WO2010089507A1

WO2010089507A1 - Derivatives of 6-(6-o-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors

Info

Publication number: WO2010089507A1
Application number: PCT/FR2010/050178
Authority: WO
Inventors: Conception Nemececk; Antonio Ugolini; Sylvie Wentzler
Original assignee: Sanofi-Aventis
Priority date: 2009-02-06
Filing date: 2010-02-04
Publication date: 2010-08-12
Also published as: IL214406A0; FR2941950A1; AU2010212232A1; MA33107B1; CA2750875A1; FR2941950B1; AR075249A1; CN102378759A; CO6400223A2; KR20110132560A; SG173559A1; MX2011008319A; TW201031670A; JP2012517408A; EP2393791A1; CL2011001879A1; EA201171011A1; BRPI1008232A2; UY32420A

Abstract

The invention relates to novel products of the formula (I) where: (II) is a single double bond; Ra is -O-Z-Rc with Z being a single bond or optionally substituted alkylene and Rc being optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Rb is H or F; if Rb is H, then Rc is not cycloalkyl when Z is a single bond, and Rc is not heterocycloalkyl when Z is alkylene; X is S, SO or SO2, A is NH or S; W is H, alkyl, cycloalkyl or COR with R being cycloalkyl; alkyl; alkoxy; O- phenyl; -O-(CH2)n-phenyl with n = 1 to 4; or NR1 R2 with R1 is H or alk and R2 is H, cycloalkyl or alkyl; or R1, R2 form a cycle with N optionally containing O, S, N and/or NH; wherein all of these radicals are optionally substituted, and said products are in any isomer or salt form and can be used as drugs, in particular as MET inhibitors.

Description

6- (6-0-SUBSTITUTED-TRIAZOLOPYRIDAZINE-SULFANYL) DERIVATIVES

BENZOTHIAZOLES AND BENZIMIDAZOLES: PREPARATION, APPLICATION

AS MEDICAMENTS AND USE AS MET INHIBITORS

The present invention relates to novel 6- (6-O-substituted-triazolopyridazine-sulfanyl) benzothiazole and benzimidazole derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the novel use of such derivatives of 6-triazolopyhdazine-sulfanyl benzothiazole and benzimidazole.

The present invention relates more particularly to novel derivatives of 6- (6-O-substituted-triazolopyhdazine-sulfanyl) benzothiazoles and benzimidazoles, 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, 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, one of the objects of the present invention is to provide compositions having anticancer activity, acting in particular vis-à-vis kinases. Of the kinases for which modulation of activity is desired, MET is preferred. In the pharmacological part below, it is shown in biochemical tests and on cell lines that the products of the present application thus inhibit, in particular, the autophosphorylation activity of MET and the proliferation of cells whose growth depends on MET. or its mutant forms. MET, or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine kinase activity expressed in particular by epithelial and endothelial cells. HGF, Hepatocyte Growth Factor, is described as the specific ligand of MET. HGF is secreted by the mesenchymal cells and activates the MET receptor that moderates. As a consequence, the receptor autophosphorylates on tyrosines of catalytic domain Y1230, Y1234 and Y1235.

MET stimulation by HGF induces proliferation, scattering (or dispersion), cell motility, resistance to apoptosis, invasion and angiogenesis. MET, like HGF, are found to be overexpressed in many human tumors and a wide variety of cancers. MET is also found amplified in gastric tumors and glioblastomas. Numerous point mutations of the MET gene have also been described in tumors, in particular in the kinase domain, but also in the juxtamembrane domain and the SEMA domain. Overexpression, amplification or mutations cause constitutive activation of the receptor and deregulation of its functions. The present invention thus relates in particular to novel inhibitors of the MET protein kinase and its mutants, which can be used for an 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

z ^zz ^ represents a single or double bond;

Rb represents a hydrogen atom or a fluorine atom; Ra represents an -O-Z-Rc radical in which:

Z represents a single bond or a linear or branched alkylene radical containing from 1 to 6 carbon atoms and optionally substituted with an alkyl group or a halogen atom;

Rc represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical;

X represents S, SO or SO2; A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, -O-cycloalkyl, -O-CO-R5, hydroxy, phenyl, heteroaryl, or heterocycloalkyl themselves optionally substituted;

an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4;

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 and optionally substituted phenyl radicals; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, with the possible S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted;

with R3 and R4, which are identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIk, N (AI k) 2 radicals and phenyl itself optionally substituted; or R3 and R4 together with the nitrogen atom to which they are bonded form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the possible S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5 -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 radicals; , -NH-CO-R5, -NHCOOR5 and the radicals alkyl, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals the radicals alkyl, alkoxy, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH 2, NHaIk and N (alk) 2; all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl being further optionally substituted with a radical Si (alk) 3;

R5 and R5 ', which may be identical or different, represent an alkyl or cycloalkyl radical containing at most 6 carbon atoms; alk represents an alkyl radical containing at most 4 carbon atoms; it being understood that: i) when Rb represents hydrogen and Z represents a single bond, then Rc does not represent a cycloalkyl radical; and ii) when Rb is hydrogen and Z is alkylene, then Rc is not heterocycloalkyl; 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 hereinafter in which

represents a single or double bond;

Ra is -O-Z-Rc wherein Z is single bond and Rc is optionally substituted aryl; Rb represents a hydrogen or fluorine atom;

X represents S, SO or SO2; A represents NH or S;

W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

a cycloalkyl radical, or an alkyl radical, optionally substituted by an NR 3 R 4, alkoxy, -O-cycloalkyl, -O-CO-R 5, hydroxy, phenyl, heteroaryl, or heterocycloalkyl radical, themselves optionally substituted;

an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR1 R2 in which R1 and R2 are such that one of R1 and

R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen (s) ) among O, S, N and NH, with the possible S being optionally in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical all optionally substituted by one or more identical or different radicals chosen from the radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH 2, NHAIk, N (Alk) 2 or optionally substituted phenyl; or R3 and R4 together with the nitrogen atom to which they are bonded form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the possible S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, being optionally substituted by one or more radicals chosen from halogen atoms, the hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, NH2, NHaIk, N (alk) 2 radicals and the alkyl radicals, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl,

CO-phenyl, heteroaryl and S-heteroaryl, such that, in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl radicals, oxo, alkyl and alkoxy containing 1 to 4 carbon atoms, NH2, NHaIk and

N (alk) 2;

R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with the 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, Rb and X have the values defined in any of the other claims and:

A represents NH or S;

W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: a cycloalkyl radical or an alkyl radical optionally substituted by a radical NR3R4, alkoxy, -O-cycloalkyl, -O-CO-R5, hydroxy, phenyl or heterocycloalkyl themselves optionally substituted;

an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical with optionally substituted phenyl and n represents an integer of 1 to 4;

or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom or a cycloalkyl radical; or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical or a heterocycloalkyl radical optionally substituted with one or more identical or different radicals chosen from alkoxy, heteroaryl, heterocycloalkyl or NH2, NHAIk radicals, N (Alk) 2, or R3 and R4 together with the nitrogen atom to which they are linked to a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, alkoxy, O-cycloalkyl, NH2, NHaIk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl radicals; and heteroaryl, such as in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

Regarding the cyclic radicals that can be formed R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, these radicals optionally containing one or more other heteroatoms selected from O, S, N and NH, with 1 any possible S possibly being in SO or SO2 form; these radicals, including any NH they contain, may therefore be optionally substituted, in particular with a radical chosen from alkyl, alkoxy, cycloalkyl or heterocycloalkyl, themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; alkyl, alkoxy, NH 2, NHAIk or N (Alk) 2; The subject of the present invention is the products of formula (I):

in which

z ^zz ^ represents a single or double bond;

Rc represents a cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical optionally substituted;

X represents S, SO or SO2; A represents NH or S;

a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted;

an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or a radical

O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4;

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally phenyl radicals; 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 y including the possible NH it contains being optionally substituted; with R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted or else R3 and R4 form with the nitrogen atom to which they are linked a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by a or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO radicals; -R5 and the radicals alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in the latter radicals the radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are they themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH 2, NHaIk and N (alk) 2, all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl being further optionally substituted with a radical Si (alk) 3;

z ^zz ^ represents a single or double bond;

X represents S, SO or SO2; A represents NH or S;

a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted; an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR1 R2 in which R1 and R2 are such that one of R1 and

R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen (s) ) among O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or else R3 and R4 form with the nitrogen atom to which they are bonded a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, NH2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl radicals; , CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in the latter radicals alkyl radicals, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHaIk and N ( alk) 2; R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4, alkoxy, hydroxy, phenyl or heterocycloalkyl radical, themselves optionally substituted;

an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom or a cycloalkyl radical; or an alkyl radical optionally substituted by an alkoxy radical, heterocycloalkyl, or NR3R4; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and, if appropriate, one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, O-cycloalkyl, NH 2, NHaIk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl and heteroaryl radicals, such as in these latter radicals; the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH 2, NHaIk and N (alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The present invention relates to the products of formula (I) as defined above or below in which ^zzz ^, Ra, Rb and X have the values defined in any of the other claims and:

A represents NH or S; W represents a hydrogen atom; an alkyl radical optionally substituted by a heterocycloalkyl radical or NR3R4; or the radical COR in which R represents:

a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4 or alkoxy radical;

an O-phenyl or O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 2;

or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom; , an alkyl radical optionally substituted with a heterocyclic radical or NR3R4, or else R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, O-cycloalkyl, NH 2, NHaIk, N (alk) 2 radicals and alkyl and phenyl radicals, the latter being themselves optionally substituted by one or more radicals chosen from the atoms of halogen and the radicals hydroxyl, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

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

Ra, Rb, X and W being chosen from among all the values defined for these radicals in any of the other claims, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or below, in which A represents S, the substituents,

Ra, Rb, X and W being chosen from among all the values defined for these radicals in any of the other claims, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or hereafter corresponding to formula (Ia) or (Ib):

wherein Ra, Rb, and W are selected from the meaning indicated in any of the other claims, said products of formula (Ia) and (Ib) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (Ia) and (Ib).

The subject of the present invention is the products of formula (I) as defined above or below, in which ^zzz represents a single bond corresponding to the products of formula (V):

the substituents Ra, Rb, X, A and W having any of the meanings indicated above or hereafter, said products of formula (I) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which represents a double bond corresponding to the products of formula (I "):

wherein the substituents Ra, Rb, X, A and W have any of the meanings indicated above or hereafter, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which ^zzz represents a single bond corresponding to the products of formula (Ia '):

wherein Ra, Rb, and W are selected from any one of the meanings given above or hereafter, said products of formula (a) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (a).

The subject of the present invention is the products of formula (I) as defined above or below, in which represents a double bond corresponding to the products of formula (I "a):

wherein Ra, Rb, and W are selected from any of the meanings given above or hereafter, said products of formula (I "a) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "a).

The subject of the present invention is the products of formula (I) as defined above or below, in which represents a single bond corresponding to the products of formula (b):

wherein Ra, Rb and W are selected from any one of the meanings given above or hereafter, said products of formula (b) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with the mineral and organic acids or with the inorganic and organic bases of said products of formula (b).

The subject of the present invention is the products of formula (I) as defined above or below, in which represents a double bond corresponding to the products of formula (I "b):

wherein Ra, Rb and W are selected from any of the meanings given above or hereafter, said products of formula (I "b) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "b).

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

the term alkyl radical (or Alk) denotes the radicals, linear and optionally branched, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl; , octyl, nonyl and decyl and their linear or branched positional isomers: alkyl radicals containing from 1 to 6 carbon atoms and more particularly alkyl radicals containing from 1 to 4 carbon atoms of the above list are preferred;

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 cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, and especially the cyclopropyl, cyclopentyl and cyclohexyl radicals;

the term "heterocycloalkyl radical" thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms; for example morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyran, tetrahydrothiopyran, oxodihydropyridazinyl, or alternatively oxetanyl or thietanyl radicals, all these radicals being optionally substituted; it may be noted that these heterocycloalkyl radicals may comprise a bridge formed from two links to form, for example, an oxa-5-azabicyclo [2.2.1] heptane or azaspiro [3.3] heptane radical or other azabicycloalkane rings or azaspiro-alkanes.

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; It may also be noted that the aryl radical such as phenyl may be optionally substituted for example by two alkoxy radicals to form a radical benzodioxol itself optionally substituted as indicated for the aryl 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, pyrannyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyhdyl, 3-pyridyl and 4-pyhdyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazolyl, all these radicals being optionally substituted, among which more particularly the thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals such as, for example, benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl; azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or oxodihydropyridino pyrazolyl, all of these radicals being optionally substituted;

As examples of heteroaryl or bicyclic radicals, there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl radicals, optionally substituted by one or more identical or different substituents as indicated above. It can be noted that two substituents on the cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl radicals as well as on the cyclic radicals that can be formed by R1 and R2 or R3 and R4 respectively with the nitrogen atom to which they are attached, can optionally form a cycloalkyl or heterocycloalkyl ring as appropriate and the usual techniques known to those skilled in the art.

The carboxyl group (s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example: - among salification compounds, mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine ,

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

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

The cyclic radicals that R 1 and R 2 can form on the one hand with the nitrogen atom to which they are bonded and on the other hand R 3 and R 4 with the nitrogen atom to which they are bonded, are optionally substituted with one or several radicals chosen from those indicated above for the possible substituents of heterocycloalkyl radicals, ie one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy and NH 2 radicals; NHaIk, N (alk) 2, and the radicals alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, and CO-phenyl, such that in these latter radicals the alkyl, heterocycloalkyl and phenyl radicals are themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy having 1 to 4 carbon atoms, NH 2; NHaIk and N (alk) 2,

The cyclic radicals that can be formed on the one hand R 1 and R 2 with the nitrogen atom to which they are bonded and on the other hand R 3 and R 4 with the nitrogen atom to which they are bonded, are in particular optionally substituted by a or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, CH 2 -pyrrolidinyl, CH 2 -phenyl, heteroaryl and phenyl radicals, in which the alkyl, pyrrolidinyl and phenyl radicals are themselves optionally substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, oxo and alkoxy radicals.

The heterocycloalkyl radicals as defined above represent, in particular, the azepanyl, morpholinyl and pyrrolidinyl, piperidyl and piperazinyl radicals themselves optionally substituted, as defined above or hereinafter.

When NR1 R2 or NR3R4 forms a ring as defined above, such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl or piperazinyl radicals, these radicals themselves being optionally substituted as indicated. above or below: for example by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and CH 2 -phenyl radicals, the alkyl or phenyl radicals being themselves optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals.

The NR 1 R 2 or NR 3 R 4 ring may more particularly be chosen from pyrrolidinyl and morpholinyl radicals optionally substituted 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 by one or more identical radicals or various selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals.

The subject of the present invention is in particular the products of formula (I) as defined above or below in which Rb represents a fluorine atom, the other substituents of said products of formula (I) having any of the definitions indicated above or below.

The subject of the present invention is in particular the products of formula (I) as defined above or below in which Ra represents a radical -O-phenyl optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, alkoxy, O-cycloalkyl, alkyl and CF3 radicals, the other substituents of said products of formula (I) having any of the definitions indicated above or hereinafter.

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

represents a single or double bond

Ra represents an -O-phenyl radical optionally substituted with one or more halogen atoms;

Rb represents a hydrogen atom;

X is S; A represents S;

W represents a hydrogen atom; or the radical COR in which R represents:

a cycloalkyl radical, or an alkyl radical; or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, and the other of R1 and R2 represents an alkyl radical optionally substituted with a heterocycloalkyl radical; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

The present invention thus relates to the products of formula (I) as defined above or below having the following formulas: 6 - [(6-phenoxy [1,2,4] triazolo [4,3- b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine

N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide

1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] 1,3-benzothiazol-2-yl} urea

1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 3- [2- (Morpholin-4-yl) ethyl] urea-6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-amine

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2 - (2-methoxyethoxy) acetamide

N ² , N ² -dienyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) glycinamide

N ² -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) glycinamide

N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxamide - N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) acetamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

1- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3 - [2- (Morpholin-4-yl) ethyl] urea - 1 - (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin) 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea

6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea

1 - [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole -2-yl] -3- [2- (morpholin-4-yl) ethyl] urea-N- (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo} [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

N - (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

N- (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2- yl) cyclopropanecarboxamide

N- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole -2-yl] cyclopropanecarboxamide

1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 yl] sulfanyl} -1,3-benzothiazol-2-yl) urea-1 - (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea

6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-6- {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

1- (6 - {[6- (1 H -indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) -3- [2- (morpholin-4-yl) ethyl] urea

N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl ) cyclopropanecarboxamide

N- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) cyclopropanecarboxamide

N - (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide - N- (6 - {[6- (1H-indol-6-yloxy) [1H] itπazolo [--blpyπdazin-5-yl] sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

N - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dimethylglycinannide

2-ethoxy-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) acetamide

2- (cyclohexyloxy) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) acetamide-6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyrimidazin-3-yl] sulfanyl} -1,3-benzothiazole 2-amine 6 - ({6- [3- (trifluoronethoxy) phenoxy] [1,2,4] tπazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine

- [3 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl} oxy) phenyl ] 2-methylpropan-2-yl-N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridin-3-yl] sulfanyl carbamate} -1,3-Benzothiazol-2-yl) cyclobutanecarboxamide

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2 - (morpholin-4-yl) acétannide

N ² -cyclohexyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) glycinamide

N - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ^2- methyl-N ² - [2- (n-morpholin-4-yl) ethyl] glycinannide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1,3-Benzothiazol-2-yl) acetannide-6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 , 3-benzothiazol-2-amine

6 - {[6- (3-aminophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

N - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ~ 2 ~ - (tetrahydro-2H-pyran-4-yl) glycinannide

N- [6 - ({6- [4- (trifluoromethyl) phenoxy] [1,2,4] tπazolo [4,3-b] pyπdazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl ] cyclopropanecarboxamide

N- [6 - ({6- [3- (trifluoromethoxy) phenoxy] [1,2,4] tπazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl cyclopropanecarboxamide - N- [6 - ({6 - [(2-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1, 3-benzothiazol-2-yl] cyclopropanecarboxamide N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

2 - [(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-acetate yl) amino] -2-oxoethyl-N- [6 - ({6 - [(6-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl } sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide

N- [6 - ({6- [4- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxamide

(3 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyπdazin-6-yl ] 2-methylpropan-2-yl oxy} phenyl) carbannate

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

N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4, 3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-yl} cyclopropanecarboxamide

N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dialylglycinamide

N - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2 -hydroxyacétamide

2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-yl) acetannide - N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetamide 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-yl) acetamide

N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-yl} acetamide

N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-yl} -2-méthoxyacétannide

2-methoxy-N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] ] tπazolo [4,3-b] pyπdazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide

6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

2- (Morpholin-4-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1,3-Benzothiazol-2-yl) acetannide-N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide

N ² , N ² -dienyl-N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 , 3-benzothiazol-2-yl) glycinamide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide

2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-yl) acetamide

N- (6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-yl) acetannide 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-benzothiazol-2-yl) acetannide as well as 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 also any process for the preparation of the products of formula (I) as defined above

The subject of the present invention is thus any process for the preparation of the products of formula (I) as defined above in which A represents NH. The subject of the present invention is thus any process for the preparation of the products of formula (I) as defined above in which A represents S.

The products according to the invention can be prepared from conventional methods of organic chemistry. Schemes 1, 2, 2bis 3, 4, 5 and 6 below are illustrative of the methods used for the preparation of the products of formula (I). As such, it can not constitute a limitation of the scope of the invention, as regards the methods of preparation of the claimed compounds.

The products of formula (I) as defined above according to the present invention can thus be prepared in particular according to the processes described in Schemes 1, 2, 2bis, 3, 4, 5 and 6 below.

The present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 1 as defined below. The present invention thus also relates to the process for preparing products of formula (I) according to Scheme 2 as defined below.

The present invention thus also relates to the process for preparing products of formula (I) according to Scheme 2bis as defined below. The present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 3 as defined below

The subject of the present invention is therefore also the process for preparing products of formula (I) according to Scheme 4 as defined below. The subject of the present invention is therefore also the process for the preparation of products of formula (I) according to schema 5 as defined below

The present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 6 as defined below

Similarly, among the products of formula (I) as defined above in which represents a single or double bond, the products of formula (V) which represent the products of formula (I) in which represents a bond are defined simple and the products of formula (I ") which represent the products of formula (I) in which ^zzz ^ represents a double bond, likewise for synthetic intermediates as defined below of formulas (a), (b) (c), (d), (e) and (f) wherein ^zzz ^ represents a single or double bond, the compounds of formulas (a ¹ ), (b ¹ ), (c ¹ ), (d ¹ ), (e ¹ ) and (f) in which ^zzz ^ represents a single bond, and compounds of formulas (a "), (b"), (c "), (d"), (e ") and (f) wherein - represents a double bond.

Scheme 1: syntheses of benzimidazole derivatives of formulas (1 a "), (1 b"), (1 "c), (1d"), (1e "), (1 a ¹ ), (1 b ¹ ), ( 1 C) ₁ (Id ¹ ) and (1 e ¹ )

In Scheme 1 above, the substituents, Ra and Rb, have the meanings indicated above for the products of formula (I ¹ ) and (I "). The substituent R 5, in the compounds of formulas (J), (1 to ¹ ) and (1 a "), represents an alkyl radical.

In scheme 1 above, the groups CONR1 R2, CO2R6 and COR7, which constitute W, can take the values of W as defined above for the products of formula (I ¹ ) and (I "), when W ≠ H In the above scheme 1, the benzimidazoles of the general formula (1a "), (1b"), (1c "), (1d") and (1e ") and their reduced analogues of the general formula ( 1 to ¹ ), (1b ¹ ), (1c '), (1d') and (1e ¹ ) can be prepared from 3,6-dichloro [1,2,4] thazolo [4,3 Commercial pyridazine of formula (S)

The compounds (E) can be obtained, for example, by reaction of phenols or alcohols in the presence of a base on the compound (S). The reaction is carried out, for example, at a temperature in the region of 20 ^° C.

The compounds (G), with Rb = H, can be obtained, for example, by reaction of 3-amino-4-nitro-benzenethiol of formula (F) with the compounds of formula (E), in the presence of a base such as sodium hydride in a solvent such as N, N-dimethylformamide at a temperature in the region of 20 ^° C. The compounds of formula (F) are obtained by reduction in situ of 3-amino-4-nitrophenyl thiocyanate (Q ) (commercial compound), for example, in the presence of sodium borohydride in a solvent such as N, N-dimethylformamide, at a temperature in the region of 20 ° C.

The compounds (G), with Rb = F, can be obtained, for example, by reaction of 2-fluoro-5-amino-4-nitro-benzenethiol of formula (F) with the compounds of formula (E) in the presence of a base such as sodium hydride in a solvent such as N, N-dimethylformamide at a temperature in the region of 20 ^° C. The compounds of formula (F), with Rb = F, are obtained by reaction of 2-nitro-4,5-difluoroaniline (Q ') (commercial compound), for example, in the presence of potassium thioacetate (C) in a solvent such as N, N-dimethylformamide, at a temperature in the region of 20 ^° C. .

The compounds (H ") as represented by a double bond can be obtained, for example, by reduction with iron (O) of compounds of formula (G), in a solvent such as methanol, in the presence of acetic acid, with a temperature close to 70 ^° C.

The compounds (H ') such that ^{zz 1} are a single bond can be obtained, for example, by reduction with zinc (O) on the compounds of formula (G), in the presence of acetic acid, at a temperature close to 20 ° C.

More particularly, the carbamates of general formula (1 a ') and (1 a ") can be prepared in particular as described in patent WO03028721A2, but from a 3,4-diamino phenyl sulfide of formula (H') respectively. and (H ") and a pseudothiourea of formula (J), in the presence of acetic acid and in a protic solvent such as methanol, at a temperature in the region of 80 ^° C.

More particularly, the benzimidazoles of general formula (1b ') and (1b ") can be prepared respectively by reaction of an amine NHR1 R2 of formula (R) (with R1 and R2 as defined above) on a carbamate of formula (1 to ¹ ) and (1 a "), for example in the presence of an aprotic solvent such as

1-methyl-2-pyrrolidinone. The reaction is carried out, for example, a temperature close to 120 ° C., in a tube sealed under microwaves. More particularly, the 2-amino benzimidazoles of general formula (1c ') and (1c ") can be prepared for example by reaction of the bromide of cyanogen on a compound of formula respectively (H ') and (H "), in the presence of a protic solvent such as ethanol The reaction is carried out at a temperature in the region of 80 ^° C.

More particularly, the carbamates of general formula (1d ') and (1d ") can be obtained by reaction with a chlorocarbonate of formula (O) (X = Cl) on a compound of general formula respectively (1c ¹ ) and (1 c "), for example in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogen carbonate, at a temperature in the region of 20 ^° C.

More particularly, the carboxamides (1 '') and (1e ") can be obtained respectively from the amines of general formula (1c ') and (1c")

by reacting the amines (1c ') and (1c ") with an acid chloride of formula (P) (X = Cl), in the presence, for example, of a solvent such as pyridine, at a temperature close to of 20 ° C.

by reaction of the amines (1c ') and (1c ") with an acid anhydride of formula (P) (X = OCOR7), in the presence, for example, of pyridine at a temperature in the region of 20 ^° C. .

by coupling the amines (1c ¹ ) and (1c ") with an acid of formula (P) (X = OH) under the conditions, for example, described by D.D.Marteau, V. Montanari (Chem Lett, 2000 (9), 1052), in the presence of 1-hydroxybenzothazole and 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as thylamine, at a temperature of 40 ° C.

Scheme 2: Synthesis of Benzothiazole Derivatives of Formulas (2a '), (2b'), (2c '), (2d'), (2a) ', (2b'), (2c '), (2d')

In Scheme 2 above, the substituents R a and R b have the meanings given above for the products of formula (V) and (I "), and the groups CONR 1 R 2, CO 2 R 6 and COR 7, which constitute W can take the values of W as defined above for the products of formula (V) and (I "), when W ≠ H

In the above scheme 2, the benzothiazoles of the general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of the general formula (2a ¹ ), (2b ¹ ), (2c ¹ ) and (2d ') with Rb = H can be prepared from 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) (commercial compound).

The carbamates of general formula (L1) can be obtained, for example, by reaction with a chlorocarbonate of formula (O) (X = Cl) on 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature in the region of 20 ^° C.

commercial

K

In Scheme 2 above, the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a ¹ ), (2b ¹ ), (2c ¹ ) and (2cT) with Rb = F can be prepared from 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate. The 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (K) can be prepared from 3-fluoroaniline as described by K, Papke and R, Pohloudek-Fabini in Pharmazie; GE; 22, 1967, P229-233, by reaction of potassium thiocyanate and 3-fluoroaniline in the presence of bromine in acetic acid.

The compounds of general formula (L2) can be obtained, for example, by reaction of carbamates of formula (L1) where R6 = phenyl, with NHR1 R2 amines of formula (R) (with Rb, R1 and R2 as defined herein above), in the presence of an aprotic solvent such as tetrahydrofuran, at a temperature in the region of 20 ^° C.

The ureas (2b ¹ ) and (2b ") can be obtained, for example, respectively from the carbamates (2a ¹ ) and (2a") where R 6 = phenyl, in the same way that the ureas (L 2) are obtained by reaction of amines on carbamates of type (L1).

The compounds of general formula (L3) can be obtained for example:

by reaction of an acid chloride of formula (P) (X = Cl) with 2-amino-1,3-benzothiazol-6-yl thiocyanate (K), in the presence, for example, of a solvent such as pyridine, at a temperature in the region of 20 ^° C.

by reaction of an acid anhydride of formula (P) (X = OCOR7) with 2-amino-1,3-benzothiazol-6-yl thiocyanate (K), in the presence, for example, of a solvent such as pyridine at a temperature in the region of 20 ^° C.

by coupling of 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) with an acid of formula (P) (X = OH) under the conditions, for example, described by

D. D. DESMARTEAU; V. Montanari (Chem Lett, 2000 (9), 1052), in the presence of 1-hydroxybenzothazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as thylamine, at a temperature of 40 ° C. In the same way that the carboxamides (L3) can be obtained by acylation of the amine (K), the carboxamides (2c ') and (2c ") can be obtained respectively from the amines (2d') and (2d" ) by coupling with an acid of formula (P) (X = OH) under the conditions, for example, described by N. Xi et al. / Bioorg. Med. Chem. Lett. (2005) 5211-5217, in the presence of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), in a solvent such as N, N-dimethylformamide, in the presence of a base such as di-isopropyl ethylamine, at a temperature in the region of 20 ^° C.

Scheme 2bis: Synthetic routes of glycinamide derivatives (2c ') and (2c ")

In Scheme 2bis above the substituent R7 may take on the meaning of an aminomethyl group. These glycinamides (2c72c ") can be obtained by coupling amines (2d ') and (2d") with a glycidic acid (P') using the methods described above for acids (P) (X = OH).

The glycidic acids (P ') can be prepared from bromoacetic acid and amines HNR3R4 under conditions similar to those described by D. T. Witiak et.al .; J. Med. Chem. 1985, 28, 1228.

Alternatively, the amines (2d ') and (2d ") can be treated with chloroacetyl chloride in the presence of a base such as pyridine, triethylamine or N-methylmorpholine, in a solvent such as dichloromethane at a temperature in the region of ^0.degree. C at 20 ^° C. The alpha-chloroacetamides

(2e '/ 2e ") thus formed can react with amines of HNR3R4 type, as defined above, in a solvent such as pyridine at a temperature of 20 ^° C. to give the derivatives (2c' / 2c" ) as defined in Figure 2bis above.

The compounds of general formula (M1), (M2) and (M3) can be obtained, for example, by reduction of compounds of general formula (L1), (L2), (L3) with DL-dithiotreitol, in the presence of sodium dihydrogen carbonate in a solvent such as ethanol and at a temperature in the region of 80 ° C. The compound of general formula (N) can be prepared in situ by reduction of the compound of formula (K), for example with sodium borohydride in a solvent such as N, N-dimethylformamide, in the presence of a base such as triethylamine and at a temperature in the region of 95 ° C. or between 20 ^° C. and 95 ° C.

The aryl-thiol intermediates above can exist in the form of free thiols or in the form of disulphides or a mixture of the two forms which can be engaged indifferently in the course of the reactions. More particularly, the benzothiazoles of general formula (2d ') and (2d ") can also be prepared respectively from carbamates of formula (2a ¹ ) and (2a ¹ ) where R 6 = t-butyl by reaction, for example, with trifluoroacetic acid in a solvent such as dichloromethane, at a temperature in the region of 20 ^° C. Conversely, the benzothiazoles of general formula (2a ¹ ) and (2a ") may also be prepared from benzothiazoles of formula ( 2d ') and (2d "), for example, by reaction with a chlorocarbonate of formula (O) (X = Cl), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature of temperature close to 20 ^° C.

More particularly, the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a '), (2b'), (2c ') and (2d ') can be prepared for example:

1) or by coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of derivatives (L1), (L2), (L3) and (K) with sodium borohydride, in a solvent such as N, N- dimethylformamide and in the presence of a base such as thylamine, at a temperature of about 95 ° C or between 50 ⁰ C and 95 ° C.

2) or by coupling the isolated derivatives (M1), (M2) and (M3) and a compound of formula (E), in the presence of sodium borohydride in a solvent such as N, N-dimethylformamide and in the presence of a base such as triethylamine, at a temperature of about 95 ° C.

3) or by coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of derivatives (L1), (L2), (L3) and (K) in the presence of DL-dithiotreitol and sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 80 ^° C.

Reducing conditions 1) and 2) can give products of formula

(2a), (2b), (2c) and (2d) as represent a single or double bond while conditions 3) and 4) give products of formula (2a),

(2b), (2c) and (2d) such that ^zzz ^ represent a double bond. Scheme 3: Synthetic routes of the triazolopyridazine derivatives of formula (E)

In Scheme 3 above, the substituents Ra, Z and Rc have the meanings given above for the products of formula (I ') and (I ").

The compounds of formula (E) can be obtained, for example, as shown in scheme 3 above, from commercially available 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine of formula (S).

More particularly, the compounds of formula (E) wherein Ra represents an OZ-Rc radical can be obtained by the treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine (S) at a temperature in the region of 20 ^° C. in a solvent such as tetrahydrofuran with an alcoholate of formula (U), even obtained by treatment of the corresponding alcohol with a base such as sodium hydride at a temperature in the region of 0 ^° C. to 20 ^° C.

Scheme 4: Synthesis of benzothiazole derivatives of formula (2e ¹ ) and (2e ")

According to scheme 4 above, the benzothiazoles of general formula (2e ¹ ) and (2e ") can be prepared respectively from the compounds of formulas (2a ¹ ) and (2a").

In scheme 4 above, the substituent OR6 is preferably O-t-butyl. The substituent R 9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR 3 R 4 radical (R 3 and R 4 as defined above).

The carbamates of general formula (T) and (T ") can be obtained respectively by reaction of carbamates of general formula (2a ¹ ) and (2a") with R 6 = tBu preferably, for example, with alkyl halides of formula (W), in a solvent such as N, N-dimethylformamide, in the presence of sodium hydride, at a temperature of between 20 and 90 ^° C. The benzothiazoles of general formula (2e ¹ ) and (2e ") may also be prepared from compounds of formula (L1), preferably with R6 = tBu, via compounds of formula (T) and (T").

More particularly, the compounds of general formula (2e ¹ ) and (2e ") can be obtained respectively by treatment of compounds (T) and (T") isolated, for example, with trifluoroacetic acid, in a solvent such as dichloromethane, at a temperature of 20 ⁰ C,

Alternatively, the compounds of general formula (2e ") can be obtained directly by reaction of the compounds of formula (L4) and (E), via the compound (T") formed in situ, for example, in the presence of DL-dithiotreitol and of sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature of about 80 ^° C., optionally followed by an in situ treatment with trifluoroacetic acid at 20 ° C. if necessary.

L4 carbamates of general formula (L4) can be obtained by reaction of carbamates of general formula (L1), for example with alkyl halides of formula (W), in a solvent such as N, N-dimethylformamide, in presence of sodium hydride, at a temperature of between 20 and 90 ^° C.

Scheme 5: Synthesis of benzothiazole derivatives of formula (2e ') and (2e ")

Alternatively, according to scheme 5 above, the benzothiazoles of the general formula (2e ") can be prepared from the compounds of formulas (L6) and (E), for example, in the presence of DL-dithiotreitol and sodium dihydrogen carbonate in a solvent such as ethanol and at a temperature in the region of 80 ^° C.

The benzothiazoles of general formula (2e ¹ ) can be prepared from compounds of formula (2e "), according to the methods described below for the preparation of compounds (I ¹ ) from compounds (I").

The compounds of formulas (L6) can be prepared from the 2-bromo benzothiazole derivative (L5) by treatment with an NH 2 R 9 derivative, for example, in a solvent such as tetrahydrofuran, at a temperature in the region of 20 ^° C.

The substituent R 9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR 3 R 4 radical (R 3 and R 4 as defined above).

The compounds of formulas (L5) can be prepared from 2-amino-1,3-benzothiazol-6-yl (K) thiocyanate (commercial compound), for example by treatment with an alkyl nitrite and bromide. cuprous in a solvent such as acetonitrile, at a temperature of 0-20 ° C, according to the method described by Jagabandhu Das et. al. in J. Med. Chem. 2006, 49, 6819-6832. Figure 6 Other synthesis routes of reduced derivatives of formulas (V)

According to Scheme 6 above, the benzothiazoles of general formula (T) may also be prepared, starting from the compounds of formula (I "), by reduction, for example, with sodium borohydride, in a solvent such as ethanol, at a temperature of about 80 ⁰ C or by reduction with zinc (0) in the presence of acetic acid, at a temperature of 20 ⁰ C.

Alternatively the compounds (V) can also be prepared from compounds of formula (E ') by coupling with compounds of type M1, M2, M3 or N, obtained as intermediates by reduction of compounds L1, L2, L3 or K in situ, as described above in Scheme 2. The M1, M2 or M3 compounds can also be isolated and used for coupling with (E '). The compounds (E ') can be obtained from the compounds of formula (E) by reduction, for example, by reduction with zinc (O) in the presence of acetic acid, at a temperature of 20 ° C.

Alternatively, the compounds (V) may also be prepared from other compounds (I ') by transformation of the group W into a group W of the same nature as defined above for W and according to the type of reactions defined in scheme 2: transformations of 2d '/ 2d "into 2a' / 2a" and into 2c '/ 2c ", transformations from 2a' / 2a" into 2d '/ 2d "and into 2b' / 2b".

In the compounds of general formula (I) as defined above, the sulfur S can be oxidized to SO 2 sulfoxide or SO 2 sulfone according to the methods known to those skilled in the art and protecting, if necessary, the optionally reactive groups by the appropriate protective groups.

Among the starting products of formula J, K, O, P, P ', Q, Q', R, S, U, W are known and can be obtained either commercially or according to the usual methods known to man of the trade, 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, thmethylsilyl, 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 it is possible to subject, if desired and if necessary, intermediate products or products of formula (I) thus obtained by the processes indicated above, to obtain other intermediates or other products of formula (I), one or more reactions of transformations known to those skilled in the art such as for example: a) an esterification reaction function acid, b) an ester functional saponification reaction in the acid function, c) a reduction reaction of the free or esterified carboxy function depending on the alcohol, d) an alkoxy functional conversion reaction with hydroxyl function, or even hydroxyl function alkoxy function, e) an elimination reaction of the protective groups that the protected reactive functions can carry, f) a salification reaction with an inorganic or organic acid or a base to obtain the corresponding salt, g) a doubling reaction racemic forms of split products, said products of formula (I) thus obtained being in all possible isomeric forms racemic, enantiomers and dias téréoisomères.

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

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

b) The possible acid-functional ester function transformations of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in the middle alcoholic such as, for example, in methanol or by 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:

6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine-N- {6 - [(6 phenoxy [1,2,4] thazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3 - [2- (morpholin-4-yl) ethyl] urea

6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-N- (6-allyl); {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) ) acetamide

N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxamide

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 1- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3 - [2- (morpholin-4-yl) ethyl] urea

1- (6 - {[6- (3-Fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2- yl) -3- [2- (morpholin-4-yl) ethyl] urea-6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea

1 - [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole -2-yl] -3- [2- (morpholin-4-yl) ethyl] urea

N- (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) cyclopropanecarboxamide - N- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) cyclopropanecarboxamide

1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 yl] sulfanyl} -1,3-benzothiazol-2-yl) urea

1- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) -3- [2- (morpholin-4-yl) ethyl] urea-1 - (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3- b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-1 - ( 6 - {[6- (1 H -indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea

N - (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

N- (6 - {[6- (1 H -indol-6-yloxy) [1H] triazolo [5-yl] -sulfanyl] -3-benzothiazol-2-yl} cyclopropanecarboxamide - N- (6- {N [6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyrimidazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide

N - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dimethylglycinannide

2- (cyclohexyloxy) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) acetamide

6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-6- ( {6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine - [3 - ({3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl} oxy) phenyl ] 2-methylpropan-2-yl carbamate

N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyrimidazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide - N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1,3-benzothiazol-2-yl) acetannide

6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-6- {[6- (3-aminophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ~ 2 ~ - (tetrahydro-2H-pyran-4-yl) glycinannide

N- [6 - ({6- [3- (trifluoromethoxy) phenoxy] [1,2,4] tπazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl ] cyclopropanecarboxamide

N- [6 - ({6 - [(2-methylpyridin-3-yl) oxy] [1,2,4] tπazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole -2-yl] cyclopropanecarboxamide - N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 -benzothiazol-2-yl) cyclopropanecarboxamide 2 - [(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-acetate yl) amino] -2-oxoethyl

N- [6 - ({6 - [(6-methylpyridin-3-yl) oxy] [1,2,4] tπazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole 2-yl] cyclopropanecarboxamide - N- [6 - ({6- [4- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl -1,3-Benzothiazol-2-yl] cyclopropanecarboxamide

(3 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl 2-methylpropan-2-yl-N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyπdazin-3-oxy} phenyl) carbamate yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] tπazolo [4, 3-b] pyrimidazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide - N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2] 4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dialylglycinannide

2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-yl) acetannide

N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 2- (4-ethylpiperazin-1-yl) acetamide - 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo} [4,3-b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-yl} acetamide

N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-yl} -2-methoxyacetanid-2-methoxy-N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl} ] phenoxy} [1,2,4] tπazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide

6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-2- ( morpholin-4-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 -benzothiazol-2-yl) acétannide

N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetannide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-yl) acetannide - 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo} [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetannide 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).

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

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

Such pharmaceutical compositions of the present invention may also, if appropriate, contain active principles of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating agents of DNA and others. These pharmaceutical compositions may be administered orally, parenterally or locally by topical application to the skin and mucous membranes or by intravenous or intramuscular injection.

These compositions may be solid or liquid and may be in any of the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, pills, lozenges, capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods. The active ingredient can be incorporated into the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, the fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersing or emulsifying agents, preservatives. The usual dosage, variable according to the product used, the subject treated and the condition in question, may be, for example, from 0.05 to 5 g per day in the adult, or preferably from 0.1 to 2 g. per day.

The subject of the present invention is also the use of the products of formula (I) as defined above or of pharmaceutically acceptable salts of these products for the preparation of a medicament intended for inhibiting the activity of a protein kinase.

The subject of the present invention is also the use of products of formula (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 group following: blood vessel proliferation disorders, 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 M1, M2, M3 and N with Rb representing a fluorine atom F, as defined above and recalled hereinafter:

in which the groups CONR1 R2, CO2R6 and COR7, which constitute W, can take the values of W as defined above for the products of formulas (I ¹ ) and (I "), when W ≠ H.

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 11.0.

Microwave oven used:

Biotage, lnitiator EXP-EU, 300W max, 2450MHz

The 1 H NMR spectra at 400 MHz and 1 H at 300 MHz were carried out on BRUKER AVANCE DRX-400 or BRUKER AVANCE DPX-300 spectrometer with chemical shifts (δ in ppm) in the solvent dimethylsulfoxide-d6 (DMSO-d6) referenced at 2.5 ppm at the temperature of

303K.

Mass spectra were made either by analysis:

- LC-MS-DAD-ELSD (MS = Waters ZQ) - LC-MS-DAD-ELSD (MS = Platform II Waters Micromass)

- UPLC-MS-DAD-ELSD (MS = Quattro First XE Waters) DAD considered wavelength λ = 210-400 nm

ELSD: Sedere SEDEX 85; nebulization temperature = 35 ° C, nebulization pressure = 3.7 bar

Example 1

6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine a) 6 - [(6-Phenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine can be prepared as follows: through a solution of 622 mg of sodium thiocyanate 2-amino-1,3-benzothiazol-6-yl (commercial) in 30 cm ³ of ethanol, a stream of argon is bubbled for 5 minutes. 14 mg of potassium dihydrogenphosphate are then added in 0.3 cm ³ of water, 1.39 g of DL-dithiothreitol and 740 mg of 3-chloro-6-phenoxy [1,2,4] triazolo [4,3-b] pyridazine . The reaction mixture is heated at 80 ^° C. for 24 hours and then concentrated to dryness under reduced pressure. The residue is purified on silica by solid deposition, eluting with a gradient of dichloromethane / (dichloromethane 38 / methanol 17 / aqueous ammonia 2) from 95: 1 to 80:20. 717 mg of 6 - [(6-phenoxy [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine in the form of a white powder having the following characteristics: 1 H NMR SPECTRUM ( 400 MHz, DMSO-cfe) δ ppm 7.13 (dd, J = 8.3, 2.0 Hz, 1H) 7.21 (d, J = 8.3 Hz, 1H) 7.25 - 7.32 (m, 2H) 7.32 - 7.39 (m, 2H) 7.50 (t, J = 7.8 Hz, 2H) 7.61 (d, J = 1.5 Hz, 1H) 7.64 (s, 2H) 8.43 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: UPLC-SQD Waters: MH + m / z = 393 +; MH = 391 - b) 3-Chloro-6-phenoxy [1,2,4] triazolo [4,3-b] pyridazine can be prepared in the following manner: to a solution of 996 mg of phenol in 20 cm ³ of tetrahydrofuran, at 0 ^° C. 254 mg of sodium hydride at 60% in oil are added under argon. After stirring for 15 minutes, 1 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyhdazine (commercial) is added. The reaction medium is stirred and allowed to return gradually to 20 ^° C. for 23 h. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate. The organic phase is concentrated to dryness under vacuum. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a cyclohexane / ethyl acetate gradient of 95: 5 to 50:50. There is thus obtained 1. 07 g of 3-chloro-6-phenoxy [1,2,4] triazolo [4,3-b] pyridazine in the form of a white powder whose characteristics are as follows: MASS SPECTRUM: Waters UPLC-SQD : MH + m / z = 247 +

Example 2

N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide a) The N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide may be prepared as follows to a mixture of 250 mg of 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine (1a) in 5 cm ³ of pyridine at 20 ⁰ C is added 0.120 cm ³ of cyclopropane carboxylic acid chloride. After 2.5 h, the reaction mixture is concentrated to dryness and the solid residue is chromatographed by solid deposition on Biotage Quad 12/25 (KP-SIL, 6OA, 32-63 μM), eluting with a dichloromethane 100% gradient to dichloromethane / methanol. 96/4. 221 mg of N- {6 - [(6-phenoxy [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl are thus obtained. cyclopropanecarboxamide in the form of a white powder whose characteristics are as follows: NMR 1 H NMR SPECTRUM (400 MHz, DMSO-cfe) δ ppm 0.93 - 0.98 (m, 4H)

1.99 (qu, J = 6.2 Hz, 1H) 7.20-7.45 (m, 7H) 7.60 (d, J = 8.3Hz, 1H) 7.86 (d, J = 1.7Hz, 1H) 8.46 (d, J) = 10.0 Hz, 1H) 12.67 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 461 +; MH = 459-

Example 3

N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide can be prepared from similarly to Example 2a but from 302 mg of 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-amine (1a) in 10 cm ³ of pyridine with 0.220 cm ³ of acetyl chloride after 24h of reaction at 20 ^° C. 280 mg of N- {6 - [(6-phenoxy [1, 2 , 4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide as a white powder having the following characteristics:

NMR spectrum 1 H NMR (400 MHz, DMSO-cfe) δ ppm 2.20 (s, 3H) 7.23 (d, J = 7.6 Hz, 2H) 7.26 - 7.33 (m, 2H) 7.34 - 7.44 (m, 3 H) 7.61 (d, J = 8.6 Hz, 1H) 7.87 (d, J = 1.7 Hz, 1H) 8.46 (d, J = 9.8 Hz, 1H) 12.39 (brs, 1H) SPECTRUM OF MASS: Waters UPLC-SQD: MH + m / z = 435 +; MH = 433-

Example 4

1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1 3-Benzothiazol-2-yl} urea a) 1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4.3] b) pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea can be prepared in a manner similar to Example 1a but from 533 mg of 1 - [2- (morpholine) 4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea, 10 cm ³ of degassed ethanol, 6 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water , 606 mg of DL-dithiothreitol and 324 mg of 3-chloro-6-phenoxy [1,2,4] thazolo [4,3-b] pyhdazine (1b), after 32 hours at 80 ^° C. thus 320 mg of 1- [2- (morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl ] -1,3-benzothiazol-2-yl} urea as a white powder whose characteristics are as follows: NMR spectrum 1 H NMR (400 MHz, DMSO-cfe) δ ppm 2.36 - 2.46 (m, 6 H) 3.24 - 3.29 (m, 2H) 3.59 (t, J = 4.4 Hz, 4H) 6.80 (t, J = 5.7 Hz, 1H) 7.20 - 7.28 (m, 3H) 7.29 - 7.34 (m, 1H) H) 7.36 (d, J = 9.8 Hz, 1H) 7.44 (t, J = 7.8 Hz, 2H) 7.49 (d, J = 8.6Hz, 1H) 7.80 (d, J = 1.7Hz, 1H) 8.45 (d, J = 9.8 Hz, 1H) 10.93 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 549 +; MH = 547- b) 1- (2-Morpholin-4-ylethyl) -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea can be prepared in the following manner: in a mixture of 900 mg of 2 - {[(2-morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate and 40 cm ³ of ethanol at 20 ^° C., a stream of argon is bubbled through. for 5min. 11 mg of potassium dihydrogenphosphate are then added to 0.4 cm ³ of water and 1.1 g of dithiothreitol. The mixture is heated at 80 ^° C. for 3.5 h. The reaction mixture is cooled to 20 ° C and then poured onto water. The suspension is stirred for 45 minutes while maintaining a slight argon bubbling. The precipitate formed is drained and washed with 3x10cm ³ of water and then dried in vacuo at 20 ⁰ C. This gives 633mg of 1 - (2-morpholin-4-ylethyl) -3- (6-sulfanyl-1, 3 benzothiazol-2-yl) urea, in the form of a white solid whose characteristics are as follows:

MASS SPECTRUM: LC-MS-DAD-ELSD: MH + m / z = 339 +; (MH) - = 337- (c) 2 - {[(2-Morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate can be prepared as follows: to a solution of 1 g of phenyl ester (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate in 30 cm ³ of tetrahydrofuran, 0.44 cm ³ of 2-morpholin-4-ylethanamine is added at 20 ° C. After 24 hours, the reaction mixture is evaporated to dryness and the residue obtained is chromatographed on a Merck 70g cartridge (solid deposit, elution with a dichloromethane gradient and then 90/10 dichloromethane / methanol). 902 mg of thiocyanate are thus recovered. of 2 - {[(2-morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl as a colorless foam, the characteristics of which are as follows: MASS SPECTRUM: UPLC-MS -DAD-ELSD: MH + m / z = 364 + d) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate was prepared as follows: to a solution of 2.5 g of thiocyanate of commercial 2-amino-1,3-benzothiazol-6-yl in 94 cm ³ of tetrahydrofuran is added at 20 ^° C., 7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogencarbonate and 9.4 g of cm ³ of water. The resulting mixture is then stirred at 20 ^° C. for 20 h and then extracted with 2x150 cm ³ of ethyl acetate. The organic phases are combined and washed with ³ × 50 cm ³ of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm ³ of water and then filtered off and dried under vacuum at 20 ° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows: MASS SPECTRUM: LC-MS-DAD -LSD: MH + m / z = 328 +; (MH) - = 326-

Example 5

1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3 - [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl) ] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 1a but from 305 mg of 1 - [2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (4b), 5 cm ³ of degassed ethanol, 4 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 347 mg of DL-dithiothreitol and 202 mg of 3-chloro-6- (3-fluorophenoxy) [1,2,4] thazolo [4,3-b] pyridazine. 253 mg of 1 - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-is thus obtained. benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea as a white powder having the following characteristics: NMR SPECTRUM 1 H NMR (400 MHz, DMSO-cfe) δ ppm 2.36 - 2.45 (m, 6H) 3.25 - 3.28 (m, 2H) 3.59 (t, J = 4.3 Hz, 4H) 6.78 (brs, 1H) 7.14 (dd, J = 8.3, 1.7 Hz, 1H) 7.18 (td, J = 8.5, 2.3 Hz, 1H) 7.23 - 7.31 (m, 2H) 7.38 (d, J = 9.8 Hz, 1H) 7.42 - 7.51 (m, 2H) 7.84 (d, J = 1.7 Hz, 1H) 8.47 (d, J = 9.8 Hz, 1H) 10.89 (brs, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 567 +; MH = 565- (b) 3-Chloro-6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in a manner similar to Example 1b but from 1.19 g of 3-fluorophenol in 15 cm ³ of tetrahydrofuran, 254 mg of sodium hydride at 60% in oil and 1 g of 3,6-dichloro [1,2,4] triazolo [4,3- b] pyhdazine (commercial). 837 mg of 3-chloro-6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazine are thus obtained in the form of a white powder, the characteristics of which are as follows:

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 265 +

Example 6

6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared from in a manner similar to Example 1a but from 529 mg of 3-chloro-6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazine (5b), 10 mg of dihydrogenphosphate of potassium in 0.1 cm ³ of water, 926 mg of DL-dithiothreitol and 414 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial) in 10 cm 3 of ethanol. 587 mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine are thus obtained. form of a white powder whose characteristics are as follows: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 7.11 to 7.25 (m, 4H); 7.32 (td, J = 2.3 and 10.0 Hz, 1H); 7.37 (d, J = 9.8 Hz, 1H); 7.53 (dt, J = 6.8 and 8.3 Hz, 1H); 7.63 (bs, 2H); 7.65 (d, J = 2.0 Hz, 1H); 8.45 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 411; [MH] -: m / z 409

Example 7

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -

1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide a) N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide can be prepared in the following manner: a mixture of 131 mg (2-methoxyethoxy) acetic acid ( commercial), 0.17 cm ³ of diisopropyl ethylamine and 371 mg of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) in ³ cm ³ of N, N dimethylformamide at 20 ^° C. is stirred for 1 h at 20 ^° C. 200 mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin are added to the reaction medium. -3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6). After 18h the brown solution is poured on ice water and the precipitate is filtered. After drying the precipitate, 219 mg of N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide in the form of a white powder having the following characteristics: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 3.29 (s partially masked, 3 H); 3.48 to 3.54 (m, 2H); 3.66 to 3.71 (m, 2H); 4.29 (s, 2H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1H); 7.16 (dt, J = 2.2 and 8.3 Hz, 1H); 7.24 (td, J = 2.2 and 10.0 Hz, 1H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.42 (dt, J = 6.9 and 8.3 Hz, 1H); 7.63 (d, J = 8.6 Hz, 1H); 7.93 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.20 (spread m, 1 H) MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 527; [MH] -: m / z 525 Example 8

N ² , N ² -dienyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3- benzothiazol-2-yl) glycinamide a) N ² , N ² -dienethyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3 -yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinannide can be prepared as follows: a mixture of 373 mg of sodium N, N-diethylglycinate (commercial) in 2.4 cm ³ of a 2N solution of hydrogen chloride in ether is stirred for 1 h at 20 ^° C. The resulting suspension is evaporated to dryness under vacuum. To the white residue obtained are added, at 20 ^° C., 4 cm ³ of pyridine, 100 mg of 6- {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl ] sulfanyl} -1,3-benzothiazol-2-amine (6) and 467mg of N- (3-dimethylaminopropyl) N-ethylcarbodiimide hydrochloride. After 4.5h, the brown reaction medium is evaporated to dryness. The residue is taken up in water and the mixture is extracted with ethyl acetate. The organic phase is evaporated to dryness. The oily brown residue is taken up in ether and the precipitate is drained. 76 mg of N ² , N ² -dienyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl are thus obtained. -1,3-benzothiazol-2-yl) glycinamide in the form of a beige powder, the characteristics of which are as follows:

¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): for this batch, all the ignals are broad with: 1.00 (t, J = 6.9 Hz, 6 H); 2.63 (q, J = 6.9 Hz, 4H); 3.41 (s, 2H); 7.06 to 7.20 (m, 2H); 7.24 (d, J = 9.5 Hz, 1H); 7.31 (d, J = 8.3 Hz, 1H); 7.35 to 7.47 (m, 2H); 7.61 (d, J = 8.3 Hz, 1H); 7.92 (s, 1H); 8.49 (d, J = 9.8 Hz, 1H); 9.44 to 14.07 (m very spread, 1 hour)

MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 524; [M-H] -: m / z 522

Example 9: N ² -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3- benzothiazol-2-yl) glycinamide a) N ² -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) glycinannide can be prepared in the following manner: at 137mg 2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] ] Pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide (9b) in 1.5 cm ³ of pyridine at 20 ^° C. is added 0.13 cm ³ of cyclopropylamine. After stirring for 5 hours, the reaction medium is evaporated to dryness at 20 ^° C. The residue is purified by solid Merck silica cartridge chromatography eluting with a gradient of 100% dichloromethane to 97: 3 dichloromethane / methanol. 52 mg of N ² -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 are thus obtained; 3-benzothiazol-2-yl) glycinamide in the form of a white solid, the characteristics of which are as follows: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 0.19 to 0.42 (m , 4H); 2.18 (m, 1H); 3.52 (s, 2H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1H); 7.16 (ddt, J = 1.0 and 2.3 and 8.3 Hz, 1H); 7.25 (td, J = 2.3 and 10.0 Hz, 1H); 7.31 (dd, J = 2.0 and 8.3 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.45 (dt, J = 6.9 and 8.3 Hz, 1H); 7.45 (spread m, 1H); 7.60 (d, J = 8.3 Hz, 1H); 7.91 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 508; [MH] -: m / z 506 b) 2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl} ] sulfanyl} -1,3-benzothiazol-2-yl) acetamide can be prepared in the following manner: 205 mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6) in 2 cm ³ of dichloromethane and

0.5 cm ³ of pyridine at 0-5 ° C is added dropwise 0.06 cm ³ of chloroacetyl chloride. The resulting white suspension is stirred for 30 min at 20 ^° C. 0.03 cm ³ of chloroacetyl chloride are added and stirring is continued for a further ³⁰ minutes. A little methanol is added to the mixture, then the medium is evaporated to dryness under argon at 20 ° C. The residue is purified by Merck silica cartridge chromatography by solid deposition eluting with a gradient of 100% dichloromethane at 92: 8 dichloromethane / (dichloromethane: 38 / methanol: 17 / ammonia: 2). There is thus obtained 137 mg of 2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) acetamide in the form of a white solid, the characteristics of which are as follows:

MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 487; [M-H] -: m / z 485

Example 10

N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole 2-yl] cyclopropanecarboxamide a) N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl Sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide can be prepared in a manner similar to Example 2a but from 85 mg of 6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl) -1,3-benzothiazol-2-amine (10b) in 5 cm ³ of pyridine with 0.124 cm ³ of sodium chloride. cyclopropanecarbonyl after 3.5h of reaction at 50 ^° C. is thus obtained 57.3 mg of N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] thazolo [4, 3-b] pyridazin-3-yl) sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide as a white powder having the following characteristics:

¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 0.88 to 1.00 (m, 4H); 1.92 to 2.04 (m, 1H); 2.30 at 2.35 (m, 4H); 3.39 (s, 2H); 3.51 to 3.57 (m, 4H); 7.09 to 7.14 (m, 1H); 7.20 to 7.25 (m, 2H); 7.28 (dd, J = 2.0 and 8.6 Hz, 1H); 7.31 to 7.39 (m, 2H); 7.59 (d, J = 8.6 Hz, 1H); 7.83 (d, J = 2.0 Hz, 1H); 8.47 (d, J = 9.8 Hz, 1H); 12.68 (spread m, 1 H)

MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 560; [MH] -: m / z 558 b) 6 - ({6- [3- (Morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl Sulfanyl) -1,3-benzothiazol-2-amine (10b) can be prepared in a manner similar to Example 1a but from 133 mg of 3-chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazine (10c), 3 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 176 mg of DL-dithiothreitol and 79 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial) in 5 cm 3 of ethanol. 111 mg of 6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1 are thus obtained. 3-benzothiazol-2-amine as a colorless oil having the following characteristics:

MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 492; [M + 2H] 2 +: m / z 246.5 (base peak); [MH] -: m / z 490 c) 3-Chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazine (10c) can be prepared in a manner similar to Example 1b but from 310 mg of 3- (morpholin-4-ylmethyl) phenol (10d) in 5 cm ³ of tetrahydrofuran, 76 mg of sodium hydride at 60% in oil and 275 mg of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial). 138 mg of 3-chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] thazolo [4,3-b] pyridazine are thus obtained in the form of a brown oil, the characteristics of which are as follows: : MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 346 d) 3- (morpholin-4-ylmethyl) phenol (10d) can be prepared as follows: to a solution of 188 mg of 3 - (bromomethyl) phenol (10e) in 5cm3 of THF at 20 ^° C are added 438mg of morpholine. After 24 hours, the white suspension is concentrated to dryness under reduced pressure. The residue is taken up in water and then extracted with dichloromethane. The organic phase is evaporated to dryness to give a colorless oil which crystallizes gradually. 182 mg of 3- (morpholin-4-ylmethyl) phenol are thus obtained, the characteristics of which are as follows: MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 194 e) 3- (bromomethyl) phenol (10e) can be prepared in the following way: to a solution of 500 mg of 1- (chloromethyl) -3-methoxybenzene (commercial) in 5 cm3 of dichloromethane at 20 ^° C. are added 3.19 cm3 of a 1 M solution of boron tribromide in dichloromethane. After 19h, the red solution is poured into ice water and then extracted with dichloromethane. The organic phase is evaporated to dryness under vacuum to give a violet oil which crystallizes. This residue is purified by chromatography on a SPOT II apparatus, equipped with a SVF D26 silica cartridge of 15-40 μM, after solid deposition eluting with a gradient of 100% dichloromethane to 100% methanol. 328 mg of 3- (bromomethyl) phenol in the form of pinkish crystals are thus obtained, the characteristics of which are as follows: MASS SPECTRUM: Waters ZQ: [MH] -: m / z 185

Other examples and their intermediates prepared by analogy with the examples above, are described in the table below:

the product characteristics of the table above are as follows:

Example 76: Pharmaceutical composition Tablets having the following formula were prepared:

Product of Example 2 0.2 g

Excipient for a tablet finished at 1 g

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

Example 77: Pharmaceutical composition

Tablets having the following formula were prepared:

Product of Example 5 0.2 g Excipient for a tablet finished at 1 g

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

Examples 2 and 5 are taken as examples of pharmaceutical preparation, this preparation can be carried out if desired with other products examples in the present application.

Pharmacological part:

Experimental protocols

I) Expression and Purification of MET, Cytoplasmic 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 expression of the protein of interest.

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

Purification:

Cell pellets are resuspended in lysis buffer

(A buffer [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 1 OkDa) 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 after electrophoresis (SDS PAGE), are finally collected and stored at -80 ^° C. For the production of autophosphorylated protein, the preceding fractions are incubated for 1 h at room temperature after addition of 2 mM ATP, 2 mM MgCl 2, and Na 3 VO 4. 4 mM. 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 and C

A) Test A: HTRF MET assay in 96-well format

In a final volume of 50 μl of enzymatic reaction, final 5nM MET is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 μM, DMSO 3% final) in MOPS buffer 1 OmM pH 7.4 , 1mM DTT, 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 a 10 min incubation at room temperature, the reaction is stopped by a 30 μl mix to obtain a final solution of 50 mM Hepes pH 7.5, 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 ThS ₁ HCl pH 7.4, 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 PMSF and cocktail anti proteases.

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 14C-Thymidine

The cells are seeded 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 the rate of 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 less than 50OnM and the sign ++ corresponds to less than 10OnM. for the C test the + sign corresponds to less than 10 microM and the sign ++ corresponds to less than I microM.

Table of pharmacological results:

1) Products of formula (I):

in which

represents a single or double bond;

X represents S, SO or SO2; A represents NH or S;

Claims

R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 radicals, optionally substituted phenyl; 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, with the possible S possibly being in SO or SO2 form; this radical including the eventual

NH it contains being optionally substituted;

with R3 and R4, which are identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH 2, NHAIk, N (Alk) 2 radicals, optionally substituted phenyl; or R3 and R4 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O,

S, N and NH, with the optional S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the radicals R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, -O- CO-R 5, -OR 5 -COOH, COOR 5, -CONH 2, CONHR 5, NH 2, NHR 5, NR 5 R 5 ', -NH-CO-R 5, -NHCOOR 5 and the radicals alkyl, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that, in the latter radicals, the alkyl, alkoxy, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2; all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl being further optionally substituted with a radical Si (alk) 3; R5 and R5 ', which may be identical or different, represent an alkyl or cycloalkyl radical containing at most 6 carbon atoms; alk represents an alkyl radical containing at most 4 carbon atoms; Being heard that :

1) when Rb is hydrogen and Z is a single bond, then Rc is not a cycloalkyl radical; and ii) when Rb represents

Hydrogen and Z represents an alkylene radical, then Rc does not represent a heterocycloalkyl radical; 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).

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

z ^zz ^ represents a single or double bond; Ra is -OZ-Rc wherein Z is single bond and Rc is optionally substituted aryl; Rb represents a hydrogen or fluorine atom;

X represents S, SO or SO2; A represents NH or S;

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached; linked to a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, with the optional S possibly being in the SO or SO2 form; this radical including the possible NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical all optionally substituted by one or more identical or different radicals chosen from the radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH 2, NHAIk, N (Alk) 2 or optionally substituted phenyl; or R3 and R4 together with the nitrogen atom to which they are bonded form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the possible S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, being optionally substituted by one or more radicals chosen from halogen atoms, the hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, NH2, NHaIk, N (alk) 2 radicals and the alkyl radicals, cycloalkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in the latter radicals the radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or a plurality of radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2; R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). 3) Products of formula (I) as defined in any one of claims wherein Ra, Rb and X have the values defined in any one of the other claims and:

a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4, alkoxy, -O-cycloalkyl, -O-CO-R 5, hydroxy, phenyl or heterocycloalkyl radical, themselves optionally substituted;

an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom or a cycloalkyl radical; or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical or a heterocycloalkyl radical optionally substituted with one or more identical or different radicals chosen from alkoxy, heteroaryl, heterocycloalkyl or NH2, NHAIk radicals, N (Alk) 2, or R3 and R4 together with the nitrogen atom to which they are attached form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, alkoxy, O-cycloalkyl, NH2, NHaIk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl radicals; and heteroaryl, such as in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

4) Products of formula (I) as defined in any one of claims wherein Ra, Rb and X have the values defined in any one of the other claims and:

A represents NH or S;

W represents a hydrogen atom; an alkyl radical optionally substituted by a heterocycloalkyl radical or NR3R4; or the radical COR in which R represents:

an O-phenyl or O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 2; or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom; , an alkyl radical optionally substituted with a heterocyclic radical or NR3R4, or else R1 and R2 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with NR3R4, such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, -O-cycloalkyl, NH 2, NHaIk, N (alk) 2 radicals and alkyl and phenyl radicals, the latter being themselves optionally substituted with one or more radicals chosen from among the atoms; halogen and hydroxyl, alkyl and alkoxy radicals having from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

5) Products of formula (I) as defined in any one of claims wherein A represents NH, the substituents, Ra, Rb, X and W being chosen from all the values defined for these radicals to any of the other claims, said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as addition salts with mineral and organic acids or with the mineral and organic bases of said products. of formula (I).

6) Products of formula (I) as defined in any one of claims wherein A represents S, the substituents ^zzz , Ra, Rb, X and W being chosen from among all the values defined for these radicals in one any of the other claims, said products of formula (I) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula ( I).

7) Products of formula (I) as defined in any one of the claims corresponding to formula (Ia) or (Ib):

wherein Ra, Rb, and W are selected from the meaning indicated in any of the other claims, said products of formula (Ia) and (Ib) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as salts addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (Ia) and (Ib).

8) Products of formula (I) as defined in any one of claims wherein represents a double bond corresponding to the products of formula (I "):

9) Products of formula (I) as defined in any one of claims wherein represents a double bond corresponding to the products of formula (I "a):

wherein Ra, Rb, and W are selected from any of the meanings given above or hereafter, said products of formula (I "a) being in any isomeric possible racemic, enantiomeric and diastereoisomeric forms, as well as salts addition with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "a).

10) Products of formula (I) as defined in any one of claims wherein represents a double bond corresponding to the products of formula (I "b):

11) Products of formula (I) as defined in any one of the claims in which

represents a single or double bond

Rb represents a hydrogen atom;

X is S; A represents S;

W represents a hydrogen atom; or the radical COR in which R represents:

a cycloalkyl radical, or an alkyl radical; or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, and the other of R1 and R2 represents an alkyl radical optionally substituted with a heterocycloalkyl radical; 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 thus the products of formula (I) as defined above or below, corresponding to the following formulas: 6 - [(6-phenoxy [1,2,4] triazolo [4, 3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine

1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3 - [2- (Morpholin-4-yl) ethyl] urea - 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1,3-Benzothiazol-2-amine

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyhdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2 - (2-methoxyethoxy) acetamide

N ² -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) glycinamide N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxamide

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide - N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

1- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3 - [2- (morpholin-4-yl) ethyl] urea

1- (6 - {[6- (3-Fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2- yl) -3- [2- (morpholin-4-yl) ethyl] urea

6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-1-[2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl} ] sulfanyl} -1,3-benzothiazol-2-yl) urea

N- (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) cyclopropanecarboxamide

N- (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2- yl) cyclopropanecarboxamide - N- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1 , 3-benzothiazol-2-yl] cyclopropanecarboxamide 1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 yl] sulfanyl} -1,3-benzothiazol-2-yl) urea

1- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) -3- [2- (morpholin-4-yl) ethyl] urea-1 - (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3- b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea

6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl cyclopropanecarboxamide - N- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 -benzothiazol-2-yl) cyclopropanecarboxamide

N- (6 - {[6- (1 H -indol-6-yloxy) [1H] itπazolo [--blpyπdazin-5-yl] sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dimethylglycinannide - 2-ethoxy-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 , 3-benzothiazol-2-yl) acetamide 2- (cyclohexyloxy) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole -2-yl) acetamide

6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine-6- ( {6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine

- [3 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl} oxy) phenyl ] 2-methylpropan-2-yl carbamate

N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyrimidazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide

N ² -cyclohexyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 -yl) glycinamide - N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 -yl) -N ² -methyl-N ² - [2- (n-morpholin-4-yl) ethyl] glycinannide

6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

N - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ~ 2 ~ - (tetrahydro-2H-pyran-4-yl) glycinannide - N- [6 - ({6- [4- (trifluoromethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin 3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6- [3- (tfluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl ] cyclopropanecarboxamide

N- [6 - ({6 - [(2-methylpyin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole -2-yl] cyclopropanecarboxamide - N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 -benzothiazol-2-yl) cyclopropanecarboxamide

2 - [(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-acetate yl) amino] -2-oxoethyl

N- [6 - ({6 - [(6-methylpyridin-3-yl) oxy] [1,2,4] tπazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole -2-yl] cyclopropanecarboxamide

N- [6 - ({6- [4- (morpholin-4-ylmethyl) phenoxy] [1,2,4] tπazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxamide

(3 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl ] oxy} phenyl) 2-methylpropan-2-yl carbamate

N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] tπazolo [4, 3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ^2, N ² -diéthylglycinannide - N- (6 - {[6- (3-fluorophenoxy) [1, 2,4] triazolo [4,3-b] pyπdazin-3-yl] sulfanyl} -1, 3 - benzothiazol-2-yl) -2-hydroxyacetamide 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-yl) acetannide

N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 2- (4-ethylpiperazin-1-yl) acetamide - 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo} [4,3-b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide

N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-yl} acetamide - N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-Benzothiazol-2-yl} -2-methoxyacetanide

2-methoxy-N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] tπazolo [4,3-b] pyπdazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide-6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo} [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine

2- (Morpholin-4-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1,3-benzothiazol-2-yl) acetannide

N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acétannide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetannide-2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-yl) acetannide - 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo} [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetannide as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said formula (I).

13) Process for preparing the products of formula (I) as defined in any one of the other claims.

14) Process for the preparation of the products of formula (I) as defined in any one of the other claims in which A represents NH.

15) Process for the preparation of the products of formula (I) as defined in any one of the other claims in which A represents S. 16) As medicaments, the products of formula (I) as defined in one any of claims 1 to 12, 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).

17) As medicaments, the products of formula (I) as defined in claim 12, 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 ).

18) Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any one of claims 1 to 12, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier. 19) Use of the products of formula (I) as defined in any one of claims 1 to 12, or pharmaceutically acceptable salts of these products for the preparation of a medicament for inhibiting the activity of the MET protein kinase and its mutant forms 20) The use as defined in claim 19 wherein the protein kinase is in a cell culture.

21. The use as defined in claim 19 or 20 wherein the protein kinase is in a mammal.

22) Use of a product of formula (I) as defined in any one of claims 1 to 12, for the preparation of a medicament for the treatment or prevention of a disease selected from the following group: disorders of blood vessel proliferation, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.

23) Use of a product of formula (I) as defined in any one of claims 1 to 12 for the preparation of a medicament for the treatment of cancers. 24) Use according to claim 23 for the treatment of solid or liquid tumors.

25) Use according to claim 23 or 24 for the treatment of cancers resistant to cytotoxic agents.

The use according to one or more of claims 23 to 24 for the treatment of primary tumors and / or metastases, particularly in gastric, hepatic, renal, ovarian, colon, prostate and lung cancers (NSCLC and SCLC), glioblastoma, thyroid, bladder, breast cancer, melanoma, hematopoietic tumors lymphoid or myeloid, in sarcomas, in cancers of the brain, larynx, lymphatic system, cancers of the bones and pancreas.

27) Use of the products of formula (I) as defined in claims 1 to 12, for the preparation of medicaments for the chemotherapy of cancers.

28) Use of the products of formula (I) as defined in claims 1 to 12, for the preparation of medicaments for cancer chemotherapy alone or in combination.

29) Products of formula (I) as defined in any one of claims 1 to 12 as kinase inhibitors.

30) Products of formula (I) as defined in any one of claims 1 to 12 as MET inhibitors.

31) As new industrial products, the synthetic intermediates of formulas M1, M2, M3 and N with Rb represents a fluorine atom F, as defined below:

in which the groups CONR1 R2, CO2R6 and COR7, which constitute W, can take the values of W as defined in any one of claims 1 to 11 for the products of formulas (V) and (I "), when W ≠ H.