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  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to novel imidazo [1,2-a] pyridine derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such imidazo derivatives [1, 2-a] pyhdine.
• the present invention relates more particularly to novel imidazo [1,2-a] pyhdine derivatives exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.
• 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.
• Ra represents a hydrogen atom; a halogen atom; an aryl radical; or a heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below;
• Rb represents a hydrogen atom, an Rc radical, -COORc, -CO-Rc or a -CO-NRcRd radical; with Rc represents an alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl radical, all these radicals being optionally substituted as indicated below;
• Rd represents a hydrogen atom or an alkyl or cycloalkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted with one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy, CN, CF3, -NR1 R2, -COOH radicals; , -COOaIk, -CONR1 R2, -NR1 COR2, COR1, oxo and heterocycloalkyl itself optionally substituted by one or more radicals selected from halogen atoms, and hydroxyl, alkoxy, alkyl, CN, CF3, -NR3R4 radicals; COOH, -COOaIk, -CONR3R4, -NR3COR4, -COR3 and oxo; the alkyl and cycloalkyl radicals being furthermore optionally substituted with an aryl or heteroaryl
• NR1 R2 being such that: either, R1 and R2 being identical or different, 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 radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; hydroxyl, alkyl, alkoxy, NH 2; NHaIk and N (alk) 2; either 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 possible NH; that it contains being optionally substituted;
• NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 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, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl radicals; alkoxy, NH2; NHaIk and N (alk) 2; or R3 and R4 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 (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R
• alkyl, phenyl, CH 2 -phenyl and heteroaryl radicals such as in the latter radicals the alkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen from halogen atoms.
• Ra represents a hydrogen atom; a halogen atom; or an aryl or heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below;
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents an alkyl radical or a cycloalkyl radical, both optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NR1 R2, heterocycloalkyl, aryl and heteroaryl radicals themselves optionally substituted as indicated below; Rd represents a hydrogen atom or an alkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted by one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy, -NR1 R2, -COOH, -COOaIk radicals, -CONR1 R2, alkyl and heterocycloalkyl itself optionally substituted with one or more radicals selected from halogen atoms, and alkyl, COOH, -COOaIk and
• NR1 R2 being such that: either, R1 and R2 being identical or different, 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 radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; hydroxyl, alkyl, alkoxy, NH 2; NHaIk and N (alk) 2; 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 1 any NH it contains being optionally substituted; NR3R4 being such that: either, R3 and R4 being identical or
• Ra represents a hydrogen atom; a halogen atom; an aryl radical; or a heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below;
• Rb represents a hydrogen atom, an Rc radical, -COORc, -CO-Rc or a -CO-NRcRd radical; with Rc represents an alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl radical, all these radicals being optionally substituted as indicated below;
• Rd represents a hydrogen atom or an alkyl or cycloalkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted with one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy, CN, CF3, -NR1 R2, -COOH radicals; , -COOaIk, -CONR1 R2 and -NR1 COR2; the alkyl radicals being furthermore optionally substituted with an aryl or heteroaryl radical, themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy and NR3R4 radicals; the cycloalkyl, heterocycloalkyl, aryl or heteroaryl radicals being furthermore optionally substituted by an alkyl radical, itself optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl
• NR1 R2 being such that: either, R1 and R2 being identical or different, 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 radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted; 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 1 any NH it contains being optionally substituted;
• NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl radical; or an alkyl radical optionally substituted with one or more identical radicals or different from the hydroxyl, alkoxy, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted, or R3 and R4 together with the nitrogen atom to which they are bonded form a cyclic radical 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; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, oxo
• Ra represents a hydrogen atom; a halogen atom; or an aryl or heteroaryl radical, these aryl and heteroaryl radicals being optionally substituted as indicated below;
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents an alkyl radical or a cycloalkyl radical, both optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NR 1 R 2, heterocycloalkyl, aryl and heteroaryl radicals themselves optionally substituted as indicated below;
• Rd represents a hydrogen atom or an alkyl radical; all the radicals defined above, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, being optionally substituted with one or more radicals chosen from halogen atoms, and hydroxyl and alkoxy radicals,
• NR1 R2 being such that: either, R1 and R2 being identical or different, 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 radical cycloalkyl or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted; 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 1 any NH it contains being optionally substituted;
• NR3R4 being such that: either, R3 and R4 being identical or different, one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 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, heterocycloalkyl, heteroaryl or phenyl radicals, themselves optionally substituted, or R 3 and R 4 form, with the nitrogen atom to which they are bonded, 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; the cyclic radicals that can be formed by R 1 and R 2 or R 3 and R 4 respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals,
• Ra represents a hydrogen atom; a halogen atom; or a phenyl or pyrazolyl radical optionally substituted by one or more radicals chosen from halogen atoms, and the hydroxyl, alkoxy, -NR1 R2, -COOH, -COOaIk, -CONR1 R2, alkyl and heterocycloalkyl radicals, which may itself be substituted.
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical
• Rc represents an alkyl or cycloalkyl radical, both optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NR1 R2 radicals and phenyl itself optionally substituted by one or more radicals chosen from halogen atoms, radicals; hydroxyl, alkoxy, alkyl, NH 2, NHaIk and N (alk) 2;
• Rd represents a hydrogen atom or an alkyl radical
• NR1 R2 is such that either, where R1 and R2 are the same or different, one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 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, NR 3 R 4 radicals, or phenyl radical, itself optionally substituted with one or more radicals chosen from among the radicals; halogen atoms and hydroxyl, alkyl, alkoxy, NH 2 radicals; NHaIk and N (alk) 2; or R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 4 to 7 members and optionally another heteroatom selected from O, S, N and NH, this radical including the optional NH that it contains being optionally substituted; NR3R4 being such that either R3 and R4 are identical or different, represent a
• Ra represents a hydrogen atom; a halogen atom; or a phenyl or pyrazolyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl and heterocycloalkyl radicals, itself optionally substituted by one or more radicals chosen from halogen atoms and alkyl and -COOaIk radicals;
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents an alkyl or cycloalkyl radical optionally substituted by one or more radicals chosen from hydroxyl, alkoxy and NR1 R2 radicals;
• Rd represents a hydrogen atom;
• NR1 R2 being such that either R1 and R2, which may be identical or different, represent a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and NH2 radicals; NHaIk and N (alk) 2 or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 4 to 7 members and optionally another heteroatom chosen from O, S, N and NH, optionally substituted by an alkyl, phenyl or -CH 2 -phenyl radical, the latter radicals themselves being optionally substituted with one or more identical or different radicals chosen 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: Ra represents a hydrogen atom; a halogen atom; or an optionally substituted phenyl radical as indicated below;
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents an alkyl or cycloalkyl radical, both optionally substituted with one or more radicals chosen from hydroxyl, alkoxy, NR1 R2 radicals and phenyl itself optionally substituted by one or more radicals chosen from halogen atoms, radicals; hydroxyl, alkoxy, alkyl, NH 2, NHaIk and N (alk) 2; Rd represents a hydrogen atom or an alkyl radical;
• NR1 R2 is such that either, R1 and R2 being identical or different, 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 one or more identical or different radicals chosen from hydroxyl, alkoxy, NR3R4 or phenyl radicals, themselves optionally substituted; or R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 4 to 7 members and optionally another heteroatom selected from O, S, N and NH, this radical including the optional NH that it contains being optionally substituted; NR3R4 being such that either R3 and R4 are identical or different, represent a hydrogen atom or an alkyl radical optionally substituted by one or more identical or different radicals chosen from hydroxyl or alkoxy radicals, or R3 and R4 form with the atom of nitrogen to which they are attached
• the subject of the present invention is the products of formula (I) as defined above or below, in which: Ra represents a hydrogen atom; a halogen atom; or a phenyl radical optionally substituted by a halogen atom;
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents an alkyl or cycloalkyl radical optionally substituted by one or more radicals chosen from hydroxyl, alkoxy and NR1 R2 radicals;
• Rd represents a hydrogen atom
• NR1 R2 being such that either R1 and R2, which may be identical or different, represent a hydrogen atom or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy and NH2 radicals; NHaIk and N (alk) 2 or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 4 to 7 members and optionally another heteroatom chosen from O, S, N and NH, optionally substituted by an alkyl, phenyl or -CH 2 -phenyl radical, the latter radicals themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals.
• alkyl (or alk) radical denotes the radicals, linear and, if 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: 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;
• 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; morpholinyl, thiomorpholinyl, homomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyran, oxodihydropyridazinyl, or alternatively oxetanyl, all these radicals being optionally substituted; mention may in particular be made of morpholinyl, thiomorpholinyl, homomorpholinyl, piperazinyl, piperidyl, homopiperazinyl or pyrrol
• 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, pyranyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyhdyl, 3-pyhdyl and 4-pyhdyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiathazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazolyl
• heteroaryl or bicyclic radicals there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl, benzothiazolyl or benzimidazolyl 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 ,
• 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-d
• the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these radicals alkyls which may be substituted with radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, for example in the chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl or methylthiomethyl groups, dimethylaminoethyl, benzyl or phenethyl.
• alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl
• these radicals alkyls which may be substituted with radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl
• the addition salts with the mineral or organic acids of the products of formula (I) may 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.
• hydrochloric hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic,
• 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 rings, often called geometric isomerism 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.
• 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 and morpholinyl radicals.
• homomorpholinyl piperazinyl or homopiperazinyl, these radicals themselves being optionally substituted as indicated above or hereafter: for example by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals, phenyl and CH 2 -phenyl, the alkyl or phenyl radicals themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals.
• NH2 NHaIk and N (alk) 2
• the NR 1 R 2 or NR 3 R 4 ring may more particularly be chosen from pyrrolidinyl and morpholino 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 optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals.
• Ra represents a hydrogen atom or a phenyl or pyrazolyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl and piperidyl radicals, itself optionally substituted with -COOaIk;
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents a cyclopropyl radical or an alkyl radical optionally substituted by an alkoxy radical or NR1 R2;
• Rd represents a hydrogen atom
• NR1 R2 being such that either R1 and R2 are identical or different, represent a hydrogen atom or an alkyl radical or R1 and R2 form with the nitrogen atom to which they are attached a morpholinyl radical; the above alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all the 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).
• Ra represents a hydrogen atom or a phenyl radical optionally substituted with a halogen atom
• Rb represents a hydrogen atom, a -CO-Rc radical or a -CO-NRcRd radical; with Rc represents a cyclopropyl radical or an alkyl radical optionally substituted by an alkoxy radical or NR1 R2;
• Rd represents a hydrogen atom
• NR1 R2 being such that either R1 and R2 are identical or different, represent a hydrogen atom or an alkyl radical or R1 and R2 form with the nitrogen atom to which they are attached a morpholinyl radical; the above alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all the 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).
• the subject of the present invention is particularly the products of formula (I) as defined above, corresponding to the following formulas: ⁇ - ⁇ 6- (imidazo [1,2-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl ⁇ cyclopropanecarboxamide
• the present invention also relates to any process for preparing the products of formula (I) as defined above.
• Diagrams 1, 2 and 3 below are illustrative of the methods used for the preparation of the products of formula (I). As such, they 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 method described in diagrams 1, 2 and 3 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 present invention thus also relates to the process for preparing products of formula (I) according to Scheme 3 as defined below.
• Rb CON (Rc) Rd
• a Glennon et al. Journal of Medicinal Chemistry, 1981, 24, 766-769).
• the compounds (C) can be obtained by hydrolysis of the acetamide function of the compounds (B) according to a method customary for those skilled in the art, for example with the aid of acid such as hydrochloric acid, in a solvent such as ethanol, at a temperature of between 20 ° C. and the reflux of the solvent.
• the compounds (B) can be obtained by coupling the compounds (A) with Ra as defined above with N- (4-sulfanylphenyl) acetamide (commercial product) under the conditions described for example by R. Varala et al. . (Chemistry Letters, 2004, 33 (12), 1614-1615), by M. Winn et al. (Journal of Medicinal Chemistry, 2001, 44, 4393-4403) in the presence of a base such as potassium carbonate in a solvent such as dimethylsulfoxide at a temperature between 20 ° C and the reflux temperature of the solvent. Such reactions can also be carried out under microwave irradiation.
• the compounds (B) can also be obtained by coupling the compounds (A) as described above with other 4-aminothiophenol derivatives such as (4-NHR) Ph-SH derivatives or the amine function is free ((4 -NH 2 ) Ph-SH, commercial product) or protected by a t-butyloxycarbonyl group for example ((4-NHCO 2 tBu) Ph-SH, known product).
• 4-aminothiophenol derivatives such as (4-NHR) Ph-SH derivatives or the amine function is free ((4 -NH 2 ) Ph-SH, commercial product) or protected by a t-butyloxycarbonyl group for example ((4-NHCO 2 tBu) Ph-SH, known product).
• the compounds (II) for which Rc and Rd have the same meanings indicated above can be obtained for example by reducing the compounds (G) with DL-dithiotreitol, in the presence of hydrogen carbonate.
• the compounds (F) can be obtained from 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial product) as described above for the preparation of the compounds (D).
• the compounds (K) for which Rc has the same meanings given above can be obtained, for example, by reducing the compounds (J) with DL-dithiotreitol, in the presence of sodium hydrogen carbonate or potassium dihydrogen phosphate in a solvent. such as ethanol and at a temperature between 20 0 C and the reflux of the solvent.
• hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
• 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 peptide chemistry,
• the acid functions can 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.
• intermediate products or products of formula (I) thus obtained can be subjected, if desired and if necessary, to the processes described 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) a saponification reaction of ester function in acid function, c) a reduction reaction of the free or esterified carboxy function as a function of alcohol, d) an alkoxy function-to-hydroxyl function conversion reaction, or also an alkoxy-functional hydroxyl function, e) an elimination reaction of the protective groups that the protected reactive functions, f) a salification reaction with an inorganic or organic acid or a base to obtain the corresponding salt, g) a racially structured split reaction
• These products of formula (I) thus obtained are in all possible isomeric forms racemic, 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.
• 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 methylene chloride, for example by hydrobromide or pyridine hydrochloride or again with hydrobromic or hydrochloric acid in water or refluxing trifluoroacetic acid.
• 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. 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: - ⁇ / - ⁇ [6- (imidazo [1,2-a] pyridin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl ⁇ cyclopropanecarboxamide
• 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.
• 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.
• 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, tablets, capsules, drops, granules, preparations and the like. injectables, 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 (I) 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.
• 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 (A), (B), (C), (D), (E), (F), (G), (H ), (J) and (K) as defined above and recalled below:
• the nomenclature of the compounds of this invention was carried out with ACDLABS software version 10.0.
• the microwave oven used is a Biotage device, Initiator TM 2.0, 400W max, 2450 MHz.
• Example 1a ⁇ - ⁇ 6- (imidazo [1,2-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl ⁇ cyclopropanecarboxamide
• the compound can be prepared in the following manner:
• Example 1b 6- [Imidazo [1,2-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine
• the compound can be prepared in the following manner:
• Example 1 c 1- [2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea
• the compound can be prepared in the following manner: A suspension of 900 mg of 2 - ( ⁇ [2- (morpholin-4-yl) ethyl] carbamoyl ⁇ amino) -1,3-benzothiazol-6-yl thiocyanate in 35 ml of ethanol at 20 0 C is added a solution of 11 mg of potassium dihydrogenphosphate in 2.3 ml of water followed by 1.1 g of DL-dithiothreitol. The white suspension is stirred for 18 hours under reflux. We cool the mixture reaction at 20 0 C and then added 30 ml of water and stirred for 15 minutes. The precipitate formed is drained and washed with large volumes of water.
• Example 1d 2 - ( ⁇ [2- (Morpholin-4-yl) ethyl] carbamoyl ⁇ amino) -1,3-benzothiazol-6-yl thiocyanate
• the compound can be prepared in the following manner: To a solution of 1 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate in 30 ml of tetrahydrofuran is added 0.44 ml of 2- morpholin-4-ylethanamine at 20 ° C. The reaction medium is stirred at 20 ° C for 24 hours and then concentrated by evaporation under reduced pressure. The residue obtained is chromatographed on a Merck 70g cartridge (solid deposit, elution with a dichloromethane gradient and then 90/10 dichloromethane / methanol).
• Example 1 e Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate
• the compound can be prepared in the following manner:
• Example 2a 6 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-amine
• the compound can be prepared in the following manner:
• Example 2b 4 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ aniline
• the compound can be prepared in the following manner:
• Example 2c ⁇ - (4 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ phenyl) acetamide
• the compound can be prepared in the following manner:
• Example 2d 3-bromo-6- (4-fluorophenyl) imidazo [1,2-a] pyridine
• the compound can be prepared in the following manner:
• Example 2e 6- (4-fluorophenyl) imidazo [1,2-a] pyridine
• the compound can be prepared as follows: To a mixture of 3.44 g of 6-iodoimidazo [1,2-a] pyridine, 110 g of dioxane, 132 mg of palladium tetrakistriphenylphosphine and 2.1 g of sodium hydrogencarbonate dissolved in 65 ml of water are added 1.76 g of 4-fluorophenylboronic acid. The reaction medium is heated at 90 ° C. for 1.5 hours. 0.3 g of 4- acid are then added. fluorophenylboronic and the medium is again heated at 80 0 C for 1 hour.
• the compound can be prepared as described by C. Enguehard et al., Helvetica Chimica Acta (2001), 84, 3610-3614.
• the compound can be prepared in the following manner:
• the compound can be prepared in the following manner:
• Example 5 1- (6 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- (2- methoxyethyl) urea
• Example 5a 1- (6 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- (2-methoxyethyl) urea
• the compound can be prepared in the following manner: To a suspension of 0.1 g of (6 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate. phenyl in 3 ml of tetrahydrofuran is added 18.6 ⁇ l of 2-methoxyethanannine. After stirring for 5 hours at a temperature in the region of 20 ° C., 18 ⁇ l of 2-methoxyethanamine dissolved in 2 ml of tetrahydrofuran are added and the reaction mixture is stirred overnight at a temperature in the region of 20 ° C.
• Example 5b Phenyl 6 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) carbamate
• the compound can be prepared as follows:
• Example 6 1- (6 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea
• the compound can be prepared as in Example 5a but starting from 0.15 g of (6 - ⁇ [6- (4-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1 Phenyl 3-benzothiazol-2-yl) carbamate, 46 ⁇ l of 2- (morpholin-4-yl) ethanamine and 5 ml of tetrahydrofuran.
• Example 7a ⁇ - (6 - ⁇ [6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazole 2-yl) cyclopropanecarboxamide
• the compound can be prepared as in Example 1b but starting from 0.57 g of 3-bromo-6- (1-methyl-1H-pyrazol-4-yl) imidazo [1, 2-a] pyridine, 0.618 g of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 0.852 g of potassium carbonate and 5 ml of dimethylsulfoxide.
• Example 7b (6-Sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide
• the compound can be prepared in the following manner:
• Example 7c (6-thiocyanato-1,3-benzothiazol-2-yl) cyclopropane carboxamide
• the compound can be prepared in the following manner:
• Example 7d 3-bromo-6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine
• the compound can be prepared as in Example 2d but from 1, 5 6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine, 0.46 ml of bromine, 20 ml of water and 30 ml of ethanol. There is thus obtained 1.72 g of 3-bromo-6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyhidine as a cream solid.
• the compound can be prepared as in Example 2e but starting from 3 g of 6-iodoimidazo [1,2-a] pyhidine, 27 ml of dimethylformamide, 125 mg of palladium tetrakistriphenylphosphine, 1,4 g of sodium hydrogen carbonate in solution in 18 ml of water and 2.7 g of (1-methyl-1H-pyrazol-4-yl) boronic acid. There is thus obtained 1.5 g of 6- (1-methyl-1H-pyrazol-4-yl) imidazo [1,2-a] pyridine.
• Example 8 ⁇ - (6 - ⁇ [6- (1H-pyrazol-4-yl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide
• Example 8a ⁇ - (6 - ⁇ [6- (1H-pyrazol-4-yl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide
• the compound can be prepared as in Example 1b but from 0.331 g of 3-bromo-6- (1H-pyrazol-4-yl) imidazo [1,2-a] pyhidine, 0.252 g of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 0.278 g of potassium carbonate and 3.3 ml of dimethylsulfoxide.
• Example 8b 3-bromo-6- (1H-pyrazol-4-yl) imidazo [1,2-a] pyridine
• the compound can be prepared as in Example 2d but from 0.789 g of 6- (1H-pyrazol-4-yl) imidazo [1,2-a] pyridine H-pyrazol-4-yl) imidazo [1,2-a] pyridine, 0.263 ml of bromine, 10 ml of water and 16 ml of ethanol. There is thus obtained 1 g of 3-bromo-6- (1H-pyrazol-4-yl) imidazo [1,2-a] pyridine as a brown solid.
• the compound can be prepared as in Example 2e but from 2 g of 6-iodoimidazo [1,2-a] pyhidine, 18 ml of dimethylformamide, 85 mg of tetrakistriphenylphosphine palladium, 0.84 g of sodium hydrogencarbonate dissolved in 12 ml of water and 0.96 g of (1H-pyrazol-4-yl) boronic acid. 0.789 g of 6- (1H-pyrazol-4-yl) imidazo [1,2-a] pyridine are thus obtained.
• Example 9a ⁇ - (6 - ⁇ [6- (3-fluorophenyl) imidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2-yl) cyclopropanecarboxamide
• the compound can be prepared as in Example 1b but starting from 0.9 g of 3-bromo-6- (3-fluorophenyl) imidazo [1,2-a] pyridine, 0.9 g of (6 sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 0.910 g of potassium carbonate and 9 ml of dimethylsulfoxide.
• Example 9b 3-bromo-6- (3-fluorophenyl) imidazo [1,2-a] pyridine
• the compound can be prepared as in Example 2d but from 1.7 g of 6- (3-fluorophenyl) imidazo [1,2-a] pyridine, 0.42 ml of bromine, 20 ml of water and 35 ml of ethanol. There is thus obtained 1 g of 3-bromo-6- (3-fluorophenyl) imidazo [1,2-a] pyridine as a brown solid.
• the compound can be prepared as in Example 2e but from 2 g of 6-iodoimidazo [1,2-a] pyhidine, 35 ml of dimethylformamide, 83 mg of palladium tetrakistriphenylphosphine, 1.64 g of sodium hydrogen carbonate in solution in 23 ml of water and 1.23 g of 3-fluorophenylboronic acid. 1.7 g of 6- (3-fluorophenyl) imidazo [1,2-a] pyhidine are thus obtained.
• Example 10a ⁇ - (6 - ⁇ [6 - ((3-fluoro, 4-methyl) phenyl) innidazo [1,2-a] pyridin-3-yl] sulfanyl ⁇ -1,3-benzothiazol-2 yl) Cyclopropanecarboxamide
• the compound can be prepared as in Example 1b but starting from 1.22 g of 3-bromo-6 - ((3-fluoro, 4-methyl) phenyl) imidazo [1,2-a] pyridine, 1.03 g of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 1.3 g of potassium carbonate and 9 ml of dimethylsulfoxide.
• Example 10b 3-Bromo-6 - ((3-fluoro, 4-methyl) phenyl) imidazo [1,2-a] pyridine
• the compound can be prepared as in Example 2d but from 1.7 g of 6 - ((3-fluoro, 4-methyl) phenyl) imidazo [1,2-a] pyridine, 0.37 ml of bromine, 15 ml of water and 30 ml of ethanol. There is thus obtained 1.22 g of 3-bromo-6 - ((3-fluoro, 4-methyl) phenyl) imidazo [1,2-a] pyhidine as a gray solid.
• Example 10c 6 - ((3-fluoro, 4-methyl) phenyl) imidazo [1,2-a] pyridine
• the compound can be prepared as in Example 2e but starting from 2.1 g of 6-iodoimidazo [1,2-a] pyridine, 30 ml of dimethylformamide, 85 mg of palladium tetrakistriphenylphosphine, 1.73 g. sodium hydrogen carbonate in solution in 23 ml of water and 1.38 g of (3-fluoro, 4-methyl) phenylboronic acid.
• 1.7 g of 6 - ((3-fluoro, 4-methyl) phenyl) imidazo [1,2-a] pyridine are thus obtained in the form of a brown solid.
• Example 11 4- ⁇ 4- [3 - ( ⁇ 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl ⁇ sulfanyl) imidazo [1,2-a] pyridin-6-yl] -1H pyrazol-1-yl ⁇ tert-butyl piperidine-1-carboxylate
• Example 11a 4- ⁇ 4- [3 - ( ⁇ 2 - [(Cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl ⁇ sulfanyl) imidazo [1,2-a] pyridin-6-yl] 1H-pyrazol-1-yl ⁇ piperidine-1-tert-butylcarboxylate.
• the compound can be prepared in the following manner:
• the medium After bubbling argon in the reaction medium for 5 minutes, the medium is heated under microwaves at 160 ° C. for 25 minutes. After returning to a temperature in the region of 20 ° C., the medium is diluted with 25 ml of a dichloromethane / methanol mixture 95/5 by volume and the organic phase is then washed with 2 times 30 ml of distilled water, dried over sulphate. of magnesium, filtered and concentrated to dryness under reduced pressure. The evaporation residue is chromatographed under argon pressure on silica gel (dichloromethane / methanol eluent 96/4 by volume).
• Example 11 b tert-butyl 4- [4- (3-bromoimidazo [1,2-a] pyridin-6-yl) -1H-pyrazol-1-yl] piperidine-1-carboxylate.
• the compound can be prepared in the following manner: A mixture of 860 mg of 4- [4- (imidazo [1,2-a] pyridin-6-yl) -1H-pyrazol-1-yl] piperidine-1 - tert-butyl carboxylate, 80 ml of chloroform and 417 mg of N-bromosuccinimide is refluxed overnight. The medium is cooled to a temperature in the region of 20 ° C. and then concentrated by evaporation under reduced pressure. The isolated residue is chromatographed under argon pressure on silica gel (eluent ethyl acetate / methanol 80/20 by volume).
• Example 11 c tert-butyl 4- [4- (1-imidazo [1,2-a] pyridin-6-yl) -1H-pyrazol-1-yl] piperidine-1-carboxylate
• the compound can be prepared in the following manner:
• reaction medium is then poured into 450 ml of distilled water and extracted with 4 times 60 ml of dichloromethane.
• the combined organic extracts are washed with 60 ml of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure.
• the residue obtained is chromatographed under argon pressure on silica gel (eluent dichloromethane / methanol 96/4 by volume).
• Example 11 d Tert-Butyl 4- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazol-1-yl] -piperidine-1-carboxylate
• the compound can be prepared as described in WO200 / 066187 p.34.
• Example 12 ⁇ - [6 - ( ⁇ 6- [1- (Piperidin-4-yl) -1H-pyrazol-4-yl] imidazo [1,2-a] pyridin-3-yl ⁇ sulfanyl) -1 3-benzothiazol-2-yl] cyclopropanecarboxamide
• the compound can be prepared in the following manner:
• Example 13 Pharmaceutical composition Tablets having the following formula were prepared:
• Example 1 is taken as an example of a pharmaceutical preparation, this preparation can be carried out if desired with other products examples in the present application.
• 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 protein expression. interest.
• the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at -80 ° C. Purification:
• 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).
• the fractions containing the protein of interest in view of the electrophoretic analysis are pooled, concentrated by ultrafiltration (cut-off 1OkDa) and injected on an exclusion chromatography column (Superdex TM 200, GE HealthCare) balanced. in buffer A.
• the protein 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 of interest after electrophoresis (SDS PAGE), are finally collected and stored at -80 ° C.
• IMAC Nickel Chelate chromatography column His-Trap 6 Fast Flow TM, GE HealthCare
• the previous fractions are incubated for 1 h at room temperature after addition of 2 mM ATP, 2 mM MgCl 2, and 4 mM Na3VO4.
• 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. II) Tests A and B
• 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.
• Dilution of the products Stock at 1 ⁇ M in pure DMSO - Range of 1 ⁇ M at 30 ⁇ M with a step of 3 in pure DMSO - Dilutions intermediate to 1/50 in culture medium then 10 ⁇ l sample directly added to the cells (200 ⁇ l) : final range of 10000 to 3OnM. At the end of the incubation, gently remove the supernatant and rinse with 200 ⁇ l of PBS. Then put 10O ⁇ l of lysis buffer directly into the wells on the ice and incubate at 4 ° C for 30 minutes.
• Lysis buffer 1 Omm ThS 1 HCl pH 7.4, 10OmM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 2OmM NaF, 2 mM Na3VO4, 1 mM PMSF and anti protease cocktail.
• 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 14 C-Thymidine Cells are inoculated 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 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 ⁇ 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 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 greater 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 I microM.

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