FR2941949A1 - DERIVATIVES OF 6- (6-O-CYCLOALKYL OR 6-NH-CYCLOALKYL-TRIAZOLOPYRIDAZINE-SULFANYL) BENZOTHIAZOLES AND BENZIMIDAZOLES PREPARATION, APPLICATION AS MEDICAMENTS AND USE AS INHIBITORS OF MET. - Google Patents

Abstract

The invention relates to new products of formula (I): in which represents a single or double bond; Ra represents -O-cycloalkyl or -NH-cycloalkyl; X is S, SO or SO; A represents NH or S; W is H, alkyl or COR with R is cycloalkyl; alkyl; alkoxy; O-phenyl; -O- (CH 2) n-phenyl with n = 1 to 4; or NR1R2 with R1 is H or alk and R2 is H, cycloalkyl or alkyl; or R1, R2 together with N form a ring optionally containing O, S, N and / or NH; all these radicals being optionally substituted; these products being in all isomeric forms and salts, as medicaments especially as MET inhibitors.

Description

1

FIELD OF 6- (6-O-CYCLOALKYL or 6-NH-CYCLOALKYL-TRIAZOLOPYRIDAZINE-SULFANYL) BENZOTHIAZOLES AND BENZIMIDAZOLES: PREPARATION, APPLICATION AS MEDICAMENTS AND USE AS MET INHIBITORS The present invention relates to novel 6-O-cycloalkyl derivatives or 6-NH-cycloalkyl-triazolopyridazine-sulfanyl benzothiazole and benzimidazole, process for their preparation, the novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such derivatives of 6-triazolopyridazinesulfanyl benzothiazole and benzimidazole.

The present invention relates more particularly to novel 6-O-cycloalkyl or 6'NH-cycloalkyl-triazolopyridazin-sulfanyl benzothiazole and benzimidazole derivatives, exhibiting anticancer activity, via modulation of the activity of proteins, in particular kinases. To date, most of the commercial compounds used in chemotherapy are cytotoxic drugs that pose significant problems of side effects and tolerance by patients. These effects could be limited insofar as the drugs used act selectively on cancer cells, excluding healthy cells. One of the solutions to limit the undesirable effects of chemotherapy may therefore consist in the use of drugs acting on metabolic pathways or constitutive elements of these pathways, mainly expressed in cancer cells, and which would not be or only rarely expressed in healthy cells. Protein kinase is a family of enzymes that catalyze the phosphorylation of hydroxy groups of protein-specific residues such as tyrosine, serine or threonine residues. Such phosphorylations can greatly alter the function of proteins: thus, protein kinases play an important role in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell adhesion and motility, Cell differentiation or cell survival, with some protein kinases playing a central role in the initiation, development, and completion of cell cycle events.

Among the various cellular functions in which the activity of a protein kinase is involved, some processes represent attractive targets for treating certain diseases. Examples include angiogenesis and cell cycle control as well as cell proliferation, in which protein kinases can play a critical role. These processes are particularly essential for the growth of solid tumors as well as other diseases: in particular inhibitory molecules of such kinases are able to limit unwanted cell proliferations such as those observed in cancers, and can intervene in the prevention, control and treatment of cancer. regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or neuronal apoptosis. The present invention relates to novel derivatives with inhibitory effects vis-à-vis protein kinases. The products according to the present invention can thus notably be used for the prevention or the treatment of diseases that can be modulated by the inhibition of protein kinases. The products according to the present invention exhibit in particular an anticancer activity, via the modulation of the activity of kinases. Of the kinases for which modulation of activity is desired, MET as well as MET protein mutants are preferred. The present invention also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans.

Thus, one of the objects of the present invention is to provide compositions having an anticancer activity, acting in particular vis-à-vis kinases. Of the kinases for which modulation of activity is desired, MET is preferred.

In the pharmacological part below, it is shown in biochemical tests and on cell lines that the products of the present application thus inhibit, in particular, the autophosphorylation activity of MET and the proliferation of cells whose growth depends on MET. or its mutant forms.

MET, or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine kinase activity expressed in particular by epithelial and endothelial cells. HGF, Hepatocyte Growth Factor, is described as the specific ligand of MET. HGF is secreted by the mesenchymal cells and activates the MET receptor that moderates. As a consequence, the receptor autophosphorylates on tyrosines of catalytic domain Y1230, Y1234 and Y1235. MET stimulation by HGF induces proliferation, scattering (or dispersion), cell motility, resistance to apoptosis, invasion and angiogenesis.

MET, like HGF, are found to be overexpressed in many human tumors and a wide variety of cancers. MET is also found amplified in gastric tumors and glioblastomas. Numerous point mutations of the MET gene have also been described in tumors, in particular in the kinase domain, but also in the juxtamembrane domain and the SEMA domain. Overexpression, amplification or mutations cause constitutive activation of the receptor and deregulation of its functions.

The present invention thus relates in particular to new inhibitors of the MET protein kinase and its mutants, which can be used for anti-proliferative and anti-metastatic treatment, especially in oncology. The present invention also relates to novel inhibitors of the MET protein kinase and mutants thereof, which can be used for anti-angiogenic treatment, particularly in oncology. The subject of the present invention is the products of formula (I): embedded image in which represents a single or double bond; Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl all optionally substituted; X represents S, SO or SO2; A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the COR radical in which R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR 1 R 2 in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted or else R3 and R4 form with the nitrogen atom to which they are linked a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5 radicals and radicals; alkyl, cycloalkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in the latter radicals the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2, all the radicals defined above cycloalkyl, heterocycloalkyl radical; HOMED and wherein phenyl and phenyl are further optionally substituted with an Si (alk) 3 radical; R5 and R5 ', which may be identical or different, represent an alkyl or cycloalkyl radical containing at most 6 carbon atoms; alk represents an alkyl radical containing at most 4 carbon atoms; it being understood that W does not represent H when A represents S, X represents S, Ra represents the 0-cyclohexyl radical or the unsubstituted NH-cyclohexyl radical and represents a double bond, said products of formula (I) being in all forms racemic isomers, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or hereinafter in which represents a single or double bond; Ra represents an optionally substituted -O-cycloalkyl radical or -NH-cycloalkyl radical; X represents S, SO or SO2; A represents NH or S; W represents a hydrogen atom, an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the COR radical in which R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl themselves optionally substituted; an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR 1 R 2 in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals, or R1 and R2 form with the nitrogen atom to which they are bonded; a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or else R3 and R4 form with the nitrogen atom to which they are bonded a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, NH2, NHalk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2- radicals; phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that, in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; hydroxyl, oxo, alkyl and alkoxy having 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2; R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or below, in which Ra and X have the values defined in any one of the other claims and A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: a cycloalkyl radical or an alkyl radical optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl or heterocycloalkyl themselves optionally substituted; an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR1R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and, if appropriate, one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl and heteroaryl radicals, such as in the latter radicals, alkyl radicals; , heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N (alk) 2 ; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which Ra and X have the values defined in any one of the other claims and A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted by a heterocycloalkyl radical or NR3R4; or the COR radical in which R represents: a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4 or alkoxy radical; a 0-phenyl or O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 2; or the radical NR1R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, an alkyl radical optionally substituted with a heterocyclic radical or NR3R4, or else R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 radicals and alkyl and phenyl radicals, the latter being themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals of 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below in which A represents NH, the substituents Ra, X and W being chosen from among all the values defined for these radicals in one any of the other claims, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula ( I). The subject of the present invention is the products of formula (I) as defined above or below, in which A represents S, the substituents Ra, X and W being chosen from among all the values defined for these radicals in one any of the other claims, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula ( I). The subject of the present invention is the products of formula (I) as defined above or hereafter corresponding to formula (Ia) or (Ib): ## STR1 ## in which Ra and W are chosen from the meaning indicated in any of the other claims, said products of formula (Ia) and (Ib) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (Ia) and (Ib). The subject of the present invention is the products of formula (I) as defined above or below, in which represents a single bond corresponding to the products of formula (I '): ## STR5 ## the substituents Ra, X, A and W having the meanings indicated in any one of the other claims, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral and organic acids or with inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or below, in which represents a double bond corresponding to the products of formula (I "): Ra in which the substituents Ra, X, A and W have the meanings indicated in any one of the other claims, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the The present invention relates to the products of formula (I) as defined above or below, in which represents a single bond corresponding to the products of formula (I '). Ra in which Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (a) being in any isomeric form possible racemates, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (a).

The present invention relates to the products of formula (I) as defined above or below in which represents a double bond corresponding to the products of formula (I "a): Ra in which Ra and W are chosen from meanings indicated in any one of the other claims, said products of formula (I "a) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids or with bases The present invention relates to the products of formula (I) as defined above or below in which represents a single bond corresponding to the products of formula (I '). b): (Pb) Ra in which Ra and W are chosen from the meanings indicated in any one of the other claims, said products of formula (b) being in any isomeric form poss Racemic, enantiomeric and diastereoisomeric targets, as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (b).

The subject of the present invention is the products of formula (I) as defined above or below, in which represents a double bond corresponding to the products of formula (I "b): Tb) Ra in which Ra and W are chosen among the meanings indicated in any one of the other claims, said products of formula (I "b) being in all isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I "b) In the products of formula (I) and in the following: the term alkyl radical (or Alk) denotes the radicals, linear and, where appropriate, branched, methyl ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl and their linear or branched positional isomers: preferred are alkyl radicals containing from 1 to 6 carbon atoms and more particularly alkyl radicals containing from 1 to 4 carbon atoms of the above list; the term "alkoxy radical" denotes the linear and, if appropriate, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy radicals, as well as their linear or branched positional isomers; alkoxy radicals containing from 1 to 4 carbon atoms from the above list; the term "halogen atom" denotes the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom. the term "cycloalkyl radical" denotes a saturated carbocyclic radical containing 3 to 10 carbon atoms and thus particularly denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, and especially the cyclopropyl, cyclopentyl and cyclohexyl radicals; the term "heterocycloalkyl radical" thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms; for example, morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxodihydropyridazinyl radicals, or alternatively oxetanyl or thietanyl radicals, these radicals being optionally substituted; the terms aryl and heteroaryl denote unsaturated or partially unsaturated, respectively carbocyclic and heterocyclic, monocyclic or bicyclic radicals, containing at most 12 members, possibly containing a -C (O) - linkage, heterocyclic radicals containing one or more identical or different heteroatoms; selected from O, N, or S with N, if appropriate, optionally substituted; the term "aryl radical" thus denotes monocyclic or bicyclic radicals containing 6 to 12 members, such as, for example, the phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly the phenyl and naphthyl radicals and even more particularly the phenyl radical. It may be noted that a carbocyclic radical containing a C (O) linkage is, for example, the tetralone radical; the term "heteroaryl radical" thus denotes monocyclic or bicyclic radicals containing 5 to 12 members: monocyclic heteroaryl radicals such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3-furyl, pyrannyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazolyl, all these radicals being optionally substituted, among which more particularly the thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals such as, for example, benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl; azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or oxodihydropyridino pyrazolyl, all of these radicals being optionally substituted; As examples of heteroaryl or bicyclic radicals, there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl radicals, optionally substituted by one or more identical or different substituents as indicated above.

The carboxyl group (s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example: - among salification compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine among the esterification compounds, the alkyl radicals to form alkoxycarbonyl groups, such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being substitutable; by radicals chosen from, for example, halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl groups; or phenethyl.

The addition salts with the mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as, for example, methanesulfonic acid, ethanesulphonic acid, propanesulphonic acid, alkylsulphonic acids such as, for example, methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulphonic acid and aryldisulphonic acids.

It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or cis-trans isomerism. The term stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above. The cyclic radicals that can be formed on the one hand R 1 and R 2 with the nitrogen atom to which they are bonded and on the other hand R 3 and R 4 with the nitrogen atom to which they are bonded, are optionally substituted with one or several radicals chosen from those indicated above for the possible substituents of heterocycloalkyl radicals, ie one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy and NH 2 radicals; NHalk, N (alk) 2, and the radicals alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, and CO-phenyl, such that in these latter radicals the alkyl, heterocycloalkyl and phenyl radicals are themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals having 1 to 4 carbon atoms, NH 2; NHalk and N (alk) 2, the cyclic radicals that can form on the one hand R1 and R2 with the nitrogen atom to which they are attached and on the other hand R3 and R4 with the nitrogen atom to which they are linked, are in particular optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, CH 2 -pyrrolidinyl, CH 2 -phenyl, heteroaryl and phenyl radicals, in which the alkyl and pyrrolidinyl radicals are used. and phenyl are themselves optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl, oxo and alkoxy radicals.

The heterocycloalkyl radicals as defined above represent, in particular, the azepanyl, morpholinyl and pyrrolidinyl, piperidyl and piperazinyl radicals themselves, optionally substituted, as defined above or hereinafter. When NR1R2 or NR3R4 forms a ring as defined above, such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl or piperazinyl radicals, these radicals themselves being optionally substituted as indicated hereinabove. above or below: for example by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and CH 2 -phenyl radicals, the alkyl or phenyl radicals being themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals. The NR 1 R 2 or NR 3 R 4 ring may more particularly be chosen from pyrrolidinyl and morpholinyl radicals optionally substituted by one or two alkyl or piperazinyl radicals optionally substituted on the second nitrogen atom by an alkyl, phenyl or or CH 2 -phenyl radical, themselves same optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals. The subject of the present invention is the products of formula (I) as defined above or below in which represents a single or double bond. Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl optionally substituted with a hydroxyl, alkoxy or -O-CO-R5 radical; X is S; A represents S; W represents a hydrogen atom or an alkyl radical optionally substituted by heterocycloalkyl or the COR radical in which R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted by an NR3R4 radical, or alkoxy; a 0-phenyl radical; or the NR 1 R 2 radical in which R 1 and R 2 are such that one represents a hydrogen atom and the other represents an alkyl radical optionally substituted with a heterocycloalkyl radical; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical; R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). In particular in the products of formula (I), the cycloalkyl radicals may represent a cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl radical; Especially in the products of formula (I), the heterocycloalkyl radicals may represent a morpholinyl or pyrrolidinyl radical. The present invention thus relates to the products of formula (I) as defined above or below having the following formulas: N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [ 4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4, 3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- ( cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl)) 1- [6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) ethyl] urea N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl [3- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide; N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3] -3-benzothiazol-2-yl) -3- [2- (pyrrolidin-1-yl) ethyl] urea b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cy N- [6 - ({6 - [(trans-4-Hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-clopropanecarboxamide N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl] cyclopropanecarboxamide yl) 1- (6 - {[6- (Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} 1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said formula (I).

The subject of the present invention is also any process for the preparation of the products of formula (I) as defined above. The subject of the present invention is thus any process for the preparation of the products of formula (I) as defined above in which A represents NH. The subject of the present invention is thus any process for the preparation of the products of formula (I) as defined above in which A represents S. The products according to the invention can be prepared from conventional methods of organic chemistry. Schemes 1, 2, 3, 4, 5 and 6 below are illustrative of the methods used for the preparation of the products of formula (I). As such, it can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds. The products of formula (I) as defined above according to the present invention can thus be prepared in particular according to the processes described in Schemes 1, 2, 3, 4, 5 and 6 below. The present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 1 as defined below. The present invention thus also relates to the process for preparing products of formula (I) according to Scheme 2 as defined below.

The subject of the present invention is therefore also the process for preparing products of formula (I) according to Scheme 3 as defined below. The subject of the present invention is therefore also the process for the preparation of products of formula (I) according to The present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 5 as defined below. The subject of the present invention is therefore also the process for the preparation of products of formula (I) according to scheme 6 as defined below

Similarly, among the products of formula (I) as defined above in which represents a single or double bond, the products of formula (I ') which represent the products of formula (I) in which a single bond and the products of formula (I ") which represent the products of formula (I) in which represents a double bond, and for the synthesis intermediates as defined below of formulas (a), (b) (c), (d), (e) and (f) wherein represents a single or double bond, the compounds of formulas (a '), (b'), (c '), (d') are defined , (e ') and (f') wherein represents a single bond, and compounds of formulas (a "), (b"), (c "), (d"), (e ") and (f" Figure 1: Syntheses of Benzimidazole Derivatives of Formulas (1a "), (Ib"), (1 "c), (1d"), (Ie "), (Ia), (Ib) (1c '), (ld') and (le ') 15 NH S1-NH2 reduction HS NH2 NO2 NO2 QF HS, NH, N-CO, R, MeS- <' N- CO, R, H

(.) NR a H '/ H "R Nci 1 according to Scheme 3 S commercial Ra ER, HN (R) R, R6000X (O) CI NO, (F) In Scheme 1 above, the substituent Ra can to take the meanings indicated above for the products of formula (I ') and (I "), the substituent R5, in the compounds of formulas (J), (1 a') and (la"), represents an alkyl radical and the substituent R 6 in the compounds of formulas (O), (1d ') and (1d ") represents an alkyl radical optionally substituted with NR 3 R 4 (a radical - (CH 2) n -NR 3 R 4), alkoxy, hydroxy, heterocycloalkyl, phenyl, - (CH 2) nphenyl, with optionally substituted phenyl and n represents an integer of 1 to 4. The substituent R 7 in the compounds of formulas (P) and (1e) / (1e ") represents a cycloalkyl or optionally alkyl radical substituted by an NR 3 R 4, alkoxy, hydroxy phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted, In Scheme 1 above, the groups CONR 1 R 2, CO 2 R 6 and COR 7 which constitute W may take the values of W as defined above for the products of formula (I ') and (I "), when W # H In the above scheme 1, the benzimidazoles of general formula (the ), (1b "), (1c"), (1d ") and (le") as well as their reduced analogues of the general formula (la '), (Ib'), (lc '), (ld') and ( 1 ') can be prepared from commercial 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine of formula (S). The compounds (E) can be obtained, for example, by reacting alcohols or amines in the presence or absence of a base on the compound (S). The reaction is carried out, for example, at a temperature in the region of 20 ° C to 80 ° C. Compounds (G) can be obtained, for example, by reaction of 3-amino-4-nitro-benzenethiol of formula (F) with compounds of formula (E). The compounds of formula (F) are obtained by in situ reduction of 3-amino-4-nitrophenyl thiocyanate (Q) (commercial compound), for example, in the presence of sodium borohydride in a solvent such as N, N- dimethylformamide, at a temperature of 20 ° C.

The compounds (H ") as represented by a double bond can be obtained, for example, by reduction with iron (O) on the compounds of formula (G), in a solvent such as methanol, in the presence of acetic acid, at a temperature in the region of 70 ° C. The compounds (H ') as represented by a single bond may be obtained, for example, by reduction with zinc (0) on the compounds of formula (G), in the presence of acid. at a temperature in the region of 20 ° C. More particularly, the carbamates of general formula (1 a ') and (la ") can be prepared in particular as described in patent WO03028721A2, respectively from a diamino phenyl sulfide of formula (H ') and (H ") and a pseudothiourea of formula (J), in the presence of acetic acid and in a protic solvent such as methanol, at a temperature of 80 ° C. More particularly, the benzimidazoles of the general formula (1b ') and (Ib ") can be prepared respectively by reaction of an amine NHR1 R2 of formula (R) (with R1 and R2 as defined above) on a carbamate of formula (la ') and (la "), for example in the presence of an aprotic solvent such as 1-methyl-2-pyrrolidinone. The reaction is carried out, for example, a temperature close to 120 ° C., in a tube sealed under microwaves. More particularly, the 2-amino benzimidazoles of general formula (1c and (1c ") can be prepared, for example, by reaction of cyanogen bromide with a compound of formula (H ') and (H"), respectively, in 27H. "IH" presence of a protic solvent such as ethanol The reaction is carried out at a temperature of about 80 ° C. More particularly, the general carbamates of formula (1d ') and (1d ") can be obtained by reaction with a chlorocarbonate of formula (O) (X = Cl) on a compound of general formula respectively (1c ') and (1c "), for example in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature in the region of 20 ° C. More particularly, the carboxamides (1 ') and (1 ") can be obtained respectively from the amines of general formula (1c') and (1c") - by reaction of the amines (1c ') and (1c ") with an acid chloride of formula (P) (X = Cl), in the presence, for example, of a solvent such as pyridine, at a temperature of 20 ° C. by reacting the amines (1c ') and (1c ") with an acid anhydride of formula (P) (X = OCOR7), in the presence, for example, of a solvent such as pyridine at a temperature in the vicinity of 20 ° C - by coupling the amines (1c ') and (1c ") with an acid of formula (P) (X = OH) under the conditions, for example, described by DD. DESMARTEAU; V. Montanari (Chem Lett, 2000 (9), 1052), in the presence of 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as triethylamine, at temperature close to 40 ° C. Scheme 2: Synthesis of Benzothiazole Derivatives of Formulas (2a '), (2b'), (2c '), (2d'), (2a) ', (2b'), (2c '), (2d') /% N Ri reduction N L2 O R2 NHR, R2

(R) reduction NC, S to R6 i 2 HS NC S HS N R E HS R E MI NC S NC, S z reduction reduction R, COX (P) N CI In scheme 2 above, the substituent Ra can take the meanings given above for the products of formula (I ') and (I ").

In scheme 2 above, the groups CONR1 R2, CO2R6 and COR7, which constitute W, can take the values of W as defined above for the products of formula (I ') and (I "), when W #H In the above scheme 2, benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a '), (2b') ), (2c ') and (2d') can be prepared from 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) (commercial compound). general formula (L1) can be obtained, for example, by reaction with a chlorocarbonate of formula (O) (X = Cl) on 2-amino-1,3-benzothiazol-6-yl thiocyanate (K), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature in the region of 20 ° C. The compounds of general formula (L2) can be obtained, for example, by reaction of carbamates of formula (L1) where R6 = phenyl, with d NHR 1 R 2 amines of formula (R) (with R 1 and R 2 as defined above), in the presence of an aprotic solvent such as tetrahydrofuran, at a temperature in the region of 20 ° C. The ureas (2b ') and (2b ") can be obtained, for example, respectively from the carbamates (2a') and (2a") where R6 = phenyl, in the same way that the ureas (L2) are obtained by reaction of amines on carbamates of type (L1). The compounds of general formula (L3) can be obtained for example: by reaction of an acid chloride of formula (P) (X = Cl) with 2-amino-1,3-benzothiazol-6 thiocyanate yle (K), in the presence, for example, of a solvent such as pyridine, at a temperature of 20 ° C. by reacting an acid anhydride of formula (P) (X = OCOR7) with 2-amino-1,3-benzothiazol-6-yl thiocyanate (K), in the presence, for example, of a solvent such as pyridine at a temperature of 20 ° C. by coupling of 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) with an acid of formula (P) (X = OH) under the conditions, for example, described by D.D. DESMARTEAU; V. Montanari (Chem Lett, 2000 (9) 1052), in the presence of NC-L3 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as triethylamine, at temperature close to 40 ° C. In the same way that the carboxamides (L3) can be obtained by acylation of the amine (K), the carboxamides (2c ') and (2c ") can be obtained respectively from the amines (2d') and (2d" ). The compounds of general formula (III), (M2) and (M3) can be obtained, for example, by reduction of compounds of general formula (L1), (L2), (L3) with DL-dithiotreitol, in the presence of sodium dihydrogen carbonate in a solvent such as ethanol and at a temperature in the region of 80 ° C. The compound of general formula (N) can be prepared in situ by reduction of the compound of formula (K), for example with sodium borohydride in a solvent such as N, N-dimethylformamide, in the presence of a base such as triethylamine and at a temperature of about 95 ° C or between 20 ° C and 95 ° C. More particularly, the benzothiazoles of general formula (2d ') and (2d ") can also be prepared respectively from carbamates of formula (2a') and (2a ') where R6 = t-butyl by reaction, for example, with trifluoroacetic acid in a solvent such as dichloromethane, at a temperature of 20 ° C. Conversely, the benzothiazoles of general formula (2a ') and (2a ") can also be prepared from benzothiazoles of formula respectively ( 2d ') and (2d "), for example, by reaction with a chlorocarbonate of formula (O) (X = Cl), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature of temperature close to 20 ° C. More particularly, the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a '), (2b') ), (2c ') and (2d') can be prepared, for example: 1) by coupling a compound of formulas e (E) with derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of the derivatives (L1), (L2), (L3) and (K) by sodium borohydride, in a solvent such as N, N-dimethylformamide and in the presence of a base such as triethylamine, at a temperature of 95 ° C or between 50 ° C and 95 ° C. 2) or by coupling the isolated derivatives (M1), (M2) and (M3) and a compound of formula (E), in the presence of sodium borohydride in a solvent such as N, N-dimethylformamide and in the presence of a base such as triethylamine, at a temperature of about 95 ° C. 3) or by coupling the isolated derivatives (M1), (M2) and (M3) and a compound of formula (E) under the conditions, for example, described by U. Schopfer et al (Tetrahedron, 2001, 57, 3069) in the presence of n-tributyl phosphine, potassium tertbutylate, tris (dibenzylideneacetone) dipalladium (O) and bis (2-diphenylphosphinophenyl) ether in a solvent such as toluene at a temperature in the region of 110 ° C. by coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of derivatives (L1), (L2), (L3) and (K ) in the presence of DL-dithiotreitol and sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature of 80 ° C.

The reducing conditions 1) and 2) can give products of formula (2a), (2b), (2c) and (2d) such that represent a single or double bond while conditions 3) and 4) give products of formulas (2a), (2b), (2c) and (2d) as represent a double bond. Scheme 3: Synthetic routes of the triazolopyridazine derivatives of formula (E) Cl R80-NE (U), / e Ra = In Scheme 3 above, the substituent Ra has the meanings given above for the products of formula (I ') and (I "). The substituent R8 represents a cycloalkyl radical as defined above for the products of formula (I). The compounds of formula (E) can be obtained, for example, as indicated in scheme 3 above, starting from 3.6. commercial dichloro [1,2,4] triazolo [4,3-b] pyridazine of formula (S), More particularly, the compounds of formula (E) in which Ra represents an OR8 radical may be obtained by the treatment of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (S) at a temperature in the region of 20 ° C to 80 ° C and in a solvent such as tetrahydrofuran with an alcoholate of formula ( U), itself obtained by treating an alcohol (HORS) with, for example, sodium hydride in a solvent such as tetrahydrofuran at a temperature in the region of 0 ° C. to 20 ° C., compounds of formula (E) wherein Ra represents an R8NH radical can be obtained by treatment of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (S) with an amine of formula ( R8NH2), at a temperature in the region of 20 ° C to 50 ° C and in a solvent such as N, N-dimethylformamide. Scheme 4: Synthesis of benzothiazole derivatives of formula (2e ') and (2e ") R9X (W) Ra deprotection NO T'I T., O RB reductive conditions EO p Re via T" LI L4 Ra 2e "According to scheme 4 above, the benzothiazoles of general formula (2e ') and (2e ") can be prepared respectively from the compounds of formulas (2a') and (2a").

In scheme 4 above, the substituent OR6 is preferably O-t-butyl. The substituent R 9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR 3 R 4 radical (R 3 and R 4 as defined above). Ra T '! T "carbamates of general formula (T ') and (T") can be obtained respectively by reaction of carbamates of general formula (2a') and (2a ") with R6 = tBu preferentially, for example, with halides of alkyl of formula (W), in a solvent such as N, N-dimethylformamide, in the presence of sodium hydride, at a temperature between 20 and 90 ° C.

The benzothiazoles of general formula (2e ') and (2e ") may also be prepared from compounds of formula (L1), preferably with R6 = tBu, via compounds of formula (T') and (T"). More particularly, the compounds of general formula (2e ') and (2e ") can be obtained respectively by treatment of the compounds (T') and NC'S H KR (T") isolated, for example, with trifluoroacetic acid, in a solvent such as dichloromethane, at a temperature of 20 ° C, alternatively, the compounds of general formula (2e ") can be obtained directly by reaction of the compounds of formula (L4) and (E), via the compound (T" ) formed in situ, for example, in the presence of DL-dithiotreitol and sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature of 80 ° C, optionally followed by an in situ treatment with trifluoroacetic acid at 20 ° C if necessary. NC L4 carbamates of general formula (L4) can be obtained by reaction of carbamates of general formula (L1), for example with alkyl halides of formula (W), in a solvent such as N, N-dimethylformamide, in the presence of sodium hydride at a temperature between 20 and 90 ° C. Scheme 5: Synthesis of benzothiazole derivatives of formula (2e ') and (2e ") K diazotization bromination NH, CuBr2 NaNOZ L5 L6 Alternatively, according to scheme 5 above, the benzothiazoles of general formula (2e") can be prepared at from the compounds of formulas (L6) and (E), for example, in the presence of DL-dithiotreitol and sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 80 ° C. The benzothiazoles of the general formula (2e ') may be prepared from the compounds of the formula (2e "), according to the methods described below for the preparation of the compounds (I') from the compounds (I"). The compounds of formulas (L6) can be prepared from the 2-bromo benzothiazole derivative (L5) by treatment with an NH 2 R 9 derivative, for example, in a solvent such as tetrahydrofuran, at a temperature in the region of 20 ° C. The substituent R 9 represents an alkyl or cycloalkyl radical optionally substituted by an alkoxy, heterocycloalkyl or NR 3 R 4 radical (R 3 and R 4 as defined above). The compounds of formulas (L5) may be prepared from 2-amino-1,3-benzothiazol-6-yl (K) thiocyanate (commercial compound), for example, by treatment with an alkyl nitrite and cuprous bromide in a solvent such as acetonitrile, at a temperature of 0-20 ° C, according to the method described by Jagabandhu Das et. al. in J. Med. Chem. 2006, 49, 6819-6832. Scheme 6 Other synthetic routes of reduced derivatives of the formulas (1 ') reaction on the group WN Ra (1') coupled Mlou M2 or M3 or N Ni CI \ reduction} ùN NNE 'Ra 20 According to scheme 6 above the benzothiazoles of the general formula (I ') can also be prepared from the compounds of the formula (I ") by reduction, for example with sodium borohydride, in a solvent such as ethanol, at a similar temperature at 80 ° C. or else by reduction with zinc (0) in the presence of acetic acid, at a temperature in the region of 20 ° C. Alternatively, the compounds (I ') can also be prepared from compounds of formula (E ') by coupling with the compounds of type M1, M2, M3 or N, obtained as intermediates by reduction of compounds L1, L2, L3 or K in situ, as described above in scheme 2. The compounds of type M1, M2 or M3 can also be isolated and used for coupling with (E '). be obtained from the compounds of formula (E) by reduction, for example, by reduction with zinc (0) in the presence of acetic acid, at a temperature of 20 ° C. Alternatively, the compound (I ') may also be prepared from other compounds (I') by transformation of the group W into a group W 'of the same nature as defined above for W and according to the type of reactions defined in scheme 2 : the transformations of 2d '/ 2d "into 2a' / 2a" and into 2c '/ 2c ", the transformations of 2a' / 2a" into 2d '/ 2d "and into 2b' / 2b". In the compounds of general formula (I) as defined above, sulfur S can be oxidized to sulfoxide SO or sulfone SO 2 according to the methods known to those skilled in the art and, if necessary, protecting the optionally reactive groups by appropriate protective groups. Among the starting products of formula J, K, O, P, Q, R, S, U, V, W are known and can be obtained either commercially or according to the usual methods known to those skilled in the art, by example from commercial products. It is understood by those skilled in the art that, for the implementation of the methods according to the invention described above, it may be necessary to introduce protective groups of the amino, carboxyl and alcohol functions in order to avoid side reactions.

The following non-exhaustive list of examples of protection of reactive functions may be mentioned: the hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl, - the amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, BOC, benzyloxycarbonyl, phthalimido or other radicals known in the peptide chemistry, the acid functions may be protected for example in the form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry. A list of different protecting groups for use in the manuals known to those skilled in the art and for example in the patent BF 2 499 995 can be found. It can be noted that it is possible to subject, if desired and if necessary, intermediate products. or products of formula (I) thus obtained by the processes indicated above, to obtain other intermediates or other products of formula (I), one or more reactions of transformations known to those skilled in the art such as for example: a) an esterification reaction of acid function, b) an ester function saponification reaction in acid function, c) a reduction reaction of the free or esterified carboxy function in alcohol function, d) a reaction of conversion of alkoxy function to hydroxyl function, or even of hydroxyl function to alkoxy function; e) elimination reaction of protective groups that can be carried by protected reactive functions f) a salification reaction with an inorganic or organic acid or a base to obtain the corresponding salt, g) a resolving reaction of the racemic forms into split products, said products of formula (I) thus obtained being in any form possible racemic isomers, enantiomers and diastereoisomers. The reactions a) to g) can be carried out under the usual conditions known to those skilled in the art such as, for example, those indicated below. a) The products described above may, if desired, be subjected, on the possible carboxy functions, to esterification reactions which may be carried out according to the usual methods known to those skilled in the art. b) The possible acid-functional ester function transformations of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in an alcoholic medium such as, for example, in methanol or in hydrochloric or sulfuric acid. The saponification reaction can be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide. c) The optional free or esterified carboxy functions of the products described above may, if desired, be reduced according to the alcohol by the methods known to those skilled in the art: the optional esterified carboxy functions may, if desired, be reduced according to alcohol by the methods known to those skilled in the art and in particular by lithium hydride and aluminum in a solvent such as for example tetrahydrofuran or dioxane or ethyl ether. The optional free carboxy functions of the products described above may, if desired, be reduced in particular alcohol function by boron hydride. d) The optional alkoxy functions, such as methoxy in particular, of the products described above may, if desired, be converted into hydroxyl function under the usual conditions known to those skilled in the art, for example by boron tribromide in a solvent such as For example, methylene chloride, with hydrobromide or pyridine hydrochloride or with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux. e) The elimination of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzene sulfonic acid or para-toluenesulphonic, formic or trifluoroacetic or catalytic hydrogenation. The phthalimido group can be removed by hydrazine. f) The products described above may, if desired, be the subject of salification reactions, for example by a mineral or organic acid or by a mineral or organic base according to the usual methods known to those skilled in the art: such salification reaction can be carried out for example in the presence of hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol. g) The optional optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art. The products of formula (I) as defined above, as well as their addition salts with acids, have interesting pharmacological properties, in particular because of their kinase inhibiting properties as indicated above. The products of the present invention are especially useful for tumor therapy.

The products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents. These properties justify their application in therapeutics and the subject of the invention is particularly useful as medicaments, the products of formula (I) as defined above, said products of formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). The subject of the invention is, as medicaments, the products corresponding to the following formulas: N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin] 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3- yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (mp-n-4-yl) ethyl] -1- (6 - {[6- (Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2] N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol- (morpholin-4-yl) ethyl] urea 2-yl) 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl acetamide N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] -3- [2- (pyrrolidin-1-yl) ethyl] urea sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarbox N- [6 - ({6 - [(trans-4-Hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-amide N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-benzothiazol-2-yl] cyclopropanecarboxamide 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl cyclopropanecarboxamide 1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] -3- [2- (morpholin-4-yl) ethyl] urea] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea as well as addition salts with inorganic and organic acids or with inorganic and organic pharmaceutically acceptable bases acceptable of said products of formula (I). The invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, optionally, a pharmaceutically acceptable carrier. The invention thus extends to pharmaceutical compositions containing as active principle at least one of the drugs as defined above.

Such pharmaceutical compositions of the present invention may also, if appropriate, contain active principles of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating agents of DNA and others.

These pharmaceutical compositions may be administered orally, parenterally or locally by topical application to the skin and mucous membranes or by intravenous or intramuscular injection.

These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, pills, lozenges, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods. The active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives. The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 0.05 to 5 g per day in the adult, or preferably from 0.1 to 2 g. per day. The subject of the present invention is also the use of the products of formula (I) as defined above or of pharmaceutically acceptable salts of these products for the preparation of a medicament intended for inhibiting the activity of a protein kinase. The subject of the present invention is also the use of products of formula (1) as defined above for the preparation of a medicament intended for the treatment or prevention of a disease characterized by the dysregulation of a protein kinase. Such a medicament may especially be intended for the treatment or prevention of a disease in a mammal.

The present invention also relates to the use defined above in which the protein kinase is a protein tyrosine kinase. The subject of the present invention is also the use defined above in which the protein tyrosine kinase is MET or its mutant forms.

The present invention also relates to the use defined above in which the protein kinase is in a cell culture. The present invention also relates to the use defined above in which the protein kinase is in a mammal. The present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the prevention or treatment of diseases related to uncontrolled proliferation. The present invention particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders proliferation of blood vessels, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers. The present invention thus particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diseases in oncology and in particular for treatment of cancers.

Among these cancers, one is interested in the treatment of solid or liquid tumors, in the treatment of cancers resistant to cytotoxic agents. The products of the present invention cited can in particular be used for the treatment of primary tumors and / or metastases, particularly in gastric, hepatic, renal, ovarian, colon, prostate, lung cancers (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid hematopoietic tumors or myeloid, in sarcomas, in cancers of the brain, larynx, lymphatic system, cancers of the bones and pancreas. The subject of the present invention is also the use of the products of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers. Such drugs for cancer chemotherapy may be used alone or in combination. The products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or in combination with other therapeutic agents, for example. Such therapeutic agents may be commonly used anti-tumor agents. As kinase inhibitors, there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomucine. The subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas E ', M1, M2, M3 and N20 as defined above and referred to hereinafter: ## STR1 ## In which the groups CONR1R2, CO2R6 and COR7, which constitute W, may take the values of W as defined above for the products of formula (I). ), when W # H, and the substituent Ra can take the meanings indicated above for the products of formula (I) The following examples which are products of formula (I) illustrate the invention without however limiting it. Experimental part The nomenclature of the compounds of this invention was carried out with ACDLABS software version 10.0. Microwave oven used: Biotage, Initiator EXP-EU, 300W max, 2450MHz 1H NMR spectra at 400 MHz and 1H at 300 MHz were carried out on BRUKER AVANCE DRX-400 or BRUKER AVANCE DPX-300 spectrometer with chemical shifts (8 ppm) in dimethylsulfoxide-d6 solvent (DMSO-d6) referenced to 2.5 ppm at a temperature of 303K. Mass spectra were performed either by analysis: - LC-MS-DAD-ELSD (MS = Waters ZQ) - LC-MS-DAD-ELSD (MS = Platform II Waters Micromass) - UPLC-MS-DAD-ELSD ( MS = Quattro First XE Waters) DAD considered wavelength at = 210-400 nm ELSD: Sedere SEDEX 85; nebulization temperature = 35 ° C, nebulization pressure = 3.7 bar Example 1: N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide a) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl} ] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide can be prepared in the following manner: to 2 cm3 of pyridine at 20 ° C are added 75 mg of 6 - {[6- (cyclohexyloxy) [1,2,4 ] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine and 20 μl of cyclopropane carboxylic acid chloride. After 3h, 20 μl of cyclopropane carboxylic acid chloride are added and the mixture is stirred for 18 h. 20 μl of cyclopropane carboxylic acid chloride are added and the reaction is allowed to take an additional hour. The reaction mixture is concentrated to dryness and the solid residue is chromatographed by solid deposition on Biotage Quad 12/25 (KP-SIL, 60A, 32-63pM) eluting with a 99.5 / 0.5 dichloromethane / methanol gradient. at 90/10. The solid obtained is washed with ethyl ether. 66 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. cyclopropanecarboxamide in the form of a white powder, the characteristics of which are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) 6 ppm 0.88 - 1.01 (m, 4H) 1.13-1.53 (m, 6H) 1.52-1.66 (m, 2H) 1.71 -1.86 (m, 2H) 1.92-2.04 (m, 1H) 4.61 - 4.74 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.0, 2.0Hz, 1H) 7.67 (d, J = 8.0 Hz, m.p. 1H) 8.05 (d, J = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 12.67 (brs, 1H)

MASS SPECTRUM: UPLC-SQD: MH + m / z = 467 +; MH = 465-. B) 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared from In a following manner: a solution of149 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial) in 20 cm 3 of ethanol is bubbled through a stream of argon for 5 minutes. 4 mg of potassium dihydrogenphosphate in 0.2 cm 3 of water, 333 mg of DL-dithiothreitol and 182 mg of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine are then added. The reaction mixture is heated at 80 ° C. for 23 h and then concentrated to dryness under vacuum. The residue is purified on silica by solid deposition eluting with a gradient of 100% dichloromethane to dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) 80/20. 130 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazol [4,3-b] pyridazin-3-yl] sulfonyl} -1,3-benzothiazol are thus obtained. -2-amine in the form of a yellowish powder whose characteristics are as follows: MASS SPECTRUM: LC / MS Electrospray on WATERS UPLC - SQD: 10 MH + m / z = 399+; MH = 397-

c) 3-Chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in the following manner: to a solution of 3,18g of cyclohexanol in 30cm3 of tetrahydrofuran to 15 ° C. under argon are added 762 mg of sodium hydride at 60% in the oil. After stirring for 15 minutes, 3 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial) are added. The brown suspension is stirred for 22 hours, gradually returning to 20 ° C. The reaction medium is then poured into ice water and the mixture is extracted with ethyl acetate. After dry concentration of the organic phase under vacuum, a brown oil is obtained. The oily residue is chromatographed on Biotage Quad 12/25 (KPSIL, 60, 32-63 μM) eluting with a cyclohexane / ethyl acetate gradient of 95/5 to 65/35. 2.7 g of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine are thus obtained in the form of a yellowish powder, the characteristics of which are as follows: MASS SPECTRUM: LC / MS Electrospray on WATERS UPLC - SQD: MH + = 253+

Example 2 1- (6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 3- [2- (Morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared as follows: through a solution of 339 mg of 1- [2] - (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea in 20 cm3 of ethanol, a stream of argon is bubbled for 5 minutes. 5 mg of potassium dihydrogenphosphate are then added in 0.2 cm 3 of water, 463 mg of DL-dithiothreitol and 253 mg of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine ( 1 C). The reaction mixture is then heated at 80 ° C. for 47 h, then the whitish solution is evaporated to dryness under vacuum. The residue is purified on silica by solid deposition eluting with a gradient of 100% dichloromethane to dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) 85/15. 246 mg of 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3- [2- (morpholin-4-yl) ethyl] urea as a white powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) & ppm 1.00 - 1.55 (m , 6H) 1.62 (m, 2H) 1.73 - 1.90 (m, 2H) 2.29 - 2.47 (m, 6H) 3.19 - 3.28 (m, 2H) 3.59 (m, 4H) 4.57 - 4.80 (m) , 1H) 6.77 (brs, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.36 (dd, J = 8.5, 1.5Hz, 1H) 7.54 (d, J = 8.5Hz, 1H) H) 7.99 (d, J = 1.5Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) 10.90 (brs, 1H)

MASS SPECTRUM: UPLC-SQD: MH + m / z = 555 +; MH- = 553- b) 1- (2-Morpholin-4-ylethyl) -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea can be prepared in the following manner: in a mixture of 900 mg of 2 - {[(2-morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate and 40 cm 3 of ethanol at 20 ° C. are bubbled with a stream of argon for 5 minutes. . 11 mg of potassium dihydrogenphosphate are then added to 0.4 cm3 of water and 1.1 g of dithiothreitol. The mixture is heated at 80 ° C for 3.5h. The reaction medium is cooled to 20 ° C and then poured onto water. The suspension is stirred for 45 minutes while maintaining a slight argon bubbling. The precipitate formed is drained and washed with 3.times.10 cm.sup.3 of water and then dried under vacuum at 20.degree. 633 mg of 1- (2-morpholin-4-ylethyl) -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea are thus obtained in the form of a white solid, the characteristics of which are as follows:

MASS SPECTRUM: LC-MS-DAD-ELSD: MH + m / z = 339 +; (MH) - = 337- (c) 2 - {[(2-Morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate can be prepared as follows: to a solution of 1 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate ester in 30 cm3 of tetrahydrofuran was added 0.44 cm3 of 2-morpholin-4-ylethanamine at 20 ° C. After 24 hours, the reaction mixture is evaporated to dryness and the residue obtained is chromatographed on a Merck 70g cartridge (solid deposit, elution with a dichloromethane gradient and then 90/10 dichloromethane / methanol). 902 mg of 2 - {[(2-morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate are thus recovered in the form of a colorless foam, the characteristics of which are as follows: SPECTRUM MASS: UPLC-MS-DAD-ELSD: MH + m / z = 364 +

d) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate was prepared as follows: to a solution of 2.5 g of 2-amino-1,3-benzothiazol-6 thiocyanate In 7.5 ml of phenylchlorocarbonate and 7.55 g of sodium hydrogencarbonate and 9.4 cm3 of water are added at 20 ° C., the mixture is added at -20.degree. The resulting mixture is then stirred at 20 ° C for 20h and then extracted with 2x150cm3 of ethyl acetate. The organic phases are combined and washed with 3 × 50 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of water and then filtered off and dried under vacuum at 20 ° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows:

MASS SPECTRUM: LC-MS-DAD-ELSD: MH + m / z = 328 +; (M-H) - = 326-

Example 3 N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide be prepared in the following manner: to 2 cm3 of pyridine at 20 ° C are added 0.276 cm3 of acetic anhydride and 160 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b). After 5h, add 0.3 cm3 of acetic anhydride and stir for 17h. The reaction mixture is concentrated to dryness under vacuum. The yellowish solid residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient of 100% dichloromethane to dichloromethane / methanol 97.5 / 2.5. 123 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) acetamide in the form of a white powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) S ppm 1.05 - 1.53 (m, 6H) 1.52 - 1.68 (m, 2H) 1.71 - 1.85 (m, 2H) 2.19 (s, 3H) 4.56 - 4.73 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.40 (dd, J = 8.5, 2.0Hz, 1H) 7.66 (d, J = 8.5 Hz, 1H) 8.06 (d, J = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 12.37 (br.s., 1H) MASS SPECTRUM: UPLC -SQD: MH + m / z = 441 +; MH = 439 Example 4: (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) phenyl carbamate (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) Phenyl carbamate may be prepared in the following manner: at 200 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine (1b) in 5 cm 3 of pyridine is added at 20 ° C, 0.13 cm 3 of phenyl chlorocarbonate. After 4 hours, the yellow suspension is concentrated under vacuum. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient of 100% dichloromethane to dichloromethane / methanol 92.5 / 7.5. 224 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate are thus obtained. phenyl in the form of a white powder whose characteristics are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 - 1.42 (m, 5H) 1.43 - 1.66 (m, 3H) 1.72 - 1.85 (m, 2H) 4.63 - 4.74 (m, 1H) 7.03 (d, J = 10.0 Hz, 1H) 7.25 - 7.35 (m, 3H) 7.40 - 7.50 (m, 3H) 7.69 (d, J = 9.0 Hz, 1H) 8.07 (d, J = 2.0 Hz) , 1H) 8.28 (d, J = 10.0 Hz, 1H) 12.66 (brs, 1H)

MASS SPECTRUM: UPLC-SQD: MH + m / z = 519 +; MH = 517-

Example 5: 1- (6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 3- [2- (pyrrolidin-1-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl) ] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (pyrrolidin-1-yl) ethyl] urea can be prepared in the following manner: to a solution of 200 mg of (6 - {[6- Phenyl (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate (4) in 5 cm3 of tetrahydrofuran, 0, 06 cm3 of 2- (pyrrolidin-1-yl) ethanamine and 0.14 cm3 of triethylamine at 20 ° C. After 2h at 20 ° C the reaction medium is heated at 60 ° C for 3h. The yellow solution is evaporated to dryness under reduced pressure. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 NM), eluting with a 99/1 to 50/50 dichloromethane / methanol gradient. 171 mg of 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3- [2- (pyrrolidin-1-yl) ethyl] urea, in the form of a white powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 - 1.87 ( m, 14H) 2.52 - 2.63 (masked m, 6H) 3.32 - 3.38 (masked m, 2H) 4.57 - 4.80 (m, 1H) 6.82 (br s, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.36 (dd, J = 8.5, 2.0Hz, 1H) 7.55 (d, J = 8.5 Hz, 1H) 8.00 (d, J = 2.0Hz, 1H) 8.27 (d, J = 10.0 Hz, 1 H) 10.78 (s, 1 H)

MASS SPECTRUM: UPLC-SQD: MH + m / z = 539 +; MH- = 537-

Example 6: 6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N- [2- (pyrrolidin-1-yl) ethyl] -1,3-Benzothiazol-2-amine a) 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N- [2] - (pyrrolidin-1-yl) ethyl] -1,3-benzothiazol-2-amine can be prepared as follows: to a solution of 534 mg of 2-bromo-1,3-benzothiazol-6-yl thiocyanate in 7 cm3 of tetrahydrofuran are added 686 mg of 2- (pyrrolidin-1-yl) ethanamine. The reaction medium is stirred for 18 h at 20 ° C. and the suspension is then concentrated to dryness under reduced pressure. The oily brown residue obtained is taken up in 20 cm3 of ethanol. The mixture is degassed by bubbling argon for 5 min at 20 ° C., then 5 mg of potassium dihydrogenphosphate are added in 0.2 cm 3 of water followed by 617 mg of DL-Dithiothreitol and 253 mg of 3-chloro-6- (cyclohexyloxy) [ 1,2,4] triazolo [4,3-b] pyridazine (1c). After 23 hours under reflux, the red suspension is concentrated to dryness under reduced pressure. The residue is purified by dry deposition on Biotage Quad 25M (KP-SIL, 60A, 32-63 μM) eluting with a gradient of 95: 5 to 85:15 of dichloromethane / (dichloromethane: 38 / methanol: 17 / aqueous ammonia: 2). The yellow solid obtained is washed with ether and with pentane. 218 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N- [2- (pyrrolidin-1-yl) are thus obtained. ) ethyl] -1,3-benzothiazol-2-amine as a yellow powder having the following characteristics: 1H NMR SPECTRUM NMR (400 MHz, DMSO-d6) S ppm 1.17 - 1.59 (m, 7H) 1.60 - 1.73 (m, 7 H) 1.79 - 1.94 (m, 2 H) 2.45 (masked m, 2 H) 2.55 - 2.71 (m, 2H) 3.47 (q, J = 6.0 Hz, 2H) 4.68 - 4.81 (m, 1H) 7.01 (d, J = 10.0 Hz, 1H) 7.24 - 7.35 (m, 2H) 7.82 (d, J = 1.5 Hz, 1H) 8.15 (t, 1H) 8.25 (d, J = 10.0 Hz, 1 MASS SPECTRUM: UPLC-SQD: MH + m / z = 496 +; MH- = 494-

b) The 2-bromo-1,3-benzothiazol-6-yl thiocyanate can be prepared in the following manner: A solution of 6.5 g of cuprous bromide in 666 cm3 of acetonitrile is purged with argon for 5 min. The resulting solution is cooled to 0-5 ° C and then 4.3 cm3 of tert-butyl nitrite is added. 5 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial) are then added portionwise at 0 ° C. The reaction mixture is stirred for 3 h at 20 ° C. and then concentrated to dryness under reduced pressure. The residue is taken up in ethyl acetate and the resulting solution is washed with a saturated solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate and then concentrated to dryness under vacuum. 5.05 g of 2-bromo-1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a gold-yellow powder whose characteristics are the following: MASS SPECTRUM: UPLC-SQD: MH + m / z = 271 +

Example 07: N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3,5-benzothiazol-2-yl) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl -2-methoxyacetamide 2-methoxyacetamide can be prepared in a manner similar to Example 1a but from 200 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin). 3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 5cm3 of pyridine with 0.165cm3 of methoxyacetyl chloride after 23h of reaction at 20 ° C. 196 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. 2-methoxyacetamide in the form of a white powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) S ppm 1.09 - 1.40 (m, 5H) 1.41 - 1.65 (m, 3H) 1.72 - 1.86 (m, 2H) 3.36 (s, 3H) 4.19 (s, 2H) 4.61 - 4.72 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.5) , 2.0 Hz, 1H) 7.68 (d, J = 8.5Hz, 1H) 8.07 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 10.0 Hz, 1H) 12.32 (brs), 1 H) MASS SPECTRUM: UPLC-SQD: MH + m / z = 469 +; MH = 471-

Example 8: N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) N- (6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) N, N 2 -dimethylglycinamide -N2, N2-dimethylglycinamide can be prepared in a manner similar to Example 1a but from 100 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin -3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 10cm3 of dichloromethane with 300mg of N, N-dimethylglycyl chloride, 0.33cm3 of triethylamine and 11mg of 4-N, N-20 dimethylaminopyridine, after 27 hours of reaction at 20 ° C. 75 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -N2, N2-dimethylglycinamide in the form of a yellowish powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) S ppm 1.10 - 1.64 (m, 8H) 1.69 - 1.87 (m, 2H) 2.29 (s, 6H) 3.37 - 3.52 (m, 2H) 4.52 - 4.75 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.5, 2.0 Hz) , 1H) 7.67 (d, J = 8.5 Hz, 1H) 8.07 (d, J = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 11.92 (brs, 1H) MASS SPECTRUM: Waters-ZQ: MH + m / z = 484 +; MH = 482-

Example 9: N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl -3-methylbutanamide ) -3-methylbutanamide can be prepared in a manner similar to Example 1a but from 102 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin) 3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 5cm3 of pyridine with 0.437cm3 of 3-methylbutanoyl chloride after 46h of reaction at 20 ° C. There is thus obtained 98 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl. ) -3-methylbutanamide in the form of a white powder having the following characteristics: NMR spectrum 1H NMR (400 MHz, DMSO-d6) S ppm 0.93 (d, J = 6.8 Hz, 6H) 1.08 - 1.63 ( m, 8H) 1.71 - 1.82 (m, 2H) 2.03 - 2.17 (m, 1H) 2.36 (d, J = 7.1 Hz, 2H) 4.56 - 4.69 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.4, 1.8 Hz, 1H) 7.66 (d, J = 8.6Hz, 1H) 8.07 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 9.8 Hz, 1H) 12.34 (br.s., 1H) 5 7 MASS SPECTRUM: UPLC-SQD: MH + m / z = 483 +; MH = 481-

Example 10: N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3,5-benzothiazol-2-yl) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl -3-methoxypropanamide ) -3-methoxypropanamide can be prepared in a manner similar to Example 1a but from 146 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin] 3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 5cm3 of pyridine with 0.191cm3 of 3-methoxypropanoyl chloride after 23h of reaction at 20 ° C. 132 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3-methoxypropanamide as a white powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 - 1.65 (m, 8H) 1.74 - 1.83 (m, 2H) ) 2.72 (t, J = 6.1 Hz, 2H) 3.23 (s, 3H) 3.64 (t, J = 6.1 Hz, 2H) 4.62 - 4.72 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.41 (dd, J = 8.3, 2.0Hz, 1H) 7.66 (d, J = 8.6Hz, 1H) 8.06 (d, J = 2.0Hz, 1H) 8.28 (d, J = 9.8Hz, m.p. 1H) 12.37 (br s, 1 h)

MASS SPECTRUM: Waters-ZQ: MH + m / z = 485 +; MH = 483-

Example 11: 6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine a) The 6- {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared in a similar manner to Example 1b but from 889 mg of 3-chloro-6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazine in 30 cc of degassed ethanol, 17 mg of potassium dihydrogenphosphate in 0, 3 cm3 of water, 1.72 g of DL-dithiothreitol and 772 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 h at 80 ° C. 1.04 g of 6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine are thus obtained. form of a white powder whose characteristics are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 - 1.76 (m, 6H) 1.83 - 1.97 (m, 2H) 5.12 - 5.22 (m, 1H) 6.99 (d, J = 9.8 Hz, m.p. 1H) 7.28 (d, J = 8.6 Hz, 1H) 7.34 (dd, J = 8.3, 2.0Hz, 1H) 7.61 (s, 2H) 7.90 (d, J = 2.0 Hz, 1H) 8.23 (d , J = 9.8 Hz, 1H)

MASS SPECTRUM: UPLC-SQD: MH + m / z = 385 +

b) 3-Chloro-6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in a manner similar to Example 1c but from 914mg of cyclopentanol in 20cm3 of tetrahydrofuran, 254 mg of sodium hydride at 60% in oil and of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial), after 6.5 h of reaction. 896 mg of 3-chloro-6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazine are thus obtained in the form of a colorless oil which crystallizes and whose characteristics are as follows:

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 239 +

Example 12 N- (6 - {[6- (Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 , 3-benzothiazol-2-amine (11a) in 5cm3 of pyridine with 0.140cm3 of cyclopropane carboxylic acid chloride after 3h of reaction at 20 ° C. 277 mg of N- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) cyclopropanecarboxamide as a white powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) νppm 0.84 - 1.00 (m, 4H) 1.44 - 1.71 (m, 6H) 1.73 - 1.88 (m, 2H) 1.92 - 2.04 (m, 1H) 5.04 - 5.17 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.4, 1.8 Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.13 (d, J = 2.0 Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 12.67 (brs, 1H) 10 MASS SPECTRUM : UPLC-SQD Waters: MH + m / z = 453 +; MH- = 451-

Example 13: N- (6 - {(6- (Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) N- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide be prepared in a manner similar to Example 1a but from 250 mg of 6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-amine 11a in 5 cm 3 of pyridine with 2.5 cm 3 of acetic anhydride after 48 hours of reaction at 20 ° C. 255 mg of N- (6 - {[6- (cyclopentyloxy)) are thus obtained. [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide in the form of a white powder, the characteristics of which are as follows: NMR spectrum 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 - 1.71 (m, 6H) 1.71 - 1.88 (m, 2H) 2.19 (s, 3H) 5.04 - 5.15 (m, 1H) 7.01 ( d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.6, 2.0Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.14 (d, J = 2.0 Hz, 1H) 8.26 ( d, J = 9.8 Hz, 1H) 12.37 (s, 1H) SPECTRUM MASS E: Waters UPLC-SQD: MH + m / z = 427 +; MH = 425; Example 14: 1- (6 - {[6- (Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfa-nyl} -1,3-benzothiazole -2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 5a but from 778 mg of a mixture of (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol- 2-yl) Phenyl carbamate and (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 -yl) diphenyl imidodicarbonate in 10 cm3 of tetrahydrofuran, 0.32 cm3 of 2- (morpholin-1-yl) ethanamine and 1.04 cm3 of triethylamine at 20 ° C. 127 mg of 1- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. 3- [2- (morpholin-4-yl) ethyl] urea, in the form of a white powder, the characteristics of which are as follows:

NMR spectrum 1H NMR (500 MHz, DMSO-d6) δ ppm 1.48 - 1.71 (m, 6H) 1.78 - 1.92 (m, 2H) 2.32 - 2.46 (m, 6H) 3.27 (q, J = 5.9 Hz, 2H) 3.54 - 3.64 (m, 4H) 5.09 - 5.17 (m, 1H) 6.80 (ss, 1H) 7.01 (d, J = 9.6 Hz, 1H) 7.41 (dd, J = 8.5) , 1.6 Hz, 1H) 7.55 (d, J = 8.5 Hz, 1H) 8.08 (d, J = 1.6Hz, 1H) 8.26 (d, J = 9.6Hz, 1H) 10.93 (brs), 1 H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 541 +; MH = 539-

(b) The mixture of (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate of phenyl and (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) imidodicarbonate diphenyl can be prepared in a manner similar to Example 4a but from 326 mg of 6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] 1, 3-Benzothiazol-2-amine (11a) and 0.21 cm3 of phenyl chlorocarbonate in 5 cm3 of pyridine. 892 mg of a beige powder of a mixture of (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 are thus obtained. Phenyl and (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate, 3-Benzothiazol-2-yl) diphenyl imidodicarbonate, initiated as such in the following step:

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 505 +; MH = 503-10 Example 15: 1- (6 - {[6- (Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 1b but from 305 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1, 3-benzothiazol-2-yl) urea (2b), 5 cm3 of degassed ethanol, 4 mg of potassium dihydrogenphosphate in 0.1 cm 3 of water, 347 mg of DL-dithiothreitol and 202 mg of 3-chloro-6 (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine . 253 mg of 1- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3- [2- (morpholin-4-yl) ethyl] urea as a white powder whose characteristics are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.24 - 1.40 (m, 2H) 1.42 - 1.58 (m, 6H) 1.58 - 1.70 (m, 2H) 1.78 - 1.93 (m, 2H) 2.36 - 2.45 (m, 6H) 3.22 - 3.28 (m, 2H) 3.59 (t, J = 4.4 Hz, 4H) 4.81 - 4.91 (m, 1H) 6.77 (brs, 1H) 7.01 (d, J = 10.0 Hz, 1H) 7.36 (dd, J = 8.6, 2.0Hz, 1H) 7.55 (d, J = 8.6Hz, 1H) 8.00 (d, J = 1.7Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 10.87 (br s, 1 H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 569 +; MH- = 567- b) 3-Chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in a manner similar to Example 1c but from 1.21 g of cycloheptanol in 15 cm 3 of tetrahydrofuran, 254 mg of sodium hydride at 60% in oil and 1 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine ( commercial). 453 mg of 3-chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine are thus obtained in the form of a colorless oil which crystallizes and whose characteristics are as follows: MASS SPECTRUM: Waters ZQ: MH + m / z = 267 + EXAMPLE 16: 6 - {(6- (Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine 6 - {[6- (Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine may be prepared in a manner similar to Example 1b but from 249 mg of 3-chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine (15b) in 5 cm 3 of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.1 cm 3 of water, 432 mg of DL-dithiothreitol and 193 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 h at 80 ° C. 260 mg of 6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine as a powder the characteristics of which are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.29 - 1.74 (m, 10H) 1.86 - 1.97 (m, 2H) 4.87 - 4.99 (m, 1H) 7.00 (d, J = 9.8 Hz , 1H) 7.23 - 7.31 (m, 2H) 7.60 (s, 2H) 7.80 - 7.85 (m, 1H) 8.24 (d, J = 9.8 Hz, 1H)

MASS SPECTRUM: Waters ZQ: MH + m / z = 413 +; MH = 411- Example 17: N- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) acetamide N- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 -yl) acetamide can be prepared in a manner similar to Example 1a but from 85 mg of 6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 -yl] sulfanyl} -1,3-benzothiazol-2-amine (16a) in 5cm3 of pyridine with 0.160cm3 of acetic anhydride after 24h of reaction at 20 ° C. 90 mg of N- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) acetamide in the form of a yellow powder, the characteristics of which are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 - 1.35 (m, 2H) 1.40 - 1.55 (m, 6H) 1.54 - 1.66 (m, 2H) 1.76 - 1.89 (m, 2H) 2.19 (s, 3H) 4.78 - 4.88 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.6, 2.0Hz, 1H) 7.67 (d, J = 8.6 Hz , 1H) 8.06 (d, J = 2.0Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) 12.38 (brs, 1H) MASS SPECTRUM: Waters ZQ: MH + m / z = 455+; MH = 453-

Example 18: N- (6 - {[6- (Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide a) N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide can be prepared in a manner similar to Example 1a but from 150 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine in 1cm3 of pyridine with 0.5cm3 of acetic anhydride after 18h of reaction at 20 ° C. There is thus obtained 65 mg of N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl. ) acetamide in the form of a pale beige powder whose characteristics are as follows:

NMR spectrum 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 - 1.32 (m, 5H) 1.45 - 1.67 (m, 3H) 1.68 - 1.84 (m, 2H) 2.19 (s, 3H) 3.35 - 3.45 (m, 1H) 6.79 (d, J = 10.0 Hz, 1H) 7.25 (d, J = 7.0 Hz, 1H) 7.38 (dd, J = 8.5, 2.0Hz, 1H) 7.64 (d, J) = 8.5 Hz, 1H) 7.92 (d, J = 10.0 Hz, 1H) 8.05 (d, J = 2.0Hz, 1H) 12.35 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 440 +; MH = 438-

b) 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine can be prepared in a manner similar to Example 1b but from 607 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine in 10 cm 3 of degassed ethanol, 12 mg of potassium dihydrogenphosphate in 1 cm3 of water, 1.12 g of DL-dithiothreitol and 500 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 hours at 80 ° C. 768 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine are thus obtained. form of a white powder whose characteristics are as follows:

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 398 +; MH = 396-25 c) 3-Chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine can be prepared as follows: to a solution of 5 g of Commercially available 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine in 50 cm 3 of N, N-dimethylformamide are added 2.3 cm 3 of cyclohexylamine and 3.7 cm 3 of triethylamine. The reaction is stirred at 20 ° C for 18h. 1.1 cm 3 of cyclohexylamine and 7.5 cm 3 of triethylamine are then added and the reaction is stirred at 50 ° C. for 4 h. The reaction mixture is cooled to 20 ° C and then 60 cm3 of water are added. The white precipitate is drained and then washed successively with water and ether. 3 g of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine are thus obtained in the form of a white powder. After one night, the precipitate formed in the first filtrate, obtained above, is filtered off and washed successively with N, N-dimethylformamide, demineralised water and methanol. A second batch of 1.42 g of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine is thus obtained in the form of a yellow powder whose characteristics are following:

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 252 +; MH = 250-

Example 19: 1- (6 - {[6- (Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 3- [2- (pyrrolidin-1-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl) ] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (pyrrolidin-1-yl) ethyl] urea VAC.DPN1.107.2 may be prepared in a manner similar to Example 1b but from 300 mg of 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate in 6 cm3 of degassed ethanol, 4 mg of potassium dihydrogenphosphate in 0.6 cm 3 of water, 400 mg of DL-dithiothreitol and 240 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (18c) after 18h at 80 ° C. 193 mg of 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3- [2- (pyrrolidin-1-yl) ethyl] urea as a pale yellow powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) S ppm 1.00 - 1.34 ( m, 6H) 1.46 - 1.74 (m, 6H) 1.75 - 1.86 (m, 2H) 2.40 - 2.57 masked (m, 6H) 3.21 - 3.28 (m, 2H) 3.39 - 3.49 (m, 1H) ) 6.79 (d, J = 10.0 Hz, 1H) 6.81 - 6.88 (m, 1H) 7.25 (d, J = 7.0 Hz, 1H) 7.35 (dd, J = 8.5, 2.0Hz, 1H) 7.52 ( d, J = 8.5 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 2.0Hz, 1H) 10.81 (br.s., 1H) MASS SPECTRUM: Waters UPLC -SQD: MH + m / z = 538 +; MH = 536-

b) 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate may be prepared as follows: to a solution of 3 g of (6-thiocyanato-1,3) phenyl benzothiazol-2-yl) carbamate in 90 cm 3 of tetrahydrofuran, 1.4 cm 3 of 2-pyrrolidinylethanamine is added at 20 ° C. After 24 hours, the reaction mixture is concentrated to dryness under reduced pressure. To the oily yellow residue obtained, ethyl ether is added. The precipitate formed is drained. 3.33 g of 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a yellowish powder, the characteristics of which are as follows:

MASS SPECTRUM: Waters ZQ: MH + m / z = 348 +; MH = 346- (c) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate was prepared as follows: to a solution of 2.5 g of 2-amino-1 thiocyanate, Commercial 3-benzothiazol-6-yl in 94 cm3 of tetrahydrofuran is added at 20 ° C, 7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogencarbonate and 9.4 cm3 of water. The resulting mixture is then stirred at 20 ° C for 20h and then extracted with 2x150 cm3 of ethyl acetate. The organic phases are combined and then washed with 3 × 50 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm3 of water and then filtered off and dried under vacuum at 20 ° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows:

MASS SPECTRUM: LC-MS-DAD-ELSD: MH + m / z = 328 +; MH = 326-5 Example 20: trans-4 - {[3 - ((2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo cyclopropanecarboxylate [4,3-b] pyridazin-6-yl] amino} cyclohexyl a) Trans-4 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl cyclopropanecarboxylate } sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] amino} cyclohexyl can be prepared in a manner similar to Example 1a but from 300 mg of trans-4- ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl} amino) cyclohexanol in 2, 1 cm3 of pyridine with 0.133 cm3 of cyclopropane carboxylic acid chloride after 18 hours of reaction at 20 ° C. There is thus obtained 303 mg of trans-4 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo cyclopropanecarboxylate [4.3]. [b] pyridazin-6-yl] amino} cyclohexyl in the form of a white powder having the following characteristics:

NMR spectrum 1H NMR (400MHz, DMSO-d6) 6, ppm 0.76 - 1.01 (m, 8H) 1.06 - 1.32 (m, 4H) 1.51 - 1.65 (m, 1H) 1.67 - 1.81 (m, 4H) ) 1.93 - 2.05 (m, 1H) 3.30 - 3.38 (m, 1H) 4.44 - 4.61 (m, 1H) 6.78 (d, J = 9.8 Hz, 1H) 7.20 - 7.34 (m, 2H) 7.62 (d, J = 8.6 Hz, 1H) 7.93 (d, J = 9.8 Hz, 1H) 8.05 (d, J = 2.0Hz, 1H) 12.64 (brs, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 550 +; MH = 548- (b) Trans-4 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl} amino) cyclohexanol can be prepared in a manner similar to Example 1b but from 1 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 20 cm3 of degassed ethanol, 23 mg of potassium dihydrogenphosphate in 2 cm3 of water, 2.32 g of DL-dithiothreitol and 1.29 g of trans-4 - [(3-chloro [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino] cyclohexanol after 18h at 80 ° C. 1.8 g of trans-4 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin are thus obtained. 6-yl} amino) cyclohexanol in the form of a creamy white powder having the following characteristics:

MASS SPECTRUM: Waters ZQ: MH + m / z = 414 +; MH = 412-

c) Trans-4 - [(3-chloro [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino] cyclohexanol can be prepared in a manner similar to Example 18c but from 5 g of commercial 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine in 50 cm 3 of N, N-dimethylformamide, 6 g of trans-4-aminocyclohexanol hydrochloride and 17 cm 3 of triethylamine after 48 hours. at 20 ° C and 4h at 50 ° C. 3.5 g of trans-4 - [(3-chloro [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino] cyclohexanol are thus obtained in the form of a white powder whose characteristics are the following :

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 268 +; MH = 266 Example 21: N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) cyclopropanecarboxamide N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2- yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfonyl] -N-cyclohexyl [ 1, 2,4] triazolo [4,3-b] pyridazin-6-amine (18b) in 2.1 cm3 of pyridine with 0.14 cm3 of cyclopropane carboxylic acid chloride, after 18 h reaction at 20 ° vs. 268 mg of N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. cyclopropanecarboxamide in the form of a creamy white powder having the following characteristics:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) 6, ppm 0.86 - 1.00 (m, 4H) 1.01 - 1.28 (m, 5H) 1.48 - 1.66 (m, 3H) 1.70 - 1.83 (m, 2H) ) 1.92 - 2.04 (m, 1H) 3.36 - 3.45 (m, 1H) 6.79 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 7.1 Hz, 1H) 7.39 (d, J = 8.6) Hz, 1H) 7.65 (d, J = 8.3Hz, 1H) 7.91 (d, J = 9.8Hz, 1H) 8.03 (s, 1H) 12.65 (brs, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 466 +; MH = 464; Example 22: N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-Benzothiazol-2-yl] acetamide a) N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin -3-yl} sulfanyl) -1,3-benzothiazol-2-yl] acetamide can be prepared as follows: to a solution of 114mg of trans-4 - ({3 - [(2-amino-1,3) benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino) cyclohexanol (20b) in 2 cm 3 of dichloromethane is added 0.08 cm 3 of acetyl chloride and 0.16 cc of triethylamine at 20 ° C. After 18h, the reaction medium is concentrated to dryness under reduced pressure. The residue is taken up in water. The yellow-white precipitate formed is drained and washed with water and is then purified by dry deposition on Biotage Quad 25M (KP-SIL, 60A, 32-63 NM) eluting with a gradient of 95: 5 to 70:30 of dichloromethane. / (dichloromethane: 38 / methanol: 17 / ammonia: 2). 46 mg of N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1 are thus obtained. 3-benzothiazol-2-yl] acetamide in the form of a beige powder whose characteristics are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) 6. ppm 1.01 - 1.27 (m, 4H) 1.68 - 1.86 (m, 4H) 2.19 (s, 3H) 3.35 - 3.44 (m, 2H) 4.51 (d, J = 4.6 Hz, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 6.8 Hz, 1H) 7.42 (dd, J = 8.4, 1.8 Hz, 1H) 7.65 (d, J = 8.3 Hz, 1H) 7.92 (d, J = 9.8 Hz, 1H) 8.01 (d, J = 1.7 Hz, 1H) 12.34 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 456 +; MH- = 454-

Example 23: N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3- benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) 1,3-Benzothiazol-2-yl] cyclopropanecarboxamide can be prepared in a manner similar to Example 1a but from 300 mg of trans-4 - ({3 - [(2-amino-1,3-benzothiazol) 6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl} amino) cyclohexanol (20b) in 3 cm 3 of pyridine with 0.235 cm 3 of cyclopropane carboxylic acid chloride, after 16 hours of reaction at 20 ° C. 51 mg of N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) are thus obtained. 1,3-benzothiazol-2-yl] cyclopropanecarboxamide in the form of a beige powder whose characteristics are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.89 - 0.99 (m, 4H) 1.02-1.27 (m, 4H) 1.68-1.87 (m, 4H) 1.92-2.03 (m, 1H) 3.31 - 3.45 (m, 2H) 4.51 (d, J = 4.4 Hz, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 7.1 Hz, 1H) 7.43 (dd, J = 8.6) , 2.0 Hz, 1H) 7.65 (d, J = 8.6 Hz, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.00 (d, J = 1.7 Hz, H) 12.64 (brs, 1 H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 482 +; MH = 480 Example 24: 3 - ((2-Amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6 -amine a) 3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine be prepared in a manner similar to Example 1b but from 1.4 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 41 cc of degassed ethanol, 32 mg of potassium dihydrogenphosphate in 4 cc of water, 3.13 g of DL-dithiothreitol and 1.42 g of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine after 18 hours at 80 ° C. vs. Thus 1.22 g of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6 are obtained. amine in the form of a creamy white powder whose characteristics are as follows:

NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) 6. ppm 0.41 - 0.48 (m, 2H) 0.71 - 0.79 (m, 2H) 2.56 - 2.65 (m, 1H) 6.76 (d, J = 9.8 Hz , 1H) 7.27 (d, J = 8.3 Hz, 1H) 7.42 (dd, J = 8.3, 2.0 Hz, 1H) 7.67 (brs, 3H) 7.92 (d, J = 9.8 Hz, 1H) H) 7.95 (d, J = 1.7 Hz, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 356 +; MH = 354-25

b) 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine DPN1.150 can be prepared in a similar manner to Example 18c but from 2 g of 3.6 commercial dichloro [1,2,4] triazolo [4,3-b] pyridazine in 20 cm 3 of N, N-dimethylformamide, 1.1 cm 3 of cyclopropylamine and 3 cm 3 of triethylamine, after 18 h at 20 ° C. and 3 h at 50 ° C. 1.53 g of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine are thus obtained in the form of a white powder, the characteristics of which are as follows:

MASS SPECTRUM: Waters ZQ: MH + m / z = 210 +; MH- = 208-5 Example 25: N- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) acetamide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3- benzothiazol-2-yl) acetamide can be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N- cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (24a) in 2.11 cm 3 of pyridine with 1.04 cm 3 of acetic anhydride after 18 hours of reaction at 20 ° C. There is thus obtained 100 mg of N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) acetamide in the form of a white powder whose characteristics are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6)? Ppm 0.34 - 0.45 (m, 2H) 0.61 - 0.74 (m, 2H) 2.19 (s, 3H) 2.53 - 2.58 (m, 1H) 6.77 (m.p. d, J = 9.5 Hz, 1H) 7.53 (d, J = 8.3 Hz, 1H) 7.62 - 7.73 (m, 2H) 7.94 (d, J = 9.8 Hz, 1H) 8.19 (s, 1H) 12.38 (br s, 1 h)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 398 +; MH = 396-25 Example 26: N- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) cyclopropanecarboxamide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3- benzothiazol-2-yl) cyclopropanecarboxamide can be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (24a) in 3cm3 of pyridine with 0.16cm3 of cyclopropane carboxylic acid chloride, after 18h of reaction at 20 ° C. There is thus obtained 208 mg of N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl. cyclopropanecarboxamide in the form of a white powder, the characteristics of which are as follows:

1H NMR SPECTRUM NMR (400 MHz, DMSO-d6) S. ppm 0.34 - 0.44 (m, 2H) 0.62 - 0.73 (m, 2H) 0.89 - 1.01 (m, 4H) 1.93 - 2.03 (m, 1H) ) 2.52 - 2.61 (m, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.53 (dd, J = 8.6, 1.7 Hz, 1H) 7.61 - 7.71 (m, 2H) 7.94 (d, J) = 9.8 Hz, 1H) 8.19 (d, J = 1.5Hz, 1H) 12.66 (brs, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 424 +; MH = 422-15 Example 27: 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 1b but from 300 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 7.5 cm 3 of ethanol degassed, 6 mg of potassium dihydrogenphosphate in 0.7 cm 3 of water, 552 mg of DL-dithiothreitol and 403 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazine 6-amine (18c). 370 mg of 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3- [2- (morpholin-4-yl) ethyl] urea as a white powder whose characteristics are as follows:

1H nmr Spectrum NMR (400 MHz, DMSO-d6) δ, ppm 1.08 - 1.30 (m, 5H) 1.47 - 1.70 (m, 3H) 1.71 - 1.89 (m, 2H) 2.32 - 2.46 (m, 6H) H) 3.22 - 3.28 (masked m, 2H) 3.36 - 3.52 (m, 1H) 3.59 (t, J = 4.3 Hz, 4H) 6.69 - 6.93 (m, 2H) 7.25 (d, J = 7.1 Hz , 1H) 7.35 (dd, J = 8.3, 2.0 Hz, 1H) 7.52 (d, J = 8.3 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 1.7 Hz) , 1H) 10.90 (br s, 1 H) MASS SPECTRUM: Waters ZQ: MH + m / z = 554 +; MH = 552-

Example 28: N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 3-Methoxypropanamide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) -3-methoxypropanamide can be prepared in a manner similar to Example 1a but from 220 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [ 1,2,4] triazolo [4,3-b] pyridazin-6-amine (24a) in 7cm3 of pyridine with 0.2cm3 of 3-methoxypropanoyl chloride after 18h of reaction at 20 ° C. 81 mg of N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 are thus obtained Yl) -3-methoxypropanamide as a light beige powder having the following characteristics: NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) 6 ppm 0.33 - 0.43 (m, 2H) 0.62 - 0.73 (m, 2H) 2.53 - 2.59 (m, 1H) 2.73 (t, J = 6.1 Hz, 2H) 3.24 (s, 3H) 3.64 (t, J = 6.0 Hz, 2H) 6.77 (d, J = 9.5) Hz, 1H) 7.53 (dd, J = 8.4, 1.6 Hz, 1H) 7.68 (d, J = 8.6Hz, 1H) 7.72 (d, J = 2.7Hz, 1H) 7.96 (d, J = 9.8 Hz, 1H) 8.22 (d, J = 1.5Hz, 1H) 12.46 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 442 +

Example 29: 1- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (Morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3- yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 1b but from 300 mg of 1- [2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 12 cc of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 1.2 cc of water, 410 mg of DL-dithiothreitol and 187 mg of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (24b), after 18h at 80 ° C. There is thus obtained 133 mg of 1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl. 3- [2- (morpholin-4-yl) ethyl] urea as a cream-white powder having the following characteristics:

NMR spectrum 1H NMR (400 MHz, DMSO-d6CD3COOD) S. ppm 0.36 - 0.49 (m, 2H) 0.65 - 0.82 (m, 2H) 2.57 - 2.65 (m, 1H) 2.96 - 3.16 (m, 6H) 3.50 (t, J = 5.7 Hz, 4H) 3.79 (ss, 2H) 6.79 (d, J = 9.8 Hz, 1H) 6.90 - 7.05 (m, 1H) 7.48 - 7.63 (m, 2) H) 7.66 (brs, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.16 (s, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 512 +; MH = 510 Example 30: N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) -N2, N2-dimethylglycinamide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 3-benzothiazol-2-yl) -N 2, N 2 -dimethylglycinamide can be prepared in a manner similar to Example 1a but from 220 mg of 3 - [(2-amino-1,3-benzothiazol-6-) yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (24a) in 8cm3 of dichloromethane with 197mg of N, N-dimethylglycyl chloride hydrochloride and 0.26cm3 of triethylamine, after 18 hours of reaction at 20 ° C. There is thus obtained 167 mg of N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl. ) -N2, N2-dimethylglycinamide in the form of a light beige powder whose characteristics are as follows:

NMR spectrum 1H NMR (500 MHz, DMSO-d6) S. ppm 0.39 (brs, 2H) 0.69 (d, J = 5.2 Hz, 2H) 2.29 (s, 6H) 2.52 - 2.59 (m, 1 H) 3.10 - 3.25 (masked m, 2H) 6.77 (d, J = 9.6 Hz, 1H) 7.53 (d, J = 8.2 Hz, 1H) 7.61 - 7.74 (m, 2H) 7.95 (d, J = 9.6 Hz, 1H) 8.20 (s, 1H) 12.06 (brs, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 441 +; MH = 439-10 Example 31: 3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4] 3-b] pyridazin-6-amine a) 3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine can be prepared in a manner similar to Example 1b but from 250 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate, 8 cm 3 degassed ethanol, 6 mg of potassium dihydrogenphosphate in 0.8 cm 3 of water, 660 mg of DL-dithiothreitol and 306 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3- b] pyridazin-6-amine. 202 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] are thus obtained. pyridazin-6-amine SAR201923 in the form of a creamy white powder, the characteristics of which are as follows:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) δ ppm 1.00 - 1.35 (m, 5H) 1.48 - 1.74 (m, 3H) 1.78 - 1.90 (m, 2H) 2.56 (t, J = 7.7 Hz, 2H) 2.96 (t, J = 7.7 Hz, 2H) 3.45 - 3.55 (m, 1H) 7.08 (d, J = 7.6 Hz, 1H) 7.16 - 7.37 (m, 2H) 7.66 (br ss, 2H) 7.81 (s, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 400 +; MH = 398- (b) 3-Chloro-N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine can be prepared in the following manner: 500 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (18c) in 16 cm 3 of glacial acetic acid at 20 ° C. are added 1.3 g of powder of zinc. After stirring for 2 hours, the suspension is filtered on filter paper and the filtrate is concentrated to dryness under reduced pressure. The solid residue obtained is purified by chromatography on silica by dry deposition on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a 95/5 to 90/10 dichloromethane / methanol gradient. 317 mg of 3-chloro-N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine are thus obtained in the form of a white powder whose characteristics are the following: MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 254 +; MH = 252 Example 32 Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 1 0.2 g Excipient for a tablet finished at 1 g (detail of excipient: lactose, talc, starch magnesium stearate). Example 33: Pharmaceutical composition Tablets having the following formula were prepared: Product of Example 4- 0.2 g Excipient for a tablet finished at 1 g (detail of the excipient: lactose, talc, starch, stearate magnesium). Examples 1 and 4 are taken as examples of a pharmaceutical preparation, this preparation can be carried out if desired with other products as examples in the present application.30 Pharmacological part: Experimental protocols I) Expression and purification of MET, domain Cytoplasmic Baculovirus Expression: Recombinant His-Tev-MET (956-1390) DNA in pFastBac (Invitrogen) is transfected into insect cells and after several viral amplification steps, the final baculovirus stock is tested for expression of the protein of interest. After infection for 72 h at 27 ° C with the recombinant virus, the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at -80 ° C.

Purification: Cell pellets are resuspended in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, 10% Glycerol, 1 mM TECP] + Roche Diagnostics protease inhibitor cocktail without EDTA ref 1873580), stirred at 4 ° C until homogeneous, then mechanically lysed using a Dounce type apparatus. After centrifugation, the lysing supernatant is incubated for 2 hours at 4 ° C with Nickel Chelate resin (His-Trap 6 Fast Flow ™, GE HealthCare). After washing with 20 volumes of Tp A, the suspension is packaged in a column, and the proteins are eluted by a gradient of buffer B (TpA + 290 mM imidazole). The fractions containing the protein of interest in view of the electrophoretic analysis (SDS PAGE) are pooled, concentrated by ultrafiltration (cut-off 10kDa) and injected onto an exclusion chromatography column (Superdex TM 200, GE HealthCare). balanced in buffer A. After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6Flow 30 FlowTM, GE HealthCare) equilibrated in Buffer A. The fractions eluted by a gradient of buffer B and containing the protein of interest after electrophoresis (SDS PAGE), are finally pooled and stored at -80 ° C. For the production of autophosphorylated protein, the preceding fractions are incubated for 1 hour at room temperature after addition of 2 mM ATP, 2 mM MgCl 2, and 4 mM Na 3 V0 4. After stopping the reaction with 5mM EDTA, the reaction mixture is injected onto a HiPrep desalting column (GE HealthCare) previously equilibrated with 4mM A + Na3VO4 buffer, the fractions containing the protein of interest (SDS PAGE analysis) are pooled. and stored at -80 ° C. The level of phosphorylation is verified by mass spectrometry (LC-MS), and by peptide mapping. II) Tests A and BA) Test A: HTRF MET assay in 96-well format In a final volume of 50 μl of enzymatic reaction, final 5nM MET is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM 10 NM, DMSO 3% final) in 10 mM MOPS buffer pH 7.4, 1 mM DTT, 0.01% Tween 20. The reaction is initiated by the substrate solution to obtain the final concentrations of 1 μg / ml poly- (GAT), 10 μM ATP and 5 μM MgCl 2. After a 10 min incubation at room temperature, the reaction is stopped by a 30 μl mix to obtain a final solution of 50 mM Hepes pH 7.5, 500 mM potassium fluoride, 0.1% BSA and 133 mM EDTA in the presence of 80 μg Streptavidin. 61SAXLB Cis-Bio Int. and 18ng anti-Phosphotyrosine Mab PT66-Europium Cryptate per well. After 2 hours incubation at room temperature, the reading is made at 2 wavelengths 620 nm and 665 nm on a reader for the TRACE / HTRF technique and the% inhibition is calculated according to the 665/620 ratios. The results obtained by this test A for the products of formula (I) as examples in the experimental part are such that IC50 is less than 500 nm and in particular 100 nm. B) Test B: Inhibition of MET autophosphorylation; ELISA technique (pppY1230,1234,1235) a) Cell lysates: Inoculate MKN45 cells in 96-well plate (BD polylysine cell coat) at 20,000 cells / well in 200 μl in RPMI + 10% FCS + 1% L-glutamine medium . Allow 24 hours to adhere to the incubator. The cells are treated the day after seeding with the products at 6 concentrations in duplicate for 1 h. At least 3 control wells are treated with the same amount of final DMSO. Dilution of products: Stock at 10mM in pure DMSO - Range of 10mM to 30pM with a step of 3 in pure DMSO - Dilutions intermediate to 1/50 in culture medium then 10p sample added directly to the cells (200pl): range final from 10000 to 30nM. At the end of the incubation, gently remove the supernatant and rinse with 200 μl of PBS. Then put 100 μl lysis buffer directly into the wells on the ice and incubate at 4 ° C for 30 minutes. Lysis buffer: 10mM Tris, pH 7.4 HCl, 100mM NaCl, 1mM EDTA, 1mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20mM NaF, 2mM Na3VO4, 1mM PMSF and anti protease cocktail. The 100 μl lysates are transferred to a V-bottom polypropylene plate and the ELISA is carried out immediately or the plate is frozen at -80 ° C. b) ELISA PhosphoMET BioSource Kit KH00281 In each well of the kit plate, add 7Opl of kit dilution buffer + 30pL of cell lysate or 30pl of lysis buffer for the blanks. Incubate for 2h with gentle shaking at room temperature. Rinse the wells four times with 400 μl of kit wash buffer. Incubate with 100 μl of anti-phospho MET antibody for 1 h at room temperature. Rinse the wells four times with 400 μl of kit wash buffer. Incubate with 100 μl of HRP Anti-Rabbit Antibody for 30 minutes at room temperature (except for chromogen wells alone).

Rinse the wells four times with 400 μl of kit wash buffer. Put 100 μl of chromogen and incubate 30 minutes in the dark at room temperature. Stop the reaction with 100 μl of stop solution. Read without delay at 450nM 0.1 seconds at Wallac Victor flat reader. C) Test C: Measurement of Cell Proliferation by 14C-Thymidine Pulse The cells are seeded in Cytostar 96-well plates at 180 μl for 4 hours at 37 ° C. and 5% CO 2: HCT116 cells at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L-Glutamine and MKN45 cells at 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine. After these 4 hours of incubation, the products are added under 10 μl in 20-fold concentrated solution according to the dilution method mentioned for the ELISA. The products are tested at 10 duplicate concentrations of 10000 nM to 0.3 nM with a step of 3. After 72 hours of treatment, add 10 μl of 14 C-thymidine at 10 μCi / ml to obtain 0.1 μCi per well. The incorporation of 14 C-thymidine is measured on a Micro-Beta (Perkin-Elmer) after 24 hours of pulse and 96 hours of treatment. All stages of the test are automated on BIOMEK 2000 20 or TECAN stations. The results obtained by this test B for the products of formula (I) as examples in the experimental part are such that IC50 less than 10 microM and especially 1 microM. The results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below, as follows: for test A, the sign + corresponds to less than 500 nm and the sign ++ corresponds to less than 100 nM. 5 for test B the sign + corresponds to less than 500nM and the sign ++ corresponds to less than 100nM. for the C test the + sign corresponds to less than 10 microM and the sign ++ corresponds to less than 1 microM.

Table of pharmacological results: number ex test A test B test C 1 ++ ++ ++ 2 ++ ++ ++ 3 ++ ++ ++ 4 ++ + ++ ++ ++ ++ 6 ++ + + 7 ++ ++ ++ 8 ++ + ++ g ++ ++ ++ ++ ++ ++ 11 ++ ++ ++ 12 ++ ++ ++ 1J TT TT 14 ++ ++ ++ ++ ++ ++ 16 ++ + ++ 17 ++ ++ ++ 18 ++ ++ ++ 19 ++ ++ ++ ++ + ++ 21 ++ ++ ++ 22 ++ ++ 23 ++ ++ ++ 24 ++ ++ ++ 25 ++ ++ ++ 26 ++ ++ ++ 27 ++ ++ ++ 28 ++ ++ ++ 29 ++ ++ + + 30 ++ ++ ++ 31 ++ ++ 10 15

Claims (4)

CLAIMS1 Products of formula (I): Ra in which represents a single or double bond; Ra represents a -O-cycloalkyl radical, or an optionally substituted -NH-cycloalkyl radical; X represents S, SO or SO2; A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the COR radical in which R represents: - a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR 1 R 2 in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form a radical; cyclic ring containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or else R3 and R4 form with the nitrogen atom to which they are bonded a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen among the halogen atoms, the hydroxyl, oxo, alkoxy, -O-CO-R5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5 radicals and the alkyl radicals, cycloalkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in the latter radicals the radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or a plurality of radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2, all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryland phenyl being further optionally substituted by an Si (alk) 3 radical; R 5 and R 5 ', which may be identical or different, represent an alkyl or cycloalkyl radical containing at most 6 carbon atoms; alk represents an alkyl radical containing at most 4 carbon atoms; it being understood that W does not represent H when A represents S, X represents S, Ra represents the 0-cyclohexyl radical or the unsubstituted NH-cyclohexyl radical and represents a double bond ", said products of formula (I) being under all racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 2 - Products of formula (I) as defined in claim 1 wherein represents a single or double bond; Ra represents a -O-cycloalkyl radical, or an optionally substituted -NH-cycloalkyl radical; X represents S, SO or SO2; A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the COR radical in which R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl themselves optionally substituted; an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR1R2 in which R1 and R2 are such that one of R1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected (s); ) among O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or else R3 and R4 form with the nitrogen atom to which they are bonded a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen among the halogen atoms, the hydroxyl, oxo, alkoxy, -O-CO-R5, NH2, NHalk, N (alk) 2 radicals and the alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl radicals, CO-phenyl, heteroaryl and S-heteroaryl, such that, in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl radicals, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2; R 5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 3 - Products of formula (I) as defined in any one of the other claims wherein Ra and X have the values defined in any one of the other claims and A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the COR radical in which R represents: a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4, alkoxy, hydroxy, phenyl or heterocycloalkyl radical, themselves optionally substituted; an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR1R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by an alkoxy, heterocycloalkyl or NR3R4 radical; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted, with NR3R4 such that R3 and R4, identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form with the nitrogen atom to which they are linked to a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl and heteroaryl radicals, such as in the latter radicals, alkyl radicals; , heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N (alk) 2 ; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 4 - Products of formula (I) as defined in any one of the other claims wherein Ra and X have the values defined in any of the other claims and A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted by a heterocycloalkyl radical or NR3R4; or the COR radical in which R represents: a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4 or alkoxy radical; a 0-phenyl or O- (CH 2) n -phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 2; or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom; , an alkyl radical optionally substituted with a heterocyclic radical or NR3R4, or else R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 radicals and alkyl and phenyl radicals, the latter being themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals of 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). - Products of formula (I) as defined in any one of the other claims wherein A represents NH, the substituents, Ra, X and W being chosen from among all the values defined for these radicals to any of the other claims, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). Products of formula (I) as defined in any one of the other claims in which A represents S, the substituents, Ra, X and W being chosen from among all the values defined for these radicals in any of the other claims. , said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 7- Products of formula (I) as defined in any one of the other claims corresponding to formula (Ia) or (Ib): RaH i NW 92 Ra in which Ra and W are chosen from the meanings indicated in any of the other claims, said products of formula (Ia) and (Ib) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral and organic acids or with mineral bases and organic products of said formula (la) and (Ib). 8- Products of formula (I) as defined in any one of the other claims, wherein represents a double bond corresponding to the products of formula (I "): Ra in which the substituents Ra, X, A and W have the meanings as indicated in any of the other claims, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids or with mineral bases and organic compounds of said products of formula (I) 209 - Products of formula (la) as defined in any one of the other claims wherein represents a double bond corresponding to the products of formula (I "a): Ra in which Ra and W are chosen from the meanings indicated in any one of the other claims, said products of formula (I "a) being in all isomeric possible racemic forms, enanti omegins and diastereoisomers, as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "a). - Products of formula (Ib) as defined in any one of the other claims, wherein represents a double bond corresponding to the products of formula (I "b): Ra in which Ra and W are chosen from the meanings indicated in any of the other claims, said products of formula (I "b) being in any possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I "b) 11 - Products of formula (I) as defined in any one of the preceding claims in which represents a single or double bond Ra represents a radical -O-cycloalkyl, or a radical -NH -cycloalkyl, optionally substituted with a hydroxyl, alkoxy or -O-CO-R5 radical, X represents S, A represents S, W represents a hydrogen atom or an optionally alkyl radical; is substituted with heterocycloalkyl or radical COR in which R represents: a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, or alkoxy; a 0-phenyl radical; or the radical NR1R2 in which R1 and R2 are such that one represents a hydrogen atom and the other represents an alkyl radical optionally substituted with a heterocycloalkyl radical; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical; R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 12 - Products of formula (I) as defined in any one of the other claims, having the following formulas: N- (6 - {[6- (cyclohexyl) [1,2,4] triazolo [4, 3-b] pyridazi n-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4.3] 1- (6 - {[6- (cyclopentyloxy) -1- (6 - {[6- (cyclopentyloxy)] -2- (1-pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [ N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl 2- (morpholin-4-yl) ethyl] 1- (6 - {[6- (Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] -benzothiazol-2-yl) -3- [2- (pyrrolidin-1-yl) ethyl] urea pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecar N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazolboxamide N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl 2-yl] cyclopropanecarboxamide cyclopropanecarboxamid 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} 1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea, and the addition salts with the mineral and organic acids or with the inorganic and organic bases of said formula (I). 13 - Process for the preparation of the products of formula (I) as defined in any one of the other claims described in the following schemes: Scheme 1: NH 2 reduction NH 2 reduction NH 2 NO 2 NO 2 QF HS NH, Ra-H i according to scheme Embedded image ## STR2 ## wherein R 5 represents a radical, ## STR2 ## wherein R 5 represents a radical, ## STR2 ## wherein R 5 represents a radical; alkyl; R6 represents an alkyl radical optionally substituted with NR3R4 (a - (CH2) n-NR3R4 radical), alkoxy, hydroxy, heterocycloalkyl, phenyl, - (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 at 4, R7 represents a cycloalkyl or alkyl radical optionally substituted with a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted, and Scheme 2: Ra E Ra E R7COX (P) t S NC HS reduction HS N t reduction L2 0 R2 NC, S Ra E // NR 'N M2 o R2 NHR1R2 (R) NC NC, SN reduction M1 HS o Re reduction S wherein R8 is cycloalkyl; Scheme 4R9 deprotection ~ ù O O Re Ra R9X (W) O reductive conditions E R9X (W) NCS ft9 E L4 NC 'LI Ra 2e "HN, R9 in which OR6 represents Ot-Butyl; Scheme 5: K diazotization bromination NH, CuBr2 NaNO2 N 111 L5 L6 Diagram 6 Reduction reaction on the group W il coupling Mlou M2 or M3 or NE 'reduction in all these schemes, if any, the groups CONRIR2, CO2R6 and COR7, which constitute W, can take the values of W such as defined in any one of claims 1 to 11 when WOH; R9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical as defined in any one of claims 1 to 11, and Ra and NR3R4 may take the meanings indicated in any one of claims 1 to 11. 14- Process for preparing the products of formula (I) as defined in any one of claims 1 to 11 wherein A represents NH, described in diagrams 1 and 3 as defined in claim 13 - The process defined in claim 13 for the preparation of the products of formula (I) as defined in any one of claims 1 to 11 in which A represents S, described in any one of Schemes 2, 3, 4 or 5 as defined in claim 13. As medicaments, the products of formula (I) as defined in any one of claims 1 to 12, as well as the salts of addition with the inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). 17 - As medicaments, the products of formula (I) as defined in claim 12, as well as addition salts with inorganic acids and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). 18 - Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any one of Claims 1 to 12, or a pharmaceutically acceptable salt of this product or a prodrug thereof. product and a pharmaceutically acceptable carrier. 19 - Use of the products of formula (I) as defined in any one of claims 1 to 12, or of pharmaceutically acceptable salts of these products for the preparation of a medicament for inhibiting the activity of MET protein kinase and its mutant forms - Use as defined in claim 19, wherein the protein kinase is in a cell culture. The use as defined in claim 19 or 20 wherein the protein kinase is in a mammal. 22 - Use of a product of formula (I) as defined in any one of claims 1 to 12, for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders of blood vessel proliferation, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers. 23 - Use of a product of formula (I) as defined in any one of claims 1 to 12 for the preparation of a medicament for the treatment of cancers. 24 - Use according to claim 23 for the treatment of solid or liquid tumors. 2941949 101 25 - Use according to claim 23 or 24 for the treatment of cancers resistant to cytotoxic agents. Use according to one or more of claims 23 to 24 for the treatment of primary tumors and / or metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC) cancers. and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system cancers bones and pancreas. 27 - Use of the products of formula (I) as defined in claims 1 to 12, for the preparation of medicaments for the chemotherapy of cancers. 28 - Use of the products of formula (I) as defined in claims 1 to 12, for the preparation of medicaments for cancer chemotherapy alone or in combination. 29 - Products of formula (I) as defined in any one of claims 1 to 12 as kinase inhibitors. - Products of formula (I) as defined in any one of claims 1 to 12 as MET inhibitors. As novel industrial products, the synthetic intermediates of formulas E ', M1, M2, M3 and N: 2 M1 HS HS HS HS HS M3 N in which R6 represents an alkyl radical optionally substituted with a group NR3R4 (a radical - (CH 2) n -NR 3 R 4), alkoxy, hydroxy, heterocycloalkyl, phenyl, - (CH 2) n -phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4, such that OR 6 represent the corresponding values of R as defined above; R7 represents a cycloalkyl or alkyl radical optionally substituted by a radical NR3R4, alkoxy, hydroxy or a phenyl radical, heteroaryl, or heterocycloalkyl, themselves optionally substituted as indicated in claim 1; and Ra, R1, R2, R3 and R4 have the meanings given in claim 1.