WO2008107322A1 - Indole, benzimidazole or benzotriazole derivatives including a piperidine or piperazine core as anti-neoplasic agents or cell proliferation inhibitors - Google Patents

Abstract

The invention relates to compounds of the formula (I), as well as to their pharmaceutically acceptable salts, in which: Ar<SUB>1</SUB> is an aryl or heteroaryl group, each optionally substituted; X and Y are identical or different and represent a nitrogen atom of a CH group; n is an integer between 4 and 6; D is a carbon or nitrogen atom. The invention also relates to a manufacturing method, to pharmaceutical compositions containing the same, and to their use as anti-neoplasic agents and/or cell proliferation inhibitors.

Description

 "Indole derivatives, benzimidazole or benzotriazole, comprising a piperidine or piperazine ring, as anti-neoplastic agents or inhibitors of cell proliferation"

The present invention relates to novel piperidine or piperazine derivatives, their method of manufacture, the pharmaceutical compositions containing them, and their use as anti-neoplastic agents and / or inhibitors of cell proliferation.

These new derivatives can be in addition derivatives of indole, benzimidazole or benzotriazole.

Despite the progress made in recent years in the development of new therapeutic treatments for neoplastic diseases such as cancer or leukemia, the incidence and prevalence rates of these diseases continue to increase. The discovery of new treatments therefore remains a major challenge for public health. The use of currently available chemical treatments all too often causes the appearance of undesirable side effects. As a result, there is a continuing need to develop new molecules for chemotherapy.

The term neoplasia refers to abnormal, disrupted and disorganized cell proliferation. The accumulation of neoplastic cells constitutes a mass, the neoplasm - or tumor - which can be benign or malignant. Cancer more specifically refers to a process of malignant growth. A metastasis is the growth of a tumor cell at a distance from the site initially reached.

The compounds of the present invention are considered anti-neoplastic agents because they possess the property of inhibiting the proliferation of a large number of tumor cells.

The products of the present invention can thus be used for the prevention or treatment of neoplastic diseases such as cancers (solid tumors and acute and chronic leukemias). The products of the present invention can also be used for the prevention or treatment of diseases associated with abnormal cell proliferation such as psoriasis, rheumatoid arthritis, Kaposi's sarcoma, nephropathies acute and chronic, atherosclerosis, autoimmune diseases or acute and chronic inflammatory diseases.

The subject of the present invention is the compounds of general formula (I) below:

C) ainsi que leurs sels pharmaceutiquement acceptables, dans laquelle :

C) as well as their pharmaceutically acceptable salts, in which:

A ₁ represents an aryl or heteroaryl group, each optionally substituted one to five times with groups chosen from a halogen atom, a (C 1 -C 6) alkyl, hydroxy and hydroxy (C 1 -C 6) alkyl radical, ₁ -

C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (dC ₆ ) thioalkoxy, cyano, (C 1 -C 6) haloalkyl, (C 1 -C 6) haloalkoxy, an aryl group, an N-group (C ₁ -C ₆ ) alkylamino or N ₅ N- (C 1 -C 6) dialkylamino;

• X and Y, identical or different, represent a nitrogen atom or a CH group;

• n represents an integer between 4 and 6;

D represents a carbon atom or a nitrogen atom:

- When D is a nitrogen atom:

R ¹ represents a group G, an aryl group, an aryl (C 1 -C 6) alkyl group, a heteroaryl group, a heteroaryl (C 1 -C 6) alkyl group, a heterocyclic group or a (C 1 -C 6) alkyl heterocycle group, each optionally substituted, and R ² represents a doublet of electrons; - When D is a carbon atom:

R ¹ represents a hydrogen atom, a hydroxyl group, a (C ¹ -C ⁶ ) alkylcarbonyl group or a cyano group and R ² an optionally substituted aryl group; and where G is represented by the following general formula (II):

(H) for which,

• L represents a group CO or (CH2) _m ;

M represents an integer between 1 and 3; and R ³ and R ⁴ , which may be identical or different, represent a hydrogen atom, a (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or (C ₃ -C ₇ ) cycloalkyl (Ci-C) group; ₆ ) alkyl, heterocyclic, (C 1 -C ₆ ) alkyl heterocycle, aryl (C 1 -C ₆ ) alkyl, heteroaryl (C 1 -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆ ) dialkylamino (C 1 -C 6) alkyl, each optionally substituted; or,

R ³ and R ⁴ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic radical.

All radicals (Ci-Ce) alkyl, (C 3 -C ₇₎ cycloalkyl, (C 3 -C ₇₎ cycloalkyl (Ci-C6) alkyl, aryl, aryl (Ci-C6) alkyl, heteroaryl, heteroaryl (Ci-C6) alkyl, heterocyclic, (C ₁ -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, N ₅ N- (C ₁ -C ₆ ) alkyl,

C6) dialkylamino (C1-C6) alkyl, (C1-C6) alkylcarbonyl, defined above for R ¹ , R ² , R ³ and R ⁴ , may be optionally substituted by one or more identical or different radicals chosen from the atoms of halogen and cyano, hydroxyl, (C 1 -C 6) alkyl, alkoxy, (C 1 -C 6) alkylthio, nitro, oxo, acetyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -

C ₇ ) (C ₁ -C ₆ ) cycloalkyl, heterocyclic, (C ₁ -C ₆ ) heterocycle alkyl, aryl, aryl (C 1 -C 6)

C ₆ ) alkyl, heteroaryl, heteroaryl (C ₁ -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino, N ₅ N- (C ₁ -C ₆ )

C ₆₎ dialkylamino ₅ N- (Ci-C ₆₎ alkylamino (Ci-C ₆₎ alkyl ₅ N ₅ N- (C iC ₆₎ dialkylamino (-C

C ₆₎ alkyl, N- (Ci-C ₆₎ alkylamino (Ci-C ₆₎ alkylcarbonyl ₅ N- (C6) alkylaminocarbonyl (Ci-C6) alkyl, N ₅ N- (C i-C6) dialkylamino (C -C6) alkylcarbonyl, hydroxy (C1-C6) alkyl, halo (C1-C6) alkyl, (C1-C6) alkoxycarbonyl or arylcarbonyl.

The present invention also comprises salts of the compounds of formula (I) ₅ pharmaceutically acceptable. These salts can be obtained with acids non-toxic and therapeutically acceptable inorganic or organic minerals, especially hydrochloric, sulfuric, phosphoric, methanesulfonic, citric, maleic, fumaric, oxalic, tartaric and acetic acids.

The object of the present invention also extends to the solvates, hydrates, optical isomers and geometric isomers of the compounds of formula (I), including preferred sub-families or compounds mentioned hereinafter, as well as their products. drug addicts.

According to the present invention, the terms used to describe the compounds of formula (I) can be defined as follows:

The term "alkyl" refers to a saturated monovalent hydrocarbon radical, linear or branched, composed of 1 to 12 carbon atoms, preferably composed of 1 to 6 carbon atoms. The alkyl groups of small sizes, that is to say the alkyl groups composed of 1 to 6 carbon atoms are preferred. When a number appears in index after the symbol "C", the index defines exactly the number of carbon atoms contained in the alkyl group. For example, the term "(C ₁ -C ₆ ) alkyl" denotes an alkyl radical comprising from 1 to 6 carbon atoms, such as a methyl, ethyl, n-propyl, isopropyl, n-butyl or t-butyl group. pentyl, etc. The term "(C1-C6) alkylcarbonyl" refers to an alkyl radical comprising from 1 to 6 carbon atoms connected to the rest of the molecule by a carbonyl group. the term "(C 1 -C 6) alkylsulfonyl" denotes an alkyl radical comprising from 1 to 6 carbon atoms connected to the rest of the molecule by an SO ₂ group.

When the term "alkyl" is used as a suffix in combination with a second group, as in "arylalkyl", "hydroxyalkyl", "cycloalkylalkyl", the second group is then connected to the remainder of the molecule by an alkyl radical. For example, the term "hydroxy (C1-C6) alkyl" refers to a hydroxyl group connected to the remainder of the molecule by an alkylene radical having 1 to 6 carbon atoms; the term "aryl (Ci-C6) alkyl" means an aryl radical connected to the remainder of the molecule by an alkylene radical comprising from 1 to 6 carbon atoms. The term "aryl (Ci-C6) alkyl" refers in particular to the benzyl, 4-chloro-benzyl, phenylethyl and the like.

The term "cycloalkyl" denotes an alkyl group of 3 to 10 carbon atoms forming a saturated or unsaturated monocyclic system. By way of example, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexene. indane, indene. The term "(C3-C8) cycloalkyl" refers to a cycloalkyl radical having 3 to 8 carbon atoms.

The term "aryl" refers to mono- or bi-cyclic aromatic hydrocarbon systems, generally 5 or 6-membered, having from 6 to 14 carbon atoms. Mention may in particular be made of the phenyl, 1-naphthyl or 2-naphthyl radical.

The term "heteroaryl" refers to mono-, bi- or tri-cyclic aromatic hydrocarbon systems having on the ring (s) at least one heteroatom, such as nitrogen, sulfur or oxygen. By way of example of monocyclic "heteroaryl", mention may especially be made of pyridyl, furanyl, thienyl, pyrazolyl, pyrrolyl, imidazolyl and the like. By way of example of bicyclic "heteroaryl" mention may especially be made of benzofuranyl, benzothienyl and the like. By way of example of tricyclic "heteroaryl", mention may be made especially of the dibenzo furanyl group, and the like.

The term "cyclic" refers to saturated or unsaturated mono-, bi- or polycyclic hydrocarbon systems. They can be aromatic or not. They are preferably non-aromatic. As a cycle, there may be mentioned the cyclopentane group, cyclohexane, indene, indane, naphthalene, etc.

The term "heterocyclic" refers to mono-, bi- or poly-cyclic hydrocarbon systems, saturated or unsaturated, having on the ring (s) at least one heteroatom, such as nitrogen, sulfur or sulfur. oxygen. They can be aromatic or not. They are preferably non-aromatic. As heterocycle, there may be mentioned piperidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, phthalane, phthalide, thiazolidinedione, sulfolane, benzo [1,3] dioxolane, benzo [1,4] dioxane, [2,3] ] dihydrobenzofuran, quinazolinone, benzothiadiazinone, 1-methyl-piperidin-4-yl or 1-methyl-piperidin-4-ylmethyl. The term "(C 1 -C 6) alkyl heterocycle" denotes a heterocyclic radical as defined above connected to the remainder of the molecule by an alkylene radical comprising from 1 to 6 carbon atoms.

The term "alkoxy" refers to an alkyl radical as defined above connected to the remainder of the molecule through a -O- (ether) bond. An "alkoxyalkyl" group corresponds to an alkyl radical interrupted by an oxygen atom. Examples of alkoxy radicals that may be mentioned include methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and the like. By "(Ci-Ce) alkoxy", means an alkyl radical comprising from 1 to 6 carbon atoms connected to the remainder of the molecule via an -O- (ether) bond. The term "(C 1 -C 6) alkoxy (C 1 -C 3) alkyl" refers to an alkyl radical having from 1 to 6 carbon atoms connected through an -O- (ether) bond to an alkylene radical comprising from 1 to to 3 carbon atoms, linked to the rest of the molecule. The term "(C1-C6) alkoxycarbonyl" denotes an alkyl radical comprising from 1 to 6 carbon atoms connected via an -O- (ether) bond to a carbonyl radical which is itself linked to the remainder of the molecule .

The term "thioalkoxy" refers to an alkyl radical as defined above connected to the remainder of the molecule via a sulfur atom. Mention may be made by way of example of thioalkoxy radicals, the methylthio, ethylthio, propylthio, n-butylthio, sec-butylthio, tert-butylthio and the like radicals.

The terms "N-alkylamino" and "N, N-dialkylamino" denote respectively one and two "alkyl" groups as defined above, connected to the rest of the molecule by a nitrogen atom. By "N- (C 1 -C 4) alkylamino" is meant an alkyl radical comprising from 1 to 4 carbon atoms connected to the rest of the molecule by a nitrogen atom.

The term "alkylene" denotes a divalent group corresponding to the alkyl radical as defined above by removal of a hydrogen atom. By (C ₂ -C ₆ ) alkylene is meant an alkylene radical comprising from 2 to 6 carbon atoms. By "halogen" is meant a fluorine, chlorine, bromine or iodine atom. The term "haloalkyl" refers to an alkyl radical as defined above, substituted by at least one halogen. By "(C 1 -C 6) haloalkyl" is meant an alkyl radical comprising from 1 to 6 carbon atoms, substituted by at least one halogen. As an example of a "(C 1 -C 6) haloalkyl" group, there may be mentioned the trifluoromethyl radical.

The term "haloalkoxy" refers to an alkoxy radical as defined above, substituted by at least one halogen. By "(C 1 -C 6) haloalkoxy" is meant an alkyl radical comprising from 1 to 6 carbon atoms, substituted by at least one halogen and connected to the remainder of the molecule by means of a -O- (ether) bond. ). By way of example of a "(C 1 -C 6) haloalkoxy" group, there may be mentioned the trifluoromethoxy radical (-OCF 3). By "heteroatom" is meant an atom selected from O, N and S.

The term "pharmaceutically acceptable salts" means the addition salts which can be obtained by reaction of these compounds of formula (I) with a mineral or organic acid, according to a method known per se. Among the salts formed by the addition of an acid, mention may be made of acetates (for example those prepared from acetic or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulphates and borates. , butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (prepared from hydrochloric acid), hydrobromides (prepared from hydrobromic acid) , 2-hydroxyethanesulfonates, lactates, maleates (prepared from maleic acid), methanesulfonates (prepared from methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates , pivalates, propionates, salicylates, succinates, sulfates (eg those prepared for sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates.

The term "pro-drug" represents a compound which may be, after administration, chemically transformed either by a chemical process or by a metabolic pathway, to give a compound of formula (I), and / or a compound of formula

(I) in the form of salt, solvate and / or hydrate. For example, esters capable of being hydrolysed in the body may constitute "pro-drugs" of compounds of formula (I) comprising a carboxylic function. The "pro-drugs" are preferably administered orally.

For the purposes of the present invention, the compounds of formula (I) may exist in the various forms of geometric isomers and / or optical isomers. This includes the tautomeric forms obtained after migration of one or more hydrogen atoms within the molecule and therefore a rearrangement of certain bonds of the molecule, trans or cis isomers and / or, if there is one or more asymmetric centers in the molecule, enantiomers or diastereoiso mothers. According to the present invention, the compounds of formula (I) can also exist in the form a mixture of isomers (a mixture of trans and cis isomers, a mixture of diastereoisomers, a racemic mixture of enantiomers). By default, when the stereochemistry of a compound (trans or cis isomer, asymmetric carbon R or S) is not specified, this compound may exist within the meaning of the invention, in all forms of isomers or mixtures at least one of its isomers. The preparation of compounds in the form of a single stereoisomer can be carried out for example by asymmetric synthesis or by separation of a racemic mixture of enantiomers or a mixture of diastereoisomers. This separation can be carried out according to techniques (such as liquid chromatography, asymmetric splitting, or fractional crystallization) known to those skilled in the art. Furthermore, according to the present invention, the compounds of formula (I) may also exist in a hydrated form.

According to the present invention, the compounds of formula (I) can be defined as a combination of all the groups, substituted or unsubstituted, as defined above.

Preferred compounds within the meaning of the invention are compounds of formula (I), as well as their pharmaceutically acceptable salts, in which:

Ari, X, Y and n are as defined in formula (I) above; D represents a carbon atom;

R ¹ represents a hydroxyl group, and R ^{2 represents} an optionally substituted aryl group, where the optional substitution of R ² is as defined above.

Another family of preferred compounds within the meaning of the invention is a family of compounds of formula (I), as well as their pharmaceutically acceptable salts, in which:

Ari, X, Y and n are as defined in formula (I) above;

D represents a nitrogen atom; • R ¹ represents a heterocyclic group and R ^{2 represents} an electron pair. Another family of preferred compounds within the meaning of the invention is a family of compounds of formula (I), as well as their pharmaceutically acceptable salts, in which:

Ari, X, Y and n are as defined in formula (I) above;

D represents a nitrogen atom;

• R ¹ represents a group G and R ² a pair of electrons; and

G is represented by the following general formula (II):

(H) for which, • L represents a CO group; and

R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C) cycloalkyl, (C 3 -C) cycloalkyl (C 1 -C 6) alkyl, heterocyclic or heterocycle group; (C 1 -C ₆ ) alkyl, aryl (C 1 -C ₆ ) alkyl, heteroaryl (C 1 -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C 1 -C ₆ ) ₆ ) dialkylamino (C 1 -C 6) alkyl, each optionally substituted, or

R ³ and R ⁴ form, with the nitrogen atom to which they are bonded, an optionally substituted heterocyclic radical, in which the optional substitution of R ³ and R ⁴ , or of the radical formed by R ³ and R ⁴ , is as defined previously ,

A subfamily of preferred compounds within the meaning of the invention is a series of compounds of formula (I), as well as their pharmaceutically acceptable salts, in which: ## STR1 ## is as defined in formula (I) below. above ;

X and Y represent a CH group;

D represents a nitrogen atom;

• R ¹ represents a group G and R ² a pair of electrons; and

G is represented by the following general formula (II):

(H) for which,

• L represents a CO group; and

R ³ and R ⁴ , which may be identical or different, represent a hydrogen atom, a (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or (C ₃ -C ₇ ) cycloalkyl (C ₁ -C _{6) group;} ) alkyl, heterocyclic, (C 1 -C ₆ ) heterocycle alkyl, aryl (C 1 -C ₆ ) alkyl, heteroaryl (C 1 -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N (C ₁ -C ₆ ) dialkylamino (C 1 -C 6) alkyl, each optionally substituted, or R ³ and R ⁴ together with the nitrogen atom to which they are bonded form an optionally substituted heterocyclic radical, where the optional substitution of R ³ and R ^4, or the radical formed by R ³ and R ⁴ is as defined above.

A subfamily of preferred compounds within the meaning of the invention is a series of compounds of formula (I), as well as their pharmaceutically acceptable salts, in which:

• Al-I is as defined in formula (I) above;

X represents a CH group; Y represents a nitrogen atom;

D represents a nitrogen atom;

• R ¹ represents a group G and R ² a pair of electrons; and

G is represented by the following general formula (II):

(H) for which,

• L represents a CO group; and

R ³ and R ⁴ , which may be identical or different, represent a hydrogen atom, a (C ₁ -C ₆ ) alkyl, (C ₃ -C ₇ ) cycloalkyl or (C ₃ -C ₇ ) cycloalkyl (C ₁ -C _{6) group;} ) alkyl, heterocyclic, (C 1 -C 6) heterocycle alkyl, aryl (C 1 -C 6) alkyl, heteroaryl (C 1 -C 6) alkyl,

C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆ ) dialkylamino (C 1 -C 6) alkyl, each optionally substituted, or

R ³ and R ⁴ form, with the nitrogen atom to which they are bonded, an optionally substituted heterocyclic radical, in which the optional substitution of R ³ and R ⁴ , or of the radical formed by R ³ and R ⁴ , is as defined previously .

A subfamily of preferred compounds within the meaning of the invention is a series of compounds of formula (I), as well as their pharmaceutically acceptable salts, in which:

• Al-I is as defined in formula (I) above;

X represents a nitrogen atom;

Y represents a nitrogen atom; D represents a nitrogen atom;

• R ¹ represents a group G and R ² a pair of electrons; and

G is represented by the following general formula (II):

(H) for which,

• L represents a CO group; and

R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkyl (C 1 -C 6) alkyl or heterocyclic group; , (C 1 -C 6) heterocycle alkyl, aryl (C 1 -C 6) alkyl, heteroaryl (C 1 -C 6) alkyl, C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆ ) dialkylamino (C 1 -C 6) alkyl, each optionally substituted, or

R ³ and R ⁴ form, with the nitrogen atom to which they are bonded, an optionally substituted heterocyclic radical, in which the optional substitution of R ³ and R ⁴ , or of the radical formed by R ³ and R ⁴ , is as defined previously .

Another family of preferred compounds within the meaning of the invention is a family of compounds of formula (I), as well as their pharmaceutically acceptable salts, in which:

Ari, X, Y and n are as defined in formula (I) above;

D represents a nitrogen atom;

• R ¹ represents a group G and R ² a pair of electrons; and G is represented by the following general formula (II):

(H) for which,

• L represents a group (CH2) _m ;

M represents an integer between 1 and 3; and R ³ and R ⁴ , which may be identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C 5) cycloalkyl or (C 3 -C) cycloalkyl (C 1 -C 6) alkyl group, N- (Ci-C ₆₎ alkylamino (Ci-C ₆₎ alkyl or N, N- (Ci-C ₆₎ dialkylamino (Ci-C ₆₎ alkyl, each optionally substituted or R ³ and R ⁴ together with the atom nitrogen to which they are bonded an optionally substituted heterocyclic radical, where the optional substitution of R ³ and R ⁴ , or of the radical formed by R ³ and R ⁴ , is as defined above, Another family of preferred compounds within the meaning of the invention is a family of compounds of formula (I), as well as their pharmaceutically acceptable salts, in which:

• Ar represents an aryl group, preferably phenyl, optionally substituted with at least one halogen atom, preferably a chlorine atom;

• X and Y, identical or different, represent a nitrogen atom or a CH group;

• n represents an integer between 4 and 6;

• D represents a carbon atom or a nitrogen atom: - When D is a nitrogen atom:

R ¹ represents a group G, a heterocyclic group or a (C 1 -C 6) alkyl heterocycle group, each optionally substituted with at least one group chosen from a (C 1 -C 6) alkyl radical, and R ² represents a pair of electrons. ;

- When D is a carbon atom:

R ¹ represents a hydrogen atom, a hydroxyl group, a (C ¹ -C ⁶ ) alkylcarbonyl group or a cyano group and R ² an aryl group, preferably phenyl, optionally substituted with at least one halogen atom, preferably a chlorine atom; and where G is represented by the following general formula (II):

(H) for which • L represents a group CO or (CH ₂ ) _m ;

M represents an integer between 1 and 3; and

R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C ₁ -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- ( C ₁ -C ₆ ) dialkylamino (C ₁ -C ₆ ) alkyl. Particularly preferred compounds within the meaning of the invention include the compounds named below, as well as their pharmaceutically acceptable salts, solvates and hydrates.

2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide

4- (4-Chloro-phenyl) -1- {5- [1- (4-chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperidin-4-ol • 1 - (4- Chloro-phenyl) -5- {5- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -pentyloxy} -1H-indole

2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethyl-acetamide

2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N- (2-dimethyl-amino-ethyl) acetamide

[2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) ethyl] dimethylamine

2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide • 2 - (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethylacetamide

2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide

2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide

2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N- (2-dimethyl-amino-ethyl) acetamide

[2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -ethyl] -dimethyl-amine • 2- ( 4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethylacetamide 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide

2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide • 2 - (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N- (2-dimethyl-amino-ethyl) -acetamide

[2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) ethyl] -dimethyl-amine

2- (4- {4- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -butyl} -piperazin-1-yl) -N, N-dimethyl-acetamide

2- (4- {6- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -hexyl} -piperazin-1-yl) -N, N-dimethyl-acetamide

The present invention also relates to the various synthetic routes, which are illustrated in the diagrams and in the examples hereinafter. The starting compounds can be obtained commercially or synthesized according to usual methods. It is understood that the present application is not limited to a particular synthetic route, and extends to other methods for producing the indicated compounds. In general, the present invention relates to a process for the synthesis of compounds of formula (I) which consists in reacting in an organic solvent in the presence of a base, the compounds of formulas (III) and (IV):

in which Ar ₁ , X, Y, n, D, R ¹ and R ² are as defined above, and Z 1 is a hydroxyl group or a nucleofugal group such as a chlorine atom, a bromine atom, a mesylate radical, a tosylate radical or a triflate radical. Another aspect of the present invention relates to a process for synthesizing compounds of formula (I) which consists in reacting in an organic solvent, the compounds of formulas (V) and (VI):

in which ArI, X, Y, n, D, R ¹ and R ² are as defined above, and Z ₂ is a hydroxyl group or a nucleofugal group such as a chlorine atom, a bromine atom, a mesylate radical, a tosylate radical or a triflate radical.

The compounds of formula (III), (IV), (V) and (VI) may be prepared from known compounds, or according to known reactions, and more particularly according to the following schemes.

In all the schemes presented below, the group Gp represents a methyl group or a protective group such as tert-butyloxycarbonyl, benzyloxycarbonyl or tertbutyldimethylsilyl groups. The groups Z ₁ and Z ₂ represent a nucleofugal group such as a chlorine atom, bromine atom, a mesylate, tosylate or triflate group.

The abbreviations used are recalled in the introduction of the experimental part. Scheme 1 groups together synthesis routes that make it possible to access compounds of general formula (I) for which X = Y = CH. The groups Ar ₁ , n, D, R ¹ and R ² are as defined previously in formula (I). These compounds belong to the sub-family of compounds of general formula (I) -I.

Le 5-méthoxy-indole Al peut être ajouté dans un solvant organique, tel que le

5-methoxyindole Al can be added in an organic solvent, such as

DMF, DMSO or dioxane, to an aryl or heteroaryl halide Ari-Hal (where

HaI = F, I, Br or Cl), in the presence of a base such as NaH or K2CO3 and optionally copper powder and copper iodide to give the derivative Bl- (J. Med. Chem.

1985, 28 (1), 66-73; JACS 2001, 123 (31), 7727-7729).

The demethylation of this intermediate B1 leading to the hydroxyl derivative C12 can be carried out according to various procedures. By way of example, it can be carried out by the action of boron tribromide in dichloromethane (Santini C. et al Bioorg, Med Chem 2003, 13, 1, 1277-1280). pyridinium hydrochloride (Zoubir B. et al., J. Heterocycl Chem, 1999, 36, 2, 509-514), hydrobromic acid in acetic acid (Laschober R. et al., Synthesis 1990, 5, 387). 388) or alternatively aluminum trichloride in toluene or dichloromethane in the presence or absence of a mercaptan derivative (Kitagawa M. et al Chem Chem, 1991, 39, 9, 2400-2407). The introduction of an alkyl chain on the derivative C 1 can be carried out according to different experimental conditions. By way of example, it may be carried out at reflux of an organic solvent (such as acetonitrile) in the presence of an alkyl derivative comprising at least at one of its ends a nucleophilic group (such as a halogenide). ) and in the presence of a base (such as K 2 CO 3) to give the D 1 derivative (Watanabe T. et al Chem Chem, 1998, 46, 1, 53-68, Massa S. et al. Chem Chem 1995, 38, 5, 803-809). The nucleophilic group Z ¹ of the derivative D 1 is directly in place in the case for example of a halide or is obtained by transformation of a non-nucleophilic group such as a hydroxyl group into a nucleophilic group such as a triflate, may then be displaced by addition of a cyclic amine leading to the product of general formula (I) -I. Thus, in the case of the presence of a halogen atom as a nucleophilic group Z ¹ , the nucleophilic substitution with an amine may be carried out in an organic solvent (such as acetonitrile), in the presence of a base (such as as K2CO3) at reflux of the solvent (Kamal A. et al Bioorg Med Med Chem 2005, 15, 10, 2621-2624). An alternative route of synthesis can be carried out by indole protection by a suitable group such as an acetyl group, an arylsulfonyl group, or a silyl group, followed by desmethylation of the group. methoxy unit to lead to the hydroxylated product E1 according to the experimental conditions previously described. The introduction of an alkyl chain is carried out as previously seen to lead to the FL intermediate. A cyclic amine is then introduced by displacement of a nucleophilic group leading to the GL compound. The latter may then be deprotected according to known conditions of the invention. skilled in the art to lead to the product HL This derivative H1 can then react with an aryl or heteroaryl halide Ari-Hal (where HaI = F, I, Br or Cl) according to the conditions described above, to drive to the product of general formula (I) -L

Scheme 2 groups together synthesis routes that make it possible to access compounds of general formula (I) for which X = Y = N. The groups Ar ₁ , n, D, R ¹ , and R ² are as defined previously in FIG. formula (I). These compounds belong to the subfamily of compounds of general formula (I) -2.

Le schéma 3 regroupe des voies de synthèse permettant d'accéder aux composés de formule générale (I) pour lesquels X=CH et Y= N. Les groupements Ar₁, n, D, R¹, et R² sont tels que définis précédemment dans la formule (I). Ces composés appartiennent à la sous famille de composés de formule générale (I)-3. La formation du dérivé benzimidazolyl D3 à partir de l'intermédiaire Ç_2 peut être réalisée suivant diverses procédures. A titre d'exemple, elle peut être réalisée par l'action du formaldéhyde (Justus Liebigs Ann. Chem. 1922, 427, 219), de l'acide formique (J. Chem. Soc. 1893, 63, 1404) ou du trimethoxymethane (Bioorg. Med. Chem. Lett. 2003, 13 (15), 2485-2488). La désméthylation de cet intermédiaire D3 conduisant au dérivé hydroxylé E3 peut être réalisée suivant des conditions expérimentales précédemment décrites. L'introduction d'une chaîne alkyle est réalisée comme vu précédemment pour conduire à l'intermédiaire F3. Enfin, une aminé cyclique est alors introduite par déplacement d'un groupement nucléophuge conduisant aux composés de formule générale (I)-3. Le schéma 4 décrit une voie de synthèse d'accès aux composés de formule (I) pour lesquels D = N et L = CO. Les groupements Ar₁, n, D, R¹, R², R³ et R⁴ sont tels que définis précédemment dans la formule (I). Ces composés appartiennent à la sous famille de composés de formule générale (I)-4.Aniline A2 ((4-methoxy-2-nitro-phenyl) -amine) can be substituted and react in an organic solvent, such as DMF, DMSO or dioxane, with an aryl or heteroaryl halide. Ari-Hal (where HaI = F, I, Br or Cl), in the presence of a base such as NaH or K2CO3 and optionally copper powder and copper iodide to lead to the B2 derivative (J. Med. 1989, 42 (13), 2373). The nitro group present in compound B2 can then be reduced to amine in the presence of hydrazine and Raney nickel or tin chloride or under a hydrogen atmosphere in the presence of catalytic amounts of palladium on charcoal (Heterocycl. Commun 2003, 9 (2), 153-160, Bioorg Med Med Chem 2003, 13 (3), 507-512, Bioorg Med Med Chem 2000, 10 (18), 2119-2122. ) to lead to the intermediary Ç_2. The latter can lead to the benzotriazolyl derivative D2 in the presence of sodium nitrite in an acidic medium (Bioorg Med Chem, Lett 1999, 7 (11), 2457-2464). The demethylation of the intermediate D2 leading to the hydroxylated derivative E2 can be carried out according to the experimental conditions previously described. The introduction of an alkyl chain is carried out as previously seen to lead to the intermediate F2. A cyclic amine is then introduced by displacement of a nucleophilic group leading to the compounds of general formula (I) -2.

Scheme 3 groups together synthetic routes for accessing the compounds of general formula (I) for which X = CH and Y = N. The groups Ar ₁ , n, D, R ¹ and R ² are as defined previously. in formula (I). These compounds belong to the sub-family of compounds of general formula (I) -3. The formation of the benzimidazolyl derivative D3 from the intermediate C2 can be carried out by various procedures. By way of example, it can be carried out by the action of formaldehyde (Justus Liebigs Ann Chem 1922, 427, 219), formic acid (J. Chem Soc., 1893, 63, 1404) or trimethoxymethane (Biochem Med Chem 2003, 13 (15), 2485-2488). The demethylation of this intermediate D3 leading to the hydroxylated derivative E3 can be carried out according to the experimental conditions previously described. The introduction of an alkyl chain is carried out as previously seen to lead to the intermediate F3. Finally, a cyclic amine is then introduced by displacement of a nucleophilic group leading to the compounds of general formula (I) -3. Scheme 4 describes a route of synthesis of access to the compounds of formula (I) for which D = N and L = CO. The groups Ar ₁ , n, D, R ¹ , R ² , R ³ and R ⁴ are as defined previously in formula (I). These compounds belong to the subfamily of compounds of general formula (I) -4.

The derivative A4 can lead to the derivatives B4, C4, D4, and (I) -4 by displacement of the nucleophilic group by the corresponding piperazine available commercially or previously synthesized, according to the method previously described in Scheme 1. Alternatively the compound B4 can be derivatized C4 by displacement of the protecting group. Alkylation of the piperazine derivative C14 leads to the compound D4 with a haloacetate derivative (Ohtaka H. et al Chem Chem Pharm, 1988, 36, 12, 4825-4833) and to the compound (I) -4 with a chloroacetamide derivative (Tahtaoui C. et al., J. Med Chem 2004, 47, 17, 4300-4315, Zhao H. et al Bioorg, Chem Chem Lett, 2002, 12, 21, 3105-3110). Compound D4 can also be converted to compound (I) -4 by conversion of the carboxylate function to the corresponding amide function.

Le schéma 5 décrit une voie de synthèse d'accès aux composés de formule (I) pour lesquels D = N et L = (CH2)_m. Les groupements Ar₁, n, m, D, R¹, R², R³ et R⁴ sont tels que définis précédemment dans la formule (I). Ces composés appartiennent à la sous famille de composés de formule générale (I)-5.

Scheme 5 describes an access synthesis route for the compounds of formula (I) for which D = N and L = (CH 2) _m . The groups Ar ₁ , n, m, D, R ¹ , R ² , R ³ and R ⁴ are as defined previously in formula (I). These compounds belong to the sub-family of compounds of general formula (I) -5.

Intermediate C 4 seen previously in Scheme 4 can also be alkylated with various haloalkyl derivatives. When the haloalkyl derivatives are substituted by amines they can lead directly to the products of general formula (I) -S. When the haloalkyl derivatives are substituted with a leaving group Z1, they can lead to AS-type intermediates which are in turn converted into products of general formula (I) -S according to the method previously described in Scheme 1. Certain products of the type (I) -S (for which the value of m is equal to 1) can also be obtained by reduction, by the action of a reducing agent such as LiAlH ₄ , of the amide function of the compounds (I) -4 seen previously in scheme 4 in amino function.

Les composés selon l'invention possèdent de manière inattendue la propriété d'inhiber la prolifération d'un grand nombre de cellules tumorales d'origines diverses. Ils possèdent généralement une CI50, c'est-à-dire la concentration de composé à laquelle 50 % de la prolifération cellulaire est inhibée, telle que déterminée ci-dessous, préférentiellement inférieure ou égale à 10 μM, avantageusement inférieure ou égale à lμM et très avantageusement inférieure ou égale à 0.1 μM.

The compounds according to the invention unexpectedly possess the property of inhibiting the proliferation of a large number of tumor cells of various origins. They generally possess an IC 50, that is to say the concentration of compound at which 50% of the cell proliferation is inhibited, as determined below, preferably less than or equal to 10 μM, advantageously less than or equal to 1 μM and very advantageously less than or equal to 0.1 μM.

The compounds according to the invention are particularly interesting and may be used as anti-neoplastic agents and / or as inhibitors of cell proliferation. The compounds of the present invention can thus be used for the prevention or treatment of neoplastic diseases such as cancers (solid tumors and acute and chronic leukemias).

The compounds of the present invention can also be used for the prevention or treatment of diseases associated with abnormal cell proliferation such as psoriasis, rheumatoid arthritis, Kaposi's sarcoma, acute and chronic nephropathies, atherosclerosis, autoimmune diseases or acute and chronic inflammatory diseases.

The subject of the present invention is therefore the compounds of formula (I) as defined above as medicaments. The present invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound according to the invention, alone or in combination with at least one pharmaceutically acceptable excipient.

The present invention also relates to the use of a compound according to the invention for the preparation of a medicament for preventing or treating a neoplastic disease, such as cancer.

The present invention also relates to the compounds of formula (I) as defined above for the prevention or treatment of a neoplastic disease, such as cancer.

The present invention also relates to the use of a compound according to the invention for the preparation of a medicament for treating solid tumors or chronic or acute leukemias, or for preventing or treating metastases. By treatment of cancer or metastasis is meant according to the present invention essentially the ability for a compound to selectively kill tumor cells without substantially reaching healthy cells, it being understood that this selectivity may be variable depending on the condition of the patient and the patient. type of cancer treated. The subject of the present invention is also the compounds of formula (I) as defined above for the treatment of solid tumors or chronic or acute leukemias or for the prevention or treatment of metastases.

The present invention thus relates to a method for killing tumor cells comprising bringing said cells into contact with the compounds according to the invention.

In the context of the present invention, the term "treatment" refers to the preventive, curative, palliative, as well as the treatment of patients (reduction of suffering, improvement of living conditions, slowing of the progression of the disease) . The treatment may further be carried out in combination with other agents or treatments.

Said cancer or said metastasis may be derived from a cancer selected from prostate cancer, osteosarcomas, lung cancer, non-small cell lung cancer, breast cancer, endometrial cancer or cancer. colon cancer, chronic or acute leukemia, solid tumors of the child, lymphocytic lymphoma, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, cancer of the head and neck, cancer uterine cancer, ovarian cancer, gynecological tumors, Hodgkin's disease, bone cancer, rectal cancer, anal cancer, stomach cancer, cancer of the uterus esophagus, small bowel cancer, endocrine system cancer, soft tissue sarcomas, urethral cancer, penile cancer, bladder cancer, kidney cancer, cancer of the ureter, pediatric malignancies and tumors of the central nervous system, in particular brain tumors.

The present invention also relates to the use of a compound according to the invention for the preparation of a medicament for preventing or treating a disease associated with abnormal cell proliferation, such as psoriasis, rheumatoid arthritis, Kaposi's sarcoma, acute and chronic nephropathy, atherosclerosis, autoimmune diseases or acute and chronic inflammatory diseases.

The present invention also relates to the compounds of formula (I) as defined above for the prevention or treatment of a disease associated with abnormal cell proliferation, such as psoriasis, rheumatoid arthritis, sarcoma Kaposi, acute and chronic nephropathy, atherosclerosis, autoimmune diseases or acute and chronic inflammatory diseases.

The pharmaceutical compositions according to the invention advantageously comprise one or more pharmaceutically acceptable carriers, excipients or carriers. For example, saline, physiological, isotonic, buffered, compatible with a pharmaceutical use and known to those skilled in the art. The compositions may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles that can be used in formulations (liquid and / or injectable and / or solid) include methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, and the like. acacia.

The compositions may be formulated as injectable suspension, gels, oils, tablets, suppositories, powders, capsules, capsules. It may in some cases be advantageous to provide controlled release forms including sustained release by known galenic shaping.

The compounds or compositions according to the invention can be administered in a pharmaceutically acceptable form by one of the different routes known for this type of active principle, although the oral route, in particular in the form of capsules or tablets, is the preferred route. . The injectable route may also be used when necessary, and in particular, the intravenous route but also the intraperitoneal route, the intranasal route, the transdermal route, the intramuscular route or the intra-arterial route.

For the oral route, the pharmaceutical compositions according to the invention can be in the form of tablets, capsules or liquid preparations such as elixirs and suspensions containing various masking substances of color, flavor and stabilization. To achieve oral dosage forms according to the invention, In particular capsules, the active substance can be mixed with various conventional materials such as starch, calcium carbonate, lactose, sucrose and dicalcium phosphate to facilitate the encapsulation process. Magnesium stearate, as an additive, provides a useful lubricant function if necessary. For the injectable route, the active substances of the pharmaceutical compositions according to the invention may be dissolved or suspended in a pharmaceutically acceptable sterile injectable liquid, such as sterile water, a sterile organic solvent or a mixture of these two liquids for a period of time. intravenous administration. Other routes of administration may include, but are not limited to, subcutaneous implants, as well as oral, sublingual, transdermal, topical, intranasal, or rectal administrations. Biodegradable and non-biodegradable delivery systems may also be employed.

According to a particular embodiment, the subject of the invention is the use of compounds according to the invention for the preparation of a pharmaceutical composition which can be administered according to one of the preceding routes, dosed with 1 to 1000 mg of active principle for a composition formulated in the form of capsules or tablets, or from 0.1 to 500 mg of active ingredient for a composition formulated as suppositories, ointments, creams, gels or aerosol preparations, administered in human therapy in one or more daily doses. In the case of use for animals, the usable daily dose is between 0.01 and 100 mg per kg.

Other aspects and advantages of the present invention will appear on reading the examples which follow, which should be considered as illustrative and not limiting.

EXAMPLES

Abbreviations

ACN = acetonitrile APTS = para-toluene sulfonic acid BBr3 = bromine tribromide Bn = benzyl t-Bu = tert-butyl

Boc = tert-butyloxycarbonyl

CDC13 = Deuterated chloroform

CDI = 1,1'-carbonyldiimidazole DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene

DCM = dichloromethane

DMAP = N-dimethylaminopyridine

DMF = dimethylformamide

DMSO = dimethylsulfoxide Eq. = equivalent

Et = ethyl

And ₂ O = diethyl ether or ethyl ether

EtOAc = ethyl acetate

EtOH = ethanol HCl = hydrochloric acid

HOBT = 1-hydroxybenzotriazole hydrate

H ₂ SO ₄ = sulfuric acid

K ₂ CO ₃ = potassium carbonate

KI = potassium iodide KOH = potassium hydroxide

LDA = lithium diisopropylamide

LAH = lithium aluminum hydride

Me = methyl

MeOH = methanol MgSO ₄ = magnesium sulfate

NaBH ₄ = sodium borohydride

NaBHsCN = sodium cyanoborohydride

NaBH (OAc) ₃ = sodium triacetoxyborohydride NaCl = sodium chloride

Na ₂ CCh = sodium carbonate

NaH = sodium hydride

NaHCO ₃ = sodium hydrogencarbonate NaOH = sodium hydroxide

Na ₂ SO ₄ = sodium sulphate

NH ₄ Cl = ammonium chloride

Ph = phenyl

PI13P = triphenylphosphine TBME = tert-butyl methyl ether

TEA = triethylamine

TFA = trifluoroacetic acid

THF = tetrahydrofuran

Yield = yield L = liter (s) mL = milliliter (s) μL = micro liter (s) mM = millimolar μM = micro molar nM = nano molar mmol = millimole (s) μmol = micromole (s) g = gram (s) mg = milligram (s) μg = microgram (s)

TA = ambient temperature

Pf = melting point

HPLC = high pressure liquid chromatography LCMS or HPLC / MS = liquid chromatography coupled with APCI mass spectroscopy = chemical ionization at atmospheric pressure. = Retention time FM = molecular formula PM = molecular weight

NMR = Nuclear Magnetic Resonance

Materials and methods

I. Procedures used to prepare and characterize chemical molecules

The compounds of the invention were obtained using conventional methods of organic synthesis and parallel synthesis.

The HPLC spectra were carried out on a Shimadzu SCL10A apparatus and a UP50DB-5m Cl 8 Uptisphere column (4.6 x 50 mm) with a flow rate of 4 ml / min and at a wavelength of 220 nm.

HPLC / MS analyzes were performed on a Plateform LC spectrometer

Micromass (TSK gel super ODS column 4.6 mm ID x 5 cm, flow rate 2.75 ml / min, gradient: 100% A to 100% B in 3 min, 100% B plateau 1 min, solvent A = water / 0.05 % trifluoroacetic acid and solvent B = acetonitrile / water / trifluoroacetic acid 80/20 / 0.05).

The 1 H NMR spectra were obtained on a BRUCKER Avance 400 pulsed wave spectrometer operating at 400 MHz for proton NMR. Chemical shift values (δ) are expressed in parts per million (ppm). The reference used is tetramethylsilane (TMS, δ = 0.00 ppm). In the description of the spectra, the multiplicities of the signals are indicated by means of the following abbreviations: s, d, dd, t, q, m, M respectively signifying singlet, doublet, doublet of doublet, triplet, quadruplet, multiplet and massive .

Unless otherwise mentioned the products used for the preparation of the compounds of general formula (I) are commercial and have been used without preliminary purification. The experimental protocols described below are in no way limiting and are given by way of illustration.

I. Procedure for Determining an IC50 on U937 Leukemia-like Cells The test compound is dissolved in DMSO (100%) at a concentration of 1.10 ² M (stock solution) and then 8 samples of 8 different concentrations are prepared by dilution. sequentially with the complete cell culture medium (RPMI 1640 Cambrex + 10% FBS + 1% L-Glutamine + 40 μg / ml Gentamycin). For each sample, the dilution volume is adjusted to obtain a concentration equal to twice the final concentration C _x chosen. For example, ⁴ M 1.10, 5.10 ⁵ M, ⁵ M 2.5.10, 1.3.10 ^"5 M, ^{6,3.10" 6} M, 3,1.10 ^"6 M, l, ^{6.10" 6} M and 7, 8.10 ^"7 M is a standard range of 8 final concentrations In parallel, 8 control samples are prepared by successively diluting a solution of DMSO (100%) with the same cell culture medium (RPMI 1640 Cambrex + 10% FBS + 1 % L-Glutamine + 40 μg / ml Gentamycin), the dilution volumes chosen being strictly identical to those used for the preparation of the samples of the test compound.

In a 96-well white non-transparent plate (fluoronunc 96F Nunclon Delta), 100 μl of a suspension of U937 cells at a concentration of 2.5 × 10 ⁴ cells / ml in RPMI1640 Cambrex medium + 10% FBS + 1% L-Glutamine + 40 μg / ml of Gentamycin are deposited in each well, ie 2500 cells per well. 100 μL of a 2 _x C _x sample are added (one sample per well) and the medium is homogenized. After 144h of incubation at 37 ° C. under one atmosphere (5% CO ₂ , 90-95% humidity), the quantification of the viability of the cells in culture is carried out by measuring the levels of ATP using the test. CellTiter-Glo ™ Luminescent Assay System supplied by Promega Corporation according to the supplier's instructions. The luminescence in each well is measured using a counter, VICTOR ₂ 1420 (Wallac, PerkinElmer, Courtaboeuf, France).

For each final concentration C _x of the test compound, the percentage inhibition of cell proliferation (% Inh (C _x )) is obtained by applying the following formula:

[Lum. (Cx compound) - Lum. (White)]

% lnh. (Cx) = 100 x [1 -

[Lum. (Check Cx control) - Lum. (White)] in which

• Lum. (Compound C _x ) = average of the luminescence measurements of three wells of the test sample at the final concentration C _x .

• Lum. (Control C _x ) = average of the luminescence measurements of three wells of the corresponding control sample

• Lum. (white) = average luminescence measurements of eight wells comprising only 200 μl of cell culture medium (RPMI 1640 Cambrex + 10% FBS + 1% L-Glutamine + 40 μg / ml Gentamycin)

IC50 is the concentration of the compound required to achieve a 50% inhibition of cell proliferation; these values are calculated with XLfït 3 software (ID Business Solutions Ltd., UK) from semi-logarithmic curves.

II. Procedure for Determining an IC50 on MDA-MB231 Breast Cancer Cells

The test compound is dissolved in DMSO (100%) at a concentration of 1.10 ² M (mother solution) and then 8 samples of 8 different concentrations are prepared by successive dilution with the complete cell culture medium (E-MEM Cambrex + 10% FBS, + 1% nonessential amino acids + 1% Napyruvate + 1% L-Glutamine + 40μg / ml Gentamycin). For each sample, the dilution volume is adjusted to obtain a concentration equal to twice the final concentration C _x chosen. For example, 1.10 ^"4 M, ^{5.10" 5} M, 2.5x10 ^"5 M, ^{1.3.10" 5} M, 6,3.10 ^"6 M, ^{3,1.10" 6} M, ⁶ M and 1.6.10 7.8.10 ⁷ M is a standard range of 8 final concentrations. In parallel, 8 control samples are prepared by diluting a solution of DMSO (100%) with even the cell culture medium (E-MEM Cambrex + 10% FBS, + 1% non-essential amino acids + 1% Napyruvate + 1% L-Glutamine + 40 μg / ml Gentamycin), the dilution volumes chosen being strictly identical to those used for the preparation of the samples of the test compound. In a 96-well white, non-transparent plate (fluoronunc 96F

Nunclon Delta), 100 μL of a suspension of MDA-MB231 cells at a concentration of 1.25 × 10 ⁴ cells / ml in an E-MEM Cambrex medium + 10% FBS, + 1% of acids non-essential amines + 1% Napyruvate + 1% L-Glutamine + 40 μg / ml Gentamycin are deposited in each well, ie 2500 cells per well. 100 μL of a 2 _x C _x sample are added (one sample per well) and the medium is homogenized. After 144h of incubation at 37 ° C. under one atmosphere (5% CO ₂ , 90-95% humidity), the quantification of the viability of the cells in culture is carried out by measuring the levels of ATP using the test. CellTiter-Glo ™ Luminescent Assay System supplied by Promega Corporation according to the supplier's instructions. The luminescence in each well is measured using a counter, VICTOR ₂ 1420 (Wallac, PerkinElmer, Courtaboeuf, France). For each final concentration C _x of the test compound, the percentage inhibition of cell proliferation (% Inh (C _x )) is obtained by applying the following formula:

[Lum. (Cx compound) - Lum. (White)]

% lnh. (Cx) = 100 x [1 -

[Lum. (Check Cx control) - Lum. (White)] in which • Lum. (Compound C _x ) = average of the luminescence measurements of three wells of the test sample at the final concentration C _x .

• Lum. (Control C _x ) = average of the luminescence measurements of three wells of the corresponding control sample

• Lum. (white) = average of eight well luminescence measurements comprising only 200 μL of cell culture medium (E-MEM

Cambrex + 10% FBS, + 1% non-essential amino acids + 1% Napyruvate + 1% L-Glutamine + 40μg / ml Gentamycin)

IC50 is the concentration of the compound required to achieve a 50% inhibition of cell proliferation; these values are calculated with XLfït 3 software (ID Business Solutions Ltd., UK) from semi-logarithmic curves.

III. Procedure for determining percent inhibition or IC50 on PHA-stimulated peripheral blood mononuclear cells (PBMCs) Proliferation of peripheral blood mononuclear cells (PBMC) is measured by the incorporation of a labeled base (tritiated thymidine) in the DNA of newly formed cells.

In sterile round bottom 96-well plates (NUNC 163320), 160 μL of a PBMC cell suspension at a concentration of 312,500 cells / ml in RPMI 1640 medium with Hepes and Glutamax (GIBCO BRL 72400-021) + 10% inactivated FCS (GIBCO BRL 10500-064) + 1% antibiotics (Penicillin - Streptomycin, GIBCO BRL 15070-063) are deposited in each well, ie 50000 cells per well. 20 μl of a sample at the concentration 10 times C _x are added (one sample per well) and the medium is homogenized. After 30 minutes of incubation at 37 ° C. under one atmosphere (5% CO ₂ , 90-95% humidity), 20 μl of PHA at 20 μg / ml are added. The plates are incubated at 37 ° C. under an atmosphere (5% CO ₂ , 90-95% humidity) for 66 hours, then 20 μl of a mixture of [ ³ H] thymidine at 50 μCi / ml and cold thymidine are added. at 200 μM in the culture medium. Incubation of the plates at 37 ° C under an atmosphere (CO ₂ 5%, humidity 90-95%) is continued for 6 hours then the samples are transferred and filtered through a multiscreen filtering plate (Millipore - MADV N65 ( 0.65 μm durapore)). The filters are rinsed 3 times with 200 μl of PBS and then transferred into flasks containing 4 ml of Formula 989 glittering liquid. The radioactivity is measured using an LS 1701 meter (LS series, Beckman).

For each final concentration C _x of the test compound, the percentage inhibition of cell proliferation (% Inh (C _x )) is obtained by applying the following formula:

[Rad. Compound (Cx)]% lnh. (Cx) = 100 x [1 -]

[Rad. Control] in which

• Rad. Compound (C _x ) = average of the radioactivity measurements of the three wells of the sample to be tested at the final concentration C _x .

• Rad. Control = average of the absorbance measurements of the eight control wells (no compound) IC50 is the concentration of the compound required to achieve a 50% inhibition of cell proliferation; these values are calculated with HiIl software (Application RCI, DPM, LS 1701)) from semi-logarithmic curves.

Example Ex-I:

2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide

Step 1: Preparation of Int-1 (1- (4-chloro-phenyl) -5-methoxy-1H-indole)

In a tricolor, 2.61 g of 5-methoxy-indole (17.75 mmol, 1 eq), 4.78 g of 1-chloro-4-iodobenzene (20.06 mmol, 1.13 eq), 9.81 g of anhydrous K ₂ CO ₃ (4 eq. ), 200 mg of copper iodide and 1.27 of copper (0) powder are suspended in 20 ml of dimethylacetamide. The reaction medium is stirred for 9 h at 140 ^° C. and then at room temperature for 15 h. The mixture is then poured into a water / EtOAc mixture. The organic phase is washed successively with 3 × 100 ml of water and then 100 ml of a saturated aqueous solution of NaCl. The organic phase is collected, dried over MgSO ₄ , filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: Cyclohexane: EtOAc 80:20) to give the compound Int-1 in the form of a brown solid (3.5 g, yield: 80.6%, FM = Cl _{5 2} ClNO, MW = 257.72, NMR (CDCl ₃ ): 7.44 (5H, M), 7.26 (1H, d), 7.12 (1H, d), 6.88 (1H, dd), 6.60 (1H, d), 3.90 ( 3H, s)).

Step 2: Preparation of Int-2 (1- (4-chloro-phenyl) -5-hydroxy-1H-indole)

In a 100 ml flask, 780 mg of AlCl ₃ (5.85 mmol, 1.5 eq) are slowly added at 0 ^° C. to 9.1 ml of phenyl methanethiol (78 mmol, 20 eq.), Followed by a solution of dichloromethane (20 ml). mL) containing 1 g 1- (4-chlorophenyl) -5-methoxy-1H-indole Int-1 (3.9 mmol, 1 eq) is added dropwise. Stirring is continued at 0 ^° C. for 1 h and then 9.1 ml of phenyl methanethiol and 780 mg of AlCl ₃ are again added. The reaction medium is stirred for 4 h at 0 ^° C. and then poured into 50 ml of an aqueous solution of hydrochloric acid (3M). The medium is extracted with dichloromethane. The organic phase is washed successively with 3 × 100 ml of water and then 100 ml of a saturated aqueous solution of NaCl. The organic phase is collected, dried over MgSO ₄ , filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: 100% DCM) to provide the compound Int-2 in the form of a white solid (620 mg, Yield: 65%, FM = C 14 H 10 CINO, MW = 243.69, NMR (CDCl ₃ ): 7.42 (5H, M), 7.25 (1H, d), 7.07 (1H, d), 6.79 (1H, dd), 6.55 (1H, d), 4.88 (1H, s)).

Step 3: Preparation of Int-3 ((5-bromo-pentyloxy) -1- (4-chloro-phenyl) -1H-indole) In a 100-mL flask, 310 mg of 1- (4-chlorophenyl) 5-hydroxy-1H-indole Int-2 (1.25 mmol, 1 eq) are dissolved in 35 ml of acetonitrile, then 360 mg of K 2 CO 3 (2.6 mmol) are added and the reaction medium is stirred at room temperature for 30 minutes. then 0.7 ml of 1,5-dibromopentane (5.2 mmol) are added, the mixture is refluxed with the solvent for 5 hours, the reaction mixture is cooled to ambient temperature and filtered and the filtrate is concentrated to dryness by distillation. solvent under reduced pressure The residue is taken up in 50 ml of dichloromethane The organic phase is washed successively with 3 × 50 ml of water and then 50 ml of saturated aqueous NaCl solution, the organic phase is collected, dried over MgSO 4 ₄ , filtered and then concentrated to dryness by distillation of the solvent under reduced pressure The residue obtained is purified by chromatography silica gel (eluent: Cyclohexane: EtOAc; 95: 5) to provide Int-3 as an oil compound (360 mg; yield: 75%; FM = Ci ₉ Hi ₉ BrClNO MW = 392.73; NMR (CDCl _3): 7.44 (5H, M ), 7.26 (1H, d), 7.12 (1H, d), 6.88 (1H, dd), 6.60 (1H, d), 4.03 (2H, t), 3.45 (2H, t), 1.96 (2H, m) , 1.85 (2H, m), 1.66 (2H, m)).

Step 4: Preparation of Ex-I (2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} piperazin-1-yl) -N-isopropyl In a 50 ml flask, 360 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-indole Int-3 (0.92 mmol., 1 eq.) are dissolved. in 25 ml of methyl ethyl ketone and then 186 mg of K ₂ CO ₃ (1.35 mmol), 180 mg of NaI (1.2 mmol) and 203 mg of N-isopropyl-2-piperazin-1-yl-acetamide are added . The reaction medium is heated at reflux of the solvent for 5 hours. The reaction medium is cooled to ambient temperature, taken up in 20 ml of water and then extracted with dichloromethane. The organic phase is collected, dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified on silica gel (eluent: DCM / MeOH / NH ₄ OH; 95/5 / 0.5) and then taken up in ethyl ether. The insoluble compound is filtered to provide the compound Ex-I as a white powder (182 mg, yield: 40%, FM = C ₂₈ H ₃₇ ClN ₄ O ₂ , MW = 497.09, LCMS (ES): purity = 100%, m / z = 497.2 [M + H] ⁺ ; NMR (CDCl ₃ ): 7.44 (5H, M), 7.26 (1H, d), 7.12 (1H, d), 6.88 (2H, M), 6.59 (1H, d), 4.09 (1H, m), 4.02 (2H, t), 2.97 (2H, s), 2.35-2.7 (1OH, M), 1.82 (2H, m), 1.56 (4H, M). , 1.16 (6H, d)).

Example Ex-2:

4- (4-Chloro-phenyl) -1- {5- [1- (4-chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperidin-4-ol

Ex-2 is obtained from 118 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-indole Int-3 and 102 mg of 4- (4-chlorophenyl) ) 4-hydroxy-piperidine following a protocol equivalent to that followed for the preparation of compound Ex-I. The compound Ex-2 in hydrochloride salt form is isolated in the form of a white powder (5 mg, yield 3%, FM K ₃₀ H ₃₂ Cl ₂ N ₂ O ₂ HCl, PM excluding salt = 523.51; (ES): purity = 100%, m / z = 523.5 [M + H] ⁺ ; NMR (MeOD): 7.52 (6H, M), 7.41 (4H, M), 7.15 (1H, d), 6.88 (1H); , dd), 6.59 (1H, d), 4.124 (2H, t), 3.5 (6H, M), 3.25 (2H, M), 2.28 (2H, M), 1.95 (6H, M), 1.71 (2H, M)).

Example Ex-3: 1- (4-Chloro-phenyl) -5- {5- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -pentyloxy} -1H-indole

Ex-3 is obtained from 118 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-indole Int-3 and 116 mg of 4- (1-methyl-piperidin). -4-yl) -piperazine following a protocol equivalent to that followed for the preparation of the compound Ex-I. The compound Ex-3 is isolated in the form of a white powder (115 mg, Yield: 37%, FM = C ₂₉ Η ₃₉ ClN ₄ O, MW = 495.11, LCMS (ES): purity = 100%, m / z = 495.8 [M + H] ⁺ ; NMR (CDCl ₃ ): 7.44 (5H, M), 7.26 (1H, d), 7.11 (1H, d), 6.87 (2H, M), 6.59 (1H, d); , 4.01 (2H, t), 2.89 (2H, M), 2.55 (8H, M), 2.38 (2H, M), 2.25 (3H, s), 2.21 (1H, m), 1.95 (2H, M), 1.82 (4H, M), 1.55 (6H, M)).

Example Ex-4: 2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethylacetamide

Ex-4 is obtained from 118 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-indole Int-3 and 94 mg of N, N-dimethyl-2- piperazin-1-yl-acetamide following a protocol equivalent to that followed for the preparation of compound Ex-I. Ex-4 compound is isolated as a maleate salt as a white powder (86 mg; yield: 34%; FM ^ ₂₇ H ₃₅ ClN ₄ O ₂ 2C ₄ H ₄ O _4; PM. excluding salt = 483.06;

LCMS (ES): purity = 100%, m / z = 483.2 [M + H] ⁺ ; NMR (MeOD): 7.54 (4H, M),

7.42 (2H, M), 7.12 (1H, d), 6.88 (1H, dd), 6.59 (1H, d), 6.30 (4H, s), 4.17 (2H, t), 3.48 (2H, s), 3.15. (2H, M), 3.07 (3H, s), 2.96 (3H, s), 2.90 (8H, M), 1.88 (4H, M), 1.64 (2H,

M)).

Example Ex-5: 2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N- (2-dimethyl) -2- amino-ethyl) -acetamide

Step 1: Preparation of tert-butyl 4-ethoxy-4-ethoxycarbonylmethyl-piperazine-1-carboxylate

To a solution of acetonitrile (150 mL) containing 15.1 g of tert-butyric piperazine-1-carboxylate (81.2 mmol) and 11.3 mL of TEA (81.2 mmol, 1 eq.), 9 mL of ethyl bromoacetate (81.2 mmol, 1 eq). After stirring for 16 hours at room temperature, the reaction medium is concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: dichloromethane: methanol, 95: 5) to yield the expected product Int-4 in the form of a white solid (3.85 g, Yield: 35.5%, FM = Cl ₃ H ₂₄ N ₂ O ₄ , MW = 272.35, ¹ H NMR (CDCl ₃ ): 4.19 (2H, q), 3.48 (4H, t), 3.23 (2H, s), 2.53 (4H, t), 1.46 ( 9H, s), 1.28 (3H, t)).

Step 2: Preparation of tert-butyio Int-5 (4-carboxymethyl-piperazine-1-carboxylate) To a solution in ethanol (300 mL) of Int-4 intermediate (17.7 g, 65.1 mmol), 65.25 ml of a 2N aqueous sodium hydroxide solution (130.2 mmol, 2 eq) were added. After stirring for 16 hours at room temperature, the reaction medium is poured into 300 ml of water and then acidified by bubbling SO ₂ gas. The environment The reaction mixture is then concentrated to dryness by distillation of the solvent under reduced pressure and the Int-5 intermediate is isolated in the form of a white solid (12.07 g, yield: 75.9%, FM = CnH ₂₀ N ₂ O ₄ , MW = 244.29). ; ¹ H NMR (DMSO-d6): 3.31 (4H, t), 3.06 (2H, s), 2.44 (4H, t), 1.39 (9H, s)).

Step 3: Preparation of tert-butyl (4 - [(2-dimethylaminoethylcarbamoyl) methyl] piperazine-1-carboxylate

To a solution in dichloromethane (30 ml) of Intermediate Int-5 (500 mg, 1.94 mmol) was added 627 mg of CDI (3.88 mmol, 2 eq.) Followed by 238 mg of 2-dimethylaminoethylamine (2.33 mmol, 1.2 eq.). The reaction medium is stirred at room temperature for 16 hours, then washed with a molar solution of Na ₂ CO ₃ . The organic phase is dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure to provide intermediate Int-6 in the form of an oil (580 mg, Yield: 95%, FM = C ₅ H _30). N ₄ O ₃ , MW = 314.43, ¹ H NMR (CDCl ₃ ): 7.48 (1H, m), 3.45 (4H, t), 3.33 (2H, dt), 3.02 (2H, s), 2.48 (4H, t). ), 2.42 (2H, t), 2.23 (6H, s), 1.46 (9H, s)).

Step 4: Preparation of Int-7 (N- (2-dimethylaminoethyl) -2-piperazyn-1-ylacetamide) To a solution in dichloromethane (600 mL) Intermediate Int-6 (12.76 g, 410 mmol) 300 ml of hydrochloric ether (2M) are added. The reaction medium is stirred at room temperature for 16 hours and then filtered to provide the Int-7 intermediate in the form of a white solid (13 g, Yield: 98%, FM = C ₁₀ H ₂₂ N ₄ O 3). HCl MW = 214.31; ¹ H NMR (DMSO-d6): 10.8 (IH, s), 10.1 (2H, s), 9.09 (IH, t), 4.07 (2H, s), 3.30-3.70 (1OH, M ), 3.21 (2H, m), 2.78 (6H, s)).

Step 5: Preparation of Ex-5 (2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N- ( 2-dimethyl-amino-ethyl) -acetamide)

Ex-5 is obtained from 200 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-indole Int-3 and 197.5 mg of N- (2-dimethylaminoethyl) - 2-piperazyn-1-yl acetamide Int-7 following a protocol equivalent to that followed for the preparation of compound Ex-I. The compound Ex-5 is isolated in the form of a white powder (3 mg; Yield: 1%; FM ^ ₂₉ H ₄₀ ClN ₅ O ₂ ; PM excluding salt = 526.13; LCMS (ES): purity = 96%; m / z = 526.9 [M + H] ⁺ ; NMR (MeOD): 7.54 (4H, M), 7.42 (2H, M), 7.12 (1H, d), 6.88 (1H, dd), 6.59 (1H, d), 4.60 (1H, brs), 4.17 ( 2H, t), 3.38 (2H, t), 3.18 (2H, s), 2.60 (8H, M), 2.48 (4H, M), 2.30 (6H, s), 1.85 (2H, M), 1.61 (4H); , M)).

Example Ex-6:

[2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -ethyl] -dimethyl-amine

Ex-6 is obtained from 160 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-indole Int-3 and 96 mg of dimethyl- (2-piperazin-1). -yl-ethyl) -amine following a protocol equivalent to that followed for the preparation of the compound Ex-I. Ex-6 is isolated as an oil (37 mg, Yield: 19%, FM K ₇ H ₃₇ ClN ₄ O, MW = 469.08, LCMS (ES): purity = 100%, m / z = 469.42 [M + H] ⁺ ; NMR (CDCl ₃ ): 7.48-7.38 (5H, M), 7.27 (1H, s), 7.11 (1H, d), 6.87 (1H, dd), 6.59 (1H, d); ), 4.01 (2H, t), 2.63-2.35 (14H, M), 2.26 (6H, s), 1.83 (2H, m), 1.62-1.49 (4H, M)).

Example Ex-7:

2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide Step 1 preparation of Int-8 (4- (isopropyl-carbamoyl-methyl) -piperazine-1-carboxylate tert-butyio)

To a solution of THF (100 mL) containing 10 g of N-isopropyl-piperazin-1-yl-acetamide (54 mmol) was added portionwise 11.78 g of BoC ₂ O (54 mmol, 1 eq).

Stirring is continued at ambient temperature for 4 h and then the reaction medium is concentrated to dryness by distillation of the solvent under reduced pressure. The expected product

Int-8 is isolated as a yellowish solid (16.1 g; Yield: 100%; FM =

C ₄ H ₂₇ N ₃ O ₃ ; PM = 285.39; ¹ H NMR (CDCl ₃ ): 6.87 (1H, d), 4.09 (1H, m), 3.45 (4H, t), 2.98 (2H, s), 2.46 (4H, t), 1.46 (9H, s), 1.16 (6H, d)).

Step 2: Preparation of Int-9 (4 - [(Isopropyl-methyl-carbamoyl) -methyl] -piperazine-1-tert-butyl carboxylate In a 500 mL three-necked flask, a DMF solution (150 mL) containing 12 g of 4- (isopropyl-carbamoyl-methyl) -piperazine-1-carboxylate tert-butyl Int-8 (42 mmol) was added dropwise at 0 ⁰ C on a suspension of 1.8 g of NaH (44.15 mmol, 1.05 eq.) in 60 ml of DMF. The reaction medium is stirred at 0 ° C. for 1 hour and then 2.61 ml of methyl iodide are added dropwise. Stirring is continued at ambient temperature for 16 hours and then the reaction medium is neutralized by adding 50 ml of a saturated aqueous solution of NaHCO 3. The reaction medium is concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in 500 ml of dichloromethane and then washed with 5 × 200 ml of water. The organic phase is dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: Cyclohexane: EtOAc, 20: 80) to yield the expected product Int-9 as a solid (10.4 g; yield: 83%; FM = Ci ₅ H ₂₉ N ₃ O ₃ , MW = 299.42, ¹ H NMR (CDCl ₃ ): 4.84 and 4.30 (1H, m), 3.45 (4H, M), 3.20 and 3.15 (2H, s), 2.86 and 2.77 (3H, s), 2.46 (4H, M), 1.46 (9H, s), 1.18 and 1.08 (6H, d)).

Step 3: Preparation of Int-10 (N-isopropyl-N-methyl-piperazin-1-yl-acetamide)

To a solution in dichloromethane (200 ml) of Intermediate Int-9 (10.4 g, 34.7 mmol) is added 60 ml of hydrochloric ether (2M). The reaction medium is stirred at ambient temperature for 5 days, and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in ether and then filtered to provide Interm Int-10 in the form of a white solid (18.4 g, Yield: 89%, FM = Cl ₀ H ₂ IN ₃ O 2 HCl; MP excluding salt = 199.30, ¹ H NMR (MeOD): 4.75 and 3.91 (1H, m), 4.53 and 4.44 (2H, s), 3.60-3.85 (8H, M), 2.86 (3H, s), 1.27 and 1.16. (6H, d)).

Step 4: Preparation of Ex-7 (2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} piperazin-1-yl) -N-isopropyl -N-methyl-acetamide)

The compound Ex-7 is obtained from 200 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-indole Int-3 and 208 mg of N-isopropyl-N-methyl- piperazin-1-yl-acetamide Int-10 following a protocol equivalent to that followed for the preparation of compound Ex-I. Ex-7 is isolated as an oil (79 mg; % FM = C ₂₉ H ₃₉ ClN ₄ O ₂ ; PM = 511.11; LCMS (ES): purity = 100%, m / z = 511.44 [M + H] ⁺ ; NMR (CDCl ₃ ): 7.49-7.38 (5H, M), 7.27 (1H, s), 7.11 (1H, d), 6.87 (1H, dd), 6.59 (1H, d), 4.84 (0.5H, m); , 4.32 (0.5H, m), 4.01 (2H, t), 3.19 (1H, s), 3.13 (1H, s), 2.86 (1.5H, s), 2.76 (1.5H, s), 2.63-2.35 ( 1OH, M), 1.83 (2H, m), 1.62-1.47 (4H, M), 1.17 (3H, d), 1.08 (1.5H, d)).

Example Ex-8:

2- (4- {5- [l- (4-Chloro-phenyl) -LH-benzotriazol-5-yloxy] -pentyl} -piperazin-l-yl) -

N, N-dimethylacetamide Step 1: Preparation of Int-11 ((4-chloro-phenyl) - (4-methoxy-2-nitro-phenyl) -amine) In a tricolor of IL, 23.4 g of 1-chloro 4-iodo-benzene (99 mmol) are dissolved in 300 ml of dimethylacetamide, then 15 g of (4-methoxy-2-nitro-phenyl) -amine, 48 g of K ₂ CO ₃ , 6 g of powder of copper, 990 mg of copper iodide are added. The reaction medium is heated at 140 ^° C. for 6 hours. The reaction medium is cooled to ambient temperature, taken up in 1500 ml of water and then extracted with ethyl acetate (3 × 500 ml). The organic phase is collected, filtered on celite and washed again with water. The organic phase is then dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified on silica gel (eluent: DCM, 100%) to give the compound Int-11 in the form of an orange solid (17.5 g, Yield: 72%, FM = Cl ₃ ΗnClN ₂ O ₃ ; MW = 278.5 NMR (CDCl ₃ ): 9.23 (1H, brs), 7.64 (1H, d), 7.35 (2H, d), 7.19 (3H, M), 7.10 (1H, dd), 3.83 (3H, s)).

Step 2: Preparation of Int-12 (N ^1- (4-chloro-phenyl) -4-methoxy-benzene-1,2-diamine) 17.5 g of (4-chloro-phenyl) - ( 4-methoxy-2-nitro-phenyl) -amine Int-11 (63 mmol) are dissolved in 250 ml of DMF and then a solution of concentrated HCl (430 ml) containing 160 g of tin chloride is slowly added dropwise at 0 ^° C. The stirring is continued at room temperature for 24 hours. The reaction medium is poured dropwise into a mixture of 350 g of KOH (50%) / 700 g of ice. The reaction medium is then extracted with 600 mL of ethyl acetate. The organic phase is collected, filtered on celite and then washed again with sodium hydroxide solution (IN), then with water and saturated aqueous NaCl solution. The organic phase is then dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified on silica gel (eluent: DCM / MeOH, 98/2) to provide Int-12 compound as an oil (9.7 g; yield: 62%; FM = Ci ₃ Hi ₃ ClN ₂ O; MW = 248.5; NMR (CDCl ₃ ): 7.10 (2H, d), 6.96 (1H, d), 6.53 (2H, d), 6.35 (1H, d), 6.31 (1H, dd), 3.77 ( 3H, s)).

Step 3: Preparation of Int-13 (1- (4-chloro-phenyl) -5-methoxy-1H-benzotriazole) In a 100 mL tricol, 2 g of N ¹ - (4-chloro-phenyl) -4- methoxy-benzene-1,2-diamine Int-12 are dissolved in 24 ml of EtOΗ / DMF (2: 1) and then 16 ml of a solution of hydrochloric acid (IN) are added dropwise. . Stirring is continued at room temperature for 30 minutes. The medium is cooled to 0 ^° C. and 4 ml of an aqueous solution containing 690 mg of NaNO ₂ are added dropwise. Stirring is continued at room temperature for 48 hours. The reaction medium is concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified on silica gel (eluent: DCM 100%) to provide Int-13 compound as a violet solid (1.7 g; yield: 82%; FM = Ci _{0 3} Ηi ClN ₃ O; MW = 259.5 NMR (CDCl ₃ ): 7.74 (2H, d), 7.59 (3H, M), 7.46 (1H, d), 7.2 (1H, dd), 3.93 (3H, s)).

Step 4: Preparation of Int-14 (1- (4-chloro-phenyl) -5-hydroxy-1H-benzotriazole) In a 25 mL flask, 500 mg of 1- (4-chloro-phenyl) -5-methoxy 1H-benzotriazole Int-13 (1.9 mmol) are dissolved in 4 mL of acetic acid and then 2.5 mL of hydrobromic acid (47%) are added dropwise. The reaction medium is heated under reflux (120 ^° C.) for 24 hours. The medium is cooled to room temperature and diluted with water. The precipitate formed is filtered off, dried and then taken up in dichloromethane and purified by chromatography on silica gel (eluent: CH ₂ Cl ₂ ZAcOEt, 90/10 then CH ₂ Cl ₂ / MeOH, 95/5) to give the compound 14 as a brown solid (320 mg, Yield: 69%, FM = Cl ₂ H ₈ ClN ₃ O, MW = 245.5, NMR (DMSO-d 6): 10.0 (1H, brs), 7.90 (2H); , d), 7.73 (3H, M), 7.31 (1H, d), 7.20 (1H, dd)).

Step 5: Preparation of Int-15 ((5-bromo-pentyloxy) -1- (4-chloro-phenyl) -1H-benzotriazole)

In a 250 ml flask, 320 mg of 1- (4-chlorophenyl) -5-hydroxy-1H-benzotriazole Int-14 (1.3 mmol, 1 eq.) Are dissolved in 20 ml of DMF, then 359 ml. mg of K2CO3 (2.6 mmol) are added. The reaction medium is stirred at room temperature for 30 min. then 0.71 mL of 1,5-dibromopentane (5.2 mmol) is added. The whole is heated at 80 ^° C. for 4 hours. The reaction medium is cooled to room temperature and filtered. The filtrate is concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: CH ₂ Cl _2; 100%) to provide the compound Int-15 as a solid (190 mg; yield: 37%; FM = Ci ₇ Hi ₇ BrClN ₃ O, MW = 394.5, NMR (CDCl ₃ ): 7.73 (2H, d), 7.58 (3H, M), 7.43 (1H, s), 7.22 (1H, dd), 4.08 (2H, t), 3.47 (2H, t), 1.96 (2H, m), 1.88 (2H, m), 1.67 (2H, m)).

Step 6: Preparation of Ex-8 (2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N -dimethyl-acetamide)

In a 250-mL flask, 190 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzotriazole Int-15 (0.48 mmol, 1 eq) are dissolved in 20 mL. of methyl ethyl ketone, then 86 mg of K ₂ CO ₃ , 86 mg of KI and 94 mg of N, N-dimethyl-2-piperazin-1-yl-acetamide are added. The reaction medium is heated at reflux of the solvent for 3h. The reaction medium is cooled to room temperature, filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in 20 ml of ethyl acetate and then washed with water. The organic phase is collected, dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified on silica gel (eluent: DCM / MeOΗ / NΗ ₄ OΗ, 95/5 / 0.5) to give compound Ex-8 in the form of a white powder (172 mg, Yield: 74%; ₂₅ H ₃₃ ClN ₆ O ₂ , MW = 485.03, LCMS (ES): purity = 100%, m / z = 485.2 [M + H] ⁺ , NMR (CDCl ₃ ): 7.74 (2H, d), 7.58 (3H, M), 7.43 (1H, d), 7.21 (1H, dd), 4.06 (2H, t), 3.16 (2H, s), 3.07 (3H, s), 2.94 (3H, s), 2.45- 2.7 (8H, M), 2.38 (2H, M), 1.88 (2H, m), 1.56 (4H, M)).

Example Ex-9:

2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide

The compound Ex-9 is obtained from 200 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzotriazole Int-15 and 141 mg of N-isopropyl-piperazin-1 yl-acetamide following a protocol equivalent to that followed for the preparation of compound Ex-8. Ex-9 is isolated as a solid (128 mg, Yield: 50%, FM K ₂₆ H ₃₅ ClN ₆ O ₂ , MW = 499.06, LCMS (ES): purity = 100%, m / z = 499.47 [M + H] ⁺ ; NMR (CDCl ₃ ): 7.74 (2H, d), 7.58 (3H, d), 7.43 (1H, d), 7.22 (1H, dd), 6.94 (1H, d), 4.14-4.05 (3H, M), 2.97 (2H, s), 2.55-2.49 (8H, M), 2.40 (2H, t), 1.88 (2H, m), 1.63-1.50 (4H, M), 1.16 ( 6H, d)).

Ex-IO Example:

2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide

The compound Ex-10 is obtained from 200 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzotriazole Int-15 and 207 mg of N-isopropyl-N-methyl- piperazin-1-yl-acetamide following a protocol equivalent to that followed for the preparation of compound Ex-8. Ex-10 is isolated as a solid (152 mg, Yield: 58%, FM K ₂₇ H ₃₇ ClN ₆ O ₂ , MW = 513.09, LCMS (ES): purity = 92%, m / z = 513.46 [M + H] ⁺ ; NMR (CDCl ₃ ): 7.74 (2H, d), 7.58 (3H, d), 7.43 (1H, d), 7.21 (1H, dd), 4.84 (0.5H, m); , 4.32 (0.5H, m), 4.06 (2H, t), 3.19 (1H, s), 3.13 (1H, s), 2.86 (1.5H, s), 2.76 (1.5H, s), 2.65-2.36 ( 10H, M), 1.88 (2H, m), 1.63-1.50 (4H, M), 1.17 (3H, d), 1.08 (1.5H, d)).

Example Ex-II:

2- (4- {5- [l- (4-Chloro-phenyl) -LH-benzotriazol-5-yloxy] -pentyl} -piperazin-l-yl) -N-

(2-dimethylamino-ethyl) -acetamide

The compound Ex-II is obtained from 200 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzotriazole Int-15 and 246 mg of N- (2-dimethylaminoethyl) - 2- piperazyn-1-yl acetamide Int-7 following a protocol equivalent to that followed for the preparation of compound Ex-8. The compound Ex-II is isolated in the form of a solid (113 mg, Yield: 42%, FM K ₂₇ H ₃₈ ClN ₇ O ₂ , MW = 528.10, LCMS (ES): purity = 100%, m / z = 528.44 [M + H] ⁺ ; NMR (CDCl ₃ ): 7.74 (2H, d), 7.58 (3H, d), 7.46-7.42 (2H, M), 7.21 (1H, dd), 4.06 (2H, t); ), 3.35 (2H, q), 3.00 (2H, s), 2.56-2.37 (12H, M), 2.25 (6H, s), 1.88 (2H, m), 1.63-1.50 (4H, M)). Example Ex-12:

[2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -ethyl] -dimethyl-amine

Ex-12 is obtained from 170 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzotriazole Int-15 and 101 mg of dimethyl- (2-piperazin-1). -yl-ethyl-amine following a protocol equivalent to that followed for the preparation of the compound

; PM = 471.05 ; L.C.M.S.(E.S.) : pureté = 100%, m/z = 471.41Ex-8. Ex-12 is isolated as a solid (51 mg, Yield: 25%;

; PM = 471.05; LCMS (ES): purity = 100%, m / z = 471.41

[M + H] ⁺ ; NMR (CDCl ₃ ): 7.74 (2H, d), 7.58 (3H, d), 7.42 (1H, s), 7.21 (1H, dd), 4.06 (2H, t), 2.65-2.37 (14H, M), 2.27 (6H, s), 1.88 (2H, m), 1.63-1.50 (4H, M)).

Example Ex-13:

2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethylacetamide

Step 1: Preparation of Int-16 (1- (4-chloro-phenyl) -5-methoxy-1H-benzoimidazole) In a 100 mL tricol, 2.5 g of N ¹ - (4-chloro-phenyl) -4- methoxy-benzene-1,2-diamine Int-12 are dissolved in 50 ml of formic acid. Stirring is continued at reflux for 4 hours. The medium is cooled to room temperature and then poured into an aqueous solution (200 mL) of NaOH (2N). The precipitate formed was filtered, rinsed with water and dried to provide the Int-16 compound as a brown solid (2.28 g, Yield: 88%, FM = Cl ₄ · ClN ₂ O, MW = 258.71, NMR; (MeOD): 8.35 (1H, s), 7.62 (4H, M), 7.47 (1H, d), 7.24 (1H, d), 7.00 (1H, dd), 3.86 (3H, s)).

Step 2: Preparation of Int-17 (1- (4-chloro-phenyl) -5-hydroxy-1H-benzoimidazole)

In a 25 ml flask, 1.5 g of 1- (4-chlorophenyl) -5-methoxy-1H-benzoimidazole Int-16 are dissolved in 12 ml of acetic acid and then 7.5 ml of hydrobromic acid (47 ml). %) are added dropwise. The reaction medium is heated under reflux (120 ^° C.) for 24 hours. The medium is cooled to room temperature and then concentrated to dryness by distillation of the solvent under reduced pressure to provide the compound Int-17 in the form of a black solid (1.9 mg, Yield: 100%, FM = Cl ₃ Η ₉ ClN ₂ O. HBr; PM off = 244.68; NMR (MeOD): 9.60 (1H, s), 7.75 (4H, M), 7.60 (1H, d), 7.19 (2H, M)).

Step 3: Preparation of Int-18 ((5-bromo-pentyloxy) -1- (4-chloro-phenyl) -1H-benzoimidazole)

In a 250 ml flask, 1.7 g of 1- (4-chlorophenyl) -5-hydroxy-1H-benzoimidazole Int-17 (5.22 mmol, 1 eq.) Are dissolved in 50 ml of acetonitrile, and then 2.2 g of K2CO3 (15.7 mmol) are added. The reaction medium is stirred at room temperature for 30 min. 2.2 ml of 1,5-dibromopentane (15.7 mmol) are then added. The whole is heated at reflux for 1Oh. The reaction medium is cooled to room temperature and filtered. The filtrate is concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is taken up in dichloromethane and washed with water. The organic phase is dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: CH ₂ Cl _2; 100%) to afford compound Int-18 as a solid (904 mg; yield: 44%; FM = Ci ₈ Hi ₈ BrClN ₂ O; MW = 393.71; NMR (MeOD): 8.37 (IH, s), 7.64 (4H, s), 7.590 (IH, d), 7.26 (IH, d), 7.03 (IH, dd), 4.07 (2H, t), 3.51 (2H, t), 1.94 (2H, m), 1.84 (2H, m), 1.68 (2H, m)).

Step 4: Preparation of Ex-13 (2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N -dimethyl-acetamide)

The compound Ex-13 is obtained from 150 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzoimidazole Int-18 and 94 mg of N, N-dimethyl-2- piperazin-1-yl-acetamide following a protocol equivalent to that followed for the preparation of compound Ex-8. The compound Ex-13 is isolated in the form of a white powder (90 mg, Yield: 49%, FM ₂₆ H ₃₄ ClN ₅ O ₂ , MW = 484.02, LCMS (ES): purity = 100%, m / cm). z = 484.43 [M + H] ⁺ ; NMR (CDCl ₃ ): 8.03 (1H, s), 7.54 (2H, d), 7.45 (2H, d), 7.36;

(1H, d), 7.31 (1H, d), 6.97 (1H, dd), 4.04 (2H, t), 3.17 (2H, s), 3.06 (3H, s), 2.94 (3H, s),

2.59-2.28 (1OH, M), 1.85 (2H, m), 1.65-1.48 (4H, M)).

Example Ex-14: 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide

Ex-14 is obtained from 150 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzoimidazole Int-18 and 106 mg of N-isopropyl-piperazin-1. yl-acetamide following a protocol equivalent to that followed for the preparation of compound Ex-8. Ex-14 is isolated as an oil (129 mg;

68%; FM _{27 27} H ₃₆ ClN ₅ O ₂ ; PM = 498.07; LCMS (ES): purity = 100%, m / z =

498.45 [M + H] ⁺ ; NMR (CDCl ₃ ): 8.03 (1H, s), 7.54 (2H, d), 7.45 (2H, d), 7.37 (1H, d),

7.32 (1H, d), 6.99-6.94 (2H, M), 4.12-4.02 (3H, M), 2.97 (2H, s), 2.60-2.45 (8H, M), 2.40 (2H, t), 1.85 ( 2H, m), 1.61-1.50 (4H, M), 1.16 (6H, d)).

Example Ex-15:

2- (4- {5- [l- (4-Chloro-phenyl) -LH-benzoimidazol-5-yloxy] -pentyl} -piperazin-l-yl) -

N-Isopropyl-N-methyl-acetamide The compound Ex-15 is obtained from 150 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzoimidazole Int-18 and 156 mg N-isopropyl-N-methyl-piperazin-1-yl-acetamide following a protocol equivalent to that followed for the preparation of the compound Ex-8. Ex-15 is isolated as an oil (128 mg, Yield: 65%, FM = C ₂₈ Η ₃₈ ClN ₅ O ₂ , MW = 512.10, LCMS (ES): purity = 94%, m / z = 512.47 [M + H] ⁺ ; NMR (CDCl ₃ ): 8.02 (1H, s), 7.54 (2H, d), 7.45 (2H, d), 7.36 (1H, d), 7.31 (1H, d); , 6.97 (1H, dd), 4.84 (0.5H, m), 4.32 (0.5H, m), 4.04 (2H, t), 3.19 (1H, s), 3.14 (1H, s), 2.86 (1.5H, s), 2.76 (1.5H, s), 2.65-2.36 (10H, M), 1.85 (2H, m), 1.63-1.48 (4H, M), 1.17 (3H, d), 1.08 (1.5H, d) ).

Example Ex- 16:

2- (4- {5- [l- (4-Chloro-phenyl) -LH-benzoimidazol-5-yloxy] -pentyl} -piperazin-l-yl) -

N- (2-dimethylamino-ethyl) -acetamide

Ex-16 is obtained from 150 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzoimidazole Int-18 and 185 mg of N- (2-dimethylaminoethyl) - 2- piperazyn-1-yl acetamide Int-7 following a protocol equivalent to that followed for the preparation of compound Ex-8. Ex-16 is isolated as a solid (94 mg, Yield: 47%, FM K ₂₈ H ₃₉ ClN ₆ O ₂ , MW = 527.12, LCMS (ES): purity = 100%, m / z = 527.44 [M + H] ⁺ ; NMR (CDCl ₃ ): 8.03 (1H, s), 7.54 (2H, d), 7.45 (3H, m), 7.37 (1H, d), 7.31 (1H, d), 6.97 (1H, dd), 4.04 ( 2H, t), 3.35 (2H, q), 3.00 (2H, s), 2.56-2.36 (12H, M), 2.25 (6H, s), 1.85 (2H, m), 1.62-1.48 (4H, M). ).

Example Ex-17:

[2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -ethyl] -dimethyl-amine

The compound Ex-17 is obtained from 120 mg of (5-bromo-pentyloxy) -1- (4-chlorophenyl) -1H-benzoimidazole Int-18 and 72 mg of dimethyl- (2-piperazin-1). -yl-ethyl-amine following a protocol equivalent to that followed for the preparation of compound Ex-8. Ex-17 is isolated as a solid (46 mg, yield 32%, FM K ₆ H ₃₆ ClN ₅ O, MW = 470.06, LCMS (ES): purity = 100%, m / z = 470.41 [M + H] ⁺ ; NMR (CDCl ₃ ): 8.02 (1H, s), 7.54 (2H, d), 7.45 (2H, d), 7.36 (1H, d), 7.31 (1H, d), 6.97 (1H, dd), 4.04 (2H, t), 2.65-2.36 (14H, M), 2.26 (6H, s), 1.85 (2H, m), 1.62-1.49 (4H, M)).

Example Ex 18:

2- (4- {4- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -butyl} -piperazin-1-yl) -N, N-dimethyl-acetamide Step 1: Preparation of Int-19 (5- (4-bromo-butyloxy) -1- (4-chloro-phenyl) -1H-indole) In a 100-mL flask, 500 mg of 1- (4-chlorophenyl) -5- hydroxyl-1H-indole Int-2 (2.05 mmol, 1 eq.) are dissolved in 5 ml of acetonitrile, then 567 mg of K ₂ CO ₃ (4.1 mmol) are added. The reaction medium is stirred at room temperature for 30 min. 0.97 ml of 1,4-dibromobutane (8.2 mmol) are then added. The whole is brought to reflux of the solvent for 16h. The reaction medium is cooled to room temperature and filtered. The filtrate is concentrated to dryness by distillation of the solvent under reduced pressure. The residue is taken up in 50 ml of dichloromethane. The organic phase is washed successively with 3 × 50 ml of water and then 50 ml of a saturated aqueous solution of NaCl. The organic phase is collected, dried over MgSO ₄ , filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: Cyclohexane: EtOAc, 95: 5) to give compound Int-19 in the form of an oil (498 mg, yield: 64%; Ci ₈ Hi ₇ BrClNO; PM = 378.70; NMR (CDCl ₃ ): 7.44 (5H, M), 7.26 (1H, d), 7.12 (1H, d), 6.88 (1H, dd), 6.60 (1H, d), 4.06 (2H, t), 3.51 ( 2H, t), 2.11 (2H, m), 1.96 (2H, m)).

Step 2: Preparation of Ex-18 (2- (4- {4- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] butyl} -piperazin-1-yl) -N, N -dimethyl-acetamide)

In a 50 mL flask, 327 mg of (4-bromo-butyloxy) -1- (4-chlorophenyl) -1H-indole Int-19 (0.86 mmol, 1 eq) are dissolved in 5 mL. acetonitrile, then 358 mg of K ₂ CO ₃ (2.59 mmol), 215 mg of KI (1.3 mmol) and 177 mg of N, N-dimethyl-2-piperazin-1-yl-acetamide are added. The reaction medium is heated at reflux of the solvent for 5 hours. The reaction medium is cooled to ambient temperature, taken up in 20 ml of water and then extracted with dichloromethane. The organic phase is collected, dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified on silica gel (eluent: DCM / MeOΗ / NΗ4θΗ, 95/5 / 0.5) and then taken up in ethyl ether. The insoluble compound is filtered to provide the compound Ex-18 as a white powder after conversion to the maleic acid salt (395 mg, Yield: 65%, mp ₂₆ H ₃₃ ClN ₄ O ₂ 2C ₄ H ₄ O ₄ , PM excluding salt = 469.03, LCMS (ES): purity = 100%, m / z = 469.32 [M + H] ⁺ , NMR (MeOD): 7.54 (4H, M), 7.42 (2H, M) 7.12 (1H, d), 6.88 (1H, dd), 6.60 (1H, d), 6.30 (4H, s), 4.17 (2H, t), 3.48 (2H, s), 3.20 (2H, M), 3.07 (3H, s), 2.96 (3H, s), 2.90 (8H, M), 1.95 (4H, M)).

Ex-example 19:

2- (4- {6- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -hexyl} -piperazin-1-yl) -N, N-dimethyl-acetamide Step 1: Preparation of Int-20 (5- (6-bromohexyloxy) -1- (4-chlorophenyl) -1H-indole) In a 100 mL flask, 500 mg of 1- (4-chlorophenyl) -5- hydroxyl-1H-indole Int-2 (2.05 mmol, 1 eq.) are dissolved in 5 ml of acetonitrile, then 567 mg of K ₂ CO ₃ (4.1 mmol) are added. The reaction medium is stirred at room temperature for 30 min. then 1.25 mL of 1,6-dibromohexane (8.2 mmol) is added. The whole is brought to reflux of the solvent for 5 hours. The reaction medium is cooled to room temperature and filtered. The filtrate is concentrated to dryness by distillation of the solvent under reduced pressure. The residue is taken up in 50 ml of dichloromethane. The sentence The organic phase is washed successively with 3 × 50 ml of water and then with 50 ml of a saturated aqueous solution of NaCl. The organic phase is collected, dried over MgSO ₄ , filtered and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluent: Cyclohexane: EtOAc, 95: 5) to give the compound Int-20 in the form of an oil (627 mg, yield 75%, FM = C ₂₀ H ₂ IBrClNO MW = 406.75; NMR (CDCl _3): 7.44 (5H, M), 7.26 (IH, d), 7.12 (IH, d), 6.88 (IH, dd), 6.60 (IH, d), 4.02 ( 2H, t), 3.43 (2H, t), 1.92 (2H, m), 1.83 (2H, m), 1.54 (4H, M)).

Step 2: Preparation of Ex-19 (2- (4- {6- [1- (4-chloro-phenyl) -1H-indol-5-yloxy] -butyl} piperazin-1-yl) -N, N -dimethyl-acetamide)

In a 50 mL flask, 620 mg of (6-bromo-hexyloxy) -1- (4-chlorophenyl) -1H-indole Int-20 (1.52 mmol, 1 eq) are dissolved in 5 mL. acetonitrile, then 632 mg of K ₂ CO ₃ (4.57 mmol), 380 mg of KI (2.29 mmol) and 313 mg of N, N-dimethyl-2-piperazin-1-yl-acetamide are added. The reaction medium is heated at reflux of the solvent for 5 hours. The reaction medium is cooled to ambient temperature, taken up in 20 ml of water and then extracted with dichloromethane. The organic phase is collected, dried over MgSO ₄ and then concentrated to dryness by distillation of the solvent under reduced pressure. The residue obtained is purified on silica gel (eluent: DCM / MeOΗ / NΗ4θΗ, 95/5 / 0.5) and then taken up in ethyl ether. The insoluble compound is filtered to afford the compound Ex-19 as a white powder after conversion to the maleic acid salt (750 mg, Yield: 63%, mp ₂₈ H ₃₇ ClN ₄ O ₂ 2C ₄ H ₄ O ₄ , PM excluding salt = 497.09, LCMS (ES): purity = 100%, m / z = 497.36 [M + H] ⁺ , NMR (MeOD): 7.54 (4H, M), 7.42 (2H, M) 7.12 (1H, d), 6.88 (1H, dd), 6.60 (1H, d), 6.30 (4H, s), 4.17 (2H, t), 3.48 (2H, s), 3.20 (2H, M), 3.07 (3H, s), 2.96 (3H, s), 2.90 (8H, M), 1.82 (4H, M), 1.62 (2H, M), 1.50 (2H, M)).

Pharmacological results

Determination of IC50s on U937 Leukemia-like Cells The method described above was applied to determine the IC50 values of the compounds on U937 cells. The IC50 values of some examples are summarized in the table below (Table 1) Table 1

These results show that examples of compounds of formula (I) possess the property of inhibiting the proliferation of U937 leukemia-type cells and consequently antitumor activity.

The compounds of formula (I) are particularly useful and may be used as anti-neoplastic agents and as inhibitors of cell proliferation.

The products of formula (I) can thus be used for the prevention or treatment of neoplastic diseases such as acute and chronic leukemias.

Determination of IC50 on breast cancer cells MDA-MB231 The method described above was applied to determine the IC50 values of the compounds on MDA-MB231 cells. The IC50 value of the Ex-I compound is summarized in the table below (Table 2)

Table 2

The compounds of formula (I) are particularly useful and may be used as anti-neoplastic agents and as inhibitors of cell proliferation.

The products of formula (I) can thus be used for the prevention or treatment of neoplastic diseases such as solid cancers and more particularly breast cancer.

Determination of antiproliferative effects on PBMC cells The method described above was applied to determine the percentages of inhibition of proliferation of PBMC cells. The percentage inhibition value at 1 μM and 10 μM of the compound Ex-I is summarized in the table below (Table 3).

Table 3

Ce résultat montre qu'au moins un exemple de composés de formule (I) possède la propriété d'inhiber la prolifération des cellules PBMC.

This result shows that at least one example of compounds of formula (I) has the property of inhibiting the proliferation of PBMC cells.

The compounds of formula (I) are particularly interesting and may be used as inhibitors of cell proliferation.

The products of formula (I) can thus be used for the prevention or the treatment of diseases associated with abnormal cell proliferation such as psoriasis, rheumatoid arthritis, Kaposi's sarcoma, acute and chronic nephropathies, atherosclerosis, autoimmune diseases or acute and chronic inflammatory diseases.

Claims

1. Compounds of general formula (I):

C) as well as their pharmaceutically acceptable salts, in which: A ₁ represents an aryl or heteroaryl group, each optionally substituted one to five times with groups chosen from a halogen atom, a (C 1 -C 6) alkyl, hydroxy and hydroxy (C 1 -C 6) alkyl radical, ₁ - C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (dC ₆ ) thioalkoxy, cyano, (C 1 -C 6) haloalkyl, (C 1 -C 6) haloalkoxy, an aryl group, an N-group (C ₁ -C ₆ ) alkylamino or N ₅ N- (C 1 -C 6) dialkylamino; • X and Y, identical or different, represent a nitrogen atom or a CH group; • n represents an integer between 4 and 6; D represents a carbon atom or a nitrogen atom: - When D is a nitrogen atom: R ¹ represents a group G, an aryl group, an aryl (C 1 -C 6) alkyl group, a heteroaryl group, a heteroaryl (C 1 -C 6) alkyl group, a heterocyclic group or a (C 1 -C 6) alkyl heterocycle group, each optionally substituted, and R ² represents a doublet of electrons; - When D is a carbon atom: R ¹ represents a hydrogen atom, a hydroxyl group, a (C ¹ -C ⁶ ) alkylcarbonyl group or a cyano group and R ² an optionally substituted aryl group; and where G is represented by the following general formula (II):

(H) for which, • L represents a group CO or (CH2) _m ; M represents an integer between 1 and 3; and R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C) cycloalkyl, (C 3 -C) cycloalkyl (C 1 -C 6) alkyl or heterocyclic group, heterocycle (C 1 -C ₆ ) alkyl, aryl (C 1 -C ₆ ) alkyl, heteroaryl (C 1 -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆₎ dialkylamino (C 1 -C 6) alkyl, each optionally substituted; or, R ³ and R ⁴ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic radical. 2. Compounds according to claim 1, characterized in that: • Ar ₁ , X, Y and n are as defined in claim 1; D represents a carbon atom; R ¹ represents a hydroxyl group, and R ^{2 represents} an optionally substituted aryl group. 3. Compounds according to claim 1, characterized in that: Ar ₁ , X, Y and n are as defined in claim 1; D represents a nitrogen atom; • R ¹ represents a heterocyclic group and R ^{2 represents} an electron pair. 4. Compounds according to claim 1, characterized in that: Ar ₁ , X, Y and n are as defined in claim 1; D represents a nitrogen atom; • R ¹ represents a group G and R ² a pair of electrons; and G is represented by the following general formula (II):

(H) for which, • L represents a CO group; and R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C) cycloalkyl, (C 3 -C) cycloalkyl (C 1 -C 6) alkyl or heterocyclic group, heterocycle (C 1 -C ₆ ) alkyl, aryl (C 1 -C ₆ ) alkyl, heteroaryl (C 1 -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆₎ ) dialkylamino (C 1 -C 6) alkyl, each optionally substituted, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic radical. 5. Compounds according to claim 1, characterized in that: • Ari and n are as defined in claim 1; X and Y represent a CH group; D represents a nitrogen atom; • R ¹ represents a group G and R ² a pair of electrons; and G is represented by the following general formula (II):

CI) for which, • L represents a CO group; and R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C) cycloalkyl, (C 3 -C) cycloalkyl (C 1 -C 6) alkyl, heterocyclic or heterocycle group; (C1-C6) alkyl, aryl (C1-C6) alkyl, heteroaryl (C1- C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆ ) dialkylamino (C 1 -C 6) alkyl, each optionally substituted, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic radical. 6. Compounds according to claim 1, characterized in that: Ar ₁ and n are as defined in claim 1; X represents a CH group; Y represents a nitrogen atom; D represents a nitrogen atom; • R ¹ represents a group G and R ² a pair of electrons; and G is represented by the following general formula (II):

(H) for which, • L represents a CO group; and R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C) cycloalkyl, (C 3 -C) cycloalkyl (C 1 -C 6) alkyl, heterocyclic or heterocycle group; (C 1 -C ₆ ) alkyl, aryl (C 1 -C ₆ ) alkyl, heteroaryl (C 1 -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆ ) dialkylamino (-C C6) alkyl, each optionally substituted, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic radical. 7. Compounds according to claim 1, characterized in that: Ar ₁ and n are as defined in claim 1; X represents a nitrogen atom; Y represents a nitrogen atom; D represents a nitrogen atom; • R ¹ represents a group G and R ² a pair of electrons; and G is represented by the following general formula (II):

(H) for which, • L represents a CO group; and R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C) cycloalkyl, (C 3 -C) cycloalkyl (C 1 -C 6) alkyl, heterocyclic or heterocycle group; (C 1 -C ₆ ) alkyl, aryl (C 1 -C ₆ ) alkyl, heteroaryl (C 1 -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- (C ₁ -C ₆ ) dialkylamino (-C C6) alkyl, each optionally substituted, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic radical. 8. Compounds according to claim 1, characterized in that: Ar ₁ , X, Y and n are as defined in claim 1; D represents a nitrogen atom; • R ¹ represents a group G and R ² a pair of electrons; and "G is represented by the following general formula (II):

(H) for which, • L represents a group (CH ₂ ) _m ; M represents an integer between 1 and 3; and R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C 1 -C 6) alkyl, (C 3 -C) cycloalkyl, (C 3 -C) cycloalkyl (C 1 -C 6) alkyl, N- ( C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N, N- (C ₁ -C ₆ ) dialkylamino (C ₁ -C ₆ ) alkyl, each optionally substituted, or R ³ and R ⁴ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic radical. 9. Compounds according to claim 1, characterized in that: • Ai-I represents an aryl group, preferably phenyl, optionally substituted by at least one halogen atom, preferably a chlorine atom; • X and Y, identical or different, represent a nitrogen atom or a CH group; • n represents an integer between 4 and 6; D represents a carbon atom or a nitrogen atom: - When D is a nitrogen atom: R ¹ represents a group G, a heterocyclic group or a (C 1 -C 6) alkyl heterocycle group, each optionally substituted with at least one group chosen from a (C 1 -C 6) alkyl radical, and R ² represents a pair of electrons. ; - When D is a carbon atom: R ¹ represents a hydrogen atom, a hydroxyl group, a (C ¹ -C ⁶ ) alkylcarbonyl group or a cyano group and R ² an aryl group, preferably phenyl, optionally substituted with at least one halogen atom, preferably a chlorine atom; and where G is represented by the following general formula (II):

(H) for which, • L represents a group CO or (CH ₂ ) _m ; M represents an integer between 1 and 3; and R ³ and R ⁴ , which are identical or different, represent a hydrogen atom, a (C ₁ -C ₆ ) alkyl, N- (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or N ₅ N- ( This- C6) dialkylamino (Ci-C6) alkyl. Compounds according to claim 1, selected from the following group: 2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide 4- (4-Chloro-phenyl) -1- {5- [1- (4-chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperidin-4-ol 1- (4-Chloro-phenyl) -5- {5- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -pentyloxy} -1H-indole • 2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethyl-acetamide 2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N- (2-dimethyl-amino-ethyl) acetamide [2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -ethyl] -dimethyl-amine 2- (4- {5- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethyl-acetamide • 2- ( 4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) - N-isopropyl-acetamide 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -N- (2-dimethyl-amino-ethyl) acetamide [2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzotriazol-5-yloxy] -pentyl} -piperazin-1-yl) -ethyl] -dimethyl-amine 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N, N-dimethylacetamide 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-acetamide • 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N-isopropyl-N-methyl-acetamide 2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -N- (2-dimethyl-amino-ethyl) acetamide [2- (4- {5- [1- (4-Chloro-phenyl) -1H-benzoimidazol-5-yloxy] -pentyl} -piperazin-1-yl) -ethyl] -dimethyl-amine 2- (4- {4- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -butyl} -piperazin-1-yl) -N, N-dimethyl-acetamide 2- (4- {6- [1- (4-Chloro-phenyl) -1H-indol-5-yloxy] -hexyl} -piperazin-1-yl) -N, N-dimethyl-acetamide 11. Compounds according to any one of the preceding claims, as medicaments. 12. Pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10, alone or in combination with at least one pharmaceutically acceptable excipient. 13. Compounds according to any one of claims 1 to 11 for the prevention or treatment of a neoplastic disease, such as cancer. 14. Compounds according to claim 13, for the treatment of solid tumors or chronic or acute leukemias, or for the treatment or prevention of metastases. 15. Compounds according to claim 13, characterized in that the cancer is chosen from prostate cancer, osteosarcomas, lung cancer, non-small cell lung cancer, breast cancer, cancer of the prostate endo meter or colon cancer, chronic or acute leukemia, solid tumors of the child, lymphocytic lymphoma, pancreatic cancer, skin cancer, cutaneous or intraocular melanoma, head and neck cancer, uterine cancer, ovarian cancer, gynecological tumors, Hodgkin, bone cancer, rectal cancer, anal cancer, stomach cancer, esophageal cancer, small bowel cancer, endocrine system cancer, sarcomas soft tissues, urethral cancer, penile cancer, bladder cancer, kidney cancer, ureter cancer, pediatric malignancies and tumors of the central nervous system, especially brain tumors . Compounds according to any of claims 1 to 11 for the prevention or treatment of a disease associated with abnormal cell proliferation, such as psoriasis, rheumatoid arthritis, Kaposi's sarcoma, acute nephropathies and chronic, atherosclerosis, autoimmune diseases or acute and chronic inflammatory diseases.