HK1236534A1 - Derivatives of macrocyclic n-aryl-tricyclopyrimidine-2-amine polyethers as inhibitors of ftl3 and jak - Google Patents

Description

Macrocyclic N-aryl-tricyclic pyrimidin-2-amine polyether derivatives as FTL3 and JAK inhibitors

Technical Field

The present invention relates to derivatives of macrocyclic N-aryl-tricyclic pyrimidin-2-amine polyethers and to their therapeutic use, in particular their therapeutic use for the treatment of cancer, and to methods for their synthesis.

Background

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

The new generation of FLT3 inhibitors being clinically evaluated have shown encouraging results for the treatment of LAM expressing the mutant form of FLT 3. However, most patient responses remain inadequate because they are incomplete and transient, resulting in a still high recurrence rate. There are many reasons for these relapses/intolerances. They may result in secondary mutations of the FLT3 receptor or activation of alternative signaling pathways that lead to downstream reactivation of the FLT3 receptor pathway. Furthermore, although Leukemia cells circulating in the patient's blood may be relatively sensitive to tyrosine kinase inhibitors, Leukemia cells living in the patient's bone marrow are more resistant to treatment, suggesting a role for the bone marrow (microenvironment) in treatment tolerance (Weisberg et al 2012Leukemia 26: 2233-2244). This stromal microenvironment of leukemia cells, consisting of bone marrow, will protect leukemia cells from the action of tyrosine kinase inhibitors. The IL-6/JAK/STAT signaling pathway is one of the major pathways contributing to the survival advantage conferred on leukemia cells expressing the mutant form of FLT 3. Furthermore, therapeutic combinations of JAK inhibitors and FLT3 inhibitors have been shown to increase the effects of FLT3 inhibition and overcome tolerance induced by the stromal microenvironment (Weisberg et al, supra). In general, the JAK family of kinases is described as playing an important role in the control of proliferation, cell survival and apoptosis. These JAK kinases are the subject of genetic alterations associated with many tumor pathologies, including hematologic malignancies.

Surprisingly, the present invention enables the identification of compounds having dual activity as inhibitors of JAK and FLT 3. These compounds further showed significant activity.

Disclosure of Invention

The invention relates more particularly to compounds of the following general formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein:

w represents an oxygen atom or a sulphur atom,

-X represents a saturated or unsaturated hydrocarbon chain comprising from 1 to 3 carbon atoms, optionally substituted by a group chosen from halogen atoms, (C)₁-C₆) Alkyl, oxo (═ O), OH and (C)₁-C₆) One or more radicals of alkoxy, one or more, in particular 1 or 2, carbon atoms of the chain being optionally each independently of the others substituted by an oxygen atom or a sulfur atom,

-Y represents a nitrogen atom or a CRy group, in which Ry represents a hydrogen atom, a halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, OH, CN, NO₂、NR₁₂R₁₃、CO₂H or CO₂((C₁-C₆) An alkyl) group, or a pharmaceutically acceptable salt thereof,

-Q represents a single, double or triple bond, an oxygen or sulfur atom, or (C)₁-C₆) Alkyl, S (O) or S (O)₂The radical(s) is (are),

-A₁and A₂Independently of one another, represents a single bond or (C) optionally substituted by an OH group₁-C₆) Alkyl, or A₁And A₂Form an optionally substituted monocyclic carbocyclic or monocyclic heterocyclic ring with Q and the carbon atoms to which Q is attached,

-R₁、R₂、R₃、R₄、R₅、R₆、R₇and R₈Independently of one another representA hydrogen atom or (C)₁-C₆) An alkyl group, a carboxyl group,

-R₉and R₁₀Independently of one another, represents a hydrogen atom, a halogen atom, optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl, optionally substituted (C)₂-C₆) Alkynyl, optionally substituted (C)₁-C₆) Alkoxy, optionally substituted (C)₁-C₆) Thioalkoxy, CN, NO₂、NR₁₄R₁₅、OH、SH、CO₂R₅₄、CONR₅₅R₅₆A group, an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring,

-R₁₁represents a hydrogen atom, a halogen atom, or (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkoxy or (C)₁-C₆) A haloalkoxy group, and

-R₁₂、R₁₃、R₁₄and R₁₅、R₅₄、R₅₅And R₅₆Independently of one another, represents a hydrogen atom or optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl, or optionally substituted (C)₂-C₆) Alkynyl, or R₁₂And R₁₃And/or R₁₄And R₁₅And/or R₅₅And R₅₆Independently of one another, form, with the nitrogen atom bearing them, an optionally substituted nitrogen-containing heterocycle.

Stereoisomers of the compounds of the general formula (I) and mixtures thereof, in particular in the form of racemic mixtures, also form part of the invention.

Tautomers of compounds of general formula (I) also form part of the present invention.

Within the meaning of the present invention, "stereoisomers" refer to geometric isomers (or configurational isomers) or optical isomers.

The geometric isomers result from substituents at different positions on the double bond, which may then have either the Z or E configuration, also known as cis or trans.

Optical isomers are caused in particular by substituents at different spatial positions on a carbon atom comprising four different substituents. The carbon atoms form a chiral or asymmetric center. Optical isomers include diastereomers and enantiomers. Optical isomers that are non-superimposable mirror images of each other are referred to as "enantiomers". Optical isomers that are not superimposable mirror images of each other are referred to as "diastereomers".

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

Within the meaning of the present invention, "tautomers" refer to structural isomers of compounds obtained by proton transfer rearrangement (prototropie), i.e. by migration of hydrogen atoms and change of position of double bonds. Different tautomers of a compound are usually interconvertible and exist in equilibrium in solution in proportions that may vary depending on the solvent, temperature or pH used.

In the present invention, "pharmaceutically acceptable" means that it is useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and that are acceptable for both veterinary and human pharmaceutical use.

By "pharmaceutically acceptable salt and/or solvate" of a compound is meant a pharmaceutically acceptable salt and/or solvate, as defined herein, and which possesses the desired pharmacological activity of the parent compound.

Pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention, such as those formed from organic or inorganic acids or from organic or inorganic bases. By way of example, mention may be made of salts derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and those derived from organic acids, such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, methanesulfonic acid, stearic acid, lactic acid. 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 according to conventional chemical methods from a compound of the present invention containing a base moiety or an acid moiety and the corresponding acid or base.

Pharmaceutically acceptable solvates of the compounds of the invention include conventional solvates, such as those formed during the final step of preparing the compounds of the invention due to the presence of a solvent. By way of example, mention may be made of solvates resulting from the presence of water (hydrates) or ethanol.

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

Within the meaning of the present invention, "(C)₁-C₆) Alkyl "means a straight or branched saturated hydrocarbon chain having 1 to 6, in particular 1 to 4, carbon atoms. By way of example, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

Within the meaning of the present invention, "(C)₂-C₆) Alkenyl "means a straight or branched hydrocarbon chain having at least one double bond and having 2 to 6, in particular 2 to 4, carbon atoms. By way of example, mention may be made of vinyl or allyl.

Within the meaning of the present invention, "(C)₂-C₆) Alkynyl "means a straight or branched hydrocarbon chain having at least one triple bond and having 2 to 6, in particular 2 to 4, carbon atoms. By way of example, mention may be made of ethynyl or propynyl.

Within the meaning of the present invention, "(C)₁-C₆) Haloalkyl "means (C) as defined above₁-C₆) Alkyl in which one or more hydrogen atoms have each been replaced by a halogen atom as defined above. It may in particular be CF₃A group.

Within the meaning of the present invention, "(C)₁-C₆) Alkoxy "means (C) as defined above₁-C₆) An alkyl group attached to the rest of the molecule via an oxygen atom. By way of example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy.

Within the meaning of the present invention, "(C)₁-C₆) Haloalkoxy "means (C) as defined above₁-C₆) A haloalkyl group attached to the remainder of the molecule via an oxygen atom. It may in particular be an OCF₃A group.

Within the meaning of the present invention, "(C)₁-C₆) Thioalkoxy "means (C) as defined above₁-C₆) An alkyl group, which is attached to the rest of the molecule via a sulfur atom. Mention may be made, by way of example, of thiomethoxy, thioethoxy, thiopropoxy, thioisopropoxy, thiobutoxy or thio-tert-butoxy.

Within the meaning of the present invention, "(C)₁-C₆) Alkyl-amino "means (C) as defined above₁-C₆) An alkyl group, which is attached to the rest of the molecule via an NH group. By way of example, mention may be made of methylamino, ethylamino, propylamino or butylamino.

Within the meaning of the present invention, "di ((C)₁-C₆) Alkyl) amino "means (C) as defined above₁-C₆) Alkyl, which is linked to the remainder of the molecule via a NAlk group, wherein Alk represents (C) as defined above₁-C₆) An alkyl group. By way of example, mention may be made of dimethylamino,Diethylamino, methylethylamino, and the like.

In the meaning of the present invention, "carbocycle" means a saturated, unsaturated or aromatic monocyclic or polycyclic hydrocarbon system comprising 3 to 12 carbon atoms. Polycyclic ring systems comprise at least 2, in particular 2 or 3, fused or bridged rings. Each ring of the monocyclic or polycyclic ring system advantageously comprises 3 to 8, in particular 4 to 7, in particular 5 or 6 carbon atoms. Mention may be made, by way of example, of adamantyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexenyl, phenyl, naphthyl.

In the meaning of the present invention, "aryl" means an aromatic hydrocarbon group, preferably having 6 to 10 carbon atoms, and comprising one or more fused rings, such as phenyl or naphthyl. Advantageously, it is phenyl.

Within the meaning of the invention, "aryl- (C)₁-C₆) Alkyl "refers to aryl as defined above via (C) as defined above₁-C₆) The alkyl chain is attached to the rest of the molecule. By way of example, benzyl may be mentioned.

Within the meaning of the present invention, "(C)₁-C₆) Alkyl-aryl "means (C) as defined above₁-C₆) An alkyl group which is linked to the remainder of the molecule via an aryl group as defined above. By way of example, mention may be made of tolyl (CH)₃Ph)。

In the meaning of the present invention, "heterocycle" means a saturated, unsaturated or aromatic monocyclic or bicyclic hydrocarbon radical, preferably saturated or unsaturated but not aromatic, containing from 3 to 12 carbon atoms, in which from 1 to 4, in particular 1 or 2, carbon atoms are each, independently of one another, replaced by a heteroatom selected from N, O and S, in particular from N and O. Bicyclic groups comprise two fused or bridged rings. The monocyclic or bicyclic group advantageously comprises from 3 to 8, in particular from 4 to 7, in particular 5 or 6, carbon atoms or heteroatoms forming the ring per ring. By way of example, azetidine, oxetane, thioxetane, pyrrolidine, pyrroline, pyrrole, tetrahydrofuran, dihydrofuran, furan, tetrahydrothiophene, dihydrothiophene, thiophene, piperidine, dihydropyridine, tetrahydropyridine, pyridine, pyran, dihydropyran, tetrahydropyran, thiopyran, 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 heterocycles may be mentioned. Preferably, the heterocyclic ring will be non-aromatic and may in particular be an azetidine, oxetane, thioxetane, 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 ring.

In the meaning of the present invention, "nitrogen-containing heterocycle" means a heterocycle as defined above, which contains at least one nitrogen atom, in particular is non-aromatic, preferably saturated. It may in particular be a monocyclic or bicyclic group, comprising from 5 to 7, preferably 5 or 6 members per ring, and optionally comprising, in addition to the nitrogen atom, another heteroatom, preferably selected from oxygen and nitrogen. It will in particular be piperidine, an optionally bridged piperazine (for example a piperazine, 2, 5-diazabicyclo [4.2.0] octane, 3, 8-diazabicyclo [3.2.1] octane or 2, 5-diazabicyclo [2.2.1] heptane group; in particular piperazine, 2, 5-diazabicyclo [4.2.0] octane or 2, 5-diazabicyclo [2.2.1] heptane), morpholine, perhydropyrrolo [3,4-c ] pyrrole, diazepane (for example 1, 3-diazepane or 1, 4-diazepane) or a pyrrolidine group.

In the meaning of the present invention, a "fused" ring refers to two rings which are connected to one another via two adjacent carbon atoms.

In the meaning of the present invention, a "bridged" ring refers to two rings which are connected to each other by two non-adjacent carbon atoms.

In the meaning of the present invention, "bridged piperazine" means a piperazine ring in which two non-adjacent carbon atoms are connected by a saturated or unsaturated (preferably saturated) hydrocarbon chain, said hydrocarbon chain advantageously containing from 1 to 5, in particular from 1 to 3, preferably 1 or 2 carbon atoms. It may in particular be 2, 5-diazabicyclo [4.2.0] octane, 3, 8-diazabicyclo [3.2.1] octane or 2, 5-diazabicyclo [2.2.1] heptane.

In the meaning of the present invention, an "unsaturated" group refers to a group comprising at least one C ═ C bond or C ≡ C bond.

In the meaning of the present invention, an "unsaturated" ring refers to a ring that contains at least one C ═ C bond, but is not aromatic.

In the meaning of the present invention, an "optionally substituted" group refers to a group optionally substituted with one or more substituents. This/these substituent(s) may be chosen in particular from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆、SR₁₇、NR₁₈R₁₉One or more radicals substituted by carbocyclic or heterocyclic ring (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), CN, NO₂、OR₂₀、SR₂₁、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、S(O)R₂₇、SO₂R₂₈、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁、SR₄₂And NR₄₃R₄₄One or more groups of (a) or (b),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅、SR₄₆And NR₄₇R₄₈A heterocycle substituted with one or more groups of (a), and

--O(CH₂)_nan O-group in which n represents an integer from 1 to 5, in particular from 2 to 3 (the two oxygens of the group may be bound to the same atom or to two different atoms, advantageously they are bound to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆to R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic rings of these radicals being optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic rings of these radicals being optionally substituted by a halogen atom, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom bearing them forming an optionally substituted halogen atom, (C)₁-C₆) Nitrogen-containing heterocycles substituted with one or more groups of alkyl and oxo (═ O).

X will more particularly represent a saturated or unsaturated hydrocarbon chain comprising from 1 to 3, in particularRespectively 1 or 2 carbon atoms, optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo, OH and (C)₁-C₆) One or more groups of alkoxy groups, one carbon atom of the chain being optionally replaced by an oxygen atom or a sulfur atom.

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

X will advantageously represent a saturated or unsaturated hydrocarbon chain comprising from 1 to 3, in particular 1 or 2, carbon atoms, and more particularly CH₂-CH₂Or CH ═ CH chain.

Y will more particularly represent a nitrogen atom or a CRy group, in which Ry represents a hydrogen atom, a halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, NR₁₂R₁₃、CO₂H or CO₂((C₁-C₆) Alkyl) group, wherein R₁₂And R₁₃Independently of one another, represents a hydrogen atom or (C) optionally substituted by one or more halogen atoms₁-C₆) Alkyl, or R₁₂And R₁₃Preferably with the nitrogen atom which carries them, form a non-aromatic 5-or 6-membered heterocyclic ring which optionally comprises a further heteroatom selected from O, N and S, in particular O and N, said heterocyclic ring optionally being substituted by (C)₁-C₆) Alkyl substitution.

Y will more particularly represent a nitrogen atom or a CRy group, in which Ry represents a hydrogen atom, a halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy or NR₁₂R₁₃Group, wherein R₁₂And R₁₃Independently of one another, represents a hydrogen atom or (C) optionally substituted by one or more halogen atoms₁-C₆) Alkyl, or R₁₂And R₁₃Preferably with the nitrogen atom which carries them, form a non-aromatic 5-or 6-membered heterocyclic ring which optionally comprises a further heteroatom selected from O, N and S, in particular O and N, said heterocyclic ring optionally being substituted by (C)₁-C₆) Alkyl substitution.

Y will more particularly represent a nitrogen atom or a CRy group, in which Ry represents a hydrogen atom, a halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy, OH, or NR₁₂R₁₃Group, wherein R₁₂And R₁₃Independently of one another, represents a hydrogen atom or (C)₁-C₆) An alkyl group.

Y will more particularly represent a CRy group, wherein Ry is as defined in one of the preceding definitions. Ry will in particular represent a hydrogen atom, a halogen atom, a (C)₁-C₆) Alkyl or (C)₁-C₆) A haloalkyl group; advantageously represents a hydrogen atom or a halogen atom (for example F). Y will in particular represent a CH or CF group.

W may more particularly represent an oxygen atom.

Q will in particular represent a single or double bond, an oxygen atom or (C)₁-C₆) An alkyl group.

Q will more particularly represent an oxygen atom.

A₁And A₂In particular independently of one another represents a single bond or (C) optionally substituted by an OH group₁-C₆) Alkyl, or A₁And A₂With Q and the carbon atom to which Q is attached forming a group optionally selected from OH, (C)₁-C₆) Monocyclic carbocyclic or monocyclic heterocyclic ring substituted with one or more groups of alkyl and oxo (═ O).

Monocyclic carbocycle may in particular be C₃To C₆In particular C₅Or C₆Monocyclic carbocycles, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The monocyclic heterocycle may in particular be C₃To C₆In particular C₅Or C₆Monocyclic heterocycles, which are preferably non-aromatic, advantageously comprise oxygen atoms, such as ethylene oxide, oxetane, tetrahydrofuran or tetrahydropyran.

A₁And A₂Will in particular represent, independently of one another, a single bond or (C) optionally substituted by an OH group₁-C₆) Alkyl, and especially represents a single bond or (C)₁-C₆) An alkyl group.

A₁And A₂Will each particularly represent a single bond.

R₁、R₂、R₃、R₄、R₅、R₆、R₇And R₈Will more particularly represent a hydrogen atom.

According to a particular embodiment, W and Q each, independently of one another, represent O or S, preferably O, and A₁And A₂Each represents a single bond.

According to another particular embodiment, W ═ Q ═ O, a₁And A₂Each represents a single bond, and R₁＝R₂＝R₃＝R₄＝R₅＝R₆＝R₇＝R₈＝H。

R₁₁Will especially represent a hydrogen atom, a halogen atom, a (C) atom₁-C₆) Alkyl or (C)₁-C₆) An alkoxy group. R₁₁Will more particularly represent a hydrogen atom, a halogen atom or (C)₁-C₆) An alkyl group. Advantageously, R₁₁Will represent a hydrogen atom.

R₉And R₁₀Independently of one another, represents a hydrogen atom, a halogen atom, optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl, optionally substituted (C)₂-C₆) Alkynyl, optionally substituted (C)₁-C₆) Alkoxy, optionally substituted (C)₁-C₆) Thioalkoxy, CN, NO₂、NR₁₄R₁₅、OH、SH、CO₂R₅₄、CONR₅₅R₅₆An optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring.

R₉And R₁₀More particularly, independently of one another, represents a hydrogen atom, a halogen atom, optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl, optionally substituted (C)₂-C₆) Alkynyl, optionally substituted (C)₁-C₆) Alkoxy, optionally substituted (C)₁-C₆) Thioalkoxy, NR₁₄R₁₅、CONR₅₅R₅₆Optionally substituted carbocycle or optionally substituted heterocycle, especially wherein R₁₅Not equal to H and R₅₅≠H。

R₉And R₁₀In particular independently of one another, represents a hydrogen atom, a halogen atom, optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl, optionally substituted (C)₂-C₆) Alkynyl, optionally substituted (C)₁-C₆) Alkoxy, optionally substituted (C)₁-C₆) Thioalkoxy, NR₁₄R₁₅Or an optionally substituted heterocycle, especially wherein R₁₅≠H。

R₉And R₁₀In particular independently of one another, represents a hydrogen atom, a halogen atom or (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Thioalkoxy, (C)₁-C₆) Alkyl-amino, di ((C)₁-C₆) Alkyl) amino or heterocyclic group, said groups being optionally substituted.

R₉And R₁₀May more particularly represent, independently of one another, a hydrogen atom or an optionally substituted heterocycle.

In the preceding R₉And R₁₀In the definition of (1), R₁₄And R₁₅Independently of one another, represents a hydrogen atom or optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl or optionally substituted (C)₂-C₆) Alkynyl, or R₁₄And R₁₅Form, together with the nitrogen atom bearing them, an optionally substituted nitrogen-containing heterocycle. In particular, R₁₄May represent a hydrogen atom or (C)₁-C₆) Alkyl, and R₁₅May represent a hydrogen atom or optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl or optionally substituted (C)₂-C₆) Alkynyl, or R₁₄And R₁₅Will form, with the nitrogen atom bearing them, an optionally substituted nitrogen-containing heterocycle. Advantageously, R₁₄Will represent a hydrogen atom or (C)₁-C₆) Alkyl, and R₁₅Will represent a hydrogen atom or optionally substituted (C)₁-C₆) Alkyl, or R₁₄And R₁₅Will form, with the nitrogen atom bearing them, an optionally substituted nitrogen-containing heterocycle. Preferably, the optionally substituted nitrogen-containing heterocycle will be in particular a non-aromatic, preferably saturated, monocyclic or bicyclic nitrogen-containing heterocycle comprising 5 to 7, preferably 5 or 6 members per ring, which optionally comprises, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as optionally bridged piperazine, piperidine, morpholine, perhydropyrrolo [3,4-c ] s]Pyrrole, diazepane (e.g. 1, 3-diazepane or 1, 4-diazepane) or a pyrrolidine ring, said heterocyclic ring being optionally selected in particular from halogen atoms, (C)₁-C₆) Alkyl and oxo (═ O).

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

In the preceding R₉And R₁₀In the definition of (1), the carbocycle is more particularly C₃To C₆In particular C₅Or C₆Monocyclic carbocycles, in particular nonaromatic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexenyl.

In the preceding R₉And R₁₀In the definition of (a), the heterocycle is more particularly a saturated, unsaturated or aromatic (preferably saturated or unsaturated), monocyclic heterocycle or bicyclic heterocycle, each ring having 5,6 or 7 members, preferably 5 or 6 members, which contains 1 or 2 heteroatoms selected from N, O and S, in particular from N and O, and preferably at least one nitrogen atom, the heteroatom being preferably N. The heterocycle may be, for example, pyrrolidine, pyrroline, pyrrole, tetrahydrofuran, dihydrofuran, furan, tetrahydrothiophene, dihydrothiophene, thiophene, piperidine, dihydropyridine, tetrahydropyridine, pyridine, pyran, dihydropyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, pyrazine, pyrimidine, pyridazine, perhydropyrrolo [3,4-c ] pyrrolo]Pyrrole, 2, 5-diazabicyclo [4.2.0]Octane, 3, 8-diazabicyclo [3.2.1]Octane, 2, 5-diazabicyclo [2.2.1]Heptane or imidazole ring. The heterocycle will be in particular pyrrolidine, pyrroline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, piperidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, tetrahydropyran, thiochroman, tetrahydrothiopyran, morpholine, thiomorpholine, piperazine, perhydropyrrolo [3,4-c ] pyrrole]Pyrrole, 2, 5-diazabicyclo [4.2.0]Octane, 3, 8-diazabicyclo [3.2.1]Octane or 2, 5-diazabicyclo [2.2.1]And (4) heptane ring. The heterocycle will be in particular pyrrolidine, pyrroline, tetrahydrofuran, dihydrofuran, piperidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, tetrahydropyran, morpholine, piperazine or perhydropyrrolo [3,4-c ]]An azole ring. The heterocycle will more particularly be pyrrolidine, pyrroline, piperidine, dihydropyridine, tetrahydropyridine, piperazine or perhydropyrrolo [3,4-c ]]An azole ring. The heterocycle may advantageously be pyrrolidine, piperidine, tetrahydropyridine (in particular 1,2,3, 6-tetrahydropyridine), piperazine or perhydropyrrolo [3,4-c ]]An azole ring. Advantageously, the heterocycle will be in particular a non-aromatic, preferably saturated, monocyclic or bicyclic nitrogen-containing heterocycle containing from 5 to 7, preferably 5 or 6, per ringA member optionally containing, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as an optionally bridged piperazine (e.g. 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 a pyrrolidine ring. It may in particular be a saturated monocyclic or bicyclic nitrogen-containing heterocycle comprising 5 or 6 members per ring, which optionally comprises, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as an optionally bridged piperazine (e.g. 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]An azole or pyrrolidine ring, in particular an optionally bridged piperazine, in particular piperazine. The nitrogen-containing heterocycle will preferably be attached to the rest of the molecule through its nitrogen atom.

In the preceding R₉、R₁₀、R₁₄And R₁₅In the definition of (a), an optionally substituted group or ring is a group or ring optionally substituted with one or more substituents advantageously selected from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆、SR₁₇、NR₁₈R₁₉One or more radicals substituted by carbocyclic or heterocyclic ring (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), CN, NO₂、OR₂₀、SR₂₁、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、S(O)R₂₇、SO₂R₂₈、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁、SR₄₂And NR₄₃R₄₄One or more groups of (a) or (b),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅、SR₄₆And NR₄₇R₄₈A heterocycle substituted with one or more groups of (a), and

--O(CH₂)_nan O-group in which n represents an integer from 1 to 5, in particular from 2 to 3 (the two oxygens of the group may be bound to the same atom or to two different atoms, advantageously they are bound to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆to R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic rings of these radicals being optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic rings of these radicals being optionally substituted by a halogen atom, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom bearing them forming an optionally substituted halogen atom, (C)₁-C₆) Nitrogen-containing heterocycles substituted with one or more groups of alkyl and oxo (═ O).

In the preceding R₉、R₁₀、R₁₄And R₁₅In the definition of (a), optionally substituted groups or rings are in particular optionally substituted by one or more substituents selected from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆、NR₁₈R₁₉One or more radicals substituted by carbocyclic or heterocyclic ring (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀Group, and more particularly oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄C substituted by one or more radicals of₃To C₆The carbon ring is a carbon ring,

-a 3-to 6-membered heterocycle, preferably saturated, comprising 1 or 2 heteroatoms selected from N and O, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

--O(CH₂)_no-groups in which n represents an integer equal to 2 or 3 (the two oxygens of the group may be bound to the same atom or to two different atoms, advantageously they are bound to a phaseTo the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆、R₁₈to R₂₀、R₂₂To R₂₆、R₂₉To R₄₁、R₄₃To R₄₅、R₄₇And R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms, (C)₁-C₆) Alkyl, aryl or aryl- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms or (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic ring of these radicals being phenyl, and which is optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic ring of these groups is a 3-to 6-membered, in particular 5-or 6-membered heterocyclic ring, which comprises 1 or 2 heteroatoms selected from N and O, and which is optionally substituted by a group selected from halogen atoms, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a 5-or 6-membered nitrogen-containing heterocyclic ring, in particular non-aromatic, preferably saturated, optionally containing, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, said heterocyclic ring being optionally selected from halogen atoms, (C)₁-C₆) Alkyl and oxo (═ O).

In the preceding R₉、R₁₀、R₁₄And R₁₅In the definition of (1), is optionally takenThe substituted group or ring is advantageously optionally substituted by one or more substituents selected from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆And NR₁₈R₁₉Is substituted by one or more groups of (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄C substituted by one or more radicals of₃To C₆The carbon ring is a carbon ring,

-a 3-to 6-membered heterocycle, preferably saturated, comprising 1 or 2 heteroatoms selected from N and O, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

--O(CH₂)_nan O-group in which n represents an integer equal to 2 or 3 (the two oxygens of the group may be bonded to the same atom or to two different atoms, advantageously they are bonded to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆、R₁₈to R₂₀、R₂₂、R₂₃、R₂₅、R₃₁To R₄₁、R₄₃To R₄₅、R₄₇And R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, arylOr aryl- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms, or (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic ring of these groups is preferably phenyl, and it is optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a 5-or 6-membered nitrogen-containing heterocyclic ring, in particular non-aromatic, preferably saturated, optionally containing, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, said heterocyclic ring being optionally selected from halogen atoms, (C)₁-C₆) Alkyl and oxo (═ O).

Radical R₉And R₁₀Can in particular represent, independently of one another:

-a hydrogen atom or a halogen atom,

-(C₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Thioalkoxy, (C)₁-C₆) Alkyl-amino or di ((C)₁-C₆) Alkyl) amino, said group being optionally substituted with one or more substituents selected from: halogen atom, OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀(ii) a In particular from OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀(ii) a Is in particular selected from NR₂₂R₂₃、NR₃₃CO₂R₃₄And NR₃₇CONR₃₈R₃₉Or is or

-a monocyclic or bicyclic heterocycle having 5,6 or 7, preferably 5 or 6, members per ring, comprising 1 or 2 heteroatoms selected from N and O, preferably saturated or containing double bonds but not aromatic, (which heterocycle may in particular be an optionally bridged piperazine (such as a 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 ring; in particular a piperazine, piperidine, pyrrolidine, perhydropyrrolo [3,4-c ] pyrrole or tetrahydropyridine ring), optionally substituted with one or more substituents selected from:

a halogen atom,

optionally selected from halogen atoms, OR₁₆、NR₁₈R₁₉、C₃To C₆(C) substituted by one or more groups of monocyclic carbocycles (in particular saturated) and 3-to 6-membered monocyclic heterocycles (in particular saturated)₁-C₆) An alkyl group; preferably, optionally selected from halogen atoms, OR₁₆And NR₁₈R₁₉Is substituted by one or more groups of (C)₁-C₆) An alkyl group, a carboxyl group,

oxo (═ O), OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀A group; and more particularly oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄C substituted by one or more radicals of₃To C₆The carbon ring is a carbon ring,

3-to 6-membered heterocyclic rings, in particular saturated or unsaturated, preferably saturated, containing 1 or 2 heteroatoms selected from N and O, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

·-O(CH₂)_nan O-group in which n represents an integer equal to 2 or 3 (the two oxygens of the group may be bonded to the same atom or to two different atoms, advantageously they are bonded to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆、R₁₈to R₂₀、R₂₂To R₂₆、R₂₉To R₄₁、R₄₃To R₄₅、R₄₇And R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms, (C)₁-C₆) Alkyl, aryl, or aryl- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms or (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic ring of these radicals being phenyl, and which is optionally substituted by a group selected from halogen atoms and (C)₁-C₆) Alkyl radicalIs substituted with one or more groups of (a) and

the heterocyclic ring of these groups is a 3-to 6-membered, in particular 5-or 6-membered heterocyclic ring, which comprises 1 or 2 heteroatoms selected from N and O, and which is optionally substituted by a group selected from halogen atoms, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a 5-or 6-membered nitrogen-containing heterocyclic ring, preferably saturated, in particular non-aromatic, which optionally comprises, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, said heterocyclic ring optionally being selected from halogen atoms, (C)₁-C₆) Alkyl and oxo (═ O).

Radical R₉And R₁₀Can more particularly represent, independently of one another:

-a hydrogen atom or a halogen atom,

--Z-(CH₂)_m-R₄₉group, wherein Z represents a single bond, CH₂-CH₂CH, C.ident. C, O, S or NR₅₀(ii) a m represents an integer of 1 to 6, in particular 1 to 4; r₅₀Represents a hydrogen atom or (C)₁-C₆) An alkyl group; and R is₄₉Represents a halogen atom, OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀(ii) a In particular OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀(ii) a In particular NR₂₂R₂₃、NR₃₃CO₂R₃₄Or NR₃₇CONR₃₈R₃₉Or is or

-a monocyclic or bicyclic heterocycle having 5,6 or 7, preferably 5 or 6, members per ring, comprising 1 or 2 heteroatoms selected from N and O, preferably saturated or containing a double bond, (which heterocycle may especially be an optionally bridged piperazine (such as a 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 ring; especially a piperazine, piperidine, pyrrolidine, perhydropyrrolo [3,4-c ] pyrrole or tetrahydropyridine ring), optionally substituted with one or more substituents selected from:

a halogen atom,

optionally selected from halogen atoms, OR₁₆、NR₁₈R₁₉、C₃To C₆(C) substituted by one or more groups of monocyclic carbocycles (in particular saturated) and 3-to 6-membered monocyclic heterocycles (in particular saturated)₁-C₆) An alkyl group; preferably, optionally selected from halogen atoms, OR₁₆And NR₁₈R₁₉Is substituted by one or more groups of (C)₁-C₆) An alkyl group, a carboxyl group,

oxo (═ O), OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀A group; and more particularly oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀The radical(s) is (are),

optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄C substituted by one or more radicals of₃To C₆The carbon ring is a carbon ring,

3-to 6-membered heterocyclic rings, in particular saturated or unsaturated, preferably saturated, containing 1 or 2 heteroatoms selected from N and O, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

·-O(CH₂)_nan O-group in which n represents an integer equal to 2 or 3 (the two oxygens of the group may be bonded to the same atom or to two different atoms, advantageously they are bonded to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆、R₁₈to R₂₀、R₂₂To R₂₆、R₂₉To R₄₁、R₄₃To R₄₅、R₄₇And R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms, (C)₁-C₆) Alkyl, aryl, or aryl- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms or (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic ring of these radicals being phenyl, and which is optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic ring of these groups is a 3-to 6-membered, in particular 5-or 6-membered heterocyclic ring, which comprises 1 or 2 heteroatoms selected from N and O, and which is optionally substituted by a group selected from halogen atoms, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a 5-or 6-membered nitrogen-containing heterocyclic ring, in particular non-aromatic, preferably saturated, optionally containing, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, said heterocyclic ring being optionally selected from halogen atoms, (C)₁-C₆) Alkyl and oxo (═ O).

According to a particular embodiment of the invention, R₉And R₁₀At least one (preferably R) of₉) And does not represent a hydrogen atom. According to another particular embodiment of the invention, R₉And R₁₀At least one (preferably R) of₉) And does not represent a hydrogen atom or a halogen atom. In both cases, R may be defined according to any of the preceding embodiments₉And R₁₀One of the radicals other than the two radicals cannot represent a hydrogen atom, in particular a hydrogen atom or a halogen atom.

According to another embodiment of the invention, R₉And R₁₀One (preferably R)₁₀) Represents a hydrogen atom, and the other (preferably R)₉) Does not represent a hydrogen atom, and particularly does not represent a hydrogen atom or a halogen atom. R, which does not represent a hydrogen atom or a halogen atom, may be defined according to any of the preceding embodiments₉Or R₁₀Groups other than hydrogen atoms or even halogen atoms.

R₁₀Will more particularly represent a hydrogen atom. Then, R₉May be as in any of the preceding implementationsAs defined by the scheme, and preferably will not be a hydrogen atom, in particular will not be a hydrogen atom or a halogen atom.

According to a first particular embodiment, X represents CH₂-CH₂Or CH-CH chain, Y-CRy, W-Q-O, A₁And A₂Each represents a single bond, and R₁＝R₂＝R₃＝R₄＝R₅＝R₆＝R₇＝R₈＝R₁₁＝H。

Thus, the compounds of formula (I) correspond to compounds of formula (Ia) below:

and pharmaceutically acceptable salts and/or solvates thereof,

wherein:

-represents a single bond or a double bond,

-Ry is as defined above and advantageously represents a hydrogen atom, a halogen atom, (C)₁-C₆) Alkyl or (C)₁-C₆) A haloalkyl group; particularly represents a hydrogen atom or a halogen atom (e.g. F), and

-R₉and R₁₀As described with respect to R above₉And R₁₀As defined in any one of the embodiments herein.

According to a second particular embodiment, X represents CH₂-CH₂Or CH-CH chain, Y-CRy, W-Q-O, A₁And A₂Each represents a single bond, and R₁＝R₂＝R₃＝R₄＝R₅＝R₆＝R₇＝R₈＝R₁₀＝R₁₁＝H。

Thus, the compounds of formula (I) correspond to compounds of formula (Ib) below:

and pharmaceutically acceptable salts and/or solvates thereof,

wherein:

-represents a single bond or a double bond,

-Ry is as defined above and advantageously represents a hydrogen atom, a halogen atom, (C)₁-C₆) Alkyl or (C)₁-C₆) A haloalkyl group; particularly represents a hydrogen atom or a halogen atom (e.g. F), and

-R₉as described with respect to R above₉As defined in any one of the embodiments herein.

According to a particularly advantageous embodiment, the compounds according to the invention are compounds of the formula (Ib), in which R₉Represents an optionally substituted heterocycle.

Advantageously, the heterocyclic ring will in particular be a non-aromatic, preferably saturated, monocyclic or bicyclic nitrogen-containing heterocyclic ring, each ring of which comprises 5 to 7, preferably 5 or 6, members, which optionally comprises, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as an optionally bridged piperazine (e.g. 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 (in particular 1,2,3, 6-tetrahydropyridine) or pyrrolidine ring. It may in particular be a saturated monocyclic or bicyclic nitrogen-containing heterocycle, each ring of which comprises 5 or 6 members, which optionally comprises, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as an optionally bridged piperazine (e.g. 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 ring, in particular an optionally bridged piperazine, in particular piperazine. The nitrogen-containing heterocycle will preferably be attached to the rest of the molecule through its nitrogen atom.

The heterocycle will in particular be optionally substituted by one or more substituents selected from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆、SR₁₇、NR₁₈R₁₉One or more radicals substituted by carbocyclic or heterocyclic ring (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), CN, NO₂、OR₂₀、SR₂₁、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、S(O)R₂₇、SO₂R₂₈、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁、SR₄₂And NR₄₃R₄₄One or more groups of (a) or (b),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅、SR₄₆And NR₄₇R₄₈A heterocycle substituted with one or more groups of (a), and

- -O(CH₂)_nan O-group, wherein n represents an integer from 1 to 5, in particular from 2 to 3 (the two oxygens of the group may be bound to the same atom or to two different atoms)Advantageously they are linked to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆to R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic rings of these radicals being optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic rings of these radicals being optionally substituted by a halogen atom, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom bearing them forming an optionally substituted halogen atom, (C)₁-C₆) Nitrogen-containing heterocycles substituted with one or more groups of alkyl and oxo (═ O).

The heterocyclic ring will advantageously be optionally substituted by one or more substituents selected from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆、NR₁₈R₁₉One or more radicals substituted by carbocyclic or heterocyclic ring (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀Group, and more particularly oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄C substituted by one or more radicals of₃To C₆The carbon ring is a carbon ring,

-a 3-to 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O, preferably saturated, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

- -O(CH₂)_nan O-group in which n represents an integer equal to 2 or 3 (the two oxygens of the group may be bonded to the same atom or to two different atoms, advantageously they are bonded to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆、R₁₈to R₂₀、R₂₂To R₂₆、R₂₉To R₄₁、R₄₃To R₄₅、R₄₇And R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms, (C)₁-C₆) Alkyl, aryl or aryl- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms or (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic ring of these radicals being phenyl, and which is optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic ring of these groups is a 3-to 6-membered, in particular 5-or 6-membered heterocyclic ring, which comprises 1 or 2 heteroatoms selected from N and O, and which is optionally substituted by a group selected from halogen atoms, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a 5-or 6-membered nitrogen-containing heterocyclic ring, in particular non-aromatic, preferably saturated, optionally containing, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, said heterocyclic ring being optionally selected from halogen atoms, (C)₁-C₆) Alkyl and oxo (═ O).

The heterocycle will in particular be optionally substituted by one or more substituents selected from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆And NR₁₈R₁₉Is substituted by one or more groups of (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄C substituted by one or more radicals of₃To C₆The carbon ring is a carbon ring,

-a 3-to 6-membered heterocycle, preferably saturated, comprising 1 or 2 heteroatoms selected from N and O, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

- -O(CH₂)_nan O-group in which n represents an integer equal to 2 or 3 (the two oxygens of the group may be bonded to the same atom or to two different atoms, advantageously they are bonded to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

■R₁₆、R₁₈to R₂₀、R₂₂、R₂₃、R₂₅、R₃₁To R₄₁、R₄₃To R₄₅、R₄₇And R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl, or aryl- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms or (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic ring of these groups is preferably phenyl, and it is optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a 5-or 6-membered nitrogen-containing heterocyclic ring, in particular non-aromatic, preferably saturated, optionally containing, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, said heterocyclic ring being optionally selected from halogen atoms, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O)And (4) substitution.

The compounds of the present invention may be selected in particular from compounds 1 to 44, in particular compounds 1 to 36, and pharmaceutically acceptable salts and/or solvates thereof, as described in the examples below.

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

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

The invention also relates to a method for the treatment of cancer, comprising administering to a human in need thereof an effective dose of a compound of formula (I) as defined above.

In this case, the cancer may more particularly be colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, glioblastoma, lung cancer, neuroblastoma, inflammatory myofibroblast tumors, lymphoma, leukemia, myelodysplastic syndrome, myelofibrosis, 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 composition according to the invention may be especially formulated for oral administration or for administration by injection (especially intravenously), said composition being intended for mammals, including humans.

The active ingredients can be administered to animals or humans in unit dosage form, in admixture with standard pharmaceutical excipients.

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

When the solid composition is prepared in the form of a tablet, 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 may be coated with sucrose or other suitable material, or they may be treated so that they have a prolonged or delayed activity and so that they continuously release a predetermined amount of the active ingredient.

The capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the obtained mixture into a soft or hard capsule.

Formulations in the form of syrups or elixirs may contain the active ingredient together with sweetening agents, preservatives, and flavour enhancers and suitable dyes.

The water-dispersible powders or granules may contain the active ingredient in admixture with dispersing or wetting agents, or suspending agents, and flavor enhancers or sweeteners.

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

The active ingredient may also be formulated in microcapsule form, optionally with one or more additional excipients.

The compounds of the invention as active ingredients can be used in doses ranging from 0.01mg to 1000mg per day, given once per day in a single dose, or administered in multiple doses per day, for example twice per day in equal doses. The dose administered per day is advantageously from 5mg to 500mg, even more advantageously from 10mg to 200 mg. It may be desirable to use dosages outside of these ranges, as will be apparent to those skilled in the art.

The pharmaceutical composition according to the present invention may further 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 anti-cancer agent,

as a combination product for simultaneous, separate or sequential use.

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

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

The invention also relates to a process for the preparation of the compounds of formula (I) according to the invention.

Accordingly, the present invention relates to a first process for the preparation of a compound of formula (I) comprising a compound of formula (II) below:

w, X, Y, R therein₉、R₁₀And R₁₁As defined above, in the above-mentioned manner,

a coupling reaction with a compound of the following formula (III):

q, A therein₁、A₂And R₁To R₈As defined above, and LG₁And LG₂Each independently of the other represents a leaving group.

In the meaning of the present invention, "leaving group" refers to a chemical group that can be easily displaced by a nucleophile, herein an alcohol or thiol, during a nucleophilic substitution reaction. Such a leaving group may more particularly be a halogen atom such as a chlorine atom or bromine atomAtoms or sulfonates. The sulfonate may be in particular-OSO₂-R₅₁Group, wherein R₅₁Is represented by (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl or (C)₁-C₆) An alkyl-aryl group, said group being optionally substituted with one or more halogen atoms, such as fluorine atoms. The sulfonate ester may in particular be a mesylate (-OS (O)₂)-CH₃) Triflate (-OS (O))₂-CF₃) Or p-toluenesulfonate (-OS (O)₂-(p-Me-C₆H₄))。

Group LG₁And LG₂Will more particularly represent a halogen atom such as bromine.

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

This process is illustrated in more detail in scheme 1 below.

According to the following references (J.Med.chem.2007,50,4516-4527), usually by reaction in a polar solvent (such as N, N' -dimethylformamide) and in an organic base such as triethylamine or an alcoholate (in particular (C)₁-C₆) alkyl-OM, wherein M ═ Na, K or Li), or an inorganic base such as sodium carbonate, potassium carbonate or cesium carbonate or potassium acetate, heating to a temperature of 20 ℃ to 200 ℃, or in a microwave reactor without solvent, to carry out the compoundBAnd guanidineCTo obtain the formulaDThe compound of (1).

According to the reference (J.Med.chem.2008,51,4804-4822), by means of a signal at the BBr₃In an anhydrous solvent such as dichloromethane at a temperature of-78 ℃ to 100 ℃, by demethylation of the general formulaDTo intermediates of the general formulaEAn intermediate of (1). By reaction with a compoundFThe macrocyclization reaction of (a) is carried out,general formula (II)EInto a product of general formula (I).

The invention also relates to a second process for the preparation of a compound of formula (I), wherein R₉And/or R₁₀Represents optionally substituted (C)₁-C₆) Alkoxy, optionally substituted (C)₁-C₆) Thioalkoxy or NR₁₄R₁₅A group or an optionally substituted heterocyclic ring comprising a heteroatom directly attached to the phenyl ring, said method comprising a compound of formula (IVa) or (IVb):

w, X, Y, Q, A therein₁、A₂And R₁To R₁₁As defined above, and X₁Represents a halogen atom such as Br, Cl or I, in particular Br,

are each independently of the formula R₉H or R₁₀Coupling of compounds of H, wherein R₉And R₁₀As defined above.

Can be in the presence of an organic or inorganic base such as Et₃N、iPr₂NEt, NaH, pyridine, Cs₂CO₃、Na₂CO₃Or K₂CO₃Optionally in the presence of a salt as catalyst, e.g. KI, Bu₄NI、CuI、LiI、AgBF₄、AgClO₄、Ag₂CO₃、KF、Bu₄The reaction is carried out in the presence of NF or CsF. The solvent used will preferably be an anhydrous polar solvent such as tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone or mixtures thereof. The reaction can advantageously be carried out at a temperature of from-20 ℃ to 140 ℃. According to the nucleophilic reagent R₉H and R₁₀The nature of H, the experimental conditions and choice of reagents for carrying out the reaction are obvious and will be carried out according to methods and techniques well known to those skilled in the art.

According to the reference (J.org.chem.2009,74,5075-5078), the reaction can also be carried out in "screw-top or sealed test tubes" heated by thermal or microwave energy, in particular at temperatures of from 80 ℃ to 180 ℃.

The reaction can also be carried out by catalytic coupling, as described in the reference org.Lett.2002,17, 2885-2888. In catalytic amounts of palladium complexes (e.g. (dppf)₂PdCl₂·CH₂Cl₂) In the presence of a catalyst. The coupling reaction is advantageously carried out at a temperature of from 25 ℃ to 100 ℃. The solvent used will preferably be a polar aprotic solvent such as tetrahydrofuran or dioxane.

The invention also relates to a third process for the preparation of a compound of formula (I), wherein R₉And/or R₁₀Represents optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl or optionally substituted (C)₂-C₆) An alkynyl group, an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring attached to the phenyl ring via a carbon atom, the method comprising a compound of the following formula (Va) or (Vb):

w, X, Y, Q, A therein₁、A₂And R₁To R₁₁As defined above, and X₂Represents Br, Cl, I or OTf (OSO)₂CF₃)，

Are each independently of the formula R₉-BR₅₂R₅₃Or R₁₀-BR₅₂R₅₃The coupling of a compound of (1), wherein R₉And R₁₀As defined above, and R₅₂And R₅₃Independently of one another, OH, (C)₁-C₆) Alkyl or (C)₁-C₆) Alkoxy, or R₅₂And R₅₃Together form-X₃-or-O-X₃-O-chain, wherein X₃Representative includes 2 to 15, especially 2A divalent hydrocarbon group of up to 10 carbon atoms.

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

The reaction is advantageously carried out in the presence of a palladium-based catalyst, such as palladium acetate, tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0).

Organic or inorganic bases may be present, such as alcoholates (in particular (C)₁-C₆) alkyl-OM, wherein M ═ Na, K or Li), NMP (N-methyl-morpholine), Et₃N、iPr₂NEt、K₃PO₄、NaH、Cs₂CO₃、Na₂CO₃Or K₂CO₃。

Polar solvents such as tetrahydrofuran, dimethylformamide, acetonitrile, acetone, methyl ethyl ketone, ethanol, dimethyl ether, dioxane, water or mixtures thereof may be used. The reaction can advantageously be carried out at a temperature of from 20 ℃ to 140 ℃.

-BR₅₂R₅₃The radicals may be, for example, -B (OH)₂、-B((C₁-C₆) Alkyl radical)₂、-B(O(C₁-C₆) Alkyl radical)₂(e.g., -B (OiPr)₂)、Groups, and the like.

Finally, the invention relates to a fourth process for the preparation of compounds of formula (I), wherein R₉And/or R₁₀represents-Z- (CH)₂)_m-R₄₉Wherein Z represents CH₂-CH₂CH ═ CH or C ≡ C, the method comprising the steps of:

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

And formula HC ≡ C- (CH)₂)_m-R₄₉The Sonogashira coupling of compounds of (a) wherein m and R₄₉As defined above, in the above-mentioned manner,

to give a compound of the formula (I) in which R₉Or R₁₀represents-C ≡ C- (CH)₂)_m-R₄₉And are and

(2) optionally reducing the alkyne function of the compound of formula (I) obtained in the preceding step to obtain a compound of formula (I), wherein R₉Or R₁₀represents-CH ═ CH- (CH)₂)_m-R₄₉Or- (CH)₂)_m+2-R₄₉。

Step (1):

sonogashira coupling is a reaction well known to those skilled in the art, and those skilled in the art will be able to determine the reaction conditions. It is described in particular in the article by sonogashira et al Tetrahedron lett.1975,16, 4467-4470.

The coupling involves the reaction of an acetylene derivative and a halide or aryl triflate catalyzed by a complex of palladium and copper.

Typically in an inert atmosphere, in catalytic amounts of a palladium complex (e.g., PdCl)₂(PPh₃)₂Or Pd (PPh)₃)₄) This reaction is carried out in the presence of a catalytic amount of a copper salt (e.g. CuI) and a base, which may be an organic base (such as triethylamine or DIPEA (diisopropylethylamine)) or an inorganic base (such as sodium carbonate, potassium carbonate or caesium carbonate). The operating conditions generally include a reaction temperature of 20 ℃ to 45 ℃, in particular in a solvent comprising dimethylformamide, tetrahydrofuran, dioxane or diethyl ether or mixtures thereof.

Step (2):

reducing the triple bond of the alkyne function C ≡ C to give a double bond CH ═ CH or a single bond CH₂-CH₂The reactions of (a) are well known to those skilled in the art and those skilled in the art will be able to determine the reaction conditions.

For example, the reduction can be carried out by hydrogen in the presence of a catalyst, for example of palladium on carbon type, in particular in a common solvent of the ethanol type, to obtain a single bond CH₂-CH₂。

The four general methods described above can be supplemented, as required, by any standard procedure described in the literature, known to the person skilled in the art or exemplified in the experimental part, in particular by additional functionalization and/or protection/deprotection reactions.

At the end of these three processes, one or more additional salification and/or solvation steps may be carried out in order to obtain pharmaceutically acceptable salts and/or solvates of the compounds of formula (I).

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

When the compound of formula (I) is in the form of a solvate, which is in this case the reaction medium solvent, the solvation is generally carried out in the last step of the process.

The compound of formula (I) obtained by one of the four methods mentioned above can be isolated from the reaction medium by methods well known to the person skilled in the art, for example by extraction, solvent evaporation or by precipitation and filtration.

If desired, the compounds of formula (I) may be further purified by techniques well known to those skilled in the art, such as by recrystallization (if the compound is crystalline), by distillation, by silica gel column chromatography or by High Performance Liquid Chromatography (HPLC).

The invention is illustrated by the following non-limiting examples.

Detailed Description

Examples

1. Synthesis of Compounds according to the invention

The following abbreviations were used:

DMSO, DMSO: dimethyl sulfoxide

HPLC: high performance liquid chromatography

IE: bombardment by electrons

LAH: lithium aluminum hydride (LiAlH)₄)

LCMS: liquid chromatography and mass spectrometry

RMN: nuclear magnetic resonance

1.1. Synthesis of intermediates

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

In a 50mL round-bottom flask, 1g (4.95mmol) of 4-bromo-3-methoxyaniline and 3.57mL of hydrochloric acid were combined. Then, 2.91g (69.3mmol) of cyanamide were added in small portions. The reaction mixture was heated to 60 ℃ for 2 hours. After returning to room temperature, the reaction was hydrolyzed by addition of water, basified and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to give 1.1g (93%) of 1- (4-bromo-3-methoxyphenyl) guanidine as a yellow solid.

LCMS(IE,m/z):(M+1)245.08

RMN 1H:dH ppm(400MHz,DMSO):6.54(4H,s,NH),7.27-7.29(1H,d,CH_{Fragrance composition}),6.51(1H,s,CH_{Fragrance composition}),6.31-6.33(1H,d,CH_{Fragrance composition}),3.77(3H,s,CH₃)。

Intermediate 2: n, N '-bis (tert-butoxycarbonyl) -N' - (3-methoxyphenyl) guanidine

To 0.77g (6.26mmol) of 3-methoxyaniline in 18mL of N, N-dimethylformamide was added 2g (6.89mmol) of 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea, 1.915mL (13.78mmol) of triethylamine, and then 1.7g (6.26mmol) of mercury chloride at 0 ℃. The reaction mixture was stirred at 0 ℃ for 5 hours and then atAnd (4) filtering. The filtrate was washed with water and extracted with ethyl acetate. The organic phase was 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 2.25g (98%) of N, N' -bis (tert-butoxycarbonyl) -N "- (3-methoxyphenyl) guanidine as a white solid.

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

RMN 1H:dH ppm(400MHz,DMSO):11.37(1H,s,NH),9.98(1H,s,NH),7.25-7.27(2H,m,CH_{Fragrance composition}),7.09-7.11(1H,m,CH_{Fragrance composition}),6.72-6.74(1H,m,CH_{Fragrance composition}),3.74(3H,s,CH₃),1.50(9H,s,CH₃),1.40(9H,s,CH₃)。

Intermediate 3: 1- (3-methoxyphenyl) guanidine

To 2.45g (6.70mmol) N, N '-bis (tert-butoxycarbonyl) -N' - (3-methoxyphenyl) guanidine in 16mL dichloromethane was added 16.53mL (215mmol) trifluoroacetic acid at 0 deg.C. The reaction mixture was stirred at 25 ℃ for 24 hours, then concentrated to give 1.3g of 1- (3-methoxyphenyl) guanidine, which was used in the next step without purification.

LCMS(IE,m/z):(M+1)166.19

Intermediate 4: (E) -2- ((dimethylamino) methylene) -7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one

To 7g (39.7mmol) of 7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one was added 79mL of N, N-dimethylformamide dimethyl acetal (596 mmol). The reaction mixture was refluxed for 15 hours. After evaporation of the solvent under reduced pressure, the residue was purified by chromatography on silica gel (eluent: dichloromethane/AcOEt: 80:20 to 100% AcOEt) to give 5.90g (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

RMN 1H:dH ppm(400MHz,DMSO):7.55(1H,s,CH_{Fragrance composition}),7.30-7.31(1H,d,CH_{Fragrance composition}),7.14-7.16(1H,m,CH_{Fragrance composition}),6.95-6.98(1H,m,CH_{Fragrance composition}),3.75(3H,s,CH₃),3.10(6H,s,CH₃),2.82-2.85(2H,t,CH₂),2.67-2.71(2H,t,CH₂)。

Intermediate 5: 9-methoxy-N- (3-methoxyphenyl) -5, 6-dihydrobenzo [ h]Quinazolin-2-amines

To 0.578g (2.5mmol) of (E) -2- ((dimethylamino) methylene) -7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one and 0.496g (3.00mmol) of 2- (3-methoxyphenyl) guanidine in 25mL of ethanol was added 1.037g (7.50mmol) of potassium carbonate. The reaction mixture was refluxed for 15 hours. After returning to room temperature, the solvent was evaporated and the solid formed was filtered and washed with methanol to give 0.56g (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

RMN 1H:dH ppm(400MHz,DMSO):9.54(1H,s,NH),8.46(1H,s,CH_{Fragrance composition}),7.78-7.79(1H,d,CH_{Fragrance composition}),7.70(1H,s,CH_{Fragrance composition}),7.14-7.28(3H,m,CH_{Fragrance composition}),7.02-7.05(1H,m,CH_{Fragrance composition}),6.51-6.54(1H,m,CH_{Fragrance composition}),3.84(3H,s,CH₃),3.76(3H,s,CH₃),2.78-2.86(4H,m,CH₂)。

Intermediate 6: n- (4-bromo-3-methoxyphenyl) -9-methoxy-5, 6-dihydrobenzo [ h]Quinazolin-2-amines

To 14.19g (58.1mmol) of 1- (4-bromo-3-methoxyphenyl) guanidine in ethanol (120mL) was added 10.34g (44.7mmol) of (E) -2- ((dimethylamino) methylene) -7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one. The reaction mixture was refluxed for 36 hours. After returning to room temperature, the solvent was evaporated and the solid formed was filtered and washed with methanol to give 12.90g (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

RMN 1H:dH ppm(400MHz,DMSO):9.71(1H,s,NH),8.43(1H,s,CH_{Fragrance composition}),7.82-7.83(1H,d,CH_{Fragrance composition}),7.76-7.77(1H,d,CH_{Fragrance composition}),7.44-7.46(1H,d,CH_{Fragrance composition}),7.38-7.41(1H,dd,CH_{Fragrance composition}),7.27-7.30(1H,d,CH_{Fragrance composition}),7.04-7.06(1H,dd,CH_{Fragrance composition}),3.87(3H,m,CH3),3.82(3H,m,CH3),2.77-2.87(4H,m,CH₂)。

Intermediate 7: 2- ((3-hydroxyphenyl) amino) -5, 6-dihydrobenzo [ h]Quinazolin-9-ols

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.51(1H,s,NH),8.35(1H,s,CH_{Fragrance composition}),7.63-7.64(1H,d,CH_{Fragrance composition}),7.29-7.31(1H,d,CH_{Fragrance composition}),7.23-7.24(1H,d,CH_{Fragrance composition}),7.14-7.16(1H,d,CH_{Fragrance composition}),7.07-7.11(1H,m,CH_{Fragrance composition}),6.86-6.89(1H,d,CH_{Fragrance composition}),6.39-6.42(1H,d,CH_{Fragrance composition}),2.76-2.78(4H,m,CH₂)。

Intermediate 8：

Intermediate 8 was prepared according to the protocol described for the preparation of intermediate 4, starting from 500mg of 6-fluoro-7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one and 2.394mL of N, N-dimethylformamide dimethyl acetal to give 600mg (93%) of intermediate 8.

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

RMN 1H:dH ppm(400MHz,DMSO):7.55(1H,s,CH_{Fragrance composition}),7.49-7.51(1H,d,CH_{Fragrance composition}),7.10-7.13(1H,d,CH_{Fragrance composition}),3.84(3H,s,CH₃),3.10(6H,s,CH₃),2.84-2.87(2H,t,CH₂),2.65-2.71(2H,t,CH₂)。

Intermediate 9：

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

LCMS(IE,m/z):(M+1)431.27

RMN 1H:dH ppm(400MHz,DMSO):9.70(1H,s,NH),8.42(1H,s,CH_{Fragrance composition}),7.89-7.92(1H,d,CH_{Fragrance composition}),7.66(1H,s,CH_{Fragrance composition}),7.45-7.52(2H,m,CH_{Fragrance composition}),7.26-7.29(1H,d,CH_{Fragrance composition}),3.93(3H,m,CH₃),3.94(3H,m,CH₃),2.79-2.85(4H,m,CH₂)。

Intermediate 10：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.64(1H,s,NH),8.23(1H,s,CH_{Fragrance composition}),7.81-7.84(1H,d,CH_{Fragrance composition}),7.42-7.43(1H,d,CH_{Fragrance composition}),7.33-7.41(2H,m,CH_{Fragrance composition}),7.15-7.18(1H,d,CH_{Fragrance composition}),2.76-2.79(4H,m,CH₂)。

Intermediate 11：

Intermediate 11 was prepared according to the protocol described for the preparation of compound 2, starting from 600mg of intermediate 10 to give 527mg of intermediate 11, 90% yield.

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

RMN 1H:dH ppm(400MHz,DMSO):9.81(1H,s,NH),8.67(1H,s,CH_{Fragrance composition}),8.42(1H,s,CH_{Fragrance composition}),8.14-8.17(1H,d,CH_{Fragrance composition}),7.41-7.43(1H,d,CH_{Fragrance composition}),7.26-7.29(1H,d,CH_{Fragrance composition}),6.83-6.85(1H,d,CH_{Fragrance composition}),4.26-4.30(4H,m,CH₂),3.79-3.82(4H,m,CH₂),2.78-2.82(4H,m,CH₂)。

1.2. Synthesis of Compounds according to the invention

Compound 1：

To a stirred solution of 0.93g (2.11mmol)2- ((3-hydroxyphenyl) amino) -5, 6-dihydrobenzo [ h ] quinazolin-9-ol in 100mL N, N-dimethylformamide was added 135mg (0.9mmol) potassium carbonate followed by 0.099g (0.426mmol) 1-bromo-2- (2-bromoethoxy) ethane in 10mL N, N-dimethylformamide for one hour. The reaction mixture was stirred at 75 ℃ for 20 hours. After returning to room temperature, the solvent was evaporated, water was added and the solid formed was filtered and dried in vacuo to give 0.01g (6%) of compound 1 as a beige powder.

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

RMN 1H:dH ppm(400MHz,DMSO):9.67(1H,s,NH),8.71(1H,s,CH_{Fragrance composition}),8.42(1H,s,CH_{Fragrance composition}),8.07(1H,s,CH_{Fragrance composition}),7.24-7.26(1H,d,CH_{Fragrance composition}),7.16(1H,t,CH_{Fragrance composition}),7.02(1H,d,CH_{Fragrance composition}),6.80-6.82(1H,d,CH_{Fragrance composition}),6.52(1H,d,CH_{Fragrance composition}),4.28(2H,m,CH₂),4.09(2H,m,CH₂),3.87-3.92(4H,m,CH₂),2.67-2.85(4H,m,CH₂)。

Compound 2：

To a stirred solution of 2.615g (27.2mmol)2- ((4-bromo-3-hydroxyphenyl) amino) -5, 6-dihydrobenzo [ h ] quinazolin-9-ol in 362mL N, N-dimethylformamide was added 4.7g (136mmol) potassium carbonate followed by 6.31g (27.2mmol) 1-bromo-2- (2-bromoethoxy) ethane in 123mL N, N-dimethylformamide for one hour. The reaction mixture was stirred at 80 ℃ for 20 hours. After returning to room temperature, the solvent was evaporated, water was added and the solid formed was filtered and dried in vacuo to give 12.2g (80%) of compound 2 as a beige powder.

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

RMN 1H:dH ppm(400MHz,DMSO):9.81(1H,s,NH),8.71-8.72(1H,s,CH_{Fragrance composition}),8.44(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.40-7.43(1H,d,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),6.88-6.83(1H,dd,CH_{Fragrance composition}),4.24-4.27(4H,m,CH₂),3.75-3.82(4H,m,CH₂),2.78-2.85(4H,m,CH₂)。

Compound 3：

In a 50mL round-bottom flask, 14mg (0.029mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6 ' -triisopropylbiphenyl and 53mg (0.058mmol) (dppf) were placed under argon₂PdCl₂·CH₂Cl₂328mg (0.722mmol) of Compound 2 and 1.01g (10.11mmol) of 1-methylpiperazine are mixed. 4mL of tetrahydrofuran and 5.78mL (5.78mmol) of lithium bis (trimethylsilyl) amide (LiHMDS) were added at room temperature. The reaction mixture was heated to 80 ℃ for 1h 45 min. After returning to room temperature, the reaction was hydrolyzed by slow addition of water at 0 ℃ and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to obtain 35.4mg (10%) of compound 3 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.46(1H,s,NH),8.51-8.52(1H,d,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,d,CH_{Fragrance composition}),6.79-6.85(2H,m,CH_{Fragrance composition}),4.23-4.25(4H,m,CH₂),3.75-3.77(4H,m,CH₂),2.94(4H,m,CH₂),2.76-2.86(4H,m,CH₂),2.45(4H,m,CH₂),2.21(3H,s,CH₃)。

Compound 4：

Compound 4 was prepared according to the protocol described for the preparation of compound 3, starting from 0.7g of compound 2 and 2.29g of aminopiperazine-1-carboxylic acid tert-butyl ester to give 380mg (44%) of compound 4.

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

RMN 1H:dH ppm(400MHz,DMSO):9.48(1H,s,NH),8.54-8.55(1H,d,CH_{Fragrance composition}),8.39(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.06-7.08(1H,dd,CH_{Fragrance composition}),6.86-6.87(1H,m,CH_{Fragrance composition}),6.79-6.82(1H,dd,CH_{Fragrance composition}),4.23-4.25(4H,m,CH₂),3.75-3.81(4H,m,CH₂),2.46(4H,m,CH₂),2.77-2.89(8H,m,CH₂),1.4(9H,s,CH₃)。

Compound 5：

To 380mg (0.679mmol) of Compound 4, 5mL of an isopropanol solution of hydrochloric acid (5N) was added dropwise. The solution was stirred at 45 ℃ for 2h 50 min. The solid formed was filtered and then washed twice with 20mL of water. The solid formed was placed in a basic medium and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to give 168mg (54%) of compound 5 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.45(1H,s,NH),8.51-8.52(1H,d,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),6.81-6.84(2H,m,CH_{Fragrance composition}),4.24(4H,m,CH₂),3.74-3.78(4H,m,CH₂),3.76-3.84(12H,m,CH₂)。

Compound 6：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.46(1H,s,NH),8.51-8.52(1H,d,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),6.80-6.88(1H,m,CH_{Fragrance composition}),6.78-6.80(1H,m,CH_{Fragrance composition}),4.22-4.26(4H,m,CH₂),3.90(4H,s,CH₂),2.74-3.79(4H,m,CH₂),2.97-3.01(4H,m,CH₂),2.75-2.85(4H,m,CH₂),1.73-1.77(4H,m,CH₂)。

Compound 7：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.45(1H,s,NH),8.51(1H,s,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.79-6.85(2H,m,CH_{Fragrance composition}),4.22-4.25(4H,m,CH₂),3.78-3.79(4H,m,CH₂),3.50-3.54(2H,m,CH₂),2.94(4H,m,CH₂),2.74-3.86(4H,m,CH₂),2.43-2.58(4H,m,CH₂),2.75-2.85(5H,m,CH₂And CH).

Compound 8：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.35(1H,s,NH),8.45-8.47(1H,d,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.04-7.07(1H,dd,CH_{Fragrance composition}),6.75-6.77(1H,dd,CH_{Fragrance composition}),6.65-6.67(1H,dd,CH_{Fragrance composition}),4.02-4.25(4H,m,CH₂),3.74-3.79(4H,m,CH₂),3.58-3.61(4H,m,CH₂),3.10-3.25(3H,m,CH₂),2.73-2.86(6H,m,CH₂),2.52(4H,m,CH₂)。

Compound 9：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.44(1H,s,NH),8.52-8.51(1H,d,CH_{Fragrance composition}),8.37(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.80-6.86(2H,m,CH_{Fragrance composition}),4.22-4.25(4H,m,CH₂),3.76-3.77(4H,m,CH₂),2.74-2.86(4H,m,CH₂),2.46-2.56(7H,m,CH₂),2.02(1H,m,CH),1.89-1.90(2H,m,CH₂),1.47-1.57(2H,m,CH₂),1.68(4H,m,CH₂)。

Compound 10：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.44(1H,s,NH),8.50-8.51(1H,d,CH_{Fragrance composition}),8.37(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.82-6.84(1H,d,CH_{Fragrance composition}),6.77-6.79(1H,dd,CH_{Fragrance composition}),4.22-4.25(4H,m,CH₂),3.75-3.79(4H,m,CH₂),3.35-3.39(2H,m,CH₂),2.75-2.86(4H,m,CH₂),2.46-2.56(6H,m,CH₂),2.27(1H,m,CH),1.75-1.80(2H,m,CH₂),1.35-1.62(8H,m,CH₂)。

Compound 11：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.44(1H,s,NH),8.50-8.51(1H,d,CH_{Fragrance composition}),8.37(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.82-6.84(1H,d,CH_{Fragrance composition}),6.77-6.79(1H,dd,CH_{Fragrance composition}),4.22-4.25(4H,m,CH₂),3.75-3.79(4H,m,CH₂),2.93(4H,m,CH₂),2.75-2.86(4H,m,CH₂),2.31-2.47(8H,m,CH),2.14(6H,m,CH₃)。

Compound 12：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.45(1H,s,NH),8.52(1H,s,CH_{Fragrance composition}),8.38(1H,d,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),6.80(2H,s,CH_{Fragrance composition}),4.22-4.25(4H,m,CH₂),3.75-3.79(4H,m,CH₂),2.85-2.87(4H,m,CH₂),2.76-2.78(4H,m,CH₂),2.60(2H,m,CH),1.12(6H,s,CH₃)。

Compound 13：

In a microwave reactor, 200mg (0.44mmol) of compound 2, 84mg (0.44mmol) of cuprous iodide and 112mg (0.660mmol) of (diethylamino) ethanethiol, HCl are combined. The reaction mixture was heated to 200 ℃ for 45 minutes. After returning to room temperature, water was added and the solid formed was filtered and purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to give 72mg (29%) of compound 13 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.70(1H,s,NH),8.60-8.61(1H,d,CH_{Fragrance composition}),8.43(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.20-7.22(1H,d,CH_{Fragrance composition}),7.05-7.06(1H,dd,CH_{Fragrance composition}),6.82-6.85(1H,dd,CH_{Fragrance composition}),4.23-4.26(4H,m,CH₂),3.74-3.83(4H,m,CH₂),2.75-2.88(6H,m,CH₂),2.45-2.60(6H,m,CH₂),0.81-0.93(6H,t,CH₃)。

Compound 14：

In a microwave reactor, 200mg (0.44mmol) of compound 2, 84mg (0.44mmol) of cuprous iodide and 0.515mL (hydroxyethyl) pyrrolidine (4.44mmol) are combined. The reaction mixture was heated to 200 ℃ for 45 minutes. After returning to room temperature, water was added and the solid formed was filtered and purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to give 16.6mg (7.5%) of compound 14 as a yellow solid.

LCMS(IE,m/z):(M+1)489.58

RMN 1H:dH ppm(400MHz,DMSO):9.47(1H,s,NH),8.54(1H,s,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.04-7.06(1H,dd,CH_{Fragrance composition}),6.93-6.95(1H,d,CH_{Fragrance composition}),6.80-6.82(1H,dd,CH_{Fragrance composition}),4.20-4.26(4H,m,CH₂),3.73-3.78(4H,m,CH₂),2.74-2.86(6H,m,CH₂),2.45-2.58(6H,m,CH₂),1.69(4H,m,CH₃)。

Compound 15：

In a 50mL vial, 2.5mg (5.50mmol) of Compound 2, 0.603g (1.266mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6 ' -triisopropylbiphenyl, 106mg (0.275mmol) of bis (benzonitrile) palladium (II) chloride, 1.53g (9.90mmol) of prop-2-yn-1-yl-carbamic acid tert-butyl ester and 5.38g (16.51mmol) of cesium carbonate were mixed in 23mL of N, N-dimethylformamide at room temperature. 2.19g (6.6mmol) tetrabutylammonium bromide were added to the reaction mixture. The reaction mixture was heated to 80 ℃ for 15 hours. After returning to room temperature, the reaction was hydrolyzed by slow addition of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by chromatography on silica gel (eluent: ethyl acetate/cyclohexane: 60:40) to give 1.3g (45%) of compound 15 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.86(1H,s,NH),8.62-8.63(1H,d,CH_{Fragrance composition}),8.45(1H,s,CH_{Fragrance composition}),8.03-8.04(1H,d,CH_{Fragrance composition}),7.32(1H,t,CH_{Fragrance composition}),7.27-7.29(1H,d,CH_{Fragrance composition}),7.20-7.22(1H,dd,CH_{Fragrance composition}),7.06-7.08(1H,dd,CH_{Fragrance composition}),6.82-6.84(1H,dd,CH_{Fragrance composition}),4.24-4.26(4H,m,CH₂),3.96-3.98(2H,m,CH₂),3.76-3.82(4H,m,CH₂),2.77-2.88(4H,m,CH₂),1.41(9H,m,CH₃)。

Compound 16：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.90(1H,s,NH),9.25(1H,s,CH_{Fragrance composition}),8.72(1H,s,CH_{Fragrance composition}),8.69(1H,s,CH_{Fragrance composition}),7.90-7.95(1H,d,CH_{Fragrance composition}),7.65-7.70(2H,m,CH_{Fragrance composition}),7.40-7.45(1H,dd,CH_{Fragrance composition}),6.90-6.95(2H,m,CH_{Fragrance composition}),4.40-4.45(2H,t,CH₂),4.30(2H,t,CH₂),3.90(2H,t,CH₂),3.80(2H,t,CH₂),2.94(4H,m,CH₂),2.76-2.86(4H,m,CH₂),2.21(3H,s,CH₃)。

Compound 17：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.47(1H,s,NH),8.51-8.52(1H,s,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.80-6.86(2H,m,CH_{Fragrance composition}),4.54-4.57(2H,m,CH₂),4.45-4.47(2H,m,CH₂),4.22-4.24(4H,m,CH₂),3.73-3.78(4H,m,CH₂),3.43-3.48(1H,m,CH),2.97(4H,m,CH₂),2.82-2.86(2H,m,CH₂),2.75-2.79(2H,m,CH₂),2.40(4H,m,CH₂)。

Compound 18：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.46(1H,s,NH),8.51-8.52(1H,s,CH_{Fragrance composition}),8.38(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.79-6.85(2H,m,CH_{Fragrance composition}),4.22-4.26(4H,m,CH₂),3.74-3.79(4H,m,CH₂),2.97(4H,m,CH₂),2.82-2.87(2H,m,CH₂),2.75-2.79(2H,m,CH₂),2.40(4H,m,CH₂),2.30-2.33(2H,m,CH₂),2.19-2.23(2H,m,CH₂),2.11(6H,m,CH₃),1.52-1.60(2H,m,CH₂)。

Compound 19：

To 100mg (0.212mmol) of compound 32 in 1mL of methanol and 1mL of THF at 0 deg.C was added 24mg (0.63mmol) of NaBH₄. The reaction mixture was stirred at 25 ℃ for 15 hours. The reaction was hydrolyzed by slowly adding 1N HCl solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 90:8:2) to give 46mg (42%) of compound 19 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.45(1H,s,NH),8.50-8.51(1H,d,CH_{Fragrance composition}),8.37(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.78-6.86(2H,m,CH_{Fragrance composition}),4.61-4.62(1H,d,OH),4.24(4H,m,CH₂),3.75-3.79(4H,m,CH₂),3.55(1H,m,CH),3.18-3.21(2H,m,CH₂),2.76-2.84(4H,m,CH₂),2.59-2.64(2H,m,CH₂),1.81-1.85(2H,m,CH₂),1.49-1.57(2H,m,CH₂)。

Compound 20：

In a microwave reactor, 200mg (0.44mmol) of Compound 2, 126mg (0.66mmol) of cuprous iodide, 287mg (0.88mmol) of cesium carbonate and 156mg (0.880mmol) of tert-butyl (2-mercaptoethyl) carbamate are combined. The reaction mixture was heated to 200 ℃ for 45 minutes. After returning to room temperature, water was added and the solid formed was filtered and then purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to give 17mg (7%) of compound 20 as a yellow solid.

LCMS(IE,m/z):(M+1)451.55

RMN 1H:dH ppm(400MHz,DMSO):9.71(1H,s,NH),8.60-8.61(1H,d,CH_{Fragrance composition}),8.43(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.22-7.28(2H,m,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),6.83-6.86(1H,dd,CH_{Fragrance composition}),4.23-4.26(4H,m,CH₂),3.80-3.83(4H,m,CH₂),3.74-3.77(2H,m,CH₂),2.76-2.84(6H,m,CH₂),2.66-2.67(2H,m,CH₂)。

Compound 21：

In a round-bottom flask and under argon, 0.3g (0.568mmol) of compound 33 in 50mL of a mixture of THF/MeOH (1:1) are introduced. The mixture was degassed under argon and vacuum. 6.04mg (0.057mmol) of Pd-C were added. The mixture was degassed under argon and vacuum and then placed in a hydrogen round bottom flask. The reaction mixture was stirred at 25 ℃ overnight, then filtered over silica and washed with ethyl acetate, then concentrated. The residue was dissolved in 10mL of isopropanol hydrochloride solution (5N). The solution was stirred at 45 ℃ for 1 hour. The solvent was evaporated and the reaction was hydrolyzed by slow addition of 1N NaOH solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 90:8:2) to obtain 11.5mg (7%) of compound 21 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.53(1H,s,NH),8.50(1H,s,CH_{Fragrance composition}),8.40(1H,s,CH_{Fragrance composition}),8.03(1H,d,CH_{Fragrance composition}),7.25-7.28(1H,m,CH_{Fragrance composition}),7.00-7.07(2H,m,CH_{Fragrance composition}),6.74-6.79(1H,dd,CH_{Fragrance composition}),4.18-4.24(4H,m,CH₂),3.73-3.84(4H,m,CH₂),2.75-2.85(4H,m,CH₂),1.59-1.66(2H,m,CH₂),2.51-2.59(4H,m,CH₂)。

Compound 22：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.52(1H,s,NH),8.50(1H,s,CH_{Fragrance composition}),8.40(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.25-7.28(1H,m,CH_{Fragrance composition}),7.04-7.07(1H,d,CH_{Fragrance composition}),6.99-7.01(1H,d,CH_{Fragrance composition}),6.74-6.76(1H,d,CH_{Fragrance composition}),4.18-4.23(4H,m,CH₂),3.75-3.83(4H,m,CH₂),2.75-2.84(4H,m,CH₂),2.65-2.67(2H,m,CH₂),2.45-2.57(6H,m,CH₂),2.32(1H,m,CH),2.10(3H,m,CH₃),1.81-1.86(2H,m,CH₂),1.70-1.75(2H,m,CH₂),1.60-1.64(2H,m,CH₂),1.15-1.28(1H,m,CH₂)。

Compound 23：

In a 50mL round-bottom flask, 50mg (0.09mmol) of compound 34 and 2mL of tetrahydrofuran were combined, followed by the addition of 0.5mL (0.5mmol) of Lithium Aluminum Hydride (LAH) at 0 ℃. The reaction mixture was heated to 85 ℃ for 5 hours. After returning to room temperature, the reaction was hydrolyzed by addition of sodium sulfate decahydrate, followed by ethyl acetate. This was followed by a filtration step on silica, followed by an extraction step with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to obtain 15mg (35%) of compound 23 as a yellow solid.

LCMS(IE,m/z):(M+1)471.56

RMN 1H:dH ppm(400MHz,DMSO):9.65(1H,s,NH),8.56-8.57(1H,d,CH_{Fragrance composition}),8.42(1H,s,CH_{Fragrance composition}),8.03-8.04(1H,s,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),7.01-7.04(1H,dd,CH_{Fragrance composition}),6.79-6.82(1H,dd,CH_{Fragrance composition}),5.75(1H,m,CH),4.14-4.25(4H,m,CH₂),3.74-3.79(4H,m,CH₂),2.76-2.86(4H,m,CH₂),2.99(2H,m,CH₂),2.45-2.53(4H,m,CH₂),2.27(3H,s,CH₃)。

Compound (I)24：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.56(1H,s,NH),8.57(1H,d,CH_{Fragrance composition}),8.42(1H,s,CH_{Fragrance composition}),8.03-8.04(1H,s,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),7.01-7.04(1H,d,CH_{Fragrance composition}),6.80-6.82(1H,dd,CH_{Fragrance composition}),5.78(1H,m,CH),4.15-4.24(4H,m,CH₂),3.75-3.80(4H,m,CH₂),2.77-2.85(4H,m,CH₂),2.99(2H,m,CH₂),2.45-2.53(4H,m,CH₂)。

Compound 25：

In a 50mL round-bottom flask, 100mg (0.09mmol) of Boc-protected form of compound 21 and 4mL of tetrahydrofuran were combined, followed by the addition of 0.93mL (0.93mmol) of LAH at 0 ℃. The reaction mixture was heated to 85 ℃ for 5 hours. After returning to room temperature, the reaction was hydrolyzed by addition of sodium sulfate decahydrate, followed by ethyl acetate. This was followed by a filtration step and a step of extraction with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to obtain 10mg (12%) of compound 25 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.52(1H,s,NH),8.50-8.51(1H,d,CH_{Fragrance composition}),8.40(1H,s,CH_{Fragrance composition}),8.03-8.04(1H,s,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.04-7.07(1H,dd,CH_{Fragrance composition}),6.99-7.01(1H,d,CH_{Fragrance composition}),6.74-6.76(1H,dd,CH_{Fragrance composition}),4.18-4.24(4H,m,CH₂),3.75-3.83(4H,m,CH₂),2.76-2.84(4H,m,CH₂),2.43-2.55(5H,m,CH₂),2.26(3H,m,CH₃)。

Compound 26：

In a 10mL vial, 1g (2.201mmol) of Compound 2, 0.24g (0.50mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6 ' -triisopropylbiphenyl, 42mg (0.11mmol) of benzonitrile palladium (II) chloride, 0.72g (3.96mmol) of 1- (prop-2-yn-1-yl) pyrrolidine and 2.15g (6.60mmol) of cesium carbonate were mixed at room temperature in 9mL of dimethylformamide. 0.85g (2.64mmol) tetrabutylammonium bromide was added to the reaction mixture. The reaction mixture was heated to 80 ℃ for 5 hours. After returning to room temperature, the reaction was hydrolyzed by slow addition of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to obtain 233mg (21%) of compound 26 as a yellow solid.

LCMS(IE,m/z):(M+1)483.57

RMN 1H:dH ppm(400MHz,DMSO):9.85(1H,s,NH),8.64(1H,s,CH_{Fragrance composition}),8.45(1H,s,CH_{Fragrance composition}),8.03(1H,s,CH_{Fragrance composition}),7.27-7.29(1H,d,CH_{Fragrance composition}),7.21-7.23(1H,d,CH_{Fragrance composition}),7.07-7.08(1H,d,CH_{Fragrance composition}),6.81-6.83(1H,d,CH_{Fragrance composition}),4.24-4.27(4H,m,CH₂),3.76-3.79(4H,m,CH₂),3.59(2H,m,CH₂),2.80-2.83(4H,m,CH₂),2.50-2.58(4H,m,CH₂),1.72(4H,m,CH₂)。

Compound 27：

To a solution of 100mg (0.23mmol) of compound 32 in 2.5mL of methanol were added 0.7g of 4A molecular sieve and 100mg (2.30mmol) of ammonium acetate. The reaction mixture was stirred at room temperature for 20 minutes, then 116mg (1.84mmol) of sodium cyanoborohydride were added. The reaction mixture was stirred at 60 ℃ for 16 hours. The solvent was then concentrated, and the reaction mixture was extracted with ethyl acetate and washed with saturated sodium hydroxide solution. The organic phases were combined, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 95:4:1) to give 20mg (17%) of compound 27 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.44(1H,s,NH),8.50(1H,s,CH_{Fragrance composition}),8.37(1H,s,CH_{Fragrance composition}),8.01-8.03(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.09(1H,dd,CH_{Fragrance composition}),6.77-6.85(2H,m,CH_{Fragrance composition}),4.22-4.25(4H,m,CH₂),3.74-3.82(4H,m,CH₂),3.24-3.29(2H,m,NH₂),2.74-2.86(4H,m,CH₂),2.48-2.86(6H,m,CH₂),1.75-1.80(2H,m,CH₂),1.35-1.44(1H,m,CH)。

Compound 28：

In a round-bottom flask and under argon, 0.20g (0.42mmol) of compound 26 in 50mL of a mixture of THF/MeOH (1:1) are introduced. The mixture was degassed under argon and vacuum. 4.56mg (0.043mmol) of Pd-C were added. The mixture was degassed under argon and vacuum and then placed in a hydrogen round bottom flask. The reaction mixture was stirred at 25 ℃ overnight, then filtered over silica and washed with ethyl acetate, then concentrated. The residue obtained is purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 90:8:2) to yield 71mg (34%) of compound 28 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.52(1H,s,NH),8.50(1H,s,CH_{Fragrance composition}),8.40(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.04-7.07(1H,dd,CH_{Fragrance composition}),6.99-7.01(1H,m,CH_{Fragrance composition}),6.74-6.76(1H,d,CH_{Fragrance composition}),4.18-4.23(4H,m,CH₂),3.75-3.82(4H,m,CH₂),2.76-2.88(4H,m,CH₂),2.32-2.39(8H,m,CH₂),1.62-1.70(6H,m,CH₂)。

Compound 29：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.40(1H,s,NH),8.50-8.51(1H,d,CH_{Fragrance composition}),8.36(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.07(1H,dd,CH_{Fragrance composition}),6.70-6.79(2H,m,CH_{Fragrance composition}),4.14-4.25(4H,m,CH₂),3.74-3.80(4H,m,CH₂),3.09-3.13(2H,m,CH₂),2.91-2.97(4H,m,CH₂),2.73-2.84(4H,m,CH₂),2.66(2H,m,CH₂),2.50-2.55(2H,m,CH₂)。

Compound 30：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.35(1H,s,NH),8.47-8.48(1H,d,CH_{Fragrance composition}),8.35(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.24-7.25(1H,d,CH_{Fragrance composition}),7.04-7.06(1H,dd,CH_{Fragrance composition}),6.75-6.77(1H,dd,CH_{Fragrance composition}),6.64-6.66(1H,d,CH_{Fragrance composition}),4.05-4.27(4H,m,CH₂),3.73-3.79(4H,m,CH₂) 3.10-3.23(3H, m, CH and CH)₂),2.69-2.84(4H,m,CH₂),2.17(6H,m,CH₃),1.99-2.05(2H,m,CH₂),1.66-1.73(2H,m,CH₂)。

Compound 31：

Compound 31 was prepared according to the protocol described for the preparation of compound 3, starting from 300mg of intermediate 11 and 127mg of 1-methylpiperazine to give 37mg (11%) of compound 31.

LCMS(IE,m/z):(M+1)492.56

RMN 1H:dH ppm(400MHz,DMSO):9.47(1H,s,NH),8.49-8.50(1H,d,CH_{Fragrance composition}),8.36(1H,s,CH_{Fragrance composition}),8.13-8.16(1H,d,CH_{Fragrance composition}),7.25-7.28(1H,d,CH_{Fragrance composition}),6.80-6.86(2H,m,CH_{Fragrance composition}),4.23-4.29(4H,m,CH₂),3.75(4H,m,CH₂),2.94(4H,m,CH₂),2.74-2.87(4H,m,CH₂),2.45(4H,m,CH₂),2.21(3H,s,CH₃)。

Compound 32：

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

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

Compound 33：

In a 10mL vial, 2.5g (5.5mmol) of Compound 2, 0.60g (1.26mmol) of 2- (dicyclohexylphosphino) -2 ', 4', 6 ' -triisopropylbiphenyl, 106mg (0.27mmol) of benzonitrile palladium (II) chloride, 1.53g (9.90mmol) of prop-2-ynyl-carbamic acid tert-butyl ester and 5.38g (16.5mmol) of cesium carbonate were mixed in 24mL of dimethylformamide at room temperature. 2.12g (6.60mmol) tetrabutylammonium bromide were added to the reaction mixture. The reaction mixture was heated to 80 ℃ for 5 hours. After returning to room temperature, the reaction was hydrolyzed by slow addition of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to give 1.3g (45%) of compound 33 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.86(1H,s,NH),8.62-8.63(1H,d,CH_{Fragrance composition}),8.45(1H,s,CH_{Fragrance composition}),8.03-8.04(1H,d,CH_{Fragrance composition}),7.25(1H,t,NH),7.27-7.29(1H,d,CH_{Fragrance composition}),7.20-7.22(1H,d,CH_{Fragrance composition}),7.06-7.08(1H,dd,CH_{Fragrance composition}),6.82-6.84(1H,dd,CH_{Fragrance composition}),4.25-4.29(4H,m,CH₂),3.96-3.98(2H,m,CH₂),3.76-3.81(4H,m,CH₂),2.79-2.86(4H,m,CH₂),1.41(9H,s,CH₃)。

Compound 34：

In a microwave reactor 463mg (1.01mmol) of compound 2, 0.3g (0.970mmol) of N-Boc-1,2,3, 6-tetrahydropyridine-4-boronic acid pinacol ester and 0.056g (0.049mmol) of tetrakis (triphenylphosphine) palladium (0) are combined in 8mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for 10 minutes, then 0.25g (2.426mmol) of sodium carbonate dissolved in 1mL of water was added at room temperature. The reaction mixture was heated to 150 ℃ for 20 minutes. After returning to room temperature, ethyl acetate was added and the organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was usedPurification by silica gel column chromatography (eluent: dichloromethane/methanol/ammonia: 95:4:1) gave 87mg (12%) of compound 34 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.67(1H,s,NH),8.57(1H,s,CH_{Fragrance composition}),8.42(1H,s,CH_{Fragrance composition}),8.03-(1H,s,CH_{Fragrance composition}),7.26-7.28(1H,m,CH_{Fragrance composition}),7.03-7.06(1H,m,CH_{Fragrance composition}),7.01-7.04(1H,dd,CH_{Fragrance composition}),6.79-6.82(1H,dd,CH_{Fragrance composition}),5.76(1H,m,CH),4.16-4.24(4H,m,CH₂),3.74-3.79(4H,m,CH₂),2.76-2.88(4H,m,CH₂),2.99(2H,m,CH₂),2.45-2.53(4H,m,CH₂),1.42(9H,s,CH₃)。

Compound 35：

Compound 35 was prepared according to the protocol described for the preparation of compound 3, starting from 400mg of compound 2 and 748mg of tert-butyl hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylate to give 200mg (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, starting from 200mg of compound 2 and 442mg of tert-butyl 2, 2-dimethylpiperazine-1-carboxylate to give 100mg (12%) of compound 36.

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

Compound 37：

In a 50mL round-bottom flask, 68mg (0.11mmol) of compound 35 in 2.47mL THF and 0.58mL of a 1MLAH solution in THF (0.58mmol) were combined at 0 ℃. The reaction mixture was heated to 85 ℃ for 3 hours. After returning to room temperature, the reaction was hydrolyzed by addition of sodium sulfate decahydrate, followed by ethyl acetate. The mixture was filtered over silica and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to obtain 14mg (23%) of compound 37 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.41(1H,s,NH),8.51-8.52(1H,d,CH_{Fragrance composition}),8.37(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),6.76-6.79(1H,dd,CH_{Fragrance composition}),6.70-6.72(1H,d,CH_{Fragrance composition}),4.16-4.25(4H,m,CH₂),3.74-3.80(4H,m,CH₂),3.11-3.15(2H,m,CH₂),2.91-2.95(2H,m,CH₂),2.82-2.86(2H,m,CH₂),2.71-2.78(4H,m,CH₂),2.61-2.66(2H,m,CH₂),2.24-2.26(2H,m,CH),2.21(3H,m,CH₃)。

Compound 38：

In a round-bottom flask and under argon, 0.49g (0.89mmol) of compound 34 in 50mL of a mixture of 1, 4-dioxane/ethanol (345mL/25mL) was introduced. The mixture was degassed again under argon and vacuum. 3.15g (2.96mmol) Pd-C was added. The degassing of the mixture was repeated under argon and vacuum and then placed in a hydrogen round bottom flask. The reaction mixture was stirred at 25 ℃ overnight, filtered over silica, washed with ethyl acetate, and concentrated to give 300mg (60%) of compound 38 as a yellow oil. LCMS (IE, M/z): (M +1)559.66

Compound 39：

To 300mg (0.53mmol) of compound 38, 1mL of a solution of hydrochloric acid (5N) in isopropanol was added dropwise. The solution was stirred at 45 ℃ for 3 hours. The solvent was evaporated. The solid formed was placed in a basic medium and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to obtain 29mg (11%) of compound 39 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO):9.56(1H,s,NH),8.50(1H,d,CH_{Fragrance composition}),8.40(1H,s,CH_{Fragrance composition}),8.03-8.04(1H,s,CH_{Fragrance composition}),7.26-7.28(1H,d,CH_{Fragrance composition}),7.03-7.08(2H,m,CH_{Fragrance composition}),6.79-6.82(1H,dd,CH_{Fragrance composition}),4.15-4.24(4H,m,CH₂),3.74-3.80(5H,m,CH₂And CH),2.99-3.02(2H, m, CH)₂),2.77-2.89(4H,m,CH₂),2.99(2H,m,CH₂),1.50(4H,m,CH₂)。

Compound 40：

In a 50mL round-bottom flask, 100mg (0.17mmol) of compound 36 in 3.62mL THF and 0.85mL of a 1MLAH solution in THF (0.85mmol) were combined at 0 ℃. The reaction mixture was heated to 85 ℃ for 5 hours. After returning to room temperature, the reaction was hydrolyzed by addition of sodium sulfate decahydrate, followed by ethyl acetate. The mixture was filtered over silica and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to obtain 8.10mg (10%) of compound 40 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,MeOH):8.58(1H,s,CH_{Fragrance composition}),8.25(1H,s,CH_{Fragrance composition}),8.14(1H,s,CH_{Fragrance composition}),7.20-7.22(1H,d,CH_{Fragrance composition}),7.03-7.04(1H,dd,CH_{Fragrance composition}),6.87-6.89(1H,d,CH_{Fragrance composition}),6.68-6.71(1H,dd,CH_{Fragrance composition}),4.27-4.34(4H,m,CH₂),3.81-3.88(4H,m,CH₂),2.88(2H,s,CH₂),2.27-2.87(8H,m,CH₂),2.28(3H,s,CH₃),1.17(6H,s,CH₃)。

Compound 41：

Compound 41 was prepared according to the protocol described for the preparation of compound 3 starting from 0.37g of compound 2 and 0.34g of tert-butyl amine (1R,5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate.

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

Compound 42：

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

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

RMN 1H:dH ppm(400MHz,DMSO):9.39(1H,s,NH),8.50(1H,d,CH_{Fragrance composition}),8.36(1H,s,CH_{Fragrance composition}),8.02-8.03(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.05-7.08(1H,dd,CH_{Fragrance composition}),6.74(2H,m,CH_{Fragrance composition}),4.23-4.25(4H,m,CH₂),3.86(2H,m,CH₂),3.74-3.79(4H,m,CH₂),2.94-2.97(2H,m,CH₂),2.73-2.86(4H,m,CH₂),2.54-2.57(2H,m,CH₂And CH),1.79(4H, m, CH)₂)。

Compound 43：

Compound 43 was prepared according to the protocol described for the preparation of compound 3 starting from 0.40g of compound 2 and 0.34g of tert-butyl amine (1S,4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate. Compound 43 thus obtained was used as it was.

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

Compound 44：

To 200mg (0.35mmol) of compound 43 was added dropwise a solution of 5mL hydrochloric acid (5N) in isopropanol. The solution was stirred at 45 ℃ for 1h 15 min. The solvent was evaporated and the solid formed was placed in a basic medium and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by chromatography on silica gel (eluent: ethyl acetate/methanol/ammonia: 94:4:2) to give 16mg (9%) of compound 44 as a yellow solid.

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

RMN 1H:dH ppm(400MHz,DMSO)9.31(1H,s,NH),8.44-8.45(1H,d,CH_{Fragrance composition}),8.34(1H,s,CH_{Fragrance composition}),8.01-8.02(1H,d,CH_{Fragrance composition}),7.25-7.27(1H,d,CH_{Fragrance composition}),7.04-7.06(1H,dd,CH_{Fragrance composition}),6.73-6.75(1H,dd,CH_{Fragrance composition}),6.56-6.58(1H,d,CH_{Fragrance composition}),4.01-4.26(4H,m,CH₂),3.99-3.01(1H,m,CH),3.74-3.79(4H,m,CH₂),3.60-3.63(1H,m,CH),3.49(1H,m,CH),2.99-3.02(1H,m,CH),2.80-2.85(4H,m,CH₂),2.72-2.77(2H,m,CH₂),1.54-1.74(2H,m,CH₂)。

2. Biological Activity of the Compounds according to the invention

The following abbreviations were used:

ATP: adenosine-5' -triphosphate

IMDM: iscove's modified Dulbecco's medium

PSFG: penicillin streptomycin amphotericin B

RPMI: culture medium for Roswell park memorial place

SVF: fetal bovine serum

Measurement of in vitro inhibitory activity of the compounds according to the invention:

FLT3(# PV3182), JAK2(# PV4210), and JAK3(# PV3855) recombinases were purchased from Life technologies. FLT3-ITD (#0778-^D835YThe (#14-610) proteins were purchased from Proquinase and Merck Millipore, respectively. All tests were performed in 384-well plates. The principle of these binding tests is based on from Life technologiesTR-FRET methodology.

FLT3 test. The reaction mixture (total volume 15 μ L) contained the following compounds: 15nM FLT3, FLT3-ITD or FLT3^D835Y3nM kinase tracer 236(Life Technologies, # PV5592), and 6nM for FLT3-ITD and FLT3^D835YCoupled to europium chelatesanti-GST antibody (Life Technologies, # PV5594), or 6nM conjugated to europium chelate for FLT3anti-His antibody (Life technologies, # PV 5596).

JAK testing. The reaction mixture (total volume 15 μ L) contained the following compounds: 15nM JAK2 or JAK3, 150nM kinase tracer 236 for JAK2 (Life Technologies, # PV5592) or 3nM kinase tracer 236 for JAK3 (Life Technologies, # PV5592), and 6nM for both enzymes coupled to europium chelateanti-GST antibody (Life Technologies, # PV 5594).

Compounds were evaluated at 8 different concentrations, prepared by making dilutions from the initial 10mM stock solution in dimethyl sulfoxide (DMSO) (Sigma, # D8418). The final DMSO concentration in the assay was 1%. The reaction was carried out at 25 ℃ for 1 hour and was carried out according to the recommendations of the supplier (Life Technologies)Measured on a microplate reader (Perkinelmer).

The results are expressed (table 1) as concentration values of the compounds inhibiting kinase activity by 50%: IC (integrated circuit)₅₀(μ M) generated using PRISM software (GraphPad).

TABLE 1: inhibition of FLT3, FLT3ID, FLT3D835Y, JAK2 and JAK3 enzymes by compounds according to the Invention (IC)₅₀(μ M)) (ND ═ not determined).

Compounds/enzymes	FLT3	FLT3-ITD	FLT3D835Y	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	0.0011	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	0.110
29	0.00370	0.000790	0.00190	0.0115	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	0.0011	ND	0.00670	0.0130
44	0.0052	0.0015	ND	0.0335	0.035

The compounds according to the invention have strong inhibitory activity against both the FLT3 enzyme (wild or mutated form) and the JAK2 and 3 enzymes.

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

a cell line.

The cell lines used were characterized as follows (table 2):

TABLE 2: the characteristics of the cell line used.

Measurement of antiproliferative activity.

MV4-11 and MOLM-13 cell lines were cultured in the medium indicated in Table 2 above, according to the supplier's recommendations. The assay was performed in 96-well plates. At J0, the cells were divided into two parts. At J1, willThey were inoculated and treated with different concentrations of the compound and at 37 ℃ and 5% CO₂And (5) performing medium incubation for 72 h. Dilutions of compounds from DMSO (Sigma, # D8418) stock solutions were performed in a semi-logarithmic manner to give a final concentration of 0.1% in the culture medium. On day 4, useThe kit (PerkinElmer, #6016947) assesses cell viability by measuring ATP released by living cells. Calculation of EC Using Curve fitting software₅₀Value (concentration of compound required to obtain 50% of maximum effect). Results are in EC₅₀The form of the values is shown in table 3.

TABLE 3: cytotoxicity (in M) of the compounds according to the invention on MV411 and MOLM13 cell lines.

Claims (18)

1. A compound of the following general formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein:

w represents an oxygen atom or a sulphur atom,

-X represents a saturated or unsaturated hydrocarbon chain comprising from 1 to 3 carbon atoms, optionally substituted by a halogenAtom, (C)₁-C₆) Alkyl, oxo, OH and (C)₁-C₆) One or more radicals of alkoxy, one or more, in particular 1 or 2, carbon atoms of the chain being optionally each, independently of the others, replaced by an oxygen atom or a sulfur atom,

-Y represents a nitrogen atom or a CRy group, in which Ry represents a hydrogen atom, a halogen atom, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Haloalkoxy, OH, CN, NO₂、NR₁₂R₁₃、CO₂H or CO₂((C₁-C₆) An alkyl) group, or a pharmaceutically acceptable salt thereof,

-Q represents a single, double or triple bond, an oxygen or sulfur atom, or (C)₁-C₆) Alkyl, S (O) or S (O)₂The radical(s) is (are),

-A₁and A₂Independently of one another, represents a single bond or (C) optionally substituted by an OH group₁-C₆) Alkyl, or A₁And A₂Form an optionally substituted monocyclic carbocyclic or monocyclic heterocyclic ring with Q and the carbon atoms to which Q is attached,

-R₁、R₂、R₃、R₄、R₅、R₆、R₇and R₈Independently of one another, represents a hydrogen atom or (C)₁-C₆) Alkyl, -R₉And R₁₀Independently of one another, represents a hydrogen atom, a halogen atom, optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl, optionally substituted (C)₂-C₆) Alkynyl, optionally substituted (C)₁-C₆) Alkoxy, optionally substituted (C)₁-C₆) Thioalkoxy, CN, NO₂、NR₁₄R₁₅、OH、SH、CO₂R₅₄、CONR₅₅R₅₆A group, an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring,

-R₁₁represents a hydrogen atom, a halogen atom, or (C)₁-C₆) Alkyl, (C)₁-C₆) Alkyl halidesBase, (C)₁-C₆) Alkoxy or (C)₁-C₆) A haloalkoxy group, and

-R₁₂、R₁₃、R₁₄、R₁₅、R₅₄、R₅₅and R₅₆Independently of one another, represents a hydrogen atom or optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl, or optionally substituted (C)₂-C₆) Alkynyl, or R₁₂And R₁₃And/or R₁₄And R₁₅And/or R₅₅And R₅₆Independently of one another, form, with the nitrogen atom bearing them, an optionally substituted heterocycle.

2. A compound according to claim 1, wherein X represents CH₂-CH₂Or CH ═ CH chain.

3. A compound according to any one of claims 1 and 2, wherein Y represents a CRy group, wherein Ry represents a hydrogen atom or a halogen atom such as F.

4. A compound according to any one of claims 1 to 3, wherein W and Q each independently of the other represent O or S, preferably O, and a₁And A₂Each represents a single bond.

5. A compound according to any one of claims 1 to 4, wherein W and Q each represent an oxygen atom, A₁And A₂Each represents a single bond, and R₁、R₂、R₃、R₄、R₅、R₆、R₇And R₈Each represents a hydrogen atom.

6. A compound according to any one of claims 1 to 5, wherein R₁₁Represents a hydrogen atom.

7. A compound according to any one of claims 1 to 6, wherein R₉And R₁₀Independently of one another, represents a hydrogen atom, a halogen atom or (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₂-C₆) Alkynyl, (C)₁-C₆) Alkoxy group, (C)₁-C₆) Thioalkoxy, (C)₁-C₆) Alkyl-amino, di ((C)₁-C₆) Alkyl) amino or heterocyclic group, said group being optionally substituted with one or more substituents selected from:

-a halogen atom,

-optionally substituted by a halogen atom, OR₁₆、SR₁₇And NR₁₈R₁₉Is substituted by one or more groups of (C)₁-C₆) An alkyl group, a carboxyl group,

-oxo (═ O), CN, NO₂、OR₂₀、SR₂₁、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、S(O)R₂₇、SO₂R₂₈、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁、SR₄₂And NR₄₃R₄₄One or more groups of (a) or (b),

-optionally substituted by a halogen atom, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅、SR₄₆And NR₄₇R₄₈A heterocycle substituted with one or more groups of (a), and

--O(CH₂)_nan O-group, wherein n represents an integer of 1 to 5, in particular 2 to 3,

wherein:

■R₁₆to R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) An alkyl group, a carboxyl group,

the aromatic rings of these radicals being optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic rings of these radicals being optionally substituted by a halogen atom, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom bearing them forming an optionally substituted halogen atom, (C)₁-C₆) Nitrogen-containing heterocycles substituted with one or more groups of alkyl and oxo (═ O).

8. A compound according to any one of claims 1 to 7, wherein R₉And R₁₀Represents, independently of one another:

-a hydrogen atom or a halogen atom,

--Z-(CH₂)_m-R₄₉group, wherein Z represents a single bond, CH₂-CH₂CH, C.ident. C, O, S or NR₅₀(ii) a m represents an integer of 1 to 6, in particular 1 to 4; r₅₀Represents a hydrogen atom or (C)₁-C₆) An alkyl group; and R is₄₉Represents a halogen atom, OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀(ii) a In particular OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀(ii) a In particular NR₂₂R₂₃、NR₃₃CO₂R₃₄Or NR₃₇CONR₃₈R₃₉Or is or

-a monocyclic or bicyclic heterocycle having 5,6 or 7 members, preferably 5 or 6 members, per ring, comprising 1 or 2 heteroatoms selected from N and O, preferably saturated or containing a double bond, optionally substituted with one or more substituents selected from:

● a halogen atom, and (b) a halogen atom,

● optionally substituted by a halogen atom, OR₁₆、NR₁₈R₁₉、C₃To C₆(C) substituted by one or more groups of monocyclic carbocycles (in particular saturated) and 3-to 6-membered monocyclic heterocycles (in particular saturated)₁-C₆) An alkyl group; preferably, optionally selected from halogen atoms, OR₁₆And NR₁₈R₁₉Is substituted by one or more groups of (C)₁-C₆) An alkyl group, a carboxyl group,

● oxo (═ O), OR₂₀、NR₂₂R₂₃、C(O)R₂₄、CO₂R₂₅、OC(O)R₂₆、NR₂₉C(O)R₃₀、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀A group; and more particularly oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉Or OCO₂R₄₀The radical(s) is (are),

● are optionally selected from halogen atoms, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄One or more radicals ofC substituted by radicals₃To C₆The carbon ring is a carbon ring,

● 3 membered to 6 membered heterocyclic ring, in particular saturated or unsaturated, preferably saturated, comprising 1 or 2 heteroatoms selected from N and O, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

●-O(CH₂)_nan O-group, in which n represents an integer equal to 2 or 3,

wherein:

■R₁₆、R₁₈to R₂₀、R₂₂To R₂₆、R₂₉To R₄₀、R₄₅And R₄₇To R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl- (C)₁-C₆) Alkyl, heterocycle or heterocycle- (C)₁-C₆) Alkyl radicals, the aromatic rings of which are phenyl radicals, and which are optionally substituted by radicals selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, and

the heterocyclic ring of these groups is a 3-to 6-membered, in particular 5-or 6-membered heterocyclic ring, which comprises 1 or 2 heteroatoms selected from N and O, and which is optionally substituted by a group selected from halogen atoms, (C)₁-C₆) One or more radicals of alkyl and oxo (═ O), or

■R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉、R₄₃And R₄₄And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a preferably saturated 5-or 6-membered nitrogen-containing heterocyclic ring which, in addition to the nitrogen atom, optionally contains 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring, said heterocyclic ring optionally being selected from halogen atoms, (C)₁-C₆) Alkyl and oxo (═ O).

9. According toThe compound of any one of claims 1 to 8, wherein R₁₀Represents a hydrogen atom.

10. The compound according to any one of claims 1 to 9, wherein it is a compound of formula (Ib) below:

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein:

-represents a single or double bond, preferably a single bond,

-Ry represents a hydrogen atom, a halogen atom, a (C)₁-C₆) Alkyl or (C)₁-C₆) A haloalkyl group; in particular represents a hydrogen atom or a halogen atom, and

-R₉represents a saturated monocyclic or bicyclic nitrogen-containing heterocycle containing 5 or 6 members per ring, optionally containing, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as piperazine, 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]An azole or pyrrolidine ring, the nitrogen-containing heterocycle being attached to the remainder of the molecule through its nitrogen atom and which is optionally substituted with one or more substituents selected from:

■ a halogen atom, and (b) a halogen atom,

■ optionally substituted by a halogen atom, OR₁₆And NR₁₈R₁₉Is substituted by one or more groups of (C)₁-C₆) An alkyl group, a carboxyl group,

■ oxo (═ O), OR₂₀、NR₂₂R₂₃、CO₂R₂₅、C(O)NR₃₁R₃₂、NR₃₃CO₂R₃₄、OC(O)NR₃₅R₃₆、NR₃₇CONR₃₈R₃₉And OCO₂R₄₀The radical(s) is (are),

■ is optionally selected from halogen atoms, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₁And NR₄₃R₄₄C substituted by one or more radicals of₃To C₆The carbon ring is a carbon ring,

■ 3 membered to 6 membered heterocyclic ring, preferably saturated, containing 1 or 2 heteroatoms selected from N and O, optionally substituted by atoms selected from halogen, (C)₁-C₆) Alkyl, oxo (═ O), OR₄₅And NR₄₇R₄₈Is substituted with one or more groups of (a), and

■-O(CH₂)_nan O-group in which n represents an integer equal to 2 or 3 (the two oxygens of the group may be bonded to the same atom or to two different atoms, advantageously they are bonded to the same atom, in particular to the same carbon atom, so that in this case a cyclic acetal can be formed),

wherein:

◆R₁₆、R₁₈to R₂₀、R₂₂、R₂₃、R₂₅、R₃₁To R₄₁、R₄₃To R₄₅、R₄₇And R₄₈Independently of one another, represents a hydrogen atom, (C)₁-C₆) Alkyl, aryl, or aryl- (C)₁-C₆) Alkyl radicals, especially hydrogen atoms, or (C)₁-C₆) An alkyl group, a carboxyl group,

◆ the aromatic ring of these radicals is preferably phenyl, and it is optionally substituted by a group selected from halogen atoms and (C)₁-C₆) One or more radicals of alkyl being substituted, or

◆R₂₂And R₂₃、R₃₁And R₃₂、R₃₅And R₃₆、R₃₈And R₃₉And/or R₄₇And R₄₈Together with the nitrogen atom which carries them, form a 5-or 6-membered nitrogen-containing heterocycle, in particular nonaromatic, preferably saturated, which optionally contains, in addition to the nitrogen atom, 1 heteroatom selected from N and O, such as a piperazine, piperidine, morpholine or pyrrolidine ring,said heterocycle being optionally substituted by a halogen atom, (C)₁-C₆) Alkyl and oxo (═ O).

11. Compound according to claim 1, characterized in that it is selected from the following compounds:

and pharmaceutically acceptable salts and/or solvates thereof.

12. A compound according to any one of claims 1 to 11 for use as a medicament.

13. A compound according to any one of claims 1 to 11 for use in the treatment of cancer.

14. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 11 and at least one pharmaceutically acceptable excipient.

15. A process for the preparation of a compound according to any one of claims 1 to 11, comprising a compound of formula (II):

w, X, Y, R therein₉、R₁₀And R₁₁As defined in claim 1, wherein the first and second groups are,

a coupling reaction with a compound of the following formula (III):

q, A therein₁、A₂And R₁To R₈As defined in claim 1, and LG₁And LG₂Each independently of the other represents a leaving group.

16. A process for the preparation of a compound according to any one of claims 1 to 11, wherein R₉Or R₁₀Represents optionally substituted (C)₁-C₆) Alkoxy, optionally substituted (C)₁-C₆) Thioalkoxy or NR₁₄R₁₅A group or an optionally substituted heterocyclic ring comprising a heteroatom directly attached to the phenyl ring, said method comprising a compound of formula (IVa) or (IVb):

w, X, Y, Q, A therein₁、A₂And R₁To R₁₁As defined in claim 1, and X₁Represents a halogen atom such as Br, Cl or I,

are each independently of the formula R₉H or R₁₀Coupling of compounds of H, wherein R₉And R₁₀As defined above.

17. A process for the preparation of a compound according to any one of claims 1 to 11, wherein R₉And/or R₁₀Represents optionally substituted (C)₁-C₆) Alkyl, optionally substituted (C)₂-C₆) Alkenyl or optionally substituted (C)₂-C₆) An alkynyl group, an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring attached to the phenyl ring via a carbon atom, the method comprising a compound of the following formula (Va) or (Vb):

w, X, Y, Q, A therein₁、A₂And R₁To R₁₁As defined in claim 1, and X₂Represents Br, Cl, I or OTf,

are each independently of the formula R₉-BR₅₂R₅₃Or R₁₀-BR₅₂R₅₃The coupling of a compound of (1), wherein R₉And R₁₀As defined above, and R₅₂And R₅₃Independently of one another, OH, (C)₁-C₆) Alkyl or (C)₁-C₆) Alkoxy, or R₅₂And R₅₃Together form-X₃-or-O-X₃-O-chain, wherein X₃Represents a divalent hydrocarbon group containing 2 to 15, in particular 2 to 10, carbon atoms.

18. A process for the preparation of a compound according to claim 8, wherein R₉And/or R₁₀represents-Z- (CH)₂)_m-R₄₉Group, wherein Z represents CH₂-CH₂CH ═ CH or C ≡ C, the method comprising the steps of:

(1) a compound of the following formula (Va) or (Vb):

w, X, Y, Q, A therein₁、A₂And R₁To R₁₁As defined in claim 1, and X₂Represents Br, Cl, I or OTf,

and formula HC ≡ C- (CH)₂)_m-R₄₉The sonogashira coupling of compounds of (1), wherein m and R₄₉As defined in claim 8, the first and second,

to give a compound of the formula (I) in which R₉Or R₁₀represents-C ≡ C- (CH)₂)_m-R₄₉And are and

(2) optionally reducing the alkyne function of the compound of formula (I) obtained in the preceding step to obtain a compound of formula (I), wherein R₉Or R₁₀represents-CH ═ CH- (CH)₂)_m-R₄₉Or- (CH)₂)_m+2-R₄₉。