CA2751525A1 - 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 - Google Patents

Abstract

The invention relates to novel products of formula (I) wherein - - - - represents a single or double bond; Ra represents -O-cycloalkyl or -NH-cycloalkyl; X is S, SO or SO 2, A is NH or S; W is H, alkyl or COR with R is cycloalkyl; alkyl; alkoxy; O-phenyl; -O- (CH 2) n-phenyl with n = 1 to 4; or NR1 R2 with R1 is H or alk and R2 is H, cycloalkyl, heterocycloalkyl, or alkyl; or R1, R2 together with N form a ring optionally containing O, S, N and / or NH; all these radicals being optionally substituted; these products being in all isomeric forms and salts, as medicaments especially 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 derivatives or -6-NH-cycloalkyl-triazolopyridazine-sulfanyl benzothiazole and benzimidazole, their process of preparation, the new intermediates obtained, their application cation as medicaments, the pharmaceutical compositions containing and the new use of such 6-triazolopyridazine derivatives sulfanyl benzothiazole and benzimidazole.

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

To date, most commercial compounds used in chemotherapy are cytotoxic that pose significant problems of effects side effects and tolerance by patients. These effects could be limited insofar as the drugs used act selectively on the cancer cells, excluding healthy cells. One of the solutions to limit the adverse effects of chemotherapy may therefore consist in the use of drugs acting on metabolic pathways or constitutive elements of these pathways, mainly expressed in cells cancerous, and which would not be expressed in the cells healthy. Protein kinase is a family of enzymes that catalyze the phosphorylation of hydroxy groups of specific protein residues such as than tyrosine, serine or threonine residues. Such phosphorylations can greatly alter the function of proteins: thus, proteins kinases play an important role in regulating a wide variety of cellular processes, including metabolism, proliferation

2 cell, adhesion and cellular motility, differentiation cell or the cell survival, with some protein kinases playing a central role in initiation, development and completion of cycle events cellular.

Among the different cellular functions in which the activity of a protein kinase is involved, some processes represent targets attractive for treating certain diseases. As an example, mention may be made including angiogenesis and control of the cell cycle and as well as cell proliferation, in which protein kinases can play a vital role. These processes are particularly essential for the growth of solid tumors and other diseases, including inhibiting molecules of such kinases are likely to limit unwanted cell proliferations such as those observed in the cancers, and may intervene in the prevention, regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or else neuronal apoptosis.

The present invention relates to novel derivatives having effects inhibitors vis-à-vis protein kinases. The products according to this In particular, the invention can be used for the prevention or treatment of diseases that can be modulated by protein inhibition kinases.

The products according to the present invention exhibit in particular an activity anticancer, via modulation of kinase activity. Among the kinases for which a modulation of the activity is sought, MET as well as Mutants of the MET protein are preferred.

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

3 Thus, one of the objects of the present invention is to propose compositions having anticancer activity, in particular by acting against to kinases. Among the kinases for which modulation of the activity is sought, MET is preferred.

In the pharmacological part below, it is shown in tests biochemical and on cell lines, that the products of this In particular, the application inhibits 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 an activity receptor tyrosine kinase expressed particularly by epithelial cells and Endothelial. HGF, Hepatocyte Growth Factor, is described as the ligand specific to MET. HGF is secreted by the mesenchymal cells and activates the MET receiver that moderates. Consequently, 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, as well as HGF, have been found to be overexpressed in many human tumors and a wide variety of cancers. MET is also found amplified in gastric tumors and glioblastomas. Many Point mutations of the MET gene have also been described in tumors, especially in the kinase domain but also in the field juxtamembranaire and the SEMA domain. Overexpression, amplification or mutations cause constitutive activation of the receptor and a deregulation of its functions.

4 The present invention thus relates in particular to novel inhibitors of MET protein kinase and its mutants, which can be used for anti-proliferative and anti-metastatic treatment, especially in oncology.

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

The subject of the present invention is the products of formula (I):
NXAH
AH
//> - N \
W
IN

Ra in which represents a single or double bond;

Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl all optionally substituted, X is S, SO or SO2;
A represents NH or S;

W represents a hydrogen atom; an alkyl radical 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 with NR 3 R 4, alkoxy, hydroxy or heterocycloalkyl; a 0-phenyl radical or a radical O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4, or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an alkyl radical optionally substituted with one or more identical radicals or different radicals chosen from hydroxyl, alkoxy and heteroaryl radicals, heterocycloalkyl, NR3R4, optionally substituted phenyl or R1 and R2 form with the nitrogen atom to which they are attached a radical cyclic ring containing from 3 to 10 members and optionally one or several other heteroatoms chosen from O, S, N and NH, with the optional S possibly being in SO or SO 2 form; this radical including the eventual NH it contains being possibly substituted, with R3 and R4, identical or different, represent an atom of hydrogen, an alkyl radical, a cycloalkyl radical, a radical heterocycloalkyl, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical radicals or different radicals chosen from hydroxyl, alkoxy and heteroaryl radicals, heterocycloalkyl, NH2, NHAIk, N (Alk) 2 or optionally phenyl substituted; or else R3 and R4 form with the nitrogen atom to which they are linked to a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, with the optional S possibly being in SO or SO 2 form; this radical including the eventual NH it contains being possibly 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 with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy radicals, -O-CO-R5, -000H, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5 and the alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl radicals, phenyl, CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals, the radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or several radicals chosen from halogen atoms and radicals hydroxyl, oxo, alkyl and alkoxy containing 1 to 4 carbon atoms, NH 2, NHalk 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 can be optionally substituted on one of the ring carbons by a radical spirocycloalkyl or spiroheterocycloalkyl or possibly on two of the carbons of the ring with a fused cycloalkyl or heterocycloalkyl radical;
R5 and R5 ', which may be identical or different, represent an alkyl radical or cycloalkyl 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 0-cyclohexyl radical or the NH-unsubstituted cyclohexyl and represents a double bond, said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a single or double bond;

Ra represents a radical -O-cycloalkyl or a radical -NH-cycloalkyl optionally substituted, X is S, SO or SO2;
A represents NH or S;

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

a cycloalkyl radical or an alkyl radical, optionally substituted with a halogen atom or a cycloalkyl radical, NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl themselves optionally substituted, an alkoxy radical optionally substituted with NR 3 R 4, alkoxy, hydroxy or heterocycloalkyl; a 0-phenyl radical or a radical O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4, or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an alkyl radical optionally substituted with one or more identical radicals or different radicals chosen from hydroxyl, alkoxy and heteroaryl radicals, heterocycloalkyl, NR3R4, optionally substituted phenyl or R1 and R2 form with the nitrogen atom to which they are attached a radical cyclic ring containing from 3 to 10 members and optionally one or several other heteroatoms chosen from O, S, N and NH, with the possible S possibly being in the SO or S02 form, this radical including the eventual NH it contains being possibly substituted, with R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with by one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIk radicals, N (Alk) 2 or optionally substituted phenyl; or else R3 and R4 form with the nitrogen atom to which they are attached, a cyclic radical containing from 3 to 10 links and optionally one or more other heteroatoms selected among O, S, N and NH, with the possible S possibly being under form SO or S02, this radical including the eventual 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 chosen radicals among the halogen atoms, the radicals hydroxyl, oxo, alkoxy, -O-CO-R5, NH2, NHalk, N (alk) 2 and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves possibly substituted by one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl radicals and alkoxy containing 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2;

R5 represents an alkyl or cycloalkyl radical containing at most 6 atoms of carbon;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

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

A represents NH or S;

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

a cycloalkyl radical or an alkyl radical optionally substituted with a halogen atom or a cycloalkyl radical, NR3R4, alkoxy, hydroxy, phenyl or heterocycloalkyl themselves optionally substituted;

an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or heterocycloalkyl; a 0-phenyl radical or a radical O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4;

or the radical NR1 R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an optionally substituted alkyl radical with an alkoxy, heterocycloalkyl or NR3R4 radical; 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 y including the possible NH that it contains being possibly substituted, with NR3R4, such that R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical or a radical heterocycloalkyl, all optionally substituted with one or more identical or different radicals chosen from alkoxy radicals, heterocycloalkyl or NH2, NHAIk or N (Alk) 2; or else R3 and R4 form with the nitrogen atom to which they are attached a cyclic radical containing from 3 to 10 links and possibly one or more others heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted;

all cycloalkyl, heterocycloalkyl and phenyl radicals as well as cyclic radicals that can form R1 and R2 or R3 and R4 with the atom to which they are linked, as defined above, possibly being substituted by one or more radicals selected from halogen atoms, hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 radicals and alkyl radicals, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl, such as in these last radicals, alkyl radicals, heterocycloalkyl, phenyl and heteroaryl are themselves possibly substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms carbon, NH2, NHalk and N (alk) 2;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

Concerning the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, these radicals containing optionally one or more other heteroatoms selected from O, S, N
and NH, with the optional S possibly being in SO or SO 2 form;
these radicals including the eventual NH they contain can therefore be optionally substituted in particular by a radical chosen from alkyl, alkoxy, cycloalkyl or heterocycloalkyl themselves optionally substituted by one or more radicals selected from halogen atoms and alkyl, alkoxy, NH2, NHAIk or N (Alk) 2 radicals;

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

X
AH
NOT' NOT
NW
IN

Ra in which represents a single or double bond;

Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl all optionally substituted, X is S, SO or SO2;
A represents NH or S;

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

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

an alkoxy radical optionally substituted with NR 3 R 4, alkoxy, hydroxy or heterocycloalkyl; a 0-phenyl radical or a radical O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4, or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, or an optionally substituted alkyl radical by one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 radicals, optionally substituted phenyl or else R1 and R2 form with the nitrogen atom to which they are attached a cyclic radical containing 3 10-membered 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 radical phenyl, all optionally substituted or else R3 and R4 form with the nitrogen atom to which they are attached, a cyclic radical containing from 3 to 10 links and optionally one or more other heteroatoms selected among O, S, N and NH, 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 with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy radicals, -O-CO-R5, -000H, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5 and the alkyl, cycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl radicals, CO-phenyl, heteroaryl and S-heteroaryl, as in the latter radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals, oxo, alkyl and alkoxy containing 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2, all the radicals defined above cycloalkyl, heterocycloalkyl, heteroaryl and phenyl being further optionally substituted with an Si (alk) 3 radical;

R5 and R5 ', which may be identical or different, represent an alkyl radical or cycloalkyl 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 0-cyclohexyl radical or the NH-unsubstituted cyclohexyl and represents a double bond, said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a single or double bond;

Ra represents a radical -O-cycloalkyl or a radical -NH-cycloalkyl optionally substituted, X is S, SO or SO2;
A represents NH or S;

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

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

an alkoxy radical optionally substituted with NR 3 R 4, alkoxy, hydroxy or heterocycloalkyl; a 0-phenyl radical or a radical O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4, or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 radicals, optionally substituted phenyl or else R1 and R2 form with the nitrogen atom to which they are attached a cyclic radical containing 3 10-membered 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 radical optionally substituted phenyl or R3 and R4 together with the atom of 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, this radical including any NH that 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 with one or more radicals selected from halogen atoms, hydroxyl radicals, oxo, alkoxy, -O-CO-R5, NH2, NHalk, N (alk) 2 and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in the latter radicals alkyl radicals, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or more radicals selected from halogen atoms and the hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N (alk) 2, R5 represents an alkyl or cycloalkyl radical containing at most 6 atoms of carbon;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

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

A represents NH or S;

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

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

an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or heterocycloalkyl; a 0-phenyl radical or a radical O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4;

or the radical NR1 R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a radical alkyl optionally substituted by an alkoxy radical, heterocycloalkyl, or NR3R4; or else R1 and R2 form with the nitrogen atom to which they are bound a cyclic radical containing 3 to 10 members and optionally one or several other heteroatoms chosen from O, S, N and NH, this radical y including the possible NH that it contains being possibly 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 attached, a cyclic radical containing from 3 to 10 links and optionally one or more other heteroatoms selected among O, S, N and NH, this radical including the possible NH it contains being optionally substituted;

all cycloalkyl, heterocycloalkyl and phenyl radicals as well as cyclic radicals that can form R1 and R2 or R3 and R4 with the atom to which they are linked, as defined above, possibly being substituted by one or more radicals selected from halogen atoms, hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 radicals and alkyl radicals, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl, such as in these last radicals, alkyl radicals, heterocycloalkyl, phenyl and heteroaryl are themselves possibly substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms carbon, NH2, NHalk and N (alk) 2;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

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

A represents NH or S;

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

a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, or alkoxy;

a 0-phenyl or O- (CH 2) n-phenyl radical with phenyl optionally substituted and n represents an integer of 1 to 2, or the radical NR1 R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a radical alkyl and the other of R1 and R2 represents a hydrogen atom, a radical alkyl optionally substituted with a heterocyclic radical or NR3R4, or R1 and R2 together with the nitrogen atom to which they are attached form a radical cyclic optionally containing 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 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 attached a cyclic radical containing optionally one or more other heteroatoms selected from O, S, N
and NH, this radical including the eventual NH it contains being possibly substituted, all the cycloalkyl, heterocyclic and phenyl radicals as well as the radicals cyclic that can be formed R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, defined above, being possibly substituted by a or more radicals selected from halogen atoms, radicals hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 and alkyl and phenyl radicals, these the latter being themselves possibly substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals, alkyl and alkoxy containing 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2, said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

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

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

The subject of the present invention is the products of formula (I) such that defined above or hereafter answering the formula (la) or (Ib) N, N ~ SNH
NN /> - \
W
NOT

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

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a single link responding to the products of formula (I '):

NOAH
N / _N
NW
IN
Ra the substituents Ra, X, A and W having the meanings indicated in one any of the other claims, said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a double bond responding to the products of formula (I ") NOAH
N / _N
NW
Ra in which the substituents Ra, X, A and W have the indicated meanings at any of the other claims, said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a single link responding to products of formula (I ') N, NS NH
\ N -N \
NW
N (Pa) Ra in which Ra and W are selected from the meanings indicated in Moon any of the other claims, said products of formula (a) being in all isomeric forms possible racemic, enantiomeric and diastereoisomeric, as well as salts of addition with mineral and organic acids or with bases inorganic and organic of said products of formula (a).

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a double bond Answering the products of formula (I "a):

, NS NH
NOT
N iN, NW
N (P'a) Ra in which Ra and W are selected from the meanings indicated in Moon any of the other claims, said products of formula (I "a) being in all isomeric forms possible racemic, enantiomeric and diastereoisomeric, as well as salts of addition with mineral and organic acids or with bases inorganic and organic of said products of formula (I "a).

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a single link responding to products of formula (I'b) NyS SH
NNI / N / N \ W

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

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a double bond responding to the products of formula (I "b):
N \ / SSH
NNI / / N \
NW
Ra in which Ra and W are selected from the meanings indicated in Moon any of the other claims, said products of formula (I "b) being in all isomeric forms possible racemic, enantiomeric and diastereoisomeric, as well as salts of addition with mineral and organic acids or with bases inorganic and organic 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 linear radicals and the case branched, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl and their positional isomers linear or branched: alkyl radicals having from 1 to 6 carbon atoms are preferred carbon and more particularly the alkyl radicals containing from 1 to 4 carbon atoms from the above list;

the term "alkoxy radical" denotes linear radicals and, where appropriate, branched, methoxy, ethoxy, propoxy, isopropoxy, linear butoxy, secondary or tertiary, pentoxy or hexoxy and their linear position isomers or branched: alkoxy radicals containing from 1 to 4 carbon atoms are preferred carbon from the list above, the term halogen atom denotes the chlorine, bromine and iodine atoms or fluorine and preferably the chlorine atom, bromine or fluorine.

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

the term heterocycloalkyl radical thus denotes a carbocyclic radical monocyclic or bicyclic, containing from 3 to 10 members interrupted by one or more heteroatoms, identical or different, chosen from oxygen, nitrogen or sulfur atoms: there may be mentioned for example the morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl radicals, piperidyl, homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxodihydropyridazinyl, or oxetanyl or thietannyl all these radicals being optionally substituted; we can note that these heterocycloalkyl radicals may comprise a bridge formed from two chains to form, for example, an oxa-5- radical azabicyclo [2.2.1] heptane or azaspiro [3.3] heptane or other cycles azabicycloalkanes or azaspiroalkanes.

the terms aryl and heteroaryl designate unsaturated radicals or partially unsaturated, respectively carbocyclic and heterocyclic, monocyclic or bicyclic, containing not more than 12 links, optionally contain a -C (O) - chain, heterocyclic radicals containing one or more identical or different heteroatoms chosen from 0, N, or S with N, if appropriate, optionally substituted;

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

the term heteroaryl radical thus designates monocyclic radicals or bicyclic compounds containing 5 to 12 members: heteroaryl radicals monocyclic such as, for example, thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, 3-furyl, pyranyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such as 3- or 4-isoxazolyl, furazannyl, free or salified tetrazolyl, all these radicals being optionally substituted among which more especially thienyl radicals such as 2-thienyl and 3-thienyl, furyle tel 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, adamyl, benzofuryl, isobenzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thianthrenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl, azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl or oxodihydropyridino-pyrazolyl, all these radicals being optionally substituted, Examples of heteroaryl or bicyclic radicals include more especially the pyrimidinyl, pyridyl, pyrrolyl and azaindolyl radicals, indazolyl or pyrazolyl, optionally substituted with one or more identical or different substituents as indicated above.

The carboxy radical (s) of the products of formula (I) may be salified or esterified by 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, example, one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, the N-methyl, - among the esterification compounds, the alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these radicals alkyls which may be substituted with radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy radicals, alkylthio, amino or aryl such as, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl.

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

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

Cyclical radicals that can form on the one hand R1 and R2 with the atom of nitrogen to which they are attached and on the other hand R3 and R4 with the nitrogen atom to which they are linked, are eventually substituted by one or more radicals selected from those indicated above for potential substituents of heterocycloalkyl radicals ie one or more radicals chosen from halogen atoms, hydroxyl, oxo and alkoxy radicals, NH2; NHalk, N (alk) 2, and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, and CO-phenyl, such that in these radicals the radicals alkyl, heterocycloalkyl and phenyl are themselves optionally substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals, oxo, alkyl and alkoxy having 1 to 4 carbon atoms, NH 2; NHalk and N (alk) 2, Cyclical radicals that can form on the one hand R1 and R2 with the atom of nitrogen to which they are attached and on the other hand R3 and R4 with the nitrogen atom to which they are linked, are in particular possibly substituted by one or several identical or different radicals chosen from among the atoms of halogen and the radicals alkyl, hydroxyl, alkoxy, CH2-pyrrolidinyl, CH2-phenyl, heteroaryl, and phenyl, in which the alkyl radicals, pyrrolidinyl and phenyl are themselves optionally substituted with one or several identical or different radicals chosen from among the atoms of halogen and the alkyl, hydroxyl, oxo and alkoxy radicals.

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

When NR1 R2 or NR3R4 forms a ring as defined above, such the amino ring may be chosen in particular from pyrrolidinyl radicals, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl or piperazinyl, these radicals being themselves optionally substituted as indicated above or hereafter: for example by one or more identical or different radicals selected from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and CH2-phenyl radicals, radicals alkyl or phenyl being themselves optionally substituted with one or several identical or different radicals chosen from among the atoms of halogen and the alkyl, hydroxyl and alkoxy radicals.

The NR1 R2 or NR3R4 cycle may more particularly be chosen from the pyrrolidinyl radicals, morpholinyl optionally substituted with one or two alkyl or piperazinyl radicals optionally substituted on the second atom nitrogen with an alkyl radical, phenyl, or and CH2-phenyl, themselves optionally substituted with one or more identical radicals or different ones chosen from halogen atoms and alkyl radicals, hydroxyl and alkoxy.

The subject of the present invention is the products of formula (I) such that defined above or below in which represents a single or double bond Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl optionally substituted with a hydroxyl, alkoxy or -O-CO-R5 radical;

X is S;
A represents S;

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

a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, or alkoxy;

a 0-phenyl radical;

or the radical NR1 R2 in which R1 and R2 are such that one represents one hydrogen atom and the other represents an alkyl radical optionally substituted by a heterocycloalkyl radical, with NR3R4 such that R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical;

R5 represents an alkyl or cycloalkyl radical containing at most 6 atoms of carbon;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

Especially in the products of formula (I), cycloalkyl radicals can represent a cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl;

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

The subject of the present invention is thus the products of formula (I) such that defined above or below with 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] triazolo [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] triazolo [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] 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 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 - (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl 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] pyridazin-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-methoxyacetamide N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-d imethylglycinamide 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-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] cyclopropanecarboxylate 1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] am ino} cyclohexyl N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-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-amine 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] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -3-methoxypropanamide N- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -N2, N2-d imethylglycinamide 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine - (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) ethyl 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) -N2-cyclopropylglycinamide 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-ethylpiperazin-1-yl) acetam ide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-d-ethylglycinamide 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] pyridazin-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] carbamoyl} amino) -1,3-benzothiazol-6-yl] sulfanyl} [1,2,4] triazolo [4,3-b] pyridazin-6-yl) oxy] cyclohexyl} acetamide N- {6 - [(6 - {[4- (trifluoromethyl) cyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin yl) sulfanyl] -1,3-benzothiazol-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- (4-morpholin-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-benzothiazol-2-amine 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclobutyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine 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 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-N2, N2-diethyl-N- [6 - ({6 - [(trans-2-fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3 b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] glycinamide - 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} acetamide rac-N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin yl) sulfanyl] -1,3-benzothiazol-2-yl} -2- (morpholin-4-yl) acetamide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide - 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} acetamide 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) acetamide 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) acetamide 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) acetamide 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} cyclopropanecarboxamide 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] cyclopropanecarboxamide 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 yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide rac-1- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin 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-carboxamide 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-oxa-n-3-yl 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} cyclopropanecarboxamide as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

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

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

The products according to the invention can be prepared using methods conventional organic chemistry. Diagrams 1, 2, 3, 4, 5 and 6 below below are illustrative of the methods used for the preparation of 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 In particular, the present invention can be prepared according to the processes described.
in diagrams 1, 2, 2bis, 3, 4, 5 and 6 below.

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

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

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

The present invention thus also relates to the preparation process of products of formula (I) according to scheme 3 as defined below The present invention thus also relates to the preparation process of products of formula (I) according to scheme 4 as defined below The present invention thus also relates to the preparation process of products of formula (I) according to scheme 5 as defined below The present invention thus also relates to the preparation process 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, we define the products of formula (I ') which represent the products of formula (I) in which represents a single bond and the products of formula (I ") which represent the products of formula (I) in which represents a double bond, similarly for synthetic intermediates as defined below formulas (a), (b), (c), (d), (e) and (f) wherein represents a bond single or double, we define the compounds of formulas (a '), (b'), (c '), (d'), (E ') and (f ') in which 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 (la "), (Ib"), (1 "c), (1 d"), (1 e "), (1 a '), (1 b'), (1 c '), (1 d') and (1 e ') NC 'S \ NHz reduction HSNHZ
NOZ \ I NOZ
QF

HS NH, NN Ra-H NO, N INYy S / NHz NN NO
N according to diagram 3 ~ N ~ \ N 3 S Ra Ra G
commercial E
reduction N-CoZr, / R MeS- </
H; H-COzR5 N ~ N \ S / z NH
NH v NY H (R) Rz NiS / NH ~~) N ' N / N / I / NR ~ NN INN ON
%
\ \ NN` / O R6 NO Rz R a R 1b '/ 1b "Ra to the 'I' BrCN
iN H R6000X N g H
N \ s NH Ne N
/ N (G) N / NHz there N \ NO \ \ N

Ra 1d '/ 1d "Re 1c' / 1c"

NH
NL SI ~ H
NOT
\ \ NR
NOT

Ra the '/ the' In Scheme 1 above, the substituent Ra can take the meanings given above for the products of formula (I ') and (I "), the substituent R5, in the compounds of formulas (J), (la ') and (la "), represents a radical alkyl and the substituent R6 in the compounds of formulas (O), (1d ') and (1d "), represents an alkyl radical optionally substituted with NR3R4 (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 R7 in the compounds of formulas (P) and (le ') / (le ") represents a cycloalkyl or alkyl radical optionally substituted with a radical NR3R4, alkoxy, hydroxy phenyl, heteroaryl, or heterocycloalkyl, themselves possibly substituted.

In Figure 1 above, the groups CONR1 R2, C02R6 and COR7, which constitute W, can take the values of W as defined above for the products of formula (I ') and (I "), when W # H

In the above scheme 1, the benzimidazoles of the general formula (la "), (Ib "), (1c"), (1d ") and (the") as well as their reduced analogues of formula (1 '), (1'), and (1 ') can be prepared from of the Commercial 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine of formula (S).

N -N

BORN
Ra Compounds (E) can be obtained, for example, by reaction of 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 of 20 C to 80 C.

HS / NHZ
k F
NOZ
NN / y `S / NHZ
NG
NOZ
NOT

Ra The compounds (G) can be obtained, for example, by reaction of 3-amino-4-nitro-benzenethiol of formula (F) on the 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 of 20 C.

NO` .S NH2 I \ NI H '/ H "
~ N NH2 Ra The compounds (H ") as represented by a double bond can for example, by reduction with iron (0) on the compounds of formula (G), in a solvent such as methanol, in the presence of acetic acid, a temperature close to 70 C.

The compounds (H ') as represented by a single bond can for example, by reduction with zinc (0) on the compounds of formula (G), in the presence of acetic acid, at a temperature close to C.

More particularly, the carbamates of general formula (la ') and (la ") can be prepared especially as described in the patent W003028721A2, respectively from a 3,4-diamino phenyl sulphide of formula (H ') and (H ") and a pseudothiourea of formula (J), in the presence acetic acid and in a protic solvent such as methanol, at a temperature around 80 C.

More particularly, the benzimidazoles of the general formula (Ib ') and (Ib ") 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 (la ') and (la "), 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, 2-amino benzimidazoles of general formula (1c ') and (1c ") can be prepared for example by reaction of the bromide of cyanogen on a compound of formula respectively (H ') and (H "), in presence of a protic solvent such as ethanol. The reaction is carried out a temperature around 80 C.

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

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

Scheme 2: Synthesis of Benzothiazole Derivatives of Formulas (2a '), (2b'), (2c '), (2d'), (2a) ', (2b'), (2c '), (2d') NN 'NrS <), - SH
~ CI \ / N i NNN ~ N
NC ~ S / SH HS / S / NO RZ
NR reduction H Ra E
N ~ NR 0 IN /> - CNR '- ~ Ra 2b' / 2b "

N RZ NN
N% ~ CI N \ N`yS / SH
(R) i 1 / N
HS S ~ NNN ~ O
NC'S / I Sj ~ N reduction / I /> _ N Ra t / NO Rs N ~ 'R - N -O - ~ Ra 2a' / 2a "

(O) N ~ CI
SS
NC'S / S lily reduction / SI Ra EN \ NN ~ 11- IN NH2 \ N> -NH2 -, \ I N> -NH2 N
2d '/ 2d "
KN Ra R7COX NN% _CI
(P) HS reduction HS SH Ra E 'NS SH
NC ~ \ N ~ NR -y \ IN ~ R7 \ NN 0 N> -N -R7 L3 M3 2c '/ 2c "
Ra In Scheme 2 above, the substituent Ra can take the meanings indicated above for the products of formula (I ') and (I ").

In Figure 2 above, the groups CONR1 R2, C02R6 and COR7, which constitute W, can take the values of W as defined above for the products of formula (I ') and (I "), when W # H

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

~ S \
S NC / S ~ H L1 NC
I` \ NHZ Uej N

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 hydrogen carbonate sodium, at a temperature of 20 C.

NC "S" j: e: ~ j SH
/ eN NR 'L2 NOT
0 Rz The compounds of general formula (L2) can be obtained, for example, by reaction of carbamates of formula (L1) where R6 = phenyl, with amines NHR1 R2 of formula (R) (with R1 and R2 as defined above), in presence of an aprotic solvent such as tetrahydrofuran, at a temperature close to 20 C.

Ureas (2b ') and (2b ") can be obtained, for example, respectively from carbamates (2a ') and (2a ") where R6 = phenyl, in the same way as the ureas (L2) are obtained by reaction of amines on the carbamates of type (L1).

NC "S / NH

N ~ O

The compounds of general formula (L3) can be obtained for example by reaction of an acid chloride of formula (P) (X = Cl) on the thiocyanate of 2-amino-1,3-benzothiazol-6-yl (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) on the 2-amino-1,3-benzothiazol-6-yl thiocyanate (K), in the presence, by for example, a solvent such as pyridine at a temperature of 20 C.

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

In the same way that carboxamides (L3) can be obtained by acylation of the amine (K), carboxamides (2c ') and (2c ") can be obtained respectively from amines (2d ') and (2d ") by coupling with an acid of formula (P) (X = OH) under the conditions, for example, described by N. Xi and al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211-5217, in the presence of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), in a solvent such as N, N-dimethylformamide, in the presence of a base such as di-isopropyl ethylamine, at a temperature of 20 C.
Scheme 2bis: Synthetic routes of glycinamide derivatives (2c ') and (2c ") HO
N'N \ / SS hNR3R4 N
N /> - NH2 NSH
`IV N ~ P,) tN% / N
N -R
~~ NO
Ra 2d '/ 2d "202c"
Ra R7 = CH2-NR3R4 \ NSS
CI N ~ N NR3R4 O CI t ~ N
% hcl 2e12e "
Ra In Scheme 2bis above the substituent R7 can take on the meaning an aminomethyl group. These glycinamides (2c '/ 2c ") can be obtained by coupling amines (2d ') and (2d ") with a glycidic acid (P') in using the methods described above for acids (P) (X = OH).

The glycidic acids (P ') can be prepared from the acid bromoacetic acid and amines HNR3R4 under conditions similar to those described by DT Witiak et.al .; J. Med. Chem. 1985, 28, 1228.

Alternatively, the amines (2d ') and (2d ") can be treated with the 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 (2e '/ 2e ") thus formed can react with HNR3R4 amines, such as as defined above, in a solvent such as pyridine at a temperature 20 C, to give the derivatives (2c '/ 2c ") as defined in Figure 2bis above.

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

More particularly, benzothiazoles of general formula (2d ') and (2d ") can also be prepared respectively from carbamates of formula (2a ') and (2a') where R6 = t-butyl by reaction, for example, with trifluoroacetic acid in a solvent such as dichloromethane, at a temperature close to 20 C.

Reciprocally, benzothiazoles of general formula (2a ') 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 hydrogen carbonate sodium, at a temperature of 20 C.

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

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

2) 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 around 95 C.

3) 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, tert-potassium butylate, tris (dibenzylideneacetone) dipalladium (0) and bis (2-diphenylphosphinophenyl) ether in a solvent such as toluene at a temperature close to 110 C

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

Reducing conditions 1) and 2) can give products of formula (2a), (2b), (2c) and (2d) as represent a single bond or double while conditions 3) and 4) give products of formula (2a), (2b), (2c) and (2d) as represent a double bond.

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

BORN
(U) i Ra = OR8 Ra N_N HZNRB NN
NCI (R) N ~ _CI
iN
y E
CI s R a Ra = NHR8 In Scheme 3 above, the substituent Ra has the indicated meanings above for the products of formula (I ') and (I ").

The substituent R8 represents a cycloalkyl radical as defined above for products of formula (I) The compounds of formula (E) can be obtained, for example, as shown in Figure 3 above, from 3.6 commercial dichloro [1,2,4] triazolo [4,3-b] pyridazine of formula (S).

More particularly, the compounds of formula (E) wherein Ra represents a OR8 radical can be obtained by treatment of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (S) at a temperature in the region of 20 ° C
at 80 ° C. and in a solvent such as tetrahydrofuran with an alcoholate of formula (U), itself obtained by treating an alcohol (HOR8) with, for example, for example, sodium hydride in a solvent such as tetrahydrofuran a temperature close to 0 C to 20 C, More particularly, the compounds of formula (E) wherein Ra represents a radical R8NH can be obtained by the treatment of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (S) with an 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 ') and (2e ") NS Rgx N \ y S / S, R9 "t N / I
/ I / `N 1W) N \ / Il / ~ deprotection N Rg % \ NO
N ~ ON
/ NO TV Rs T., O Rs Ra 2a '/ 2a "R has 20 2nd"
Ra terms reductive E

x NSS
NCS / SH (W) NC'S / S R9 EN \ H
~ N ~ O ~ N ~ / N
/ ---> -NN Rg O Rs O Rs via T "
L1 L4 R a 2nd "
According to scheme 4 above, benzothiazoles of general formula (2e ') and (2e ") can be prepared respectively from compounds of formula (2a ') and (2a ").

In scheme 4 above, the OR6 substituent represents preferentially Ot-Butyl. The substituent R 9 represents an alkyl radical or cycloalkyl optionally substituted by an alkoxy radical, heterocycloalkyl or NR3R4 (R3 and R4 as defined above).

el 1 S / s NNS
/NOT
N \ N -O
Z: bl NO R6 * "OC
Ra TY T "

Carbamates of general formula (T) and (T ") can be obtained respectively by reaction of carbamates of general formula (2a ') and (2a ") with R6 = tBu preferentially, for example, with halides of formula (W), in a solvent such as N, N-dimethylformamide, in presence of sodium hydride at a temperature between 20 and 90 C.
Benzothiazoles of general formula (2e ') and (2e ") may also be prepared from compounds of formula (L1), preferably with R6 = tBu, via the compounds of formula (T) and (T ").

More particularly, the compounds of general formula (2e ') and (2e ") can be obtained respectively by treatment of the compounds (T) and (T ") isolated, for example, with trifluoroacetic acid, in a solvent such dichloromethane, at a temperature 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 close to 80 C, possibly followed by an in situ treatment with trifluoroacetic acid at 20 C if necessary.

NC'S / S, 8 ~ N ~ -O

Carbamates of general formula (L4) can be obtained by reaction carbamates of general formula (L1), for example, with halides of formula (W), in a solvent such as N, N-dimethylformamide, in presence of sodium hydride at a temperature between 20 and 90 C.
Scheme 5: Synthesis of benzothiazole derivatives of formula (2e ') and (2e ") -'N CI
N`N / \ TN III Ili R9_NH2 NEN
diazotization III N, y S / SH
S `
bromination s ', / SSS Ra' N
H t \ N
S N> -NH CuB - I ~ Br 3- / N \ N 01N Rs 2 V _N
NaNO N R9 K z 2nd "
L5 L6 Ra N \ YS / SH
NOT

2nd ' Ra Alternatively, according to scheme 5 above, benzothiazoles of formula (2e ") can be prepared from 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 around 80 C.

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

The compounds of formulas (L6) can be prepared from derivative 2 bromo benzothiazole (L5) by treatment with an NH 2 R 9 derivative, for example, in a solvent such as tetrahydrofuran, at a temperature of 20 C.
The substituent R 9 represents an optionally substituted alkyl or cycloalkyl radical substituted by an alkoxy, heterocycloalkyl or NR3R4 radical (R3 and R4 such as defined above).

The compounds of formulas (L5) can be prepared from thiocyanate 2-amino-1,3-benzothiazol-6-yl (K) (commercial compound), for example, by treatment with an alkyl nitrite and cuprous bromide in a solvent such as acetonitrile, at a temperature in the region of 0-20 C, according to the method described by Jagabandhu Das and. al. in J. Med. Chem. 2006, 49, 6819-6832.
Figure 6 Other synthetic routes of reduced derivatives of formulas (I ') NS / A ~ NSAH reaction N_N SA
reduction N / SU on 114- H
N \ \ IN \ \ NI ~ N WNI / N group IN ~ NN
Ra Ra Mlou coupling M2 or M3 or NN ycl N ~ Ycl N
N reduction tN \
. \
E Ra E 'Ra According to scheme 6 above, benzothiazoles of general formula (I ') can also be prepared from the compounds of formula (I ") by reduction, for example, with sodium borohydride, in a solvent such as ethanol, at a temperature in the region of 80 C or by reduction with zinc (0) in the presence of acetic acid, at a temperature of 20 C.

Alternatively the compounds (I ') can also be prepared from compounds of formula (E) by coupling with compounds of M1 type, M2, M3 or N, obtained as intermediates by reducing the compounds L1, L2, L3 or K in situ, as described above in Scheme 2. The compounds type M1, M2 or M3 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 presence of acetic acid, at a temperature of 20 C.
Alternatively the compounds (I ') can also be prepared from other compounds (I ') by transformation of the group W into a group W 'of the same nature as defined above for W and according to the type of reactions defined in diagram 2: the 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, it is possible to to oxidize sulfur S to sulfoxide SO or sulfone S02 according to the methods known to those skilled in the art and protecting, if necessary, the optionally reactive groups with protective groups appropriate.

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

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

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

the hydroxyl groups can be protected for example by the alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl, the amino groups can be protected for example by radicals acetyls, 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 esters or butyl esters or esters known in peptide chemistry.

A list of different protective groups can be found in manuals known to those skilled in the art and for example in the BF patent 2,499,995.

It may be noted that it is possible to submit, if desired and if necessary, products intermediates or products of formula (I) thus obtained by the processes above, to obtain other intermediaries or other products of formula (I), one or more reactions of known transformations of the skilled person such as for example:

a) an esterification reaction of an acid function, b) an ester functional saponification reaction in the acid function, c) a reduction reaction of the free or esterified carboxy function as a function of alcohol d) a conversion reaction of alkoxy function to hydroxyl function, or still hydroxyl function in alkoxy function, e) an elimination reaction of the protective groups that can carry protected reactive functions, f) a salification reaction with a mineral or organic acid or with a base to get the corresponding salt, (g) a split reaction of the racemic forms into products split, said products of formula (I) thus obtained being in any form possible racemic isomers, enantiomers and diastereoisomers.

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.
after.

(a) The products described above may, if desired, be the subject of possible carboxy functions, esterification reactions which can be performed according to the usual methods known to those skilled in the art.

b) Possible ester function transformations in acidic functions of products described above may be, if desired, carried out in common conditions known to those skilled in the art in particular by hydrolysis acid or alkaline for example by soda or potash in medium alcoholic such as, for example, in methanol or by acid hydrochloric or sulfuric.

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 methanol or ethanol, dioxane or dimethoxyethane, in the presence soda or potash.

c) Possible free or esterified carboxy functions of the products described this-above can be, if desired, reduced in alcohol function by the methods Known to those skilled in the art: the possible esterified carboxy functions can be, if desired, reduced in alcohol function by known methods of the skilled person and in particular by lithium aluminum hydride in a solvent such as, for example, tetrahydrofuran or else dioxane or ethyl ether.

The possible free carboxy functions of the products described above may if desired, reduced in particular alcohol function by hydride of boron.

d) the possible alkoxy functions such as in particular methoxy products described above can be, if desired, transformed into hydroxyl in the usual conditions known to those skilled in the art by example by boron tribromide in a solvent such as for example the methylene chloride, with hydrobromide or pyridine hydrochloride or still with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux.

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

The phthalimido group can be removed by hydrazine.

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

g) Any optically active forms of the products described above can be prepared by splitting the racemates according to the usual methods known to those skilled in the art.

The products of formula (I) as defined above and their salts addition with acids have interesting properties particularly because of their inhibitory properties.
kinases as indicated above.

The products of the present invention are particularly useful for the therapy tumors.

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

These properties justify their application in therapeutics and the invention has particularly for the purpose of medicaments, formula products (I) as defined above, said products of formula (I) being under all the possible racemic isomeric forms, enantiomers and diastereoisomers, 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 subject of the invention is, in particular, as medicaments, the products 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] triazolo [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] triazolo [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] 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 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 - (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl 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] pyridazin-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-methoxyacetamide N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-d imethylglycinamide 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-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] cyclopropanecarboxylate 1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] am ino} cyclohexyl N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-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-amine 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] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -3-methoxypropanamide N- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -N2, N2-d imethylglycinamide 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine - (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) ethyl 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) -N2-cyclopropylglycinamide 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-ethylpiperazin-1-yl) acetamide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-d-ethylglycinamide 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] pyridazin-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] carbamoyl} amino) -1,3-benzothiazol-6-yl] sulfanyl} [1,2,4] triazolo [4,3-b] pyridazin-6-yl) oxy] cyclohexyl} acetamide N- {6 - [(6 - {[4- (trifluoromethyl) cyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin yl) sulfanyl] -1,3-benzothiazol-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- (4-morpholin-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-benzothiazol-2-amine 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclobutyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine 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 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-N2, N2-diethyl-N- [6 - ({6 - [(trans-2-fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3 b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] glycinamide - 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} acetamide rac-N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin yl) sulfanyl] -1,3-benzothiazol-2-yl} -2- (morpholin-4-yl) acetamide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide - 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} acetamide 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) acetamide 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) acetamide 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) acetamide 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} cyclopropanecarboxamide 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] cyclopropanecarboxamide 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-l-carboxamide rac-N- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide rac-1- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin 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-carboxamide 1- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-oxa-n-3-yl 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} cyclopropanecarboxamide 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) such as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, a pharmaceutically acceptable carrier acceptable.

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

Such pharmaceutical compositions of the present invention may also, where appropriate, contain other active ingredients antimitotic drugs such as, in particular, those based on taxol, cis-platinum, intercalating agents of DNA and others.

These pharmaceutical compositions may be administered by oral, parenterally or locally applied topically to the skin and mucous membranes or by intravenous or intravenous injection muscular.

These compositions may be solid or liquid and may be all pharmaceutical forms commonly used in medicine such as, for example, simple or sugar-coated tablets, pills, tablets, capsules, drops, granules, preparations injectables, ointments, creams or gels; they are prepared according to the usual methods. The active ingredient can be incorporated into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, stearate, magnesium, cocoa butter, aqueous vehicles or not, fatty substances animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The usual dosage, variable depending on 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 present invention also relates to the use of the products of formula (I) as defined above or pharmaceutically acceptable salts of these products for the preparation of a medicinal product intended for inhibiting the activity of a protein kinase.

The present invention also relates to the use of formula (I) as defined above for the preparation of a medicament for the treatment or prevention of a disease characterized by disruption of the activity of a protein kinase.

Such a medicament may in particular be intended for treatment or for prevention of a disease in a mammal.

The present invention also relates to the use defined above wherein the protein kinase is a protein tyrosine kinase.

The present invention also relates to the use defined above wherein the protein tyrosine kinase is MET or its mutant forms.

The present invention also relates to the use defined above wherein the protein kinase is in a cell culture.

The present invention also relates to the use defined above wherein the protein kinase is in a mammal.

The subject of the present invention is in particular the use of a product of formula (I) as defined above for the preparation of a medicament intended for the prevention or treatment of diseases related to proliferation not controlled.

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 selected disease in the group next: disorders of blood vessel proliferation, disorders fibrotic, mesangial cell proliferation disorders, disorders metabolic, allergies, asthma, thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, degeneration muscle and cancers.

The subject of the present invention is therefore particularly the use 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 the treatment of cancers.

Among these cancers, we are interested in the treatment of solid tumors or for 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), glioblastomas, cancers of the thyroid, bladder, breast, in melanomas, in tumors lymphoid or myeloid haematopoietic diseases, in sarcomas, in patients with cancers of the brain, larynx, lymphatic system, bone and pancreas.

The present invention also relates to the use of the products of formula (I) as defined above for the preparation of medicinal products intended 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 still in combination for example with other therapeutic agents.

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

As inhibitors of kinases, mention may be made of butyrolactone, flavopiridol and 2 (2-hydroxyethylamino) -6-benzylamino-9-methylpurine called olomucin.
The present invention also relates to industrial products new, synthetic intermediates of formulas E, M1, M2, M3 and N
as defined above and recalled below:

N IN CI
HS SH HS / SH

NN \ O \ I> -N NR% R6 M2 o R2 E-R a mi HS / SH HS

\ IN ~ R, M3 O ~ NFi2 NOT
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 meanings indicated above for products of formula (I) The following examples which are products of formula (I) illustrate the invention without limiting it.

Experimental part The nomenclature of the compounds of this invention has been carried out with ACDLABS version 10.0 and version 11 software Microwave oven used:

Biotage, Initiator EXP-EU, 300W max, 2450MHz 1 H NMR spectra at 400 MHz and 1 H at 300 MHz were BRUKER AVANCE DRX-400 or BRUKER AVANCE DPX-300 spectrometer with chemical shifts (8 ppm) in the solvent dimethylsulfoxide-d6 (DMSO-d6) referenced at 2.5 ppm at the temperature of 303K.
Mass spectra were made either by analysis:
LC-MS-DAD-ELSD (MS = Waters ZQ) - LC-MS-DAD-ELSD (MS = Platform Il Waters Micromass) - UPLC-MS-DAD-ELSD (MS = Quattro Premier XE Waters) - UPLC-SQD (Waters) DAD considered wavelength A = 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) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide can be prepared from following way:
at 2cm3 of pyridine at 20 ° C are added 75mg 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 mixing for 18h. 20 μl of cyclopropane acid chloride are added carboxylic acid and allows an additional hour to react. The mixture The reaction is concentrated to dryness and the solid residue is chromatographed by solid deposit on Biotage Quad 12/25 (KP-SIL, 60A; 32-63pM) eluting with a dichloromethane / methanol gradient of 99.5 / 0.5 to 90/10. The solid obtained is washed with ethyl ether. This gives 66 mg of N- (6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) cyclopropanecarboxam ide in the form of a white powder whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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, 1 H) 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 (brs, 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 as follows:

through a solution of 49mg of 2-amino-1,3-benzothiazol thiocyanate 6-yl (commercial) in 20 cm3 of ethanol is bubbled a stream of argon for 5 minutes. 4 mg of dihydrogenphosphate is then added.
potassium in 0.2cm3 of water, 333mg of DL-dithiothreitol and 182mg of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine. The mixture The reaction is heated at 800 ° C. for 23 h and then concentrated to dryness in vacuo.
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. This gives 130mg of 6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine in the form of a yellowish powder whose characteristics are the following:
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 cm3 of tetrahydrofuran 0 C under argon are added 762mg 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). The brown suspension is stirred for 22 hours in letting it gradually return to 20 ° C. The reaction medium is then poured on ice water and the mixture is extracted with ethyl acetate. After dry concentration of the organic phase under vacuum, an oil is obtained Brown. The oily residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A; 32-63 μM) eluting with a cyclohexane / acetate gradient of ethyl from 95/5 to 65/35. 2.7 g of 3-chloro-6- are thus obtained.
(cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine as a yellowish powder whose characteristics 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 from following way:
through a solution of 339 mg of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl) 1,3-benzothiazol-2-yl) urea in 20 cm3 of ethanol, a current is bubbled through of argon for 5 minutes. 5 mg of dihydrogenphosphate is then added of potassium in 0.2cm3 of water, 463mg of DL-dithiothreitol and 253mg of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine (1c). The mixture reaction is then heated at 80 C for 47h, then the whitish solution is evaporated to dryness under vacuum. The residue is purified on silica by deposit solid 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] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea in the form of a white powder whose characteristics are the following :
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S 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 (ss, 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) 10.90 (brs, 1H) 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 as follows:
in a mixture of 900 mg of 2 - {[(2-morpholin-4) thiocyanate ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl and 40 cm3 of ethanol at 20 ° C
a stream of argon is bubbled for 5 minutes. 11 mg is then added of potassium dihydrogenphosphate in 0.4 cm3 of water and 1.1 g of dithiothreitol. The mixture is heated at 80 ° C for 3.5h. The environment The reaction mixture is cooled to 20 ° C. and then poured into water. The suspension is stirred for 45min maintaining a slight argon bubbling. The precipitate formed is drained and washed with 3x10cm3 of water, and then dried under vacuum at 20 ° C.
633 mg of 1- (2-morpholin-4-ylethyl) -3- (6-sulphanyl) -1,3-benzothiazol-2-yl) urea, in the form of a white solid whose characteristics are the following :
MASS SPECTRUM: LC-MS-DAD-ELSD: MH + m / z = 339 +; (MH) - = 337-c) 2 - {[(2-Morpholin-4-ylethyl) carbamoyl] amino} -1,3-thiocyanate benzothiazol-6-yl may be prepared as follows:
to a solution of 1 g of (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate phenyl ester in 30 cm3 of tetrahydrofuran, 0.44 cm3 of 2-morpholin-4-ylethanamine at 20 ° C. After 24h, the reaction mixture is evaporated to dryness and the residue obtained chromatographed on a Merck cartridge 70 g (solid deposit, elution with a dichloromethane gradient and 90/10 dichloromethane / methanol). 902 mg of thiocyanate are thus recovered.
of 2 - {[(2-morpholin-4-ylethyl) carbamoyl] amino} -1,3-benzothiazol-6-yl under form of a colorless foam whose characteristics are as follows MASS SPECTRUM: UPLC-MS-DAD-ELSD: MH + m / z = 364 +
(d) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate has been prepared as follows:
to a solution of 2.5 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of tetrahydrofuran, 7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogencarbonate and 9.4 cm3 of water. The resulting mixture is then stirred at 20 ° C. for 20 hours.
then extracted with 2x150cm3 of ethyl acetate. The organic phases are collected and washed with 3X50cm3 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. We take up the residue in 50 cm3 of water and then wring and dry under vacuum at C. Thus 3.45 g of (6-thiocyanato-1,3-benzothiazol-2-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 +; (MH) - = 326-Example 3 N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetam ide N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamid can be prepared in the following manner:
2 cc of pyridine at 20 ° C. are added 0.276 cm 3 of acetic anhydride and 160 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b). After 5h, we add 0.3 cm3 of anhydride acetic acid and allowed to agitate for 17 hours. The reaction mixture is concentrated to dry 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. We obtain thus 123 mg of N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3 [Sulfanyl] -1,3-benzothiazol-2-yl) acetamide as a white powder whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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, 2.0Hz, 1H) 7.66 (d, J = 8.5Hz, 1H) 8.06 (d, J = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 12.37 (brs, 1H) MASS SPECTRUM: UPLC-SQD: MH + m / z = 441 +; MH = 439-Example 4 (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl carbamate (6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl carbamate can be prepared in a next :

to 200 mg of 6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (1b) in 5 cm 3 of pyridine is added at 20 ° C, 0.13 cm3 of phenyl chlorocarbonate. After 4h, the yellow suspension is concentrated in dry vacuum. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient of 100%
dichloromethane to dichloromethane / methanol 92.5 / 7.5. We obtain 224 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -Phenyl 1,3-benzothiazol-2-yl) carbamate in the form of a powder the characteristics of which are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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 = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 12.66 (brs, 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 can be prepared from following way:
to a solution of 200 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl carbamate (4) in 5 cm3 of tetrahydrofuran, 0.06 cm3 of 2- (pyrrolidin-1 yl) ethanamine and 0.14 cm3 of triethylamine at 20 C. After 2h at 20 C the The reaction medium is heated at 60 ° C. for 3 hours. 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 gradient dichloromethane / methanol 99/1 to 50/50. 171 mg of 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 as a powder the characteristics of which are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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 (ss, 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, 1H) 8.00 (d, J = 2.0 Hz, 1H) 8.27 (d, J = 10.0 Hz, 1H) 10.78 (s, 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] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N-[2- (pyrrolidin-1-yl) ethyl] -1,3-benzothiazol-2-amine can be prepared from following way:
to a solution of 534 mg of 2-bromo-1,3-benzothiazol-6-yl thiocyanate in 7 cm3 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 20cm3 of ethanol. The mixture is degassed by argon bubbling during 5min at 20 C then 5mg of dihydrogenphosphate are added potassium in 0.2cm3 of water followed by 617mg of DL-Dithiothreitol and 253mg 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine (1c). After 23h at reflux, the red suspension is concentrated to dryness under reduced pressure. The residue is purified by dry deposition on Biotage Quad 25M (KP-SIL, 60A; 32-63 pM) eluting with a gradient of 95: 5 to 85:15 dichloromethane /
(dichloromethane: 38 / methanol: 17 / ammonia: 2). The yellow solid obtained is washed with ether and with pentane. This gives 218mg of 6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -N- [2- (pyrrolidin yl) ethyl] -1,3-benzothiazol-2-amine in the form of a yellow powder whose characteristics are as follows:

NMR SPECTRUM 1H NMR (400MHz, DMSO-d6) S ppm 1.17 - 1.59 (m, 7H) 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, m.p.

MASS SPECTRUM: UPLC-SQD: MH + m / z = 496 +; MH- = 494-b) 2-bromo-1,3-benzothiazol-6-yl thiocyanate can be prepared from the following way:
a solution of 6.5 g of cuprous bromide in 666 cm3 of acetonitrile is purged with argon for 5min. The resulting solution is cooled to 0-5 C, then 4.3 cm3 of tert-butyl nitrite is added. Then 5g of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial), per serving, at 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 solution obtained is washed with a saturated solution of sodium bicarbonate. The organic phase is dried over magnesium sulfate and then concentrated to dryness under vacuum. 5.05 g of 2-bromo-1,3-thiocyanate are thus obtained.
benzothiazol-6-yl in the form of a yellow-gold powder whose characteristics are the following :
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 may be prepared in a manner similar to example la but from 200mg of 6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine (1b) in 5cm3 of pyridine with 0.165cm3 of methoxyacetyl after 23 hours of reaction at 20 C. This gives 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 whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S ppm 1.09 - 1.40 (m, 5H) 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 (brs, 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) -N2, N2-d imethylglycinamide 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 similar to example la but from 100mg of 6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine (1b) in 10 cm 3 of dichloromethane with 300 mg of N, N
dimethylglycyl, 0.33cm3 of triethylamine and 11 mg of 4-N, N-dimethylaminopyridine, after 27h of reaction at 20 C. Thus 75mg is obtained 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 powder yellowish with the following characteristics:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S 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, 2.0 Hz, 1H) 7.67 (d, J = 8.5 Hz, 1H) 8.07 (d, J = 2.0Hz, 1H) 8.28 (d, J = 10.0Hz, 1H) 11.92 (brs, 1H) 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-methylbutanam ide N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methylbutanamide can be prepared in a manner similar to example la but from 102mg of 6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine (1b) in 5cm3 of pyridine with 0.437cm3 of chloride of 3-methylbutanoyl after 46h of reaction at 200C. We thus obtain 98mg of N-(6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methylbutanamide as a white powder whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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 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 la but from 146mg of 6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine (1b) in 5cm3 of pyridine with 0.191cm3 of chloride of 3-methoxypropanoyl after 23 hours of reaction at 20 ° C., thus giving 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 white powder whose characteristics are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S ppm 1.11 - 1.65 (m, 8H) 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, H) 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) 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] triazolo [4,3-b] pyridazine in 30 cc of degassed ethanol, of 17 mg of potassium dihydrogenphosphate in 0.3 cm3 of water, 1.72g of DL-dithiothreitol and 772mg of 2-amino-1,3-thiocyanate benzothiazol-6-yl after 24h at 80 C. This gives 1.04 g of 6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine in the form of a white powder whose characteristics are the following:
NMR SPECTRUM 1H NMR (400MHz, DMSO-d6) S 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 = 8.6 Hz, 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] triazolo [4,3-b] pyridazine may be prepared in a manner similar to Example 1c but from 914 mg of cyclopentanol in 20cm3 of tetrahydrofuran, 254mg of hydride 60% sodium in oil and 3,6-dichloro [1,2,4] triazolo [4,6-dichloroate]
b] pyridazine (commercial), after 6.5h of reaction. We thus obtain 896mg of 3-chloro-6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazine as an oil colorless which crystallizes and whose characteristics are as follows MASS SPECTRUM: Waters UPLC-SQD: 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 N- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxam ide can be prepared in a manner similar to example la but from 300mg of 6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine (11a) in 5cm3 of pyridine with 0.140cm3 of acid chloride cyclopropane carboxylic acid 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 as a white powder whose characteristics are as follows:
NMR SPECTRUM 1H NMR (400 MHz, DMSO-d6) 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, H) 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, 1H);
H) 8.13 (d, J = 2.0Hz, 1H) 8.26 (d, J = 9.8Hz, 1H) 12.67 (brs, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 453 +; MH- = 451-Example 13 N- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetam ide N- (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetam ide can be prepared in a manner similar to the example the but from 250mg of 6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine 11a in 5cm3 of pyridine with 2.5cm3 of acetic anhydride after 48h of reaction at 20 C. Thus 255 mg of N- (6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) acetamide in the form of a white powder whose characteristics are the following :

NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S 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, 1 H) 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 can be prepared in a similar to Example 5a, but from 778 mg of a mixture of {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl carbamate and (6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) diphenyl imidodicarbonate in 10 cm3 of tetrahydrofuran, 0.32 cm3 of 2- (morpholin-1-yl) ethanamine and 1.04 cm3 of triethylamine at 127 ° C. 127 mg of 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, in the form of a white powder whose characteristics are the following :
NMR 1 H NMR SPECTRUM (500 MHz, DMSO-d6) S 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] triazolo [4,3-b] pyridazin-3-phenyl sulphanyl} -1,3-benzothiazol-2-yl) carbamate and (6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) diphenyl imidodicarbonate can be prepared in a similar manner in example 4a but from 326mg of 6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine (11a) and 0.21cm3 of phenyl chlorocarbonate in 5cm3 of pyridine. This gives 892 mg of a beige powder of a mixture of (6 - {[6-(Cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) phenyl carbamate and (6 - {[6- (cyclopentyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) imidodicarbonate diphenyl, initiated as such in the next 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 can be prepared in a similar to Example 1b but from 305 mg of 1- [2- (morpholinic) 4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 5cm3 of ethanol degassed, 4 mg of potassium dihydrogenphosphate in 0.1 cm3 of water, 347 mg of DL-dithiothreitol and 202 mg of 3-chloro-6-(Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine. We thus obtain 253mg of 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 as a powder the characteristics of which are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S 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, m.p.

H) 3.22 - 3.28 (m, 2H) 3.59 (t, J = 4.4 Hz, 4H) 4.81 - 4.91 (m, 1H) 6.77 (br.
s., 1H) 7.01 (d, J = 10.0 Hz, 1H) 7.36 (dd, J = 8.6, 2.0 Hz, 1H) 7.55 (d, J = 8.6 Hz, m.p.
1H) 8.00 (d, J = 1.7 Hz, 1H) 8.26 (d, J = 9.8 Hz, 1H) 10.87 (brs, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 569 +; MH = 567-b) 3-Chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine may be prepared in a manner similar to Example 1a but from 1.21 g of cycloheptanol in 15cm3 of tetrahydrofuran, 254mg of hydride 60% sodium in oil and 1 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial). This gives 453 mg of 3-chloro-6-(cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine as a colorless oil who 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 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 the example lb but from 249 mg of 3-chloro-6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazine (15b) in 5 cm3 degassed ethanol, 5 mg of potassium dihydrogenphosphate in 0.1 cm3 of water, 432 mg of dithiothreitol and 193 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24h at 80 C. This gives 260 mg of 6 - {[6-(Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine in the form of a white powder whose characteristics are the following:
NMR spectrum 1H NMR (400 MHz, DMSO-d6) 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) acetam ide N- (6 - {[6- (cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetam ide can be prepared in a manner similar to the example the but from 85mg of 6 - {[6-(Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-amine (16a) in 5cm3 of pyridine with 0.160cm3 of acetic anhydride after 24 hours of reaction at 20 ° C., 90 mg of N- (6 - {[6-(Cycloheptyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) acetamide in the form of a yellow powder whose characteristics are the following :
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S 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 = 2.0Hz, 1H) 8.27 (d, J = 9.8Hz, 1H) 12.38 (br.
s., 1 H) 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) acetam ide a) N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide can 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] triazolo [4,3-b] pyridazin-6-amine in 1 cm3 of pyridine with 0.5 cm3 of acetic anhydride after 18 hours of reaction at 20 C. Thus 65 mg of N- (6 - {[6-(Cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetam ide in the form of a pale beige powder whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (300 MHz, DMSO-d6) S 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 similar to Example 1b but from 607 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine in 10cm3 of ethanol degassed, 12 mg of potassium dihydrogenphosphate in 1 cm3 of water, 1.12 g of DL-dithiothreitol and 500 mg of 2-amino-1,3-thiocyanate benzothiazol-6-yl after 24h at 80 ° C.. 768 mg of 3 - [(2-amino) 1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine in the form of a white powder whose characteristics are the following:
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 may be prepared in the following way:
to a solution of 5g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine in 50cm3 of N, N-dimethylformamide are added 2.3cm3 of cyclohexylamine and 3.7 cm3 of triethylamine. The reaction is stirred at 20 ° C
during 18h. Then we add 1.1 cm3 of cyclohexylamine and 7.5 cm3 of triethylamine and the reaction is stirred at 50 ° C. for 4 h. The mixture The reaction mixture is cooled to 20 ° C. and then 60 cm3 of water are added. The white precipitate is drained, then washed successively with water and ether. We obtain thus 3 g of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine under form of a white powder. After one night, the precipitate formed in the first filtrate, obtained above, is drained and washed successively with N, N-dimethylformamide, demineralized water and methanol. We obtain a second batch of 1.42 g of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine in the form of a yellow powder whose characteristics are the following :
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 may be prepared in a similar manner to Example 1b but from 300mg of 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-benzothiazol-6- thiocyanate yle in 6cm3 of degassed ethanol, 4mg of dihydrogenphosphate potassium in 0.6 cm3 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 18h at 80 C. This gives 193mg of 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 as a powder pale yellow whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S ppm 1.00 - 1.34 (m, 6H) 1.46 - 1.74 (m, 6H) 1.75 - 1.86 (m, 2H) 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, 1) H) 7.25 (dd, J = 7.0 Hz, 1H) 7.35 (dd, J = 8.5, 2.0Hz, 1H) 7.52 (d, J = 8.5Hz, 1H) H) 7.90 (d, J = 10.0 Hz, 1H) 7.98 (d, J = 2.0Hz, 1H) 10.81 (brs, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 538 +; MH = 536-b) 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-thiocyanate benzothiazol-6-yl may be prepared as follows:
to a solution of 3 g of (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate phenyl in 90 cm3 of tetrahydrofuran, 1.4 cm3 of 2-pyrrolidine idinylethanamine at 20 C. After 24h, the reaction mixture is concentrated to dryness under reduced pressure. To the oily yellow residue obtained, add ethyl ether. The precipitate formed is drained. We obtain 3.33 g of 2 - {[(2-pyrrolidinylethyl) carbamoyl] amino} -1,3-thiocyanate benzothiazol-6-yl in the form of a yellowish powder whose characteristics are the following :

MASS SPECTRUM: Waters ZQ: MH + m / z = 348 +; MH- = 346-(c) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl) carbamate has been prepared as follows:
to a solution of 2.5 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of tetrahydrofuran, 7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogencarbonate and 9.4 cm3 of water. The resulting mixture is then stirred at 20 ° C. for 20 hours.
then extracted with 2x150 cm3 of ethyl acetate. The organic phases are collected and washed with 3X50 cm3 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. We take up the residue in 50 cm3 of water and then wring and dry under vacuum at C. Thus 3.45 g of (6-thiocyanato-1,3-benzothiazol-2-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 +; 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) 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 can be prepared in a similar manner in example la 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 in 2.1 cm3 of pyridine with 0.133 cm3 of chloride cyclopropane carboxylic acid after 18 hours of reaction at 20 C.
303 mg of 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 in the form of a white powder whose characteristics are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S ppm 0.76 - 1.01 (m, 8H) 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 similar manner to Example lb but from 1g of 2-amino-1,3-benzothiazol-6-yl thiocyanate in 20 cm3 of degassed ethanol, 23mg of potassium dihydrogenphosphate in 2cm3 of water, 2.32g 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. Thus 1.8 g is obtained 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 cream-white powder whose characteristics are as follows:
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 manner similar to the example 18c but from 5g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine commercial in 50cm3 of N, N-dimethylformamide, 6g of hydrochloride of trans-4-aminocyclohexanol and 17 cm 3 of triethylamine after 48 h at 20 ° C.
and 4h at 50 ° C. Thus 3.5 g of trans-4 - [(3-chloro [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino] cyclohexanol in the form of a white powder of which the characteristics are as follows:
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) cyclopropanecarboxam ide N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxam ide can 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] triazolo [4,3-b] pyridazin-6-amine (18b) in 2.1cm3 of pyridine with 0.14cm3 of acid chloride cyclopropane carboxylic acid, after 18 hours of reaction at 20 ° C.
268 mg of N- (6 - {[6- (cyclohexylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide as a cream white powder whose characteristics are as follows:
NMR SPECTRUM 1H NMR (400MHz, DMSO-d6) S 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, m.p.

H) 3.36 - 3.45 (m, 1H) 6.79 (d, J = 9.8 Hz, 1H) 7.25 (d, J = 7.1 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] [I, 2,4] triazolo [4,3 b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] acetam ide 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 114mg 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 2cm3 of dichloromethane is added 0.08cm3 of acetyl chloride and 0.16cm3 of triethylamine at 20 C. After 18h the reaction medium is concentrated to dryness under reduced pressure. The residue is taken up in water. The white precipitate formed yellow is drained and washed with water and is 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). In this way 46 mg of N- [6 - ({6 - [(trans-4 hydoxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) 1,3 benzothiazol-2-yl] acetam ide in the form of a beige powder whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S ppm 1.01 - 1.27 (m, 4H) 1.68 - 1.86 (m, 4H) 2.19 (s, 3H) 3.35 - 3.44 (m, 2H) 4.51 (d, J = 4.6 Hz, 1) H) 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-hydroxyoxy) loylyl) amin] [1,2,4] triazo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxam ide N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazine 3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide may be prepared in a similar manner to example la but from 300mg 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 3cm3 of pyridine with 0.235cm3 of cyclopropane carboxylic acid chloride, after 16h of reaction at 20 ° C. This gives 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] cyclopropanecarboxam ide in the form of a beige powder whose characteristics are as follows:
NMR SPECTRUM 1H NMR (400MHz, DMSO-d6) S 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, 2) H) 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 = 1.7 Hz, 1H) 12.64 (brs, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 482 +; MH = 480-Example 24:
3 - [(2-amino-l, 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] pyridazin-6-amine can be prepared in a similar to Example 1b but from 1.4 g of thiocyanate of 2-amino-1,3-benzothiazol-6-yl in 41 cc of degassed ethanol, 32 mg of potassium dihydrogenphosphate in 4 cm3 of water, 3.13 g of dithiothreitol and 1.42 g of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine after 18 hours at 80 ° C. Thus 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 white-cream powder whose characteristics are the following :
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S ppm 0.41 - 0.48 (m, 2H) 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, 2.0Hz, 1H) 7.67 (bps, 3H) 7.92 (d, J = 9.8 Hz, 1 H) 7.95 (d, J = 1.7 Hz, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 356 +; MH- = 354-(b) 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine DPN1.150 can be prepared in a manner similar to Example 18c but from 2 g of commercial 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine in 20 cm3 of N, N-dimethylformamide, 1.1 cm3 of cyclopropylamine and 3 cm3 of triethylamine, after 18h at 20 C and 3h at 50 C. This gives 1.53g of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine in the form of a white powder whose characteristics 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) acetam ide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide can 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 cc of pyridine with 1.04 cc of acetic anhydride after 18 hours of reaction at 20 ° C., thus obtaining 100 mg of N- (6 - {[6-(Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetam ide in the form of a white powder whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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, 1) H) 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, 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) cyclopropanecarboxam ide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide can be prepared in a manner similar to Example la 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 3cm3 of pyridine with 0.16cm3 of chloride cyclopropane carboxylic acid after 18 hours of reaction at 20 ° C.
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 the following:

NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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, m.p.

H) 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 (brs, 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] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea may be prepared in a similar manner to Example 1b but from 300mg of 1-[2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), from 7.5 cc of degassed ethanol, 6 mg of potassium dihydrogenphosphate in 0.7 cm3 of water, 552 mg of DL-dithiothreitol and 403 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (18c). We obtain 370 mg of 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 in the form a white powder whose characteristics are as follows:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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 = 7.1 Hz, 1H) 7.35 (dd, J = 8.3, 2.0 Hz, 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 N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-methoxypropanam ide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-[Sulfanyl] -1,3-benzothiazol-2-yl) -3-methoxypropanamide can be prepared in a manner similar to Example la but from 220 mg of 3 - [(2-aminomo-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (24a) in 7cm3 of pyridine with 0.2cm3 of 3-methoxypropanoyl after 18h of reaction at 200C. This gives 81 mg N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -3-methoxypropanam ide in the form of a beige powder the characteristics of which are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S ppm 0.33 - 0.43 (m, 2H) 0.62 - 0.73 (m, 2H) 2.53 - 2.59 (m, 1H) 2.73 (t, J = 6.1 Hz, 2H) 3.24 (s, 3) H) 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 = 8.6 Hz, 1H) 7.72 (d, J = 2.7 Hz, 1H) 7.96 (d, J = 9.8 Hz, 1H) 8.22 (D, J = 1.5Hz, 1H) 12.46 (brs, 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 may be prepared in a similar manner to Example 1b but from 300mg of 1-[2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), from 12cc degassed ethanol, 5mg potassium dihydrogenphosphate in 1.2 cm3 of water, 41 mg of DL-dithiothreitol and 187 mg of 3-chloro-N-cyclopropyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (24b), after 18h at 80 ° C.
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 in the form of a cream-white powder whose characteristics are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6CD3000D) S 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 (br s, 1H) 7.91 (d, J = 9.8 Hz, 1H) 8.16 (s, 1 H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 512 +; MH = 510-Example 30 N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-d imethylg lycinam ide a) N- (6 - {[6- (cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-dimethylglycinamide may be prepared in a manner similar to Example la 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 8cm3 of dichloromethane with 197mg of N, N-dimethylglycyl chloride hydrochloride and triethylamine 0.26 cc after 18 hours of reaction at 20 ° C., 167 mg of 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 in the form of a beige powder the characteristics of which are as follows:
NMR SPECTRUM 1H NMR (500MHz, DMSO-d6) S ppm 0.39 (brs, 2H) 0.69 (d, J = 5.2 Hz, 2H) 2.29 (s, 6H) 2.52 - 2.59 (m, 1H) 3.10 - 3.25 (m) masked, 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-l, 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 similar to Example 1b, but from 250 mg of thiocyanate of 2-amino-1,3-benzothiazol-6-yl, 8 cm3 of degassed ethanol, 6 mg of potassium dihydrogen phosphate in 0.8 cm 3 of water, 660 mg of 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-benzothiazole) are thus obtained.
6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine in the form of a creamy white powder whose characteristics are the following:
NMR 1 H NMR SPECTRUM (400 MHz, DMSO-d6) S 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 = 7.6Hz, 1H) 7.16 - 7.37 (m, 2H) 7.66 (sr, 2h) 7.81 (s, 1 H) 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 as follows:
500 mg of 3-chloro-N-cyclohexyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine (18c) in 16 cm3 of glacial acetic acid at 20 C are added 1.3 g of powder of zinc. 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 silica chromatography by dry deposition on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient dichloromethane / methanol 95/5 to 90/10. We get 317mg of 3-chloro-N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine, under form of a white powder whose characteristics are as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 254 +; MH = 252-Example 32 (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) ethyl carbamate a) (6 - {[6- (Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -Ethyl 1,3-benzothiazol-2-yl) carbamate can be prepared in the manner next :
In a vial for microwave of 10cm3 equipped with a stirring, at 20 C, one introduced 320 mg of 2 - [(morpholin-4-ylcarbonyl) amino] -1,3-thiocyanate benzothiazol-6-yl (32b) in 7cm3 of ethanol. A current is bubbled of argon through the mixture for 5 minutes then 408mg of potassium dihydrogenphosphate in 0.25 cm3 of water, 463 mg of dithiothreitol and 252 mg of 3-chloro-6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazine (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 then the residue is purified by two successive chromatographies on cartridge of Merck silica by solid deposition eluting with a 99: 1 to 97: 3 gradient of dichloromethane / methanol. This gives 77mg of (6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) ethyl carbamate in the form of a white solid whose characteristics are the following :
MASS SPECTRUM: LC / MS Electrospray on WATERS UPLC - SQD:
Retention time Tr (min) = 1.06; [M + H] +: m / z 471; [MH] -: m / z 469 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 1.15-1.40 (m, 8H); 1.42 at 1.64 (m, 3H); 1.79 (d, J = 13.2 Hz, 2H); 4.24 (q, J = 7.1 Hz, 2H); 4.67 (m, 1 H); 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 (s large, 1 H) b) 2 - [(Morpholin-4-ylcarbonyl) amino] -1,3-benzothiazol thiocyanate 6-yl 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 70cm3 of tetrahydrofuran and 0.602cm3 of morpholine at 50 C for 26h. 2.12 g of 2-thiocyanate are thus obtained.
[(Morpholin-4-ylcarbonyl) amino] -1,3-benzothiazol-6-yl as a white solid whose characteristics 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] su lfanyl} -1,3-benzothiazol-2-yl) acetam ide a) 2-Chloro-N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-[Sulfanyl] -1,3-benzothiazol-2-yl) acetamide can be prepared in the next :
to 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-to-drop 0.1cm3 of chloride chloroacetyl. The resulting solution is stirred for 30 min at 20 ° C., and then the medium is 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 at 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-yl] sulfanyl} -1,3-benzothiazol 2-yl) acetamide in the form of a white solid whose characteristics are the following:
MASS SPECTRUM: Waters UPLC-SQD:
Retention time Tr (min) = 1.03; [M + H] +: m / z 475, [MH] -: m / z 473 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 1.10 to 1.38 (m, 5H); 1.41 at 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) -N2-cyclopropylglycinamide a) N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2-cyclopropylglycinamide can be prepared from following way:
to 280 mg 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 4cm3 of pyridine 0.35 cm3 of cyclopropylamine is added. After 5 hours of agitation the medium The reaction mixture is evaporated to dryness at 20 ° C. The residue is purified by Merck silica cartridge chromatography by solid deposition eluting with a gradient of 100% dichloromethane to 97: 3 dichloromethane /
methanol. We thus obtain 110 mg of N- (6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) -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, [MH] -: m / z 494 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 0.19 to 0.40 (m, 4H); 1.14 at 1.26 (m, 3H); 1.33 (m, 2H); 1.41 to 1.66 (m, 3H); 1.78 (m, 2H); 2.17 (m, H); 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, 1 H) Example 35 6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine a) 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 the example lb but from 1.07 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate, degassed ethanol (15 cc), 20 mg of dihydrogenphosphate potassium in 0.1 cm3 of water, 1.99 g of DL-dithiothreitol and 964 mg of 3-chloro-6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazine. We obtain 1.1g of 6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine in the form of 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 1H NMR Spectrum (400MHz, b ppm, DMSO-d6): 1.66 (m, 1H); 1.80 (m, 1 H); 2.01 to 2.13 (m, 2H); 2.31 to 2.40 (m, 2H); 4.96 (qd, J = 7.1 and 7.3 Hz, 1 H);

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, 1 H); 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 may be prepared in a manner similar to Example 1c but from 954 mg of cyclobutanol in 10cm3 of tetrahydrofuran, 317mg of hydride 60% sodium in oil and 1 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial). This gives 1.03 g of 3-chloro-6-(cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazine as a beige powder whose characteristics are as follows:
1H NMR Spectrum (400 MHz, b ppm, DMSO-d6): 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-ethyl-piperazin-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 from the following way:
a mixture of 273 mg of (4-ethylpiperazin-1-yl) acetic acid (commercial), of 0.28 cm3 of diisopropyl ethylamine and 411 mg of O- (7-azabenzotriazol) 1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) in 3cm3 of N, N-dimethylformamide at 20 ° C. is stirred for 1 h at 20 ° C. in the middle 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 The solution is poured over ice water and the precipitate is filtered. Dough yellow isolated is taken up in a 90:10 mixture of ethyl acetate / methanol. The solution obtained is dried over magnesium sulphate, filtered and 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) in eluent with a dichloromethane / methanol gradient of 96: 4 to 100% of methanol. This gives 127 mg of N- (6 - {[6-(Cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol yl) -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 1H NMR Spectrum (400 MHz, δ ppm, DMSO-d6): 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 at 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) -N2, N2-diethylglycinamide 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 -diethylglycinamide can be prepared from following way:
a mixture of 827mg of (diethylamino) sodium acetate (commercial) in

5.5 cm3 of a 2N solution of hydrogen chloride in ether is stirred for 1 h at 20 C. The resulting suspension is evaporated to dryness under vacuum.
To the white residue obtained are added, at 20 ° C., 8 cm 3 of pyridine, 200 mg of {[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-chlorohydrate) dimethylaminopropyl) N'-ethylcarbodiimide. After 5h, the reaction medium brown is evaporated to dryness. The residue is taken up in toluene and the mixture again evaporated to dryness under vacuum. The residue is taken up in water and the 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, 60A, 32-63 μM) eluting with a gradient dichloromethane / methanol from 100/0 to 98/2. 135 mg of N- (6-WO 2010/08950

6 PCT / FR2010 / 050177 {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N 2, N 2-diethylglycinamide in the 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); [MH] -: m / z 482 1 H NMR spectrum (400 MHz, δ ppm, DMSO-d6): 1.00 (t, J = 7.2 Hz, 6H), 1.52 to 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 as well as their intermediaries prepared by analogy with the above examples are described in the table below.

Q Quantity Ex. Name from: isolated x i ~ 4J

N- (6 - {[6- 86mg of 6 - {[6-(cycloheptyloxy) [1,2,4] triazolo [(cycloheptyloxy) [1,2,4] triazolo [4,3-38 4,3-b] pyridazin-3-yl] sulfanyl} b] pyridazin-3-yl] sulfanyl} -1,3-52mg 1,3-benzothiazol-2-benzothiazol-2-amine (16a) 44mg of yl) cyclopropane carboxamide chloride cyclopropane carboxylic 1- (6 - {[6-105mg of 3-chloro-N-(cyclohexylamino) [1,2,4] triazol cyclohexyl [1,2,4] triazolo [4,3-39 o [4,3-b] pyridazin-3-bb] pyridazin-6-amine (18c) and 155mg of 168m 2 - ({[3- (morpholin-4- g) -2-benzothiazol-2-thiocyanate]
yl) -3- [3- (morpholin-4-yl) propyl] carbamoyl} amino) -1,3-yl) propyl] urea benzothiazol-6-yl (39b) thiocyanate of 2 - ({[3- 500mg of (6-thiocyanato-1,3-(morpholin-4-benzothiazol-2-yl) carbamate 39b yl) propyl] carbamoyl} amino) -2c phenyl (2d) and 264mg of N- (3-634mg) 1,3-benzothiazol-6-yl aminopropyl) morpholine (commercial) 1- (6 - {[6- 200mg of 3-chloro-6-(cyclohexyloxy) [1,2,4] triazolo [(cyclohexyloxy) [1,2,4] triazolo [4,3-40,3,3-b] pyridazin-3-yl] sulfanyl} - 1bb] pyridazine (1c) and 299mg 149mg 1,3-Benzothiazol-2-yl) -3- [3-thiocyanate 2 - ({[3- (morpholin-4-(morpholin-4-yl) propyl] urea yl) propyl] carbamoyl} amino) -1,3-benzothiazol-6-yl (39b) 1- (6 - {[6- 200mg of 3-chloro-6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-41, 3-b] pyridazin-3-yl] sulfanyl} -2a b] pyridazine (35b) and 422 mg of 1- [2-245mg 1,3-benzothiazol-2-yl) -3- [2- (morphol-4-yl) ethyl] -3- (6-sulfanyl-1, 3-(morpholin-4-yl) ethyl] urea benzothiazol-2-yl) urea (2b) rac-1- [2- (morpholin-4-yl) ethyl] 200mg of rac-3-chloro-6 - {[trans-4-3- {6 - [(6 - {[trans-4- (trifluoromethyl) cyclohexyl] oxy} [1,2,4] tri 42 (trifluoromethyl) cyclohexyl] oxy 2a azolo [4,3-b] pyridazine (42b) and 295mg 199mg } [1,2,4] triazolo [4,3-b] pyridazin of 1- [2- (morpholin-4-yl) ethyl] -3- (6-3-yl) sulfanyl] -1,3-benzothiazol sulfanyl-1,3-benzothiazol-2-yl) urea (2b) 2-yl} urea rac-3-chloro-6 - {[trans-4- g of 3,6-dichloro [1,2,4] triazolo [4,3-42b (trifluoromethyl) cyclohexyl] oxy] b] pyridazine (commercial) and 2.19 g of 997m g 1,2,4] triazolo [4,3-rac-trans-4- (trifluoromethyl) cyclohexan b] pyridazine g 1-01 (commercial) N- (6 - {[6- 252mg of 3-chloro-6-(cyclohexyloxy) [1,2,4] triazolo [(cyclohexyloxy) [1,2,4] triazolo [4,3-43,3,3-b] pyridazin-3-yl] sulfanyl} -32a b] pyridazine (1c) and 289 mg of 110 mg 1,3-benzothiazol-2-yl) -2-thiocyanate of 2-cyclopropylacetamide [(cyclopropylacetyl) amino] -1,3-benzothiazol-6-yl (43b) 2-830mg thiocyanate of 2-amino-1,3-thiocyanate 43b [(cyclopropylacetyl) amino] -1,3 benzothiazol-6-yl and leq of a 383mg benzothiazol-6-yl chloride solution cyclopropylacetyl (43c) 1 g of cyclopropylacetic acid and 0.75cm3 of SOCI2 according to solution 43C cyclopropylacetyl chloride conditions similar to those described used te by Kreimeyer et al. J. Med. Chem. what 1999, 42, 4394 N- (6 - {[6-70mg of 6 - {[6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-44, 3-b] pyridazin-3-yl] sulfanyl} -b] pyridazin-3-yl] sulfanyl} -1,3- 64mg 1,3-benzothiazol-2-benzothiazol-2-amine (35a) and yl) cyclopropanecarboxamide 0.037cm3 acid chloride cyclopropane carboxylic rac-cis / trans N- {4 - [(3 - {[2 - ({[2- 200mg of rac-cis / trans N- {4 - [(3-(morpholin-4- 89mg chloro [1,2,4] triazolo [4,3-b] pyridazin-6-yl) ethyl] carbamoyl} amino) -1,3 yl) oxy] cyclohexyl} acetamide (45b) and mixture Benzothiazol-6- 2a 306 mg of 1- [2- (morpholin-4-yl) ethyl] -3-isomer yl] sulfanyl} [1,2,4] triazolo [4,3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (30/70 b] pyridazin-6- (2b) cis / trans) yl) oxy] cyclohexyl} acetamide 45b rac-cis / trans N- {4 - [(3- 1c 1g of 3,6-dichloro [1,2,4] triazolo [4,3- 2,49g chloro [1,2,4] triazolo [4,3-b] pyridazine (commercial) and 2.04 g of mixture b] pyridazin-6- N- (4-hydroxycyclohexyl) acetam ide isomer yl) oxy] cyclohexyl} acetamide (commercial) s (30/70 cis / trans) N- {6 - [(6 - {[4- 440mg of 6 - [(6 - {[4-(trifluoromethyl) cyclohexyl] oxy (trifluoromethyl) cyclohexyl] oxy} [1,2,4] tri 46} [1,2,4] triazolo [4,3-b] pyridazin azolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3- 330mg 3-yl) sulfanyl] -1,3-benzothiazol benzothiazol-2-amine (46b) and 197mg 2-yl} cyclopropanecarboxamid cyclopropanecarbonyl chloride 6 - [(6 - {[4-323mg of 2-amino-1,3-thiocyanate (trifluoromethyl) cyclohexyl] oxy benzothiazol-6-yl and 500 mg of 3-46b} [1,2,4] triazolo [4,3-b] pyridazin 1b chloro-6 - {[4-496mg 3-yl) sulfanyl] -1,3-benzothiazol (trifluoromethyl) cyclohexyl] oxy} [1,2,4] tri 2-amine azolo [4,3-b] pyridazine (42b) 1- [6 - ({6 - [(trans-4- 250mg of trans-4 - [(3-hydroxycyclohexyl) oxy] [1,2,4] t chloro [1,2,4] triazolo [4,3-b] pyridazin-6-47 riazolo [4,3-b] pyridazin-3-yl) oxy] cyclohexanol (47b) and 378 mg of 232 mg (Sulfanyl) -1,3-benzothiazol-1- [2- (morpholin-4-yl) ethyl] -3-2-yl] -3- [2- (morpholin-4-sulfanyl-1,3-benzothiazol-2-yl) urea (2b) yl) ethyl] urea trans-4 - [(3- [g] 3,6-dichloro [1,2,4] triazolo [4,3- 256mg]
47b chloro [1,2,4] triazolo [4,3-1c b] pyridazine (commercial) and 3,07g of trans (and b] pyridazin-6- 1,4-cyclohexanediol (mixture 214mg yl) oxy] cyclohexanol cis / trans) cis) 6 - {[6- (bicyclo [3.1.0] hex-3-550mg 6- (bicyclo [3.1.0] hex-3-yloxy) -48 yloxy) [1,2,4] triazolo [4,3-b] 3-chloro [1,2,4] triazolo [4,3-b] pyridazine 574mg 3- (48b) and 455 mg of thiocyanate of 2-benzothiazol-2-amine g amino-1,3-benzothiazol-6-yl 6- (bicyclo [3.1.0] hex-3-yloxy) -1g of 3,6-dichloro [1,2,4] triazolo [4,3-48b 3-chloro [1,2,4] triazolo [4,3-1c b] pyridazine (commercial) and 1.04 g of 968mg b] pyridazine bicyclo [3. 1.0] hexan-3-ol 3 - [(2-Amino-1,3-benzothiazole-500mg 3-chloro-N-49 6-yl) sulfanyl] -N-1-bicyclobutyl [1,2,4] triazolo [4,3-b] pyridazine-417mg 6-amine (49b) and 463 mg of thiocyanate b] pyridazin-6-amine of 2-amino-1,3-benzothiazol-6-yl 3-chloro-N-2g of 3,6-dichloro [1,2,4] triazolo [4,3-49b cyclobutyl [1,2,4] triazolo [4,3-18c b] pyridazine (commercial) and 1,17cc 2,14g b] pyridazin-6-amine cyclobutylamine N- (6 - {[6- (bicyclo [3.1.0] hex-3-530mg of 6 - {[6- (bicyclo [3.1.0] hex-3-yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-B) pyridazin-3-yl] sulfanyl} -1,3-yl] sulfanyl} -1,3-benzothiazol-2-amine 568mg benzothiazol-2- (48) and 0.24cm3 chloride of yl) cyclobutanecarboxamide cyclobutanecarbonyl rac-6 - ({6 - [(trans-2-550 mg of rac-3-chloro-6 - [(trans-2-51 fluorocyclohexyl) oxy] [1,2,4] tria lb fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3- 249mg zolo [4,3-b] pyridazin-3-b] pyridazine (51b) and 421 mg of 2-amino-1,3-benzothiazolthiocyanate 2-amine benzothiazol-6-yl rac-3-ch loro-6 - [(trans-2-fluorocyclohexyl) oxy] [1,2,4] tria 650mg of 3,6-51b zolo [4,3-b] pyridazine 1c dichloro [1,2,4] triazolo [4,3-b] pyridazine 829mg and 813mg of rac-trans-2-fluorocyclohexanol (commercial) rac-N- {6 - [(6 - {[(trans-2-95mg of rac-6 - ({6 - [(trans-2-fluorocyclohexyl] oxy} [1,2,4] tria fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3-52 zolo [4,3-b] pyridazin-3-b] pyridazin-3-yl} sulfanyl) -1,3-103mg yl) sulfanyl] -1,3-benzothiazol-2-benzothiazol-2-amine (51) and 0.085cm3 cyclopropanecarbonyl chloride cyclopropanecarboxamide N- (6 - {[6- 120mg of 3 - [(2-amino-1,3-(cyclobutylamino) [1,2,4] triazol benzothiazol-6-yl) sulfanyl] -N-87mg 53 o [4,3-b] pyridazin-3-cyclobutyl [1,2,4] triazolo [4,3-b] pyridazin yl] sulfanyl} -1,3-benzothiazol-2,6-amine (49) and 0.06cm3 of the yl) cyclopropanecarboxamide cyclopropanecarbonyl N- (6 - {[6- (bicyclo [3.1.0] hex-3-110mg 6 - {[6- (bicyclo [3.1.0] hex-3-yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-B) pyridazin-3-yl] sulfanyl} -1,3-yl] sulfanyl} -1,3-benzothiazol-2-amine 112mg Benzothiazol-2- (48) and 0.051cm3 of yl) cyclopropanecarboxamide cyclopropanecarbonyl rac-N2, N2-diethyl-N- [6 - ({6- 200mg of rac-6 - ({6 - [(trans-2-[(trans-2-fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3-Fluorocyclohexyl) oxy] [1,2,4] tria 37a b] pyridazin-3-yl} sulfanyl) -1,3- 164mg benzothiazol-2-amine (51) and 735 mg of g yl} sulfanyl) -1,3-benzothiazol- (diethylamino) sodium acetate 2-yl] glycinamide (commercial) rac-2- (4-ethylpiperazin-1-yl) - 300mg of 6 - ({6 - [(trans-2-N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy] [1,2,4] triazolo [4,3-trifluoromethyl]
fluorocyclohexyl] oxy} [1,2,4] tria [b] pyridazin-3-yl} sulfanyl) -1,3-56 zolo [4,3-b] pyridazin-3-benzothiazol-2-amine (51) and 1,828 of 120mg yl) sulfanyl] -1,3-benzothiazol-2-hydrobromide acid (4-yl} ethylpiperazin-1-yl) acetic acetamide (commercial) rac-N- {6 - [(6 - {[trans-2- 300mg of 6 - ({6 - [(trans-2-fluorocyclohexyl] oxy} [1,2,4] tria fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3-57 zolo [4,3-b] pyridazin-3- (3a) pyridazin-3-yl) sulfanyl) -1,3-156m yl) sulfanyl] -1,3-benzothiazol-2-benzothiazol-2-amine (51) and 1.05 g yl} -2- (morpholin-4-morpholin-4-ylacetic acid yl) acetamide (commercial) N- (6 - {[6- 200mg of 6 - {[6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-58 3-b] pyridazin-3-yl] sulfanyl} -37a b] pyridazin-3-yl] sulfanyl} -1,3-96mg 1,3-benzothiazol-2-yl) -2-benzothiazol-2-amine (35a) and 784mg (morpholin-4-yl) 4-morpholin-4-ylacetic acid acetamide (commercial) rac-2- (4-cyclopropylpiperazine-200mg of 6 - ({6 - [(trans-2-1-yl) -N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy] [1,2,4] triazolo [4,3-59 fluorocyclohexyl] oxy} [1,2,4] tria 37a b] pyridazin-3-yl} sulfanyl) -1,3- 98mg benzothiazol-2-amine (51) and 990 mg of g yl) sulfanyl] -1,3-benzothiazol-2 (4-cyclopropylpiperazin-1-yl) -acetate yl} acetamide potassium (59b) 2.1g of bromoacetic acid and 3g of 4-(4-cyclopropylpiperazin-1-cyclopropylpiperazine.HCl according to 59b yl) potassium acetate conditions similar to those described 2.66g by DT Witiak et.al .; J. Med. Chem.
1985, 28, 1228 N- (6 - {[6- 150mg of 6 - {[6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-60 3-b] pyridazin-3-yl] sulfanyl} -37a b] pyridazin-3-yl] sulfanyl} -1,3-143m 1,3-benzothiazol-2-yl) -2- (4-benzothiazol-2-amine (35a) and 418 mg / g cyclopropylpiperazin-1- (4-cyclopropylpiperazin-1-yl) acetate yl) potassium acetamide (59b) N- (6 - {[6- 150mg of 6 - {[6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-3-b] pyridazin-3-yl] sulfanyl} -37a b] pyridazin-3-yl] sulfanyl} -1,3- 109m 1,3-benzothiazol-2-yl) -2- (1,1-benzothiazol-2-amine (35a) and 391 mg.
dioxidothiomorpholin-4- acid (1,1-di-oxidothiomorpholin-4-yl) acetamide yl) acetic (commercial) N- (6 - {[6- 200mg of 6 - {[6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-62 3-b] pyridazin-3-yl] sulfanyl} -37a b] pyridazin-3-yl] sulfanyl} -1,3-152mg 1,3-benzothiazol-2-yl) -2- (1,4-benzothiazol-2-amine (35a) and 489mg oxazepan-4-yl) 1,4-oxazepan-4-yl acetate acetate potassium (62b) 2,32g of bromoacetic acid and 2,3g of 1,4-Oxazepane hydrochloride 1,4-oxazepan-4-yl acetate 62b potassium conditions similar to those 2,77g described by DT Witiak et.al .; J. Med.
Chem. 1985, 28, 1228 N- (6 - {[6- 300mg from 6 - {[6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-63 3-b] pyridazin-3-yl] sulfanyl} b] pyridazin-3-yl] sulfanyl} -1,3-101mg 1,3-benzothiazol-2-yl) -3-benzothiazol-2-amine (35a) and 200mg be methoxypropanamide of 3-methoxypropanoyl chloride (commercial) N- (6 - {[6- 200mg of 6 - {[6-(cyclobutyloxy) [1,2,4] triazolo [4 (cyclobutyloxy) [1,2,4] triazolo [4,3-64, 3-b] pyridazin-3-yl] sulfanyl} -37a b] pyridazin-3-yl] sulfanyl} -1,3-183mg 1,3-benzothiazol-2-yl) -2- (3,3-benzothiazol-2-amine (35a) and 484mg difluoropiperidin-1- (3,3-difluoropiperidin-1-yl) acetate yl) acetamide potassium (64b) 1.6 g of bromoacetic acid and 1.8 g of (3,3-difluoropiperidin-1-3,3-d ifluoropiperidine according to 64b yl) potassium acetate conditions similar to those described 1.16g by DT Witiak et.al .; J. Med. Chem.
1985, 28, 1228 The characteristics of the products in the table above are as follows Ex SM NMR

1 H NMR spectrum (400MHz, b ppm, DMSO-d6): 0.88 to Retention time 0.98 (m, 4H); 1.16 to 1.35 (m, 2H); 1.39 to 1.54 (m, 6H);
Tr (min) = 1.09; 1.55 to 1.69 (m, 2H); 1.74 to 1.89 (m, 2H); 1.93 to 2.04 (M, [M + H] +: m / z 481; 1H); 4.73 to 4.90 (m, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.41 [MH] -: m / z 479 (dd, J = 2.1 and 8.4 Hz, 1H); 7.67 (d, J = 8.6 Hz, 1H); 8.05 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H); 12.67 (s wide, 1 H) 1 H NMR spectrum (400 MHz, b ppm, DMSO-d6): 0.97 at Retention time 1.32 (m, 5H); 1.47 to 1.68 (m, 5H); 1.80 (m, 2H); 2.25 at Tr (min) = 3.03; 2.37 (m, 6H); 3.13 to 3.23 (m, 2H); 3.37 at 3.49 (m, 1H);
39 [M + H] +: m / z 568; 3.57 (m, 4H); 6.71 to 6.82 (m, 1H); 6.79 (d, J = 10.0 Hz, 1 [MH] -: m / z 566H); 7.25 (d, J = 7.1Hz, 1H); 7.35 (dd, J = 2.0 and 8.6 Hz, 1 H) ; 7.52 (d, J = 8.6 Hz, 1H); 7.91 (d, J = 10.0 Hz, 1H); 7.98 (d, J = 2.0 Hz, 1H); 10.80 (spread m, 1 H) 1 H NMR spectrum (400 MHz, b in ppm, DMSO-d6): 1.53 to 1.70 (m, 2H); 2.28 at 2.37 (m, 6H); 3.15 to 3.24 (m, 2H);
39b 3.52 to 3.63 (m, 4H); 6.76 to 6.82 (m, 1H); 7.48 (dd, J = 2.0 and 8.6 Hz, 1H); 7.58 (d, J = 8.6 Hz, 1H); 8.08 (d, J = 2.0 Hz, 1H); 10.86 (spread m, 1H) 1H NMR spectrum (400MHz, b in ppm, DMSO-d6): 1.15 to Retention time 1.43 (m, 5H); 1.45 to 1.53 (m, 1H); 1.57 to 1.66 (m, 4H);
Tr (min) = 0.73; 1.78 to 1.86 (m, 2H); 2.27 at 2.37 (m, 6H); 3.19 (q, J = 5.6 40 [M + H] +: m / z 569; Hz, 2H); 3.57 (t, J = 4.8 Hz, 4H); 4.66 to 4.75 (m, 1H);
6.77 [MH] -: m / z 567 (brs, 1H); 7.02 (d, J = 9.8 Hz, 1H); 7.36 (dd, J = 2.0 and 8.6 Hz, 1H); 7.54 (d, J = 8.3 Hz, 1H); 8.00 (d, J = 2.0 Hz, 1 H); 8.27 (d, J = 9.8 Hz, 1H); 10.81 (s wide, 1H) 1H NMR Spectrum (400MHz, b ppm, DMSO-d6): 1.62 Retention time (m, 1H); 1.76 (m, 1H); 2.04 (m, 2H); 2.30 (m, 2H); 2.37 at Tr (min) = 2.98; 2.45 (m, 6H); 3.23 to 3.28 (masked m, 2H); 3.59 (t, J = 4.6 [M + H] +: m / z 527; Hz, 4H); 4.92 (qd, J = 7.1 and 7.3 Hz, 1H); 6.77 (s large, 1 [MH] -: m / z 525 H); 7.05 (d, J = 9.8 Hz, 1H); 7.42 (dd, J = 2.1 and 8.4 Hz, 1H);

7.57 (d, J = 8.6 Hz, 1H, 8.06 (d, J = 2.2 Hz, 1H, 8.28 (d, J = 9.8 Hz, 1H); 10.89 (s wide, 1H) 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 1.22 Retention time (m, 2H); 1.33 (m, 2H); 1.75 (d, J = 13.2 Hz, 2H); 1.94 (d, Tr (min) = 0.75; J = 11.5 Hz, 2H); 2.19 to 2.35 (m, 1H); 2.36 to 2.45 (m, 6H);
42 [M + H] +: m / z 623; 3.23 to 3.28 (masked m, 2H); 3.59 (t, J = 4.8 Hz, 4H);
4.65 [MH] -: m / z 621 (m, 1H); 6.76 (bs, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.32 (dd, J = 2.0 and 8.6 Hz, 1H); 7.52 (d, J = 8.6 Hz, 1H); 7.96 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 10.87 (s wide, 1H) 1 H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 1.32 to 42b 1.66 (m, 4H); 1.99 (m, 2H); 2.30 (m, 2H); 2.37 to 2.45 (m, 1H); 4.91 to 5.04 (m, 1H); 7.09 (d, J = 9.8 Hz, 1H);

8.28 (d, J = 9.8 Hz, 1H) 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 0.20 Retention time (m, 2H); 0.49 (m, 2H); 1.06 (m, 1H); 1.14 to 1.40 (m, 5 H);
Tr (min) = 4.56; 1.42 to 1.65 (m, 3H); 1.72 to 1.84 (m, 2H); 2.37 (d, J = 7.1 43 [M + H] +: m / z 481 Hz, 2H); 4.60 to 4.73 (m, 1H); 7.02 (d, J = 9.8 Hz, 1H);
[MH] -: m / z 479 7.41 (dd, J = 2.0 and 8.6 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); 12.30 (s wide, 1H) 1 H NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): -0.03 to 0.03 (m, 2H); 0.27 to 0.32 (m, 2H); 0.81 to 0.93 (m, 1H);
43b 2.20 (d, J = 7.1 Hz, 2H); 7.48 (dd, J = 2.0 and 8.6 Hz, 1H);
7.63 (dd, J = 0.5 and 8.6 Hz, 1H); 8.18 (dd, J = 0.5 and 2.0 Hz, 1H), 12.24 (spread m, 1H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 0.92 to Retention time 0.98 (m, 4H); 1.60 (m, 1H); 1.75 (m, 1H); 2.01 (m, 3H);
Tr (min) = 0.97; 2.27 (m, 2H); 4.90 (quin, J = 7.3 Hz, 1H); 7.06 (d, J = 9.8 [M + H] +: m / z 439; Hz, 1H); 7.47 (dd, J = 2.0 and 8.6 Hz, 1H); 7.69 (d, J = 8.6 Hz, [MH] -: m / z 437 H); 8.11 (d, J = 2.0 Hz, 1H); 8.29 (d, J = 9.8 Hz, 1H); 12.67 (large s, 1 H) 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6) Mixture isomers 70% Trans 30% Cis: 1.12 to 1.65 (m, 4H); 1.67 Retention time at 1.85 (m, 5H); 1.87 to 1.97 (m, 2H); 2.35 to 2.45 (m, 6H);
Tr (min) = 0.50; 3.26 (masked m, 2H); 3.51 to 3.68 (m, 5H); 4.66 (m, 0.7 45 [M + H] +: m / z 612; H); 4.98 (m, 0.3H); 6.77 (brs, 1H); 6.98 to 7.06 (m, 1 [MH] -: m / z 610 H); 7.39 (m, 1H); 7.56 (m, 1H); 7.66 (d, J = 8.6 Hz, 0.7 H);
7.74 (d, J = 8.1 Hz, 0.3H); 7.95 (d, J = 2.0 Hz, 0.7 H); 8.03 (d, J = 2.0 Hz, 0.3 H); 8.28 (d, J = 9.5 Hz, 1H); 10.88 (s large, 1 H) 1 H NMR spectrum (400 MHz, b ppm, DMSO-d6) of isomers 70% trans (diaxial) and 30% cis (CHN ax - CHO
45b eq) with: 1.29 to 2.23 (m, 8H), 1.78 (s, 0.9 H), 1.80 (s, 2.1 H); 3.50 to 3.72 (m, 1H); 4.94 (tt, J = 4.2 and 10.3 Hz, 0.7 H), 5.14 (m, 0.3H), 7.03-7.13 (m, 1H); 7.79 to 7.90 (m, 1H); 8.21 to 8.30 (m, 1 H) 1 H NMR spectrum (400MHz, b ppm, DMSO-d6): 0.90 to Retention time 0.98 (m, 4H); 1.14 (m, 2H); 1.31 (m, 2H); 1.69 (d, J = 12.2 Tr (min) = 1.05; Hz, 2H); 1.87 (d, J = 1 0.5 Hz, 2H); 1.98 (m, 1H); 2.24 (M, [M + H] +: m / z 535, 1H); 4.51 (m, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.35 (dd, J = 2.0 [MH] -: m / z 533 and 8.6 Hz, 1H); 7.64 (d, J = 8.6 Hz, 1H); 8.02 (d, J = 2.0 Hz, 1H); 8.31 (d, J = 9.8 Hz, 1H); 12.66 (s large, 1 H) Retention time 46b Tr (min) = 3.86;
[M + H] +: m / z 467;
[MH] -: m / z 465 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 1.24 Retention time (m, 2H); 1.36 (m, 2H); 1.75 (m, 2H); 1.91 (m, 2H); 2.35 at Tr (min) = 0.51; 2.45 (m, 6H); 3.23 to 3.29 (masked m, 2H); 3.47 (m, 1H);
47 [M + H] +: m / z 571; 3.59 (t, J = 4.6 Hz, 4H); 4.57 (d, J = 4.2 Hz, 1H); 4.72 (m, 1 [MH] -: m / z 569 H); 6.79 (bs, 1H); 7.01 (d, J = 9.8 Hz, 1H); 7.40 (dd, J = 2.1 and 8.4 Hz, 1H); 7.56 (d, J = 8.6 Hz, 1H); 7.96 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1H); 10.87 (s wide, 1H) 1 H NMR spectrum (400 MHz, b in ppm, DMSO-d6): 1.29 to 1.43 (m, 2H); 1.49 to 1.63 (m, 2H); 1.82 to 1.92 (m, 2H);
47b 2.09 to 2.22 (m, 2H); 3.58 (m, 1H); 4.59 (d, J = 3.9 Hz, 1 H); 4.98 (m, 1H); 7.07 (d, J = 10.0 Hz, 1H); 8.26 (d, J = 10.0 Hz, 1H) 1H NMR Spectrum (400MHz, b ppm, DMSO-d6): 0.38 Retention time (q, J = 4.2 Hz, 1 H); 0.49 (m, 1H); 1.32 (m, 2H); 1.86 (m, Tr (min) = 3.65; H); 2.20 (m, 2H); 5.25 (t, J = 6.7 Hz, 1H); 6.96 (d, J = 9.8 [M + H] +: m / z 397; Hz, 1H); 7.28 (d, J = 8.3 Hz, 1H); 7.33 (dd, J = 2.0 and 8.6 Hz, [MH] -: m / z 395 1H); 7.62 (s, 2H); 7.90 (d, J = 2.0 Hz, 1H); 8.22 (d, J = 9.8 Hz, 1H) 1 H NMR Spectrum (400 MHz, b ppm, DMSO-d6): 0.44 (q, J = 4.2 Hz, 1H); 0.53 (m, 1H); 1.33 to 1.44 (m, 2H);
48b 1.99 (d, J = 14.9 Hz, 2H); 2.23 to 2.37 (m, 2H); 5.44 (t, J = 6.7 Hz, 1H); 7.03 (d, J = 9.8 Hz, 1H); 8.24 (d, J = 9.8 Hz, 1 H) 1 H NMR spectrum (400 MHz, b ppm, DMSO-d6): 1.66 to Retention time 1.78 (m, 2H), 1.80 to 1.96 (m, 2H); 2.16 to 2.31 (m, 2H) ;
Tr (min) = 0.68; 3.95 to 4.18 (m, 1H); 6.76 (d, J = 9.8 Hz, 1H), 7.31 (d, [M + H] +: m / z 370, J = 8.6 Hz, 1H); 7.37 (dd, J = 1.8 and 8.6 Hz, 1H); 7.72 (d [MH] -: m / z 368 broad, J = 7.0 Hz, 1H); 7.87 to 7.95 (m, 2H), 8.04 (m spread, 2H) Retention time 49b Tr (min) = 0.70;
[M + H] +: m / z 224, [MH] -: m / z 222 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 0.35 Retention time (q, J = 3.9 Hz, 1 H); 0.47 (m, 1H); 1.27 (m, 2H); 1.72 to 2.03 Tr (min) = 1.08; (m, J = 14.9 Hz, 4H); 2.07 at 2.33 (m, 6H); 3.35 to 3.47 (m 50 [M + H] +: m / z 479, masked, 1H); 5.21 (t, J = 6.8 Hz, 1H); 6.98 (d, J = 9.8 Hz, [MH] -: m / z 477H); 7.45 (dd, J = 2.1 and 8.4 Hz, 1H); 7.67 (d, J = 8.3 Hz, 1H);
8.16 (d, J = 2.0 Hz, 1H); 8.25 (d, J = 9.8 Hz, 1H); 12.25 (s wide, 1H) Retention time 1 H NMR spectrum (400MHz, 5 ppm, DMSO-d6): 1.29 Tr (min) = 0.76; (d, J = 8.6 Hz, 3H); 1.43 to 1.76 (m, 3H); 1.90 to 2.18 (m, 2 51 [M + H] +: m / z 417, H); 4.50 to 4.88 (m, 2H); 7.07 (d, J = 9.8 Hz, 1H); 7.27 (D, [MH] -: m / z 415 J = 8.6 Hz, 1H); 7.31 (dd, J = 1.7 and 8.3 Hz, 1H); 7.61 (s, 2 H); 7.83 (d, J = 2.0 Hz, 1H); 8.29 (d, J = 10.0 Hz, 1H) 1 H NMR spectrum (400 MHz, b in ppm, DMSO-d6): 1.32 to 51b 1.53 (m, 3H), 1.56-1.79 (m, 3H), 2.12 (m, 1H); 2.30 (m, 1H); 4.61 to 4.87 (m, 1H); 5.01 to 5.17 (m, 1H); 7.14 (d, J = 9.8 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H) 1H NMR Spectrum (400MHz, b ppm, DMSO-d6): 0.95 Retention time (m, 4H); 1.07 to 1.33 (m, 3H); 1.43 (m, 2H); 1.62 (m, Tr (min) = 0.97; J = 15.7 Hz, 1H); 1.85 (m, 1H); 1.93 to 2.12 (m, 2H);
4.46 to [M + H] +: m / z 485, 4.78 (m, 2H); 7.08 (d, J = 9.8 Hz, 1H); 7.44 (dd, J = 2.0 and [MH] -: m / z 483 8.3 Hz, 1H); 7.68 (d, J = 8.3 Hz, 1H); 8.08 (d, J = 2.0 Hz, 1 H); 8.32 (d, J = 9.8 Hz, 1H); 12.67 (s wide, 1 H) 1 H NMR spectrum (400 MHz, b in ppm, DMSO-d6): 0.90 to Retention time 0.99 (m, 4H), 1.61 to 1.73 (m, 2H); 1.77 to 1.90 (m, 2H) ;
Tr (min) = 0.89; 1.94 to 2.04 (m, 1H); 2.12 to 2.24 (m, 2H); 3.95 to 4.07 (M, [M + H] +: m / z 438; 1H); 6.75 (d, J = 9.8 Hz, 1H); 7.45 (dd, J = 1.8 and 8.4 Hz, [MH] -: m / z 436 H); 7.63-7.72 (m, 2H); 7.93 (d, J = 9.8 Hz, 1H); 8.12 (D, J = 1.8 Hz, 1H); 12.66 (spread m, 1 H) Retention time 1H NMR Spectrum (400MHz, ben ppm, DMSO-d6): 0.34 Tr (min) = 1.03; (q, J = 4.3 Hz, 1H); 0.47 (m, 1H); 0.95 (m, 4H); 1.27 (m, 2 [M + H] +: m / z 465, H); 1.72 to 1.84 (m, 2H); 1.98 (m, 1H); 2.12 (m, 2H); 5.20 [MH] -: m / z 463 (t, J = 6.7 Hz, 1H); 6.98 (d, J = 9.8 Hz, 1H); 7.45 (dd, J = 2.0 and 8.6 Hz, 1H); 7.68 (d, J = 8.6 Hz, 1H); 8.13 (d, J = 2.0 Hz, 1H); 8.24 (d, J = 9.8 Hz, 1H); 12.66 (s large, 1 H) 1H NMR Spectrum (400MHz, 5 ppm, DMSO-d6): 0.99 (t, Retention time J = 7.2 Hz, 6 H); 1.04 to 1.33 (m, 3H), 1.34 to 1.50 (m, 2H) Tr (min) = 0.71; ; 1.56 to 1.70 (m, 1H), 1.85 (d, J = 6.1 Hz, 1H), 1.95 to 2.10 [M + H] +: m / z 530; (m, 1H); 2.62 (q, J = 7.1 Hz, 4H); 3.40 (s, 2H); 4.42 at [M + 2H] 2 +: m / z 4.76 (m, 2H); 7.08 (d, J = 9.8 Hz, 1H); 7.43 (dd, J = 1.8 and 265.5 (base peak) 8.4 Hz, 1H); 7.67 (d, J = 8.4 Hz, 1H); 8.10 (d, J = 1.8 Hz, 1 [MH] -: m / z 528H); 8.32 (d, J = 9.8 Hz, 1H); 10.73 to 12.94 (m very spread, 1 H) 1H NMR spectrum (400MHz, b ppm, DMSO-d6): 0.98 (t, Retention time J = 7.1 Hz, 3 H); 1.08 to 1.33 (m, 3H); 1.35 to 1.50 (m, 2 H) Tr (min) = 0.70; ; 1.63 (m, 1H); 1.84 (m, 1H); 2.04 (m, 1H); 2.20 to 2.58 56 [M + H] +: m / z 571; (partially masked m, 10H); 3.20 to 3.40 (m [M + 2H] 2+: m / z 286 partially masked, 2H); 4.45 to 4.76 (m, 2H); 7.08 (D, (base peak) [MH] - J = 9.8 Hz, 1H); 7.44 (dd, J = 1.7 and 8.8 Hz, 1H); 7.68 (D, m / z 569 J = 8.8 Hz, 1H); 8.10 (d, J = 1.7 Hz, 1H); 8.32 (d, J = 9.8 Hz, 1H), 12.09 (spread m, 1H) 1 H NMR spectrum (400 MHz, bp ppm, DMSO-d6): 1.10 to Retention time 1.32 (m, 3H); 1.34 to 1.51 (m, 2H); 1.58 to 1.68 (m, 1 H) ;
Tr (min) = 0.71; 1.81 to 1.92 (m, 1H); 1.96 to 2.11 (m, 1H); 2.45 to 2.55 (m 57 [M + H] +: m / z 544; partially masked, 4H); 3.34 (s, 2H); 3.56 to 3.66 (M, [M + 2H] 2+: m / z 4H); 4.48 to 4.78 (m, 2H); 7.08 (d, J = 9.8 Hz, 1H); 7.44 272.5 (base peak) (dd, J = 2.0 and 8.6 Hz, 1H); 7.68 (d, J = 8.6 Hz, 1H);
8.10 [MH] -: m / z 542 (d, J = 2.0 Hz, 1H); 8.32 (d, J = 9.8 Hz, 1H); 12.15 (m spread, 1H) Retention time 1 H NMR spectrum (400 MHz, 5 ppm, DMSO-d6): 1.61 Tr (min) = 0.71; (m, 1H); 1.74 (m, 1H); 1.95 to 2.09 (m, 2H); 2.20 to 2.31 58 [M + H] +: m / z 498; (m, 2H); 2.53 (m, 4H); 3.33 (s, 2H); 3.60 (m, 4H) ; 4.90 [M + 2H] 2+: m / z (m, 1H); 7.06 (d, J = 9.8 Hz, 1H); 7.47 (dd, J = 2.0 and 8.8 249.5 (peak base) Hz, 1H); 7.70 (d, J = 8.8 Hz, 1H); 8.13 (d, J = 2.0 Hz, 1 H);
[MH] -: m / z 496, 8.30 (d, J = 9.8 Hz, 1H); 12.14 (spread m, 1 H) Retention time 1 H NMR spectrum (400 MHz, b ppm, DMSO-d6): 0.26 Tr (min) = 0.72; (m, 2H); 0.39 (m, 2H); 1.02 to 1.33 (m, 3H); 1.35 to 1.50 [M + H] +: m / z 583; (m, 2H); 1.61 (d, J = 3.2 Hz, 2H); 1.79 to 1.92 (m, 1H);
59 [M + 2H] 2 +: m / z 292 2.04 (m, 1H); 2.45 to 2.59 (partially masked m, 8 H);
(base peak) [MH] - 3.37 to 3.41 (m, 2H); 4.46 to 4.75 (m, 2H); 7.08 (d, J = 9.8 m / z 581 Hz, 1H); 7.44 (d, J = 8.7 Hz, 1H); 7.68 (d, J = 8.7 Hz, 1H; 8.10 seconds wide, 1H; 8.32 (d, J = 9.8 Hz, 1H; 12.12 (m spread, 1H) Retention time 59b Tr (min) = 0.10;
[M + H] +: m / z 185;

1 H NMR spectrum (400 MHz, b in ppm, DMSO-d6): 0.20 to Retention time 0.30 (m, 2H); 0.36 to 0.45 (m, 2H), 1.54 to 1.66 (m, 2H) ;
Tr (min) = 0.71; 1.69 to 1.81 (m, 1H); 1.96 to 2.09 (m, 2H); 2.22 to 2.31 (M, 60 [M + H] +: m / z 537.2H); 2.42 to 2.60 (partially masked m, 8H); 3.18 to [M + 2H] 2 +: m / z 269 3.46 (partially masked m, 2H); 4.90 (m, 1H); 7.06 (base peak) [MH] - (d, J = 9.8 Hz, 1H); 7.47 (dd, J = 1.9 and 8.6 Hz, 1H);
7.70 (d, m / z 535 J = 8.6 Hz, 1H); 8.13 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 9.8 Hz, 1H); 11.23 to 13.22 (m very spread, 1 hour) 1H NMR Spectrum (400 MHz, b ppm, DMSO-d6): 1.60 Retention time (m, 1H); 1.75 (m, 1H); 1.96 to 2.10 (m, 2H); 2.23 to 2.34 Tr (min) = 0.86; (m, 2H), 3.03 to 3.19 (m, 8H); 3.58 (s, 2H); 4.91 (m, [M + H] +: m / z 546, H); 7.06 (d, J = 9.8 Hz, 1H); 7.48 (dd, J = 2.0 and 8.6 Hz, 1 H) [MH] -: m / z 544; 7.71 (d, J = 8.6 Hz, 1H); 8.14 (d, J = 2.0 Hz, 1H); 8.30 (D, J = 9.8 Hz, 1H); 12.23 (spread m, 1 H) 1 H NMR spectrum (400 MHz, b in ppm, DMSO-d6): 1.54 to 1.66 (m, 1H), 1.68 to 1.78 (m, 1H), 1.82 (quin, J = 5.9 Hz, Retention time 2H); 1.95 to 2.10 (m, 2H); 2.22 to 2.32 (m, 2H); 2.75 to Tr (min) = 3.10; 2.85 (m, 4H); 3.53 (s, 2H); 3.60 to 3.65 (m, 2H);
3.69 (t, [M + H] +: m / z 512, J = 5.9 Hz, 2H); 4.90 (m, 1H), 7.06 (d, J = 9.8 Hz, 1H);
[MH] -: m / z 510 7.47 (dd, J = 2.0 and 8.6 Hz, 1H); 7.70 (d, J = 8.6 Hz, 1H);
8.13 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 12.12 (m spread, 1H) Retention time 62b Tr (min) = 0.13;
[M + H] +: m / z 160;
[MH] -: m / z 158 Retention time 1 H NMR spectrum (400 MHz, b ppm, DMSO-d6): 1.61 (m, 1H); 1.74 (m, 1H); 1.92 to 2.09 (m, 2H); 2.22 to 2.32 Tr (min) = 0.91; (m, 2H); 2.73 (t, J = 6.1 Hz, 2H); 3.23 (s, 3H); 3.65 (T, 63 [M + H] +: m / z 457; J = 6.1 Hz, 2H); 4.90 (m, 1H); 7.06 (d, J = 10.0 Hz, 1 H);
[MH]: m / z 455 7.47 (dd, J = 2.0 and 8.6 Hz, 1H); 7.69 (d, J = 8.6 Hz, 1H);
8.12 (d, J = 2.0 Hz, 1H); 8.29 (d, J = 10.0 Hz, 1H); 12.41 (m spread, 1H) Retention time NMR spectrum 1 H (400 MHz, b in ppm, DMSO-d6): 1.51 to Tr (min) = 1.04; 1.80 (m, 4H); 1,82à1,94 (m, 2H); 1,96à2,10 (m, 2H);
[M + H] +: m / z 532; 2.22 to 2.31 (m, 2H; 2.62 (m, 2H; 2.90 (t, J = 11.7 Hz, 2 [MH] -: m / z 530 H); 3.50 (s, 2H); 4.90 (m, 1H); 7.06 (d, J = 9.8 Hz, 1H) ;
7.48 (dd, J = 2.0 and 8.6 Hz, 1H); 7.71 (d, J = 8.6 Hz, 1H);
8.14 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 12.19 (m spread, 1H) Retention time 64b Tr (min) = 0.13;
[M + H] +: m / z 180;
[MH] -: m / z 178 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 (majority) 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] urea may be prepared in a manner similar to that described for Example 2a, but with 0.240g of a 1/1 mixture of cis- and trans-3-chloro-6- {[3-racemic methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazine, in solution in 12 cm3 of ethanol, then, added at a temperature of 20 C, 0.457g of 1- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 0.416 g of DL-dithiothreitol, and a solution of 0.061 g of potassium dihydrogen phosphate in 0.600 cm3 of distilled water. After 8h stirring at reflux, the reaction medium is concentrated to dryness under pressure reduced (2.7 kPa). The residue is taken up in 40 cm3 of dichloromethane and the mixture obtained is washed successively with 2 times 30 cm3 of distilled water and 15 cm3 of a saturated solution of sodium chloride, then dried on anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7kPa) to give 0.370g 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% V / y of an aqueous solution 20% ammonia). After concentration of the fractions under pressure reduced, we obtain 0.121 g of a 15/85 mixture of cis- and trans-1- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 racemic benzothiazol-2-yl} -3- [2- (morpholin-4-yl) ethyl] urea as a white solid melting at 197.6 C and whose characteristics are the following:

NMR spectrum (400 MHz, ppm, DMSO-d6) 85% isomer mixture H1ax-15% Hleq with 0.71 (d, J = 6.3 Hz, 0.45 H); 0.81 (d, J = 6.6 Hz, 2.55 H) 0.72 to 1.80 (m, 7H); 1.85 to 1.94 (m, 2H); 2.36 to 2.44 (m, 6H); 3.26 (m partially masked, 2H); 3.59 (m, 4H); 4.64 (m, 0.85H); 5.07 (m, 0.15 H); 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, 0.15H); 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-racemic methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazine may be prepared in a manner similar to that described in Example 1c but from 0.628g of a 1/1 mixture of racemic cis- and trans-3-methyl-cyclohexanol in solution in 6cm3 of tetrahydrofuran under a stream of argon add at a temperature close to 0 C, 0.220 g of 60% sodium hydride in the oil. The reaction medium is maintained at a temperature close to 0 C for 15 minutes then 0.650g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine. After a stirring hold at a temperature close to 20 C for 24h, 10 cm3 of a aqueous solution of saturated ammonium chloride and 20 cm3 of acetate ethyl. After separation of the 2 phases, the organic phase is washed successively with 2 times 10cm3 of distilled water and 15cm3 of a solution saturated with sodium chloride and then dried over magnesium sulphate anhydrous, 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-racemic methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazine in the form of a brown oil whose characteristics 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-yl} cyclopropanecarboxamide, mixture 15/85 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] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 racemic benzothiazol-2-yl} cyclopropanecarboxamide can be prepared from similar way to that described for Example 2a, but from 0.500g N- (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide, 0.616g of DL-dithiothreitol, a solution of 0.090 g of dihydrogenphosphate potassium in 1cm3 of distilled water, 0.355g of 1/1 mixture of cis- and trans-3-chloro-6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazine racemic (65b) and 18cm3 ethanol. After 8 hours of agitation at reflux then treatment and purification by flash chromatography on silica [eluent:
dichloromethane / methanol / acetonitrile (90/5/5 by volume)], we obtain 0.198 g of a 15/85 mixture of cis and trans isomers of N- {6 - [(6 - {[3-methylcyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 racemic benzothiazol-2-yl} cyclopropanecarboxamide in the form of a white solid melting at 216.5 C and whose characteristics are the following:

NMR spectrum (400 MHz, ppm, DMSO-d6) 85% isomer mixture H1ax - 15% Hleq 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, 0.15 H); 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, Og of 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6- thiocyanate yle, 22.44 g of DL-dithiothreitol, a solution of 0.235 g of potassium dihydrogen phosphate in 60cm3 of distilled water and 450cm3 ethanol. After stirring for 5 hours under reflux, the reaction medium is poured onto 700 cm3 of ice water under an argon flow. The yellow solid formed is filtered on VF3, washed twice with 70 cm3 of ice water and dried in a pressure oven reduced (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 whose characteristics are as follows:
ES +/- Mass Spectrum: [M + H] +: m / z 251; [MH] -: m / z 249.
c) 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl thiocyanate can be prepared in a manner similar to that described in Example la but at from 15, Og of 2-amino-1,3-benzothiazol-6-yl thiocyanate, 7.88cm3 of cyclopropane carboxylic acid chloride and 150 cm 3 of pyridine.
After stirring for 5 hours at a temperature in the region of 20 ° C., the reaction medium over 500 cm3 of ice water. The solid formed is filtered on filtered VF3 then washed with 5 times 70cm3 of ice water before drying in the oven under reduced pressure (2.7 kPa) at 40 C for 10h, to give 19 g of 2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl thiocyanate under pink solid form whose characteristics are as follows ES +/- Mass Spectrum: [M + H] +: m / z 276; [MH] -: 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 isomers (majority) a) The 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 can be prepared from similar to that described for Example 2a, but from 0.876g 1-[2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (2b), 0,798g of DL-dithiothreitol, a solution of 0.117 g of dihydrogenphosphate potassium in 1.15 cm3 of distilled water, 0.460 g of a 1/1 mixture of cis-and trans-3-chloro-6- (4-methyl-cyclohexyloxy) -1,2,4-triazolo [4,3-b] pyridazine and 23cm3 of ethanol. After 16 hours of stirring at reflux, then treatment and purification by flash chromatography on silica [eluent: dichloromethane /
methanol / acetonitrile (90/5/5 by volume + 0.1% "/, of an aqueous solution 20% ammonia), 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-(Sulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (morpholin-4-yl) ethyl] urea in the form of of white solid melting at 155.9 C and whose characteristics are the following:

NMR spectrum (400 MHz, a ppm, DMSO-d6) isomeric mixture 85%
H1ax-15% Hleq with: 0.86 (d, J = 6.4 Hz, 3H); 0.88 to 0.93 (m, 2H); 1.17 to 1.63 (m, 5H); 1.76 to 1.93 (m, 2H); 2.35 to 2.45 (m, 6H); 3.26 (m partially masked, 2H); 3.59 (m, 4H); 4.40 to 4.57 (m, 1H); 6.78 (m broad, 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, 0.85H); 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-triazolo [4,3-b] pyridazine can be prepared in a manner similar to that described in Example 1a but from 0.628 g of a mixture 1/1 cis- and trans-4-methyl cyclohexanol, 6 cm3 of tetrahydrofuran, 0.220g of 60% sodium hydride in the oil and 0.650g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine. After a stirring hold at temperature close to 20 C for 24h and treatment, we obtain 0.880g a 1/1 mixture of cis- and trans-3-chloro-6- (4-methyl-cyclohexyloxy) -1,2,4-triazolo [4,3-b] pyridazine as a brown oil that solidifies whose characteristics are as follows 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] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) phenyl carbamate (4) in 10cm3 of THF and 10cm3 of DMF with 75 mg of 1- (azetidin-3-yl) piperidine dihydrochloride and 0.160 cm3 of triethylamine after 66h of reaction at 20 C. 155 mg of 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 in the form of a pale yellow solid whose characteristics are as follows:
NMR'H SPECTRUM (400 MHz, DMSO-d6, bppm): 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 (m broad, 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; [MH] -: m / z 563.

Example 69:
N- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-[Sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide, mixture 15/85 cis and trans isomers (majority) The 85/18 mixture of cis- and trans-N- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxamide can be prepared in a 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 dihydrogenphosphate potassium in 1.05 cm3 of distilled water, 0.420 g of a 1/1 mixture of 3-chloro-6- (4-methyl-cyclohexyloxy) -1,2,4-triazolo [4,3-b] pyridazine (67b) and 20cm3 of ethanol. After 16 hours of stirring at reflux then treatment and purification by flash chromatography on silica [eluent: dichloromethane /
methanol / acetonitrile (90/5/5 by volume)], 0.336 g of a mixture is obtained.
15/85 of the cis and trans isomers of N- [6 - ({6 - [(4-methylcyclohexyl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxam ide as a white solid melting at 230 C whose characteristics are as follows:

NMR spectrum (400 MHz, ppm, DMSO-d6) 85% isomer mixture H1ax - 15% Hleq with: 0.72 to 0.99 (m, 6H); 0.82 (d, J = 6.6 Hz, 2.55 H), 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, 0.15H); 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, 0.15 H); 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-carboxam ide 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-carboxam ide may be prepared in a manner similar to that described in Example 5 but from of 150 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -Phenyl 1,3-benzothiazol-2-yl) carbamate (4), 65mg 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.
then treatment gives 0.056g of 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 as a solid white whose characteristics are as follows:
ES +/- mass spectrum: [M + H] +: m / z 524; [MH] -: m / z 522.

1H NMR Spectrum (400 MHz, a ppm, DMSO-d6): 1.15 to 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, 1 H);
7.55 (broad d, J = 8.6 Hz, 1H); 8.00 (d, J = 2.0 Hz, 1H); 8.27 (d, J = 9.8 Hz, 1 H) ; 11.36 (spread m, 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-Iler, 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 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 may be prepared in a manner similar to Example 5 but from 182 mg of (6-{[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) carbamate of phenyl (4) in 10cm3 of THF, 106mg of 4- (azetidin-3-yl) morpholine dihydrochloride and 0.167 cm3 of triethylamine, after 22h of reaction at 20 C. Thus 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-carboxamide in the form of a white solid whose characteristics are as follows:
NMR spectral (400 MHz, DMSO-d6, bppm): 1.11 to 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 (broad d, J = 8.6 Hz, 1 H) 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-benzothiazol-2-yl} cyclopropanecarboxam ide 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 0.636g 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 dihydrogen phosphate in 1.27 cm3 distilled water, 0.428 g of a 1/1 mixture of cis- and trans-3-chloro-6- (2-Racemic methyl-cyclopentyloxy) -1,2,4-triazolo [4,3-b] pyridazine and 23cm3 ethanol. After 16 hours stirring at reflux and treatment and purification with 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 white solid melting at 197.7 C, the characteristics of which are as follows:

NMR spectrum (400 MHz, α ppm, DMSO-d6): 0.89 (d, J = 7.1 Hz, 3H), 0.92 to 1.00 (m, 4H); 1.06 to 1.21 (m, 1H); 1.46 to 1.69 (m, 3H); 1.78 to 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) -Racemic 1,2,4-triazolo [4,3-b] pyridazine can be prepared in a similar to that described in Example 1c but from 0.678 g of a mixture 1/1 of cis- and trans-2-methylcyclopentanol, of 10 cm3 of tetrahydrofuran, 0.271g of 60% sodium hydride in oil, 0.800g and 3.6-dichloro [1,2,4] triazolo [4,3-b] pyridazine. After a stirring hold at temperature close to 20 C for 24h and treatment, we get 1.033g a 1/1 mixture of cis- and trans-3-chloro-6- (2-methyl-cyclopentyloxy) -Racemic 1,2,4-triazolo [4,3-b] pyridazine as a brown oil with the characteristics 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-benzothiazol-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 can to be prepared in a manner similar to that described for Example 2a, but from 0.609 g of 1- [2- (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 0.85cm3 distilled water, 0.303g a 1/1 mixture of cis- and trans-3-chloro-6- (2-methyl-cyclopentyloxy) -Racemic 1,2,4-triazolo [4,3-b] pyridazine (72b) and 17cm3 of ethanol. After 16 h stirring at reflux and treatment and purification by chromatography flash on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 in volumes + 0.1% "/, of an aqueous ammonia solution at 20%)], gets 0.223g of 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 as a solid pale yellow melting at 203.3 C, the characteristics of which are as follows:
NMR spectrum (400 MHz, α ppm, DMSO-d6): 0.92 (d, J = 7.1 Hz, 3H), 1.16 (m, 1H); 1.50 to 1.69 (m, 3H); 1.79 to 2.12 (m, 3H); 2.37 to 2.44 (m, H); 3.26 (partially masked m, 2H); 3.59 (m, 4H); 4.52 to 4.60 (m, 1 H) 6.79 (m spread, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.37 (dd, J = 2.0 and 8.5 Hz, 1 H) 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] pyridazin-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] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) phenyl carbamate (4) in 5cm3 of dimethylformamide, 69mg of 3-methoxyazetidine hydrochloride and 0.078cm3 of triethylamine after 20 hours of reaction at 20 C. This gives 120 mg of N- (6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [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:
NMR spectral (400 MHz, DMSO-d6, bppm): 1.14 to 1.42 (m, 5H); 1.44 at 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, 1 H) 8.27 (d, J = 9.8 Hz, 1H); 11.36 (spread m, 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-ylurea 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 similar to Example 5 but from 191 mg of (6 - {[6-(Cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) phenyl carbamate (4) in 3cm3 of dimethylformamide, 40mg of oxetan-3-amine after 20 hours of reaction at 20 ° C., thus obtaining 95 mg of (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3-oxetan-3-ylurea as a white solid whose characteristics are as follows:
NMR spectral (400 MHz, DMSO-d6, bppm): 1.12 to 1.43 (m, 5H); 1.47 at 1.54 (m, 1H); 1.62 (m, 2H); 1.83 (m, 2H); 4.47 (t, J = 6.4 Hz, 2H); 4.67 at 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, 1 H); 10.99 (spread m, 1H).
MASS SPECTRUM (Electrospray on WATERS UPLC - SQD):
[M + H] +: m / z 498; [MH] -: 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 isomers (majority) racemic a) The mixture 2/3 of the 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 can be prepared from similar way to that described for Example 2a, but from 0.643g of 1- (6-Mercapto-benzothiazol-2-yl) -3- (2-morpholin-4-yl-ethyl) -urea (2b), from 0.586 g of DL-dithiothreitol, a solution of 0.086 g of potassium dihydrogen phosphate in 0.95cm3 distilled water, 0.320g of a 1: 1 mixture of racemic cis and trans isomers of 3-chloro-6- (3-methyl-cyclopentyloxy) -1,2,4-triazolo [4,3-b] pyridazine and 19 cm 3 of ethanol.
After 16 hours stirring at reflux and treatment and purification with flash chromatography on silica [eluent: dichloromethane / methanol /
acetonitrile (90/5/5 by volume with 0.1% "/, of an aqueous solution 20% ammonia)], 0.065 g of a 2/3 mixture of the isomers is obtained.
cis and trans racemic 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 melting at 174.7 C, the characteristics of which are as follows:

1H NMR Spectrum (400 MHz, a ppm, DMSO-d6) isomeric mixture 2/3 -1/3 with: 0.90 (d, J = 6.8 Hz, 1H); 0.94 (d, J = 6.6 Hz, 2H); 1.00 to 1.35 (m, 2 H); 1.57 to 2.16 (m, 5H); 2.36 to 2.44 (m, 6H); 3.26 (partially m masked, 2H); 3.59 (m, 4H); 5.05 (m, 0.66H); 5.11 (m, 0.34 H); 6.79 (m broad, 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, H); 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 the cis and trans racemic isomers of 3-chloro-6- (3-methyl-cyclopentyloxy) -1,2,4-triazolo [4,3-b] pyridazine can be prepared from similar to that described in Example 1c but from 0.678 g of a 1/1 mixture of racemic cis and trans-3-methylcyclopentanol isomers, 10cm3 of tetrahydrofuran, 0.271g of 60% sodium hydride in the oil and 0.800g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine. After a keeping stirring at a temperature of 20 C for 24 hours and treatment, 0.860 g of a 1/1 mixture of cis and trans isomers is obtained of 3-chloro-6- (3-methyl-cyclopentyloxy) -1,2,4-triazolo [4,3-b] pyridazine in the form of a brown oil, the characteristics of which are following:
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-yl} cyclopropanecarboxamide, mixture 2/3 of the cis and trans isomers (majority) racemic Two-thirds of the racemic cis and trans 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 similar to that described for Example 2a, but from 0.505g of N- (6-sulfanyl-1,3-benzothiazol-2-yl) cyclopropanecarboxamide (66b), 0.622 g of DL-dithiothreitol, a solution of 0.091 g of dihydrogenphosphate potassium in 1.01 cm3 of distilled water, 0.340 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 (76b) and 23cm3 of ethanol. After 16h stirring at reflux and treatment and purification by flash chromatography on silica [eluent: dichloromethane / methanol / acetonitrile (90/5/5 volumes)], 0.172 g of a 2/3 mixture of cis and trans isomers are obtained.
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 whose characteristics are the following:

1H NMR Spectrum (400 MHz, a ppm, DMSO-d6) 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, 6 H) ;
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, 1 H) 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; [MH] -: 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 preparation this preparation can be carried out if desired with other products as examples in this application.

Pharmacological part:
Experimental protocols I) Expression and Purification of MET, Cytoplasmic Domain Baculovirus expression:
Recombinant His-Tev-MET (956-1390) DNA in pFastBac (Invitrogen) is transfected into insect cells and after several stages viral amplification, the final baculovirus stock is tested for expression of the protein of interest.
After infection for 72h at 27 C with the recombinant virus, the cultures of SF21 cells are harvested by centrifugation and the cell pellets are stored at -80 C.
Purification:
Cell pellets are resuspended in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, Glycerol 10%, TECP 1 mM]; + Roche Diagnostics protease inhibitor cocktail without EDTA, ref 1873580), stirred at 4 C until homogeneous, then mechanically lysed using a Dounce type device.
After centrifugation, the lysis supernatant is incubated for 2 hours at 4 ° C. with Nickel Chelate Resin (His-Trap 6 Fast FlowTM, 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).
Fractions containing the protein of interest in view of the analysis electrophoretic data (SDS PAGE) are collected, concentrated by Ultrafiltration (cut-off 1 OkDa) and injected on a column of chromatography exclusion (Superdex TM 200, GE HealthCare) balanced in buffer A.
After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Chromatography column Nickel Chelate (His-Trap 6 Fast Flow TM, GE HealthCare) balanced in Buffer A. Fractions eluted by a gradient of buffer B and containing the protein of interest after electrophoresis (SDS PAGE), are finally collected and stored at -80 C.
For the production of autophosphorylated protein, the previous fractions are incubated for 1 h at room temperature after addition of 2 mM ATP, MgCl 2 2mM, and 4mM Na3VO4. After stopping the reaction with 5mM EDTA, the reaction mixture is injected onto a HiPrep desalting column (GE
HealthCare) previously balanced in buffer A + Na3VO4 4mM, the Fractions containing the protein of interest (SDS PAGE analysis) are collected and stored at -80 C. The phosphorylation rate is verified by mass spectrometry (LC-MS), and by peptide mapping.

II) Tests A and B

A) Test A: HTRF MET assay in 96-well format In a final volume of 50 μl of enzymatic reaction, final MET 5nM is incubated in the presence of the test molecule (for a concentration range final 0.17 nM to 10 μM, DMSO 3% final) in MOPS buffer 10 mM 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, ATP 10 μM and MgCl2 5mM. After a 10 min incubation at room temperature, the reaction is stopped by a mix of 30 μl to obtain a final solution of Hepes 50mM pH 7.5, 500mM potassium fluoride, 0.1% BSA and EDTA
133mM in the presence of 80ng Streptavidin 61SAXLB Cis-Bio Int. and 18ng anti-Phosphotyrosine Mab PT66-Europium Cryptate per well. After 2 hours of incubation at room temperature, the reading is made at 2 length of 620nm and 665nm waves on a reader for the TRACE / HTRF technique and the% inhibition is calculated from the 665/620 ratios.

The results obtained by this test A for the products of formula (I) in examples in the experimental part are such that IC50 less than 500nM
and especially at 100nM.

B) Test B: Inhibition of MET autophosphorylation; ELISA technique (PppY1230,1234,1235) a) Cell lysates: Inoculate MKN45 cells in 96-well plate (Ceil 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 products: Stock at lOmM in pure DMSO - Range of 10mM
at 30pM with a step of 3 in pure DMSO - Intermediate 1/50 dilutions in culture medium and then 10p cells (200pl): final range of 10000 to 30nM.

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

The 100pl of lysates are transferred into a polypropylene plate in V and the ELISA is carried out immediately or the plate is frozen at -80 C.

b) ELISA PhosphoMET BioSource Kit KH00281 In each well of the kit plate, add 70 μl of the dilution buffer of the kit + 30pL of cell lysate or 30pl of lysis buffer for whites.
Incubate for 2h with gentle shaking at room temperature.

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

Rinse the wells four times with 400 μl of kit wash buffer. Put 100pL
of chromogen and incubate 30 minutes in the dark at room temperature.
Stop the reaction with 100 μl stop solution. Read without delay at 450nM 0.1 second at Wallac Victor flat reader.

C) Test C: Measurement of 14C-Thymidine Pulse Cell Proliferation The cells are seeded in 96-well Cytostar plates under 180 μl for 4 hours at 37 ° C. and 5% CO 2: HCT1 cells 16 at a rate of 2500 cells per well in DMEM medium + 10% fetal calf serum +
1% L-Glutamine and MKN45 cells at 7500 cells per well in RPMI medium + 10% fetal calf serum + 1% L-Glutamine.
After these 4 hours of incubation, the products are added under 10pl in solution 20 times concentrated according to the dilution method cited for the ELISA.
The products are tested at 10 duplicate concentrations of 10000nM at 0.3nM with a step 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 14C-thymidine is measured on a Micro-Beta (Perkin-Elmer) after 24 hours of pulse and 96h of treatment.
All stages of the test are automated on BIOMEK 2000 stations or TECAN.

The results obtained by this test B for the products of formula (I) in examples in the experimental part are such that IC50 less than 1 OmicroM and especially 1 microM.

The results obtained for the products in examples in the part experimental data are given in the pharmacological results table below.
after, as follows:

for test A, the sign + corresponds to less than 500nM and the sign ++
corresponds to less than 100nM.

for test B the sign + corresponds to less than 500nM and the sign ++
corresponds to less than 100nM.

for the C test, the + sign corresponds to less than 10 microM and the sign ++
corresponds to less than 1 microM.

Table of pharmacological results number ex test A test B test C
1 ++ ++ ++
2 ++ ++ ++
3 ++ ++ ++
4 ++ + ++
++ ++ ++
6 ++ ++
7 ++ ++ ++
8 ++ + ++

9 ++ ++ ++

++ ++ ++
11 ++ ++ ++
12 ++ ++ ++
13 ++ ++ ++
14 ++ ++ ++
++ ++ ++
16 ++ + ++
17 ++ ++ ++
18 ++ ++ ++
19 ++ ++ ++
++ + ++
21 ++ ++ ++
22 ++ ++
23 ++ ++ ++
24 ++ ++ ++
++ ++ ++
26 ++ ++ ++
27 ++ ++ ++
28 ++ ++ ++
29 ++ ++ ++
++ ++ ++
31 ++ ++
32 ++ ++ ++
33 ++ + ++
34 ++ ++ ++
++ ++ ++
36 ++ ++ ++
37 ++ + ++
38 ++ ++ ++
39 ++ ++ ++

40 ++ ++ ++
41 ++ ++ ++
42 ++ ++ ++
43 ++ ++ ++
44 ++ ++ ++
45 ++ +
46 + ++ ++
47 ++ ++
48 ++ + ++
49 ++ ++ ++
50 ++ ++ ++
51 ++ ++ ++
52 ++ ++ ++
53 ++ ++ ++
54 ++ ++ ++
55 ++ ++ ++
56 ++ ++ ++
57 ++ ++ ++
58 ++ ++ ++
59 ++ ++ ++
60 ++ ++ ++
61 ++ + ++
62 ++ ++ ++
63 ++ ++ ++
64 ++ ++ ++
65 ++ ++ ++
66 ++ ++ ++
67 ++ ++ ++
68 ++ + ++
69 ++ ++ ++

70 ++ + ++
71 + + ++
72 ++ ++ ++
73 ++ ++ ++
74 ++ + ++
75 ++ ++ ++
76 ++ ++ ++
77 ++ ++ ++

Claims (31)

1- Products of formula (I):
in which 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 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 with NR 3 R 4, alkoxy, hydroxy or 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 NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an alkyl radical optionally substituted with one or more identical radicals or different radicals chosen from hydroxyl, alkoxy and heteroaryl radicals, heterocycloalkyl, NR3R4, optionally substituted phenyl or R1 and R2 form with the nitrogen atom to which they are attached a radical cyclic ring containing from 3 to 10 members and optionally one or several other heteroatoms chosen from O, S, N and NH, with the optional S possibly being in SO or SO2 form; this radical including the eventual NH it contains being possibly substituted;

with R3 and R4, identical or different, represent an atom of hydrogen, an alkyl radical, a cycloalkyl radical, a radical heterocycloalkyl, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more identical radicals or different radicals chosen from hydroxyl, alkoxy and heteroaryl radicals, heterocycloalkyl, NH2, NHAlk, N (Alk) 2 or optionally phenyl substituted; or else R3 and R4 form with the nitrogen atom to which they are linked to a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms chosen from O, S, N and NH, with the optional S possibly being in SO or SO2 form; this radical including the eventual NH it contains being possibly 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 with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, -O-CO-R5, -COOH radicals, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5 and the alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl radicals, phenyl, CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals, the radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or several radicals chosen from halogen atoms and radicals hydroxyl, oxo, alkyl and alkoxy containing 1 to 4 carbon atoms, NH 2, NHalk 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 can be optionally substituted on one of the ring carbons by a radical spirocycloalkyl or spiroheterocycloalkyl or possibly on two of the carbons of the ring with a fused cycloalkyl or heterocycloalkyl radical;
R5 and R5 ', which may be identical or different, represent an alkyl radical or cycloalkyl 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 NH-unsubstituted cyclohexyl and represents a double bond, said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I). 2- products of formula (I) as defined in claim 1 wherein represents a single or double bond;

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

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

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

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

an alkoxy radical optionally substituted with NR 3 R 4, alkoxy, hydroxy or heterocycloalkyl; an O-phenyl radical or a radical O- (CH2) n-phenyl, with optionally substituted phenyl and n represents an integer of 1 to 4;

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

with R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted with by one or more identical or different radicals chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk radicals, N (Alk) 2 or optionally substituted phenyl; or else R3 and R4 form with the nitrogen atom to which they are attached, a cyclic radical containing from 3 to 10 links and optionally one or more other heteroatoms selected among O, S, N and NH, with the possible S possibly being under form SO or S02, this radical including the eventual 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 chosen radicals among the halogen atoms, the radicals hydroxyl, oxo, alkoxy, -O-CO-R5, NH2, NHalk, N (alk) 2 and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves possibly substituted by one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl radicals and alkoxy containing 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2;

R5 represents an alkyl or cycloalkyl radical containing at most 6 atoms of carbon;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I). 3- Products of formula (I) as defined in any one of the other claims in which , Ra and X have the values defined in one any of the other claims and:

A represents NH or S;

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

a cycloalkyl radical or an alkyl radical optionally substituted with a halogen atom or a cycloalkyl radical, NR3R4, alkoxy, hydroxy, phenyl or heterocycloalkyl themselves optionally substituted;

an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy or 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 NR1R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an optionally substituted alkyl radical with an alkoxy, heterocycloalkyl or NR3R4 radical; 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 y including the possible NH it contains being optionally substituted;

with NR3R4, such that R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical or a radical heterocycloalkyl, all optionally substituted with one or more identical or different radicals chosen from alkoxy radicals, heterocycloalkyl or NH2, NHAlk or N (Alk) 2; or else R3 and R4 form with the nitrogen atom to which they are attached a cyclic radical containing from 3 to 10 links and possibly one or more others heteroatoms chosen from O, S, N and NH, this radical including the optional NH it contains being optionally substituted;

all cycloalkyl, heterocycloalkyl and phenyl radicals as well as cyclic radicals that can form R1 and R2 or R3 and R4 with the atom to which they are linked, as defined above, possibly being substituted by one or more radicals selected from halogen atoms, hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 radicals and alkyl radicals, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl, such as in these last radicals, alkyl radicals, heterocycloalkyl, phenyl and heteroaryl are themselves possibly substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms carbon, NH2, NHalk and N (alk) 2;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I). 4- Products of formula (I) as defined in any one of the other claims in which , Ra and X have the values defined in one any of the other claims and:

A represents NH or S;

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

a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, or alkoxy;

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

or the radical NR1R2, in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or a radical alkyl and the other of R1 and R2 represents a hydrogen atom, a radical alkyl optionally substituted with a heterocyclic radical or NR3R4, or R1 and R2 together with the nitrogen atom to which they are attached form a radical cyclic optionally containing 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 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 attached a cyclic radical containing optionally one or more other heteroatoms selected from O, S, N
and NH, this radical including the eventual NH it contains being possibly substituted;

all the cycloalkyl, heterocyclic and phenyl radicals as well as the radicals cyclic that can be formed R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, defined above, being possibly substituted by a or more radicals selected from halogen atoms, radicals hydroxyl, alkoxy, NH 2, NHalk, N (alk) 2 and alkyl and phenyl radicals, these the latter being themselves possibly substituted by one or more radicals chosen from halogen atoms and hydroxyl radicals, alkyl and alkoxy containing 1 to 4 carbon atoms, NH 2, NHalk and N (alk) 2;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I). 5- Products of formula (I) as defined in any one of the other wherein A is NH, the substituents , Ra, X
and W being selected from all the values defined for these radicals in one 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 the mineral acids and organic or with the inorganic and organic bases of the said products of formula (I). 6- Products of formula (I) as defined in any one of the other wherein A is S, the substituents , Ra, X and W being selected from all the values defined for these radicals in one 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 the mineral acids and organic or with the inorganic and organic bases of the said products of formula (I). 7- Products of formula (I) as defined in any one of the other claims having formula (Ia) or (Ib) in which , Ra and W are selected from the meanings indicated any of the other claims, said products of formula (Ia) and (Ib) being in all isomeric forms possible racemic, enantiomeric and diastereoisomeric, as well as salts of addition with mineral and organic acids or with bases inorganic and organic 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 answering to the products of formula (I "):

in which the substituents Ra, X, A and W have the indicated meanings at any of the other claims, said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I). 9- Products of formula (la) as defined in any one of the other claims in which represents a double bond answering to the products of formula (I "a) in which Ra and W are selected from the meanings indicated in Moon any of the other claims, said products of formula (I "a) being in all isomeric forms possible racemic, enantiomeric and diastereoisomeric, as well as salts of addition with mineral and organic acids or with bases inorganic and organic of said products of formula (I "a). 10- Products of formula (Ib) as defined in any one of the other claims in which represents a double bond answering with the products of formula (I "b):

in which Ra and W are selected from the meanings indicated in Moon any of the other claims, said products of formula (I "b) being in all isomeric forms possible racemic, enantiomeric and diastereoisomeric, as well as salts of addition with mineral and organic acids or with bases inorganic and organic of said products of formula (I "b). 11- Products of formula (I) as defined in any one of the preceding claims in which represents a single or double bond Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl optionally substituted with a hydroxyl, alkoxy or -O-CO-R5 radical;

X is S;
A represents S;

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

a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, or alkoxy;

an O-phenyl radical;

or the radical NR1R2 in which R1 and R2 are such that one represents one hydrogen atom and the other represents an alkyl radical optionally substituted with a heterocycloalkyl radical;

with NR3R4 such that R3 and R4, which are identical or different, represent a hydrogen atom or an alkyl radical;

R5 represents an alkyl or cycloalkyl radical containing at most 6 atoms of carbon;

said products of formula (I) being in all isomeric forms possible racemates, enantiomers and diastereoisomers, as well as the addition salts with mineral and organic acids or with mineral bases and organic compounds of said formula (I). 12- Products of formula (I) as defined in any one of the other claims, having 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] triazolo [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] triazolo [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] 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 -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 - (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) phenyl 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] pyridazin-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-methoxy-acetamide -N- (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-dimethylglycinamide -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-méthoxypropanamide -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] cyclopropanecarboxylate 1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] amino} cyclohexyl N- [6 - ({6 - [(trans-4-hydroxycyclohexyl) amino] [1,2,4] triazolo [4,3-b] pyridazin-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-amine 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] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -3-méthoxypropanamide N- (6 - {[6- (Cyclopropylamino) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -N2, N2-dimethylglycinamide 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclohexyl-7,8-dihydro [1,2,4] triazolo [4,3-b] pyridazin-6-amine - (6 - {[6- (cyclohexyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) ethyl 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) -N2-cyclopropylglycinamide 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) acetamide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-diéthylglycinamide 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] pyridazin-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-cyclopropylacétamide 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] carbamoyl} amino) -1,3-benzothiazol-6-yl] sulfanyl} [1,2,4] triazolo [4,3-b] pyridazin-6-yl) oxy] cyclohexyl} acetamide N- {6 - [(6 - {[4- (trifluoromethyl) cyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin yl) sulfanyl] -1,3-benzothiazol-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- (4-morpholin-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-benzothiazol-2-amine 3 - [(2-amino-1,3-benzothiazol-6-yl) sulfanyl] -N-cyclobutyl [1,2,4] triazolo [4,3-b] pyridazin-6-amine 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 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-N2, N2-diethyl-N- [6 - ({6 - [(trans-2-fluorocyclohexyl) oxy] [1,2,4] triazolo [4,3 b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] glycinamide - 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} acetamide rac-N- {6 - [(6 - {[trans-2-fluorocyclohexyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin yl) sulfanyl] -1,3-benzothiazol-2-yl} -2- (morpholin-4-yl) acetamide N- (6 - {[6- (cyclobutyloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide 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} acetamide 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) acetamide 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) acetamide 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-méthoxypropanamide 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) acetamide 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} cyclopropanecarboxamide 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] cyclopropanecarboxamide 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 yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide rac-1- {6 - [(6 - {[trans-2-methylcyclopentyl] oxy} [1,2,4] triazolo [4,3-b] pyridazin 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-carboxamide -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 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} cyclopropanecarboxamide 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 the preparation of the products of formula (I) as defined in Moon any of the other claims. 14- Process for the preparation of the products of formula (I) as defined in Moon any of the other claims wherein A is NH. 15- Process for the preparation of the products of formula (I) as defined in Moon any of the other claims wherein A is S. 16- As medicaments, the products of formula (I) as defined in any of claims 1 to 12, as well as the addition salts with mineral and organic acids or with mineral and organic bases pharmaceutically acceptable salts of said products of formula (I). 17- As medicaments, the products of formula (I) as defined in claim 12, as well as the addition salts with the mineral acids and organic or with the mineral and organic bases pharmaceutically acceptable of said products of formula (I). 18- Pharmaceutical compositions containing as active ingredient one to products of formula (I) as defined in any one of the Claims 1 to 12, or a pharmaceutically acceptable salt thereof product or a prodrug of this product and a pharmaceutically acceptable carrier acceptable. 19- Use of the products of formula (I) as defined in any one Claims 1 to 12, or pharmaceutically acceptable salts of these products for the preparation of a medicament for the inhibition of the activity of the MET protein kinase and its mutant forms 20. The use as defined in claim 19, in which the protein kinase is in a cell culture. 21. The use as defined in claim 19 or 20, in which the protein kinase is in a mammal. 22- Use of a product of formula (I) as defined in any one of the Claims 1 to 12 for the preparation of a medicament for treatment or prevention of a selected disease in the following group:
disorders of the proliferation of blood vessels, fibrotic disorders, disorders of the proliferation of 'mesangial' cells, metabolic disorders, allergies, asthma, thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers. 23- Use of a product of formula (I) as defined in any one of the Claims 1 to 12 for the preparation of a medicament for cancer treatment. 24- Use according to claim 23 for the treatment of tumors solid or liquid. 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 at treatment of primary tumors and / or metastases, particularly in gastric, hepatic, renal, ovarian, colon, prostate, lung cancer (NSCLC and SCLC), glioblastomas, thyroid cancer, bladder, breast, in melanoma, in hematopoietic tumors lymphoids or myeloid, in sarcomas, in brain cancers, 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 drugs for chemotherapy of cancers. 28. Use of the products of formula (I) as defined in claims 1 to 12, for the preparation of drugs for chemotherapy of cancers alone or in combination. 29- Products of formula (I) as defined in any one of the Claims 1 to 12 as kinase inhibitors. Products of formula (I) as defined in any one of the Claims 1 to 12 as MET inhibitors. 31- As new industrial products, synthetic intermediates of formulas E ', M1, M2, M3 and N:

in which R6 represents an alkyl radical optionally substituted by a group NR3R4 (a - (CH2) n-NR3R4 radical), alkoxy, hydroxy, heterocycloalkyl, phenyl, - (CH2) n-phenyl, optionally with phenyl substituted and n represents an integer of 1 to 4, such that OR6 represent 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, the same optionally substituted as indicated in claim 1; and Ra, R1, R2, R3 and R4 have the meanings given in claim 1.