WO2010089506A1

WO2010089506A1 - Derivatives of 6-(6-o-cycloalkyl or 6-nh-cycloalkyl-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as met inhibitors

Info

Publication number: WO2010089506A1
Application number: PCT/FR2010/050177
Authority: WO
Inventors: Eric Bacque; Conception Nemecek; Antonio Ugolini; Sylvie Wentzler
Original assignee: Sanofi-Aventis
Priority date: 2009-02-06
Filing date: 2010-02-04
Publication date: 2010-08-12
Also published as: AU2010212231A1; IL214407A0; SG173558A1; BRPI1011354A2; JP2012517407A; UY32419A; EP2393790A1; FR2941949B1; CA2751525A1; EA201171010A1; TW201040187A; MX2011008312A; CN102388029A; KR20110126660A; AR075248A1; FR2941949A1; CO6400222A2; MA33102B1

Abstract

The invention relates to novel products of the formula (I) where: - - - - is a single or double bond; Ra is -O-cycloalkyl or -NH-cycloalkyl; X is S, SO or SO2, A is NH or S; W is H, alkyl or COR with R being cycloalkyl; alkyl; alkoxy; O-phenyl; -O-(CH2)n-phenyl with n = 1 to 4; or NR1R2 with R1 is H or alk and R2 is H, cycloalkyl, heterocycloalkyl, or alkyl; or R1, R2 form a cycle with N optionally containing O, S, N and/or NH; wherein all of said radicals are optionally substituted; and wherein said products are in any isomer or salt form and can be used as drugs, in particular as MET inhibitors.

Description

6- (6-O-CYCLOALKYL OR 6-NH-CYCLOALKYL-TRIAZOLOPYRIDAZINE DERIVATIVES

SULFANYL) BENZOTHIAZOLES AND BENZIMIDAZOLES: PREPARATION, APPLICATION AS MEDICAMENTS AND USE AS INHIBITORS OF

MET

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

The present invention relates more particularly to novel 6-O-cycloalkyl or 6-NH-cycloalkyl-triazolopyridazine-sulfanyl benzothiazole and benzimidazole derivatives, exhibiting anticancer activity, via the modulation of the activity of proteins, in particular kinases.

To date, most of the commercial compounds used in chemotherapy are cytotoxic drugs that pose significant problems of side effects and tolerance by patients. These effects could be limited insofar as the drugs used act selectively on cancer cells, excluding healthy cells. One of the solutions to limit the undesirable effects of chemotherapy may therefore consist of the use of drugs acting on metabolic pathways or constitutive elements of these pathways, mainly expressed in cancer cells, and which would be little or no expression in healthy cells. Protein kinases are a family of enzymes that catalyze the phosphorylation of hydroxy groups of protein-specific residues such as tyrosine, serine or threonine residues. Such phosphorylations can greatly alter the function of proteins: thus, protein kinases play an important role in the regulation of a wide variety of cellular processes, including metabolism, proliferation cell adhesion and motility, cell differentiation or cell survival, with some protein kinases playing a central role in the initiation, development and completion of cell cycle events.

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

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

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

The present invention also relates to the use of said derivatives for the preparation of a medicament for the treatment of humans. Thus, one of the objects of the present invention is to provide compositions having anticancer activity, acting in particular vis-à-vis kinases. Of the kinases for which modulation of activity is desired, MET is preferred.

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

MET, or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine kinase activity expressed in particular by epithelial and endothelial cells. HGF, Hepatocyte Growth Factor, is described as the specific ligand of MET. HGF is secreted by the mesenchymal cells and activates the MET receptor that moderates. As a consequence, the receptor autophosphorylates on tyrosines of catalytic domain Y1230, Y1234 and Y1235.

MET stimulation by HGF induces proliferation, scattering (or dispersion), cell motility, resistance to apoptosis, invasion and angiogenesis.

MET, like HGF, are found to be overexpressed in many human tumors and a wide variety of cancers. MET is also found amplified in gastric tumors and glioblastomas. Numerous point mutations of the MET gene have also been described in tumors, in particular in the kinase domain, but also in the juxtamembrane domain and the SEMA domain. Overexpression, amplification or mutations cause constitutive activation of the receptor and deregulation of its functions. The present invention thus relates in particular to novel inhibitors of the MET protein kinase and its mutants, which can be used for an anti-proliferative and anti-metastatic treatment, especially in oncology.

The present invention also relates to novel inhibitors of the MET protein kinase and its mutants, which can be used for anti-angiogenic treatment, in particular in oncology.

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

in which

z ^zz ^ represents a single or double bond;

Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl all optionally substituted;

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

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

a cycloalkyl radical, or an alkyl radical, optionally substituted by a halogen atom or a cycloalkyl, NR3R4, 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, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl 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 form with the atom; nitrogen to which they are attached a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the optional S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH 2, NHAIk, N (Alk) 2 or optionally substituted phenyl radicals; or R3 and R4 together with the nitrogen atom to which they are bonded form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the possible S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; all the radicals defined above alkyl, 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 chosen from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH- radicals; CO-R5 and the radicals alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in the latter radicals the radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH 2, NHaIk and N (alk) 2, all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl being further optionally substituted with an Si (alk) 3 radical; all the radicals defined above cycloalkyl and heterocycloalkyl which may be optionally substituted on one of the ring carbons by a spirocycloalkyl or spiroheterocycloalkyl radical or possibly on two of the ring carbons by a fused cycloalkyl or heterocycloalkyl radical;

R5 and R5 ', which may be identical or different, represent an alkyl or cycloalkyl radical containing at most 6 carbon atoms; alk represents an alkyl radical containing at most 4 carbon atoms; it being understood that W does not represent H when A represents S, X represents S, Ra represents the O-cyclohexyl radical or the unsubstituted NH-cyclohexyl radical and represents a double bond, said products of formula (I) being in all forms racemic isomers, 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 the products of formula (I) as defined above or hereinafter in which represents a single or double bond;

Ra represents an optionally substituted -O-cycloalkyl radical or -NH-cycloalkyl radical;

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 a halogen atom or a cycloalkyl 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, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl 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 form with the atom; nitrogen to which they are attached a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the optional S possibly being in SO or SO2 form, this radical including any 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 heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH 2, NHAIk, N (Alk) 2 or optionally substituted phenyl radicals; or R3 and R4 together with the nitrogen atom to which they are bonded form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the possible S possibly being in SO or SO2 form, this radical including the 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, -O-CO-R5, NH2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2- radicals; phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that, in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2;

R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I). The subject of the present invention is the products of formula (I) as defined above or below in which ^zzz , Ra and X have the values defined in any of the other claims and:

A represents NH or S;

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

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

or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom or a cycloalkyl radical; a heterocycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, heterocycloalkyl or NR3R4 radical; or R1 and R2 together with the nitrogen atom to which they are attached form a cyclic radical containing 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted;

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

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

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

in which

represents a single or double bond;

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

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

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

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;

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

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, optionally substituted phenyl radicals or R1 and R2 together with the nitrogen atom to which they are attached 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, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or an optionally substituted phenyl radical or else R3 and R4 form with the nitrogen atom to which they are bonded a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the radicals defined above 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, -O-CO-R5, NH2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2- radicals; phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that, in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2;

R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as addition salts with the inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

The subject of the present invention is the products of formula (I) as defined above or below, in which Ra and X have the values defined in any one of the other claims and:

A represents NH or S;

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

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

A represents NH or S;

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

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

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

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

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

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

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

The subject of the present invention is the 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 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 inorganic and organic acids or with the inorganic and organic bases of said products of formula (I).

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

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

wherein Ra 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). The subject of the present invention is the products of formula (I) as defined above or hereinafter in which ^zzz 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).

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

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

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

the term "alkoxy radical" denotes the linear and, if appropriate, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy radicals, as well as their linear or branched positional isomers: the 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, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl 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, tetrahydrothiopyranyl, oxodihydropyridazinyl radicals, or alternatively oxetanyl or thietanyl radicals, these radicals being optionally substituted; it may be noted that these heterocycloalkyl radicals may comprise a bridge formed from two links to form, for example, an oxa-5- radical. azabicyclo [2.2.1] heptane or azaspiro [3.3] heptane or other azabicycloalkane or azaspiroalkane rings.

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, pyrannyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyhdyl, 3-pyridyl and 4-pyhdyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl as 3- or 4-isoxazolyl, furazannyl, free or salt tetrazolyl, all these radicals being optionally substituted, among which more particularly the thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals such as, for example, benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamentyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl, azaindolyl, indazolyl, purinyl, thiénopyrazolyle, tétrahydroindazolyle, tétrahydrocyclopentapyrazolyle, dihydrofuropyrazolyle, tétrahydropyrrolopyrazolyle, oxotétrahydropyrrolopyrazolyle, tétrahydropyranopyrazolyle, tétrahydropyridinopyrazolyle or oxodihydropyridino-pyrazolyl, all 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 in groups chloromethyl, hydroxypropyl, methoxynethyl, propionyloxymethyl, methylthionethyl, dimethylanninoethyl, benzyl or phenethyl.

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

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 selected from halogen atoms, hydroxyl, oxo, alkoxy, NH 2 radicals; NHaIk, N (alk) 2, and the radicals alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, and CO-phenyl, such that in these latter radicals the alkyl, heterocycloalkyl and phenyl radicals are themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals having 1 to 4 carbon atoms, NH 2; NHaIk and N (alk) 2,

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

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

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

represents a single or double bond

Ra represents a -O-cycloalkyl radical, or a -NH-cycloalkyl radical optionally substituted with a hydroxyl, alkoxy or -O-CO-R5 radical;

X is S; A represents S;

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

a cycloalkyl radical, or an alkyl radical, optionally substituted with an NR 3 R 4 radical, or alkoxy radical; an O-phenyl radical;

or the radical NR1 R2 in which R1 and R2 are such that one represents a hydrogen atom and the other represents an alkyl radical optionally substituted with a heterocycloalkyl radical; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical; R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

In particular in the products of formula (I), the cycloalkyl radicals may represent a cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl radical;

In particular in the products of formula (I), the heterocycloalkyl radicals may represent a morpholinyl or pyrrolidinyl radical.

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

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

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

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

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

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

N - (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] tπazolo [4,3-b] pyπdazin-3-yl} sulfanyl) -1,3-benzothiazol 2-yl] cyclopropanecarboxamide

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

1- (6 - {[6- (Cyclohexylamino) [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} -1,3-benzothiazol-2-yl) -3- [ 2- (morpholin-4-yl) ethyl] urea

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

Phenyl 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate

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

6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyrimidazin-3-yl] sulfanyl} -N- [2- (pyrrolidin-1-yl) ethyl] -1, 3-benzothiazol-2-amine

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

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

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

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

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

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

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

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

trans-4 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyπdazin cyclopropanecarboxylate -6-yl] amino} cyclohexyl

N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] tπazolo [4,3-b] pyπdazin-3-yl} sulfanyl) -1,3-benzothiazol 2-yl] acetamide

3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-annin

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

N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- méthoxypropanannide

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

3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-annin

Ethyl (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate

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

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

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

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

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

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

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

1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6 - {[4- (trifluoromethyl) cyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyπdazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea

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

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

rac-cis / trans N- {4 - [(3 - {[2 - ({[2- (morpholin-4-yl) ethyl] carbannoyl} amino) -1,3-benzothiazol-6-yl] sulfanyl} [1,2,4] triazolo [4,3-b] pyridazin-6-yl) oxy] cyclohexyl} acetamide

N- {6 - [(6 - {[4- (tfluoromethyl) cyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole -2-yl} cyclopropanecarboxamide 1 - [6 - ({6 - [(trans-4-hydroxycyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2 yl] -3- [2- (morpholin-4-yl) ethyl] urea

6 - {[6- (bicyclo [3.1.0] hex-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole. 2-amine

3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclobutyl [1,2,4] triazolo [4,3-b] pyridazin-6-annin

N- (6 - {[6- (bicyclo [3.1.0] hex-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclobutanecarboxamide rac-6 - ({6 - [(trans-2-fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1 , 3-benzothiazol-2-amine

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

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

N- (6 - {[6- (bicyclo [3.1.0] hex-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxamide

rac-N ² , N ² -dienyl-N- [6 - ({6 - [(trans-2-fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl } sulfanyl) -1,3-benzothiazol-2-yl] glycinannide rac-2- (4-ethylpiperazin-1-yl) -N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1] 2,4-triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetannide

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

N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- ( morpholin-4-yl) acetannide rac-2- (4-cyclopropylpiperazin-1-yl) -N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1,2,4] triazolo [4] , 3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetannide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- ( 4-cyclopropylpipérazin-1-yl) acétannide

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

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

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

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

rac-cis / trans-1 - {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1, 3-Benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea rac-cis / trans-N- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1, 2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxanide

rac-cis / trans-1 - [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1, 3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) ethyl] urea

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- ( piperidin-1-yl) azetidine-1-carboxamide rac-cis / trans-N- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin 3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxanide

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2-oxa -6-azaspiro [3.3] heptane-6-carboxamide

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

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

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

1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-oxetan -3-ylurea rac-cis / trans-1 - {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-Benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea rac-cis / trans-N- {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxanide, 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 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, 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 present invention thus also relates to the process for preparing products of formula (I) according to Scheme 4 as defined below

The present invention thus also relates to the process for the preparation of products of formula (I) according to Scheme 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 represents a single or double bond, the compounds of formulas (a ¹ ), (b ¹ ), (c ¹ ), (d ¹ ) are defined , (e ¹ ) and (f) in which ^zzz ^ represents a single bond, and the compounds of formulas (a "), (b"), (c "), (d"), (e ") and (f) in which 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 C) ₁ (Id ') and (1 e ¹ )

_-S> ,, NH ₂ r _e duction _HS> ^ NH,

NC

"NO," NO,

In Scheme 1 above, the substituent Ra can take the meanings indicated above for the products of formula (I ¹ ) and (I "), the substituent R 5, in the compounds of formulas (J), (1a). ¹ ) and (1 a ") represents an alkyl radical and the substituent R 6 in the compounds of formulas (O), (1d ') and (1d") represents an alkyl radical optionally substituted with NR 3 R 4 (a radical - ( CH2) n-NR3R4), alkoxy, hydroxy, heterocycloalkyl, phenyl, - (CH2) n- phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4. The substituent R 7 in the compounds of formulas (P) and (1 e ') / (1 e ") represents a cycloalkyl or alkyl radical optionally substituted with a radical NR3R4, alkoxy, hydroxy phenyl, heteroaryl, or heterocycloalkyl, themselves optionally substituted.

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

In the above scheme 1, the benzimidazoles of the general formula (1a "), (1b"), (1c "), (1d") and (1e ") and their reduced analogues of the general formula ( 1 to ¹ ), (1 b ¹ ), (1c '), (1cT) and (1 e ¹ ) can be prepared from 3,6-dichloro [1,2,4] triazolo [4,3 commercial pyridazine of formula (S).

The compounds (E) can be obtained, for example, by reacting alcohols or amines in the presence or absence of a base on the compound (S). The reaction is carried out, for example, at a temperature in the region of 20 ^° C. to 80 ^° C.

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

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

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

More particularly, the carbamates of general formula (1 a ') and (1 a ") can be prepared in particular as described in patent WO03028721A2, from a 3,4-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 a ') and (1 a "), for example in the presence of an aprotic solvent such as 1-methyl-2-pyrrolidinone. The reaction is carried out, for example, a temperature close to 120 ° C., in a tube sealed under microwaves.

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 ¹ ) and (1 c "), for example in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogen carbonate, at a temperature in the region of 20 ^° C.

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

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

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

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

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

In Scheme 2 above, the substituent Ra can take the meanings indicated above for the products of formula (I ¹ ) and (I ").

In scheme 2 above, the groups CONR1 R2, CO2R6 and COR7, which constitute W, can take the values of W as defined above for the products of formula (I ¹ ) and (I "), when W ≠ H

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

The carbamates of general formula (L1) can be obtained, for example, by reaction with a chlorocarbonate of formula (O) (X = Cl) on thiocyanate of 2-amino-1,3-benzothiazol-6-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 ') and (2b ") can be obtained, for example, respectively from the carbamates (2a') and (2a") where R6 = phenyl, in the same way that the ureas (L2) are obtained by reaction of amines on carbamates of type (L1).

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

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

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

by coupling of 2-amino-1,3-benzothiazol-6-yl (K) thiocyanate with an acid of formula (P) (X = OH) under the conditions, for example, described by D. D. DESMARTEAU; V. Montanari (Chem Lett, 2000 (9), 1052), in the presence of 1-hydroxybenzothazole and 1 - (3-dimethylaminopropyl) -3-ethylcarbodiimide and in the presence of a base such as triethylamine, at a temperature in the region of 40 ^° C.

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

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

In Scheme 2bis above the substituent R7 may take on the meaning of an aminomethyl group. These glycinamides (2c '/ 2c ") 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 ^° C. to 20 ^° C. The alpha-chloroacetamides (2e72e) thus formed can react with amines of the HNR3R4 type, as defined above, in a solvent such as pyridine at a temperature of 20 ⁰ C, to give the derivatives (2c72c ") 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-dimethylformamide, in the presence of a base such as triethylamine and at a temperature in the region of 95 ° C. or between 20 ^° C. and 95 ° C.

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 ¹ ), (2c ¹ ) and (2d ') can be prepared for example: 1) or by coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of derivatives (L1), (L2), (L3) and (K) with sodium borohydride, in a solvent such as N, N-dimethylformamide and in the presence of a base such as thylamine, at a temperature in the region of 95 ° C or between 50 ^° 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-butylate, tπs (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) such that ^zzz ^ represent a double bond.

Scheme 3: Routes of synthesis of the triazolopyridazine derivatives of formula (E)

In Scheme 3 above, the substituent Ra has the meanings given above for the products of formula (I ¹ ) and (I ").

The substituent R8 represents a cycloalkyl radical as defined above for the products of formula (I)

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

More particularly, the compounds of formula (E) 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 a temperature of about 20 ⁰ C to 80 ⁰ C and in a solvent such as tetrahydrofuran with an alkoxide of formula (U), itself obtained by treatment of an alcohol (HOR8) with, for example, sodium hydride in a solvent such as tetrahydrofuran at a temperature in the region of 0 ° C. to 20 ^° C.,

More particularly, the compounds of formula (E) wherein Ra represents an R8NH radical can be obtained by treatment of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyhdazine (S) with a amine of formula (R8NH2), at a temperature in the region of 20 ° C to 50 ° C and in a solvent such as N, N-dimethylformamide.

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

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

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

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

The benzothiazoles of general formula (2e ¹ ) and (2e ") may also be prepared from compounds of formula (L1), preferably with R6 = tBu, via compounds of formula (T) and (T").

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

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

L4

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

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

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

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

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

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

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

Figure 6 Other synthesis routes of reduced derivatives of formulas (V)

reduction

<v reduction

According to Scheme 6 above, the benzothiazoles of general formula (T) may also be prepared, starting from the compounds of formula (I "), by reduction, for example, with sodium borohydride, in a solvent such as ethanol, at a temperature of about 80 ⁰ C or by reduction with zinc (0) in the presence of acetic acid, at a temperature of 20 ° C. Alternatively the compounds (I ¹ ) 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 type 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 in the region of 20 ^° C.

Alternatively, the compounds (I ') may also be prepared from other compounds (T) by transformation of the group W into a group W of the same nature as defined above for W and according to the type of reactions defined in scheme 2: transformations of 2d '/ 2d "into 2a' / 2a" and into 2c '/ 2c ", the transformations of 2a' / 2a" into 2d '/ 2d "and into 2b' / 2b".

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

Among the starting products of formula J, K, O, P, Q, R, S, U, V, W are known and can be obtained either commercially or according to the usual methods known to those skilled in the art, by 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 intermediate products or products of formula (I) thus obtained can be subjected, if desired and if necessary, to the processes described above, to obtain other intermediates or other products of formula (I), one or more reactions of transformations known to those skilled in the art such as for example: a) an esterification reaction of acid function, b) a saponification reaction of ester function in acid function, c) a reduction reaction of the free or esterified carboxy function as a function of alcohol, d) an alkoxy function-to-hydroxyl function conversion reaction, or also an alkoxy-functional hydroxyl function, e) an elimination reaction of the protective groups that the protected reactive functions, f) a salification reaction with 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 any isomeric possible racemic, enantiomeric and diastereoisomeric forms.

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 methoxy in particular, 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, as well as their addition salts with acids, have interesting pharmacological properties, in particular because of their kinase inhibiting properties as indicated above.

The products of the present invention are especially useful for tumor therapy.

The products of the invention can also increase the therapeutic effects of commonly used anti-tumor agents.

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

The subject of the invention is, as medicaments, the products corresponding to the following formulas:

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

N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 1- (6 - {[6- (Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [ 2- (pyrrolidin-1-yl) ethyl] urea

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

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

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

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

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

3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-annin Ethyl (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate

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

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

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

N - (6 - {[6- (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide rac-cis / trans N- {4 - [(3 - {[2 - ({[2- (morpholin-4-yl) ethyl] carbannoyl} amino) -1,3-benzothiazol-6-yl] sulfanyl} [1,2,4] triazolo [4,3-b] pyridazin-6-yl) oxy] cyclohexyl} acetamide

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

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

6 - {[6- (bicyclo [3.1.0] hex-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-amine

rac-N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} -2- (morpholin-4-yl) acétannide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- ( morpholin-4-yl) acetannide rac-2- (4-cyclopropylpiperazin-1-yl) -N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1,2,4] tπazolo [4] , 3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetannide

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

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

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2-oxa -6-azaspiro [3.3] heptane-6-carboxamide N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- ( morpholin-4-yl) azetidine-1-carboxannide

rac-N- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] tπazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} cyclopropanecarboxamide

- rac-1 - {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [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- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-oxetan -3-ylurea rac-cis / trans-1 - {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-Benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea rac-cis / trans-N- {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxanide, as well as addition salts with mineral 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, where appropriate, contain active ingredients of other antimitotic drugs such as in particular those based on taxol, cisplatin, intercalating DNA agents 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 proliferation of blood vessels, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.

The present invention thus particularly relates to the use of a product of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of diseases in oncology and in particular for treatment of cancers.

Among these cancers, one is interested in the treatment of solid or liquid tumors, in the treatment of cancers resistant to cytotoxic agents. The products of the present invention cited can in particular be used for the treatment of primary tumors and / or metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate, lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder, breast, melanoma, lymphoid or myeloid hematopoietic tumors, sarcomas, brain, larynx, lymphatic system, bone and pancreas.

The subject of the present invention is also the use of the products of formula (I) as defined above for the preparation of medicaments intended for the chemotherapy of cancers.

Such drugs for cancer chemotherapy may be used alone or in combination.

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

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

As kinase inhibitors, there may be mentioned butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomucine.

The subject of the present invention is also, as new industrial products, the synthetic intermediates of formulas E ', M1, M2, M3 and N as defined above and recalled hereinafter:

in which the groups CONR1 R2, CO2R6 and COR7, which constitute W, can take the values of W as defined above for the products of formula (I), when W ≠ H, and the substituent Ra can take the indicated meanings above for products of formula (I)

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 the software ACDLABS version 10.0 and version 11

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 dimethylsulfoxide-d6 solvent (DMSO-d6). ) referenced at 2.5ppm 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 Premier XE Waters)

- UPLC-SQD (Waters) DAD considered wavelength λ = 210-400 nm

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

Example 1

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide a) The N- (6 - {[6- (cyclohexyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in the following manner: at 2 cm ³ of pyridine at 20 ⁰ C are added 75 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-amine and 20 μl of cyclopropane carboxylic acid chloride. After 3h, 20 μl of cyclopropane carboxylic acid chloride are added and the mixture is stirred for 18 h. 20 μl of cyclopropane carboxylic acid chloride are added and the reaction mixture is allowed to react for an additional hour. The reaction mixture is concentrated to dryness and the solid residue is chromatographed by solid deposition on Biotage Quad 12/25 (KP-SIL, 6OA, 32-63 μM), eluting with a 99.5 / 0.5 dichloromethane / methanol gradient. at 90/10. The solid obtained is washed with ethyl ether. 66 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. cyclopropanecarboxamide in the form of a white powder, the characteristics of which are as follows:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-c / 6) δ ppm 0.88 - 1.01 (m, 4H) 1.13 - 1.53 (m, 6H) 1.52 - 1.66 (m, 2H) 1.71 - 1.86 (m, 2H) 1.92 - 2.04 (m, 1H) 4.61 - 4.74 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.0, 2.0 Hz, 1H) 7.67 (d , J = 8.0 Hz, 1H) 8.05 (d, J = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 12.67 (br.s., 1H) MASS SPECTRUM: UPLC-SQD : MH + m / z = 467 +; MH = 465-. b) 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared from following way: A solution of 149 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial) in 20 cm ³ of ethanol was bubbled through a stream of argon for 5 minutes. ⁴ mg of potassium dihydrogenphosphate are then added in 0.2 cm ³ of water, 333 mg of DL-dithiothreitol and 182 mg of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyhdazine . The reaction mixture is heated at 80 ^° C. for 23 h and then concentrated to dryness under vacuum. The residue is purified on silica by solid deposition eluting with a gradient of 100% dichloromethane to dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) 80/20. There is thus obtained 130 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine in the form of a yellowish powder whose characteristics are as follows:

MASS SPECTRUM: LC / MS Electrospray on WATERS UPLC - SQD: MH + m / z = 399+; MH- = 397- (c) 3-Chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared as follows: 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 sodium hydride at 60% 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 medium is then poured into ice water and the mixture is extracted with ethyl acetate. After dry concentration of the organic phase under vacuum, a brown oil is obtained. The oily residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60, 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] thazolo [4,3-b] pyridazine 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

1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [ 2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexyloxy) [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 as follows: through a solution of 339 mg of 1- [2- (morpholinic) 4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea in 20 cm ³ of ethanol, a stream of argon is bubbled through for 5 minutes. 5 mg of potassium dihydrogenphosphate are then added in 0.2 cm ³ of water, 463 mg of DL-dithiothreitol and 253 mg of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyhdazine (1 C). The reaction mixture is then heated at 80 ^° C. for 47 hours, then the whitish solution is evaporated to dryness under vacuum. The residue is purified on silica by solid deposition eluting with a gradient of 100% dichloromethane to dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) 85/15. 246 mg of 1- (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. 3- [2- (morpholin-4-yl) ethyl] urea as a white powder whose characteristics are as follows:

NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.00 - 1.55 (m, 6H) 1.62 (m, 2H) 1.73 - 1.90 (m, 2H) 2.29 - 2.47 (m, 6H) ) 3.19 - 3.28 (m, 2H) 3.59 (m, 4H) 4.57 - 4.80 (m, 1H) 6.77 (brs, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.36 ( dd, J = 8.5, 1.5 Hz, 1H) 7.54 (d, J = 8.5 Hz, 1H) 7.99 (d, J = 1.5 Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) MS, 1 H) MASS SPECTRUM: UPLC-SQD: MH + m / z = 555 +; MH = 553- b) 1- [2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea can be prepared in the following manner: A mixture of 900 mg of 2 - {[(2-morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate and 40 cm ³ of ethanol at 20 ^° C. is bubbled through. argon for 5min. 11 mg of potassium dihydrogenphosphate are then added to 0.4 cm ³ of water and 1.1 g of dithiothreitol. The mixture is heated at 80 ^° C. for 3.5 h. The reaction medium is cooled to 20 ^° C. and then poured onto water. The suspension is stirred for 45 minutes while maintaining a slight argon bubbling. The precipitate formed is drained and washed with 3x10cm ³ of water and then dried under vacuum at 20 ° C. 633 mg of 1- (2-morpholin-4-ylethyl) -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea are thus obtained in the form of a white solid, the characteristics of which are as follows: MASS SPECTRUM: LC-MS-DAD-ELSD: MH + m / z = 339 +; (MH) - = 337- (c) 2 - {[(2-Morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate can be prepared as follows: to a solution of 1 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate ester in 30 cm ³ of tetrahydrofuran, 0.44 cm ³ of 2-morpholin-4-ylethanamine is added at 20 ^° C. After 24 h, the reaction mixture is evaporated to dryness and the residue obtained is chromatographed on a Merck 70 g cartridge (solid deposit, elution with a dichloromethane gradient and then 90/10 dichloromethane / methanol). 902 mg of 2 - {[(2-morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate are thus recovered in the form of a colorless foam, the characteristics of which are as follows: SPECTRUM MASS: UPLC-MS-DAD-ELSD: MH + m / z = 364 + d) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate was prepared as follows: to a solution 2.5 g of commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm ³ of tetrahydrofuran are added, at 20 ° C., 7.5 g of phenyl chlorocarbonate and then 4.05 g of hydrogencarbonate. of sodium and 9.4 cm ³ of water. The resulting mixture is then stirred at 20 ° C. for 20 h and then extracted with 2x150 cm ³ of ethyl acetate. The organic phases are combined and washed with ³ × 50 cm ³ of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm ³ of water and then filtered off and dried under vacuum at 20 ^° C. 3.45 g of (6-thiocyanato-1,3-benzothiazol-2-) are thus obtained. yl) phenyl carbamate, in the form of a pale yellow solid whose characteristics are as follows:

MASS SPECTRUM: LC-MS-DAD-ELSD: MH + m / z = 328 +; (M-H) - = 326-

Example 3

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide may be prepared in the following manner: at 2 cm ³ of pyridine at 20 ^° C. are added 0.276 cm ³ of acetic anhydride and 160 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b). After 5h, 0.3 cm ³ of acetic anhydride is added and the mixture is stirred for 17 h. The reaction mixture is concentrated to dryness under vacuum. The yellowish solid residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient of 100% dichloromethane to dichloromethane / methanol 97.5 / 2.5. 123 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) acetamide in the form of a white powder whose characteristics are as follows:

NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.05 - 1.53 (m, 6H) 1.52 - 1.68 (m, 2H) 1.71 - 1.85 (m, 2H) 2.19 (s, 3H) ) 4.56 - 4.73 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.40 (dd, J = 8.5, 2.0 Hz, 1H) 7.66 (d, J = 8.5 Hz, 1H) 8.06 ( d, J = 2.0 Hz, 1H) 8.28 (d, J = 10.0 Hz, 1H) 12.37 (brs, 1H) MASS SPECTRUM: UPLC-SQD: MH + m / z = 441 +; MH = 439-

Example 4

Phenyl (6 - {[6- (cyclohexyloxy) [1,2,4] tertzolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate may be prepared as follows: to 200mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 5cm ³ of pyridine is added at 20 ⁰ C, 0.13 cm ³ of phenyl chlorocarbonate. After 4 hours, the yellow suspension is concentrated under vacuum. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 6OA, 32-63 μM), eluting with a gradient of 100% dichloromethane to dichloromethane / methanol 92.5 / 7.5. 224 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate are thus obtained. phenyl in the form of a white powder whose characteristics are as follows:

SPECTRUM NMR 1 H NMR (400 MHz, DMSO-C / 6) 5 ppm 1.13 - 1.42 (m, 5H) 1.43 - 1.66 (m, 3H) 1.72 - 1.85 (m, 2H) 4.63 - 4.74 (m, 1H) 7.03 (d, J = 10.0 Hz, 1H) 7.25 - 7.35 (m, 3H) 7.40 - 7.50 (m, 3H) 7.69 (d, J = 9.0 Hz, 1H) 8.07 (d, J) = 2.0 Hz, 1H) 8.28 (d, J = 10.0 Hz, 1H) 12.66 (br.s., 1H) MASS SPECTRUM: UPLC-SQD: MH + m / z = 519 +; MH = 517-

Example 5

1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [ 2- (pyrrolidin-1-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} 1,3-Benzothiazol-2-yl) -3- [2- (pyrrolidin-1-yl) ethyl] urea may be prepared as follows: to a solution of 200 mg of (6- {6- (cyclohexyloxy)} [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl carbamate (4) in 5 cm ³ of tetrahydrofuran, 0, 6 cm ³ of 2- (pyrrolidin-1-yl) ethanamine and 0.14 cm ³ of triethylamine at 20 ^° C. After 2 h at 20 ° C the reaction medium is heated at 60 ^° C. for 3 h. The yellow solution is evaporated to dryness under reduced pressure. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM), eluting with a 99/1 to 50/50 dichloromethane / methanol gradient. 171 mg of 1- (6- {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 are thus obtained. benzothiazol-2-yl) -3- [2- (pyrrolidin-1-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-c / 6) δ ppm 1.08 - 1.87 (m, 14 H) 2.52 - 2.63 (masked m, 6H) 3.32 - 3.38 (masked m, 2H) 4.57 - 4.80 ( m, 1H) 6.82 (brs, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.36 (dd, J = 8.5, 2.0 Hz, 1H) 7.55 (d, J = 8.5 Hz, m.p. 1H) 8.00 (d, J = 2.0 Hz, 1H) 8.27 (d, J = 10.0 Hz, 1H) 10.78 (s, 1

H)

MASS SPECTRUM: UPLC-SQD: MH + m / z = 539 +; MH- = 537-

Example 6

6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N- [2- (pyrrolidin-1-yl) ethyl] -1, 3-benzothiazol-2-amine a) 6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N- [2- (pyrrolidine) 1-yl) ethyl] -1,3-benzothiazol-2-amine can be prepared as follows: to a solution of 534 mg of 2-bromo-1,3-benzothiazol-6-yl thiocyanate in 7cm ³ of tetrahydrofuran are added 686 mg of 2- (pyrrolidin-1-yl) ethanamine. The reaction medium is stirred for 18 h at 20 ^° C. and then the suspension is concentrated to dryness under reduced pressure. The oily brown residue obtained is taken up in 20 cm ³ of ethanol. The mixture is degassed by bubbling argon for 5 min at 20 ^° C., then ⁵ mg of potassium dihydrogenphosphate are added in 0.2 cm ³ of water followed by 617 mg of DL-Dithiothreitol and 253 mg of 3-chloro-6- (cyclohexyloxy). [1,2,4] triazolo [4,3-b] pyhdazine (1c). After 23 hours under reflux, the red suspension is concentrated to dryness under reduced pressure. The residue is purified by dry deposition on Biotage Quad 25M (KP-SIL, 60, 32-63 μM) eluting with a gradient of 95: 5 to 85:15 of dichloromethane / (dichloromethane: 38 / methanol: 17 / aqueous ammonia: 2). The yellow solid obtained is washed with ether and with pentane. 218 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N- [2- (pyrrolidin-1-yl) are thus obtained. ethyl] -1,3-benzothiazol-2-amine in the form of a yellow powder, the characteristics of which are as follows: NMR 1 H NMR SPECTRUM (400 MHz, DMSO-C / 6) δ ppm 1.17 - 1.59 (m, 7 H)

1.60 - 1.73 (m, 7 H) 1.79 - 1.94 (m, 2 H) 2.45 (masked m, 2 H) 2.55 - 2.71 (m, 2H) 3.47 (q, J = 6.0 Hz, 2H) 4.68 - 4.81 (m, 1H) 7.01 (d, J = 10.0 Hz, 1H) 7.24 - 7.35 (m, 2H) 7.82 (d, J = 1.5 Hz, 1H) 8.15 (t, 1H) 8.25 (d, J = 10.0 Hz, 1 MASS SPECTRUM: UPLC-SQD: MH + m / z = 496 +; MH- = 494- b) 2-Bromo-1,3-benzothiazol-6-yl thiocyanate can be prepared from following procedure: a solution of 6.5 g of cuprous bromide in 666 cm ³ of acetonitrile is purged with argon for 5 min. The resulting solution is cooled to 0-5 ^° C., then 4.3 cm ³ of tert-butyl nitrite is added. 5 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial) are then introduced portionwise at 0 ^° C. The reaction mixture is stirred for 3 h at 20 ° C. and then concentrated to dryness under reduced pressure. The residue is taken up in ethyl acetate and the resulting solution is washed with a saturated solution of sodium bicarbonate. The organic phase is dried over magnesium sulphate and then concentrated to dryness under vacuum. There is thus obtained 5.05 g of 2-bromo-1,3-benzothiazol-6-yl thiocyanate in the form of a gold-yellow powder whose characteristics are as follows: MASS SPECTRUM: UPLC-SQD: MH + m / z = 271 +

Example 7

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

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- methoxyacetamide can be prepared in a manner similar to Example 1a but from 200 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 5cm ³ of pyridine with 0.165 cm ³ of methoxyacetyl chloride after 23h of reaction at 20 ^° C. 196 mg of N- (6 - {[6 - (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -2-methoxyacetamide in the form of a white powder having the following characteristics:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-c / 6) δ ppm 1.09 - 1.40 (m, 5 H) 1.41 - 1.65 (m, 3H) 1.72 - 1.86 (m, 2H) 3.36 (s, 3H) ) 4.19 (s, 2H) 4.61 - 4.72 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.5, 2.0Hz, 1H) 7.68 (d, J = 8.5) Hz, 1H) 8.07 (d, J = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 12.32 (bursts, 1H) MASS SPECTRUM: UPLC-SQD: MH + m / z = 469 +; MH = 471 -

Example 8

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

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² N ² -dimethylglycinamide can be prepared in a manner similar to Example 1a, but from 100 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin). 3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 10cm ³ of dichloromethane with 300mg of N ₁ N-dimethylglycyl chloride, 0.33cm ³ of triethylamine and 11mg of 4-N, N- dimethylaminopyridine, after 27 hours of reaction at 20 ^° C. is thus obtained 75 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-yl) -N ² , N ² -dimethylglycinamide in the form of a yellowish powder, the characteristics of which are as follows: NMR SPECTRUM 1 H NMR (400 MHZ, DMSO-C / 6) δ ppm 1.10 - 1.64 (m, 8H) 1.69 - 1.87 (m, 2H) 2.29 (s, 6H) 3.37 - 3.52 (m, 2H) 4.52 - 4.75 (m, 1H) 7.02 (d, J = 10.0 Hz, 1H) 7.41 (dd, J = 8.5, 2.0Hz, 1H) 7.67 (d, J = 8.5 Hz, 1H) 8.07 (d, J = 2.0Hz, 1H) 8.28 (d, J = 1 0.0 Hz, 1H) 11.92 (br. s., 1 H) MASS SPECTRUM: Waters-ZQ: MH + m / z = 484 +; MH = 482-

Example 9

N - (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methylbutanamide N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- methylbutanannide can be prepared in a manner similar to Example 1a but from 102 mg of 6 - {[6-

(cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole

2-amine (1b) in 5 cm ³ of pyridine with 0.437 cm ³ of 3-methylbutanoyl chloride after 46h of reaction at 20 ^° C., thus obtaining 98 mg of N-

(6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methylbutanamide in the form of a white powder whose characteristics are as follows:

NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) 5 ppm 0.93 (d, J = 6.8 Hz, 6

H) 1.08 - 1.63 (m, 8H) 1.71 - 1.82 (m, 2H) 2.03 - 2.17 (m, 1H) 2.36 (d, J = 7.1)

Hz, 2H) 4.56 - 4.69 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.4, 1.8 Hz,

1H) 7.66 (d, J = 8.6 Hz, 1H) 8.07 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 9.8 Hz, 1H)

12.34 (sr, 1h)

MASS SPECTRUM: UPLC-SQD: MH + m / z = 483 +; MH- = 481 -

Example 10

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- methoxypropanamide can be prepared in a manner similar to Example 1a but from 146 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 5cm ³ of pyridine with 0.191 cm ³ of 3-methoxypropanoyl chloride after 23h of reaction at 20 ^° C. Thus 132 mg of N- (6- { [6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methoxypropanamide as a powder the characteristics of which are as follows:

NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.11 - 1.65 (m, 8 H) 1.74 - 1.83 (m, 2H) 2.72 (t, J = 6.1 Hz, 2H) 3.23 (s) , 3H) 3.64 (t, J = 6.1 Hz, 2H) 4.62 - 4.72 (m, 1H) 7.02 (d, J = 9.8 Hz, 1H) 7.41 (dd, J = 8.3, 2.0 Hz, 1H) ) 7.66 (d, J = 8.6 Hz, 1H) 8.06 (d, J = 2.0 Hz, 1H) 8.28 (d, J = 9.8 Hz, 1H) 12.37

(brs, 1h)

MASS SPECTRUM: Waters-ZQ: MH + m / z = 485 +; MH = 483-

Example 11

6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine a) The 6 - {[6 (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared in a manner similar to Example 1b but from 889 mg of 3-chloro-6-

(cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyhdazine in 30cm ³ degassed ethanol, 17mg potassium dihydrogenphosphate in 0.3cm ³ water, 1.72g DL-dithiothreitol and 772 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 h at 80 ^° C. This gives 1. 04 g of 6 - {[6- (cyclopentyloxy) [1,2,4] thazolo [ 4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine as a white powder having the following characteristics:

NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.49 - 1.76 (m, 6H) 1.83 - 1.97 (m, 2H) 5.12 - 5.22 (m, 1H) 6.99 (d, J = 9.8 Hz, 1H) 7.28 (d, J = 8.6Hz, 1H) 7.34 (dd, J = 8.3, 2.0Hz, 1H) 7.61 (s, 2H) 7.90 (d, J = 2.0Hz, 1H) 8.23 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: UPLC-SQD: MH + m / z = 385 + b) 3-chloro-6- (cyclopentyloxy) [1,2,4] thazolo [4, 3-b] pyridazine can be prepared in a manner similar to Example 1c but from 914 mg of cyclopentanol in 20 cm ³ of tetrahydrofuran, 254 mg of sodium hydride at 60% in oil and 1 g of 3, 6-dichloro [1,2,4] triazolo [4,3-b] pyhdazine (commercial), after 6.5h of reaction. 896 mg of 3-chloro-6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyhdazine are thus obtained in the form of a colorless oil which crystallizes and whose characteristics are as follows: MASS SPECTRUM: UPLC-SQD Waters: MH + m / z = 239 + Example 12

N- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 6 - {[6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1, 3-benzothiazol-2-amine (11a) in 5 cm ³ of pyridine with 0.140 cm ³ of cyclopropane carboxylic acid chloride after 3 hours of reaction at 20 ^° C. 277 mg of N- (6 - {[ 6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide in the form of a white powder having the characteristics are the following: NMR SPECTRUM 1H NMR (400MHz, DMSO-c / 6) ppm 0.84 - 1.00 (m, 4H) 1.44 - 1.71 (m, 6H) 1.73 - 1.88 (m, 2H) 1.92 - 2.04 (m, 1H) 5.04 - 5.17 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.4, 1.8 Hz, 1H) 7.67 (d, J = 8.6 Hz, m.p. 1H) 8.13 (d, J = 2.0 Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 12.67 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 453 +; MH- = 451 -

Example 13

N- (6 - {[6- (cyclopentyloxy) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 250 mg of 6 - {[6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1, 3-benzothiazol-2-amine 11a in 5 cm ³ of pyridine with 2.5 cm ³ of acetic anhydride after 48h of reaction at 20 ⁰ C. are thus obtained 255mg of N- (6 - {[6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide in the form of a white powder, the characteristics of which are as follows: NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.44 - 1.71 (m, 6H) 1.71 - 1.88 (m, 2H) 2.19 (s, 3H) 5.04 - 5.15 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.46 (dd, J = 8.6, 2.0 Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.14 (d, J = 2.0 Hz, 1H) ) 8.26 (d, J = 9.8 Hz, 1H) 12.37 (s, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 427 +; MH = 425-

Example 14

1- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [ 2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} 1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea may be prepared in a manner similar to Example 5a but from 778 mg of a mixture of Phenyl (6- {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate and Diphenyl 6 - {[6- (cyclopentyloxy) [1,2,4] tertzolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) imidodicarbonate in 10cm ³ of tetrahydrofuran, 0.32 cm ³ of 2- (morpholin-1-yl) ethanamine and 1.14 cm ³ of thethylamine at 20 ^° C. 127 mg of 1 - (6 - {[6- (cyclopentyloxy)) are thus obtained. 2,4-triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea, form of a white powder whose characteristics are as follows:

NMR spectrum 1 H NMR (500 MHz, DMSO-c / 6) δ ppm 1.48 - 1.71 (m, 6H)

1.78 - 1.92 (m, 2H) 2.32 - 2.46 (m, 6H) 3.27 (q, J = 5.9 Hz, 2H) 3.54 - 3.64

(m, 4H) 5.09 - 5.17 (m, 1H) 6.80 (ss, 1H) 7.01 (d, J = 9.6 Hz, 1H) 7.41

(dd, J = 8.5, 1.6 Hz, 1H) 7.55 (d, J = 8.5Hz, 1H) 8.08 (d, J = 1.6Hz, 1H) 8.26

(d, J = 9.6 Hz, 1H)

10.93 (br s, 1 h)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 541 +; MH = 539- b) The mixture of (6 - {[6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) phenyl and (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazolecarbamate carbamate 2-yl) Diphenyl imidodicarbonate can be prepared in a manner similar to Example 4a but from 326 mg of 6 - {[6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (11a) and 0.21 cm ³ of phenyl chlorocarbonate in 5 cm ³ of pyridine. 892 mg of a beige powder of a mixture of (6 - {[6- (cyclopentyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1 are thus obtained. Phenyl and (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate diphenyl imidodicarbonate -benzothiazol-2-yl), initiated as such in the following step: MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 505 +; MH = 503-

Example 15

1- (6 - {[6- (Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [ 2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} 1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea may be prepared in a manner similar to Example 1b but from 305 mg of 1 - [2 - (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 5 cm ³ of degassed ethanol, 4 mg of potassium dihydrogenphosphate in 0, 1 cm ³ of water, 347 mg of DL-dithiothreitol and 202 mg of 3-chloro-6- (cycloheptyloxy) [1,2,4] thazolo [4,3-b] pyhdazine. 253 mg of 1- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3- [2- (morpholin-4-yl) ethyl] urea as a white powder having the following characteristics: NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.24 - 1.40 (m, 2H)

1.42 - 1.58 (m, 6H) 1.58 - 1.70 (m, 2H) 1.78 - 1.93 (m, 2H) 2.36 - 2.45 (m, 6H) 3.22 - 3.28 (m, 2H) 3.59 (t, J) = 4.4 Hz, 4H) 4.81 - 4.91 (m, 1H) 6.77 (brs, 1H) 7.01 (d, J = 10.0 Hz, 1H) 7.36 (dd, J = 8.6, 2.0 Hz, 1H) H) 7.55 (d, J = 8.6 Hz, 1H) 8.00 (d, J = 1.7 Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 10.87 (br.s., 1H) SPECTRUM OF MASS: Waters UPLC-SQD: MH + m / z = 569 +; MH = 567- b) 3-Chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in a manner similar to Example 1c but from 1.21 g of cycloheptanol in 15cm ³ of tetrahydrofuran, 254mg of 60% sodium hydride in oil and 1g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyhdazine (commercial). 453 mg of 3-chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyhdazine are thus obtained in the form of a colorless oil which crystallizes and whose characteristics are as follows: MASS SPECTRUM: Waters ZQ: MH + m / z = 267 +

Example 16

6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared in a manner similar to Example 1b but starting from 249 mg of 3-chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine (15b) in 5 cm ³ of degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 432 mg of DL-dithiothreitol and 193 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 hours at 80 ^° C. 260 mg is thus obtained from 6 - {[6-

(Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine as a white powder having the following characteristics:

NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.29 - 1.74 (m, 10H) 1.86 - 1.97 (m, 2H) 4.87 - 4.99 (m, 1H) 7.00 (d, J = 9.8 Hz, 1H) 7.23 - 7.31 (m, 2H) 7.60 (s, 2H) 7.80 - 7.85 (m, 1H) 8.24 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: Waters ZQ: MH + m / z = 413 +; MH = 411 -

Example 17

N- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 85 mg of 6 - {[6- (cycloheptyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1,3-benzothiazol-2-amine (16a) in 5 cm ³ of pyridine with 0.160 cm ³ of acetic anhydride after 24 hours of reaction at 20 ^° C. 90 mg of N- (6 - {[6- (cycloheptyloxy) are thus obtained ) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide as a yellow powder, the characteristics of which are as follows:

NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.20 - 1.35 (m, 2H) 1.40 - 1.55 (m, 6H) 1.54 - 1.66 (m, 2H) 1.76 - 1.89 (m, 2H) 2.19 (s, 3H)

4.78 - 4.88 (m, 1H) 7.01 (d, J = 9.8 Hz, 1H) 7.40 (dd, J = 8.6, 2.0 Hz, 1H) 7.67 (d, J = 8.6 Hz, 1H) 8.06 (d , J = 2.0 Hz, 1H) 8.27 (d, J = 9.8 Hz, 1H) 12.38 (brs, 1H)

MASS SPECTRUM: Waters ZQ: MH + m / z = 455 +; MH = 453-

Example 18

N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide a) The N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 150 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] thazolo [4] , 3-b] pyridazin-6-amine in 1 cm ³ of pyridine with 0.5 cm ³ of acetic anhydride after 18h of reaction at 20 ⁰ C. are thus obtained 65 mg of N- (6 - {[6- (cyclohexylamino [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide in the form of a pale beige powder, the characteristics of which are as follows: :

NMR 1 H NMR SPECTRUM (300 MHz, DMSO-c / 6) δ ppm 0.95 - 1.32 (m, 5H) 1.45 - 1.67 (m, 3H) 1.68 - 1.84 (m, 2H) 2.19 (s, 3H) ) 3.35 - 3.45 (m, 1H)

6.79 (d, J = 10.0 Hz, 1H) 7.25 (d, J = 7.0 Hz, 1H) 7.38 (dd, J = 8.5, 2.0 Hz, 1H) 7.64 (d, J = 8.5 Hz, 1H) 7.92 (d, J = 10.0 Hz, 1H) 8.05 (d, J = 2.0 Hz, 1H) 12.35

(brs, 1h)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 440 +; MH = 438- b) 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6 -amine can be prepared in a manner similar to Example 1b but from 607mg of 3-chloro-N-cyclohexyl [1,2,4] thazolo [4,3-b] pyridazin-6-amine in 10cm ³ degassed ethanol, 12 mg of potassium dihydrogenphosphate in 1 cm ³ of water, 1, 12 g of DL-dithiothreitol and 500 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 hours at 80.degree. ⁰ C. This gives 768mg of 3 - [(2-amino-1, 3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1, 2,4] thazolo [4,3-b] pyridazin-6 amine in the form of a white powder whose characteristics are as follows:

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 398 +; MH = 396- (c) 3-Chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine can be prepared as follows: to a solution of 5 g of 3 Commercial 6-dichloro [1,2,4] triazolo [4,3-b] pyhdazine in 50cm ³ of N, N-dimethylformamide are added 2.3cm ³ of cyclohexylamine and 3.7cm ³ of theethylamine. The reaction is stirred at 20 ^° C. for 18 h. Is then added 1, 1 cm ³ of cyclohexylamine and 7.5 cm ³ of triethylamine and the reaction was stirred at 50 ° C for 4h. The reaction mixture is cooled to 20 ^° C. and then 60 cm ³ of water are added. The white precipitate is drained and then washed successively with water and ether. 3 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. After one night, the precipitate formed in the first filtrate, obtained above, is filtered and washed successively with N ₁ N- dimethylformamide, with demineralized water and with methanol. A second batch of 1.42 g of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine is thus obtained in the form of a yellow powder, the characteristics of which are MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 252 +; MH = 250- Example 19

1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [ 2- (pyrrolidin-1-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} 1,3-Benzothiazol-2-yl) -3- [2- (pyrrolidin-1-yl) ethyl] urea can be prepared in a manner similar to Example 1b but from 300 mg of 2-thiocyanate. {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl in 6 cm ³ of degassed ethanol, ⁴ mg of potassium dihydrogenphosphate in 0.6 cm ³ of water, 400 mg of DL-dithiothreitol and 240 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (18c) after 18 hours at 80 ^° C. 193 mg of 1 - (6 is thus obtained. {{6- (cyclohexylamino) [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (pyrrolidine)} -1-yl) ethyl] urea in the form of a pale yellow powder, the characteristics of which are as follows:

NMR SPECTRUM 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.00 - 1.34 (m, 6 H) 1.46 - 1.74 (m, 6 H) 1.75 - 1.86 (m, 2 H) 2.40 - 2.57 masked (m , 6H) 3.21 - 3.28 (m, 2H) 3.39 - 3.49 (m, 1H) 6.79 (d, J = 10.0 Hz, 1H) 6.81 - 6.88 (m, 1H) 7.25 (d, J = 7.0) Hz, 1H) 7.35 (dd, J = 8.5, 2.0Hz, 1H) 7.52 (d, J = 8.5 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 2.0) Hz, 1H) 10.81 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 538 +; MH = 536- b) 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate can be prepared as follows: to a solution of 3 g of thiocyanato-1, 3-benzothiazol-2-yl) carbamate in 90 cm ³ of tetrahydrofuran is added 1, ³ 4cm 2- pyrrolidinyléthanamine to 20 ⁰ C. After 24 h, the reaction mixture is concentrated to dryness under reduced pressure. To the oily yellow residue obtained, ethyl ether is added. The precipitate formed is drained. 3.33 g of 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a yellowish powder, the characteristics of which are as follows: MASS SPECTRUM: Waters ZQ: MH + m / z = 348 +; MH = 346- (c) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate was prepared as follows: to a solution of 2.5 g of 2-amino-1 thiocyanate, Commercial 3-benzothiazol-6-yl in 94 cm ³ of tetrahydrofuran is added at 20 ⁰ C, 7.5 g of phenyl chlorocarbonate then 4.05 g of sodium hydrogen carbonate and 9.4 cm ³ of water. The resulting mixture is then stirred at 20 ^° C. for 20 h and then extracted with 2x150 cm ³ of ethyl acetate. The organic phases are combined and then washed with 3X50 cm ³ of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase obtained is dried over magnesium sulphate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm ³ of water and then filtered off and dried under vacuum at 20 ° C. 3.45 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate are thus obtained in the form of a pale yellow solid, the characteristics of which are as follows: MASS SPECTRUM: LC-MS-DAD -LSD: MH + m / z = 328 +; MH- = 326-

Example 20: cyclopropanecarboxylate of trans-4 - {[3 - (2-

[(Cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl] sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] amino} cyclohexyl a) The trans-cyclopropanecarboxylate of 4 - {[3 - ({2-

[(Cyclopropylcarbonyl) amino] -N-benzothiazol-e-yl] sulfanyl] triazolo [b] pyrimidazin-6-yl] amino} cyclohexyl may be prepared in a manner similar to Example 1a but from 300 mg of trans-4 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] tetrazolo [4,3-b] pyridazin-6-yl} amino ) cyclohexanol in 2.1 cm ³ of pyridine with 0,133cm ³ of the chloride of cyclopropanecarboxylic acid after 18 hours of reaction at 20 ⁰ C. This gives 303mg cyclopropanecarboxylate of trans-4 - {[3 - ({2- [(cyclopropylcarbonyl) amino] -1,4-benzothiazol-4-yl] sulfanyl] triazoloyl. b] pyridazin-6-yl] amino} cyclohexyl in the form of a white powder whose characteristics are as follows:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-c / 6) δ ppm 0.76 - 1.01 (m, 8 H)

1.06 - 1.32 (m, 4H) 1.51 - 1.65 (m, 1H) 1.67 - 1.81 (m, 4H) 1.93 - 2.05 (m, 1)

H) 3.30 - 3.38 (m, 1H) 4.44 - 4.61 (m, 1H) 6.78 (d, J = 9.8 Hz, 1H) 7.20 - 7.34

(m, 2H) 7.62 (d, J = 8.6Hz, 1H) 7.93 (d, J = 9.8Hz, 1H) 8.05 (d, J = 2.0Hz, 1H);

H) 12.64 (br s, 1 h)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 550 +; MH- = 548- b) Trans-4 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin 6-yl) amino) cyclohexanol can be prepared in a manner similar to Example 1b but from 1 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 20 cm ³ of degassed ethanol, 23 mg of potassium dihydrogenphosphate in 2 cm ³ of water, 2.32 g of DL-dithiothreitol and 1.29 g of trans-4 - [(3-chloro [1,2,4] triazolo [4,3-b]). ] pyridazin-6-yl) amino] cyclohexanol after 18h at 80 ^° C. This gives 1.8 g of trans-4 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl} amino) cyclohexanol in the form of a creamy white powder having the following characteristics:

MASS SPECTRUM: Waters ZQ: MH + m / z = 414 +; MH = 412- (c) Trans-4 - [(3-chloro [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino] cyclohexanol can be prepared in a similar manner to Example 18c but from 5 g of commercial 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine in 50 cm ³ of N, N-dimethylformamide, 6 g of trans-4 hydrochloride aminocyclohexanol and 17cm ³ of triethylamine after 48h at 20 ⁰ C and 4h at 50 ° C. 3.5 g of trans-4 - [(3-chloro [1,2,4] triazolo [4,3-b] pyrimidazin-6-yl) amino] cyclohexanol are thus obtained in the form of a white powder whose characteristics are the following :

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 268 +; MH- = 266-

Example 21 N - (6 - {[6- (Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide

N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] thazolo [ 4,3-b] pyridazin-6-amine (18b) in 2.1 cm ³ of pyridine with ³ 0,14cm chloride of cyclopropanecarboxylic acid, after 18h of reaction at 20 ⁰ C. This gives 268mg of N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide in the form of a creamy white powder having the following characteristics: NMR spectrum 1H NMR (400 MHz, DMSO-c / 6) δ ppm 0.86 - 1.00 (m, 4H) 1.01 - 1.28 (m, 5H) 1.48 - 1.66 (m, 3H) 1.70 - 1.83 (m, 2H) 1.92 - 2.04 (m, 1H) 3.36 - 3.45 (m, 1H) 6.79 (d, J = 9.8 Hz, 1H) 7.25 (d, J) = IA Hz, 1H) 7.39 (d, J = 8.6 Hz, 1H) 7.65 (d, J = 8.3Hz, 1H) 7.91 (d, J = 9.8Hz, 1H) 8.03 (s, 1H) 12.65 (br s, 1 H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 466 +; MH- = 464-

Example 22

N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2 -yl] acetamide a) N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) 1,3-Benzothiazol-2-yl] acetamide can be prepared as follows: to a solution of 114 mg of trans-4 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl) ] [1,2,4] thazolo [4,3-b] pyridazin-6-yl} amino) cyclohexanol (20b) in 2 cm ³ of dichloromethane is added 0.08 cm ³ of acetyl chloride and 0.16 cm ³ of the thylamine at 20 ⁰ C. After 18h the reaction medium is concentrated to dryness under reduced pressure. The residue is taken up in water. The yellow-white precipitate formed is drained and washed with water and then purified by dry deposition on Biotage Quad 25M (KP-SIL, 60A, 32-63 μM) eluting with a gradient of 95: 5 to 70:30 dichloromethane / (dichloromethane: 38 / methanol: 17 / ammonia: 2). 46 mg of N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] thalzolo [4,3-b] pyridazin-3-yl} sulfanyl) -1 are thus obtained. 3-benzothiazol-2-yl] acetamide in the form of a beige powder whose characteristics are as follows:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-c / 6) δ ppm 1.01 - 1.27 (m, 4 H)

1.68 - 1.86 (m, 4H) 2.19 (s, 3H) 3.35 - 3.44 (m, 2H) 4.51 (d, J = 4.6 Hz, 1H)

6.77 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 6.8 Hz, 1H) 7.42 (dd, J = 8.4, 1.8 Hz, 1H)

7.65 (d, J = 8.3 Hz, 1H) 7.92 (d, J = 9.8 Hz, 1H) 8.01 (d, J = 1.7 Hz, 1H) 12.34

(brs, 1h)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 456 +; MH- = 454-

Example 23

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

N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole 2-yl] cyclopropanecarboxamide can be prepared in a manner similar to Example 1a but from 300 mg of trans-4 - ({3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino) cyclohexanol (20b) in 3cm ³ of pyridine with 0.235cm ³ of cyclopropane carboxylic acid chloride, after 16h of reaction at 20 ⁰ C. in this way 51 mg of N- [6 - ({6 - [(trans-4- hydroxycyclohexyl) amino] [1, 2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide in the form of a beige powder, the characteristics of which are as follows:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-c / 6) δ ppm 0.89 - 0.99 (m, 4H) 1.02 - 1.27 (m, 4H) 1.68 - 1.87 (m, 4H) 1.92 - 2.03 (m, 1H) 3.31 - 3.45 (m, 2H) 4.51 (d, J = 4.4 Hz, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 7.1 Hz, 1H) 7.43 ( dd, J = 8.6, 2.0 Hz, 1H) 7.65 (d, J = 8.6 Hz, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.00 (d, J = U Hz, 1H) brs, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 482 +; MH = 480-

Example 24:

3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine a) 3- [ (2-Amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyrimidazin-6-annin can be prepared in a manner similar to Example 1b but starting from 1.4 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 41 cm ³ of degassed ethanol, 32 mg of potassium dihydrogenphosphate in 4 cm ³ of water, 3.13 g of DL-dithiothreitol and 1.4 g of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine after 18 h at 80 ° C. There is thus obtained 1.22 g of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6- amine in the form of a creamy white powder whose characteristics are as follows:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-c / 6) δ ppm 0.41 - 0.48 (m, 2 H)

0.71 - 0.79 (m, 2H) 2.56 - 2.65 (m, 1H) 6.76 (d, J = 9.8 Hz, 1H) 7.27 (d, J = 8.3 Hz, 1H) 7.42 (dd, J = 8.3, 2.0 Hz, 1H) 7.67 (sr, 3H) 7.92 (d, J = 9.8 Hz, 1H) 7.95 (d, J = U Hz, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 356 +; MH- = 354- b) S-chloro-N-cyclopropyl, 2,4] tπazolo [4,3-b] pyπdazin-6-amine DPN1.150 can be prepared in the same manner as in Example 18c but in from 2 g of commercial 3,6-dichloro [1,2,4] triazolo [4,3-b] pyhdazine in 20 cm ³ of N, N-dimethylformamide, 1.1 cm ³ of cyclopropylamine and ³ cm ³ of triethylamine after 18h at 20 ^° C. and 3h at 50 ° C. 1.53 g of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine are thus obtained in the form of a white powder, the characteristics of which are as follows:

MASS SPECTRUM: Waters ZQ: MH + m / z = 210 +; MH = 208-

Example 25 N- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide a) The N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide may be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4] , 3-b] pyridazin-6-amine (24a) in 2.1 cm ³ of pyridine with 1. 04 cm ³ of acetic anhydride after 18 hours of reaction at 20 ^° C. There is thus obtained 100 mg of N- (6- { [6-

(cyclopropylamino) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide in the form of a white powder, the characteristics of which are following:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-c / 6) δ ppm 0.34 - 0.45 (m, 2 H)

0.61 - 0.74 (m, 2H) 2.19 (s, 3H) 2.53 - 2.58 (m, 1H) 6.77 (d, J = 9.5 Hz, 1H)

7.53 (d, J = 8.3 Hz, 1H) 7.62 - 7.73 (m, 2H) 7.94 (d, J = 9.8 Hz, 1H) 8.19 (s, 1)

H) 12.38 (br s, 1 h)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 398 +; MH = 396-

Example 26:

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

1,3-benzothiazol-2-yl) cyclopropanecarboxamide a) N- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} - 1,3-Benzothiazol-2-yl) cyclopropanecarboxamide may be prepared in a manner similar to Example 1a but from 300 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] N-cyclopropyl [1,2,4] triazolo [4,3-b] pyπdazin-6-amine (24a) in ³ cm ³ of pyridine with 0.16 cm ³ of cyclopropane carboxylic acid chloride, after 18 hours of reaction at 20 ^° C. There is thus obtained 208 mg of N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxamide in the form of a white powder whose characteristics are as follows: NMR spectrum 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 0.34 - 0.44 (m, 2H) 0.62 - 0.73 (m, 2H) 0.89 - 1.01 (m, 4H) 1.93 - 2.03 (m, 1H) 2.52 - 2.61 (m, 1H) 6.77 (d, J = 9.8 Hz, 1H) 7.53 (dd, J = 8.6, 1.7 Hz, 1H) 7.61 - 7.71 (m, 2H) 7.94 (d , J = 9.8 Hz, 1H) 8.19 (d, J = 1.5Hz, 1H) 12.66 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 424 +; MH- = 422-

Example 27:

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

1,3-Benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [ 4,3-b] pyπdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 1b but from 300 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), of 7, 5 cm ³ of degassed ethanol, 6 mg of potassium dihydrogen phosphate in 0.7 cm ³ of water, 552 mg of DL-dithiothreitol and 403 mg of 3-chloro-N-cyclohexyl [1,2,4] thazolo [4, 3-b] pyridazin-6-amine (18c). 370 mg of 1 - (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -3- [2- (morpholin-4-yl) ethyl] urea as a white powder whose characteristics are as follows: NMR SPECTRUM 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 1.08 - 1.30 (m, 5H) 1.47 - 1.70 (m, 3H) 1.71 - 1.89 (m, 2H) 2.32 - 2.46 (m, 6H) 3.22 - 3.28 (m masked, 2H) 3.36 - 3.52 (m, 1H) 3.59 (t, J = 4.3 Hz, 4H) 6.69 - 6.93 (m, 2H) 7.25 (d, J = 7.1Hz, 1H) 7.35 (dd, J = 8.3, 2.0Hz, 1H) 7.52 (d, J = 8.3 Hz, 1H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 1.7 Hz, 1H) 10.90 (brs, 1H) MASS SPECTRUM: Waters ZQ: MH + m / z = 554 +; MH = 552-

Example 28

1,3-benzothiazol-2-yl) -3-methoxypropanamide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methoxypropanamide may be prepared in a manner similar to Example 1a but from 220 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4] , 3-b] pyπdazin-6-amine (24a) in 7cm ³ of pyridine with 0.2 cm ³ of 3-methoxypropanoyl chloride after 18h of reaction at 20 ^° C. Thus 81 mg of N- (6- { [6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methoxypropanamide as a powder light beige with the following characteristics: NMR SPECTRUM 1 H NMR (400 MHz, DMSO-c / 6) δ ppm 0.33 - 0.43 (m, 2 H)

0.62 - 0.73 (m, 2H) 2.53 - 2.59 (m, 1H) 2.73 (t, J = 6.1 Hz, 2H) 3.24 (s, 3H) 3.64 (t, J = 6.0 Hz, 2H) 6.77 (d, J = 9.5 Hz, 1H) 7.53 (dd, J = 8.4, 1.6 Hz, 1H) 7.68 (d, J = 8.6Hz, 1H) 7.72 (d, J = 2.7Hz, 1H) 7.96 (d, J = 9.8 Hz, 1H) 8.22 (d, J = 1.5Hz, 1H) 12.46 (br.s., 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 442 +

Example 29

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

1,3-Benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) 1- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [ 4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea can be prepared in a manner similar to Example 1b but from 300 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 12cm ³ degassed ethanol, 5 mg of potassium dihydrogenphosphate in 1.2 cm ³ of water, 41 mg of DL-dithiothreitol and 187 mg of 3-chloro-N-cyclopropyl [1,2,4] thazolo [4,3 b) pyridazin-6-amine (24b), after 18h at 80 ^° C. is thus obtained 133 mg of 1 - (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea as a creamy white powder, the characteristics of which are following:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-C / 6CD3COOD) δ ppm 0.36 - 0.49 (m, 2H) 0.65 - 0.82 (m, 2H) 2.57 - 2.65 (m, 1H) 2.96 - 3.16 (m, 6H) 3.50 (t, J = 5.7 Hz, 4H) 3.79 (ss, 2H) 6.79 (d, J = 9.8 Hz, 1H) 6.90 - 7.05 (m, 1H) 7.48 - 7.63 (m, 2H) 7.66 (bursts, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.16 (s, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 512 +; MH = 510-

Example 30

1,3-benzothiazol-2-yl) -N ² , N ² -dimethylglycinamide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin) 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dimethylglycinamide can be prepared in a manner similar to Example 1a but from 220 mg of 3-

[(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (24a) in 8cm ³ of dichloromethane with 197 mg of N, N-dimethylglycyl chloride hydrochloride and 0.26 cm ³ of thethylamine, after 18 hours of reaction at 20 ^° C., thus giving 167 mg of N- (6 - {[6-

(Cyclopropylamino) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dimethylglycinamide in the form of a light beige powder whose characteristics are as follows:

NMR 1 H NMR SPECTRUM (500 MHz, DMSO-c / 6) δ ppm 0.39 (br.s., 2 H)

0.69 (d, J = 5.2 Hz, 2H) 2.29 (s, 6H) 2.52 - 2.59 (m, 1H) 3.10 - 3.25 (masked m, 2H) 6.77 (d, J = 9.6 Hz, 1H) 7.53 (d, J = 8.2 Hz, 1H) 7.61 - 7.74 (m, 2)

H) 7.95 (d, J = 9.6 Hz, 1H) 8.20 (s, 1H) 12.06 (brs, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 441 +; MH = 439-

Example 31:

3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine a) 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin 6-amine can be prepared in a manner similar to Example 1b but from 250 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate, 8 cm ³ of degassed ethanol, 6 mg of dihydrogenphosphate. of potassium in 0.8cm ³ of water, 660mg of DL- dithiothreitol and 306 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine. 202 mg of 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] are thus obtained. pyπdazin-6-annine in the form of a cream-white powder whose characteristics are as follows:

NMR spectrum 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 - 1.35 (m, 5H) 1.48 - 1.74 (m, 3H) 1.78 - 1.90 (m, 2H) 2.56 (t, J = 7.7 Hz , 2H) 2.96 (t, J = 7.7 Hz, 2H) 3.45 - 3.55 (m, 1H) 7.08 (d, J = 7.6 Hz, 1H) 7.16 - 7.37 (m, 2H) 7.66 (br. s., 2H) 7.81 (s, 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 400 +; MH = 398- b) 3-Chloro-N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine can be prepared in the following manner: 500 mg of 3-chloro-N-cyclohexyl [1,2,4] thazolo [4,3-b] pyridazin-6-amine (18c) in 16 cm ³ of glacial acetic acid at 20 ^° C. are added 1.3 g of zinc powder. After stirring for 2 hours, the suspension is filtered on filter paper and the filtrate is concentrated to dryness under reduced pressure. The solid residue obtained is purified by chromatography on silica by dry deposition on Biotage Quad 12/25 (KP-SIL, 6OA, 32-63 μM), eluting with a dichloromethane / methanol gradient of 95/5 to 90/10. 317 mg of 3-chloro-N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine are thus obtained in the form of a white powder whose characteristics are the following: MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 254 +; MH = 252-

Example 32

Ethyl (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate a) Ethyl (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate can be prepared in the following way:

In a 10 cm ³ microwavable vial equipped with stirring at 20 ^° C., 320 mg of 2 - [(morpholin-4-ylcarbonyl) amino] -1,3-thiocyanate are introduced. benzothiazol-6-yl (32b) in 7cm ³ of ethanol. A stream of argon was bubbled through the mixture for 5 minutes and then 408 mg of potassium dihydrogenphosphate was added in 0.25 cm ³ of water, 463 mg of dithiothreitol and 252 mg of 3-chloro-6- (cyclohexyloxy) [1 , 2,4] thazolo [4,3-b] pyhdazine (1c). The mixture is stirred in a microwave oven for 1 h at 120 ^° C. The reaction mixture is then concentrated to dryness under vacuum and the residue is then purified by two successive Merck silica cartridge chromatography solid deposition eluting with a 99: 1 to 97: 3 gradient of dichloromethane / methanol. 77 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate are thus obtained. of ethyl in the form of a white solid whose characteristics are as follows:

MASS SPECTRUM: LC / MS Electrospray on WATERS UPLC - SQD: Retention Time Tr (min) = 1, 06; [M + H] +: m / z 471; [MH] -: m / z 469 1 H NMR Spectrum (400MHz, δ in ppm, DMSO-d6): 1.15 to 1.40 (m, 8H); 1.42 to 1.64 (m, 3H); 1.79 (d, J = 13.2 Hz, 2H); 4.24 (q, J = 7.1 Hz, 2H); 4.67 (m, 1H); 7.02 (d, J = 9.8 Hz, 1H); 7.39 (dd, J = 1, 8 and 8.2 Hz, 1H); 7.62 (d, J = 8.6 Hz, 1H); 8.05 (s, 1H); 8.28 (d, J = 9.8 Hz, 1H); 12.06 (bs, 1H) b) 2 - [(Morpholin-4-ylcarbonyl) amino] -1,3-benzothiazol-6-yl thiocyanate can be prepared in a manner similar to Example 2c but from 2.29 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate (2d) in a mixture of 70 cm ³ of tetrahydrofuran and 0.60 cm ³ of morpholine at 50 ^° C. for 26 h . 2.12 g of 2 - [(morpholin-4-ylcarbonyl) amino] -1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a white solid, the characteristics of which are as follows: MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.73; [M + H] +: m / z 321; [MH] -: m / z 319

Example 33:

2-chloro-N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide a) 2-chloro-N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 -yl) acetamide can be prepared in the following manner: at 200 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1, 3-benzothiazol-2-amine (1b) in 2 cm ³ of dichloromethane and 0.5 cm ³ of pyridine at 0-5 ^° C. is added drop-by-drop 0.1 cm ³ of chloroacetyl chloride. The resulting solution is stirred for 30 min at 20 ^° C. and the medium is then evaporated to dryness under argon at 20 ° C. The residue is purified by chromatography on Merck silica cartridge by solid deposition eluting with a gradient of 100% dichloromethane to 92: 8 dichloromethane / (dichloromethane: 38 / methanol: 17 / ammonia: 2). After pasting in ether and drying under vacuum, 102 mg of 2-chloro-N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 are obtained. -yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide as a white solid whose characteristics are as follows:

MASS SPECTRUM: Waters UPLC-SQD:

Retention time Tr (min) = 1.03; [M + H] +: m / z 475; [M-H] -: m / z 473 1 H NMR Spectrum (400MHz, δ in ppm, DMSO-d6): 1.10 to 1.38 (m, 5H); 1.41 to 1.65 (m, 3H); 1.77 (m, J = 12.2 Hz, 2H); 4.44 (s, 2H); 4.66 (m, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.42 (dd, J = 2.0 and 8.6 Hz, 1H); 7.70 (d, J = 8.6 Hz, 1H); 8.08 (d, J = 2.0 Hz, 1H); 8.29 (d, J = 10.0 Hz, 1H); 12.75 (s wide, 1 H)

Example 34

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² - cyclopropylglycinamide a) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² -cyclopropylglycinamide can be prepared in the following manner: at 280mg of 2-chloro-N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 - yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide (33) in 4cm ³ of pyridine at 20 ⁰ C is added 0.35cm ³ of cyclopropylamine. After 5 hours of agitation the medium The residue is evaporated to dryness at 20 ^° C. The residue is purified by solid Merck silica cartridge chromatography eluting with a gradient of 100% dichloromethane to 97: 3 dichloromethane / methanol. N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl is thus obtained. ) -N ² -cyclopropylglycinamide in the form of a yellow solid whose characteristics are as follows: MASS SPECTRUM: Waters UPLC-SQD:

Retention time Tr (min) = 0.74; [M + H] +: m / z 496; [M-H] -: m / z 494 1 H NMR Spectrum (400MHz, δ in ppm, DMSO-d6): 0.19 to 0.40 (m, 4H); 1, 14 to 1, 26 (m, 3H); 1.33 (m, 2H); 1.41 to 1.66 (m, 3H); 1.78 (m, 2H); 2.17 (m, 1H); 3.51 (s, 2H); 4.60 to 4.72 (m, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.41 (dd, J = 1.5 and 8.3 Hz, 1H); 7.68 (d, J = 8.8 Hz, 1H); 8.08 (s, 1H); 8.28 (d, J = 9.8 Hz, 1H)

Example 35

6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine a) The 6 - {[6 - (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared in a manner similar to Example 1b but starting from 1.07 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate, 15 cm ³ of degassed ethanol, 20 mg of potassium dihydrogenphosphate in 0.1 cm ³ of water, 1 g. 99g of DL-dithiothreitol and 964mg of 3-chloro-6- (cyclobutyloxy) [1,2,4] thazolo [4,3-b] pyridazine. 1.1 g of 6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine are thus obtained. a whitish powder whose characteristics are as follows: MASS SPECTRUM: Waters ZQ:

Retention time Tr (min) = 3.39; [M + H] +: m / z 371; [MH] -: m / z 369 1 H NMR Spectrum (400MHz, δ in ppm, DMSO-d ₆ ): 1.66 (m, 1H); 1.80 (m, 1H); 2.01 to 2.13 (m, 2H); 2.31 to 2.40 (m, 2H); 4.96 (qd, J = 7.1 and 7.3 Hz, 1H); 7.04 (d, J = 9.8 Hz, 1H); 7.29 (d, J = 8.3 Hz, 1H); 7.34 (dd, J = 2.0 and 8.6 Hz, 1H); 7.62 (s, 2H); 7.88 (d, J = 1.7 Hz, 1H); 8.26 (d, J = 9.8 Hz, 1H) b) 3-Chloro-6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazine can be prepared in a similarly to example 1c but from 954 mg of cyclobutanol in 10 cm ³ of tetrahydrofuran, 317 mg of sodium hydride at 60% in oil and 1 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial). In this way, 1.03 g of 3-chloro-6- (cyclobutyloxy) [1,2,4] thazolo [4,3-b] pyridazine is 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 36

N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -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} -1, 3-Benzothiazol-2-yl) -2- (4-ethylpiperazin-1-yl) acetamide can be prepared in the following manner: a mixture of 273 mg of (4-ethylpiperazin-1-yl) acetic acid (commercial), 0.28cm ³ of diisopropyl ethylamine and 411 mg of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) in 3cm ³ of N, N-dimethylformamide at C ⁰ is stirred for 1 h at 20 ^° C. in the reaction medium are added 200 mg of 6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (35a). After 18h the solution is poured on ice water and the precipitate is filtered. The isolated yellow paste is taken up in a 90:10 ethyl acetate / methanol mixture. The solution obtained is dried over magnesium sulphate, filtered and then concentrated to dryness under vacuum. The oily residue is purified on SPOT II by chromatography on a silica cartridge (SVF D26 Si60, 15-40 μM, 25 g), eluting with a dichloromethane / methanol gradient of 96: 4 to 100% of methanol. 127 mg of N- (6 - {[6- (cyclobutyloxy) [1,2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl are thus obtained. ) -2- (4-ethylpiperazin-1-yl) acetamide in the form of a yellow powder whose characteristics are as follows: MASS SPECTRUM: Waters ZQ

Retention time Tr (min) = 3.10; [M + H] +: m / z 525; [MH] -: m / z 523 1 H NMR Spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 1.00 (t, J = 7.2 Hz, 3H); 1.59 (m, 1H); 1.73 (m, 1H); 1.94 to 2.09 (m, 2H); 2.20 to 2.31 (m, 2H); 2.32 to 2.58 (partially masked m, 10H); 3.34 (s, 2H); 4.90 (m, 1H); 7.06 (d, J = 9.8 Hz, 1H); 7.48 (dd, J = 1, 8 and 8.6 Hz, 1H); 7.71 (d, J = 8.6 Hz, 1H); 8.14 (d, J = 1.8 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 12.12 (m very spread, 1 hour)

Example 37

N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dialylglycinamide a) N- (6 - {[6- (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2 -yl) -N ² , N ² -dialylglycinamide can be prepared in the following manner: a mixture of 827 mg of sodium (diethylamino) acetate (commercial) in 5.5 cm ³ of a 2N solution of hydrogen chloride in the The ether is stirred for 1 h at 20 ^° C. The resulting suspension is evaporated to dryness under vacuum. To the white residue obtained are added, at 20 ^° C., 8 cm ³ of pyridine, 200 mg of 6- {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl } -1,3-Benzothiazol-2-amine (35a) and 1.03 g of N- (3-dimethylaminopropyl) N-ethylcarbodiimide hydrochloride. After 5h, the brown reaction medium is evaporated to dryness. The residue is taken up in toluene and the mixture again evaporated to dryness in vacuo. The residue is taken up in water and the mixture is extracted with ethyl acetate and then evaporated to dryness. The residue is purified by dry deposition on silica and chromatographed on Biotage Quad 12/25 (KP-SIL, 6OA, 32-63 μM), eluting with a dichloromethane / methanol gradient of 100/0 to 98/2. 135 mg of N- (6- {[6- (Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N ² , N ² -dialylglycinamide under form of a beige powder whose characteristics are as follows:

MASS SPECTRUM: Waters UPLC-SQD:

Retention time Tr (min) = 0.72; [M + H] +: m / z 484; [M + 2H] 2+: m / z 242.5

(base peak); [M-H] -: m / z 482

1 H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 1.00 (t, J = 7.2 Hz, 6H);

1, 52-1.66 (m, 1H); 1.68 to 1.80 (m, 1H); 1.95 to 2.09 (m, 2H); 2.20 to 2.31

(m, 2H); 2.62 (q, J = 7.2 Hz, 4H); 3.40 (s, 2H); 4.90 (m, 1H); 7.06 (d, J = 9.8

Hz, 1H); 7.47 (dd, J = 1, 9 and 8.5 Hz, 1H); 7.69 (d, J = 8.5 Hz, 1H); 8.13 (d,

J = 1.9 Hz, 1H); 8.29 (d, J = 9.8 Hz, 1H); 11, 54 (m very spread, 1H)

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

The characteristics of the products in the table above are as follows:

Example 65

Rac-1- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2 -yl-3- [2- (morpholin-4-yl) ethyl] urea, 15/85 mixture of cis and trans isomers (predominant) a) 1 - {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] The urea can be prepared in a manner similar to that described for Example 2a, but with 0.240 g of a 1/1 mixture of cis- and trans-3-chloro-6 - {[3-methylcyclohexyl] oxy} [ Racemic 1, 2,4] triazolo [4,3-b] pyridazine, dissolved in 12 cm ³ of ethanol, then, at a temperature in the region of 20 ^° C., 0.457 g of 1 - [2- (morpholine) 4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 0.416g of DL-dithiothreitol, and a solution of 0.061 g of potassium dihydrogenphosphate in 0.600 cm ³ distilled water. After stirring for 8 hours under reflux, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 40 cm ³ of dichloromethane and the mixture obtained is washed successively with 2 times 30 cm ³ of distilled water and 15 cm ³ of a saturated solution of sodium chloride, then is dried over anhydrous magnesium sulfate, filtered and filtered. concentrated to dryness under reduced pressure (2.7 kPa) to give 0.370 g of an orange meringue. This orange meringue is purified by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume + 0.1% 7 _V of a 20% aqueous ammonia solution)]. After concentrating the fractions under reduced pressure, 0.121 g of a 15/85 mixture of cis- and trans-1- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] is obtained. triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 racemic benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea in the form of a white solid melting at 197.6 ^° C. and having the following characteristics: ¹ H NMR spectrum ( 400 MHz, δ in ppm, DMSO-d ₆ ) mixture of isomers 85%

H1 ax- 15% H1 eq with 0.71 (d, J = 6.3 Hz, 0.45 H); 0.81 (d, J = 6.6Hz, 2.55H); 0.72 to 1.80 (m, 7H); 1.85 to 1.94 (m, 2H); 2.36 to 2.44 (m, 6H); 3.26 (partially masked m, 2H); 3.59 (m, 4H); 4.64 (m, 0.85H); 5.07 (m, 0.15H); 6.78 (t broad, J = 6.1 Hz, 1H); 7.01 (d, J = 10.0 Hz, 0.85 H); 7.03 (d, J = 10.0 Hz, 0.15 H); 7.34 (dd, J = 2.0 and 8.6 Hz, 0.85 H); 7.37 (dd, J = 2.0 and 8.6 Hz, 0.15 H); 7.54 (d, J = 8.6 Hz, 1H); 7.96 (d, J = 2.0 Hz, 0.85H); 8.03 (d, J = 2.0 Hz, 0.15 H); 8.25 (d, J = 10.0 Hz, 0.15 H); 8.27 (d, J = 10.0 Hz, 0.85 H); 10.90 (spread m, 1H).

ES +/- Mass Spectrum: [M + H] +: m / z 569; [MH] -: m / z 567. b) The 1/1 mixture of cis- and trans-3-chloro-6 - {[3-methylcyclohexyl] oxy} [1,2,4] thazolo [4.3 racemic pyhdazine can be prepared in a manner similar to that described in Example 1c but from 0.628 g of a 1/1 mixture of racemic cis- and trans-3-methylcyclohexanol in solution in 6 cm ³ tetrahydrofuran under an argon stream to which is added at a temperature of 0 ⁰ C, 0.220 g of 60% sodium hydride in the oil. The reaction medium is maintained at a temperature in the region of 0 ^° C. for 15 minutes and then 0.650 g of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine is added. After stirring at a temperature in the region of 20 ^° C. for 24 hours, 10 cm ³ of a saturated aqueous ammonium chloride solution and 20 cm ³ of ethyl acetate are added. After separation of the two phases, the organic phase is washed successively with 2 times 10 cm ³ of distilled water and 15 cm ³ of a saturated solution of sodium chloride and is then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. (2.7 kPa) to give 0.950 g of a 1/1 mixture of cis- and trans-3-chloro-6 - {[3-methylcyclohexyl] oxy} [1,2,4] thazolo [4,3- b] racemic pyridazine in the form of a brown oil, the characteristics of which are as follows: ES + mass spectrum: [M + H] +: m / z 267.

Example 66

Rac-N- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2 cyclopropanecarboxamide, 15/85 mixture of cis and trans isomers (majority) a) The 15/85 mixture of cis and trans isomers of N- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1, 2,4] tertzolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide may be prepared in a manner similar to that described for Example 2a, but from 0.500 g of N- (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 0.616 g of DL-dithiothreitol, a solution of 0.090 g of potassium dihydrogenphosphate in 1 cm ³ of water distilled, 0.355 g of 1/1 mixture of racemic cis- and trans-3-chloro-6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazine (65b ) and 18cm ³ of ethanol. After stirring for 8 h at reflux and then treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume)], 0.198 g of a 15/85 mixture of cis and isomers is obtained. trans N- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2 racyl cyclopropanecarboxamide in the form of a white solid melting at 216.5 ° C. and having the following characteristics:

¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ) isomer mixture 85% H1 ax -15% H1 eq with 0.70 (d, J = 6.4 Hz, 0.45 H); 0.78 (d, J = 6.4 Hz, 2.55 H); 0.72 to 1.78 (m, 11H); 1.85 (m, 2H); 1.97 (m, 1H); 4.62 (m, 0.85 H); 5.03 (m, 0.15H); 7.01 (d, J = 9.8 Hz, 0.85 H); 7.03 (d, J = 9.8 Hz, 0.15 H); 7.39 (dd, J = 2.0 and 8.6 Hz, 0.85 H); 7.41 (dd, J = 2.0 and 8.6 Hz, 0.15 H); 7.66 (d, J = 8.6 Hz, 1H); 8.02 (d, J = 2.0 Hz, 0.85H); 8.09 (d, J = 2.0 Hz, 0.15 H); 8.26 (d, J = 9.8 Hz, 0.15H); 8.28 (d, J = 9.8 Hz, 0.85 H); 12.67 (m spread, 1H). ES +/- mass spectrum: [M + H] +: m / z 481; [MH] -: m / z 479. b) N- (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide can be prepared in a manner similar to that described in Example 2b but from 14.0 g of 2 - [(cyclopropylcarbonyl) thiocyanate ) amino] -1,3-benzothiazol-6-yl, 22.44 g of DL-dithiothreitol, a solution of 0.235 g of potassium dihydrogenphosphate in 60 cm ³ of distilled water and 450 cm ³ of ethanol. After stirring for 5 hours under reflux, the reaction medium is poured onto 700 cm ³ of ice water under a stream of argon. The yellow solid formed is filtered on VF3, washed with twice 70 cm ³ of ice water and then dried in an oven under reduced pressure (2.7 kPa) at 40 ^° C. for 24 hours, to give 12.74 g of N- (6). -sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a yellow solid, the characteristics of which are as follows:

ES +/- Mass Spectrum: [M + H] +: m / z 251; [MH] -: m / z 249. c) The 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl thiocyanate can be prepared in a manner similar to that described in Example 1a but from 15.0 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate, 7.88 cm ³ of cyclopropane carboxylic acid chloride and 150 cm ³ of pyridine. After stirring for 5 h at a temperature in the region of 20 ^° C., the reaction medium is poured into 500 cm ³ of ice water. The solid formed is filtered on a VF3 filter and then washed with 5 times 70 cm ³ of ice water before drying in an oven under reduced pressure (2.7 kPa) at 40 ° C. for 10 h to give 19 g of 2 - [( cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl as a pink solid whose characteristics are as follows:

ES +/- Mass Spectrum: [M + H] +: m / z 276; [M-H] -: m / z 274.

Example 67

1- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl ] -3- [2- (morpholin-4-yl) ethyl] urea, 15/85 mixture of cis and trans (predominant) isomers a) The 15/85 mixture of cis- and trans-1 - [6- ( {6 - [(4-methylcyclohexyl) oxy] [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] -3- [2] - (morpholin-4-yl) ethyl] urea can be prepared from similarly to that described for Example 2a, but from 0.876 g 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 0.798 g of DL-dithiothreitol, a solution of 0.117 g of potassium dihydrogenphosphate in 1.15 cm ³ of distilled water, 0.460 g of a 1/1 mixture of cis- and trans-3- chloro-6- (4-methyl-cyclohexyloxy) -1,2,4-thazolo [4,3-b] pyhdazine and 23cm ³ of ethanol. After stirring for 16 h at reflux, then treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume + 0.1% 7 _V of a 20% aqueous ammonia solution) ], 0.261 g of a 15/85 mixture of cis- and trans-1- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3- b] pyridazin-3-yl] sulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) ethyl] urea as a white solid, mp 155.9 ° C, and whose characteristics are as follows:

¹ H NMR Spectrum (400 MHz, δ in ppm, DMSO-d ₆ ) isomeric mixture 85% H1 ax-15% H1 eq with: 0.86 (d, J = 6.4 Hz, 3 H); 0.88 to 0.93 (m, 2H); 1.17-1.63 (m, 5H); 1.76 to 1.93 (m, 2H); 2.35 to 2.45 (m, 6H); 3.26 (partially masked m, 2H); 3.59 (m, 4H); 4.40 to 4.57 (m, 1H); 6.78 (m wide, 1H); 7.00 (d, J = 9.8 Hz, 0.85 H); 7.04 (d, J = 9.8 Hz, 0.15 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 0.85 H); 7.40 (dd, J = 2.0 and 8.6 Hz, 0.15 H); 7.53 (d, J = 8.6 Hz, 0.85 H); 7.55 (d, J = 8.6 Hz, 0.15H); 8.00 (d, J = 2.0 Hz, 0.85 H); 8.04 (d, J = 2.0 Hz, 0.15 H); 8.25 (d, J = 9.8 Hz, 0.15 H); 8.27 (d, J = 9.8 Hz, 0.85 H); 10.91 (spread m, 1H).

ES +/- Mass Spectrum: [M + H] +: m / z 569; [MH] -: m / z 567. b) The 1/1 mixture of cis- and trans-3-chloro-6- (4-methyl-cyclohexyloxy) -1,2,4-thazolo [4,3- b] pyridazine can be prepared in a manner similar to that described in Example 1c but from 0.628 g of a mixture 1/1 of cis- and trans-4-methyl cyclohexanol, ⁶ cm ³ of tetrahydrofuran, 0.220 g 60% sodium hydride in oil and 0.650 g of 3,6-dichloro [1,2,4] thazolo [4,3-b] pyridazine. After stirring at a temperature of 20 ^° C. for 24 hours and treatment, 0.880 g of a 1/1 mixture of cis- and trans-3-chloro-6- (4-methylcyclohexyloxy) are obtained. 1,2,4-triazolo [4,3-b] pyridazine as a solidifying brown oil having the following characteristics: ES + Mass Spectrum: [M + H] +: m / z 267.

Example 68

N- (6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- ( piperidin-1-yl) azetidine-1-carboxamide

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- (Piperidin-1-yl) azetidine-1-carboxamide can be prepared in a manner similar to Example 5 but from 185 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [ Phenyl 4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate (4) in 10cm ³ of THF and 10cm ³ of DMF with 75mg of 1 - (azetidin) dihydrochloride. 3-yl) pipéhdine and 0.160 cm ³ of triethylamine after 66h of reaction at 20 ^° C. is thus obtained 155 mg of N- (6- {[6- (cyclohexyloxy) [1,2,4] triazolo [4.3 pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- (piperidin-1-yl) azetidine-1-carboxamide as a pale yellow solid, the characteristics of which are following: ¹ H NMR SPECTRUM (400 MHz, DMSO-d ₆ , δppm): 1, 13 to 1, 67 (m, 14H); 1.81 (m, 2H); 2.24 (m wide, 4H); 2.99 to 3.20 (wide m, 1H); 3.70 to 4.15 (wide, 4H); 4.64 to 4.74 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.37 (dd, J = 2.0 and 8.3 Hz, 1H); 7.55 (d, J = 8.3 Hz, 1H); 8.00 (s wide, 1H); 8.27 (d, J = 9.8 Hz, 1H), 11.32 (m, spread, 1H).

MASS SPECTRUM (Electrospray on WATERS UPLC - SQD): [M + H] +: m / z 565; [M-H] -: m / z 563.

Example 69:

N- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl ] cyclopropanecarboxamide, 15/85 mixture of cis and trans isomers (predominant)

The 85/18 mixture of cis- and trans-N- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] thazolo [4,3-b] pyridazin-3-yl} sulfanyl ) -1, 3- benzothiazol-2-yl] cyclopropanecarboxamide can be prepared in a manner similar to that described for Example 2a, but from 0.592 g of N- (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide (66b) , 0.729 g of DL-dithiothreitol, a solution of 0.107 g of potassium dihydrogenphosphate in 1.05 cm ³ of distilled water, 0.420 g of a 1/1 mixture of 3-chloro-6- (4) -methylcyclohexyloxy) -1,2,4-thazolo [4,3-b] pyhdazine (67b) and 20cm ³ of ethanol. After stirring for 16 hours under reflux and then treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume)], 0.336 g of a 15/85 mixture of cis isomers is obtained. and trans N- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] tetrazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazole. 2-yl] cyclopropanecarboxamide in the form of a white solid melting at 230 ^° C., the characteristics of which are as follows: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ) isomer mixture 85% H1 ax - 15% H1 eq with: 0.72 to 0.99 (m, 6H); 0.82 (d, J = 6.6Hz, 2.55H); 0.88 (d, J = 6.6Hz, 0.45H); 1.06 to 1.59 (m, 5H); 1.82 (d, J = 9.0 Hz, 2H); 1.94 to 2.04 (m, 1H); 4.35 to 4.51 (m, 1H); 7.00 (d, J = 9.8 Hz, 0.85 H); 7.04 (d, J = 9.8 Hz, 0.15 H); 7.35 (dd, J = 2.0 and 8.6 Hz, 0.85 H); 7.45 (dd, J = 2.0 and 8.6 Hz, 0.15 H); 7.66 (d, J = 8.6 Hz, 0.85 H); 7.68 (d, J = 8.6 Hz, 0.15 H); 8.06 (d, J = 2.0 Hz, 0.85 H); 8.11 (d, J = 2.0 Hz, 0.15H); 8.26 (d, J = 9.8 Hz, 0.15H); 8.28 (d, J = 9.8 Hz, 0.85 H); 12.68 (spread m, 1H). ES +/- mass spectrum: [M + H] +: m / z 481; [MH] -: m / z 479.

Example 70

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- oxa-6-azaspiro [3.3] heptane-6-carboxamide can be prepared in a manner similar to that described in Example 5 but from 150 mg of (6 - {[6- (cyclohexyloxy) [1, 2, 4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl carbamate (4), 65 mg of mono oxalate of 2-oxa-6-aza-spiro [3.3] heptane, 0.144 cm ³ of triethylamine and 10 cm ³ of tetrahydrofuran. After stirring for 15 hours at a temperature in the region of 20 ^° C. and then treating, 0.056 g of N- (6 - {[6-

2-yl) -2-oxa-6-azaspiro [3.3] heptane-6-carboxamide as a white solid, the characteristics of which are as follows:

ES +/- mass spectrum: [M + H] +: m / z 524; [M-H] -: m / z 522.

¹ H NMR spectrum (400 MHz, δ ppm, DMSO-d _6): 1, 15-1, 42 (m, 5H); 1, 49

(m, 1H); 1.61 (m, 2H); 1.81 (m, 2H); 4.20 (bs, 4H); 4.66 (s, 4H);

4.68 to 4.74 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.37 (dd, J = 2.0 and 8.6 Hz, 1H);

7.55 (broad d, J = 8.6 Hz, 1H); 8.00 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H)

; 11, 36 (m spread, 1H).

The oxalate monooxalate of 2-oxa-6-aza-spiro [3.3] heptane can be prepared as described by Georg Wunschik, Mark Rogers-Evans, Andreas Buckl, Maurizio

Bernasconi, Moritz M_rki, Thierry Godel, Holger Fischer, Bjr Wagner,

Isabelle Parrilla, Franz Schuler, Josef Schneider, Andre Alker, W. Bernd

Schweizer, Klaus M-ller, and Erick M. Carreira, Angew. Chem. Int. Ed. 2008,

47, 4512-4515.

Example 71

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- (morpholin-4-yl) azetidine-1-carboxamide can be prepared in a manner similar to Example 5 but from 182 mg of (6- {[6- (cyclohexyloxy) [1,2,4] triazolo [ Phenyl 4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate (4) in 10cm ³ THF, 106mg 4- (azetidin-3-yl) dihydrochloride ) morpholine and 0.167 cm ³ of triethylamine, after 22 hours of reaction at 20 ^° C. is thus obtained 60 mg of N- (6- {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] ] pyridazin-3-yl] sulfanyl} -1, 3- benzothiazol-2-yl) -3- (morpholin-4-yl) azetidine-1-carboxannide in the form of a white solid whose characteristics are as follows: ¹ H NMR SPECTRUM (400 MHz, DMSO-d ₆ , δ ppm) : 1, 11-1.42 (m, 5H); 1.50 (m, 1H); 1.62 (m, 2H); 1.82 (m, 2H); 2.31 (m, 4H); 3.09 to 3.19 (m, 1H); 3.59 (m, 4H); 3.85 (m, 2H); 4.04 (m, 2H); 4.63 to 4.78 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.36 (dd, J = 2.0 and 8.6 Hz, 1H); 7.52 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H); 8.26 (d, J = 9.8 Hz, 1H); 11, 38 (spread m, 1H). MASS SPECTRUM (Electrospray WATERS ZQ): [M + H] +: m / z 567; [MH] -: m / z 565.

Example 72:

Rac-N- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole 2-yl} cyclopropanecarboxamide a) Rac-N- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide can be prepared in a manner similar to that described for Example 2a, but from 0.636 g of N- (6-sulfanyl-1,3-benzothiazol- 2- yl) cyclopropanecarboxamide (66b), 0.784 g of DL-dithiothreitol, a solution of 0.115 g of potassium dihydrogenphosphate in 1.27 cm ³ of distilled water, 0.428 g of a 1/1 mixture of racemic cis- and trans-3-chloro-6- (2-methyl-cyclopentyloxy) -1,2,4-triazolo [4,3-b] pyhdazine and 23cm ³ of ethanol. After stirring for 16 hours at reflux and then treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume)], 0.260 g of rac-N- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide as a solid white melting at 197.7 ° C., the characteristics of which are as follows: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 0.89 (d, J = 7.1 Hz, 3 H);

0.92 to 1.00 (m, 4H); 1, 06 to 1, 21 (m, 1H); 1.46 to 1.69 (m, 3H); 1.78-2.12 (m, 4H); 4.45 to 4.56 (m, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.43 (dd, J = 2.0 and 8.6 Hz, 1H); 7.68 (d, J = 8.6 Hz, 1H); 8.09 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H); 12.67 (m spread, 1H).

ES +/- Mass Spectrum: [M + H] +: m / z 467; [MH] -: m / z 465. b) The 1/1 mixture of cis- and trans-3-chloro-6- (2-methyl-cyclopentyloxy) -1,2,4-triazolo [4,3- b] racemic pyridazine can be prepared in a manner similar to that described in Example 1c but from 0.678 g of a 1/1 mixture of cis- and trans-2-methylcyclopentanol, 10 cm ³ of tetrahydrofuran, 0.271 g of 60% sodium hydride in oil, 0.800 g and 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine. After stirring at a temperature of 20 ^° C. for 24 hours and treatment, 1.033 g of a 1/1 mixture of cis- and trans-3-chloro-6- (2-methyl-cyclopentyloxy) are obtained. Racemic 1, 2,4-thazolo [4,3-b] pyridazine in the form of a brown oil, the characteristics of which are as follows: ES + Mass Spectrum: [M + H] +: m / z 253.

Example 73:

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

Rac-1 - {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 Benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea may be prepared in a manner similar to that described for Example 2a, but from 0.609 g of 1- [2- (2-morpholin-4-yl) ethyl] urea. morpholin-4-yl) ethyl] -3- (6-sulfanyl-1, 3-benzothiazol-2-yl) urea (2b), 0.555 g of DL-dithiothreitol, a solution of 0.081 g of potassium dihydrogen phosphate in 0.85 cm ³ of distilled water, 0.303 g of a 1/1 mixture of cis- and trans-3-chloro-6- (2-methyl-cyclopentyloxy) -1,2,4-thazolo [4] , 3-b] racemic pyridazine (72b) and 17cm ³ ethanol. After stirring for 16 hours at reflux and then treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume + 0.1% 7 _V of a 20% aqueous ammonia solution)] we obtain 0.223 g of rac-1 - {6 - [(6 - {[trans-2- methylcyclopentyl] oxy} [1,2,4] tπazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ) ethyl] urea in the form of a pale yellow solid melting at 203.3 ^° C., the characteristics of which are as follows: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ): 0.92 (d, J = 7.1 Hz, 3H); 1.16 (m, 1H); 1.50 to 1.69 (m, 3H); 1.79 at 2.12 (m, 3H); 2.37 to 2.44 (m, 6H); 3.26 (partially masked m, 2H); 3.59 (m, 4H); 4.52 to 4.60 (m, 1H); 6.79 (m spread, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.37 (dd, J = 2.0 and 8.5 Hz, 1H); 7.55 (d, J = 8.5 Hz, 1H); 8.03 (d, J = 2.0 Hz, 1H); 8.26 (d, J = 9.8 Hz, 1H); 10.90 (spread m, 1H). ES +/- Mass Spectrum: [M + H] +: m / z 555; [MH] -: m / z 553.

Example 74:

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

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyhdazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- methoxyazetidine-1-carboxamide can be prepared in a manner similar to Example 5 but from 192 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] pyridazine Phenyl-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate (4) in 5 cm ³ of dimethylformamide, 69 mg of 3-methoxyazetidine hydrochloride and 0.078 cm ³ of the methylamine after 20 hours of reaction with 20 ⁰ C. are thus obtained 120 mg of N- (6 - {[6- (cyclohexyloxy) [1, 2,4] thazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1, 3-benzothiazol - 2-yl) -3-methoxyazetidine-1-carboxamide as an off-white solid whose characteristics are as follows:

¹ H NMR SPECTRUM (400 MHz, DMSO-d ₆ , δppm): 1.14 to 1.42 (m, 5H); 1.44 to 1.53 (m, 1H); 1.61 (m, 2H); 1.81 (m, 2H); 3.21 (s, 3H); 3.83 (m, 2H); 4.13 to 4.30 (m, 3H); 4.64 to 4.74 (m, 1H); 7.02 (d, J = 9.8 Hz, 1H); 7.37 (dd, J = 2.0 and 8.6 Hz, 1H); 7.54 (broad d, J = 8.6 Hz, 1H); 8.00 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 9.8 Hz, 1H); 11, 36 (m spread, 1H). MASS SPECTRUM (Electrospray WATERS ZQ): [M + H] +: m / z 512; [MH] -: m / z 510. Example 75:

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

1- (6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- oxetan-3-ylurea can be prepared in a manner similar to Example 5 but from 191 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] thazolo [4,3-b] phenyl pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate (4) in ³ cm ³ of dimethylformamide, 40 mg of oxetan-3-amine after 20 hours of reaction at 20 ^° C. thus obtaining 95 mg of 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-oxetan-3-ylurea in the form of a white solid, the characteristics of which are as follows:

¹ H NMR SPECTRUM (400 MHz, DMSO-d ₆ , δppm): 1, 12 to 1, 43 (m, 5H); 1.47 to 1.54 (m, 1H); 1.62 (m, 2H); 1.83 (m, 2H); 4.47 (t, J = 6.4 Hz, 2H); 4.67 to 4.76 (m, 3H); 4.77 to 4.86 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.35 (dd, J = 1, 8 and 8.4 Hz, 1H); 7.52 (broad m, 2H); 7.97 (brs, 1H); 8.26 (d, J = 9.8 Hz, 1H); 10.99 (spread m, 1H).

MASS SPECTRUM (Electrospray on WATERS UPLC - SQD): [M + H] +: m / z 498; [M-H] -: m / z 496.

Example 76

Rac-1- {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2 -yl-3- [2- (morpholin-4-yl) ethyl] urea, mixture 2/3 of the cis and trans (majority) isomers racemic a) The mixture 2/3 of the cis and trans racemic isomers of the 1 - {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} - 3- [2- (morpholin-4-yl) ethyl] urea may be prepared in a manner similar to that described for Example 2a, but from 0.643 g of 1- (6-mercapto-benzothiazol-2-yl) 3- (2-morpholin-4-yl-ethyl) -urea (2b), 0.586 g of DL-dithiothreitol, a solution of 0.086 g of potassium dihydrogen phosphate in 0.95 cm ³ of distilled water, 0.320 g of a 1/1 mixture of cis and trans racemic isomers of 3-chloro-6- (3-methyl-cyclopentyloxy) -1,2,4 triazolo [4,3-b] pyridazine and ¹⁹ cm ³ of ethanol. After stirring for 16 hours at reflux and then treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume with 0.1% 7 _V of a 20% aqueous ammonia solution)] 0.065 g of a 2/3 mixture of cis and trans racemic isomers of 1 - {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3- b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea as a white solid, mp 174.7 ° C the characteristics are the following: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ) mixture of isomers 2/3 -

1/3 with: 0.90 (d, J = 6.8 Hz, 1H); 0.94 (d, J = 6.6 Hz, 2H); 1.00 - 1.35 (m, 2H); 1.57 to 2.16 (m, 5H); 2.36 to 2.44 (m, 6H); 3.26 (partially masked m, 2H); 3.59 (m, 4H); 5.05 (m, 0.66H); 5.11 (m, 0.34 H); 6.79 (m wide, 1H); 7.00 (d, J = 9.8 Hz, 0.34 H); 7.02 (d, J = 9.8 Hz, 0.66 H); 7.38 (dd split, J = 2.0 and 8.6 Hz, 1H); 7.54 (d, J = 8.6 Hz, 1H); 8.04 (d, J = 2.0 Hz, 1H); 8.25 (d split, J = 9.8 Hz, 1H); 10.92 (m spread, 1H). ES +/- Mass Spectrum: [M + H] +: m / z 555; [MH] -: m / z 553. b) The 1: 1 mixture of cis and trans racemic isomers of 3-chloro-6- (3-methyl-cyclopentyloxy) -1,2,4-triazolo [4.3 pyhdazine can be prepared in a manner similar to that described in Example 1c but from 0.678 g of a 1/1 mixture of cis and trans-3-methylcyclopentanol isomers racemic, 10 cm ³ of tetrahydrofuran, 0.271 60% sodium hydride in oil and 0.800 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine. After stirring at a temperature in the region of 20 ^° C. for 24 hours and treatment, 0.860 g of a 1/1 mixture of the cis and trans racemic isomers of 3-chloro-6- (3-methyl-cyclopentyloxy) are obtained. -1,2,4-triazolo [4,3-b] pyhdazine as a brown oil having the following characteristics: ES + / - Mass Spectrum: [M + H] +: m / z 253. Example 77

Rac-N- {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2 cyclopropanecarboxamide, 2/3 mixture of cis and trans isomers (majority) racemic

The 2/3 mixture of the cis and trans racemic isomers of N- {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide can be prepared in a manner similar to that described for Example 2a, but from 0.505 g of N- (6-sulfanyl-1,3-benzothiazol-2 -yl) cyclopropanecarboxamide (66b), 0.622 g of DL-dithiothreitol, a solution of 0.091 g of potassium dihydrogenphosphate in 1 01 cm ³ of distilled water, 0.340 g of a 1/1 mixture of the isomers cis and trans racemic 3-chloro-6- (3-methyl-cyclopentyloxy) -1,2,4-thazolo [4,3-b] pyridazine (76b) and 23cm ³ ethanol. After stirring for 16 hours at reflux and then treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 by volume)], 0.172 g of a 2/3 mixture of the cis isomers and trans-racemic N- {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol 2-yl} cyclopropanecarboxamide in the form of a white solid melting at 98 ° C., the characteristics of which are as follows: ¹ H NMR spectrum (400 MHz, δ in ppm, DMSO-d ₆ ) isomeric mixture 2/3 -

1/3 with: 0.84 to 0.97 (m, 7H); 0.99 to 1.30 (m, 2H); 1.54 to 2.14 (m, 6H);

5.03 (m, 0.66H); 5.10 (m, 0.34 H); 7.00 (d, J = 9.8 Hz,

0.34 H); 7.02 (d, J = 9.8 Hz, 0.66 H); 7.41 (dd split, J = 2.0 and 8.6 Hz, 1H)

; 7.65 (d, J = 8.6 Hz, 1H); 8.08 (brs, 1H); 8.26 (d split, J = 9.8

Hz, 1H); 12.64 (spread m, 1H).

ES +/- Mass Spectrum: [M + H] +: m / z 467; [M-H] -: m / z 465.

Example 78: Pharmaceutical composition Tablets having the following formula were prepared:

Product of Example 1 0.2 g

Excipient for a tablet finished at 1 g

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

Example 79: Pharmaceutical composition

Tablets having the following formula were prepared:

Product of Example 4 0.2 g

Excipient for a tablet finished at 1 g

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

Examples 1 and 4 are taken as examples of a pharmaceutical preparation, this preparation can be carried out if desired with other products as examples in the present application.

Pharmacological part:

Experimental protocols

I) Expression and Purification of MET, Cytoplasmic Domain Expression in Baculovirus:

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

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

The cell pellets are resuspended in 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 1 OkDa) and injected on an exclusion chromatography column (Superdex ™ 200, GE HealthCare). balanced in buffer A. After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast Flow ™, GE HealthCare) equilibrated in Buffer A. The fractions eluted by a buffer B gradient and containing the protein after electrophoresis (SDS PAGE), are finally collected and stored at -80 ^° C. For the production of autophosphorylated protein, the preceding fractions are incubated for 1 h at room temperature after addition of 2 mM ATP, 2 mM MgCl 2, and Na 3 VO 4. 4 mM. After stopping the reaction with 5mM EDTA, the reaction mixture is injected onto a HiPrep desalting column (GE HealthCare) previously equilibrated with 4mM A + Na3VO4 buffer, the fractions containing the protein of interest (SDS PAGE analysis) are pooled. and stored at -80 ^° C. The phosphorylation level is verified by mass spectrometry (LC-MS), and by peptide mapping.

Il) Tests A and B

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

In a final volume of 50 μl of enzymatic reaction, final 5 nM MET is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 μM, final DMSO 3%) in MOPS 1 OmM buffer pH 7.4, DTT 1 mM, Tween 20 0.01%. The reaction is initiated by the substrate solution to obtain the final concentrations of poly- (GAT) 1 μg / ml, 10μM ATP and 5mM MgCl 2. After incubation for 10 min at room temperature, the reaction is stopped by a 30 μl mix to obtain a final solution of 50 mM Hepes pH 7.5, 50 mM potassium fluoride, 0.1% BSA and 133 mM EDTA in the presence of 80 ng Streptavidin. 61 SAXLB Cis-Bio Int. and 18ng anti-Phosphotyrosine Mab PT66-Europium Cryptate per well. After 2 hours incubation at room temperature, the reading is made at 2 wavelengths 620 nm and 665 nm on a reader for the TRACE / HTRF technique and the% inhibition is calculated according to the 665/620 ratios.

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

B) Test B: Inhibition of MET autophosphorylation; ELISA technique (pppY1230,1234,1235) a) Cell lysates: Inoculate MKN45 cells in 96-well plate (CeII coat BD polylysine) at 20,000 cells / well under 200 μl in RPMI medium + 10% FCS + 1% L-glutamine. Allow 24 hours to adhere to the incubator.

The cells are treated the day after seeding with the products at 6 concentrations in duplicate for 1 h. At least 3 control wells are treated with the same amount of final DMSO.

Dilution of the products: Stock at 1 μM in pure DMSO - Range of 1 μM at 30 μM with a step of 3 in pure DMSO - Dilutions intermediate at 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 PMSF and anti protease cocktail.

The 10Oμl of lysates are transferred into a V-bottom polypropylene plate and the ELISA is carried out immediately or the plate is frozen at -80 ^° C. b) ELISA PhosphoMET BioSource Kit KHO0281

In each well of the kit plate, add 70μl of kit dilution buffer + 30μl of cell lysate or 30μl of lysis buffer for the blanks. Incubate for 2h with gentle shaking at room temperature.

Rinse the wells 4 times with 400 μl of kit wash buffer. Incubate with 10μl of anti-phospho MET antibody for 1h at room temperature.

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

Rinse the wells 4 times with 400 μl of kit wash buffer. Put 100μL of chromogen and incubate 30minutes in the dark at room temperature.

Stop the reaction with 100 μl of stop solution. Read without delay at 45OnM 0.1 seconds at Wallac Victor flat reader.

C) Test C: Measurement of Cell Proliferation Using 14C-Thymidine

The cells are seeded in 96-well Cytostar plates at 180 μl for 4 hours at 37 ° C. and 5% CO 2: HCT116 cells at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum + 1% L Glutamine and MKN45 cells at the rate of 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine. After these 4 hours of incubation, the products are added under 10 μl in 20-fold concentrated solution according to the dilution method mentioned for the ELISA. The products are tested at 10 concentrations in duplicate from 1000OnM to 0.3nM with a pitch of 3. After 72 hours of treatment, add 10 μl of 14 C-thymidine at 10 μCi / ml to obtain 0.1 μCi per well. The incorporation of 14 C-thymidine is measured on a Micro-Beta (Perkin-Elmer) after 24 hours of drawing and 96 hours of treatment.

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

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

The results obtained for the exemplary products in the experimental part are given in the table of pharmacological results below, as follows: for test A, the sign + corresponds to less than 50 nm and the sign ++ corresponds to less than 100 nm. . for test B the sign + corresponds to less than 50OnM and the sign ++ corresponds to less than 10OnM. for the C test the + sign corresponds to less than 10 microM and the sign ++ corresponds to less than I microM.

Table of pharmacological results:

1- Products of formula (I):

in which

represents a single or double bond;

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

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom,

Claims

a cycloalkyl radical, a heterocycloalkyl 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 form with the atom; nitrogen to which they are attached a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the optional S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; with R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH 2, NHAIk, N (Alk) 2 or optionally substituted phenyl radicals; or R3 and R4 together with the nitrogen atom to which they are bonded form a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the possible S possibly being in SO or SO2 form; this radical including the possible NH it contains being optionally substituted; all the radicals defined above alkyl, 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 chosen from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5 radicals and radicals; alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals the alkyl, cycloalkyl, 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. carbon, NH2, NHaIk and N (alk) 2, all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl being further optionally substituted with a radical Si (alk) 3; all the radicals defined above cycloalkyl and heterocycloalkyl which may be optionally substituted on one of the ring carbons by a spirocycloalkyl or spiroheterocycloalkyl radical or possibly on two of the ring carbons by a fused cycloalkyl or heterocycloalkyl radical;

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

z ^zz ^ represents a single or double bond;

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:

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl 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 form with the atom; nitrogen to which they are attached a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the optional S possibly being in SO or SO2 form, this radical including any 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 heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH 2, NHAIk, N (Alk) 2 or optionally substituted phenyl radicals; or else R3 and R4 form with the nitrogen atom to which they are attached, a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, with the optional S possibly being in the SO form. or SO2, 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, -O-CO-R5, NH2, NHaIk, N (alk) 2 radicals and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2- radicals; phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such that, in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and radicals; hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH2, NHaIk and N (alk) 2;

R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon atoms; said products of formula (I) being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms, as well as the addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

3- Products of formula (I) as defined in any one of 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; an alkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

with NR 3 R 4, such that R 3 and R 4, which may be identical or different, represent a hydrogen atom or an alkyl radical or a heterocycloalkyl radical, all optionally substituted with one or more identical or different radicals chosen from alkoxy, heterocycloalkyl or NH 2, NHAIk radicals; or N (Alk) 2; 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 cycloalkyl, heterocycloalkyl and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH2, NHaIk, N (alk) 2 radicals and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such as in the latter radicals, alkyl radicals; heterocycloalkyl, 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 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).

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

or the radical NR 1 R 2, in which R 1 and R 2 are such that one of R 1 and R 2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other of R 1 and R 2 represents a hydrogen atom; , a radical alkyl optionally substituted by a heterocyclic radical or 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 may be identical or different, represent a hydrogen atom or an alkyl radical or else R3 and R4 form, with the nitrogen atom to which they are bonded, a cyclic radical optionally containing one or more other heteroatoms chosen (s) from O, S, N and NH, this radical including the optional NH it contains being optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals as well as the cyclic radicals that can be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are bonded, defined above, being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkoxy, NH 2, NHaIk, N (alk) 2 radicals and alkyl and phenyl radicals, the latter being themselves optionally substituted with one or more radicals chosen from 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).

5. 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 isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with mineral acids and organic 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 A represents S, the substituents, Ra, X and

W being chosen from among all the values defined for these radicals in any of the other claims, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with acids inorganic and organic 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 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).

8- 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).

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

11- Products of formula (I) as defined in any one of the preceding claims wherein

represents a single or double bond

Ra represents an -O-cycloalkyl radical, or a -NH-cycloalkyl radical; optionally substituted with a hydroxyl, alkoxy or -O-CO-R5 radical;

X is S; A represents S;

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

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

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

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

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

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

3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine

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

6 - [(6 - {[4- (tfluoromethyl) cyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- ( 4-ethyl-piperazin-1-yl) acétannide

N-α-tert-β-trifluoromethyl-cyclohexyloxy-1H-triazolo-β-B-pyridazin-5-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide

6 - {[6- (bicyclo [3.1.0] hex-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole. 2-amine 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclobutyl [1,2,4] triazolo [4,3-b] pyridazin-6-annin

rac-N ² , N ² -dienyl-N- [6 - ({6 - [(trans-2-fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl } sulfanyl) -1,3-benzothiazol-2-yl] glycinannide rac-2- (4-ethylpiperazin-1-yl) -N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1] 2,4,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetonide rac-N- {6 - [(6 - {[trans-2- fluorocyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} -2- (morpholin-4-yl) acetannide

N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- ( morpholin-4-yl) acetannide rac-2- (4-cyclopropylpiperazin-1-yl) -N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1,2,4] triazolo [4] , 3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetannide

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

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

N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methoxyazetidine -1-carboxamide 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-oxetan -3-ylurea rac-cis / trans-1 - {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-Benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea rac-cis / trans-N- {6 - [(6 - {[3-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxanide, as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

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

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

15- Process for preparing 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 12, as well as the addition salts with inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases. said products of formula (I).

17-As medicaments, the products of formula (I) as defined in claim 12, as well as the addition salts with inorganic and organic acids or with the pharmaceutically acceptable mineral and organic bases of said products of formula (I ).

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

20. The use as defined in claim 19, wherein the protein kinase is in a cell culture.

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

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

23- Use of a product of formula (I) as defined in any one of claims 1 to 12 for the preparation of a medicament for the treatment of cancers.

24- Use according to claim 23 for the treatment of solid or liquid tumors.

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

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

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

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

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

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

As new industrial products, synthetic intermediates of formulas E ', 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; R7 represents a cycloalkyl or alkyl radical optionally substituted by an NR3R4 radical, 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.