Cytatotoxic compounds as inhibitors of tubulin polymerization

Description

FIELD OF THE INVENTION

[0001] The present invention relates to tubulin polymerization inhibitor compounds, their preparation methods and their uses. STATE OF THE ART

[0002] Cancer is a leading cause of death worldwide, accounting for 7.6 million deaths in 2008, or about 13% of global mortality. According to WHO estimates, cancer mortality will continue to rise, reaching over 13 million deaths by 2030. About 30% of cancer deaths are due to five major behavioral and dietary risk factors: ( i ) a high body mass index, ( ii ) low consumption of fruits and vegetables, ( iii ) lack of physical exercise, ( iv ) smoking and ( v) alcohol consumption. Cancer can be reduced and contained by applying evidence-based strategies for prevention, early detection, patient management, and specific treatments. Regarding the latter, there are three main modalities for treating cancer: surgery, radiotherapy, and chemotherapy. For certain types of cancer, it is also possible to use hormone therapy, immunotherapy, or recent targeted therapies. Depending on the case, these modalities can be prescribed alone, successively, or in combination. Chemotherapy or polychemotherapy involves using several compounds that are cytotoxic to the cancer cell.Unlike surgery, these are systemic treatments that affect the entire body and not a specific organ, and which will, however, have consequences on healthy cells, such as more or less marked side effects.

[0003] One of the characteristics of cancer cells is that they divide very quickly to allow the tumor to grow. This characteristic is "targeted" by various agents that disrupt cell division, such as DNA intercalators (daunorubicin, doxorubicin, mitoxandrone, etc.), topoisomerase I and II inhibitors that modify the tertiary structure of DNA (irinotecan, etoposide, etc.), or even mitotic spindle poisons.

[0004] The importance of microtubules as anticancer targets is underscored by the clinical use of several microtubule-targeting agents in the treatment of cancers, such as Madagascar periwinkle alkaloids of the Vinca type and taxanes. Periwinkle alkaloids (vincristine, vinblastine, etc.) establish a specific binding to tubulin and inhibit its polymerization into microtubules, thus preventing the formation of the mitotic spindle. Taxanes (paclitaxel, docetaxel) prevent the depolymerization of tubulin and also disrupt the tubulin-microtubule balance. Thus, the disassembly of the mitotic spindle is blocked, causing the arrest of mitosis, resulting in cell death. Docetaxel is recommended in the treatment of many cancers. It is used alone or in combination with an anti-inflammatory (prednisone, etc.) in advanced prostate cancer (the leading cancer in men in France).In cases of breast cancer (the first cancer in women), docetaxel is used alone or in combination with other antitumor agents (doxorubicin, trastuzmab, etc.). In non-small cell lung cancer (the second cancer in men and the third in women), it has shown its effectiveness alone or in combination with cis-platin. Finally, docetaxel, in combination with 5-fluorouracil, is given to treat cases of stomach, head and neck cancer. Taxol has found its application in first-line treatments, in breast cancer associated with an anthracycline and in ovarian cancer associated with cis-platin.

[0005] Despite the therapeutic efficacy of these treatments, these various compounds are the cause of numerous side effects (alopecia, neutropenia, nausea, mucositis, muscle pain, etc.). For example, periwinkle alkaloids have been associated with neuro-, hemato- and cardiotoxicity problems. Furthermore, resistance phenomena due to phenotypic changes in cancer cells are increasingly observed, as for example in the case of non-hormone-dependent prostate cancers treated with docetaxel.

[0006] Research has been undertaken to identify and develop new molecules that disrupt the assembly of tubulin into microtubules.

[0007] In this context, combretastatin A-4 (CA-4), belonging to the family of combretastatins, natural stilbenes isolated by GR Pettit from the bark of a South African willow, Combretum caffrum 1< ,has been identified. CA-4 is a Z-configuration stilbene substituted by two aromatic rings of the 3,4,5-trimethoxyphenyl (ring A) and 3-hydroxy-4-methoxyphenyl (ring B) types. CA-4 has been shown to be highly cytotoxic (Cl 50 = 1-2 nM) against many human cancer lines as well as against lines resistant to conventional therapies using, for example, daunorubicin 2< . CA-4 is also a mitotic spindle poison since it strongly inhibits the assembly of tubulin into microtubules by binding to the colchicine site (Cl 50 = 1 µM). CA-4 has also been shown to exhibit 3< nanomolar antivascular activity in vitroby inhibition of endothelial cell proliferation. A water-soluble prodrug of CA-4, fosbretabulin (CA-4P), is currently in phase III clinical development for the treatment of thyroid cancer and in phase II clinical development for the treatment of non-small cell lung cancer and for the treatment of cis-platin-resistant ovarian cancer. Similarly, the hydrochloride of a structural analog of CA-4, ombrabulin, is currently used to treat advanced soft tissue sarcomas.

[0008] While these compounds are effective, they exhibit chemical instability due to isomerization of the ethylenic double bond.

[0009] L' isoCombretastatin A-4 (CA-4), a 4< non-natural isomer of CA-4, whose biological profile (cytotoxicity, inhibition of tubulin polymerization, induction of apoptosis, etc.) is rigorously identical to that of the natural molecule, without however presenting the risk of isomerization has recently been identified. This molecule, particularly stable, is metabolized only very little (<10%) in the presence of hepatocytes. 5<

[0010] It has also been shown that it is possible to reduce the double bond of isoCA-4 without significant loss of antitumor activity. 6< Thus, isoerianin, an unnatural isomer of erianin, has been shown to be cytotoxic at nanomolar concentrations (25 <GI 50 <45 nM) sur de nombreuses lignées tumorales humaines et inhibe la polymérisation de la tubuline à des concentrations micromolaire en bloquant le cycle cellulaire en phase G2 / M.

[0011] Application WO 2008 / 122620 discloses tubulin polymerization inhibitors useful for the treatment of cancer and of a structure analogous to isocomberetastatin A-4.

[0012] The combrestatin A-4 analogues synthesized to date contain a 3,4,5-trimethophenyl moiety. Since this group is suspected of causing side effects, such as neurotoxicity or cardiotoxicity, there is a need for the provision of new agents that inhibit tubulin polymerization. Ideally, these compounds should: (i) be effective at doses that are of little or no toxicity to humans, ( ii ) be stable and easy to produce industrially, ( iii ) be soluble in water to simplify their mode of administration, ( iv ) have an identified mechanism of action and, ( v ) be free of side effects if possible. BRIEF DESCRIPTION OF THE INVENTION

[0013] The present invention is defined solely by the claims. It relates to a compound of formula (Ib) as defined in the claims. Said formula (Ib) is related to the following formula (I): in which: R 2 and R 3 are different and one of the two represents a group A 1 of the following formula: wherein: the dotted bond is present or absent, preferably present; Z 1 and Z 2 independently represent a hydrogen atom, a halogen atom or a methyl group; (Het)Aryl represents an aryl or heteroaryl group, said heteroaryl being selected from indolyl, benzothiophenyl and benzofuranyl groups, said aryl or heteroaryl possibly being substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -OMe, -SMe, -OCX 3 with X denoting a halogen atom, -NH 2 , with R denoting a C 1 to C 6 alkyl group, with m representing 1 or 2, with m representing 1 or 2, and the other then representing a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a group -COYR' with Y denoting O or N and R' denoting H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, a group -SO 2 NR'R" with R', R", each denoting, independently of one another, H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, an aryl group, a heteroaryl group a group -NHSO 2 R' with R' denoting a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C alkynyl group 2 to C 4 , an aryl group, a heteroaryl group, a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, a C 1 to C 6 alkoxy group or a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or an alkyl group;A and E each represent a hydrogen atom or A and E participate in the structure of an enclosed aromatic ring of the following formula: ; wherein A, B and E independently represent a carbon or nitrogen atom, n represents 0 or 1 and R 4 , R 5 , R 6 , R 7 are as described below; X, Y and Z independently represent a carbon or nitrogen atom with the proviso that if X and Z represent a nitrogen atom, Y represents a carbon atom; at least one of A, B, E, X, Y and Z represents a nitrogen atom; R 1 , R 4 , R 5 , R 6 , R 7 , if present, represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxyl group, a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, a C 1 to C 6 alkoxy group or a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or a C 1 to C 6 alkyl group; as well as its pharmaceutically acceptable salts, stereoisomers and prodrugs.

[0014] The present invention also relates to a pharmaceutical composition comprising at least one compound of the present invention.

[0015] The present invention also relates to the compounds or compositions of the present invention for their use as a medicament, in particular intended to treat or prevent proliferative diseases or anti-vascular medicament. DEFINITIONS

[0016] The term "halogen", as used in the description of the present invention, denotes the atoms of fluorine, chlorine, bromine and iodine. Advantageously, this will be fluorine, bromine and chlorine and even more advantageously fluorine or chlorine.

[0017] The term "C 1 -C 6 alkyl", as used in the description of the present invention, denotes any saturated hydrocarbon group having from 1 to 6 carbon atoms, linear or branched, in particular the methyl, ethyl, n -propyl, isopropyl, n -butyl, iso -butyl, dry -butyl, tert -butyl, pentyl and hexyl.

[0018] The term "C 2 -C 4 alkenyl", as used in the description of the present invention, means any hydrocarbon group having from 2 to 4 carbon atoms, linear or branched, and having at least one double bond, such as a vinyl (ethenyl) group.

[0019] The term "C 2 -C 4 alkynyl", as used in the description of the present invention, means any hydrocarbon group having from 2 to 4 carbon atoms, linear or branched, and having at least one triple bond, such as an ethynyl or propynyl group.

[0020] The term "C 1 -C 6 alkoxy" as used in the description of the present invention means any -O-alkyl group, alkyl being as defined above. Examples of alkoxy groups include methoxy, ethoxy, propoxy, n -butoxy, iso -butoxy and tert -butoxy.

[0021] The term "(het)Aryl", as used in the description of the present invention, means aryl or heteroaryl.

[0022] The term "aryl", as used in the description of the present invention, denotes one or more aromatic rings having from 5 to 10 carbon atoms, which may be joined. In particular, the aryl groups may be monocyclic or bicyclic groups, such as, for example, the phenyl or naphthyl group. Advantageously, the aryl group is a phenyl.

[0023] The term "heteroaryl", as used in the description of the present invention, means an aromatic group comprising from 5 to 10 ring atoms. The ring atoms comprise carbon atoms and one or more heteroatoms, such as for example sulfur, nitrogen or oxygen atoms. The heteroaryl according to the present invention may consist of one or two fused rings. Preferably, the heteroaryl group will be an indolyl, benzothiophenyl, benzofuranyl or benzoimidazolyl group.

[0024] The term "cyano" as used in the description of the present invention denotes a -CN group.

[0025] The formula "-COYR'", as used in the description of the present invention, denotes an acid or an ester when Y is O, an amide when Y is N.

[0026] The formula "-SO 2 NR'R" or "- NHSO 2 R'", as used in the description of the present invention, denotes a sulfonamide.

[0027] The term "pharmaceutically acceptable," as used in the description of the present invention, means that which is useful in the preparation of a pharmaceutical composition, is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and is acceptable for human veterinary and / or pharmaceutical use.

[0028] The term "pharmaceutically acceptable salts," as used in the description of the present invention, refers to salts of a compound that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: (1) hydrates and solvates, (2) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like.Advantageously, it is hydrochloric acid; or (3) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Advantageously, the acidic proton is displaced by a Na +< ion, especially using sodium hydroxide. Acid addition salts are formed especially with an amine function or with a pyridine. Base addition salts are formed in particular with a carboxylic acid (-COOH), phosphate (-OP(O)(OH) 2 ) or sulfate (-OSO 3 H) function.

[0029] The term "stereoisomers," as used in the description of the present invention, refers to diastereomers or enantiomers. These are therefore configurational isomers. Stereoisomers that are not mirror images of each other are thus referred to as "diastereomers," and stereoisomers that are mirror images of each other but not superimposable are referred to as "enantiomers," also called "optical isomers." A carbon atom bonded to four non-identical substituents is called a "chiral center." When a molecule has such a chiral center, it is said to be chiral and has two enantiomeric forms. When a molecule has multiple chiral centers, then it will have multiple diastereomeric and enantiomeric forms. An equimolar mixture of two enantiomers is called a racemic mixture.

[0030] The term "prodrug", as used in the description of the present invention, refers to a compound which is administered in an inactive (or less active) form and which is metabolized in vivo, in particular by the action of enzymes or gastric acid, into an active (or more active) form. The use of a prodrug makes it possible to improve in particular the physicochemical parameters of a molecule such as solubility as well as pharmacokinetics (vectorization, bioavailability, etc.), in order to promote its assimilation by an organism after administration.

[0031] According to the invention, a prodrug of a molecule carrying an amino group (NH 2 ) may result in particular from the acylation or phosphorylation of this amino group. When a molecule carries a hydroxyl group (OH), the prodrug may result in particular from the acylation or phosphorylation of this hydroxyl group.

[0032] The expression "compounds of the present invention" as used in this description means compounds of formula (Ib) or (Ic) as defined in the claims. DETAILED DESCRIPTION OF THE INVENTION

[0033] The inventors have demonstrated that the compounds of the present invention disrupt the assembly of tubulin into microtubules. These compounds possess nanomolar cytotoxic activities on various human cancer lines, including lines resistant to standard treatments. These compounds inhibit tubulin polymerization at micromolar or even submicromolar concentrations, thus constituting compounds of choice in therapeutics.

[0034] Due to their chemical structure, the compounds of the present invention present reduced risks of being metabolized unlike CA-4 derivatives which are subject to (i) demethylation reactions on the 3,4,5-trimetoxyphenyl ring or (ii) isomerization of the double bond leading to a significant loss of activity. Compounds of the present invention

[0035] The subject of the invention is therefore compounds of formula (Ib) as defined in claim 1 and which is linked to the following formula (I): in which: R 2 and R 3 are different and one of the two represents a group A 1 of the following formula: wherein: the dotted bond is present or absent, preferably present; Z 1 and Z 2 independently represent a hydrogen atom, a halogen atom or a methyl group; (Het)Aryl represents an aryl or heteroaryl group, said heteroaryl being selected from indolyl, benzothiophenyl and benzofuranyl groups, said aryl or heteroaryl possibly being substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -OMe, -SMe, -OCX 3 with X denoting a halogen atom, -NH 2 , with R denoting a C 1 to C 6 alkyl group, with m representing 1 or 2, with m representing 1 or 2, and the other representing: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a group -COYR' with Y denoting O or N and R' denoting H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -SO 2 NR'R" with R', R", each denoting, independently of one another, H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -NHSO 2 R' with R' denoting a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, an aryl group, a heteroaryl group; a C 1 to C 6 alkyl group; a C 2 to C 4 alkenyl group; a C 2 to C 4 alkynyl group; a C 1 to C 6 alkoxy group; or a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or an alkyl group;A and E each represent a hydrogen atom or A and E participate in the structure of an enclosed aromatic ring of the following formula: ; wherein A, B and E represent, independently of each other, a carbon or nitrogen atom, n represents 0 or 1 and R 4 , R 5 , R 6 , R 7 are as described below; X, Y and Z represent, independently of each other, a carbon or nitrogen atom with the proviso that if X and Z represent a nitrogen atom, Y represents a carbon atom; at least one of A, B, E, X, Y and Z represents a nitrogen atom; R 1 , R 4 , R 5 , R 6 , R 7 , if present, represent, independently of each other: a hydrogen atom; a halogen atom; a hydroxyl group; a C 1 -C 6 alkyl group; a C 2 -C 4 alkenyl group; a C 2 -C 4 alkynyl group; a C 1 to C 6 alkoxy group; or a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or a C 1 to C 6 alkyl group; as well as its pharmaceutically acceptable salts, stereoisomers and prodrugs.

[0036] Formula (Ib) of the invention is also related to the following formula (I'): in which: n represents 0 or 1; A, B and E represent, independently of each other, a carbon or nitrogen atom; X, Y and Z represent, independently of each other, a carbon or nitrogen atom provided that if X and Z represent a nitrogen atom, Y represents a carbon atom; at least one of A, B, E, X, Y and Z represents a nitrogen atom; R 1 , R 4 , R 5 , R 6 , R 7 , if present, represent, independently of each other: a hydrogen atom; a halogen atom; a hydroxyl group; a C 1 to C 6 alkyl group; a C 2 to C 4 alkenyl group; a C 2 to C 4 alkynyl group; a C 1 to C 6 alkoxy group; or a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or a C 1 to C 6 alkyl group; R 2 and R 3 are different and one of the two represents a group A 1 of the following formula: wherein: the dotted bond is present or absent, preferably present; Z 1 and Z 2 independently represent a hydrogen atom, a halogen atom or a methyl group; (Het)Aryl represents an aryl or heteroaryl group, said heteroaryl being selected from indolyl, benzothiophenyl and benzofuranyl groups, said aryl or heteroaryl possibly being substituted by one or more substituents selected from a halogen atom, a hydroxyl group, -OMe, -SMe, -OCX 3 with X denoting a halogen atom, -NH 2 , with R denoting a C 1 to C 6 alkyl group, with m representing 1 or 2, with m representing 1 or 2, and and the other represents: a hydrogen atom; a halogen atom; a hydroxyl group; a cyano group; a group -COYR' with Y denoting O or N and R' denoting H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -SO 2 NR'R" with R', R", each denoting, independently of one another, H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -NHSO 2 R' with R' denoting a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, an aryl group, a heteroaryl group; a C 1 to C 6 alkyl group; a C 2 to C 4 alkenyl group; a C 2 to C 4 alkynyl group; a C 1 to C 6 alkoxy group; a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or a C 1 to C 6 alkyl group; as well as its pharmaceutically acceptable salts, stereoisomers and prodrugs.

[0037] The expression "R 1 , R 4 , R 5 , R 6 or R 7 , if present" as used in the description of the present invention means that the groups R 1 , R 4 , R 5 , R 6 or R 7 will be present if the valence of the atom to which the group is, or would be, bonded allows it. Those skilled in the art will readily determine whether such a group is present.

[0038] The subject of the invention is compounds of formula (I') as represented above in which R 3 is a group A 1 as represented above, or compounds of the following formula (Ib): in which: n, A, B, E, X, Y, Z, R 1 , R 4 , R 5 , R 6 , R 7 , (Het)Aryl, Z 1 and Z 2 are as described in claim 1; and R 2 represents: a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a group -COYR' with Y denoting O or N and R' denoting H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -SO 2 NR'R" with R', R", each denoting, independently of one another, H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -NHSO 2 R' with R' denoting a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, an aryl group, a heteroaryl group; a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, a C 1 to C 6 alkoxy group or a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or an alkyl group.

[0039] In certain embodiments, the invention relates to compounds of formula (Ib) in which the (Het)Aryl group represents a phenyl group which may be substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, -OMe, -SMe, -OCX 3 with X denoting a halogen atom, -NH 2 , with R denoting a C 1 to C 6 alkyl group, with m representing 1 or 2, with m representing 1 or 2 and

[0040] Preferably, the (Het)Aryl group represents a substituted phenyl group having the following formula: in which: R 8 represents a hydrogen atom, a halogen atom, a hydroxyl group, - OMe, -SMe, -NH 2 , with R denoting a C 1 to C 6 alkyl group, with m representing 1 or 2, with m representing 1 or 2 or and R 9 represents a C 1 -C 6 alkoxy group, in particular -OMe, -SMe or -OCX 3 with X denoting a halogen atom.

[0041] Preferably, R 8 represents a hydrogen atom, a halogen atom, preferably fluorine or chlorine, a hydroxyl group or a -NH 2 group.

[0042] Preferably, R 9 represents a C 1 -C 6 alkoxy group, preferably C 1 -C 4 alkoxy, preferably methoxy, -SMe or -OCX 3 with X denoting a halogen atom, preferably fluorine.

[0043] Thus, in certain embodiments, the invention relates to compounds of the following formula (Ic): in which: n, A, B, E, X, Y, Z, R 1 , R 4 , R 5 , R 6 , R 7 are as defined in the claims; R 2 represents: a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a group -COYR' with Y denoting O or N and R' denoting H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -SO 2 NR'R" with R', R", each denoting, independently of one another, H or a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group; a group -NHSO 2 R' with R' denoting a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, an aryl group, a heteroaryl group; a C 1 to C 6 alkyl group, a C 2 to C 4 alkenyl group, a C 2 to C 4 alkynyl group, a C 1 to C 6 alkoxy group or a group -NR'R" with R' and R" representing, independently of each other, a hydrogen or an alkyl group;the dotted bond is absent or present, preferably present; Z 1 and Z 2 independently represent a hydrogen atom, a halogen atom or a methyl group; R 8 represents a hydrogen atom, a halogen atom, a hydroxyl, -OMe, -SMe, -NH 2 , ; with R denoting a C 1 to C 6 alkyl group, with m representing 1 or 2, with m representing 1 or 2 or and R 9 represents a C 1 -C 6 alkoxy group, in particular -OMe, -SMe or -OCX 3 with X denoting a halogen atom; as well as its pharmaceutically acceptable salts, stereoisomers and prodrugs.

[0044] Preferably, in formula (Ic) above, R 8 represents a hydrogen atom, a halogen atom, preferably fluorine or chlorine, a hydroxyl group, a -NH 2 group, or with m representing 1 or 2.

[0045] Preferably, in formula (Ic) above, R 9 represents a C 1 -C 6 alkoxy group, preferably C 1 -C 4 , preferably methoxy, -SMe or -OCX 3 with X denoting a halogen atom, preferably fluorine.

[0046] Preferably, the compounds of the present invention have the formula (Ib) or (Ic) in which Z 1 and Z 2 are identical and represent a hydrogen or fluorine atom.

[0047] According to the invention, the dotted connection is present.

[0048] In certain embodiments, the compounds of the present invention have the formula (I') shown above and related to formula (Ib) of claim 1 wherein: n, A, B, EX, Y, Z, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , are as defined in the claims; and R 3 represents a group A 2 of the following formula: in which: the dotted bond is present; Z 1 and Z 2 independently represent a hydrogen atom, a halogen atom or a methyl group.

[0049] In certain embodiments, the compounds of the present invention have the formula (I') shown above and related to formula (Ib) of claim 1 wherein: n, A, B, EX, Y, Z, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , are as defined in the claims; and R 3 represents a group A 3 of the following formula: in which: the dotted bond is present; Z 1 and Z 2 independently represent a hydrogen atom, a halogen atom or a methyl group; R 10 represents a hydrogen atom or a methyl group.

[0050] The compounds of the present invention have the formula (Ib) or (Ic) shown above wherein n is 1, X is nitrogen and A, E, Z, Y and B are

[0051] Preferably, when n is 1, X is nitrogen, and A, E, Z, Y, and B are carbon, the compounds of the present invention have the formula (Ib) or (Ic) shown above wherein R 4 , R 5 , R 6 , and R 7 are hydrogen. In some embodiments, the compounds of the present invention have the formula (Ib) or (Ic) wherein n is 1, X is nitrogen, A, E, Z, Y, and B are carbon, R 4 , R 5 , R 6 , and R 7 are hydrogen, and R 2 is as defined above. Preferably, R 2 is other than hydrogen.

[0052] In certain embodiments, the compounds of the present invention have the formula (Ib) or (Ic) shown above wherein: n is equal to 1; A, B, E, Y and Z are a carbon atom; X is a nitrogen atom.

[0053] In these embodiments, preferably, R 4 , R 5 , R 6 and R 7 represent a hydrogen atom.

[0054] In particular, the compounds of the present invention may have the formula (Ib) or (Ic) shown above in which n is equal to 1, A, B, E, Y and Z are a carbon atom, X is a nitrogen atom and R 2 is as defined above, preferably R 2 is other than a hydrogen atom.

[0055] In certain particular embodiments, the compounds of the present invention have the following formula: wherein, suitably, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 are as defined above and the dotted bond is present.

[0056] In particular, in some embodiments, Z 1 and Z 2 each represent a hydrogen or each a fluorine atom and R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 are as defined above. In other embodiments, R 9 denotes a methoxy and Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are as defined above.

[0057] In other embodiments, Z 1 and Z 2 each represent hydrogen or each a fluorine atom, R 9 represents methoxy and R 1 , R 2 , R 3 , R 4 , R 5 and R 8 are as defined above.

[0058] In particular, the compounds of the invention may be chosen from compounds I-16 and I-19 below. The other compounds are not part of the invention: I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 I-13 I-14 I-15 I-16 I-17 I-18 I-19 II-1 II-2 II-3 II-4

[0059] The absence of an ethylenic double bond in the compounds of formula (I) makes it possible to solve the problem of isomerization which may occur in vivo, leading to drops (or absences) of cytotoxic activity as is the case for example with CA-4. The reduction of the double bond located between the two aromatic rings leads to derivatives that are less cytotoxic than their precursors. Process for synthesizing the compounds of the present invention

[0060] The invention also relates to the methods of synthesizing the compounds of the present invention. It is defined by claim 14 attached hereto.

[0061] The synthesis processes are short, advantageously comprising 2 to 3 steps. These processes are compatible with industrial requirements.

[0062] The coupling of an easily accessible tosylhydrazone with a halogenated derivative bearing the nitrogenous bicycle leads to the compounds according to the invention with excellent yields, advantageously without resorting to protection-deprotection steps.

[0063] The compounds according to the invention can be prepared according to methods known to those skilled in the art, from commercially available products or prepared according to methods known to those skilled in the art.

[0064] In particular, the compounds of formula (I), (I'), (Ib) and (Ic) can be prepared by a process comprising the following successive steps: a) reaction of a compound of formula (II) with tosylhydrazine to yield the tosylhydrazone compound of formula (III) b) coupling the compound of formula (III) with the compound of formula (IV), (V), (VI) or (VII) in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y, Z, A, B, E and n are as defined previously and X 1 represents a halogen atom or trifluoromethanesulfonate; b) where appropriate, reduction of the compound (I), in which the dotted double bond is present, obtained following step b) to yield the compound (I) in which the dotted double bond is absent; c) separation of the reaction medium from the compound (I) obtained following step b)

[0065] The person skilled in the art will know how to protect appropriately, if necessary, the groups R 1 to R 7 so that only the group X 1 reacts or adapt the synthesis strategy accordingly.

[0066] For example, when the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and / or R 7 (if present) represent a halogen atom: X 1 is an iodine atom if the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 (if present) are a bromine, chlorine or fluorine atom; if the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 (if present) are a chlorine or fluorine atom, then X 1 is a bromine atom.

[0067] In particular, compounds of formula (I'), (Ib) or (Ic) in which n is equal to 1, A, B, E and Y are carbon atoms and X and Z are nitrogen atoms can be prepared by a process comprising the following successive steps: a) reaction of a compound of formula (II) with tosylhydrazine to yield the tosylhydrazone compound of formula (III) b) coupling of the compound of formula (III) with the compound of formula (IV') or (V') in which R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined above and X 1 represents a halogen atom or trifluoromethanesulfonate; c) where appropriate, reduction of the compound (I), in which the dotted double bond is present, obtained following step b) to yield the compound (I) in which the dotted double bond is absent; d) separation of the reaction medium from the compound (I) obtained following step b) or c).

[0068] This step c) can be followed by possible additional classical steps of modification of the substituents of the (Het)Aryl group and possibly of Z 1 / Z 2 .

[0069] The compound thus obtained may be separated from the reaction medium by methods well known to those skilled in the art, such as for example by extraction, evaporation of the solvent or by precipitation and filtration.

[0070] The compound may also be purified if necessary by techniques well known to those skilled in the art, such as by recrystallization if the compound is crystalline, by distillation, by column chromatography on silica gel or by high performance liquid chromatography (HPLC).

[0071] In step b), the coupling is advantageously carried out in the presence of a palladium complex, a ligand, in catalytic quantity and a base. In particular, the coupling can be carried out using a palladium complex such as PdCl 2 (MeCN) 2 ], the ligand dppf in catalytic quantity and the base tBuOLi. In particular, the coupling can be carried out in the presence of 10 mol% of PdCl 2 (MeCN) 2 , 20 mol% of dppf, 2.2 molar equivalents of tBuOLi in the presence of dioxane, at 90°C, for 2 to 4 hours.

[0072] In step c), the reduction is advantageously carried out by hydrogenation. The hydrogenation is advantageously carried out under a hydrogen atmosphere, in particular in the presence of palladium on carbon (Pd / C) as a catalyst or possibly PtO 2 . Advantageously, 5 to 30 mol%, preferably approximately 10 mol% of catalyst are used during this reaction. In addition, ethyl acetate will advantageously be used as a solvent during this step.

[0073] In particular, the compounds of formula (I), (I'), (Ib) and (Ic) can be prepared by a process comprising the following successive steps:

[0074] In particular, certain compounds of the present invention can be prepared according to the following scheme: Uses of the compounds of the present invention

[0075] In certain aspects, the invention relates to compounds of formula (Ib) or (Ic), as well as their pharmaceutically acceptable salts, their stereoisomers and their prodrugs, for their use as a medicament.

[0076] In particular, the compounds of the present invention may be used as medicaments inhibiting tubulin polymerization, advantageously as medicaments for treating or preventing proliferative diseases, such as cancer, psoriasis or fibrosis, in particular cancer. In particular, the compounds of the invention may be useful in the treatment of cancer, such as those susceptible to treatment by CA-4 or by taxotere.

[0077] The compounds of the present invention can also be used as anti-vascular drugs.

[0078] The invention also relates to a pharmaceutical composition comprising at least one compound according to the present invention, typically in association with one or more pharmaceutically acceptable excipients.

[0079] In certain aspects, the invention also relates to a pharmaceutical composition comprising at least one compound according to the present invention in association with at least one other active ingredient, in particular an anti-cancer compound, cytotoxic or not, and one or more pharmaceutically acceptable excipients.

[0080] In a non-limiting manner, the active ingredients that can be combined with the compound of the present invention can be chosen from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen,octreotide, lanreotide, (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]-propionic acid, 4-((9-chloro-7-(2,6-difluorophenyl)-5H-pyrimidol(5,4-d)(2)benzazepin-2-yl)amino)benzoic acid, 5,6-dimethylxanthenone-4-acetic acid and 3-(4-(1,2-diphenylbut-1-enyl)phenyl)acrylic acid.,

[0081] The invention also relates to a pharmaceutical composition comprising at least one compound according to the present invention in association with an antibody. The composition may comprise one or more pharmaceutically acceptable excipients. The antibody makes it possible to target the tumor. In particular, the pharmaceutical composition may comprise at least one compound according to the present invention in association with a monoclonal antibody. The association of the compound of the present invention with the antibody may be in the form of “antibody-compound of the present invention” conjugates. The antibody and the compound of the present invention are typically covalently linked via a linker. Those skilled in the art will be able to determine the nature of the linker suitable for the binding of the compound of the present invention with an antibody.Thus, in one aspect, the present invention provides a conjugate comprising a compound according to the present invention covalently linked to an antibody.

[0082] The compounds and compositions according to the invention can be administered orally, sublingually, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, locally or rectally.

[0083] The compounds according to the present invention may be used at doses between 0.01 mg and 1000 mg per day, given as a single dose once a day or preferably administered in several doses throughout the day, for example twice a day in equal doses. The dose administered per day is advantageously between 5 mg and 500 mg, even more advantageously between 10 mg and 200 mg. It may be necessary to use doses outside these ranges, which a person skilled in the art can appreciate himself.

[0084] The compounds according to the invention can be used to decrease or inhibit the polymerization of tubulin, in particular in vitro and also in vivo.

[0085] The present invention also relates to a pharmaceutical composition comprising: (i) at least one compound of the present invention, (ii) at least one other active ingredient, as combination products for simultaneous, separate or spread out use over time.

[0086] The active ingredient(s) may be as mentioned above. In particular, the active ingredient may be useful for the treatment of proliferative diseases such as cancer, psoriasis or fibrosis, advantageously an anti-cancer agent such as an anti-vascular, cytotoxic or anti-angiogenic agent,

[0087] Pharmaceutical compositions as described above may be useful for the treatment of proliferative diseases, such as cancer, psoriasis or fibrosis, particularly cancer.

[0088] The present invention finally relates to the compounds of the invention for their use in a method of treating proliferative diseases, such as cancer, psoriasis or fibrosis, and in particular cancer, comprising the administration, to a patient in need thereof, of a compound of the present invention alone or in combination, advantageously synergistic, with at least one other active ingredient as defined above.

[0089] The present invention also relates to pharmaceutical compositions in the form of nanoparticulate formulations. In such embodiments, the pharmaceutical compositions comprise at least one compound of the present invention covalently coupled to at least one molecule of a hydrocarbon compound having a squalenic structure. In particular, the pharmaceutical compositions comprise at least one compound of the present invention covalently coupled to at least one molecule of a hydrocarbon compound having a squalenic structure and a polar solvent or water.

[0090] The hydrocarbon compound with a squalenic structure and the covalent coupling of this compound with the compounds of the present invention may be as described in WO 2006 / 090029 or FR 2 924 024.

[0091] In particular, hydrocarbon compounds with a squalenic structure designate linear hydrocarbon structures formed of isoprene units, more particularly of 6 isoprene units. For example, the hydrocarbon compounds with a squalenic structure may be squalenic acid and its derivatives, in particular its substituted derivatives. The hydrocarbon compounds with a squalenic structure may carry a function capable of reacting with a function present on the compounds of the present invention so as to form a covalent bond between the two compounds, in particular a covalent bond of the ester, ether, thiaether, disulfide, phosphate or amide type. Alternatively, the covalent bond between the two compounds may be produced by means of a linker arm. Such linkers are well known to those skilled in the art.

[0092] The invention will now be illustrated, in a non-limiting manner, by Examples I-16 and I-19 which follow; the other compounds not forming part of the invention: EXAMPLES General procedure for the synthesis of compounds I-1 to I-19

[0093] To a solution of N -tosylhydrazone (1.5 mmol), t-BuOLi (2.2 mmol), PdCl 2 (CH 3 CN) 2 (0.1 mmol), and dppf (0.2 mmol) in dioxane (1 mL) is added 4-chloroquinazoline (1 mmol). The reaction medium is sealed and then heated at 90 °C for 2 h before being brought back to room temperature. The suspension obtained is filtered on a celite column (eluent AcOEt) to separate the inorganic salts. After evaporation of the solvents under vacuum, the residue formed is chromatographed on a silica column.

[0094] 4-[1-(4-Methoxy-phenyl)-vinyl]-2-methyl-quinazoline I-1. Yellow oil, 50%. TLC: RF0.3 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1608, 1554, 1511, 1250, 1180. 1< H NMR (300 MHz, CDCl 3 ): 7.97 (d, 1H, J = 8.5 Hz), 7.87 (d, 1H, J = 8.5 Hz), 7.81 (td, 1H, J = 8.5 Hz, J = 0.9 Hz), 7.41 (td, 1H, J = 8.3 Hz, J = 0.9 Hz), 7.23 (d, 2H, J = 8.9 Hz), 6.82 (d, 2H, J = 8.9 Hz), 6.04 (s, 1H), 5.46 (s, 1H), 3.78 (s, 3H), 2.93 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.9, 164.1, 159.8, 151.1, 145.0, 133.9, 131.4, 128.1, 128.0 (2), 127.1, 126.7, 121.7, 116.9, 114.1 (2C), 55.4, 26.8. m / z MS (ESI +< ): 277 (M + H) +< .

[0095] 4-[1-(3,4-Dimethoxy-phenyl)-vinyl]-2-methyl-quinazoline I-2. Huile jaune, 48%. TLC: Rf 0.1 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1554, 1514, 1464, 1326, 1221, 1143. 1< H NMR (300 MHz, CDCl 3 ): 7.96 (d, 1H, J = 8.4 Hz), 7.87-7.78 (m, 2H), 7.41 (t, 1H, J = 7.6 Hz), 6.97 (d, 1H,J = 1.6 Hz), 6.76-6.68 (m, 2H), 6.03 (s, 1H), 5.48 (s, 1H), 3.84 (s, 3H), 3.41 (s, 3H), 2.93 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.7, 164.1, 151.1, 149.5, 149.1, 145.3, 133.9, 131.8, 128.1, 127.0, 126.7, 121.7, 120.1, 117.4, 111.1, 109.5, 56.0 (2C), 26.8. m / z MS (APCI +< ): 307 (M + H) +< . 2-Methyl-4-(1-(4-(trifluoromethoxy)phenyl)vinyl)quinazoline I-3. Huile jaune, 78%. TLC: Rf 0.3 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1554, 1509, 1490, 1254, 1207, 1164. 1< H NMR (300 MHz, CDCl 3 ): 8.00 (d, 1H, J = 8.2 Hz), 7.85-7.82 (m, 2H), 7.49-7.43 (td, 1H, J = 7.4 Hz, J = 1.1 Hz), 7.36 (d, 2H, J = 8.9 Hz), 7.15 (d, 2H, J = 8.1 Hz), 6.16 (s, 1H), 5.62 (s, 1H), 2.93 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.2, 164.1, 151.1, 149.3, 144.3, 137.4, 134.3, 128.3 (2C), 128.2, 127.1, 126.7, 121.6, 121.1 (2C), 120.4 (q, J= 256.5 Hz), 119.9, 26.8. 19< F NMR (188 MHz, CDCl 3 ): -58.23. m / z MS (APCI +< ): 331 (M + H) +< .

[0096] 2-Methyl-4-(1-(4-(methylthio)phenyl)vinyl)quinazoline I-4. Yellow oil, 43%. TLC: RF 0.4 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1751, 1554, 1492, 1326, 1215. 1< H NMR (300 MHz, CDCl 3 ): 7.96 (d, 1H, J = 8.4 Hz), 7.83-7.76 (m, 2H), 7.42-7.36 (m, 1H), 7.20 (d, 2H, J = 8.6 Hz), 7.14 (d, 2H, J = 8.7 Hz), 6.09 (s, 1H), 5.52 (s, 1H), 2.91 (s, 3H), 2.42 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.4, 164.1, 151.1, 145.0, 139.2, 135.4, 133.9, 128.1, 127.0 (2C), 126.9, 126.8, 126.3 (2C), 121.6, 118.1, 26.7, 15.5. m / z MS (APCI +< ): 293 (M + H) +< .

[0097] 4-[1-(3-Fluoro-4-methoxy-phenyl)-vinyl]-2-methyl-quinazoline I-5. Huile jaune, 46%. TLC: RF0.2 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1615, 1554, 1517, 1275, 1134, 1027. 1< H NMR (300 MHz, CDCl 3 ): 7.99 (d, 1H, J = 8.3 Hz), 7.86-7.80 (m, 2H), 7.46-7.41 (td, 1H, J = 7.2 Hz, J = 1.0 Hz), 7.13 (dd, 1H, J = 12.5 Hz, J = 2.2 Hz), 6.96-6.92 (m, 1H), 6.85 (t, 1H, J = 8.5 Hz), 6.06 (s, 1H), 5.51 (s, 1H), 3.86 (s, 3H), 2.93 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.3, 164.1, 154.1, 150.9 (d, 1C, J = 23.7 Hz), 147.9 (d, 1C, J = 11.1 Hz), 144.1, 134.1, 131.9 (d, 1C, J = 6.3 Hz), 128.2, 126.9, 126.8, 122.9 (d, 1CH, J = 3.3 Hz), 121.6, 118.1, 114.3 (d, 1C, J = 19.4 Hz), 113.3 (d, 1C, J = 1.9 Hz), 56.4, 26.7. 19< F NMR (188 MHz, CDCl 3 ): -132.7. m / z MS (APCI +< ): 295 (M + H) +< .

[0098] 2-Methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)phenol I-6. A un mélange contenant la N-silylated tosylhydrazone (1.5 mmol), t-BuOLi (2.2 mmol), PdCl 2 (CH 3 CN) 2 (0.1 mmol) and dppf (0.2 mmol) in dioxane (1 mL) is added 4-chloroquinazoline (1 mmol). The reaction medium is sealed and then heated to 90 °C for 2 h before being brought back to room temperature. The suspension obtained is filtered on a celite column (eluent AcOEt) to separate the inorganic salts. After evaporation of the solvents under vacuum, the residue formed is dissolved in MeOH (1 mL) then K 2 CO 3 (2 mmol) is added and the reaction medium is stirred at room temperature for 6 h. The suspension thus formed is filtered, the organic solvents are evaporated and the residue formed is chromatographed on a silica column.

[0099] Yellow oil, 34%. TLC: RF 0.1 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1<): 1615, 1554, 1512, 1439, 1279, 1135. 1< H NMR (300 MHz, CDCl 3): 7.98 (d, 1H, J = 8.4 Hz), 7.87 (d, 1H, J = 8.3 Hz), 7.81 (td, 1H,J = 7.1 Hz, J = 1.2 Hz), 7.42 (t, 1H, J = 7.4 Hz), 6.92 (s, 1H), 6.75 (s, 2H), 6.12 (brs, 1H), 6.04 (s, 1H), 5.46 (s, 1H), 3.87 (s, 3H), 2.90 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 170.1, 164.0, 150.7, 147.1, 145.9, 145.0, 134.1, 132.3, 127.8, 127.1, 126.9, 121.8, 118.9, 117.4, 113.0, 110.8, 56.1, 26.5. m / z MS (ESI +< ): 293 (M + H) +< .

[0100] 2-Methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)aniline I-7. A un mélange contenant la N- tosylhydrazone NH-acétyle (1.5 mmol), t-BuOLi (2.2 mmol), PdCl 2 (CH 3 CN) 2 (0.1 mmol) and dppf (0.2 mmol) in dioxane (1 mL) is added 4-chloroquinazoline (1 mmol). The reaction medium is sealed then heated at 90 °C for 2 h before being brought back to room temperature. The suspension obtained is filtered on a celite column (eluent AcOEt) to separate the inorganic salts. After evaporation of the solvents under vacuum, the residue formed is dissolved in MeOH (1 mL) then KOH (20 mmol) is added and the reaction medium is sealed then stirred at 100 °C for 12 h. The suspension thus formed is filtered, the organic solvents are evaporated and the residue formed is chromatographed on a silica column.

[0101] Yellow oil, 27%. TLC: RF 0.1 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1<): 1614, 1567, 1553, 1441, 1330, 1219. 1< H NMR (300 MHz, CD 3 COCD 3): 7.94-7.84 (m, 3H), 7.52-7.46 (m, 1H), 6.76 - 6.72 (m, 2H), 6.54 (dd, 1H, J = 8.3 Hz, J= 2.3 Hz), 5.96 (s, 1H), 5.33 (s, 1H), 4.41 (brs, 2H), 3.81 (s, 3H), 2.79 (s, 3H). 13< C NMR (75 MHz, CD 3 COCD 3 ): 170.7, 164.6, 152.1, 148.2, 147.1, 138.5, 134.4, 133.1, 128.9, 127.8, 127.3, 122.9, 116.6, 116.1, 113.0, 111.0, 55.8, 26.6. m / z MS (APCI +< ): 292 (M + H) +< .

[0102] 2-Methyl-4-(1-(naphthalen-2-yl)vinyl)quinazoline I-8. Solide blanc, 36%. M.p.: 113.6 °C. TLC: Rf 0.2 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1614, 1568, 1490, 1325, 1168, 906. 1< H NMR (300 MHz, CDCl 3 ): 8.01 (d, 1H, J = 8.4 Hz), 7.86 (d, 1H, J = 8.4 Hz), 7.83-7.77 (m, 3H), 7.68-7.65 (m, 1H), 7.60-7.57 (m, 2H), 7.46-7.34 (m, 3H), 6.28 (s, 1H), 5.68 (s, 1H), 2.98 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.6, 164.1, 151.1, 145.6, 136.1, 134.0, 133.3, 133.1, 128.5, 128.4, 128.0, 127.6, 127.0, 126.8, 126.5, 126.4, 126.4, 124.1, 121.7, 119.3, 26.8. m / z MS (ESI +< ): 297 (M + H) +< .

[0103] 2-Methyl-4-(1-(1-methyl-1H-indol-5-yl)vinyl)quinazoline I-9. Huile rougeatre, 46%. TLC: RF 0.2 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1612, 1565, 1490, 1332, 1246. 1< H NMR (300 MHz, CDCl 3 ): 8.00 (d, 1H, J = 8.4 Hz), 7.91 (dd, 1H, J = 8.4 Hz, J = 0.7 Hz), 7.83-7.77 (ddd, 1H, J = 8.4 Hz, J = 6.9 Hz, J = 1.4 Hz), 7.50-7.49 (m, 1H), 7.40-7.34 (ddd, 1H, J = 8.4 Hz, J = 6.7 Hz, J = 1.3 Hz), 7.30-7.27 (m, 2H), 7.03 (d, 1H, J = 3.1 Hz), 6.41 (d, 1H, J = 3.1 Hz), 6.12 (d, 1H, J = 0.7 Hz), 5.53 (d, 1H, J = 0.7 Hz), 3.77 (s, 3H), 2.99 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 170.6, 164.1, 151.0, 146.8, 136.7, 133.7, 130.7, 129.7, 128.6, 127.9, 127.4, 126.6, 121.9, 120.6, 119.7, 116.7, 109.5, 101.7, 33.0, 26.8. m / z MS (APCI +< ): 300 (M + H) +< .

[0104] 2-Chloro-4-[1-(4-methoxy-phenyl)-vinyl]-quinazoline I-10. Huile brune, 46%. TLC: RF 0.4 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1673, 1597, 1511, 1246, 1175. 1< H NMR (300 MHz, CDCl 3 ): 8.0 (dd, 1H, J = 8.5 Hz, J = 1.1 Hz), 7.90-7.85 (m, 2H), 7.49 (td, 1H, J = 8.5 Hz, J = 1.1 Hz), 7.23 (d, 2H, J = 8.8 Hz), 6.84 (d, 2H, J = 8.8 Hz), 6.06 (s, 1H), 5.55 (s, 1H), 3.79 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 173.1, 160.1, 157.3, 152.7, 144.2, 135.1, 131.1, 128.1 (2C), 128.1, 127.9, 127.5, 122.4, 118.6, 114.3 (2C), 55.4. m / z MS (APCI +< ): 297 (M + H) +< .

[0105] 2-Chloro-4-[1-(3,4-dimethoxy-phenyl)-vinyl]-quinazoline I-11. Huile jaune, 19%. TLC: Rf 0.3 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1665, 1595, 1563, 1514, 1465, 1264, 1143. 1< H NMR (300 MHz, CDCl 3 ): 8.00 (d, 1H, J = 8.9 Hz), 7.91-7.85 (m, 2H), 7.49 (td, 1H, J= 8.2 Hz, J = 1.2 Hz), 6.95 (d, 1H, J = 2.0 Hz), 6.77 (d, 1H, J = 8.4 Hz), 6.71 (dd, 1H, J = 8.3 Hz, J = 2.0 Hz), 6.05 (s, 1H), 5.59 (s, 1H), 3.86 (s, 3H), 3.83 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 172.8, 157.2, 152.7, 149.7, 149.2, 144.5, 135.2, 131.5, 128.0, 128.0, 127.4, 122.4, 120.2, 119.2, 111.2, 109.6, 56.1, 56.0 . m / z MS (APCI +< ): 327 (M + H) +< .

[0106] 2-Chloro-4-[1-(3,4,5-trimethoxy-phenyl)-vinyl]-quinazoline I-12. Solide blanc, 34%. M.p.: 135-136 °C. TLC: RF 0.4 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1580, 1528, 1401, 1316, 1277, 1243, 1121. 1< H NMR (300 MHz, CDCl 3 ): 8.01 (d, 1H, J= 8.9 Hz), 7.92-7.87 (m, 2H), 7.55-7.49 (m, 1H), 6.52 (s, 2H), 6.09 (s, 1H), 5.66 (s, 1H), 3.85 (s, 3H), 3.66 (s, 6H). 13< C NMR (75 MHz, CDCl 3 ): 172.4, 157.2, 153.5 (2C), 152.7, 144.9, 138.8, 135.3, 134.3, 128.1 (2C), 127.3, 122.3, 120.8, 104.5 (2C), 61.1, 56.4 (2C). m / z MS (ESI +< ): 357 (M + H) +< .

[0107] 4-[1-(3,5-Dimethoxy-phenyl)-vinyl]-2-methyl-quinazoline I-13. Solide blanc, 36%. F. 89-91 °C. RF 0.3 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1592, 1460, 1424, 1294, 1206, 1161. 1< H NMR (300 MHz, CDCl 3 ): 7.96 (d, 1H, J = 8.4 Hz), 7.87-7.78 (m, 2H), 7.42 (td, 1H, J = 8.1 Hz, J = 1.0 Hz), 6.45 (d, 2H, J =2.1 Hz), 6.41 (d, 1H, J = 2.0 Hz), 6.12 (s, 1H), 5.58 (s, 1H), 3.72 (s, 6H), 2.93 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.3, 164.1, 161.0 (2C), 151.1, 145.7, 141.0, 134.0, 128.1, 127.0, 126.8, 121.7, 119.5, 105.4 (2C), 100.2, 55.5 (2C), 26.8. m / z MS (APCI +< ): 307 (M + H) +< .

[0108] 2-Methyl-4-[1-(3,4,5-trimethoxy-phenyl)-vinyl]-quinazoline I-14. Solide jaune, 40%. F. 127-128 °C. RF 0.2 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1553, 1506, 1464, 1410, 1331, 1242, 1128. 1< H NMR (300 MHz, CDCl 3 ): 7.97 (d, 1H, J = 8.5 Hz), 7.90-7.80 (m, 2H), 7.45 (td, 1H, J = 8.2 Hz, J = 1.1 Hz), 6.54 (s, 2H), 6.07 (s, 1H), 5.56 (s, 1H), 3.84 (s, 3H), 3.72 (s, 6H), 2.94 (s, 3H). 13< C NMR (75 MHz, CDCl 3 ): 169.3, 164.1, 153.4 (2C), 151.2, 145.7, 138.6, 134.7, 134.0, 128.1, 127.0, 126.9, 121.7, 119.0, 104.5 (2C), 61.0, 56.3 (2C), 26.8. m / z MS (ESI +< ): 359 (M + Na) +< .

[0109] Le composé 3-(2-Méthoxy-5-(1-(2-méthylquinazolin-4-yl)vinyl)phényl)prop-2-yn-1-ol I-15 was prepared in 3 steps from commercial 3-iodo-4-methoxyacetophenone (Scheme 1). The first step is a Sonogashira reaction to install the acetylenic function. The ketone thus formed is transformed into the N-tosylhydrazone derivative and then coupled under pallado-catalyzed conditions with 4-chloroquinazoline to provide the compound I-15.

[0110] Yellow oil, 17%, TLC: Rf 0.1 (Cyclohexane / EtOAc, 1 / 1). IR (neat, cm -1<): 3272, 2927, 2840, 2247, 1777, 1599, 1361, 873. 1< H NMR (300 MHz, CDCl 3): 8.01 (d, 1H, J = 8.3 Hz), 7.82 (m, 2H), 7.46, (t, 1H, J = 7.5 Hz), 7.41 (s, 1H), 7.22 (d, 1H, J = 7.5 Hz), 6.77 (d, 1H, J= 8.5 Hz), 6.02 (s, 1H), 5.50 (s, 1H), 4.50 (s, 2H), 3.78 (s, 3H), 2.90 (s, 3H), OH not seen). 13< C NMR (300 MHz, CDCl 3): 169.5, 163.9, 160.0, 150.7, 144.1, 134.1, 131.9, 131.2, 128.4, 127.8, 126.9, 126.8, 121.5, 117.9, 112.1, 110.7, 92.0, 81.3, 55.9, 51.6, 26.5. HRMS (ESI +<): m / z calculated for C 21 H 19 N 2 O 2 [M+H] +< 331.1447; found 331.1441.

[0111] The compound 4-(1-(4-Methoxyphenyl)vinyl)quinoline-2-carbonitrile I-16 is prepared from 2,4-dichloroquinoline by first carrying out a selective cyanation reaction at the C2 position (Scheme 2). The 2-cyano-4-chloroquinoline thus formed with a yield of 83% is then coupled with the N-tosylhydrazone of 4-methoxyacetophenone.

[0112] Yellow oil, 62%, TLC: Rf 0.4 (Cyclohexane / EtOAc, 9 / 1). R (neat, cm -1<): 3062, 3004, 2958, 2934, 2838, 2236, 1675, 1605, 1576, 1545, 1511, 1459, 1218, 1153, 1098, 909. 1< H NMR (300 MHz, CDCl 3): 8.20 (d, 1H,J = 9.1 Hz), 7.91-7.78 (m, 2H), 7.65 (s, 1H), 7.61-7.50 (m, 1H), 7.18 (d, 2H, J = 9.0 Hz), 682 (d, 2H, J = 9.0 Hz), 6.01 (s, 1H), 5.36 (s, 1H), 3.79 (s, 3H). 13< C NMR (300 MHz, CDCl 3): 160.1, 150.8, 148.7, 144.3, 133.7, 131.7, 131.1, 130.4, 129.4, 127.9 (2C), 126.4, 123.8, 117.7, 116.6, 114.3 (2C), 55.4. HRMS (ESI +<): m / z calculated for C 19 H 14 N 2 O [M+H] +< 287.1184; found 287.1180. The compound 4-Chloro-2-(1-(4-methoxyphenyl)vinyl)quinoline I-17 is prepared from 2,4-dichloroquinoline)

[0113] Brown oil, 47%, TLC: Rf 0.5 (Cyclohexane / EtOAc, 9 / 1). IR (neat, cm -1<): 3400, 3063, 3001, 2956, 2933, 2907, 2836, 1939, 1652, 1607, 1440, 1245, 907, 846. 1< H NMR (300 MHz, CDCl 3): 8.25-8.17 (m, 2H), 7.81-7.75 (td, 1H, J = 6.9 Hz, J = 1.5 Hz), 7.69-7.61 (td, 1H, J = 6.9 Hz, J = 1.5 Hz), 7.50 (s, 1H), 7.30 (d, 2H, J= 9.0 Hz), 6.89 (d, 2H, J = 9.0 Hz), 6.04 (d, 1H, J = 1.3 Hz), 5.75 (d, 1H, J = 1.3 Hz), 3.79 (s, 3H). 13< C NMR (300 MHz, CDCl 3): 159.8, 159.1, 148.5, 147.9, 143.0, 132.0, 130.8, 130.0, 129.7 (2C), 127.6, 125.7, 124.0, 121.4, 118.7, 114.0 (2C), 55.5. HRMS (ESI +<): m / z calculated for C 18 H 15 ClNO [M+H] +< 296.0842; found 296.0842.

[0114] The compound 1-(1-(4-Methoxyphenyl)vinyl)-3-methylisoquinoline I-18 is prepared from 1-chloro-3-methylisoquinoline) White solid, 40%, M.P. = 66°C, TLC: Rf 0.42 (Cyclohexane / EtOAc, 3 / 7). IR (neat, cm -1< ): 2955, 2835, 1621, 1606, 1589, 1464, 1298, 1285, 1098, 879. 1< H NMR (300 MHz, CDCl 3 ): 7.82 (d, 1H, J = 9.0 Hz), 7.66 (d, 1H, J = 9.0 Hz), 7.51 (t, 1H, J = 9.0 Hz), 7.40 (s, 1H), 7.27 (t, 1H, J = 9.0 Hz), 7.16 (d, 2H, J = 9.1 Hz), 6.69 (d, 2H, J= 9.1 Hz), 5.94 (s, 1H), 5.31 (s, 1H), 3.69 (s, 3H), 2.65 (s, 3H). 13< C NMR (300 MHz, CDCl 3): 160.9, 159.4, 150.9, 146.6, 137.2, 132.5, 130.0, 127.8 (2C), 127.4, 126.2, 126.1, 125.4, 118.2, 115.4, 113.7 (2C), 55.2, 24.5. HRMS (ESI +<): m / z calculated for C 19 H 18 NO [M+H] +< 276.1388; found 276.1385. The compound 4-(1-(4-Methoxyphenyl)vinyl)-2-methylquinoline I-19 is prepared from 4-chloro-2-methylquinoline)

[0115] White solid, 65%, F = 94°C, TLC: Rf 0.24 (Cyclohexane / EtOAc, 8 / 2). IR (neat, cm -1<): 2961, 2929, 1734, 1651, 1607, 1560, 1440, 1409, 1378, 1097, 902, 836. 1< H NMR (300 MHz, CDCl 3): 8.04 (d, 1H, J = 8.2 Hz), 7.72 (d, 1H, J = 8.3 Hz), 7.62 (dd, 1H, J = 8.35, J = 6.92), 7.22 (t, 1H, J = 8.3 Hz), 7.18 (m, 3H), 6.80 (d, 2H, J= 8.0 Hz), 5.80 (s, 1H), 5.31 (s, 1H), 3.77 (s, 3H), 2.76 (s, 3H). 13< C NMR (300 MHz, CDCl 3): 158.5, 157.7, 147.7, 147.1, 144.5, 131.3, 128.2, 127.8, 126.7 (2C), 125.0, 124.5, 124.4, 121.3, 113.9, 112.8 (2C), 54.2, 24.3. HRMS (ESI +<): m / z calculated for C 19 H 18 NO [M+H] +< 276.1388; found 276.1388. General procedure for the synthesis of compounds II-1 to II-4

[0116] A solution of 1-quinazoline-1-arylethylenes ( I ) (1 mmol) in EtOAc (1 mL) is placed under atmospheric hydrogen pressure in the presence of Pd / C (20% by mass) and then stirred for 2 to 5 h. After filtration on Celite, the solvents are evaporated under vacuum, and the residue formed is chromatographed on a silica column.

[0117] 4-[1-(4-Methoxy-phenyl)-ethyl]-2-methyl-quinazoline II-1. Brown oil, 99%. TLC: RF 0.4 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1<): 2925, 1612, 1564, 1511, 1463, 1247, 1178. 1< H NMR (300 MHz, CDCl 3): 8.07 (d, 1H, J= 8.4 Hz), 7.91 (d, 1H, J = 8.4 Hz), 7.75-7.69 (m, 1H), 7.45-7.39 (m, 1H),7.24 (d, 2H, J = 8.7 Hz), 6.79 (d, 2H, J = 8.7 Hz), 4.95 (q, 1H, J = 6.9 Hz), 3.71 (s, 3H), 2.92 (s, 3H), 1.78 (d, 3H, J =6.9 Hz). 13< C NMR (75 MHz, CDCl 3 ): 172.4, 163.8, 158.2, 150.7, 136.5, 133.0, 128.6 (2C), 128.5, 126.4, 124.6, 121.4, 114.1 (2C), 55.2, 42.2, 26.8, 21.3. m / z MS (APCI +< ): 279 (M + H) +< .

[0118] 4-[1-(3,4-Dimethoxy-phenyl)-ethyl]-2-methyl-quinazoline II-2. Huile jaune, 97%. TLC: RF 0.2 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1563, 1514, 1491, 1418, 1328, 1262, 1140. 1< H NMR (300 MHz, CDCl 3 ): 8.10 (d, 1H, J = 8.2 Hz), 7.90 (d, 1H, J = 8.3 Hz), 7.75 (ddd, 1H, J =8.2 Hz, J = 6.9 Hz, J = 1.2 Hz), 7.45 (ddd, 1H, J = 8.2 Hz, J = 6.8 Hz, J = 1.1 Hz), 6.92 (d, 1H, J= 2.0 Hz), 6.86 (dd, 1H, J = 8.2 Hz, J = 2.0 Hz), 6.75 (d, 1H, J = 8.2 Hz), 4.94 (q, 1H, J = 6.9 Hz), 3.82 (s, 3H), 3.81 (s, 3H), 2.91 (s, 3H), 1.78 (d, 3H, J = 6.9 Hz). 13< C NMR (75 MHz, CDCl 3 ): 172.3, 163.8, 150.8, 149.1, 147.8, 137.0, 133.2, 128.6, 126.5, 124.7, 121.4, 119.8, 111.3, 111.0, 56.0, 55.9, 42.6, 26.9, 21.4. m / z MS (APCI +< ): 309 (M + H) +< .

[0119] 2-Methyl-4-[1-(3,4,5-trimethoxy-phenyl)-ethyl]-quinazoline II-3. Huile jaune, 97%. RF 0.2 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1587, 1564, 1492, 1461, 1420, 1328, 1238, 1122. 1< H NMR (300 MHz, CDCl 3 ): 8.1 (d, 1H, J = 8.2 Hz), 7.91 (d, 1H, J = 8.3 Hz), 7.76 (ddd, 1H, J = 8.2 Hz, J = 7.1 Hz, J = 1.3 Hz), 7.47 (ddd, 1H, J = 8.2 Hz, J = 7.0 Hz, J = 1.2 Hz), 6.58 (s, 2H), 4.91 (q, 1H, J= 6.9 Hz), 3.79 (s, 6H), 3.77 (s, 3H), 2.91 (s, 3H), 1.78 (d, 3H, J = 6.9 Hz). 13< C NMR (75 MHz, CDCl 3 ): 172.0, 163.8, 153.3 (2C), 150.8, 140.0, 136.8, 133.2, 128.6, 126.6, 124.6, 121.5, 105.0 (2C), 60.9, 56.2 (2C), 43.2, 26.8, 21.5. m / z MS (APCI +< ): 339 (M + H) +< .

[0120] 4-[1-(3,5-Dimethoxy-phenyl)-ethyl]-2-methyl-quinazoline II-4. Huile brune, 89%.Rf 0.3 (Cyclohexane / EtOAc, 7 / 3). IR (neat, cm -1< ): 1609, 1593, 1564, 1428, 1205, 1157. 1< H NMR (300 MHz, CDCl 3 ): 8.08 (d, 1H, J = 8.2 Hz), 7.90 (d, 1H, J = 8.4 Hz), 7.77-7.72 (ddd, 1H, J = 8.2 Hz, J = 6.9 Hz, J = 1.3 Hz), 7.44 (ddd, 1H, J = 8.3 Hz, J = 7.0 Hz, J = 1.0 Hz), 6.49 (d, 2H, J = 2.2 Hz), 6.27 (t, 1H, J = 2.2 Hz), 4.90 (q, 1H, J = 6.9 Hz), 3.73 (s, 6H), 2.91 (s, 3H), 1.78 (d, 3H, J =6.9 Hz). 13< C NMR (75 MHz, CDCl 3 ): 171.8, 163.8, 161.0 (2C), 150.7, 146.9, 133.2, 128.5, 126.6, 124.7, 121.6, 106.2 (2C), 98.0, 55.4 (2C), 43.4, 26.9, 21.1. m / z MS (APCI +< ): 309 (M + H) +< . Protocol for cytotoxicity.

[0121] U87, H1299, MDA-MB231 cells were cultured in Dulbecco minimal essential medium (DMEM) containing 4.5 g / L glucose and supplemented with 10% fetal bovine serum and 1% glutamine. K562 and HCT116 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% glutamine. All cell lines were maintained in culture at 37 °C in a humid atmosphere containing 5% CO 2 . Cells were seeded in 96-well culture plates at 5000 cells per well in 50 µL of culture medium. After 24 hours of culture, the molecule to be tested, dissolved in DMSO and diluted 1 / 1000 in the appropriate culture medium, is added to each well at a rate of 50 µL per well. After 72 hours of incubation, 20 µL of resazurin is added to each well.After 1 hour of incubation, the emitted fluorescence is measured at 590 nm after excitation at 560 nm using the Victor fluorescence reader (Perkin-Elmer, USA). Each concentration is tested three times and each experiment is repeated three times. Protocol for the inhibition of tubulin polymerization.

[0122] When tubulin is placed at a temperature of 0 °C, it is in the form of free dimers. On the other hand, when the temperature increases abruptly to 37 °C, the dimers assemble into microtubules. The determination of the IPT of the different synthesized analogs was carried out on soluble tubulin according to the Shelanski method 7< from sheep brains where it constitutes 20 to 25% of the soluble proteins. The "antitubulin" activity is evaluated according to the Gaskin method 8< by measuring the turbidity which is proportional to the concentration of microtubules in the suspension. The turbidity is measured by absorption of the suspension at 350 nm using a spectrophotometer equipped with a cell thermostated at 37 °C. The different samples were dissolved in DMSO and incubated for 10 minutes at 37 °C then 5 minutes at 0 °C.

[0123] Tubulin assembly and disassembly curves are obtained by kinetics of absorption at 350 nM as a function of time. The graphically determined Cl 50 is defined as the inhibitor concentration required to decrease the maximum assembly rate of the control tubulin by 50%. Biological study in vitro compounds I-16 and I-19 of the present invention

[0124] Their effects on the proliferation of different human cancer cell lines and their ability to inhibit tubulin polymerization were tested. A. Cytotoxic activity

[0125] The cytotoxic activity of the compounds was studied in vitro mainly on the human cancer cell line HCT116 (colorectal carcinoma).The cell line selected for this study was incubated at 37°C in the presence of one of the compounds added to the culture medium at different concentrations. The inhibitory concentration inducing 50% cell death (IC 50 ) was determined after 72 hours of incubation (Table 1) for each compound. All the experiments carried out made it possible to determine the degree of toxicity of the compounds tested, taking isoCA-4 as a reference. In view of the results, it appears that several compounds have IC 50 at a nanomolar level and that the compounds I-5, I-6, I-7, 1-15, I-16, 1-19 are the most cytotoxic with Cl 50 values ​​lower than 20 nM. It should be noted that the first structure-activity relationships are in perfect agreement with the previous results observed in isoCA-4 and isoerianine series, namely that the most effective B rings are substituted at C-4 by an OMe group and at C-3 by a fluorine atom ( I-5 ), an OH group ( I-6 ) or NH 2 (I-7 ). Furthermore, by comparing the results obtained with cytotoxic compounds I-1 And I-10 , it appears that the quinazoline nucleus can be substituted at C-2 by a methyl group or by a chlorine atom without loss of effectiveness ( I-1 And I-10 : Cl 50 = 40 nM). Finally, when we examine these first results, it appears that the reduction of the double bond located between the two aromatic nuclei leads to “reduced” derivatives of the type II approximately ten times less cytotoxic than their precursors I as we had already observed during the reduction of the derivatives iso CA-4 into isoerianine-type derivatives. The molecule I-15 shows that the introduction of an acetylenic carbon substituent at C3' significantly improves cytotoxic activity compared to I-1.Furthermore, the replacement of the quinazoline nucleus by other heterocycles made it possible to identify molecules showing better cytotoxic activities at sub-nanomolar concentrations. Table 1 HCT116 (colorectal carcinoma). : Cytotoxicity results of the compounds on the human cancer cell line The cytotoxic activity (Cl 50 ) is expressed in nMol / L and corresponds to the concentration of the compounds which induces 50% cell mortality after 72 h of incubation. Compounds HCT116 Cl 50 (nM) Compounds HCT116 Cl 50 (nM) I-1 38 I-2 460 I-3 2300 I-4 52 I-5 18 I-6 10 I-7 10 I-8 130 I-9 27 I-10 34 I-11 700 I-12 900 II.1 250 II-2 950 I-15 1,5 I-16 1,6 I-17 95 I-18 87 I-19 ≤1 iso CA-4 2

[0126] The compounds I-1 And I-10 carrying a methyl substituent and a chlorine atom at C-2 and which presented equivalent levels of cytotoxicity (Cl 50 = 40 nM) against the HCT116 cell line were also evaluated on a chronic myeloid leukemia line K562 and on a non-small cell lung cancer line H1299. The compounds I-15, I-16 and I-19were also evaluated on a K562 chronic myeloid leukemia line and on an imatinib-resistant K562R chronic myeloid leukemia line. The first cytotoxicity results are reported in Table 2 below. Table 2: I-1 I-10 HCT116 K562 H1299 Cytotoxicity results of the compounds and on 3 human cancer cell lines (colorectal carcinoma), (chronic myeloid leukemia) and (non-small cell lung cancer). The cytotoxic activity (Cl 50 ) is expressed in nMol / L and corresponds to the concentration of the compounds which induces 50% cell mortality after 72 h of incubation. Compounds HCT116 Cl 50 (nM) K562 Cl 50 (nM) K562R Cl 50 (nM) H1299 Cl 50 (nM) I-1 38 34 n / A 22 I-10 34 38 n / A 25 I-15 1,5 8 ≤ 1 n / A I-16 1,6 9 ≤ 1 n / A I-19 ≤ 1 17 0,7 n / A iso CA-4 2 4 5

[0127] The results indicate that the cytotoxicity of I-1 And I-10 with respect to the K562 and H1299 lines is similar to that observed with the HCT116 line (Cl 50 between 22 and 38 nM).

[0128] Replacement of the quinazoline nucleus (I-1) with a quinoline nucleus provided the compound 1-19 possessing sub-nanomolar cytotoxic activities. It is noteworthy that the replacement of the methyl group at C2 of the compound 1-19 by a cyano group (1-16)has no influence on cytotoxic activity. B Inhibition of tubulin polymerization

[0129] The most cytotoxic compounds were selected for tubulin polymerization inhibition tests. These tests were carried out under the direction of Dr. J. Dubois in Gif sur Yvette. Tubulin is purified from sheep brains according to the Shelanski method 9< by 2 assembly-disassembly cycles. The stock solution (15-20 mg / mL), stored at -196 °C, is thawed and diluted in the assembly buffer (0.1 M MES, 0.5 mM MgCl 2 , 1 mM EGTA, and 1 mM GTP, pH 6.6) to have a final concentration of 10 µM. Tubulin assembly is monitored by fluorescence on 96-well plates according to the Barron method Andal. 10< To the tubulin solution (10 µM, 100 µL per well) is added the inhibitor (DMSO, 1 µL) and the solution is incubated for 45 min at room temperature. GTP (1 mM final) is then added, the solution is mixed quickly and the fluorescence (λ ex = 350 nm, λ em = 440 nm) is measured on a Wallac Victor fluorimeter (Perkin Elmer). The determination of the 50% inhibition of the maximum assembly rate (Cl 50 ) is carried out in duplicate or triplicate on 10 concentrations surrounding the Cl 50 . The results are reported in Table 3. Table 3: I Results of inhibition of tubulin polymerization (IPT) by selected compounds Compounds IPT (Cl 50 ) µM Compounds IPT (Cl 50 ) µM I-1 1,8 I-4 2,9 I-5 1,0 I-6 0,6 I-7 2,3 I-8 2,2 I-9 1,6 I-10 1,9 I-15 1,2 I-16 0,96 I-19 1,09 iso CA-4 1,0 CA-4 1,0

[0130] It can be noted that all the selected compounds inhibit tubulin polymerization at micromolar concentrations (0.6 µM <CI 50 <2.9 µM). En particulier, le composé I-6which was found to be highly cytotoxic to the HCT116 line, inhibits tubulin assembly with a submicromolar IC 50 (IC 50 = 0.6 µM).

[0131] The molecule I-15 shows that the introduction of an acetylenic carbon substituent at C3' significantly improves ITP activity compared to I-1. Furthermore, the replacement of the quinazoline nucleus by other heterocycles made it possible to identify molecules showing a capacity to inhibit tubulin polymerization at sub-micromolar concentrations. REFERENCES

[0132] 1. G.R. Pettit et al J. Nat. Prod. 1987, 50, 119. 2. Mc Gown et al Cancer Chemother. Pharmacol. 1990, 26, 79. 3. G. G. Dark et al Cancer Res. 1997, 57, 1829. 4. (a) S. Messaoudi et al J. Med. Chem. 2009, 52, 4538. (b) M. Alami et al WO 2008 / 122620 (c) A. Hamze et al ChemMedChem. 2009, 4, 1912. 5. M. Soussi et al ChemMedChem, 2011, 6, 1781. 6. M. Alami et al WO 2009 / 147217. 7. Shelanski, M.C.; Gaskin, F.; Cantor, C.R. Proc. Natl. Acad. Sci. USA, 1973, 70, 765-768. 8. Gaskin, F.; Cantor, C.R.; Shelanski, M. C. J. Biol. Mol., 1974, 89, 737-755. 9. Shelanski, M. L.; Gaskin, F.; Cantor, C. R. Proc. Natl. Acad. Sci. USA, 1973, 70, 765-768. 10. Barron, D. M.; Chatterjee, S. K.; Ravindra, R.; Roof, R.; Baloglu, E.; Kingston, D. G. I.; Bane, S. Anal. Biochem. 2003, 315 49-56.

Claims

1. Compound of the following formula (Ib) : wherein : - A, B, E, Y and Z represent a carbon atom, - n is equal to 1, - X represents a nitrogen atom; - R4, R5, R6 and R7 represent, independently of each other : - a hydrogen atom ; - a halogen atom ; - a hydroxyl group ; - an alkyl group with C1 to C6; - an alkenyl group with C2 to C4 ; - an alkynyl group with C2 to C4; - an alkoxy group with C1 to C6; or - an -NR'R" group with R' and R" representing, independently of each other, a hydrogen or an alkyl group with C1 to C6; - the dotted bond is present; - R2 represents : - a hydrogen atom ; - a halogen atom ; - a hydroxyl group ; - a cyano group ; - a -COYR' group with Y designating O or N and R' designating H or an alkyl group with C1 to C6, an alkenyl group with C2 to C4, an alkynyl group with C2 to C4; - an -SO2NR'R" group where R' and R", each designating , independently of each other, H or an alkyl group with C1 to C6, an alkenyl group C2 to C4, an alkynyl group C2 to C4; - an -NHSO2R' group with R' designating an alkyl group with C1 to C6, an alkenyl group with C2 to C4, an alkynyl group with C2 to C4, an aryl group, a heteroaryl group; - an alkyl group with C1 to C6; - an alkenyl group with C2 to C4; - an alkynyl group with C2 to C4; - an alkoxy group with C1 to C6; or - an -NR'R" group with R' and R" representing, independently of each other, a hydrogen or an alkyl group; - Z1 and Z2 represent, independently of each other, a hydrogen atom, a halogen atom or a methyl group; - (Het)Aryl represents an aryl or heteroaryl group, said heteroaryl being chosen from the indolyl, benzothiophenyl and benzofuranyl groups, said aryl or heteroaryl may be substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, -OMe, -SMe, -OCX3 with X designating a halogen atom, -NH2, with R designating an alkyl group with C1 to C6, with m designating 1 or 2, with m designating 1 or 2 or as well as the pharmaceutically acceptable salts thereof, the stereoisomers thereof and the prodrugs thereof resulting from the acylation or phosphorylation of a hydroxy or amino group.

2. Compound according to one of the preceding claims wherein (Het)Aryl designates a phenyl group which may be substituted by one or more substituents chosen from a halogen atom, a hydroxyl group, -OMe, -SMe, -OCX3 with X designating a halogen atom, - NH2, with R designating an alkyl group with C1 to C6, with m representing 1 or 2, with m representing 1 or 2 or 3. Compound according to claim 2 wherein the phenyl group has the following formula : wherein : - R8 represents a hydrogen atom, a halogen atom, a hydroxyl, -OMe, -SMe, -NH2, with R designating an alkyl group with C1 to C6, with m representing 1 or 2, with m representing 1 or 2 or and - Rg represents an alkoxy group with C1, -SMe or -OCX3, with X designating a halogen atom.

4. Compound according to claim 1, having the following formula (Ic) wherein : - n, A, B, E, X, Y, Z, R4, R5, R6, R7 are as defined in claim 1; - the dotted bond is present; - R2 represents : - a hydrogen atom ; - a halogen atom; - a hydroxyl group ; - a cyano group ; - a -COYR' group with Y designating O or N and R' designating H or an alkyl group with C1 to C6, an alkenyl group C2 to C4 or an alkynyl group with C2 to C4; - an -SO2NR'R" group with R' and R", each representing, independently of each other, H or an alkyl group with C1 to C6, an alkenyl group with C2 to C4, an alkynyl group with C2 to C4; - an -NHSO2R' group with R' designating an alkyl group with C1 to C6, an alkenyl group with C2 to C4, an alkynyl group with C2 to C4, an aryl group, a heteroaryl group; - an alkyl group with C1 to C6; - an alkenyl group with C2 to C4; - an alkynyl group with C2 to C4; - an alkoxy group with C1 to C6; or - an -NR'R" group with R' and R" representing, independently of each other, a hydrogen or an alkyl group; - Z1 and Z2 represent independently of each other a hydrogen atom, a halogen atom or a methyl group; - R8 represents a halogen atom, a hydroxyl, -OMe, -SMe, -NH2, with R designating an alkyl group with C1 to C6, with m representing 1 or 2, with m representing 1 or 2 or and - R9 represents OMe, -SMe, -OCX3 with X designating a halogen atom; as well as the pharmaceutically acceptable salts thereof, the stereoisomers thereof and the prodrugs thereof resulting from the acylation or phosphorylation of a hydroxy or amino group.

5. Compound according to claim 1, having the following formula : wherein : - Z1, Z2, and R2 are as defined in claim 1, R8 and R9 are as defined in claim 3 - the dotted bound is present.

6. Compound according to one of the preceding claims, characterized in that Rg represents an -OMe, -SMe or -OCX3 group with X designating a halogen atom.

7. Compound according to one of the preceding claims, characterized in that R8 represents a hydrogen atom, a halogen atom, a hydroxyl group or an -NH2 group.

8. Compound according to one of the preceding claims wherein Z1 and Z2 represent a hydrogen atom or wherein Z1 and Z2 represent a fluorine atom.

9. A compound according to one of the preceding claims represented by the formula : as well as the pharmaceutically acceptable salts thereof, the stereoisomers thereof.

10. Compound, as well as the pharmaceutically acceptable salts thereof, the stereoisomers thereof and the prodrugs thereof resulting from the acylation or phosphorylation of a hydroxy or amino group, according to any one of claims 1 to 9 for its use as a medicine.

11. Conjugate comprising a compound according to any one of claims 1 to 9 covalently bonded to an antibody.

12. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9 or a conjugate according to claim 11.

13. Pharmaceutical composition comprising : (i) at least one compound according to any one of claims 1 to 9 and (ii) at least one other active ingredient, as a combination product for simultaneous, separate or staggered use.

14. Method for preparing a compound according to any one of claims 1 to 9 comprising the following successive steps: a) reaction of a compound of formula (II) with tosylhydrazine to give the tosylhydrazone compound of formula (III) b) coupling of the compound of formula (III) with the compound of formula (V) in which R2, R4, R5, R6, R7, X, Y, Z, A, B, E and n are as defined in any one of claims 1 to 9 and X1 represents a halogen atom or trifluoromethanesulfonate; c) separation of the reaction medium from the compound according to any one of claims 1 to 9 obtained as a result of step b).