HK1139391A

HK1139391A - New phenyl-(4-phenyl-pyrimidin-2-yl)-amines derivatives, preparation thereof as drugs, pharmaceutical compositions and use thereof essentially as ikk inhibitors

Info

Publication number: HK1139391A
Application number: HK10105381.4A
Authority: HK
Inventors: Monsif Bouaboula; Pierre Casellas; Sherri Dudal; Régine FLOUTARD; Maria Mendez-Perez; Jean-Flaubert Nguefack; Jacob-Alsboek Olsen; Bernard Tonnerre; Jean Wagnon
Original assignee: Sanofi-Aventis
Priority date: 2007-01-05
Filing date: 2008-01-02
Publication date: 2010-09-17

Description

Novel phenyl (4-phenylpyrimidin-2-yl) amine derivatives, their preparation as medicaments, pharmaceutical compositions and 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 derivatives of phenyl (4-phenylpyrimidin-2-yl) amines 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- α and IKK- β, and thus inhibit NF- κ B (nuclear transcription factor κ 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-. kappa.B (family de complexes). Members of this polypeptide related to NF-. kappa.B regulate the expression of genes involved in immune and inflammatory responses (Bames PJ, Karin M (1997), N Engl. J. Med., 336, 1066-. NF-. kappa.B dimers are retained in the cytoplasm in an inactive form by inhibitory proteins of members of the IkB family under basic 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-. kappa.B. 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- κ B 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-. kappa.B, many encode pro-inflammatory (pro-inflammatory) mediators, cytokines, cell adhesion molecules, acute phase proteins, which will also induce activation of NF-. kappa.B by either autocrine or paracrine mechanisms.

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

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

Proteins produced by expression of genes regulated by NF-. kappa.B include cytokines, chemokines, adhesion molecules, cell growth mediators, angiogenesis mediators. Furthermore, various studies have shown that NF-. kappa.B plays an important role in neoplastic transformation (transformations). For example, NF-. kappa.B may be involved in cell transformation in vitro and in vivo after overexpression, amplification, rearrangement or translocation events (genetic element) (Mercurio, R. and Manning, A.M (1999), Oncogene, 18: 6163-. In some human lymphoid tumor cells, genes encoding various NF-. kappa.B members are rearranged or amplified. NF-. kappa.B has been shown to promote cell growth by causing transcription of cyclin D, which is associated with over-phosphorylation 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-. kappa.B was found after activation of IKK 2. NF-. kappa.B is constitutively activated in Hodgkin's disease (maladies de Hodgkin) and inhibition of NF-. kappa.B blocks the growth of these lymphomas. On the other hand, inhibition of NF-. kappa.B by expression of the repressor IKB leads to 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-. kappa.B (active constitutive de NF-. kappa.B) 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- κ B can promote the growth of tumor cells by activating cyclin D. The regulation of adhesion molecules and surface proteases suggests a role for NF-. kappa.B in the generation of signals in cancer metastasis.

NF-. kappa.B is involved in the induction of chemoresistance. NF-. kappa.B is activated in response to certain chemotherapeutic treatments. Inhibition of NF- κ B by the use of an 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

R represents a hydrogen atom or a halogen atom;

r2, R3 and R4, identical or different, are chosen from hydrogen atoms, halogen atoms, CN, CONH2, CONH alkyl and CON (alkyl) 2 groups and alkyl and alkoxy groups, themselves optionally substituted by one or more halogen atoms or CN, CONH2, CONH alkyl, CON (alkyl) 2, OH or OCH3 groups, with the understanding that 1 or 2 of R2, R3 and R4 represent a hydrogen atom or R2, R3 and R4 all represent three methoxy groups;

r5 represents a hydrogen atom or a halogen atom;

z represents CO or SO 2;

-N (D) (W) is such that:

a) or W represents a-ring (Y) group

D 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 D being optionally additionally substituted by a saturated OR unsaturated heterocyclic group having 5 members, which is linked through a carbon atom and is optionally substituted by one OR more groups selected from: halogen atoms and alkyl or alkoxy groups;

ring (Y) is monocyclic OR bicyclic, is composed of 4 to 10 mer, and is saturated OR partially saturated with Y, Y representing an oxygen atom O, a sulfur atom S optionally oxidized with 1 OR 2 oxygen atoms, OR a group selected from NR10, C ═ O OR its dioxolane (as a carbonyl functional protecting group), CF2, CH-OR8 OR CH-NR8R 9;

it will be understood that when Y represents R10, ring (Y) may contain a carbon bridge consisting of 1 to 3 carbons,

r10 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 hydroxyl, alkoxy, aryl and heteroaryl, the alkyl group represented by R10 being optionally additionally substituted by hydroxyl, NR8R9, CONR8R9, phosphonate, alkylthio or heterocycloalkyl optionally oxidized to sulfone, all aryl, heteroaryl and heterocycloalkyl being optionally substituted;

b) or W and D together with the nitrogen atom to which they are attached form a ring (N)

Substituted on the same carbon atom by R1 and R6, containing 4 to 7 merAre saturated and may additionally comprise carbon bridges consisting of 1 to 3 carbons:

it is understood that R1 and R6 represent one of the following 6 alternatives i) -vi):

i) r1 represents-X1-R7, wherein X1 represents- (CH2) m-and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;

r6 represents a hydrogen atom or a hydroxyl, methyl, methoxy, - (CH2) mOH, -CO-NRaRb, -CH2-Nrarb, -CO2H and-CO 2 alkyl group;

ii) R1 represents-X2-R7, wherein X2 represents:

-O-; -O- (CH2) m-; -CH (oh) - (CH2) n-; -CO-; -CO-NRc-; -CO-NRc-O-; -ch (nrarb) -; -C ═ NOH —; -C ═ N-NH2 —; - (CH2) n1-NRc- (CH2) n 2-; and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;

r6 represents hydrogen or methyl;

iii) R1 represents-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, said alkyl group being linear or branched from 3 carbon atoms, optionally substituted with a group selected from: -PO (OEt)2, -OH, -O-alkyl, -CF3, -CO-NR8R9 and SO 2-alkyl; and R6 represents hydrogen;

it is understood that when W represents a hydrogen atom, then z represents CO;

iv) R1 represents-CH 2-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, said alkyl group being linear or branched from 3 carbon atoms and optionally substituted by a group selected from: -PO (OEt)2, -OH, -OEt, -CF3, -CO-N (alkyl) 2 and SO 2-alkyl; and R6 represents hydrogen;

v) R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen;

vi) R1 represents X3-R7 wherein X3 represents-CH (OH) - (CH2) n-; -CO-; -ch (nrarb) -; -C ═ NOH —; -C ═ N-NH2 —;

and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted:

and R6 represents a hydrogen atom or a hydroxyl, methyl, methoxy, - (CH2) mOH, -CO-NRaRb, -CH2-Nrarb and-CO 2 alkyl group;

n, n1 and n2, which are the same or different, represent an integer of 0 to 3;

m represents an integer of 1 to 3;

rc and R' c, identical or different, represent a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms, optionally substituted by one or more halogen atoms;

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 a hydroxyl, alkoxy, NH2, NH alkyl, N (alkyl) 2, -CONH2, -CONH alkyl or-CON (alkyl) 2 group, the alkyl group represented by R8 being optionally substituted additionally by a phosphonate group, an alkylthio group optionally oxidized to a sulfone, or by an optionally substituted aryl group or by an optionally substituted saturated or unsaturated heterocyclic group;

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 NRc, the cyclic amine thus formed being itself optionally substituted;

all of the above-mentioned aryl, 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: a halogen atom; hydroxy, cyano or NR8R 9; and alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, which are themselves optionally substituted by one or more identical or different groups selected from: a halogen atom and a hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF3, OCF3, or NRaRb group;

NRaRb is as follows: or Ra and Rb, identical or different, represent a hydrogen atom or an alkyl or cycloalkyl group containing from 1 to 4 carbon atoms, these alkyl and cycloalkyl groups being optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl and N (alkyl) 2; or Ra and Rb together with the nitrogen atom to which they are attached form a cyclic amine which optionally may contain 1 or 2 additional heteroatoms selected from O, S, N or NRc, the cyclic amine so formed being itself optionally substituted by one or more of the same or different groups selected from: a halogen atom and an oxo group; a hydroxyl group; alkyl, which is itself optionally substituted with one or more halogen atoms; or substituted on the same carbon by methyl and hydroxy;

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

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.

Object of the present invention are the products of formula (I) as defined above, wherein the R2, R3, R4, R5, z and-n (d) (w) groups have the meaning indicated in any one of the other claims, R represents a halogen atom;

The present invention relates to a product of formula (I) as defined above, wherein the R2, R3, R4, R5, z and the group of (d) (w) have the meanings indicated in any one of the other claims, R representing a hydrogen atom;

The present invention relates to a product of formula (I) as defined above, wherein the R, R5, z and-n (d) (w) groups have the meaning indicated in any one of the other claims, R2, R3 and R4, identical or different, are selected from hydrogen atoms, halogen atoms, CN groups and alkyl and alkoxy groups, which are themselves optionally substituted by one or more halogen atoms or CN, CONH2, CONH alkyl or CON (alkyl) 2 groups, with the understanding that 1 or 2 of R2, R3 and R4 represent a hydrogen atom, or R2, R3 and R4 all represent three methoxy groups;

The invention relates in particular to products of formula (I) as defined above or below, in which the R, R5, z and-n (d) (w) groups have the meanings indicated above or below, R2, R3 and R4 are as follows: one of R2, R3 and R4 represents a CN or CH2-CN group, and the other two of R2, R3 and R4 are selected from the values defined for these groups, namely from a hydrogen atom, a halogen atom, a CN, CONH2, CONH alkyl or CON (alkyl) 2 group and alkyl and alkoxy groups, which are themselves optionally substituted by one or more halogen atoms or CN, CONH2, CONH alkyl, CON (alkyl) 2, OH or OCH3 groups, it being understood that 1 or 2 of R2, R3 and R4 represent a hydrogen atom,

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. It is clear that in the latter case R2, R3 and R4 cannot all represent three methoxy groups.

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

r has the meaning indicated above or below,

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;

z represents CO or SO 2;

and-N (D) (W) groups are as follows:

a) or W represents a ring (Y) group

D 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 D being optionally additionally substituted by a saturated OR unsaturated heterocyclic group having 5 members which is linked through a carbon atom and is optionally substituted by one OR more groups selected from halogen atom and alkyl group OR alkoxy group,

ring (Y) is monocyclic OR bicyclic, is composed 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 by 1 OR 2 oxygen atoms, OR a group selected from NR10, C ═ O OR its dioxolane (as a protecting group for the carbonyl function), CF2, CH-OR8 OR CH-NR8R 9;

it is understood that when Y represents R10, ring (Y) may include a carbon bridge consisting of 1-3 carbons,

r10 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 hydroxyl, alkoxy, aryl and heteroaryl groups, the alkyl group represented by R10 being optionally additionally substituted by hydroxyl, NR8R9, CONR8R9, phosphonate, alkylthio (optionally oxidized to sulfone) or heterocycloalkyl, all of said aryl, heteroaryl and heterocycloalkyl being optionally substituted;

Which are substituted on the same carbon atom by R1 and R6, contain 4 to 7 mer, are saturated and may additionally include a carbon bridge consisting of 1 to 3 carbons.

It is understood that R1 and R6 represent one of the following 5 alternatives i) -v):

r6 represents a hydrogen atom or a hydroxyl, - (CH2) mOH, -CO-NRaRb, -CH2-NRaRb, and-CO 2H, -CO2 alkyl group;

ii) R1 represents-X2-R7, wherein X2 represents:

-O-; -O- (CH2) m-; -CH (oh) - (CH2) n-; -CO-; -CO-NRc-; -CO-NRc-O-; -ch (nrarb) -; -C ═ NOH —; -C ═ N-NH2 —; - (CH2) n1-NRc- (CH2) n 2-; r7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;

r6 represents hydrogen;

iii) R1 represents-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, which is linear or branched from 3 carbon atoms, optionally substituted by a group selected from: -PO (OEt)2, -OH, -O-alkyl, -CF3, -CO-NR8R9, and SO 2-alkyl; r6 represents hydrogen;

it is understood that when W represents a hydrogen atom, then z represents CO;

iv) R1 represents-CH 2-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, which is linear or branched from 3 carbon atoms, and is optionally substituted by a group selected from: -PO (OEt)2, -OH, -OEt, -CF3, -CO-N (alkyl) 2 and SO 2-alkyl; and R6 represents hydrogen;

v) R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen;

n, n1 and n2, which are the same or different, represent an integer of 0 to 3;

m represents an integer of 1 to 3;

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, N (alkyl) 2, CONH2, -CONH alkyl or-CON (alkyl) 2 groups, the alkyl group represented by R8 being optionally additionally substituted by phosphonate, alkylthio (optionally oxidized to sulfone), or by an optionally substituted aryl or an optionally substituted saturated or unsaturated heterocyclyl;

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 NRc, the cyclic amine so formed being itself optionally substituted;

all of the above-mentioned aryl, 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: a halogen atom; a hydroxyl group; a cyano group; an NR8R9 group; and alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, which are themselves optionally substituted by one or more identical or different groups selected from: a halogen atom and a hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF3, OCF3, or NRaRb group;

NRaRb is as follows: or Ra and Rb, identical or different, represent a hydrogen atom or an alkyl or cycloalkyl group containing from 1 to 4 carbon atoms, these alkyl and cycloalkyl groups being optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl and N (alkyl) 2 groups; or Ra and Rb together with the nitrogen atom to which they are attached form a cyclic amine which optionally may contain 1 or 2 additional heteroatoms selected from O, S, N or NRc, the cyclic amine so formed being itself optionally substituted by one or more of the same or different groups selected from: halogen atoms and alkyl groups, which alkyl groups are themselves optionally substituted by one or more halogen atoms;

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 optionally selected from O, S, N optionally oxidized and NRc;

Accordingly, an object of the present invention is therefore a product of formula (I) as defined above corresponding to formula (IA):

wherein R, R2, R3, R4, R5, z, D and ring (Y) have the meanings as indicated above or below,

The invention therefore relates in particular to the products of formula (I) as defined above corresponding to formula (IA), wherein R, R2, R3, R4, R5, z and D are chosen from the meanings as indicated above or below and ring (Y) can be chosen from any of the following values:

-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, for example, Y represents NR10, the ring formed may be, in particular, an azetidinyl, pyrrolidinyl or piperidinyl group having a para-or meta-nitrogen atom N, which thus carries a substituent R10 as defined above: thus ring (Y) may represent pyrrolidinyl or piperidinyl optionally substituted on the nitrogen atom by R10, R10 may represent alkyl optionally substituted by hydroxy, -NR8R9, -CO-NR8R9, phosphonate or alkylthio, which is optionally oxidized to sulfone.

-when ring (Y) is such as: y represents NR10, which comprises a carbon bridge consisting of 1 to 3 carbons, the ring formed may in particular be an 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 NR10, the ring formed may in particular be a bicyclic group, such as, for example, a quinolizinyl or indolizinyl group;

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

-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.

Mention may also be made of:

-ring (Y), such as Y represents-NR 10, wherein R10 represents H;

-ring (Y), such as Y represents-NR 10, wherein R10 represents CH 3;

-ring (Y), such as Y, represents-NR 10, wherein R10 represents cycloalkyl, such as in particular cyclopropyl;

-a ring (Y), such as Y represents-NR 10, wherein R10 represents alkyl, in particular CH3, C2H5 or C3H7 substituted by phosphonate;

-a ring (Y), such as Y represents-NR 10, wherein R10 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-NR 10, wherein R10 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 which R10 may carry, mention may be made in particular of 5-membered unsaturated heterocycles comprising from 1 to 4 heteroatoms selected from N, O and S: r10 may thus represent, in particular, -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 radicals, in particular pyrazolyl, isoxazolyl, pyrrolyl or tetrazolyl, being themselves optionally substituted, in particular, by alkyl groups containing from 1 to 3 carbon atoms, such as, in particular, CH3 or C2H 5;

r10 may also bear a heterocyclic ring as defined above, such as pyridyl (with pyridine N in 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-naphthyridinyl); pyridyl-N-oxide; 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; or benzo [2, 1, 3] thiadiazolyl;

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

The present invention therefore relates in particular to the products of formula (I) as defined above corresponding to formula (IA), wherein R, R2, R3, R4, R5, z and ring (Y) are selected from the meanings as indicated above or below and D can be selected from any one of the following values:

-D represents a hydrogen atom or a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted by NH2, NH alkyl, N (alkyl) 2 or by a saturated or unsaturated heterocyclic ring, preferably a monocyclic ring containing 5 or 6 mer as defined above and optionally substituted as above or as indicated below;

-D represents a hydrogen atom or a linear or branched alkyl group containing 1 to 5 carbon atoms optionally substituted with NH2, or D represents an alkyl group substituted with a saturated or unsaturated heterocyclic ring, preferably a monocyclic heterocyclic ring having 5 members which is itself optionally substituted as above or as indicated below;

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

-D represents a CH3 group optionally substituted by a saturated or unsaturated heterocyclic ring as defined above, and R10 represents a CH3 group;

-D 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 their nitrogen atom by R10 wherein R10 is as defined above.

More precisely:

-D represents H;

-D represents CH 3;

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

-D represents an alkyl group, in particular CH3, C2H5, C3H7, substituted by one or more identical or different groups chosen from: halogen atoms and NH2, NH (alkyl), N (alkyl) 2, NH-CH2-CH2OH, NH-CH2-C3H7-OH, NH (CH2-CF3), alkoxy or OH, or saturated heterocycles, such as, for example, pyrrolidinyl, piperidinyl, morpholinyl or tetrahydrofuranyl, or unsaturated heterocycles, in particular as those defined above for R10.

Object of the present invention is therefore a product as defined above or below corresponding to formula (IA) wherein R, R2, R3, R4, R5 and z have the meanings as indicated above or below, D represents a hydrogen atom or a linear or branched alkyl group containing from 1 to 4 carbon atoms, optionally substituted by NH2, in particular CH3, ring (Y) is as follows: y represents NR10, wherein R10 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted by a group selected from: halogen atoms and hydroxyl, phosphonate, sulfone, phenyl and saturated or unsaturated monocyclic or bicyclic heterocyclic groups, which phenyl and heterocyclic groups are themselves optionally substituted as above or as indicated below,

Object of the present invention are therefore products of formula (I) as defined above or below corresponding to formula (IA) wherein R, R2, R3, R4, R5 and z have the meanings as indicated above or below,

d represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, optionally substituted with NH2, in particular CH3, ring (Y) being such as: y represents NR8R9, wherein R8 represents a hydrogen atom or an alkyl group, R9 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted by a group selected from: halogen atoms and hydroxyl, phosphonate, sulfone, phenyl, and saturated or unsaturated monocyclic or bicyclic heterocyclic groups, which phenyl and heterocyclic groups are themselves optionally substituted as above or as indicated below,

Accordingly, an object of the present invention is therefore a product of formula (I) as defined above or below, corresponding to formula (IB):

wherein R, R1, R2, R3, R4, R5, R6, z and ring (N) have the meanings indicated above or below,

Accordingly, an object of the present invention is a product of formula (I) corresponding to formula (IB) as defined above or below, wherein: r, 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;

z represents CO or SO 2;

ring (N) is

Which are substituted on the same carbon atom by R1 and R6, contain 4 to 7 mer, are saturated and may additionally comprise a carbon bridge of 1 to 3 carbons, wherein R1 and R6 are as defined above or below.

Accordingly, an object of the present invention is a product of formula (I) as defined above or below corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated above or below, and R1 and R6 are as follows: r1 represents-X1-R7, wherein X1 represents- (CH2) m-and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;

r6 represents a hydrogen atom or a hydroxyl, - (CH2) mOH, -CO-NRaRb, -CH2-Nrarb, -CO2H, and-CO 2 alkyl group;

wherein m, n and NRaRb are as defined above or below, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more identical or different groups as defined above or below,

Accordingly, an object of the present invention is a product of formula (I) as defined above or below corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated above or below, R1 and R6 are as follows: r1 represents-X2-R7, wherein X2 represents:

-O-、-O-(CH2)m-、-CH(OH)-(CH2)n-、-CO-、-CO-NRc-、-CO-NRc-O-、-CH(NRaRb)-、-C＝NOH-、-C＝N-NH2-、-(CH2)n1-NRc-(CH2)n2-；

r7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;

r6 represents hydrogen;

wherein n, n1, n2, Rc and NRaRb are as defined above or below, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more identical or different radicals as defined above or below,

Accordingly, an object of the present invention is therefore a product of formula (I) as defined above or below corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated above or below, and R1 and R6 are as follows:

or R1 represents or-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, which is linear or branched from 3 carbon atoms, and is optionally substituted by a group selected from: PO (OEt)2, -OH, -O-alkyl, -CF3, -CO-NR8R9, and SO 2-alkyl, and R6 represents hydrogen, with the understanding that when W represents a hydrogen atom, then z represents CO;

or R1 represents CH2-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, which is linear or branched from 3 carbon atoms, and is optionally substituted by a group selected from: -PO (OEt)2, -OH, -OEt, -CF3, -CO-N (alkyl) 2, and SO 2-alkyl;

and R6 represents hydrogen;

OR R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen;

wherein Rc, R' c and NR8R9 are as defined above or below,

When the ring (N) corresponding to the product of formula (I) of formula (IB) comprises a carbon bridge consisting of 1 to 3 carbons, the ring formed may in particular be an 8-azabicyclo [3.2.1] oct-3-yl ring, or a ring selected from: 9-azabicyclo [3.3.1] nonan-3-yl, 6-azabicyclo [3.2.1] octan-3-yl, 3-azabicyclo [3.2.1] octan-8-yl or 3-azabicyclo [3.3.1] nonan-9-yl.

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 the following values are chosen: vinyl (ethi e nyl) or vinyl (vinyl), propenyl or allyl, 1-propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl or hexenyl, and also 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 and 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 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 or 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 acceptable 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; 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), azetidinyl (oxiranyl), tetrahydrofuryl, 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) group" and "dialkylamino or N (alkyl) 2" thus denote an amino group NH2 substituted by 1 or 2, respectively, identical or different (in the case of dialkylamino) linear or branched alkyl groups, selected from alkyl groups as defined above and optionally substituted as above or as indicated 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 other heteroatoms selected from O, S, SO2, N or NRc, wherein Rc is as defined above: as examples of such cyclic amines, mention may be made, for example, of pyrrolyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl or azetidinyl. More particular mention may be made of piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl or azetidinyl, optionally substituted as indicated above, in particular by oxo or hydroxy and methyl on the same carbon.

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 by 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 with 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 reminded that a stereoisomerism can be defined in its broad sense as an isomer of a compound having the same developed form (formulae) but with different groups arranged differently in space, such as, in particular, in monosubstituted cyclohexane, the substituents of which 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 or below corresponding to formula (IA) wherein:

r has the meaning indicated above or below,

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;

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

ring (Y) is monocyclic OR bicyclic, is composed 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 NR10, C ═ O, CF2, CH-OR8 OR CH-NR8R 9;

r10 represents a hydrogen atom or an alkyl group optionally substituted by one or more identical or different groups selected from: halogen atoms, hydroxyl groups, alkoxy groups, phenyl groups and heteroaryl groups, which 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;

heteroaryl consists of 5-7 mer and includes 1-3 heteroatoms selected from O, S, N and NRc;

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, the alkyl and cycloalkyl groups themselves being optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, NH2, NH alkyl and N (alkyl) 2 groups;

NR8R9 is such as: or R8 and R9, the same 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 possible second nitrogen atom by alkyl which is itself optionally substituted by one or more identical or different groups chosen from halogen atoms and hydroxyl groups;

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 invention relates in particular to a product of formula (I) corresponding to formula (IA) as defined above or below, wherein:

r has the meaning indicated above or below,

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;

z represents SO2 or CO;

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

ring (Y) is selected from cyclohexyl, itself optionally substituted with amino; a tetrahydropyranyl group; dioxythienyl; and pyrrolidinyl, piperidinyl and azepinylOptionally substituted on its nitrogen atom with: methyl, propyl, butyl, isopropyl, isobutyl, isoamyl or ethyl, which are themselves optionally substituted by one or more groups selected from: halogen atoms, hydroxyl and phenyl, quinolinyl, pyridyl, thienyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazinyl, furyl and imidazolyl optionally oxidized on their nitrogen atoms, these latter cyclic groups themselves being optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxy, methyl and methoxy groups;

r has the meaning indicated above or below,

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

r5 represents a hydrogen atom;

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

the ring containing Y represents cyclohexyl, which is itself optionally substituted by amino, or piperidinyl (which is 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 a group selected from hydroxy; thiadiazolyl; tetrazolyl; phenyl (which is itself optionally substituted by halogen), quinolinyl; pyridinyl (which is optionally oxidized on its nitrogen atom), furanyl; and imidazolyl (which is itself optionally substituted by alkyl);

Particular mention may thus be made of products of formula (I) in which R5 represents a hydrogen atom, the other substituents R1, R2, R3, R4 and ring (Y) of said products of formula (I) being chosen from the values indicated above.

When NR8R9 does not form a cyclic amine, then in particular NR8R9 is such as: r8 represents a hydrogen atom or an alkyl group, R9 being selected from all the values defined for R8.

The group NR8R9 may also represent the values defined above for NRaRb.

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

r has the meaning indicated above or below,

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

r5 represents a hydrogen atom;

d represents a hydrogen atom or a methyl or ethyl group optionally substituted with NH 2;

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

Object of the present invention are in particular the products of formula (I) as defined above or below corresponding to formula (IB) wherein R2, R3, R4, R5 and z have the meanings as indicated above or below and ring (N) represents one of the rings defined below:

-an azetidinyl or pyrrolidinyl ring substituted at the 3-position with R1 and R6 as defined above or below;

-piperidinyl and azaA cyclic ring substituted at the 3 or 4 position with R1 and R6 as defined above or below;

-8-azabicyclo [3, 2, 1] octan-3-yl, 6-azabicyclo [3.2.1] octan-3-yl or 3-azabicyclo [3.2.1] octan-8-yl) ring;

Objects of the invention are in particular the products of formula (I) as defined above or below corresponding to formula (IB) wherein R, R2, R3, R4, R5 and z have the meanings as indicated above or below and ring (N) represents a pyrrolidinyl ring (which is substituted in position 3 with R1 and R6 as defined above or below) or a piperidinyl ring (which is substituted in position 3 or 4 with R1 and R6 as defined above or below),

Accordingly, an object of the present invention is in particular a product of formula (I) as defined above or below corresponding to formula (IB) wherein:

r has the meaning indicated above or below,

r5 represents a hydrogen atom or a halogen atom;

z represents CO or SO 2;

ring (N), i.e

Represents pyrrolidinyl substituted in position 3 by R1 and R6 or a piperidinyl ring substituted in position 3 or 4 by R1 and R6,

i) r1 represents-X1-R7, wherein X1 represents-CH 2 and R7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted;

r6 represents a hydrogen atom or a hydroxyl group, -CH2OH, -CO-NRaRb, and-CO 2Et group;

ii) R1 represents-X2-R7, wherein X2 represents:

-O-, -CH (OH) -CH2-, -CO-, -CH (NRaRb) -, -C ═ NOH-, -C ═ N-NH 2-and- (CH2) N1-NRc- (CH2) N2-,

and R7 represents a heterocycloalkyl, phenyl or heteroaryl ring, all optionally substituted;

and R6 represents hydrogen;

iii) R1 represents-NRc-W, wherein W represents a hydrogen atom or a linear or branched alkyl group containing 1 to 4 carbon atoms, which alkyl group is optionally substituted by a group selected from: -PO (OEt)2, -OH, -OEt, -CF3, -CO-NR8R9 and SO 2-alkyl; r6 represents hydrogen; it is understood that when W represents a hydrogen atom, then z represents CO;

iv) R1 represents-CH 2-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, which is linear or branched from 3 carbon atoms, and is optionally substituted by a SO 2-alkyl group; r6 represents hydrogen;

v) R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen;

wherein n, n1 and n2, which are the same or different, represent an integer of 0 to 2;

rc and R' c, identical or different, represent a hydrogen atom or an alkyl group comprising from 1 to 2 carbon atoms;

NRaRb is as follows: or Ra and Rb, identical or different, represent a hydrogen atom or an alkyl group comprising from 1 to 4 carbon atoms, optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl or N (alkyl) 2 groups; or Ra and Rb together with the nitrogen atom to which they are attached form morpholinyl or pyrrolidinyl optionally substituted with one or more of the same or different groups selected from halogen atoms and alkyl, which itself is optionally substituted with one or more halogen atoms;

all heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by one or more identical or different groups selected from: a halogen atom; a hydroxyl group; a cyano group; an NR8R9 group; alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, which are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxy, alkoxy, OCF3, CH3, CH2OH, CN, CF3, OCF3 or NRaRb groups;

NR8R9 is such as: or R8 and R9, identical or different, are, for example, R8 represents a hydrogen atom, a linear or branched alkyl group containing up to 4 carbon atoms or a cycloalkyl group containing 3 to 6 mer, said alkyl and cycloalkyl groups themselves being optionally substituted by one or more halogen atoms or hydroxyl groups; r9 represents a hydrogen atom or an alkyl group optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl, N (alkyl) 2, phenyl, heterocycloalkyl or heteroaryl groups, which are themselves optionally substituted by one or more groups selected from: halogen atoms and hydroxyl, OCH3, CH3, -CH2OH, CN, CF3, OCF3, NH2, NH alkyl or N (alkyl) 2 groups; or R8 and R9 together with the nitrogen atom to which they are attached form a cyclic amine selected from: pyrrolyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl and piperazinyl optionally substituted with one or more alkyl groups which are themselves optionally substituted with one or more halogen atoms;

In the products of formula (I) corresponding to formula (IB) as defined above, all heterocycloalkyl, phenyl and heteroaryl groups which may be represented by R7 may in particular be optionally substituted by one or more identical or different groups selected from: a halogen atom; an NR8R9 group; alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, which are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, OCF3, CH3, -CH2OH, CN, CF3, OCF3, NH2, NH alkyl, N (alkyl) 2, pyrrolidinyl, piperidinyl or morpholinyl, which are optionally substituted by one or more identical or different radicals from the group consisting of halogen atoms and alkyl, which is itself optionally substituted by one or more halogen atoms.

Object of the invention are in particular the products of formula (I) as defined above or below corresponding to formula (IB) wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated above or below, and R1 and R6 are as:

or R1 represents-X-R7, in which X1 represents-CH 2-and R6 represents a hydrogen atom or a hydroxyl group, CH2-OH, -CO-N (CH3)2, -CO-NHCH3, -CO-NH- (CH2)2-N (CH3)2 and-CO 2Et groups;

or R1 represents-X2-R7, wherein X represents:

-O-、-CHOH-、-CH(OH)-CH₂-、-CO-、-CHNH₂-、-NH-CH₂-、-N(CH₃)-CH₂-and CH₂-NH-CH₂-; and R6 represents hydrogen;

r7 is selected from pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, hexahydrofuranyl, phenyl, pyridinyl, thienyl, thiazolyl, dithiazolyl, pyrazolyl, pyrazinyl, furanyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, oxyindenyl, chromanyl, benzoxadiazolyl, benzothiadiazolyl, benzothiophenyl, quinolinyl, or isoquinolinyl;

all those groups represented by R7 are optionally substituted by one or more, the same or different, groups selected from: halogen atoms and hydroxy, methyl, methoxy, hydroxymethyl, alkoxymethyl, cyano, NH2, NH alkyl, N (alkyl) 2, -CH2-NH2, -CH2-NH alkyl, -CH2-N (alkyl) 2, phenyl, morpholinyl and CH 2-morpholinyl, which are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, CH3, OCH3, -CH2OH, CN, CF3, OCF3, NH2, NH alkyl or N (alkyl) 2 groups;

Object of the invention are in particular the products of formula (I) as defined above or below corresponding to formula (IB) wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated above or below, and R1 and R6 are as: or R1 represents-X1-R7, wherein X1 represents-CH 2-and R6 represents a hydrogen atom or a hydroxyl group, CH2-OH, -CO-N (CH3)2, -CO-NHCH3, -CO-NH- (CH2)2-N (CH3)2 and-CO 2Et groups; or R1 represents-X2-R7, wherein X2 represents:

and R7 is selected from pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, phenyl, pyridinyl, thienyl, thiazolyl, dithiazolyl, pyrazolyl, pyrazinyl, furanyl, imidazolyl, pyrrolyl, oxazolyl, isoxazolyl, chromanyl, benzoxadiazolyl, benzothiophenyl, quinolinyl, or isoquinolinyl;

Object of the present invention are in particular the products of formula (I) as defined above or below, wherein R, R1, R5, R6, z, D, W, ring (Y) and ring (N) have the meanings as indicated above or below; r2, R3 and R4, identical or different, are such as: one of which represents a halogen atom and the other two, identical or different, represent a hydrogen atom, a halogen atom or a methyl, methoxy, trifluoromethyl or trifluoromethoxy group; r5 represents a hydrogen atom;

Object of the invention are in particular products of formula (I) as defined above or below, wherein R, R1, R6, z, D, W, ring (Y) and ring (N) have the meanings indicated above or below, and R2, R3 and R4, identical or different, are such as: one of which represents a fluorine atom and the other two, which are the same or different, represent a hydrogen atom, a fluorine atom or a methyl group;

r5 represents a hydrogen atom;

Objects of the present invention are in particular the products of formula (I) as defined above or below, wherein R, R1, R2, R3, R4, R5, R6, W, D, ring (Y) and ring (N) have the meanings indicated above or below, z represents SO2, said products of formula (I) being in all the possible racemic, enantiomeric and diastereomeric isomeric forms, and the addition salts of said products of formula (I) with inorganic and organic acids.

Objects of the present invention are in particular the products of formula (I) as defined above or below, wherein R, R1, R2, R3, R4, R5, R6, W, D, ring (Y) and ring (N) have the meanings indicated above or below, z represents CO, said products of formula (I) being in all the possible racemic, enantiomeric and diastereomeric isomeric forms, and the addition salts of said products of formula (I) with inorganic and organic acids.

The object of the invention is in particular a product of formula (I) as defined above or below, corresponding to the following name:

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] (4- {4- [ (2-methanesulfonyl-ethyl) (methyl) amino ] piperidine-1-sulfonyl } phenyl) amine

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] (4- {4- [ (1H-imidazol-2-ylmethyl) -methyl-amino ] piperidine-1-sulfonyl } phenyl) amine

-N- (2-amino-ethyl) -4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino ] -N-piperidin-4-yl-benzenesulfonamide

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - {4- [4- (methyl-pyridin-2-ylmethyl-amino) piperidine-1-sulfonyl ] phenyl } amine

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] (4- {4- [ methyl- (3-methylthiophen-2-ylmethyl) amino ] piperidine-1-sulfonyl } phenyl) amine

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - {4- [4- (methyl-quinolin-8-ylmethyl-amino) piperidine-1-sulfonyl ] phenyl } amine

A further object of the present invention is also a process for the preparation of the product of formula (I) as defined above by using methods known to those skilled in the art.

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,

conversion to the product of formula (III):

wherein R5' has the meaning as indicated above,

reacting the product of formula (III) with an aniline of formula (IV):

to obtain a product of formula (V):

wherein R5' has the meaning as indicated above,

converting the product of formula (V) to a product of formula (VI):

wherein R5' has the meaning as indicated above,

pathway a)(z ═ SO2), reacting the product of formula (VI) with chlorosulfonic acid SO2(OH) Cl to obtain the corresponding product of formula (VII):

wherein R5' has the meaning as indicated above,

reacting the product of formula (VII)

Or with an amine of formula (VIII) 1:

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

to obtain a product of formula (IX) a 1:

wherein R5 ', D' and Y have the meanings indicated above,

or with an amine of formula (VIII) 2:

wherein R1 'and R6' have the meanings indicated above for R1 and R6, respectively, wherein possible reactive functions are optionally protected by protecting groups,

to obtain a product of formula (IX) a 2:

wherein R1 ', R5 ' and R6 ' have the meanings indicated above,

reacting the product of formula (IX) a1 or (IX) a2 with a phenylboronic acid of formula (X):

to obtain the product of formula (IA)1 separately

Wherein R2 ', R3 ', R4 ', R5 ', D ' and Y have the meanings indicated above,

or a product of formula (IA) 2:

wherein R1 ', R2, R3, R4, R5 and R6' have the meanings indicated above,

route b) toThe product of formula (III) as defined above is reacted with methyl 4-aminobenzoate to obtain a product of formula (XI):

wherein R5' has the meaning as indicated above,

reacting the product of formula (XI) with a phenylboronic acid of formula (X) as defined above to obtain a product of formula (XII):

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

converting the product of formula (XII) to its corresponding acid of formula (XIII):

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

reacting the product of formula (XIII):

orWith an amine of formula (VIII)1 as defined above to obtain a product of formula (IB) 1:

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

orWith an amine of formula (VIII)2 as defined above to obtain a product of formula (IB) 2:

wherein R1 ', R2', R3 ', R4', R5 'and R6' have the meanings indicated above,

said products of formula (IA)1, (IA)2, (IB)1 and (IB)2, which may be products of formula (I) wherein z represents SO2 or CO respectively, and which may be subjected to one or more of the following transformations, if and when necessary, in either order, in order to obtain products of formula (I) or other products of formula (I):

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 corresponding to formula (IA) as defined above, in which Y represents a NR10 group as indicated above, while R10 represents CH2-RZ and RZ represents alkyl, alkenyl or alkynyl, all optionally substituted 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,

the process is characterized by reacting a compound of formula (XIV):

wherein R2 ', R3', R4 'and R5' have the meanings indicated in any of the other claims for R2, R3, R4 and R5, respectively, wherein possible reactive functions are optionally protected with protecting groups and z represents SO2 or CO,

subjected to a deprotection reaction of the carbamate function to obtain a product of formula (XV):

wherein R1 ', R2, R3, R4 and R5 have the meanings indicated above and D' has the meanings indicated above for D, wherein possible reactive functions are optionally protected with protecting groups,

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

RZ’-CR8’O (XVI)

wherein RZ 'and R8' have the meanings indicated above for RZ and R8, respectively, wherein possible reactive functions are optionally protected by protecting groups,

to obtain a product of formula (IA):

wherein R2 ', R3 ', R4 ', R5 ', z, D ', R8 ' and RZ ' have the meanings indicated above,

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

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 converted to the product of formula (III) as defined above, in particular in water, in the presence of sodium hydroxide and methyl iodide, at the usual temperatures.

The product of formula (III) thus obtained is subjected to the action of an aniline of formula (IV) as defined above, in particular in an alcohol such as butanol or dimethylformamide, in the presence or absence of catalytic amounts of a strong acid (HCl), under reflux conditions, so as to obtain the product of formula (V) as defined above.

The product of formula (V) as defined above is converted into the product of formula (VI) by the action of phosphorus oxychloride POCl3 at 90-110 ℃ for 1-2 hours.

According to pathway a) defined above, the product of formula (VI) is subjected to chlorosulfonic acid (in particular first at 0 ℃ and then at ambient temperature) to obtain the product of formula (VII) as defined above.

The product of formula (VII) thus obtained is subjected to the action of an amine of formula (VIII)1 or (VIII)2 as defined above, in particular in dichloromethane or a dichloromethane/THF mixture or dimethylformamide, in the presence of an organic base such as triethylamine, diisopropylethylamine or N-methylmorpholine, at ambient temperature, so as to obtain a product of formula (IX) a1 or (IX) a2, respectively, as defined above.

According to the Suzuki coupling method with aryl or heteroaryl halides, the product of formula (IX) A1 or (IX) A2 is reacted with a phenylboronic acid (X) as defined above in the presence of a palladium catalyst (Pd (OAc)2 or Pd (dba)3 or Pd (dba)2 using phosphine, tri (tert-butyl) phosphine or DPPF (1, 1' -bis (diphenylphosphino) ferrocene) or tricyclohexylphosphine in a solvent (e.g. toluene, dioxane, dimethylformamide) at a temperature of 100 ℃ and 150 ℃ using a basic reagent of the K2CO3, Na2CO3 or caesium fluoride CsF type, thereby obtaining the product of formula (IA)1 or (IA)2, respectively, as defined above.

According to pathway b) as defined above, the product of formula (III) as defined above is subjected to the action of methyl 4-aminobenzoate, in particular in an alcohol such as butanol, at a temperature of 100 ℃ and 140 ℃ to give the product of formula (XI) as defined above.

Reacting said product of formula (XI) with a phenylboronic acid of formula (X) as defined above under the conditions defined above to obtain a product of formula (XII).

The product of formula (XII) is saponified to give its corresponding acid of formula (XIII) by the usual 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 (XIII) thus obtained is reacted with an amine of formula (VIII)1 or an amine of formula (VIII)2 as defined above according to coupling methods known to the person skilled in the art to obtain a product of formula (IB)1 or a product of formula (IB)2 as defined above, respectively, such as an amide coupling in a solvent (such as dimethylformamide or dichloromethane) in the presence of a coupling agent (such as BOP, DCC or TBTU).

The deprotection of the carbamate function of the compound of formula (XIV) to obtain the product of formula (XV) can be carried out by using, for example, an acid reagent (such as pure trifluoroacetic acid) at a temperature of about 0 ℃, 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).

The product of formula (XV) is subjected to reductive amination conditions in the presence of an aldehyde or ketone of formula (XVI) to obtain a product of formula (IA) 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.

According to the values of R1 ', R2 ', R3 ', R4 ', R5 ', R6 ', R8 ', D ' and RZ ', the products of formulae (IA)1, (IA)2, (IB)1 and (IB)2 as defined above may thus constitute the product of formula (I) as defined above or may be converted into the product of formula (I) by usual methods known to the person skilled in the art, for example by subjecting it 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 necessary, it is possible to protect the various reactive functions carried by certain compounds of the reaction defined above: 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 protective reactive functions may be mentioned:

the hydroxyl group may be protected, for example, by alkyl groups, 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, for example, as indicated below, the product of formula (I') can be subjected to a reaction as defined above.

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.

Can be prepared according to customary 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 by carrying out the reduction or oxidation, 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 else using oxone (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) 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 acidic 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), (IV), (VIII)1 and (VIII)2 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 reactions a) to f) described above.

The material of formula (II), which is therefore a derivative of a pyrimidine such as dichloropyrimidine or trichloropyrimidine, is a commercially available product, like a boronic acid, such as:

-3, 4, 5-trifluorophenylboronic acid

-2, 3, 4-trifluorophenylboronic acid

-2-chloro-4, 6-difluorophenylboronic acid

-2, 4, 5-trifluorophenylboronic acid

-4-fluoro-3-methylphenylboronic acid

-3-chloro-2, 4-difluorophenylboronic acid

-2, 4-dichloro-5-fluorophenylboronic acid

-4-trifluoromethylphenylboronic acid.

The amine of formula (VIII)1 or formula (VIII)2 is also commercially available, such as methyl (1-methylpiperidin-4-yl) amine.

The non-commercially available amines of formula (VIII)1 or formula (VIII)2 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) corresponding to formula (IA) as defined above, wherein R1, R2, R3, R4, R5, z and D have the meanings as indicated above, and ring (Y) is as follows: y represents NR10 and comprises a carbon bridge consisting of 1 to 3 carbons, a bicyclic amine can be used as starting product, which can be obtained from a marketed compound (such as tropinone or pseudopunicalagine) 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 Trans.1，1991，1375-1381

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

It may be noted that, in order to obtain a product of formula (I) corresponding to formula (IB) as defined above, wherein ring (N) comprises a carbon bridge consisting of 1 to 3 carbons, a bicyclic amine may be used as starting material, which is obtainable from marketed compounds (such as tropinone, pseudopunine) 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 Trans1 1991，1375-1381

J.Med.Chem.，1994，37，2831-2840

as examples of ring (N), the following compounds may be mentioned:

9-azabicyclo [3.3.1] nonan-3-amines

6-azabicyclo [3.2.1] octan-3-amine

3-azabicyclo [3.2.1] octan-8-amine

3-azabicyclo [3.3.1] nonan-9-amines

These bicyclic rings, constituting examples of ring (N), are substituted, if necessary, and optionally protected, by R1 and R6 as defined above, and are linked to z through their ring nitrogen.

Examples of aldehydes and ketones of the formula (XVI) 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) corresponding to formula (IB) 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, RB may represent (CH2) p-G, wherein G represents an optionally substituted heterocyclic group or phenyl group as defined above, and p 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 invention also relates to a process for the preparation of a product of formula (I) as defined above, wherein z represents CO, according to scheme 2 below:

scheme 2

In this scheme 2, R2 ', R3 ', R4 ', R5 ', D ' and W have the meanings indicated above.

The steps of the synthetic method of scheme 2 above can be performed by using the methyl ester of aniline in step 2 and boronic acid substituted with R2 ', R3 ' or R4 ' in step 6 and according to usual methods known to those skilled in the art or as described herein.

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 formula (XIV), (XV), (IX) A1, (IX) A2, (XII) and (XIII) as novel industrial products.

The products of formula (I) as defined above and their addition salts with 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 NF- κ B activation and cytokine production, with IC50 values below 10 μ M.

The compounds of the invention can therefore inhibit the proliferation of large sample tumor cells (large panel decellules tumors), with IC50 values below 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 the proliferation of tumour cells, these compounds are useful in the prevention and treatment of leukaemia, both primary and metastatic solid tumours, 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).

Objects of the present invention are therefore the products of formula (I) as defined above as well as the addition salts of said products of formula (I) with pharmaceutically acceptable inorganic and organic acids as medicaments.

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

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - (4- {4- [ (2-methanesulfonyl-ethyl) -methyl-amino ] piperidine-1-sulfonyl } phenyl) amine

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - (4- {4- [ (1H-imidazol-2-ylmethyl) -methyl-amino ] piperidine-1-sulfonyl } phenyl) amine

-N- (2-aminoethyl) -4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino ] -N-piperidin-4-yl-benzenesulfonamide

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - {4- [4- (methyl (pyridin-2-ylmethyl) amino) piperidine-1-sulfonyl ] phenyl } amine

- [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - (4- {4- [ methyl (3-methyl-thiophen-2-ylmethyl) amino ] piperidine-1-sulfonyl } phenyl) amine

And 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 product of formula (I) as defined above or a pharmaceutically acceptable salt of such a product or a prodrug of such a product, and 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 the diseases 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 prevention of diabetes.

The invention relates in particular to the use of the product of formula (I) as defined above for preparing a medicament for treating 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 treating cancers against 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 is directed in particular to the use of a product of formula (I) as defined above for the preparation of a medicament for cancer chemotherapy, 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 69 of the present invention.

The following examples illustrate the invention without limiting it.

The product of formula (I) as defined above is prepared according to scheme 3 below.

Scheme 3

Process 1 a:2- [ (2-Chloropyrimidin-2-yl) amino]Preparation of benzenesulfonyl chloride hydrochloride:

step 1: 2- (methylthio) pyrimidin-4-ol:

to a mixture containing 100g of commercially available 2-thio-pyrimidin-4-ol and 60g of sodium hydroxide in 800ml of water was added dropwise 38ml of methyl iodide. The reaction medium is stirred at ambient temperature for 24 hours. The solution was acidified using 135ml acetic acid and placed in a refrigerator for 24 hours. The white precipitate was filtered off and washed several times with cold water. After drying, 60g of the expected compound are obtained.

Step 2: 2-anilinopyrimidine-4-ol:

39g of 2- (methylthio) pyrimidin-4-ol are dissolved in 500ml of DMF containing 30ml of aniline. The reaction medium is stirred for 24 hours under reflux. After usual work-up, 35.81g of the expected compound are obtained.

Step 3: 4-chloro-N-phenylpyrimidin-2-amines

A solution containing 15g of 2-anilinopyrimidin-4-ol in 75ml of POCl3 was warmed to 110 ℃ for 2 hours. After evaporation of POCl3, the crude reaction product was poured into a Na2CO3 freezing solution. The precipitate was filtered to obtain 16.3g of the expected product.

Step 4: 2- [ (2-Chloropyrimidin-4-yl) amino]Hydrochloride of benzenesulfonyl chloride:

16.2g of 4-chloro-N-phenylpyrimidin-2-amine were added in small portions to a three-necked round-bottomed flask containing chlorosulfonic acid at 0 ℃ under a stream of nitrogen while maintaining the temperature at about 0 ℃. The reaction medium is allowed to stand at ambient temperature for 18 h. The mixture was poured (carefully) dropwise onto ice. The obtained precipitate was filtered and washed with distilled water. After dissolving the solid in 1L ethyl acetate, dried using Na2SO4 and concentrated in vacuo, a slightly white oil was obtained. This oil precipitated after being dispersed in 200ml iPr 2O. 7.6g of 2- [ (2-chloropyrimidin-4-yl) amino ] benzenesulfonyl chloride hydrochloride was obtained by filtering the ether-containing suspension.

MH⁺＝304.2

Process 1b: preparation of 2- [ (5-fluoro-4-chloropyrimidin-2-yl) amino]Hydrochloride of benzenesulfonyl chloride:

in preparing this compound, the same procedure is used as in process 1a, by using 2-chloro-5-fluoro-pyrimidin-4-ol instead of 2- (methylthio) pyrimidin-4-ol in stage 1 of process 1 a.

Process 2: preparation of the amines

Process 2a: 4- (2-pyrrolidin-1-yl-ethylamino) piperidine-1-carboxylic acid tert-butyl ester

A mixture comprising 25g of tert-butyl 4-oxo-piperidine-1-carboxylate, 17.2g of 2-pyrrolidin-1-ylethylamine and 37.24g of NaBH (OAc)3 in 250ml of DCE was stirred at ambient temperature for 2h 30 min. The reaction medium was poured into an separatory funnel (ampoule) and washed twice with a 10% Na2CO3 solution. The organic phase was dried and concentrated, whereby 37g of pure desired product was obtained without additional purification.

Process 2b: 4- (2-pyrrolidin-1-yl-ethylamino) tetrahydropyran

Starting with 2.15g of tetrahydropyran-4-one and 3g of 2-pyrrolidin-1-yl-ethylamine, 3.7g of the desired 4-aminotetrahydropyran are obtained according to the procedure of Process 2 a.

Process 2c: 4-pyrrolidin-1-ylmethyl-piperidin-4-ol

Step 1: 1-oxa-6-aza-spiro [2.5] octane-6-carboxylic acid tert-butyl ester

18.22g of trimethylsulfoxonium iodide and 485mg of tetrabutylammonium bromide are added to a suspension of 15g of tert-butyl 4-oxo-piperidine-1-carboxylate in 150ml of toluene. A solution of 4.5g of sodium hydroxide in 20ml of water is added dropwise. Stirred at 80 ℃ for 3 h. Dissolution was carried out using toluene, decantation, washing with water, drying and concentration to dryness. After chromatography on a silica column (DCM/AcOEt: 90/10), 13g of the expected product are obtained.

Step 2: 4-hydroxy-4-pyrrolidin-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester

2.2g of the product obtained in the preceding step were dissolved in a sealed tube using 1.46g pyrrolidine and 25ml EtOH. The reaction medium is heated at 75 ℃ for 18 h. After concentration to dryness, dissolved with water, extracted with DCM, dried and concentrated to yield 2.9g of the desired product.

And step 3: 4-pyrrolidin-1-ylmethyl-piperidin-4-ol dihydrochloride

2.9g of the above product was stirred in a dioxane/MeOH mixture (50ml) in the presence of 4M HCl solution (in dioxane) at ambient temperature for 4 h. Concentrated under vacuum and triturated in isopropyl ether, the solid was filtered off and used as such for the coupling reaction with sulfonyl chloride.

Example 1: [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - [4- (4-methylamino-piperidine-1-sulfonyl) phenyl ] amine

Stage 1：{1-[4- (4-chloro-pyrimidin-2-ylamino) -benzenesulfonyl]-piperidin-4-yl } -methyl-carbamic acid tert-butyl ester:

2.114g of the amine from Process 2a, followed by 13.74ml of DIPEA were added to a solution of 3g of the compound from Process 1a in 90ml of DCM. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction medium was washed with a 10% Na2CO3 solution and then with a saturated solution of NaCl, and dried using MgSO 4. After filtration and concentration, 3.5g of the expected product are obtained.

Stage 2: 1-tert-butoxy-1- [ (1- {4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino-)]Benzenesulfonyl } piperidin-4-yl) -methyl-amino]Ethanol:

3.55g of the product obtained in stage 1 were reacted with 1.524g of 4-fluorophenylboronic acid in the presence of 268mg of tris (tricyclohexylphosphine) palladium and 35ml of a 10% Na2CO3 solution in 70ml of dioxane. After the reaction overnight, the reaction medium is worked up according to the usual workup of the Suzuki reaction. After chromatography on a silica column (eluent: DCM/MeOH: 9/1), 1.77g of the expected product is obtained.

Stage 3: [4- (4-fluoro-phenyl) pyrimidin-2-yl][4- (4-methylamino-piperidine-1-sulfonyl) -phenyl]Amines as pesticides

The product obtained in stage 2 (1.77g) was taken up in MeOH, then a large amount of 2N HCl solution in dioxane was added. After reacting overnight, the crude reaction product was concentrated to dryness and then dissolved in AcOEt/NaOH (1N) mixture. The aqueous phase was extracted with AcOEt. After drying with MgSO4, concentration in vacuo gave 1.3g of the expected product.

MH+＝442.2

Melting point 202.9 ℃ (isopropyl ether/dichloromethane)

¹H NMR(DMSO)：

1.29(m，2)，1.80(dd，2)，2.17(s，3)，2.27(m，1)，2.47(t，2)，3.36(d，2)，7.42(t，2)，7.55(d，1)，7.69(d，2)，8.10(d，2)，8.29(dd，2)，8.65(d，1)，10.26(s，1)。

The peak at 2.5ppm was assigned to DMSO-D6(NMR solvent)

The peak at 3.33ppm was assigned to DOH.

Example 2: [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - (4- {4- [ (2-methanesulfonyl-ethyl) -methyl-amino ] piperidine-1-sulfonyl } phenyl) amine

400mg of the product from example 1 are dissolved in 18ml of methanol containing 0.38ml of TEA. 144mg of methanesulfonyl-ethene were added and the reaction medium was stirred overnight. The reaction medium is concentrated to dryness. The crude product was triturated in isopropanol and filtered. 420mg of the expected product are thus obtained.

MH+＝548.1

Melting point 166.5 ℃ (isopropyl ether/dichloromethane).

¹H NMR(DMSO)：

1.47(qd，2)，1.70(dd，2)，2.12(s，3)，2.26(t，2)，2.34(m，1)，2.76(t，2)，2.93(s，3)，3.17(t，2)，3.62(d，2)，7.42(t，2)，7.56(d，1)，7.70(d，2)，8.11(d，2)，8.29(dd，2)，8.66(d，1)，10.30(s，1)。

The peak at 2.5ppm was assigned to DMSO-D6(NMR solvent).

The peak at 3.33ppm was assigned to DOH.

Example 3: [4- (4-fluoro-phenyl) pyrimidin-2-yl ] - (4- {4- [ (1H-imidazol-2-ylmethyl) -methyl-amino ] piperidine-1-sulfonyl } phenyl) amine

400mg of the product obtained in example 1 are reacted in the presence of 105mg of 1H-imidazole-2-carbaldehyde and 384mg of NaBH (Oac)3 in 20ml of methanol. The reaction mixture was stirred at 70 ℃ for 1 h. In conventional processing and spectral separation on a SiO2 column [ gradient: DCM then DCM/MeOH (2%) ] to obtain the desired product.

MH+＝522.1

Melting point 140 ℃ (isopropyl ether/dichloromethane)

¹H NMR(DMSO)：

1.49(qd，2)，1.80(d，2)，2.08(s，3)，2.20(t，2)，2.27(m，1)，3.54(s，2)，3.64(m，2)，6.73(s，1)，6.95(s，1)，7.41(t，2)，7.55(d，1)，7.68(d，2)，8.09(d，2)，8.28(dd，2)，8.64(d，1)，10.2(s，1)，11.7(sl，1)。

The peak at 2.5ppm was assigned to DMSO-D6(NMR solvent).

The peak at 3.33ppm was assigned to DOH.

Example 4: 4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino ] -N-methyl-N-piperidin-4-yl-benzenesulfonamide

Stage 1: 4- { [4- (4-chloro-pyrimidin-2-ylamino) benzenesulfonyl]-methyl-amino } piperidine-1-carboxylic acid tert-butyl ester

Starting from 7g of the compound from process 1a and 4.932g of 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester according to the process described in stage 1 of process 2, 8.8g of the expected product are obtained.

Stage 2: 4- ({4- [4- (4-fluoro-phenyl) pyrimidin-2-ylaminoBase of]Benzenesulfonyl } -methyl-amino) piperidine-1-carboxylic acid tert-butyl ester

Starting from 2g of the compound obtained in stage 1 and 872mg of 4-fluorophenylboronic acid according to the procedure for stage 2 of process 2, 1.8g of the expected product are obtained.

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

By the same decarboxylation reaction as the reaction described in stage 3 of process 2, using 1.8g of compound from stage 2, 744mg of the desired product was obtained.

MH+＝442.2

Melting point 115.6 ℃ (isopropyl ether/dichloromethane)

Example 5: n- (2-amino-ethyl) -N- (1-benzyl-piperidin-4-yl) -4- [4- (4-fluoro-phenyl) -pyrimidin-2-ylamino ] -benzenesulfonamide

Stage 1: (2- { (1-benzyl-piperidin-4-yl) - [4- (4-chloro-pyrimidin-2-ylamino) benzenesulfonyl]Amino } ethyl) carbamic acid tert-butyl ester

Starting with 5.98g of the compound from process 1a and 6.55g of tert-butyl [2- (1-benzyl-piperidin-4-ylamino) ethyl ] carbamate according to the process described in stage 1 of process 2, 2.76g of the expected product are obtained.

Stage 2: [2- ((1-benzyl-piperidin-4-yl) {4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino ]]Benzenesulfonyl } amino) ethyl]Carbamic acid tert-butyl ester

Starting with 710mg of the compound obtained in stage 1 and 248mg of 4-fluorophenylboronic acid according to the procedure of stage 2 of process 2, 668mg of the expected product are obtained.

Stage 3: n- (2-amino-ethyl) -N- (1-benzyl-piperidin-4-yl) -4- [4- (4-fluoro-phenyl) -pyrimidin-2-ylamino]Benzenesulfonamides

By the same decarboxylation reaction as described in stage 3 of process 2, using 250mg of the compound from stage 2, 172mg of the desired product is obtained.

MH+＝561.2

Melting point 194.4 ℃ (isopropyl ether/dichloromethane)

¹H NMR(DMSO)：

1.34-1.76 (unresolved peak, 2), 2-2.4 (unresolved peak, 2), 3.03(m, 4), 3.31(m, 4), 3.65-4.16 (unresolved peak, 1), 4.10-4.88(s, 2), 6.60(d, 1), 7.27(t, 2), 7.43(m, 2), 7.56-7.70(dd, 3), 7.82(m, 4), 8.18(d, 1), 8.20-8.50 (unresolved peak, 3), 11.00(sl, 3).

Example 6: n- (2-amino-ethyl) -4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino ] -N-piperidin-4-yl-benzenesulfonamide

Stage 1: [2- ({4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino ]]-benzenesulfonyl } -piperidin-4-yl-amino) ethyl]Carbamic acid tert-butyl ester

Using 250mg of the compound obtained in stage 1 of example 5, this compound was reacted by hydrogenolysis in the presence of 50mg of ammonium formate and 20mg of Pd/C using 3ml of MeOH in a microwave reactor (250W; 80 ℃ C.; up to 5 min). 90mg of the expected product are thus obtained.

Stage 2: n- (2-amino-ethyl) -4- [4- (4-fluoro-phenyl) pyrimidin-2-ylamino]-N-piperidin-4-yl-benzenesulfonamides

By the same decarboxylation reaction as described in stage 3 of process 2, using 90mg of the compound from stage 1, 22mg of the desired product was obtained.

MH+＝471.1

¹H NMR(DMSO)：

1.56(m, 2), 1.82(m, 2), 2.68-4.21 (unresolved peak, 9), 6.50(d, 1), 7.16(t, 1), 7.40(m, 1), 7.55(m, 1), 7.90(s, 4), 8.03-8.2(dl, 4), 8.9(sl, 2), 10.60-11.25(sl, 2).

Examples 7 to 31

The following products (25 compounds in the table below which constitute examples 7 to 31 of the invention) are obtained by modifying the method according to the following operating procedure in the same way as example 2 [ reaction of the sulfonamide of example 1 with a commercially available aldehyde (or ketone) ]:

a solution of 0.12mmol of aldehyde in 1.0ml of THF and 0.3ml of AcOH was added to 0.10mmol of the product from Process 2 in 2.0ml of THF. Finally, 128mg of polymer carrying CNBH3 were added and the mixture was stirred at ambient temperature under argon atmosphere overnight. The reaction mixture was filtered and the filtrate was washed with 5ml THF and concentrated under vacuum. The crude reaction product was dissolved in 2ml DMF and purified by preparative HPLC to give the desired product, which is described as the trifluoroacetate salt.

Examples 32-47 were synthesized according to the procedure described in stage 2 of example 1 using the compound of procedure 3a (below) and the corresponding boronic acid.

Process 3a: 1- [4- (4-chloro-pyrimidin-2-ylamino) benzenesulfonyl]-4-pyrrolidin-1-ylmethyl-piperidin-4-ol

Using 3.8g of the compound obtained in stage 4 of process 1a and 3.2134g of the amine obtained in process 2b, 5.15g of the desired product (91% purity) were obtained according to the method described in stage 1 of example 1.

MH+＝452.1

Examples 48-69 were synthesized according to the procedure described in stage 2 of example 1, using the compounds of Process 3b or Process 3c (infra) and the corresponding boronic acids.

Process 3b: (4- {4- [ amino-R- (4-fluoro-phenyl) methyl]Piperidin-1-sulfonyl } phenyl) (4-chloropyrimidin-2-yl) amines

From 2.5g of the compound obtained in stage 4 of process 1a and 2.15g R- (4-fluorophenyl) (piperidin-4-yl) methylamine according to the process described in stage 1 of example 1, 1.8g of the expected product are obtained.

MH+＝476.0

Process 3c: (4- {4- [ amino-S- (4-fluoro-phenyl) methyl]Piperidine-1-sulfonyl } phenyl) - (4-chloropyrimidin-2-yl) amine

Using 2.5g of the compound obtained in stage 4 of process 1a and 2.15g S- (4-fluorophenyl) (piperidin-4-yl) methylamine according to the method described in stage 1 of example 1, 2g of the expected product is obtained.

MH+＝476.0

Example 70: pharmaceutical composition

Tablets corresponding to the following formulation were prepared:

.

As many as 1g of excipients for a tablet

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

Example 2 is taken as an example in the preparation of the medicament constituting example 32 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 of viable cells to convert MTS into a colored compound (capacit mitochondral ability) 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

R represents a hydrogen atom or a halogen atom;

r2, R3 and R4, identical or different, are chosen from hydrogen atoms, halogen atoms, CN, ONH2, CONH alkyl and CON (alkyl) 2 groups and alkyl and alkoxy groups, themselves optionally substituted by one or more halogen atoms or CN, ONH2, CONH alkyl, CON (alkyl) 2, OH or OCH3 groups, with the understanding that 1 or 2 of R2, R3 and R4 represent a hydrogen atom or R2, R3 and R4 all represent three methoxy groups;

r5 represents a hydrogen atom or a halogen atom;

z represents CO or SO 2;

-N (D) (W) is such that:

a) or W represents a-ring (Y) group

ring (Y) is monocyclic OR bicyclic, is composed 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 NR10, C ═ O, OR its dioxolane as a protecting group for carbonyl functions, CF2, CH-OR8, OR CH-NR8R 9;

r10 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 hydroxyl, alkoxy, aryl and heteroaryl groups, the alkyl group represented by R10 being optionally additionally substituted by hydroxyl, NR8R9, CONR8R9, phosphonate, alkylthio or heterocycloalkyl groups optionally oxidized to sulfone, all aryl, heteroaryl and heterocycloalkyl groups being optionally substituted;

Substituted on the same carbon atom by R1 and R6, contain 4 to 7 mer, are saturated and may additionally include a carbon bridge consisting of 1 to 3 carbons;

ii) R1 represents-X2-R7, wherein X2 represents:

r6 represents hydrogen or methyl;

it is understood that when W represents a hydrogen atom, then z represents CO;

v) R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen;

and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;

wherein n, n1 and n2, which are the same or different, represent an integer of 0 to 3;

m represents an integer of 1 to 3;

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

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 additional heteroatoms selected from O, S, N or NRc, the cyclic amine so formed being itself optionally substituted;

all of the above aryl, naphthyl, phenyl, heterocyclyl, heterocycloalkyl and heteroaryl groups as well as the 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: a halogen atom; a hydroxyl group; a cyano group; NR8R 9; and alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, which are themselves optionally substituted by one or more identical or different groups selected from: a halogen atom and a hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF3, OCF3, or NRaRb group;

2. A product of formula (I) as defined in claim 1, wherein the R2, R3, R4, R5, z and-n (d) (w) groups have the meanings indicated in any one of the other claims, R represents a halogen atom;

3. A product of formula (I) as defined in claim 1, wherein the R2, R3, R4, R5, z and-n (d) (w) groups have the meanings indicated in any of the other claims, R represents a hydrogen atom;

4. A product of formula (I) as defined in claim 1, wherein the R, R5, z and-n (d) (w) groups have the meaning indicated in any one of the other claims, R2, R3 and R4, identical or different, are selected from hydrogen atoms, halogen atoms, CN groups and alkyl and alkoxy groups which are themselves optionally substituted by one or more halogen atoms or CN, CONH2, CONH alkyl or CON (alkyl) 2 groups, with the understanding that 1 or 2 of R2, R3 and R4 represent a hydrogen atom, or R2, R3 and R4 all represent three methoxy groups;

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

r has the meaning indicated in any of the other claims,

r5 represents a hydrogen atom or a halogen atom;

z represents CO or SO 2;

and-N (D) (W) groups are as follows:

a) or W represents a ring (Y) group

ring (Y) is monocyclic OR bicyclic, is composed 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 by 1 OR 2 oxygen atoms, OR a group selected from NR10, C ═ O OR its dioxolane as carbonyl function protecting group, CF2, CH-OR8 OR CH-NR8R 9;

r10 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 hydroxyl, alkoxy, aryl and heteroaryl groups, the alkyl group represented by R10 being optionally additionally substituted by hydroxyl, NR8R9, CONR8R9, phosphonate, alkylthio or heterocycloalkyl groups optionally oxidized to sulfone, all said aryl, heteroaryl and heterocycloalkyl groups being optionally substituted;

r6 represents a hydrogen atom or a hydroxyl, - (CH2) mOH, -CO-NRaRb, -CH2-Nrarb, -CO2H and-CO 2 alkyl group;

ii) R1 represents-X2-R7, wherein X2 represents:

r6 represents hydrogen;

it is understood that when W represents a hydrogen atom, then z represents CO;

v) R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen;

m represents an integer of 1 to 3;

r8 represents a hydrogen atom or an alkyl, cycloalkyl or heterocycloalkyl group, which is itself optionally substituted by one or more groups selected from: halogen atoms and hydroxyl, 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 a phosphonate group, an alkylthio group optionally oxidized to a sulfone, or by an optionally substituted aryl group or by an optionally substituted saturated or unsaturated heterocyclic group;

all of the above aryl, naphthyl, phenyl, heterocyclyl, heterocycloalkyl and heteroaryl groups as well as the 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: a halogen atom; a hydroxyl group; a cyano group; an NR8R9 group; and alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, which are themselves optionally substituted by one or more identical or different groups selected from: a halogen atom and a hydroxyl, alkoxy, alkyl, hydroxyalkyl, alkoxyalkyl, CN, CF3, OCF3, or NRaRb group;

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

wherein R, R2, R3, R4, R5, z, D and ring (Y) have the meanings as indicated in any of the other claims,

7. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IA) wherein R2, R3, R4, R5 and z have the meanings as indicated in any one of the other claims, D represents a hydrogen atom or a linear or branched alkyl group containing from 1 to 4 carbon atoms, optionally substituted by NH2, in particular CH3, the ring (Y) being such as: y represents NR10, wherein R10 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted by a group selected from: halogen atoms and hydroxyl, 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 other claims,

8. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IA) wherein R, R2, R3, R4, R5 and z have the meanings as indicated in any one of the other claims,

d represents a linear or branched alkyl group containing from 1 to 4 carbon atoms, optionally substituted with NH2, in particular CH3, ring (Y) being such as: y represents NR8R9, wherein R8 represents a hydrogen atom or an alkyl group, R9 represents a linear or branched alkyl group containing 1 to 6 carbon atoms, optionally substituted by a group selected from: halogen atoms and hydroxyl, 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 other claims,

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

wherein R, R1, R2, R3, R4, R5, R6, z and ring (N) have the meanings as indicated in any of the other claims,

10. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IB), wherein R has the meaning as indicated in any one of the other claims; r2, R3 and R4, identical or different, are such as: 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;

z represents CO or SO 2;

ring (N) is

Substituted on the same carbon atom by R1 and R6, containing 4 to 7 mer, being saturated and may additionally comprise a carbon bridge consisting of 1 to 3 carbons, wherein R1 and R6 are as defined in claim 1.

11. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated in any one of the other claims, and R1 and R6 are as follows: r1 represents-X1-R7, wherein X1 represents- (CH2) m-and R7 represents a heterocycloalkyl, aryl or heteroaryl ring, all optionally substituted;

wherein m, n and NRaRb are as defined above or below and the heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one or more identical or different groups as defined in any one of the other claims,

12. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated in any one of the other claims, R1 and R6 are as: r1 represents-X2-R7, wherein X2 represents:

r6 represents hydrogen;

wherein n, n1, n2, Rc and NRaRb are as defined in any one of the other claims, said heterocycloalkyl, aryl and heteroaryl groups being optionally substituted by one or more identical or different radicals as defined in any one of the other claims,

13. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated in any one of the other claims, and R1 and R6 are as follows:

or R1 represents or-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, which is linear or branched from 3 carbon atoms, and is optionally substituted by a group selected from: -PO (OEt)2, -OH, -O-alkyl, -CF3, -CO-NR8R9 and SO 2-alkyl, and R6 represents hydrogen; it is understood that when W represents a hydrogen atom, then z represents CO;

or R1 represents-CH 2-NRc-W, wherein W represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, which is linear or branched from 3 carbon atoms, and is optionally substituted by a group selected from: -PO (OEt)2, -OH, -OEt, -CF3, -CO-N (alkyl) 2, and SO 2-alkyl;

and R6 represents hydrogen;

OR R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen,

wherein Rc, R' c and NR8R9 are as defined in any one of the other claims,

14. A product of formula (I) as defined in any one of the other claims corresponding to formula (IA) wherein:

r has the meaning as indicated in any of the other claims,

r5 represents a hydrogen atom or a halogen atom;

ring (Y) is monocyclic OR bicyclic, is composed 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 NR10, C-O, CF2, CH-OR8 OR CH-NR8R 9;

r10 represents a hydrogen atom or an alkyl group optionally substituted by one or more identical or different groups selected from: halogen atoms, hydroxyl groups, alkoxy groups, phenyl groups and heteroaryl groups, which 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;

said heteroaryl group is composed of 5-7 mer and comprises 1-3 heteroatoms selected from O, S, N and NRc;

NR8R9 is such as: or R8 and R9, the same 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 possible second atom by alkyl which is itself optionally substituted by one or more identical or different groups chosen from halogen atoms and hydroxyl groups;

15. A product of formula (I) as defined in any one of the other claims corresponding to formula (IA) wherein:

r has the meaning indicated in any of the other claims,

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

z represents SO2 or CO;

ring (Y) is selected from cyclohexyl, itself optionally substituted with amino; a tetrahydropyranyl group; dioxythienyl; and pyrrolidinyl, piperidinyl and azepinylOptionally substituted on its nitrogen atom with: 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, and phenyl, quinolinyl, pyridyl, thienyl, thiazolyl, thiadiazolyl, tetrazolyl, pyrazinyl, furyl and imidazolyl, optionally oxidized at the nitrogen atom thereof, these latter cyclic groups themselves being optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxy, methyl and methoxy groups;

16. A product of formula (I) as defined in any one of the other claims corresponding to formula (IA) wherein: r has the meaning as indicated in any of the other claims,

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

r5 represents a hydrogen atom;

the ring comprising Y represents cyclohexyl, optionally substituted by amino, or piperidinyl, optionally substituted on its nitrogen atom by: methyl, propyl, butyl, isopropyl, isobutyl, isoamyl or ethyl, these substituents being themselves optionally substituted by one or more halogen atoms or 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; a furyl group; and imidazolyl which is itself optionally substituted by alkyl;

17. A product of formula (I) as defined in any one of the other claims corresponding to formula (IA) wherein:

r has the meaning as indicated in any of the other claims,

r5 represents a hydrogen atom;

ring (Y) is selected from tetrahydropyranyl, dioxythiophenyl and pyrrolidinyl, piperidinyl and azaOptionally substituted at its nitrogen atom (in ring position 2 or 3) with: methyl or ethyl, propyl or butyl, which are themselves optionally substituted by one or more halogen atoms, or phenyl, pyridyl, thienyl, thiazolyl, thiadiazolyl, pyrazinyl, furyl or imidazolyl;

18. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IB), wherein R, R2, R3, R4, R5 and z have the meanings indicated in any one of the other claims and ring (N) represents one of the rings defined below:

-8-azabicyclo [3.2.1] octan-3-yl, 6-azabicyclo [3.2.1] octan-3-yl or 3-azabicyclo [3.2.1] octan-8-yl) ring;

19. A product of formula (I) as defined in any one of the other claims corresponding to formula (IB) wherein R, R2, R3, R4, R5 and z have the meanings as indicated in any one of the other claims and ring (N) represents a pyrrolidinyl ring substituted in position 3 with R1 and R6 as defined above or below or a piperidinyl ring substituted in position 3 or 4 with R1 and R6 as defined in any one of the other claims,

20. A product of formula (I) as defined above or below wherein:

r has the meaning as indicated in any of the other claims,

r5 represents a hydrogen atom or a halogen atom;

z represents CO or SO 2;

ring (N), i.e

ii) R1 represents-X2-R7, wherein X2 represents:

and R6 represents hydrogen;

v) R1 represents-CO-N (Rc) -OR' c and R6 represents hydrogen;

all heterocycloalkyl, phenyl and heteroaryl groups are optionally substituted by one or more identical or different groups selected from: a halogen atom; a hydroxyl group; a cyano group; an NR8R9 group; and alkyl, cycloalkyl, alkoxy, phenyl, heterocycloalkyl and heteroaryl, which are themselves optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxy, alkoxy, OCF3, CH3, -CH2OH, CN, CF3, OCF3 or NRaRb groups;

NR8R9 is such as: or R8 and R9, the same or different, are such as: r8 represents a hydrogen atom, a linear or branched alkyl group containing up to 4 carbon atoms or a cycloalkyl group containing 3 to 6 mer, the alkyl and cycloalkyl groups themselves being optionally substituted by one or more halogen atoms or hydroxyl groups; r9 represents a hydrogen atom or an alkyl group, optionally substituted by one or more identical or different groups selected from: halogen atoms and hydroxyl, alkoxy, NH2, NH alkyl, N (alkyl) 2, phenyl, heterocycloalkyl or heteroaryl groups, which are themselves optionally substituted by one or more groups selected from: halogen atoms and hydroxyl, OCH3, CH3, -CH2OH, CN, CF3, OCF3, NH2, NH alkyl or N (alkyl) 2 groups; or R8 and R9 together with the nitrogen atom to which they are attached form a cyclic amine selected from: pyrrolyl, piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl and piperazinyl optionally substituted with one or more alkyl groups which are themselves optionally substituted with one or more halogen atoms;

21. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated in any one of the other claims, and R1 and R6 are as follows:

or R1 represents-X2-R7, wherein X represents:

-O-, -CHOH-, -CH (OH) -CH2-, -CO-, -CHNH2-, -NH-CH2-, -N (CH3) -CH 2-and CH2-NH-CH 2-; and R6 represents hydrogen;

22. A product of formula (I) as defined in any one of the other claims, corresponding to formula (IB), wherein R, R2, R3, R4, R5, z and ring (N) have the meanings as indicated in any one of the claims, and R1 and R6 are as: or R1 represents-X1-R7, wherein X1 represents-CH 2-and R6 represents a hydrogen atom or a hydroxyl group, CH2-OH, -CO-N (CH3)2, -CO-NHCH3, -CO-NH- (CH2)2-N (CH3)2 and-CO 2Et groups; or R1 represents-X2-R7, wherein X2 represents:

23. A product of formula (I) as defined above, wherein R, R1, R5, R6, z, D, W, ring (Y) and ring (N) have the meaning as indicated in any of the other claims; r2, R3 and R4, identical or different, are such as: one of which represents a halogen atom and the other two, identical or different, represent a hydrogen atom, a halogen atom or a methyl, methoxy, trifluoromethyl or trifluoromethoxy group;

r5 represents a hydrogen atom;

24. A product of formula (I) as defined above wherein R, R1, R6, z, D, W, ring (Y) and ring (N) have the meanings indicated in any of the other claims, and R2, R3 and R4, which are identical or different, are as follows: one of which represents a fluorine atom and the other two, which are the same or different, represent a hydrogen atom, a fluorine atom or a methyl group;

r5 represents a hydrogen atom;

25. The product of formula (I) as defined above, wherein R, R1, R2, R3, R4, R5, R6, W, D, ring (Y) and ring (N) have the meanings as indicated in any of the other claims, z represents SO2, said product of formula (I) being in all possible racemic, enantiomeric and diastereomeric isomeric forms, and addition salts of said product of formula (I) with inorganic and organic acids.

26. The product of formula (I) as defined above, wherein R, R1, R2, R3, R4, R5, R6, W, D, ring (Y) and ring (N) have the meanings as indicated in any of the other claims, z represents CO, in all possible racemic, enantiomeric and diastereomeric isomeric forms, and addition salts of the product of formula (I) with inorganic and organic acids.

27. A product of formula (I) as defined above, corresponding to the following name:

- [4- (4-fluoro-phenyl) -pyrimidin-2-yl ] - (4- {4- [ (2-methanesulfonyl-ethyl) -methyl-amino ] piperidine-1-sulfonyl } -phenyl) -amine

- [4- (4-fluoro-phenyl) -pyrimidin-2-yl ] - (4- {4- [ (1H-imidazol-2-ylmethyl) -methyl-amino ] piperidine-1-sulfonyl } -phenyl) -amine

-N- (2-amino-ethyl) -4- [4- (4-fluoro-phenyl) -pyrimidin-2-ylamino ] -N-piperidin-4-yl-benzenesulfonamide

- [4- (4-fluoro-phenyl) -pyrimidin-2-yl ] - {4- [4- (methyl-pyridin-2-ylmethyl-amino) piperidine-1-sulfonyl ] -phenyl } -amine

- [4- (4-fluoro-phenyl) -pyrimidin-2-yl ] - (4- {4- [ methyl- (3-methyl-thiophen-2-ylmethyl) -amino ] piperidine-1-sulfonyl } -phenyl) -amine

- [4- (4-fluoro-phenyl) -pyrimidin-2-yl ] - {4- [4- (methyl-quinolin-8-ylmethyl-amino) piperidine-1-sulfonyl ] -phenyl } -amine

28. A process for the preparation of a product of formula (I) as defined in any one of the other claims, characterized in that a product of formula (II):

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

conversion to the product of formula (III):

wherein R5' has the meaning as indicated above,

reacting the product of formula (III) with an aniline of formula (IV):

to obtain a product of formula (V):

wherein R5' has the meaning as indicated above,

converting the product of formula (V) to a product of formula (VI):

wherein R5' has the meaning as indicated above,

reacting the product of formula (VII)

Or with an amine of formula (VIII) 1:

to obtain a product of formula (IX) a 1:

wherein R5 ', D' and Y have the meanings indicated above,

or with an amine of formula (VIII) 2:

wherein R1 'and R6' have the meanings indicated in any of the preceding claims for R1 and R6, respectively, wherein possible reactive functions are optionally protected by protecting groups,

to obtain a product of formula (IX) a 2:

wherein R1 ', R5 ' and R6 ' have the meanings indicated above,

to obtain the product of formula (IA)1 separately

Wherein R2 ', R3 ', R4 ', R5 ', D ' and Y have the meanings indicated above,

or a product of formula (IA) 2:

wherein R1 ', R2, R3, R4, R5 and R6' have the meanings indicated above,

pathway b)Reacting the product of formula (III) as defined above with methyl 4-aminobenzoate to obtain a product of formula (XI):

wherein R5' has the meaning as indicated above,

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

reacting the product of formula (XIII):

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

wherein R1 ', R2', R3 ', R4', R5 'and R6' have the meanings indicated above,

said products of formulae (IA)1, (IA)2, (IB)1 and (IB)2, which may be products of formula (I) wherein z represents SO2 or CO respectively, and which, in order to obtain products of formula (I) or other products of formula (I), may be subjected, if desired and if necessary, in any order to one or more of the following conversion reactions:

29. A process for the preparation of a product of formula (I) corresponding to formula (IA) as defined in any one of the other claims, wherein Y represents a NR10 group as indicated in any one of the preceding claims, while R10 represents CH2-RZ and RZ represents alkyl, alkenyl or alkynyl, all optionally substituted 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,

the process is characterized by reacting a compound of formula (XIV):

wherein R1 ', R2, R3, R4 and R5 have the meanings indicated above, and D' has the meaning indicated for D in any of the other claims, wherein possible reactive functions are optionally protected with protecting groups,

RZ’-CR8’O (XVI)

wherein RZ 'and R8' have the meanings indicated in any one of the other claims for RZ and R8, respectively, wherein possible reactive functions are optionally protected by protecting groups to obtain the product of formula (IA):

wherein R2, R3 ', R4', R5 ', z, D', R8 'and RZ' have the meanings indicated above,

the product of formula (IA), which may be a product of formula (I), and, if desired and necessary, may be subjected to one or more of the conversion reactions a) to f) as defined above, in any order, in order to obtain a product of formula (I) or a further product of formula (I),

30. A product of formula (I) as defined in any one of claims 1 to 23 and addition salts of said product of formula (I) with pharmaceutically acceptable inorganic and organic acids as a medicament.

31. A product of formula (I) as defined in claim 23 having the following name as a medicament:

- [4- (4-fluoro-phenyl) -pyrimidin-2-yl ] - {4- [4- (methyl-quinolin-8-ylmethyl-amino) piperidine-1-sulfonyl ] -phenyl } -amine,

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

32. A pharmaceutical composition comprising as active ingredient at least one of the products of formula (I) as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt of such a product or a prodrug of such a product, and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition comprising as active ingredient at least one of the products of formula (I) as defined in claim 27 or a pharmaceutically acceptable salt of such a product or a prodrug of such a product together with a pharmaceutically acceptable carrier.

34. Use of a product of formula (I) as defined in any one of claims 1 to 27 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.

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

36. Use of a product of formula (I) as defined in any one of claims 1 to 27 for the preparation of a medicament for the treatment or prevention of a disease selected from the following classes: inflammatory diseases, diabetes and cancer.

37. Use of a product of formula (I) as defined in any one of claims 1 to 27 for the preparation of a medicament for the treatment or prevention of an inflammatory disease.

38. Use of a product of formula (I) as defined in any one of claims 1 to 27 for the preparation of a medicament for the treatment or prevention of diabetes.

39. Use of a product of formula (I) as defined in any one of claims 1 to 27 for the preparation of a medicament for the treatment of cancer.

40. Use according to claim 34 for the treatment of solid or non-solid tumours.

41. The use according to claim 40 or 41 for the treatment of cancer against cytotoxic agents.

42. Use of a product of formula (I) as defined in any one of claims 1 to 27 for the preparation of a medicament for use in cancer chemotherapy.

43. Use of a product of formula (I) as defined in any one of claims 1 to 27 for the preparation of a medicament for use in cancer chemotherapy, alone or in combination.

44. A product of formula (I) as defined in any one of claims 1 to 27 as an IKK inhibitor.