EP2393793A1

EP2393793A1 - Derivatives of 6-(6-substituted-triazolopyridazine-sulfanyl) 5-fluoro-benzothiazoles and 5-fluoro-benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors

Info

Publication number: EP2393793A1
Application number: EP10708280A
Authority: EP
Inventors: Conception Nemecek; Antonio Ugolini; Eric Bacque; Sylvie Wentzler; Dominique Damour
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 2009-02-06
Filing date: 2010-02-04
Publication date: 2011-12-14
Also published as: JP2012517410A; FR2941952A1; EA201171012A1; AU2010212234A1; MX2011008290A; FR2941952B1; CA2751474A1; US20120165326A1; UY32422A; MA33103B1; AR075251A1; SG173561A1; CN102369191A; IL214408A0; BRPI1008019A2; CO6420339A2; WO2010089509A1; KR20110126659A; TW201036977A

Abstract

The invention relates to novel products of the formula (I) where: (II) is a single or double bond; F is a fluorine atom, Ra is H, HaI, alkoxy, O-cycloalkyl, -O- heterocycloalkyl; -NH-cycloalkyl, -NH-heterocycloalkyl, heteroaryl, phenyl, NHCOaIk, NHCOcycloalk or NR1 R2; X is S, SO or SO2, A is NH or S; W is H, alkyl, or COR with R being cycloalkyl; alkyl optionally substituted by NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl; alkoxy optionally substituted by NR3R4, i.e. a O-(CH2)n-NR3R4 radical, an O-phenyl or an O-(CH2)n-phenyl radical, with phenyl optionally substituted and n = 1 to 4; or the NR1 R2 radical; R1 is H or alk and R2 is H, cycloalkyl or alkyl; R3 and R4 are H, alk, cycloalkyl, heteroaryl or phenyl; R1, R2 and/or R3,R4 form a cycle together with N optionally containing O, S, N and/or NH; heterocycloalkyl, heteroaryl and phenyl and cycles all being optionally substituted; wherein said products can be in any isomer or salt form, and can be used as drugs, in particular as MET inhibitors.

Description

6- (6-SUBSTITUTED-TRIAZOLOPYRIDAZINE-SULFANYL) DERIVATIVES 5-FLUORO-

BENZOTHIAZOLES AND 5-FLUORO-BENZIMIDAZOLES: PREPARATION, APPLICATION AS MEDICAMENTS AND USE AS INHIBITORS

DE MET

The present invention relates to novel 6- (6-substituted-triazolopyridazin-sulfanyl) 5-fluoro-benzothiazole and 5-fluorobenzimidazole derivatives, process for their preparation, novel intermediates obtained, their use as medicaments, compositions containing them and the new use of such 6- (6-substituted-triazolopyhdazine-sulfanyl) 5-fluoro-benzothiazoles and 5-fluorobenzimidazoles derivatives.

The present invention relates more particularly to novel derivatives of 6- (6-substituted-triazolopyhdazine-sulfanyl) 5-fluoro-benzothiazoles and 5-fluorobenzimidazoles exhibiting anticancer activity, via the modulation of the activity of proteins, in particular proteins. 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 kinase is a family of enzymes that catalyze the phosphorylation of hydroxyl groups of specific protein 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 new inhibitors of the MET protein kinase and its mutants, which can be used for anti-proliferative and anti-metastatic treatment, especially in oncology. The present invention also relates to novel inhibitors of the MET protein kinase and its mutants, which can be used for anti-angiogenic treatment, in particular in oncology.

The subject of the present invention is the products of formula (I):

in which

represents a single or double bond

Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted; a radical -O-cycloalkyl, -O-heterocycloalkyl; -NH-cycloalkyl and -NH- heterocycloalkyl all optionally substituted; an optionally substituted heteroaryl radical; an optionally substituted phenyl radical; an NHCOalkyl or NHCOcycloalkyl radical; or an NR1 radical R2 as defined below;

X is S, SO or SO 2, A is NH or S;

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

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

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 or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by 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 from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl and alkoxy radicals, heteroaryl, heterocycloalkyl, NH2, NHAIk, N (AI k) 2 or optionally substituted phenyl; or else R 3 and R 4 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form

R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, being optionally substituted by one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH2, NHaIk, N (alk) radicals; ) 2 and the radicals alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, CO-phenyl and S-heteroaryl, such as in the latter radicals the radicals alkyl, 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, NH 2, NHaIk and N (alk) 2, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

In the products of formula (I), F represents a fluorine atom. The present invention relates in particular to the products of formula (I) in which Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally substituted with a heterocycloalkyl radical which is itself optionally substituted; an optionally substituted heteroaryl radical; an optionally substituted phenyl radical; an optionally substituted cycloalkyl radical; O-heterocycloalkyl optionally substituted; -NH-cycloalkyl optionally substituted; -NH-heterocycloalkyl optionally substituted; an -NHCOalkyl or -NHCOcycloalkyl radical; or a radical NR1 R2 as defined above or hereinafter. the other substituents of said products of formula (I) having any of the meanings indicated above or below.

The subject of the present invention is the products of formula (I) as defined above or hereinafter in which X and A have the meanings indicated above or below,

Ra represents an alkoxy radical optionally substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted; a -O-cycloalkyl radical; a radical -NHCOaIk; or a radical -NR 1 aR 2 a; as R1a and R2a represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 and optionally substituted phenyl; and W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

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 or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by 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 from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl and alkoxy radicals; heteroaryl, heterocycloalkyl, NH2, NHAIk, N (Alk) 2 or 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 chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl, heteroaryl, CO-phenyl and S-heteroaryl radicals; , such that, in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 atoms carbon, NH2, NHaIk and N (alk) 2, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the salts of addi 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 hereinafter in which X and A have the meanings indicated above or below;

Ra represents an alkoxy radical optionally substituted with a heterocycloalkyl radical which is itself optionally substituted; an NHCOaIk radical or an NR1 aR2a radical; such that R1a and R2a 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; and W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

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

represents a single or double bond

Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally substituted with a heterocycloalkyl radical which is itself optionally substituted; an optionally substituted heteroaryl radical; an optionally substituted phenyl radical; an NHCOalkyl or NHCOcycloalkyl radical; or an NR1 radical R2 as defined below;

X is S, SO or SO 2, A is NH or S;

W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4, alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted;

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical; containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted, with R3 and R4, identical or different , represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more radicals id entic or different selected from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIk, N (Alk) 2 or optionally substituted phenyl; or else R 3 and R 4 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 heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl radicals, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, CO-phenyl and S-heteroaryl, such as in the latter radicals the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals. chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH 2, NHaIk and N (alk) 2, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The present invention, which therefore relates to the products of formula (I) as defined above in which represents a single or double bond, therefore relates precisely to the products of formula (I ¹ ) which represent the products of formula (I) in which ^zzz ^ represents a single bond and the products of formula (I ") which represent the products of formula (I) in which represents a double bond, thus all the products of formula (I) as defined above or below. especially represent products of formula (T) in which represents a single bond.

The products of formula (I) as defined above or hereinafter also represent products of formula (I ") in which ^zzz represents a double bond.

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

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

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 NR 3 R 4 or by alkoxy, or else R 1 and R 2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 ring 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; the heterocycloalkyl, heteroaryl and phenyl radicals as well as the cyclic radicals that R1 and R2 or R3 and R4 can form 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, NH2, NHaIk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl radicals, heteroaryl, CO-phenyl and S-heteroaryl, such that, in the 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 or and alkoxy containing 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 therefore the products of formula (I) as defined above in which ^zz ^, Ra, X, A and W have any of the values defined above or below, and the radical NR1 R2 is such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom or an alkyl radical optionally substituted by NR3R4 or by alkoxy, or R1 and R2 together with the nitrogen atom to which they are bonded 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 1 any NH it contains being optionally substituted; all other substituents having the definitions indicated above; 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 represents a hydrogen atom or a halogen atom or an optionally substituted phenyl radical,

X is S, SO or SO2 A is NH or S; W represents a hydrogen atom or the COR radical in which R represents:

a cycloalkyl radical or an alkyl radical optionally substituted by a phenyl, heteroaryl, NR3R4 or heterocycloalkyl radical, themselves optionally substituted; an alkoxy radical optionally substituted with NR 3 R 4, ie a radical

O- (CH2) n-NR3R4; 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 or an alkyl radical and the other of

R1 and R2 represents a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 form with the atom nitrogen to which they are attached 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 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 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; all the radicals defined above heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, CH 2 -heterocycloalkyl, CH 2 -phenyl, CO-phenyl and S-heteroaryl radicals, such as in the latter radicals alkyl, 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, NH 2, NHaIk and N (alk) 2, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

Products of formula (I) as defined above or below in which, Ra and X have the values defined above or below and:

A represents NH or S;

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

an alkyl radical optionally substituted with OCH 3 or NR 3 R 4; a cycloalkyl radical

an alkoxy radical optionally substituted with OCH 3 or NR 3 R 4, ie an O- (CH 2) n -OCH 3 radical or an O- (CH 2) n -NR 3 R 4 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 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 an optionally alkyl radical; substituted by NR3R4, or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the any NH that 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; the 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 chosen from halogen atoms; hydroxyl, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, CH 2 -heterocycloalkyl, CH 2 -phenyl, CO-phenyl and S-heteroaryl radicals, such as in the latter radicals, alkyl radicals, heterocycloalkyl, phenyl and heteroaryl 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, 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 thus the products of formula (I) as defined above in which ^zzz , Ra and X have any of the values defined above or below,

A represents NH or S;

W represents a hydrogen atom or the COR radical in which R represents: an alkyl radical optionally substituted with NR3R4; an alkoxy radical optionally substituted with NR 3 R 4, ie an O- (CH 2) n -NR 3 R 4 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 NR1 R2, wherein R1 and R2 are such that one of R1 and

R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents an alkyl radical optionally substituted with 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 selected 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; the 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 chosen from halogen atoms; , the hydroxyl, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and the alkyl, CH 2 -heterocycloalkyl, CH 2 -phenyl, CO-phenyl and S-heteroaryl radicals, such as in the latter radicals, alkyl, heterocycloalkyl radicals; , phenyl and heteroaryl are themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2; 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 thus the products of formula (I) as defined above in which, X, A and W have the meanings indicated above or hereafter, Ra represents a hydrogen atom or a chlorine atom or the radical:

with Rb represents a halogen atom or an S-heteroaryl radical optionally substituted by a radical chosen 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 the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I) .

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

the term "alkyl radical (or Alk)" denotes the radicals, linear and, if appropriate, branched, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl as well as their linear or branched positional isomers: alkyl radicals containing from 1 to 6 carbon atoms and more particularly the 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 the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals, and especially the cyclopropyl, cyclopentyl and cyclohexyl radicals;

the term "heterocycloalkyl radical" thus denotes a monocyclic or bicyclic carbocyclic radical containing from 3 to 10 members interrupted by one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen or sulfur atoms; for example, morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, oxodihydropyridazinyl, or oxetanyl or thietanyl radicals, all of which radicals are 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;

the term "heteroaryl radical" thus denotes monocyclic or bicyclic radicals containing 5 to 12 ring members: monocyclic heteroaryl radicals such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3-furyl, pyranyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyhdyl, 3-pyhdyl and 4-pyhdyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such 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 oxodihydropyridinopyrazolyl, all of these radicals being optionally substituted;

As examples of heteroaryl or bicyclic radicals, there may be mentioned more particularly the pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl radicals, optionally substituted by one or more identical or different substituents as indicated above. The carboxyl group (s) of the products of formula (I) may be salified or esterified with the various groups known to those skilled in the art, among which may be mentioned, for example:

among the salification compounds, mineral bases such as, for example, one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine , arginine, histidine, N-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 mineral or organic acids of the products of formula (I) may be, for example, the salts formed with the hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic acids, alkylmonosulphonic acids such as, for example, methanesulfonic 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 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,

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 NR 1 R 2 or NR 3 R 4 forms a ring as defined above, such an amine ring may be chosen in particular from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholino or piperazinyl radicals, these radicals themselves being optionally substituted as indicated above. 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; by one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals.

The NR 1 R 2 or NR 3 R 4 ring may more particularly be chosen from pyrrolidinyl and morpholino radicals optionally substituted by one or two alkyl or piperazinyl radicals optionally substituted on the second nitrogen atom by an alkyl, phenyl or or CH 2 -phenyl radical, -Same optionally substituted with one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl and alkoxy radicals.

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

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

In particular, the present invention relates to the products of formula (I) corresponding to formula (Ia) or (Ib):

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

The present invention therefore particularly relates to products of formula

(I) as defined above or hereinafter in which ^zzz ^ represents a single bond corresponding to the products of formula (V):

the substituents Ra, X, A and W are chosen from all the meanings indicated above or below, said products of formula (V) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the salts of addition with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (V).

The present invention therefore particularly relates to products of formula

(I) as defined above or hereinafter in which ^zzz ^ represents a double bond corresponding to the products of formula (I "):

wherein the substituents Ra, X, A and W are selected from any of the meanings given above or below, said products of formula (I ") being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I").

The present invention therefore particularly relates to products of formula

(la) as defined above or hereinafter in which ^zzz ^ represents a single bond corresponding to the products of formula (Ia '):

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

(la) as defined as defined above or hereinafter in which ^zzz ^ represents a double bond corresponding to the products of formula (I "a):

wherein Ra 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 the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "a). The present invention therefore particularly relates to products of formula

(Ib) as defined above or below in which ^zzz ^ represents a single bond corresponding to the products of formula (b):

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

The present invention therefore particularly relates to products of formula

(Ib) as defined above or below in which represents a double bond corresponding to the products of formula (I "b):

in which Ra and W are chosen from among all the meanings indicated above or below, said products of formula (I "b) being in all the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I "b).

When in the products of formula (I), Ra represents the radical:

Rb is in particular in para position.

When Rb defined above represents a halogen atom, Rb especially represents fluorine.

The subject of the present invention is particularly the products of formula (I) as defined above, corresponding to the following formulas:

1- (6 - {[6- (cyclohexyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl ) -3- [2- (morpholin-4-yl) ethyl] urea

(5-Fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 2-methylpropan-2-yl-5-fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 carbamate , 3-benzothiazol-2-amine

1- (5-Fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 yl) -3- [2- (morpholin-4-yl) ethyl] urea

1- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea

1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea

2- (4-cyclopropylpiperazin-1-yl) -N- {6 - [(6-ethoxy [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro -1,3-Benzothiazol-2-yl} acetamide - N- (6 - {[6- (cyclobutyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5 1-Fluoro-1,3-benzothiazol-2-yl) -2- (4-cyclopropylpiperazin-1-yl) acetamide

N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro-1,3-benzothiazol-2-yl} -2 - (4-ethyl-piperazin-1-yl) acetamide

N- (6 - {[6- (cyclobutyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl -2- (4-ethylpiperazin-1-yl) acetamide

2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (oxetan-3-yloxy) [1,2,4] thazolo [4,3-b] pyridazin-3 -yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyπdazin-3 -yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 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 (1e ¹ )

In Scheme 1 above, the substituent Ra has the meanings given above for the products of formula (V) and (I "), and the groups CONR 1 R 2,

COR6 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 ( 1a ¹ ), (1b ¹ ), (1c '), (1cT) and (1e ¹ ) can be prepared from 3,6-dichloro [1,2,4] triazolo [4,3- b] Commercial pyridazine of formula (S).

Compounds (E) can be obtained by the routes described in Scheme 3, below.

The compounds (G) can be obtained, for example, by reaction of 2-fluoro-4-nitro-5-amino-benzenethiol of formula (F) with the compounds of formula (E). The compound of formula (F) can be obtained by introducing the thiol function on the 2-nitro-4,5-difluoroaniline derivative (Q) (commercial compound), for example, in the presence of potassium thioacetate 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 ') as represent a single bond can be obtained, for example, by reduction with zinc (0) compounds of formula (G), in the presence of acetic acid, at a temperature in the region of 20 ^° C.

More particularly, the carbamates of general formula (1 to ¹ ) and (1a ") can be prepared in particular as described in patent WO03028721A2, but from respectively a 2-fluoro-4,5-diamino phenyl sulfide of formula ( H ') and (H ") and a pseudothiourea of formula (J), in the presence of acetic acid and in a protic solvent such as methanol, at a temperature of 80 ⁰ 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 cyanogen bromide with a compound of formula (H') and (H") respectively, in presence of a protic solvent such as ethanol. The reaction is carried out at a temperature in the region of 80 ^° C. More particularly, the general carbamates of formula (1d ') and (1d ") can be obtained by reaction with a chlorocarbonate of formula (O) (X = Cl) on a compound of general formula respectively (1c ') and (1c "), for example in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogen carbonate, at a temperature of 20 ° C. More particularly, the carboxamides (1 ') and (1 e ") can be obtained respectively from the amines of general formula (1c') and (1c")

by reacting the amines (1c ¹ ) 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 ¹ ) and (1c ") with an acid anhydride of formula (P) (X = OCOR 7), in the presence, for example, of a solvent such as pyridine at a temperature in the vicinity of 20 ⁰ C.

by coupling the amines (1c ') 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 triethylamine, at a temperature in the region of 40 ^° C.

Scheme 2: Synthesis of benzothiazole derivatives of formulas (2a '), (2b'), (2c ¹ ), (2d '), (2a)', (2b ¹ ), (2c ¹ ), (2d ')

In Scheme 2 above, the substituent Ra has the meanings given above for the products of formula (I ¹ ) and (I ") and the groups CONR 1 R 2, COR 6 and COR 7, 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 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 (2d ') can be prepared from 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (K).

commercial

In Scheme 2 above, 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

The carbamates of general formula (L1) can be obtained, for example, by reaction with a chlorocarbonate of formula (O) (X = Cl) on 2-amino-5-fluoro-1,3-benzothiazol-6 thiocyanate. yl (K), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature in the region of 20 ^° C.

The compounds of general formula (L2) can be obtained, for example, by reaction of carbamates of formula (L1) where R6 = phenyl, with NHR1 R2 amines of formula (R) (with R1 and R2 as defined above ), in the presence of an aprotic solvent such as tetrahydrofuran, at a temperature in the region of 20 ^° C. The ureas (2b 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-5-fluoro-1,3-benzothiazol-6-yl (K) thiocyanate, 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-5-fluoro-1,3-benzothiazol-6-yl (K) thiocyanate, 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-5-fluoro-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-hydroxybenzotriazole 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" ).

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 in the region of 20 ^° C. to give the derivatives (2c '/ 2c ") as defined in Scheme 2a 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-dimethylformanide, in the presence of a base such as thylamine and at a temperature in the region of 95 ° C or between 20 ^° C and 95 ° C, or, alternatively, for example 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.

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 ") can also be prepared from benzothiazoles of formula respectively (2d ') and (2d"), for example, by reaction with a chlorocarbonate of formula (O) (X = Cl), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogencarbonate, at a temperature in the region of 20 ° C.

More particularly, the benzothiazoles of general formula (2a "), (2b"), (2c ") and (2d") as well as their reduced analogues of general formula (2a '), (2b'), (2c ') and (2d ') can be prepared for example: 1) by coupling a compound of formula (E) with derivatives (M1),

(M2) and (M3) and (N) generated in situ by reduction of the derivatives (L1), (L2), (L3) and (K) by sodium borohydride, in a solvent such as N, N-dimethylformamide and in the presence of a base such as 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 the isolated derivatives (M1), (M2) and (M3) and a compound of formula (E) under the conditions, for example, described by U. Schopfer et al (Tetrahedron, 2001, 57, 3069) in the presence of n-tributyl phosphine, potassium tert-butoxide, tris (dibenzylideneacetone) dipalladium (O) and bis (2-diphenylphosphinophenyl) ether in a solvent such as toluene at a temperature in the region of 110 ^° C.

4) 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) such that ^zzz ^ represent a single or double bond while conditions 3) and 4) give products of formula (2a),

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

NHCOR ₇

In Scheme 3 above, the substituents Ra, R 1 and R 2 have the meanings indicated above for the products of formula (I ¹ ) and (I "). The substituent R 7 represents an alkyl or cycloalkyl radical. represent : or an alkyl radical optionally substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted,

or a cyclolkyl radical The compounds of formula (E) can be obtained, for example, as indicated in scheme 3 above, from 3,6-dichloro [1,2,4] thazolo [4.3 commercial pyridazine of formula (S).

More particularly, the compounds of formula (E) in which Ra represents an OR8 radical can be obtained by treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine (S) at a temperature of temperature close to 80 ⁰ C and in a solvent such as N, N-dimethylformamide with an alkoxide of formula (U), itself obtained by treatment of the corresponding alcohol with a base such as sodium hydride at a similar temperature 0 ⁰ C to 20 ⁰ C.

More particularly, the compounds of formula (E) wherein Ra represents a radical NRiR ₂ can be obtained by the treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyhdazine (S) with an amine of formula (R), at a temperature of 20 ° C and in a solvent such as N ₁ N -dimethylformamide or, in the case NR1 R2 is NH2, with aqueous ammonia, in a solvent such as dioxane in a sealed tube at a temperature between 70 ⁰ C and 90 ° C.

More particularly, the compounds of formula (E) in which Ra represents an NHCOR7 radical can be obtained by reaction of a compound of general formula (E) with Ra = NH 2 with a compound of formula (P) as described for compounds of formula General (L3), (1e ¹⁾ and (1 e ") More specifically, compounds of formula (e) where Ra represents an aryl or heteroaryl radical can be obtained, for example.:

from the boronic acids of formula (B), in the presence of barium octahydrate hydroxide and (1,1'-bis (diphenylphosphino) ferrocene) di-chloropalladium (II) in a solvent such, for example, N, N-dimethylfornnannide, at a temperature of 80 ⁰ C.

or alternatively, starting from the boronic esters of formula (V), in the presence of palladium dichloro bis (triphenylphosphine) in a solvent such as, for example, 1,2-dimethoxyethane, in the presence of a base such as sodium hydroxide 1 N, at a temperature of 80 ⁰ C.

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

reducing conditions

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, cycloalkyl or heterocycloalkyl radical optionally substituted by 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 R6 = tBu preferentially, for example, with halides of alkyl of formula (W), in a solvent such as N, N-dimethylfornnannide, in the presence of sodium hydride, at a temperature 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 sodium dihydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 80 ° C., optionally followed by an in situ treatment with trifluoroacetic acid at 20 ^° C. if necessary.

L4

The carbamates of general formula (L4) can be obtained by reaction of carbamates of general formula (L1), for example with alkyl halides of formula (W), in a solvent such as N, N-dimethylformamide, in the presence sodium hydride at a temperature 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 R 9 substituent represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical (R3 and R4 as defined above).

The compounds of formulas (L5) can be prepared from 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (K), for example, by treatment with an alkyl nitrite and bromide. cuprous in a solvent such as acetonitrile, at a temperature of 0-20 ° C, according to the method described by Jagabandhu Das et. al. in J. Med. Chem. 2006, 49, 6819-6832.

Figure 6 Other synthetic routes of reduced derivatives of formulas (T)

According to scheme 6 above, the benzothiazoles of general formula (I ¹ ) can also be prepared from the compounds of formula (I ") by reduction, for example with sodium borohydride, in a solvent such as ethanol, at a temperature in the region of 80 ^° C. or by reduction with zinc (0) in the presence of acetic acid, at a temperature in the region of 20 ^° 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 (I ') can also be prepared from other compounds (I') by transformation of the group W into a group W of the same nature as defined above for W and according to the type of reactions defined in scheme 2: the transformations of 2d '/ 2d "into 2a' / 2a" and into 2c '/ 2c ", the transformations 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 or SO 2 sulfone by methods known to those skilled in the art and, if necessary, protecting the optionally reactive groups with the appropriate protecting groups.

Among the starting products of formula, B, D, J, K, O, P, P ', Q, R, S, U, V, W are known and can be obtained either commercially or according to the usual known methods. those skilled in the art, for example from commercial products.

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

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

the hydroxyl groups may be protected, for example, by alkyl radicals such as tert-butyl, 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 of acid function, b) an ester function saponification reaction in acid function, c ) a reduction reaction of the free or esterified carboxy function as a function of alcohol, d) an alkoxy function conversion reaction with hydroxyl function, or also an alkoxy-functional hydroxyl function, e) an elimination reaction of the protective groups which can be carrying the protected reactive functions, f) a salification reaction with a mineral or organic acid or a base to obtain the corresponding salt, g) a resolving reaction of the racemic forms into split products, said products of formula (I) thus obtained being in all possible isomeric forms racemic, enantiomeric and diastereoisomeric.

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

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

b) The possible acid-functional ester function transformations of the products described above may, if desired, be carried out under the usual conditions known to those skilled in the art, in particular by acid or alkaline hydrolysis, for example with sodium hydroxide or sodium hydroxide. potash in an alcoholic medium such as, for example, in methanol or in hydrochloric or sulfuric acid. The saponification reaction can be carried out according to the usual methods known to those skilled in the art, such as, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.

c) The optional free or esterified carboxy functions of the products described above may, if desired, be reduced 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-toluenesulphonic, formic or trifluoroacetic or catalytic hydrogenation.

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

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

The products of formula (I) as defined above 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 of formula (I) as defined above, corresponding to the following formulas: 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl ) -3- [2- (morpholin-4-yl) ethyl] urea

(5-Fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyrimidazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 2-methylpropan-2-yl-5-fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 carbamate , 3-benzothiazol-2-amine

2- (4-cyclopropylpiperazin-1-yl) -N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro -1,3-Benzothiazol-2-yl} acetamide - N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5 1-Fluoro-1,3-benzothiazol-2-yl) -2- (4-cyclopropylpiperazin-1-yl) acetannide

N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro-1,3-benzothiazol-2-yl} -2 - (4-ethyl-piperazin-1-yl) acétannide

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

2- (4-Cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyπdazin-3} -yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide

2- (4-Cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyπdazin-3 -yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 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 following group: disorders the proliferation of blood vessels, disorders fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, diseases of the nervous system, 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 as defined above and recalled hereinafter:

in which the groups CONR1 R2, COR6 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.

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

1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3- yl] sulfanyl) -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared as follows: through a mixture of 230 mg of N, N "- [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis {3- [2- (morpholin-4-yl) ethyl] urea} in 15 cm ³ of ethanol, a stream of argon was bubbled for 5 minutes, then 3 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 310 mg of DL-dithiothreitol and 170 mg of 3-chloro-6- (cyclohexyloxy) [1, were added. 2,4] thazolo [4,3-b] pyridazine (1 e) The reaction mixture is heated at 80 ^° C. for 44 h and then concentrated to dryness under reduced pressure The residue is taken up in water containing bicarbonate of sodium and extracted with ethyl acetate.The organic phase is concentrated under The white solid obtained is purified on silica by solid deposition eluting with a gradient of dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) from 95/5 to 75/25. 253 mg of 1- (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazole are thus obtained. -2-yl) -3- [2- (morpholin-4-yl) ethyl] urea in the form of a white powder, the characteristics of which are as follows: NMR spectrum 1 H NMR (400 MHz, DMSO-cfe) δ ppm 1.12 - 1.31 (m, 3H) 1.32 - 1.44 (m, 2H) 1.44 - 1.55 (m, 1H) 1.56 - 1.67 (m, 2H) ) 1.73 - 1.88 (m, 2H) 2.35 - 2.45 (m, 6H) 3.21 - 3.27 (m, 2H) 3.59 (t, J = 4.4 Hz, 4H) 4.57 - 4.77 (m, 1H) 6.75 (t, J = 4.9 Hz, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.53 (d, J = 10.3 Hz, 1H) 8.00 (d, J = 7.3 Hz, 1H) 8.27 (d , J = 9.8 Hz, 1 H) 10.99 (sr, 1h)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 573 +; MH = 571 - b) N, N "- [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis {3- [2- (morpholin-4-yl) ethyl] urea } can be prepared in the following manner: to 322 mg of phenyl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl) carbamate in 10 cm ³ of tetrahydrofuran at 20 ^° C., 0.24 cm ³ is added of 2- (morpholin-1-yl) ethanamine and 0.39 cm ³ of triethylamine The reaction medium is heated at 60 ^° C. for 5 h The clear brown solution obtained is evaporated to dryness under reduced pressure The residue is chromatographed on Biotage Isolera Oven 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient of dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) from 99/1 to 75/25, to give 231 mg of N N, N - [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis {3- [2- (morpholin-4-yl) ethyl] urea} as a whitish powder whose characteristics are as follows: MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 711 +; MH = 709- (c) Phenyl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl) carbamate can be prepared as follows: 451 mg of 2-amino-5-fluoro thiocyanate 1, 3-Benzothiazol-6-yl in 5cm ³ of pyridine is added at 20 ° C, 0.75cm ³ of phenyl chlorocarbonate. After 5.5h, the yellow suspension is concentrated to dryness under reduced pressure. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient of 100% dichloromethane to 90/10 dichloromethane / methanol. 570 mg of phenyl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are thus obtained in the form of a beige powder whose characteristics are as follows: MASS SPECTRUM: Waters ZQ: MH + m / z = 346 + d) 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate can be prepared as described by K. Papke, and R. Pohloudek-Fabini in Pharmazie; GE; 22, 1967, p229-233 e) 3-Chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in the following manner: to a solution of 3, 18 g of cyclohexanol in 30 cm ³ of tetrahydrofuran, at 0 ^° C. under argon, are added 762 mg of 60% sodium hydride in the oil. After stirring for 15 minutes, 3 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial) are added. The brown suspension is stirred for 22 h while gradually returning to 20 ^° C. The reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. After concentrating the organic phase to dryness under vacuum, a brown oil is obtained. The oily 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 65/35. 2.7 g of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyhdazine are thus obtained in the form of a yellowish powder, the characteristics of which are as follows:

MASS SPECTRUM: LC / MS Electrospray on WATERS UPLC - SQD: MH + = 253+

Example 2

(5-Fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) 2-methylpropan-2-yl carbamate a) (5-Fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl 2-Methylpropan-2-yl -1,1- (3-benzothiazol-2-yl) carbamate can be prepared in a manner similar to Example 1a but from 131 mg of (5-fluoro-6-thiocyanato) 2-methylpropan-2-yl 1, 3-benzothiazol-2-yl) carbamate, 10 cm ³ of degassed ethanol, ⁴ mg of potassium dihydrogenphosphate in 0.2 cm ³ of water, 186 mg of DL-dithiothreitol and 100 mg of 3-chloro-6- (4-fluorophenyl) -1,2,4-triazolo [4,3-b] pyridazine, after 42h at 80 ^° C., thus obtaining 33 mg of (5-fluoro-6- {[6- (4-fluorophenyl) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2- yl) 2-methylpropan-2-yl carbamate, in the form of a white powder whose characteristics are as follows:

NMR spectrum 1 H NMR (400 MHz, DMSO-cfe) δ ppm 1.50 (s, 9H) 7.40 (t, J = 8.8 Hz, 2H) 7.65 (d, J = 10.3 Hz, 1H) 8.02 (d, J = 9.8 Hz, 1H) 8.10 (dd, J = 8.8, 5.4 Hz, 2H) 8.26 (d, J = IA Hz, 1H) 8.50 (d, J = 9.8 Hz, 1H) 11.97 (br. s., 1 H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 513 +; MH = 511 - b) 2-Methylpropan-2-yl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl) carbamate can be prepared in a manner as follows: at 300mg of 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate in 5 cm ³ of dichloromethane and 0.45 cm ³ of triethylamine at 20 ^° C. are added 41 mg of dimethylamino pyridine and 348 mg of Di-tert. -butyl dicarbonate. After 3h at 20 ^° C., the reaction mixture is poured into water, the dichloromethane is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated under reduced pressure. The yellow solid residue is washed with ether and dried under vacuum. 343 mg of 2-methylpropanoyl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are thus obtained in the form of a yellow powder, the characteristics of which are as follows: MASS: LC / MS Electrospray on WATERS UPLC - SQD: MH + = 324+ c) 3-Chloro-6- (4-fluorophenyl) -1,2,4-thazolo [4,3-b] pyridazine can be prepared from as follows: a mixture of 4.16 g of 4-fluorophenylboronic acid, 9.37 g of barium hydroxide octahydrate, 2.20 g of [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) in complex with dichloromethane (1: 1) and 5.1g of

Commercial 3,6-dichloro [1,2,4] triazolo [4,3-b] pyhdazine in 40 cm ³ of N, N-dimethylformamide containing 10 cm ³ of water is heated in a bath at 80 ° C. for 1 hour. 5h. The brown-beige suspension obtained is cooled to 20 ^° C. and then poured onto about 200 cm ³ of water. The insoluble material is drained and washed successively with water and with ether and then dried under vacuum at 20 ° C. The solid The resultant beige is slurried in dichloromethane, drained and dried under vacuum at 20 ^° C. This gives 1.24 g of 3-chloro-6- (4-fluorophenyl) -1,2,4-triazolo [4,3-b]. ] pyridazine. 30 g of silica are added to the combined mother liquors and the mixture is evaporated to dryness under vacuum. This residue is deposited on a bed of 10 g of silica in a fried glass filter and eluted with dichloromethane. Thus 1.60 g of additional 3-chloro-6- (4-fluorophenyl) -1,2,4-triazolo [4,3-b] pyhdazine are recovered, the characteristics of which are as follows: MASS SPECTRUM: LC-MS -DAD-ELSD: MH + m / z = 249 +

Example 3

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

5-Fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine may be prepared in the following manner: to a mixture of 157 mg of (5-fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] 2-methylpropan-2-yl sulfanyl} -1,3-benzothiazol-2-yl) carbamate in 5 cm ³ of dichloromethane at 20 ^° C., 0.9 cm ³ of trifluoroacetic acid (at 10%) are added gradually. of anisole) over 24 hours, until the starting material disappears. The reaction mixture is concentrated under reduced pressure. The residue is purified by Biotage Quad 12/25 chromatography (KP-SIL, 6OA, 32-63 μm), eluting with a gradient of 100: 0 to 50:50 of dichloromethane / (dichloromethane: 38 / methanol: 17 / aqueous ammonia: 2). 67 mg of 5-fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol are thus obtained. 2-amine in the form of a beige powder whose characteristics are as follows:

NMR spectrum 1 H NMR (400 MHz, DMSO-cfe) δ ppm 7.26 (d, J = 10.3 Hz, 1H) 7.41 (t, J = 8.8 Hz, 2H) 7.84 (s, 2H) 7.94 - 8.06 ( m, 2H) 8.11 (dd, J = 8.8, 5.4 Hz, 2H) 8.48 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 413 +; MH = 411 -

Example 4 1- (5-Fluoro-6 - {[6- (4-fluorophenyl) [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- (5-Fluoro-6 - {[6- (4-fluorophenyl) [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 the following manner: solution of 217 mg of N, N "- [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis (3- [2- (morpholin-4-yl) ethyl] urea} (1b) in 10 cm ³ of ethanol, a stream of argon is bubbled for 5 minutes, then 3 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 282 mg of DL-dithiothreitol and 152 mg of 3-chloro-6 are added. - (4-fluorophenyl) -1,2,4-triazolo [4,3-b] pyhdazine The reaction medium is heated at 80 ^° C. for 40 hours while concentrated to dryness under reduced pressure The residue is purified on silica by solid deposition eluting with a gradient of 100% dichloromethane to 75/25 dichloromethane / (dichloromethane) This gives 104 mg of 1- (5-fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin-3-). yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea in the form of a beige powder whose characteristics are as follows: NMR SPECTRUM 1 H NMR (400 MHz, DMSO-cfe) δ ppm 2.28 - 2.47 (m, 6 H) 3.30 (masked m, 2H) 3.50 - 3.67 (m, 4H) 6.76 (br. 7.40 (t, J = 8.8 Hz, 2H) 7.57 (d, J = 10.0 Hz, 1H) 8.02 (d, J = 9.8 Hz, 1H) 8.10 (dd, J = 8.9, m.p. 5.3 Hz, 2H) 8.21 (d, J = 7.3Hz, 1H) 8.50 (d, J = 9.5Hz, 1H) 11.01 (s, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 569 +; MH = 567-

Example 5

1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (Morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-) [Sulfanyl] -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 1a but from 203 mg of N, N "- [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis {3- [2- (morpholin-4-yl) ethyl] urea} (1b) in 5 cm ³ of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.5 cm ³ of water, 265 mg of DL-dithiothreitol and 120 mg of 3-chloro -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine, after 18h at 80 ^° C. The reaction medium is cooled to 20 ^° C. and the precipitate is filtered off and washed with water. ethanol. 198 mg of 1 - (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazole are thus obtained -2-yl) -3- [2- (morpholin-4-yl) ethyl] urea as a cream-white powder having the following characteristics: NMR spectrum 1H NMR (400 MHz, DMSO-cfe) δ ppm 0.32 - 0.45 (m, 2H) 0.59 - 0.73 (m, 2H) 2.51 - 2.56 (masked m, 1H) 3.11 (bps, 2H) 3.19 - 3.29 (masked m, 2H) 3.43 - 3.62 (m, 4H) 3.64 - 3.81 (m, 2H) 3.98 (m, J = 10.5 Hz, 2H) 6.77 (d, J = 9.8 Hz, 1H) 7.22 (brs, 1 H) 7.55 (d, J = 10.3 Hz, 1H) 7.70 (d, J = 2.7 Hz, 1H) 7.93 (d, J = 9.8 Hz, 1H) 8.14 (d, J = 7.3 Hz, 1H) 10.12 (sr, 1h) 11.39 (sr, 1h)

MASS SPECTRUM: Waters ZQ: MH + m / z = 530 +; MH- = 528- b) 3-Chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine can be prepared in a manner similar to Example 1e but at from 1 cm ³ of cyclopropylamine and 2 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial) in 20 cm ³ of N, N-dimethylformamide containing 2.5 cm ³ of triethylamine, at 20 ° C for 18h. 1.83 g of 3-chloro-N-cyclopropyl [1,2,4] thalzolo [4,3-b] pyridazin-6-amine are thus obtained in the form of a white powder, the characteristics of which are as follows: MASS: Waters ZQ: Retention time Tr (min) = 2.66; MH + m / z = 210 +; MH = 208-

Example 6

1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3- [Sulfanyl] -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea may be prepared in a manner similar to Example 1a but from 226 mg of N, N "- [disulfanediylbis (5-fluoro-1,3-benzothiazole-6,2-diyl)] bis {3- [2 -

(morpholin-4-yl) ethyl] urea} (1b) in 5 cm ³ of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.5 cm ³ of water, 265 mg of DL-dithiothreitol and 160 mg of 3-chloro -N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine, after 18h at 80 ° C. The reaction medium is cooled to 20 ^° C. and the precipitate is filtered off and then washed with ethanol. 189 mg of 1 - (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazole are thus obtained. -2-yl) -3- [2- (morpholin-4-yl) ethyl] urea as a cream-white powder having the following characteristics: NMR spectrum 1H NMR (400 MHz, DMSO-cfe) δ ppm 1.00 - 1.32 (m, 5 H)

1.47 - 1.69 (m, 3H) 1.79 (d, J = 11.5 Hz, 2H) 2.36 - 2.46 (m, 6H) 3.22 - 3.28 (m, 2H) 3.32 - 3.42 (m, 1H) 3.59 ( t, J = 4.4 Hz, 4H) 6.75 (brs, 1H) 6.78 (d, J = 10.0 Hz, 1H) 7.25 (d, J = 7.1 Hz, 1H) 7.50 (d, J = 10.3 Hz, 1H) 7.90 (d, J = 9.8 Hz, 1H) 7.95 (d, J = 7.3 Hz, 1H) 10.97 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 572 +; MH- = 570- b) 3-Chloro-N-cyclohexyl [1,2,4] thazolo [4,3-b] pyridazin-6-amine can be prepared in a manner similar to Example 1e but from 3.4 cm ³ of cyclohexylamine and 5 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial) in 50 cm ³ of N, N-dimethylformamide containing 11.2 cm ³ of triethylamine, at 20 ° C. for 18 h and then for 4 hours at 50 ^° C. 4.45 g of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine are thus obtained. in the form of a white powder whose characteristics are as follows: MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.86; MH + m / z = 252 +; MH = 250-

Example 7

2- (4-cyclopropylpiperazin-1-yl) -N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro 1,3-benzothiazol-2-yl} acetamide a) 2- (4-Cyclopropylpiperazin-1-yl) -N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5 -Fluoro-1,3-benzothiazol-2-yl} acetamide can be prepared in a manner similar to Example 2a but from 189 mg of 2 - {[(4-cyclopropylpiperazin-1-yl) acetyl] thiocyanate amino} -5-fluoro-1,3-benzothiazol-6-yl (7b), 5 cm ³ of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 222 mg of DL-dithiothreitol and 96 mg of 3-chloro-6-ethoxy [1,2,4] triazolo [4,3-b] pyhdazine (7c), after 21.5 h at 90 ^° C. Thus 114 mg of 2- (4- cyclopropylpiperazin-1-yl) -N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro-1,3-benzothiazol -2-yl) acetamide, in the form of a white powder whose characteristics are as follows: 1 H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 0.27 (m, 2H); 0.39 (m, 2H); 1.27 (t, J = 7.1 Hz, 3H); 1.61 (m, 1H); 2.42 to 2.58 (partially masked m, 8H); 3.32 (s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 7.06 (d, J = 9.8 Hz, 1H); 7.68 (d, J = 10.0 Hz, 1H); 8.22 (d, J = 7.1Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 529; [MH] -: m / z 527 b) 2 - {[(4-Cyclopropylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl thiocyanate may be prepared from following procedure: a mixture of 1.34 g of the potassium salt of (4-cyclopropylpiperazin-1-yl) acetic acid (7d) in 10 cm ³ of a 2N solution of hydrogen chloride in ether is stirred during 1 h at 20 ⁰ C. The resulting suspension is evaporated to dryness under vacuum. White residue obtained was added at 20 ° C, 15 cm ³ of pyridine, thiocyanate 226mg of 2-amino-5-fluoro-1, 3-benzothiazol-6-yl (1d) and 1 N hydrochloride 92g (3-dimethylaminopropyl) N-ethylcarbodiimide. After 2.5h, the brown reaction medium is evaporated to dryness. The oily residue is taken up in water. The precipitate formed is filtered and the aqueous filtrate is extracted with a 90:10 mixture of ethyl acetate and methanol. The filtered precipitate is taken up in ethyl acetate and then combined with the organic phase. The resulting solution is dried over magnesium sulfate, filtered and then evaporated to dryness in vacuo. The brown residue is purified on SPOT II by chromatography on a silica cartridge (SVF D26 Si60, 15-40 μM, 25 g) eluting with a gradient of 97.4: 2.6 to 90:10 of dichloromethane / methanol. 191 mg of 2 - {[(4-cyclopropylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a yellow powder whose characteristics are the following: MASS SPECTRUM: Waters ZQ: Retention time Tr (min) = 2.75; [IvRH] ₊ : m / z 392; [MH] -: m / z 390 c) 3-chloro-6-ethoxy [1,2,4] triazolo [4,3-b] pyridazine can be prepared in a manner similar to Example 1e but from 19.7g of a solution of 21% sodium ethoxide in ethanol and 10g of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyhdazine (commercial) in 100cm ³ of dioxane, after reflux for 7h. 9.6 g of 3-chloro-6-ethoxy [1,2,4] thazolo [4,3-b] pyhdazine are thus obtained in the form of a beige powder, the characteristics of which are as follows: MASS SPECTRUM: Waters ZQ Retention time Tr (min) = 2.89; [M + H] ₊ : m / z 199 d) The potassium salt of (4-cyclopropylpiperazin-1-yl) acetic acid can be prepared in a manner similar to the conditions described by DT Witiak et.al .; J. Med. Chem. 1985, 28, 1228, but with 1 g of bromoacetic acid and 3 g of 4-cyclopropyl piperazine hydrochloride. 2.66 g of the potassium salt of (4-cyclopropylpiperazin-1-yl) acetic acid are thus obtained in the form of a beige powder, the characteristics of which are as follows: MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.10; [M + H] ₊ : m / z 185

Example 8

N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) 2- (4-Cyclopropylpiperazin-1-yl) acetamide a) N- (6 - {[6- (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl 5-fluoro-1,3-benzothiazol-2-yl) -2- (4-cyclopropylpiperazin-1-yl) acetamide can be prepared in a manner similar to Example 2a but from 266 mg. of 2 - {[(4-cyclopropylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl (7b) thiocyanate containing ⁵ cm ³ of degassed ethanol, 5 mg of dihydrogenphosphate, potassium in 0.1 cm ³ of water, 315 mg of DL-dithiothreitol and 153 mg of 3-chloro-6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazine (8b), after 24 h at 90 ^° C. This gives 180 mg of N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5- fluoro-1,3-benzothiazol-2-yl) -2- (4-cyclopropylpiperazin-1-yl) acetamide in the form of a white powder having the following characteristics: 1 H NMR spectrum (400 MHz, δ in ppm DMSO-d ₆ ): 0.22 to 0.30 (m, 2H); 0.36 to 0.44 (m, 2H); 1.25 to 1.65 (m, 2H); 1.69 to 1.81 (m, 1H); 1.95-2.11 (m, 2H); 2.19 to 2.30 (m, 2H); 2.43 to 2.58 (partially masked m, 8H); 3.32 (s, 2H); 4.86 (m, 1H); 7.05 (d, J = 9.8 Hz, 1H); 7.70 (d, J = 10.3 Hz, 1H); 8.15 (d, J = 7.3 Hz, 1H); 8.29 (d, J = 10.0 Hz, 1H); 10.15 to 14.69 (m very spread, 1

H) MASS SPECTRUM: Waters ZQ: [M + H] ₊ : m / z 555; [MH] -: m / z 553 b) 3-Chloro-6- (cyclobutyloxy) [1,2,4] thazolo [4,3-b] pyhdazine can be prepared in a manner similar to Example 1e but starting from 10.4 cm ³ of cyclobutanol, 3.17 g of 60% sodium hydride in the oil and 10 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] ] pyhdazine (commercial) in 100cm ³ of tetrahydrofuran. 9 g of 3-chloro-6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazine are thus obtained 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 ): 1.63 to 1.96 (m, 2H); 2.07 to 2.24 (m, 2H); 2.41 to 2.52 (partially masked m, 2H); 4.95 to 5.34 (m, 1H); 7.10 (d, J = 9.8 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H)

Example 9

N - {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro-1,3-benzothiazol-2-yl} -2 - (4-ethylpiperazin-1-yl) acetamide a) N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl} -5- Fluoro-1,3-benzothiazol-2-yl} -2- (4-ethylpiperazin-1-yl) acetamide may be prepared in a manner similar to Example 2a but from 353 mg of 2 - {[(4-ethylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl thiocyanate ( 9b), 10 cm ³ of degassed ethanol, 5 mg of potassium dihydrogen phosphate in 0.1 cm ³ of water, 430 mg of DL-dithiothreitol and 185 mg of 3-chloro-6-ethoxy [1,2,4 ] triazolo [4,3-b] pyridazine (7c), after 21 h at 90 ^° C. This gives 259 mg of N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3- b] pyridazin-3-yl) sulfanyl] -5-fluoro-1,3-benzothiazol-2-yl} -2- (4-ethylpiperazin-1-yl) acetamide as a whitish powder whose characteristics are the following: 1 H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 0.98 (t, J = 7.1 Hz, 3 H);

1.27 (t, J = 7.1 Hz, 3H); 2.31 (q, J = 7.1 Hz, 2H); 2.35 to 2.44 (m, 4H); 2.48 to 2.58 (partially masked m, 4H); 3.33 (s, 2H); 4.24 (q, J = 7.1 Hz, 2H); 7.06 (d, J = 9.8 Hz, 1H); 7.69 (d, J = 10.3 Hz, 1H); 8.23 (d, J = 7.3 Hz, 1H);

8.28 (d, J = 9.8 Hz, 1H); 12.16 (spread m, 1 H) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 517; [M + 2H] 2+: m / z 259 (base peak); [MH] -: m / z 515 b) 2 - {[(4-ethylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl thiocyanate can be prepared from a similar manner to Example 7b but from 4.6 g of (4-ethylpiperazin-1-yl) acetic acid (commercial or the potassium salt of (4-ethylpiperazin-1-yl) acetic acid can also be prepared similarly to the conditions described by DT Witiak et al in Example 7d), 1 g of 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (1d) and 8.51 g of N- (3-dimethylaminopropyl) N-ethylcarbodiimide hydrochloride in 50 cm ³ of pyridine. 714 mg of 2 - {[(4-ethylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a yellow powder whose characteristics are the following :

MASS SPECTRUM: Waters UPLC-SQD: Retention Time Tr (min) = 0.59; [M + H] +: m / z 380; [M-H] -: m / z 378

Example 10 N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) 2- (4-ethylpiperazin-1-yl) acetamide a) N- (6 - {[6- (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl 5-Fluoro-1,3-benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetannide can be prepared in a manner similar to Example 2a but from 355 mg of 2 - {[(4-ethylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl (9b) fluoro-6-thiocyanato thiocyanate, with 10 cm ³ of degassed ethanol , 5 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 430 mg of DL-dithiothreitol and 210 mg of 3-chloro-6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] ] pyridazine (8b), after 21 h at 90 ^° C. is thus obtained 232 mg of N- (6 - {[6- (cyclobutyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3- yl] sulfanyl) -5-fluoro-1,3-benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetamide as a white powder having the following characteristics: Spectrum 1 H NMR (400 MHz, δ in ppm, DMSO-d ₆ ): 0.98 (t, J = 7.1 Hz, 3H); 1, 51-1.66 (m, 1H); 1.74 (m, 1H); 1.95-2.10 (m, 2H); 2.19-2.27 (m, 2H); 2.31 (q, J = 7.1 Hz, 2H); 2.39 (m, 4H); 2.54 (m, 4H); 3.33 (s, 2H); 4.86 (m, 1H); 7.05 (d, J = 9.8 Hz, 1H); 7.70 (d, J = 10.3 Hz, 1H); 8.15 (d, J = 7.2 Hz, 1H); 8.29 (d, J = 9.8 Hz, 1H); 12.20 (spread m, 1H) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 543; [M + 2H] 2+: m / z 272 (base peak); [MH] -: m / z 541

Example 11

2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3} -yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide a) 2- (4-Cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (oxetan-3- yloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide can be prepared in a manner similar to Example 2a but from 346 mg of 2 - {[(4-cyclopropylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl (7b) thiocyanate, of 10 cm ³ of degassed ethanol , 5 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 407 mg of DL-dithiothreitol and 200 mg of 3-chloro-6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine (11b), after 22h at 90 ^° C. There is thus obtained 238 mg of 2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide, in the form of a white powder whose characteristics are as follows:

1 H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 0.22 to 0.29 (m, 2H); 0.36 to 0.42 (m, 2H); 1.60 (m, 1H); 2.43 to 2.60 (partially masked m, 8H); 3.32 (s, 2H); 4.48 (m, 2H); 4.71 (m, 2H); 5.36 to 5.46 (m, 1H); 7.20 (d, J = 9.8 Hz, 1H); 7.71 (d, J = 10.3 Hz, 1H); 8.06 (d, J = 7.3 Hz, 1H) 8.38 (d, J = 9.8 Hz, 1H); 12.15 (spread m, 1H)

MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 557; [M + 2H] 2 +: m / z 279 (base peak); [MH] -: m / z 555 b) 3-Chloro-6- (oxetan-3-yloxy) [1,2,4] thazolo [4,3-b] pyhdazine can be prepared in a manner similar to Example 1e but starting from 1, 96g of oxetan-3-ol, 634mg of sodium hydride at 60% in oil and 2g of 3,6-dichloro [1,2,4] triazolo [4.3-b] pyridazine (commercial) in 20cm ³ of tetrahydrofuran. 2.04 g of 3-chloro-6- (oxetan-3-yloxy) [1,2,4] thazolo [4,3-b] pyridazine are thus obtained in the form of a whitish powder, the characteristics of which are as follows:

MASS SPECTRUM: Waters UPLC-SQD: Retention Time Tr (min) = 0.41; [M + H] +: m / z 227

Example 12: Rac-2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide a) Rac-2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - [[ 6

(Tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide can be prepared in a similar manner in example 2a but from 325 mg of thiocyanate of 2 - {[4- cyclopropylpiperazin-1-yl) acetyl] amino} -5-fluoro-1,3-benzothiazol-6-yl (7b), 10 cm ³ of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 385mg of DL-dithiothreitol and 200mg of rac-3-chloro-6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine (12b), after 18h at 90 ^° C. 206 mg of rac-2- (4-cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] are thus obtained. triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide in the form of a white powder having the following characteristics: 1 H NMR spectrum (400 MHz δ in ppm, DMSO-d ₆ ): 0.19 to 0.30 (m, 2H); 0.36 to 0.43 (m, 2H); 1.60 (m, 1H); 1.91 to 2.02 (m, 1H); 2.07 to 2.22 (m, 1H); 2.42 to 2.60 (partially masked m, 8H); 3.32 (s, 2H); 3.60 to 3.84 (m, 4H); 5.27 (m, 1H); 7.08 (d, J = 9.8 Hz, 1H); 7.70 (d, J = 10.0 Hz, 1H); 8.14 (d, J = 7.3 Hz, 1H); 8.31 (d, J = 9.8 Hz, 1H); 12.17 (spread m, 1H) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 571; [MH] -: m / z 569 b) rac-3-chloro-6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in a similar to Example 1e but from 2.33 g of rac-tetrahydrofuran-3-ol, 634 mg of sodium hydride at 60% in oil and 2 g of 3,6-dichloro [1, 2, 4] triazolo [4,3-b] pyridazine (commercial) in 20cm ³ of tetrahydrofuran. Thus 2.09 g of rac-3-chloro-6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine is obtained in the form of a beige powder whose characteristics are MASS SPECTRUM: Waters UPLC-SQD: Retention Time Tr (min) = 0.49; [M + H] +: m / z 241

Example 13: Pharmaceutical composition

Tablets having the following formula were prepared:

Product of Example 1, 0.2 g

Excipient for a tablet finished at 1 g (detail of the excipient: lactose, talc, starch, magnesium stearate). Example 14: Pharmaceutical composition

Tablets having the following formula were prepared:

Product of Example 6 0.2 g Excipient for a tablet finished at 1 g

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

Examples 1 and β 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:

The cell pellets are resuspended in the lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, 10% glycerol, 1 mM TECP] + Roche Diagnostics protease inhibitor cocktail without EDTA, ref 1873580 ), stirred at 4 ° C until homogeneous, then mechanically lysed using a "Dounce" type apparatus.

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

The fractions containing the protein of interest in view of the electrophoretic analysis (SDS PAGE) are pooled, concentrated by ultrafiltration (cut-off 1OkDa) and injected on an exclusion chromatography column (Superdex ™ 200, GE HealthCare) balanced. in buffer A. After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast Flow ™, GE HealthCare) equilibrated in Buffer A. The fractions eluted by a buffer B gradient and containing the protein 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

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

In a final volume of 50 μl of enzymatic reaction, final 5 nM MET is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 μM, final DMSO 3%) in MOPS 1 OmM buffer pH 7.4, DTT 1 mM, Tween 20 0.01%. The reaction is initiated by the substrate solution to obtain the final concentrations of poly- (GAT) 1 μg / ml, 10μM ATP and 5mM MgCl 2. After 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 incubation hours at room temperature, the reading is made at 2 wavelengths 620 nm and 665 nm on a reader for the TRACE / HTRF technique and the% inhibition is calculated according to the 665/620 ratios.

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

B) Test B: Inhibition of MET autophosphorylation; ELISA technique (pppY1230,1234,1235) a) Cell lysates: Inoculate MKN45 cells in 96-well plate (CeII coat BD polylysine) at 20,000 cells / well under 200 μl in RPMI + medium

10% FCS + 1% L-glutamine. Allow 24 hours to adhere to the incubator.

The cells are treated the day after seeding with the products at 6 concentrations in duplicate for 1 h. At least 3 control wells are treated with the same amount of final DMSO. Dilution of the products: Stock at 1 μM in pure DMSO - Range of 1 μM at 30 μM with a step of 3 in pure DMSO - Dilutions intermediate to 1/50 in culture medium then 10 μl sample directly added to the cells (200 μl) : final range of 10000 to 3OnM.

At the end of the incubation, gently remove the supernatant and rinse with 200 μl of PBS. Then put 10Oμl of lysis buffer directly into the wells on the ice and incubate at 4 ° C for 30 minutes. Lysis buffer: 1 OmM Tris, pH 7.4 HCl, 10 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20mM NaF, 2mM Na3VO4, 1mM mM PMSF and anti protease cocktail. The 10 μl 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 100 μl of chromogen and incubate 30 minutes in the dark at room temperature.

Stop the reaction with 10Oμl of stop solution. Read without delay at 45OnM 0.1 seconds at Wallac Victor flat reader.

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

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

All stages of the test are automated on BIOMEK 2000 or TECAN stations. The results obtained by this test B for the products of formula (I) as examples in the experimental part are such that IC50 less than 10 microM and in particular to i microM.

The results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below, as follows: for test A, the sign + corresponds to less than 50 nm and the sign ++ corresponds to less than 100 nm. . for test B the sign + corresponds to 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:

Claims

1 - Products of formula (I):

in which

represents a single or double bond

Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted; a radical -O-cycloalkyl, -O-heterocycloalkyl; -NH-cycloalkyl and -NH- heterocycloalkyl all optionally substituted; an optionally substituted heteroaryl radical; an optionally substituted phenyl radical; an NHCOalkyl or NHCOcycloalkyl radical; or an NR1 radical R2 as defined below; X represents S, SO or SO ₂ , A represents NH or S;

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

an alkoxy radical optionally substituted by NR 3 R 4, alkoxy, hydroxy or by heterocycloalkyl; an O-phenyl radical or an O- (CH 2) n-phenyl radical, with optionally substituted phenyl and n represents an integer of 1 to 4; or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted by 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 from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl and alkoxy radicals, heteroaryl, heterocycloalkyl, NH2, NHAIk, N (AI k) 2 or optionally substituted phenyl; or else R 3 and R 4 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl, heteroaryl, CO-phenyl radicals; and S-heteroaryl, such that, in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH 2, NHaIk and N (alk) 2, said products of formula (I) being in all 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).

2 - Products of formula (I) as defined in any one of the other claims wherein X and A have the meanings indicated in any one of the other claims, Ra represents an alkoxy radical optionally substituted with a chlorine atom. a hydroxyl radical or a heterocycloalkyl radical which is itself optionally substituted; an O-cycloalkyl radical; an NHCOaIk radical; or a radical NR1 aR2a such that R1 a and R2a 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 and phenyl radicals; optionally substituted; and W represents a hydrogen atom; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 radicals; with the nitrogen atom to which they are bonded a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the possible NH that it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl and alkoxy radicals, heteroaryl, heterocycloalkyl, NH2, NHAIk, N (AI k) 2 or optionally substituted phenyl; or else R 3 and R 4 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 heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, NH2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, CO-phenyl and S-heteroaryl radicals; , such that, in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 atoms of carbon, 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). 3 - Products of formula (I) as defined in any one of the other claims wherein Ra and X have the values defined in any of the other claims and:

A represents NH or S;

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

a cycloalkyl radical or an alkyl radical optionally substituted by an NR 3 R 4, alkoxy, hydroxy, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted; 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 NR 3 R 4 or by alkoxy, or else R 1 and R 2 form, with the nitrogen atom to which they are bonded, a cyclic radical containing from 3 to 10 ring members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the eventual

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 linkages and optionally one or more other heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the heterocycloalkyl, heteroaryl and phenyl radicals as well as the cyclic radicals that R1 and R2 or R3 and R4 can form with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH 2 -heterocycloalkyl, phenyl, CH 2 -phenyl, heteroaryl, CO-phenyl and S-heteroaryl radicals, such as in these 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).

4 - Products of formula (I) as defined in any one of the other claims in which:

represents a single or double bond

Ra represents a hydrogen atom or a halogen atom or an optionally substituted phenyl radical;

X represents S, SO or SO ₂ ; A represents NH or S;

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

an alkoxy radical optionally substituted by NR3R4, ie an O- (CH2) n -NR3R4 radical, an O-phenyl or O- (CH2) 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 or an alkyl radical and the other of R1 and R2 represents 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 substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical optionally containing one or more other radicals; heteroatoms selected from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or else R3 and R4 form with the nitrogen atom to which they are bonded a cyclic radical 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; all the radicals defined above heterocycloalkyl, heteroaryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, oxo, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, CH 2 -heterocycloalkyl, CH 2 -phenyl, CO-phenyl and S-heteroaryl radicals, such as in the latter radicals alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted by one or more radicals selected from halogen atoms and hydroxyl, oxo, 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 the other claims in which Ra and X have the values defined in any one of the other claims and:

A represents NH or S;

an alkoxy radical optionally substituted with OCH 3 or NR 3 R 4, ie an O- (CH 2) n -OCH 3 radical or an O- (CH 2) n -NR 3 R 4 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 an optionally substituted alkyl radical; by NR3R4, or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical including the possible 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 optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; the 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 chosen from halogen atoms; hydroxyl, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, CH 2 -heterocycloalkyl, CH 2 -phenyl, CO-phenyl and S-heteroaryl radicals, such as in the latter radicals, alkyl radicals, heterocycloalkyl, phenyl and heteroaryl 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, 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).

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

A represents NH or S;

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

an alkyl radical optionally substituted with NR3R4; an alkoxy radical optionally substituted with NR 3 R 4, ie a radical, an O- (CH 2) n -NR 3 R 4 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 or an alkyl radical and the other of R 1 and R2 represents an alkyl radical optionally substituted with 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 possible 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; the 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 chosen from halogen atoms; hydroxyl, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl, CH 2 -heterocycloalkyl, CH 2 -phenyl, CO-phenyl and S-heteroaryl radicals, such as in the latter radicals, alkyl radicals, heterocycloalkyl, phenyl and heteroaryl 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, 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).

7 - Products of formula (I) as defined in any one of the other claims wherein X, A and W have the meanings indicated in any of the other claims, Ra represents a hydrogen atom or a chlorine atom or the radical: with Rb represents a halogen atom or an S-heteroaryl radical optionally substituted by a radical chosen 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 the possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I) . 8 - Products of formula (I) as defined in any one of the other claims in which A represents NH, the substituents, Ra, X and W being chosen from among all the values defined for these radicals to any of the other claims, said products of formula (I) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

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

- Products of formula (I) as defined in any one of the other claims corresponding to formula (Ia) or (Ib): in which Ra and W are chosen from the meanings indicated in any one of the other claims, said products of formula (Ia) and (Ib) being in all possible isomeric forms racemic, enantiomers and diastereoisomers, as well as salts of addition with the mineral and organic acids or with the inorganic and organic bases of said products of formula (Ia) and (Ib).

11 - Products of formula (I) as defined in any one of the other claims in which represents a single bond corresponding to the products of formula (I ¹ ):

the substituents Ra, X, A and W having the meanings indicated in any one of the other claims, said products of formula (I) being in all possible isomeric 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). 12 - Products of formula (I) as defined in any one of the other claims in which represents a double bond corresponding to the products of formula (I "):

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

13 - Products of formula (la) as defined in any one of the other claims in which represents a single bond corresponding to the products of formula (Ia '):

wherein Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (a) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (a). 14 - Products of formula (Ia) as defined in any one of the other claims in which represents a double bond corresponding to the products of formula (I "a):

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

- Products of formula (Ib) as defined in any one of the other claims, wherein represents a single bond corresponding to the products of formula (b):

wherein Ra and W are selected from the meaning indicated in any one of the other claims, said products of formula (b) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (b). 16 - Products of formula (Ib) as defined in any one of the other claims in which represents a double bond corresponding to the products of formula (I "b):

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

17 - Products of formula (I) as defined in any one of the other claims, corresponding to the following formulas:

1- (6 - {[6- (cyclohexyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl ) -3- [2- (Morpholin-4-yl) ethyl] urea - (5-fluoro-6 - {[6- (4-fluorophenyl) [1,2,4] triazolo [4,3-b] pyridazin] 2-methylpropan-2-yl-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate

1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 2- (4-cyclopropylpiperazin-1-yl) -N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5-fluoro -1,3-Benzothiazol-2-yl} acetamide

N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -5-fluoro-1,3-benzothiazol-2-yl ) -2- (4-Cyclopropylpiperazin-1-yl) acetannide - N- {6 - [(6-ethoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -5 1-Fluoro-1,3-benzothiazol-2-yl} -2- (4-ethylpiperazin-1-yl) acetannide

2- (4-Cyclopropylpiperazin-1-yl) -N- (5-fluoro-6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyπdazin-3 -yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide as well as addition salts with inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

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

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

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

As medicaments, the products of formula (I) as defined in any one of claims 1 to 17, as well as addition salts with inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases. said products of formula (I).

As medicaments, the products of formula (I) as defined in claim 17, as well as the addition salts with mineral acids and organic or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I).

23 - Pharmaceutical compositions containing as active ingredient at least one of the products of formula (I) as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier.

24 - Use of the products of formula (I) as defined in any one of claims 1 to 17, or of 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

The use as defined in claim 24, wherein the protein kinase is in a cell culture.

The use as defined in claim 24 or 25 wherein the protein kinase is in a mammal.

27 - Use of a product of formula (I) as defined in any one of claims 1 to 17, 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.

28 - Use of a product of formula (I) as defined in any one of claims 1 to 17 for the preparation of a medicament for the treatment of cancers.

29 - Use according to claim 28 for the treatment of solid or liquid tumors. 30 - Use according to claim 28 or 29 for the treatment of cancers resistant to cytotoxic agents.

31 - Use according to one or more of claims 28 to 30 for the treatment of primary tumors and / or metastases especially in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC), glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, cancer bones and pancreas.

32 - Use of the products of formula (I) as defined in claims 1 to 17, for the preparation of medicaments for the chemotherapy of cancers.

33 - Use of the products of formula (I) as defined in claims 1 to 17, for the preparation of medicaments for cancer chemotherapy alone or in combination.

34 - Products of formula (I) as defined in any one of claims 1 to 17 as kinase inhibitors.

- Products of formula (I) as defined in any one of claims 1 to 17 as MET inhibitors.

36 - As new industrial products, the synthesis intermediates of formulas M1, M2, M3 and N:

in which R 6 represents an alkyl radical optionally substituted by a group NR 3 R 4 (a - (CH 2) n -NR 3 R 4 radical), alkoxy, hydroxy, heterocycloalkyl, phenyl, - (CH 2) n -phenyl, with optionally substituted phenyl and n represents an integer from 1 to 4, such that OR6 represents the corresponding values of R as defined above; R 7 represents a cycloalkyl or alkyl radical optionally substituted by a radical NR 3 R 4, alkoxy, hydroxy or a phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally substituted as indicated in claim 1; and Ra, R1, R2, R3 and R4 have the meanings given in claim 1.