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  • A61K31/50—Pyridazines; Hydrogenated pyridazines
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to novel 6- (6-NH-substituted-triazolopyhdazine-sulfanyl) benzothiazole and benzimidazole derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such 6- (6-NH-substituted-triazolopyridazin-sulfanyl) benzothiazole and benzimidazole derivatives
• the present invention relates more particularly to novel derivatives of 6- (6-NH-substituted-triazolopyhdazine-sulfanyl) benzothiazoles and benzimidazoles exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.
• 6- (6-NH-substituted-triazolopyhdazine-sulfanyl) benzothiazoles and benzimidazoles exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.
• 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 of the use of drugs acting on metabolic pathways or constitutive elements of these pathways, mainly expressed in cancer cells, and which would be little or no expression in healthy cells.
• Protein kinases are 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.
• 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.
• 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.
• compositions having anticancer activity in particular by acting against to kinases.
• MET is preferred.
• MET or Hepatocyte Growth Factor Receptor
• HGF Hepatocyte Growth Factor
• MET is a receptor with tyrosine kinase activity expressed in particular by epithelial and endothelial cells.
• HGF Hepatocyte Growth Factor
• HGF is described as the specific ligand of MET.
• HGF is secreted by the mesenchymal cells and activates the MET receptor that moderates.
• 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 its mutants, which can be used for anti-angiogenic treatment, in particular in oncology.
• Rb represents a hydrogen atom or a fluorine atom
• Ra represents an -NH-Rc radical in which Rc represents an optionally substituted heterocycloalkyl, aryl, heteroaryl or -alkylcycloalkyl radical
• X represents S, SO or SO2;
• A represents NH or S;
• W represents a hydrogen atom; an alkyl or cycloalkyl 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 an NR3R4 radical, or by an alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted;
• Rb represents a hydrogen atom or a fluorine atom
• Ra represents an -NH-Rc radical in which Rc represents an optionally substituted heterocycloalkyl 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 radical COR in which R represents:
• a cycloalkyl radical or an alkyl radical, optionally substituted by an NR 3 R 4, alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted;
• 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, 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 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; 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
• N and NH this radical including the optional NH it contains being optionally substituted; all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl, aryl 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, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2- radicals; phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that in these latter radicals the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals
• 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).
• 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:
• R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom or 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 a plurality of 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
• A represents NH or S
• W represents a hydrogen atom; an alkyl radical optionally substituted by a heterocycloalkyl radical or NR3R4; or the radical COR in which R represents:
• 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 cyclo
• Ra, Rb, 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 possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as salts addition with the 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, Rb, 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 possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).
• Ra, Rb, and W are selected 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 the mineral 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 double bond corresponding to the products of formula (I "): wherein the substituents Ra, Rb, X, A and W have any of the meanings indicated above or hereafter, said products of formula (I) being in any isomeric possible 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).
• 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 (Ia '):
• Ra, Rb, and W are selected from any one of the meanings given above or hereafter, said products of formula (a) 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 (a).
• the subject of the present invention is the products of formula (I) as defined above or below, in which zzz represents a double bond corresponding to the products of formula (I “a): wherein Ra, Rb, and W are selected from any of the meanings given above or hereafter, said products of formula (I “a) 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 (I "a).
• Ra, Rb and W are selected from any one of the meanings given above or hereafter, said products of formula (b) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with the mineral 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): wherein Ra, Rb and W are selected from any of the meanings given above or hereafter, said products of formula (I “b) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "b).
• alkyl radical denotes the radicals, linear and optionally 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: 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 are preferred;
• 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 1 to 4 carbon atoms from the above list;
• halogen atom denotes the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom.
• 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;
• alkylcycloalkyl radical denotes linear, and if appropriate branched, alkyl radicals substituted with cycloalkyl radicals as defined above;
• 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, or alternatively oxetanyl or thietanyl radicals being optionally substituted;
• aryl and heteroaryl denote unsaturated or partially unsaturated, respectively carbocyclic and heterocyclic, monocyclic or bicyclic radicals, containing at most 12 members, which may optionally contain a -C (O) - chain, heterocyclic radicals containing one or more identical heteroatoms or different selected from O, N, or S with N, if appropriate, optionally substituted;
• 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.
• a carbocyclic radical containing a -C (O) - linkage is, for example, the tetralone radical;
• heteroaryl radical thus denotes monocyclic or bicyclic radicals containing 5 to 12 ring 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-pyhdyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such as 3- or 4-isoxazolyl, furazannyl, free or salified tetrazolyl
• 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:
• mineral bases such as, for example, one 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-methylglucanin,
• mineral bases such as, for example, one 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
• the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being able to be substituted by radicals chosen for example from the atoms of halogen, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
• alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl
• these alkyl radicals being able to be substituted by radicals chosen for example from the atoms of halogen, hydroxyl
• the addition salts with the inorganic 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.
• 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.
• stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on cycles, often called geometric isomé or cis-trans isomerism.
• 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 R 1 and R 2 can form on the one hand 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; NHaIk, 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
• 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 in particular optionally substituted by a 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, pyrrolidinyl and phenyl radicals are themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, oxo and alkoxy radicals.
• 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.
• NR1 R2 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.
• 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 selected 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 with one or two alkyl or piperazinyl radicals, optionally substituted on the second nitrogen atom by an alkyl, phenyl or CH 2 -phenyl radical, themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals.
• the subject of the present invention is in particular the products of formula (I) as defined above or below in which Rb represents a fluorine atom, the other substituents of said products of formula (I) having any of the definitions indicated above or below.
• Ra represents an optionally substituted -NH-heterocycloalkyl radical
• Rb represents a hydrogen atom
• X is S
• A represents S
• W represents a hydrogen atom
• the present invention thus relates to the products of formula (I) as defined above or below having the following formulas: 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] N- (tetrahydro-2H-pyran-4-yl) [1,2,4] triazolo [4,3-b] pyridazin-6-amine
• 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 present invention thus also relates to the process for preparing products of formula (I) according to Scheme 2 as defined below.
• the present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 3 as defined below
• the subject of the present invention is therefore also the process for preparing products of formula (I) according to Scheme 4 as defined below.
• the subject of the present invention is therefore also the process for the preparation of products of formula (I) according to schema 5 as defined below
• the present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 6 as defined below
• the products of formula (I) as defined above in which represents a single or double bond are also examples of synthetic intermediates as defined below of formulas (a), (b) ), (c), (d), (e) and (f) wherein zzz ⁇ represents a single or double bond, the compounds of formulas (a 1 ), (b 1 ), (c 1 ), ( d 1 ), (e 1 ) and (f) in which zzz ⁇ represents a single bond, and compounds of formulas (a "), (b"), (c “), (d"), (e ") and (f) wherein - represents a double bond.
• the benzimidazoles of the general formula (1a “), (1b"), (1c “), (1d") and (1e ") as well as their reduced analogues of the general formula (1a) 1 ), (1b 1 ), (1c '), (1d') and (1 e 1 ) can be prepared from 3,6-dichloro [1,2,4] thazolo [4,3-b] commercial pyridazine of formula (S)
• the compounds (E) can be obtained, for example, by reaction of amines on the compound (S).
• the reaction is carried out, for example, at a temperature in the region of 20 to 50 ° C.
• 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.
• Q 3-amino-4-nitrophenyl thiocyanate
• 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 ') such that zz 1 are a single bond can be obtained, for example, by reduction with zinc (O) on the compounds of formula (G), in the presence of acetic acid, at a temperature close to 20 ° C.
• the carbamates of general formula (1 a ') and (1 a ") can be prepared in particular as described in patent WO03028721A2, but from a 3,4-diamino phenyl sulfide of formula (H') respectively. 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 in the region of 80 ° C.
• the benzimidazoles of general formula (1b ') and (1b ") 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 (1 a ') and (1 a "), 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.
• 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 presence of a protic solvent such as ethanol. The reaction is carried out at a temperature in the region of 80 ° C.
• the 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (K) can be prepared as described by K, Papke and R, Pohloudek-Fabini in Pharmazie; GE; 22, 1967, P229-233, by reaction of potassium thiocyanate and 3-fluoroaniline in the presence of bromine in acetic acid.
• 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 (M1), (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-dimethylfornnannide, in the presence of a base such as triethylamine and at a temperature of about 95 ° C or between 20 0 C and 95 ° C.
• a solvent such as N, N-dimethylfornnannide
• a base such as triethylamine
• aryl-thiol intermediates above can exist in the form of free thiols or in the form of disulphides or a mixture of the two forms which can be engaged indifferently in the course of the reactions.
• a chlorocarbonate of formula (O) (X Cl)
• benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a 1 ), (2b 1 ), (2c 1 ) and (2d ') can be prepared for example:
• the reducing conditions 1) and 2) can give products of formula (2a), (2b), (2c) and (2d) such that zzz ⁇ represent a single or double bond whereas conditions 3) and 4) give products of formula (2a),
• the compounds of formula (E) can be obtained, for example, as shown in scheme 3 above, from commercially available 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine of formula (S).
• the compounds of formula (E) wherein Ra represents an NHRc radical can be obtained by treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyhdazine (S) with a amine of formula RcNH2, at a temperature of 20 0 C and in a solvent such as N 1 N- dimethylformamide at a temperature between 20 ° C and 50 0 C.
• Scheme 4 Synthesis of benzothiazole derivatives of formula (2e 1 ) and (2e ")
• (2e ) can be prepared respectively from compounds of formulas (2a 1 ) and (2a").
• 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).
• the compounds of general formula (2e 1 ) and (2e ") can be obtained respectively by treatment of compounds (T) and (T") isolated, for example, with trifluoroacetic acid, in a solvent such as dichloromethane, at a temperature of 20 0 C,
• 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 of sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature of about 80 ° C., optionally followed by an in situ treatment with trifluoroacetic acid at 20 ° C. if necessary.
• the 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 sodium hydride, at a temperature of between 20 and 90 ° C.
• the benzothiazoles of the general formula (2e ") can be prepared 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 general formula (2e 1 ) can be prepared from compounds of formula (2e "), according to the methods described below for the preparation of compounds (I 1 ) from 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 with an alkoxy, heterocycloalkyl or NR 3 R 4 radical (R 3 and R 4 as defined above).
• the compounds of formulas (L5) can be prepared from 2-amino-1,3-benzothiazol-6-yl (K) thiocyanate (commercial compound), for example by treatment with an alkyl nitrite and bromide. cuprous 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.
• Figure 6 Other synthetic routes of reduced derivatives of formulas (I 1 )
• the benzothiazoles of general formula (T) may also be prepared, starting from the compounds of formula (I "), by reduction, for example, with sodium borohydride, in a solvent such as ethanol, at a temperature of about 80 0 C or by reduction with zinc (0) in the presence of acetic acid, at a temperature of 20 0 C.
• the compounds (T) can also be prepared from the compounds of formula (E ') by coupling with the M1-type compounds,
• the compounds of type M1, M2 or M3 can also be isolated and used for coupling with (E ').
• the compounds (E ') can be obtained from the compounds of formula (E) by reduction, for example, by reduction with zinc (O) in the presence of acetic acid, at a temperature of 20 ° C.
• the compounds (V) 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: transformations of 2d '/ 2d "into 2a' / 2a" and into 2c '/ 2c ", transformations from 2a' / 2a" into 2d '/ 2d "and into 2b' / 2b".
• 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.
• hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, thmethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
• alkyl radicals such as tert-butyl, thmethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl
• amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl, BOC, benzyloxycarbonyl, phthalimido or other radicals known in peptide chemistry,
• esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry.
• 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.
• a solvent such as methanol or ethanol, dioxane or dimethoxyethane
• the optional free or esterified carboxy functions of the products described above may, if desired, be reduced in alcohol function by the methods known to those skilled in the art: the optional esterified carboxy functions may, if desired, be reduced depending on the 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 alkoxy functions, such as in particular methoxy, 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.
• 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.
• the phthalimido group can be removed by hydrazine.
• 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.
• hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol.
• 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.
• the subject of the invention is, as medicaments, the products corresponding to the following formulas: 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N- (tetrahydro-2H) pyran-4-yl) [1,2,4] thazolo [4,3-b] pyridazin-6-amine
• 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.
• 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.
• 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 present invention also relates to the use of products of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease characterized by the disruption of the activity 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.
• 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, in particular in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, bone and pancreas.
• NSCLC and SCLC lung cancers
• glioblastomas thyroid, bladder, breast, melanoma
• lymphoid or myeloid hematopoietic tumors sarcomas
• brain larynx
• lymphatic system bone 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.
• kinase inhibitors there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpuhne called olomucine.
• the subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas M1, M2, M3 and N as defined above and recalled hereinafter:
• N- (6 - ⁇ [6- (tetrahydro-2H-pyran-4-ylamino) [1,2,4] triazolo [4,3-b] pyridazin-3- [Sulfanyl] -1,3-benzothiazol-2-yl) acetamide can be prepared in the following manner: 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N- (tetrahydro-2H-pyran-4-yl) [1,2,4] triazolo [4,3-b] pyridazin-6-amine (1a) and 0.42 cm 3 of
• Example 3 N- (6 - ⁇ [6- (tetrahydro-2H-pyran-4-ylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3 benzothiazol-2-yl) cyclopropanecarboxamide
• N- (6 - ⁇ [6- (tetrahydro-2H-pyran-4-ylamino) [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 2a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6) -yl) sulfanyl] -N- (tetrahydro-2H-pyran-4-yl) [1,2,4] triazolo [4,
• 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 Commercial -yl in 94 cm 3 of tetrahydrofuran, is added at 20 ° C, 7.5 g of phenyl chlorocarbonate and 4,05g of sodium hydrogencarbonate and 9.4 cm 3 of water. The resulting mixture is then stirred at 20 ° C. for 20 h and then extracted with 2x150 cm 3 of ethyl acetate. The organic phases are collected and washed with 3X50cm 3 of a saturated aqueous solution of sodium hydrogencarbonate.
• N 2 , N 2 -dimethyl-N- (6 - ⁇ [6- (tetrahydro-2H-pyran-4-ylamino)] [1,2,4] ] thazolo [4,3-b] pyridazin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) glycinamide can be prepared in a manner similar to Example 1a but from 420 mg of the crude residue thiocyanate 2 - [(N 1 N-dimethylglycyl) amino] -1, 3-benzothiazol-6-yl
• Example 4 0.2 g Excipient for a tablet finished at 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).
• Examples 3 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.
• the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at -80 ° C.
• the cell pellets are resuspended in the 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.
• buffer A 50 mM HEPES, pH 7.5, 250 mM NaCl, 10% glycerol, 1 mM TECP
• the lysing supernatant is incubated for 2 hours at 4 ° C with Nickel Chelate resin (His-Trap 6 Fast Flow TM, 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).
• Fractions containing the protein of interest in view of the electrophoretic analysis are pooled, concentrated by Ultrafiltration (cut-off 1 OkDa) and injected on an exclusion chromatography column (Superdex TM 200, GE HealthCare) equilibrated in buffer A. After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast Flow TM, GE HealthCare) equilibrated in Buffer A. The fractions eluted by a buffer B gradient and containing the protein after electrophoresis (SDS PAGE), are finally collected and stored at -80 ° C.
• the preceding fractions are incubated for 1 h at room temperature after addition of 2 mM ATP, 2 mM MgCl 2, and Na 3 VO 4. 4 mM.
• 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 phosphorylation level is verified by mass spectrometry (LC-MS), and by peptide mapping.
• Test A HTRF MET assay in 96-well format
• final 5 nM MET is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 ⁇ M, final DMSO 3%) in MOPS 1 OmM buffer pH 7.4, DTT 1 mM, Tween 20 0.01%.
• the reaction is initiated by the substrate solution to obtain the final concentrations of poly- (GAT) 1 ⁇ g / ml, 10 ⁇ M ATP and 5mM MgCl 2.
• Test B Inhibition of MET autophosphorylation; ELISA technique (pppY1230,1234,1235) a) Cell lysates: Inoculate MKN45 cells in 96-well plate (CeII coat BD polylysine) at 20,000 cells / well under 200 ⁇ l in RPMI medium + 10% FCS + 1% L-glutamine. 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.
• Lysis buffer 1 OmM Tris, pH 7.4 HCl, 10 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20 mM NaF, 2 mM Na3VO4, 1 mM mM PMSF and anti protease cocktail.
• the 10 ⁇ l of lysates are transferred into a V-bottom polypropylene plate and the ELISA is carried out immediately or the plate is frozen at -80 ° C.
• kit plate In each well of the kit plate, add 70 ⁇ l of kit dilution buffer + 30 ⁇ l of cell lysate or 30 ⁇ l of lysis buffer for the blanks. Incubate for 2h with gentle shaking at room temperature. Rinse the wells 4 times with 400 ⁇ l of kit wash buffer. Incubate with 10 ⁇ l of anti-phospho MET antibody for 1h at room temperature.
• kit wash buffer Put 100 ⁇ l of chromogen and incubate 30 minutes in the dark at room temperature.
• Test C Measurement of Cell Proliferation Using 14C-Thymidine
• the cells are seeded in 96-well Cytostar plates at 180 ⁇ l 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 the rate of 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine.
• HCT116 cells at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L Glutamine
• MKN45 cells at the rate of 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine.
• the products are added under 10 ⁇ l in 20-fold concentrated solution according to the dilution method mentioned for the ELISA.
• the products are tested at 10 concentrations in duplicate from 1000OnM to 0.3nM with a pitch of 3.
• 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 in particular to i microM.
• 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 50 nm and the sign ++ corresponds to less than 100 nm. . for test B the sign + corresponds to less than 50OnM and the sign ++ corresponds to less than 10OnM. for the C test the + sign corresponds to less than 10 microM and the sign ++ corresponds to less than microM.

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