxifen; kinase inhibitors, imatinib; growth factor inhibitors; antiinflammatories such as pentosan polysulfate, corticosteroids, prednisone, dexamethasone; antitopoisomerases such as etoposide, antracyclines including doxorubicin, bleomycin, mitomycin and methramycin; anticancer metal complexes, platinum complexes, cisplatin, carboplatin, oxaliplatin; alpha interferon, triphenylthiophosphoramide, altretamine; antiangiogenic agents; thalidomide; immunotherapy adjuvants; vaccines.

  According to the present invention 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, whose names follow: - 2- {4- [4- (4-Fluoro-phenylamino) -pyrimidine) 2-ylamino] benzenesulfonylamino} -N (tetrahydro-pyran-4-yl) -acetamide - 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridin) 2-ylmethylpiperidin-4-yl) benzenesulfonamide - N- (2-dimethylaminoethyl) -4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (1-methylpiperidin-4) -yl) benzenesulfonamide - 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (2-hydroxy-ethyl) -N- (1-methyl-piperidin-4-yl) -benzenesulfonamide 4 [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridyl-3-ylmethyl-piperidin-4-yl) -benzenesulfonamide and the addition salts with acids pharmaceutically acceptable inorganic and organic compounds of said products of formula (I).

  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 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 28 of the present invention.

  The following examples illustrate the invention without, however, limiting it.

  The following examples illustrate the invention without, however, limiting it.

  Experimental part: The non-commercial amines used in step 4 of the preparation of the examples of the present invention can be prepared according to procedures 1, 2 and 3 described below.

  Procedure 1: Preparation of the amine used in Step 4 of Example 3: 1-Benzyl-piperidin-4-yl) -methylamine hydrochloride: 1-Benzylpiperidin-4-one are dissolved in 60 ml THF. 13. 3 ml of a 2M solution of methylamine in THF and then 5.6 g of sodium triacetoxyborohydride are added. The reaction medium is left at room temperature overnight. 10 ml of methanol are added to the reaction medium and then heated at 70 ° C. for 1 h 30 min. After concentration to dryness, taken up with sodium hydroxide solution, the mixture is extracted with dichloromethane and the chlorinated phase is dried over Na 2 SO 4. 6 g of a product which is dissolved in 100 ml of dichloromethane are obtained. To this solution of dichloromethane is added 3.5 g of Boc2O which causes a release of CO2. After concentration to dryness, the crude reaction product is chromatographed on a silica column to give 4.9 g of (1-benzylpiperidin-4-yl) methylcarbamic acid tert-butyl ester. 1.22 g of (1-benzylpiperidin-4-yl) -methyl-carbamic acid tert-butyl ester are left stirring in 40 ml of 2N hydrochloric ether. After one night, the reaction medium is filtered to obtain 0.9 g of expected product in hydrochloride form.

  Preparation of the amine used in Step 4 of Example 15: (1-Benzyl-azepan-4-yl) -methyl-amine hydrochloride: The procedure is as in Procedure 1 starting from 2 g of benzyl-azepan -4-one and 12.9 mL of a 2M solution of methylamine in THF. 1.9 g of expected product are thus obtained.

  Preparation of the Amine Used in Step 4 of Example 21: Methyl- (1-methyl-azepan-4-yl) -amine Hydrochloride: The procedure is as in Procedure 1 starting from 2 g of 1-methyl -azepan-4-one and 1.8 mL of a 2M solution of methylamine in THF. There is thus obtained 1.15 g of expected product.

36 Procedure 2.

  Preparation of the Amine Used in Step 4 of Example 9: Methyl- (1-pyridin-2-ylmethylpiperidin-4-yl) -amine Hydrochloride: 500 mg of pyridine2-carbaldehyde is dissolved in 10 ml of THF. 1 g of methyl-piperidin-4-yl-carbamic acid tert-butyl ester and then 1 g of sodium triacetoxyborohydride are added. The reaction medium is stirred at room temperature overnight. 10 ml of methanol are added to the reaction medium and then heated at 70 ° C. for 1 hour 30 minutes. After concentration to dryness, taken up with sodium hydroxide solution, the mixture is extracted with dichloromethane and the chlorinated phase is dried over Na 2 SO 4. 1 g of methyl- (1-pyridin-2-ylmethyl-piperidin-4-yl) -carbamic acid tert-butyl ester are obtained, which are dissolved in 40 ml of a solution of hydrochloric ether overnight. The reaction medium is filtered to obtain 900 mg of expected product in hydrochloride form.

  Preparation of the Amine Used in Step 4 of Example 10: 1-Ethyl-Piperidin-4-yl) -methylamine Hydrochloride The procedure is as in Example 1 of Procedure 2 starting from 1 g of methyl -piperidin-4-yl-carbamic acid tert-butyl ester and 210 mg of acetaldehyde. 680 mg of expected product is thus obtained.

  Preparation of the Amine Used in Step 4 of Example 22: Methyl- (1-pyridin-3-ylmethylpiperidin-4-yl) -amine Hydrochloride: The procedure is as in Example 1 of Procedure 2 from 1 g of methylpiperidin-4-yl-carbamic acid tert-butyl ester and 500 mg of pyridine-3-carbaldehyde. 880 mg of expected product is thus obtained.

  Preparation of the Amine Used in Step 4 of Example 24: Methyl- (1-Pyridin-4-ylmethylpiperidin-4-yl) -amine Hydrochloride The procedure is as in Example 1 of Procedure 2 starting from 1 g of methylpiperidin-4-yl-carbamic acid tert-butyl ester and 500 mg of pyridine-4-carbaldehyde. In this way 850 mg of expected product is obtained.

  Preparation of the Amine Used in Step 4 of Example 23: Methyl- (1-Thiazol-2-ylmethyl-10-piperidin-4-yl) -amine Hydrochloride The procedure is as in Example 1 of Procedure 2 from 1 g of methylpiperidin-4-yl-carbamic acid tert-butyl ester and 532 mg of thiazole-5-carbaldehyde. 940 mg of expected product is thus obtained.

  Preparation of the Amine Used in Step 4 of Example 16: Methyl- (1-Thiophen-3-ylmethylpiperidin-4-yl) -amine Hydrochloride The procedure is as in Example 1 of Procedure 2 starting from 1 g of methylpiperidin-4-yl-carbamic acid tert-butyl ester and 527 mg of thiophene-3-carbaldehyde. In this way 820 mg of expected product is obtained.

  Preparation of the amine used in Step 4 of Example 13: Methyl- (1-thiophen-2-ylmethylpiperidin-4-yl) -amine hydrochloride The procedure is as in Example 1 of Procedure 2 starting from 1 g of methylpiperidin-4-yl-carbamic acid tert-butyl ester and 527 mg of thiophene-2-carbaldehyde. In this way 760 mg of expected product is obtained.

  Preparation of the Amine Used in Step 4 of Example 26: Methyl- (1-pyrazin-2-ylmethylpiperidin-4-yl) -amine Hydrochloride: The procedure is as in Example 1 of Procedure 2 from 1 g of methylpiperidin-4-yl-carbamic acid tert-butyl ester and 508 mg of pyrazine-2-carbaldehyde. 795 mg of expected product are thus obtained.

  Preparation of the amine used in Step 4 of Example 27: (1-Furan-2-ylmethyl-piperidin-4-yl) -5-methylamine hydrochloride: The procedure is as in Example 1 of the procedure 2 from 1 g of methylpiperidin-4-yl-carbamic acid tert-butyl ester and 452 mg of furan-2-carbaldehyde. In this way 760 mg of expected product is obtained.

  Preparation of the amine used in Step 4 of Example 28: [1- (3H-Imidazol-4-ylmethyl) -piperidin-4-yl] -methyl-amine hydrochloride: The procedure is as in Example 1 of procedure 2 from 1 g of methyl-piperidin-4-yl-carbamic acid tert-butyl ester and 452 mg of 3H-imidazole-4-carbaldehyde. 780 mg of expected product is thus obtained.

  Procedure 3 - Preparation of the amine used in Step 4 of Example 25: 2-Amino-N-methyl-N- (1-methyl-piperidin-4-yl) -acetamide hydrochloride: To a solution containing 3.54 g of chloro-3,5-dimethoxy-triazine and 3.58 g of tert-butoxycarbonylamino-acetic acid in 20 ml of dichloromethane is added dropwise 2.25 ml of N-methyl morpholine while maintaining the reaction temperature between -5 and 0 C. Stirring is maintained for 4 hours and total consumption of 3,5-chlorodimethoxy-triazine is observed. Adding, maintaining the reaction temperature -5 and 0 C a mixture containing 2.9 ml of methyl- (1-methylpiperidin-4-yl) -amine, 2.25 ml of N-methyl morpholine in 10 ml of dichloromethane. The reaction medium is stirred at 0 ° C. for 2 hours and at room temperature overnight. The solvent is evaporated and the residue is taken up with 70 ml of ethyl acetate. The suspension is washed successively with H 2 O (30 ml), 30 ml of a 10% solution of citric acid, H 2 O (30 ml), 30 ml of a saturated solution of NaHCO 3 and H 2 O (30 ml). After drying over MgSO 2 and chromatography on silica (eluent 10% methanol in dichloromethane), 4 g of a product are obtained which are left stirring in 100 ml of ether / HCl. After one night, the reaction medium is filtered to give 2.5 g of expected product.

  Preparation of the Amine Used in Step 4 of Example 2: 2-Amino-N- (tetrahydro-pyran-4-yl) -acetamide Hydrochloride: The procedure is as in Example 1 of Procedure 2 from 1 g of tertbutoxycarbonylamino-acetic acid and 578 mg of tetrahydro-pyran-4-ylamine. 700 mg of expected product is thus obtained.

  Example 1 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-piperidin-4-yl) -benzenesulfonamide Step 1: (2-Chloro-pyrimidine) 4 yl) - (4-fluoro-phenyl) -amine To 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 are added. The reaction mixture is stirred under reflux for 2 hours. The reaction medium is cooled and concentrated to dryness. Add a solution of K 2 CO 3 to the residue and extract 3 times with ethyl acetate, wash with saturated NaCl solution and dry over Na 2 SO 4, the crude reaction product is purified by chromatography on a silica column (CH 2 Cl 2 and then 30% by weight). ethyl acetate in CH2Cl2). During the concentration 11 g of the expected compound crystallize MH + = 224), mp = 172-174 ° C. Stage 2: N-4 (4-Fluoro-phenyl) -N-2-phenyl-pyrimidine-2,4-diamine 10, 5 g of (2-chloropyrimidin-4-yl) - (4-fluoro-phenyl) -amine dissolved in 300 ml of n-butanol are brought to 140 ° C. under reflux in the presence of 4.3 ml of aniline overnight. The reaction medium is cooled. The suspension obtained is filtered. The crystals are taken up in ethyl acetate and washed with a 10% solution of K 2 CO 3 and then with a saturated solution of NaCl. After drying over Na 2 SO 4, the organic phase is concentrated in vacuo. The crude reaction product is purified by chromatography on a silica column (THF 10%, MeOH 5%, CH 2 Cl 2 O 5%). The expected N-4- (4-fluoro-phenyl) -N-2phenylpyrimidine-2,4-diamine crystallizes during the concentration and 10.5 g of the product are obtained by filtration. MH + = 281, mp = 161 ° C. Stage 3: 4- [4- (4-Fluorophenylamino) pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride in a three-necked flask under nitrogen stream containing chlorosulfonic acid 0 C, add 7.5 g of N-4- (4-fluoro-phenyl) -N-2-phenylpyrimidine-2,4-diamine in small portions while maintaining the temperature around 0 ° C. The reaction medium is left at room temperature. ambient for 18 hours. The mixture is dripped (carefully) onto the ice. The precipitate obtained is filtered and washed with distilled water. After dissolving the solid in 1 L of ethyl acetate, drying over Na 2 SO 4 and concentration in vacuo, a whitish oil is obtained. This oil precipitates after dispersion in 200 mL of ether. 10.5 g of 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride are obtained by filtration of the ethereal suspension. MH + = 360, PF = 1) Bioorg. Med. Chem. 2003, 13, 2961-2966 Step 4: 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-piperidin-4-yl) -35 benzenesulfonamide In a 400 mg solution of 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride in 30 ml of dichloromethane, 0.16 ml of methyl (1-methylpiperidin-4-yl) are added ) - amine (commercial product) then 0.7 mL of diisopropylethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction medium is concentrated to dryness and taken up with a 10% K 2 CO 3 solution. After extraction with ethyl acetate, the organic phase is washed with saturated NaCl solution and dried. on Na2SO4. The crude reaction product is purified by chromatography on a silica column (CH 2 CL 2 then 10% of methanol in CH 2 Cl 2); 210 mg of expected compound are obtained.

  MH + = 471.2; Melting point 205-210 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.20 (d, 2H); 1.58 (m, 2H); 1.90 (t, 2H); 2.11 (s, 3H); 2.65 (s, 3H); 2.73 (d, 2H); 3.60 (m, 1H); 6.28 (d, 1H); 7.17 (t, 2H); 7.56-7.84 (massive, 4H); 7.94 (d, 2H); 8.07 (d, 1H); 9.48 (brs, 1H); 9.67 (s wide, 1H).

  The preparation of the products of Examples 2 to 28 below is carried out according to the same process as for Example 1 using in Step 4 the appropriate amines of formula (VIII) selected from commercial amines or synthesized as indicated as examples in the experimental part below. Moreover, according to the values of R2, R3, R4 and R5 of the expected product, the starting materials of formulas (II) and (II) are used in stage 1. Thus: for Examples 1 to 19 and 21 to 28, for which R5 represents hydrogen, the same starting material of formula (II) is used as for example 1.

  for the product of Example 20, for which R 5 represents a chlorine atom, another starting material of formula (II) is used which carries in position 6 the appropriate substituent here a chlorine atom - for the products of Examples 1 to 10 and 13 to 28 for which R 2, R 3 and R 4 represent H, H, F, using the same starting material of formula (III) as for example 1.

  for the products of Examples 11 and 12, use is made of the starting products of formula (III) for which R 2, R 3 and R 4 have the appropriate meanings, R 2, R 3 and R 4 represent H, F and Cl.

  Then, after Stage 1, for all Examples 2 to 28, the procedure is as in Steps 2 and 3 of Example 1 and finally, the procedure is as in Step 4 of Example 1 by reacting the product obtained in Step 3 with the appropriate amine of formula (VIII) to obtain the expected product.

  Example 2: 2- {4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] benzenesulfonylamino} -N (tetrahydro-pyran-4-yl) -acetamide The procedure is as in Step 4 of the Example 1 mg. 400 mg 4 [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 204 mg of 2-amino-N-methylhydrochloride. N (tetrahydro-pyran-4-yl) acetamide. 260 mg of expected product is thus obtained.

  MH + = 501; Melting point = 253-254 ° C (Etheriopropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.28 (m, 2H); 1.56 (d, 2H); 3.25 (m, 2H); 3.38 (s, 2H); 3.47-3.83 (solid, 3H); 6.27 (d, 1H); 7.18 (t, 2H); 7.52-7. 82 (solid, 6H); 7.90 (d, 2H); 8.06 (d, 1H); 9.49 (brs, 1H); 9.63 (broad s, 1H).

  Example 3 N- (1-Benzylpiperidin-4-yl) -4- [4- (4-fluoro-phenylamino) pyrimidin-2-ylamino] -N-methylbenzenesulfonamide The procedure is as in Step 4 of Example 1 from 400 mg 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 252 mg of (1-Benzyl-piperidin-4-yl) hydrochloride. ) methylamine.

  259 mg of expected product is thus obtained.

  MH + = 547 Melting point = 186-190 ° C (Etheriopropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.23 (d, 2H); 1.57 (m, 2H); 1.94 (t, 2H); 2.66 (s, 3H); 2.76 (d, 2H); 3.40 (s, 2H); 3.62 (m, 1H); 6.29 (d, 1H); 7.077.38 (solid, 7H); 7.56-7.85 (solid, 7H); 7.56-7.85 (solid, 4H); 7.94 (d, 2H); 8.08 (d, 1H); 9.48 (brs, 1H); 9.67 (s wide, 1H).

  EXAMPLE 4 N- (1-Benzyl-pyrrolidin-3-S-yl) -4- [4- (4-fluoro-phenylamino) pyrimidin-2-ylamino] -N-methylbenzenesulfonamide The procedure is as in Step 4 of the Example 1 from 400 mg 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 200 mg of (1-Benzyl-pyrrolidin-3- S-yl) methylamine (commercial product). In this way 298 mg of expected product is obtained.

  MH + = 533; M.p. = 154-155 ° C (Etheropropyl dichloromethane); aD = -21.4 (C = 0.116, MeOH) 1H (200 MHz (CD3) 2SO d6, in ppm): 1.44 (m, 1H); 1.76 (m, 1H); 1.93-2.35 (massive, 6H); 2.56 (m, 1H); 2.66 (s, 3H); 4. 46 (m, 1H); 6.30 (d, 1H); 7.19 (d, 2H); 7.55-7.80 (solid, 4H); 7.97 (d, 2H); 8.10 (d, 1H); 9.49 (brs, 1H); 9.69 (broad s, 1H).

  Example 5 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-pyrrolidin-3-yl) -benzenesulfonamide The procedure is as in Step 4 of the Example 1 from 400 mg 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 120 mg of methyl- (1-methyl-pyrrolidin-3- racemic amine (commercial product) 215 mg of expected product are thus obtained.

  MH + = 457; Melting point = 177-181 ° C (Etheropropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.44 (m, 1H); 1.76 (m, 1H); 1.93-2. 35 (massive, 6H); 2.56 (m, 1H); 2.66 (s, 3H); 4.46 (m, 1H); 6.30 (d, 1H); 7. 19 (t, 2H); 7.55-7.80 (solid, 4H); 7.97 (d, 2H); 8.10 (d, 1H); 9.49 (brs, 1H); 9.69 (broad s, 1H).

  Example 6 N- (1,1-Dioxo-tetrahydro-10-thiophen-3-yl) -4-15 [4- (4-fluorophenylamino) pyrimidin-2-ylamino] -N-methylbenzenesulfonamide The procedure is as in Step 4 from Example 1 starting from 400 mg of 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 158 mg of 1,1-dioxo Racemic tetrahydro-1,4-thiophen-3-yl) methyl-amine (commercial product) 200 mg of expected product are thus obtained.

  MH + = 492; Melting point = 236-240 ° C (Etheropropyl-25 dichloromethane) 1H (200 MHz (CD3) ₂SO d6, ppm): 2.06 (m, 2H); 2.69 (s, 3H); 2.78-3.25 (massive, 4H); 4.78 (m, 1H); 6.30 (d, 1H); 7.19 (t, 2H); 7.607.80 (massis, 4H); 8.10 (d, 1H); 9.51 (brs, 1H); 9.74 (broad s, 1H).

  EXAMPLE 7 N- (1-Benzyl-pyrrolidin-3-R-yl) -4- [4- (4-fluorophenylamino) pyrimidin-2-ylamino] -N-methylbenzenesulfonamide The procedure is as in Step 4 of Example 1 From 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 200 mg of (1-Benzyl-pyrrolidin-3-R-yl) ) -N-methylamine (commercial product) 318.mg of expected product is thus obtained.

  MH + = 533; M.p. = 154-155 ° C (Etheropropyliquedichloromethane); (ID = +24 (C = 0.1, MeOH) 1H (200MHz (CD3) 2SO d6, ppm): 1.45 (m, 1H), 1.83 (m, 1H), 2.10 (q, 1H), 2.18-2.34 (massive, 2H), 2.60 (m, 1H), 2.68 (s, 3H), 3.43 (AB, 2H), 4.45 (m, 1H), 6.28 (d, 1H), 7, 10-7.33 (massive 7.60 (d, 2H), 7.65-7.78 (solid, 2H), 7.94 (d, 2H), 8.10 (d, 1H), 9.49 (bs, 1H), 9.67 (bs, 1H).

  Example 8: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide Step 1: Preparation of Intermediate 4 - ({4- [4 - (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester: The preparation of intermediate 4 - ({ 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl) -methylamino) piperidine-1-carboxylic acid tert-butyl ester The procedure is as in Step 4 of Example 1 starting from 800. mg 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 485 mg methyl-amino-piperidine-1-carboxylic acid tert-butyl ester. 390 mg of expected product is thus obtained.

  MH + = 557; Melting point = 174-176 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, in ppm): 1.14-1.61 (solid, 13H); 2.61 (s, 3H); 2.70 (m, 2H); 3.70-4.07 (solid, 3H); 6.27 (d, 1H); 7.16 (t, 2H); 7.57-7.79 (solid, 4H); 7.94 (d, 2H); 8.06 (d, 1H); 9.46 (sl, 1H); 9. 66 (sl, 1H).

  Step 2: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-Npiperidin-4-yl-benzenesulfonamide hydrochloride 300 mg 4 - ({4- [4- (4-Fluorophenylamino ) -pyrimidin-2-ylamino] -benzenesulfonyl) -methylamino) piperidine-1-carboxylic acid tert-butyl ester are stirred in 40 ml of 2N hydrochloric ether. After one night, the reaction medium is filtered to obtain 220 mg of expected product (end product Example 8).

  MH + = 457; M.p. = 205-210 ° C (Etheropropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.41 (d, 2H); 1.85 (m, 2H); 2.66 (s, 3H); 2.94 (m, 2H); 3.22 (d, 2H); 4.09 (m, 1H); 6.55 (d, 1H); 7.25 (t, 2H); 7. 63 (m, 2H); 7.77 (s, 4H); 8.09 (d, 1H); 8.53-9.08 (massive, 2H); 11.05 (broad, 1H); 11.11 (s wide, 1H).

  The product of Example 8 can be used as an intermediate for all the finished products of Examples 3, 9, 10, 13, 15, 16, 22, 23, 24, 26, 27, 28. by a reductive amination reaction. who would use the same procedure as procedure 2.

  Example 9 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridin-2-ylmethyl-piperidin-4-yl) -benzenesulfonamide The procedure is as in Step 4 from Example 1 starting from 400 mg 4 [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 254 mg of methyl-1 hydrochloride -pyridin-2ylmethyl-piperidin-4-yl) -amine.

  205.mg of expected product is thus obtained.

  MH + = 548; M.p. = 202-204 ° C (Etheropropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.22 (d, 2H); 1.60 (m, 2H); 2.03 (t, 2H); 2.65 (s, 3H); 2.78 (d, 2H); 3.52 (s, 2H); 3.63 (m, 1H); 6.27 (d, 1H); 7. 06-7.29 (solid, 3H); 7.53 (d, 1H); 7.63-7.80 (solid, 5H); 7.93 (d, 2H); 8.06 (d, 1H); 8.44 (d, 1H); 9.47 (brs, 1H); 9.66 (broad s, 1H).

  Example 10: N- (1-Ethyl-piperidin-4-yl) -4- [4- (4-fluoro-phenylamino) pyrimidin-2-ylamino] -N-methylbenzenesulfonamide The procedure is as in Step 4 of Example 1 starting from 400 mg 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 174 mg of (1-ethyl-piperidin-4-yl) hydrochloride. methylamine.

  205.mg of expected product is thus obtained.

  MH + = 485; Melting point = 162-163 ° C (Etheriopropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 0.90 (t, 3H); 1.21 (d, 2H); 1.54 (m, 2H); 2.24 (q, 2H); 2.64 (s, 3H); 2.81 (d, 2H); 3.60 (m, 1H); 6.27 (d, 1H); 7. 16 (t, 2H); 7.53-7.78 (solid, 4H); 7.93 (d, 2H); 8.07 (d, 1H); 9.48 (brs, 1H); 9.66 (broad s, 1H).

  Example 11: 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methylpiperidin-4-yl) -benzenesulfonamide Step 1: (2-Chloropyrimidin-4- yl) - (3,4-difluoro-phenyl) -amine The preparation of this compound is carried out according to the same process as for example 1 from the reaction of 9.21 g of dichloropyrimidine with 8 g of 3,4-difluoroaniline: 10.3 g of expected product are thus obtained.

  Step 2: N * 4 - (3,4-Difluoro-phenyl) -N * -2-phenyl-pyrimidine-2,4-diamine The preparation of this compound is carried out according to the same procedure as for Example 1 at from the reaction of 7 g of (2-chloro-pyrimidin-4-yl) - (3,4-difluoro-phenyl) -amine obtained in stage 1 above with 2.72 g of aniline: 8 g of expected product.

  Stage 3: 4- [4- (3,4-Difluorophenylamino) pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride The preparation of this compound is carried out according to the same process as for example 1 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 chlorosulfonic acid: 9 g of product are thus obtained; expected.

  Step 4: 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N (1-methylpiperidin-4-yl) -20-benzenesulfonamide The procedure is as in Step 4 of the Example 1 from 400 mg of 4- [4- (3,4-difluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 0.17 ml of methyl (1-methyl-piperidin) -4-yl) -amine (commercial product) is thus obtained 110.mg of expected product.

  MH + = 489; Melting point = 181-183 ° C (Etheropropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.22 (m, 2H); 1.60 (m, 2H); 1.98 (m, 2H); 2.14 (s, 3H); 2.64 (s, 3H); 2.76 (d, 2H); 3.62 (m, 1H); 6.31 (d, 1H); 7. 17-7.49 (massive, 2H); 7.65 (d, 2H); 7.94 (d, 2H); 8.01-8.24 (solid, 2H); 9. 70 (bs, 1H); 9.77 (broad s, 1H).

  Example 12: 4- [4- (3-Chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-piperidin-4-yl) -benzenesulfonamide Step 1: (2-Chloropyrimidine 4-yl) - (3-chloro-4-fluorophenyl) -amine The preparation of this compound is carried out according to the same process as for example 1 from the reaction of 10 g of dichloropyrimidine with 9.75 g of chloro-4-fluoroaniline: thus obtaining 11.3 g of expected product.

  Stage 2: N * 4 - (3-Chloro-4-fluoro-phenyl) -N * 2 * -phenyl-pyrimidine-2,4-diamine The preparation of this compound is carried out according to the same process as for Example 1 to from the reaction of 10 g of (2-chloro-pyrimidin-4yl) - (3-chloro-4-fluorophenyl) -amine obtained in the above stage with 3.61 g of aniline: 13 g of expected product are thus obtained.

  Stage 3: 4- [4- (3-Chloro-4-fluoro-phenylamino) pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride The preparation of this compound is carried out according to the same process as for Example 1 from of the reaction of 6 g of N * 4 - (3-chloro-4-fluoro-phenyl) -N * 2 * -phenylpyrimidine-2,4-diamine obtained in the above stage with chlorosulfonic acid: 7 g of expected product.

  Step 4: 4- [4- (3-Chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-piperidin-4-yl) -benzenesulfonamide The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (3-chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 17 mL of the methyl (1-methylpiperidin-4-yl) amine (commercial product) is thus obtained 250.mg of expected product.

  MH + = 506; M.p. = 183-186 ° C (Etheropropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.20 (d, 2H); 1.57 (m, 2H); 1.88 (t, 2H); 2.10 (s, 3H); 2.57-2.82 (massive, 5H); 3.56 (m, 1H); 6.30 (d, 1H); 7.37 (t, 1H); 7.51 (m, 1H); 7.64 (d, 2H); 7.92 (d, 2H); 8.04 (dd, 1H); 8.13 (d, 1H) 9.66 (bs, 1H); 9.78 (broad s, 1H).

  Example 13: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N (1-thiophen-2-ylmethyl-piperidin-4-yl) -benzenesulfonamide The procedure is as in Step 4 from Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride which is reacted with 261 mg of methyl (1-thiophen) hydrochloride. 2-methylmethyl-piperidin-4-yl) amine.

  261.mg of expected product is thus obtained.

  MH + = 553; Melting point = 175-176 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.26 (d, 2H); 1.56 (m, 2H); 1.96 (t, 2H); 2.65 (s, 3H); 2.81 (d, 2H); 3.48-3.77 (solid, 3H); 6. 23 (d, 1H); 6.84-6.99 (solid, 2H) 7.16 (t, 2H); 7.38 (dd, 1H); 7.54-7. 78 (solid, 4H) 7.92 (d, 2H); 8.06 (d, 1H); 9.48 (brs, 1H); 9.66 (broad s, 1H).

  Example 14: N-Cyclopropyl-4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (1-methylpiperidin-4-yl) -benzenesulfonamide The procedure is as in Step 4 of the Example 1 starting from 400 mg of 4 [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is made with 162 mg of Cyclopropyl- (1-methylpiperidin-4- yl) amine (commercial product) 181.mg of expected product is thus obtained.

  MH + = 497; Melting point = 218 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 0.62-0.92 (bulk, 4H) 1.33 (m, 2H); 1.62-2. 01 (massive, 5H); 2.09 (s, 3H) 2.72 (d, 2H); 3.62 (m, 1H); 6.28 (d, 1H); 7. 16 (t, 2H) 7.57-7.78 (solid, 4H); 7.95 (d, 2H); 8.07 (d, 2H) 9.48 (brs, 1H); 9.69 (broad s, 1H).

  Example 15: N- (1-Benzyl-pyrrolidin-3-yl) -4- [4- (4-fluoro-phenylamino) pyrimidin-2-ylamino] -N-ethyl-benzenesulfonamide The procedure is as in Step 4 of the Example 1 from 400 mg of [4 (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 205 mg of (1-Benzyl-pyrrolidin-3-yl) racemic ethylamine (commercial product) 152.mg of expected product is thus obtained.

  MH + = 547; Melting point = 125-127 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.13 (t, 3H); 1.37 (m, 1H); 1.86 (m, 1H); 2.05 (m, 1H); 2.24 (d, 2H); 2.59 (m, 1H); 3.13 (q, 2H); 3.33 (AB, 2H); 4.33 (m, 1H); 6.24 (d, 1H); 7.03-7.30 (massive, 7H); 7.517.74 (solid, 4H); 7.86 (d, 2H).

  Example 16: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N (1-thiophen-3-ylmethyl-piperidin-4-yl) -benzenesulfonamide The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride which is reacted with 261 mg of methyl- (1-thiophenylmethyl) piperidine -4-yl) amine hydrochloride.

  225.mg of expected product is thus obtained.

  MH + = 553; Melting point = 173-174 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.21 (d, 2H); 1.56 (q, 2H); 1.90 (t, 2H); 2.64 (s, 3H); 2.77 (d, 2H); 3.41 (s, 2H); 3.60 (m, 1H); 6.26 (d, 1H); 6. 98 (d, 1H); 7.06-7.31 (solid, 3H); 7.43 (m, 1H); 7.54-7.80 (solid, 4H); 7. 93 (d, 2H); 8.07 (d, 1H); 9.48 (brs, 1H); 9.66 (broad s, 1H).

  EXAMPLE 17 N- (1-Benzyl-azepan-4-yl) -4- [4- (4-fluoro-phenylamino) -6-methylpyrimidin-2-ylamino] -N-methylbenzenesulfonamide The procedure is as in Step 4 of the Example 1 from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 268 mg of (1-benzyl-4-azepan) hydrochloride -yl) racemic methylamine.

  150.mg of expected product is thus obtained.

  MH + = 561; Melting point = 147-148 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.25-1.75 (bulk, 9H) 2.32-2.59 (bulk, 4H); 2.64 (s, 3H); 3.54 (s, 2H) 3.98 (m, 1H); 6.29 (d, 1H); 7.09-7. 38 (solid, 7H) 7.62 (d, 2H); 7.71 (m, 2H); 7.95 (d, 2H); 8.09 (d, 2H) 9.49 (bs, 1H); 9.66 (broad s, 1H).

  Example 18: N- (2-Dimethylaminoethyl) -4- [4- (4-fluoro-phenylamino) pyrimidin-2-ylamino] -N- (1-methylpiperidin-4-yl) -benzenesulfonamide The procedure is as in US Pat. Step 4 of Example 1 from 400 mg of [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride which is reacted with 255 mg of N, N Dimethyl-N '- (1-methyl-piperidin-4-yl) -ethane-1,2-diamine hydrochloride (commercial product) 155 mg of expected product is thus obtained.

  MH + = 528; Melting point = 135-137 (Etheriopropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.31 (d, 2H); 1.57 (m, 2H); 1.83 (t, 2H); 2.08 (s, 3H); 2.15 (s, 6H); 2.39 (t, 2H); 2.71 (d, 2H); 3.13 (t, 2H); 4. 48 (m, 1H); 6.28 (d, 1H); 7.16 (t, 2H); 7.55-7.78 (solid, 4H); 7.92 (d, 2H); 8.07 (d, 1H); 9.48 (brs, 1H); 9.66 (broad s, 1H).

  Example 19: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (2-hydroxyethyl) -N- (1-methyl-piperidin-4-yl) -benzenesulfonamide The procedure is as in US Pat. Step 4 of Example 1 from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 230 mg of 2- (1- methyl-piperidin-4-ylamino) ethanol hydrochloride (commercial product) 40 mg of expected product is thus obtained.

  MH + = 501; Melting point = 125-135 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.29 (m, 2H); 1.57 (m, 2H); 1.85 (t, 2H); 2.09 (s, 3H); 2.71 (d, 2H); 3.09 (t, 2H); 3.47 (d, 3H); 4.73 (t, 1H); 6. 27 (d, 1H); 7.16 (t, 1H); 7.56-7.78 (solid, 4H); 7.92 (d, 2H); 8.06 (d, 1H); 9.48 (brs, 1H); 9.66 (broad s, 1H).

  Example 20: 4- [4-Chloro-6- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-piperidin-4-yl) -benzenesulfonamide Step 1: (2, 6Dichloro-pyrimidin-4-yl) - (4-fluoro-phenyl) -amine The preparation of this compound is carried out according to the same process as for example 1 from the reaction of 12 g of trichloropyrimidine with 7.38 g of 4- o

VS

  fluoroaniline: 8.7 g of expected product are thus obtained.

  Step 2: 6-Chloro-N * 4 - (4-fluoro-phenyl) -N * 4 * -methyl-N * 2-phenylpyrimidine-2,4-diamine The preparation of this compound is carried out according to the same process that for example 1 from the reaction of 4 g of (2,6-dichloro-pyrimidin-4-yl) - (4-fluoro-phenyl) -amine obtained in the above stage with 1.44 g of aniline is thus obtained 2.5 g of expected product.

  Step 3: 4- [4-Chloro-6- (4-Fluoro-phenylamino) pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride.

  The preparation of this compound is carried out according to the same process as for example 1 from the reaction of 2 g of 6-chloro-N * 4 * - (4-fluorophenyl) -N * 4 * -methyl-N * 2 * -phenyl-pyrimidine-2,4-diamine obtained in the above stage with chlorosulfonic acid: 2 g of the expected product are thus obtained.

  Step 4: 4- [4-Chloro-6- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-piperidin-4-yl) -20-benzenesulfonamide The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4-chloro-6- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride which is reacted with 0.17 ml of methyl (4-methylpiperidin-4-yl) amine (commercial product). 300 mg of expected product are thus obtained.

  MH + = 506; Melting point = 140-142 ° C (Etheropropyl-dichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.19 (m, 2H); 1.57 (m, 2H); 1.86 (t, 2H); 2.08 (s, 3H); 2.57-2.83 (solid, 5H) 3.60 (m, 1H); 6.26 (s, 1H); 7.20 (t, 2H); 7.48-7.70 (solid, 4H); 7.84 (d, 2H); 9.71 (brs, 1H) 10.05 (brs, 1H).

  Example 21: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N (1-methyl-azepan-4-yl) -benzenesulfonamide The procedure is as in Step 4 of the Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with the 185 mg of methyl- (1-methylazepan-4- yl) -amine (commercial product) 1H (200 MHz (CD3) 2SO d6, ppm): 0.90 (t, 3H); 1.21 (d, 2H); 1.54 (m, 2H); 2.24 (q, 2H); 2.64 (s, 3H); 2.81 (d, 2H); 3.60 (m, 1H); 6. 27 (d, 1H); 7.16 (t, 2H); 7.53-7.78 (solid, 4H); 7.93 (d, 2H); 8.07 (d, 1H); 9.48 (brs, 1H); 9.66 (broad s, 1H).

  This gives 214.mg of expected product.

  MH + = 485; M.p. = 122-124 ° C (Etheropropyliquedichloromethane) Example 22: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N (1-pyridyl-3-ylmethyl-piperidine) 4yl) -benzenesulfonamide The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted. with 254 mg of methyl- (1-pyridyl-3-ylmethyl-piperidin-4-yl) -amine hydrochloride.

  155 mg of expected product are thus obtained.

  MH + = 548; Melting point = 215.8 C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, in ppm): 11.11-2.36 (bulk, 4H); 2.63 (s, 3H); 2.82-4. 60 (massive, 7H); 6.30 (d, 1H); 7.17 (t, 2H); 7.28-7.83 (solid, 5H); 7.96 (d, 2H); 8.07 (d, 1H); 8.36-9.24 (massive, 2H); 9.59 (s, 1H); 9.71 (s, 1H).

  Example 23: 4- [4- (4-Fluoro-phenylamino) -6-methyl-pyrimidin-2-ylamino] -N-methyl-N- (1-thiazol-2-ylmethylpiperidin-4-yl) -benzenesulfonamide The procedure is as in US Pat. Stage 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 260 mg of methylhydrochloride ( 1-thiazol-2-ylmethyl-piperidin-4-yl) -amine.

  165.mg of expected product is thus obtained.

  MH + = 554; M.p. = 220 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.2 (d, 2H); 1.60 (q, 2H); 2.14 (t, 2H); 2. 67 (s, 3H); 2.86 (d, 2H); 3.66 (m, 1H); 3.78 (s, 2H); 6.28 (d, 1H); 7. 18 (t, 2H); 7.75-7.77 (solid, 6H); 7.95 (d, 2H); 8.08 (d, 1H); 9.48 (brs, 1H); 9.67 (broad s, 1H).

  Example 24: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridyl-4-ylmethyl-piperidin-4-yl) -benzenesulfonamide The procedure is as in Step 4 from Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 254 mg of methyl- (1- pyridyl-4-yl-methylpiperidin-4-yl) -amine hydrochloride.

  205.mg of expected product is thus obtained.

  MH + = 548; Melting point = 205.3 C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.52 (d, 2H); 1.99 (m, 2H); 2.68 (s, 3H); 3. 19 (m, 2H); 3.41 (d, 2H); 4.12 (m, 1H); 4.60 (s, 2H); 6.51 (d, 1H); 7.21 (t, 2H); 7.75-7.87 (solid, 6H); 8.05 (d, 1H); 8.22 (d, 2H); 9.06 (d, 2H); 11. 00 (s, 1H); 11.26 (s, 1H).

  Example 25: 2- {4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonylamino} -N-methyl-N- (1-methylpiperidin-4-yl) -acetamide The procedure is carried out as in Step 4 of Example 1 from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride which is reacted with 273 mg of 2-amino-N-methyl hydrochloride. -N- (1-methyl-piperidin-4-yl) -acetamide hydrochloride. 260 mg of expected product is thus obtained.

  MH + = 528; Melting point = 233-234.4 ° C. (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, in ppm): 1.44-2.08 (solid, 4H); 2.54-3.53 (massive, 10H); 3.60-4.90 (solid, 3H); 6.48 (d, 1H); 7.23 (t, 2H); 7.45-7.73 (solid, 4H); 7.80 (d, 2H); 8.03 (d, 1H); 10.97 (s, 1H); 11.16 (s, 1H.

  Example 26: 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N (1-pirazin-2-ylmethyl-piperidin-4yl) -benzenesulfonamide The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 294 mg of methylhydrochloride. -pirazin-2-ylmethyl-piperidin-4-yl) -amine.

  80.mg of expected product is thus obtained.

  MH + = 548; Melting point = 180 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.21 (d, 2H); 1.58 (m, 2H); 2.06 (t, 2H); 2. 63 (s, 3H); 2.78 (d, 2H); 3.48- 3.74 (massive, 3H); 6.26 (d, 1H); 7.15 (t, 2H); 7.50-7.77 (solid, 4H); 7.92 (d, 2H); 8.06 (d, 1H); 8.42-8.66 (massive, 3H); 9.46 (s, 1H); 9.97-10.81 (si, 1H).

  EXAMPLE 27 4- [4- (4-Fluoro-phenylamino) -6-methyl-pyrimidin-2-ylamino] -N- (1-furan-3-ylmethyl-piperidin-4-yl) -N-methylbenzenesulfonamide The procedure is as in US Pat. Stage 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 277 mg of the hydrochloride of the (1 -furan-3-ylmethyl-piperidin-4-yl) -methyl-amine. We thus obtain 220 mg of expected product.

  MH + = 537; Melting point = 156-156 ° C (Etheriopropyliquedichloromethane) 1H (200 MHz (CD3) 2SO d6, ppm): 1.19 (d, 2H); 1.53 (q, 3. 56 (m, 1H), 6.21 (d, 1H), 6.26 (d, 1H), 6.35 (t, 1H), 7.15 (t, 2H), 7.53 (s, 1H); d, 2H), 7.68 (m, 2H), 7.92 (d, 2H), 8.06 (d, 1H).

  Example 28: 4- [4- (4-Fluoro-phenylamino) -6-methyl-pyrimidin-2-ylamino] -N (1H-imidazol-2-ylmethyl-piperidin-4-yl) -N-methyl-benzenesulfonamide The procedure is as follows: in Step 4 of Example 1 from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 277 mg of 1H-imidazol-2-ylmethyl) -piperidin-4-yl] -methyl-amine hydrochloride. In this way mg of expected product is obtained.

  Example 29: Pharmaceutical Composition Tablets having the following formula were prepared: Product of Example 3 ................

  Excipient for a tablet finished with (detail of the excipient: lactose, talc, starch, magnesium stearate).

  Example 30: Pharmaceutical composition 0.2 g Tablets having the following formula: Product of Example 12 0.2 g Excipient for a tablet finished at 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

  Example 31: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 25 0.2 g Excipient for a tablet finished at 1 g (detail of excipient: lactose, talc, starch, magnesium stearate ).

  Examples 3, 12 and 25 are taken as examples in the pharmaceutical preparations which constitute Examples 29 to 31 above, this pharmaceutical preparation can be carried out differently as indicated above and if desired with other products in examples in this application.

  Pharmacological part: Biochemical test protocols on IKK.

  I) Evaluation of the compounds on 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 μl of each dilution are added to the wells of a 96-well plate in duplicate. 10 μl of kinase buffer is added to the control wells which will serve as 0% inhibition and 10 μl of 0.5 mM EDTA is added to the control wells (100% inhibition). 10 μl of the IKK1 or IKK2 mixture (0.1 μg / well), 25-55 IKB-biotinylated substrate peptide and BSA (5 μg) is added to each well. to start the kinase reaction, 10 μl of the mixture of 10 mM magnesium acetate, 1 μM cold ATP and 0.1 Ci 33 P-ATP is added to each well for a final volume of 30 μl. The reaction is incubated at 30 ° C. for 90 min and then stopped by the addition of 40 μl of 0.5 mM EDTA. After stirring, 50 μl are transferred to a flash plate coated with streptavidin.

  min after, the wells are washed twice with a solution of 50 mM TrisEDTA pH7.5 and the radioactivity determined on a microbeta counter.

  The compounds of the invention tested in this assay show an IC 50 of less than 10 gm, which shows that it can be used for their therapeutic activity.

  II) Evaluation of the compounds on the viability and proliferation of tumor cells: The compounds according to the invention were 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: breast cancer: MDA-MB231 (American type culture collection, Rockville, Maryland, USA, ATCC -HTB26), MDA-A1 or MDA-ADR (so-called MDR multi-drug resistant line, and described by E.Collomb et al., In Cytometry, 12 (1): 1525, 1991), and MCF7 (ATCC-HTB22) , - prostate cancer: DU145 (ATCCHTB81) and PC3 (ATCC-CRL1435), - colon cancer: HCT116 (ATCC-CCL247) and HCT15 (ATCC-CCL225), - lung cancer: 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), of 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, Maryla nd, USA), leukemia (CMLT1 described by Kuriyama et al. in Blood, 74: 1989, 13811387, by Soda et al. in British Journal of Haematology, 59: 1985, 671679 and by Drexler, in Leukemia Research, 18: 1994, 919-927 and issued by DSMZ, Mascheroder Weg Ib, 38124 Braunschweig, Germany).

  Proliferation and cell viability were determined in a test using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) 2- (4-sulfophenyl) -2H-tetrazolium (MTS) according to Fujishita T. et al., Oncology, 2003, 64 (4), 399-406. In this test, the mitochondrial capacity of the living cells is measured to transform the MTS into a colored compound after 72 hours of incubation of a compound of formula (I) according to the invention. The concentrations of compound according to the invention, which lead to 50% loss of proliferation and cell viability (IC50) are less than 10 M, depending on the tumor line and the test compound.

  Thus, according to the present invention, it appears that the compounds of formula (I) lead to a loss of proliferation and viability of the tumor cells with an IC 50 of less than 10 M.

Claims (21)

  1) Products of Formula (I): R3 R2 R4 O Ri S'N A 0 ( I I O (I) H   in which: R2, R3 and R4, which are identical or different, are such that one represents a halogen atom and the other two, which are identical or different, represent a hydrogen atom or a halogen atom; R5 represents a hydrogen atom or a halogen atom; R1 represents a hydrogen atom, a cycloalkyl radical or an alkyl, alkenyl or alkynyl radical, all optionally substituted by one or more radicals, which may be identical or different, chosen from halogen atoms, OR8 and NR8R9; A represents a single bond or a radical -CH2-CONR6-, and R6, which is identical to or different from R1, is chosen from the values of R1; the ring containing Y being constituted of 4 to 8 members and being saturated or partially saturated with Y representing an oxygen atom O, a sulfur atom S optionally oxidized by or two oxygen atoms or a radical chosen from N-R7, C = O, CF2, CH-OR8 or CH-NR8R9; R7 represents a hydrogen atom or an alkyl, CH2-alkenyl or CH2-alkynyl radical, all optionally substituted with a naphthyl radical or with one or more identical or different radicals chosen from halogen atoms and phenyl and heteroaryl radicals, all these naphthyl, phenyl and heteroaryl radicals being themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF 3, NH 2, NHalk or N radicals ( alk) 2; the heteroaryl radicals consisting of 5 to 10 members and containing 1 to 3 heteroatoms chosen from O, S, N and NR10; R8 represents the hydrogen atom or the alkyl, cycloalkyl or heterocycloalkyl radicals themselves optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NH2, Nalkyl or N (alkyl) 2 radicals; NR8R9 is such that either R8 and R9, which are identical or different, are chosen from the values of R8, ie R8 and R9 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; R10 represents a hydrogen atom or an alkyl radical; 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). 2) Products of formula (I) as defined in claim 1 wherein: R2, R3 and R4, identical or different, are such that one represents a fluorine or chlorine atom and the other two, identical or different , represent a hydrogen atom or a fluorine or chlorine atom; R5 represents a hydrogen atom or a fluorine or chlorine atom; R1 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atom, OR8 and NR8R9; A represents a single bond or a radical -CH2-CONR6-, and R6 represents a hydrogen atom or a linear or branched alkyl radical containing at most 4 carbon atoms; the ring containing Y being composed of 4 to 7 members and being saturated or partially saturated with Y representing an oxygen atom O, a sulfur atom S optionally oxidized by or two oxygen atoms or a radical chosen from N-R7, C = O, CF2, CH-OR8 or CH-NR8R9; R7 represents a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and phenyl and heteroaryl radicals, the phenyl and heteroaryl radicals themselves being optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NHalk or N (alk) 2 radicals; the heteroaryl radicals being 5 to 7 membered and containing 1 to 3 heteroatoms selected from O, S, N and NR10; R8 represents the hydrogen atom, linear or branched alkyl radicals containing at most 4 carbon atoms or cycloalkyl radicals containing from 3 to 6 members, alkyl and cycloalkyl themselves optionally substituted with a hydroxyl radical; NR8R9 is such that either R8 and R9, which are identical or different, are chosen from the values of R8, ie R8 and R9 form, with the nitrogen atom to which they are bonded, a cyclic amine chosen from the radicals pyrrolyl, piperidyl and morpholinyl radicals; pyrrolidinyl, azetidinyl and piperazinyl optionally substituted on its second atom by an alkyl radical; said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (1).   3) Products of formula (I) as defined in any preceding claim wherein: R2, R3 and R4, identical or different, are such that one represents a fluorine atom and the other two, identical or different, represent a hydrogen atom or a fluorine or chlorine atom; R5 represents a hydrogen atom or a chlorine atom; R1 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals chosen from the fluorine atom and the hydroxyl, amino, methylamino, dimethylamino, piperidinyl, morpholinyl, azetidinyl or piperazinyl radicals; A represents a single bond or a radical -CH2-CONR6-, and R6 represents a hydrogen atom or an alkyl radical containing at most 1 or 2 carbon atoms; the ring containing Y being composed of 4 to 7 members being saturated with Y representing an oxygen atom O, a sulfur atom S optionally oxidized by or two oxygen atoms or a radical selected from N-R7, CH-NH2, CHNHalk or CH-N (alk) 2; R7 represents a hydrogen atom or an alkyl radical optionally substituted by a phenyl, pyridyl, thienyl, thiazolyl, pyrazinyl, furyl or imidazolyl radical, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals; methoxy, methyl, hydroxymethyl, methoxymethyl, trifluoromethyl, amino, methylamino and dimethylamino; 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) 4) Products of formula (I) as defined in any one of the preceding claims wherein: R2, R3 and R4, identical or different, are such that one represents a fluorine atom and the other two represent the one, a hydrogen atom and the other a fluorine or chlorine atom; R5 represents a hydrogen atom or a chlorine atom; R1 represents a hydrogen atom; a cyclopropyl radical; a methyl radical; or an ethyl, propyl or butyl radical optionally substituted by the fluorine atom or a hydroxyl radical or a dialkylamino radical; A represents a single bond, - CH 2 -CO-NH- or -CH 2 -CO-NCH 3 - and the ring containing Y is chosen from tetrahydropyran, dioxidothienyl radicals and pyrrolidinyl, piperidyl and azepinyl radicals optionally substituted on their nitrogen atom. by a methyl or ethyl radical, themselves optionally substituted with a phenyl, pyridyl, thienyl, thiazolyl, pyrazinyl, furyl or imidazolyl radical; said products of formula (I) being in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (1).   5) Products of formula (I) as defined in any of the other claims with the following names: 2- [4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] - benzenesulfonylamino} N (tetrahydro-pyran-4-yl) -acetamide - 4- [4- (4-Fluoro-phenylamino) pyrimidin-2-ylamino] -N-methyl-N- (1-pyridin-2-ylmethyl) - piperidin-4-yl) benzenesulfonamide - N- (2-Dimethylamino-ethyl) -4- [4- (4-fluorophenylamino) -pyrimidin-2-ylamino] -N- (1-methylpiperidin-4-yl) benzenesulfonamide - 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-10 (2-hydroxy-ethyl) -N- (1-methyl-piperidin-4-yl) -benzenesulfonamide - 4- [4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N 4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridyl-3-ylmethyl-piperidin-4-yl) benzenesulfonamide, said products of formula (I) being in any isomeric form possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (1).   6) Process for the preparation of the products of formula (I) as defined in any one of the other claims, characterized in that a product of formula (II) is reacted: Cl N (II)   Wherein R5 has the meaning indicated in any one of the above claims, which is reacted with a product of formula (III). R 2 NH 2 (III) in which R 2, R 3 and R 4 have the meanings indicated in any one of the preceding claims, to obtain a product of formula (IV), R 3 R 2 R 4 NH   in which R 2, R 3, R 4 and R 5 have the meanings indicated above, a product of formula (IV) which is reacted with the aniline of formula (V): NH 2 (V) to obtain a product of formula ( VI): R3 R2 R4 NH R5 H   in which R2, R3, R4 and R5 have the meanings indicated above, product of formula (VI) which is reacted with chlorosulfonic acid SO2 (OH) Cl to obtain the corresponding product of formula (VII) : R3 R2 \\ 01 HCI O (VII) NH R4   in which R2, R3, R4 and R5 have the meanings indicated above, a product of formula (VII) which is reacted with an amine of formula (VIII): R1 'NA (VIII) in which R1' has the significance indicated in any one of the above claims for R 1, wherein the optional reactive functional groups are optionally protected by protective groups, to obtain a product of formula (II): R 3 R 2 R 4 in which R 1 ', R 2, R 3 , R4 and R5 have the meanings indicated above, products of formula (II) which may be products of formula (I) and that, to obtain or of other products of formula (I), it is possible to subject, if desired and if necessary, to one or more of the following transformation reactions, in any order: a) an oxidation reaction of an alkylthio group to the corresponding sulfoxide or sulfone, b) an alkoxy functional transformation reaction in hydroxyl function, or hy (c) an alcohol function oxidation reaction according to the aldehyde or ketone function; (d) an elimination reaction of the protective groups which the protected reactive functions can carry; (e) an acid salification reaction. mineral or organic to obtain the corresponding salt, f) a resolving reaction of the racemic forms into split products, said products of formula (I) thus obtained being in all the possible isomeric forms racemic, enantiomers and diastereoisomers.   7) Process for the preparation of the products of formula (I) as defined above in which Y represents the radical NR7 as defined as defined in any one of the preceding claims with R7 represents CH2-RZ and RZ represents a alkyl, alkenyl or alkynyl radical, all optionally substituted with a naphthyl radical or with one or more identical or different radicals chosen from halogen atoms and phenyl and heteroaryl radicals, all these naphthyl, phenyl and heteroaryl radicals being themselves optionally substituted by one or more identical or different radicals selected from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF 3, NH 2, NHalk or N (alk) 2 radicals, characterized in that the compound of formula (A): wherein R 2, R 3, R 4 and R 5 have the meanings indicated in any one of the preceding claims and Ri 'a the meaning indicated in any one of the above claims for R 1, in which the optional reactive functional groups are optionally protected by protective groups, to a deprotection reaction of the carbamate function to obtain a product of formula (IX): R N S - ",,, _ ,,,, --- ,,, I \ / NH (IX) H   in which R 1 ', R 2, R 3, R 4 and R 5 have the meanings indicated above, product of formula (IX) which is subjected to reductive amination conditions in the presence of the aldehyde of formula (X): RZ CHO (X) in which RZ 'has the meaning indicated above for RZ, in which the optional reactive functional groups are optionally protected by protective groups, to obtain a product of formula (I2): ## STR2 ## He SN / \ O \ / N-CH2-RZ '(12) R4 H   in which R1 ', R2, R3, R4, R5 and RZ' have the meanings indicated above, products of formula (I2) which can be products of formula (I) and that, for obtaining or other products of formula (I), it is possible to subject, if desired and if necessary, in any order, to one or more reactions of transformations a) to f) as defined above, said products of Formula (I2) thus obtained being in all possible isomeric forms racemic, enantiomers and diastereoisomers.   8) As medicaments, the products of formula (I) as defined in any one of claims 1 to 5 and addition salts with pharmaceutically acceptable inorganic and organic acids of said products of formula (I) 9) As medicaments, the products of formula (I) as defined in any preceding claim whose names follow: - 2- {4- [4- (4-Fluoro-phenylamino) pyrimidine); 2-ylamino] -benzenesulfonylamino} -N (tetrahydro-pyran-4-yl) acetamide - 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methylN- (1-pyridin) 2-ylmethyl-piperidin-4-yl) -benzenesulfonamide - N- (2-dimethylaminoethyl) -4- [4- (4-fluorophenylamino) -pyrimidin-2-ylamino] -N (1-methylpiperidin-4-yl) ) -benzenesulfonamide - 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -N- (2-hydroxy-ethyl) -N- (1-methylpiperidin-4-yl) -benzenesulfonamide - 4- [4- (4-Fluoro-phenylamino) pyrimidin-2-ylamino] -N-methyl-N- (1-pyridyl-3-ylmethyl-piperidin-4-yl) benzenesulfonamide, as well as addition salts with inorganic and organic acids pharmaceutically acceptable salts of said products of formula (I).   10) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in claims 8 and 9 or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier.   11) Use of the products of formula (I) as defined in any one of claims 1 to 5 or pharmaceutically acceptable salts of these products for the preparation of a medicament for the treatment or prevention of a disease by inhibition of IKK protein kinase activity.   12) Use as defined in any one of the preceding claims wherein the protein kinase is in a mammal.   13) Use of a product of formula (I) as defined in any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: diseases inflammatory diseases, diabetes and cancers.   14) Use of a product of formula (I) as defined in any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of inflammatory diseases.   15) Use of a product of formula (I) as defined in any one of claims 1 to 5 for the preparation of a medicament for the treatment or prevention of diabetes.   16) Use of a product of formula (I) as defined in any one of claims 1 to 5 for the preparation of a medicament for the treatment of cancers.   17) Use according to claim 16 for the treatment of solid or liquid tumors.   18) Use according to claim 16 or 17 for the treatment of cytotoxic resistant cancers.   19) Use of a product of formula (I) as defined as defined in any one of claims 1 to 5 for the preparation of medicaments for the chemotherapy of cancers.   20) Use of a product of formula (I) as defined as defined in any one of claims 1 to 5 for the preparation of medicaments for cancer chemotherapy alone or in combination.   21) Products of formula (I) as defined in any one of claims 1 to 5 as inhibitors of IKK.