EP2111395A1 - Derives de phenyl- (4-phenyl-pyrimidin-2-yl) - amines comme inhibiteurs de ikk, leur preparation et leur compositions pharmaceutiques - Google Patents

Derives de phenyl- (4-phenyl-pyrimidin-2-yl) - amines comme inhibiteurs de ikk, leur preparation et leur compositions pharmaceutiques

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Publication number
EP2111395A1
EP2111395A1 EP08761728A EP08761728A EP2111395A1 EP 2111395 A1 EP2111395 A1 EP 2111395A1 EP 08761728 A EP08761728 A EP 08761728A EP 08761728 A EP08761728 A EP 08761728A EP 2111395 A1 EP2111395 A1 EP 2111395A1
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Prior art keywords
formula
radicals
products
optionally substituted
radical
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German (de)
English (en)
French (fr)
Inventor
Monsif Bouaboula
Pierre Casellas
Sherri Dudal
Régine FLOUTARD
Maria Mendez-Perez
Jean-Flaubert Nguefack
Jacob-Alsboek Olsen
Bernard Tonnerre
Jean Wagnon
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Sanofi Aventis France
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Sanofi Aventis France
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • 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
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel phenyl- (4-phenyl-pyrimidin-2-yl) -amino derivatives, process for their preparation, the novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use thereof.
  • pyrimidine derivatives such as pyrimidine 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 subject of the present invention is therefore new Phenyl- (4-phenyl-pyrimidin-2-yl) -amino derivatives having inhibitory effects on protein kinases.
  • the products of the present invention can thus in particular be used for the prevention or 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), thus allowing the release and translocation of NF- ⁇ B in the nucleus where 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-regulated genes encode pro-inflammatory mediators, cytokines, cell adhesion molecules, and acute phase proteins, which in turn will induce activation of NF- ⁇ B by autocrine or paracrine mechanisms. Inhibition of NF- ⁇ B activation appears to be very important in the treatment of inflammatory diseases.
  • NF-KB plays a role in the growth of normal cells but also malignant cells. Proteins produced by expression of NF- ⁇ B regulated genes include cytokines, chemokines, adhesion molecules, cell growth mediators, angiogenesis. In addition, various studies have shown that NF-KB plays an essential role in neoplastic transformations. For example NF- ⁇ B may be associated with cell transformation in vitro and in vivo following overexpression, amplification, rearrangement or translocation events (Mercurio, R, and Manning, AM (1999) Oncogene, 18: 6163- 6171). In some human lymphoid tumor cells, the genes encoding the different NF-KB members are rearranged or amplified.
  • NF-KB 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 inhibition of apoptosis. It has been shown that in a large number of tumor cell lines, 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. On the other hand, inhibition of NF- ⁇ B by expression of the I ⁇ B ⁇ repressor induces apoptosis of cells expressing the oncogenic H-Ras allele (Baldwin, J. Clin Invest, 107: 241 (2001), Bargou et al., J. Clin Invest, 100: 2961 (1997), Mayo et al., Science 178: 1812 (1997).
  • NF-KB The constitutive activity of NF-KB seems 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.
  • R represents a hydrogen atom or a halogen atom
  • R2, R3 and R4, which are identical or different, are chosen from hydrogen, halogen atoms, CN, CONH2, CONHaIk, CON (alk) 2, and the alkyl and alkoxy radicals themselves, if appropriate; substituted by one or more halogen atoms or a radical CN,
  • R5 represents a hydrogen atom or a halogen atom
  • Z represents CO or SO2; and the radical -N (D) (W) is such that:
  • ring (Y) when Y represents RIO may contain a carbon bridge consisting of 1 to 3 carbons,
  • R10 represents a 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, aryl and heteroaryl radicals, the alkyl radicals represented by RIO being furthermore optionally substituted by a hydroxyl radical, NR8R9, CONR8R9, phosphonate, alkylthio optionally oxidized to sulphone or heterocycloalkyl, all the aryl, heteroaryl and heterocycloalkyl radicals being optionally substituted; ;
  • R1 and R6 substituted on the same carbon atom by R1 and R6, containing 4 to 7 members, being saturated and may additionally contain a carbon bridge consisting of 1 to 3 carbons, it being understood that R1 and R ⁇ represent one of the 6 - ⁇ alternatives following i) to vi): i) R1 represents -X1-R7 with X1 represents - (CH2) m- and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; and R6 is hydrogen, or hydroxyl, methyl, methoxy, - (CH2) mOH, -CO-NRaRb, -CH2-NraRb, -CO2H, and -CO2alk;
  • R1 represents -NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms optionally substituted with a radical chosen from -PO (OEt ) 2, -OH, -OaIk, -CF3, -CO-NR8R9 and SO2-alk; and R6 represents hydrogen; it being understood that when W represents a hydrogen atom then z represents CO;
  • R1 represents -CH2-NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms and optionally substituted by a radical chosen from - PO (OEt) 2, -OH, -OEt, -CF3, -CO- N (alk) 2 and SO2-alk; and R6 represents hydrogen;
  • R1 represents -CO-N (Rc) -OR 'c and R ⁇ represents hydrogen
  • n, n1 and n2, identical or different, represent an integer of 0 to 3;
  • m represents an integer of 1 to 3;
  • Rc and R 'c identical or different, represent the hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms optionally substituted with one or more halogen atoms;
  • 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 and N (alkyl) 2 radicals, -CONH2, -CONHalkyl or -CON (alkyl) 2, the alkyl radicals that R8 represents being further optionally substituted by a phosphonate radical, alkylthio optionally oxidized to sulfone or by an optionally substituted saturated or unsaturated aryl or heterocyclic 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 which may optionally contain one or two other heteroatoms chosen from O , S, N or NRc, the cyclic amine thus formed being itself optionally substituted; all the aryl, naphthyl, phenyl, heterocyclic, heterocycloalkyl and heteroaryl radicals above, as well as the cyclic amine which R8 and R9 can form with the nitrogen atom to which they are bound, being themselves optionally substituted by one or more identical or different radicals selected from halogen atoms; hydroxyl radicals; cyano; NR8R9; and the alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl radicals, themselves optionally substituted by one or more identical or different radicals chosen from hal
  • the subject of the present invention is the products of formula (I) as defined above in which R 2, R 3, R 4, R 5, Z and the radical -N (D) (W) have the meanings indicated in any one of the other claims and R represents an atom of halogen; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula
  • the subject of the present invention is the products of formula (I) as defined above in which R2, R3, R4, R5, Z and the radical -N (D) (W) have the meanings indicated for any one of other claims and R represents a hydrogen atom; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (I).
  • R, R5, Z and the radical -N (D) (W) have the meanings indicated in any one of the other claims and R 2, R 3 and R 4, which are identical or different, are chosen from hydrogen atom, halogen atoms, CN radical and alkyl and alkoxy radicals, themselves optionally substituted by one or more halogen atoms or radical CN, CONH2, CONHaIk or CON (alk) 2, it being understood that one or two of R2, R3 and R4 represent a hydrogen atom or R2, R3 and R4 all represent methoxy; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the inorganic and organic acids of said products of formula (D •
  • the present invention relates in particular to the products of formula (I) as defined above or below in which R, R5, Z and the radical -N (D) (W) have the meanings indicated above or above.
  • R2, R3, R4 are such that one of R2, R3 and R4 represents a CN or CH2-CN radical and the other two of R2, R3, R4 are selected from the other values defined for these radicals, ie hydrogen atom, halogen atoms, CN, CONH2, CONHaIk, CON (alk) 2 radical, and alkyl and alkoxy radicals, themselves optionally substituted by one or more halogen atoms or a CN radical, CONH2, CONHaIk, CON (alk) 2, OH or OCH3, it being understood that one or two of R2, R3 and R4 represent a hydrogen atom, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and
  • R has the meaning indicated above or below
  • R 2, R 3 and R 4 which are identical or different, are such that one represents a halogen atom or CF 3 and the other two, which are identical or different, represent a hydrogen atom or a halogen atom or an alkyl radical or alkoxy optionally substituted by one or more halogen atoms;
  • R5 represents a hydrogen atom or a halogen atom
  • Z represents CO or SO2; and the radical -N (D) (W) is such that:
  • RIO may contain a carbon bridge consisting of 1 to 3 carbons
  • R10 represents the hydrogen atom, a cycloalkyl radical or an alkyl radical, CH2-alkenyl or CH2-alkynyl, all optionally substituted by a naphthyl radical or by one or a plurality of identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, aryl and heteroaryl radicals, the alkyl radicals represented by RIO being furthermore optionally substituted by a hydroxyl radical, NR8R9, CONR8R9, phosphonate or alkylthio optionally oxidized to sulphone or heterocycloalkyl, all aryl, heteroaryl and heterocycloalkyl radicals being optionally substituted; b) W and D form with the nitrogen atom to which they are attached a ring (N)
  • R1 and R6 substituted on the same carbon atom by R1 and R6, containing 4 to 7 members, being saturated and may additionally contain a carbon bridge consisting of 1 to 3 carbons, it being understood that R1 and R6 represent one of the following 5 alternatives i ) to v): i) R1 represents -X1-R7 with X1 represents - (CH2) m- and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; and R6 represents hydrogen atom or hydroxyl radicals, - (CH2) mOH, -CO-NRaRb, -CH2-NRaRb and, -CO2H, - CO2alk;
  • R1 represents -NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms optionally substituted with a radical chosen from -PO (OEt ) 2, -OH, -OaIk, -CF3, -CO-NR8R9 and SO2-alk; and R6 represents hydrogen; it being understood that when W represents a hydrogen atom then z represents CO; iv) R1 represents -CH2-NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms and optionally substituted by a radical chosen from - PO (OEt) 2, -OH, -OEt, -CF3, -CO- N (alk) 2 and SO2-alk; and R6 represents hydrogen;
  • R1 represents -CO-N (Rc) -OR 'c and R6 represents hydrogen
  • n, n1 and n2, identical or different, represent an integer of 0 to 3;
  • m represents an integer of 1 to 3;
  • Rc and R 'c identical or different, represent the hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms optionally substituted with one or more halogen atoms;
  • R8 represents the hydrogen atom or the alkyl, cycloalkyl or heterocycloalkyl radicals themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkoxy and NH 2 radicals,
  • alkyl radicals represented by R8 being furthermore optionally substituted with a phosphonate, alkylthio radical optionally oxed to sulphone or with an optionally substituted saturated or unsaturated aryl or heterocyclic 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 which may optionally contain one or two other heteroatoms chosen from 0 , S, N or NRc, the cyclic amine thus formed being itself optionally substituted; all the aryl, naphthyl and phenyl radicals, heterocyclic, heterocycloalkyl and heteroaryl compounds as well as the cyclic amine which R8 and R9 can form with the nitrogen atom to which they are attached being themselves optionally substituted by one or more identical or different radicals chosen from the atoms of 'halogen; hydroxyl radicals; cyano; NR8R9; and the alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl radicals, themselves optionally substituted by one or more identical or different radicals chosen from
  • NRaRb is such that either Ra and Rb, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms or a cycloalkyl radical, these alkyl and cycloalkyl radicals being optionally substituted with one or more radicals; identical or different selected from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl and N (alkyl) 2 radicals; either Ra and Rb form, with the nitrogen atom to which they are bonded, a cyclic amine which may optionally contain one or two other heteroatoms chosen from O, S, N or NRc, the cyclic amine thus formed being itself optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl radicals themselves optionally substituted with one or more halogen atoms;
  • the present invention thus relates in particular to the products of formula (I) as defined above corresponding to formula (IA) in which R, R2, R3, R4,
  • R5, Z and D are selected from the meaning indicated above or hereafter and ring (Y) may be chosen from any one of the following values: - When ring (Y) is such that Y represents C-OH, CF2
  • the ring formed can in particular be a cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and particularly a cyclohexyl, these radicals therefore being substituted especially in para respectively by OH, 2 F, the radical OR8 or the radical NR8R9 in which R8 and R9 are selected from the meanings defined above.
  • ring (Y) When ring (Y) is such that Y represents NR10, the ring formed may in particular be an azetidinyl, pyrrolidinyl or piperidinyl radical with the N atom in para or meta, which therefore bears the substituent RIO as defined herein.
  • RIO substituent RIO as defined herein.
  • ring (Y) may represent a pyrrolidinyl or piperidinyl radical optionally substituted on the nitrogen atom by RIO which may represent an alkyl radical optionally substituted by a hydroxyl radical, -NR8R9, -CO-NR8R9, phosphonate, or alkylthio optionally oxidized to sulfone;
  • the ring formed can in particular be the 8-azabicyclo (3, 2, 1) octanoyl ring or a ring selected from N, 9-dimethyl-9-azabicyclo [3.3.1] nonan-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 [3.3.1] nonan-9-yl.
  • the ring (Y) formed can in particular be a bicyclic radical such as for example quinolizinyl or indolizinyl.
  • the ring formed can in particular be a tetrahydrothiopyranyl or a tetrahydrothiophene: when ring (Y) is such that Y represents SO 2, the ring formed can in particular be a dioxidotetrahydro-3-thiophene.
  • the ring formed can in particular be a tetrahydrofuran or tetrahydropyran.
  • the ring formed can in particular be dioxaspiro (4,5) dec-8-yl.
  • Y represents -NR10 with R10 represents cycloalkyl such as in particular cyclopropyl
  • Y represents -NR 10 with R 10 represents an alkyl radical, in particular CH 3, C 2 H 5 or C 3 H 7 substituted with a phosphonate
  • Y represents -NR 10 with R 10 represents an alkyl radical, in particular CH 3, C 2 H 5 or C 3 H 7 substituted with an alkylthio such as S-CH 3 or S-C 2 H 5 with S, optionally oxidized to sulphone, to form, for example, SO 2 -CH 3 or SO2-C2H5;
  • Y represents -NR10 with R10 represents alkyl such as in particular CH3 or C2H5 substituted with one or more radicals chosen from halogen atoms such as F, and phenyl radicals and mono or bicyclic heterocycle, 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 radicals: among these heterocycles which may be R10 may be mentioned in particular 5-membered unsaturated heterocycles containing one to four heteroatoms chosen from N, O and S: thus RIO can represent in particular the radicals -CH2-thienyl, -CH2-thiazolyl (N, S) , -CH2-thiadiazolyl (N, N, S), -CH2-furanyl (O), -CH2-pyrazolyl (N, N), -CH2-isoxazolyl
  • RIO may also carry heterocycles as defined above such as pyridinyl radicals (with N of pyridine at 3 different positions); 2,3-Dihydro-1H-indolyl; quinolyl; isoquinolyl; pyrimidinyl; 2,3-Dihydro-benzofuranyl;
  • 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-indolyl; quinolyl; isoquinolyl; pyrimidinyl; 2,3-Dihydro-benzofuranyl;
  • Such heterocycles are optionally substituted with one or more radicals as defined above or hereinafter.
  • the present invention thus relates in particular to the products of formula (I) as defined above corresponding to formula (IA) in which R, R2, R3, R4, R5 and Z and ring (Y) are chosen from the indicated meanings.
  • D can be chosen from any one of the following values: D represents a hydrogen atom or an alkyl radical containing from 1 to 6 linear or branched carbon atoms optionally substituted by an NH 2 radical; , NHaIk, N (alk) 2 or with a saturated or unsaturated heterocycle, preferably a 5- or 6-membered monocycle as defined above and optionally substituted as indicated above or hereinafter;
  • D represents a hydrogen atom or an alkyl radical containing from 1 to 5 linear or branched carbon atoms optionally substituted with NH 2 or else D represents this alkyl radical substituted with a saturated or unsaturated, preferably monocyclic, 5-membered heterocycle, itself optionally substituted as indicated above or below,
  • ring (Y) represents a cyclohexyl radical substituted by an NR8R9 radical as defined above
  • D represents a CH3 radical optionally substituted with a saturated or unsaturated heterocycle as defined above and R10 represents a CH3 radical;
  • - D represents a hydrogen atom or a CH3 radical and ring (Y) represents a piperidine or a 8-azabicyclo (3,2,1) octan-3yl ring substituted on their nitrogen atom by RIO with RIO as defined above. More precisely :
  • D represents alkenyl (3C) radicals such as allyl or alkynyl (3C) such as propargyl
  • - D represents alkyl and in particular CH3, C2H5, C3H7 substituted with one or more identical or different radicals chosen from halogen atoms and NH2, NH (alk), N (alk) 2, NH-CH2-CH2OH, NH radicals; -CH2-C3H7-OH, NH (CH2-CF3), alkoxy, OH, or a saturated heterocycle such as for example pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl or an unsaturated heterocycle such as in particular those defined above for RIO.
  • a saturated heterocycle such as for example pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl or an unsaturated heterocycle such as in particular those defined above for RIO.
  • the subject of the present invention is thus the products of as defined above or hereafter corresponding to the formula (IA) in which R, R2, R3, R4, R5 and z have the meanings indicated above or above.
  • D represents a hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms optionally substituted with NH 2 and in particular CH 3 and ring (Y) is such that Y represents NR 10 with R 10 represents an alkyl radical containing from 1 to 6 atoms of linear or branched carbon optionally substituted by a radical chosen from halogen atoms and hydroxyl, phosphonate, sulphone, phenyl and heterocyclic radicals which are saturated or unsaturated monocyclic or bicyclic, these phenyl and heterocyclic radicals being themselves optionally substituted as indicated ci above or below, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salt
  • D represents an alkyl radical containing from 1 to 4 linear or branched carbon atoms optionally substituted with NH 2 and in particular CH 3 and ring (Y) is such that Y represents NR 8 R 9 in which R 8 represents a hydrogen atom or an alkyl radical and R 9 represents an alkyl radical containing from 1 to 6 linear or branched carbon atoms optionally substituted by a radical chosen from halogen atoms and hydroxyl, phosphonate, sulphone, phenyl and heterocyclic radicals which are saturated or unsaturated monocyclic or bicyclic, these phenyl and heterocyclic radicals; being themselves optionally substituted as indicated above or hereafter, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (I).
  • R, R1, R2, R3, R4, R5, R6, Z and ring (N) have the meanings given above or hereafter, said products of formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (I).
  • the subject of the present invention is thus the products of formula (I) corresponding to formula (IB) as defined above or below, in which R, R2, R3 and R4, which are identical or different, are such that one represents a halogen atom or CF3 and the other two, identical or different, represent a hydrogen atom or a halogen atom or an alkyl radical or an alkoxy radical optionally substituted with one or more halogen atoms; R5 represents a hydrogen atom or a halogen atom;
  • R1 and R6 being substituted on the same carbon atom by R1 and R6, containing 4 to 7 members, being saturated and may additionally contain a carbon bridge consisting of 1 with 3 carbons, with R 1 and R 6 as defined above or below,
  • R1 and R6 are such that R1 represents -X1-R7 with X1 represents - (CH2) m- and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted; and R6 represents hydrogen atom or hydroxyl radicals, - (CH2) mOH, -CO-NRaRb, -CH2-NRaRb -CO2H, and -
  • R1 represents -NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms optionally substituted with a radical chosen from -PO (OEt) 2, -OH, -OaIk, -CF3, -CO-NR8R9 and SO2-alk and R6 represents hydrogen, it being understood that when W represents a hydrogen atom then z represents CO; or R1 represents -CH2-NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms and optionally substituted with a radical chosen from -PO (OEt) 2, -OH, -OEt,
  • the ring formed can in particular be the 8 aza bicyclo (3.2, l) oct 3 yl) or a ring selected from the following: 9-azabicyclo [3.3.1] nonan-3-yl, 6-azabicyclo [3.2.1] octan-3-yl, 3-azabicyclo [3.2] .1] octan-8yl or else 3-azabicyclo [3.3.1] nonan-9-yl.
  • halogen denotes the fluorine, chlorine, bromine or iodine atoms and preferably fluorine, chlorine or bromine;
  • alkyl radical denotes a linear or branched radical containing at most 6 carbon atoms and especially the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or isopentyl radicals; pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl and their linear or branched positional isomers;
  • hydroxyalkyl radical denotes the alkyl radicals indicated above substituted by one or more hydroxyl radicals;
  • alkenyl radical denotes a linear or branched radical containing at most 6 carbon atoms and preferentially 4 carbon atoms chosen for example from the following values: ethenyl or vinyl, propenyl or allyl, 1-propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl and hexenyl, as well as their linear or branched positional isomers: among the alkenyl values, mention is made more particularly of allyl or butenyl values.
  • 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 6 carbon atoms, derived from the alkyl radical above and thus chosen for example from the methylene, ethylene, propylene, isopropylene, butylene, isobutylene or sec-butylene radicals; pentylene;
  • alkoxy radical denotes a linear or branched radical containing at most 6 carbon atoms chosen, for example, from methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy, hexoxy and heptoxy radicals, and also their positional isomers; linear or branched;
  • cycloalkyl radical denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 7 ring members and in particular denotes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals;
  • aryl radical refers to unsaturated, monocyclic or fused carbocyclic ring radicals.
  • examples of such an aryl radical include, in particular, phenyl or naphthyl radicals;
  • heterocyclic radical denotes a radical saturated (heterocycloalkyl) or partially or completely unsaturated carbocylic acid (heteroaryl) comprising from 4 to 10 members interrupted by one or three heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms: from the heteroaryl radicals to 5-membered radicals which may be mentioned in particular are radicals containing one to four heteroatoms selected from optionally oxidized N, O and optionally oxidized S, such as the radicals, for example thienyl radicals such as 2-thienyl, 3-thienyl or dioxidothienyl, thiazolyl (N, S), furyl (O), 2-furyl, pyrrolyl (NH, NCH3), isothiazolyl
  • 6-membered heteroaryl radicals include, in particular, pyridyl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyridyl N-oxide, pyrimidinyl, pyridazinyl and pyrazinyl radicals; among the fused heteroaryl radicals containing at least one heteroatom chosen from sulfur, nitrogen and oxygen, mention may be made, for example, of benzothienyl, benzofuryl, benzofuranyl, benzoxazolyl, indazolyl, indolyl, indolinyl, indolinonyl, quinolyl and isoquinolyl radicals, azaindolyl, benzimidazolyl, benzothiazolyl, naphth
  • heterocycloalkyl saturated
  • heterocycloalkyl saturated
  • heterocycloalkyl saturated
  • heterocycloalkyl saturated
  • alkylamino radical or NH (alk) radical and dialkylamino radical or N (alk) 2 denotes NH 2 amino radicals substituted respectively by one or two linear or branched alkyl radicals, which are identical or different in the case of dialkylamino, chosen from alkyl radicals as defined above and optionally substituted as indicated above or below: mention may be made, for example, of methylamino, ethylamino, propylamino or butylamino radicals, and dimethylamino, diethylamino and methylethylamino radicals.
  • cycloalkylamino thus denotes an amino radical substituted in particular by a cycloalkyl radical chosen from the radicals defined above: there may thus be mentioned, for example, the cyclopropylamino, cyclobutylamino or cyclopentylamino radicals; still cyclohexylamino.
  • cyclic amine denotes a monocyclic or bicyclic radical containing from 3 to 10 members in which at least one carbon atom is replaced by a nitrogen atom, this cyclic radical possibly also containing one or more other heteroatoms chosen from O, S, SO 2, N or NRc with Rc as defined above:
  • cyclic amines include, for example, pyrrolyl, piperidyl, morpholinyl, piperazinyl, pyrrolidinyl, azetidinyl.
  • patient refers to humans but also other mammals.
  • Prodrug refers to a product that can be converted in vivo by metabolic mechanisms (such as hydrolysis) into a product of formula (I).
  • an ester of a product of formula (I) containing a hydroxyl group can be converted by in vivo hydrolysis to its parent molecule.
  • 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.
  • hydroxyl-containing products of the formula (I) can be prepared from acidic residues such as those described by Bundgaard et al. al., J. Med. Chem.
  • esters include especially (Aminomethyl) -benzoates substituted, dialkylamino-methylbenzoates wherein the two alkyl groups can be bonded together or can be interrupted by an oxygen atom or by an optionally substituted nitrogen atom or an alkylated nitrogen atom or morpholino methyl) benzoates, eg 3- or 4-
  • the addition salts with the inorganic or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.
  • stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position.
  • stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called 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.
  • R has the meaning indicated above or below, R2, R3 and R4, identical or different, are such that one represents a halogen atom or CF3 and the other two, identical or different, represent a hydrogen atom; hydrogen, a halogen atom or an alkyl or alkoxy radical optionally substituted with one or more halogen atoms;
  • R5 represents a hydrogen atom or a halogen atom
  • D 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 halogen atoms, OR 8 and NR 8 R 9
  • R10 represents a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, phenyl and heteroaryl radicals, the phenyl and heteroaryl radicals being themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and
  • 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 by one or more identical or different radicals chosen; among halogen atoms and hydroxyl radicals, NH2, NHaIk and N (alk) 2;
  • 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 the optional second atom by an alkyl radical itself optionally substituted with one or more identical or different radicals chosen from halogen atoms and the hydroxyl radical; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula (I).
  • the ring containing Y may consist of 4 to 7 members, and saturated with Y representing an oxygen atom 0, a sulfur atom S optionally oxidized with or two oxygen atoms or a radical chosen from N-R7, CH-NH2, CH-NHaIk or CH-N (alk) 2, with R7 as defined above or hereinafter.
  • R has the meaning indicated above or below
  • R2, R3 and R4, which are identical or different, are such that one represents a fluorine or chlorine atom or CF3 and the other two, which are identical or different, represent the hydrogen atom, a fluorine or chlorine atom; or a methyl or methoxy radical optionally substituted by one or more fluorine atoms;
  • R5 represents a hydrogen atom or a fluorine or chlorine atom
  • Z represents SO2 or CO
  • D represents a hydrogen atom or a cyclopropyl, methyl, ethyl, propyl or butyl radical optionally substituted with one or more identical or different radicals chosen from the fluorine atom and the hydroxyl, amino, alkylamino, dialkylamino and piperidinyl radicals, morpholinyl, azetidinyl, piperazinyl, pyrrolidinyl and pyrrolyl;
  • the ring (Y) is selected from cyclohexyl radicals itself optionally substituted by amino; tetrahydropyran; dioxidothiényle; and the pyrrolidinyl, piperidinyl and azepinyl radicals optionally substituted on their nitrogen atom with a methyl, propyl, butyl, isopropyl, isobutyl, isopentyl or ethyl radical, themselves optionally substituted with one or more radicals chosen from halogen atoms; hydroxyl radicals and phenyl quinolyl radicals, pyridyl optionally oxidized on its nitrogen atom, thienyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazinyl, furyl and imidazolyl, the latter cyclic radicals being themselves optionally substituted with one or more idnetic or different radicals chosen from halogen atoms and hydroxyl, methyl
  • R has the meaning indicated above or below, R2, R3 and R4, identical or different, are such that one represents a fluorine atom or CF3 and the other two, identical or different, represent the hydrogen atom, a fluorine or chlorine atom or a methyl radical; R5 represents a hydrogen atom;
  • D represents a methyl radical; or an ethyl radical, optionally substituted by an amino, alkylamino, dialkylamino or pyrrolidinyl radical;
  • 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, butyl, isopropyl, isobutyl, isopentyl or ethyl radical, themselves optionally substituted with one or more halogen atoms or a radical chosen from hydroxyl; thiadiazolyl; tetrazolyl; phenyl itself optionally substituted with halogen; quinolyl; pyridyl optionally oxidized on its nitrogen atom; furyl; and imidazolyl itself optionally substituted with alkyl; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastere
  • NR8R9 does not form a cyclic amine
  • NR8R9 is such that R8 represents a hydrogen atom or an alkyl radical and R9 is chosen from the set of values defined for R8.
  • the radical NR8R9 may also represent the values defined above for NRaRb.
  • R2, R3, R4 is alkoxy, methoxy is preferred.
  • R has the meaning indicated above or below, 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 the hydrogen atom, a fluorine or chlorine atom or a methyl radical; R5 represents a hydrogen atom;
  • D represents a hydrogen atom or a methyl radical or an ethyl radical optionally substituted with NH 2;
  • the cycle (Y) is chosen from the radicals tetrahydropyranyl, dioxidothienyl and pyrrolidinyl, piperidinyl and azepinyl radicals optionally substituted on their nitrogen atom (in 2 or 3 of the ring) with a methyl or ethyl, propyl or butyl radical, themselves optionally substituted with one or more halogen atoms or a phenyl, pyridyl, thienyl, or thiazolyl, thiadiazolyl, pyrazinyl, furyl or imidazolyl radical; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (D
  • the subject of the present invention is in particular the products of formula (I) as defined above or hereafter corresponding to formula (IB) in which R 2, R 3, R 4, R 5 and Z have the meanings indicated above or hereinafter and the ring (N) represents one of the rings defined below: an azetidinyl or pyrrolidinyl ring substituted at the 3-position by R 1 and R 6 as defined above or hereinafter; a piperidinyl and azepinyl ring substituted in position 3 or 4 by R 1 and R 6 as defined above or hereinafter; an 8-aza bicyclo (3,2,1) octan-3-yl, 6-azabicyclo [3.2.1] octan-3-yl or 3-azabicyclo [3.2.1] octan-8-yl ring; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids of said products of formula
  • the subject of the present invention is in particular the products of formula (I) as defined above or below. having the formula (IB) in which R, R2, R3, R4, R5 and Z have the meanings given above or hereafter and the ring (N) represents a pyrrolidinyl ring substituted at 3 by R1 and R ⁇ such that defined above or hereinafter or a piperidinyl ring substituted at the 3 or 4 position by R 1 and R ⁇ as defined above or below, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (D
  • R 2, R 3 and R 4 which are identical or different, are such that one represents a halogen atom or CF 3 and the other two, which are identical or different, represent a hydrogen atom or a halogen atom or an alkyl radical or an alkoxy radical optionally substituted with one or more halogen atoms;
  • R5 represents a hydrogen atom or a halogen atom
  • Z represents CO or SO2
  • cycle (N) is
  • R 1 and R 6 represent one of the following alternatives i) to v) i) R 1 represents -X 1 -R 7 with X 1 represents -CH 2 and R 7 represents a heterocycloalkyl, phenyl or heteroaryl, all optionally substituted; and R6 represents hydrogen atom or hydroxyl radicals, -CH2OH, -CO-NRaRb and -CO2Et;
  • R1 represents -X2-R7 with X2 represents:
  • R7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted, and R ⁇ represents hydrogen;
  • R1 represents -NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms optionally substituted with a radical chosen from -PO (OEt) 2, -OH, - OEt, -CF3, -CO-NR8R9 and SO2-alk; and R6 represents hydrogen; it being understood that when W represents a hydrogen atom then z represents CO;
  • R1 represents -CH2-NRc-W with W represents the hydrogen atom or an alkyl radical containing from 1 to 4 linear or branched carbon atoms from 3 carbon atoms and optionally substituted by a radical SO2-alk ; and R ⁇ represents hydrogen;
  • R1 represents -CO-N (Rc) -OR 'c and R ⁇ represents hydrogen
  • n, n1 and n2, identical or different, represent an integer of 0 to 2;
  • Rc and R 'c identical or different represent the hydrogen atom or an alkyl radical containing 1 to 2 carbon atoms
  • NRaRb is such that either Ra and Rb, identical or different, represent the hydrogen atom or a an alkyl radical containing from 1 to 4 carbon atoms optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl and N (alkyl) 2 radicals; or Ra and Rb form with the nitrogen atom to which they are bonded a morpholinyl or pyrrolidinyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and the alkyl radicals themselves optionally substituted with one or several halogen atoms; all the heterocycloalkyl, phenyl and heteroaryl radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms; hydroxyl radicals; cyan
  • NR8R9 is such that either R8 and R9, which are identical or different, are such that R8 represents a hydrogen atom, a linear or branched alkyl radical containing at most 4 carbon atoms or a cycloalkyl radical containing from 3 to 6 ring members, alkyl and cycloalkyl themselves optionally substituted by one or more halogen atoms or a hydroxyl radical; and R 9 represents the hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, NH 2, NHalkyl, N (alkyl) 2, phenyl or heterocycloalkyl radicals; or heteroaryl themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl radical radicals, OCH3, CH3, -CH2OH, CN, CF3, OCF3, NH2, NHaIk or N (alk) 2; or R8 and R9 form
  • all the heterocycloalkyl, phenyl and heteroaryl radicals that R7 represents may in particular be optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms; NR8R9 radicals; and the alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl radicals, themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and hydroxyl, alkoxy, OCF3, CH3, -CH2OH, CN radicals; , CF3, OCF3, NH2, NHaIk, N (alk) 2, pyrrolidinyl, piperidinyl or
  • R1, R2, R3, R4, R5, Z and the ring (N) have the meanings indicated above or below and R1 and R6 are such that: either R1 represents -X-R7 with X1 represents -CH2- and R6 represents the hydrogen atom or hydroxyl radicals, CH 2 -OH; -CO-N (CH3) 2, -CO-NHCH3, -CO-NH- (CH2) 2-N (CH3) 2 and -CO2Et; or R1 represents -X2-R7 with X represents:
  • R6 represents hydrogen
  • R7 is selected from pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuran, hexaydrofuranyl, phenyl, pyridyl, thienyl, thiazolyl, dithiazolyl, pyrazolyl, pyrazinyl, furyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, benzofuranyl, benzodihydrofuranyl and , benzoxodiazolyl, benzothiodiazolyl, benzothienyl, quinolyl, isoquinolyl
  • R1 is -X1-R7 with X1 is -CH2- and R6 is hydrogen or hydroxyl, CH2-OH; -CO-N (CH3) 2, -CO-NHCH3, -CO-NH- (CH2) 2-N (CH3) 2 and -CO2Et; or R1 represents -X2-R7 with X2 represents: -O-, -CHOH-, -CH (OH) -CH2-, -CO-, -CHNH2-, -NH-CH2-, -N (CH3) -CH2- and CH 2 -NH-CH 2 -; and R6 represents hydrogen;
  • R7 is selected from pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, phenyl, pyridyl, thienyl, thiazolyl, dithiazolyl, pyrazolyl, pyrazinyl, furyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, benzodihydrofuranyl, benzoxodiazolyl, benzothiodiazolyl and benzothienyl, quinolyl, isoquinolyl; all of these radicals represented by R7 being optionally substituted with one or more identical or different radicals chosen from halogen atoms and hydroxyl, methyl, methoxy, hydroxymethyl, alkoxymethyl, cyano, NH2, NHaIk, N (alk) 2, - radicals; CH2-NH2, -
  • the subject of the present invention is in particular the products of formula (I) as defined above or below.
  • R, R 1, R 5, R 6, Z, D, W, ring (Y) and ring (N) have the meanings given above or hereafter;
  • R2, R3 and R4, which are identical or different, are such that one represents a halogen atom and the other two, which are identical or different, represent a hydrogen atom, a halogen atom or a methyl or methoxy radical, trifluoromethyl or trifluoromethoxy; and
  • R5 represents a hydrogen atom;
  • said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (D
  • R3 and R4 which are identical or different, are such that one represents a fluorine atom and the other two, which are identical or different, represent a hydrogen atom, a fluorine atom or a methyl radical;
  • R5 represents a hydrogen atom; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids of said products of formula (D);
  • the subject of the present invention is in particular the products of formula (I) as defined above or below in which R, R1, R2, R3, R4, R5, R6, W, D, ring (Y) and cycle (N) have the meanings indicated above or below and Z represents SO 2, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral acids and organic compounds of said formula (I).
  • the subject of the present invention is in particular the products of formula (I) as defined above or below in which R, R1, R2, R3, R4, R5, R6, W, D, ring (Y) and cycle (N) have the meanings indicated above or below and Z represents CO, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and Ddiastereoisomers, as well as the addition salts with mineral acids and organic of said products of formula (I).
  • 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 converted into:
  • R 1 and R 6 have the meanings given above for R 1 and R 6, respectively, in which the possible reactive functional groups are optionally protected by protective groups,
  • R1 ', R2', R3 ', R4', R5 'and R6' have the meanings given above,
  • products of formula (IA) I, (IA) 2, (IB) I and (IB) 2 which may be products of formula (I) in which, respectively, z represents SO2 or CO, and that, to obtain or to obtain Other products of formula (I) may be subjected, if desired and if necessary, to one or more of the following reaction reactions, in any order: a) an oxidation reaction of alkylthio group to sulfoxide or corresponding sulfone, b) a conversion reaction of alkoxy function in 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 be carried by the protected reactive functions, e) a salification reaction with an inorganic or organic acid to obtain the corresponding salt, f) a doubling reaction of the racemic forms into split products, said products of formula (I) thus obtained being in all possible isomeric forms racemic,
  • the subject of the present invention is also a process for the preparation of the products of formula (I) as defined above corresponding to formula (IA) as defined above in which Y represents the radical NR10 as defined above.
  • RIO represents CH2-RZ and RZ represents an alkyl, alkenyl or alkynyl radical, all optionally substituted with a naphthyl radical or with one or more identical or different radicals chosen from halogen atoms and phenyl and heteroaryl radicals, all these radicals; naphthyl, phenyl and heteroaryl being themselves optionally substituted with 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; characterized in that the compound of formula (XIV) is subjected to:
  • R2 ', R3', R4 'and R5' have the meanings indicated in any of the other claims respectively for R2, R3, R4 and R5 in which the optional reactive functions are optionally protected by protecting groups, and z represents SO2 or CO, to a deprotection reaction of the carbamate function to obtain a product of formula (XV):
  • products of formula (IA) which can be products of formula (I) and that in order to obtain or other products of formula (I), one or more reactions of transformations a) to f) can be subjected, if desired and if necessary, in any order; as defined above, said products of formula (I) thus obtained being in all the possible isomeric forms racemic, enantiomers and diastereoisomers.
  • the processes described above can be carried out as follows:
  • the product of formula (II) is converted into a product of formula (III) as defined above, especially in water in the presence of sodium hydroxide and methyl iodide at ordinary temperature.
  • the product of formula (V) as defined above is converted into a product of formula (VI) by the action of phosphorus oxychloride POCl3 between 90 and 110 ° C. for one to two hours.
  • the product of formula (VII) thus obtained is subjected to the action of an amine of formula (VIII) I or (VIII) 2 as defined above in particular in dichloromethane or a mixture of dichloromethane / THF or dimethylformamide with ambient temperature, in the presence of an organic base such as triethylamine, diisopropylethylamine or N-methyl morpholine, to obtain a product of formula (IX) Al or (IX) A2 as defined above.
  • an organic base such as triethylamine, diisopropylethylamine or N-methyl morpholine
  • the product of formula (IX) Al or (IX) A2 is reacted with a phenylboronic acid (X) as defined above according to the coupling methods of SUZUKI with an aryl or heteroaryl halide in the presence of a palladium catalyst.
  • a palladium catalyst such as Pd (OAc) 2 or Pd (dba) 3 or else Pd (dba) 2, with a phosphine tritertiobutylphosphine or DPPF (I, 1'-bis (diphenylphosphino) ferrocene) or tricyclohexylphosphine.
  • the product of formula (III) as defined above is subjected to the action of the methyl ester of 4-amino benzoic acid in particular in an alcohol such as butanol at a temperature of 100 to 140 ° C., to give the product of formula (XI) as defined above.
  • This product of formula (XII) is saponified in its corresponding acid of formula (XIII) by proceeding according to the usual methods known to those skilled in the art such as in particular by the action of sodium hydroxide or potassium hydroxide in water.
  • the product of formula (XIII) thus obtained is reacted with an amine of formula (VIII) I or (VIII) 2 as defined above according to the coupling methods known to those skilled in the art, such as, for example, amidic coupling in the presence of coupling agent such as BOP, DCC or TBTU in a solvent such as, for example, dimethylformamide or dichloromethane to obtain respectively a product of formula (IB) I or (IB) 2 as defined herein below above.
  • the deprotection reaction of the carbamate function of the compound of formula (XIV) to obtain a product of formula (XV) can be carried out using, for example, an acidic agent such as pure trifluoroacetic acid at a temperature close to 0.degree.
  • the product of formula (XV) is subjected to reductive amination conditions in the presence of the aldehyde or ketone of formula (XVI) to obtain a product of formula (IA) as defined above, for example with 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 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 (XV) is subjected to reductive amination conditions in the presence of the aldehyde or ketone of formula (XVI) to obtain a product of formula (IA) as defined above, for example with sodium borocyanide or sodium triacetoxyborohydride in a solvent such as methanol, tetrahydro
  • the products of formulas (IA) I, (IA) 2, (IB) I and (IB) 2 as defined above can therefore constitute products of formula (I) as defined above or can be converted into products of formula (I) by the usual methods known to those skilled in the art and by example by being subjected to one or more of the reactions a) to f) indicated above.
  • the various reactive functions which certain compounds of the above-defined reactions may carry may, if necessary, be protected: for example, they are hydroxyl, acyl or amino and monoalkylamino radicals which may be protected by the appropriate protective groups.
  • the following non-exhaustive list of examples of protection of reactive functions may be mentioned: the hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl;
  • the amino groups may be substituted, for example, by the acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or phthalimido radicals or other radicals known in the peptide chemistry and may then be released under the usual conditions known to man of career.
  • the reactions to which the products of formula (I ') as defined above may be subjected, if desired or necessary, may be carried out, for example, as indicated below.
  • the saponification reactions can be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.
  • the reduction or oxidation reactions may be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as ethyl ether or tetrahydrofuran, in the presence of sodium borohydride or lithium aluminum hydride. ; or for example in a solvent such as acetone or tetrahydrofuran in the presence of potassium permanganate or pyridinium chlorochromate.
  • sulfoxide function can be favored 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 trifluoroacetic acid under reflux.
  • the phthalimido group may in particular be eliminated with hydrazine.
  • a list of different protective groups that can be used, for example, in the BF 2 499 995 patent can be found.
  • the products described above may, if desired, be the subject of salification reactions for example by a mineral or organic acid according to the usual methods known to those skilled in the art.
  • the optional optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art.
  • the starting products of formulas (II), (IV), (VIII) I and (VIII) 2 may be known, may be obtained commercially or may be prepared according to the usual methods known to those skilled in the art, in particular from commercial products for example by subjecting them to one or more reactions known to those skilled in the art such as for example the reactions described above in a) to f).
  • the products of formula (II) which are therefore pyrimidine derivatives, for example dichloropyrimidine or trichloropyrimidine, are commercial products, as are boronic acids such as: -3,4,5-trifluorophenylboronic acid - 2,3,4-Trifluorophenylboronic acid
  • the amines of formula (VIII) I or (VIII) 2 can also be commercially available, for example methyl (1- (methyl-piperidin-4-yl) amine. Preparations of the amines of formula (VIII) I or (VIII) 2 non-commercial can be carried out according to methods known to those skilled in the art.
  • aldehydes or ketones of formula (XVI) 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) corresponding to formula (IB) 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) pG with G represents an optionally substituted heterocycle or phenyl radical as defined above and p represents an integer of 0 to 5.
  • the present invention also relates to the process according to Scheme 2 below for the preparation of products of formula (I) as defined above in which z represents CO:
  • R2 ', R3', R4 ', R5', D 'and W have the meanings given above.
  • the steps of the synthesis method of Scheme 2 above can be carried out using the methyl ester of aniline in step 2 and the boronic acids substituted by R2 ', R3' or R4 'in step 6 and by proceeding according to the usual methods known to those skilled in the art or as described in the present invention.
  • Another subject of the present invention is, as new industrial products, certain compounds of formulas (XIV), (XV), (IX) Al, (IX) A2, (XII) and (XIII).
  • 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, Graves' disease, transplant rejection, psoriasis, dermatitis, allergic disorders, systemic diseases immune system, cachexia, severe acute respiratory syndrome, septic shock, heart failure, myocardial infarction, atherosclerosis, reperfusion injury, AIDS, cancers and disorders characterized by resistance to insulin such as diabetes, hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, polycystic ovarian diseases, hypertension, cardiovascular disorders, Syndrome X, autoimmune diseases such as systemic lupus, lupus erythematous, glomerular arthritis, and others.
  • the products of formula (I) according to the present invention as modulators of apoptosis may be useful in the treatment of various human diseases including aberrations in apoptosis such as cancers: such as in particular but not limited to follicular lymphomas, carcinomas with p53 mutations, hormone-dependent tumors of the breast, prostate and ovary, and precancerous lesions such as polyposis familial adenoma, viral infections (such as, but not limited to, but not limited to those caused by Herpes virus, poxvirus, Epstein - Barr virus, Sindbis virus and adenovirus), myelodysplastic syndromes, ischemic disorders associated with myocardial infarction, cerebral congestion, arrhythmia, atherosclerosis, liver disorders induced by toxins or alcohol, haematological disorders such as, but not limited to, chronic anemia and aplastic anemia, degenerative diseases of the musculoskeletal system such as, but not limited to, osteoporosis, cystic fibrosis, kidney
  • the compounds according to the invention have an anticancer activity and an activity in the treatment of other proliferative diseases such as psoriasis, restenosis, atherosclerosis, AIDS for example, as well as in diseases caused by proliferation.
  • these compounds are useful in the prevention and treatment of leukemias, both primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer, lung cancer, cancer of the lungs, small intestine, colon and rectal cancer, cancer of the respiratory tract, 1 oropharynx and 1 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 s
  • 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, anticachexie.
  • 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, the names of which 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 medicinal product intended for the treatment or the prevention of a disease chosen from the diseases indicated above.
  • the subject of the present invention is in particular the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease chosen from the following group: inflammatory diseases, diabetes and cancers.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of inflammatory diseases.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diabetes.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment of cancers.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the treatment of solid or liquid tumors.
  • the present invention particularly relates to the use of a product of formula (I) as defined above for the treatment of cancers resistant to cytotoxic agents.
  • the subject of the present invention is in particular the use of a product of formula (I) as defined above for the preparation of drugs 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 69 of the present invention.
  • the following examples illustrate the invention without, however, limiting it.
  • a solution containing 15 g of 2-anilino-pyrimidin-4-ol in 75 ml of POCl3 is heated at 110 ° C. for 2 h. After evaporation of POCL3, the crude reaction product is tranvased in an ice-cold solution of Na2CO3. 16.3 g of the expected product are obtained by filtration of the precipitate.
  • Step 4 2 - [(2-Chloropyrimidin-4-yl) amino] -benzenesulfonyl chloride hydrochloride:
  • Step 1 1-Oxa-6-aza-spiro [2.5] octane-6-carboxylic acid tert-butyl ester
  • Step 2 4-Hydroxy-4-pyrrolidin-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester
  • Step 1 ⁇ 1- [4- (4-Chloro-pyrimidin-2-ylamino) -benzenesulfonyl] -piperidin-4-yl ⁇ -methyl-carbamic acid tert-butyl ester:
  • Step 3 [4- (4-Fluoro-phenyl) -pyrimidin-2-yl] - [4- (4-methylamino-piperidine-1-sulfonyl) -phenyl] -amine:
  • the product obtained (1.77 g) at this stage 2 is put in MeOH and then a large volume of 2N solution of HCl in dioxane is added. After one night of reaction, the crude reaction product is concentrated to dryness and then taken up in a mixture AcOEt / NaOH (IN). The aqueous phase is extracted by AcOEt. After drying over MgSO 4 and concentration in vacuo, 1.3 g of expected product are obtained.
  • Step 1 4- ⁇ [4- (4-Chloro-pyrimidin-2-ylamino) -benzenesulfonyl] -methyl-amino ⁇ -piperidine-1-carboxylic acid tert-butyl ester
  • Step 1 of Procedure 2 from 7 g of the compound of Procedure la and 4,932 g of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester ester, 8.8 g of expected product are obtained. .
  • Step 2 4- ( ⁇ 4- [4- (4-Fluoro-phenyl) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -methyl-amino) -piperidine-1-carboxylic acid tert-butyl ester
  • Step 3 4- [4- (4-Fluoro-phenyl) -pyrimidin-2-ylamino] -N-methyl-N-piperidin-4-yl-benzenesulfonamide
  • Step 1 (2 - ⁇ (1-Benzyl-piperidin-4-yl) - [4- (4-chloropyrimidin-2-ylamino) -benzenesulfonyl] -amino ⁇ -ethyl) -carbamic acid tert-butyl ester
  • Step 2 [2- (1-Benzyl-piperidin-4-yl) - ⁇ 4- [4- (4-fluoro-phenyl) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -amino) -ethyl] -carbamic acid tert-butyl ester
  • Step 3 N- (2-Amino-ethyl) -N- (1-benzyl-piperidin-4-yl) -4- (4- (4-fluoro-phenyl) -pyrimidin-2-ylamino] -benzenesulfonamide
  • Step 1 [2- ( ⁇ 4- [4- (4-Fluoro-phenyl) -pyrimidin-2-ylamino] -benzenesulfonyl ⁇ -piperidin-4-yl-amino) -ethyl] -carbamic acid tert-butyl ester proceeds by hydrogenolysis reaction from 250 mg of the compound obtained in Step 1 of Example 5 which is reacted Presence of 50 mg of ammonium formate and 20 mg of Pd / C with 3 mL MeOH in a microwave reactor (250 W, 80 ° C. for 5 minutes). 90 mg of expected product is thus obtained.
  • Step 2 N- (2-Aminoethyl) -4- [4- (4-fluoro-phenyl) -pyrimidin-2-ylamino] -N-piperidin-4-yl-benzenesulfonamide
  • Example 25 In the same manner as in Example 2 [reaction of the sulfonamide of Example 1 with commercial aldehydes (or ketones)], the following compounds (Table 25 below) which are Examples 7 to 31 of this invention) are obtained by adapting the procedure according to the procedure described below: To 0.10 mmol of the product of the procedure 2 in 2.0 mL of THF, a solution of 0.12 mmol of aldehyde in 1.0 mL of THF and 0.3 mL of AcOH is added. Finally, 128 mg of CNBH3-bearing polymer are added and the mixture is stirred under an argon atmosphere overnight at RT. The reaction mixture is filtered, the filtrate is washed with 5 ml of THF and concentrated in vacuo. The crude reaction product is dissolved in 2 ml of DMF and purified by preparative preparative HPLC to give the expected product described as trifluoroacetic acid salt.
  • Examples 32 to 47 are synthesized following the procedure described in Step 2 of Example 1 from the compound of Procedure 3a (below) and corresponding boronic acids.
  • Examples 48 to 69 are synthesized following the procedure described in Step 2 of Example 1 from the compound of Procedure 3b or Procedure 3c (below) and corresponding boronic acids.
  • Procedure 3b (4- ⁇ 4- [Amino-R- (4-fluoro-phenyl) -methyl] -piperidine-1-sulfonyl ⁇ -phenyl) - (4-chloro-pyrimidin-2-yl) -amine
  • Example 2 is taken by way of example in the pharmaceutical preparation which constitutes Example 32 above, this pharmaceutical preparation being able to be carried out differently as indicated above and if desired with other products exemplified herein. request.
  • IKK2 using a kinase test on flash-plate support.
  • the compounds to be tested are dissolved at 10 mM in DMSO and then diluted in kinase buffer (50 mM Tris, pH 7.4 containing 0.1 mM EGTA, 0.1 mM sodium orthovanadate and 0.1% p-mercaptoethanol). Serial 3-to-3 dilutions are made from this solution. 10 .mu.l of each dilution are added to the wells of a 96-well plate in duplicate. 10 ⁇ l of kinase buffer is added to the control wells which will serve as 0% inhibition and 10 ⁇ l of 0.5 mM EDTA is added to the control wells (100% inhibition).
  • the compounds of the invention tested in this test show an IC50 of less than 10 ⁇ M, which shows that they can be used for their therapeutic activity.
  • the compounds according to the invention have been the subject of pharmacological tests for determining their anticancer activity.
  • the compounds of formula (I) according to the present invention have been tested in vitro on a panel of tumor lines of human origin originating from: breast cancer: MDA-MB231 (American type culture collection, Rockville, Maryland, USA, ATCC -HTB26), MDA-A1 or MDA-ADR (MDR-resistant multi-drug line, and described by E.Collomb et al., In Cytometry, 12 (1): 15-
  • HCT116 ATCC-CCL247
  • HCT15 ATCC-CCL225
  • lung cancer H460 (described by Carmichael in Cancer Research 47 (4): 936-942, 1987 and issued by
  • CLT1 described by Kuriyama et al., in Blood, 74: 1989, 1381-1387, by Soda et al in British Journal of Haematology, 59: 1985, 671-679 and by Drexler, in Leukemia Research, 18: 1994, 919-927 and issued by DSMZ, Mascheroder Weg Ib, 38124 Braunschweig, Germany.
  • Proliferation and cell viability were determined in a test using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) according to Fujishita T.
  • the mitochondrial capacity of the living cells is measured to transform the MTS into a colored compound after 72 hours of incubation of a compound of formula (I) according to the invention.
  • concentrations of compound according to the invention, which lead to 50% loss of proliferation and cell viability (IC50) are less than 10 microM, depending on the tumor line and the test compound.
  • the compounds of formula (I) lead to a loss of proliferation and viability of the tumor cells with an IC 50 of less than 10 ⁇ M.
EP08761728A 2007-01-05 2008-01-02 Derives de phenyl- (4-phenyl-pyrimidin-2-yl) - amines comme inhibiteurs de ikk, leur preparation et leur compositions pharmaceutiques Withdrawn EP2111395A1 (fr)

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FR0700065A FR2911139A1 (fr) 2007-01-05 2007-01-05 Nouveaux derives de phenyl-(4-phenyl-pyrimidin-2-yl)amines, leur preparation a titre de medicaments, compositions pharmaceutiques et notamment comme inhibiteurs de ikk
PCT/FR2008/000003 WO2008099074A1 (fr) 2007-01-05 2008-01-02 Derives de phenyl- (4-phenyl-pyrimidin-2-yl) - amines comme inhibiteurs de ikk, leur preparation et leur compositions pharmaceutiques

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TW200848048A (en) 2008-12-16
UY30858A1 (es) 2008-09-02
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US20100069417A1 (en) 2010-03-18

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