CA2750875A1 - Derivatives of 6-(6-o-substituted-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): (I) wherein (II) represents a single or double bond; Ra represents -O-Z-Rc with Z single bond or optionally substituted alkylene and Rc represents optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Rb is H or F; with if Rb is H, then Rc is not cycloalkyl when Z is single bond and Rc is not heterocycloalkyl when Z is alkylene; X is S, SO or SO 2, A is NH or S; W is H, alkyl, cycloalkyl 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 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-SUBSTITUTED-TRIAZOLOPYRIDAZINE-SULFANYL) DERIVATIVES
BENZOTHIAZOLES AND BENZIMIDAZOLES: PREPARATION, APPLICATION
AS MEDICAMENTS AND USE AS MET INHIBITORS

The present invention relates to novel derivatives of 6- (6-0-substituted triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, their process of preparation, the new intermediates obtained, their application as drugs, the pharmaceutical compositions containing them and the new use of such derivatives of 6-triazolopyridazine-sulfanyl benzothiazole and benzimidazole.

The present invention relates more particularly to novel derivatives of 6- (6-O-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, exhibiting 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):
N ~ AH

N Rb N NW
NOT

R a (I) in which represents a single or double bond;

Rb represents a hydrogen atom or a fluorine atom;
Ra represents a radical -OZ-Rc in which:
Z represents a single bond or a linear or branched alkylene radical containing from 1 to 6 carbon atoms and optionally substituted by a alkyl group or a halogen atom;
Rc represents a cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical optionally substituted, X is S, SO or SO2;
A represents NH or S;

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

a cycloalkyl radical, or an alkyl radical, optionally substituted by a radical NR3R4, alkoxy, -O-cycloalkyl, -O-CO-R5, hydroxy, phenyl, heteroaryl, or heterocycloalkyl themselves optionally substituted, an alkoxy radical optionally substituted 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, with the possible S being able to be optionally in the form of SO or S02; this radical including the eventual NH it contains being optionally 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 and phenyl itself optionally substituted; or else R3 and R4 form with the atom of nitrogen to which they are attached a cyclic radical containing from 3 to 10 links and possibly one or more other heteroatoms chosen from O, S, N and NH, with the possible S being able to be optionally in the form of SO or S02; this radical including the eventual NH it contains being optionally substituted;

6 all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as radicals cyclic that can be formed R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, possibly being substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, oxo radicals, alkoxy, -O-CO-R5, -OR5 -000H, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5, -NHCOOR5 and alkyl radicals, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals, the radicals alkyl, alkoxy, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or 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, 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;
Being heard that :
i) when Rb represents Hydrogen and Z represents a single bond, then Rc does not represent a cycloalkyl radical; and ii) when Rb represents Hydrogen and Z represents an alkylene radical, so Rc does not represent a heterocycloalkyl radical;

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).

WO 2010/08950

7 PCT / FR2010 / 050178 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 -OZ-Rc in which Z represents a single bond and Rc represents optionally substituted aryl;
Rb represents a hydrogen or fluorine atom;
X is S, SO or SO2;

A represents NH or S;

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

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

an alkoxy radical optionally substituted 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, with the possible S being able to be

8 optionally in the form of SO or S02; this radical including the eventual NH it contains being optionally substituted;

with R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical all optionally substituted with one or more identical or different radicals chosen from the radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIk, N (Alk) 2 or optionally substituted phenyl; or else R3 and R4 form 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, with the optional S possibly being in the SO or S02; this radical including the eventual NH it contains being possibly substituted;

all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as radicals cyclic that can be formed R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, possibly being substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, oxo radicals, alkoxy, -O-CO-R5, -ORS, NH2, NHalk, N (alk) 2 and alkyl radicals, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, 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, 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

9 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, Rb and X have the values defined in any one of the other claims and:

A represents NH or S;

W represents a hydrogen atom; an alkyl radical 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, -O-cycloalkyl, -O-CO-R5, 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 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, an alkyl radical or a heterocycloalkyl radical optionally substituted with one or more identical radicals or various selected from alkoxy, heteroaryl, heterocycloalkyl radicals or NH2, NHAIk, N (Alk) 2, or R3 and R4 together with the nitrogen atom they are linked to a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N
and NH, this radical including the eventual NH it contains being possibly substituted, All the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl radicals, heterocycloalkyl 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, defined above, being optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, alkoxy, O-cycloalkyl, NH 2 radicals,

NHalk, N (alk) 2 and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH 2 -phenyl and heteroaryl, as in these radicals, alkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally 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).

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):

11 N ~ ~ XAH

N Rb N NW
NOT

R a (I) in which represents a single or double bond;

Rb represents a hydrogen atom or a fluorine atom;
Ra represents a radical -OZ-Rc in which:
Z represents a single bond or a linear or branched alkylene radical containing from 1 to 6 carbon atoms and optionally substituted by a alkyl group or a halogen atom;
Rc represents a cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical subsequently substituted;

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

W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; where 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

12 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 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, aryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy radicals, -O-CO-R5, -ORS, -COOH, COORS, -CONH2, CONHRS, NH2, NHRS, NR5R5 ', -NH-CO-RS and 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,

13 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;
Being heard that :

i) when Rb represents Hydrogen and Z represents a single bond, then Rc does not represent a cycloalkyl radical;
and ii) when Rb is hydrogen and Z is alkylene, then Rc does not represent a heterocycloalkyl radical;

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 -OZ-Rc in which Z represents a single bond and Rc represents optionally substituted aryl;
Rb represents a hydrogen or fluorine atom;
X is S, SO or SO2;

A represents NH or S;

W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; where 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;

14 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 cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as the cyclic radicals that can form R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy radicals, -O-CO-R5, -ORS, NH 2, 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, Rb and X have the values defined in any of the other claims and A represents NH or S;

W is 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

16 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, O-cycloalkyl, NH 2, NHalk, N (alk) 2 radicals and alkyl radicals, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl, such as in these radicals, the radicals alkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or more radicals selected from halogen atoms and the hydroxyl, alkyl and alkoxy radicals containing 1 to 4 carbon atoms, 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, Rb and X have the defined values to any one of the other claims and:

A represents NH or S;

17 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, O-cycloalkyl, NH 2, NHalk, N (alk) 2 and alkyl radicals and phenyl, the latter being themselves optionally substituted by one or several radicals chosen from halogen atoms and radicals

18 hydroxyl, 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, Rb, X and W being chosen from all the values defined for these radicals to any one of the other claims, said formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with mineral and organic bases 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, Rb, X and W being chosen from all the values defined for these radicals to any one of the other claims, said formula (I) being in all possible racemic isomeric forms, enantiomers and diastereoisomers, as well as the addition salts with the mineral and organic acids or with mineral and organic bases 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 ~ NH
LN
N Rb NW
R a (la)

19 N \ NYS \ SH
NI / /> JN
t N Rb NW
R a (Ib) in which, Ra, Rb, and W are selected from the meanings indicated in 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 '):

NO ~~ r OC ANH
N Rb NW
(I) Ra the substituents Ra, Rb, X, A and W having any of the meanings indicated above or below, 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 "):

NO AH
t \ NN
N Rb NW
R a wherein the substituents Ra, Rb, X, A and W have any one of the meanings given above or below, said products of formula (I) being in all isomeric forms possible 5 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 Corresponding to the products of formula (I '):

11, N \ NNH
N CC
N Rb NW
R a (a) wherein Ra, Rb, and W are selected from any one of the meanings given above or below, said products of formula (a) being in all isomeric forms 15 possible racemates, enantiomers and diastereoisomers, 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):

21 NN
N / SNH% :: I ~
N Rb NW
R a (I "a) wherein Ra, Rb, and W are selected from any one of the meanings given above or below, 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 the products of formula (I'b):

NNSSH
N XNÇv R a (I'b) wherein Ra, Rb and W are selected from any one of the meanings given above or below, 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):

22 N '~~ YSSH
NOT
N CC
Rb NW
NOT

Ra (I "b) wherein Ra, Rb and W are selected from any one of the meanings given above or below, 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

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

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, tetrahydropyran, tetrahydrothiopyran, 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; We can also note that the aryl radical such as phenyl may be optionally substituted for example by two alkoxy radicals to form a radical

24 benzodioxol itself optionally substituted as indicated for the aryl 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.

It may be noted that two substituents on the cycloalkyl radicals, heterocycloalkyl, heteroaryl, aryl and phenyl as well as radicals cyclic that can be formed R1 and R2 or R3 and R4 respectively with the nitrogen atom to which they are attached, can eventually form a ring 5 cycloalkyl or heterocycloalkyl depending on the case and techniques usual known to those skilled in the art.

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,

26 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,

27 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

28 different ones chosen from halogen atoms and alkyl radicals, hydroxyl and alkoxy.

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

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

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 -O-phenyl radical optionally substituted with one or several halogen atoms;
Rb represents a hydrogen atom;
X is S;

A represents S;

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

a cycloalkyl radical, or an alkyl radical;

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

29 with mineral and organic acids or with mineral bases and organic compounds of said formula (I).

The subject of the present invention is thus the products of formula (I) such that defined above or below with the following formulas:

6 - [(6-Phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole amine N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxam ide N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide 1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin) yl) sulfanyl] -1,3-benzothiazol-2-yl} urea 1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide N2, N2-diethyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N 2 -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3 yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 1- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 5 - 1- (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (tetrahydro-2H-pyra-n-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine 6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-amine 1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydro-2H-pyran-4-) yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea 1- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3 yl} sulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (4-morpholin-yl) ethyl] urea 15 - N - (6 - {[6- (tetrahydro-2H-pyra-n-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-Yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide 1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea 25 - 1- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) -ethyl] -urea 1- (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine 6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3}
yl] sulfanyl} -1,3-benzothiazol-2-amine 1- (6 - {[6- (1 H -indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N - (6 - {[6- (1 H -indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N 2, N 2 -dimethylglycinamide 2-ethoxy-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (cyclohexyloxy) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin) yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine - [3 - ({3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin 2-methylpropan-2-yl 6-yl} oxy) phenyl] carbamate N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide N 2 -cyclohexyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N 2-methyl-N 2 - [2- (morpholin-4-yl) ethyl] glycinamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine 6 - {[6- (3-aminophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N-2 - (tetrahydro-2H-pyran-4-yl) glycinamide N- [6 - ({6- [4- (trifluoromethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6 - [(2-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 2 - [(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-acetate yl] sulfanyl} -1,3-benzothiazol-2-yl) amino] -2-oxoethyl N- [6 - ({6 - [(6-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6- [4- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide - (3 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] oxy} phenyl) carbamate of 2-methylpropan-2-yl N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} cyclopropanecarboxam ide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxam ide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N 2, N 2 -d-ethylglycinam ide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2-hydroxyacetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (4-ethyl-piperazin-1-yl) acetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) acetamide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} -2-methoxy-acetamide 2-methoxy-N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} acetamide 6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine 2- (morpholin-4-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide N2, N2-diethyl-N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide as well as addition salts with mineral and organic acids or with the inorganic and organic bases of said products of formula (I).

The present invention further relates to 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, 2bis 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 method of preparation 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 ') K + f` ~ SFZ NH2 NC-S / NH2 reduction HS / NH2 O ~ S, I NH2 /
\ I \ I

R b NO2 when R b NO2 when F N02 c F NO2 Q Rb = HF Rb = FD Q ' commercial N_N NN
ICI HS NH2 N, Nys NH2 ICI N /
N Ra-H - ~ N Rb (F) NO2 N. Rb NO
iN / N 2 according to diagram 3 S Cl Ra Ra G
commercial E
J reduction Rt N-C02R5 N
HN H MeS-e NI YS / I NH2 H 'R2 NN ~ S or, NH N-C02R5 tN%
NNS / IN ~ H R1 R) \ NN Rb IV ~ O (J) jN Rb NH2 O RS II%
Rb '\ / ~ N NS%

Ra R has H '/ H "
1b '/ 1b "Ra laI 1a" BrCN
he NO SHH R6000X N s / N
tN, N 10CN / N (0) N ~ j ~> 2% Rb 0 t N Rb \ N

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

(P) NH
NOT
tN% yS / 1 N> N
% N ~ R

N Rb \ 7 / O
Ra 1e? the"

In Scheme 1 above, the substituents, Ra and Rb, have the meanings above for the products of formula (I ') and (I ").
R5, in the compounds of formulas (J), (la ') and (la "), represents a radical alkyl.

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 a '), (1 b'), (1 c '), (1 d') and (1 e ') can be prepared for from 3,6-commercial 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 phenols or alcohols in the presence of a base on the compound (S). The reaction is carried out, for example, at a temperature of 20 C.

HS NHZ

Rb N02 N "IN` S NH2 NG
Rb NO2 NOT

Ra The compounds (G), with Rb = H, can be obtained, for example, by reaction of 3-amino-4-nitro-benzenethiol of formula (F) with the compounds of formula (E), in the presence of a base such as sodium hydride in a solvent such as N, N-dimethylformamide at a temperature of 20 C.
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.

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

NO`` g DOC NHZ
t NH '/ H "
f NRb NH2 Ra The compounds (H ") as represented by a double bond can for example, by reduction with iron (0) 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 vs.

More particularly, the carbamates of general formula (la ') and (la ") can be prepared especially as described in the patent W003028721A2, but from a 3,4-diamino phenyl respectively sulfide of formula (H ') and (H ") and a pseudothiourea of formula (J), in presence of 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 from formula (R) (with R1 and R2 as defined above) on a carbamate of formula (1 a ') and (1 a "), for example in the presence of an aprotic solvent such the 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 at a temperature around 80 C.

More particularly, the carbamates of general formula (1d ') and (1d ") Can be obtained by reaction with a chlorocarbonate of formula (O) (X = Cl) on a compound of general formula respectively (1c ') 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 the amines of the 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 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-ethylcarbodim ide 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 NIN ~ v S / SH
J - CI tN \ / / N Ri . NRb \ NN

R Ra E
NC "IN Ri DOC Discount SH
N Ra 2b '/ 2b "
Rb \ N -N` /
L2 0 R2 Rb N ~ N.

NHRlR2 NN
(R) ~ CI INS OrN SH
. NNN /> - N
, SS HS / SHN Rb ~ O
NC 'S
/ reduction I II / Ra EO Rs Rb \ N %% O. Rb \ NO \ Ra 2a '/ 2a "
Li O R6 M1 O R6 (0) N% -CI
N NINy S / S

S / S reduction HS D ::), - SEN / NH2 NC 'T ~ / NH / NHN Rb N
Rb / J \ N Rb N `` 2d12d "
KN Ra R, COX NN
N% -Cl (P) SS reduction HS / SH Ra E NINS / SH
NC 'II /> NI II /> N /> - N
Rb, NR Rb ///, N% R7, N Rb \ N-R
0 t /
L3 M3 2c '/ 2c "
Ra In scheme 2 above, the substituents, Ra and, Rb have the meanings above for products of formula (I ') and (I ").
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') with Rb = H can be prepared from 2-amino-1,3-benzothiazol-6-yl (K) thiocyanate (commercial compound).
NC ~ SII "" NC / S C> H L1 2 N -0, Rb \ NK Rb 0 R6 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.
CN
\ KSCN I
- ~ S,: Cs FI NHZ Br2 /> - NH2 AcoH FN
commercial K
In Scheme 2 above, benzothiazoles of general formula (2a "), (2b "), (2c") and (2d ") as well as their reduced analogues of the general formula (2a '), (2b'), (2c ') and (2d') with Rb = F can be prepared from 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate. Thiocyanate 2-amino-5-fluoro-1,3-benzothiazol-6-yl (K) can be prepared from 3-fluoroaniline as described by K, Papke and R, Pohloudek-Fabini in Pharmazie; GE; 22, 1967, P229-233, by reaction of the thiocyanate of potassium and 3-fluoroaniline in the presence of bromine in acetic acid.
SSH NC-Rb N
c ~ _% 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 Rb, 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 IN

Rb \ N ~ R7 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 et al. / Bioorg. Med. Chem. Lett. 15 (2005) 5211-5217, in the presence 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 close to 20 C.

Scheme 2bis: Synthetic routes of glycinamide derivatives (2c ') and (2c ") HO
NN / S / S hNR3R4 N
N /> - NH2 NSH
`IV N ~ P,) tN% / N
%
N -R
~~ N
O
Ra 2d '/ 2d "/ 202c"
Ra R7 = CH2-NR3R4 \ NSS
CI N '/ N NR3R4 O CI t \ N ~ N
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 (III), (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.
5 and 95 C.

HS / IN ~ NS /
Rb NY
Rb \

The aryl-thiol intermediates above can exist in the form of thiols free or in the form of disulfides or a mixture of the two forms which can be engaged indifferently in the following reactions.

More particularly, benzothiazoles of the 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.

Conversely, benzothiazoles of the 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 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 NN
Rc-ZO- 1 N ~ CI N CI
(U) E
/ N - 'N
Ra = OZ-Rc CI SR has In Scheme 3 above, the substituents Ra, Z and Rc have the the meanings given above for the products of formula (I ') and (I ").

The compounds of formula (E) can be obtained, for example, as shown in 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 OZ-Rc 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
in a solvent such as tetrahydrofuran with an alcoholate of formula (U), even obtained by treatment of the corresponding alcohol with a base such sodium hydride at a temperature in the region of 0 ° C. to 20 ° C.

Scheme 4: Synthesis of Benzothiazole Derivatives of Formula (2e ') and (2e ") 'N ~ SS
N, N s / S RsX, NN SS Rs deprotection y N / I / N
LN / N (W) \ / N Rb \ N Rs N Rb INN
-/ O R6 / N Rb T. ~ T .. O R6 Ra 2a '/ 2a "Ra a 2nd' / 2nd"
Ra conditions E
reducing RqX N
NC'S SH (W) NC'S / S Rs IN / I S> -N
~ NIN> / - ON Rb \ Rs Rb /
N> -O Rb ORO R6 via 7 LI 6 L4 Ra 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).

N ~ S R9 NOT
IJI ~~
NN RD ~ / N ~ - O

Ra T '/ 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 'SS Rs \ NOT
Rb 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 ") NN ~ CI
Nl NN
diazotation IIR -NH III E / NNS
S bromation / S s 2 SS Ra N \ / S ~ N =
N NHZ CuBr I / Br --- I / N. NN Rb '~ / -N Rs Rb 2 Rb N Rb ~ \ / IN Rs /
K NaNO2 2nd "
L5 L6 Ra NYS IS / N.
NN Rb \ N Rs 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 ') .IN SA eN SA reaction, NS
N \ HN \ H on the NAH
/> - N reduction e W) -N) OC% W - ~ Rp N W.
N / N / N
Ra (I .. ~ Ra ~ I) Ra ~ I) Mlou coupling M2 or M3 or N / A N / N
I \ N \ T reduction NN
NN
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 Reducing, 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 reduction of 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 in the region 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 transformation 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, P ', Q, Q', R, S, U, W
some are known and can be obtained either commercially or according to the usual methods known to those skilled in the art, for example to 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 in alcohol function, 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:

6 - [(6-Phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole amine 5 - N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxam ide N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide 1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin) 10 yl) sulfanyl] -1,3-benzothiazol-2-yl} urea 1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl}
1,3 benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide N2, N2-diethyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N 2 -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-Yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3 yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxamide 1- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (3-Fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) -ethyl] -urea 6 - {[6- (tetrahydro-2H-pyra-n-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine 6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine 1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydro-2H-pyran-4-) yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea 1- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3 yl} sulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (4-morpholin-yl) ethyl] urea N - (6 - {[6- (tetrahydro-2H-pyra-n-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide 1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea 1- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) -ethyl] -urea 1- (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine 6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3}
yl] sulfanyl} -1,3-benzothiazol-2-amine 1- (6 - {[6- (1 H -indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N - (6 - {[6- (1 H -indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-d imethylglycinamide 2-ethoxy-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (cyclohexyloxy) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin) yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine - [3 - ({3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin 2-methylpropan-2-yl 6-yl} oxy) phenyl] carbamate N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide N 2 -cyclohexyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2-methyl-N2- [2- (morpholin-4-yl) ethyl] glycinamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine 6 - {[6- (3-aminophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N-2 - (tetrahydro-2H-pyran-4-yl) glycinamide N- [6 - ({6- [4- (trifluoromethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6 - [(2-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 2 - [(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-acetate yl] sulfanyl} -1,3-benzothiazol-2-yl) amino] -2-oxoethyl N- [6 - ({6 - [(6-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6- [4- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide - (3 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] oxy} phenyl) carbamate of 2-methylpropan-2-yl N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} cyclopropanecarboxam ide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxam ide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N 2, N 2 -d -ethylglycinamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2-hydroxyacetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (4-ethyl-piperazin-1-yl) acetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) acetamide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} -2-methoxy-acetamide 5 - 2-methoxy-N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} acetamide 6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine 2- (morpholin-4-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide N2, N2-diethyl-N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-20 yl) acetamide N- (6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 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 intermediates for the synthesis of formulas Ml, M2, M3 and N with Rb represents a fluorine atom F, as defined above and recalled hereinafter after:

HS / S HS / SH
/ / N Rl Rb \ N -0 Rb N ~ _N
'R
mi O R6 M2 R2 HS / SH
\ N HS / S
Rb NR. \ INHZ
M3 Rb 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 formulas (I ') and (I "), when W # H.

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 software version 11Ø

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) 5 - LC-MS-DAD-ELSD (MS = Platform II Waters Micromass) - UPLC-MS-DAD-ELSD (MS = Quattro Premier XE Waters) DAD considered wavelength A = 210-400 nm ELSD: Sedere SEDEX 85; nebulization temperature = 35 C; nebulization pressure = 3.7 bar Example 1 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-amine a) 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine can be prepared as follows:
through a solution of 622 mg of 2-amino-1,3-benzothiazole thiocyanate 6-yl (commercial) in 30 cm3 of ethanol, a stream of argon is bubbled through for 5 minutes. 14 mg of dihydrogenphosphate are then added.
potassium in 0.3 cm3 of water, 1.39 g of DL-dithiothreitol and 740 mg of 3-chloro-6-phenoxy [1,2,4] triazolo [4,3-b] pyridazine. The reaction mixture is heated at 80 ° C. for 24 hours and then concentrated to dryness under reduced pressure. The residue is purified on silica by solid deposition eluting with a gradient dichloromethane / (dichloromethane 38 / methanol 17 / ammonia 2) from 95/05 to 80/20. Thus 717 mg of 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine as a powder the characteristics of which are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S ppm 7.13 (dd, J = 8.3, 2.0 Hz, 1H) 7.21 (d, J = 8.3Hz, 1H) 7.25 - 7.32 (m, 2H) 7.32 - 7.39 (m, 2H) 7.50 (t, J = 7.8 Hz, 2H) 7.61 (d, J = 1.5 Hz, 1H) 7.64 (s, 2H) 8.43 (d, J = 9.8 Hz, 1H) H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 393 +; MH = 391-b) 3-chloro-6-phenoxy [1,2,4] triazolo [4,3-b] pyridazine can be prepared as follows :
to a solution of 996mg of phenol in 20cm3 of tetrahydrofuran, at 0 ° C
under argon are added 254 mg of 60% sodium hydride in the oil.
After stirring for 15 minutes, 1 g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial). The reaction medium is stirred and allowed to come back gradually at 20 C for 23h. The reaction mixture is poured on water and the mixture obtained is extracted with ethyl acetate. The sentence organic is concentrated to dryness under vacuum. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A, 32-63 μM) eluting with a gradient of cyclohexane / ethyl acetate 95: 5 to 50:50. We thus obtain 1.07g of 3-chloro-6-phenoxy [1,2,4] triazolo [4,3-b] pyridazine in powder form the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 247 +
Example 2 N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} cyclopropanecarboxam ide a) N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxam ide can be prepared in the next :
to a mixture of 250 mg of 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine (1a) in 5cm3 of pyridine at 20 ° C are added 0.120 cm3 of cyclopropane carboxylic acid chloride. After 2.5 h, the reaction mixture is concentrated to dryness and the solid residue is chromatographed by solid deposition on Biotage Quad 12/25 (KP-SIL, 60A;
63pM) eluting with a dichloromethane gradient 100% to dichloromethane / methanol 96/4. In this way 221 mg of N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-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 0.93 - 0.98 (m, 4H) 1.99 (quint, J = 6.2 Hz, 1H) 7.20 - 7.45 (m, 7H) 7.60 (d, J = 8.3 Hz, 1H) 7.86 (D, J = 1.7 Hz, 1H) 8.46 (d, J = 10.0 Hz, 1H) 12.67 (brs, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 461 +; MH = 459-Example 3 N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} acetamide N- {6 - [(6-phenoxy [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 2a but starting from 302 mg of 6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine (1a) in 10cm 3 of pyridine with 0.220 cm3 of acetyl chloride after 24h reaction at 20 C.
280 mg of N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3 are thus obtained.
yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide as a white powder whose characteristics are as follows:
NMR spectrum 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 7.23 (d, J = 7.6 Hz, 2H) 7.26 - 7.33 (m, 2H) 7.34 - 7.44 (m, 3H) 7.61 (d, J = 8.6 Hz, 1H) H) 7.87 (d, J = 1.7 Hz, 1H) 8.46 (d, J = 9.8 Hz, 1H) 12.39 (brs, 1H) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 435 +; MH = 433-Example 4 1- [2- (morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3 b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea a) 1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea can be prepared in a similar to Example la but from 533 mg of 1- [2- (morpholinic acid) 4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea, 10 cc of ethanol degassed, 6 mg of potassium dihydrogenphosphate in 0.1 cm3 of water, 606mg of DL-dithiothreitol and 324mg of 3-chloro-6-phenoxy [1,2,4] triazolo [4,3-b] pyridazine (1b), after 32h at 80 ° C.

thus 320 mg of 1- [2- (morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} urea as a powder the characteristics of which are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S ppm 2.36 - 2.46 (m, 6H) 3.24 - 3.29 (m, 2H) 3.59 (t, J = 4.4 Hz, 4H) 6.80 (t, J = 5.7 Hz, 1H) 7.20 -7.28 (m, 3H) 7.29 - 7.34 (m, 1H) 7.36 (d, J = 9.8 Hz, 1H) 7.44 (t, J = 7.8 Hz, 2H) 7.49 (d, J = 8.6 Hz, 1H) 7.80 (d, J = 1.7 Hz, 1H) 8.45 (d, J = 9.8 Hz, 1H) 10.93 (brs, 1h) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 549 +; MH = 547-b) 1- (2-Morpholin-4-ylethyl) -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea can be prepared 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 mixture The reaction mixture is cooled to 20 ° C. and then poured into water. The suspension is stirred for 45 minutes while 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 5 1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea a) Lei - (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea may be prepared in a manner similar to example la but from 305mg of 1-[2- (Morpholin-4-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (4b), from 5 cm3 of degassed ethanol, 4 mg of potassium dihydrogen phosphate in 0.1 cm3 of water, 347 mg of DL-dithiothreitol and 202 mg of 3-chloro-6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazine. We thus obtain 253mg of 1-(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea as a powder the characteristics of which are as follows:
NMR SPECTRUM 1 H NMR (400 MHz, DMSO-d6) S ppm 2.36 - 2.45 (m, 6H) 3.25 - 3.28 (m, 2H) 3.59 (t, J = 4.3 Hz, 4H) 6.78 (brs, 1H) 7.14 (dd, J = 8.3, 1.7 Hz, 1H) 7.18 (td, J = 8.5, 2.3 Hz, 1H) 7.23 - 7.31 (m, 2H) 7.38 (d, J = 9.8 Hz, 1H) 7.42 - 7.51 (m, 2H) 7.84 (d, J = 1.7 Hz, 1H) 8.47 (d, J = 9.8 Hz, 1H) 10.89 (sr, 1h) MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 567 +; MH = 565-(b) 3-Chloro-6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazine may Be prepared in a manner similar to Example 1b but from 1.1 9g of 3-fluorophenol in 15cm3 of tetrahydrofuran, 254mg of sodium hydride 60% in oil and 1g of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial). Thus 837 mg of 3-chloro-6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazine as a white powder 15 whose characteristics are as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH + m / z = 265 +
Example 6 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-2-amine 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine can be prepared in a manner similar to the example but from 529 mg of 3-chloro-6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazine (5b), 10 mg of potassium dihydrogenphosphate in 0.1 cm3 of water, 926 mg of DL-dithiothreitol and 414 mg of thiocyanate of 2-amino-1,3-benzothiazol-6-yl (commercial), in 10 cm3 of ethanol. We obtain thus 587 mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine in the form of a white powder with the characteristics are as follows:

NMR spectrum (400 MHz, b ppm, DMSO-d6): 7.11 to 7.25 (m, 4H), 7.32 (td, J = 2.3 and 10.0 Hz, 1H); 7.37 (d, J = 9.8 Hz, 1H); 7.53 (dt, J = 6.8 and 8.3 Hz, 1 H); 7.63 (bs, 2H), 7.65 (d, J = 2.0 Hz, 1H); 8.45 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 411; [MH] -: m / z Example 7 N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetam ide a) N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide may be prepared as follows:
a mixture of 131 mg (2-methoxyethoxy) acetic acid (commercial), 0.17 cc of diisopropyl ethylamine and 371 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- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6). After 18h the solution brown is poured on ice water and the precipitate is filtered. After drying of the precipitate, 219 mg of N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetam ide in the form of a white powder whose characteristics are as follows:
1H NMR Spectrum (400 MHz, b ppm, DMSO-d6): 3.29 (s partially masked, 3H); 3.48 to 3.54 (m, 2H); 3.66 to 3.71 (m, 2H); 4.29 (s, 2H);
7.11 (dd, J = 2.2 and 8.3 Hz, 1H); 7.16 (dt, J = 2.2 and 8.3 Hz, 1H); 7.24 (td, J = 2.2 and 10.0 Hz, 1H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.42 (dt, J = 6.9 and 8.3 Hz, 1H); 7.63 (d, J = 8.6 Hz, 1H); 7.93 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.20 (spread m, 1 H) MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 527, [MH] -: m / z 525 Example 8 N2, N2-diethyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] su lfanyl} -1,3-benzothiazol-2-yl) g lycinam ide a) N2, N2-Diethyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide can be prepared as follows :
a mixture of 373mg of sodium N, N-diethylglycinate (commercial) in 2.4 cm 3 of a 2N solution of hydrogen chloride in ether is stirred for 1 h at 20 C. The resulting suspension is evaporated to dryness under vacuum.
To the white residue obtained are added, at 20 ° C., 4 cm3 of pyridine, 100 mg of 6-{[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6) and 467 mg of N- (3-hydrochloride) dimethylaminopropyl) N'-ethylcarbodiimide. After 4.5h, the reaction medium brown is evaporated to dryness. The residue is taken up in water and the mixture is extracted with ethyl acetate. The organic phase is evaporated to dryness.
The oily brown residue is taken up in ether and the precipitate is drained.
We thus obtaining 76mg of N2, N2-diethyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol yl) glycinamide in the form of a beige powder whose characteristics are the following :
NMR spectrum (400 MHz, b in ppm, DMSO-d6): for this batch, all the ignals are broad with: 1.00 (t, J = 6.9 Hz, 6 H); 2.63 (q, J = 6.9 Hz, 4H);
3.41 (s, 2H); 7.06 to 7.20 (m, 2H); 7.24 (d, J = 9.5 Hz, 1H); 7.31 (d, J = 8.3 Hz, 1H); 7.35 to 7.47 (m, 2H); 7.61 (d, J = 8.3 Hz, 1H); 7.92 (s, 1H);
8.49 (d, J = 9.8 Hz, 1H); 9.44 to 14.07 (m very spread, 1 hour) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 524, [MH] -: m / z Example 9 N2-Cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide (a) N 2 -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide may be prepare as follows :
to 137mg of 2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin) 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide (9b) in 1.5cm3 of pyridine C is added 0.13 cm3 of cyclopropylamine. 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. In this way 52 mg of N 2 -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol yl) glycinamide in the form of a white solid whose characteristics are the following:
1H NMR spectrum (400 MHz, b ppm, DMSO-d6): 0.19 to 0.42 (m, 4H); 2.18 (m, 1H); 3.52 (s, 2H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1H); 7.16 (ddt, J = 1.0 and 2.3 and 8.3 Hz, 1H); 7.25 (td, J = 2.3 and 10.0 Hz, 1H); 7.31 (dd, J = 2.0 and 8.3 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.45 (dt, J = 6.9 and 8.3 Hz, 1H); 7.45 (m spread, 1H); 7.60 (d, J = 8.3 Hz, 1H); 7.91 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H) MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 508, [MH] -: m / z 506 b) 2-Chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-[Sulfanyl] -1,3-benzothiazol-2-yl) acetamide can be prepared in the next :
at 205mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6) in 2 cm3 of dichloromethane and 0.5cm3 of pyridine at 0-5 ° C is added dropwise 0.06cm3 of chloroacetyl. The resulting white suspension is stirred for 30 minutes at 20 ° C.
add 0.03cm3 of chloroacetyl chloride and leave stirring for 30min Moreover. A little methanol is added to the mixture, then the medium is evaporated to dryness under argon at 20 ° C. The residue is purified by 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). This gives 137 mg of 2-chloro-N- (6 - {[6-(3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetam ide in the form of a white solid whose characteristics are as follows:
MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 487, [MH] -: m / z 485 Example 10 N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3 b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxam ide a) N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide can be prepared in a manner similar to Example 2a but from 85 mg of 6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine (10b) in 5cm3 of pyridine with 0.124 cm3 of cyclopropanecarbonyl chloride after 3.5h of reaction at 50 ° C. Thus 57.3 mg of N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3 benzothiazol-2-yl] cyclopropanecarboxamide in the form of a powder the characteristics of which are as follows:
1H NMR Spectrum (400 MHz, b ppm, DMSO-d6): 0.88 to 1.00 (m, 4H), 1.92 at 2.04 (m, 1H); 2.30 at 2.35 (m, 4H); 3.39 (s, 2H); 3.51 to 3.57 (m, 4H) , 7.09 to 7.14 (m, 1H); 7.20 to 7.25 (m, 2H); 7.28 (dd, J = 2.0 and 8.6 Hz, 1H) ;
7.31 to 7.39 (m, 2H); 7.59 (d, J = 8.6 Hz, 1H); 7.83 (d, J = 2.0 Hz, 1H);
8.47 (d, J = 9.8 Hz, 1H); 12.68 (spread m, 1 H) MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 560, [MH] -: m / z b) 6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine (10b) can be prepared in a manner similar to Example la but from 133 mg of 3-chloro-6-[3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazine (10c), from 3mg of potassium dihydrogenphosphate in 0.1cm3 of water, 176mg of DL-dithiothreitol and 79mg of 2-amino-1,3-benzothiazol-6 thiocyanate yle (commercial), in 5cm3 of ethanol. In this way 111 mg of 6 - ({6- [3-(Morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) 1,3-benzothiazol-2-amine as a colorless oil whose characteristics are as follows:
MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 492, [M + 2H] 2+:
m / z 246.5 (base peak); [MH] -: m / z 490 C) 3-Chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazine (10c) can be prepared in a manner similar to Example 1b but from 310mg of 3- (morpholin-4-ylmethyl) phenol (10d) in 5cm3 of tetrahydrofuran, 76 mg of 60% sodium hydride in the oil and 275 mg of 3,6-dichloro [1,2,4] triazolo [4,3-b] pyridazine (commercial). We 15 thus obtains 138 mg of 3-chloro-6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazine as a brown oil whose characteristics are as follows:
MASS SPECTRUM: Waters ZQ: [M + H] +: m / z 346 d) 3- (morpholin-4-ylmethyl) phenol (10d) can be prepared from 20 following way:
to a solution of 188 mg of 3- (bromomethyl) phenol (10e) in 5 cm3 of THF
at 20 ° C., 438 mg of morpholine are added. After 24 hours the white suspension is concentrated to dryness under reduced pressure. The residue is taken up in water then extracted with dichloromethane. The organic phase is evaporated to dryness To give a colorless oil that gradually crystallizes. We obtain thus 182mg of 3- (morpholin-4-ylmethyl) phenol whose characteristics are the following :
MASS SPECTRUM: Waters UPLC-SQD: [M + H] +: m / z 194 e) 3- (bromomethyl) phenol (10e) can be prepared in the same way

Following:

to a solution of 500mg of 1- (chloromethyl) -3-methoxybenzene (commercial) in 5cm3 of dichloromethane at 200C are added 3.19cm3 of a 1M solution of boron tribromide in dichloromethane. After 19h the red solution is poured on iced water and extracted with dichloromethane. The organic phase is evaporated to dryness under vacuum to give a purple oil that crystallizes. This residue is purified by chromatography on a SPOT II device, equipped with an SVF D26 cartridge silica 15-40 μM, after solid deposition eluting with a gradient of 100%
100% methanol dichloromethane. We get 328mg of 3-(bromomethyl) phenol in the form of pink crystals whose characteristics are the following :
MASS SPECTRUM: Waters ZQ: [MH] -: m / z 185 Other examples as well as their intermediaries prepared by analogy with the above examples are described in the table below:

VS
i ~ .- a Quantity Ex. Name from:
x isolated i 4J

N- (6 - {[6- (3-12mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-11,3,3-b] pyridazin-3-yl] sulfanyl} -3b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole - 201 mg 1,3-benzothiazol-2- 2-amine (6) and 41 mg of chloride yl) Acetyl acetamide N- (6 - {[6- (3- 205mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-12,3,3-b] pyridazin-3-yl] sulfanyl} -3b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-194mg 1,3-benzothiazol-2-amine (6) and 104 mg of yl) cyclopropanecarboxamide cyclopropanecarbonyl 1- (6 - {[6- (4- 200mg of 3-chloro-6- (4-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-13,3,3-b] pyridazin-3-yl] sulfanyl} -5a b] pyridazine (13b) and 358 mg of 1- [2-133mg 1,3-Benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] -3- (6-sulfanyl) -1,3-(morpholin-4-yl) ethyl] urea benzothiazol-2-yl) urea (4b) 3-chloro-6- (4- [1g] 3,6-dichloro [1,2,4] triazolo [4,3-13b fluorophenoxy) [1,2,4] triazolo I lb b] pyridazine (commercial) and 1.46g from 4- 1,11 g 4,3-b] pyridazine fluorophenol 1- (6 - {[6- (3-fluoro-4- 200mg) 3-chloro-6- (3-fluoro-4-) methylphenoxy) [1,2,4] triazol methylphenoxy) [1,2,4] triazolo [4,3-14 o [4,3-b] pyridazin-3-5a b] pyridazine (14b) and 340mg of 1- [2- 202mg yl] sulfanyl} -1,3-benzothiazolmorolin-4-eth-1-6-sulfan 11.3-2-yl) -3- [2- (morpholin-4- (p 2) y] (y yl) ethyl] urea benzothiazol-2-yl) urea (4b) 3-chloro-6- (3-fluoro-4- [g] 3,6-dichloro [1,2,4] triazolo [4,3-14b methylphenoxy) [1,2,4] triazol lb b] pyridazine (commercial) and 1.64 g of 3-1.15 g o [4,3-b] pyridazine 4-fluoro-methylphenol 6 - {[6- (tetrahydro-2H-pyran-4,500mg) 3-chloro-6- (tetrahydro-2H-pyran) Yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine 416mg (15b) and 407 mg of thiocyanate of 2-benzothiazol-2-amine g 1,3-amino-benzothiazol-6-yl (commercial) 3-chloro-6- (tetrahydro-2H-1g of 3,6-dichloro [1,2,4] triazolo [4,3-15b pyran-4- lb b] pyridazine (commercial) and 1.35g of 929mg yloxy) [1,2,4] triazolo [4,3-tetrahydro-2H-pyran-4-ol b] pyridazine 6 - {[6- (4- 350mg of 3-chloro-6- (4-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-16,3,3-b] pyridazin-3-yl] sulfanyl} - b] pyridazine (13b) and 274mg of 246mg 2-amino-1,3-benzothiazol-6-benzothiazol-2-amine thiocyanate yle (commercial) 1- [2- (morpholin-4-yl) ethyl] -3- 200 mg of 3-chloro-6- (tetrahydro-2H-pyran) (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazine 4-yloxy) [1,2,4] triazolo [4,3-5a (15b) and 372 mg of 1- [2- (morpholin-4-179mg b] pyridazin-3-yl] sulfanyl} -1,3-yl) ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-benzothiazol-2-yl) urea yl) urea (4b) 1- [6 - ({6 - [(1-ethylpiperidin-4- 200mg) 3-chloro-6 - [(1-ethylpiperidin-4-) yl) oxy] [1,2,4] triazolo [4,3-yl] oxy] [1,2,4] triazolo [4,3-b] pyridazine (18b) B) pyridazin-3-yl} sulfanyl) -1,3 5a and 336mg of 1- [2- (morpholin-4-yl) ethyl] -3-153mg benzothiazol-2-yl] -3- [2- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (4b) (Morpholin-4-yl) ethyl] urea 3-chloro-6 - [(1-ethylpiperidin-1g) 3,6-dichloro [1,2,4] triazolo [4,3-18b 4-yl) oxy] [1,2,4] triazolo [4,3-bb] pyridazine (commercial) and 168g of 1-758mg b] ethylpiperidin-4-ol pyridazine N- (6 - {[6- (tetrahydro-2H) pyran-4-354mg of 6 - {[6- (tetrahydro-2H-pyran-4-) ) [1, yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-Yloxy-yloxy [1,2,3,44] triaztriazoluo [44,3,3-1,3-yl] sulfanyl} -1,33benzothiazol-2-amine (15) 198mg benzothiazol-2- and 0.162cm of yl) cyclopropanecarboxamide cyclopropanecarbonyl N- (6 - {[6- (4-10mg of 6 - {[6- (4-Fluorophenoxy) [1,2,4] triazolo 3 fluorophenoxy) [1,2,4] triazolo [4,3- 149mg 4,3-b] pyridazin-3-yl] sulfanyl} b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 1,3-benzothiazol-2-amine (16) and 0.094cm3 of chloride of yl) cyclopropanecarboxamide cyclopropanecarbonyl N- (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazol 560 mg of 6 - {[6- (3-fluoro-4-0 [4,3-b] pyridazin-3-methylphenoxy) [1,2,4] triazolo [4,3-1H] sulfanyl} -1,3-benzothiazol-3H] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol- 326mg 2-Amine (21b) and CM3 Chloride yl) cyclopropanecarbonyl cyclopropanecarboxamide 6 - {[6- (3-fluoro-4-500mg) 3-chloro-6- (3-fluoro-4-) methylphenoxy) [1,2,4] triazol methylphenoxy) [1,2,4] triazolo [4,3-21 bo [4,3-b] pyridazin-3-b] pyridazine (14b) and 372 mg of 360mg 2-amino-1,3-benzothiazol-6-yl] sulfanyl} -1,3-benzothiazol-thiocyanate 2-amine yl (commercial) N- [6 - ({6 - [(1-ethylpiperidin-4-235mg of 6 - ({6 - [(1-ethylpiperidin-4-) yl) oxy] [1,2,4] triazolo [4,3-yl] oxy] [1,2,4] triazolo [4,3-b] pyridazin-3 B) pyridazin-3-yl} sulfanyl) -1,3 3 -yl) sulfanyl) -1,3-benzothiazol-2-amine (22b) 155mg benzothiazol-2- and 0.101cm3 chloride of yl] cyclopropanecarboxam ide cyclopropanecarbonyl 6 - ({6 - [(1-ethylpiperidine-4-500mg of 3-chloro-6- (3-fluoro-4-yl) oxy] [1,2,4] triazolo [4,3-methylphenoxy] [1,2,4] triazolo [4,3-22b b] pyridazin-3-yl} sulfanyl) -1,3 b] pyridazine (14b) and 368mg of 286mg 2-amino-1,3-benzothiazol-6-benzothiazol-2-amine thiocyanate yle (commercial) rac-1- [2- (morpholin-4- 200mg) rac-3-chloro-6- (tetrahydrofuran) yl) ethyl] -3- (6 - {[6-yloxy) [1,2,4] triazolo [4,3-b] pyridazine 23 (tetrahydrofuran-3-5a (23b) and 394mg of 1- [2- (morpholin-4-173mg) yloxy) [1,2,4] triazolo [4,3-yl] ethyl] -3- (6-sulfanyl-1,3-benzothiazol-2-b] pyridazin-3-yl] sulfanyl} -1,3-yl) urea (4b) benzothiazol-2-yl) urea rac-3-chloro-6-g of 3,6-dichloro [1,2,4] triazolo [4,3-23b (tetrahydrofuran-3 lb) pyridazine (commercial) and 954mg 410mg yloxy) [1,2,4] triazolo [4,3-rac-tetrahydrofuran-3-ol b] pyridazine 1- (6 - {[6- (1,3-benzodioxol) -5,5mg of 6- (1,3-benzodioxol-5-yloxy) -3-yloxy) [1,2,4] triazolo [4,3-chloro [1,2,4] triazolo [4,3-b] pyridazine (24b) 24 b] pyridazin-3-yl] sulfanyl} -1,3-5a and 327 mg of 1- [2- (morpholin-4-yl) ethyl] - 174mg benzothiazol-2-yl) -3- [2- 3- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (morpholin-4-yl) ethyl] urea (4b) 6- (1,3-benzodioxol-5-g) 3,6-dichloro [1,2,4] triazolo [4,3-24b chloryloxy) -3- lbb] pyridazine (commercial) and 1.8g of 1.07g chloro [1,2,4] triazolo [4,3-1,3-benzodioxol-5-ol b] pyridazine 1- (6 - {[6- (3,4- 200mg) 3-chloro-6- (3,4-dichlorophenoxy) [1,2,4] triazo Lo [4,3-b] pyridazin-3-yl dichlorophenoxy) [1,2,4] triazolo [4,3-90mg yl] sulfanyl} -1,3-benzothiazolb] pyridazine (25b) and 300mg of 1- [2-2-yl) -3- [2- (morpholin-4- (morpholin-4-yl) ethyl] -3- (6-sulfanyl) -3-yl) ethyl] urea benzothiazol-2-yl) urea (4b) 3-chloro-6- (3,4-lg of 3,6-dichloro [1,2,4] triazolo [4,3-25b dichlorophenoxy) [1,2,4] triazo [b] pyridazine (commercial) and 2.12 g of 680mg lo [4,3-b] pyridazine 3,4-dichlorophenol 6 - {[6- (3,4- 500mg) of 3-chloro-6- (3,4-dichlorophenoxy) [1,2,4] triazo dichlorophenoxy) [1,2,4] triazolo [4,3-26 lo [4,3-b] pyridazin-3-b] pyridazine (25b) and 328mg of 155mg 2-amino-1,3-benzothiazol-6-yl] sulfanyl} -1,3-benzothiazol-thiocyanate 2-amine yl (commercial) rac-6 - {[6- (tetrahydrofuran-3-500mg) rac-3-chloro-6- (tetrahydrofuran) Yloxy) [1,2,4] triazolo [4,3-layloxy] [1,2,4] triazolo [4,3-b] pyridazine 297mg (23b) and 431 mg of thiocyanate of 2-benzothiazol-2-amine g 1,3-amino-benzothiazol-6-yl (commercial) 1- (6 - {[6- (1H-indol-6- 250mg) 3-chloro-6- (1H-indol-6-) yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine (28b) B) pyridazin-3-yl] sulfanyl} -1,3-5a and 355 mg of 1- [2- (morpholin-4-yl) ethyl] -3- 298mg benzothiazol-2-yl) -3- [2- (6-sulfanyl-1,3-benzothiazol-2-yl) urea (4b) (Morpholin-4-yl) ethyl] urea 3-chloro-6- (1H-indol-6-g) 3,6-dichloro [1,2,4] triazolo [4,3-28b yloxy) [1,2,4] triazolo [4,3-bb] pyridazine (commercial) and 1.73g of 1.01 g b] pyridazine 1H-indol-6-ol rac-N- (6 - {[6- 228 mg of rac-6 - {[6- (tetrahydrofuran-3-(tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yloxy) [1,2,4] triazolo [4,3 B) pyridazin-3-yl] sulfanyl} -1,3-yl] sulfanyl} -1,33benzothiazol-2-amine (27) 164mg benzothiazol-2- and 0.108cm of yl) cyclopropanecarboxam ide cyclopropanecarbonyl N- (6 - {[6- (1,3-benzodioxol-5-300mg of 6 - {[6- (1,3-benzodioxol-5-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 (30b) 202mg benzothiazol-2- and 0.127 cm3 of chloride yl) cyclopropanecarboxamide cyclopropanecarbonyl 6 - {[6- (1,3-benzodioxol) -560mg 6- (1,3-benzodioxol-5-yloxy) -3-30b yloxy) [1,2,4] triazolo [4,3-chloro [1,2,4] triazolo [4,3-b] pyridazine (24b) 679mg and 357mg of 2-amino-1,3-g thiocyanate benzothiazol-2-amine benzothiazol-6-yl (commercial) N- (6 - {[6- (3,4- 115mg of 6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazo dichlorophenoxy) [1,2,4] triazolo [4,3-lo [4,3-b] pyridazin-3-

31-yl] sulfanyl} -1,3-benzothiazol-3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol- 75mg 2-amine (26) and 0.046CM3 chloride of yl) cyclopropanecarboxamide cyclopropanecarbonyl N- (6 - {[6- (1H-indol-6- 345 mg of 6 - {[6- (1H-indol-6-)

32-yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-396mg b] pyridazin-3-yl] sulfanyl} -1,3-yl] sulfanyl} -1,3-benzothiazol-2-amine (32b) benzothiazol-2- and 0.147 cm of chloride yl) cyclopropanecarboxamide cyclopropanecarbonyl 6 - {[6- (1H-indol-6- 500mg of 3-chloro-6- (1H-indol-6-) 32b yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine (28b) 396m b] pyridazin-3-yl] sulfanyl} -1,3- and 363mg of 2-amino-thiocyanate benzothiazol-2-amine 1,3-benzothiazol-6-yl (commercial) N- (6 - {[6- (3-200mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-

33,3,3-b] pyridazin-3-yl] sulfanyl} -3b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol- 170mg 1,3-benzothiazol-2- 2-amine (6) and 0.11cm3 of yl) cyclobutanecarboxamide cyclobutanecarbonyl N- (6 - {[6- (3-200mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol

34,3,3-b] pyridazin-3-yl] sulfanyl} - 3 129mg 1,3-benzothiazol-2-yl) -N 2N2-2-amine (6) and 116mg of hydrochloride dimethylglycinamide chloride N, N-dimethylolylcyl in the refluxing dichloromethane 2-ethoxy-N- (6 - {[6- (3-200mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-

4,3-b] pyridazin-3-yl] sulfanyl} -7b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-223mg 1,3-benzothiazol-2- 2-amine (6) and 101 mg of acid yl) acetamide ethoxyacetic acid and 371 mg of HATU
2- (cyclohexyloxy) -N- (6 - {[6- 200mg of 6 - {[6- (3-(3-fluorophenoxy) [1,2,4] triazolo [4,3-

Fluorophenoxy) [1,2,4] triazolo [b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 130m 4,3-b] pyridazin-3-yl] sulfanyl} -2-amine (6) and 154 mg of g-acid 1,3-Benzothiazol-2- (cyclohexyloxy) acetic acid and 371 mg yl) HATU acetamide 6 - {[6- (pyridin-3-460mg) 3-chloro-6- (pyridin-3-

Yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine (37b) 400m b] pyridazin-3-yl] sulfanyl} -1,3- and 347 mg of 2-amino-thiocyanate benzothiazol-2-amine 1,3-benzothiazol-6-yl (commercial) 3-chloro-6- (3-pyridin-3g of 3,6-dichloro [1,2,4] triazolo [4,3-37b yloxy) [1,2,4] triazolo [4,3-bb] pyridazine (commercial) and 1.01g of 408mg b] pyridazine pyridine-3-ol 6 - ({6- [3- 200mg of 3-chloro-6- [3-(trifluoromethoxy) phenoxy] [1 (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,

38, 2,4] triazolo [4,3-b] pyridazin-3-b] pyridazine (38b) and 126mg of 111 mg 2-amino-1,3-benzothiazol-6-yl} sulfanyl) -1,3-thiocyanate benzothiazol-2-amine-yl (commercial) 3-chloro-6- [3- 500mg of 3,6-dichloro [1,2,4] triazolo [4,3-38b (trifluoromethoxy) phenoxy] [1 lb b] pyridazine (commercial) and 950 mg of 216mg , 2,4] triazolo [4,3-b] pyridazine 3- (trifluoromethoxy) phenol

39 [3 - ({3 - [(2-amino-1,3-la) -5mg of {3 - [(3-chloro [1,2,4] triazolo [4,3-131 mg]
benzothiazol-6-b] pyridazin-6-yl) oxy] phenyl} carbamate yl) sulfanyl] [1,2,4] triazolo [4,3-2-methylpropan-2-yl (39b) and 315 mg of b] 2-amino-1,3-benzothiazol-6-pyridazin-6-thiocyanate yl} oxy) phenyl] carbamate (commercial) 2-methylpropan-2-yl {3 - [(3- [g] of 3,6-dichloro [1,2,4] triazolo [4,3-chloro [1,2,4] triazolo [4,3-b] pyridazine (commercial) and 2,21 g of 39b b] pyridazin-6- lb 1,438 yl) oxy] phenyl} carbamate of (3-hydroxyphenyl) carbamate of 2-2-methylpropan-2-yl methylpropan-2-yl N- (6 - {[6- (pyridin-3- 330mg) 6 - {[6- (pyridin-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 (37) 262mg benzothiazol-2- and 0.091cm3 chloride of yl) cyclobutanecarboxamide cyclobutanecarbonyl N- (6 - {[6- (3-225mg of 2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-

4,3-b] pyridazin-3-yl] sulfanyl} -9b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-184mg 1,3-benzothiazol-2-yl) -2-yl) acetamide (9b) and 0.40cm3 of (morpholin-4-yl) morpholine acetamide N 2 -cyclohexyl-N- (6 - {[6- (3- (2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-

42,3,3-b] pyridazin-3-yl] sulfanyl} -9b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol- 65mg 1,3-benzothiazol-2-yl) acetamide (9b) and 0.40cm3 of yl) cyclohexylamine glycinamide N- (6 - {[6- (3- 243mg) 2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-4,3-b] pyridazin-3-yl] sulfanyl} -

1,3-benzothiazol-2-yl) -N2- [b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 149mg methyl-N2- [2- (morpholin-4-yl) acetamide (9b) and 425mg of N-yl) ethyl] glycinamide methyl-2- (morpholin-4-yl) ethanamine 2- (4-ethylpiperazin-1-yl) -N-200mg of 6 - {[6- (3-(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-

Fluorophenoxy) [1,2,4] triazolo [b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 154m 4,3-b] pyridazin-3-yl] sulfanyl} -2-amine (6) and 247 mg of the hydrobromide g 1,3-benzothiazol-2- (4-ethylpiperazin-1-yl) acetic acid and yl) 371 mg HATU acetamide 6 - {[6- (3,5-350mg) of 3-chloro-6- (3,5-difluorophenoxy) [1,2,4] triazol difluorophenoxy) [1,2,4] triazolo [4,3-

45 o [4,3-b] pyridazin-3-b] pyridazine (45b) and 257mg of 85mg 2-amino-1,3-benzothiazol-6-yl] sulfanyl} -1,3-benzothiazol-thiocyanate 2-amine yl (commercial) 3-chloro-6- (3,5-lg) 3,6-dichloro [1,2,4] triazolo [4,3-45b difluorophenoxy) [1,2,4] triazol lb b] pyridazine (commercial) and 1.38 g of 363mg o [4,3-b] pyridazine 3,5-difluorophenol

46 - {[6- (3-550mg of {3 - [(3-chloro [1,2,4] triazolo [4,3-137mg]
aminophenoxy) [1,2,4] triazolo [b] pyridazin-6-yl) oxy] phenyl} carbamate [4,3-b] pyridazin-3- (2-methylpropan-2-yl) (39b) and 315mg of 2-amino-1,3-benzothiazol-6-yl] sulfanyl} -1,3-benzothiazol-thiocyanate 2-amine yl (commercial) note: carbamate 2-methylpropan-2-yl is cleaved in these operating conditions.

N- (6 - {[6- (3- 243mg) 2-chloro-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-

47,3,3-b] pyridazin-3-yl] sulfanyl} -9b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole - 81 mg 1,3-benzothiazol-2-yl) -N-2-yl) acetamide (9b) and 400mg of (tetrahydro-2H-pyran-4-yl) tetrahydro-2H-pyran-4-amine glycinamide N- [6 - ({6- [4-(trifluoromethyl) phenoxy] [1.2 85mg of 6 - ({6- [4-4] triazolo [4,3-b] pyridazin-3- (trifluoromethyl) phenoxy] [1,2,4] triazolo [4,3-

48, 1H-sulfanyl) -1,3-benzothiazol-3-pyridazin-3-yl) sulfanyl) -1,3-benzothiazol- 58mg 2-amine (48b) and 0.034CM3 chloride yl] cyclopropanecarbonyl cyclopropanecarboxamide 6 - ({6- [4- 350mg of 3-chloro-6- [4-(trifluoromethyl) phenoxy] [1,2 (trifluoromethyl) phenoxy] [1,2,4] triazolo [4,3-48b, 4] triazolo [4,3-b] pyridazin-3-b] pyridazine (45b) and 231 mg of 109mg 2-amino-1,3-benzothiazol-6-yl} sulfanyl) -1,3-benzothiazolthiocyanate 2-amine yl (commercial) 3-chloro-6- [4- 1g of 3,6-dichloro [1,2,4] triazolo [4,3-48C (trifluoromethyl) phenoxy] [1.2bb] pyridazine (commercial) and 1.29g of 4-356mg , 4] triazolo [4,3-b] pyridazine (trifluoromethyl) phenol N- [6 - ({6- [3-4mg of 6 - ({6- [3-(trifluoromethoxy) phenoxy] [1 (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4, 2,4] triazolo [4,3-b] pyridazin

49 (3-yl) sulfanyl) -1,3- [3-b] pyridazin-3-yl} sulfanyl) -1.3-61 mg benzothiazol-2-benzothiazol-2-amine (38) and 0.055cm3 yl] cyclopropanecarbonyl chloride cyclopropanecarboxamide N- [6 - ({6 - [(2-methylpyridin-3-84mg) 6 - ({6 - [(2-methylpyridin-3) yl) oxy] [1,2,4] triazolo [4,3-yl] oxy] [1,2,4] triazolo [4,3-b] pyridazin-3

B) pyridazin-3-yl} sulfanyl) -1,3 3 -yl) sulfanyl) -1,3-benzothiazol-2-amine (50b) 71mg benzothiazol-2- and 0.040cm3 chloride yl] cyclopropanecarboxam ide cyclopropanecarbonyl 6 - ({6 - [(2-methylpyridin-3-550mg) 3-chloro-6 - [(2-methylpyridin-3) 50b yl) oxy] [1,2,4] triazolo [4,3-yl] oxy] [1,2,4] triazolo [4,3-b] pyridazine (50c) 84mg and 436 mg of 2-amino thiocyanate benzothiazol-2-amine g 1,3-benzothiazol-6-yl (commercial) 3-chloro-6 - [(2-methylpyridin-1g) 3,6-dichloro [1,2,4] triazolo [4,3-50C 3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazine (commercial) and 1.16 g of 2-734mg b] pyridazine methylpyridin-3-ol N- (6 - {[6- (3,5- 75mg of 6 - {[6- (3,5-

51 difluorophenoxy) [1,2,4] triazol 3 difluorophenoxy) [1,2,4] triazolo [4,3- 37mg o [4,3-b] pyridazin-3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole yl] sulfanyl} -1,3-benzothiazol-2-amine (45) and 0.033cm of 2- cyclopropanecarbonyl yl) cyclopropanecarboxamide acetate of 2 - [(6 - {[6- (3-11mg of 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo fluorophenoxy) [1,2,4] triazolo [4,3-

4,3-b] pyridazin-3-yl] sulfanyl} -3b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol- 62mg 1,3-benzothiazol-2-amine (6) and 0.107 cc of acetate of yl) amino] -2-oxoethyl 2-chloro-2-oxoethyl N- [6 - ({6 - [(6-methylpyridin-3-6mg) 6 - ({6 - [(6-methylpyridin-3) yl) oxy] [1,2,4] triazolo [4,3-yl] oxy] [1,2,4] triazolo [4,3-b] pyridazin-3

B) pyridazin-3-yl} sulfanyl) -1,3 3 -yl) sulfanyl) -1,3-benzothiazol-2-amine (53b) 45mg benzothiazol-2- and 0.031cm3 chloride of yl] cyclopropanecarboxam ide cyclopropanecarbonyl 6 - ({6 - [(6-methylpyridin-3-255mg) 3-chloro-6 - [(6-methylpyridin-3) 53b yl) oxy] [1,2,4] triazolo [4,3-yl] oxy] [1,2,4] triazolo [4,3-b] pyridazine (53c) 69m b] pyridazin-3-yl} sulfanyl) -1.3 and 202 mg of 2-amino-thiocyanate benzothiazol-2-amine 1,3-benzothiazol-6-yl (commercial) 3-chloro-6 - [(6-methylpyridin-1g) 3,6-dichloro [1,2,4] triazolo [4,3-53C 3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazine (commercial) and 1.16 g of 6- 260mg b] pyridazine methylpyridin-3-ol N- [6 - ({6- [4- morpholin-4- 87mg of 6 - ({6- [4- (morpholin-4-(1,2,4] triazolylmethyl) phenoxy] [1,2,4] triazolylmethyl) phenoxy] [1,2,4] triazolo [4,3-

54 olo [4,3-b] pyridazin-3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-86mg yl} sulfanyl) -1,3-benzothiazol-2-amine (54b) and 0.024cm3 of chloride cyclopropanecarbonyl yl] cyclopropanecarboxamide 6 - ({6- [4- (morpholin-4- 155mg of 3-chloro-6- [4- (morpholin-4-(1,2,4] triazolylmethyl) phenoxy] [1,2,4] triazolylmethyl) phenoxy] [1,2,4] triazolo [4,3-54b olo [4,3-b] pyridazin-3-b] pyridazine (54c) and 93mg of 91mg 2-amino-1,3-benzothiazol-6-yl} sulfanyl) -1,3-benzothiazolthiocyanate 2-amine yl (commercial) 3-chloro-6- [4- (4-morpholin-189mg of 3,6-dichloro [1,2,4] triazolo [4,3-54C (methyl) phenoxy] [1,2,4] triazb1b] pyridazine (commercial) and 207mg of 158mg olo [4,3-b] pyridazine 4- (morpholin-4-ylmethyl) phenol (54d) 4- (morpholin-4- 185mg acetate 4-54d (methyl) phenol 10d (chloromethyl) phenyl and 436mg 207mg morpholine (3 - {[3 - ({2-[(cyclopropylcarbonyl) amino] 84mg of [3 - ({3 - [(2-amino-1,3-benzothiazole) -1,3-Benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin

[2- (4-yl) sulfanyl) [1,2,4] triazolo [4,3- [6-yl] oxy) phenyl] carbamate 2-59mg b] pyridazin-6-methylpropan-2-yl (39) and 0.031cm3 of yl] oxy} phenyl) cyclopropanecarbonyl chloride carbamate 2-methylpropan-2-yl N- (6 - {[6- (pyridin-3-150mg) 6 - {[6- (pyridin-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 (37) 143mg benzothiazol-2- and 0.070cm3 of chloride yl) cyclopropanecarboxamide cyclopropanecarbonyl N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-6mg of 6 - [(6- {3 - [(1S, 4S) -2-oxa-5} -azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triaz azabicyclo [2.2.1] hept-5-

57 olo [4,3-b] pyridazin-3-ylmethyl] phenoxy} [1,2,4] triazolo [4.3-3 mg y1) sulfanyl] -1,3-benzothiazolb) pyridazin-3-yl) sulfanyl] -1,3-benzothiazole 2- (2-amine (57b) and 0.10CM3 chloride Cyclopropanecarbonyl cyclopropanecarboxamide 4h at 50 ° C

6 - [(6- {3 - [(1 S, 4S) -2-oxa-5 -3mg of 3-chloro-6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-azabicyclo [2.2. 1] hept-5-57b, ylmethyl] phenoxy} [1,2,4] triazyl] phenoxy} [1,2,4] triazolo [4,3-molo [4,3-b] pyridazin-3-b] pyridazine (57c) and 60mg of g 2-amino-1,3-benzothiazol-6-yl) sulfanyl] -1,3-benzothiazolthocyanate 2-amine yl (commercial) 3-Chloro-6- {3 - [(1S, 4S) -2-oxa85mg 3,6-dichloro [1,2,4] triazolo [4,3-57c 5-azabicyclo [2.2.1] hept-5bb] pyridazine (commercial) and 110mg of 108m g ylmethyl] phenoxy} [1,2,4] triaz 3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-olo [4,3-b] pyridazine [methyl] phenol (57d) 3 - [(1S, 4S) -2-oxa-5 -mug of 3- (bromomethyl) phenol (10e) and 57d azabicyclo [2.2.1] hept-5d 10d of 163mg of (1S, 4S) -2-111mg hydrochloride ylmethyl] phenol oxa-5-azabicyclo [2.2. 1] heptane (commercial) N- {6 - [(6- {3-[(diethylamino) methyl] phenol 46mg 6 - [(6- {3-[(Diethylamino) methyl] phenoxy} [1,2,4] triazol

Xy} [1 xy] [1,2,4] t] triazriazolylo [4 [4,3-, fanyl] -1,3- 3 o [4,3-b] pyridazin) 3-yl) sulfanyl] -1,3-30mg benzothiazol-2-benzothiazol-2-amine (58b) and 0.013cm3 Cyclopropanecarbonyl chloride cyclopropanecarboxamide 6 - [(6- {3-60mg N- {3 - [(3-chloro [1,2,4] triazolo [4,3-[(diethylamino) methyl] phenol] pyridazin-6-yl) oxy] benzyl} -N-58b xy} [1,2,4] triazolo [4,3-ethylethanamine (58c) and 120mg of 157mg b] 2-amino-1,3-benzothiazol-6-pyridazin-3-yl) sulfanyl] -1,3-thiocyanate benzothiazol-2-amine-yl (commercial) N- {3 - [(3- [3- [3- [3- [3- [3,4-dichloro [1,2,4] triazolo]
chloro [1,2,4] triazolo [4,3 58c b] pyridazin-6-yl) oxy] benzyl} - 1bb] pyridazine (commercial) and 169mg of 3-163 mg N-ethylethanamine [(diethylamino) methyl] phenol (58d) 58d 3 10d 375mg 3- (bromomethyl) phenol (10e) and 188m [(diethylamino) methyl] phenol 731 mg diethylamine

59 N- (6 - {[6- (3,5- 8,200mg of 6 - {[6- (3,5-127mg) difluorophenoxy) [1,2,4] triazol difluorophenoxy) [1,2,4] triazolo [4,3-o [4,3-b] pyridazin-3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole yl] sulfanyl} -1,3-benzothiazol-2-amine (45) and 715 mg of the salt of 2-yl) -N2, N2-sodium of N, N-diethylglycine diéthylglycinamide 510mg of acetate of 2 - [(6 - {[6- (3-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-fluorophenoxy) [1,2,4] triazolo [b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole 2-yl) amino] -2-oxoethyl (52) and 42mg 262mg

60 4,3-bsulfanyl} - Lithium hydrate according to conditions 1,3-benzoazino-thiazol-3-yl] yl) -2- similar to those described by TG
Murali hydroxyacetamide Dhar et al in J. Med. Chem. 2002, 45, 2- (4-Cyclopropylpiperazin-1-243 mg of 2-chloro-N- (6 - {[6- (3-(4 (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-fluorophenoxy) [1,2,4] triazolo [b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole

61,3,3-b] pyridazin-3-yl] sulfanyl} -9-yl) acetamide (9b) and 200mg of 242mg 1,3-Benzothiazol-2-dihydrochloride 1-cyclopropyl-piperazine yl) acetamide (commercial) with triethylamine in N, N-dimethylformamide N- (6 - {[6- (3,5- 200mg of 6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazol difluorophenoxy) [1,2,4] triazolo [4,3-0 [4,3-b] pyridazin-3-

[1H] sulfanyl} -1,3-benzothiazol-8H] pyridazin-3-yl] sulfanyl} -1,3-Benzothiazol-144mg yl) -2- (4-ethylpiperazin-1- 2-amine (45) and 1.19 g of acid (4-22-yl) -2- (4-ethylpiperazin-1-yl) acetic acid; (commercial) acetamide 2- (4-Cyclopropylpiperazine-1-142mg of 6 - {[6- (3,5-2- (4- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-difluorophenoxy) [1,2,4] triazol [b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazole

63 0 [4,3-b] pyridazin-3-8 2-amine (45) and 683mg salt 65mg yl] sulfanyl} -1,3-benzothiazol-potassium of the acid (4-2-yl) cyclopropylpiperazin-1-yl) acetic acetamide (63b) (or commercial) 2.1 g of bromoacetic acid and 3 g of potassium salt of 4-cyclopropylpiperazine hydrochloride 63b (4-cyclopropylpiperazin-1- under conditions similar to those 2,66g yl) acetic acid described by DT Witiak et.al .; J. Med.
Chem. 1985, 28, 1228 N- {6 - [(6- {3- 120mg of 6 - [(6- {3-[(diethylamino) methyl] phenyl [(diethylamino) methyl] phenoxy} [1,2,4] triazol

64 xy} [1,2,4] triazolo [4,3- 3 O [4,3-b] pyridazin-3-yl) sulfanyl] -1,3- 84mg b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine (58b) and 20mg of benzothiazol-2-yl} acetamide acetyl chloride N- {6 - [(6- {3- 120mg of 6 - [(6- {3-[(Diethylamino) methyl] phenyl [(diethylamino) methyl] phenoxy} [1,2,4] triazol

65 xy} [1,2,4] triazolo [4,3- 3 O [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-76mg b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-amine (58b) and 33mg of benzothiazol-2-yl} -2-methoxyacetyl chloride methoxy 2-methoxy-N- {6 - [(6- {3-35mg of 6 - [(6- {3 - [(1S, 4S) -2-oxa-5-[(1S, 4S) -2-oxa-5-azabicyclo [2.2. 1] hept-5-azabicyclo [2.2. 1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4,3-

66-ylmethyl] phenoxy} [1,2,4] triazo [b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazole 109mg olo [4,3-b] pyridazin-3- 2-amine (57b) and 35mg of chloride of 2-yl) sulfanyl] -1,3-benzothiazol 2-yl} acetamide methoxyacetyl 6 - {[6- (Oxetan-3) 1.02g of 3-chloro-6- (oxetan-3-)

Yloxy) [1,2,4] triazolo [4,3-yloxy) [1,2,4] triazolo [4,3-b] pyridazine (67b) 383mg and 1.12 g of 2-amino-1,3-g thiocyanate benzothiazol-2-amine benzothiazol-6-yl (commercial) 3-chloro-6- (3-oxetan-3g of 3,6-dichloro [1,2,4] triazolo [4,3-67b yloxy) [1,2,4] triazolo [4,3-bb] pyridazine (commercial) and 1.96g 1.01g b] oxetan-3-ol pyridazine rac-2- (morpholin-4-yl) -N- (6- 250mg of rac-6 - {[6- (tetrahydrofuran-3-{[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-

(Yloxy) [1,2,4] triazolo [4,3-yl] sulfanyl} -1,3-benzothiazol-2-amine (27) 86mg b] pyridazin-3-yl] sulfanyl} -1,3- and 939 mg of morpholin-4- acid benzothiazol-2-yl) acetam ide ylacetic (commercial) N- (6 - {[6- (3,5- 150mg of 6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazol difluorophenoxy) [1,2,4] triazolo [4,3-0 [4,3-b] pyridazin-3-

69] sulfanyl} -1,3-benzothiazol-8b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-111mg yl) -2- (morpholin-4- 2-amine (45) and 508mg of acid yl) - morpholin-4-ylacetic tamide (commercial) yl) acetamido rac-N2, N2-diethyl-N- (6 - {[6- 250mg of rac-6 - {[6- (tetrahydrofuran-3-(tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yloxy) [1,2,4] triazolo [4,3

70 b] pyridazin-3-yl] sulfanyl} -1,3-yl] sulfanyl} -1,3-benzothiazol-2-amine (27) 48mg and 991 mg of the sodium salt of N, N-benzo diethylglycine (commercial) yl) glycinamide Thiazothiazolo- 2-rac-2- (4-ethylpiperazin-1-yl) -250mg of rac-6 - {[6-(Tetrahydrofuran-3-N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-

Yloxy) [1,2,4] triazolo [4,3-yl] sulfanyl} -1,3-benzothiazol-2-amine (27) 50mg b] pyridazin-3-yl] sulfanyl} -1,3- and 655 mg of (4-ethylpiperazin-1-benzothiazol-2-yl) acetamido (acyl) acetic acid (commercial) rac-2- (4- 198mg of rac-6 - {[6- (tetrahydrofuran-3-cyclopropylpiperazin-1-yl) -N-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-

72 (6 - {[6- (tetrahydrofuran-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (27) 83m boy Wut and 619mg of the potassium salt of g b] pyridazin-3-yl] sulfanyl} -1,3- (4-cyclopropylpiperazin-1-yl) acetic acid benzothiazol-2-yl) acetamide (63b) (or commercial) N- (6 - {[6- (oxetan-3- 60mg) 6 - {[6- (oxetan-3-)

73 yloxy) [1,2,4] triazolo [4,3-yloxy] [1,2,4] triazolo [4,3-b] pyridazin-3-42mg b] pyridazin-3-yl] sulfanyl} -1,3-yl] sulfanyl} -1,3-benzothiazol-2-amine (67) benzothiazol-2- and 0.022cm of chloride yl) cyclopropanecarboxamide cyclopropanecarbonyl 2- (4-ethylpiperazin-1-yl) -N- 150mg of 6 - {[6- (oxetan-3-) (6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3

74-yloxy) [1,2,4] triazolo [4,3-yl] sulfanyl} -1,3-benzothiazol-2-amine (67) 123mg b] pyridazin-3-yl] sulfanyl} -1,3- and 357 mg of (4-ethylpiperazin-1-yl) benzothiazol-2-yl) acetamido (acyl) acetic acid (commercial) 2- (4-Cyclopropylpiperazine-1- (3-Methyl-3- (3- (3-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-

Yloxy) [1,2,4] triazolo [4,3-yl] sulfanyl} -1,3-benzothiazol-2-amine (67) 90mg b] pyridazin-3-yl] sulfanyl} -1,3- and 427 mg of the potassium salt of benzothiazol-2-yl) acetamide (4-cyclopropylpiperazin-1-yl) acetic acid (63b) (or commercial) the characteristics of the products in the table above are as follows Ex. SM NMR

1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 2.20 (s, 3H);
7.11 (broad dd, J = 2.2 and 8.5 Hz, 1H); 7.16 (ddt, J = 1.0 and 2.2 and 8.5 11 [M + H] +: m / z 453; [M-Hz, 1H); 7.25 (td, J = 2.2 and 10.0 Hz, 1H); 7.30 (dd, J = 1.9 and 8.6 H! -: m / z 451 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.43 (dt, J = 7.1 and 8.6 Hz, 1H);
7.60 (d, J = 8.6 Hz, 1H); 7.91 (d, J = 1.9 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.39 (spread m, 1 H) 1H NMR spectrum (400MHz, 6 ppm, DMSO-d6): 0.92 to 1.00 (m, 4H); 1.94 to 2.04 (m, 1H); 7.12 (broad dd, J = 2.3 and 8.3 Hz, 1H);
12 [M + H] +: m / z 479; [M-7.16 (ddt, J = 1.0 and 2.3 and 8.3 Hz, 1H); 7.25 (td, J = 2.3 and 10.0 Hz, 1 H, m / z 477H); 7.31 (dd, J = 1.9 and 8.6 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H);
7.43 (dt, J = 6.8 and 8.3 Hz, 1H); 7.61 (d, J = 8.6 Hz, 1H); 7.90 (d, J = 1.9 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.69 (spread m, 1 H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 2.36 to 2.46 (m, [M + H] +: m / z 567; [M-6H]; 3.26 to 3.34 (partially masked m, 2H); 3.59 (m, 4H);
13H] -: m / z 565 6.78 (br m, 1H); 7.18 to 7.26 (m, 3H); 7.26 to 7.32 (m, 2H);
7.36 (d, J = 9.8 Hz, 1H); 7.50 (d, J = 8.6 Hz, 1H); 7.82 (d, J = 1.9 Hz, 1H); 8.46 (d, J = 9.8 Hz, 1H); 10.89 (spread m, 1H) Retention time Tr 13b (min) = 0.78; [M + H] +:
m / z 265;

1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 2.27 (s, 3H);
2.41 (m, 6H); 3.25 to 3.35 (partially masked m, 2H); 3.60 (m, 14 [M + H] +: m / z 581; [M-4H]; 6.78 (m wide, 1H); 7.00 (d wide, J = 8.3 Hz, 1H); 7.19 (d H] -: m / z 579 broad, J = 10.3 Hz, 1H); 7.23-7.31 (m, 2H); 7.35 (d, J = 9.8 Hz, 1 H); 7.48 (d, J = 8.6 Hz, 1H); 7.84 (d, J = 1.9 Hz, 1H); 8.46 (d, J = 9.8 Hz, 1H); 10.89 (spread m, 1H) 14b Retention time Tr (min) = 0.88; [M + H] +

m / z 279;

1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 1.55 (m, 2H);
[M + H] +: m / z 399; [M-1.87 (m, 2H); 3.41 (m, 2H); 3.72 to 3.80 (m, 2H);
4.91 (m, 1H);
H] -: m / z 401 7.04 (d, J = 9.8 Hz, 1H); 7.22 to 7.30 (m, 2H); 7.61 (s, 2H);
7.82 (d, J = 1.0 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H) Retention time Tr 15b (min) = 2.74; [M + H] +:
m / z 255;

[M + H] +: m / z 411; [M-NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 7.12 (dd, J = 1.9 16H] -: m / z 409 and 8.4 Hz, 1H); 7.22 (d, J = 8.4 Hz, 1H); 7.24 to 7.38 (m, 5 H); 7.62 (d, J = 1.9 Hz, 1H); 7.64 (bs, 2H); 8.44 (d, J = 9.8 Hz, 1H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 1.52 (m, 2H);
1.81 (m, 2H); 2.35 to 2.45 (m, 6H); 3.23 to 3.27 (masked m, 2H);
17 [M + H] +: m / z 557; [M-3.32 to 3.39 (masked m, 2H); 3.59 (t, J = 4.6 Hz, 4 H); 3.71 (m, 2H);
H, m / z 555 4.86 (m, 1H); 6.79 (bs, 1H); 7.05 (d, J = 9.8 Hz, 1H);
7.33 (dd, J = 2.0 and 8.6 Hz, 1H); 7.55 (d, J = 8.6 Hz, 1H); 8.01 (d, J = 2.0 Hz, 1 H); 8.30 (d, J = 9.8 Hz, 1H); 10.91 (wide, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.96 (t, J = 7.2 Hz, 3H); 1.49 (m, 2H); 1.76 (m, 2H); 1.93 (t, J = 9.5 Hz, 2H); 2.28 (q, J = 7.1 Hz, 2H); 2.41 (m, 6H); 2.51 to 2.59 (m, 2H); 3.24 to 3.28 18 [M + H] +: m / z 584 (concealed m, 2H); 3.59 (t, J = 4.6 Hz, 4H), 4.61 (m, 1H);
6.77 (s broad, 1H); 7.03 (d, J = 9.8 Hz, 1H); 7.28 (dd, J = 2.1 and 8.4 Hz, 1H);
7.53 (d, J = 8.6 Hz, 1H); 8.02 (d, J = 2.0 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1 H); 10.89 (s wide, 1H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 1.01 (t, J = 7.2 Hz, 3H); 1.67 to 1.86 (m, 2H); 2.03 to 2.12 (m, 2H); 2.21 to 2.28 18b (m, 2H); 2.35 (q, J = 7.2 Hz, 2H); 2.61 to 2.75 (m, 2H); 5.01 (tt, J = 4.1 and 8.2 Hz, 1H); 7.10 (d, J = 10.0 Hz, 1H); 8.27 (d, J = 10.0 Hz, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.90 to 0.98 (m, [M + H] + m / z 469; [M-4H]; 1.51 (m, 2H); 1.78 (m, 2H); 1.97 (m, 1H); 3.31 to 3.36 (m 19 H] -: m / z 467 masked, 2H); 3.70 (m, 2H); 4.84 (m, 1H); 7.05 (d, J = 9.8 Hz, 1H);
7.38 (dd, J = 2.0 and 8.8 Hz, 1H); 7.66 (d, J = 8.6 Hz, 1H); 8.06 (d, J = 1.2 Hz, 1H); 8.31 (d, J = 9.8 Hz, 1H); 12.68 (s large, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.92 to 1.00 (m, [M + H] +: m / z 479; [M-4H]; 1.96 to 2.04 (m, 1H); 7.18 (t, J = 8.3 Hz, 2 H); 7.22 to 7.32 (m, H] -: m / z 477 3H); 7.37 (d, J = 10.0 Hz, 1H); 7.62 (d, J = 8.6 Hz, 1H); 7.87 (D, J = 1.9 Hz, 1H); 8.47 (d, J = 10.0 Hz, 1H); 12.70 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.92 to 1.00 (m, 4H); 1.96 to 2.03 (m, 1H); 2.25 (d, J = 1.5 Hz, 3H); 6.97 (dd, J = 2.3 21 [M + H] +: m / z 493; [M- and 8.6 Hz, 1H); 7.16 (dd, J = 2.3 and 10.6 Hz, 1H);
7.24 (t large, H] -: m / z 491 J = 8.6 Hz, 1H); 7.30 (dd, J = 1.9 and 8.6 Hz, 1H); 7.36 (d, J = 9.8 Hz, 1H); 7.59 (d, J = 8.6 Hz, 1H); 7.89 (d, J = 1.9 Hz, 1H); 8.47 (d, J = 9.8 Hz, 1H); 12.69 (spread m, 1 H) Retention time Tr B (min) = 0.82; [M + H] +:
m / z 425; [MH] -: m / z NMR spectrum (400 MHz, 6 ppm, DMSO-d6): 0.89 (d, J = 6.1 Hz, 4H); 0.94 (t, J = 7.1 Hz, 3H); 1.48 (m, 2H); 1.75 (m, 2H); 1.84 22 [M + H] +: m / z 496; [M- at 1.95 (m, 3H); 2.26 (q, J = 7.1 Hz, 2H); 2.52 to 2.57 (masked m, 2 H] -: m / z 494H); 4.58 (m, 1H); 7.02 (d, J = 9.8 Hz, 1H); 7.29 (dd, J = 1.8 and 8.4 Hz, 1H); 7.58 (d, J = 8.3 Hz, 1H); 8.03 (d, J = 1.2 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H); 12.62 (s, 1 H) Retention time Tr (min) = 0.36; [M + H] +
22b m / z 428; M + 2H] 2+:
m / z 214.5 (peak of base); [MH] -: m / z 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 1.98 (m, 1H);
2.17 (m, 1H); 2.35 to 2.45 (m, 6H); 3.22 to 3.28 (masked m, 2H);
23 [M + H] +: m / z 543; [M-3.59 (t, J = 4.6 Hz, 4H); 3.66 to 3.85 (m, 4H); 5.32 (m, 1H); 6.78 (t, H] -: m / z 541 J = 5.9 Hz, 1H); 7.07 (d, J = 9.8 Hz, 1H); 7.42 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.57 (d, J = 8.6 Hz, 1H); 8.06 (d, J = 2.0 Hz, 1H); 8.30 (d, J = 9.8 Hz, 1H); 10.88 (s wide, 1H) Retention time Tr NMR spectrum (400 MHz, 6 ppm, DMSO-d6): 2.05 to 2.18 (M, 23b (min) = 0.49; [M + H] +: 1H); 2.25 to 2.39 (m, 1H); 3.78 (m, 1H); 3.88 (m, 1H); 3.94 (m, m / z 241 2H); 5.52 (m, 1H); 7.12 (d, J = 9.8 Hz, 1H); 8.29 (d, J = 9.8 Hz, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 2.36 to 2.45 (m, 6H); 3.25 to 3.32 (partially masked m, 2H); 3.59 (m, 4H);
24 [M + H] +: m / z 593; [M-6.12 (s, 2H); 6.72 (dd, J = 2.4 and 8.6 Hz, 1H);
6.79 (m wide, 1H);
H] -: m / z 591 6.93 (d, J = 8.6 Hz, 1H); 6.95 (d, J = 2.4 Hz, 1H); 7.27 to 7.33 (m, 2 H); 7.50 (d, J = 8.6 Hz, 1H); 7.87 (d, J = 1.9 Hz, 1H); 8.42 (d, J = 9.8 Hz, 1H); 10.90 (spread m, 1 H) Retention time Tr 24b (min) = 0.73; [M + H] +:
m / z 291 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 2.37 to 2.45 (m, 6H); 3.24 to 3.33 (partially masked m, 2H); 3.59 (m, 4H);
[M + H] +: m / z 617; [M-6.78 (m wide, 1H); 7.24 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.30 (dd, H] -: m / z 615 J = 2.7 and 8.8 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.48 (d, J = 8.3 Hz, 1 H); 7.62 (d, J = 8.8 Hz, 1H); 7.74 (d, J = 2.7 Hz, 1H); 7.84 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 10.92 (spread m, 1H) Retention time Tr 25b (min) = 0.98; [M + H] +:
m / z 315 26 [M + H] +: m / z 461; [M-NMR spectrum (400 MHz, 6 ppm, DMSO-d6): 7.13 (dd, J = 2.0 H] -: m / z 459 and 8.4 Hz, 1H); 7.20 (d, J = 8.4 Hz, 1H); 7.34 (dd, J = 2.7 and 8.8 Hz, 1H); 7.38 (d, J = 9.8 Hz, 1H); 7.64 (s, 2H); 7.66 (d, J = 2.0 Hz, 1H) ; 7.71 (d, J = 8.8 Hz, 1H); 7.79 (d, J = 2.7 Hz, 1H); 8.47 (d, J = 9.8 Hz, 1H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 2.02 (m, 1H);
27 [M + H] +: m / z 387; [M-2.22 (m, 1H); 3.69 to 3.86 (m, 4H); 5.35 (m, 1H);
7.06 (d, J = 10.0 H] -: m / z 385 Hz, 1H); 7.29 (d, J = 8.6 Hz, 1H); 7.34 (dd, J = 2.0 and 6.6 Hz, 1 H);
7.62 (s, 2H); 7.88 (d, J = 2.0 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 2.38 to 2.45 (m, 6H); 3.22 to 3.35 (partially masked m, 2H); 3.60 (m, 4H);
[M + H] +: m / z 588; [M-6.51 (m, 1H); 6.77 (m, 1H); 6.91 (dd, J = 2.3 and 8.6 Hz, 1H);
H: m / z 586 7.21 (dd, J = 2.0 and 8.6 Hz, 1H); 7.33 (d, J = 10.0 Hz, 1H);
7.34 to 7.37 (m, 2H); 7.42 (dd, J = 2.3 and 3.0 Hz, 1H); 7.58 (d, J = 8.6 Hz, 1 H); 7.88 (d, J = 2.0 Hz, 1H); 8.41 (d, J = 10.0 Hz, 1H); 10.89 (m spread, 1H); 11.25 (spread m, 1 H) Retention time Tr 28b (min) = 0.76; [M + H] +:
m / z 286; [MH] -: m / z 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 0.95 (m, 4H);
[M + H] +: m / z 455; [M-1.97 (m, 2H); 2.15 (m, 1H); 3.63 to 3.73 (m, 3H);
3.78 (q, J = 7.7 29H] -: m / z 453Hz, 1H); 5.33 (m, 1H); 7.08 (d, J = 10.0 Hz, 1H); 7.46 (dd, J = 2.1 and 8.4 Hz, 1H); 7.69 (d, J = 8.3 Hz, 1H); 8.11 (d, J = 2.0 Hz, 1H); 8.31 (d, J = 9.8 Hz, 1H); 12.67 (s wide, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.90 to 1.00 (m, 4H); 1.92 to 2.05 (m, 1H); 6.09 (s, 2H); 6.70 (dd, J = 2.3 and 8.4 Hz, [M + H] +: m / z 505; [M-1H]; 6.89 (d, J = 8.4 Hz, 1H); 6.92 (d, J = 2.3 Hz, 1 H); 7.32 (d, H] -: m / z 503 J = 9.8 Hz, 1H); 7.35 (dd, J = 2.0 and 8.6 Hz, 1H); 7.62 (d, J = 8.6 Hz, 1H); 7.92 (d, J = 2.0 Hz, 1H); 8.43 (d, J = 9.8 Hz, 1H); 12.68 (m spread, 1H) Retention time Tr 30b (min) = 0.70; [M + H] +:
m / z 437; [MH] -: m / z NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.90 to 0.99 (m, 31 [M + H] +: m / z 529; [M-4H]; 1.94 to 2.05 (m, 1H); 7.24 to 7.30 (m, 2H);
7.40 (d, J = 9.8 Hz, H] -: m / z 527 1H); 7.55 to 7.61 (m, 2H); 7.71 (d, J = 2.7 Hz, 1H); 7.89 (d, J = 2.0 Hz, 1H); 8.50 (d, J = 9.8 Hz, 1H); 12.70 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.86 to 1.03 (m, 4H); 1.94 to 2.06 (m, 1H); 6.50 (t, J = 2.2 Hz, 1H); 6.90 (dd, J = 2.2 32 [M + H] +: m / z 500; [M- and 8.6 Hz, 1H); 7.25 (dd, J = 1.9 and 8.6 Hz, 1H);
7.30 to 7.36 (m, 2 H] -: m / z 499H); 7.40 to 7.46 (m, 2H); 7.55 (d, J = 8.6 Hz, 1H); 7.94 (d, J = 1.9 Hz, 1H); 8.41 (d, J = 9.8 Hz, 1H); 11.24 (bs, 1H); 12.69 (m spread, 1H) 32b Retention time Tr (min) = 3.32; [M + H] +

m / z 432; [MH] -: m / z 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 1.76 to 1.89 (m, 1H); 1.89 to 2.04 (m, 1H); 2.07 to 2.33 (m, 4H); 3.34 to 3.45 (m, 1 [M + H] +: m / z 493; [M-H]; 7.12 (dd, J = 2.3 and 8.4 Hz, 1H); 7.17 (wide dt, J = 2.3 and 8.4 Hz, 33H] -: m / z 491 1H); 7.25 (td, J = 2.3 and 10.0 Hz, 1H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1H); 7.43 (dt, J = 6.9 and 8.4 Hz, 1H); 7.59 (d, J = 8.6 Hz, 1H); 7.91 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H) 12.25 (spread m, 1 H) 1H NMR spectrum (400MHz, 6 ppm, DMSO-d6): 2.30 (s, 6H);
3.22 to 3.42 (partially masked m, 2H); 7.11 (dd, J = 2.3 and 8.3 34 [M + H] +: m / z 496; [M-Hz, 1H); 7.16 (dt, J = 2.3 and 8.3 Hz, 1H); 7.24 (td, J = 2.3 and 9.9 Hz, H] -: m / z 494 1H); 7.31 (dd, J = 1.9 and 8.6 Hz, 1H); 7.39 (d, J = 10.0 Hz, 1 H);
7.42 (dt, J = 6.9 and 8.3 Hz, 1H); 7.61 (d, J = 8.6 Hz, 1H); 7.91 (d, J = 1.9 Hz, 1H); 8.49 (d, J = 10.0 Hz, 1H); 11.93 (very spread m, 1 H) 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 1.17 (t, J = 7.1);
Hz, 3H); 3.56 (q, J = 7.1 Hz, 2H); 4.24 (s, 2H); 7.11 (dd, J = 2.2 and [M + H] +: m / z 497; [M-8.3 Hz, 1H); 7.16 (dt, J = 2.2 and 8.3 Hz, 1H);
7.24 (td, J = 2.2 and 10.0 H] -: m / z 495 Hz, 1H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1H); 7.36 to 7.46 (m, 2 H);
7.62 (d, J = 8.6 Hz, 1H); 7.93 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.29 (spread m, 1H) 1 H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 1.11 to 1.36 (m, 5H); 1.42 to 1.53 (m, 1H); 1.68 (m, 2H); 1.88 (m, 2H); 3.36 to [M + H] +: m / z 551; [M-3.44 (m, 1H); 4.26 (s, 2H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1H); 7.16 36H] -: m / z 549 (dt, J = 2.2 and 8.3 Hz, 1H); 7.24 (td, J = 2.2 and 10.0 Hz, 1H) ; 7.31 (dd, J = 2.0 and 8.6 Hz, 1H); 7.37 to 7.46 (m, 2H); 7.62 (d, J = 8.6 Hz, 1H); 7.93 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.19 (m spread, 1H) 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 7.10 (dd, J = 1.8) [M + H] +: m / z 394; [M- and 8.4 Hz, 1H); 7.21 (d, J = 8.3 Hz, 1H); 7.42 (d, J = 9.8 Hz, 1H);
37H] -: m / z 392 7.53 (dd, J = 4.8 and 8.4 Hz, 1H); 7.61 (d, J = 2.0 Hz, 1H); 7.64 (s, 2 H); 7.76 to 7.81 (m, 1H); 8.47 (d, J = 9.8 Hz, 1H); 8.59 (dd, J = 1.2 and 4.6 Hz, 1H); 8.63 (d, J = 2.9 Hz, 1H) 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 7.46 (d, J = 10.0) 37b Hz, 1H); 7.58 (ddd, J = 0.5 and 4.7 and 8.3 Hz, 1H); 7.90 (ddd, J = 1.2 and 2.7 and 8.3 Hz, 1H); 8.49 (d, J = 10.0 Hz, 1H); 8.56 (dd, J = 1.2 and 4.7 Hz, 1H); 8.68 (broad d, J = 2.7 Hz, 1H) [M + H] +: m / z 477; 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 7.19 (dd, J = 1.9 38 and 8.5 Hz, 1H); 7.24 (d, J = 8.5 Hz, 1H); 7.37 to 7.46 (m, 3H); 7.58 H, m / z 475 (brs, 1H); 7.63 to 7.75 (m, 4H); 8.52 (d, J = 9.8 Hz, 1H) Retention time Tr 38b (min) = 4.12; [M + H] +:
m / z 331 39 [M + H] +: m / z 508; [1H NMR spectrum (400MHz, 6 ppm, DMSO-d6): 1.48 (s, 9H);
H] -: m / z 506 6.86 (broad d, J = 7.8 Hz, 1H); 7.17 (dd, J = 1.8 and 8.5 Hz, 1H) ; 7.22 (d, J = 8.5 Hz, 1H); 7.28 to 7.40 (m, 3H); 7.51 (brs, 1H); 7.62 (s wide, 2H); 7.71 (d, J = 1.8 Hz, 1H); 8.42 (d, J = 9.8 Hz, 1H);
9.59 (bs, 1H) 39b [M + H] +: m / z 362; [M
H] -: m / z 360 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 1.78 to 2.04 (m, [M + H] +: m / z 476; [M-2H]; 2.11 to 2.34 (m, 4H); 3.41 (m, 1H); 7.27 (dd, J = 2.0 and 8.3 Hz, 40H] -: m / z 474 1H); 7.38 to 7.46 (m, 2H); 7.60 (d, J = 8.3 Hz, 1H); 7.72 (dd, J = 3.9 and 8.3 Hz, 1H); 7.89 (d, J = 2.0 Hz, 1H); 8.47 to 8.55 (m, 2H); 8.58 (d, J = 2.9 Hz, 1H); 12.27 (s wide, 1H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 2.54 (m, 4H);
3.34 (s, 2H); 3.62 (m, 4H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1H); 7.16 41 [M + H] +: m / z 538; [M- (ddt, J = 0.9 and 2.3 and 8.3 Hz, 1H); 7.25 (td, J = 2.3 and 10.0 Hz, 1H);
H: m / z 536 7.31 (dd, J = 2.0 and 8.6 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.43 (Dt, J = 6.9 and 8.3 Hz, 1H); 7.61 (d, J = 8.6 Hz, 1H); 7.91 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1H); 12.21 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 1.00 to 1.29 (m, 5H); 1.50 to 1.57 (m, 1H); 1.61 to 1.72 (m, 2H); 1.83 (m, 2H);
42 [M + H] +: m / z 550; [M-2.46 (partially masked m, 1H); 3.52 (s, 2H);
7.09 to 7.20 (m, H] -: m / z 548 2H); 7.23 to 7.30 (m, 2H); 7.38 (d, J = 9.8 Hz, 1H); 7.44 (dt, J = 6.9 and 8.3 Hz, 1H); 7.57 (d, J = 8.3 Hz, 1H); 7.88 (d, J = 2.0 Hz, 1H, 8.48 (d, J = 9.8 Hz, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 2.35 to 2.46 (m, 9H); 2.65 (t, J = 6.1 Hz, 2H) 3.39 (s, 2H) 3.64 (m, 4H) 7.11 43 [M + H] +: m / z 595; [M- (dd, J = 2.2 and 8.3 Hz, 1H); 7.16 (dt, J = 2.2 and 8.3 Hz, 1H); 7.25 (td, H] -: m / z 593 J = 2.2 and 10.0 Hz, 1H); 7.31 (dd, J = 1.7 and 8.6 Hz, 1H); 7.39 (D, J = 9.8 Hz, 1H); 7.42 (m, 1H); 7.59 (d, J = 8.6 Hz, 1H); 7.91 (d, J = 1.7 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.01 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 1.00 (bt, [M + H] +: m / z 565; J = 6.8 Hz, 3H); 2.30 to 2.62 (partially masked m, 10 H) ; 3.34 [M + 2H] 2 +: m / z 283 (s, 2H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1H); 7.16 (dt, J = 2.3 and 8.3 Hz, 44 (base peak); [MH] -: 1H); 7.24 (td, J = 2.3 and 10.0 Hz, 1H); 7.32 (dd, J = 2.0 and 8.6 Hz, 1 m / z 563H); 7.39 (d, J = 9.8 Hz, 1H); 7.43 (m, 1H); 7.62 (d, J = 8.6 Hz, 1H) ; 7.92 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.11 (m spread, 1 H) [M + H] +: m / z 429; [M-NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 7.19 (s) wide, 2 45H] -: m / z 427H); 7.21 to 7.33 (m, 3H); 7.39 (d, J = 9.8 Hz, 1H); 7.64 (s wide, 2 H); 7.69 (bs, 1H); 8.48 (d, J = 9.8 Hz, 1H) Retention time Tr 45b (min) = 0.83; [M + H] +:
m / z 283 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 5.36 (brs, 2) [M + H] +: m / z 408; [M-H]; 6.36 (dd, J = 2.0 and 8.1 Hz, 1H); 6.45 (t, J = 2.0 Hz, 1H); 6.54 46H] -: m / z 406 (dd, J = 2.0 and 8.1 Hz, 1H); 7.11 (t, J = 8.1 Hz, 1H); 7.20 to 7.33 (m, 3H); 7.63 (bs, 2H); 7.74 (d, J = 1.8 Hz, 1H); 8.39 (d, J = 9.8 Hz, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 1.22 to 1.34 (m, 2H); 1.76 (m, 2H); 2.68 (m, 1H), 3.30 (m, 2H), 3.52 (s, 2H);
[M + H] +: m / z 552; [M-3.81 (m, 2H); 7.12 (dd, J = 2.0 and 8.3 Hz, 1H); 7.16 (dt, J = 2.0 and 47H] -: m / z 550 8.3 Hz, 1H); 7.25 (td, J = 2.0 and 10.0 Hz, 1H); 7.30 (dd, J = 2.0 and 8.3 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.44 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.59 (d, J = 8.3 Hz, 1H); 7.90 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.89 to 1.01 (m, 48 [M + H] +: m / z 529; [M-4H]; 2.01 (m, 1H); 7.25 (dd, J = 1.8 and 8.7 Hz, 1 H); 7.37 to 7.47 H, m / z 527 (m, 3H); 7.58 (d, J = 8.7 Hz, 1H); 7.66 (d, J = 8.6 Hz, 2H);
7.83 (d, J = 1.8 Hz, 1H); 8.53 (d, J = 9.8 Hz, 1H); 12.69 (wide, 1H) 48b [M + H] +: m / z 461; [M
H] -: m / z 459 Retention time Tr 48C (min) = 0.93; [M + H] +:
m / z 315 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.86 to 1.01 (m, 49 [M + H] +: m / z 545; [M-4H]; 1.99 (m, 1H); 7.24-7.35 (m, 3H); 7.40 (d, J = 9.8 Hz, 1H);
H, m / z 543 7.46 (brs, 1H); 7.52 (t, J = 8.3 Hz, 1H); 7.59 (d, J = 8.3 Hz, 1H) ; 7.89 (brs, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.67 (spread m, 1 H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 0.96 (m, 4H);
1.98 (m, 1H); 2.23 (s, 3H); 7.17 (dd, J = 2.0 and 8.6 Hz, 1H); 7.25 50 [M + H] +: m / z 476; [M- (dd, J = 5.1 and 8.1 Hz, 1H); 7.45 (d, J = 9.8 Hz, 1H);
7.57 (d, J = 8.6 H, m / z 474 Hz, 1H); 7.61 (dd, J = 1.6 and 8.2 Hz, 1H); 7.79 (d, J = 2.0 Hz, 1 H);
8.42 (dd, J = 1.7 and 4.6 Hz, 1H); 8.50 (d, J = 9.8 Hz, 1H); 12.67 (s wide, 1H) Retention time Tr 50b (min) = 0.48; [M + H] +:
m / z 408; [MH] -: m / z Retention time Tr 50C (min) = 0.37; [M + H] +:
m / z 262 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.91 to 1.00 (m, [M + H] +: m / z 497; [M-4H]; 1.94 to 2.03 (m, 1H); 7.11 to 7.25 (m, 3H);
7.33 (dd, J = 2.0 and 51H] -: m / z 495 8.6 Hz, 1H); 7.40 (d, J = 10.0 Hz, 1H); 7.59 (d, J = 8.6 Hz, 1 H) 7.91 (d, J = 2.0 Hz, 1H); 8.51 (d, J = 10.0 Hz, 1H); 12.67 (spread m, 1 H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 2.14 (s, 3H);
[M + H] +: m / z 511; [M-4.83 (s, 2H); 7.11 (dd, J = 2.1 and 8.5 Hz, 1H); 7.15 (dt, J = 2.1 and 8.5 52H] -: m / z 509Hz, 1H); 7.24 (td, J = 2.1 and 10.0 Hz, 1H); 7.32 (dd, J = 2.0 and 8.6 Hz, 1H); 7.36 to 7.46 (m, 2H); 7.64 (d, J = 8.6 Hz, 1H); 7.93 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.64 (spread m, 1 H) 53 [M + H] +: m / z 476; [M-NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.96 (m, 4H);

H, m / z 474 1.99 (m, 1H); 2.51 (masked, 3H); 7.20 (d, J = 8.6 Hz, 1H); 7.26 (dd, J = 2.0 and 8.3 Hz, 1H); 7.41 (d, J = 10.0 Hz, 1H); 7.55 (dd, J = 2.8 and 8.4 Hz, 1H); 7.60 (d, J = 8.6 Hz, 1H); 7.86 (d, J = 2.0 Hz, 1H);
8.40 (d, J = 2.9 Hz, 1H); 8.48 (d, J = 9.8 Hz, 1H); 12.68 (s large, 1 H) Retention time Tr 53b (min) = 0.51; [M + H] +:
m / z 408; [MH] -: m / z Retention time Tr 53C (min) = 0.40; [M + H] +:
m / z 262 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.89 to 1.00 (m, [M + H] +: m / z 560; [M-4H]; 1.93 to 2.06 (m, 1H); 2.33 (m, 4H); 3.45 (s, 2H); 3.52 to 54H] -: m / z 558 3.59 (m, 4H); 7.11 (d, J = 8.6 Hz, 2H); 7.17 to 7.26 (m, 3H) ; 7.36 (d, J = 9.8 Hz, 1H); 7.60 (d, J = 8.6 Hz, 1H); 7.83 (d, J = 2.0 Hz, 1H) ; 8.46 (d, J = 9.8 Hz, 1H); 2.70 (spread m, 1 H) Retention time Tr 54b (min) = 0.42; [M + H] +:
m / z 492; [MH] -: m / z Retention time Tr 54C (min) = 0.32; [M + H] +:
m / z 346 Retention time Tr 54d (min) = 0.3; [M + H] +:
m / z 194; [MH] -: m / z 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 0.95 (m, 4H);
[M + H] +: m / z 576; [M-1.44 (s, 9H); 1.99 (m, 1H); 6.81 (d, J = 8.3 Hz, 1H) ; 7.23 (t, J = 8.3 55H] -: m / z 574Hz, 1H); 7.33 (d, J = 9.8 Hz, 3H); 7.49 (s, 1H); 7.61 (d, J = 8.3 Hz, 1H); 7.95 (s, 1H); 8.44 (d, J = 9.8 Hz, 1H); 9.56 (s, 1H); 12.52 (m spread, 1H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 0.96 (m, 4H);
[M + H] +: m / z 462; [M-2.00 (m, 1H); 7.27 (dd, J = 1.7 and 8.6 Hz, 1H); 7.39 to 7.47 (m, 2H);
56H] -: m / z 460 7.62 (d, J = 8.3 Hz, 1H); 7.72 (dt, J = 2.0 and 8.3 Hz, 1H); 7.87 (D, J = 2.0 Hz, 1H); 8.50 (d, J = 9.8 Hz, 1H); 8.53 (d, J = 4.9 Hz, 1H);
8.58 (d, J = 2.9 Hz, 1H); 12.69 (, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.90 to 0.99 (m, 4H); 1.55 (broad d, J = 9.8 Hz, 1H); 1.73 (broad d, J = 9.8 Hz, 1H);
1.94 to 2.05 (m, 1H); 2.39 (broad d, J = 9.8 Hz, 1H); 2.70 (d wide, 57 [M + H] +: m / z 572; [M- = 9.8 Hz, 1H); 3.41 (brs, 1H); 3.49 (dd, J = 1.5 and 7.6 Hz, 1H);
H: m / z 570 3.61 (d, J = 14.0 Hz, 1H); 3.67 (d, J = 14.0 Hz, 1H); 3.87 (d, J = 7.6 Hz, 1H); 4.29 (s, 1H); 7.10 (dd, J = 2.0 and 8.3 Hz, 1H); 7.21 to 7.30 (m, 3H); 7.31 to 7.39 (m, 2H); 7.59 (d, J = 8.6 Hz, 1H); 7.84 (d, J = 2.0 Hz, 1H); 8.46 (d, J = 9.8 Hz, 1H); 12.68 (spread m, 1 H) Retention time Tr 57b (min) = 0.43; [M + H] +:
m / z 504; [MH] -: m / z Retention time Tr 57C (min) = 0.34; [M + H] +:
m / z 358 Retention time Tr 57d (min) = 0.16; [M + H] +:
m / z 206 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.93 (t, J = 7.2 Hz, 6H); 0.95 (m, 4H); 1.97 to 2.04 (m, 1H); 2.42 (q, J = 7.2 Hz, 4 58 [M + H] +: m / z 546; [M-H]; 3.45 (s, 2H); 7.08 (broad dd, J = 2.0 and 8.2 Hz, 1H); 7.19 to 7.26 H, m / z 544 (m, 2H); 7.28 (dd, J = 2.0 and 6 Hz, 1H); 7.33 (t, J = 8.2 Hz, 1 H);
7.36 (d, J = 9.8 Hz, 1H); 7.59 (d, J = 8.6 Hz, 1H); 7.84 (d, J = 2.0 Hz, 1H); 8.46 (d, J = 9.8 Hz, 1H); 12.68 (spread m, 1 H) Retention time Tr (min) = 0.46; [M + H] +:
58b m / z 478; [M + 2H] 2+:
m / z 239.5 (peak of based); [MH] -: m / z Retention time Tr 58C (min) = 0.40; [M + H] +:
m / z 332 Retention time Tr 58d (min) = 0.22; [M + H] +:
m / z 180 NMR'H spectrum (400 MHz, δ ppm, DMSO-d6): 1.00 (t, J = 7.2 [M + H] +: m / z 542; [M-Hz, 6H); 2.62 (q, J = 7.2 Hz, 4H); 3.40 (s, 2H);
7.09 to 7.25 (m, 3 59H] -: m / z 540H); 7.33 (dd, J = 2.0 and 8.6 Hz, 1H); 7.41 (d, J = 9.8 Hz, 1H) ; 7.60 (d, J = 8.6 Hz, 1H); 7.93 (d, J = 2.0 Hz, 1H); 8.52 (d, J = 9.8 Hz, 1H) 11.79 (spread m, 1 H) 1H NMR Spectrum (400MHz, δ ppm, DMSO-d6): 4.19 (brs, 2) H); 5.49 (bs, 1H); 7.11 (broad dd, J = 2.2 and 8.3 Hz, 1H); 7.16 60 [M + H] +: m / z 469; [M- (, J = 1.0 and 2.2 and 8.3 Hz, 1H); 7.25 (td, J = 2.2 and 10.0 Hz, 1H) H: m / z 467 7.31 (dd, J = 2.0 and 8.6 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.42 (Dt, J = 6.9 and 8.3 Hz, 1H); 7.61 (d, J = 8.6 Hz, 1H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1H); 12.09 (spread m, 1 H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 0.26 (m, 2H);
0.39 (m, 2H); 1.61 (m, 1H); 2.43 to 2.60 (partially masked m, 61 [M + H] +: m / z 577; [M-8H); 3.31 (bs, 2H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1H); 7.16 (dt, H] -: m / z 575 J = 2.2 and 8.3 Hz, 1H); 7.25 (td, J = 2.2 and 10.0 Hz, 1H); 7.31 (Dd, J = 2.0 and 8.6 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1H); 7.43 (dt, J = 6.9 and 8.3 Hz, 1H); 7.61 (d, J = 8.6 Hz, 1H); 7.92 (d, J = 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1H); 12.07 (spread m, 1 H) NMR'H spectrum (400MHz, δ ppm, DMSO-d6): 1.00 (t, J = 6.8 [M + H] +: m / z 583; [M-Hz, 3H); 2.28 to 2.62 (partially masked m, 10H);
3.34 (s, 2 62H] -: m / z 581H); 7.10 to 7.26 (m, 3H); 7.34 (dd, J = 2.0 and 8.6 Hz, 1H);
7.41 (d, J = 9.8 Hz, 1H); 7.61 (d, J = 8.6 Hz, 1H); 7.94 (d, J = 2.0 Hz, 1H);
8.52 (d, J = 9.8 Hz, 1H); 11.88 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.23 to 0.30 (m, [M + H] +: m / z 595; 2H); 0.35 to 0.44 (m, 2H); 1.61 (m, 1H); 2.40 to 2.60 (m 63 [M + 2H] 2 +: m / z 298 partially masked, 8H); 3.31 (s, 2H); 7.08 to 7.24 (m, 3H);
(base peak); [MH] -: 7.33 (dd, J = 1.7 and 8.6 Hz, 1H); 7.41 (d, J = 9.8 Hz, 1 H); 7.61 (d, m / z 593 J = 8.6 Hz, 1H); 7.94 (d, J = 1.7 Hz, 1H); 8.52 (d, J = 9.8 Hz, 1H);
12.10 (spread m, 1 H) Retention time Tr 63b (min) = 0.1; [M + H] +:
m / z 185 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.93 (t, J = 7.1 [M + H] +: m / z 520; [M-Hz, 6H); 2.19 (s, 3H); 2.43 (q, J = 7.0 Hz, 4H);
3.46 (s, 2H); 7.08 64H] -: m / z 518 (dd, J = 1.7 and 8.1 Hz, 1H); 7.21 to 7.38 (m, 5H); 7.58 (d, J = 8.3 Hz, 1H); 7.86 (d, J = 1.7 Hz, 1H); 8.46 (d, J = 9.8 Hz, 1H); 12.37 (m spread, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.93 (t, J = 7.1 [M + H] +: m / z 550; [M-Hz, 6H); 2.43 (q, J = 7.1 Hz, 4H); 3.37 (s, 3H);
3.46 (s, 2H); 4.19 65H] -: m / z 548 (s, 2H); 7.03 to 7.10 (m, 1H); 7.21 to 7.34 (m, 4H); 7.36 (d, J = 9.8 Hz, 1H); 7.60 (d, J = 8.6 Hz, 1H); 7.87 (d, J = 1.7 Hz, 1H); 8.46 (d, J = 9.8 Hz, 1H); 12.34 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d6): 1.55 (dd, J = 9.3 Hz, 1H); 1.73 (dd, J = 2.0 and 9.3 Hz, 1H); 2.39 (d, J = 9.9 Hz, 1H); 2.70 (dd, J = 1.7 and 9.9 Hz, 1H); 3.37 (s, 3H); 3.41 (s large, 1 66 [M + H] +: m / z 576; [M-H]; 3.49 (dd, J = 1.7 and 7.6 Hz, 1H); 3.61 (d, J = 14.0 Hz, 1H); 3.67 H 1: m / z 574 (d, J = 14.0 Hz, 1H); 3.87 (d, J = 7.6 Hz, 1H); 4.20 (s, 2H);
4.29 (s broad, 1H); 7.03 to 7.13 (m, 1H); 7.22-7.34 (m, 4H); 7.36 (d, J = 9.8 Hz, 1H); 7.61 (d, J = 8.3 Hz, 1H); 7.87 (d, J = 1.7 Hz, 1H);
8.46 (d, J = 9.8 Hz, 1H); 12.38 (spread m, 1H) 1H NMR spectrum (400MHz, δ ppm, DMSO-d6): 4.53 (m, 2H);
67 [M + H] +: m / z 373; [M-4.81 (m, 2H); 5.40-5.55 (m, 1H); 7.17 (d, J = 10.3 Hz, 1H); 7.22 H] -: m / z 371-7.36 (m, 2H); 7.61 (bs, 2H); 7.82 (brs, 1H);
8.34 (d, J = 9.8 Hz, 1H) Retention time Tr 67b (min) = 0.41; [M + H] +:
m / z 227 NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 1.91 to 2.05 (m, 68 [M + H] +: m / z 514; [M-1H]; 2.08 to 2.20 (m, 1H); 2.53 (m, 4H); 3.34 (s, 2H); 3.58 to H, m / z 512 3.63 (m, 4H); 3.65 to 3.82 (m, 4H); 5.30 (m, 1H); 7.08 (d, J = 9.8 Hz, 1H); 7.47 (dd, J = 2.1 and 8.6 Hz, 1H); 7.70 (d, J = 8.6 Hz, 1H);
8.12 (d, J = 2.1 Hz, 1H); 8.31 (d, J = 9.8 Hz, 1H); 12.16 (spread m, 1 H) NMR'H spectrum (400MHz, δ ppm, DMSO-d6): 2.53 (m, 4H) [M + H] +: m / z 556; [M-3.32 (s, 2H); 3.56 to 3.63 (m, 4H); 7.12 to 7.24 (m, 3 H); 7.32 (dd, 69H] -: m / z 554 J = 2.0 and 8.6 Hz, 1H); 7.41 (d, J = 9.8 Hz, 1H); 7.58 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1H); 8.51 (d, J = 9.8 Hz, 1H); 10.47 to 13.46 (very m, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 1.00 (t, J = 7.1 Hz, 6H); 1.90 to 2.03 (m, 1H); 2.07 to 2.22 (m, 1H); 2.62 (q, J = 7.1 70 [M + H] +: m / z 500 Hz, 4H); 3.40 (s, 2H); 3.63 at 3.84 (m, 4H); 5.29 (m, 1H); 7.08 (d, J = 9.8 Hz, 1H); 7.47 (dd, J = 2.0 and 8.3 Hz, 1H); 7.69 (d, J = 8.3 Hz, 1H); 8.12 (d, J = 2.0 Hz, 1H); 8.31 (d, J = 9.8 Hz, 1H); 12,11 (m spread, 1H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.98 (t, J = 7.1 [M + H] +: m / z 541; Hz, 3H); 1.92 to 2.03 (m, 1H); 2.10 to 2.22 (m, 1H);
2.31 (q, J = 7.1 [M + 2H] 2 +: m / z 271 Hz, 2H); 2.22 to 2.48 (partially masked wide m, 8 H) ; 3.30 (s 71 (base peak); [MH] -: partially masked, 2H); 3.64 to 3.84 (m, 4H);
5.30 (m, 1H);
m / z 539 7.08 (d, J = 9.8 Hz, 1H); 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); 8.31 (d, J = 9.8 Hz, 1H);
11.96 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.22 to 0.30 (m, [M + H] +: m / z 553 2H); 0.36 to 0.43 (m, 2H); 1.54 to 1.64 (m, 1H); 1.90 to 2.03 (m, 1 [M + 2H] 2 +: m / z 277H); 2.06 to 2.19 (m, 1H); 2.40 to 2.60 (m wide partially 72 (base peak); [MH] -: masked, 8H); 3.36 (partially masked m, 2H);
3.64 to 3.83 (m, m / z 551 4H); 5.30 (m, 1H) 7.08 (d, J = 9.8 Hz, 1H); 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); 8.31 (d, J = 9.8 Hz, 1H); 10.51 to 13.65 (m very spread, 1 hour) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.90 to 0.98 (m, [M + H] +: m / z 441; [M-4H]; 1.94 to 2.04 (m, 1H); 4.47 (m, 2H); 4.71 (m, 2H); 5.39 to 73H] -: m / z 439 5.48 (m, 1H); 7.19 (d, J = 9.8 Hz, 1H); 7.44 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.69 (d, J = 8.6 Hz, 1H); 8.05 (d, J = 2.0 Hz, 1H); 8.37 (d, J = 9.8 Hz, 1H); 12.68 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.97 (t, J = 7.1 [M + H] +: m / z 527; Hz, 3H); 2.30 (q, J = 7.1 Hz, 2H); 2.32 to 2.57 (m wide 74 [M + 2H] 2 +: m / z 264 partially masked, 8H); 3.31 (s, 2H); 4.46 (m, 2 H); 4.70 (m, (base peak); [MH] -: 2H); 5.42 (m, 1H); 7.20 (d, J = 9.8 Hz, 1H); 7.44 (dd, J = 2.0 and 8.6 m / z 525 Hz, 1H); 7.70 (d, J = 8.6 Hz, 1H); 8.06 (d, J = 2.0 Hz, 1H); 8.38 (D, J = 9.8 Hz, 1H); 12.03 (spread m, 1 H) NMR spectrum (400 MHz, 6 ppm, DMSO-d 6): 0.23 to 0.29 (m, [M + H] +: m / z 539; 2H); 0.35 to 0.42 (m, 2H); 1.60 (m, 1H); 2.40 to 2.60 (m large 75 [M + 2H] 2 +: m / z 270 partially masked, 8H); 3.31 (s, 2H); 4.46 (m, 2 H); 4.70 (m, (base peak); [MH] -: 2H); 5.42 (m, 1H); 7.20 (d, J = 9.8 Hz, 1H); 7.44 (dd, J = 2.0 and 8.6 m / z 537Hz, 1H); 7.70 (d, J = 8.6 Hz, 1H); 8.06 (d, J = 2.0 Hz, 1H); 8.38 (D, J = 9.8 Hz, 1H); 12.09 (spread m, 1 H) Example 76: Pharmaceutical composition Tablets having the following formula were prepared:

Product of Example 2 ....................... 0.2 g Excipient for a tablet finished at .......... 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

Example 77: Pharmaceutical composition Tablets having the following formula were prepared Product of Example 5 ....................... 0.2 g Excipient for a tablet finished at .......... 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

Examples 2 and 5 are taken as examples of 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 and C

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:

1 OmM Tris, pH 7.4 HCl, 100 mM NaCl, 1 mM EDTA, 1 mM 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 ++ ++ ++
5 ++ ++ ++
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 + ++

106 1) Products of formula (I):

NOT
N ~ _1X AH
NOT
N Rb W

(I) Ra in which represents a single or double bond;

Rb represents a hydrogen atom or a fluorine atom;
Ra represents a radical -OZ-Rc in which:
Z represents a single bond or a linear or branched alkylene radical containing from 1 to 6 carbon atoms and optionally substituted by a alkyl group or a halogen atom;
Rc represents a cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical optionally substituted, X is S, SO or SO2;
A represents NH or S;

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

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

Claims (31)

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 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, with the possible S being able to be optionally in SO or SO2 form; this radical including the eventual NH it contains being optionally 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, optionally phenyl substituted; or else R3 and R4 form with the nitrogen atom to which they are bound a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N and NH, with the possible S possibly being in the form SO or SO2; this radical including the eventual NH it contains being optionally substituted;

all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as radicals cyclic that can be formed R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, possibly being substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, oxo radicals, alkoxy, -O-CO-R5, -OR5 -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5 ', -NH-CO-R5, -NHCOOR5 and alkyl radicals, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH 2 -phenyl, CO-phenyl, heteroaryl and S-heteroaryl, such as in these radicals, the radicals alkyl, alkoxy, heterocycloalkyl, phenyl and heteroaryl are themselves optionally substituted with one or 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;
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;
Being heard that :
i) when R b represents Hydrogen and Z represents a single bond, then R c is not a cycloalkyl radical; and ii) when R b represents Hydrogen and Z represents an alkylene radical, then R c does not represent a heterocycloalkyl radical;

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;

R a represents a radical -OZR c in which Z represents a single bond and R c represents optionally substituted aryl;
R b represents a hydrogen or fluorine atom;
X represents S, SO or SO2;

A represents NH or S;

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

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

an alkoxy radical optionally substituted 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 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, with the possible S being able to be optionally in SO or SO2 form; this radical including the eventual NH it contains being optionally substituted;

with R3 and R4, identical or different, represent a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical all optionally substituted with one or more identical or different radicals chosen from the radicals hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, N (Alk) 2 or optionally substituted phenyl; or else R3 and R4 form 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, with the optional S possibly being in the SO or SO2; this radical including the eventual NH it contains being possibly substituted;

all the radicals defined above alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl as well as radicals cyclic that can be formed R1 and R2 or R3 and R4 with the nitrogen atom to which they are linked, possibly being substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, oxo radicals, alkoxy, -O-CO-R5, -OR5, NH2, NHalk, N (alk) 2 and alkyl radicals, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, 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;

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 claims in which ~, Ra, Rb and X have the values defined in any of the other claims and:

A represents NH or S;

W represents a hydrogen atom; an alkyl radical 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, -O-cycloalkyl, -O-CO-R5, 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 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 it contains being optionally substituted;

with NR3R4 such that R3 and R4, which are identical or different, represent a hydrogen atom, an alkyl radical or a heterocycloalkyl radical optionally substituted with one or more identical radicals or various selected from alkoxy, heteroaryl, heterocycloalkyl radicals or NH2, NHAlk, N (Alk) 2, or R3 and R4 together with the nitrogen atom they are linked to a cyclic radical containing from 3 to 10 members and optionally one or more other heteroatoms selected from O, S, N

and NH, this radical including the eventual NH it contains being possibly substituted;

all the radicals alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl 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, defined above, being optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, alkoxy, O-cycloalkyl, NH 2 radicals, NHalk, N (alk) 2 and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH 2 -phenyl and heteroaryl, as in these radicals, alkyl, heterocycloalkyl, phenyl and heteroaryl are themselves optionally 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). 4) Products of formula (I) as defined in any one of claims in which ~, Ra, Rb and X have the values defined in any of the other claims and:

A represents NH or S;

W represents a hydrogen atom; an alkyl radical 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, -O-cycloalkyl, NH2, NHalk, N (alk) 2 and alkyl radicals and phenyl, the latter being themselves optionally substituted by a or more radicals selected from halogen atoms and radicals hydroxyl, 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 wherein A is NH, the substituents ~, Ra, Rb, 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). 6) Products of formula (I) as defined in any one of wherein A is S, the substituents , Ra, Rb, X and W being chosen from all the values defined for these radicals at any of the other claims, said products of formula (I) being in all possible isomeric 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). 7) Products of formula (I) as defined in any one of the claims having formula (Ia) or (Ib) in which , Ra, Rb, and W are selected from among the meanings indicated in 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 claims in which represents a double bond answering to the products of formula (I "):

wherein the substituents Ra, Rb, X, A and W have any one of the meanings given above or below, 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 (I) as defined in any one of the claims in which represents a double bond answering with the products of formula (I "a):

wherein Ra, Rb, and W are selected from any one of the meanings given above or below, 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 (I) as defined in any one of the claims in which represents a double bond answering with products of formula (I "b) wherein Ra, Rb and W are selected from any one of the meanings given above or below, 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 claims in which represents a single or double bond Ra represents an -O-phenyl radical optionally substituted with one or several halogen atoms;
Rb represents a hydrogen atom;
X is S;

A represents S;

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

a cycloalkyl radical, or an alkyl radical;

or the radical NR1 R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom, and the other of R1 and R2 represents a alkyl radical optionally substituted with a heterocycloalkyl radical;
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) The subject of the present invention is thus the products of formula (I) such as defined above or below with the following formulas:

-6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol amine N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide N- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide 1- [2- (Morpholin-4-yl) ethyl] -3- {6 - [(6-phenoxy [1,2,4] triazolo [4,3-b] pyridazin) yl) sulfanyl] -1,3-benzothiazol-2-yl} urea 1- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (2-methoxyethoxy) acetamide N2, N2-diethyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N 2 -cyclopropyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N- [6 - ({6- [3- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3 yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 1- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (3-Fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) -ethyl] -urea 6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3}
yl] sulfanyl} -1,3-benzothiazol-2-amine 6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine 1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydro-2H-pyran-4-) yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea 1- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3 yl} sulfanyl) -1,3-benzothiazol-2-yl] -3- [2- (4-morpholin-yl) ethyl] urea N- (6 - {[6- (tetrahydro-2H-pyran-4-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (4-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3-fluoro-4-methylphenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- [6 - ({6 - [(1-ethylpiperidin-4-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide 1- [2- (Morpholin-4-yl) ethyl] -3- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) urea 1- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 1- (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea 6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine 6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3}
yl] sulfanyl} -1,3-benzothiazol-2-amine 1- (6 - {[6- (1H-Indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) -3- [2- (morpholin-4-yl) ethyl] urea N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (1,3-benzodioxol-5-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3,4-dichlorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (1H-indol-6-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-yl) cyclopropanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-dimethylglycinamide 2-ethoxy-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (cyclohexyloxy) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin) yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine (6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-amine - [3 - ({3 - [(2-Amino-1,3-benzothiazol-6-yl) sulfanyl] [1,2,4] triazolo [4,3-b] pyridazin 2-methylpropan-2-yl 6-yl} oxy) phenyl] carbamate N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclobutanecarboxamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide N 2 -cyclohexyl-N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2-methyl-N2- [2- (morpholin-4-yl) ethyl] glycinamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3 benzothiazol-2-amine 6 - {[6- (3-aminophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N-2 ~ - (tetrahydro-2H-pyran-4-yl) glycinamide N- [6 - ({6- [4- (trifluoromethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6- [3- (trifluoromethoxy) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide N- [6 - ({6 - [(2-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 2 - [(6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-acetate yl] sulfanyl} -1,3-benzothiazol-2-yl) amino] -2-oxoethyl -N- [6 - ({6 - [(6-methylpyridin-3-yl) oxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide -N- [6 - ({6- [4- (morpholin-4-ylmethyl) phenoxy] [1,2,4] triazolo [4,3-b] pyridazin-3-yl} sulfanyl) -1,3-benzothiazol-2-yl] cyclopropanecarboxamide - (3 - {[3 - ({2 - [(cyclopropylcarbonyl) amino] -1,3-benzothiazol-6-yl} sulfanyl) [1,2,4] triazolo [4,3-b] pyridazin-6-yl] oxy} phenyl) carbamate of 2-methylpropan-2-yl -N- (6 - {[6- (pyridin-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide -N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} cyclopropanecarboxamide -N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3-benzothiazol-2-yl} cyclopropanecarboxamide -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -N2, N2-diéthylglycinamide -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2-hydroxyacetamide -2- (4-cyclopropylpipérazin-1-yl) -N- (6 - {[6- (3-fluorophenoxy) [1,2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (4-ethyl-piperazin-1-yl) acetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol 2-yl) acetamide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} acetamide N- {6 - [(6- {3 - [(diethylamino) methyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3 yl) sulfanyl] -1,3-benzothiazol-2-yl} -2-methoxy-acetamide 2-methoxy-N- {6 - [(6- {3 - [(1S, 4S) -2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl] phenoxy} [1,2,4] triazolo [4,3-b] pyridazin-3-yl) sulfanyl] -1,3 benzothiazol-2-yl} acetamide 6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-amine 2- (morpholin-4-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N - (6 - {[6- (3,5-difluorophenoxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) -2- (morpholin-4-yl) acetamide N2, N2-diethyl-N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin 3-yl] sulfanyl} -1,3-benzothiazol-2-yl) glycinamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3 b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (4-cyclopropylpiperazin-1-yl) -N- (6 - {[6- (tetrahydrofuran-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide N- (6 - {[6- (Oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) cyclopropanecarboxamide 2- (4-ethylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 2- (4-Cyclopropylpiperazin-1-yl) -N- (6 - {[6- (oxetan-3-yloxy) [1,2,4] triazolo [4,3-b] pyridazin-3-yl] sulfanyl} -1,3-benzothiazol-2-yl) acetamide 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 addition salts with mineral and organic acids or with mineral bases and pharmaceutically acceptable organic compounds 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 of the following:
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) Use as defined in claim 19 wherein the protein kinase is in a cell culture. 21) The use as defined in claim 19 or 20 wherein the protein kinase is in a mammal. 22) Use of a product of formula (I) as defined in any one of 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. 26) 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. 30) Products of formula (I) as defined in any one of Claims 1 to 12 as MET inhibitors. 31) As new industrial products, synthesis intermediates of formulas M1, M2, M3 and N with Rb represents a fluorine atom F, such that defined below:

in which the groups CONR1R2, CO2R6 and COR7, which constitute W, can take the values of W as defined in any of the Claims 1 to 11 for the products of formulas (I ') and (I "), when W ~ H.