EP1904479A2 - Nouveaux derives de 2,4-dianilinopyrimidines, leur preparation, a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk - Google Patents

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

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Publication number
EP1904479A2
EP1904479A2 EP06778795A EP06778795A EP1904479A2 EP 1904479 A2 EP1904479 A2 EP 1904479A2 EP 06778795 A EP06778795 A EP 06778795A EP 06778795 A EP06778795 A EP 06778795A EP 1904479 A2 EP1904479 A2 EP 1904479A2
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EP
European Patent Office
Prior art keywords
formula
radical
pyrimidin
products
radicals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06778795A
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German (de)
English (en)
French (fr)
Inventor
Jean Wagnon
Jean-Flaubert Nguefack
Samir Jegham
Michaël BOSCH
Monsif Bouaboula
Pierre Casellas
Bernard Tonnerre
Jacob-Alsboek Olsen
Serge Mignani
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Sanofi SA
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Sanofi Aventis France
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Priority claimed from FR0507370A external-priority patent/FR2888239B1/fr
Priority claimed from FR0511950A external-priority patent/FR2893941B1/fr
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Publication of EP1904479A2 publication Critical patent/EP1904479A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • 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.
  • WO2004046118-A2 discloses 2,4-diphenylaminopyrimidine derivatives as inhibitors of cell proliferation.
  • a series of 5-cyano-2-aminopyrimidines are presented as inhibitors of KDR and FGFR kinases, in WO200078731-A1, other pyrimidines as inhibitors of FAK and IGFR in WO2004080980A-1, and also ZAP-70, FAK and / or Syk tyrosine kinase in WO2003078404A1, and PLK polokinases in WO2004074244-A2, as cytostatic agents.
  • the present invention thus relates to novel 2,4-dianilinopyrimidine derivatives having inhibitory effects vis-à-vis protein kinases.
  • the products of the present invention can thus notably be used for the prevention or control of treatment of conditions capable of being modulated by the inhibition of the activity of protein kinases.
  • the protein kinase IKK-alpha (IKK ⁇ ) and IKK-beta (IKK ⁇ ) are more particularly mentioned.
  • the compounds of the present invention are kinase inhibitors, in particular IKK-alpha and IKK-beta, therefore inhibit NF-KB (nuclear factor kappa B) activity, so they can be used in the treatment of prophylaxis and inflammatory diseases, in cancer and diabetes.
  • kinase inhibitors in particular IKK-alpha and IKK-beta, therefore inhibit NF-KB (nuclear factor kappa B) activity, so they can be used in the treatment of prophylaxis and inflammatory diseases, in cancer and diabetes.
  • NF-kB Nuclear factor kappa B
  • NF-kB belongs to a family of transcription factor complexes consisting of different combinations of Rel / NF-KB polypeptides.
  • Members of this family of NF- ⁇ B-related polypeptides regulate the expression of genes involved in immune and inflammatory responses. ((Bames PJ, Karin M (1997) N Engl J Med 336, 1066-1071) and (Baeuerle PA, Baichwal VR (1997) Adv Immunol 65, 111-137)).
  • NF- ⁇ B dimers are retained in inactive form in the cytoplasm by inhibitory proteins members of the IKB family (Beg et al., Genes Dev., 7: 2064-2070, 1993; Morin, Trends Genet 9: 427-43) 3), 199 '); Haskil and. al., Cell 65: 1281-1289, 1991).
  • the proteins of the IKB family mask the NF-KB nuclear translocation signal.
  • IKB-Kinase complex IKB-Kinase complex
  • IKK IKB-Kinase complex
  • IKB will be subject to ubiquitination leading to its degradation by the proteasome (26S), allowing thus the release and the translocation of NF- ⁇ B in the nucleus or it will bind to specific sequences at the level of the promoters of target genes thus inducing their transcription.
  • IKK IKB-Kinase complex
  • IKKa IKK1
  • IKK2 IKK ⁇
  • IKK2 IKK2 is the dominant kinase (Mercurio et al., Mol., Cell Biol., 19: 1526, 1999-, Zandi et al., Science, 28: 1, 3) 60, 1998; Lee and. al, Proe. Natl. Acad. Sci. USA 95:93) 19, 1998).
  • NF-KB genes regulated by NF-KB encode pro-inflammatory mediators, cytokines, cell adhesion molecules, and acute phase proteins, which in turn will induce the activation of NF- ⁇ B by autocrine or paracrine mechanisms.
  • NF-KB plays a role in the growth of normal cells but also malignant cells. Proteins produced by expression of NF- ⁇ B regulated genes include cytokines, chemokines, adhesion molecules, cell growth mediators, angiogenesis. In addition, various studies have shown that NF-KB plays an essential role in neoplastic transformations. For example NF- ⁇ B may be associated with cell transformation in vitro and in vivo following overexpression, amplification, rearrangement or translocation events (Mercurio, R, and Manning, AM (1999) Oncogene, 18: 6163- 6171). In some human lymphoid tumor cells, the genes encoding the different NF- ⁇ B members are rearranged or amplified. It has been shown that NF- ⁇ B can promote cell growth by inducing transcription of cyclin D, which associated with Rb hyperphosphorylation results in the transition of G1 to S phases and the inhibition of apoptosis.
  • NF- ⁇ B constitutive activity of NF- ⁇ B is found following the activation of IKK2.
  • NF- ⁇ B is constitutively activated in Hodgkin's disease and the inhibition of NF- ⁇ B blocks the growth of these lymphomas.
  • I ⁇ B ⁇ repressor induces apoptosis of cells expressing the H-Ras oncogenic allele (Baldwin, J. Clin Invest, 107: 241 (2001), Bargou et al., J. Clin Invest, 100: 2961 (1997), Mayo et al., Science 178: 1812 (1997).
  • NF- ⁇ B The constitutive activity of NF- ⁇ B appears to contribute to oncogenesis through the activation of several anti-apoptotic genes such as Al / Bfi-1, IEX-I, MAP, thus resulting in the suppression of the death pathway. cellular.
  • NF-KB 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- ⁇ B by the use of the super-repressor form of I ⁇ B ⁇ in parallel with chemotherapy treatment has been shown to increase the efficacy of chemotherapy in xenograft models.
  • the subject of the present invention is the products of formula (I): in which:
  • 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 halogen atom or an alkyl radical or a radical; alkoxy;
  • 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 with one or more radicals, which may be identical or different, chosen from halogen atoms, OR8 and NR8R9, the alkyl radicals represented by R1 being further optionally substituted by a 5-membered saturated or unsaturated heterocyclic radical attached by a carbon atom and optionally substituted with one or more radicals selected from halogen atoms and alkyl or alkoxy radicals,
  • A represents a single bond or a radical -CH2-CO-
  • NR6-, and R6, identical to or different from R1, is selected from the values of R1; the cycle containing -Y (or cycle (Y)) consisting of 4 to
  • R7 represents the hydrogen atom, a cycloalkyl radical 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 hydroxyl, alkoxy, phenyl and heteroaryl radicals, the alkyl radicals represented by R7 being furthermore optionally substituted with a phosphonate radical, with an optionally substituted alkylthio radical with a sulfone or with an optionally substituted heterocycloalkyl radical, R8 represents the hydrogen atom or the alkyl, cycloalkyl or heterocycloalkyl radicals themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl or N (alkyl) 2 radicals, the alkyl radicals which R 8 represents being moreover optionally substituted by an alkylthio radical, an
  • RIO represents a hydrogen atom or an alkyl radical, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula ( D -
  • the ring formed can in particular be a cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and particularly a cyclohexyl, these radicals being therefore substituted in particular in para, respectively, with OH, 2 F, the radical OR8 or the radical NR8R9 in which R8 and R9 are chosen from the meanings defined above.
  • the ring formed can in particular be an azetidine, pyrrolidine or piperidine radical with the N atom in para or in meta, which therefore bears the substituent R 7 as defined. above.
  • the ring formed can in particular be the 8 aza bicyclo (3,2,1) octyl cycle or a ring chosen from the following N, 9-dimethyl-9-azabicyclo [3.3.1] nona-3-yl, N, 6-dimethyl-6-azabicyclo [3.2.1] octan-3-yl, N, 3- dimethyl-3-azabicyclo [3.2.1] octan-8yl or else N, 3-dimethyl-3-azabicyclo [3.3. l] nonan-9-yl
  • the ring formed 'can' be in particular tetrahydro-2H-thiopyran or a tetrahydro-2H-thiofurane: when ring (Y) is such
  • Y represents SO2
  • the ring formed can in particular be a dioxidotetrahydro-3-thienyl
  • the ring formed can in particular be a tetrahydrofuran or tetrahydropyran.
  • the present invention particularly relates to the products of formula (I) as defined above 'wherein R2, R3, R4, R5, A and ring (Y) have the meanings indicated above and R represents a hydrogen atom or an alkyl radical containing from 1 to 5 linear or branched carbon atoms or else R 1 represents this alkyl radical substituted by a saturated or unsaturated, preferably monocyclic 5-membered heterocycle, itself optionally substituted as indicated above.
  • R 1 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms linear or branched optionally substituted and in particular CH3 and ring (Y) is such that Y represents NR7 with R7 represents an alkyl radical containing from 1 to 6 linear or branched carbon atoms substituted by a radical chosen from radicals hydroxyl, CF3, phosphonate, sulfone, phenyl and heterocyclic saturated or unsaturated monocyclic or bicyclic, these phenyl radicals and heterocyclic themselves being optionally substituted as indicated above.
  • R 1 represents an alkyl radical containing from 1 to 4 carbon atoms.
  • linear or branched carbon and especially CH3 and ring (Y) is such that Y represents NR8R9 in which R8 represents a hydrogen atom or CH3 and R9 represents an alkyl radical containing from 1 to 6 linear or branched carbon atoms substituted by a radical chosen from among the hydroxyl, CF 3, phosphonate, sulphone, phenyl and saturated or unsaturated monocyclic or bicyclic unsaturated heterocyclic radicals, these phenyl and heterocyclic radicals themselves being optionally substituted as indicated above: in particular, R 9 represents an alkyl radical containing from 1 to 4; linear or branched carbon atoms, in particular CH3 or C2H5, substituted by a saturated or unsaturated heterocyclic ring, preferably monocyclic, at 5
  • R1 represents a hydrogen atom, a CH3 radical or an alkyl radical containing from 1 to 4 linear or branched carbon atoms optionally substituted with an NH2, NHaIk, N (alk) 2 radical or by a saturated or unsaturated heterocycle, preferably a 5-membered monocycle such as pyrrolidine and ring (Y) represents a piperidine substituted on its nitrogen atom by R7 which represents an alkyl radical carrying a phosphonate
  • R1 is chosen from the values defined above and ring (Y) represents a cyclohexyl radical substituted with an NR8R9 radical as defined above
  • R1 represents a CH3 radical optionally substituted with a saturated or unsaturated heterocycle as defined above and R7 represents a CH3 radical;
  • R1 represents a hydrogen atom or a CH3 radical and ring (Y) represents a piperidine or a ring 8 aza bicyclo (3.2, 1) octyl substituted on their nitrogen atom by R7 with R7 as defined herein; -above.
  • Y represents -N-R7 with R7 represents an alkyl radical including CH3, C2H5 or C3H7 substituted by a phosphonate
  • Y represents -N-R7 with R7 represents an alkyl radical including CH3, C2H5 or C3H7 substituted by an alkylthio such as S-CH3 or S-C2H5 with S optionally oxidized to sulfone to form, for example SO2- CH3 or SO2-C2H5;
  • R7 represents alkyl such as in particular CH3 or C2H5 substituted with one or more radicals chosen from halogen atoms such as F, and phenyl and mono or bicyclic heterocycle radicals; , phenyl and heterocycle themselves optionally substituted by one or more radicals chosen from halogen atoms and alkyl, alkoxy, OH, CN, CF3, NH2, NHaIk and N (alk) 2: among these heterocycles which R7 carries, mention may be made in particular of 5-membered unsaturated heterocycles containing one to three heteroatoms selected from N, O and S: thus R 7 may especially represent the CH 2 -thienyl radicals, -CH2-thiazole (N, S), -CH2-thiadiazole (N, N, S), CH2-furan (O), -CH2-pyrazole (N, N), -CH2-isoxazole (N, O),
  • R7 may also carry heterocycles as defined above such as pyridine radicals (with N of pyridine at 3 different positions); 2,3-Dihydro-1H-indole; quinoline; isoquinoline; pyrimidine; 2,3-Dihydro-benzofuran; ([1,8] naphthyridin-pyridine N-oxide; 4 - [(Benzo [1,2,5] oxadiazole; (2,3-dihydro-benzofuran.
  • heterocycles as defined above such as pyridine radicals (with N of pyridine at 3 different positions); 2,3-Dihydro-1H-indole; quinoline; isoquinoline; pyrimidine; 2,3-Dihydro-benzofuran; ([1,8] naphthyridin-pyridine N-oxide; 4 - [(Benzo [1,2,5] oxadiazole; (2,3-dihydro-benzofuran.
  • Y represents CH-NR8R9 with NR8R9 such that R8 represents a hydrogen atom or an alkyl radical such as in particular CH3 and R9 represents a linear or branched alkyl radical such as in particular CH3, C2H5 or -CH2- or -CH (CH3) - or -CH (CH3) -CH2- substituted with either an optionally substituted saturated mono- or bicyclic heterocycle or an optionally substituted phenyl radical.
  • heterocycles carried by R9 mention may be made especially of the following radicals: pyridine (with N of pyridine at 3 different positions); 2,3-Dihydro-1H-indol; quinoline; isoquinoline; pyrimidine; 2,3-Dihydro-benzofuran; ([1,8] naphthyridine; 4 - [(Benzo [1, 2, 5] oxadiazole; (2,3-Dihydro-benzofuran;
  • Such heterocycles are optionally substituted with one or more radicals as defined above and chosen especially from the radicals CH3, CN, NH2, NHCH3.
  • the phenyl radical is optionally substituted by one or more radicals chosen especially from OH and CF3.
  • R 2 is chosen from among the following definitions:
  • R1 represents H
  • R1 represents CH3
  • R1 represents alkenyl (3C) radicals such as allyl or alkynyl (3C) such as propargyl
  • R1 represents alkyl and especially CH3, C2H5, C3H7 substituted with a radical chosen from NH2, NH (alk), N (alk) 2, NH-CH2-CH2OH, NH-CH2-C3H7-OH, NH (CH2-CF3); , alkoxy, OH, or a saturated heterocycle such as for example pyrrolidine, tetrahydrofuran or an unsaturated heterocycle such as in particular those defined above for R7: thus R1 may especially represent the radicals ⁇ CH2-thienyl, -CH2-thiazole (N, S), -CH2-thiadiazole (N, N, S), CH2-furan (O), -CH2-pyrazole (N, N), -CH2-isoxazole (N, O), -CH2-pyrrole (NH, NCH3) ), these radicals, in particular pyrazole, isoxazole or pyrrole, being themselves optionally substituted, in particular with alkyl containing from 1 to 3
  • R2, R3 and R4, which may be identical or different, are such that one represents a halogen atom and the other two, which are identical or different. different, represent a hydrogen atom or a halogen atom or an alkyl radical;
  • 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 -CH 2 -CO-NR 6 -, and R 6, which is identical to or different from R 1, is chosen from the values of R 1;
  • 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 hydroxyl, phenyl and heteroaryl, all these naphthyl, phenyl and heteroaryl radicals being themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl radicals, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NHaIk or " N (alk) 2;
  • 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 by 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.
  • R2, R3 and R4, 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 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 -CH 2 -CO-NR 6 -, and R 6, which is identical to or different from R 1, is chosen from the values of R 1; •
  • 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 themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF 3, NH 2, NHaIk or N radicals ( alk) 2;
  • heteroaryl radicals consisting of 5 to 10 members and containing 1 to 3 heteroatoms selected from O, S, N and NR10;
  • R8 represents the hydrogen atom or the alkyl, cycloalkyl or heterocycloalkyl radicals themselves optionally substituted by 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 0 S, N or NR10;
  • R10 represents a hydrogen atom or an alkyl radical; said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (D
  • halogen means fluorine, chlorine, bromine or iodine atoms and preferably fluorine, chlorine or bromine .
  • alkyl radical denotes a linear or branched radical containing at most 6 carbon atoms and especially the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or isopentyl radicals; pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and their linear or branched positional isomers.
  • hydroxyalkyl radical denotes the alkyl radicals indicated above substituted with at least one hydroxyl radical
  • 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, n-pentenyl and hexenyl, as well as their linear or branched positional isomers: among the alkenyl values, the allyl or butenyl values are more particularly mentioned.
  • 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- methylbut-2-ynyl, pentynyl or hexynyl and their linear or branched positional isomers: among the alkynyl values, the propargyl value is more particularly mentioned.
  • 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, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene;
  • 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 positional isomers,
  • cycloalkyl radical denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 7 ring members and in particular denotes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals,
  • -O-cycloalkyl radical denotes a radical in which the cycloalkyl radical has the meaning indicated above
  • aryl radical refers to unsaturated, monocyclic or fused carbocyclic ring radicals. Examples of such an aryl radical include phenyl or naphthyl radicals.
  • heterocyclic radical denotes a saturated (heterocycloalkyl) or partially or completely unsaturated (heteroaryl) carbocyclic radical consisting of 4 to 10 members interrupted by one or three heteroatoms, identical or different, chosen from oxygen, nitrogen or sulfur.
  • heteroaryl radicals containing at least one heteroatom selected from sulfur, nitrogen and oxygen mention may be made, for example, of benzothienyl such as 3-benzothienyl, benzofuryl, benzofuranyl, benzimidazolyl, benzoxazolyl, indolyl, quinolyl, isoquinolyl and azaindolyl. naphthyridinyl.
  • fused heteroaryl radicals there may be mentioned more particularly 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 with one or two identical or different radicals chosen in particular from alkyl radicals, and cycloalkyl and heterocycloalkyl radicals as defined above, in particular to give alkylamino radicals NHaIk, 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) and dialkylamino radical or N (alk) 2 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
  • cycloalkylamino thus denotes an amino radical substituted in particular by a cycloalkyl radical chosen from the radicals defined above: there may thus be mentioned for example the cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino radicals.
  • cyclic amine denotes a monocyclic or bicyclic radical containing from 3 to 10 members in which at least one carbon atom is replaced by a nitrogen atom, this cyclic radical possibly also containing one or more other heteroatoms chosen from O, S, SO 2, N or NR 10 with R 10 as defined above:
  • examples of such cyclic amines include, for example, pyrrolyl, piperidyl, morpholinyl, piperazinyl, pyrrolidinyl and azetidinyl radicals. Mention may more particularly be made of piperidinyl, morpholinyl, piperazinyl or azetidinyl radicals.
  • patient refers to humans but also other mammals.
  • Prodrug refers to a product that can be converted in vivo by metabolic mechanisms (such as hydrolysis) into a product of formula (I).
  • metabolic mechanisms such as hydrolysis
  • an ester of a product of formula (I) containing a hydroxyl group can be converted by in vivo hydrolysis to its parent molecule.
  • hydroxyl group-containing esters of the formula (I) such as acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bisulfates and the like.
  • Esters of products of formula (I) particularly Useful hydroxyl-containing compounds can be prepared from acidic residues such as those described by Bundgaard et al. al., J. Med. Chem. , 1989, 32, page 2503-2507: these esters include especially
  • the addition salts with the inorganic or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid and aryldisulphonic acids.
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but of which the different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent may be in axial or equatorial position.
  • stereoisomerism due to the different spatial arrangements of attached substituents, either on double bonds or on rings, often referred to as E / Z geometrical isomerism or cis-trans or diastereoisomeric isomerism.
  • stereoisomer is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
  • 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 the fluorine atom, OR8 and NR8R9;
  • A represents a single bond or a radical -CH2-CO-NR6-, and R6 represents a hydrogen atom or a linear or branched alkyl radical containing at most 4 carbon atoms;
  • 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, NHaIk or N (alk) 2 radicals;
  • 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 pyrrolyl, piperidyl and morpholinyl radicals, pyrrolidinyl, azetidinyl and piperazinyl optionally substituted on its second atom by an alkyl radical;
  • R2, R3 and R4, which are identical or different, are such that one represents a fluorine atom and the other two, which are identical or different, represent a hydrogen atom 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-CO-NR6-, 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, CH-NHaIk 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 themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, methoxy, methyl, hydroxymethyl, methoxymethyl, trifluoromethyl, amino, methylamino and dimethylamino;
  • R2, R3 and R4, which are identical or different, are such that one represents a fluorine atom and the two others represent one, a hydrogen atom and the other a fluorine or chlorine atom or a radical; methyl;
  • 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 an amino, alkylamino, dialkylamino or pyrrolidinyl radical;
  • A represents a single bond, -CH 2 -CO-NH- or -CH 2 -CO-NCH 3 - and the ring containing Y is selected from cyclohexyl radicals itself optionally substituted by amino; tetrahydropyran; dioxidothiényle; and pyrrolidinyl, piperidinyl and azepinyl radicals optionally substituted on their nitrogen atom by a methyl, propyl, isopropyl, isobutyl, isopentyl or ethyl radical, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radical
  • R2, R3 and R4, which are identical or different, are such that one represents a fluorine atom and the two others represent one, a hydrogen atom and the other a fluorine or chlorine atom or a radical; methyl;
  • R5 represents a hydrogen atom
  • R1 represents a methyl radical; or an ethyl radical, optionally substituted by an amino, alkylamino, dialkylamino or pyrrolidinyl radical,
  • A represents a single bond and the ring containing Y represents a cyclohexyl radical, itself optionally substituted with amino, or a piperidinyl radical optionally substituted on its nitrogen atom by a methyl, propyl, isopropyl or isobutyl radical; isopentyl or ethyl, themselves optionally substituted by one or more halogen atoms or a radical chosen from hydroxyl; phenyl itself optionally substituted with halogen; quinolyl; pyridyl optionally oxidized on its nitrogen atom; furyl; and imidazolyl itself optionally substituted with alkyl;
  • R2, R3 and R4, which are identical or different, are such that one represents a fluorine atom and the two others represent 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, -CH2 -CO-NH- or -CH2-CO-NCH3- and the ring containing Y is chosen from tetrahydropyran, dioxidothienyl and pyrrolidinyl, piperidyl and azepinyl radicals; optionally substituted on their nitrogen atom with a methyl or ethyl radical, themselves optionally substituted with a phenyl, pyridyl, thienyl, & thiazolyl, pyrazinyl, furyl or imidazolyl radical;
  • R 1 represents hydrogen
  • A preferably represents the -CH 2 -CO-NR 6 radical as defined above.
  • the subject of the present invention is particularly the products of formula (I) corresponding to the following names: 2- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonylamino ⁇ -N (tetrahydro 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridin-2-ylmethyl-piperidin-4-yl] -pyran-4-yl) -acetamide N- (2-Dimethylamino-ethyl) -4- [4- (4-fluorophenylamino) -pyrimidin-2-ylamino] -N- (1-methylpiperidin-4-yl) -benzenesulfonamide benzenesulfonamide 4 [4- (4-Fluoro-phenylamino) -pyrimidin-2-
  • 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-yl) benzenesulfonamide N- (2-Dimethylamino-ethyl) -4- [4- (4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (1-methyl-piperidin-4-yl) -benzenesulfonamide 4- [4- (4-Fluoro-phenylamino) -
  • the subject of the present invention is also 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) is reacted:
  • products of formula (II) which can be products of formula (I) and that, to obtain or of other products of formula ( I), one or more of the following transformation reactions may be subjected, if desired and if necessary, in any order: a) an oxidation reaction of an alkylthio group to the corresponding sulphoxide or sulfone, b) a conversion reaction of alkoxy function to hydroxyl function, or of hydroxyl function in alkoxy function, c) an oxidation reaction of alcohol function as an aldehyde or ketone function, d) an elimination reaction of the protective groups that can carry the protected reactive functions, e) a salification reaction with a mineral or organic acid for to obtain the corresponding salt; f) a reaction of resolution of the racemic forms into split products, said products of formula (I) thus obtained being in all the possible isomeric forms racemic, enantiomers and diastereois
  • the subject of the present invention is also a process for the preparation of the products of formula (I) as defined above in which Y represents the radical NR7 as defined above with R7 represents CH2-RZ and RZ represents an alkyl radical, 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 by a or more identical or different radicals selected from halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NHaIk or N (alk) 2 radicals.
  • Y represents the radical NR7 as defined above with R7 represents CH2-RZ and RZ represents an alkyl radical, alkenyl or alkynyl, all optionally substituted with a naphthy
  • Such a process is characterized in that the compound of formula (A) is subjected to: above, to a deprotection reaction of the carbamate function to obtain a product of formula (IX):
  • the product of formula (II) is subjected to the action of the product of formula (III) as defined above in particular in an alcohol such as for example butanol, propanol, ethanol or dimethylformamide between 80 and 140 0 C, to give a product of formula (IV) as defined above.
  • an alcohol such as for example butanol, propanol, ethanol or dimethylformamide between 80 and 140 0 C
  • the product of formula (IV) thus obtained is subjected to the action of the aniline of formula (V) as defined above in particular in an alcohol such as for example butanol or dimethylformamide, in the presence or absence of a strong acid (HCl) in catalytic amount under reflux conditions to give a product of formula (VI) as defined above.
  • the product of formula (VI) thus obtained is subjected to the action of chlorosulfonic acid, in particular firstly 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, in the presence of an organic base such as triethylamine, diisopropylethylamine or N-methyl morpholine, to give a product of formula (I ') as defined above.
  • an organic base such as triethylamine, diisopropylethylamine or N-methyl morpholine
  • the deprotection reaction of the carbamate function of the compound of formula (A) to obtain a product of formula (IX) can be carried out using, for example, an acidic agent such as pure trifluoroacetic acid at a temperature close to 0 ° C. or to a mixture of this acid with a suitable solvent such as methylene chloride at about 0 ° C. or else using hydrochloric acid dissolved in ether or dioxane at a temperature of between 0 ° C. and room temperature .
  • an acidic agent such as pure trifluoroacetic acid at a temperature close to 0 ° C. or to a mixture of this acid with a suitable solvent such as methylene chloride at about 0 ° C. or else using hydrochloric acid dissolved in ether or dioxane at a temperature of between 0 ° C. and room temperature .
  • the product of formula (IX) is subjected to reductive amination conditions in the presence of the aldehyde or ketone of formula (X) to give a product of formula (12) 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.
  • a solvent such as methanol, tetrahydrofuran (THF) or their mixture in a pH medium of between 4 and 7.
  • the products of formulas (II) and (12) 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 of known to those skilled in the art and for example by being subjected to one or more of reactions a) to f) • foundedes- above.
  • the hydroxyl groups may be protected, for example, by alkyl radicals .
  • alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl
  • the amino groups can be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, phthalimido or other radicals radicals.
  • the amino functions can in particular be protected by a group such as Boc or CH 2 -phenyl and can then be released under the usual conditions known to those skilled in the art.
  • the reactions to which the products of formula (I ') as defined above may be subjected, if desired or necessary, may be carried out, for example, as indicated below.
  • the saponification reactions may be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.
  • the reduction or oxidation reactions may be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as ethyl ether or tetrahydrofuran, in the presence of sodium borohydride or lithium aluminum hydride. ; or for example in a solvent such as acetone or tetrahydrofuran in the presence of potassium permanganate or pyridinium chlorochromate.
  • sulfoxide function can be promoted by an equimolar mixture of the product containing an alkylthio group and the reagent such as in particular a peracid.
  • sulphone function can be promoted by a mixture of the product containing an alkylthio group with an excess of the reagent such as in particular a peracid.
  • the optional alkoxy functions, such as methoxy in particular, of the products described above may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as for example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or refluxing trifluoroacetic acid.
  • a solvent such as for example, methylene chloride
  • hydrobromide or pyridine hydrochloride hydrobromic or hydrochloric acid in water or refluxing trifluoroacetic acid.
  • the possible alcohol functions of the products described above can be, if desired, transformed into.
  • oxidation aldehyde or ketone function under the usual conditions known to those skilled in the art such as for example by the action of manganese oxide to obtain the aldehydes or by the action of potassium permanganate or pyridinium chlorochromate to access the ketones for to access ketones.
  • 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 para-toluene sulfonic, formic or trifluoroacetic or by catalytic hydrogenation.
  • the phthalimido group may in particular be removed by hydrazine.
  • the products of formula (II) which are therefore pyrimidine derivatives and the products of formulas (III), which are aniline derivatives can be marketed products such as the dichloropyrimidine, trichloropyrimidine, 4-fluoroaniline 3,4-difluoroaniline, 4-fluoro-3-chloroaniline, or aniline.
  • the anilines of formula (III) may in particular be commercial anilines such as, for example, the following trihalogenated anilines: -3,4,5-trifluoroaniline -2,3,4-trifluoroaniline -2-chloro-4,6-difluoroaniline -2 4,4,5-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.
  • non-commercial amines of formula (VIII) can be prepared according to methods known to those skilled in the art and in particular by the three procedures 1, 2 and 3 indicated below in the experimental part.
  • aldehydes or ketones of formula (X) are given in the experimental part • As non-limiting examples.
  • the present invention also relates to the process according to Scheme 1 below, for the preparation of products of formula (I) as defined above:
  • the radical NR8-CH (RA) (RB) represents certain values of NR8R9 as defined above with R8 as defined above and R9 represents -CH (RA) (RB) ie, as defined for R 9, a linear or branched alkyl radical optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl, N (alkyl) 2, alkylthio, phenyl and saturated or unsaturated heterocycle radicals, phenyl and heterocycle themselves optionally substituted as indicated above.
  • RA may represent a hydrogen atom or CH3
  • RB may represent (CH2) nA with A represents an optionally substituted heterocycle or phenyl radical as defined above and n represents an integer of 0 to 5.
  • the steps of the synthesis method of Scheme 1 above can be carried out according to the usual methods known to those skilled in the art and in particular as described below for the preparation of Examples 66 to 85.
  • the present invention also relates to the process according to Scheme 2 below, for the preparation of products of formula (I) as defined above:
  • R 1, R 2, R 3, R 4, A and ring (Y) have the meanings indicated above for the products of formula (I).
  • 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 10 ⁇ M.
  • the compounds of the present invention can thus inhibit the activation of NF- ⁇ B, and the production of cytokines with IC 50 of less than 10 ⁇ M.
  • the compounds of the present invention can thus inhibit the proliferation of a large panel of tumor cells with IC50 values of less than 10 ⁇ M.
  • the compounds of formula (I) may therefore have drug activity in particular as inhibitors of IKK1 and IKK2 and may be used in the prevention or treatment of diseases in which the inhibition of IKK1 or IKK2 is beneficial.
  • diseases such as inflammatory diseases or diseases with an inflammatory component such as inflammatory arthritis including rheumatoid arthritis, spondyl osteoarthritis, Reiters syndrome, psoriatic arthritis, bone resorption diseases; multiple sclerosis, inflammatory bowel disease including Crohn's disease; asthma, chronic pulmonary obstruction, emphysema, rhinitis, acquired myasthenia gravis, graft disease, transplant rejection, psoriasis, dermatitis, allergic disorders, immune system diseases, cachexia, severe acute respiratory syndrome, septic shock, heart failure, myocardial infarction, atherosclerosis, reperfusion injury, AIDS, cancer and insulin resistance disorders such as diabetes , hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, polycystic ovarian diseases, hypertension, cardiovascular disorders, Syndrome X, autoimmune diseases such as in particular systemic lupus, lupus erythematosus, glomerulonep
  • the products of formula (I) according to the present invention as modulators of apoptosis may be useful in the treatment of various human diseases including aberrations in apoptosis such as cancers: such as in particular but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone-dependent tumors of the breast, prostate and ovary, and precancerous lesions such as polyposis familial adenoma, viral infections (such as, but not limited to, but not limited to those caused by Herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), myelodysplastic syndromes, ischemic disorders associated with myocardial infarction, cerebral congestion, arrhythmia, atherosclerosis, hepatic disorders induced by toxins or alcohol, haematological disorders such as, but not limited to, chronic anemia.
  • t Aplastic anemia degenerative diseases of the musculoskeletal system such as, but not limited to, osteoporosis, cystic
  • the compounds according to the invention have an anticancer activity and an activity in the treatment of other proliferative diseases such as psoriasis, restenosis, atherosclerosis, AIDS for example, as well as in diseases caused by proliferation.
  • these compounds are useful in the prevention and treatment of leukemias, both primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer, lung cancer, cancer of the lungs, the small intestine, colon and rectal cancer, cancer of the respiratory tract, oropharynx and hypopharynx, esophageal cancer, liver cancer, stomach cancer, bile duct cancer, cancer of the gall bladder, pancreatic cancer, urinary tract cancers including kidney, urothelium and bladder, cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma; cancers of the male genital tract including prostate cancer, seminal vesicles, testes, germ cell tumors; cancers of the endocrine glands including thyroid, pituitary, adrenal gland cancer; skin cancers including hemangiomas, melanomas, sarcomas, including Kaposi's sar
  • the compound (s) of formula (I) may be administered in combination with one or more anti-cancer active principle (s), in particular antitumor compounds such as alkylating agents such as alkylsulfonates ( busulfan), dacarbazine, procarbazine, nitrogen mustards (chlormethine, melphalan, chlorambucil), cyclophosphamide, ifosfamide; nitrosoureas such as carmustine, lomustine, semustine, streptozocin; antineoplastic alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel or taxotere; antineoplastic antibiotics such as actinomycin; intercalators, antineoplastic antimetabolites, folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogues such as mercaptopurine, 6-thioguanine; inhibitors of pyrimidine synthesis, aromatase
  • the compounds of formula (I) may also be administered in combination with one or more other active ingredients useful in one of the pathologies indicated above, for example an anti-emetic, anti-pain, anti-inflammatory agent, anticachexia.
  • the subject of the present invention is thus, as medicaments, the products of formula (I) as defined above as well as the addition salts with pharmaceutically acceptable inorganic and organic acids of said products of formula (I).
  • the subject of the present invention is, in particular, as medicaments, the products of formula (I) as defined above whose names follow:
  • 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 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 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 169 of the present invention.
  • non-commercial amines used in step 4 of the preparation of the examples of the present invention may be prepared according to procedures 1, 2 and 3 described hereinafter.
  • pyridine-2-carbaldehyde 500 mg 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 mixture and then the mixture is 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.
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-fluoro-phenyl) -amine
  • dichloropyrimidine a mixture containing 15 g of dichloropyrimidine in 200 ml of n-butanol, with stirring, 10 ml of 4-fluoroaniline and then 18 ml of di-isopropyl-ethylamine are added.
  • the reaction mixture is stirred under reflux for 2 hours.
  • the reaction medium is cooled and concentrated to dryness.
  • Step 2 N-4- (4-Fluoro-phenyl) -N-2-phenyl-pyrimidine-2,4-diamine
  • Step 3 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride
  • Step 4 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-piperidin-4-yl) benzenesulfonamide
  • 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 Example 1 starting from 400 mg of 4- [4- (4-Fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 204 mg of 2-amino-N-methyl-N- (tetrahydro-pyran-4-yl) acetamide hydrochloride. 260 mg of expected product is thus obtained.
  • Step 4 of Example 1 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 252 mg of (1-Benzyl-piperidin-4-yl) methyl-amino hydrochloride.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluoro) chloride hydrochloride. phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl which is reacted with 200 mg of (1-Benzyl-pyrrolidin-3-S-yl) methylamino (commercial product). In this way 298 mg of expected product is obtained.
  • Example 8 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide
  • Step 1 Preparation of the intermediate 4- (4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] - benzenesulfonyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester:
  • Step 4 of Example 1 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.
  • Step 2 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride
  • Example 8 can serve 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. which would use the same procedure as procedure 2.
  • Step 4 of Example 1 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 g. mg of methyl- (1-pyridin-2-ylmethyl-piperidin-4-yl) -amine hydrochloride.
  • Step 4 of Example 1 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 174 mg of (1-ethyl-piperidin-4-yl) -methyl-amino hydrochloride.
  • Example 11 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methylpiperidin-4-yl) benzenesulfonamide
  • Step 1 4-Chloro-N- (3,4-difluorophenyl) pyrimidin-2-alminine
  • Step 2 N 2 - (3,4-difluorophenyl) -N 4 -phenylpyrimidine-2,4-diamine
  • Step 3 4- [4- (3,4-Difluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride
  • Step 4 4- [4- (3,4-Difluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methylpiperidin-4-yl) benzenesulfonamide
  • Step 1 4-Chloro-N- (3-chloro-4fluorophenyl) pyrimidin-2-amine
  • stage 2 N 2 - (3-chloro-4fluorophenyl) -N 4 -phenylpyrimidine-2,4-diamine
  • Step 4 4- [4- (3-Chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methylpiperidin-4-yl) benzenesulfonamide
  • Step 4 of Example 1 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) to obtain 250 mg of expected product.
  • Example 13 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-thiophen-2-ylmethyl-piperidin-4-yl) -benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 261 mg. of methyl (1-thiophen-2-ylmethyl-piperidin-4-yl) amine hydrochloride.
  • Example 16 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-thiophen-3-ylmethyl-piperidin-4-yl) -benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 261 mg. of methyl- (1-thiophen-3-ylmethyl-piperidin-4-yl) amine hydrochloride.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of [4- (4-Fluorophenylamino) -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)
  • Example 19 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (2-hydroxy-ethyl) -N- (1-methyl-piperidin-4-yl) benzenesulfonamide
  • Step 1 (2,6-Dichloro-pyrimidin-4-yl) - (4-fluorophenyl) -amine
  • Step 2 6-Chloro-N * 4 * - (4-fluoro-phenyl) -N * 4 * -methyl-N * 2-phenyl-pyrimidine-2,4-diamine
  • Step 3 4- [4-Chloro-6- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride.
  • Step 4 of Example 1 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 the methyl (4-methyl-piperidin-4-yl) amine (commercial product). 300 mg of expected product are thus obtained.
  • Example 21 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-methyl-azepan-4-yl) benzenesulfonamide
  • Step 4 of Example 1 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 g. mg of methyl- (1-pyridyl-3-yl-methyl-piperidin-4-yl) -amine hydrochloride.
  • Example 23 4- [4- (4-Fluoro-phenylamino) -6-methyl-pyrimidin-2-ylamino] -N-methyl-N- (1-thiazol-2-ylmethyl-piperidin-4-yl) -benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 260 mg of methyl- (1-thiazol-2-ylmethyl-piperidin-4-yl) -amine hydrochloride.
  • Example 24 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-pyridyl-4-ylmethyl-piperidin-4-yl) -benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 254 g. mg of methyl- (1-pyridyl-4-yl-methyl-piperidin-4-yl) -amine hydrochloride.
  • Example 25 2- ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonylamino ⁇ -N-methyl-N- (1-methylpiperidin-4-yl) -acetamide
  • Step 4 of Example 1 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 273 mg. of 2-Amino-N-methyl-N- (1-methyl-piperidin-4-yl) -acetamide hydrochloride. 260 mg of expected product is thus obtained.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 294 mg of hydrochloride. methyl- (1-pirazin-2-yl-methyl-piperidin-4-yl) -amine.
  • Example 27 4- [4- (4-Fluoro-phenylamino) -6-methyl-pyrimidin-2-ylamino] -N- (1-furan-3-ylmethyl-piperidin-4-yl) -N-methyl-benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with sodium chloride. mg of (1-furan-3-ylmethyl-piperidin-4-yl) -methyl-amine hydrochloride. This gives 220 mg of expected product.
  • Example 24 4- [4- (4-Fluoro-phenylamino) -6-methyl-pyrimidin-2-ylamino] -N- (1H-imidazol-2-ylmethyl-piperidin-4-yl) -N-methyl-benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with sodium chloride. mg of [1- (1H-imidazol-2-ylmethyl) -piperidin-4-yl] -methyl-amine hydrochloride. 246 mg of expected product is thus obtained.
  • Example A The procedure is as in Example A starting from 2 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 920 mg N * 1 *, N * 1 * -Dimethyl-ethane-1,2-diamine. 1.3 g of expected product are obtained.
  • Example A The procedure is as in Example A starting from 2 g of 4-Oxopiperidine.-1-carboxylic acid tert-butyl ester and 1.22 g of N * 1 *, N * 1 * -Diethyl-ethane-1,2 -dia ⁇ nine. 1.35 g of expected product are obtained.
  • Example A The procedure is as in Example A starting from 2 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 1.2 g of 2-pyrrolidin-1-yl-ethylamine. 1.17 g of expected product is obtained.
  • Methyl- [2- (1-methyl-piperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester We proceed as. in Example A starting from 2 g of 1-methyl-piperidin-4-one and 2.05 g of (2-aminoethyl) -tnethylcaramic acid tert-butyl ester. 550 mg of expected product is obtained.
  • Example A The procedure is as in Example A starting from 2 g of 1-methylpiperidin-4-one and 2.88 g of (2-amino-ethyl) carbamic acid tert-butyl ester. 950 mg of expected product is obtained.
  • Example 29 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- [1- (1-N-oxide-pyridin-4-ylmethyl) -piperidin-4-yl] -N-methyl- benzenesulphonamide
  • a reductive amination reaction is carried out starting from 300 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride. (Example 8) which is reacted with 67 mg of 1-N-oxide-pyridine 4-carbaldehyde. 225 mg of expected product is thus obtained.
  • Example 30 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- [1- (2-methyl-3H-imidazol-4-ylmethyl) -piperidin-4- yl] benzenesulfonamide
  • a reductive amination reaction is carried out starting from 300 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride. (Example 8) which is reacted with 60 mg of 2-methyl-3H-imidazole-4-carbaldehyde. 190 mg of expected product is thus obtained.
  • a reductive amination reaction is carried out starting from 300 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride. (Example 8) which is reacted with 66 mg of 2-fluoro-benzaldehyde
  • a reductive amination reaction is carried out starting from 300 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride. (Example 8), which is reacted with 66 mg of 3-fluoro-benzaldehyde to give 195 mg of expected product.
  • Example 34 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- [1- (1-methyl-1H-imidazol-2-ylmethyl) -piperidin-4- yl] benzenesulfonamide
  • a reductive amination reaction is carried out starting from 300 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride. (Example 8) which is reacted with 60 mg of 1-methyl-1H-imidazole-5-carbaldehyde.
  • Example 35 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- (1-quinolin-3-ylmethyl-piperidin-4-yl) -benzenesulfonamide
  • reaction is carried out by means of a reductive amination reaction starting from 300 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride. (Example 8) which is reacted with 84 mg of quinoline-3-carbaldehyde.
  • Example 36 4- [4- (3-Chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N- [1- (4-fluoro-benzyl) -piperidin-4-yl] -N-methyl benzenesulfonamide
  • a reductive amination reaction is carried out starting from 600 mg of 4- [4- (3-chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl hydrochloride (product obtained in Step 3 of the invention). example 12) that we do react with 66 mg of 4-fluoro-benzaldehyde
  • Example 37 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (1-isopropyl-piperidin-4-yl) -N-methylbenzenesulfonamide
  • a reductive amination reaction is carried out starting from 300 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide hydrochloride. (Example 8) which is reacted with 38 mg of Propan-2-one.
  • Example 38 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- (1-isobutyl-piperidin-4-yl) -N-ethylbenzenesulfonamide
  • reaction is carried out by means of a reductive amination reaction starting from 300 mg of 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl hydrochloride hydrochloride.
  • benzenesulfonamide (Example 8) reacted with 48 mg of 2-methyl-propionaldehyde
  • Example 39 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- [1- (3-methyl-butyl) -piperidin-4-yl] benzenesulfonamide
  • reaction is carried out by means of a reductive amination reaction starting from 300 mg of 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl hydrochloride hydrochloride.
  • benzenesulfonamide (Example 8) which is reacted with 56 mg of 3-methyl-butyraldehyde
  • Example 40 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- [1- (4,4,4-trifluorobutyl) -piperidin-4-yl] benzenesulfonamide
  • a reductive amination reaction is carried out starting from 300 mg of hydrochloride hydrochloride of 4- [4- (4-Fluoro-phenylamino) -pyriendin-2- ⁇ lamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide (Example 8) which is reacted with 82 mg of 4,4,4-trifluoromethyl- butyraldehyde.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride (product obtained in Step 3 of the invention).
  • Example 1 which is reacted with 230 mg of [2- (1-methyl-piperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester.
  • Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride (product obtained in Step 3 of the invention).
  • Example 1 is reacted with 241 mg of ester 4- (2-dimethylaminoethylamino) -piperidine-1-carboxylic acid tert-butyl.
  • Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride (product obtained in Step 3 of the invention).
  • Example 1 is reacted with 265 mg of ester 4- (2-Diethylaminoethylamino) -piperidine-1-carboxylic acid tert-butyl.
  • Example 45 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-piperidin-4-yl-N- (2-pyrrolidin-1-yl-ethyl) -benzenesulfonamide hydrochloride
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride. (product obtained in Step 3 of Example 1) is reacted with 264 mg of ester 4- (2-pyrrolidin-1-yl-ethylamino) -piperidine-1-carboxylic acid tert-butyl.
  • Example 46 4- [4- (4-Fluoro-phenylamino) pyrimidin-2-ylamino] -N- (2-methylamino-ethyl) -N- (1-methylpiperidin-4-yl) -benzenesulfonamide hydrochloride
  • Example 1 420 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride (product obtained in Stage 3 of Example 2) is used as in Step 4 of Example 1.
  • Example 1) which is reacted with 300 mg of Methyl- [2- (1-methylpiperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride (product obtained in Step 3 of the invention).
  • Example 1 which is reacted with 202 mg of (4-Methylamino-cyclohexyl) -carbamic acid tert-butyl ester.
  • This compound 47 is in the form of a 60/40 mixture of two cis and trans isomers, and is used as a starting material in the reductive amination reaction for the synthesis of the compounds of Examples 65 to 85 as well as Examples 157 and 158. .
  • Example 48 N- (2-Amino-ethyl) -4- [4- (4-fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -N-piperidin-4-yl-benzenesulfonamide hydrochloride
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride.
  • Step 1 (2-Chloro-pyrimidin-4-yl) - (4-fluoro-3-methylphenyl) -amine
  • Step 2 N * 4 - (4-Fluoro-3-methyl-phenyl) -N * 2-phenyl-pyrimidine-2,4-diamine
  • Step 3 4- [4- (4-Fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride
  • Step 4 4- ((2-tert-Butoxycarbonylamino-ethyl) - ⁇ 4- [4- (4-fluoro-3-methyl-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -amino) -piperidine-1 -carboxylic acid tert-butyl ester
  • Example 49 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- [1- (2-hydroxy-2-methyl-propyl) -piperidin-4-yl] -N-methyl benzenesulfonamide
  • a nucleophilic substitution reaction is carried out starting from 300 mg of 4- [4- (4-Fluoro-phenylamino) -pyrrolidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide (Example 8). ) that is reacted with 81 mg of 1, 2-epoxy-2-methyl propane in a microwave reactor (power: 200 W, temperature: 140 0 C). In this way 150 mg of expected product is obtained.
  • Example 50 N- (2-Aminoethyl) -4- [4- (3-chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -N- hydrochloride himself
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 400 mg of 4- [4- (3-chloro-4-fluoro-phenylamino) -pyrimidin-2-ylamin] -benzenesulfonyl chloride hydrochloride (product obtained at this stage). 3 of Example 12) which is reacted with 264 mg of 4- (2-pyrrolidin-1-yl-ethylamino) -piperidine-1-carboxylic acid tert-butyl ester ester.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 1 g of 4- [4- (2,4,5-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl hydrochloride which is reacted with 828 mg of Methyl- [2- (1-methyl-piperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester.
  • Step 1 Diethyl [(4-tert-Butoxycarboxylamino piperidin-1-yl) ethyl] phosphonate: A mixture containing 4 g of tert-butyl 4-piperidin-4-yl-carbamic acid ester, 5.38 g of diethyl 2-bromoethylphosphonate, 3.2 g of sodium carbonate in 50 ml of ethanol is refluxed for 18 hours. After cooling the reaction medium, the solid is filtered off and the filtrate is concentrated under vacuum.
  • Step 2 Diethyl [(4-aminopiperidin-1-yl) ethyl] phosphonate: According to procedure 2 of Example 8, a decarboxylation reaction, starting from 6.6 g of diethyl [(4-tert-butoxycarboxylamino) piperidin-1 yl) ethyl] phosphonate synthesized in stage 1 makes it possible to obtain a 3.7 g of expected product.
  • Step 3 The procedure is as in Step 4 of Example 1 starting from 500 mg of 4- [4- (3,4-difluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 400 mg of diethyl [(4-aminopiperidin-1-yl) ethyl] phosphonate, 480 mg of expected product is obtained with a yield of 62%.
  • Example 54 Diethyl ( ⁇ 4- [ ⁇ [4 ( ⁇ 4- [(3,4-difluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ (methyl) amino] piperidin-1-yl ⁇ methyl ) phosphonate
  • Step 1 Diethyl [(4-tert-Butoxycarboxylamino piperidin-1-yl) methyl] phosphonate: To a solution containing 4 g of tert-butyl 4-piperidin-4-yl-carbamic acid ester in 5 mL of dioxane is added successively 5.3 mL of a 37% aqueous solution of formaldehyde, followed by 8.75 mL of diethylphosphate. The reaction medium is refluxed for 30 minutes.
  • Stage 3 The procedure is as in Step 4 of Example 1 starting from 500 mg of 4- [4- (3,4-difluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which It is reacted with 412 mg of diethyl [(4-aminopiperidin-1-yl) methyl] phosphonate dihydrochloride. In this way 150 mg of expected product is obtained with a yield of 23%.
  • Stage 1 4- (benzyloxycarbonyl-methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester: To a solution of 5 g of 4-methylamino-peperidin-1-carboxylic acid tert-butyl ester and 3.9 ml of triethylamine in 25 ml of dichloromethane, 4 ml of benzyl chloroformate are added dropwise at 0 ° C. After stirring for 90 minutes at room temperature, 100 ml of water are added and then the mixture is extracted with twice 100 ml of dichlorometan. The organic phase is dried over sodium sulfate and concentrated in vacuo. Purification by chromatography on silica (Dichloromethane-ethyl acetate 95-5) makes it possible to obtain 6 g of the expected product with a yield of 73%.
  • Step 2 4- (Benzyloxycarbonyl-methylamino) -1H-piperidine hydrochloride:
  • Step 3 Diethyl ( ⁇ 2- [4- (benzyloxycarbonyl-methyl-amino) -piperidin-1-yl ⁇ ethyl) phosphonate: According to the method described in Step 1 of Example 53, from 4.9 g of compound synthesized in stage 1, in the presence of 4.6 g of diethyl 2-bromoethylphosphonate and 4.5 g of sodium carbonate, 6.4 g of expected product is obtained.
  • Step 4 Diethyl ⁇ 2- [4- (methylamino) piperidin-1-yl) ethyl] phosphonate: A mixture containing 6.4 g of diethyl ( ⁇ 2- [4- (benzyloxycarbonyl-methyl-amino) -piperidine is refluxed. -1-yl ⁇ ethyl) phosphonate, 1.5 mL of cyclohexene and 210 mg of palladium hydroxide in 60 mL of ethanol. After 4 hours of reaction, the reaction medium is filtered through Celite and concentrated in vacuo. After purification by chromatography on silica (Dichloromethane-methanol: 95-5), 800 mg of the desired compound are obtained.
  • Step 5 The procedure is as in Step 4 of Example 1 starting from 500 mg of 4- [4-]
  • Example 56 Diethyl (2- ⁇ 4 - [(2-aminoethyl) ⁇ [4 ( ⁇ 4- [(3,4-difluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ amino] piperidin-1 -yl ⁇ ethyl) phosphonate
  • Step 1 Diethyl [2- (4-oxo-piperidin-1-yl) ethyl] phosphonate: Following the procedure described in Step 1 of Example 53 from 10 g of 4-piperidone hydrochloride monohydrate and 15.7 g of diethyl 2-bromoethylphosphonate, 10 g of the expected phosphonate are obtained.
  • Stage 3 The procedure is as in Stage 4 of Example 1 starting from 800 mg of 4- [4- (3,4-difluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which it is reacted with 900 mg of diethyl (2- ⁇ 4- [2- (benzyloxycarbonylaminoethyl) amino] piperidin-1-yl ⁇ ethyl) phosphonate to give 600 mg of a compound which undergoes a hydrogenolysis reaction according to The process described in Step 4 of Example 55 gives 170 mg of diethyl (2- ⁇ 4- [(2-aminoethyl) ⁇ [4 ( ⁇ 4- [(3,4-difluorophenyl) amino] pyrimidin-2 -yl ⁇ amino) phenyl] sulfonyl ⁇ amino] piperidin-1-yl ⁇ ethyl) phosphonate expected.
  • Example 57 Diethyl (2- ⁇ 4- [(3-aminopropyl) ⁇ [4 ( ⁇ 4- [(3,4-difluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ amino] piperidin-1 -yl ⁇ ethyl) phosphonate
  • Step 1 Diethyl ⁇ 2- ⁇ 4- [3- (benzyloxycarbonylaminopropyl) amino] piperidin-1-yl ⁇ ethyl) phosphonate: The procedure is as in Step 1 of Example 55 starting from 2 g of diethyl [2- (4-oxo-piperidin-1-yl) ethyl] phosphonate and 2.2 g of (3-aminopropyl) carbamic acid benzyl ester hydrochloride. 3.4 g of expected product are obtained.
  • Step 2 The procedure is as in Step 4 of Example 1 starting from 800 mg of 4- [4-]
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 450 mg of 4- [4- (4-fluorophenylamino) -pyrimidin-2-ylamino] benzenesulfonyl chloride hydrochloride which is reacted with 400 mg of diethyl ⁇ 2- [4- (methylamino) piperidin-1-yl) ethyl] phosphonate. 400 mg of expected product is thus obtained with a yield of 54%.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 1 g of 4- [4- (4-fluorophenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl chloride hydrochloride which is reacted with 1.39 g of diethyl (2- ⁇ 4- [2- (benzyloxycarbonylaminoethyl) amino] piperidin-1-yl ⁇ ethyl) phosphonate (Stage 2 Example 56). 688 mg of a compound which undergoes a hydrogenolysis reaction are thus obtained according to the process described in Step 4 of Example 55 to give 50 mg of the expected product with a yield of 26%.
  • IH RIVIN (DMSO): 1.09 to 1.40 (massive, 8) 1.55 (q, 2) 1.72 to 2.10 (massive, 4); 2.41 (m, 2): 2.64 (t, 2); 2.81 (d, 2); 3.02 (t, 2); 3.50 (m, 1); 3.95 (who, 4);
  • Step 1 Ester [4- (4-amino-piperidin-1-yl) -butyl] phosphonic acid diethyl: Following the procedure described in Step 1 of Example 53, starting from 5 g of piperidine ester 4-yl-carbamic acid tert-butyl 106 PCT / FRZD ⁇ b / UU l D is
  • Step 2 Following the procedure described in Step 4 of Example 1 starting from 800 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 670 mg of dihydrochloride (4-bromo-butyl) -phosphonic acid diethyl ester, 6.9 g of [4- (4-amino-piperidin-1-yl) -butyl] -phosphonic acid diethyl ester are obtained, after chromatography on silica ( dichloromethane - methanol 88/12) 400 mg of expected product.
  • Step 1 [2- (4-Methylamino-piperidin-1-yl) -ethyl] -phosphonic acid diethyl ester ester: According to the procedure described in Step 2 of Example 56, from 1 g of diethyl compound [2- (4-oxo-piperidin-1-yl) ethyl] phosphonate obtained in Step 1 of Example 56 in 2.3 ml of a 2 N solution of methylamine in THF, 800 mg of
  • Step 2 The procedure is as in Step 4 of Example 1 starting from 600 mg of 4- [4- (3-methyl-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and ester of 510 mg of [2- (4-methylamino-piperidin-1-yl) -ethyl] -phosphonic acid diethyl, 640 mg of expected product is obtained.
  • Example 62 Diethyl (2- ⁇ 4- [(Pyrrolidin-2-ylmethyl) ⁇ [4 ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ amino] piperidine -1-yl ⁇ ethyl) phosphonate
  • Step 1 (2- ⁇ 4- [(Pyrrolidin-2-R-ylmethyl) amino] -piperidin-1-ylcarbamic acid tert-butyl ester ⁇ -ethyl) -phosphonic acid diethyl ester:
  • Stage 2 The procedure is as in Stage 4 of Example 1 starting from 800 mg of 4- [4- (3-methyl-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 1.13 g of (2- ⁇ 4- [(pyrrolidin-2-ylmethyl) amino] piperidin-1-ylcarbamic acid tert-butyl ester ⁇ -ethyl) -phosphonic acid diethyl ester give 700 mg of a compound which is treated by a decarboxylation reaction according to procedure 2 of Example 8 to give 550 of expected product in hydrochloride form.
  • Step 1 Ester of (2- ⁇ 4- [(pyrrolidin-2-S-ylmethyl) amino] -piperidin-1-yl-carbamic acid tert-butyl ester ⁇ • ethyl) -phosphonic acid diethyl:
  • Step 2 The procedure is as in Step 4 of Example 1 starting from 800 mg of 4- [4- (3-methyl-4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 1.13 g of (2- ⁇ 4 - [(Pyrrolidin-2-S-ylmethyl) -amino] -piperidin-1-yl-carbamic acid tert-butyl ester ⁇ -ethyl) -phosphonic acid diethyl ester, 660 mg of a compound is obtained which is treated by a decarboxylation reaction according to procedure 2 of example 8 to give 490 of expected product in hydrochloride form.
  • Example 64 Diethyl (2- ⁇ 4 - [(3-aminopropyl) ⁇ [4 ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) phenyl] sulfonyl ⁇ amino] piperidin-1-yl ⁇ ethyl) phosphonate
  • Stage 1 ⁇ 2- [4- (2-Pyrrolidin-1-yl-ethylamino) -piperidin-1-yl] -ethyl ⁇ -phosphonic acid diethyl ester: As in Example A, from 2 g of diethyl [2- (4-oxo-piperidin-1-yl) ethyl] phosphonate compound obtained in Step 1 of Example 56 and 1 g of 2-pyrrolidin-1-yl-ethylamine, 2.7 g of expected compound are obtained .
  • Step 2 Following the procedure described in Step 4 of Example 1 starting from 600 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 680 mg ester of ⁇ 2- [4- (2-Pyrrolidin-1-yl-ethylamino) -piperidin-1-yl] -ethyl ⁇ - 19
  • Examples 66 to 85 may in particular be prepared according to Scheme 1 above, according to the reaction conditions indicated below.
  • the product thus obtained comprises 2 cis and trans diastereoisomers and may further comprise two enantiomers.
  • the reaction crude is 20 ml of ethyl acetate and washed with 20 ml of a 5% solution of Na2CO3 and washed with 20 ml of a saturated solution of NaCl. After drying over Na 2 SO 4 and concentration to dryness, the crude is purified on a rp-HPLC preparative column (MeCN / H 2 O / TFA gradient), and the product obtained is freeze-dried.
  • Example 66 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- [4- (1-pyridin-4-yl-ethylamino) -cyclohexyl] trifluoroacetic acid benzenesulfonamide.
  • Example 61 N- ⁇ 4 - [(2,3-Dihydro-1H-indol-7-ylmethyl) -amino] -cyclohexyl ⁇ -4- [4- (4-fluoro-phenylamino) -pyrimidin-2 trifluoroacetic acid -ylamino] -N-methylbenzenesulfonamide.
  • the procedure is as indicated above using the compound II, 2,3-dib.hydro-1H-indole-7-carbaldehyde, and 24.3 mg of expected compound is obtained.
  • Example 68 4- [4- (4-Fluoro-phenylamino) -Pyristin-2-ylamino] -N-methyl-N- [4- (1-methyl-2-pyridin-4-yl-ethylamino) trifluoroacetic acid) cyclohexyl] benzenesulfonamide.
  • Example 69 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- [4- (4-hydroxy-3-trifluoromethyl-benzylamino) -cyclohexyl] -N-methyl-trifluoroacetic acid benzenesulfonamide.
  • Example 70 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4- [(quinolin-5-ylmethyl) -amino] -cyclohexyl trifluoroacetic acid benzenesulfonamide.
  • Example 71 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [(pyrimidin-5-ylmethyl) -amino] -cyclohexyl trifluoroacetic acid benzenesulfonamide.
  • Example 72 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [(pyridin-2-ylmethyl) -amino] -cyclohexyl trifluoroacetic acid benzenesulfonamide.
  • Example 73 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [(1-methyl-1H-pyrrol-3-ylmethyl) trifluoroacetic acid amino] -cyclohexyl ⁇ benzenesulfonamide.
  • Example 74 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [(2-methylamino-pyridin-3-ylmethyl) -amino] trifluoroacetic acid cyclohexyl ⁇ benzenesulfonamide.
  • Example 76 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [(pyridin-4-ylmethyl) -amino] -cyclohexyl trifluoroacetic acid benzenesulfonamide.
  • Example 77 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- [4- (1-pyridin-2-yl-ethylamino) -cyclohexyl] trifluoroacetic acid benzenesulfonamide.
  • Example 78 Trifluoroacetic acid of N- ⁇ 4 - [(2,3-dihydro-benzofuran-5-ylmethyl) -amino] -cyclohexyl ⁇ -4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methylbenzenesulfonamide.
  • Example 79 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [(pyridin-3-ylmethyl) -amino] -cyclohexyl trifluoroacetic acid benzenesulfonamide.
  • Example 80 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [(quinolin-6-ylmethyl) -amino] -cyclohexyl trifluoroacetic acid benzenesulfonamide.
  • Example 81 N- ⁇ 4- [(2-amino-pyridin-3-ylmethyl) -amino] -cyclohexyl ⁇ -4- [4- (4-fluorophenylamino) -pyrimidin-2-ylamino] trifluoroacetic acid N-methylbenzenesulfonamide.
  • Example 82 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N- ⁇ 4 - [(isoquinolin-4-ylmethyl) -amino] -cyclohexyl ⁇ -N-methyl trifluoroacetic acid benzenesulfonamide.
  • Example 83 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-methyl-N- ⁇ 4 - [([1, 8] naphthyridin-2-ylmethyl) -amino trifluoroacetic acid ] -cyclohexyl ⁇ - benzenesulfonamide.
  • Example 84 N- ⁇ 4- [(Benzo [1,2,5] oxadiazol-5-ylmethyl) -amino] -cyclohexyl ⁇ -4- [4- (4-fluoro-phenylamino) -pyrimidin-2 trifluoroacetic acid -ylamino] -N-methylbenzenesulfonamide.
  • Example 85 N- ⁇ 4 - [(2,3-Dihydro-benzofuran-7-ylmethyl) -amino] -cyclohexyl ⁇ -4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino trifluoroacetic acid ] -N-methylbenzenesulfonamide.
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 450 mg of 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -benzene sulphonyl chloride hydrochloride. that is reacted with 170 mg of methyl- (1-methylpiperidin-4-yl) -amine. 181 mg of expected product is obtained.
  • Example 87 4- ( ⁇ 4 - [(4-Fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N- (1-ethylpiperidin-4-yl) -N- (2-pyrrolidin-1) - ylethyl) benzenesulfonamide 006/001619
  • Step 1 (1-Methyl-piperidin-4-yl) - (2-pyrrolidin-1-yl-ethyl) -amine: As in Example A, from 3 ml 1-methyl-piperidin-4-one and 3.35 mL of 2-pyrrolidin-1-yl-ethylamine give 4.4 g of the expected product.
  • Step 2 (1-Methyl-piperidin-4-yl) - (2-pyrrolidin-1-yl-ethyl) -carbamic acid tert-butyl ester: A mixture containing 4.4 g of the compound obtained in stage 1 is dissolved in 100 mL of dichloromethane. 4.7 g Boc20 are added to the reaction medium and the mixture is heated at 50 ° C. for 1 h 30 min. After concentrating to dryness, the crude is purified on an alumina column (gradient dichloromethane up to 2% methanol). 2.35 g of the expected compound are obtained in total.
  • Stage 3 (1-Methyl-piperidin-4-yl) - (2-pyrrolidin-1-yl-ethyl) -amine hydrochloride: From 1.85 g of product obtained in Stage 2 1.65 g of expected product are obtained after a decarboxylation reaction according to the procedure of Example 8.
  • Step 4 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N- (1-methylpiperidin-4-yl) -N- (2-pyrrolidin-1) - ylethyl) benzenesulfonamide: The procedure is as in Step 4 of Example 1 starting from 390 mg of 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ chloride chloride hydrochloride. amino) -benzene sulfonyl and 300 mg of (1-methyl-piperidin-4- yl) - (2-pyrrolidin-1-yl-ethyl) -amine. 145 mg of expected product is thus obtained.
  • Example 88 4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N- (2-pyrrolidin-1-ylethyl) -N- (tetrahydro-2H-thiopyran-4-yl) ) benzenesulfonamide
  • Step 1 (2-Pyrrolidin-1-yl-ethyl) - (tetrahydro-thiopyran-4-yl) -amine: As in Example A, from 5 g of tetrahydro-thiopyran-4-one and 5.90 g of 2-pyrrolidin-1-yl-ethylamine gives 3.9 g of (2-pyrrolidin-1-yl-ethyl) - (tetrahydro-thiopyran-4-yl) -amine.
  • Example 89 4- ( ⁇ 4 - [(4-Fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N- (1-methylpiperidin-4-yl) -N- (2-pyrrolidin-1-ylethyl) benzenesulfonamide
  • Step 1 4- (2-Pyrrolidin-1-yl-ethylamino) -piperidine-1-carboxylic acid tert-butyl ester: As in Example A, from 3 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester acid and 2 g of 2-pyrrolidin-1-yl-ethylamine, 1.5 of 4- (-2-pyrrolidin-1-yl-ethylamino) -piperidine-1-carboxylic acid tert-butyl ester are obtained.
  • Step 2 4 - [ ⁇ 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ - (2-pyrrolidin-1-yl-ethyl) -amino] -piperidine-1-carboxylic tert-butyl ester acid:
  • the procedure is as in Step 4 of Example 1 starting from 720 mg of 4 - ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino chloride hydrochloride) - benzene sulfonyl which is reacted with 570 mg of 4- (2-pyrrolidin-1-yl-ethylamino) -piperidine-1-carboxylic acid tert-butyl ester. 230 mg of expected product is thus obtained
  • Step 3 4- [4- (4-Fluoro-phenylamino) -pyrimidin-2-ylamino] -N-piperidin-4-yl-N- (2-pyrrolidin-1-yl-ethyl) benzenesulfonamide: From 230 mg of the compound obtained in Stage 1, 160 mg of expected product is obtained after a decarboxylation reaction according to procedure 2 of Example 8.
  • Step 4 4- ( ⁇ 4- [(4-Fluorophenyl) amino] -pyrimidin-2-yl ⁇ amino) -N- (1-methyl-piperidin-4-yl) -N- (2-pyrrolidin) -1- yl-ethyl) -benzenesulfonamide: As in Example A, from 160 mg of product obtained in Stage 3 and 0.05 ml of formaldehyde. 146 mg of expected product is obtained.
  • Example 90 N- (2-aminoethyl) -N- (1-benzylpiperidin-4-yl) -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) benzenesulfonamide hydrochloride
  • Step 1 [2- (1-Benzyl-piperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester: As in Example A, from 4 g of 4-benzyl-piperidone and 3.4 g (2-aminoethyl) -carbamic acid tert-butyl ester, 3.2 g of [2- (1-benzylpiperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester are obtained.
  • Step 2 [2- (1-Benzyl-piperidin-4-yl) - ⁇ 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -amino) -ethyl] -carbamic tert-butyl ester acid: We proceed 6 001619
  • Step 3 N- (2-aminoethyl) -N- (1-benzylpiperidin-4-yl) -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) benzenesulfonamide hydrochloride: From of 640 mg of product obtained in stage 2, 630 mg of expected product is obtained after a decarboxylation reaction according to procedure 2 of example 8.
  • Step 1 3- (2-tert-butoxycarbonylaminoethylamino) azetidine-1-carboxylic acid tert-butyl ester: As in Example A, from 1.7 g of 3-oxo-azetidine-1-carboxylic acid tert -butyl ester and 1.6 g of (2-aminoethyl) carbamic acid tert-butyl ester. We obtain 2 g of FR2006 / 001619
  • Step 2 3- ((2-tert-Butoxycarbonylamino-ethyl) - ⁇ 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -amino) -azetidine-1-carboxylic acid tert Butyl Ester: The procedure is as in Step 4 Example 1 starting from 500 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 420 mg 3- (2-tert-butoxycarbonylaminoethylamino) azetidine-1-carboxylic acid tert-butyl ester. 300 mg of expected product is thus obtained.
  • Step 3 N- (2-aminoethyl) -N-azetidin-3-yl-4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) benzenesulfonamide hydrochloride: From 300 mg of product obtained in stage 2, 255 mg of expected product is obtained after a decarboxylation reaction according to procedure 2 of example 8.
  • Example 92 N- (3-aminopropyl) -4 - ((4 - [(4-fluorophenyl) amino] pyrimidin-2-yl) amino) -N-piperidin-4-ylbenzenesulfonamide hydrochloride
  • Stage 1 4- (3-tert-butoxycarbonylamino-propylamino) -piperidine-1-carboxylic acid tert-butyl ester: As in Example A, starting from 3 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester. butyl ester and 2.62 g of (3-aminopropyl) -carbamic acid tert-butyl ester, 4 g of 4- (3-tert-tutoxycarbonylamino-propylamino) -piperidine-1-carboxylic acid tert-butyl ester are obtained.
  • Step 2 N- (3-aminopropyl) -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N-piperidin-4-ylbenzenesulfonamide hydrochloride: The procedure is as in Step 4 Example 1 starting from 600 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 600 mg of 4- (3-tert-butoxycarbonylamino); propylamino) -piperidine-1-carboxylic acid tert-butyl ester. 163 mg of expected product is thus obtained after a decarboxylation reaction according to procedure 2 of Example 8.
  • Stage 1 Ethyl- (2-hydroxyethyl) carbamic acid tert-butyl ester: A solution is prepared from 15.2 g of Boc 2 O and 30 ml of dichlorothane. This solution is added dropwise to a mixture containing 7.36 g of 2-ethylaminoethanol and 30 ml of cold dichloromethane. The reaction medium is left for 24 hours at room temperature. After concentration to dryness, the reaction medium is taken up in a solution of NaCl. The mixture is extracted three times with ethyl acetate and then washed with a saturated solution of NaCl. The organic phase is dried over sodium sulphate and then concentrated to dryness using the paddle pump to give 12 g of expected product.
  • Step 2 [2- (1,3-Dihydro-isoindol-2-yl) -ethyl] -ethyl-carbamic acid tert-butyl ester: A solution of 10.2 g of diethyl azodicarboxylate in 60 mL of THF is added dropwise to a mixture containing 11.92 g of Ethyl- (2-hydroxy-ethyl) -carbamic acid tert-butyl ester, 15.2 g isoindole-1,3-dione and 8.6 g of triphenylphosphine in 40 mL of THF. The mixture is stirred overnight at room temperature and then concentrated to dryness.
  • Step 3 (2-Amino-ethyl) -ethyl-carbamic acid tert-butyl ester: 3.2 g of hydrazine, 7.6 g of [2- (1,3-dihydroisoindol-2-yl) -ethyl] -ethyl- carbamic acid tert-butyl ester in 70 mL of ethanol are allowed to stir at room temperature overnight. The precipitate formed is removed. The filtrate is concentrated to dryness, taken up with a potassium carbonate solution and extracted with dichloromethane. After drying over sulphate 01619
  • Stage '4 4- [2- (tert-Butoxycarbonyl-ethylamino) - ethylamino] -piperidine-l ⁇ carboxylic acid tert-butyl ester: As in Example A, from 3.3 g of 4- oxo- piperidine-1-carboxylic acid tert-butyl ester and 3.1 g of (2-aminoethyl) -ethyl-carbamic acid tert-butyl ester, 2.45 g of expected product are obtained.
  • Step 5 N- [2- (ethylamino) ethyl] -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N-piperidin-4-ylbenzenesulfonamide hydrochloride: The procedure is as follows: in Step 4 of Example 1 starting from 650 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 650 mg of 4- [2- (tert-Butoxycarbonyl-ethyl-amino) -ethylamino] -piperidine-1-carboxylic acid tert-butyl ester. 254 mg of expected product is thus obtained after a decarboxylation reaction according to procedure 2 of Example 8.
  • Stage 1 [2- (tetrahydro-pyran-4-ylamino) -ethyl] -carbamic acid tert-butyl ester: As in Example A, from 2.7 g of tetrahydro-pyran-4-one and 1.7 g of (2-aminoethyl) -carbamic acid tert-butyl ester, 2 g of the expected product are obtained.
  • Step 2 N- [2- (ethylamino) ethyl] -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N-piperidin-4-ylbenzenesulfonamide hydrochloride: The procedure is as follows: in Step 4 of Example 1 starting from 460 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 300 mg of [2- (tetrahydro pyran-4-ylamino) -ethyl] -carbamic acid tert-butyl ester. 254 mg of expected product is thus obtained after a decarboxylation reaction according to procedure 2 of Example 8.
  • Stage 1 [2- (1-methyl-piperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester: As in Example A, from 2.7 g of 1-methyl-piperidin-4-one and 1.7 g of (2-aminoethyl) -carbamic acid tert-butyl ester, 2.2 g of expected product are obtained.
  • Step 2 N- (2-aminoethyl) -4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N- (1-methylpiperidin-4-yl) hydrochloride ) benzenesulfonamide:
  • the procedure is as in Step 4 of Example 1 starting from 380 mg of 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino chloride hydrochloride) benzenesulfonyl and 300 mg of [2- (1-methyl-piperidin-4-ylamino) -ethyl] -carbamic acid tert-butyl ester. This gives 168 mg of expected product after a decarboxylation reaction according to procedure 2 of Example 8.
  • Step 1 3- (2-Pyrrolidin-1-yl-ethylamino) -azetidine-1-carboxylic acid tert-butyl ester: As in Example A, from 3.32 g 3-oxo-azetidine-1-carboxylic acid tert-butyl ester and 2.5 mL of 2-pyrrolidin-1-yl-ethylamine, 1.15 g of the expected product are obtained.
  • Step 2 N- [2- (ethylamino) ethyl] -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N-piperidin-4-ylbenzenesulfonamide hydrochloride: The procedure is as follows: in Step 4 Example 1 from 780 mg of 4- [4- (4-fluoro-phenylamino) -pyrimidin-2-ylamino] -benzene sulfonyl chloride hydrochloride and 560 mg of 3- (2-pyrrolidine) -1-yl-ethylamino) -azetidine-1-carboxylic acid tert-butyl ester. 230 mg of expected product is thus obtained after a de-carboxylation reaction according to procedure 2 of Example 8.
  • Step 1 3- (2-Pyrrolidin-1-yl-ethylamino) -azetidine-1-carboxylic acid tert-butyl ester: As in Example A, from 3.32 g 3-oxo-azetidine-1-carboxylic acid tert-butyl ester and 2.5 mL of 2-pyrrolidin-1-yl-ethylamine, 1.15 g of the expected product.
  • Step 2 N-Azetidin-3-yl-4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) -amino] -pyrimidin-2-yl ⁇ -amino) -N- (2-pyrrolidin-1-ylethyl) hydrochloride ) benzenesulfonamide:
  • the procedure is as in Step 4
  • Example 1 starting from 660 mg of 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino chloride hydrochloride) - benzene sulfonyl and 440 mg of 3- (2-pyrrolidin-1-yl-ethylamino) azetidine-1-carboxylic acid tert-butyl ester. 264 mg of expected product are thus obtained after a decarboxylation reaction according to procedure 2 of Example 8.
  • Stage 1 3- (2-tert-butoxycarbonylaminoethylamino) -azetidine-1-carboxylic acid tert-butyl ester: As in Example A, starting from ester of 1.7 g of 3-oxo-azetidine-1 carboxylic acid tert-butyl and 1.6 g of (2-aminoethyl) -carbamic acid tert-butyl ester. 2 g of expected product are obtained.
  • Step 2 N- (2-aminoethyl) -N-azetidin-3-yl-4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) -amino] -pyrimidin-2-yl ⁇ amino) benzenesulfonamide hydrochloride
  • the procedure is as in Step 4 of Example 1 starting from 800 mg of 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -benzene chloride hydrochloride.
  • Step 1 1- (2,2,2-trifluoro-ethyl) -piperidin-4-one.
  • a mixture containing 1.6 g of piperidin-4-one hydrochloride and 2.6 g of sodium hydrogen carbonate in 15 ml of ethanol is stirred for 10 minutes.
  • the nitrogen is bubbled for 2 minutes and then 2.3 g of trifluoro-methanesulfonic acid 2,2,2-trifluoroethyl ester are added.
  • the reaction medium is stirred at 80 ° C. for 6 hours.
  • a solution of potassium carbonate is added and then the mixture is extracted three times with dichloromethane.
  • the organic phase is dried over sodium sulfate, concentrated in vacuo and chromatographed (1% methanol in dichloromethane) on a silica column. 1.3 g of expected product are obtained.
  • Step 2 Ester of ⁇ 2- [1- (2,2,2-trifluoroethyl) piperidin-4-ylamino] -ethyl ⁇ -carbamic acid tert-butyl ester: As in Example A, from 1.3 g of 1- (2,2,2-trifluoroethyl) -piperidin-4-one and 1.3 g of (2-amino-ethyl) -carbamic acid tert-butyl ester are obtained, 2.2 g of expected product. .
  • Step 3 N- (2-aminoethyl) -4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N- [1- [2,2-aminoethyl] -hydrochloride , 2-trifluoroethyl) piperidin-4-yl] benzenesulfonamide:
  • the procedure is as in Step 4 of Example 1 starting from 700 mg of 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) chloride hydrochloride.
  • Example 100 N- (2-aminoethyl) -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N- [1- (2,2,2-trifluoroethyl) hydrochloride) piperidin-4-yl] benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 600 mg of 4 - ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -benzene sulphonyl chloride hydrochloride and 515 mg of ⁇ 2- [1- (2,2,2-trifluoro-ethyl) -piperidin-4-ylamino] -ethyl ⁇ -carbamic acid tert-butyl ester. 193 mg of expected product is thus obtained after a decarboxylation reaction according to procedure 2 of Example 8.
  • Example 102 4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N- ⁇ 2 - [(2-hydroxy-2-methylpropyl) amino] ethyl ⁇ -N-piperidin 4-ylbenzenesulfonamide
  • Example 103 N- (1-Benzylpiperidin-4-yl) -4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N- ⁇ 2- [(2, 2, 2) trifluoroethyl) amino] ethyl ⁇ benzenesulfonamide
  • the reaction involves 420 mg of N- (2-aminoethyl) -N- (1-benzylpiperidin-4-yl) -4- [4- [4- [ (4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) benzenesulfonamide (Example 90) and 170 mg of trifluoro-methanesulfonic acid ester 2,2,2-trifluoro-ethyl. After recrystallization, 140 mg of expected product are obtained.
  • Example 104 N- (1-ethylazetidin-3-yl) -4 - ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N- (2-pyrrolidin-1) -ylethyl) benzenesulfonamide
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 1.95 g of 4 - ( ⁇ 4 - [(3,4-difluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -benzene sulfonyl chloride hydrochloride and 1.1 g of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester is thus obtained .1.25 g of expected product after a decarboxylation reaction according to procedure 2 of Example 8.
  • Example 106 4- ( ⁇ 4 - [(4-Fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N-methyl-N-piperidin-4-ylbenzenesulfonamide hydrochloride
  • Step 4 of Example 1 The procedure is as in Step 4 of Example 1 starting from 3 g of 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -benzene sulphonyl chloride hydrochloride and 1.8 g of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester. 1.86 g of expected product are thus obtained after a decarboxylation reaction according to procedure 2 of Example 8.
  • Example 107 4- ( ⁇ 4 - [(4-fluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N-methyl-N- [1- (3,3,3-trifluoropropyl) piperidin-4-yl] benzenesulphonamide
  • Example 109 4- ( ⁇ 4- [(3,4-difluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N-methyl-N- [1- (3,3,3-trifluoropropyl) piperidin-4- yl] benzenesulfonamide
  • Example 105 As in Example A starting from 360 mg of 4 - ( ⁇ 4- [(3,4-difluorophenyl) amino] pyrimidin-2-yl ⁇ amino) -N-methyl- Regenerated N-piperidin-4ylbenzenesulfonamide (Example 105) and 80 mg of 3,3,3-trifluoropropionaldehyde give 100 mg of the expected product.
  • Example 110 4- ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N-methyl-N- ⁇ 1 - [(1-methyl-1H-pyrrol-2) ⁇ -yl) methyl] piperidin-4-yl ⁇ benzenesulfonamide
  • Example 106 As in Example A from 500 mg of 4 - ( ⁇ 4 - [(4-fluoro-3-methylphenyl) amino] pyrimidin-2-yl ⁇ amino) -N-methyl-N-piperidin-4-ylbenzenesulfonamide (Example 106) regenerated and 120 mg of 1H-pyrrole-3-carbaldehyde. 144 mg expected product is obtained.

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Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
ATE451104T1 (de) 2002-07-29 2009-12-15 Rigel Pharmaceuticals Inc Verfahren zur behandlung oder pruvention von autoimmunkrankheiten mit 2,4-pyrimidindiamin- verbindungen
PL1656372T3 (pl) 2003-07-30 2013-08-30 Rigel Pharmaceuticals Inc Związki 2,4-pirymidynodiaminy do stosowania w leczeniu lub zapobieganiu chorobom autoimmunologicznym
BRPI0606318B8 (pt) 2005-01-19 2021-05-25 Rigel Pharmaceuticals Inc composto, composição, e, uso de um composto
US20070203161A1 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2006133426A2 (en) 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
BRPI0617376A2 (pt) * 2005-10-13 2011-07-26 Morphochem Ag derivados de 5-quinolina tendo uma atividade antibacteriana
SI1984357T1 (sl) 2006-02-17 2014-02-28 Rigel Pharmaceuticals, Inc. Spojine 2,4-pirimidindiamina za zdravljenje ali preventivo avtoimunih bolezni
ES2622493T3 (es) 2006-02-24 2017-07-06 Rigel Pharmaceuticals, Inc. Composiciones y métodos para la inhibición de la ruta de JAK
WO2007118853A1 (en) 2006-04-13 2007-10-25 Euro-Celtique S.A. Benzenesulfonamide compounds and their use as blockers of calcium channels
WO2007118854A1 (en) 2006-04-13 2007-10-25 Euro-Celtique S.A. Benzenesulfonamide compounds and the use thereof
US8219697B2 (en) * 2006-05-17 2012-07-10 Oracle International Corporation Diameter protocol and SH interface support for SIP server architecture
EP2222647B1 (en) 2006-10-23 2015-08-05 Cephalon, Inc. Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors
FR2911138B1 (fr) * 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de n, n'-2,4-dianilinopyrimidines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
FR2911140B1 (fr) * 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de 2-anilino 4-heteroaryle pyrimides, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
FR2911137B1 (fr) * 2007-01-05 2009-02-20 Sanofi Aventis Sa Nouveaux derives de 2,4-dianilinopyrimides, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
FR2919869B1 (fr) * 2007-08-09 2009-09-25 Sanofi Aventis Sa Nouveaux derives de n, n'-2,4-dianilinopyrimidines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
US8765736B2 (en) * 2007-09-28 2014-07-01 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
AU2013205510A1 (en) * 2008-05-21 2013-05-16 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
HUE035029T2 (en) 2008-05-21 2018-03-28 Ariad Pharma Inc Kinase inhibitor phosphorus derivatives
US9273077B2 (en) 2008-05-21 2016-03-01 Ariad Pharmaceuticals, Inc. Phosphorus derivatives as kinase inhibitors
KR20130031296A (ko) 2010-05-21 2013-03-28 케밀리아 에이비 신규한 피리미딘 유도체
US9150547B2 (en) 2010-11-29 2015-10-06 Hetero Research Foundation Process for the preparation of pazopanib using novel intermediate
DK2688883T3 (en) 2011-03-24 2016-09-05 Noviga Res Ab pyrimidine
JP5999177B2 (ja) 2011-05-04 2016-09-28 アリアド・ファーマシューティカルズ・インコーポレイテッド Ｅｇｆｒ発動性がんの細胞増殖阻害用化合物
AU2013204563B2 (en) 2012-05-05 2016-05-19 Takeda Pharmaceutical Company Limited Compounds for inhibiting cell proliferation in EGFR-driven cancers
US9611283B1 (en) 2013-04-10 2017-04-04 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in ALK-driven cancers
US11175268B2 (en) 2014-06-09 2021-11-16 Biometry Inc. Mini point of care gas chromatographic test strip and method to measure analytes
EP3152557A4 (en) 2014-06-09 2017-12-13 Biometry Inc. Low cost test strip and method to measure analyte
CN109715067B (zh) 2016-07-19 2022-05-17 生物统计股份有限公司 使用批量可校准测试条测量分析物的方法和系统
NZ763766A (en) 2017-03-20 2023-07-28 Novo Nordisk Healthcare Ag Pyrrolopyrrole compositions as pyruvate kinase (pkr) activators
EP3852791B1 (en) 2018-09-19 2024-07-03 Novo Nordisk Health Care AG Activating pyruvate kinase r
BR112021005188A2 (pt) 2018-09-19 2021-06-08 Forma Therapeutics, Inc. tratamento de anemia falciforme com um composto de ativação de piruvato cinase r
WO2023212574A1 (en) * 2022-04-26 2023-11-02 Olivia Szu Hsieh Lee Nakaya Compositions and methods for modulating rhythmic activity of pacemaker cardiomyocytes

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9828511D0 (en) * 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
GB0004888D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
US6939874B2 (en) * 2001-08-22 2005-09-06 Amgen Inc. Substituted pyrimidinyl derivatives and methods of use
EP1472233A1 (en) * 2002-02-08 2004-11-03 SmithKline Beecham Corporation Pyrimidine compounds
GB0206215D0 (en) * 2002-03-15 2002-05-01 Novartis Ag Organic compounds
US20050113398A1 (en) * 2003-08-07 2005-05-26 Ankush Argade 2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
CN100584832C (zh) * 2003-09-18 2010-01-27 诺瓦提斯公司 可用于治疗增殖性病症的2,4-二(苯基氨基)嘧啶类
CA2670730A1 (en) * 2006-12-13 2008-06-26 Gilead Sciences, Inc. Monophosphates as mutual prodrugs of anti-inflammatory signal transduction modulators (aistm's) and beta-agonists for the treatment of pulmonary inflammation and bronchoconstriction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007006926A2 *

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