EP3189061A1

EP3189061A1 - Derivatives of macrocyclic n-aryl-tricyclopyrimidine-2-amine polyethers as inhibitors of ftl3 and jak

Info

Publication number: EP3189061A1
Application number: EP15757491.4A
Authority: EP
Inventors: El Bachir Kaloun; Serge Grisoni; Anna Kruczynski; Philippe Schmitt
Original assignee: Pierre Fabre Medicament SA
Current assignee: Pierre Fabre Medicament SA
Priority date: 2014-09-02
Filing date: 2015-09-02
Publication date: 2017-07-12
Also published as: FR3025200A1; CN106715445B; BR112017003880A2; US20170283432A1; US10323043B2; CN106715445A; WO2016034637A1; RU2017108937A; FR3025200B1; MX2017002747A; RU2017108937A3; JP2017525733A

Abstract

The present invention relates to a compound with the following formula (I): (I) or a salt and/or a pharmaceutically acceptable solvate thereof, in particular for use as a drug, in particular in the treatment of cancer, as well as to the pharmaceutical compositions that contain same and to the methods for preparing same.

Description

MACROCYCLIC POLYETHERS N-ARYL-TRICYCLOPYRIMIDINE-2-AMINE DERIVATIVES AS INHIBITORS OF FTL3 AND JAK

The present invention relates to macrocyclic N-aryl-tricyclopyrimidine-2-amine polyethers derivatives, as well as their therapeutic use, especially in the treatment of cancer, and their methods of synthesis.

Mutations of receptors with tyrosine kinase activity play a crucial role in the pathogenesis of many cancers. For example, the FLT3 receptor is frequently mutated in acute myeloid leukemia (in about 30% of cases) (Gilliland et al., 2002 Blood 100: 1532-1542). Mutations that result in increased FLT3 receptor kinase activity make the tumor cell relatively dependent on this receptor for proliferation and survival, making this mutated receptor a relevant target in oncology. Three types of activating mutations of FLT3 are identified today in acute myeloid leukemia (AML): tandem internal duplication (FLT3-ITD), which is detected in about 20% of cases, point mutations in the catalytic domain of the receptor , which constitute 6-8% of cases, and point mutations of juxtamembranous and extracellular domains, which are rare (2%) (Kayser et al., 2014 Leukemia & Lymphoma 55: 243-255).

The new generations of FLT3 inhibitors undergoing clinical evaluation have shown encouraging results for the treatment of AML expressing a mutated form of FLT3. However, most patient responses are still inadequate because they are incomplete and transient, resulting in a relapse rate that remains too high. The causes of these relapses / resistances are multiple. They may involve secondary mutations of the FLT3 receptor or the activation of alternative signaling pathways that lead to reactivation downstream of the FLT3 receptor pathway. On the other hand, while leukemic cells circulating in the patient's blood may be relatively sensitive to tyrosine kinase inhibitors, leukemic cells nested in the patient's marrow are more refractory to treatment, suggesting a role for the bone marrow (micro -environment) in therapeutic resistance (Weisberg et al., 2012 Leukemia 26: 2233-2244). This stromal microenvironment of leukemic cells, consisting of the bone marrow, would protect leukemic cells from the effects of tyrosine kinase inhibitors. The I-6 / J AK / STAT signaling pathway is one of the major routes that would contribute to confer a survival advantage to leukemic cells expressing a mutated form of FLT3. In addition, the therapeutic combination of a JAK inhibitor and an FLT3 inhibitor has been shown to increase the effects of FLT3 inhibition and to overcome the resistance induced by the stromal microenvironment (Weisberg et al op cit). In general, the JAK kinase family is described as playing an important role in controlling the proliferation of cell survival and apoptosis. These JAK kinases are subject to genetic alterations associated with numerous tumoral pathologies, including malignant hemopathies.

The present invention has surprisingly enabled compounds with dual activity to be identified as both an inhibitor of JAK and FLT3. These compounds also have a remarkable activity.

The present invention therefore more particularly relates to a compound of general formula (I) below:

or a pharmaceutically acceptable salt and / or solvate thereof,

in which :

W represents an oxygen or sulfur atom,

X represents a hydrocarbon chain, saturated or unsaturated, comprising 1 to 3 carbon atoms, optionally substituted by one or more groups chosen from a halogen atom, a group (CrC ₆ ) alkyl, oxo (= O), OH and ( d- C ₆ ) alkoxy, one or more, especially 1 or 2, carbon atoms of said chain being optionally each replaced, independently of each other, by an oxygen or sulfur atom,

Y represents a nitrogen atom or a CRy group with Ry representing a hydrogen atom, a halogen atom, a (CrC ₆ ) alkyl group, (C C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) haloalkoxy, OH, CN, NO ₂ , NR ₁₂ R ₁₃ , CO ₂ H or CO ₂ ((C ₁ -C ₆ ) alkyl),

Q represents a single, double or triple bond, an oxygen or sulfur atom, or a (C ₁ -C ₆ ) alkyl, S (O) or S (O) _{2 group} ,

A ₁ and A ₂ represent, independently of one another, a single bond or a (C ₁ -C ₆ ) alkyl group optionally substituted by an OH group, or and A ₂ form with Q and the carbon atoms attached to Q a carbocycle or optionally substituted monocyclic heterocycle,

R 1, R ₂ , R 3, R ₄ , R ₅ , R 6, R 7, and R ₈ represent, independently of one another, a hydrogen atom or a (C ₁ -C ₆ ) alkyl group,

R ₉ and R ₁₀ represent, independently of one another, a hydrogen atom, a halogen atom, an optionally substituted (CrC ₆ ) alkyl, optionally substituted (C ₂ -C ₆ ) alkenyl group, ( C ₂ -C ₆ ) optionally substituted alkynyl, optionally substituted (C ₁ -C ₆ ) alkoxy, optionally substituted (C ₁ -C ₆ ) thioalkoxy, CN, NO ₂ , NR ₁₄ R ₁₅ , OH, SH, C0 ₂ R ₅₄ , CONR ₅₅ R ₅ 6 an optionally substituted carbocycle or an optionally substituted heterocycle,

R 11 represents a hydrogen atom, a halogen atom, or a (CC ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) haloalkoxy group, and

Ri2, Ri _3, R and R _15, R _54, R ₅₅ and R ₅₆ represent, independently each other, a hydrogen atom or a (CrC ₆₎ alkyl, optionally substituted (C ₂ -C ₆₎ alkenyl optionally substituted, or (C ₂ -C ₆ ) alkynyl optionally substituted, or R ₂ and R ₁₃ , and / or R and R ₁₅ and / or R 55 and R ₅₆ , independently of each other, form with the atom nitrogen which carries them an optionally substituted nitrogenous heterocycle.

The stereoisomers of the compounds of general formula (I) are also part of the present invention, as well as their mixtures, in particular in the form of a racemic mixture.

The tautomers of the compounds of general formula (I) are also part of the present invention.

For the purpose of the present invention, the term "stereoisomer" means a geometric isomer (or configuration isomer) or an optical isomer.

The geometric isomers result from the different position of the substituents on a double bond which can then have a Z or E configuration, also called cis or trans. The optical isomers result in particular from the different position in the space of the substituents on a carbon atom comprising 4 different substituents. This carbon atom then constitutes a chiral or asymmetrical center. Optical isomers include diastereoisomers and enantiomers. Optical isomers which are images of each other in a mirror but not superimposable are referred to as "enantiomers". Optical isomers that are not mirror images of each other in a mirror are referred to as "diastereoisomers".

A mixture containing equal amounts of two individual enantiomeric forms of opposite chirality is referred to as a "racemic mixture".

For the purposes of the present invention, the term "tautomer" means an isomer of constitution of the compound obtained by prototropy, ie by migration of a hydrogen atom and change of localization of a double bond. . The different tautomers of a compound are generally interconvertible and present in equilibrium in solution, in proportions that may vary depending on the solvent used, the temperature or the pH.

In the present invention, the term "pharmaceutically acceptable" is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical.

The term "pharmaceutically acceptable salt and / or solvate" is intended to mean a compound, a salt and / or solvate which is pharmaceutically acceptable, as defined herein, and which has the desired pharmacological activity of the parent compound.

Pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the invention such as those formed from organic or inorganic acids or organic or inorganic bases. By way of example, mention may be made of salts derived from inorganic acids, such as hydrochloric, hydrobromic, phosphoric and sulfuric acids, and those derived from organic acids such as acetic, trifluoroacetic, propionic, succinic, fumaric, malic or tartaric acids. citric, ascorbic, maleic, glutamic, benzoic, salicylic, toluenesulfonic, methanesulfonic, stearic, lactic. By way of example, mention may be made of salts derived from inorganic bases such as sodium hydroxide, potassium hydroxide or calcium hydroxide and salts derived from organic bases such as lysine or arginine. These salts can be synthesized from the compounds of the invention containing a basic or acidic part and the corresponding acids or bases according to conventional chemical methods.

The pharmaceutically acceptable solvates of the compounds of the present invention include conventional solvates such as those formed in the last step of preparing the compounds of the invention due to the presence of solvents. By way of example, mention may be made of solvates due to the presence of water (hydrates) or ethanol.

The term "halogen" represents a fluorine, chlorine, bromine or iodine.

For the purposes of the present invention, the term "(CrC ₆ ) alkyl" group is intended to mean a linear or branched saturated hydrocarbon-based chain containing 1 to 6, especially 1 to 4, carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, β-butyl, pentyl or hexyl groups.

By "(C ₂ -C ₆ ) alkenyl" group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, comprising at least one double bond and comprising 2 to 6, in particular 2 to 4, carbon atoms. carbon. By way of example, mention may be made of ethenyl or allyl groups.

By "(C ₂ -C ₆ ) alkynyl" group is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, comprising at least one triple bond and comprising 2 to 6, in particular 2 to 4, carbon atoms. carbon. By way of example, mention may be made of ethynyl or propynyl groups.

For the purposes of the present invention, the term "(C ₁ -C ₆ ) haloalkyl" means a (C ₁ -C ₆ ) alkyl group, as defined above, in which one or more hydrogen atoms have each been replaced by one atom. halogen as defined above. It can be in particular a CF ₃ group.

By "(C ₁ -C ₆ ) alkoxy" group is meant, within the meaning of the present invention, a (C ₁ -C ₆ ) alkyl group as defined above, linked to the remainder of the molecule through an atom of oxygen. By way of example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or even n-butoxy groups.

For the purposes of the present invention, the term "(C ₁ -C ₆ ) haloalkoxy" means a (C ₁ -C ₆ ) haloalkyl group, as defined above, linked to the remainder of the molecule via an atom of oxygen. This may include an OCF ₃ group.

For the purposes of the present invention, the term "(C ₁ -C ₆ ) thioalkoxy group" means a (C ₁ -C ₆ ) alkyl group as defined above, linked to the remainder of the molecule via a sulfur atom. . By way of example, mention may be made of groups thiomethoxy, thioethoxy, thiopropoxy, thio-isopropoxy, thiobutoxy or thio-β-butoxy.

For the purposes of the present invention, the term "(C ₁ -C ₆ ) alkyl-amino group" means a (C ₁ -C ₆ ) alkyl group, as defined above, linked to the remainder of the molecule via a NH group. By way of example, mention may be made of methylamino, ethylamino, propylamino or even butylamino groups.

By "di ((C ₁ -C ₆ ) alkyl) amino" group is meant, in the sense of the present invention, a (C ₁ -C ₆ ) alkyl group, as defined above, linked to the remainder of the molecule via a group Alk with Alk representing a group (CrC ₆ ) alkyl as defined above. By way of example, mention may be made of dimethylamino, diethylamino, methylethylamino and the like.

For the purposes of the present invention, the term "carbocycle" is intended to mean a saturated, unsaturated or aromatic hydrocarbon monocyclic or polycyclic system comprising from 3 to 12 carbon atoms. The polycyclic system comprises at least 2, in particular 2 or 3, rings. contiguous or decked. Each cycle of the monocyclic or polycyclic system advantageously comprises 3 to 8, in particular 4 to 7, in particular 5 or 6, carbon atoms. By way of example, mention may be made of an adamantyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexenyl, phenyl or naphthyl group.

For the purposes of the present invention, the term "aryl" means an aromatic hydrocarbon group, preferably comprising from 6 to 10 carbon atoms, and comprising one or more contiguous rings, for example a phenyl or naphthyl group. Advantageously, it is phenyl.

For the purposes of the present invention, the term "aryl- (CrC ₆ ) alkyl" means an aryl group as defined above, linked to the remainder of the molecule via a (CrC ₆ ) alkyl chain. as defined above. By way of example, mention may be made of the benzyl group.

For the purposes of the present invention, the term "(CrC ₆ ) alkyl-aryl" means a (CrC ₆ ) alkyl group as defined above, linked to the remainder of the molecule by means of an aryl group. as defined above. By way of example, mention may be made of the tolyl group (CH ₃ Ph).

For the purposes of the present invention, the term "heterocycle" is intended to mean a saturated, unsaturated or aromatic, preferably saturated or unsaturated but non-aromatic hydrocarbon-based monocycle or bicycle containing from 3 to 12 carbon atoms, in which 1 to 4 , in particular 1 or 2, carbon atoms are each replaced, independently from each other, with a heteroatom selected from N, O and S, in particular selected from N and O. The bicycle comprises two contiguous or bridged cycles. Each cycle of the unicycle or the bicycle advantageously comprises 3 to 8, in particular 4 to 7, in particular 5 or 6, carbon atoms or heteroatoms forming the ring. By way of example, mention may be made of the heterocycles azetidine, oxetane, thiooxetane, pyrrolidine, pyrroline, pyrrole, tetrahydrofuran, dihydrofuran, furan, tetrahydrothiophene, dihydrothiophene, thiophene, piperidine, dihydropyridine, tetrahydropyridine, pyridine, pyran, dihydropyran, tetrahydropyran, thiopyran, dihydrothiopyran, tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, homopiperazine, azepine, pyrazine, pyrimidine, pyridazine, perhydropyrrolo [3,4-c] pyrrole, 2,5-diazabicyclo [4.2.0] octane, 2,5-diazabicyclo [2.2. 1] heptane, 3,8-diazabicyclo [3.2.1] octane and imidazole. Preferably, the heterocycle will be non-aromatic and may be in particular a ring azetidine, oxetane, thiooxetane, pyrrolidine, pyrroline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, piperidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, tetrahydropyran, thiopyran, dihydrothiopyran, tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, homopiperazine (or diazepane), perhydropyrrolo [3,4-c] pyrrole, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane and 2, 5-diazabicyclo [2.2.1] heptane.

For the purposes of the present invention, the term "nitrogenous heterocycle" is intended to mean a heterocycle as defined above comprising at least one nitrogen atom, in particular a non-aromatic nitrogen atom, which is preferably saturated. It may be in particular a monocycle or a bicycle, each cycle comprising 5 to 7, preferably 5 or 6 members and optionally comprising, in addition to the nitrogen atom, another heteroatom preferably chosen among oxygen and nitrogen. In particular, this will be a piperidine, optionally piperazine group (eg piperazine, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane, especially piperazine, 2,5-diazabicyclo [4.2.0] octane, or 2,5-diazabicyclo [2.2.1] heptane), morpholine, perhydropyrrolo [3,4-c] pyrrole, diazepane ( e.g., 1,3-diazepane or 1,4-diazepane) or pyrrolidine.

By "contiguous" cycles is meant in the sense of the present invention, two rings linked together by two adjacent carbon atoms.

By "bridged" rings is meant, in the sense of the present invention, two rings linked together by two non-adjacent carbon atoms. By "bridged piperazine" is meant, in the sense of the present invention, a piperazine ring in which two non-adjacent carbon atoms are connected by a saturated or unsaturated hydrocarbon chain, preferably saturated, advantageously comprising 1 to 5, especially 1 to 3, preferably 1 or 2, carbon atoms. This may include 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane .

By "unsaturated" group is meant, within the meaning of the present invention, a group comprising at least one C = C or C≡C bond.

By "unsaturated" cycle is meant in the sense of the present invention, a ring comprising at least one C = C bond but not aromatic.

By "optionally substituted" group is meant, within the meaning of the present invention, a group optionally substituted by one or more substituents. This (s) substituent (s) can be chosen from:

a halogen atom,

a (CrC ₆ ) alkyl group optionally substituted by one or more groups chosen from a halogen atom, ORi ₆ , SRu, NR ₁₈ R ₁₉ , a carbocycle and a heterocycle,

the groups oxo (= O), CN, NO ₂ , OR ₂₀ , SR ₂ , NR ₂₂ R ₂₃ , C (O) R ₂₄ , C0 ₂ R ₂₅ , OC (O) R ₂₆ , S (O) R ₂₇ , SO ₂ R ₂₈ , NR ₂₉ C (O) R ₃ o, C (O) NR ₃ R ₃₂ , NR _{3 3} CO ₂ R ₃₄ , OC (O) NR ₃₅ R ₃₆ , NR ₃₇ CONR ₃₈ R 39 and OCO ₂ R ₄₀ ,

a carbocycle optionally substituted with one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, oxo (= O), OR ₄ i, SR ₄₂ and NR ₄₃ R ₄₄ , a heterocycle optionally substituted with one or several groups selected from a halogen atom, a group (CrC ₆ ) alkyl, oxo (= O), OR ₄₅ , SR ₄₆ and NR ₄₇ R ₄₈ , and - a group -O (CH ₂ ) _n O- with n representing an integer between 1 and 5, in particular between 2 and 3 (the two oxygens of this group can be attached to the same atom or to two distinct atoms, advantageously, they will be attached to the same atom, in particular to the same atom of carbon which will in this case to form a cyclic acetal),

or :

^■ R 16 to R ₄₈ represent, independently each other, a hydrogen atom, a (CrC ₆₎ alkyl, aryl, aryl- (Ci-C ₆₎ alkyl, heterocycle or heterocycle (CrC ₆₎ alkyl,

the aryl ring of these groups being optionally substituted by one or more groups selected from a halogen atom and a (CrC ₆ ) alkyl group, and the heterocycle ring of these groups being optionally substituted by one or more groups selected from a halogen atom, a (C ₁ -C ₆ ) alkyl, and oxo (= O) group, or

R ₂₂ and R _23, R ₃ 1 and R _32, R ₃₅ and R _36, R ₃₈ and R _39, R ₄₃ and R _44, and / or R ₄₇ and R ₄₈ together form, with the nitrogen atom which gate, a nitrogen heterocycle optionally substituted with one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= 0).

X will more particularly represent a hydrocarbon chain, saturated or unsaturated, comprising 1 to 3, in particular 1 or 2, carbon atoms, optionally substituted with one or more groups chosen from a halogen atom, a (CrC ₆ ) alkyl, oxo group; , OH and (C ₁ -C ₆ ) alkoxy, a carbon atom of said chain optionally being replaced by an oxygen or sulfur atom.

X will in particular represent a hydrocarbon chain, saturated or unsaturated, comprising 1 to 3, in particular 1 or 2, carbon atoms, a carbon atom of said chain optionally being replaced by an oxygen or sulfur atom.

X will advantageously represent a hydrocarbon chain, saturated or unsaturated, comprising 1 to 3, in particular 1 or 2, carbon atoms, and more particularly a chain CH ₂ -CH ₂ or CH = CH.

Y will more particularly represent a nitrogen atom or a CRy group with Ry representing a hydrogen atom, a halogen atom, a (CrC ₆ ) alkyl, (CrC ₆ ) haloalkyl, (CrC ₆ ) alkoxy, (CrC ₆ ) haloalkoxy, NR ₁₂ R 13, CO ₂ H or CO ₂ ((C ₁ -C ₆ ) alkyl), with R 12 and R ₁₃ representing, independently of one another, a hydrogen atom or a (C ₁ -C ₆ ) alkyl group optionally substituted by one or more halogen atoms, or R 12 and R ₃ forming together with the nitrogen atom carrying them a 5- or 6-membered non-aromatic preferably optionally comprising another heteroatom selected from O, N and S, and especially O and N, said heterocycle being optionally substituted by a (C ₁ -C ₆ ) alkyl group.

Y will more particularly represent a nitrogen atom or a CRy group with

R 1 representing a hydrogen atom, a halogen atom, a (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) haloalkoxy or NR ₁₂ R13 group, with R 12 and R ₁ representing , independently of one another, a hydrogen atom or a (C ₁ -C ₆ ) alkyl group optionally substituted with one or more halogen atoms, or R 12 and R ₁₃ forming with the nitrogen atom which carry them a heterocycle with 5 or 6 linkages, preferably non-aromatic, optionally comprising another heteroatom selected from O, N and S, and in particular O and N, said heterocycle being optionally substituted with a (C ₁ -C ₆ ) alkyl group.

Y will more particularly represent a nitrogen atom or a CRy group with Ry representing a hydrogen atom, a halogen atom, a (CrC ₆ ) alkyl group,

(CrC ₆ ) alkoxy, OH, or NR ₁₂ R ₁₃ , with R 12 and R ₁₃ representing, independently of each other, a hydrogen atom or a (C ₁ -C ₆ ) alkyl group.

Y will represent in particular a CRy group with Ry as defined according to one of the preceding definitions. Ry will especially represent a hydrogen atom, a halogen atom, a group (CrC ₆ ) alkyl or (CrC ₆ ) haloalkyl; preferably a hydrogen atom or a halogen atom (eg F). Y will represent in particular a CH or CF group.

W may more particularly represent an oxygen atom.

Q will especially represent a single or double bond, an oxygen atom, or a (C ₁ -C ₆ ) alkyl group.

Q will more particularly represent an oxygen atom.

A ₁ and A ₂ independently represent, independently of each other, a single bond or a (C ₁ -C ₆ ) alkyl group optionally substituted by an OH group, or A ₁ and A ₂ form with Q and the carbon atoms attached to Q a monocyclic carbocycle or heterocycle optionally substituted with one or more groups selected from OH, (dC ₆ ) alkyl and oxo (= O).

The monocyclic carbocycle may in particular be a C ₃ to C ₆ monocyclic carbocycle, especially C ₅ or C ₆ , for example a cyclopropyl, a cyclobutyl, a cyclopentyl or a cyclohexyl.

The monocyclic heterocycle may in particular be a monocyclic C ₃ to C ₆ , especially C ₅ or C ₆ , preferably nonaromatic heterocycle, advantageously comprising an oxygen atom, for example an oxirane, an oxetane, a tetrahydrofuran or a tetrahydropyran.

In particular, A ₁ and A ₂ represent, independently of each other, a single bond or a (C ₁ -C ₆ ) alkyl group optionally substituted by an OH group, and in particular a single bond or a (C ₁ -C ₆ ) alkyl group.

A ₁ and A _{2 will} each in particular represent a single bond.

R 1, R 2, R 3, R ₄ , R ₅ , R 6, R 7 and R _{8 will} more particularly represent a hydrogen atom. According to a particular embodiment, W and Q each represent, independently of one another, O or S, preferably O, and A ₁ and A ₂ each represent a single bond.

According to another particular embodiment, W = Q = O, A ₁ and A ₂ each represent a single bond, and R 1 = R ₂ = R 3 = R ₄ = R ₅ = = 7 = Re = H.

R 11 will especially represent a hydrogen atom, a halogen atom, a (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy group. Ru will more particularly represent a hydrogen atom, a halogen atom, or a (CrC ₆ ) alkyl group. Advantageously, Ru will represent a hydrogen atom.

R ₉ and R ₁₀ represent, independently of one another, a hydrogen atom, a halogen atom, an optionally substituted (CrC ₆ ) alkyl, optionally substituted (C ₂ -C ₆ ) alkenyl group, ( C ₂ -C ₆ ) optionally substituted alkynyl, (CC ₆ ) optionally substituted alkoxy, (CrC ₆ ) optionally substituted thioalkoxy, CN, NO ₂ , NR ₁₄ R ₁₅ , OH, SH, CO ₂ R ₅₄ , CONR ₅₅ R ₅₆ , an optionally substituted carbocycle or an optionally substituted heterocycle.

R ₉ and R 1 ₀ are particularly, independently of one another, a hydrogen atom, a halogen atom, a (CrC ₆₎ alkyl, optionally substituted (C ₂ -C ₆₎ alkenyl optionally substituted (C ₂ -C ₆ ) optionally substituted alkynyl, optionally substituted (C ₁ -C ₆ ) alkoxy, optionally substituted (C ₁ -C ₆ ) thioalkoxy, NR ₁₄ R ₁₅ , CONR ₅₅ R ₅₆ , an optionally substituted carbocycle or an optionally substituted heterocycle, especially with R15 ≠ H and R ₅₅ ≠ H.

Rg and R1 ₀ represent in particular independently of one another, a hydrogen atom, a halogen atom, a (CrC ₆₎ alkyl, optionally substituted (C ₂ -C ₆₎ alkenyl optionally substituted ( C ₂ -C ₆ ) optionally substituted alkynyl, optionally substituted (CrC ₆ ) alkoxy, optionally substituted (CrC ₆ ) thioalkoxy, NR ₄ R ₅ , or an optionally substituted heterocycle, especially with R 15 ≠ H.

R 8 and R ₁₀ represent in particular, independently of one another, a hydrogen atom, a halogen atom or a (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl group, (C ₂ - C ₆ ) alkynyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) thioalkoxy, (C ₁ -C ₆ ) alkylamino, di ((C ₁ -C ₆ ) alkyl) amino or heterocycle, said group being optionally substituted.

R 8 and R ₁₀ may more particularly represent, independently of one another, a hydrogen atom or an optionally substituted heterocycle. In the definitions of R ₉ and R ₀ above, R and R ₅ represent, independently of one another, a hydrogen atom or a (CrC ₆₎ alkyl, optionally substituted (C ₂ -C ₆₎ alkenyl optionally substituted, or (C ₂ -C ₆ ) alkynyl optionally substituted, or R and Re together with the nitrogen atom carrying them an optionally substituted nitrogenous heterocycle. In particular, R ₄ may represent a hydrogen atom or a group (CrC ₆ ) alkyl and R ₁₅ may represent a hydrogen atom or an optionally substituted (CrC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl group substituted, or (C ₂ -C ₆ ) alkynyl optionally substituted, or R and R ₅ will form with the nitrogen atom which carries them an optionally substituted nitrogenous heterocycle. Advantageously, R _{4 will} represent a hydrogen atom or a group (CrC ₆ ) alkyl and R _{15 will} represent a hydrogen atom or an optionally substituted (CrC ₆ ) alkyl group, or R and Re will form with the nitrogen atom which carry them an optionally substituted nitrogen heterocycle. Preferably, the optionally substituted nitrogenous heterocycle will be a monocyclic or bicyclic nitrogenous heterocycle, in particular non-aromatic, preferably saturated, of which each ring comprises 5 to 7, preferably 5 or 6 members, optionally comprising 1 heteroatom in addition to the atom. nitrogen selected from N and O, such as optionally piperazine, piperidine, morpholine, perhydropyrrolo [3,4-c] pyrrole, diazepane (e.g., 1,3-diazepane or 1,4-diazepane) or pyrrolidine, the heterocycle being optionally substituted in particular with one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl and oxo (= 0).

Preferentially, the optionally bridged piperazine will be a piperazine ring, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane; especially a piperazine ring, 2,5-diazabicyclo [4.2.0] octane, or 2,5-diazabicyclo [2.2.1] heptane.

In the above definitions of R ₉ and R ₁₀ , a carbocycle is more particularly a C ₃ to C ₆ monocyclic carbocycle, in particular C ₅ or C ₆ , in particular a non-aromatic ring, for example a cyclopropyl, a cyclobutyl, a cyclopentyl, a cyclohexyl or cyclohexenyl

In the above definitions of R ₉ and R ₀ , a heterocycle is more particularly a monocyclic or a bicyclic heterocycle, each ring being 5, 6 or 7-membered, preferably 5 or 6-membered, saturated, unsaturated or aromatic, preferably saturated. or unsaturated, comprising 1 or 2 heteroatoms chosen from N, O and S, in particular from N and O, and preferably comprising at least one nitrogen atom, the heteroatom (s) being preferably N. The heterocycle could be for example a pyrrolidine, pyrroline, pyrrole, tetrahydrofuran, dihydrofuran, furan, tetrahydrothiophene, dihydrothiophene, thiophene, piperidine, dihydropyridine, tetrahydropyridine, pyridine, pyran, dihydropyran, tetrahydropyran, thiopyran, dihydrothiopyran, tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, pyrazine, pyrimidine, pyridazine ring Perhydropyrrolo [3,4-c] pyrrole, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane 2,5-diazabicyclo [2.2.1] heptane or imidazole. The heterocycle will be in particular a pyrrolidine, pyrroline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, piperidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, tetrahydropyran, thiopyran, dihydrothiopyran, tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, perhydropyrrolo [3,4-c ] pyrrole, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane. The heterocycle will be in particular a pyrrolidine, pyrroline, tetrahydrofuran, dihydrofuran, piperidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, tetrahydropyran, morpholine, piperazine or perhydropyrrolo [3,4-c] pyrrole ring. The heterocycle will be more particularly a pyrrolidine, pyrroline, piperidine, dihydropyridine, tetrahydropyridine, piperazine or perhydropyrrolo [3,4-c] pyrrole ring. The heterocycle may advantageously be a pyrrolidine, piperidine, tetrahydropyridine (especially 1, 2,3,6-tetrahydropyridine), piperazine or perhydropyrrolo [3,4-c] pyrrole ring. Advantageously, the heterocycle will be a monocyclic or bicyclic nitrogenous heterocycle, in particular non-aromatic, preferably saturated, of which each ring comprises 5 to 7, preferably 5 or 6 members, optionally comprising 1 heteroatom selected from N and O in addition to nitrogen atom, such as an optionally bridged piperazine ring (eg piperazine, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2 .1] heptane), piperidine, morpholine, perhydropyrrolo [3,4-c] pyrrole, diazepane (e.g., 1,3-diazepane or 1,4-diazepane), tetrahydropyridine (especially 1,2,3,6-tetrahydropyridine) ) or pyrrolidine. It may be in particular a monocyclic or bicyclic nitrogenous heterocycle, saturated, each ring comprising 5 or 6 members, optionally comprising 1 heteroatom selected from N and O in addition to the nitrogen atom, such as a Piperazine ring, optionally bridged (eg piperazine, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane), piperidine, morpholine , perhydropyrrolo [3,4-c] pyrrole or pyrrolidine, especially an optionally bridged piperazine, in particular a piperazine. The nitrogen heterocycle will preferably be linked to the rest of the molecule by its nitrogen atom. In the definitions of R ₉ , R ₁₀ , R ₁₀ and R _{15 above} , an optionally substituted group or ring is a group or a ring optionally substituted with one or more substituents, advantageously chosen from:

a halogen atom,

a (CrC ₆ ) alkyl group optionally substituted with one or more groups chosen from a halogen atom, ORi ₆ , SR ₁₇ , NR ₁₈ R ₁₉ , a carbocycle and a heterocycle,

the groups oxo (= O), CN, NO ₂ , OR ₂₀ , SR ₂ , NR ₂₂ R ₂₃ , C (O) R ₂₄ , C0 ₂ R ₂₅ , OC (O) R ₂₆ , S (O) R ₂₇ , SO ₂ R ₂₈ , NR ₂₉ C (O) R ₃ o, C (O) NR ₃ R ₃₂ , NR ₃₃ CO ₂ R ₃₄ , OC (O) NR ₃₅ R ₃₆ , NR ₃₇ CONR ₃₈ R 39 and OCO ₂ R ₄₀ ,

a carbocycle optionally substituted with one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, oxo (= O), OR ₄ i, SR ₄₂ and NR ₄₃ R ₄₄ , a heterocycle optionally substituted with one or several groups selected from a halogen atom, a group (CrC ₆ ) alkyl, oxo (= O), OR ₄₅ , SR ₄₆ and NR ₄₇ R ₄₈ , and a group -O (CH ₂ ) _n O- with n representing an integer between 1 and 5, in particular between 2 and 3 (the two oxygens of this group may be attached to the same atom or to two distinct atoms, advantageously they will be attached to the same atom, in particular to the same carbon atom which will allow in this case to form a cyclic acetal),

or :

the aryl ring of these groups being optionally substituted by one or more groups selected from a halogen atom and a (C ₁ -C ₆ ) alkyl group, and the heterocycle ring of these groups being optionally substituted by one or more groups selected from a hydrogen atom; halogen, a (CrC ₆ ) alkyl, and oxo (= O) group, or

R ₂₂ and R ₂₃ , R ₃₁ and R ₃₂ , R ₃₅ and R ₃₆ , R ₃₈ and R ₃₉ , R ₄₃ and R ₄₄ , and / or R ₄₇ and R ₄₈ together with the nitrogen atom which gate, a nitrogen heterocycle optionally substituted with one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= 0).

In the definitions of R _9, R 10, R ₁₅ and R previous, groups or optionally substituted rings are optionally substituted in particular by one or more substituents selected from: a halogen atom,

a (CrC ₆ ) alkyl group optionally substituted by one or more groups chosen from a halogen atom, ORi ₆ , NR ₁₈ R ₁₉ , a carbocycle and a heterocycle,

the groups oxo (= O), OR ₂₀ , NR ₂₂ R ₂₃ , C (O) R ₂₄ , C0 ₂ R ₂₅ , OC (O) R ₂₆ , NR ₂₉ C (O) R ₃ o,

C (0) NR ₃ iR _32, NR ₃ 3C0 ₂ R _34, OC (0) NR ₃₅ R ₃ 6, NR37CONR38R39 and OCO ₂ R _40, and more particularly oxo groups (= 0) OR _20, NR ₂₂ R ₂₃ , C0 ₂ R ₂₅ , C (O) NR ₃₁ R ₃₂ ,

NR ₃ 3C0 ₂ R _34, OC (0) NR ₃₅ R ₃ 6, NR37CONR38R39 and OCO ₂ R _40,

a C ₃ to C ₆ carbocycle optionally substituted by one or more groups selected from a halogen atom, a (C ₁ -C ₆ ) alkyl, oxo (= O), OR _{4 group} and a 3 to 6 membered heterocycle, comprising 1 or 2 heteroatoms chosen from N and O, preferably saturated, optionally substituted with one or more groups chosen from a halogen atom, a (CrC ₆ ) alkyl, oxo (= O), OR ₄₅ and NR ₄₇ R _{48 group;} , and

a group -O (CH ₂ ) _n O- where n represents an integer equal to 2 or 3 (the two oxygens of this group may be attached to the same atom or to two distinct atoms, advantageously they will be attached to the same atom, in particular at the same carbon atom which will in this case to form a cyclic acetal),

Rie, Rie at R ₂₀ , R ₂₂ at R ₂₆ , R ₂₉ at R ₄₁ , R ₄₃ at R ₄₅ , R ₄₇ and R ₄₈ represent, independently of each other, a hydrogen atom, a group (CC ₆ ) alkyl, aryl, aryl- (C ₁ -C ₆ ) alkyl, heterocycle or heterocycle- (C ₁ -C ₆ ) alkyl, especially a hydrogen atom, a (C ₁ -C ₆ ) alkyl, aryl, or aryl- (C ₆ -C ₆ ) alkyl group, in particular a hydrogen atom or a (C ₁ -C ₆ ) alkyl group, the aryl ring of these groups being a phenyl group and being optionally substituted with one or more groups chosen from a halogen atom and a group (CrC ₆ ) alkyl, and

the heterocycle ring of these groups being a 3- to 6-membered heterocyclic ring, especially a 5- or 6-membered ring, comprising 1 or 2 heteroatoms chosen from N and O and being optionally substituted with one or more groups chosen from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= O), or

R 22 and R _23, R ₃₁ and R _32, R ₃₅ and R _36, R ₃₈ and R _39, R ₄₃ and R _44, and / or R ₄₇ and R ₄₈ together form, with the nitrogen atom carrying them, , a nitrogen heterocycle at 5 or 6 linkages, especially non-aromatic, preferably saturated, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, the heterocycle being optionally substituted by a or more than one group selected from halogen, (C ₁ -C ₆ ) alkyl, and oxo (= O).

In the definitions of R ₉ , R ₁₀ , R ₁₁ and R _{15 above} , the optionally substituted groups or rings are advantageously optionally substituted by one or more substituents chosen from:

a halogen atom,

a (CrC ₆ ) alkyl group optionally substituted with one or more groups chosen from a halogen atom, ORi ₆ and NR ₈ Rig,

- the oxo groups (= 0) OR _20, NR22R23, CO2R25, C (0) NR ₃ R ₃ i 2, NR33CO2R34, OC (0) NR ₃₅ R ₃ 6, NR37CONR38R39 and OC0 ₂ R ₄ o,

a C ₃ to C ₆ carbocycle optionally substituted with one or more groups selected from a halogen atom, a (C ₁ -C ₆ ) alkyl, oxo (= O), OR 41 group and a 3- to 6-membered heterocycle, comprising 1 or 2 heteroatoms chosen from N and O, preferably saturated, optionally substituted by one or more groups chosen from a halogen atom, a group (CrC ₆ ) alkyl, oxo (= O), OR 45 and a group -O (CH ₂ ) _n O- with n representing an integer equal to 2 or 3 (the two oxygens of this group can be attached to the same atom or to two distinct atoms, advantageously they will be attached to the same atom, in particular to the same carbon atom which will allow in this case to form a cyclic acetal),

or :

R ₁₆ , R ₁₈ to R ₂₀ , R ₂₂ , R ₂₃ , R ₂₅ , R 31 to R ₄₁ , R ₄₃ to R ₄₅ , R ₄₇ and R ₄₈ represent, independently of one another, a hydrogen atom, a (CC ₆ ) alkyl, aryl group or aryl- (C ₁ -C ₆ ) alkyl, in particular a hydrogen atom, or a (C ₁ -C ₆ ) alkyl group,

the aryl ring of these groups being preferably a phenyl group and being optionally substituted by one or more groups selected from a halogen atom and a (C ₁ -C ₆ ) alkyl group, or

■ R 22 and R ₂ 3, R 31 and R _32, R35 and _R36, R38 and _R39 and / or R47 and _R48 taken together with the nitrogen atom which carries them, a nitrogen-containing heterocyclic 5 or 6 membered in particular non-aromatic, preferably saturated, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, the heterocycle being optionally substituted by one or more groups selected from a halogen atom, a (C ₁ -C ₆ ) alkyl, and oxo (= O) group.

The groups R ₉ and R ₀ can in particular represent, independently of one another:

a hydrogen or halogen atom,

a (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) thioalkoxy, (C ₁ -C ₆ ) alkylamino or di ( (CrC ₆ ) alkyl) amino, said group being optionally substituted by one or more substituents chosen from a halogen atom, OR ₂₀ , NR ₂₂ R ₂₃ , C (O) R ₂₄ , C0 ₂ R ₂₅ , OC (O) R _26, NR ₂₉ C (0) o R _3, C (0) N R3lR32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36, NR37CONR38R39 and OCO ₂ R _40; in particular selected from OR _20, NR ₂₂ R _23, C0 ₂ R _25, C (0) NR ₃₁ R _32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36, NR ₃₇ CONR ₃ 8R ₃ g and OCO ₂ R ₄₀ ; in particular chosen from NR ₂₂ R ₂₃ , NR ₃₃ CO ₂ R ₃₄ and NR ₃₇ CONR ₃₈ R ₃₉ , or

a monocyclic or bicyclic heterocycle, each ring being 5, 6 or 7-membered, preferably 5 or 6-membered, comprising 1 or 2 heteroatoms selected from N and O, preferably saturated or comprising a double bond but not aromatic, (1 heterocycle may be in particular an optionally bridged piperazine ring (eg piperazine, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane), piperidine, perhydropyrrolo [3,4-c] pyrrole, tetrahydropyridine or pyrrolidine, in particular a piperazine, piperidine, pyrrolidine, perhydropyrrolo [3,4-c] pyrrole or tetrahydropyridine ring) optionally substituted by one or more substituents chosen from :

• a halogen atom,

A (CrC ₆ ) alkyl group optionally substituted with one or more groups chosen from a halogen atom, ORi ₆ , NR ₁₈ R ₆ , a C ₃ to C ₆ monocyclic carbocycle (in particular saturated) and a monocyclic heterocycle with 3 to 6 links (especially saturated); preferably optionally substituted by one or more groups selected from a halogen atom, ORi ₆ and

The groups oxo (= O), OR ₂₀ , NR ₂₂ R ₂₃ , C (O) R ₂₄ , C0 ₂ R ₂₅ , OC (O) R ₂₆ , NR ₂₉ C (O) R ₃₀ , C (O) NR ₃₁ R ₃₂ , NR ₃₃ C0 ₂ R ₃₄ , OC (O) NR ₃₅ R ₃₆ , NR ₃₇ CONR ₃₈ R ₃₉ and OCO2 40; and more particularly oxo groups (= 0) OR ₂ o NR22R23, C0 ₂ R 25, C (0) NR ₃ i R ₃ 2, NR33CO2R34, OC (0) NR ₃₅ R ₃ 6, NR37CONR38R39 and OC0 ₂ R ₄ o

A C ₃ to C ₆ carbocycle optionally substituted with one or more groups chosen from a halogen atom, a (CrC ₆ ) alkyl, oxo group;

A 3- to 6-membered heterocycle, comprising 1 or 2 heteroatoms chosen from N and O, in particular saturated or unsaturated, preferably saturated, optionally substituted by one or more groups chosen from a halogen atom, a (CrC ₆ ) group; alkyl, oxo (= O), OR45 and NR47R48, and

A group -O (CH ₂ ) _n O- where n represents an integer equal to 2 or 3 (the two oxygens of this group can be attached to the same atom or to two distinct atoms, advantageously they will be attached to the same atom , in particular at the same carbon atom which in this case will make it possible to form a cyclic acetal),

Rie, Rie at R ₂₀ , R22 at R ₂₆ , R29 at R41, R43 at R45, R47 and R ₄₈ represent, independently of one another, a hydrogen atom, a (CC ₆ ) alkyl, aryl, aryl, (CrC ₆ ) alkyl, heterocycle or heterocycle- (C ₁ -C ₆ ) alkyl, especially a hydrogen atom, a (C ₁ -C ₆ ) alkyl, aryl, or aryl- (d-C ₆ ) alkyl group, in particular an atom of hydrogen, or a (C ₁ -C ₆ ) alkyl group, the aryl ring of these groups being a phenyl group and being optionally substituted by one or more groups selected from a halogen atom and a (C ₁ -C ₆ ) alkyl group, and

the heterocycle ring of these groups being a 3- to 6-membered heterocyclic ring, especially a 5- or 6-membered ring, comprising 1 or 2 heteroatoms chosen from N and O, and being optionally substituted with one or more groups chosen from a halogen atom, a group (CrC ₆ ) alkyl and oxo (= 0), or

R ₂₂ and R ₂₃ , R ₃₁ and R ₃₂ , R ₃₅ and R ₃₆ , R ₃₈ and R ₃₉ , R ₄₃ and R ₄₄ , and / or R ₄₇ and R ₄₈ together with the nitrogen atom carrying them nitrogenous heterocycle with 5 or 6 members, preferably saturated, in particular nonaromatic, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring; heterocycle being optionally substituted with one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= 0). Groups R ₉ and R ₁₀ may more particularly represent, depending on each other:

a hydrogen or halogen atom,

a group -Z- (CH ₂ ) _m -R49 wherein Z is a single bond, CH ₂ -CH ₂ , CH = CH, C≡C, O, S or NR ₅₀ ; m represents an integer between 1 and 6, in particular between 1 and 4; R ₅₀ represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl group; and R ₄₉ represents a halogen atom, OR ₂ o, NR ₂₂ R ₂₃ , C (O) R ₂₄ , CO ₂ R ₂₅ , OC (O) R ₂₆ , NR ₂₉ C (O) R ₃ o, C (O) NR ₃₁ R _32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36i 7CONR NR ₃ ₃ ₃ eR 9 or OCO ₂ R _40; particularly OR20, NR22R23i C0 ₂ R _25, C (0) N R3lR32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36, NR ₃ 7CONR eR ₃ ₃ 9 or OCO ₂ R _40; in particular NR22R23, NR ₃₃ C0 ₂ R ₃₄ , or NR ₃₇ CONR ₃₈ R ₃₉ , or

a monocyclic or bicyclic heterocycle, each ring being 5, 6 or 7-membered, preferably 5 or 6-membered, comprising 1 or 2 heteroatoms selected from N and O, preferably saturated or comprising a double bond, (the heterocycle may be in particular an optionally bridged piperazine ring (eg piperazine, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane), piperidine, perhydropyrrolo [3,4-c] pyrrole, tetrahydropyridine or pyrrolidine, in particular a piperazine, piperidine, pyrrolidine, perhydropyrrolo [3,4-c] pyrrole or tetrahydropyridine ring) optionally substituted with one or more substituents chosen from:

• a halogen atom,

The groups oxo (= O), OR ₂₀ , NR ₂₂ R ₂₃ , C (O) R ₂₄ , C0 ₂ R ₂₅ , OC (O) R ₂₆ , NR ₂₉ C (O) R ₃₀ , C (O) N R ₃₁ R 32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36, NR ₃ 7CONR eR ₃ ₃ 9 or OCO ₂ R _40; and more particularly oxo groups (= 0) OR ₂ o NR22R23, C0 ₂ R _25, C (0) N R3lR32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36, NR ₃ 7CONR ₃ eR ₃ 9 or OCO ₂ R ₄₀ ,

A C ₃ to C ₆ carbocycle optionally substituted with one or more groups chosen from a halogen atom, a (C ₁ -C ₆ ) alkyl, oxo (= O), OR 41 and NR ₄₃ R _{44 group} , A 3- to 6-membered heterocycle, comprising 1 or 2 heteroatoms chosen from N and O, in particular saturated or unsaturated, preferably saturated, optionally substituted by one or more groups chosen from a halogen atom, a (CrC ₆ ) group; alkyl, oxo (= O), OR45 and NR47R48, and

A -O (CH ₂ ) _n O- group with n representing an integer equal to 2 or 3

(The two oxygens of this group can be attached to the same atom or to two distinct atoms, advantageously, they will be attached to the same atom, in particular to the same carbon atom which in this case will make it possible to form a cyclic acetal).

or :

R ₁₆ , R ₁₈ to R ₂₀ , R ₂₂ to R ₂₆ , R 29 to R ₄₁ , R ₄₃ to R ₄₅ , R ₄₇ and R ₄₈ represent, independently of one another, a hydrogen atom, a (CC ₆ ) alkyl, aryl group; , aryl- (C ₁ -C ₆ ) alkyl, heterocycle or heterocycle- (C ₁ -C ₆ ) alkyl, especially a hydrogen atom, a (C ₁ -C ₆ ) alkyl, aryl, or aryl- (C ₆ -C ₆ ) alkyl group, in particular a hydrogen atom, or a (C ₁ -C ₆ ) alkyl group, the aryl ring of these groups being a phenyl group and being optionally substituted by one or more groups selected from a halogen atom and a (C ₁ -C ₆ ) alkyl group, and

R ₂₂ and R ₂₃ , R ₃₁ and R ₃₂ , R ₃₅ and R ₃₆ , R ₃₈ and R ₃₉ , R ₄₃ and R ₄₄ , and / or R ₄₇ and R ₄₈ together with the nitrogen atom which carries them, a 5- or 6-membered, especially non-aromatic, preferably saturated nitrogen heterocycle, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring; heterocycle being optionally substituted by one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= 0).

According to a particular embodiment of the invention, at least one of R ₉ and R 10, and preferably R ₉ , does not represent a hydrogen atom. According to another particular embodiment of the invention, at least one of R ₉ and R ₀ , and preferably R ₉ , represents neither a hydrogen atom nor a halogen atom. In these two cases, R ₉ and R ₁₀ can be defined according to any of the modes of Previous embodiment, except that one of the two groups can not represent a hydrogen atom, in particular can not represent a hydrogen or halogen atom.

According to yet another embodiment of the invention, one of R ₉ and R ₀ (preferably Rio) represents a hydrogen atom and the other (preferably R ₉ ) does not represent a hydrogen atom. and in particular does not represent a hydrogen atom or a halogen atom. The group R ₉ or Rio not representing a hydrogen atom, or even a halogen atom, may be defined according to any one of the preceding embodiments, with the exception of hydrogen or even halogen. .

Rio will more particularly represent a hydrogen atom. R ₉ may then be as defined according to any one of the preceding embodiments, and preferably will not be a hydrogen atom, in particular will be neither a hydrogen atom nor a halogen atom. According to a first particular embodiment, X represents a chain CH ₂ -

CH ₂ or CH = CH, Y = CRY, Q = W = O, Ai and _A2 each represent a single bond, and Ri ⁼ R2 ⁼ R3 ⁼ R ₄ ⁼ R5 ⁼ Re ⁼ R7 ⁼ Re ⁼ R 11 ⁼ H.

The compounds of formula (I) then correspond to compounds of formula (Ia) below:

and their pharmaceutically acceptable salts and / or solvates,

in which :

= represents a single bond or a double bond,

Ry is as defined above and advantageously represents a hydrogen atom, a halogen atom, a group (CrC ₆ ) alkyl or (d-

C ₆ ) haloalkyl; especially a hydrogen atom or a halogen atom (eg F), and R ₉ and R ₁₀ are as defined in any one of the previously described embodiments for R ₉ and R ₁₀ .

According to a second particular embodiment, X represents a chain CH ₂ -CH ₂ or CH = CH, Y = CRy, W = Q = O, A ₁ and A ₂ each represent a single bond, and R 1 = R 2 ⁼ R 3 ⁼ R ₄ ⁼ R5 ⁼ R6 ⁼ R7 ⁼ Re ⁼ R10 ⁼ R11 ⁼ H.

The compounds of formula (I) then correspond to compounds of formula (Ib) below:

and their pharmaceutically acceptable salts and / or solvates,

in which :

= represents a single bond or a double bond,

Ry is as defined above and advantageously represents a hydrogen atom, a halogen atom, a (CrC ₆ ) alkyl or (d-C ₆ ) haloalkyl group; especially a hydrogen atom or a halogen atom

(eg F), and

R ₉ is as defined according to any one of the previously described embodiments for R ₉ . According to a particularly advantageous embodiment, the compound according to the invention is a compound of formula (Ib) with R ₉ representing an optionally substituted heterocycle.

Advantageously, the heterocycle will be a monocyclic or bicyclic nitrogenous heterocycle, in particular non-aromatic, preferably saturated, of which each ring comprises 5 to 7, preferably 5 or 6 members, optionally comprising 1 heteroatom selected from N and O in addition to Nitrogen atom, such as an optionally bridged piperazine ring (eg piperazine, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2 .1] heptane), piperidine, morpholine, perhydropyrrolo [3,4-c] pyrrole, diazepane (e.g., 1,3-diazepane or 1,4-diazepane), tetrahydropyridine (especially 1,2,3,6-tetrahydropyridine) or pyrrolidine. It may be in particular a monocyclic or bicyclic nitrogenous heterocycle, saturated, each ring comprising 5 or 6 members, optionally comprising 1 heteroatom selected from N and O in addition to the nitrogen atom, such as a Potentially piperazine ring (eg piperazine, 2,5-diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.1] heptane), piperidine, morpholine , perhydropyrrolo [3,4-c] pyrrole or pyrrolidine, especially an optionally bridged piperazine, in particular a piperazine. The nitrogen heterocycle will preferably be linked to the rest of the molecule by its nitrogen atom.

The heterocycle will in particular be optionally substituted with one or more substituents chosen from:

a halogen atom,

or :

The heterocycle will advantageously be optionally substituted by one or more substituents chosen from:

a halogen atom,

- oxo them (= 0) OR _20, NR22R23, C (0) R _24, C0 ₂ R ₂ 5, OC (0) R _26, NR ₂₉ C (0) R ₃ o, C (0) NR ₃ iR ₃ 2, NR ₃ 3C0 ₂ R _34, OC (0) NR ₃₅ R ₃ 6, NR37CONR38R39 and OCO ₂ R _40, and more particularly oxo groups (= 0) OR ₂ o NR22R23, C0 ₂ R ₂ 5 , C (0) NR ₃₁ R ₃₂ ,

a C ₃ to C ₆ carbocycle optionally substituted by one or more groups selected from a halogen atom, a (C ₁ -C ₆ ) alkyl, oxo (= O), OR ₄ and NR ₄₃ R _{44 group} ,

a 3- to 6-membered heterocycle, comprising 1 or 2 heteroatoms chosen from N and O, preferably saturated, optionally substituted by one or more groups chosen from a halogen atom, a (C ₁ -C ₆ ) alkyl, oxo (= O) group; ), OR ₄₅ and NR ₄₇ R ₄₈ , and

or :

R _16, R ₁₈ to R _20, R 22 to R _26, R 29 to R ₄ i, R ₄₃ to R _45, R ₄₇ and R ₄₈ represent, independently each other, a hydrogen atom, a group (CC ₆ ) alkyl, aryl, aryl- (C ₁ -C ₆ ) alkyl, heterocyclic or heterocyclic (C ₁ -C ₆ ) alkyl, especially a hydrogen atom, a (C ₁ -C ₆ ) alkyl, aryl, or aryl- (C 1 -C ₆ ) alkyl group; , in particular a hydrogen atom, or a (CrC ₆ ) alkyl group, the aryl ring of these groups being a phenyl group and being optionally substituted by one or more groups selected from a halogen atom and a (CrC ₆ ) alkyl group, and

R ₂₂ and R ₂₃ , R ₃₁ and R ₃₂ , R ₃₅ and R ₃₆ , R ₃₈ and R ₃₉ , R ₄₃ and R ₄₄ , and / or R ₄₇ and R ₄₈ together with the nitrogen atom which carries them a 5- or 6-membered, especially non-aromatic, preferably saturated nitrogen heterocycle, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, the heterocycle being optionally substituted by one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= 0).

The heterocycle will in particular optionally be substituted with one or more substituents chosen from:

a halogen atom,

the groups oxo (= O), OR ₂₀ , NR ₂₂ R ₂₃ , C0 ₂ R ₂₅ , C (O) NR ₃₁ R ₃₂ , NR ₃₃ CO ₂ R ₃₄ , OC (O) NR ₃₅ R ₃₆ , NR ₃₇ CONR ₃₈ R ₃₉ and OCO ₂ R ₄₀ ,

a 3- to 6-membered heterocycle comprising 1 or 2 heteroatoms chosen from N and O, preferably saturated, optionally substituted by one or more groups chosen from a halogen atom, a (C ₁ -C ₆ ) alkyl, oxo (= 0), OR ₄₅ and NR ₄₇ R ₄₈ , and

or : R ₁₆ , R ₁₈ to R ₂₀ , R ₂₂ , R ₂₃ , R ₂₅ , R 31 to R ₄₁ , R ₄₃ to R ₄₅ , R ₄₇ and R ₄₈ represent, independently of each other a hydrogen atom, a (CC ₆ ) alkyl group aryl, or aryl- (C ₁ -C ₆ ) alkyl, in particular a hydrogen atom, or a (C ₁ -C ₆ ) alkyl group,

■ R 22 and R ₂ 3, R 31 and R _32, R 35 and R _36, R 38 and R ₃₉ and / or R ₄₇ and R ₄₈ together form, with the nitrogen atom which carries them, a nitrogen-containing heterocyclic 5 or 6-membered, in particular non-aromatic, preferably saturated, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, the heterocycle being optionally substituted by one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= 0).

The compounds of the present invention may be chosen in particular from compounds 1 to 44, especially compounds 1 to 36, described in the examples below, and their pharmaceutically acceptable salts and / or solvates. The present invention also relates to a compound of formula (I) as defined above, for its use as a medicament, in particular for the treatment of cancer.

The present invention also relates to the use of a compound of formula (I) as defined above, for the manufacture of a medicament, in particular for the treatment of cancer.

The present invention also relates to a method of treating cancer, comprising administering to a person in need of an effective dose of a compound of formula (I) as defined above.

The cancer may be more particularly in this case colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, glioblastoma, lung cancer, neuroblastoma , inflammatory myofibroblastic tumor, lymphoma, leukemia, myelosplastic syndrome, myelo-fibrosis, ovarian cancer, head and neck cancer. The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above, and at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions according to the invention may be formulated especially for oral administration or by injection (especially intravenously), said compositions being intended for mammals, including humans.

The active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals or humans.

Suitable unit dosage forms for oral administration include tablets, capsules, powders, granules and oral solutions or suspensions.

When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.

A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

A syrup or elixir preparation may contain the active ingredient together with a sweetener, an antiseptic, as well as a flavoring agent and a suitable colorant.

Water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, as well as with taste correctors or sweeteners.

For administration by injection, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents are used.

The active ingredient may also be formulated as microcapsules, optionally with one or more additive carriers. The compounds of the invention as active ingredients can be used at doses of between 0.01 mg and 1000 mg per day, given as a single dose once a day or administered in several doses throughout the day, for example twice a day in equal doses. The dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the skilled person can realize himself.

The pharmaceutical compositions according to the invention may also comprise at least one other active ingredient, such as an anticancer agent.

The present invention also relates to a pharmaceutical composition comprising:

(i) at least one compound of formula (I) as defined above, and

(ii) at least one other active ingredient, such as an anticancer agent,

as a combination product, for simultaneous, separate or spread use over time.

The present invention also relates to a pharmaceutical composition as defined above for its use as a medicament, in particular for the treatment of cancer.

The present invention also relates to a method of treating cancer, comprising administering to a person in need of an effective dose of a pharmaceutical composition as defined above.

The present invention also relates to processes for preparing the compounds of formula (I) according to the invention.

The present invention thus relates to a first process for preparing a compound of formula (I) comprising the coupling reaction between:

a compound of formula (II) below:

for which W, X, Y, R ₉ , R ₁₀ and Ru are as defined above, and a compound of formula (III) below:

for which Q, A ₂ and R ₈ are as defined above and Ld and LG ₂ each represent, independently of each other, a leaving group.

For the purposes of the present invention, the term "leaving group" is intended to mean a chemical group which can be easily displaced by a nucleophile during a nucleophilic substitution reaction, the nucleophile being in this case an alcohol or a thiol. Such a leaving group may be more particularly a halogen atom such as a chlorine or bromine atom or a sulfonate. The sulfonate may in particular be a group -OSO 2 -R 51 with R 51 representing a (C ₁ -C ₆ ) alkyl, aryl, aryl- (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl-aryl group, said group being optionally substituted by one or more halogen atoms such as fluorine atoms. The sulphonate may in particular be a mesylate (-OS (O ₂ ) -CH ₃ ), a triflate (-OS (O) ₂ -CF ₃ ) or a tosylate (-OS (O) 2- (p-Me- C ₆ H ₄ )).

Groups and Ld and LG _{2 will} more particularly represent a halogen atom such as bromine.

The coupling reaction (or macrocyclization) will be performed advantageously in the presence of a base such as potassium or sodium carbonate. Dimethylformamide may be used as a reaction solvent.

Such a method is illustrated in more detail in the following Scheme 1.

Diagram 1

The second cyclization step between compound B and guanidine C according to the following reference (J. Med Chem 2007, 50, 4516-4527) is typically conducted by heating at a temperature between 20 ° C and 200 ° C in a polar solvent, such as N-N'-dimethylformamide, and in the presence of an organic base, such as triethylamine or an alcoholate (in particular (CrC ₆ ) alkyl-OM with M = Na, K or Li), or inorganic, such as sodium carbonate, potassium or cesium carbonate or potassium acetate, or else without a solvent in a microwave reactor to yield the compound of formula D.

The intermediate of general formula D is converted into an intermediate of general formula E by a demethylation reaction in the presence of BBr ₃ in an anhydrous solvent such as dichloromethane at a temperature between -78 ° C. and 100 ° C. depending on the reference ( J. Med Chem 2008, 51, 4804-4822). The intermediate of general formula E is converted into product of general formula (I) by a macrocyclization reaction with compound F.

The present invention also relates to a second process for the preparation of a compound of formula (I) for which R ₉ and / or Rio represents an optionally substituted (CrC ₆ ) alkoxy, optionally substituted (CrC ₆ ) thioalkoxy or NR14R15 group or a heterocycle optionally substituted comprising a heteroatom directly linked to the phenyl ring, comprising the coupling between a compound of formula (IVa) or (IVb) below:

for which W, X, Y, Q, A ₂ and R | at Ru are as defined above and Χ · ι represents a halogen atom such as Br, Cl or I, in particular Br,

and respectively a compound of formula R ₉ H or R ₁₀ H for which R ₉ and R ₀ are as defined above.

This reaction may be carried out in the presence of an organic or inorganic base, such as Et ₃ N, iPr ₂ NEt, NaH, pyridine, Cs ₂ CO ₃ , Na ₂ CO ₃ or K ₂ CO ₃ , optionally in the presence of a salt as catalyst such as Kl, BU4NI, Ass, Lil,

AgBF ₄ , AgClO ₄ , Ag ₂ CO ₃ , KF, Bu ₄ NF or CsF. The solvent used will preferably be a polar anhydrous solvent such as tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone or a mixture thereof. The reaction may advantageously be carried out at a temperature of between -20 ° C. and 140 ° C. The choice of experimental conditions and reagents to achieve this reaction is well obviously depending on the nature of nucleophiles R ₉ H and R ₀ H and will be carried out according to methods and techniques well known to those skilled in the art.

The reaction can also be carried out in a "sealed or screwed tube" heated by thermal energy or microwave energy, in particular at temperatures between 80 ° C. and 180 ° C. according to the reference (J. Org. 74, 5075-5078).

This reaction can also be carried out by catalytic coupling as described in reference (Org Lett, 2002, 17, 2885-2888). This reaction is carried out in the presence of a catalytic amount of a palladium complex such as (dppf) ₂ PdCl ₂ .CH ₂ Cl ₂ . The coupling reaction is conveniently carried out at temperatures between 25 ° C and 100 ° C. The solvent used will preferably be an aprotic polar solvent such as tetrahydrofuran or dioxane.

The present invention also concerns a third process for preparing a compound of formula (I), wherein R ₉ and / or R is (d- C ₆₎ alkyl, optionally substituted (C ₂ -C ₆₎ alkenyl optionally substituted or optionally substituted (C ₂ -C ₆ ) alkynyl, an optionally substituted carbocycle or an optionally substituted heterocycle bonded to the phenyl ring by means of a carbon atom, comprising coupling between a compound of formula (Va) or (Vb) next :

or

for which W, X, Y, Q, A ₂ and R | at Ru are as defined above and X ₂ represents Br, Cl, I or OTf (OSO ₂ CF ₃ ),

and respectively a compound of formula R9-BR52R53 or R ₁₀ -BR ₅ 2R53 wherein R ₉ and R 10 are as defined above and R ₅₂ and R ₅₃ represent, independently of one another, OH, (CrC ₆ ) alkyl or (CrC ₆ ) alkoxy or R52 and R ₅₃ together form a chain -X ₃ - or -O-X ₃ -O- for which X ₃ represents a divalent hydrocarbon group comprising 2 to 15, in particular 2 to 10, carbon atoms.

The reaction conditions of such coupling are well known to those skilled in the art since it is a Suzuki coupling.

This reaction is advantageously carried out in the presence of a palladium-based catalyst, for example palladium acetate, tetrakistriphenylphosphine palladium (O) or tris (dibenzylideneacetone) dipalladium (O).

An organic or inorganic base may be present, such as an alcoholate (in particular (CrC ₆ ) alkyl-OM with M = Na, K or Li), NMP (N-methyl-morpholine), and ₃ N, iPr ₂ NEt, K ₃ PO ₄ , NaH, Cs ₂ CO ₃ , Na ₂ CO ₃ or K ₂ CO ₃ .

A polar solvent may be used such as tetrahydrofuran, dimethylformamide, acetonitrile, acetone, methyl ethyl ketone, ethanol, dimethyl ether, dioxane, water or a mixture thereof. The reaction may advantageously be carried out at a temperature of between 20 ° C. and 140 ° C. The group -BR ₅₂ R ₅ 3 may for example be a group -B (OH) ₂ , -B ((C 1 (C ₁ -C ₆ ) alkyl) ₂ (for example -B (0

The present invention finally relates to a fourth process for preparing a compound of formula (I) for which R ₉ and / or Rio represents -Z- (CH ₂ ) _m -R49 with Z representing CH ₂ -CH ₂ , CH = CH or C≡C, comprising the following steps:

(1) coupling of Sonogashira between a compound of formula (Va) or (Vb) as defined above

and a compound of formula HC≡C- (CH ₂ ) _m -R ₄₉ for which m and R ₄₉ are as defined above,

to give a compound of formula (I) wherein R ₉ or Rio represents -C≡C- (CH ₂ ) _m -R ₄₉ , and

(2) optionally reducing the alkyne function of the compound of formula (I) obtained in the preceding step to give a compound of formula (I) for which R ₉ or Rio represents -CH = CH- (CH ₂ ) _m -R ₄₉ or - (CH ₂ ) _{m + 2} -R ₄₉ .

Step 1 ) :

Coupling of Sonogashira is a reaction well known to those skilled in the art who will know how to determine the reaction conditions. It is described in particular in the article by Sonogashira et al. in Tetrahedron Lett. 1975, 16, 4467-4470.

This coupling involves a reaction between an acetylenic derivative and an aryl halide or triflate catalyzed by palladium and copper complexes. Such a reaction is typically carried out under an inert atmosphere, in the presence of a catalytic amount of a palladium complex (for example PdCl ₂ (PPh ₃ ) ₂ or Pd (PPh ₃ ) ₄ ), a catalytic amount of a copper salt (eg, Cul), and a base that can be organic, such as triethylamine or DIPEA (diisopropylethylamine), or inorganic, such as sodium, potassium or cesium carbonate. The operating conditions generally include reaction temperatures between 20 ° C and 45 ° C, especially in solvents including dimethylformamide, tetrahydrofuran, dioxane or diethyl ether or a mixture thereof.

2nd step) :

The reduction reaction of the triple bond of the CcyC alkyne function to give a CH = CH double bond or a single CH ₂ -CH ₂ bond is well known to those skilled in the art who will know how to determine the reaction conditions.

This reduction may be carried out for example by hydrogen in the presence of a catalyst, for example palladium on charcoal, especially in a common solvent of ethanol type, to obtain a single bond CH ₂ -CH ₂ .

The four general methods described above may be supplemented, if necessary, by any standard manipulations described in the literature, known to those skilled in the art or else exemplified in the experimental part, in particular by functionalization reactions and / or additional protection / deprotection.

An additional step or steps of salification and / or solvation may be carried out at the end of these three processes in order to obtain a pharmaceutically acceptable salt and / or solvate of the compound of formula (I).

The salification step may be carried out under conditions well known to those skilled in the art, in the presence of a pharmaceutically acceptable acid or base.

When the compound of formula (I) is in a solvated form, this solvation generally takes place in the last stage of the process, the solvent of the solvated form being in this case the solvent of the reaction medium.

The compound of formula (I) obtained by one of these four processes mentioned above may be separated from the reaction medium by well known methods of those skilled in the art, for example by extraction, evaporation of the solvent or by precipitation and filtration.

The compound of formula (I) may be further purified if necessary by techniques well known to those skilled in the art, such as by recrystallization if the compound is crystalline, by distillation, by column chromatography on silica gel or by chromatography high performance liquid (HPLC).

The invention is illustrated by the following nonlimiting examples. EXAMPLES

1. Synthesis of the compounds according to the invention

The following abbreviations have been used:

DMSO: Dimethyl sulfoxide

HPLC: high performance liquid chromatography

IE: Electronic Impact

LAH: Lithium aluminum hydride (LiAIH ₄ )

LCMS: liquid chromatography coupled to a mass spectrometer

NMR: Nuclear Magnetic Resonance 1.1. Synthesis of intermediaries

Intermediate 1: 1 - (4-bromo-3-methoxyphenyl) guanidine

In a 50 ml flask are mixed 1 g (4.95 mmol) of 4-bromo-3-methoxyaniline and 3.57 ml of hydrochloric acid. In small portions, 2.91 g (69.3 mmol) of cyanamide is then added. The reaction mixture is heated at 60 ° C for 2 hours. After returning to ambient temperature, the reaction is hydrolysed by addition of water, basified and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated to give 1.1 g (93%) of 1- (4-bromo-3-methoxyphenyl) guanidine as a yellow solid.

LCMS (IE, m / z): (M + 1) 245.08 1 H NMR: dH ppm (400 MHz, DMSO): 6.54 (4H, s, NH), 7.27-7.29 (1H, d, CH arom), 6.51 (1H, s, CH arom) ), 6.31-6.33 (1H, d, CH arom), 3.77 (3H, s, CH ₃ ).

Intermediate 2: N, N'-Bis (tert-butoxycarbonyl) -N "- (3-methoxyphenyl) guanidine

To 0.77 g (6.26 mmol) of 3-methoxyaniline in 18 ml of N, N-dimethylformamide is added 2 g (6,89 mmol) of 1,3-bis (tert-butoxycarbonyl) -2-methyl- 2-thiopseudourea, 1, 915 mL (13.78 mmol) of triethylamine and then 1.7 g (6.26 mmol) of mercuric chloride at 0 ° C. The reaction mixture is stirred at 0 ° C. for 5 hours and then filtered through Celite®. The filtrate is washed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane: 50/50 to 100% ethyl acetate) to yield 2.25 g (98%) of N, N'-bis (tert-butoxycarbonyl) -N "- (3-methoxyphenyl) guanidine as a white solid.

LCMS (IE, m / z): (M + 1) 366.42

1 H NMR: dH ppm (400 MHz, DMSO): 1.17 (1H, s, NH), 9.98 (1H, s, NH), 7.25-7.27 (2H, m, CHarom), 7.09-7.1 (1H, m, CH arom), 6.72-6.74 (1H, m, CH arom), 3.74 (3H, s, CH ₃ ), 1, 50 (9H, s, CH ₃ ), 1.40 (9H, s, CH ₃ ).

Intermediate 3: 1 - (3-methoxyphenyl) guanidine

To 2.45 g (6.70 mmol) of N, N'-bis (tert-butoxycarbonyl) -N "- (3-methoxyphenyl) guanidine in 16 mL of dichloromethane are added at 0 ° C. The reaction mixture is stirred at 25 ° C. for 24 hours and then concentrated to yield 1.3 g of 1- (3-methoxyphenyl) guanidine, which is used as it is, without purification, in the form of trifluoroacetic acid. 'next step.

LCMS (IE, m / z): (M + 1) 166.19 Intermediate 4: (E) -2 - ((Dimethylamino) methylene) -7-methoxy-3,4-dihydro-naphthalen-1 (2H) -one

7 ml (39.7 mmol) of 7-methoxy-3,4-dihydronaphthalen-1 (2H) -one are added 79 ml of Ν, Ν-dimethylformamide dimethyl acetal (596 mmol). The reaction mixture is refluxed for 15 hours. After evaporation of the solvent under reduced pressure, the residue is purified by chromatography on silica gel (eluent: dichloromethane / AcOEt: 80/20 to 100% AcOEt) to deliver 5.90 g (64%) of (E 2 - ((dimethylamino) methylene) -7-methoxy-3,4-dihydronaphthalen-1 (2H) -one as a yellow solid.

LCMS (IE, m / z): (M + 1) 232.29

1 H NMR: dH ppm (400 MHz, DMSO): 7.55 (1H, s, CH arom), 7.30-7.31 (1H, d, CH arom), 7.14-7.16 (1H, d H, m, CHarom), 6.95-6.98 (1H, m, CH arom), 3.75 (3H, s, CH ₃ ), 3.10 (6H, s, CH ₃ ), 2.82 -2.85 (2H, t, CH ₂ ), 2.67-2.71 (2H, t, CH ₂ ).

Intermediate 5: 9-methoxy-N- (3-methoxyphenyl) -5,6-dihydrobenzo [h] which nazolin-2-amine

0.578 g (2.5 mmol) of (E) -2 - ((dimethylamino) methylene) -7-methoxy-3,4-dihydronaphthalen-1 (2H) -one and 0.496 g (3.00 mmol) of 2 - (3-methoxyphenyl) guanidine in 25 mL of ethanol is added 1.037 g (7.50 mmol) of potassium carbonate. The reaction mixture is refluxed for 15 hours. After returning to ambient temperature, the solvent is evaporated and the solid formed is filtered, rinsed with methanol to yield 0.56 g (67%) of 9-methoxy-N- (3-methoxyphenyl) -5,6-dihydrobenzo [h] quinazolin-2-amine as a yellow powder.

LCMS (IE, m / z): (M + 1) 334.38

1 H NMR: dH ppm (400 MHz, DMSO): 9.54 (1H, s, NH), 8.46 (1H, s, CH arom), 7.78-7.79 (1H, d, CHarom), 7.70 (1H, s, CHarom), 7.14-7.28 (3H, m, CHarom), 7.02-7.05 (1H, m, CHarom), 6.51-6.54 (1H, m, CH arom), 3.84 (3H, s, CH ₃ ), 3.76 (3H, s, CH ₃ ), 2 , 78-2.86 (4H, m, CH ₂ ).

Intermediate 6: N- (4-Bromo-3-methoxyphenyl) -9-methoxy-5,6-dihydrobenzo [h] quinazolin-2-amine

To 14.19 g (58.1 mmol) of 1- (4-bromo-3-methoxyphenyl) guanidine in ethanol (120 mL) are added 10.34 g (44.7 mmol) of (E) -2 - ((dimethylamino) methylene) -7-methoxy-3,4-dihydronaphthalen-1 (2H) -one. The reaction mixture is refluxed for 36 hours. After returning to ambient temperature, the solvent is evaporated and the solid formed is filtered, rinsed with methanol to yield 12.90 g (70%) of N- (4-bromo-3-methoxyphenyl) -9-methoxy-5 6-dihydrobenzo [h] quinazolin-2-amine as a yellow powder.

LCMS (IE, m / z): (M + 1) 413.28

1 H NMR: dH ppm (400 MHz, DMSO): 9.71 (1H, s, NH), 8.43 (1H, s, CH arom), 7.82-7.83 (1H, d, CHarom), 7.76-7.77 (1H, d, CHarom), 7.44-7.46 (1H, d, CHarom), 7.38-7.41 (1H, dd, CHarom) , 7.27-7.30 (1H, d, CHarom), 7.04-7.06 (1H, dd, CHarom), 3.87 (3H, m, CH 3), 3.82 (3H, m, CH 3), 2.77-2.87 (4H, m, CH ₂ ). Intermediate 7: 2 - ((3-hydroxyphenyl) amino) -5,6-dihydrobenzo [h] quinazolin-9-ol

To a solution of 300 mg (0.9 mmol) of 9-methoxy-N- (3-methoxyphenyl) -5,6-dihydrobenzo [h] quinazolin-2-amine in 10 ml of dichloromethane is added 0.45 ml of tribromo-borane at -78 ° C. The reaction medium is then stirred at 45 ° C for 5 hours and then overnight at room temperature. 2 ml of methanol are added to the reaction mixture at 0 ° C. which is then heated at 35 ° C. for 25 minutes. minutes. The solid formed is filtered and then washed twice with 20 ml of ether to give 130 mg (47%) of 2 - ((4-bromo-3-hydroxyphenyl) amino) -5,6-dihydrobenzo [h] quinazolin. 9-ol in the form of a yellow powder.

LCMS (IE, m / z): (M + 1) 306.33

1 H NMR: dH ppm (400 MHz, DMSO): 9.51 (1H, s, NH), 8.35 (1H, s, CH arom), 7.63-7.64 (1H, d, CHarom), 7.29-7.31 (1H, d, CH arom), 7.23-7.24 (1H, d, CH arom), 7.14-7.16 (1H, d, CH arom) , 7.07-7.1 (1H, m, CH arom), 6.86-6.89 (1H, d, CH arom), 6.39-6.42 (1H, d, CH arom), 2.76-2.78 (4H, m, CH ₂ ). Intermediate 8

Intermediate 8 was prepared according to the protocol described for the preparation of Intermediate 4 from 500 mg of 6-fluoro-7-methoxy-3,4-dihydronaphthalen-1 (2H) -one and 2,394 ml of Ν, Ν-dimethylformamide dimethyl acetal to yield 600 mg (93%) of intermediate 8.

LCMS (IE, m / z): (M + 1) 250.28

1 H NMR: dH ppm (400 MHz, DMSO): 7.55 (1H, s, CH arom), 7.49-7.51 (1H, d, CH arom), 7.10-7.13 ( H, d, CHarom), 3.84 (3H, s, CH ₃ ), 3.10 (6H, s, CH ₃ ), 2.84-2.87 (2H, t, CH ₂ ), 2.65 -2.71 (2H, t, CH ₂ ).

Intermediate 9:

Intermediate 9 was prepared according to the procedure described for the preparation of intermediate 5 from 600 mg of intermediate 8 and 0.76 g of 1- (4-bromo-3-methoxyphenyl) guanidine to conduct 550 mg (53%) of Intermediate 9.

LCMS (IE, m / z): (M + 1) 431, 27 1H NMR: dH ppm (400MHz, DMSO): 9.70 (1H, s, NH), 8.42 (1H, s, CH arom), 7.89-7.92 (1H, d, CH arom), , 66 (1H, s, CH arom), 7.45-7.52 (2H, m, CH arom), 7.26-7.29 (1H, d, CH arom), 3.93 (3H, m, CH _3). ), 3.94 (3H, m, CH ₃ ), 2.79-2.85 (4H, m, CH ₂ ). Intermediate 10

Intermediate 10 was prepared according to the protocol described for the preparation of Intermediate 7 from 550 mg of Intermediate 9 to yield 600 mg (97%) of Intermediate 10.

LCMS (IE, m / z): (M + 1) 403.21

1 H NMR: dH ppm (400 MHz, DMSO): 9.64 (1H, s, NH), 8.23 (1H, s, CH arom), 7.81-7.84 (1H, d, CH arom), , 42-7.43 (1H, d, CH arom), 7.33-7.41 (2H, m, CH arom), 7.15-7.18 (1H, d, CH arom), 2.76-2, 79 (4H, m, CH ₂ ).

Intermediate 11 was prepared according to the protocol described for the preparation of Compound 2 from 600 mg of Intermediate 10 to yield 527 mg of Intermediate 11 in 90% yield.

LCMS (IE, m / z): (M + 1) 473.30

1 H NMR: dH ppm (400 MHz, DMSO): 9.81 (1H, s, NH), 8.67 (1H, s, CH arom), 8.42 (1H, s, CH arom), 8.14-8. 17 (1H, d, CH arom), 7.41-7.43 (1H, d, CH arom), 7.26-7.29 (1H, d, CH arom), 6.83-6.85 (1H, d, CHarom), 4.26-4.30 (4H, m, CH ₂ ), 3.79-3.82 (4H, m, CH ₂ ), 2.78-2.82 (4H, m, CH ₂ ). 1.2. Synthesis of the compounds according to the invention

To a stirred solution of 0.93 g (2.1 mmol) of 2 - ((3-hydroxyphenyl) amino) -5,6-dihydrobenzo [h] quinazolin-9-ol in 100 ml of Ν, Ν- dimethylformamide are added

135 mg (0.9 mmol) of potassium carbonate and then 0.099 g (0.426 mmol) of 1-bromo-2- (2-bromoethoxy) ethane in 10 mL of Ν, Ν-dimethylformamide for one hour. The reaction mixture is stirred at 75 ° C for 20 hours. After cooling to room temperature, the solvent was evaporated, water was added and the solid formed was filtered and dried under vacuum to yield 0.01 g (6%) of compound 1 as a beige powder.

LCMS (IE, m / z): (M + 1) 376.42

1 H NMR: dH ppm (400 MHz, DMSO): 9.67 (1H, s, NH), 8.71 (1H, s, CHarom), 8.42 (1H, s, CHarom), 8 , 07 (1H, s, CHarom), 7.24-7.26 (1H, d, CHarom), 7.16 (1H, t, CHarom), 7.02 (1H, d, CHarom) , 6.80-6.82 (1H, d, CHarom), 6.52 (1H, d, CHarom), 4.28 (2H, m, CH ₂ ), 4.09 (2H, m, CH), ₂ ), 3.87-3.92 (4H, m, CH ₂ ), 2.67-2.85 (4H, m, CH ₂ ).

Compound 2:

To a stirred solution of 2,615 g (27.2 mmol) of 2 - ((4-bromo-3-hydroxyphenyl) amino) -5,6-dihydrobenzo [h] quinazolin-9-ol in 362 mL of N, N - dimethylformamide is added 4.7 g (136 mmol) of potassium carbonate and 6.31 g (27.2 mmol) of 1-bromo-2- (2-bromoethoxy) ethane in 123 mL of N, N-dimethylformamide for one hour. The reaction mixture is stirred at 80 ° C for 20 hours. After cooling to room temperature, the solvent was evaporated, water was added and the solid formed was filtered and dried under vacuum to yield 12.2 g (80%) of compound 2 as a beige powder.

LCMS (IE, m / z): (M + 1) 455.31

1 H NMR: dH ppm (400 MHz, DMSO): 9.81 (1H, s, NH), 8.71 -8.72 (1H, s, CH arom), 8.44 (1H, s, CHarom), 8.02-8.03 (1H, d, CHarom), 7.40-7.43 (1H, d, CHarom), 7.26-7.28 (1H, d, CHarom) , 7.05-7.08 (1H, dd, CHarom), 6.88-6.83 (1H, dd, CHarom), 4.24-4.27 (4H, m, CH ₂ ), 3 , 75-3.3,82 (4H, m, CH ₂ ), 2.78-2.85 (4H, m, CH ₂ ).

Compound 3

In a 50 ml flask are mixed 14 mg (0.029 mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl, 53 mg (0.058 mmol) of (dppf) ₂ PdCl ₂ .CH ₂ Cl ₂ , 328. mg (0.722 mmol) of compound 2 and 1.01 g (10.1 mmol) of 1-methylpiperazine under argon. 4 mL of tetrahydrofuran and 5.78 mL (5.78 mmol) of lithium bis (trimethylsilyl) amide (LiHMDS) are added at room temperature. The reaction medium is brought to 80 ° C. for 1 h 45. After cooling to room temperature, the reaction is hydrolysed by slow addition of water at 0 ° C. and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 35.4 mg (10%) of compound 3 in the form of a yellow solid. .

LCMS (IE, m / z): (M + 1) 474.56

1 H NMR: dH ppm (400 MHz, DMSO): 9.46 (1H, s, NH), 8.51 -8.52 (1H, d, CH arom), 8.38 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, d, CHarom) , 6.79-6.85 (2H, m, CH arom), 4.23-4.25 (4H, m, CH ₂ ), 3.75-3.77 (4H, m, CH ₂ ), 2, 94 (4H, m, CH ₂ ), 2.76-2.86 (4H, m, CH ₂ ), 2.45 (4H, m, CH ₂ ), 2.21 (3H, s, CH ₃ ). Compound 4:

Compound 4 was prepared according to the protocol described for the preparation of compound 3 from 0.7 g of compound 2 and 2.29 g of tert-butyl amine piperazine-1-carboxylate to yield 380 mg. (44%) of compound 4.

LCMS (IE, m / z): (M + 1) 560.65

1 H NMR: dH ppm (400 MHz, DMSO): 9.48 (1H, s, NH), 8.54-8.55 (1H, d, CH arom), 8.39 (1H, s, CHarom), 8.02-8.03 (1H, d, CHarom), 7.26-7.28 (1H, d, CHarom), 7.06-7.08 (1H, dd, CHarom) , 6.86-6.87 (1H, m, CHarom), 6.79-6.82 (1H, dd, CHarom), 4.23-4.25 (4H, m, CH ₂ ), 3 , 75-3.81 (4H, m, CH ₂ ), 2.46 (4H, m, CH ₂ ), 2.77-2.89 (8H, m, CH ₂ ), 1, 4 (9H, s , CH ₃ ).

Compound 5

To 380 mg (0.679 mmol) of compound 4 are added, drop by drop, 5 ml of a solution of hydrochloric acid in isopropanol (5N). The solution is stirred at 45 ° C. for 2 h 50 min. The solid formed is filtered and then washed twice with 20 ml of water. The solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated to yield 168 mg (54%) of compound 5 as a yellow solid.

LCMS (IE, m / z): (M + 1) 460.54

1 H NMR: dH ppm (400 MHz, DMSO): 9.45 (1H, s, NH), 8.51 -8.52 (1H, d, CH arom), 8.38 (1H, s, CHarom), 8.02-8.03 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.08 (1H, dd, CHarom) , 6.81 -6.84 (2H, m, CH arom), 4.24 (4H, m, CH ₂ ), 3.74-3.78 (4H, m, CH ₂ ), 3.76-3, 84 (12H, m, CH ₂ ). Compound 6:

Compound 6 was prepared according to the protocol described for the preparation of compound 3 starting from 1 g of compound 2 and of 1.26 g of amine 1,4-dioxa-8-azaspiro [4.5] decane to lead to 246 mg (22%) of compound 6.

LCMS (IE, m / z): (M + 1) 517.58

1 H NMR: dH ppm (400 MHz, DMSO): 9.46 (1H, s, NH), 8.51 -8.52 (1H, d, CH arom), 8.38 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.08 (1H, dd, CHarom) , 6.80-6.88 (1H, m, CHarom), 6.78-6.80 (1H, m, CH arom), 4.22-4.26 (4H, m, CH ₂ ), 3 , 90 (4H, s, CH ₂ ), 2.74-3.79 (4H, m, CH ₂ ), 2.97-3.01 (4H, m, CH ₂ ), 2.75-2.85 (4H, m, CH ₂ ), 1.73-1.77 (4H, m, CH ₂ ).

Compound 7

Compound 7 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 275 mg of 4- (pyrrolidin-3-yl) morpholine amine to yield 10 mg (4% ) of compound 7.

LCMS (IE, m / z): (M + 1) 530.63

1 H NMR: dH ppm (400 MHz, DMSO): 9.45 (1H, s, NH), 8.51 (1H, s, CH arom), 8.38 (1H, s, CH arom), , 01-8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom), 6.79 -6.85 (2H, m, CH arom), 4.22-4.25 (4H, m, CH ₂ ), 3.78-3.79 (4H, m, CH ₂ ), 3.50-3, 54 (2H, m, CH ₂ ), 2.94 (4H, m, CH ₂ ), 2.74-3.86 (4H, m, CH ₂ ), 2.43-2.58 (4H, m, CH ₂₎ ), 2.75-2.85 (5H, m, CH ₂ and CH). Compound 8:

Compound 8 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 229 mg of amine 2- (piperazin-1-yl) ethanol to yield 27 mg (11%). ) of compound 8.

LCMS (IE, m / z): (M + 1) 504.59

1 H NMR: dH ppm (400 MHz, DMSO): 9.35 (1H, s, NH), 8.45-8.47 (1H, d, CH arom), 8.38 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.04-7.07 (1H, dd, CHarom) , 6.75-6.77 (1H, dd, CHarom), 6.65-6.67 (1H, dd, CHarom), 4.02-4.25 (4H, m, CH ₂ ), 3 , 74-3.79 (4H, m, CH ₂ ), 3.58-3.61 (4H, m, CH ₂ ), 3.10-3.25 (3H, m, CH ₂ ), 2.73 -2.86 (6H, m, CH ₂ ), 2.52 (4H, m, CH ₂ ). Compound 9:

Compound 9 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 272 mg of 4- (pyrrolidin-1-yl) piperidine amine to yield 7.3 mg (3). %) of compound 9.

LCMS (IE, m / z): (M + 1) 528.66

1 H NMR: dH ppm (400 MHz, DMSO): 9.44 (1H, s, NH), 8.52-8.51 (1H, d, CH arom), 8.37 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom) , 6.80-6.86 (2H, m, CH arom), 4.22-4.25 (4H, m, CH ₂ ), 3.76-3.77 (4H, m, CH ₂ ), 2, 74-2.86 (4H, m, CH ₂ ), 2.46-2.56 (7H, m, CH ₂ ), 2.02 (1H, m, CH), 1.89-1.90 ( 2H, m, CH ₂ ), 1, 47-1, 57 (2H, m, CH ₂ ), 1.68 (4H, m, CH ₂ ). Compound 10:

Compound 10 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 296 mg of 1,4'-bipiperidine amine to yield 23 mg (9%) of compound 10 .

LCMS (IE, m / z): (M + 1) 542.68

1 H NMR: dH ppm (400 MHz, DMSO): 9.44 (1H, s, NH), 8.50-8.51 (1H, d, CH arom), 8.37 (1H, s, CH arom), 8 , 01-8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom), 6.82-6 , 84 (1H, d, CHarom), 6.77-6.79 (1H, dd, CHarom), 4.22-4.25 (4H, m, CH ₂ ), 3.75-3.79 (4H, m, CH ₂ ), 3.35-3.39 (2H, m, CH ₂ ), 2.75-2.86 (4H, m, CH ₂ ), 2.46-2.56 (6H , m, CH ₂ ), 2.27 (1H, m, CH), 1.75-1.80 (2H, m, CH ₂ ), 1.35-1.62 (8H, m, CH ₂ ). Compound 11

Compound 11 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 277 mg of N, N-dimethyl-2- (piperazin-1-yl) ethanamine to yield 43 mg ( 19%) of compound 11.

LCMS (IE, m / z): (M + 1) 531.66

1 H NMR: dH ppm (400 MHz, DMSO): 9.44 (1H, s, NH), 8.50-8.51 (1H, d, CH arom), 8.37 (1H, s, CH arom), 8 , 01-8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom), 6.82-6, 84 (1H, d, CHarom), 6.77-6.79 (1H, dd, CHarom), 4.22-4.25 (4H, m, CH ₂ ), 3.75-3.79 (4H, m, CH ₂ ), 2.93 (4H, m, CH ₂ ), 2.75-2.86 (4H, m, CH ₂ ), 2.31-2.47 (8H, m, CH), 2 , 14 (6H, m, CH ₃ ). Compound 12:

To 100 mg (0.17 mmol) of compound 36 is added, dropwise, 5 ml of a solution of hydrochloric acid (5N) in isopropanol. The solution is stirred at 45 ° C for 2 hours. The solid formed is filtered and then washed twice with 20 ml of water. The solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 26 mg (31%) of compound 12 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 488.59

1 H NMR: dH ppm (400 MHz, DMSO): 9.45 (1H, s, NH), 8.52 (1H, s, CH arom), 8.38 (1H, d, CH arom), , 02-8.03 (1H, d, CHarom), 7.26-7.28 (1H, d, CHarom), 7.05-7.08 (1H, dd, CHarom), 6.80 (2H, s, CHarom), 4.22-4.25 (4H, m, CH ₂ ), 3.75-3.79 (4H, m, CH ₂ ), 2.85-2.87 (4H, m, CH ₂ ), 2.76-2.78 (4H, m, CH ₂ ), 2.60 (2H, m, CH), 1, 12 (6H, s, CH ₃ ).

Compound 13:

200 mg (0.44 mmol) of compound 2, 84 mg (0.44 mmol) of cuprous iodide and 12 mg (0.660 mmol) of (diethylamino) ethanethiol, HCl are mixed in a microwave reactor. The reaction mixture is heated at 200 ° C for 45 minutes. After returning to ambient temperature, water is added and the solid formed is filtered and purified by chromatography on silica gel (eluent: acetate ethyl / methanol / ammonia: 94/4/2) to give 72 mg (29%) of compound 13 as a yellow solid

LCMS (IE, m / z): (M + 1) 507.66

1 H NMR: dH ppm (400 MHz, DMSO): 9.70 (1H, s, NH), 8.60-8.61 (1H, d, CH arom), 8.43 (1H, s, CHarom), 8.02-8.03 (1H, d, CHarom), 7.26-7.28 (1H, d, CHarom), 7.20-7.22 (1H, d, CHarom) , 7.05-7.06 (1H, dd, CHarom), 6.82-6.85 (1H, dd, CHarom), 4.23- 4.26 (4H, m, CH ₂ ), 3 , 74-3.83 (4H, m, CH ₂ ), 2.75-2.88 (6H, m, CH ₂ ), 2.45-2.60 (6H, m, CH ₂ ), 0.81 -0.93 (6H, t, CH ₃ ). Compound 14

200 mg (0.44 mmol) of compound 2, 84 mg (0.44 mmol) of cuprous iodide and 0.515 ml of (hydroxyethyl) pyrrolidine (4.44 mmol) are mixed in a microwave reactor. The reaction mixture is heated at 200 ° C for 45 minutes. After returning to ambient temperature, water is added and the solid formed is filtered and purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to yield 16.6. mg (7.5%) of compound 14 as a yellow solid. LCMS (IE, m / z): (M + 1) 489.58

1 H NMR: dH ppm (400 MHz, DMSO): 9.47 (1H, s, NH), 8.54 (1H, s, CH arom), 8.38 (1H, s, CH arom), , 02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.04-7.06 (1H, dd, CHarom), 6.93-6.95 (1H, d, CHarom), 6.80-6.82 (1H, dd, CHarom), 4.20-4.26 (4H, m, CH ₂ ), 3.73-3.78 (4H , m, CH _2), 2.74 to 2.86 (6H, m, CH _2), 2.45 to 2.58 (6H, m, CH _2), 1, 69 (4H, m, CH ₃₎ . Compound 15:

In a vial of 50 ml are mixed 2.5 g (5.50 mmol) of compound 2, 0.603 g (1.266 mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl, 106 mg. (0.275 mmol) bis-benzonitrile palladium (II) dichloride, 1.53 g (9.90 mmol) tert-butyl prop-2-yn-1-yl-carbamate and 5.38 g (16.51 g) mmol) of cesium carbonate in 23 ml of Ν, Ν-dimethylformamide at room temperature. To the reaction mixture was added 2.19 g (6.6 mmol) of tetrabutylammonium bromide. The reaction medium is heated at 80 ° C. for 15 hours. After returning to ambient temperature, the reaction is hydrolysed by slow addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / cyclohexane: 60/40) to give 1, 3 g (45%) of compound 15 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 529.59

1 H NMR: dH ppm (400 MHz, DMSO): 9.86 (1H, s, NH), 8.62-8.63 (1H, d, CH arom), 8.45 (1H, s, CHarom), 8.03-8.04 (1H, d, CHarom), 7.32 (1H, t, CHarom), 7.27-7.29 (1H, d, CHarom), 7.20 -7.22 (1H, dd, CHarom), 7.06-7.08 (1H, dd, CHarom), 6.82-6.84 (1H, dd, CHarom), 4.24-4 , 26 (4H, m, CH ₂ ), 3.96-3.98 (2H, m, CH ₂ ), 3.76-3.82 (4H, m, CH ₂ ), 2.77-2.88 (4H, m, CH ₂ ), 1, 41 (9H, m, CH ₃ ).

Compound 16:

In a 50 ml flask are successively introduced 150 mg (0.32 mmol) of compound 3 and 57 mg (0.25 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 15 ml. chloroform. The reaction mixture is refluxed overnight, the solvent is evaporated and the reaction crude is purified by preparative HPLC to yield 1.3 mg (0.7%) of compound 16 as a yellow solid.

LCMS (IE, m / z): (M + 1) 472.55

1 H NMR: dH ppm (400 MHz, DMSO): 9.90 (1H, s, NH), 9.25 (1H, s, CHarom), 8.72 (1H, s, CHarom), 8 , 69 (1H, s, CHarom), 7.90-7.95 (1H, d, CHarom), 7.65-7.70 (2H, m, CHarom), 7.40-7.45 ( 1 H, dd, CHarom), 6.90-6.95 (2H, m, CH arom), 4.40-4.45 (2H, t, CH ₂ ), 4.30 (2H, t, CH ₂ ), 3.90 (2H, t, CH ₂ ), 3.80 (2H, t, CH ₂ ), 2.94 (4H, m, CH ₂ ), 2.76 - 2.86 (4H, m, CH ₂ ), 2.21 (3H, s, CH ₃ ).

Compound 17:

Compound 17 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 250 mg of 1- (oxetan-3-yl) piperazine to yield 58 mg (25%) of compound 17.

LCMS (IE, m / z): (M + 1) 516.60

1 H NMR: dH ppm (400 MHz, DMSO): 9.47 (1H, s, NH), 8.51 -8.52 (1H, s, CH arom), 8.38 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.26-7.28 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom) , 6.80-6.86 (2H, m, CH arom), 4.54-4.57 (2H, m, CH ₂ ), 4.45-4.47 (2H, m, CH ₂ ), 4, 22-4.24 (4H, m, CH ₂ ), 3.73-3.78 (4H, m, CH ₂ ), 3.43-3.48 (1H, m, CH), 2.97 ( 4H, m, CH ₂ ), 2.82-2.86 (2H, m, CH ₂ ), 2.75-2.79 (2H, m, CH ₂ ), 2.40 (4H, m, CH ₂₎ ).

Compound 18

Compound 18 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 302 mg of N, N-dimethyl-3- (piperazin-1-yl) propan-1-amine to conduct 32 mg (13%) of compound 18.

LCMS (IE, m / z): (M + 1) 545.69

1 H NMR: dH ppm (400 MHz, DMSO): 9.46 (1H, s, NH), 8.51 -8.52 (1H, s, CH arom), 8.38 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom) , 6.79-6.85 (2H, m, CH arom), 4.22-4.26 (4H, m, CH ₂ ), 3.74-3.79 (4H, m, CH ₂ ), 2, 97 (4H, m, CH ₂ ), 2.82-2.87 (2H, m, CH ₂ ), 2.75-2.79 (2H, m, CH ₂ ), 2.40 (4H, m, CH ₂ ), 2.30-2.33 (2H, m, CH ₂ ), 2.19-2.23 (2H, m, CH ₂ ), 2.1 (6H, m, CH ₃ ), 1, 52-160 (2H, m, CH ₂ ).

To 100 mg (0.212 mmol) of compound 32 in 1 mL of methanol and 1 mL of THF is added 24 mg (0.63 mmol) of NaBH ₄ at 0 ° C. The reaction medium is stirred at 25 ° C. for 15 hours. The reaction is hydrolysed by slow addition of 1N HCl solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 90/8/2) to give 46 mg (42%) of compound 19 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 475.55

1 H NMR: dH ppm (400 MHz, DMSO): 9.45 (1H, s, NH), 8.50-8.51 (1H, d, CH arom), 8.37 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom) , 6.78-6.86 (2H, m, CH arom), 4.61-4.62 (1H, d, OH), 4.24 (4H, m, CH ₂ ), 3.75-3, 79 (4H, m, CH ₂ ), 3.55 (1H, m, CH), 3.18-3.21 (2H, m, CH ₂ ), 2.76-2.84 (4H, m, CH _2), 2.59 to 2.64 (2H, m, CH _2), 1, 81 -1, 85 (2H, m, CH _2), 1, 49-1, 57 (2H, m, CH ₂ ).

Compound 20

In a microwave reactor are mixed 200 mg (0.44 mmol) of compound 2, 126 mg (0.66 mmol) of cuprous iodide, 287 mg (0.88 mmol) of cesium carbonate and 156 mg (0.880 mmol) tert-butyl (2-mercaptoethyl) carbamate. The reaction mixture is heated at 200 ° C for 45 minutes. After return to temperature ambient, water is added and the solid formed is filtered and then purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to yield 17 mg (7%) of the compound 20 as a yellow solid. LCMS (IE, m / z): (M + 1) 451, 55

1 H NMR: dH ppm (400 MHz, DMSO): 9.71 (1H, s, NH), 8.60-8.61 (1H, d, CH arom), 8.43 (1H, s, CHarom), 8.02-8.03 (1H, d, CHarom), 7.22-7.28 (2H, m, CH arom), 7.05-7.08 (1H, dd, CH arom), 6.83-6.86 (1H, dd, CHarom), 4.23-4.26 (4H, m, CH ₂ ), 3.80-3.83 (4H, m, CH ₂ ), 3, 74-3.77 (2H, m, CH ₂ ), 2.76-2.84 (6H, m, CH ₂ ), 2.66-2.67 (2H, m, CH ₂ ). Compound 21

In a flask and under argon, add 0.3 g (0.568 mmol) of compound 33 in 50 ml of THF / MeOH (1/1). Degas the medium under argon and under vacuum. Add 6.04 mg (0.057 mmol) of Pd-C. Degas the medium under argon and under vacuum then place a hydrogen balloon. The reaction mixture is stirred at 25 ° C overnight and then filtered through silica and rinsed with ethyl acetate and concentrated. The residue is dissolved in 10 ml of a solution of hydrochloric acid in isopropanol (5N). The solution is stirred at 45 ° C for 1 hour. The solvent is evaporated and the reaction is hydrolysed by slow addition of a 1N NaOH solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 90/8/2) to give 1 1.5 mg (7%) of compound 21 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 433.51

1 H NMR: dH ppm (400 MHz, DMSO): 9.53 (1H, s, NH), 8.50 (1H, s, CH arom), 8.40 (1H, s, CH arom), , 03 (1H, d, CHarom), 7.25-7.28 (1H, m, CHarom), 7.00-7.07 (2H, m, CHarom), 6.74-6.79 ( 1H, dd, CHarom), 4.18-4.24 (4H, m, CH ₂ ), 3.73-3.84 (4H, m, CH ₂ ), 2.75-2.85 (4H, m.p. m, CH _2), 1, 59-1, 66 (2H, m, CH _2), 2.51 -2.59 (4H, m, CH _2). Compound 22:

To a solution of 100 mg (0.23 mmol) of compound 21 in 7 ml of 1,2-dichloroethane is added 28 μί (0.23 mmol) of 1-methyl-4-piperidone then 13 μΙ (0.23 mmol) of 'acetic acid. To the reaction medium, 186 mg (0.87 mmol) of sodium triacetoxyborohydride are added in small portions. The reaction medium is stirred for 16 hours at room temperature. The solvent is then concentrated, the reaction mixture is extracted with ethyl acetate and washed with saturated sodium hydroxide solution. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: dichloromethane / methanol / ammonia: 95/4/1) to give 14 mg (11%) of compound 22 as a yellow solid.

LCMS (IE, m / z): (M + 1) 560.67

1 H NMR: dH ppm (400 MHz, DMSO): 9.52 (1H, s, NH), 8.50 (1H, s, CH arom), 8.40 (1H, s, CH arom), , 02-8.03 (1H, d, CHarom), 7.25-7.28 (1H, m, CHarom), 7.04-7.07 (1H, d, CHarom), 6.99 -7.01 (1H, d, CHarom), 6.74-6.76 (1H, d, CHarom), 4.18-4.23 (4H, m, CH ₂ ), 3.75-3 , 83 (4H, m, CH ₂ ), 2.75-2.84 (4H, m, CH ₂ ), 2.65-2.67 (2H, m, CH ₂ ), 2.45-2.57 (6H, m, CH ₂ ), 2.32 (1H, m, CH), 2.10 (3H, m, CH ₃ ), 1.81-1.86 (2H, m, CH ₂ ), 1 , 70-1, 75 (2H, m, CH ₂ ), 1, 60-1, 64 (2H, m, CH ₂ ), 1, 15-1, 28 (1H, m, CH ₂ ).

Compound 23

50 ml (0.09 mmol) of compound 34 in 2 ml of tetrahydrofuran are mixed in a 50 ml flask and then 0.5 ml (0.5 mmol) of lithium aluminum hydride (LAH) is added to 0 ° C. The reaction medium is heated at 85 ° C. for 5 hours. After returning to ambient temperature, the reaction is hydrolysed by addition of sulphate sodium decahydrate and then ethyl acetate. Follow a filtration step on silica and then extraction with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 15 mg (35%) of compound 23 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 471, 56

1 H NMR: dH ppm (400 MHz, DMSO): 9.65 (1H, s, NH), 8.56-8.57 (1H, d, CH arom), 8.42 (1H, s, CHarom), 8.03-8.04 (1H, s, CHarom), 7.26-7.28 (1H, d, CHarom), 7.05-7.08 (1H, dd, CHarom) , 7.01-7.04 (1H, dd, CHarom), 6.79-6.82 (1H, dd, CHarom), 5.75 (1H, m, CH), 4.14-4. , (4H, m, CH ₂ ), 3.74-3.79 (4H, m, CH ₂ ), 2.76-2.86 (4H, m, CH ₂ ), 2.99 (2H, m). , CH ₂ ), 2.45-2.53 (4H, m, CH ₂ ), 2.27 (3H, s, CH ₃ ).

Compound 24

To 50 mg (0.09 mmol) of compound 34 is added, dropwise, 1 ml of a solution of hydrochloric acid (5N) in isopropanol. The solution is stirred at 45 ° C. for 2 h 50 min. The solid formed is filtered and then washed twice with 20 ml of water. The solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 25 mg (51%) of compound 24 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 457.54

1 H NMR: dH ppm (400 MHz, DMSO): 9.56 (1H, s, NH), 8.57 (1H, d, CH arom), 8.42 (1H, s, CH arom), , 03-8.04 (1H, s, CHarom), 7.26-7.28 (1H, d, CHarom), 7.05-7.08 (1H, dd, CHarom), 7.01 -7.04 (1H, d, CHarom), 6.80-6.82 (1H, dd, CHarom), 5.78 (1H, m, CH), 4.15-4.24 (4H) , m, CH ₂ ), 3.75-3.80 (4H, m, CH ₂ ), 2.77-2.85 (4H, m, CH ₂ ), 2.99 (2H, m, CH ₂ ) 2.45-2.53 (4H, m, CH ₂ ). Compound 25:

In a 50 ml flask are mixed 100 mg (0.09 mmol) of compound 21 in its Boc-protected form in 4 mL of tetrahydrofuran and then 0.93 mL (0.93 mmol) of LAH at 0 ° is added. vs. The reaction medium is heated at 85 ° C. for 5 hours. After returning to ambient temperature, the reaction is hydrolysed by addition of sodium sulfate decahydrate and then ethyl acetate. Follow a filtration step and an extraction step with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 10 mg (12%) of compound 25 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 447.54

1 H NMR: dH ppm (400 MHz, DMSO): 9.52 (1H, s, NH), 8.50-8.51 (1H, d, CH arom), 8.40 (1H, s, CHarom), 8.03-8.04 (1H, s, CHarom), 7.25-7.27 (1H, d, CHarom), 7.04-7.07 (1H, dd, CHarom) , 6.99-7.01 (1H, d, CHarom), 6.74-6.76 (1H, dd, CHarom), 4.18-4.24 (4H, m, CH ₂ ), 3 , 75-3.83 (4H, m, CH ₂ ), 2.76-2.84 (4H, m, CH ₂ ), 2.43-2.55 (5H, m, CH ₂ ), 2.26 (3H, m, CH ₃ ).

Compound 26:

In a vial of 10 ml is mixed 1 g (2.201 mmol) of compound 2, 0.24 g (0.50 mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl, 42 mg (0, 11 mmol) of benzonitrile palladium (II) chloride, 0.72 g (3.96 mmol) of 1- (prop-2-yn-1-yl) pyrrolidine and 2.15 g (6.60 mmol) of cesium carbonate in 9 mL of dimethylformamide at room temperature. 0.85 g (2.64 mmol) of tetrabutylammonium bromide is added to the reaction mixture. The reaction medium is brought to 80 ° C for 5 hours. After returning to ambient temperature, the reaction is hydrolysed by slow addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to yield 233 mg (21%) of compound 26 as a yellow solid. LCMS (IE, m / z): (M + 1) 483.57

1 H NMR: dH ppm (400 MHz, DMSO): 9.85 (1H, s, NH), 8.64 (1H, s, CH arom), 8.45 (1H, s, CH arom), , 03 (1H, s, CHarom), 7.27-7.29 (1H, d, CHarom), 7.21 -7.23 (1H, d, CHarom), 7.07-7.08 (1H, d, CHarom), 6.81 -6.83 (1H, d, CHarom), 4.24-4.27 (4H, m, CH ₂ ), 3.76-3.79 (4H , m, CH ₂ ), 3.59 (2H, m, CH ₂ ), 2.80-2.83 (4H, m, CH ₂ ), 2.50-2.58 (4H, m, CH ₂ ) , 1.72 (4H, m, CH ₂ ).

Compound 27

To a solution of 100 mg (0.23 mmol) of compound 32 in 2.5 ml of methanol is added 0.7 g of molecular sieve 4A and 100 mg (2.30 mmol) of ammonium acetate. The reaction medium is stirred for 20 minutes at room temperature and then 1 16 mg (1.84 mmol) of sodium cyanoborohydride are added. The reaction medium is stirred for 16 hours at 60 ° C. The solvent is then concentrated, the reaction mixture is extracted with ethyl acetate and washed with saturated sodium hydroxide solution. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 95/4/1) to give 20 mg (17%) of compound 27 as a yellow solid.

LCMS (IE, m / z): (M + 1) 474.57

1 H NMR: dH ppm (400 MHz, DMSO): 9.44 (1H, s, NH), 8.50 (1H, s, CH arom), 8.37 (1H, s, CH arom), , 01-8.03 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.09 (1H, dd, CHarom), 6.77 -6.85 (2H, m, CH arom), 4.22-4.25 (4H, m, CH ₂ ), 3.74-3.82 (4H, m, CH ₂ ), 3.24-3, 29 (2H, m, NH ₂ ), 2.74-2.86 (4H, m, CH ₂ ), 2.48-2.86 (6H, m, CH ₂ ), 1.75- 1.80 ( 2H, m, CH ₂ ), 1, 35-1, 44 (1H, m, CH). Compound 28:

In a flask and under argon, introduce 0.20 g (0.42 mmol) of compound 26 in 50 mL of THF / MeOH (1/1). Degas the medium under argon and under vacuum. Add 4.56 mg (0.043 mmol) of Pd-C. Degas the medium under argon and under vacuum then place a hydrogen balloon. The reaction mixture is stirred at 25 ° C overnight and then filtered through silica and rinsed with ethyl acetate and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 90/8/2) to yield 71 mg (34%) of compound 28 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 487.61

1 H NMR: dH ppm (400 MHz, DMSO): 9.52 (1H, s, NH), 8.50 (1H, s, CH arom), 8.40 (1H, s, CH arom), , 02-8.03 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.04-7.07 (1H, dd, CHarom), 6.99 -7.01 (1H, m, CHarom), 6.74-6.76 (1H, d, CHarom), 4.18-4.23 (4H, m, CH ₂ ), 3.75-3 , 82 (4H, m, CH ₂ ), 2.76-2.88 (4H, m, CH ₂ ), 2.32-2.39 (8H, m, CH ₂ ), 1.62-1, 70 (6H, m, CH ₂ ).

Compound 29:

To 40 mg (0.07 mmol) of compound 35 is added, dropwise, 1 ml of a solution of hydrochloric acid (5N) in isopropanol. The solution is stirred at 45 ° C. for 2 h 50 min. The solid formed is filtered and then washed twice with 20 ml of water. The solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: acetate ethyl / methanol / ammonia: 94/4/2) to give 11 mg (33%) of compound 29 as a yellow solid.

LCMS (IE, m / z): (M + 1) 486.58

1 H NMR: dH ppm (400 MHz, DMSO): 9.40 (1H, s, NH), 8.50-8.51 (1H, d, CH arom), 8.36 (1H, s, CHarom), 8.02-8.03 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.07 (1H, dd, CHarom) , 6.70-6.79 (2H, m, CHarom), 4.14-4.25 (4H, m, CH ₂ ), 3.74-3.80 (4H, m, CH ₂ ), 3, 09-3.13 (2H, m, CH ₂ ), 2.91 -2.97 (4H, m, CH ₂ ), 2.73-2.84 (4H, m, CH ₂ ), 2.66 ( 2H, m, CH ₂ ), 2.50-2.55 (2H, m, CH ₂ ). Compound 30:

Compound 30 was prepared according to the protocol described for the preparation of compound 3 from 100 mg of compound 2 and 352 mg of N, N-dimethylpyrrolidin-3-amine to yield 2.4 mg (2.4 %) of compound 30.

LCMS (IE, m / z): (M + 1) 488.59

1 H NMR: dH ppm (400 MHz, DMSO): 9.35 (1H, s, NH), 8.47-8.48 (1H, d, CH arom), 8.35 (1H, s, CHarom), 8.01 -8.02 (1H, d, CHarom), 7.24-7.25 (1H, d, CHarom), 7.04-7.06 (1H, dd, CHarom) , 6.75-6.77 (1H, dd, CHarom), 6.64-6.66 (1H, d, CH arom), 4.05-4.27 (4H, m, CH ₂ ), 3 , 73-3.79 (4H, m, CH ₂ ), 3.10-3.23 (3H, m, CH and CH ₂ ), 2.69-2.84 (4H, m, CH ₂ ), 2 17 (6H, m, CH ₃ ), 1.99-2.05 (2H, m, CH ₂ ), 1.66-1.73 (2H, m, CH ₂ ).

Compound 31:

Compound 31 was prepared according to the protocol described for the preparation of compound 3 from 300 mg of intermediate 11 and 127 mg of 1-methylpiperazine to yield 37 mg (11%) of compound 31. LCMS (IE, m / z): (M + 1) 492.56

1 H NMR: dH ppm (400 MHz, DMSO): 9.47 (1H, s, NH), 8.49-8.50 (1H, d, CH arom), 8.36 (1H, s, CHarom), 8.13-8.16 (1H, d, CH arom), 7.25-7.28 (1H, d, CH arom), 6.80-6.86 (2H, m, CH arom), 4.23-4.29 (4H, m, CH ₂ ), 3.75 (4H, m, CH ₂ ), 2.94 (4H, m, CH ₂ ), 2.74-2.87 (4H, m, CH ₂ ), 2.45 (4H, m, CH ₂ ), 2.21 (3H, s, CH ₃ ).

Compound 32

To 246 mg (0.476 mmol) of compound 6 is added, dropwise, 3.6 ml of a solution of hydrochloric acid in isopropanol (5N). The solution is stirred at 100 ° C for 12 hours. The solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated to yield 209 mg (93%) of compound 32 as a yellow solid.

LCMS (IE, m / z): (M + 1) 573.53

Compound 33:

In a vial of 10 ml are mixed 2.5 g (5.5 mmol) of compound 2, 0.60 g (1.26 mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6'-triisopropylbiphenyl, 106 mg (0.27 mmol) of benzonitrile palladium (II) chloride, 1.53 g (9.90 mmol) of tert-butyl ester and prop-2-ynyl-carbamic acid and 5.38 g. 5 mmol) of cesium carbonate in 24 ml of dimethylformamide at room temperature. To the reaction mixture was added 2.12 g (6.60 mmol) of tetrabutylammonium bromide. The reaction medium is heated at 80 ° C. for 5 hours. After returning to ambient temperature, the reaction is hydrolysed by slow addition of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to yield 1.3 g (45%) of compound 33 as a yellow solid. LCMS (IE, m / z): (M + 1) 529.59

1 H NMR: dH ppm (400 MHz, DMSO): 9.86 (1H, s, NH), 8.62-8.63 (1H, d, CH arom), 8.45 (1H, s, CHarom), 8.03-8.04 (1H, d, CHarom), 7.25 (1H, t, NH), 7.27-7.29 (1H, d, CHarom), 7.20 -7.22 (1H, d, CHarom), 7.06-7.08 (1H, dd, CHarom), 6.82-6.84 (1H, dd, CHarom), 4.25-4 , 29 (4H, m, CH ₂ ), 3.96-3.98 (2H, m, CH ₂ ), 3.76-3.81 (4H, m, CH ₂ ), 2.79-2.86 (4H, m, CH ₂ ), 1, 41 (9H, s, CH ₃ ). Compound 34

In a microwave reactor are mixed 463 mg (1.01 mmol) of compound 2, 0.3 g (0.970 mmol) of pinacol ester and N-Boc-1, 2,3,6-tetrahydropyridine acid Boronic and 0.056 g (0.049 mmol) of tetrakis (triphenylphosphine) palladium (0) in 8 ml of tetrahydrofuran. The reaction mixture is stirred at ambient temperature for 10 minutes and 0.25 g (2.466 mmol) of sodium carbonate dissolved in 1 ml of water are then added at ambient temperature. The reaction mixture is heated at 150 ° C for 20 minutes. After returning to ambient temperature, ethyl acetate is added and the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulfate and filtered. The filtrate is evaporated and the residue purified by chromatography on a silica column using Companion® (eluent: dichloromethane / methanol / ammonia: 95/4/1) to yield 87 mg (12%) of compound 34 a yellow solid

LCMS (IE, m / z): (M + 1) 557.65

1 H NMR: dH ppm (400 MHz, DMSO): 9.67 (1H, s, NH), 8.57 (1H, s, CH arom), 8.42 (1H, s, CH arom), , 03- (1H, s, CHarom), 7.26-7.28 (1H, m, CH arom), 7.03-7.06 (1H, m, CH arom), 7.01-7, 04 (1H, dd, CHarom), 6.79-6.82 (1H, dd, CHarom), 5.76 (1H, m, CH), 4.16-4.24 (4H, m, CH ₂ ), 3.74-3.79 (4H, m, CH ₂ ), 2.76-2.88 (4H, m, CH ₂ ), 2.99 (2H, m, CH ₂ ), 2, 45-2.53 (4H, m, CH ₂ ), 1.42 (9H, s, CH ₃ ). Compound 35:

Compound 35 was prepared according to the protocol described for the preparation of compound 3 from 400 mg of compound 2 and 748 mg of tert-butyl hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxylate to yield 200 mg (38%) of compound 35.

LCMS (IE, m / z): (M + 1) 586.69

Compound 36

Compound 36 was prepared according to the protocol described for the preparation of compound 3 from 200 mg of compound 2 and 442 mg of tert-butyl 2,2-dimethylpiperazine-1-carboxylate to yield 100 mg (12% ) of compound 36.

LCMS (IE, m / z): (M + 1) 586.69

Compound 37

In a 50 ml flask are mixed 68 mg (0.1 mmol) of compound 35 in 2.47 ml of THF and 0.58 ml of a 1 M solution in THF of LAH (0.58 mmol). at 0 ° C. The reaction medium is heated at 85 ° C. for 3 hours. After returning to ambient temperature, the reaction is hydrolysed by addition of sodium sulfate decahydrate then with ethyl acetate. It is filtered through silica and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 14 mg (23%) of compound 37 as a yellow solid.

LCMS (IE, m / z): (M + 1): 500.60

1 H NMR: dH ppm (400 MHz, DMSO): 9.41 (1H, s, NH), 8.51 -8.52 (1H, d, CH arom), 8.37 (1H, s, CHarom), 8.02-8.03 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.08 (1H, dd, CHarom) , 6.76-6.79 (1H, dd, CHarom), 6.70-6.72 (1H, d, CHarom), 4.16-4.25 (4H, m, CH ₂ ), 3 , 74-3.80 (4H, m, CH ₂ ), 3.1 1 -3.15 (2H, m, CH ₂ ), 2.91 -2.95 (2H, m, CH ₂ ), 2, 82-2.86 (2H, m, CH ₂ ), 2.71 -2.78 (4H, m, CH ₂ ), 2.61 -2.66 (2H, m, CH ₂ ), 2.24- 2.26 (2H, m, CH), 2.21 (3H, m, CH ₃ ).

Compound 38

In a flask and under argon, add 0.49 g (0.89 mmol) of compound 34 in 50 mL of a mixture of 1,4-dioxane / ethanol (345 mL / 25 mL). Degas the medium again under argon and under vacuum. Add 3.15 g (2.96 mmol) of Pd-C. Repeat the degassing of the medium under argon and under vacuum then place a hydrogen balloon. The reaction mixture is stirred at 25 ° C overnight, filtered through silica, rinsed with ethyl acetate and then concentrated to yield 300 mg (60%) of compound 38 as a yellow oil. LCMS (IE, m / z): (M + 1) 559.66

Compound 39

300 ml (0.53 mmol) of compound 38 is added dropwise 1 ml of a solution of hydrochloric acid (5N) in isopropanol. The solution is stirred at 45 ° C for 3 hours. The solvent is evaporated. The solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 29 mg (1 1%) of compound 39 as a yellow solid.

LCMS (IE, m / z): (M + 1) 459.55.

1 H NMR: dH ppm (400 MHz, DMSO): 9.56 (1H, s, NH), 8.50 (1H, d, CH arom), 8.40 (1H, s, CH arom), , 03-8.04 (1H, s, CHarom), 7.26-7.28 (1H, d, CHarom), 7.03-7.08 (2H, m, CHarom), 6.79- 6.82 (1H, dd, CHarom), 4.15-4.24 (4H, m, CH ₂ ), 3.74-3.80 (5H, m, CH ₂ and CH), 2.99- 3.02 (2H, m, CH _2), 2.77 to 2.89 (4H, m, CH _2), 2.99 (2H, m, CH _2), 1, 50 (4H, m, CH ₂ ). Compound 40:

In a 50 ml flask are mixed 100 mg (0.17 mmol) of compound 36 in 3.62 ml of THF and 0.85 ml of a solution of 1 M LAH in THF (0.85 mmol) at room temperature. 0 ° C. The reaction medium is heated at 85 ° C. for 5 hours. After returning to ambient temperature, the reaction is hydrolysed by addition of sodium sulfate decahydrate and then with ethyl acetate. It is filtered through silica and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to yield 8.10 mg (10%) of compound 40 in the form of a yellow solid. .

LCMS (IE, m / z): (M + 1) 502.62

1 H NMR: dH ppm (400 MHz, MeOH): 8.58 (1H, s, CH arom), 8.25 (1H, s, CH arom), 8.14 (1H, s, CH arom), , 20-7.22 (1H, d, CHarom), 7.03-7.04 (1H, dd, CHarom), 6.87-6.89 (1H, d, CHarom), 6.68 -6.71 (1H, dd, CHarom), 4.27-4.34 (4H, m, CH ₂ ), 3.81 -3.88 (4H, m, CH ₂ ), 2.88 (2H , s, CH ₂ ), 2.27-2.87 (8H, m, CH ₂ ), 2.28 (3H, s, CH ₃ ), 1, 17 (6H, s, CH ₃ ). Compound 41:

Compound 41 was prepared according to the protocol described for the preparation of compound 3 from 0.37 g of compound 2 and 0.34 g of amine (1 R, 5S) -3,8-diazabicyclo [3.2 Tert-butyl octane-8-carboxylate.

LCMS (IE, m / z): (M + 1) 586.69

Compound 42

477 mg (0.81 mmol) of compound 41 is added, dropwise 15 ml of a solution of hydrochloric acid (5N) in isopropanol. The solution is stirred at 45 ° C for 1 h 30. The solvent is evaporated and the solid formed is placed in basic medium and then extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue thus obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to yield 98 mg (25%) of compound 42 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 486.57

1 H NMR: dH ppm (400 MHz, DMSO): 9.39 (1H, s, NH), 8.50 (1H, d, CH arom), 8.36 (1H, s, CH arom), , 02-8.03 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.05-7.08 (1H, dd, CHarom), 6.74 (2H, m, CHarom), 4.23-4.25 (4H, m, CH ₂ ), 3.86 (2H, m, CH ₂ ), 3.74-3.79 (4H, m, CH ₂₎ ), 2.94-2.97 (2H, m, CH ₂ ), 2.73-2.86 (4H, m, CH ₂ ), 2.54-2.57 (2H, m, CH ₂ and CH), 1.79 (4H, m, CH ₂ ). Compound 43:

Compound 43 was prepared according to the protocol described for the preparation of compound 3 from 0.40 g of compound 2 and 0.34 g of amine (1S, 4S) -2,5-diazabicyclo [2.2 .1] tert-butyl heptane-2-carboxylate. The compound 43 thus obtained was used as it is.

LCMS (IE, m / z): (M + 1) 572.66

Compound 44

To 200 mg (0.35 mmol) of compound 43 is added dropwise 5 ml of a solution of hydrochloric acid (5N) in isopropanol. The solution is stirred at 45 ° C for 1 h15. The solvent is evaporated and the solid formed is placed in basic medium and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate / methanol / ammonia: 94/4/2) to give 16 mg (9%) of compound 44 in the form of a yellow solid.

LCMS (IE, m / z): (M + 1) 472.55

1 H NMR: dH ppm (400 MHz, DMSO) 9.31 (1H, s, NH), 8.44-8.45 (1H, d, CH arom), 8.34 (1H, s, CH arom) ), 8.01 -8.02 (1H, d, CHarom), 7.25-7.27 (1H, d, CHarom), 7.04-7.06 (1H, dd, CHarom), 6.73-6.75 (1H, dd, CHarom), 6.56-6.58 (1H, d, CH arom), 4.01-4.26 (4H, m, CH ₂ ), 3, 99-3.01 (1H, m, CH), 3.74-3.79 (4H, m, CH ₂ ), 3.60-3.63 (1H, m, CH), 3.49 ( 1 H, m, CH), 2.99-3.02 (1H, m, CH), 2.80-2.85 (4H, m, CH ₂ ), 2.72-2.77 (2H, m, CH ₂ ), 1, 54-1, 74 (2H, m, CH ₂ ). 2. Biological activity of the compounds according to the invention

The following abbreviations have been used:

ATP: Adenosine-5'-triphosphate

IMDM: Dulbecco's Iscove's Modified Medium

PSFG: Penicillin Streptomycin FunGizone

RPMI: Roswell Park Memorial Institute medium

SVF: Fetal calf serum

Measurement of In Vitro Inhibition Activities of the Compounds According to the Invention

The recombinant enzymes FLT3 (# PV3182), JAK2 (# PV4210) and JAK3 (# PV3855) were purchased from Life Technologies. The FLT3-ITD (# 0778-0000-1) and FLT3 ^D835Y (# 14-610) proteins were purchased from Proquinase and Merck Millipore, respectively. All the tests were carried out in 384-well plates. The principle of these binding tests is based on LanthaScreen® TR-FRET methodology from Life Technologies.

FLT3 tests. The reaction mixture of 15 μl of total volume contains the following compounds: 15nM of FLT3, FLT3-ITD or FLT3D ^835Y , 3nM of tracer kinase 236 (Life Technologies, # PV5592) and 6nM of LanthaScreen® anti-GST antibody coupled to a europium chelate (Life Technologies, # PV5594) for FLT3-ITD and FLT3D ^835Y or 6nM of LanthaScreen® anti-His antibody coupled to a europium chelate (Life Technologies, # PV5596) for FLT3.

JAK tests. The reaction mixture of 15 μl of total volume contains the following compounds: 15nM of JAK2 or JAK3, 150nM of tracer kinase 236 (Life Technologies, # PV5592) for JAK2 or 3nM for JAK3 and 6nM of LanthaScreen® anti-GST antibody coupled to a europium chelate (Life Technologies, # PV5594) for both enzymes. The compounds are evaluated at 8 different concentrations prepared by making dilutions from a 10mM starting stock solution in dimethylsulfoxide (DMSO) (Sigma, # D8418). The final concentration of DMSO in the test is 1%. The reaction is carried out at 25 ° C. for 1 hour and detected on the EnVision® reader (Perkin Elmer) according to the recommendations of the Life Technologies supplier.

The results are presented (Table 1) in the form of compound concentration values for inhibiting 50% of the kinase activity, IC ₅ o (μΜ), generated using the Prism software (GraphPad). Compound / enzyme FLT3 FLT3-ITD _{F |} _ _T3 D835Y JAK2 JAK3

3 0.0025 0.00014 0.003 0.0175 0.054

5 0.0044 0.0013 0.00066 0.013 0.030

7 0.018 0.0064 0.0072 0.0400 0.120

10 0.006 0.0013 0.001 1 0.0077 0.060

14 0.007 0.002 0.0032 0.034 0.070

19 0.0036 0.0024 0.0053 0.020 0.030

23 0.0045 0.0017 0.0045 0.130 0.1 10

29 0.00370 0.000790 0.00190 0.01 15 0.0180

30 0.0032 0.001 0.0032 0.010 0.0180

40 0.0019 0.00051 0.0010 0.00725 0.0176

42 0.0032 0.001 1 N / A 0.00670 0.0130

44 0.0052 0.0015 ND 0.0335 0.035

Table 1: Inhibition (IC ₅₀ (μΜ)) of FLT3, FLT3 ID, FLT3 D835Y, JAK2 and JAK3 enzymes by the compounds according to the invention (ND = Not Determined). The compounds according to the invention exhibit a strong inhibiting activity of both FLT3 enzymes (wild-type or mutated form) and enzymes JAK2 and 3.

In vitro measurement of the antiproliferative activity of the compounds according to the invention:

Cell lines.

The characteristics of the cell lines used are as follows (Table 2):

Table 2: Characteristics of the cell lines used. Measurement of antiproliferative activity.

The MV4-1 and MOLM-13 cell lines are cultured in the culture medium specified in Table 2 above and according to the supplier's recommendations. The tests are carried out in 96-well plates. The cells are split on D0. On day 1, they are inoculated and treated with the compounds at different concentrations and incubated for 72 hours at 37 ° C. and 5% CO ₂ . Dilution of the compounds from stock solutions in DMSO (Sigma, # D8418) was done semi logarithmically for a final concentration in the culture medium of 0.1%. At day 4, cell viability is assessed by assaying ΓΑΤΡ released from living cells using the ATPLite® kit (Perkin Elmer, # 6016947). The EC ₅₀ values (compound concentration needed to achieve 50% of the maximum effect) are calculated using curve fitting software. The results in the form of EC ₅ o values are shown in Table 3.

Table 3: Cytotoxicity of the compounds according to the invention (in M) on cell lines MV41 1 and MOLM13.

Claims

CLAIMS 1. Compound of general formula (I) below:

or a pharmaceutically acceptable salt and / or solvate thereof,

in which :

W represents an oxygen or sulfur atom,

X represents a hydrocarbon chain, saturated or unsaturated, comprising 1 to 3 carbon atoms, optionally substituted by one or more groups chosen from a halogen atom, a (CrC ₆ ) alkyl, oxo, OH and (d-C _{6) group;} ) alkoxy, one or more, especially 1 or 2, carbon atoms of said chain being optionally each replaced, independently of each other, by an oxygen or sulfur atom,

Y represents a nitrogen atom or a CRy group with Ry representing a hydrogen atom, a halogen atom, a (CrC ₆ ) alkyl, (CC ₆ ) haloalkyl, (CC ₆ ) alkoxy, (CC ₆ ) group; haloalkoxy, OH, CN, NO ₂ , NR ₁₂ R ₁₃ , CO ₂ H or CO ₂ ((C ₁ -C ₆ ) alkyl),

R 1, R ₂ , R 3, R ₄ , R ₅ , R 6, R 7, and R ₈ represent, independently of one another, a hydrogen atom or a (C ₁ -C ₆ ) alkyl group, R ₉ and Rio represent, independently of one another, a hydrogen atom, a halogen atom, an optionally substituted (CrC ₆ ) alkyl, optionally substituted (C ₂ -C ₆ ) alkenyl group, (C ₂ -C ₆ ) optionally substituted alkynyl, optionally substituted (CrC ₆ ) alkoxy, optionally substituted (CrC ₆ ) thioalkoxy, CN, NO ₂ , NR ₁₄ R ₁₅ , OH, SH, CO ₂ R ₅₄ , CONR55R56, optionally substituted carbocycle or an optionally substituted heterocycle,

Ru represents a hydrogen atom, a halogen atom, or a (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) haloalkoxy group, and

R12, Ri3, R _4, Ris, R _4, R 55 and R ₅₆ represent, independently each other, a hydrogen atom or a (CrC ₆₎ alkyl, optionally substituted (C ₂ -C ₆₎ alkenyl optionally substituted or (C ₂ -C ₆ ) optionally substituted alkynyl, or R 12 and R ₁₃ , and / or R and R ₁₅ and / or R 55 and R ₅₆ , independently of one another, form with the nitrogen atom which carry an optionally substituted heterocycle.

2. Compound according to claim 1, characterized in that X represents a chain CH ₂ -CH ₂ or CH = CH.

3. Compound according to any one of claims 1 and 2, characterized in that Y represents a CRy group with Ry representing a hydrogen atom or a halogen atom such as F.

4. Compound according to any one of claims 1 to 3, characterized in that W and Q each represent, independently of each other, O or S, preferably O, and Ai and A ₂ each represent a bond simple.

5. Compound according to any one of claims 1 to 4, characterized in that W and Q each represent an oxygen atom, Ai and A ₂ each represent a single bond and R 1, R ₂ , R 3, R ₄ , R _5, R6, R7 and R ₈ each represent a hydrogen atom.

6. Compound according to any one of claims 1 to 5, characterized in that Ru represents a hydrogen atom.

7. Compound according to any one of claims 1 to 6, characterized in that R ₉ and R ₀ represent, independently of one another, a hydrogen atom, a halogen atom or a group (CrC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, (CC ₆ ) alkoxy, (C ₁ -C ₆ ) thioalkoxy, (C ₁ -C ₆ ) alkylamino, di ((C ₁ -C ₆ ) alkyl) amino or heterocycle, said group being optionally substituted by one or more substituents chosen from:

a halogen atom,

a (CrC ₆ ) alkyl group optionally substituted with one or more groups chosen from a halogen atom, ORi ₆ , SRu and NR ₁₈ R ₁₉ ,

the groups oxo (= O), CN, NO ₂ , OR ₂₀ , SR ₂ , NR ₂₂ R ₂₃ , C (O) R ₂₄ , C0 ₂ R ₂₅ , OC (O) R ₂₆ , S (O) R ₂₇ , S0 ₂ R ₂₈ , NR ₂₉ C (O) R ₃₀ , C (O) NR ₃ R ₃₂ , NR ₃₃ CO ₂ R ₃₄ , OC (O) NR ₃₅ R ₃₆ , NR ₃₇ CONR ₃₈ R ₃₉ and OCO ₂ R ₄₀ ,

a carbocycle optionally substituted with one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, oxo (= O), OR ₄ i, SR ₄₂ and NR ₄₃ R ₄₄ , - a heterocycle optionally substituted with a or more than one group selected from halogen, (C ₁ -C ₆ ) alkyl, oxo (= O), OR ₄₅ , SR ₄₆ and NR ₄₇ R ₄₈ , and -O (CH ₂ ) _n O- with n representing an integer between 1 and 5, in particular between 2 and 3,

or :

R ₆ to R ₄₈ represent, independently of each other, a hydrogen atom, a (C ₁ -C ₆ ) alkyl, aryl, aryl- (C ₁ -C ₆ ) alkyl, heterocycle or heterocycle- (C ₁ -C ₆ ) alkyl group,

8. Compound according to any one of claims 1 to 7, characterized in that R ₉ and R ₀ represent, independently of one another:

a hydrogen or halogen atom, a group -Z- (CH ₂ ) _m -R49 wherein Z is a single bond, CH ₂ -CH ₂ , CH = CH, C≡C, O, S or NR ₅₀ ; m represents an integer between 1 and 6, in particular between 1 and 4; R ₅₀ represents a hydrogen atom or a (C ₁ -C ₆ ) alkyl group; and R ₄₉ represents a halogen atom, OR ₂ o, NR ₂₂ R ₂₃ , C (O) R ₂₄ , CO ₂ R ₂₅ , OC (O) R ₂₆ , NR ₂₉ C (O) R ₃ o, C (O) NR ₃₁ R _32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36i 7CONR NR ₃ ₃ ₃ eR 9 or OCO ₂ R _40; particularly OR20, NR22R23i C0 ₂ R _25, C (0) N R3lR32, NR ₃₃ C0 ₂ R _34, OC (0) N R35R36, NR ₃ 7CONR eR ₃ ₃ 9 or OCO ₂ R _40; in particular NR22R23, NR ₃₃ C0 ₂ R ₃₄ , or NR ₃₇ CONR ₃₈ R ₃₉ , or

a monocyclic or bicyclic heterocycle, each ring being 5, 6 or 7-membered, preferably 5 or 6-membered, comprising 1 or 2 heteroatoms chosen from N and O, preferably saturated or comprising a double bond, optionally substituted with one or more substituents chosen from:

• a halogen atom,

A 3- to 6-membered heterocycle, comprising 1 or 2 heteroatoms chosen from N and O, in particular saturated or unsaturated, preferably saturated, optionally substituted by one or more groups chosen from a halogen atom, a (CrC ₆ ) group; alkyl, oxo (= O), OR ₄₅ and NR ₄₇ R ₄₈ , and

A -O (CH ₂ ) _n O- group with n representing an integer equal to 2 or 3, R16, ie R ₂ o, R 22 to R ₂ 6, R29 to R40, R45 and R ₄₇ to R ₄₈ represent, independently each other, a hydrogen atom, a (CrC ₆₎ alkyl, aryl, aryl - (d-C ₆ ) alkyl, heterocycle or heterocycle- (C ₁ -C ₆ ) alkyl,

the aryl ring of these groups being a phenyl group and being optionally substituted by one or more groups selected from a halogen atom and a (CrC ₆ ) alkyl group, and

R ₂₂ and R ₂₃ , R ₃₁ and R ₃₂ , R ₃₅ and R ₃₆ , R ₃₈ and R ₃₉ , R ₄₃ and R ₄₄ , and / or R ₄₇ and R ₄₈ together with the nitrogen atom which carries them, a 5- or 6-membered nitrogen heterocycle, preferably saturated, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, the heterocycle optionally being substituted with one or more groups selected from halogen, (C ₁ -C ₆ ) alkyl, and oxo (= O).

9. Compound according to any one of claims 1 to 8, characterized in that R10 represents a hydrogen atom.

10. Compound according to any one of claims 1 to 9, characterized in that it is a compound of formula (Ib) below:

or a pharmaceutically acceptable salt and / or solvate thereof,

in which :

= represents a single bond or a double bond, preferably a single bond, Ry represents a hydrogen atom, a halogen atom, a (CC ₆ ) alkyl or (C ₁ -C ₆ ) haloalkyl group; in particular a hydrogen atom or a halogen atom, and

R ₉ represents a saturated monocyclic or bicyclic nitrogenous heterocycle, each ring comprising 5 or 6 members, optionally comprising 1 heteroatom selected from N and O in addition to the nitrogen atom, such as a piperazine ring, 2.5 diazabicyclo [4.2.0] octane, 3,8-diazabicyclo [3.2.1] octane, 2,5-diazabicyclo [2.2.1] heptane, piperidine, morpholine, perhydropyrrolo [3,4-c] pyrrole or pyrrolidine, l nitrogen heterocycle being bound to the rest of the molecule by its nitrogen atom and being optionally substituted by one or more substituents chosen from:

^■ a halogen atom,

^■ a (CrC ₆₎ alkyl optionally substituted with one or more groups selected from a halogen atom, ORi ₆ and NR ₈ Rig,

^■ oxo (= 0) OR _20, NR22R23, CO2R25, C (0) NR ₃ ₃ iR 2, NR33CO2R34, OC (0) NR ₃₅ R ₃ 6, NR37CONR38R39 and OC0 ₂ R ₄ o,

^■ a carbocyclic C ₃ -C ₆ optionally substituted by one or more groups selected from a halogen atom, a (CrC ₆₎ alkyl, oxo (= 0) OR41 and

^■ a heterocycle with 3 to 6 members, comprising 1 or 2 heteroatoms selected from N and O, preferably saturated, optionally substituted by one or more groups selected from a halogen atom, a (CrC ₆₎ alkyl, oxo (= 0), OR45 and N R47R48, and

^■ a group -0 (CH ₂₎ _n O- where n is an integer equal to 2 or 3 (both oxygens of this group can be attached to the same atom or two separate atoms, preferably, they will be attached to the same atom , in particular at the same carbon atom which in this case will make it possible to form a cyclic acetal),

or :

♦ R16, Rie at R20, R22! R23! R25! R31 to R41, R43 to R45, R47 and R48 represent, independently of one another, a hydrogen atom, a (CC ₆ ) alkyl, aryl or aryl- (C ₁ -C ₆ ) alkyl group, in particular a hydrogen atom. , or a group (CrC ₆ ) alkyl, the aryl ring of these groups being preferably a phenyl group and being optionally substituted by one or more groups selected from a halogen atom and a (C ₁ -C ₆ ) alkyl group, or

R ₂₂ and R ₂₃ , R ₃₁ and R ₃₂ , R ₃₅ and R ₃₆ , R ₃₈ and R ₃₉ , and / or R ₄₇ and R ₄₈ together with the nitrogen atom carrying them, form a nitrogen heterocycle at 5 or 6-membered, in particular non-aromatic, preferably saturated, optionally comprising 1 heteroatom in addition to the nitrogen atom chosen from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, the heterocycle being optionally substituted by one or more groups selected from a halogen atom, a group (CrC ₆ ) alkyl, and oxo (= 0).

1 1. Compound according to Claim 1, characterized in that it is chosen from the following compounds:

77

79

and their pharmaceutically acceptable salts and / or solvates.

12. A compound according to any one of claims 1 to 1 1 for use as a medicament.

13. A compound according to any one of claims 1 to 1 for its use in the treatment of cancer.

14. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 1 1 and at least one pharmaceutically acceptable excipient.

15. Process for the preparation of a compound according to any one of claims 1 to 1 1 comprising the coupling reaction between:

a compound of formula (II) below:

for which W, X, Y, R ₉ , R ₁₀ and Ru are as defined in claim 1, and a compound of formula (III) below:

for which Q, A ₂ and R | to R ₈ are as defined in claim 1 and Ld and LG ₂ each represent, independently of each other, a leaving group.

16. Process for the preparation of a compound according to any one of claims 1 to 1 1, wherein R ₉ or Rio represents an optionally substituted (CrC ₆ ) alkoxy, optionally substituted (CrC ₆ ) thioalkoxy or NR ₄ R _{5 group.} or an optionally substituted heterocycle comprising a heteroatom directly attached to the phenyl ring, comprising the coupling between a compound of the following formula (IVa) or (IVb):

or

for which W, X, Y, Q, A ₂ and R | at Ru are as defined in claim 1 and X1 represents a halogen atom such as Br, Cl or I,

and respectively a compound of formula R ₉ H or Ri ₀ H for which R ₉ and R ₀ are as defined above.

17. Process for the preparation of a compound according to any one of claims 1 to 1 1, for which R ₉ and / or Rio represents an optionally substituted (CrC ₆ ) alkyl, optionally substituted (C ₂ -C ₆ ) alkenyl group. or optionally substituted (C ₂ -C ₆ ) alkynyl, an optionally substituted carbocycle or an optionally substituted heterocycle bonded to the phenyl ring by means of a carbon atom, comprising coupling between a compound of the following formula (Va) or (Vb) :

or

wherein W, X, Y, Q, A ₂ and R 1 -R 1 are as defined in claim 1 and X ₂ represents Br, Cl, I or OTf,

and respectively a compound of formula R9-BR52R53 or R ₁₀ -BR ₅ 2R53 wherein R ₉ and R 1 ₀ are as defined above and R ₅₂ and R ₅₃ represent, independently of one another, OH , (CrC ₆ ) alkyl or (CrC ₆ ) alkoxy or R ₅ 2 and R ₅₃ together form a chain -X ₃ - or -O-X ₃ -O- for which X ₃ represents a divalent hydrocarbon group comprising 2 to 15, in particular 2 to 10, carbon atoms.

18. A process for the preparation of a compound according to claim 8, wherein R ₉ and / or R 10 represents a group -Z- (CH ₂ ) _m -R49 with Z representing CH ₂ -CH ₂ , CH = CH or C≡ C, comprising the following steps:

(1) Coupling of Sonogashira between a compound of formula (Va) or (Vb) below:

for which W, X, Y, Q, A ₂ and R | at Ru are as defined in claim 1 and X ₂ represents Br, Cl, I or OTf,

and a compound of formula HC≡C- (CH ₂ ) _m -R49 for which m and R ₄₉ are as defined in claim 8,

(2) optionally reducing the alkyne function of the compound of formula (I) obtained in the preceding step to give a compound of formula (I) for which R ₉ or Rio represents -CH = CH- (CH ₂ ) mR ₄ 9 or - (CH ₂ ) _{m + 2} -R ₄₉ .