EP2310366A2 - Novel triazolo(4,3-a)pyridine derivatives, process for the preparation thereof, use thereof as medicaments, pharmaceutical compositions and novel use, in particular as met inhibitors - Google Patents

Abstract

The invention relates to the novel products of formula (I): in which: Ra represents H, Hal, aryl or heteroaryl, which is optionally substituted; Rb represents H, Rc, -COORc-CO-Rc or -CO-NRcRd; where Rc represents alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, all optionally substituted; Rd represents H, alk or cycloalkyl; these products being in all the isomer forms and the salts, as medicaments, in particular as MET inhibitors.

Description

 NOVEL TRIAZOLO [4,3-alPYRIDINE DERIVATIVES, THEIR PROCESS FOR

PREPARATION, THEIR APPLICATION AS MEDICINES,

PHARMACEUTICAL COMPOSITIONS AND NEW USE

NOTABLY AS MET INHIBITORS

The present invention relates to novel triazolo [4,3-a] pyhidine derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such triazolo derivatives [4, 3-a] pyridine.

The present invention relates more particularly to new triazolo [4,3-a] pyhdine derivatives exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.

To date, most of the commercial compounds used in chemotherapy are cytotoxic drugs that pose significant problems of side effects and tolerance by patients. These effects could be limited insofar as the drugs used act selectively on cancer cells, excluding healthy cells. One of the solutions to limit the undesirable effects of chemotherapy may therefore consist 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.

Among the various cellular functions in which the activity of a protein kinase is involved, some processes represent attractive targets for treating certain diseases. Examples include angiogenesis and cell cycle control as well as cell proliferation, in which protein kinases can play a critical role. These processes are particularly essential for the growth of solid tumors as well as other diseases: in particular inhibitory molecules of such kinases are able to limit unwanted cell proliferations such as those observed in cancers, and may intervene in the prevention, control and treatment of cancer. regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or neuronal apoptosis.

The present invention relates to novel derivatives with inhibitory effects vis-à-vis protein kinases. The products according to the present invention can thus notably be used for the prevention or the treatment of diseases that can be modulated by the inhibition of protein kinases.

The products according to the present invention exhibit in particular an anticancer activity, via the modulation of the activity of kinases. Of the kinases for which modulation of activity is desired, MET as well as MET protein mutants are preferred.

The present invention also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans.

Thus, it is an object of the present invention to provide compositions having anticancer activity, in particular by acting against to kinases. Of the kinases for which modulation of activity is desired, MET is preferred.

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

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

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

The present invention thus relates in particular to new inhibitors of the MET protein kinase and its mutants, which can be used for anti-proliferative and anti-metastatic treatment, especially in oncology. The present invention also relates to novel inhibitors of the MET protein kinase and its mutants, which can be used for anti-angiogenic treatment, in particular in oncology. The subject of the present invention is the products of formula (I):

in which :

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, CF 3, -NR 1 R 2, heterocycloalkyl radicals, -COOH, -COOaIk, -CONR1 R2 and -NR1 COR2; the alkyl and cycloalkyl radicals being additionally optionally substituted with an aryl or heteroaryl radical, themselves optionally substituted by 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 by one or more radicals chosen from halogen atoms and hydroxyl, O-heterocycloalkyl, alkyl, alkoxy and NR3R4 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, oxo radicals, alkoxy, NH2; NHaIk, N (alk) 2, and the alkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals the alkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen among the halogen atoms and the hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2; NHaIk and N (alk) 2; all the above alkyl (alk) and alkoxy radicals containing from 1 to 6 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic 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 in which:

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 and heterocycloalkyl radicals, -NR 1 R 2, -COOH, COOaIk and -CONR1 R2, the aryl or heteroaryl radicals being further optionally substituted with an alkyl radical which is itself optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, O-heterocycloalkyl 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, alkoxy radicals; and the alkyl, phenyl and CH 2 -phenyl radicals, in which the alkyl or phenyl radicals are themselves 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; all the above alkyl (alk) or alkoxy radicals containing from 1 to 6 carbon atoms, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or below, in which:

Ra represents a hydrogen atom; a halogen atom; an optionally substituted phenyl radical as indicated below; or a pyrazolyl radical optionally substituted with a heterocycloalkyl radical or with an alkyl radical, itself optionally substituted by a hydroxyl radical or by an O-heterocycloalkyl radical;

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 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 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 with one or more identical or different radicals as defined in any one of Claims 1 or 2; ; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which: Ra represents a hydrogen atom; a halogen atom; or a phenyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals; or a pyrazolyl radical optionally substituted with a piperidyl radical or with an alkyl radical which is itself optionally substituted with a hydroxyl radical or with a tetrahydro-2H-pyran-2-yl) oxy radical;

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. NH2, NHaIk and N (alk) 2; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which: Ra represents a hydrogen atom; an iodine atom; a phenyl radical optionally substituted with one or two radicals chosen from halogen atoms and the methyl radical; or a pyrazolyl radical optionally substituted with a piperidyl radical or with an ethyl radical itself optionally substituted with a hydroxyl radical or with a tetrahydro-2H-pyran-2-yl) oxy radical;

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,

NR 1 R 2 being such that either R 1 and R 2, which are identical or different, represent a hydrogen atom or an alkyl radical, or R 1 and R 2 form, with the nitrogen atom to which they are bonded, a morpholinyl or piperazinyl radical optionally substituted on the second atom; azole with an alkyl 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 thus the products of formula (I):

in which :

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 and cycloalkyl radicals being additionally optionally substituted by a heterocycloalkyl, 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, alkyl, alkoxy and NR3R4 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, oxo radicals, alkoxy, NH2; NHalk,

N (alk) 2, and the 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. and hydroxyl, alkyl and alkoxy radicals having 1 to 4 carbon atoms, NH 2; NHaIk and N (alk) 2; all the above alkyl (alk) and alkoxy radicals containing from 1 to 6 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

In particular, in the products of formula (I), 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. , CN, CF3, -NR1 R2, -COOH, -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, alkyl, alkoxy and NR3R4 radicals; The subject of the present invention is the products of formula (I) as defined above in which:

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 with one or more radicals chosen from halogen atoms, and hydroxyl and alkoxy radicals,

-NR1 R2, -COOH, -COOaIk and -CONR1 R2,

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 a radical alkyl optionally substituted by one or more identical or different radicals chosen from hydroxyl, alkoxy, heterocycloalkyl, heteroaryl or phenyl radicals themselves optionally substituted, or R3 and R4 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; 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, alkoxy radicals; and the alkyl, phenyl and CH 2 -phenyl radicals, in which the alkyl or phenyl radicals are themselves 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; all the above-mentioned alkyl (alk) or alkoxy radicals containing from 1 to 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 inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which:

Ra 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 the hydroxyl, alkoxy, NR1 R2 and phenyl radicals, optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, alkoxy, alkyl, NH2, NHaIk and N (alk) 2 radicals;

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

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 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 it contains being optionally substituted; the cyclic radicals that R 1 and R 2 or R 3 and R 4 may form respectively with the nitrogen atom to which they are bonded, being optionally substituted by one or more identical or different radicals as defined above; all the above alkyl or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral acids and organic or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or below, in which:

Ra 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. NH2, NHaIk and N (alk) 2; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

In the products of formula (I) and in the following:

the term "alkyl radical" (or alk) 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 radicals are preferred alkyl containing 1 to 4 carbon atoms from the above list;

the term "alkoxy radical" denotes the linear and, if appropriate, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy radicals, as well as their linear or branched positional isomers: alkoxy radicals containing 1 to 4 carbon atoms from the above list;

the term "halogen atom" denotes the chlorine, bromine, iodine or fluorine atoms and preferably the chlorine, bromine or fluorine atom.

the term "cycloalkyl radical" denotes a saturated carbocyclic radical containing 3 to 10 carbon atoms and thus particularly denotes the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, and especially the cyclopropyl, cyclopentyl and cyclohexyl radicals;

the term "heterocycloalkyl radical" thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms; for example morpholinyl, thiomorpholinyl, homomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, tetrahydropyran, oxodihydropyridazinyl radicals, or alternatively oxetanyl, all these radicals being optionally substituted; mention may in particular be made of tetrahydropyranyl, morpholinyl, thiomorpholinyl, homomorpholinyl, piperazinyl, piperidyl, homopiperazinyl or pyrrolidinyl radicals, the radical -O-heterocycloalkyl denotes a heterocycloalkyl radical as defined above bearing a -O- (oxy) function: mention may be made, for example, of the morpholinyloxy, thiomorpholinyloxy, homomorpholinyloxy, aziridyloxy, azetidyloxy, piperazinyloxy, piperidyloxy and homopiperazinyloxy radicals, pyrrolidinyloxy, imidazolidinyloxy, pyrazolidinyloxy, tetrahydrofuryloxy, tetrahydrothienyloxy, tetrahydropyranyloxy, hexahydropyranyloxy, oxodihydropyridazinyloxy, or oxetanyloxy all of these radicals being optionally substituted; mention may in particular be made of tetrahydro-2H-pyran-2yloxy, morpholinyloxy, thiomorpholinyloxy, homomorpholinyloxy, piperazinyloxy, piperidyloxy, homopiperazinyloxy or pyrrolidinyloxy radicals;

the terms 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;

the term "aryl radical" thus denotes monocyclic or bicyclic radicals containing 6 to 12 members, such as, for example, the phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly the phenyl and naphthyl radicals and even more particularly the phenyl radical. It may be noted that a carbocyclic radical containing a -C (O) - linkage is, for example, the tetralone radical;

the term "heteroaryl radical" thus denotes monocyclic or bicyclic radicals containing 5 to 12 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 salified tetrazolyl, all these radicals being optionally substituted, among which more particularly the thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl and pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals such as, for example, benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl; azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyhdinopyrazolyl or oxodihydropyridino pyrazolyl, all of these radicals being optionally substituted;

As examples of heteroaryl or bicyclic radicals, there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl, 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 the salification compounds, 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,

from the esterification compounds, 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.

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.

It may be recalled that the stereoisomerism can be defined in its broad sense as the isomerism of compounds having the same developed formulas, but whose different groups are arranged differently in space, such as in particular in monosubstituted cyclohexanes whose substituent can be in axial or equatorial position, and the different possible rotational conformations of the ethane derivatives. However, there is another type of stereoisomerism, due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, often called geometric isomerism or cis-trans isomerism. The term stereoisomers is used in this application in its broadest meaning and therefore concerns all the compounds indicated above.

When NR 1 R 2 or NR 3 R 4 forms a ring as defined above, such an amino ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl, homomorpholinyl, piperazinyl or homopiperazinyl radicals, 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, alkoxy, phenyl and CH 2 -phenyl radicals, the alkyl or phenyl radicals being they themselves 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.

The subject of the present invention is the products of formula (I) as defined above or below, in which:

Ra represents a hydrogen atom; an iodine 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 a cyclopropyl radical or an alkyl radical optionally substituted by an alkoxy radical or NR1 R2;

Rd represents a hydrogen atom, NR 1 R 2 being such that either R 1 and R 2, which are identical or different, represent a hydrogen atom or an alkyl radical, or R 1 and R 2 form, with the nitrogen atom to which they are bonded, a morpholinyl or piperazinyl radical optionally substituted on the second atom; azole with an alkyl 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:

- Λ / - [6 - ([1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide - 1 - [2- (morpholine) 4-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea

1- [2- (4-methylpiperazin-1-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3 benzothiazol-2-yl] urea.

1- (2-Methoxyethyl) -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea

6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyhdin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine

6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine - Λ / - { 6- [6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazole -2-amine - Λ- (6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1 , 3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ- (6 - {[6- (1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) cyclopropanecarboxamide - Λ / - (6 - {[6 - ((3-fluoro-4-methyl) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

N - (6 - {[6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ / - (6 - {[6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4] , 3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ - (6 - {[6- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxanide

- Λ / - (6 - {[6- (1-Piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The present invention also relates to any process for preparing the products of formula (I) as defined above. The products according to the invention can be prepared from conventional methods of organic chemistry.

Preparation of compounds of formula (I)

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. Figure 1:

cychsat ⁱ on

(I)

Rb = H

In Scheme 1 above, the substituents Ra and Rb have the meanings given above.

Compounds (I) for which Ra and Rb have the same meanings can be obtained from compounds (I) for which Rb = H. Rc-COCl

(I) Rb = H Rb = CORc

More particularly, the compounds (I) for which Rb = CORc (with Rc as defined above) can be obtained, for example: by reaction of an acid chloride of formula Rc-COCI in the presence, for example, of a solvent such as pyridine at a temperature in the region of 20 ^° C., by reacting an acid anhydride of formula Rc-CO-O-CO-Rc in the presence of, for example, a solvent such as pyridine at a temperature of temperature close to 20 ^° C., by reaction with a carboxylic acid of formula Rc-COOH under the conditions, for example, described by D. DesMarteau et al., (Chem Lett, 2000, 9, 1052) in the presence of 1 -hydroxybenzotriazole and 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as triethylamine, at a temperature between 20 ° C and the reflux temperature of the solvent.

(I) (I)

Rb = H Rb = CO-O-Rc

More particularly, the compounds (I) for which Rb = CO-O-Rc (with Rc as defined above) can be obtained, for example, by reaction with an Rc-O-COX chlorocarbonate (X = Cl) on compounds (I) for which Rb = H, in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, or in pyridine, at a temperature in the region of 20 ^° C.)

(I) Rb = H

Rc (Rd) NH

Rb = CON (Rc) Rd

More particularly, compounds (I) for which Rb = CON (Rc) Rd (with Rc and Rd as defined above) can be obtained, for example, by reaction of carbamates (D) where R = phenyl with amines Rc (Rd) NH (with Rc and Rd as defined above) in the presence of an aprotic solvent such as tetrahydrofuran, at a temperature in the region of 20 ^° C.

The carbamates (D) can be obtained, for example, by reaction with a chlorocarbonate RO-COX (X = Cl) on the compounds (I) for which Rb = H, in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, or in pyridine, at a temperature in the region of 20 ° C.

(I) (I)

Rb = H Rb = Rc

More particularly, the compounds (I) for which Rb = Rc (with Rc as defined above) can be obtained, for example:

by deprotection of carbamates (E) with R = t-butyl according to a method customary for those skilled in the art, for example with trifluoroacetic acid, in a solvent such as dichloromethane at a temperature in the region of 20 ^° C.

from the compounds (I) for which Rb = H by application of the methods described in patent EP 0408437 or by R. A Glennon et al. (Journal of Medicinal Chemistry, 1981, 24, 766-769).

The carbamates (E) can be obtained, for example, by reaction of the carbamates (D) where R = t-butyl, with Rc-X halides (with Rc as defined above) in the presence of a solvent such as N, N-dimethylformamide, in the presence of a base such as sodium hydride, at a temperature of between 20 ^° C. and 90 ° C.

The compounds (I) for which Rb = H can be obtained by cyclization of the compounds (C) according to a method customary for those skilled in the art, for example by applying the methods described by H. Masaichi et al. (Journal of Medicinal Chemistry, 2007, 50 (18), 4453-4470), by reaction of potassium thiocyanate and bromine in the presence of acid such as acetic acid at a temperature between 20 ⁰ C and the reflux temperature of the solvent.

The compounds (C) can be obtained by reducing the compounds (B) according to a method customary for those skilled in the art, for example using tin chloride in a solvent such as ethanol, or alternatively to the using hydrogen in the presence of a catalyst such as palladium on carbon or Raney nickel.

The compounds (B) can be obtained by coupling the compounds (A) with Ra as defined above with 4-nitrobenzenediazonium tetrafluoroborate (commercial product) under the conditions described for example by A.A. Biamonte et al. (Journal of Organic Chemistry, 2005, 70,

717-720) in the presence or absence of a base such as sodium hydrogencarbonate, for example in a solvent such as dimethylsulfoxide, acetone or acetonitrile at a temperature of between 20 ^° C. and the reflux temperature of the solvent .

(A1) (A2) (A)

The compounds (A) are either commercially available or prepared by applying the methods described in patent EP 0254623 or in US Pat. No. 4,244,953 from the hydrazino derivatives of formula (A2) by reaction with carbon disulfide in a solvent such as pyridine or chloroform at a temperature between 20 ° C and the reflux of the solvent.

Compounds (A2) are either commercially available or obtained by the methods described in EP 0254623, US Pat. No. 4,244,953 or according to R. Church et al. (Journal of Organic Chemistry 1995, 60, 3750- 3758) from the 2-chloro pyridines derivatives (A1) by the action of hydrazine or hydrate of hydrazine.

The compounds (A1) are either commercially available or can be obtained from 2-chloro-5-iodopyridine (commercial compound), for example: from boronic acids of formula Ra-B (OH) 2 in the presence of phosphate of potassium and palladium tetrakistriphenylphosphine in a solvent such as dimethylsulfoxide at a temperature in the region of 80 ^° C., from the boronic esters Ra-B (OR) 2 in the presence of palladium dichloro-bis (triphenylphosphine) in a solvent such as for example, 1, 2-dimethoxyethane, in the presence of a base such as 1N sodium hydroxide, at a temperature in the region of 80 ^° C.

Ra-B (OH) ₂

(D (I)

Ra = I and Rb = H Rb = H

Compounds (I) for which Rb = H can also be obtained from compound (I) for which Rb = H and Ra = I by reaction of boronic acids of formula Ra-B (OH) 2 or by reaction of boronic esters R-B (OR) 2 as described for the preparation of the compounds (A1).

Figure 2: O ₂ N. _^ S functionalization 0 N _x / - \ s reduction H ₂ N ^ / \ s

-NH, // - N _/ \) - ^H N

^{^} N Rb c ^^ - N Rb

( BOY WUT )

diazotization

coupling

(H)

( AT )

In Scheme 2 above, the substituents Ra and Rb have the meanings given above. The compounds (I) for which Ra and Rb have the same meanings indicated above can be obtained by coupling reaction of the compounds (A) with Ra as defined above with the compounds (H) with Rb as defined above. above, as described for the preparation of the compounds (B) above. The compounds (II) for which Rb has the same meanings indicated above can be obtained by diazotisation of the compounds (G) according to a method customary for those skilled in the art, for example by the action of nitrous acid (HNO 2) or of sodium nitrite (NaNO 2) in the presence of acid, such as aqueous tetrafluoroboric acid, at a temperature in the region of 20 ^° C. The compounds (G) for which Rb has the same meanings indicated above, may be obtained by reduction compounds (F) according to a method customary for those skilled in the art, for example, using hydrogen in the presence of a catalyst such as palladium on carbon or Raney nickel, in a solvent such as tetrahydrofuran by for example, at a temperature of between 20 ^° C. and the reflux of the solvent. Compounds (F) for which Rb has the same meanings given above, can be obtained from 2-amino-6-nitro-benzothiazole (commercial product) as described above for the preparation of compounds (I) to from compounds (I) for which Rb = H.

Figure 3:

reduction

(L)

In Scheme 3 above, the substituents Ra and Rc have the meanings given above.

The compounds (I) for which Ra has the same meanings as above and for which Rb = CORc can be obtained by coupling reaction of the compounds (L) with Ra as defined above with the compounds (K) with Rc as defined above, 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 ⁰ C and the reflux temperature of the solvent. Such reactions can also be carried out under microwave. 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.

Compounds (J) for which Rc has the same meanings given above can be obtained from 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial product) as described above for the preparation of compounds (I) with Rb = CORc from compounds (I) with Rb = H.

bromination

(L1) (L)

Compounds (L) are either commercial (Ra = H) or prepared by bromination of compounds (L1), according to a method customary for those skilled in the art, for example according to the conditions described by ES Hand et al., (Journal of Organic Chemistry, 1980, 45, 3738-3745) or with the aid of bromine in a solvent such as ethanol at a temperature of between 20 ^° C. and the reflux of the solvent.

Compounds (L1) are either commercial (Ra = H) or can be obtained from 6-bromo [1,2,4triazolo [4,3-a] pyridine (commercial product) by coupling reaction by application of methods described by C. Enguehard et al. (Helvetica Chimica Acta (2001), 84, 3610-3614), for example:

from boronic acids of formula Ra-B (OH) 2 in the presence of sodium hydrogen carbonate and palladium tetrakistriphenylphosphine in a solvent such as dimethylsulfoxide or dioxane at a temperature in the region of 80.degree. from the boronic esters Ra-B (OR) 2 in the presence of palladium dichloro-bis (triphenylphosphine) in a solvent such as, for example, 1,2-dimethoxyethane, in the presence of a base such as sodium hydroxide 1 N, at a temperature of about 80 ^° C.

Among the starting products of formula (A), (A1), (A2), (F), (G), (L) and (L1), some are known and can be obtained either commercially or according to the usual methods known to those skilled in the art, for example from commercial products.

It is understood by those skilled in the art that, for the implementation of the methods according to the invention described above, it may be necessary to introduce protective groups of the amino, carboxyl and alcohol functions in order to avoid side reactions.

The following non-exhaustive list of examples of protection of reactive functions can be cited:

the hydroxyl groups may be protected for example by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,

the amino groups may be protected for example by the acetyl, trityl, benzyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl, phthalimido or other radicals known in 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.

A list of different protective groups used in the manuals known to those skilled in the art and for example in the patent FR 2,499,995. It may be noted that 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) a conversion reaction of alkoxy function with hydroxyl function, or of hydroxyl function with alkoxy function, e) an elimination reaction of the protective groups that can be carried by protected reactive functions, f) a salification reaction with an inorganic or organic acid or a base to obtain the corresponding salt, g) a reaction of duplication of the forms rac nomic resolved products, said products of formula (I) thus obtained being in all possible racemic, enantiomeric and diastereoisomeric.

The reactions a) to g) can be carried out under the usual conditions known to those skilled in the art such as, for example, those indicated below.

a) The products described above may, if desired, be subjected, on the possible carboxy functions, to esterification reactions which may be carried out according to the usual methods known to those skilled in the art.

b) The possible ester function transformations in acid function of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by hydrolysis acid or alkali for example with sodium hydroxide or potassium hydroxide in an alcoholic medium such as, for example, in methanol or with hydrochloric or sulfuric acid.

The saponification reaction can be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.

c) The optional free or esterified carboxy functions of the products described above may, if desired, be reduced 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 free carboxy functions of the products described above may, if desired, be reduced in particular alcohol function by boron hydride.

d) The optional alkoxy functions, such as 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.

e) The elimination of protective groups such as for example those indicated above can be carried out under the usual conditions known to those skilled in the art, in particular by acid hydrolysis carried out with an acid such as hydrochloric acid, benzene sulfonic acid or para-toluene sulfonic, formic or trifluoroacetic acid or catalytic hydrogenation.

The phthalimido group can be removed by hydrazine.

f) The products described above may, if desired, be the subject of salification reactions, for example by a mineral or organic acid or by a mineral or organic base according to the usual methods known to those skilled in the art: such salification reaction can be carried out for example in the presence of hydrochloric acid for example or tartaric acid, citric or methanesulfonic acid in an alcohol such as for example ethanol or methanol.

g) The optional optically active forms of the products described above may be prepared by resolution of the racemates according to the usual methods known to those skilled in the art.

The products of formula (I) as defined above and their addition salts with acids have interesting pharmacological properties, in particular because of their kinase inhibiting properties as indicated above.

The products of the present invention are especially useful for tumor therapy. The products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents.

These properties justify their application in therapeutics and the subject of the invention is particularly useful as medicaments, the products of formula (I) as defined above, said products of formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I). The subject of the invention is, as medicaments, the products corresponding to the following formulas:

- Λ / - [6 - ([1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide - 1 - [2- (morpholine) 4-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea

1- [2- (4-methylpiperazin-1-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3 benzothiazol-2-yl] urea.

1- (2-Methoxyethyl) -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea

6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyhdin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine

6 - {[6- (4-fluorophenyl) [1,2,4] tetrazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine - Λ / - { 6- [6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazole -2-amine

- Λ- (6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1 , 3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ- (6 - {[6- (1H-pyrazol-4-yl) [1H-triazolo] -S-alpyhdin-5-ylsulfanylH, 3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ - (6 - {[6 - ((3-fluoro-4-methyl) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxamide - Λ- (6 - {[6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyhdin-3-yl] sulfanyl} -1, 3-Benzothiazol-2-yl) cyclopropanecarboxamide - Λ / - (6 - {[6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4] , 3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ - (6 - {[6- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxanide

- Λ - (6 - {[6- (1-Piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as well as addition salts with inorganic and organic acids or with the pharmaceutically acceptable mineral and organic bases of said products of formula (I).

The invention also relates to pharmaceutical compositions containing as active principle at least one of the products of formula (I) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, optionally, a pharmaceutically acceptable carrier.

The invention thus extends to pharmaceutical compositions containing as active principle at least one of the drugs as defined above.

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

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

These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, pills, 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.

Among these cancers, one is interested in the treatment of solid or liquid tumors, in the treatment of cancers resistant to cytotoxic agents.

The products of the present invention cited can in particular be used for the treatment of primary tumors and / or metastases, 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.

The subject of the present invention is also the use of the products of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers. Such drugs for cancer chemotherapy may be used alone or in combination.

The products of the present application can in particular be administered alone or in combination with chemotherapy or radiotherapy or in combination with other therapeutic agents, for example.

Such therapeutic agents may be commonly used anti-tumor agents.

As kinase inhibitors, there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-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), (H), (L), (L1 ), (J) and (K) as defined above and recalled below:

(L; (L1 as defined above wherein Ra, Rb and Rc are as defined above and R is t-butyl or phenyl.

The following examples which are products of formula (I) illustrate the invention without however limiting it.

Experimental part

The nomenclature of the compounds of this invention was carried out with ACDLABS software version 10.0.

The 1 H NMR spectra at 400 MHz were carried out on BRUKER AVANCE DRX-400 spectrometer with chemical shifts (δ in ppm) in dimethylsulfoxide-dβ (DMSO-dβ) solvent referenced at 2.5 ppm at a temperature of 303K.

The infrared (IR) spectra were carried out on a Nicolet Nexus Fourier transform infrared spectrometer, the spectral range is between 4000 and 400 cm ^-1 with a resolution of 2 cm ^-1 .

Mass spectra (SM) were obtained either by Method A or by Method B:

Method A:

WATERS UPLC-SQD apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: ACQUITY BEH Ciβ 1, 7 μm - 2.1 x 50 mm; Solvents: A: H ₂ O (0.1% formic acid) B: CH ₃ CN (0.1% formic acid); Column temperature: 50 ^° C .; Flow rate: 1 ml / min; Gradient (2 min): 5 to 50% B in 0.8 min; 1, 2 min: 100% B; 1.85 min: 100% B; 1, 95: 5% B; Retention time = Tr (min). Method B:

WATERS ZQ apparatus; Ionisation: electrospray in positive and / or negative mode (ES +/-); Chromatographic conditions: Column: XBridge Ci ₈ 2.5 μm - 3 x 50 mm; Solvents: A: H ₂ O (0.1% formic acid) B: CH ₃ CN (0.1% acidic) formic); Column temperature: 70 ⁰ C; Flow rate: 0.9 ml / min; Gradient (7 min): from 5 to 100% of B in 5.3 min; 5.5 min: 100% B; 6.3 min: 5% B; Retention time = Tr (min).

Example 1: 6 - ([1,2,4] Triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-amine

Example 1a: 6 - ([1,2,4] thazolo [4,3-a] pyhdin-3-ylsulfanyl) -1,3-benzothiazol-2-amine

The compound can be prepared in the following manner: To a solution of 1.15 g of 4 - ([1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl) aniline in 33 ml of acid glacial acetic are added at once 1.84 g of potassium thiocyanate. After stirring for about 15 minutes, 0.243 ml of bromine diluted in 5 ml of glacial acetic acid are poured drop by drop while maintaining the temperature at about 20 ^° C. A precipitate is formed little by little and the reaction mixture is agitated approximately 18 hours at a temperature of 20 ° C and then poured on 100 ml of water. The pH is brought to about 8 by addition of potassium carbonate. After stirring for 3 hours at a temperature in the region of 20 ^° C., the precipitate is filtered off with suction and washed with 3 times 20 ml of water and dried in a desiccator under reduced pressure over phosphorus pentoxide. 1.31 g of 6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-amine are obtained in the form of a yellow solid.

Melting point: 260-266 ° C (Buchi)

SM: method B; [M + H] ⁺ m / z = 300; [MH] ^"m / z = 298, Rt = 2.38 min.

1H NMR (400MHz, DMSO-c / ₆ ) δ ppm 7.10 (td, J = 6.8, 1.0Hz, 1H) 7.26 (m, 2H) 7.48 (ddd, J = 9.3, 6.8.1.0Hz, 1H NMR (CDCl3)? H) 7.61 (bs, 2H) 7.80 (m, 1H) 7.88 (dt, J = 9.3.1.0 Hz, 1H) 8.48 (dt, J = 6.8.1.0 Hz, 1H)

Example 1b: 4 - ([1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl) aniline The compound can be prepared in the following manner: To a solution of 6.21 g of stannous chloride, dihydrate in 8 ml of ethanol is added 1.5 g of 3 - [(4-nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a ] pyhdine. The orange solution obtained is brought to around 60 ^° C. 8.2 ml of a 10N aqueous solution of hydrochloric acid is poured dropwise at this temperature and the reaction mixture is stirred for approximately 30 minutes at this same temperature. After returning to a temperature in the region of 20 ^° C., 200 ml of water are added and the pH of the suspension is adjusted to approximately 12 by addition of 30% sodium hydroxide. The medium is extracted with 3 times 250 ml of ethyl acetate. The combined organic phases are washed with 3 times 200 ml of water, 200 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 0.99 g of 4 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) aniline are obtained in the form of a beige solid.

Melting point: 210 ° C (Banc-Kόfler) SM: Method A; [M + H] ⁺ m / z = 243; Tr = 0.42 min.

1H NMR (400MHz, DMSO-c / ₆ ) δ ppm 5.43 (bs, 2H) 6.50 (d, J = 8.5Hz, 2H) 7.08 (td, J = 6.9, 1.0Hz, 1H) 7.21 (d, J = 8.5 Hz, 2H) 7.45 (ddd, J = 9.3, 6.9, 1.0Hz, 1H) 7.84 (dt, J = 9.3, 1.0Hz, 1H) 8.47 (dd, J = 6.9, 1.0) Hz, 1H)

Example 1 c: 3 - [(4-nitrophenyl) sulfanyl] [1,2,4] tetrazolo [4,3-a] pyhidine The compound can be prepared in the following manner:

To a solution of 1 g of [1,2,4] thazolo [4,3-a] pyridine-3-thiol in 15 ml of dimethylsulfoxide is added in small portions 1 577 g of 4-nitrobenzenediazonium tetrafluoroborate. After stirring for 4 days at a temperature in the region of 20 ^° C., the mixture is poured into 100 ml of water. The precipitate is drained, washed with 3 times 20 ml of water, 1 time with 10 ml of ethanol and 10 ml of diethyl ether and then dried in air. 1.22 g of 3 - [(4-nitrophenyl) sulfanyl] [1,2,4] thalzolo [4,3-a] pyhidine are obtained in the form of a yellow solid.

Melting point: 178-180 ° C (Banc-Kόfler) SM: method B; [M + H] ⁺ m / z = 273; Tr = 3.10 min.

1 H NMR (400 MHz, DMSO-c / ₆ ) δ ppm 7.16 (td, J = 6.7, 1.1 Hz, 1H) 7.31 (d, J = 9.0 Hz, 2H) 7.58 (ddd, J = 9.3, 6.8 , 1.1 Hz, 1H) 8.01 (dt, J = 9.3, 1.1 Hz, 1H) 8.14 (d, J = 9.0 Hz, 2H) 8.42 (dt, J = 6.8, 1.1 Hz, 1H)

Example 2: Λ- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide

Example 2a: Λ- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide The compound can be prepared from following way:

To a suspension of 0.1 g of 6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-amine and 2 ml of pyridine, 0.037 ml of cyclopropanecarbonyl chloride is added. After one night at a temperature of 20 ^° C., 0.037 ml of cyclopropanecarbonyl chloride is added. After a night at a temperature in the region of 20 ^° C., 0.037 ml of cyclopropanecarbonyl chloride is again added. After one night at a temperature of 20 ° C, 10 ml of water are added and the precipitate is filtered off, washed with 3 times 2 ml of water, 3 times 2 ml of ethanol, 2 times 2 ml of oxide of diethyl and dried in an oven at 50 ⁰ C under reduced pressure. 0.068 g of Λ- [6 - ([1,2,4] tetrazolo [4,3-a] pyhdin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide are obtained in the form of a solid.

Melting point: 187-190 ° C (Banc-Kόfler)

SM: method A; [M + H] ⁺ m / z = 368; [MH] ^"m / z = 366; Tr = 0.71 min.

1H NMR (400MHz, DMSO-c / ₆ ) δ ppm 0.94 (m, 4H) 1.96 (m, 1H) 7.10 (td, J = 6.8, 1.0Hz, 1H) 7.35 (dd, J = 8.6) , 2.2 Hz, 1H) 7.51 (ddd, J = 9.3, 6.8, 1.0 Hz, 1H) 7.66 (d, J = 8.6 Hz, 1H) 7.91 (d wide, J = 9.3Hz, 1H) 8.05 ( d, J = 2.0Hz, 1H) 8.47 (bs, J = 6.8Hz, 1H) 12.67 (bs, 1H) The compound Λ / - [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide may also be prepared in the following manner :

To a suspension of 36.44 mg of [1,2,4] triazolo [4,3-a] pyhdine-3-thiol and 20.25 mg of sodium hydrogencarbonate and 2 ml of acetonitrile are added 100 mg of 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazole-6-diazonium tetrafluoroborate. After stirring for 6 days at a temperature in the region of 20 ^° C., the mixture is poured into 20 ml of water. The precipitate is filtered off, washed with twice 10 ml of diethyl ether and then dried in air. There is thus obtained 40 mg of Λ- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide.

Example 2b: 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazole-6-diazonium tetrafluoroborate

The compound can be obtained in the following manner: To a solution of 0.5 g of Λ- (6-amino-1,3-benzothiazol-2-yl) cyclopropanecarboxamide and 2 ml of aqueous tetrafluoroboric acid (50% solution). 48%) are added 133.1 mg of sodium nitrite and 1.5 ml of water. The reaction medium is stirred at room temperature for 16 hours. The precipitate formed is filtered off, washed with diethyl ether and then dried in air. 566 mg of 2- [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-diazonium tetrafluoroborate are thus obtained in the form of a white solid.

Melting point: 200 ^° C. (Banc-Kόfler)

SM: method A; [M] ⁺ : m / z = 245; [BF4] ^": m / z = 87; Tr = 0.28 min IR: 2253 ^{cm." 1} (aryl diazonium cation); 1150-1000 cm ^"1, 533 and 523 ^{cm" 1} (tetrafluoroborate)

Example 2c: Λ- (6-amino-1,3-benzothiazol-2-yl) cyclopropanecarboxamide The compound can be prepared in the following manner: 1.5 g of Λ- (6-nitro-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 150 mg of palladium-on-charcoal (10%) and 150 ml of tetrahydrofuran are charged to an autoclave. The medium is then stirred under hydrogen pressure at 15 bar and heated at 50 ^° C. After returning to ordinary pressure and at ambient temperature, the mixture is filtered on celite and the filtrate is concentrated by evaporation under reduced pressure. 1.3 g of N- (6-amino-1,3-benzothiazol-2-yl) cyclopropanecarboxamide are thus obtained in the form of a white solid.

Melting point> 260 ^° C. (Banc-Kόfler) SM: method A; [IvRH] ⁺ : m / z 234; Tr = 0.34 min. Example 2d: Λ- (6-nitro-1,3-benzothiazol-2-yl) cyclopropanecarboxamide The compound can be prepared in the following manner:

To a suspension of 5 g of 2-amino-6-nitro-benzothiazole (commercial product) and 50 ml of anhydrous pyridine, 2.3 ml of cyclopropanecarbonyl chloride are added dropwise. The reaction medium is then stirred at room temperature for 24 hours. The precipitate formed is filtered, rinsed with 100 ml of water, twice 10 ml of ethanol, 2 times 20 ml of diethyl ether and then filtered off and dried in air. 5.14 g of Λ- (6-nitro-1,3-benzothiazol-2-yl) cyclopropanecarboxamide are thus obtained in the form of a white powder. Melting point> 260 ° C (Banc-Kόfler)

1H NMR (400MHz, DMSO-c / ₆ ) δppm 0.92 - 1.05 (m, 4H) 1.97 - 2.08 (m, 1H) 7.86 (d, J = 8.9Hz, 1H) 8.26 (dd, J) = 8.9, 2.4 Hz, 1H) 9.01 (d, J = 2.4Hz, 1H) 13.02 (spread m, 1H)

Example 3: 1- [2- (Morpholin-4-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1.3- benzothiazol-2-yl] urea

Example 3a: 1- [2- (Morpholin-4-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3 benzothiazol-2-yl] urea

The compound can be prepared in the following manner: To a suspension of 0.3 g of phenyl [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] carbamate in 7 ml of tetrahydrofuran is added 0.1 ml of 2- (morpholin-4-yl) ethanamine. After stirring overnight at a temperature in the region of 20 ^° C., 0.028 ml of 2- (morpholin-4-yl) ethanamine is added and the reaction mixture is stirred overnight at a temperature in the region of 20 ^° C. The mixture is then poured on 100 ml of dichloromethane. The organic phase is washed with 50 ml of a 2N aqueous sodium hydroxide solution. The aqueous phase is treated with glacial acetic acid to adjust the pH to around 4, extracted with 3 times 100 ml of dichloromethane, 3 times 100 ml of ethyl acetate, 3 times 100 ml of n-butanol, dried over magnesium sulphate, filtered and concentrated under reduced pressure. A solid is obtained which is taken up in 20 ml of water, drained washed with 2 times 2 ml of water, 3 times 5 ml of acetonitrile, 3 times 5 ml of diethyl ether and dried in air. 0.13 g of 1- [2- (morpholin-4-yl) ethyl] -3- [6- ([1,2,4] tetrazolo [4,3-a] pyridin-3-ylsulfanyl) are obtained. 1,3-benzothiazol-2-yl] urea as a white solid.

Melting point: 204-207 ° C (Banc-Kόfler)

SM: method A; [M + H] + m / z = 456; [M + H-C 7 H 12 N 2 O 2] + m / z = 300; [C7H13N2O2] + m / z = 157 (base peak); [MH] - m / z = 454; Tr = 0.45 min. 1H NMR (400MHz, DMSO-c / ₆ ) δppm 2.35 - 2.44 (m, 6H) 3.25 (partially masked m, 2H) 3.58 (m, 4H) 6.88 (br m, 1H) 7.11 (d broad, J = 6.8 Hz, 1H) 7.29 (dd, J = 8.3, 2.0 Hz, 1H) 7.44 - 7.53 (m, 2H) 7.90 (broad d, J = 9.3 Hz, 1H) 7.95 (brs) 1H) 8.48 (broad d, J = 6.8 Hz, 1H) 11.23 (m spread, 1H) Example 3b: [[6 - ([1,2,4] thazolo [4,3-a] pyhdin- Phenyl 3-ylsulfanyl) -1,3-benzothiazol-2-yl] carbamate.

The compound can be prepared in the following manner:

To a suspension of 1 g of 6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-amine in 27 ml of tetrahydrofuran are added 68 ml of phenyl chlorocarbonate followed by 2.7 ml of water and 1.12 g of sodium hydrogencarbonate. The mixture is stirred at a temperature of about 20 ^° C. for about 48 hours. The precipitate is filtered off, washed with 10 ml of 10% tetrahydrofuran water, 3 times with 10 ml of ethyl acetate and dried in air. 0.59 g of phenyl [[6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] carbamate are obtained.

SM: method B; [M + H] + m / z = 420; [M-H] - m / z = 418; Tr = 3.71 min.

1H NMR (400MHz, DMSO-c / ₆ )? Ppm 7.11 (td, J = 6.8, 1.0Hz, 1H) 7.25-7.33 (m, 3H) 7.36 (dd, J = 8.5, 2.0Hz, 1H NMR (CDCl3)? H) 7.45 (t, J = 7.8 Hz, 2H) 7.51 (ddd, J = 9.3, 6.8, 1.0 Hz, 1H) 7.66 (d, J = 8.5 Hz, 1H) 7.91 (broad d, J = 9.3) Hz, 1H) 8.05 (broad, J = 2.0 Hz, 1H) 8.48 (broad d, J = 6.8 Hz, 1H) 12.68 (spread m, 1H)

Example 4: 1- [2- (4-methylpiperazin-1-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1, 3-benzothiazol-2-yl] urea. The compound can be prepared as in Example 3a but from 0.2 g of [[6 - ([1,2,4] thalzolo [4,3-a] pyhdin-3-ylsulfanyl) -1,3 phenylbenzothiazol-2-yl] carbamate and 75.15 mg of 2- (4-methylpiperazin-1-yl) ethanamine. After drying the precipitate formed, washing with 3 times 0.5 ml of tetrahydrofuran, twice 0.5 ml of diethyl ether and drying in air, 0.110 g of 1 - [2- (4-methylpiperazin) is obtained. 1-yl) ethyl] -3- [6 - ([1,2,4] tetrazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea in the form of a white solid.

Melting point: 180-185 ^° C (Banc-Kόfler)

SM: method A; [M + H] + m / z = 469; [M + H-C 8 H 15 N 3 O] + m / z = 300 (base peak); [C8H16N3O] + m / z = 170; [M-H] - m / z = 467; Tr = 0.44 min.

1H NMR (400MHz, DMSO-c / ₆ ) δ ppm 2.15 (s, 3H) 2.21 - 2.43 (m, 10H) 3.25 (partially masked m, 2H) 6.72 (br m, 1H) 7.11 ( td, J = 6.8, 1.0 Hz, 1H) 7.30 (dd, J = 8.3, 2.0 Hz, 1H) 7.47 - 7.54 (m, 2H) 7.90 (dt, J = 9.3, 1.0 Hz, 1H) 7.98 (d, J = 2.0Hz, 1H) 8.48 (dt, J = 6.8, 1.0Hz, 1H) 10.91 (m, spread, 1H) Example 5: 1- (2-Methoxyethyl) -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea

The compound can be prepared as in Example 3a but from 0.2 g of [[6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3 phenyl benzothiazol-2-yl] carbamate and 0.05 ml of 2-methoxyethanamine. After wringing off the precipitate formed, washing with 3 times 2 ml of diisopropyl ether, drying in an oven at around 50 ^° C. under reduced pressure, is obtained

0.143 g of 1- (2-methoxyethyl) -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea in the form of a white solid.

Melting point: 252-257 ° C (Banc-Kόfler)

SM: method A; [M + H] + m / z = 401; [M-H] - m / z = 399; Tr = 0.62 min.

1H NMR (400MHz, DMSO-c / ₆ ) δ ppm 3.27 (s, 3H) 3.31 (partially masked m, 2H) 3.40 (t, J = 5.4Hz, 2H) 6.83 (t broad, J = 5.6 Hz, 1H) 7.11 (td, J = 6.8, 1.0Hz, 1H) 7.31 (dd, J = 8.3, 2.0Hz, 1H) 7.50 (ddd, J = 9.3, 6.8, 1.0Hz, 1H) 7.55 (d, J = 8.3Hz, 1H) 7.91 (dt, J = 9.3, 1.0Hz, 1H) 8.01 (d, J = 2.0Hz, 1H) 8.49 (dt, J = 6.8, 1.0Hz, 1H) H) 10.73 (broad m, 1H).

Example 6: 6 - [(6-Iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine

Example 6a: 6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyhdin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine

The compound can be obtained as described in Example 1a from 230 mg of 4 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] aniline , 13 ml of acetic acid, 0.24 g of potassium thiocyanate and 32 μl of bromine. 0.25 g of 6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine are thus obtained. of orange powder.

Melting point ~ 190 ^° C. (Banc-Kόfler). SM: method B; [M + H] ⁺ m / z = 426; [MH] ^: m / z = 424, Tr = 2.98 min.1H NMR (400 MHz, DMSO-c / ₆ ) δ ppm7.27 (d, J = 8.6 Hz, 1H) 7.31 (dd, J) = 8.6, 2.0Hz, 1H) 7.61 (s wide, 2H) 7.65 (dd, J = 9.5, 1.4Hz, 1H) 7.73 (d, J = 9.5Hz, 1H) 7.81 (d, J = 2.0) Hz, 1H) 8.71 (bs, 1H) Example 6b: 4 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] aniline

The compound can be prepared as in Example 1b from 4.02 g of stannous chloride, dihydrate, 60 ml of ethanol, and 1.89 g of 6-iodo-3- [(4-nitrophenyl) sulfanyl] [1,2,4] triazolo [4,3-a] pyridine and 4.45 ml of a 12N aqueous solution of hydrochloric acid. 0.23 g of 4 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] aniline are thus obtained in the form of an orange-brown solid.

SM: method B; [M + H] ⁺ m / z = 369; Tr = 3.06 min.

Example 6c: 6-iodo-3 - [(4-nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a] pyridine

The compound can be prepared as in Example 1c from 1.18 g of 6-iodo- [1,2,4] tetrazolo [4,3-a] pyridine-3-thiol, 10 ml of dimethylsulfoxide. and 1.21 g of 4-nitrobenzenediazonium tetrafluoroborate. Thus 899 g of 6-iodo-3 - [(4-nitrophenyl) sulfanyl] [1,2,4] tetrazolo [4,3-a] pyhidine are obtained in the form of an orange powder.

SM: method B; [M + H] ⁺ : m / z 399; Tr = 3.74 min. Example 6d: 6-iodo- [1,2,4] triazolo [4,3-a] pyhdine-3-thiol The compound can be prepared in the following manner:

A solution of 1.37 g of 2-hydrazinyl-5-iodopyridine, 40 ml of tetrahydrofuran and 1.25 g of N, N'-thiocarbonyldiimidazole is refluxed for one hour. After cooling, the reaction medium is concentrated by evaporation under reduced pressure and the powder thus obtained is then stirred cold in the presence of 25 ml of water. The precipitate thus obtained is filtered off, washed twice with 10 ml of water and dried in air. There is thus obtained 1.40 g of 6-iodo- [1,2,4] thazolo [4,3-a] pyhdine-3-thiol.

Melting point> 264 ° C (Banc-Kόfler). SM: method A; [M + H] ⁺ : m / z 278; [MH] ^": m / z 276, Rt = 0.57 min Example 6: 2-hydrazinyl-5-iodopyridine.

The compound can be obtained as described in patent WO 2006/114213, example 32A page 40.

Example 7: 6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

Example 7a: 6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine The compound can be prepared as described in Example 1a from 0.24 g of 4 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} aniline, 10 ml of acetic acid, 0.28 g of potassium thiocyanate and 37 .mu.l of bromine diluted in 2 ml of glacial acetic acid. 0.14 g of 6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2 are thus obtained. -amine as a pale pink solid.

Melting point:> 264 ° C (Banc-Kόfler)

SM: method B; [M + H] ⁺ m / z = 394; [MH] ^"m / z = 392, Rt = 3.47 min.

1 H NMR (400 MHz, DMSO-c / ₆ ) δ ppm 7.27 (d, J = 8.3 Hz, 1H) 7.31 - 7.38 (m, 3H) 7.60 (bs, 2H) 7.77 (dd, J = 8.6, 5.4 Hz, 2H) 7.82 (dd, J = 9.8, 1.5 Hz, 1H) 7.87 (d, J = 1.7Hz, 1H) 7.98 (d, J = 9.9Hz, 1H) 8.59 (brs) , 1H)

The compound 6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can also be obtained as follows: To a solution of 20 mg of 6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2 -amine and 1 ml of dimethylsulfoxide are added 35 mg of potassium phosphate, 80 mg of 4-fluorophenylboronic acid and 3 mg of palladium tetrakistriphenylphosphine. The The reaction medium is heated at 80 ^° C. for 18 hours. 5 mg of palladium tetrakistriphenylphosphine are then added and the medium is again brought to 80 ^° C. for 2 days. After cooling the reaction medium with an ice bath, 15 ml of water are added and the medium is kept under cold stirring for one hour and then for 18 hours at room temperature. The aqueous phase is extracted with 3 times 30 ml of ethyl acetate, the combined organic phases are dried over sodium sulfate, filtered and concentrated by evaporation under reduced pressure. There is thus obtained 20 mg of 6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine. .

Example 7b: 4 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} aniline

The compound can be prepared as in Example 1b from 1.88 g of stannous chloride, dihydrate, 25 ml of ethanol, 0.61 g of 6- (4-fluorophenyl) -3 - [(4 -Nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a] pyridine and 2.06 ml of a 10N aqueous solution of hydrochloric acid. 0.24 g of 4 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyhdin-3-yl] sulfanyl} aniline are thus obtained in the form of a yellow solid. .

Melting point: 217 ° C (Banc-Kόfler) SM: Method A; [M + H] ⁺ : m / z 337 (base peak); [2IvRNa] ⁺ : m / z 695; Tr = 0.81 min.

Example 7c 6- (4-fluorophenyl) -3 - [(4-nitrophenyl) sulfanyl] [1,2,4] triazolo [4,3-a] pyridine

The compound can be prepared as in Example 1c from 0.83 g of 6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-3-thiol, from 8 ml of dimethylsulfoxide and 0.80 g of 4-nitrobenzenediazonium tetrafluoroborate. 0.61 g of 6- (4-fluorophenyl) -3 - [(4-nitrophenyl) sulfanyl] [1,2,4] thazolo [4,3-a] pyhidine are thus obtained in the form of a brown meringue. SM: method A; [M + H] ⁺ : m / z = 367; Tr = 0.98 min. Example 7d: 6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-3-thiol The compound can be prepared in the following manner:

A solution of 1.2 g of 5- (4-fluorophenyl) -2-hydrazinylpyridine, 15 ml of carbon disulfide and 50 ml of chloroform is refluxed for 18 hours. 15 ml of carbon disulphide are then added and the reaction mixture is kept under reflux for 4 hours, then 15 ml of carbon disulphide and the reaction medium is kept under reflux for 2 hours, then 20 ml of carbon disulphide and the medium The reaction mixture is refluxed for 24 hours. The reaction medium is then stirred at room temperature for 24 hours. After adding 20 ml of ethanol, the mixture is refluxed for 29 hours. After cooling, the medium is concentrated by evaporation under reduced pressure and the resulting yellow powder is purified by chromatography, under argon pressure, on silica gel (eluent: dichloromethane / methanol 97/3). 0.63 g of 6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhdine-3-thiol are thus obtained in the form of a yellow powder.

Melting point: 249 ° C (Banc-Kόfler)

SM: method A; [M + H] ⁺ : m / z = 246; [MH] ^- : m / z = 244, Tr = 0.77 min.

Example 7e: 5- (4-Fluorophenyl) -2-hydroxyrazine The compound can be prepared as described by R. Church et al., Journal of Organic Chemistry (1995), 60 (12), 3750-8.

Example 8: Λ- {6- [6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide The compound can be prepared as in Example 2 from 0.13 g of 6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3- yl] sulfanyl} -1,3-benzothiazol-2-amine, 0.081 ml of cyclopropanecarbonyl chloride and 5 ml of pyridine. 0.11 g of Λ / - {6- [6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide as a yellow solid.

SM: method B; [M + H] ⁺ m / z = 462; [MH] ^"m / z = 460; Tr = 0.97 min.

1 H NMR (400 MHz, DMSO-c / ₆ ) δ ppm 0.92 (m, 4H) 1.96 (m, 1H) 7.34 (t, J = 8.8 Hz, 2H) 7.45 (dd, J = 8.4, 2.0 Hz, 1H) 7.66 (d, J = 8.4 Hz, 1H) 7.77 (dd, J = 8.8, 5.5 Hz, 2H) 7.84 (dd, J = 9.6, 1.7Hz, 1H) 8.01 (dd, J) = 9.6, 1.0 Hz, 1H) 8.11 (d, J = 2.0 Hz, 1H) 8.61 (brs, 1H) 12.57 (m spread, 1H).

Example 9: 6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3 -benzothiazol-2-amine

The compound can be prepared in the following manner:

A solution of 0.25 g of 6 - [(6-iodo [1,2,4] triazolo [4,3-a] pyridin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine, 5 ml of 2-dimethoxyethane, 1.2 ml of NaOH (1N aqueous solution) and 0.14 g of (1-methyl-1H-pyrazol-4-yl) boronic acid are stirred under argon. during 30 minutes. Then 20 mg of palladium di-chlorobis (triphenylphosphine) are added and the reaction medium is heated at 65 ° C. for 30 minutes. 20 mg of palladium di-chlorobis (thphenylphosphine) are then added and the reaction mixture is refluxed overnight. A further 20 mg of palladium di-chlorobis (triphenylphosphine) and 0.61 g of (1-methyl-1H-pyrazol-4-yl) boronic acid are added. The medium is refluxed for 4 hours and left stirring at a temperature of about 20 ^° C. for 2 days. 10 ml of dioxane, 1 ml of water and 20 mg of palladium di-chlorobis (thphenylphosphine) are then added and the medium is transferred into a sealed tube and heated under microwaves at 150 ^° C. for 15 minutes. After returning to a temperature of 20 ° C, the medium is concentrated by evaporation under reduced pressure. The residue thus obtained is chromatographed under argon pressure on silica gel (eluent dichloromethane / methanol 95/5). 0.14 g of 6 - {[6- (1-methyl) 1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine as an orange solid. Brown.

SM: method A; [M + H] ⁺ m / z = 380; [MH] ^"m / z = 378, Rt = 0.5 min.

1H NMR (400MHz, DMSO-c / ₆ ) δ ppm3.88 (s, 3H) 7.27 (d, J = 8.3Hz, 1H) 7.35 (dd, J = 8.3, 2.0Hz, 1H) 7.60 (s, 2H) 7.75 (dd, J = 9.5, 1.3Hz, 1H) 7.87 (d, J = 2Hz, 1H) 7.91 (d, J = 9.5Hz, 1H) 8.02 (s, 1H) ) 8.33 (s, 1H) 8.57 (s, 1H)

Example 10: Λ- (6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} 1,3-benzothiazol-2-yl) cyclopropanecarboxamide

The compound can be prepared as in Example 2 from 0.13 g of 6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4, 3-a] pyhdin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine, 0.034 ml of cyclopropanecarbonyl chloride and 2 ml of pyridine. 0.1 g of Λ- (6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyhdin-3 are thus obtained. -yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a pale yellow solid.

Melting point ~ 196 ° C (Banc-Kόfler).

SM: method B; [M + H] ⁺ m / z = 448; [MH] ^"m / z = 446; Tr = 3.32 min.

1 H NMR (400 MHz, DMSO-c / ₆ ) δ ppm 0.89 - 1.00 (m, 4H) 1.94 - 2.01 (m, 1H) 3.87 (s, 3H) 7.43 (dd, J = 8.5, 2.0 Hz , 1H) 7.67 (d, J = 8.5Hz, 1H) 7.77 (dd, J = 9.5, 1.5Hz, 1H) 7.94 (d, J = 9.5Hz, 1H) 8.01 (s, 1H) 8.12 (d, J = 2Hz, 1H) 8.33 (s, 1H) 8.58 (s, 1H) 12.62 (brs, 1H)

Example 11: Λ- (6 - {[6- (1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3 -benzothiazol-2-yl) cyclopropanecarboxamide

Example 11a: Λ- (6 - {[6- (1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1, 3-benzothiazol-2-yl) cyclopropanecarboxamide

The compound can be prepared in the following manner: In a sealed glass tube, 104 mg of 3-bromo-6- (1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a] pyhidine, 100 mg of ( 6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 110 mg of potassium carbonate and 1 ml of dimethylsulfoxide. The medium is heated under microwave at 185 ° C for 12 minutes. After returning to a temperature of 20 ⁰ C, the medium is thrown on 60 ml of water and the precipitate thus formed is filtered on sintered glass, washed with water, drained and dried. The solid thus obtained is chromatographed under argon pressure on silica gel (eluent dichloromethane / methanol 85/15 then 90/10). This gives a solid which is triturated in 2 ml of ethanol, filtered, washed twice with 1 ml of ethanol and then 3 times with 1 ml of diethyl ether and dried. 82 mg of Λ- (6 - {[6- (1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} are thus obtained. 1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a pale yellow solid.

Melting point> 260 ^° C. (Banc-Kόfler). SM: method A; [M + H] ⁺ m / z = 434; Tr = 0.65 min.

1 H NMR (400 MHz, DMSO-c / ₆ ) δ ppm 0.89 - 0.99 (m, 4H) 1.94 - 2.03 (m, 1H) 7.45 (dd, J = 8.5, 2.0Hz, 1H) 7.67 (d , J = 8.5 Hz, 1H) 7.83 (dd, J = 9.5, 1.7 Hz, 1H) 7.94 (dd, J = 9.5, 1.0 Hz, 1H) 8.08 (brs, 1H) 8.15 (d , J = 2.0Hz, 1H) 8.39 (bursts, 1H) 8.59 - 8.65 (m, 1H) 12.66 (bursts, 1H) 13.11 (bursts, 1H) Example 11 b: (6-Sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide The compound can be prepared in the following manner:

To a suspension of 2 g of (6-thiocyanato-1,3-benzothiazol-2-yl) cyclopropanecarboxamide and 70 ml of ethanol is added a solution of 33.6 mg of potassium dihydrogenphosphate in 8 ml of water. at 20 ° C., followed by 3.2 g of DL-dithiothreitol. The reaction medium is stirred under reflux for 5 hours and then brought to a temperature in the region of 20 ^° C. 400 ml of water are then added and the precipitate formed is filtered off on sintered glass, washed extensively with water, drained and then dried. 1.5 g of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide are thus obtained in the form of a pale yellow solid. SM: method B; [M + H] ⁺ m / z = 251; [MH] ^"m / z = 249, Rt = 3.77 min.

Example H: (6-thiocyanato-1,3-benzothiazol-2-yl) cyclopropanecarboxamide

The compound can be prepared in the following manner: To a solution of 10 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial product) and 100 ml of pyridine is added 5.3 ml of cyclopropanecarbonyl chloride while maintaining the temperature of 20 ⁰ C. The reaction medium is stirred for 4 hours and then 500 ml of water are added. The precipitate formed is filtered on sintered glass, washed well with water, drained and then dried. 13 g of (6-thiocyanato-1,3-benzothiazol-2-yl) cyclopropanecarboxamide are thus obtained in the form of a pale yellow solid which is used as it is in the subsequent steps.

Example 11 d: 3-bromo-6- (1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a] pyhidine The compound can be prepared in the following manner: A solution of 170 mg of 6- (1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a] pyhidine in 4 ml of ethanol is added a solution of 0.058 ml of bromine and 2 ml of water. The reaction mixture is stirred for about 2 days at a temperature in the region of 20 ^° C. and then 20 ml of a saturated aqueous solution of sodium hydrogencarbonate are added. After stirring for 30 minutes, the precipitate formed is filtered on sintered glass, washed with three times 5 ml of water, drained and then dried. The solid residue obtained is chromatographed under argon pressure on silica gel (eluent ethyl acetate / methanol 85/15). There is thus obtained 110 mg of 3-bromo-6- (1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a] pyhidine as a white solid. SM: method A; [M + H] ⁺ m / z = 264; [MH] ^"m / z = 262, Rt = 0.35 min Example 11C: 6- (1 H -pyrazol-4-yl) - [1, 2,4] thazolo [4,3-a] pyridine. The compound can be prepared in the following manner:

To a mixture of 400 mg of 6-bromo- [1,2,4] triazolo [4,3-a] pyridine (commercial product), 8 ml of dimethyl sulfoxide, 69 mg of Palladium tetrakistriphenylphosphine and 424 mg of sodium carbonate in solution in 2 ml of water are added 272 mg of (1H-pyrazol-4-yl) boronic acid. The reaction medium is heated under microwaves at 150 ^° C. for 20 minutes. After returning to a temperature in the region of 20 ^° C., the medium is concentrated by evaporation under reduced pressure and then taken up in 40 ml of water. The aqueous phase is extracted with 3 times 20 ml of ethyl acetate. The precipitate formed in the aqueous phase is filtered on sintered glass, washed with water, drained and then dried. There is thus obtained 200 mg of 6- (1H-pyrazol-4-yl) - [1,2,4] triazolo [4,3-a] pyhidine as a white solid. SM: method A; [M + H] ⁺ m / z = 186; [MH] ^"m / z = 184; Tr = 0.21 min.

Example 12: Λ- (6 - {[6 - ((3-fluoro-4-methyl) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} 1,3-benzothiazol-2-yl) cyclopropanecarboxamide

Example 12a: Λ- (6- (f6 - ((3-fluoro-4-methyl-phenyl) -1,2,41-triazolof-3,4-aipyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

The compound can be prepared as in Example 11a from 348 mg of 3-bromo-6 - ((3-fluoro-4-methyl) phenyl) - [1,2,4] triazolo [4,3- a] pyhdine, 250 mg of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 280 mg of potassium carbonate and 4 ml of dimethylsulfoxide. 146 mg of Λ- (6 - {[6 - ((3-fluoro-4-methyl) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl are thus obtained. -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a white solid.

Melting point = 191 ° C (Banc-Kόfler).

SM: method A; [M + H] ⁺ m / z = 476; [MH] ^"m / z = 474, Rt = 1, 04 min 1 H NMR (400 MHz, DMSO-c / ₆₎ δ ppm 0.89 - 0.96 (m, 4 H) 1.93 - 2.00 (m, 1H). 2.28 (d, J = 1.5Hz, 3H) 7.40-7.49 (m, 3H) 7.57 (dd, J = 11.2, 1.5Hz, 1H) 7.67 (d, J = 8.5Hz, 1H) 7.87 (dd , J = 9.5, 1.5 Hz, 1H) 7.99 (dd, J = 9.5, 1.5 Hz, 1H) 8.13 (d, J = U Hz, 1H) 8.61 - 8.66 (m, 1H) 12.65 (br. s., 1 h) Example 12b: 3-Bromo-6 - ((3-fluoro-4-methyl) phenyl) - [1,2,4] triazolo [4,3-a] pyridine

The compound can be prepared in the following manner:

A mixture of 450 mg of 6 - ((3-fluoro-4-methyl) phenyl) - [1,2,4] thalzolo [4,3-a] pyhidine, 10 ml of chloroform and 356 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 residue thus obtained is chromatographed under argon pressure on silica gel (eluent ethyl acetate / methanol 80/20). 534 mg of 3-bromo-6 - ((3-fluoro-4-methyl) phenyl) - [1,2,4] triazolo [4,3-a] pyhidine are thus obtained in the form of a beige solid.

SM: method A; [M + H] ⁺ m / z = 306; Tr = 0.88 min.

Example 12c: 6 - ((3-fluoro-4-methyl) phenyl) - [1,2,4] triazolo [4,3-a] pyhidine

The compound can be prepared as in Example 11e from 400 mg of 6-bromo- [1,2,4] triazolo [4,3-a] pyhidine (commercial product), 8 ml of dimethysulfoxide, 69 mg tetrakistriphenylphosphine palladium,

424 mg of sodium carbonate dissolved in 2 ml of water and 370 mg of ((3-fluoro-4-methyl) phenyl) boronic acid. In this way 456 mg of

((3-fluoro-4-methyl) phenyl) - [1,2,4] triazolo [4,3-a] pyhidine as a white solid.

Melting point = 236 ° C (Banc-Kόfler).

SM: method A; [M + H] ⁺ m / z = 228; Tr = 0.71 min.

Example 13: Λ- (6 - {[6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) cyclopropanecarboxamide

Example 13a: Λ- (6 - {[6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) cyclopropanecarboxamide The compound can be prepared as in Example 11a from 480 mg of 3-bromo-6- (3-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine, 411 mg (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 454 mg of potassium carbonate and 10 ml of dimethylsulfoxide. 148 mg of Λ- (6 - {[6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazole are thus obtained. -2-yl) cyclopropanecarboxamide in the form of a beige solid.

Melting point> 260 ^° C. (Banc-Kόfler).

SM: method A; [M + H] ⁺ m / z = 462; [MH] ^"m / z = 460, Rt = 0.98 min 1 H NMR (400 MHz, DMSO-c / ₆₎ δ ppm 0.92 (br s, 4H.). 1.95 (br s, 1... H) 7.23 - 7.31 (m, 1H) 7.46 (d, J = 8.6 Hz, 1H) 7.50 - 7.70 (m, 4H) 7.88 (dd, J = 9.5, 1.5Hz, 1H) 8.01 (dd, J = 9.5, 1.5 Hz, 1H) 8.13 (br.s., 1H) 8.69 (brs, 1H)

Example 13b: 3-Bromo-6- (3-fluorophenyl) - [1,2,4] thazolo [4,3-a] pyhidine

The compound can be prepared as in Example 12b from 360 mg of 6- (3-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhidine, 10 ml of chloroform and 300 mg N-bromosuccinimide. 480 mg of 3-bromo-6- (3-fluorophenyl) - [1,2,4] thazolo [4,3-a] pyhdine are thus obtained in the form of an ocher solid.

SM: method A; [M + H] ⁺ m / z = 292; Tr = 0.77 min. Example 13c: 6- (3-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhidine The compound can be prepared as in Example 12c from 400 mg of 6-bromo- [1] , 2,4] triazolo [4,3-a] pyhdine (commercial product), 8 ml of dimethysulfoxide, 69 mg of palladium tetrakistriphenylphosphine, 424 mg of sodium carbonate dissolved in 2 ml of water and 345 mg of (3-fluorophenyl) boronic acid. 361 mg of 6 - ((3-fluoro, 4-methyl) phenyl) - [1,2,4] triazolo [4,3-a] pyhidine are thus obtained in the form of a white solid.

Melting point = 210 ^° C. (Banc-Kόfler).

SM: method A; [M + H] ⁺ m / z = 214; Tr = 0.59 min. Example 14: Λ- (6 - {[6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

Example 14a: Λ- (6 - {[6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

The compound can be prepared as in Example 11a from 240 mg of 3-bromo-6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4 yl)

[1,2,4] triazolo [4,3-a] pyridine, 170 mg of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 170 mg of potassium carbonate and 4 ml of dimethylsulfoxide. 240 mg of Λ- (6 - {[6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1.2] are thus obtained. 4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a white solid. Melting point ~ 110 ^° C. (Banc-Kόfler).

SM: method A; [M + H] ⁺ m / z = 562; [MH] ^"m / z = 560; Tr = 0.84 min.

1 H NMR (400 MHz, DMSO-c / ₆ ) δ ppm 0.90 - 0.98 (m, 4H) 1.27 - 1.67 (m, 6H) 1.91 - 2.01 (m, 1H) 3.32 - 3.39 (m, 1H) ) 3.52 (ddd, J = 11.5, 8.6, 3.4 Hz, 1H) 3.70 - 3.80 (m, 1H) 3.89 - 3.98 (m, 1H) 4.23 - 4.36 (m, 2H) 4.51 (t, J = 3.3 Hz, 1H) 7.42 (dd, J = 8.6, 2.0Hz, 1H) 7.66 (d, J = 8.6Hz, 1H) 7.78 (dd, J = 9.5, 1.5Hz, 1H) 7.94 (dd, J = 9.5, 1.0 Hz, 1H) 8.05 (s, 1H) 8.11 (d, J = 2.0Hz, 1H) 8.36 (s, 1H) 8.58 (s, 1H) 12.65 (brs), 1H).

Example 14b: 3-Bromo-6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4.3 The compound can be prepared as in Example 12b starting from 440 mg of 6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-ol. yl)

[1,2,4] triazolo [4,3-a] pyhidine, 10 ml of chloroform and 226 mg of N-bromosuccinimide. There is thus obtained 245 mg of 3-bromo-6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [ 4.3-a] pyhdine as a colorless lacquer. SM: method A; [M + H] ⁺ m / z = 392; Tr = 0.64 min.

Example 14c: 6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridine

The compound can be prepared as in Example 9 from 320 mg of 6-bromo- [1,2,4] triazolo [4,3-a] pyridine (commercial product), 15 ml of 1 -

2-dimethoxyethane, 69 mg of palladium di-chlorobis (thphenylphosphine), 3.2 ml of NaOH (1 N aqueous solution) and 990 mg of 1 - [2-

(tetrahydro-2H-pyran-2-yloxy) ethyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan)

2-yl) -1H-pyrazole. There is thus obtained 445 mg of 6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3- a] pyridine as a yellow oil which crystallizes.

SM: method A; [M + H] ⁺ m / z = 314; Tr = 0.49 min.

Example 14d: 1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H pyrazole. The compound can be prepared as described in US2007 / 0265272, p. 39.

Example 15_L Λ / - (6 - {[6- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl)

[1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

The compound can be prepared in the following manner:

To a solution of 215 mg Λ / - (6 - {[6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2] , 4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide and 10 ml of methanol are added 45 mg of Amberlyst 15 resin H + and the reaction medium is stirred for 16 h at a temperature in the region of 20 ^° C. After addition of 5 ml of dichloromethane, the resin is added to complete the reaction (followed by LC / MS), ie successively 45 mg, 40 mg and then 150 mg of resin while stirring at a temperature of 20 ⁰ C and over a total period of 4 days. The reaction medium is then filtered and the resin is washed with 4 times 15 ml of a 28% CH ₂ Cl ₂ / MeOH / NH ₄ OH mixture (12/3 / 0.5 by volume). The filtrate obtained is concentrated by evaporation under reduced pressure. 65 mg of Λ- (6 - {[6- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridine are thus obtained. 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a white solid.

Melting point ~ 182 ° C (Banc-Kόfler).

SM: method A; [IvRH] ⁺ m / z = 478; [MH] ^"m / z = 476; Tr = 0.63 min.

1 H NMR (400 MHz, DMSO-c / ₆ ) δ ppm 0.88 - 1.00 (m, 4H) 1.91 - 2.03 (m, 1H) 3.75 (q, J = 5.5 Hz, 2H) 4.16 (t, J) = 5.6 Hz, 2H) 4.95 (t, J = 5.3Hz, 1H) 7.44 (dd, J = 8.6, 2.0Hz, 1H) 7.67 (d, J = 8.3 Hz, 1H) 7.81 (dd, J) = 9.5, 1.5 Hz, 1H) 7.95 (d, J = 9.3 Hz, 1H) 8.06 (s, 1H) 8.12 (d, J = 2.0Hz, 1H) 8.38 (s, 1H) 8.62 (s) , 1H)

Example 16: Λ- (6 - {[6- (1-Piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3- yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

Example 16a: Λ- (6 - {[6- (1-piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3- yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

The compound can be prepared as follows: A mixture of 102 mg of 4- {4- [3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1, 2,4] tertzolo [4,3-a] pyridin-6-yl] -1H-pyrazol-1-yl} piperidine-1-carboxylic acid 2-methylpropan-2-yl and 1.52 ml of acid hydrochloric acid (4N solution in dioxane) is stirred at a temperature in the region of 20 ^° C. overnight, and then concentrated by evaporation under reduced pressure. The residue thus obtained is taken up in 5 ml of diisopropyl ether and then filtered on sintered glass, washed with twice 2 ml of diisopropyl ether, drained and dried. 101 mg of Λ- (6 - {[6- (1-piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] thazolo [4,3-a] pyhdin are thus obtained. -3-yl] sulfanyl} -1, 3- benzothiazol-2-yl) cyclopropanecarboxamide hydrochloride as an ocher solid.

Melting point> 260 ^° C. (Banc-Kόfler).

SM: method B; [M + H] ⁺ m / z = 517; [MH] ^"m / z = 515, Rt = 2.66 min 1 H NMR (400 MHz, DMSO-c / ₆₎ δ ppm 0.85 - 1.01 (m, 4 H) 1.93 - 2.05 (m, 1H). 2.05 - 2.30 (m, 4H) 3.02 - 3.18 (m, 2H) 3.33 - 3.44 (m, 2H) 4.42 - 4.57 (m, 1H) 7.44 (dd, J = 8.7, 1.6 Hz, 1H) 7.68 (d, J = 8.6 Hz, 1H) 7.86 (d, J = 9.5 Hz, 1H) 7.98 (d, J = 9.8 Hz, 1H) 8.13 (s, 2H) 8.48 (s, 1H) 8.67 (s, 1H) 12.70 (s, 1H) Example 16b: 4- {4- [3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [ 1,2,4] tertzolo [4,3-a] pyhdin-6-yl] -1H-pyrazol-1-yl} piperidine-1-carboxylic acid 2-methylpropan-2-yl

The compound can be prepared as in Example 11a from 134 mg of 4- {4 - [(3-bromo [1,2,4] triazolo [4,3-a] pyhdin) -6-yl] 2-methylpropan-2-yl 3H-pyrazol-1-yl} piperidine-1-carboxylate, 83 mg of (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 83 mg of potassium and 3.5 ml of dimethylsulfoxide. There is thus obtained 103 mg of 4- {4- [3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] tetrazolo [4,3- a 2-methylpropan-2-yl a] pyhdin-6-yl] -1H-pyrazol-1-yl} pipéhdine-1-carboxylate as a beige solid.

SM: method A; [M + H] ⁺ m / z = 617; [MH] ^"m / z = 615, Rt = 0.99 min.

Example 16c: 4- {4 - [(3-bromo [1,2,4] triazolo [4,3-a] pyhdin) -6-yl] -1H-pyrazol-1-yl} piperidine-1-carboxylate 2-methylpropan-2-yl

The compound can be prepared as in Example 12b from 120 mg of 4- [4 - ([1,2,4] triazolo [4,3-a] pyridin-6-yl) -1H-pyrazol 2-methylpropan-2-yl 1-yl] piperidine-1-carboxylate, 5 ml chloroform and 58 mg N-bromosuccinimide. 134 mg of 4- {4 - [(3-bromo [1,2,4] triazolo [4,3-a] pyridin-6-yl] -1H-pyrazol-1-yl} piperidine are thus obtained. 1 - 2-methylpropan-2-yl carboxylate as a green solid. SM: method B; [M + H] ⁺ m / z = 447; [MH] ^"+ HCOOH m / z = 491, Rt = 3.71 min.

Example 16d: 2-Methylpropan-4- [4 - ([1,2,4] triazolo [4,3-a] pyπdin-6-yl) -1H-pyrazol-1-yl] piperidine-1-carboxylate 2-yl The compound can be prepared as in Example 9 from 180 mg of 6-bromo- [1,2,4] triazolo [4,3-a] pyridine (commercial product), 10 ml of 1 2-dimethoxyethane, 35 mg of palladium di-chlorobis (triphenylphosphine), 1.8 ml of NaOH (1N aqueous solution) and 377 mg of 4- [4- (4,4,5,5- Tert-butyl tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazol-1-yl] -piperidine-1-carboxylate. There is thus obtained 120 mg of 4- [4 - ([1,2,4] triazolo [4,3-a] pyhdin-6-yl) -1H-pyrazol-1-yl] piperidine-1-carboxylate of 2 methylpropan-2-yl in the form of a colorless lacquer.

SM: method B; [M + H] ⁺ m / z = 369; [MH] ^"+ HCOOH m / z = 413; Rt = 3.25 min Example 16: 4- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl). pyrazol-1-yl] tert-butyl piperidine-1-carboxylate

The compound can be prepared as described in WO2007 / 066187, p 34.

Example 17: Pharmaceutical composition Tablets having the following formula were prepared:

Product of Example 7 0.2 g

Excipient for a tablet finished at 1 g

(details of the excipient: lactose, talc, starch, magnesium stearate).

Example 7 is taken as an example of a pharmaceutical preparation, this preparation can be carried out if desired with other products as examples in the present application.

Pharmacological part: Experimental protocols I) Expression and Purification of MET, cvtoplasmic domain

Baculovirus expression:

Recombinant His-Tev-MET (956-1390) DNA in pFastBac (Invitrogen) is transfected into insect cells and after several viral amplification steps, the final baculovirus stock is tested for protein expression. interest.

After infection for 72 hours at 27 ° C. with the recombinant virus, the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at -80 ^° C. Purification:

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.

After centrifugation, the lysing supernatant is incubated for 2 hours at 4 ° C with Nickel Chelate resin (His-Trap 6 Fast Flow ™, GE HealthCare). After washing with 20 volumes of Tp A, the suspension is packaged in a column, and the proteins are eluted by a gradient of buffer B (TpA + 290 mM imidazole).

The fractions containing the protein of interest in view of the electrophoretic analysis (SDS PAGE) are pooled, concentrated by ultrafiltration (cut-off 1OkDa) and injected on an exclusion chromatography column (Superdex ™ 200, GE HealthCare) balanced. in buffer A. After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast Flow ™, 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. For the production of autophosphorylated protein, 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. After stopping the reaction with 5mM EDTA, the reaction mixture is injected onto a HiPrep desalting column (GE HealthCare) previously equilibrated with 4mM A + Na3VO4 buffer, the fractions containing the protein of interest (SDS PAGE analysis) are pooled. and stored at -80 ^° C. The phosphorylation level is verified by mass spectrometry (LC-MS), and by peptide mapping.

II) Tests A and B A) Test A: HTRF MET assay in 96-well format

In a final volume of 50 μl of enzymatic reaction, final 5 nM MET is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 μM, 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 μg / ml, 10μM ATP and 5mM MgCl 2. After incubation for 10 min at room temperature, the reaction is stopped by a 30 μl mix to obtain a final solution of 50 mM Hepes pH 7.5, 50 mM potassium fluoride, 0.1% BSA and 133 mM EDTA in the presence of 80 ng Streptavidin 61 SAXLB Cis-Bio Int. and 18ng anti-Phosphotyrosine Mab PT66-Europium Cryptate per well. After 2 hours incubation at room temperature, the reading is made at 2 wavelengths 620 nm and 665 nm on a reader for the TRACE / HTRF technique and the% inhibition is calculated according to the 665/620 ratios.

The results obtained by this test A for the products of formula (I) as examples in the experimental part are such that IC50 less than 50 nm and especially 10 nm.

B) 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 μl 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 μM in pure DMSO - Range of 1 μM at 30 μM with a step of 3 in pure DMSO - Dilutions intermediate to 1/50 in culture medium then 10 μl sample directly added to the cells (200 μl) : final range of 10000 to 3OnM.

At the end of the incubation, gently remove the supernatant and rinse with 200 μl of PBS. Then put 10Oμl of lysis buffer directly into the wells on the ice and incubate at 4 ° C for 30 minutes. 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 10Oμl 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. b) ELISA PhosphoMET BioSource Kit KHO0281 In each well of the kit plate, add 70μl of kit dilution buffer + 30μL of cell lysate or 30μl of lysis buffer for the blanks. Incubate for 2h with gentle shaking at room temperature.

Rinse the wells 4 times with 400 μl of kit wash buffer. Incubate with 10μl of anti-phospho MET antibody for 1h at room temperature. Rinse the wells 4 times with 400 μl of kit wash buffer. Incubate with 100 μl HRP Anti-rabbit Antibody for 30 minutes at room temperature (except for chromogen wells alone).

Rinse the wells 4 times with 400 μl of kit wash buffer. Put 100μL of chromogen and incubate 30minutes in the dark at room temperature. Stop the reaction with 10Oμl of stop solution. Read without delay at 45OnM 0.1 seconds at Wallac Victor flat reader.

C) Test C: Measurement of Cell Proliferation Using 14 C-Thymidine Cells are inoculated in 96-well Cytostar plates at 180 μl for 4 hours at 37 ° C. and 5% CO 2: HCT116 cells at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L-Glutamine and MKN45 cells at 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine. After these 4 hours of incubation, the products are added under 10 μl in 20-fold concentrated solution according to the dilution method mentioned for the ELISA. The products are tested at 10 concentrations in duplicate from 1000OnM to 0.3nM with a pitch of 3.

After 72 hours of treatment, add 10 μl of 14 C-thymidine at 10 μCi / ml to obtain 0.1 μCi per well. The incorporation of 14 C-thymidine is measured on a Micro-Beta (Perkin-Elmer) after 24 hours of drawing and 96 hours of treatment.

All stages of the test are automated on BIOMEK 2000 or TECAN stations.

The results obtained by this test B for the products of formula (I) as examples in the experimental part are such that IC50 less than 10 microM and in particular to i microM.

The results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below, as follows: for test A, the sign + corresponds to less than 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 microM.

Table of pharmacological results:

Claims

1) Products of formula (I):

in which :

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, CF 3, -NR 1 R 2, heterocycloalkyl radicals, -COOH, -COOaIk, -CONR1 R2 and -NR1 COR2; the alkyl and cycloalkyl radicals being additionally optionally substituted with an aryl or heteroaryl radical, themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl, alkoxy and NR3R4 radicals; the cycloalkyl, heterocycloalkyl, aryl or heteroaryl radicals being moreover optionally substituted by an alkyl radical which is itself optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, O-heterocycloalkyl, alkyl, alkoxy and NR3R4 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, oxo radicals, alkoxy, NH2; NHaIk, N (alk) 2, and the alkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals the alkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals selected from the group consisting of halogen and hydroxyl, alkyl and alkoxy radicals having 1 to 4 carbon atoms, NH 2; NHaIk and N (alk) 2; all the above alkyl (alk) and alkoxy radicals containing from 1 to 6 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

2) Products of formula (I) as defined in claim 1 wherein:

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 with one or more radicals chosen from halogen atoms, and hydroxyl, alkoxy and heterocycloalkyl radicals, -NR 1 R 2, -COOH, COOaIk and -CONR1 R2, the aryl or heteroaryl radicals being further optionally substituted by an alkyl radical, itself optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, O-heterocycloalkyl 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 a radical alkyl optionally substituted by 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, alkoxy radicals; and the alkyl, phenyl and CH 2 -phenyl radicals, in which the alkyl or phenyl radicals are themselves 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; all the above-mentioned alkyl (alk) or alkoxy radicals containing from 1 to 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 inorganic and organic acids or with the inorganic and organic bases of said products of formula (I). 3) Products of formula (I) as defined in claim 1 or 2 wherein:

Ra represents a hydrogen atom; a halogen atom; an optionally substituted phenyl radical as indicated below; or a pyrazolyl radical optionally substituted with a heterocycloalkyl radical or with an alkyl radical, itself optionally substituted by a hydroxyl radical or by an O-heterocycloalkyl radical;

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 bonded to 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 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 with one or more identical or different radicals as defined in any one of Claims 1 or 2; ; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

4) Products of formula (I) as defined in any preceding claim wherein:

Ra represents a hydrogen atom; a halogen atom; or a phenyl radical optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals; or a pyrazolyl radical optionally substituted with a piperidyl radical or with an alkyl radical which is itself optionally substituted with a hydroxyl radical or with a tetrahydro-2H-pyran-2-yl) oxy radical;

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. NH2, NHaIk and N (alk) 2; all the above alkyl (alk) or alkoxy radicals containing from 1 to 4 carbon atoms, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

5) Products of formula (I) as defined in any one of the preceding claims wherein: Ra represents a hydrogen atom; an iodine atom; a phenyl radical optionally substituted with one or two radicals chosen from halogen atoms and the methyl radical; or a pyrazolyl radical optionally substituted with a piperidyl radical or with an ethyl radical itself optionally substituted with a hydroxyl radical or with a tetrahydro-2H-pyran-2-yl) oxy radical;

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,

NR 1 R 2 being such that either R 1 and R 2, which are identical or different, represent a hydrogen atom or an alkyl radical, or R 1 and R 2 form, with the nitrogen atom to which they are bonded, a morpholinyl or piperazinyl radical optionally substituted on the second atom; azole with an alkyl 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).

6) Products of formula (I) as defined in any one of the other claims, having the following formulas: - Λ / - [6 - ([1,2,4] triazolo [4,3-a] pyhdin) 3-ylsulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide

1- [2- (Morpholin-4-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazole 2-yl] urea

1- [2- (4-methylpiperazin-1-yl) ethyl] -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3 benzothiazol-2-yl] urea.

1- (2-Methoxyethyl) -3- [6 - ([1,2,4] triazolo [4,3-a] pyridin-3-ylsulfanyl) -1,3-benzothiazol-2-yl] urea

6 - [(6-Iodo [1,2,4] triazolo [4,3-a] pyhdin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine-6-{[6- (4-allyl)} -fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

N - {6- [6- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyhdin-3-ylsulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide 6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazole -2-amine

- Λ- (6 - {[6- (1-methyl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1 3-Benzothiazol-2-yl) cyclopropanecarboxamide - Λ- (6 - {[6- (1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3- yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ / - (6 - {[6 - ((3-fluoro-4-methyl) phenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3 -benzothiazol-2-yl) cyclopropanecarboxamide

N - (6 - {[6- (3-fluorophenyl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ / - (6 - {[6- (1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1H-pyrazol-4-yl) [1,2,4] triazolo [4] , 3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ - (6 - {[6- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

- Λ / - (6 - {[6- (1-Piperidin-4-yl-1H-pyrazol-4-yl) [1,2,4] triazolo [4,3-a] pyridin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

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).

7) Process for preparing the products of formula (I) as defined in any one of the other claims according to Scheme 1 as defined below. Figure 1: coupling reduction

(A) (B) (C)

cychsation functionalization

(I) Rb = H

wherein the substituents Ra and Rb have the meanings given in any one of claims 1 to 5.

8) Process for preparing the products of formula (I) as defined in any one of the other claims according to scheme 2 as defined below.

Figure 2:

diazotization

( AT )

in which the substituents Ra and Rb have the meanings indicated in any one of claims 1 to 5. 9) Process for the preparation of the products of formula (I) as defined in any one of the other claims according to scheme 3 such as defined below.

Figure 3:

reduction

(L) wherein the substituents Ra and Rc have the meanings given in any one of claims 1 to 5. 10) As medicaments, the products of formula (I) as defined in any one of claims 1 to 6, as well as addition salts with inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases. said products of formula (I). 11) As medicaments, the products of formula (I) as defined in claim 6, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I ).

12) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier.

13) Use of the products of formula (I) as defined in any one of claims 1 to 6, or pharmaceutically acceptable salts thereof for the preparation of a medicament for inhibiting the activity of the MET protein kinase and its mutant forms

14) The use as defined in claim 13, wherein the protein kinase is in a cell culture. 15) Use of a product of formula (I) as defined in any one of claims 1 to 6, for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders of blood vessel proliferation, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.

16) Use of a product of formula (I) as defined in any one of claims 1 to 6 for the preparation of a medicament for the treatment of cancers. 17) Use according to claim 16 for the treatment of solid or liquid tumors.

18) Use according to claim 16 or 17 for the treatment of cancers resistant to cytotoxic agents. 19) Use according to one or more of claims 16 or 17 for the treatment of primary tumors and / or metastases especially in gastric, hepatic, renal, ovarian, colon, prostate, lung cancers (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, cancer bones and pancreas.

20) Use of the products of formula (I) as defined in claims 1 to 6, for the preparation of medicaments for the chemotherapy of cancers.

21) Use of the products of formula (I) as defined in claims 1 to 6 for the preparation of medicaments for cancer chemotherapy alone or in combination.

22) Products of formula (I) as defined in any one of claims 1 to 6 as kinase inhibitors.

23) Products of formula (I) as defined in any one of claims 1 to 6 as MET inhibitors.

24) As new industrial products, synthetic intermediates of formulas (A), (B), (C), (D), (E), (H), (L), (L1), (J) and (K) as defined in claims 7, 8 and 9 above and recalled below:

(A) (C)

(J)

(L1

wherein Ra, Rb and Rc are as defined in any one of claims 1 to 5 and R is t-butyl or phenyl.