HK1139670A

HK1139670A - New n,n'-2,4-dianilinopyrimidines derivatives, preparation thereof as drugs, pharmaceutical compositions and use thereof essentially as ikk inhibitors

Info

Publication number: HK1139670A
Application number: HK10105728.6A
Authority: HK
Inventors: Michaël BOSCH; Monsif Bouaboula; Pierre Casellas; Jean-Flaubert Nguefack; Bernard Tonnerre; Jean Wagnon
Original assignee: Sanofi-Aventis
Priority date: 2007-01-05
Filing date: 2008-01-02
Publication date: 2010-09-24

Description

Novel N, N' -2, 4-dianilinopyrimidine derivatives, their preparation as medicaments, pharmaceutical compositions and use in particular as IKK inhibitors

The present invention relates to novel derivatives of phenyl (4-phenylpyrimidin-2-yl) amines, to processes for their preparation, to novel intermediates obtained, to their use as medicaments, to pharmaceutical compositions comprising them and to novel uses of the above pyrimidine derivatives.

Patent WO 200164654-a1 mentions 2, 4-di (hetero) arylpyrimidines substituted in position 5 as inhibitors of the kinases CDK2 and FAK, as well as other aminopyrimidines which are inhibitors of serine-threonine kinases (CDKs) appear in WO 2003030909-a 1. WO 2004046118-A2 describes derivatives of 2, 4-diphenylaminopyrimidine as inhibitors of cell proliferation.

A series of 5-cyano-2-aminopyrimidines are described in WO 200078731-A1 as inhibitors of the kinases KDR and FGFR, other pyrimidines as inhibitors of FAK and IGFR in WO 2004080980A-1 and ZAP-70, FAK and/or Syk tyrosine kinases in WO 2003078404-A1, and polo kinase PLK as a cytostatic in WO 2004074244-A2.

Similarly, other patents describe pyrimidines as reverse transcriptase inhibitors for the treatment of HIV-associated infections (WO 200185700-A2, WO 200185699-A2, WO 200027825A1 and WO 2003094920A 1).

The object of the present invention is therefore novel N, N' -2, 4-dianilinopyrimidine derivatives which have an inhibitory effect on protein kinases.

The products of the invention are therefore particularly useful in the prevention or treatment of conditions which can be modulated by inhibition of the activity of protein kinases.

Among these protein kinases, the protein kinases IKK-alpha (IKK alpha) and IKK-beta (IKK beta) are more particularly mentioned.

The compounds of the invention are kinase inhibitors, in particular inhibitors of IKK-alpha and IKK-beta, and thus inhibit NF-KB (nuclear transcription factor kappa B) activity, and thus they are useful for the treatment or prevention of inflammatory diseases, cancer and diabetes.

NF-. kappa.B (nuclear factor. kappa.B) belongs to the family of complexes of transcription factors consisting of different combinations of the polypeptides Rel/NF-KB. Members of this polypeptide related to NF-KB regulate the expression of genes involved in immune and inflammatory responses (Bames PJ, Karin M (1997), N Engl. J. Med., 336, 1066-. NF-KB dimers are retained in the cytoplasm in an inactive form by the inhibitory proteins of members of the IKB family under basal conditions (Beg et al, GenesDev., 7: 2064-2070, 1993; Gilmore and Morin, Trends Genet., 9: 427-43)3), 199'); haskil et al, Cell, 65: 1281-1289, 1991). Proteins of the IKB family mask the nuclear translocation signal of NF-KB. Stimulation of cells by various types of ligands (e.g., cytokines, anti-CD 40 ligands, Lipopolysaccharide (LPS)), oxidizing agents, mitogens (e.g., phorbol esters), viruses, and many other stimuli results in activation of the IKB-kinase (IKK) complex, which will subsequently phosphorylate IKB at serine residues 32 and 34. Once phosphorylated, IKB will undergo ubiquitination which causes its breakdown by the proteasome (26S) and therefore NF-KB can be released and translocated into the nucleus where it will bind to specific sequences of the target gene promoter, thus causing their transcription.

In the IKB-kinase (IKK) complex, the major kinases are IKK1(IKK α) and IKK2(IKK β), which are capable of directly phosphorylating various IKBs. Among such IKK complexes, IKK2 is the dominant kinase. (Mercurio et al, Mol Cell Biol, 19: 1526, 1999-, Zandi et al, Science, 281: 13) 60, 1998; lee et al, proc.natl.acad.sci.usa, 95: 93)19, 1998).

Among the genes regulated by NF-KB, many encode pro-inflammatory (pro-inflammatory) mediators, cytokines, cell adhesion molecules, acute phase proteins, which will also induce activation of NF-KB through either autocrine or paracrine mechanisms.

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

In addition, NF-KB plays a role in the growth of normal cells as well as malignant cells.

Proteins produced by expression of genes regulated by NF-KB include cytokines, chemokines, adhesion molecules, cell growth mediators, angiogenesis mediators. Moreover, various studies have shown that NF-KB plays an important role in neoplastic transformation (transformations). NF-KB can be associated, for example, with cell transformation in vitro and in vivo after overexpression, amplification, rearrangement or translocation events (Mercurio, R., and Manning, A.M (1999), Oncogene, 18: 6163-. In some human lymphoid tumor cells, genes encoding various NF-KB members are rearranged or amplified. NF-KB has been shown to promote cell growth by causing transcription of cyclin D, which is associated with hyperphosphorylation of Rb, resulting in a shift from the G1 phase to the S phase and inhibition of apoptosis.

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

The constitutive activity of NF-KB (active constitutive de NF-KB) appears to contribute to tumorigenesis by activating several anti-apoptotic genes (e.g., Al/Bfi-1, IEX-1, MAP), which consequently lead to the inhibition of the cell death pathway. NF-KB can promote the growth of tumor cells by activating cyclin D. The regulation of adhesion molecules and surface proteases suggests a role for NF-KB in the signaling of cancer metastasis.

NF-KB is involved in the induction of chemoresistance. NF-KB is activated in response to certain chemotherapeutic treatments. Inhibition of NF-KB by the supersepressor form of IKB in parallel with the chemotherapy has been shown to increase the efficacy of chemotherapy in xenograft models.

The object of the invention is therefore in particular a product of formula (I):

wherein

R2, R3 and R4, identical or different, are such as: wherein 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 or alkoxy group, optionally substituted by one or more halogen atoms;

r5 represents a hydrogen atom or a halogen atom;

r1 represents a hydrogen atom, a cycloalkyl or alkyl, alkenyl or alkynyl group, all optionally substituted by one or more identical or different groups selected from: halogen atom, OR8 and NR8R9, the alkyl group represented by R1 being optionally additionally substituted by a saturated OR unsaturated 5-membered heterocyclic group, which is linked through a carbon atom and is optionally substituted by one OR more groups selected from: a halogen atom and an alkyl or alkoxy group,

a represents a single bond or-CH 2-CO-NR6-, and R6, which is the same or different from R1, is selected from the values of R1;

the ring comprising Y (OR ring (Y)) is monocyclic OR bicyclic, is made up of 4 to 10 segments, and is saturated OR partially saturated with Y, wherein Y represents an oxygen atom O, a sulfur atom S (which is optionally oxidized by 1 OR 2 oxygen atoms), OR a group selected from N-R7, C ═ O OR its dioxolanes (as carbonyl-functional protecting groups), CF2, CH-OR8, OR CH-NR8R 9;

it will be appreciated that when Y represents NR7, the ring comprising Y (or ring (Y)) may comprise a carbon bridge consisting of 1 to 3 carbons,

r7 represents a hydrogen atom, a cycloalkyl or alkyl group, a CH 2-alkenyl or CH 2-alkynyl group, all optionally substituted by a naphthyl group or by one or more identical or different groups selected from: halogen atoms and hydroxy, alkoxy, phenyl and heteroaryl groups, the alkyl group represented by R7 being optionally additionally substituted by hydroxy, -NR8R9, -CO-NR8R9, phosphonate, alkylthio (which is optionally oxidized to sulfone) or optionally substituted heterocycloalkyl;

r8 represents a hydrogen atom or an alkyl, cycloalkyl or heterocycloalkyl group, which groups are themselves optionally substituted by one or more groups selected from: halogen atoms and hydroxy, alkoxy, NH2, NH alkyl, N (alkyl) 2, -CONH2, -CONH alkyl or-CON (alkyl) 2 groups, the alkyl group represented by R8 being optionally additionally substituted by alkylthio, by optionally substituted phenyl or by optionally substituted saturated or unsaturated heterocyclyl;

NR8R9 is such as: or R8 and R9, identical or different, are selected from the values of R8 (valeur), or R8 and R9 form, together with the nitrogen atom to which they are attached, a cyclic amine which optionally may comprise 1 or 2 further heteroatoms selected from O, S, N or NR10, the cyclic amine thus formed being itself optionally substituted;

all of the above heterocyclyl, heterocycloalkyl and heteroaryl groups are composed of 4 to 10 mer (unless otherwise specified) and contain 1 to 4 heteroatoms, which are suitably selected from O, S (optionally oxidized), N and NR 10;

all of the above naphthyl, phenyl, heterocyclyl, heterocycloalkyl and heteroaryl groups and cyclic amines (which may be formed by R8 and R9 together with the nitrogen atom to which they are attached) are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF3, NH2, or NH alkyl or N (alkyl) 2;

r10 represents a hydrogen atom or an alkyl group,

the products of formula (I) are in all possible racemic, enantiomeric and diastereomeric isomeric forms, and the addition salts of the products of formula (I) with inorganic and organic acids.

In the products of formula (I) as defined above, in which R1, R2, R3, R4, R5 and a have the meanings as indicated above, mention may in particular be made of those in which ring (Y) may be chosen from those defined below:

-when ring (Y) is such as: when Y represents C-OH, CF2, CH-OR8 OR CH-NR8R9, the ring formed may be, in particular, cyclobutyl, cyclopentyl, cyclohexyl OR cycloheptyl, in particular cyclohexyl, and these radicals may thus be substituted, in particular in the para-position, by OH, 2F, OR8 OR NR8R9 groups respectively, where R8 and R9 are selected from the meanings defined above.

When ring (Y) is such as Y represents NR7, the ring formed may in particular be an azetidinyl, pyrrolidinyl or piperidinyl group having a para-or meta-nitrogen atom N, which thus carries a substituent R7 as defined above. When ring (Y) is such that Y represents NR7, it comprises a carbon bridge consisting of 1 to 3 carbons, the ring formed may in particular be the 8-azabicyclo [3.2.1] octane-3-yl 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-8-yl or N, 3-dimethyl-3-azabicyclo [3.3.1] nonan-9-yl.

-when ring (Y) is such as: when Y represents NR7, the ring formed may in particular be a bicyclic group, such as, for example, a quinolyl or indolizinyl group;

-when ring (Y) is such as: when Y represents S, the ring formed may be in particular tetrahydrothiopyranyl or tetrahydrothienyl: when ring (Y) is as follows: when Y represents SO2, the ring formed may be, in particular, dioxotetrahydro-3-thiophenyl.

-when ring (Y) is such as: when Y represents O, the ring formed may be, in particular, tetrahydrofuran or tetrahydropyran. When ring (Y) is as follows: when Y represents a dioxolane of C ═ O, the ring formed may be in particular the dioxaspiro [4.5] decan-8-yl group.

The invention relates in particular to products of formula (I) as defined above, in which R2, R3, R4, R5, A and the ring (Y) have the meanings indicated above, R1 represents a hydrogen atom or a linear or branched alkyl radical comprising 1 to 5 carbon atoms, or R1 represents an alkyl radical substituted by a saturated or unsaturated heterocyclic ring which is itself optionally substituted as indicated above, said heterocyclic ring preferably being a 5-membered monocyclic heterocyclic ring,

The invention relates in particular to products of formula (I) as defined above, in which R2, R3, R4, R5 and a have the meanings indicated above, R1 represents a hydrogen atom or an optionally substituted, linear or branched alkyl radical comprising 1 to 4 carbon atoms, in particular CH3, ring (Y) is as defined above: y represents NR7, wherein R7 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted by a group selected from: hydroxy, CF3, phosphonate, sulfone, phenyl and saturated or unsaturated monocyclic or bicyclic heterocyclic groups, which phenyl and heterocyclic groups are themselves optionally substituted as indicated above,

The invention very particularly relates to products of the formula (I) as defined above, in which R2, R3, R4, R5 and A have the meanings indicated above,

r1 represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms, in particular CH3, ring (Y) being such as: y represents NR8R9, wherein R8 represents a hydrogen atom or CH3, R9 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted with a group selected from: hydroxy, CF3, phosphonate, sulfone, phenyl, and saturated or unsaturated monocyclic or bicyclic heterocyclic groups, which phenyl and heterocyclic groups themselves are optionally substituted as indicated above,

The invention therefore relates in particular to products of formula (I) as defined above, in which R2, R3, R4, R5 and a are selected from the meanings indicated above, the other substituents being selected from the preferred values defined below:

-R1 represents a hydrogen atom, a CH3 group or a linear or branched alkyl group containing 1 to 4 carbon atoms, optionally substituted by NH2, NH (alkyl), N (alkyl) 2 or by a saturated or unsaturated heterocyclic ring, preferably a monocyclic ring having 5 or 6 mer as defined above and optionally substituted as indicated above or below, and ring (Y) represents piperidinyl or pyrrolidinyl, substituted on its nitrogen atom by R7, R7 represents an alkyl group optionally substituted by: hydroxy, -NR8R9, -CO-NR8R9, phosphonate, or alkylthio (which is optionally oxidized to sulfone);

-R1 is selected from the values defined above and ring (Y) represents cyclohexyl substituted by a NR8R9 group as defined above;

-R1 represents CH3, optionally substituted by a saturated or unsaturated heterocyclic ring as defined above, R7 represents a CH3 group;

-R1 represents a hydrogen atom or a CH3 group, and ring (Y) represents a piperidine or 8-azabicyclo [3.2.1] octane-3-yl ring substituted on the nitrogen atom by R7, wherein R7 is as defined above.

In the products of formula (I) as defined above, in which R1, R2, R3, R4, R5 and a have the meanings as indicated above, mention may be made, for example, of those in which ring (Y) is chosen from those defined below:

-ring (Y), such as Y represents-N-R7, wherein R7 represents H;

-ring (Y), such as Y represents-N-R7, wherein R7 represents CH 3;

-ring (Y), such as Y, represents-N-R7, wherein R7 represents cycloalkyl, such as cyclopropyl in particular;

-a ring (Y), such as Y represents-N-R7, wherein R7 represents alkyl, in particular CH3, C2H5 or C3H7 substituted with phosphonate;

-a ring (Y), such as Y represents-N-R7, wherein R7 represents alkyl, in particular CH3, C2H5 or C3H7 substituted with alkylthio, such as S-CH3 or S-C2H5, wherein S is optionally oxidized to a sulfone to form, for example, SO2-CH3 or SO2-C2H 5;

-ring (Y) such as Y represents-N-R7, wherein R7 represents alkyl, in particular such as CH3 or C2H5, substituted with one or more groups selected from: halogen atoms (such as F in particular), and phenyl and mono-or bicyclic heterocyclic groups, which phenyl and heterocyclic groups themselves are optionally substituted by one or more groups selected from: halogen atoms and alkyl, alkoxy, OH, CN, CF3, NH2, NH alkyl and N (alkyl) 2 groups: among these heterocycles carried by R7, mention may be made in particular of 5-membered unsaturated heterocycles comprising from 1 to 4 heteroatoms selected from N, O and S: thus R7 may particularly represent-CH 2-thienyl, -CH 2-thiazolyl (N, S), -CH 2-thiadiazolyl (N, S), -CH 2-furyl (O), -CH 2-pyrazolyl (N, N), -CH 2-isoxazolyl (N, O), -CH 2-pyrrolyl (NH, NCH3), these groups, in particular pyrazolyl, isoxazolyl, pyrrolyl or tetrazolyl, being themselves optionally substituted, in particular, by alkyl groups comprising 1 to 3 carbon atoms, such as, in particular, CH3 or C2H 5;

r7 may also bear a heterocyclic ring as defined above, such as pyridyl (with pyridine N at 3 different positions); 2, 3-dihydro-1H-indolyl; a quinolyl group; an isoquinolinyl group; a pyrimidinyl group; 2, 3-dihydro-benzofuranyl; [1, 8] -naphthyridinyl ([1, 8] -naphthyridinylene); a pyridyl-N-oxide group; or 4-benzo [1, 2, 5] oxadiazolyl; 2, 3-dihydro-benzofuranyl.

-ring (Y) such as Y represents CH-NR8R9, wherein NR8R9 such as R8 represents a hydrogen atom or an alkyl group (particularly such as CH3), and R9 represents a linear or branched alkyl group (particularly such as CH3, C2H5 or-CH 2-or-CH (CH3) -or-CH (CH3) -CH2-, which is substituted either by an optionally substituted, saturated or unsaturated, mono-or bicyclic heterocyclic group or by an optionally substituted phenyl group). Among the heterocycles carried by R9, mention may in particular be made of the following groups: pyridyl (with pyridine N at 3 different positions); 2, 3-dihydro-1H-indolyl; a quinolyl group; an isoquinolinyl group; a pyrimidinyl group; 2, 3-dihydro-benzofuranyl; [1, 8] naphthyridinyl; 4-benzo [2, 1, 3] oxadiazolyl; benzo [2, 1, 3] thiadiazolyl;

the above heterocyclic ring is optionally substituted by one or more groups as defined above or below.

In the products of formula (I) as defined above, in which R2, R3, R4, R5 and a and ring (Y) have the meanings as indicated above, mention may be made, for example, of those in which R1 may be selected from the following definitions:

-R1 represents H;

-R1 represents CH 3;

-R1 represents an alkenyl (3C) group, such as allyl or an alkynyl (3C) group, such as propargyl;

-R1 represents an alkyl group, in particular CH3, C2H5, C3H7, substituted by one or more identical or different groups selected from: halogen atoms and NH2, NH (alkyl), N (alkyl) 2, NH-CH2-CH2OH, NH-CH2-C3H7-OH, NH (CH2-CF3), alkoxy, OH, or saturated heterocycles, such as, for example, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuryl, or unsaturated heterocycles, in particular as defined above for R7.

An object of the present invention is therefore a product of formula (I) as defined above, in which:

r2, R3 and R4, identical or different, are such as: wherein one represents a halogen atom or CF3 and the other two, identical or different, represent a hydrogen atom, a halogen atom or an alkyl or alkoxy group, optionally substituted by one or more halogen atoms;

r5 represents a hydrogen atom or a halogen atom;

r1 represents a hydrogen atom, a cycloalkyl OR alkyl, alkenyl OR alkynyl group, all optionally substituted by one OR more identical OR different groups selected from halogen atoms, OR8 and NR8R 9;

the ring comprising Y (OR ring (Y)) is monocyclic OR bicyclic, is made up of 4 to 10 segments, and is saturated OR partially saturated with Y, wherein Y represents an oxygen atom O, a sulfur atom S optionally oxidized with 1 OR 2 oxygen atoms, OR a group selected from N-R7, C-O, CF2, CH-OR8, OR CH-NR8R 9;

r7 represents a hydrogen atom or an alkyl, CH 2-alkenyl or CH 2-alkynyl group, all optionally substituted by naphthyl or by one or more identical or different groups selected from: halogen atoms and hydroxyl, phenyl and heteroaryl groups, all of which naphthyl, phenyl and heteroaryl groups are themselves optionally substituted; said heteroaryl group is composed of 5 to 10 mer and contains 1 to 4 heteroatoms selected from O, S, N and NR 10;

r8 represents a hydrogen atom or an alkyl, cycloalkyl or heterocycloalkyl group, which group is itself optionally substituted by one or more groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl or N (alkyl) 2;

NR8R9 is such as: or R8 and R9, identical or different, are selected from the values of R8 (valeur), or R8 and R9 form, together with the nitrogen atom to which they are attached, a cyclic amine which optionally may comprise 1 or 2 further heteroatoms selected from O, S, N or optionally substituted NR 10;

r10 represents a hydrogen atom or an alkyl group;

all of the above naphthyl, phenyl and heteroaryl and cyclic amines (which may be formed by R8 and R9 together with the nitrogen atom to which they are attached) are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NH alkyl or N (alkyl) 2;

In the products of the formula (I) and hereinafter, the terms mentioned have the following meanings:

the term "halogen" denotes a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom;

the term "alkyl" denotes a straight-chain or branched group comprising up to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, and their straight-chain or branched positional isomers;

the term "hydroxyalkyl" denotes an alkyl group as indicated above substituted by one or more hydroxyl groups;

the term "alkenyl" denotes a straight or branched chain group comprising up to 6 carbon atoms, preferably 4 carbon atoms, for example selected from the following values: vinyl or vinyl, propenyl or allyl, 1-propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl or hexenyl, and their linear or branched positional isomers: among said alkenyl values, mention is more particularly made of allyl or butenyl values;

the term "alkynyl" denotes a straight or branched chain group comprising up to 6 carbon atoms, preferably 4 carbon atoms, selected for example from the following values: ethynyl, propynyl or propargyl, butynyl, n-butynyl, isobutynyl, 3-methylbut-2-ynyl, pentynyl or hexynyl, and the linear or branched positional isomers thereof: among the alkynyl values, mention is made more particularly of propargyl;

the term "alkylene" denotes a linear or branched divalent radical from the above-mentioned alkyl radicals comprising up to 6 carbon atoms and is therefore selected, for example, from methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene or pentylene;

the term "alkoxy" denotes a linear or branched group comprising up to 6 carbon atoms, for example selected from methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy, hexoxy and heptoxy, and their linear or branched positional isomers;

the term "cycloalkyl" denotes a monocyclic or bicyclic carbocyclic group comprising 3 to 7 mer, and in particular denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;

the term "aryl" denotes an unsaturated monocyclic or carbocyclic group consisting of fused rings. As examples of such aryl groups, mention may be made in particular of phenyl or naphthyl;

the term "heterocyclyl" denotes a saturated carbocyclic group (heterocycloalkyl) or a partially or fully unsaturated carbocyclic group (heteroaryl) consisting of 4 to 10 mer interrupted by 1 or 3 identical or different heteroatoms selected from oxygen, nitrogen or sulfur atoms:

among heteroaryl groups having 5 links, mention may in particular be made of groups comprising from 1 to 4 heteroatoms selected from N (optionally oxidized), O and S (optionally oxidized), as groups which may be mentioned are thienyl, such as 2-thienyl, 3-thienyl, dioxythienyl (dioxidothie), -thiazolyl (N, S), -furyl (O), 2-furyl, pyrrolyl (NH, NCH3), isothiazolyl, oxadiazolyl, thiadiazolyl (N, S), 1, 3, 4-thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl (N, O), 3-isoxazolyl, 4-isoxazolyl, imidazolyl, pyrazolyl (N, N), triazolyl, tetrazolyl, more in particular oxazolyl, isoxazolyl (N, O) or pyrazolyl; all of these rings are optionally substituted with one or more groups as defined above or below, with these substituents of course being located at chemically suitable positions for each of these rings.

Among the heteroaryl groups having 6 mer, mention may in particular be made of pyridyl groups, such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyridyloxy, pyrimidinyl, pyridazinyl and pyrazinyl;

among the fused heteroaryl groups comprising at least one heteroatom selected from S, N and O, mention may be made, for example, of benzothienyl, benzofuranyl, oxyindenyl, benzoxazolyl, indazolyl, indolyl, indolinyl, indolinonyl (indolinonyl), quinolyl, isoquinolyl, azaindolyl, benzimidazolyl, benzothiazolyl, naphthyridinyl (naphthyridinyl) such as 1, 8-naphthyridinyl; imidazo [4.5] pyridinyl; indolizinyl, quinazolinyl; 2, 3-dihydro-1H-indolyl; 2, 3-dihydro-benzofuranyl or 4-benzo [1, 2, 5] oxadiazolyl; 2, 3-dihydro-benzofuranyl;

among the fused heterocycloalkyl groups, mention may be made more particularly of benzothienyl, benzofuranyl, benzodihydrofuranyl, indolyl, indolinyl, indolinonyl, benzimidazolyl, benzothiazolyl, benzooxadiazolyl, benzothiadiazolyl, naphthyridinyl, indazolyl, quinolinyl, such as 4-or 5-quinolinyl, isoquinolinyl, azaindolyl, such as 4-or 3-azaindolyl, imidazo [4.5] pyridyl, indolizinyl or quinazolinyl;

as (saturated) heterocycloalkyl, mention may be made, for example, of oxiranyl (oxiranyl), oxetanyl (oxiranyl), tetrahydrofuranyl, dioxolanyl (dioxalanyl), dithiopentanoyl (dithiolanyl), tetrahydropyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azanylRadicals (az apinyle), diazaPiperazinyl, morpholinyl, thiomorpholinyl, dioxodomorphlinyl, imidazolidinyl; mention may more particularly be made of pyrrolidinyl, piperidinyl, azepinylA group, piperazinyl or morpholinyl;

all cyclic groups are optionally substituted as above or as indicated below;

the terms "alkylamino or NH (alkyl)" and "dialkylamino or N (alkyl) 2" thus denote an amino NH2 group substituted respectively by 1 or 2 identical or different (in the case of dialkylamino) linear or branched alkyl groups, selected from alkyl groups as defined above and optionally substituted as indicated above or below: mention may be made, for example, of methylamino, ethylamino, propylamino or butylamino groups or dimethylamino, diethylamino or methyl-ethylamino groups;

the term "cycloalkylamino" thus denotes an amino group substituted in particular by a cycloalkyl group chosen from the groups defined above: mention may thus be made, for example, of cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino;

the term "cyclic amine" denotes a monocyclic or bicyclic group comprising 3 to 10 mer in which at least one carbon atom is replaced by a nitrogen atom, such cyclic group may also comprise one or more further heteroatoms selected from O, S, SO2, N or NR10, wherein R10 is as defined above: as examples of such cyclic amines, mention may be made, for example, of pyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl or azetidinyl. Mention may more particularly be made of piperidinyl, morpholinyl, piperazinyl or azetidinyl.

The term "patient" refers to humans and other mammals.

The term "prodrug" denotes a product which can be converted in vivo by metabolic mechanisms such as hydrolysis into the product of formula (I). For example, an ester of the formula (I) product containing a hydroxyl group may be converted to its parent molecule by in vivo hydrolysis.

As examples of esters of the products of formula (I) containing hydroxyl groups, mention may be made of, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, glycocholates, isethionates, di (p-toluoyl) tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinic acid esters.

Particularly useful esters of the products of formula (I) containing hydroxyl groups can be prepared starting from acid residues such as those described by Bundgaard et al, J.Med.chem., 1989, 32, page 2503-2507: these esters include in particular substituted (aminomethyl) benzoates, dialkylaminomethyl benzoates in which the two alkyl groups may be linked together or may be interrupted by an oxygen atom or an optionally substituted nitrogen atom, i.e. an alkylated nitrogen atom, or (morpholinomethyl) benzoates, such as 3-or 4- (morpholinomethyl) benzoate, and (4-alkylpiperazin-1-yl) benzoates, such as 3-or 4- (4-alkylpiperazin-1-yl) benzoate.

When the products of formula (I) contain amino groups which can be salified by acids, it is clearly understood that these acid salts also form part of the invention. Mention may be made, for example, of the salts obtained using hydrochloric acid or methanesulfonic acid.

The addition salts with inorganic or organic acids of the product of formula (I) can be, for example, the salts with the following acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid or ascorbic acid, alkyl monosulfonic acids, such as methanesulfonic acid, ethanesulfonic acid or propanesulfonic acid, alkyl disulfonic acids, such as methanedisulfonic acid or α, β -ethanedisulfonic acid, aryl monosulfonic acids, such as benzenesulfonic acid and aryl disulfonic acids.

It can be mentioned that a stereoisomerism can be defined in its broadest sense as a compound having the same structural formula (formulae) but with different groups arranged in different positions in space, such as, in particular, in monosubstituted cyclohexane, the substituents thereof can be in the upright or in the equatorial position. However, there is another type of stereoisomerism which arises due to the different spatial arrangement of the substituents fixed (either on the double bond or on the ring), which is commonly referred to as E/Z geometric isomerism or cis-trans isomerism or diastereoisomerism. The term "stereoisomer" is used in the present patent application in its broadest sense and thus relates to all compounds as described above.

Accordingly, an object of the present invention is in particular a product of formula (I) as defined above, in which:

r2, R3 and R4, identical or different, are such as: wherein one represents a fluorine or chlorine atom or CF3 and the other two, identical or different, represent a hydrogen atom, a fluorine or chlorine atom or a methyl or methoxy group, optionally substituted by one or more fluorine atoms;

r5 represents a hydrogen atom or a fluorine or chlorine atom;

r1 represents a hydrogen atom, a cycloalkyl or an alkyl group, optionally substituted by one or more identical or different groups selected from: fluorine atom, OR8 and NR8R 9;

a represents a single bond or a group-CH 2-CO-NR 6-and R6 represents a hydrogen atom or a linear or branched alkyl group comprising up to 4 carbon atoms;

the ring comprising Y (OR ring (Y)) is monocyclic OR bicyclic, is made up of 4 to 10 segments and is saturated OR partially saturated with Y, wherein Y represents an oxygen atom O, a sulphur atom S (optionally oxidised by 1 OR 2 oxygen atoms) OR a group selected from NR7, C-O, CF2, CH-OR8 OR CH-NR8R 9;

r7 represents a hydrogen atom or an alkyl group optionally substituted by one or more identical or different groups selected from: halogen atoms and phenyl and heteroaryl groups, which are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NH alkyl or N (alkyl) 2 groups;

heteroaryl consists of 5-7 mer and comprises 1-3 heteroatoms selected from O, S, N and NR 10;

r8 represents a hydrogen atom, a linear or branched alkyl group comprising up to 4 carbon atoms or a cycloalkyl group comprising 3 to 6 mer, said alkyl and cycloalkyl groups themselves being optionally substituted by hydroxyl;

NR8R9 is such as: or R8 and R9, identical or different, are selected from the values of R8, or R8 and R9 form, together with the nitrogen atom to which they are attached, a cyclic amine selected from: pyrrolyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl and piperazinyl, optionally substituted on a second atom with alkyl;

In particular, the ring comprising Y may be made up of 4 to 7 segments and may be saturated with Y, wherein Y represents an oxygen atom O, a sulphur atom S (optionally oxidized by 1 or 2 oxygen atoms) or a group selected from: N-R7, CH-NH2, CH-NH alkyl or CH-N (alkyl) 2, wherein R7 is as defined above or below.

The object of the present invention is in particular a product of formula (I) as defined above, in which:

r2, R3 and R4, identical or different, are such as: one of which represents a fluorine atom or CF3, and the other two: one represents a hydrogen atom and the other represents a fluorine or chlorine atom or a methyl group;

r5 represents a hydrogen atom or a chlorine atom;

r1 represents a hydrogen atom or a cyclopropyl, methyl, ethyl, propyl or butyl group, optionally substituted by one or more identical or different groups selected from: fluorine atoms and hydroxyl, amino, alkylamino, dialkylamino, piperidinyl, morpholinyl, azetidinyl, piperazinyl, pyrrolidinyl and pyrrolyl groups;

a represents a single bond, -CH 2-CO-NH-or-CH 2-CO-NCH3-, the ring comprising Y being selected from cyclohexyl which is itself optionally substituted by amino; a tetrahydropyran; dioxythienyl; and pyrrolidinyl, piperidinyl, aza-a radical, a indolizinyl radical and a quinazolinyl radical, optionally substituted by one or more identical or different radicals selected from the group consisting of: methyl, propyl, butyl, isopropyl, isobutyl, isopentyl or ethyl, which are themselves optionally substitutedSubstituted with one or more groups selected from: halogen atoms and hydroxy, phenyl (which itself is optionally substituted by one or more halogen atoms), quinolinyl, pyridyl (which is optionally oxidized at its nitrogen atom), thienyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazinyl, furyl and imidazolyl (which themselves are optionally substituted by alkyl);

r2, R3 and R4, identical or different, are such as: one of which represents a fluorine atom or CF3, and the other two: one represents a hydrogen atom and the other represents a fluorine or chlorine atom, or a methyl group;

r5 represents a hydrogen atom;

r1 represents methyl or ethyl, optionally substituted by amino, alkylamino, dialkylamino or pyrrolidinyl;

a represents a single bond, the ring comprising Y represents cyclohexyl, optionally substituted on its nitrogen atom by amino, or piperidinyl or pyrrolidinyl, optionally substituted on its nitrogen atom by methyl, propyl, butyl, isopropyl, isobutyl, isopentyl or ethyl, which substituents are themselves optionally substituted by one or more halogen atoms or by a group selected from hydroxy; thiadiazolyl; tetrazolyl; phenyl (optionally substituted on its nitrogen atom by halogen), quinolinyl; pyridinyl (optionally oxidized on its nitrogen atom), furanyl and imidazolyl (optionally substituted on its nitrogen atom by alkyl);

Mention may in particular be made of products of formula (I) in which a represents a single bond, the other substituents R1, R2, R3, R4, R5 and the ring (Y) of which are selected from the values indicated above.

Particular mention is therefore made of products of formula (I) in which R5 represents a hydrogen atom, the other substituents R1, R2, R3, R4, a and ring (Y) of which are selected from the values indicated above.

Preference is given to products of the formula (I) as defined above, in which, when NR8R9 does not form a cyclic amine, then NR8R9 is as follows: r8 represents a hydrogen atom or an alkyl group, R9 being selected from all the values defined for R8.

Methoxy is preferred when one of R2, R3 and R4 represents alkoxy.

A product of formula (I) as defined above, wherein:

r5 represents a hydrogen atom;

r1 represents a hydrogen atom or a methyl group;

a represents a single bond, the ring comprising Y is selected from tetrahydropyranyl or dioxythienyl and pyrrolidinyl, piperidinyl and azepinyl optionally substituted at its nitrogen atom (in position 2 or 3 of the ring) withBase: methyl or ethyl, propyl or butyl, which are themselves optionally substituted by one or more halogen atoms or phenyl, pyridyl, thienyl or thiazolyl, thiadiazolyl, pyrazinyl, furyl or imidazolyl;

The invention relates in particular to products of formula (I) corresponding to the following names:

-4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino ] -N-methyl-N- (1-methylpiperidin-4-yl) benzamide

-4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino ] -N-methyl-N- [1- (4, 4, 4-trifluorobutyl) piperidin-3-yl ] benzamide

-4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino ] -N-methyl-N- (1[1, 2, 3] thiadiazol-4-ylmethyl-piperidin-3-yl ] benzamide

-N-methyl-N- (1-methylpiperidin-4-yl) -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzamide

-N-methyl-N- (tetrahydropyran-4-yl) -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzamide

-N- (1-methylpiperidin-4-yl) -N- (2-pyrrolidin-1-yl-ethyl) -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzamide,

-4- ({4- [ (4-fluorophenyl) amino ] pyrimidin-2-yl } amino) -N- (octahydroindolinizin-7-yl) benzamide

The present invention also relates to a process for the preparation of the product of formula (I) as defined above.

The subject of the present invention is in particular a process for the preparation of the product of formula (I) as defined above, characterized in that a product of formula (II):

wherein R5' has the meaning indicated above for R5, wherein possible reactive functions are optionally protected,

with the product of formula (III):

wherein R2 ', R3 ' and R4 ' have the meanings indicated above for R2, R3 and R4, respectively, wherein possible reactive functions are optionally protected,

to obtain a product of formula (IV):

wherein R2 ', R3', R4 'and R5' have the meanings as indicated above,

reacting the product of formula (IV) as defined above with methyl 4-aminobenzoate of formula (V) to obtain a product of formula (VI):

wherein R2 ', R3', R4 'and R5' have the meanings indicated above, saponifying said product of formula (VI) to obtain its corresponding acid of formula (VII):

wherein R2 ', R3', R4 'and R5' have the meanings as indicated above,

reacting the product of formula (VII) with an amine of formula (VIII):

wherein R1' has the meaning indicated above for R1, wherein possible reactive functions are optionally protected by protecting groups, to give a product of formula (I1):

wherein R1 ', R2 ', R3 ', R4 ' and R5 ' have the meanings as indicated above,

the product of formula (I1), which may be a product of formula (I), and to obtain a product of formula (I) or other product of formula (I), may be subjected to one or more of the following conversion reactions, if desired and necessary, in either order:

a) reaction of the alkylthio group oxidation to the corresponding sulfoxide or sulfone,

b) a reaction which converts an alkoxy function into a hydroxy function, or a reaction which converts a hydroxy function into an alkoxy function,

c) a reaction to oxidize the alcohol function to an aldehyde or ketone function,

d) elimination of the protecting group carried by the protected reactive function,

e) salt-forming reactions with inorganic or organic acids to obtain the corresponding salts,

f) a reaction for resolving the racemic form into the resolved product (produits deubes),

the product of formula (I) thus obtained is in all possible racemic, enantiomeric and diastereomeric isomeric forms.

The present invention also has for its object a process for the preparation of a product of formula (I) as defined above, in which Y represents a NR7 group as defined above, while R7 represents CH2-RZ and RZ represents alkyl, alkenyl or alkynyl, all optionally substituted as indicated above, in particular by naphthyl or by one or more identical or different groups selected from: halogen atoms and phenyl and heteroaryl groups, all of which naphthyl, phenyl and heteroaryl groups are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NH alkyl or N (alkyl) 2 groups.

This process is characterized in that a compound of formula (A):

wherein R1 ', R2 ', R3 ', R4 ', R5 ' and the ring (N) have the meanings indicated above,

subjected to deprotection of the carbamate function to obtain the product of formula (IX):

subjecting the product of formula (IX) to reductive amination conditions in the presence of an aldehyde or ketone of formula (X):

RZ’-CR8’O (X)

wherein RZ' has the meaning indicated above and represents alkyl, alkenyl or alkynyl, which are optionally substituted as indicated in any of the preceding claims, wherein possible reactive functions are optionally protected by protecting groups,

wherein R8' has the meaning indicated above for R8, wherein possible reactive functions are optionally protected by protecting groups,

to obtain a product of formula (I2):

wherein R1 ', R2 ', R3 ', R4 ', R5 ', Ring (N), RZ ' and R8 ' have the meanings indicated above,

said product of formula (I2), which may be a product of formula (I), and in order to obtain a product of formula (I) or another product of formula (I), if desired and if necessary, the above-mentioned products may be subjected in any order to one or more of the conversion reactions a) to f) as defined above,

the product of formula (I2) thus obtained is in all possible racemic, enantiomeric and diastereomeric isomeric forms.

Under preferred conditions for carrying out the invention, the above process can be carried out in the following manner:

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 butanol, propanol or ethanol) or dimethylformamide at 80-140 ℃ to obtain the product of formula (IV) as defined above.

The product of formula (IV) as defined above is subjected to the action of methyl 4-aminobenzoate of formula (V) in particular in an alcohol such as butanol at a temperature of 100 ℃ and 140 ℃ to give a product of formula (VI) as defined above.

The product of formula (VI) is saponified to the corresponding acid of formula (XII) by treatment according to conventional methods known to those skilled in the art, such as in particular by the action of sodium or potassium hydroxide in water.

The product of formula (VII) thus obtained is reacted with an amine of formula (VIII) as defined above according to coupling methods known to those skilled in the art, such as by amide coupling in the presence of a coupling agent (such as BOP, DCC or TBTU) in a solvent (such as dimethylformamide or dichloromethane), to obtain the product of formula (I1) as defined above.

The deprotection of the carbamate function of the compound of formula (a) to obtain the product of formula (IX) can be carried out, for example, by using an acid reagent at a temperature of about 0 ℃ (such as pure trifluoroacetic acid), or a mixture of such an acid with a suitable solvent (such as dichloromethane) at about 0 ℃, or using a solution of hydrochloric acid in ether or dioxane (at a temperature of 0 ℃ to ambient temperature).

Subjecting the product of formula (IX) to reductive amination conditions in the presence of an aldehyde or ketone of formula (X) to obtain a product of formula (I2) as defined above, for example using sodium borocyanide or sodium triacetoxyborohydride in a solvent such as methanol, Tetrahydrofuran (THF) or mixtures thereof in a medium at pH 4-7.

Depending on the values of R1 ', R2, R3, R4 and R5 and RZ', the products of formula (I1), (I2) as defined above may thus constitute the products of formula (I) as defined above or may be converted into the products of formula (I) by usual methods known to the person skilled in the art, for example by subjecting them to one or more of the reactions a) to f) as indicated above.

Moreover, it can be noted that: the reactions a) to f) described above for converting substituents into other substituents can also be carried out on the starting products and on intermediates as defined above (before continuing the synthesis according to the reactions indicated in the above-described methods).

If desired, various reactive functions carried by certain of the above-defined reactive compounds may be protected: these are, for example, hydroxyl, acyl or amino and monoalkylamino groups, which may be protected by suitable protecting groups.

The following non-exhaustive list of examples of protection of reactive functions may be mentioned:

the hydroxyl group may be protected, for example, by an alkyl group, such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,

the amino group can be protected, for example, by acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, phthalimido or other groups known in peptide chemistry and can therefore be released under the usual conditions known to the person skilled in the art.

If desired or necessary, the reactions to which the products of formula (I') as defined above can be subjected can be carried out, for example, as indicated below.

The saponification reaction may be carried out according to a usual method known to those skilled in the art, such as in a solvent (e.g., methanol or ethanol, dioxane or dimethoxyethane) in the presence of sodium hydroxide or potassium hydroxide.

The reduction or oxidation reaction can be carried out according to the usual methods known to the person skilled in the art, such as, for example, in a solvent (such as diethyl ether or tetrahydrofuran) in the presence of sodium borohydride or lithium aluminium hydride, or, for example, in a solvent (such as acetone or tetrahydrofuran) in the presence of potassium permanganate or pyridinium chlorochromate.

a) If desired, the possible alkylthio groups of the above products can be converted into the corresponding sulfoxide or sulfone function under the usual conditions known to the person skilled in the art, for example using peracids, such as peracetic or m-chloroperbenzoic acid, or using oxone, sodium periodate, in solvents such as dichloromethane or dioxane, at ambient temperature.

The sulfoxide functionality may be facilitated by an equimolar mixture of the product comprising the alkylthio group and a reactant, such as a peracid in particular.

The obtainment of the sulfone function can be facilitated by a product mixture of the product comprising alkylthio groups with an excess of reactants, such as, in particular, peracids.

b) If desired, possible alkoxy functions (such as, in particular, methoxy functions) of the products described above can be converted into hydroxy functions under customary conditions known to the person skilled in the art, for example using boron tribromide in a solvent such as dichloromethane, using pyridine hydrobromide or pyridine hydrochloride or using hydrobromic acid or hydrochloric acid in water or refluxing trifluoroacetic acid.

c) If desired, the possible alcohol functions of the above products can be converted into aldehyde or ketone functions by oxidation under the usual conditions known to the person skilled in the art, such as by the action of manganese oxide to give an aldehyde or by the action of potassium permanganate or pyridinium chlorochromate to give a ketone.

d) For example, the elimination of the protecting group (such as those indicated above) can be carried out under the usual conditions known to the person skilled in the art, in particular by acid hydrolysis using an acid (such as hydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid or trifluoroacetic acid) or by catalytic hydrogenation.

The phthalimido group can be eliminated particularly with hydrazine.

A list of different protecting groups that can be used is found in patent BF 2499995.

e) If desired, the products as described above can be the subject of salt-forming reactions using inorganic or organic acids, for example according to the usual methods known to the person skilled in the art.

f) Possible optically active forms of the above products can be prepared by resolution of the racemate according to usual methods known to the person skilled in the art.

The reactions defined above are illustrated in the preparation of the examples described below.

The starting products of formulae (II), (III) and (VIII) may be known, commercially available or may be prepared according to the usual methods known to the person skilled in the art, in particular from commercial products, for example by subjecting them to one or more reactions known to the person skilled in the art, such as, for example, the above-mentioned a) -f) reactions.

The products of formula (II), which are therefore derivatives of pyrimidines, the products of formula (III), which are derivatives of anilines, may be commercially available products such as dichloropyrimidine, trichloropyrimidine, 4-fluoroaniline, 3, 4-difluoroaniline, 4-fluoro-3-chloroaniline or aniline.

The aniline of formula (III) may in particular be a commercially available aniline, such as the following trihalogenated aniline:

-3, 4, 5-trifluoroaniline

-2, 3, 4-trifluoroaniline

-2-chloro-4, 6-difluoroaniline

-2, 4, 5-trifluoroaniline

-3-chloro-2, 4-difluoroaniline

-2, 4-dichloro-5-fluoroaniline

-4-trifluoromethylaniline

The amines of formula (VIII) are also commercially available, such as methyl- (1-methyl-piperidin-4-yl) amine.

The non-commercially available amines of formula (VIII) may be prepared according to methods known to those skilled in the art.

It may be noted that, in order to obtain a product of formula (I) as defined above, wherein R1, R2, R3, R4, R5 and a have the meanings indicated above, and ring (Y) is as follows: y represents NR7 and comprises a carbon bridge consisting of 1-3 carbons, a bicyclic amine can be used as starting product, which can be obtained from a compound marketed, such as tropinone or pseudopunicalagine (pseudo-pelletrine), according to the following references:

Tetrahedron，2002，58，5669-5674

J.Org.Chem.，1996，61，3849-3862

J.Med.Chem.，1993，36，3703-3720

J.Chem.Soc.Perkin Transl 1991，1375-1381

J.Med.Chem.，1994，37，2831-2840

by way of example, the following compounds may be mentioned:

n, 9-dimethyl-9-azabicyclo [3.3.1] nonan-3-amine

N, 6-dimethyl-6-azabicyclo [3.2.1] octan-3-amine

N, 3-dimethyl-3-azabicyclo [3.2.1] octan-8-amine

N, 3-dimethyl-3-azabicyclo [3.3.1] nonan-9-amine

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

The present invention also relates to a process for the preparation of the product of formula (I) as defined above, according to scheme 1 below:

scheme 1

In this scheme 1, the NR8-ch (ra) (rb) group represents certain values of NR8R9 as defined above, wherein R8 is as defined above, and R9 represents-ch (ra) (rb), i.e. a linear or branched alkyl group, as defined for R9, optionally substituted with one or more groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl, N (alkyl) 2, alkylthio, phenyl and saturated or unsaturated heterocycles which are themselves optionally substituted as indicated above.

In particular, RA may represent a hydrogen atom or CH3, and RB may represent (CH2) n-A, wherein A represents an optionally substituted heterocyclic group or phenyl group as defined above, and n represents an integer of 0 to 5.

The steps of the synthetic method of scheme 1 above may be performed according to conventional methods known to those skilled in the art.

The present invention also relates to a process for the preparation of a product of formula (I) as defined above according to scheme 2 below:

scheme 2

In this scheme 2, R1, R2, R3, R4, a and ring (Y) have the meanings indicated above for the products of formula (I).

The steps of the synthetic method of scheme 2 above can be carried out by using the methyl ester of aniline in step 2 and aniline substituted with R2 ', R3 ' or R4 ' in step 6 and operating according to usual methods known to the person skilled in the art or as described in the present invention.

Non-limiting examples of the preparation of the products of formula (I) according to the invention, and non-limiting examples of the starting products used in these preparations, are given in the experimental section below.

Finally, the present invention is directed to certain compounds of formulae (A), (IX), (VI) and (VII) as novel industrial products.

The products of formula (I) as defined above and their addition salts with said acids show advantageous pharmacological properties.

The compounds of the invention may therefore inhibit the activity of kinases (in particular IKK1 and IKK2), with an IC50 of less than 10 μ M.

The compounds of the invention can therefore inhibit the activation of NF-KB and the production of cytokines, with IC50 values below 10. mu.M.

The compounds of the invention can therefore inhibit the proliferation of large sample tumor cells (large panel decellules tumors), with an IC50 of less than 10 μ M.

The compounds of formula (I) may therefore have pharmaceutical activity, particularly as inhibitors of IKK1 and IKK2, and may be used in the prevention or treatment of diseases in which inhibition of IKK1 or IKK2 is beneficial, for example in the prevention or treatment of diseases in which: inflammatory diseases or diseases with an inflammatory component (composant), such as, for example: inflammatory arthritis, including rheumatoid arthritis, spondyloosteoarthritis, Reiter's syndrome, psoriatic arthritis, bone resorption disease (maladies' resorption disease); multiple sclerosis, inflammatory bowel disease, including Crohn's disease; asthma, chronic obstructive pulmonary disease, emphysema, rhinitis, acquired muscle weakness (myasthenia gravis), Graves' disease, transplant rejection, psoriasis, dermatitis, allergic disorders (tromubles alloergiques), immune system disorders, cachexia, severe acute respiratory syndrome, septic shock, cardiac insufficiency (insufficiency cardiac), myocardial infarction, atherosclerosis, reperfusion injury (necrosis recovery), SIDA, cancer and conditions characterized by insulin resistance, such as diabetes, hyperglycemia, hyperinsulinemia, lipid metabolism disorders, obesity, polycystic ovary syndrome, hypertension, cardiovascular disease, syndrome X, autoimmune diseases, in particular systemic lupus, lupus erythematosus, glomerulonephritis induced by immune system deficiency, autoimmune insulin-dependent diabetes mellitus, retinitis pigmentosa, aspirin-allergic rhinosinusitis.

The products of formula (I) according to the invention, as modulators of apoptosis (modulateurs), may be used in the treatment of various human diseases, including aberrations in apoptosis (aberrations dansl' apoptosis), such as cancer: such as in particular but not in a limiting way: follicular lymphomas, cancers with a p53 mutation, hormone-related tumors of the breast, prostate and ovary, and pre-malignant lesions (such as familial adenomatous polyposis), viral infections (such as those caused by herpes viruses (virus Herp), poxviruses (poxviruses), Epstein Barr viruses (virus d' Epstein Barr), sindbis viruses (virus deSindbis) and adenoviruses (ad novirus), myelodysplastic syndrome, ischemic disorders associated with myocardial infarction, cerebral congestion, arrhythmia, atherosclerosis, liver diseases caused by toxins or alcohol, hematological disorders (d sorderesiology), such as, in particular but not limited to: chronic anemia and aplastic anemia, degenerative diseases of the musculoskeletal system, such as osteoporosis, cystic fibrosis, kidney disease and cancer, in particular but not exclusively.

It is therefore evident that the compounds according to the invention have anticancer activity and activity in the treatment of other proliferative diseases, such as, for example, psoriasis, restenosis, atherosclerosis, SIDA, as well as in diseases caused by the proliferation of angiogenic vascular smooth muscle cells, and in rheumatoid polyarthritis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, angiogenesis and endotoxic shock.

These medicaments have in particular a therapeutic use in the treatment or prevention of diseases which are caused or aggravated by cell (in particular tumour cell) proliferation.

As inhibitors of tumor cell proliferation, these compounds are useful in the prevention and treatment of leukemias, solid tumors (primary and metastatic), carcinomas (carcinomes) and cancers, in particular: breast cancer, lung cancer, small intestine cancer, colon and rectal cancer, cancer of the respiratory tract, oropharynx and hypopharynx, cancer of the esophagus, liver cancer, stomach cancer, bile duct cancer, cancer of the gallbladder, pancreatic cancer, cancer of the urinary tract (including kidney, urothelium and bladder), cancer of the female reproductive tract (including cancer of the uterus, cervix or ovary), choriocarcinoma and chorioepithelioma; male genital tract cancer, including cancer of the prostate, seminal vesicles, or testes, and blastomas; endocrine adenocarcinomas, including cancers of the thyroid, pituitary, or adrenal glands; skin cancer, including hemangioma, melanoma, or sarcoma, including kaposi's sarcoma; brain, nerve, eye or meningeal tumors, including astrocytoma, glioma, glioblastoma, retinoblastoma, schwannomas (neurinomes), neuroblastoma, schwannomas (schwannomas), or meningioma; hematopoietic malignancies (tumeurs malignes)) Diseases such as acute lymphoblastic leukemia, myelogenous leukemia, chronic lymphocytic leukemia, chloromycetic leukemia, plasmacytoma, T-or B-cell leukemia, non-Hodgkinins or Hodgkinins lymphomas, myelomas, various hematological malignancies.

The object of the invention is in particular the combination defined below.

According to the invention, one or more compounds of formula (I) can be administered in combination with one or more anticancer active ingredients, in particular antitumor compounds, such as alkylating agents, e.g. alkylsulfonates (busulfan), dacarbazine, procarbazine, nitrogen mustards (nitrogen mustards, melphalan, chlorambucil), cyclophosphamide or ifosfamide; nitrosoureas, such as nitrosourea nitrogen mustard, cyclohexylnitrosourea, methylcyclohexylnitrosourea or streptozotocin; antineoplastic alkaloids, such as vincristine or vinblastine; taxanes, such as paclitaxel or docetaxel; anti-tumor antibiotics, such as actinomycin; an intercalating agent, an antineoplastic antimetabolite, a folate antagonist, or methotrexate; a purine synthesis inhibitor; purine analogs, such as mercaptopurine or 6-thioguanine; pyrimidine synthesis inhibitors, aromatase inhibitors, capecitabine or pyrimidine analogues, such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside; dorbiqual; topoisomerase inhibitors, such as camptothecin or etoposide; agonists and antagonists of anticancer hormones, including tamoxifen; kinase inhibitors, imatinib; a growth factor inhibitor; anti-inflammatory agents, such as pentosan polysulfate, corticosteroids, prednisone or dexamethasone; anti-topoisomerase enzymes such as etoposide, anthracyclines including adriamycin, bleomycin, mitomycin and mithramycin; an anticancer metal complex, platinum complex, cisplatin, carboplatin or oxaliplatin; interferon-alpha, triphenylthiophosphoramide or hexamethylmelamine; an anti-angiogenic agent; thalidomide; an immunotherapeutic adjuvant; or a vaccine.

According to the invention, the compounds of formula (I) can also be administered in combination with one or more other active ingredients for one of the conditions indicated above, for example agents for the antiemetic, analgesic, anti-inflammatory or anti-cachexia (anti-cachexia).

The object of the present invention is therefore a product of formula (I) as defined above as well as the addition salts of said product of formula (I) with pharmaceutically acceptable inorganic and organic acids as a medicament.

The invention relates in particular to a product of formula (I) as defined above, as a medicament, having the following name:

-4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino ] -N-methyl-N- (1- [1, 2, 3] thiadiazol-4-ylmethyl-piperidin-3-yl) benzamide

-N- (1-methylpiperidin-4-yl) -N- [2- (pyrrolidin-1-yl) ethyl ] -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzamide,

And to the addition salts of said products of formula (I) with pharmaceutically acceptable inorganic and organic acids.

A further object of the present invention is a pharmaceutical composition comprising as active ingredient at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of such a product or a prodrug of such a product, together with a pharmaceutically acceptable carrier.

The invention relates in particular to the use of the products of formula (I) as defined above or of pharmaceutically acceptable salts of these products for producing a medicament for the treatment or prevention of a disease by inhibiting the IKK activity of the protein kinase.

An object of the present invention is therefore the use as defined above, wherein the protein kinase is in a mammal.

An object 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 selected from those indicated above.

The present invention 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 a disease selected from the following classes: inflammatory diseases, diabetes and cancer.

The present invention 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 relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prophylaxis of diabetes.

The invention relates in particular to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment of cancer.

The present invention relates in particular to the use of the products of formula (I) as defined above for the treatment of solid or non-solid tumors (tumors).

The invention relates in particular to the use of the product of formula (I) as defined above for the treatment of cancers which are resistant to cytotoxic agents.

The invention relates in particular to the use of the product of formula (I) as defined above for the preparation of a medicament for the chemotherapy of cancer.

The present invention relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the chemotherapy of cancer, alone or in combination as defined above.

The present invention is directed in particular to the use of a product of formula (I) as defined above as an IKK inhibitor.

The present invention very particularly relates to the products of formula (I) as defined above, which constitute examples 1 to 6 of the present invention.

The following examples illustrate the invention without limiting it.

Experimental part

Process 1: 4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino]Preparation of benzoic acid

Stage 1: (2-chloro-pyrimidin-4-yl) (4-fluoro-phenyl) amine

To a mixture containing 6.3g dichloropyrimidine in 100ml n-butanol was added 5.3g 4-fluoro-3-methyl-phenyl amine and then 7ml diisopropylethylamine with stirring. The reaction mixture was refluxed for 2 hours with stirring. The reaction medium is cooled and concentrated to dryness. K2CO3 solution was added to the residue and extracted 3 times with ethyl acetate, washed with saturated NaCl solution and dried using Na2SO4, the reaction crude was purified by chromatography on a silica column (DCM then 30% AcOEt in DCM). 3.8g of the expected product are obtained (melting point 130 ℃ C.).

Stage 2: 4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino]Benzoic acid methyl ester

A mixture comprising 8g of the chloropyrimidine obtained in stage 1 and 5.1g of methyl 4-aminobenzoate in n-butanol is heated at 140 ℃ overnight. After cooling, the precipitate was filtered off. The precipitate was washed with Et2O and recrystallized from DCM/MeOH/iPr2O mixture. 10.5g of the expected product are thus obtained.

Stage 3: 4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino]Benzoic acid

2.08g of the product obtained in stage 2 are left at 40 ℃ overnight in the presence of 410mg of sodium hydroxide in a mixture of MeOH (5ml), water (5ml) and dioxane (20 ml). The reaction medium is concentrated to dryness and the residue is dissolved in 100ml of water. The impurity was extracted using two volumes of Et2O, and the aqueous phase was acidified to pH6 using 1N HCl. The precipitate formed was filtered off, washed with distilled water and suspended in DCM and the solvent was evaporated. 1.3g of the desired acid are obtained.

And (2) a process: 4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzoic acid

Stage 1: (2-chloro-pyrimidin-4-yl) - (4-trifluoromethyl-phenyl) amine

Starting from 15g of dichloropyrimidine in 200ml of n-butanol, 16g of 4-trifluoromethyl-phenyl amine and then 18ml of diisopropyl-ethylamine were added with stirring in the same manner as in example 1 of procedure 1. The reaction mixture was refluxed overnight with stirring. The reaction medium is cooled and concentrated to dryness. K2CO3 solution was added to the residue, extracted 3 times with ethyl acetate, washed with saturated NaCl solution and dried using Na2SO4, and the crude reaction product was purified by chromatography on a silica column (DCM then 2% methanol in DCM). 5g of the expected product are obtained.

MH+＝274.3

Stage 2: 4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino]Methyl benzoate as in stage 2 of Process 1, starting from 4.6g of the chloropyrimidine obtained in stage 1 and 2.6g of methyl 4-aminobenzoate, 6.4g of the expected product are obtained.

Stage 3: 4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino]Benzoic acid

Starting from 6.4g of the ester obtained in stage 2 and 2.26g of sodium hydroxide, as in stage 3 of process 1, 4.2g of the expected product are obtained.

MH+＝375.1

Example 1: 4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino ] -N-methyl-N- (1-methyl-piperidin-4-yl) benzamide

A mixture comprising 470mg of the acid obtained in Process 1 and 230. mu.l of methyl- (1-methylpiperidin-4-yl) -amine is reacted for 3 hours at ambient temperature in the presence of 610mg BOP and 700. mu.l of DIPEA (in 15ml DCM). The evaporation to dryness, addition of 10% potassium carbonate solution and extraction with ethyl acetate were carried out. The organic phase was washed with water, dried over Na2SO4 and chromatographed on a silica column using DCM/MeOH (88/12; v/v) as eluent. Evaporated to dryness and recrystallized in DCM/iPr2O mixture to obtain 289mg of the desired product.

MH+＝449.2

Melting point of 88 DEG C

¹H NMR (DMSO): 1.57(m, 2), 1.81(m, 4), 2.14(ls, 3), 2.25(s, 3), 2.74-2.94 (unresolved peak, 5), 4.03(ls, 1), 6.21(d, 1), 7.09(t, 1), 7.25(d, 2), 7.46(m, 1), 7.59(d, 1), 7.77(d, 2), 8.03(d, 1), 9.33(s, 1), 9.37(s, 1)

Example 2: 4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino ] -N-methyl-N- [1- (4, 4, 4-trifluorobutyl) piperidin-3-yl ] benzamide

Stage 1: 3- ({4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino]Benzoyl } -methyl-amino) piperidine-1-carboxylic acid tert-butyl ester

Starting with 1.3g of the acid obtained in Process 1 and 800mg of tert-butyl 3-methylamino-piperidine-1-carboxylate according to the procedure described in example 1, 1.1g of the expected product are obtained.

Stage 2: 4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino]-N-methyl-N-piperidin-3-yl-benzamides

1.05g of the product obtained in stage 1 are dissolved in 5ml of methanol. 15ml of 2N HCl ether (2N) are added at ambient temperature and stirred overnight. Evaporated several times in the presence of DCM. 940mg of the desired piperidine hydrochloride are obtained.

And (3) stage:4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino]-N-methyl-N- [1- (4, 4, 4-trifluorobutyl) piperidin-3-yl]Benzamide derivatives

The hydrochloride salt obtained in stage 2 (300mg) in the presence of 90mg 4, 4, 4-trifluoro-butyraldehyde and 250mg NaBH (OAc)3 in 10ml THF. After the reaction overnight, it was dissolved with sodium hydroxide solution, extracted with DCM, the organic phase was washed and dried with Na2SO 4. The chromatographic separation was carried out on a silica column by using CH2Cl2/CH3OH (99/1; v/v) as eluent. Evaporated to dryness and recrystallized from a CH2Cl 2/isopropyl ether mixture to yield 141mg of the desired product.

MH+＝545.3

Melting point of 100℃ and 110 DEG C

¹H NMR (DMSO): 1.62-2.09 (unresolved peak, 6), 2.24(s, 3), 2.38(m, 2), 2.89(s, 3), 2.96(m, 1), 3.16-3.33(2m, 3), 3.49(m, 2), 4.47(m, 1), 6.48(d, 1), 7.13(t, 1), 7.37(m, 1), 7.42(d, 2), 7.49(m, 1), 7.59(d, 2), 8.00(d, 1)

Example 3: 4- [4- (4-fluoro-3-methyl-phenylamino) pyrimidin-2-ylamino ] -N-methyl-N- (1- [1, 2, 3] thiadiazol-4-ylmethyl-piperidin-3-yl ] benzamide

Starting with 330mg of the hydrochloride salt obtained in stage 2 of example 2 and 100mg of [1, 2, 3] thiadiazole-4-carbaldehyde according to the procedure described in stage 3 of example 2, 191mg of the desired product are obtained.

MH+＝533.2

Melting point of 125-130 deg.C

¹H NMR (DMSO): 1.08-2.04 (unresolved peak, 5), 2.23(s, 4), 2.63-2.99 (unresolved peak, 5), 3.46-4.66 (unresolved peak, 3), 6.22(d, 1), 7.08(t, 1), 7.22(m, 2), 7.47(m, 1), 7.58(d, 1), 7.64(d, 2), 8.04(d, 1), 9.03(ls, 1), 9.34(s, 1), 9.37(s, 1)

Example 4: N-methyl-N- (1-methylpiperidin-4-yl) -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzamide

Starting with 400mg of the acid obtained in process 2 and 130mg of methyl- (1-methyl-piperidin-4-yl) amine according to the procedure described in example 1, 285mg of the expected product are obtained.

MH+＝485.0

Melting point of 238℃ and 244 DEG C

¹H NMR(DMSO)：

1.59(m, 2), 1.77-1.93 (unresolved peak, 4), 2.15(s, 3), 2.82(d, 2), 2.85(s, 3), 3.86(bs, 1), 6.36(d, 1), 7.28(d, 2), 7.61(d, 2), 7.77(d, 2), 7.92(d, 2), 8.13(d, 1), 9.12(s, 1), 9.52(s, 1).

Example 5: N-methyl-N- (tetrahydro-pyran-4-yl) -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzamide

Starting with 400mg of the acid obtained in process 2 and 115mg of methyl- (tetrahydropyran-4-yl) amine according to the procedure described in example 1, 288mg of the expected product are obtained.

MH+＝471.9

Melting point of 254-256 deg.C

¹H NMR(DMSO)：

1.56(bl，2)，1.81(m，2)，2.83(s，3)，3.25(bs，2)，3.88(bd，2)，4.13(bs，1)，6.34(d，1)，7.32(d，2)，7.63(d，2)，7.80(d，2)，7.97(d，2)，8.14(d，1)，9.51(s，1)，9.83(s，1).

Example 6: n- (1-methylpiperidin-4-yl) -N- (2-pyrrolidin-1-yl-ethyl) -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino ] benzamide

Stage 1: (1-methylpiperidin-4-yl) (2-pyrrolidin-1-yl-ethyl) amine

Starting from 3ml of 1-methyl-piperidin-4-one and 3.35ml of 2-pyrrolidin-1-yl-ethylamine as in stage 3 of example 2, 4.4g of the expected product are obtained.

Stage 2: (1-methyl-piperidin-4-yl) (2-pyrrolidin-1-yl-ethyl) carbamic acid tert-butyl ester

The mixture containing 4.4g of the compound obtained in stage 1 was dissolved in 100ml of dichloromethane. 4.7g of BOC₂O is added to the reaction medium and heated at 50 ℃ for 1 hour 30 minutes. After concentration to dryness, the crude product was purified on a column of alumina (dichloromethane with a gradient up to 2% methanol). In total, 2.35g of the expected compound are obtained.

Stage 3: (1-methyl-piperidin-4-yl) - (2-pyrrolidin-1-yl-ethyl) amine hydrochloride

Starting with 1.85g of the amine obtained in stage 2, 1.65g of the desired aminopiperidine are obtained according to the decarboxylation reaction described in stage 2 of example 2.

Stage 4: n- (1-methyl-piperidin-4-yl) -N- (2-pyrrolidin-1-yl-ethyl) -4- [4- (4-trifluoromethyl-phenylamino) pyrimidin-2-ylamino]Benzamide derivatives

Starting with 400mg of the acid obtained in process 2 and 310mg of the aminopiperidine obtained in stage 4 according to the procedure described in example 1, 44mg of the desired product are obtained.

MH+＝558.1

Melting point of 115-120 deg.C

¹H NMR(DMSO)：

1.52-1.96 (unresolved peak, 10), 2.12(s, 3), 2.43 (unresolved peak, 4), 2.56(t, 2), 2.78(d, 2), 3.38(t, 2), 3.68(m, 1), 6.35(d, 1), 7.25(d, 2), 7.66(d, 2), 7.77(d, 2), 7.94(d, 2), 8.13(d, 1), 9.24(s, 1), 9.62(s, 1)

Example 7: 4- ({4- [ (4-fluorophenyl) amino ] pyrimidin-2-yl } amino) -N- (octahydroindolinizin-7-yl) benzamide

Stage 1: hexahydroindolizin-7 (1H) -ones

3.6ml of but-3-en-2-one were added dropwise at low temperature to a mixture comprising 6ml of 4, 4-diethoxy-1-amine in 20ml of Et2O, according to the procedure described in J.chem.Soc.Perkin Trans.I, 1986, 447-453. The reaction medium is stirred at ambient temperature for 1 hour. The reaction medium is poured into 50ml of 2.5M HCl solution and extracted with ether. The aqueous phase was heated for 3 h. After cooling and evaporation to dryness, the crude product was dissolved with H2O/K2CO3 and extracted with DCM, dried and concentrated.

The desired product was obtained by vacuum distillation (40 ℃, 0.3 mmHg). 1.5g of the expected product are obtained.

Stage 2: N-Methylooctahydroindolizin-7-amines

Starting from 1.5g of the ketone obtained in stage 1, 10.7ml of a 2M solution of methylamine in THF and 3g of NaBH (OAc)3 in 20ml of THF by a reductive amination reaction, the reaction medium is heated at 60 ℃ for 1 h. After evaporation, dissolution with H2O/NaOH and extraction with DCM, drying and, after concentration to dryness, 1.25g of the expected amine are obtained.

And (3) stage: 4- ({4- [ (4-fluorophenyl) amino ] pyrimidin-2-yl } amino) -N- (octahydroindolinizin-7-yl) benzamide

Starting with 600mg of the acid obtained in process 1 and 255mg of N-methyloctahydroindolizin-7-amine according to the procedure described in example 1, 172mg of the desired benzamide are obtained.

MH+＝461.1

Melting point 230 ℃ and 235 DEG C

¹H NMR(DMSO)：

1.2-2.14 (unresolved peak, 11), 2.84(s, 3), 2.92(t, 1), 3.03(m, 1), 3.96(m, 1), 6.23(d, 1), 7.13(t, 2), 7.25(d, 2), 7.65(m, 2), 7.77(d, 2), 8.04(d, 1), 9.04(s, 1), 9.15(s, 1).

Example 8: pharmaceutical composition

Tablets corresponding to the following formulation were prepared:

… … … … … … … 0.2.2 g of the product of example 1

Excipients for tablets up to … … … … 1g

(details of excipients: lactose, mica, starch, magnesium stearate).

Example 1 is taken as an example in the preparation of the medicament constituting example 8 above, for which the preparation can be carried out differently from that indicated above, if necessary using the other products in the examples of the present application.

Pharmacological part:

protocol for IKK biochemical assays

I) The compounds were evaluated for IKK1 and IKK 2:

the compounds were tested for inhibition of IKK1 and IKK2 using a kinase assay on scintillation-plate (flash-plate) carriers. The compound to be tested was dissolved to 10mM in DMSO and then diluted in kinase buffer (50mM Tris, pH7.4, containing 0.1mM EGTA, 0.1mM sodium orthovanadate and 0.1% p-mercaptoethanol).

Three-fold serial dilutions were made starting from this solution. 10 μ l of each dilution was added in duplicate to wells of a 96-well plate. Mu.l of kinase buffer was added to control wells, which were used for 0% inhibition, and 10. mu.l of 0.5mM EDTA was added to control wells (100% inhibition). Mu.l of IKK1 or IKK2 cocktail (0.1. mu.g/well), 25-55 biotinylated IKB substrate peptide and BSA (5. mu.g) were added to each well. To start the kinase reaction, 10 μ l of 10mM magnesium acetate, 1 μ M cold ATP and 0.1 μ Ci33P-ATP were added to each well to obtain a final volume of 30 μ l. The reaction was then incubated at 30 ℃ for 90min and stopped by adding 40. mu.l of 0.5mM EDTA. After stirring, 50. mu.l were transferred to scintillation plates covered with streptavidin.

After 30min, the wells were washed twice with 50mM Tris-EDTA pH7.5 solution and the radioactivity was measured on a Microbeta counter.

The compounds of the invention tested in this assay showed an IC50 of less than 10 μ M, which indicates that they can be used for their therapeutic activity.

II) evaluation of the compounds with respect to viability and proliferation of tumor cells:

the compounds according to the invention constitute the subject of pharmacological tests which make it possible to determine their anticancer activity.

The compounds of formula (I) according to the invention are tested in vitro on a set of samples of tumor lines of human origin, derived from:

-breast cancer: MDA-MB231(American Type Culture Collection, Rockville, Maryland, USA, ATCC-HTB26), MDA-A1 or MDA-ADR (referred to as the multiple drug resistance MDR line (ligne Multi-drug resistant MDR), described by E.Collomb et al in Cytometry, 12(1), 15-25, 1991), and MCF7(ATCC-HTB22),

-prostate cancer: DU145(ATCC-HTB81) and PC3(ATCC-CRL1435),

-colon cancer: HCT116(ATCC-CCL247) and HCT15(ATCC-CCL225),

-lung cancer: h460 (described by Carmichael in Cancer Research, 47(4), 936-,

-malignant gliomas: SF268 (described by Westphal in Biochemical & Biophysicals Research Communications, 132(1), 284 289, 1985 and supplied by national Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland, USA),

-leukemia: CMLT1 (described by Kuriyama et al in Blood, 74, 1989, 1381-.

Cell proliferation and viability were determined in an assay using 3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazole (MTS) according to Fujishita T. et al, Oncology, 2003, 64(4), 399-. In this assay, the mitochondrial capacity (ca pactit mitogenic activity) of living cells to convert MTS into a colored compound is measured after incubation of a compound of formula (I) according to the invention for 72 hours. The concentration of the compound of the invention (IC50) that resulted in a 50% loss of cell proliferation and viability was below 10 μ M, depending on the tumor line and the test compound.

Thus, according to the present invention, it appears that the compound of formula (I) results in a loss of proliferation and viability of tumor cells, with an IC50 of less than 10 μ M.

Claims

1. A product of formula (I):

wherein

r5 represents a hydrogen atom or a halogen atom;

a represents a single bond or a group-CH 2-CO-NR6-, and R6, which is the same or different from R1, is selected from the values of R1;

the ring comprising Y (OR ring (Y)) is monocyclic OR bicyclic, is made up of 4 to 10 segments, and is saturated OR partially saturated with Y, wherein Y represents an oxygen atom O, a sulfur atom S (which is optionally oxidized by 1 OR 2 oxygen atoms) OR a group selected from N-R7, C ═ O OR its dioxolanes as carbonyl-functional protecting groups, CF2, CH-OR8 OR CH-NR8R 9;

r7 represents a hydrogen atom, a cycloalkyl or alkyl group, a CH 2-alkenyl or CH 2-alkynyl group, all optionally substituted by a naphthyl group or by one or more identical or different groups selected from: halogen atoms and hydroxy, alkoxy, phenyl and heteroaryl groups, the alkyl group represented by R7 being optionally additionally substituted by hydroxy, -NR8R9, -CO-NR8R9, phosphonate, alkylthio optionally oxidized to sulfone or by optionally substituted heterocycloalkyl;

NR8R9 is such as: or R8 and R9, identical or different, are selected from the values of R8, or R8 and R9, together with the nitrogen atom to which they are attached, form a cyclic amine which optionally may include 1 or 2 further heteroatoms selected from O, S, N or NR10, the cyclic amine so formed being itself optionally substituted;

all of the above heterocyclic, heterocycloalkyl and heteroaryl groups are composed of 4 to 10 segments (unless otherwise specified) and contain 1 to 4 heteroatoms, which are selected, where appropriate, from O, optionally oxidized S, N and NR 10;

all of the above naphthyl, phenyl, heterocyclyl, heterocycloalkyl and heteroaryl groups and cyclic amines which may be formed by R8 and R9 together with the nitrogen atom to which they are attached, are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF3, NH2, or NH alkyl or N (alkyl) 2;

r10 represents a hydrogen atom or an alkyl group,

2. A product of formula (I) as defined in claim 1, wherein R2, R3, R4, R5, A and the ring (Y) have the meanings indicated in any one of the claims, R1 represents a hydrogen atom or a linear or branched alkyl group containing 1 to 5 carbon atoms, or R1 represents an alkyl group substituted by a saturated or unsaturated heterocyclic ring which is itself optionally substituted as indicated in any one of the claims, said heterocyclic ring preferably being a 5-membered monocyclic heterocyclic ring,

3. A product of formula (I) as defined in any one of the claims, wherein R2, R3, R4, R5 and a have the meanings indicated in any one of the claims, R1 represents a hydrogen atom or an optionally substituted, linear or branched, alkyl group containing from 1 to 4 carbon atoms, in particular CH3, ring (Y) is as follows: y represents NR7, wherein R7 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted by a group selected from: hydroxy, CF3, phosphonate, sulfone, phenyl and saturated or unsaturated monocyclic or bicyclic heterocyclic groups, which phenyl and heterocyclic groups are themselves optionally substituted as indicated in any of the claims,

4. A product of formula (I) as defined in any one of the preceding claims, wherein R2, R3, R4, R5 and A have the meanings indicated in any one of the claims,

r1 represents a linear or branched alkyl radical containing from 1 to 4 carbon atoms, in particular CH3, ring (Y) being such as: y represents NR8R9, wherein R8 represents a hydrogen atom or CH3, R9 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted with a group selected from: hydroxy, CF3, phosphonate, sulfone, phenyl, and saturated or unsaturated mono-or bicyclic heterocyclic radicals which are themselves optionally substituted as indicated in any of the claims,

5. A product of formula (I) as defined in any one of the claims wherein:

r5 represents a hydrogen atom or a halogen atom;

r8 represents a hydrogen atom or an alkyl, cycloalkyl or heterocycloalkyl group, which groups are themselves optionally substituted by one or more groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl or N (alkyl) 2;

NR8R9 is such as: or R8 and R9, the same or different, are selected from the values of R8, or R8 and R9 together with the nitrogen atom to which they are attached form a cyclic amine which optionally may include 1 or 2 further heteroatoms selected from O, S, N or optionally substituted NR 10;

r10 represents a hydrogen atom or an alkyl group;

all of the above naphthyl, phenyl and heteroaryl groups and cyclic amines which may be formed by R8 and R9 together with the nitrogen atom to which they are attached, are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CF3, NH2, NH alkyl or N (alkyl) 2;

6. A product of formula (I) as defined in any one of the claims wherein:

r5 represents a hydrogen atom or a fluorine or chlorine atom;

7. A product of formula (I) as defined in any one of the claims wherein:

r5 represents a hydrogen atom or a chlorine atom;

a represents a single bond, -CH 2-CO-NH-or-CH 2-CO-NCH3-, the ring comprising Y being selected from cyclohexyl which is itself optionally substituted by amino; a tetrahydropyran; dioxythienyl; and pyrrolidinyl, piperidinyl, azepinyl, indolizinyl and quinazolinyl, optionally substituted with one or more of the same or different groups selected from: methyl, propyl, butyl, isopropyl, isobutyl, isoamyl or ethyl, which are themselves optionally substituted by one or more groups selected from: halogen atoms and hydroxyl groups, phenyl groups optionally themselves substituted by one or more halogen atoms, quinolyl groups, pyridyl groups optionally oxidized at the nitrogen atom thereof, thienyl groups, thiazolyl groups, thiadiazolyl groups, tetrazolyl groups, pyrazinyl groups, furyl groups and imidazolyl groups optionally themselves substituted by alkyl groups;

8. A product of formula (I) as defined in any one of the other claims wherein:

r5 represents a hydrogen atom;

a represents a single bond, the ring comprising Y represents cyclohexyl, optionally substituted by amino itself, or piperidinyl or pyrrolidinyl, optionally substituted on its nitrogen atom by methyl, propyl, butyl, isopropyl, isobutyl, isopentyl or ethyl, these substituents being optionally substituted by one or more halogen atoms themselves or by groups selected from: a hydroxyl group; a thiadiazolyl group; a tetrazolyl group; phenyl which is itself optionally substituted by halogen; a quinolyl group; a pyridyl group optionally oxidized at its nitrogen atom; furyl and imidazolyl which is itself optionally substituted by alkyl;

9. A product of formula (I) as defined in any one of the other claims wherein:

r5 represents a hydrogen atom;

r1 represents a hydrogen atom or a methyl group;

a represents a single bond, the ring comprising Y is selected from tetrahydropyranyl, dioxythienyl and pyrrolidinyl, piperidinyl and azepinyl optionally substituted at its nitrogen atom (in position 2 or 3 of the ring) withBase: methyl or ethyl, propyl or butyl, or a mixture thereofOptionally substituted by one or more halogen atoms or phenyl, pyridyl, thienyl or thiazolyl, thiadiazolyl, pyrazinyl, furyl or imidazolyl;

10. A product of formula (I) as defined in any one of the other claims corresponding to the name:

11. Process for the preparation of a product of formula (I) as defined in any one of the preceding claims, characterized in that a product of formula (II):

wherein R5' has the meaning indicated in any of the claims for R5, wherein possible reactive functions are optionally protected,

with the product of formula (III):

wherein R2 ', R3 ' and R4 ' have the meanings indicated in any one of the claims for R2, R3 and R4, respectively, wherein possible reactive functions are optionally protected,

to obtain a product of formula (IV):

wherein R2 ', R3', R4 'and R5' have the meanings as indicated above,

wherein R2 ', R3', R4 'and R5' have the meanings indicated above, saponifying the product of formula (VI) into its corresponding acid of formula (VII):

wherein R2 ', R3', R4 'and R5' have the meanings as indicated above,

reacting the product of formula (VII) with an amine of formula (VIII):

wherein R1 ', R2 ', R3 ', R4 ' and R5 ' have the meanings as indicated above,

f) resolving the racemic form into a resolved product,

12. Process for the preparation of the product of formula (I) as defined in any one of the preceding claims, characterized in that a compound of formula (a):

wherein R1 ', R2 ', R3 ', R4 ', R5 ' and the ring (N) have the meanings as indicated in any of the preceding claims,

RZ’-CR8’O (X)

wherein RZ' represents alkyl, alkenyl or alkynyl, optionally substituted as indicated in any of the preceding claims, wherein possible reactive functions are optionally protected by a protecting group,

wherein R8' has the meaning indicated for R8 in any of the preceding claims, wherein possible reactive functions are optionally protected by protecting groups,

to obtain a product of formula (I2):

13. A product of formula (I) as defined in any one of claims 1 to 10 and addition salts of said product of formula (I) with pharmaceutically acceptable inorganic and organic acids as a medicament.

14. A product of formula (I) as defined in any one of the preceding claims, having the following name, as a medicament:

And addition salts of said product of formula (I) with pharmaceutically acceptable inorganic and organic acids.

15. A pharmaceutical composition comprising as active ingredient at least one of the products of formula (I) as defined in claim 13 or 14 or a pharmaceutically acceptable salt of such a product or a prodrug of such a product, together with a pharmaceutically acceptable carrier.

16. Use of a product of formula (I) as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt of such a product for the manufacture of a medicament for the treatment or prevention of a disease by inhibiting the activity of the protein kinase IKK.

17. The use as defined in any one of the preceding claims, wherein the protein kinase is in a mammal.

18. Use of a product of formula (I) as defined in any one of claims 1 to 10 for the preparation of a medicament for the treatment or prevention of a disease selected from the following classes: inflammatory diseases, diabetes and cancer.

19. Use of a product of formula (I) as defined in any one of claims 1 to 10 for the preparation of a medicament for the treatment or prevention of an inflammatory disease.

20. Use of a product of formula (I) as defined in any one of claims 1 to 10 for the preparation of a medicament for the treatment or prevention of diabetes.

21. Use of a product of formula (I) as defined in any one of claims 1 to 10 for the preparation of a medicament for the treatment of cancer.

22. Use according to claim 21 for the treatment of solid or non-solid tumours.

23. Use according to claim 21 or 22 for the treatment of cancer against cytotoxic agents.

24. Use of a product of formula (I) as defined in any one of claims 1 to 10 for the preparation of a medicament for use in the chemotherapy of cancer.

25. Use of a product of formula (I) as defined in any one of the preceding claims for the preparation of a medicament for use, alone or in combination, in the chemotherapy of cancer.

26. A product of formula (I) as defined in any one of claims 1 to 10 as an IKK inhibitor.