AU2010212232A1

AU2010212232A1 - Derivatives of 6-(6-O-substituted-triazolopyridazine-sulfanyl) benzothiazoles and benzimidazoles, preparation thereof, use thereof as drugs, and use thereof as MET inhibitors

Info

Publication number: AU2010212232A1
Application number: AU2010212232A
Authority: AU
Inventors: Eric Bacque; Dominique Damour; Conception Nemececk; Antonio Ugolini; Sylvie Wentzler
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 2009-02-06
Filing date: 2010-02-04
Publication date: 2011-08-25
Also published as: FR2941950B1; BRPI1008232A2; CA2750875A1; IL214406A0; SG173559A1; CN102378759A; UY32420A; CL2011001879A1; TW201031670A; WO2010089507A1; AR075249A1; JP2012517408A; EP2393791A1; FR2941950A1; CO6400223A2; MX2011008319A; EA201171011A1; KR20110132560A; MA33107B1

Abstract

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

Description

WO 2010/089507 PCT/FR2010/050178 DERIVATIVES OF 6

-(

6 -0-SUBSTITUTED-TRIAZOLOPYRIDAZINE-SULFANYL) BENZOTHIAZOLES AND BENZIMIDAZOLES, PREPARATION THEREOF, USE THEREOF AS DRUGS, AND USE THEREOF AS MET INHIBITORS 5 The present invention relates to novel 6 -(6-O-substituted triazolopyridazine sulfanyl) benzothiazole and benzimidazole derivatives, to a process for preparing them, to the novel intermediates obtained, to their use as medicaments, to pharmaceutical compositions containing them and to the novel use of such 6 -triazolopyridazine-sulfanyl benzothiazole and 10 benzimidazole derivatives. The present invention more particularly relates to novel 6-( 6 -0-substituted triazolopyridazine-sulfanyl) benzothiazole and benzimidazole derivatives with anticancer activity, via modulation of the activity of proteins, in particular 15 kinases. To date, most of the commercial compounds used in chemotherapy are cytotoxic and pose major problems of side effects and tolerance by patients. These effects can be limited if the medicaments used act selectively on 20 cancer cells, to the exclusion of healthy cells. One of the solutions for limiting the undesirable effects of a chemotherapy may thus consist in using medicaments that act on metabolic pathways or constituent elements of these pathways, predominantly expressed in cancer cells, and not expressed or only sparingly expressed in healthy cells. Kinase proteins are a family of 25 enzymes that catalyse the phosphorylation of hydroxyl groups of specific protein residues such as tyrosine, serine or threonine residues. Such phosphorylations may widely modify the function of proteins: thus, kinase proteins play an important role in regulating a wide variety of cellular processes, especially including cell metabolism and proliferation, cellular 30 adhesion and motility, cell differentiation or cell survival, certain kinase WO 2010/089507 PCT/FR2010/050178 2 proteins playing a central role in the initiation, development and completion of cell cycle events. Among the various cellular functions in which the activity of a kinase protein is 5 involved, certain processes represent attractive targets for treating certain diseases. Examples that may especially be mentioned include angiogenesis and control of the cell cycle and also that of cell proliferation, in which kinase proteins may play an essential role. These processes are especially essential for the growth of solid tumours and also other diseases: in particular, 10 molecules that inhibit such kinases are capable of limiting undesired cell proliferations such as those observed in cancers, and can intervene in the prevention, regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or neuronal apoptosis. 15 One subject of the present invention is novel derivatives endowed with inhibitory effects on kinase proteins. The products according to the present invention may thus be used especially for preventing or treating diseases that can be modulated by inhibiting kinase proteins. 20 The products according to the present invention especially show anticancer activity, via modulation of the activity of kinases. Among the kinases for which activity modulation is desired, MET and also mutants of the protein MET are preferred. 25 The present invention also relates to the use of the said derivatives for preparing a medicament for treating man. Thus, one of the objects of the present invention is to propose compositions with anticancer activity, by acting in particular on kinases. Among the kinases 30 for which activity modulation is desired, MET is preferred.

WO 2010/089507 PCT/FR2010/050178 3 In the pharmacological section hereinbelow, it is shown in biochemical tests and on cell lines that the products of the present patent application thus especially inhibit the autophosphorylation activity of MET and the proliferation of cells whose growth is dependent on MET or mutants forms thereof. 5 MET, or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine kinase activity that is expressed in particular in epithelial and endothelial cells. HGF, Hepatocyte Growth Factor, is described as the specific ligand of MET. HGF is secreted by mesenchymal cells and activates the MET receptor, 10 which homodimerizes. Consequently, the receptor becomes autophosphorylated on tyrosines Y1230, Y1234 and Y1235 of the catalytic domain. Stimulation of MET with HGF induces cell proliferation, scattering (or 15 dispersion) and motility, resistance to apoptosis, invasion and angiogenesis. MET and likewise HGF are found to be overexpressed in many human tumours and a wide variety of cancers. MET is also found to be amplified in gastric tumours and glioblastomas. Many point mutations of the MET gene 20 have also been described in tumours, in particular in the kinase domain, but also in the juxtamembrane domain and the SEMA domain. Overexpression, amplification or mutations cause constitutive activation of the receptor and deregulation of its functions. 25 The present invention thus relates especially to novel inhibitors of the kinase protein MET and mutants thereof, which may be used for anti-proliferative and anti-metastatic treatment especially in oncology. The present invention also relates to novel inhibitors of the kinase protein 30 MET and mutants thereof, which may be used for anti-angiogenic treatment, especially in oncology.

WO 2010/089507 PCT/FR2010/050178 4 One subject of the present invention is the products of formula (1): N Rb N W \/I R a in which 5 represents a single or double bond; Rb represents a hydrogen atom or a fluorine atom; Ra represents a radical -O-Z-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 with an alkyl group or a 10 halogen atom; Rc represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical; X represents S, SO or S02; A represents NH or S; 15 W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: - a cycloalkyl radical or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -0-cycloalkyl, -O-CO-R5, hydroxyl, phenyl, 20 heteroaryl or heterocycloalkyl, which are themselves optionally substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyl; a radical 0-phenyl or a radical 0-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 25 4; - or the radical NR1 R2 in which RI and R2 are such that one from among RI and R2 represents a hydrogen atom, a cycloalkyl radical or WO 2010/089507 PCT/FR2010/050178 5 an alkyl radical and the other from among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from the following radicals: hydroxyl, alkoxy, 5 heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally substituted; or alternatively R1 and R2 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, with the optional S possibly being in the form SO or S02; this radical, including 10 the possible NH it contains, being optionally substituted; - with R3 and R4, which may be identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalky radical, a heteroaryl radical or a phenyl radical, all optionally substituted with one or more radicals, which may be identical or 15 different, chosen from the following radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, N(Alk)2 and phenyl, which is itself optionally substituted; or alternatively R3 and R4 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen 20 from 0, S, N and NH, with the optional S possibly being in the form SO or S02; this radical, including the possible NH it contains, being optionally substituted; all the alkyl, alkoxy, -0-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl and phenyl radicals defined above, and also the cyclic radicals that 25 may be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5 -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5', -NH-CO-R5, -NHCOOR5 and alkyl, heterocycloalkylalkyl, cycloalkyl, 30 heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl, WO 2010/089507 PCT/FR2010/050178 6 alkoxy, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkyl and alkoxy containing from I to 4 carbon atoms, NH2, NHalk and N(ak)2; 5 all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined above being furthermore optionally substituted with a radical Si(alk)3; R5 and R5', which may be identical or different, represent an alkyl or cycloalkyl radical containing not more than 6 carbon atoms; alk represents an alkyl radical containing not more than 4 carbon atoms; 10 it being understood that: i) when Rb represents hydrogen and Z represents a single bond, then Rc does not represent a cycloalkyl radical; and ii) when Rb represents hydrogen and Z represents an alkylene radical, then Rc does not represent a heterocycloalkyl radical; 15 the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (1). 20 A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, in which -- represents a single or double bond; Ra represents a radical -O-Z-Rc in which Z represents a single bond and Rc represents optionally substituted aryl; 25 Rb represents a hydrogen or fluorine atom; X represents S, SO or S02; A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in 30 which R represents: WO 2010/089507 PCT/FR2010/050178 7 - a cycloalkyl radical or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -0-cycloalkyl, -O-CO-R5, hydroxyl, phenyl, heteroaryl or heterocycloalkyl, which are themselves optionally substituted; 5 - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyl; a radical O-phenyl or a radical 0-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 4; - or the radical NR1 R2 in which R1 and R2 are such that one from 10 among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other from among RI and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from the following radicals: hydroxyl, alkoxy, 15 heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally substituted or alternatively R1 and R2 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, with the optional S possibly being in the form SO or S02; this radical, including 20 the possible NH it contains, being optionally substituted; with R3 and R4, which may be identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a heteroaryl radical or a phenyl radical all optionally substituted with one or more radicals, which may be identical or different, chosen from the following 25 radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, N(Alk)2 or phenyl, optionally substituted; or alternatively R3 and R4 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, with the optional S possibly being in the form SO or S02; this radical, 30 including the possible NH it contains, being optionally substituted; WO 20101089507 PCT/FR2010/050178 8 all the alkyl, alkoxy, -0-cycloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl and phenyl radicals defined above, and also the cyclic radicals that may be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted with one or more radicals S chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S heteroaryl radicals, such that in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally 10 substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkyl and alkoxy containing from I to 4 carbon atoms, NH2, NHalk and N(alk)2; R5 represents an alkyl or cycloalkyl radical containing not more than 6 carbon atoms; 15 the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (1). 20 A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, 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 optionally substituted with 25 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, -0-cycloalkyl, -O-CO-R5, hydroxyl, phenyl or heterocycloalkyl, which are themselves optionally substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or 30 heterocycloalkyl; a radical 0-phenyl or a radical 0-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from I to 4; WO 2010/089507 PCT/FR2010/050178 9 - or the radical NR1 R2, in which R1 and R2 are such that one from among R1 and R2 represents a hydrogen atom or an alkyl radical and the other from among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy or 5 heterocycloalkyl radical, or NR3R4; or alternatively R1 and R2 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; 10 with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical or a heterocycloalkyl radical, optionally substituted with one or more radicals, which may be identical or different, chosen from alkoxy, heteroaryl or heterocycloalkyl radicals or NH2, NHAlk, N(Alk)2, or alternatively R3 and R4 form, with the nitrogen atom to 15 which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; all the alkyl, alkoxy, -0-cycloalkyl, cycloalkyl, heterocycloalkyl and phenyl radicals, and also the cyclic radicals that may be formed by R1 and R2 or R3 20 and R4 with the nitrogen atom to which they are attached, defined above, being optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, alkoxy, 0-cycloakyl, NH2, NHalk, N(alk)2 and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals, the alkyl, 25 heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2; the said products of formula (I) being in any possible racemic, enantiomeric or 30 diastereoisomeric isomer form, and also the addition salts with mineral and WO 2010/089507 PCT/FR2010/050178 10 organic acids or with mineral and organic bases of the said products of formula (1). As regards the cyclic radicals that can be formed by RI and R2 or R3 and R4 5 with the nitrogen atom to which they are attached, these radicals optionally containing one or more other heteroatoms chosen from 0, S, N and NH, with the optional S possibly being in the form SO or S02; these radicals, including the optional NH they contain, may thus be optionally substituted especially with a radical chosen from alkyl, alkoxy, cycloalkyl and heterocycloalkyl, 10 which are themselves optionally substituted with one or more radicals chosen from halogen atoms and the radicals alkyl, alkoxy, NH2, NHAlk and N(Alk)2. One subject of the present invention is the products of formula (1): N Rb R a 15 in which represents a single or double bond; Rb represents a hydrogen atom or a fluorine atom; Ra represents a radical -O-Z-Rc in which: Z represents a single bond or a linear or branched alkylene radical containing 20 from I to 6 carbon atoms and optionally substituted with an alkyl group or a halogen atom; Rc represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical; X represents S, SO or S02; 25 A represents NH or S; WO 2010/089507 PCT/FR2010/050178 11 W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: a cycloalkyl radical or an alkyl radical, optionally substituted with a 5 radical NR3R4, alkoxy, hydroxyl, phenyl, heteroaryl or heterocycloalkyl, which are themselves optionally substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyl; a radical 0-phenyl or a radical 0-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 10 4; - or the radical NRIR2 in which RI and R2 are such that one from among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other from among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally 15 substituted with one or more radicals, which may be identical or different, chosen from the following radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally substituted or alternatively R1 and R2 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one 20 or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; with R3 and R4, which may be identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl radical, all optionally substituted, or alternatively R3 and R4 form, with the 25 nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; all the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl radicals 30 defined above, and also the cyclic radicals that may be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being WO 2010/089507 PCT/FR2010/050178 12 optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, -COOH, COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5', -NH-CO-R5 and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl,

CO

5 phenyl, heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2, 10 all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined above being furthermore optionally substituted with a radical Si(alk)3; R5 and R5', which may be identical or different, represent an alkyl or cycloalkyl radical containing not more than 6 carbon atoms; alk represents an alkyl radical containing not more than 4 carbon atoms; 15 it being understood that: i) when Rb represents hydrogen and Z represents a single bond, then Rc does not represent a cycloalkyl radical; and ii) when Rb represents hydrogen and Z represents an alkylene radical, then Rc does not represent a heterocycloalkyl radical; 20 the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 25 A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, in which represents a single or double bond; Ra represents a radical -O-Z-Rc in which Z represents a single bond and Rc represents optionally substituted aryl; 30 Rb represents a hydrogen or fluorine atom; X represents S, SO or S02; WO 2010/089507 PCT/FR2010/050178 13 A represents NH or S; W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: 5 - a cycloalkyl radical or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, hydroxyl, phenyl, heteroaryl or heterocycloalkyl, which are themselves optionally substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyl; a radical 0-phenyl or a radical 0-(CH2)n-phenyl, 10 with phenyl optionally substituted and n represents an integer from 1 to 4; - or the radical NR1R2 in which RI and R2 are such that one from among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other from among R1 and R2 represents a 15 hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, chosen from the following radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally substituted or alternatively R1 and R2 form, with the nitrogen atom to which they are 20 attached, a 3- to 1 0-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; with R3 and R4, which may be identical or different, representing a hydrogen atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl 25 radical, which is optionally substituted, or alternatively R3 and R4 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; 30 WO 2010/089507 PCT/FR2010/050178 14 all the cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl radicals defined above, and also the cyclic radicals that may be formed by R1 and R2 or R3 and R4 with the nitrogen atom to which they are attached, being optionally substituted with one or more radicals chosen from halogen atoms 5 and the following radicals: hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more 10 radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2; R5 represents an alkyl or cycloalkyl radical containing not more than 6 carbon atoms; 15 the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (1). 20 A subject of the present invention is the products of formula (I) as defined hereinabove or hereinbelow, 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 optionally substituted with 25 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, hydroxyl, phenyl or heterocycloalkyl, which are themselves optionally substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or 30 heterocycloalkyl; a radical O-phenyl or a radical 0-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 4; WO 2010/089507 PCT/FR2010/050178 15 - or the radical NR1R2, in which R1 and R2 are such that one from among R1 and R2 represents a hydrogen atom or an alkyl radical and the other from among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy- or 5 heterocycloalkyl radical, or NR3R4; or alternatively R1 and R2 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; 10 with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or alternatively R3 and R4 form, with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being 15 optionally substituted; all the cycloalkyl, heterocycloalkyl and phenyl radicals, and also the cyclic radicals that may be formed by RI 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 chosen from halogen atoms and the following 20 radicals: hydroxyl, alkoxy, 0-cycloalkyl, NH2, NHalk, N(alk)2 and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals 25 containing from I to 4 carbon atoms, NH2, NHalk and N(alk)2; the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 30 WO 2010/089507 PCT/FR2010/050178 16 A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, in which , Ra, Rb and X have the values defined in any one of the other claims, and: A represents NH or S; 5 W represents a hydrogen atom; an alkyl radical optionally 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 radical O-phenyl or O-(CH2)n-phenyl, with phenyl optionally 10 substituted and n represents an integer from 1 to 2; - or the radical NR1R2, in which R1 and R2 are such that one from among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical and the other from among R1 and R2 represents a hydrogen atom, an alkyl radical optionally substituted with a heterocyclic radical or 15 NR3R4, or alternatively R1 and R2 form, with the nitrogen atom to which they are attached, a cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; with NR3R4 such that R3 and R4, which may be identical or different, 20 represent a hydrogen atom or an alkyl radical or alternatively R3 and R4 form, with the nitrogen atom to which they are attached, a cyclic radical optionally containing one or more other heteroatoms chosen from 0, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; all the cycloalkyl, heterocyclic and phenyl radicals, and also the cyclic radicals 25 that may be formed by 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 chosen from halogen atoms and the following radicals: hydroxyl, alkoxy, 0-cycloalkyl, NH2, NHalk, N(alk)2 and alkyl and phenyl radicals, the latter radicals themselves being optionally substituted with one or 30 more radicals chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2; WO 2010/089507 PCT/FR2010/050178 17 the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (1). 5 A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, in which A represents NH, the substituents , Ra, Rb, X and W being chosen from all the values defined for these radicals in any one of the other claims, the said products of formula 10 (1) being in any possible racemic, enantiomeric or diastereolsomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (1). A subject of the present invention is the products of formula (1) as defined 15 hereinabove or hereinbelow, in which A represents S, the substituents , Ra, Rb, X and W being chosen from all the values defined for these radicals in any one of the other claims, the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic 20 bases of the said products of formula (1). One subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow corresponding to formula (la) or (Ib): S N H N b N W Ra (la) 25 WO 2010/089507 PCT/FR2010/050178 18 N N NR a Ra (1b) in which , Ra, Rb and W are chosen from the meanings indicated in any one of the other claims, 5 the said products of formula (la) and (Ib) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formulae (la) and (lb). 10 A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, in which represents a single bond, corresponding to the products of formula (I'): N NN W Rb Ra (I') the substituents Ra, Rb, X, A and W having any one of the meanings 15 indicated hereinabove or hereinbelow, the said products of formula (I) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 20 A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, in which represents a double bond, corresponding to the products of formula (1"): WO 2010/089507 PCT/FR2010/050178 19 N X I A H N / N Rb N W Ra in which the substituents Ra, Rb, X, A and W have any one of the meanings indicated hereinabove or hereinbelow, the said products of formula (1) being in any possible racemic, enantiomeric or 5 diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (1). A subject of the present invention is the products of formula (1) as defined 10 hereinabove or hereinbelow, in which represents a single bond, corresponding to the products of formula (la'): NX S H NN NN /N \H NRb N W R a (I'a) in which Ra, Rb and W are chosen from any one of the meanings indicated 15 hereinabove or hereinbelow, the said products of formula (l'a) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (Pa). 20 WO 2010/089507 PCT/FR2010/050178 20 A subject of the present invention is the products of formula (I) as defined hereinabove or hereinbelow, in which - represents a double bond, corresponding to the products of formula (l"a): A H NZ N N H N / \ NRb W Ra (l"a) 5 in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, the said products of formula (l"a) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and 10 organic acids or with mineral and organic bases of the said products of formula (l"a). A subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow, in which represents a single bond, 15 corresponding to the products of formula (l'b): "I -" SS H \NRb N W R a (l'b) in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, 20 the said products of formula (I'b) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I'b).

WO 2010/089507 . PCT/FR2010/050178 21 A subject of the present invention is the products of formula (I) as defined hereinabove or hereinbelow, in which - represents a double bond, corresponding to the products of formula (I"b): N NSNRb N 5 R a (l"b) in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, the said products of formula (l"b) being in any possible racemic, enantiomeric 10 or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (l"b). In the products of formula (1) and in the text hereinbelow: 15 - the term alkyl radical (or Alk) denotes linear and, where appropriate, branched methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl radicals, and also the linear or branched positional isomers thereof: alkyl radicals containing from 1 to 6 carbon atoms and more particularly alkyl 20 radicals containing from 1 to 4 carbon atoms of the above list are preferred; - the term alkoxy radical denotes linear and, where appropriate, branched methoxy, ethoxy, propoxy or isopropoxy, secondary or tertiary linear butoxy, pentoxy or hexoxy, and also the linear or branched positional isomers thereof: alkoxy radicals containing from 1 to 4 carbon atoms of the above list are 25 preferred; - the term halogen atom denotes a chlorine, bromine, iodine or fluorine atom and preferably the chlorine, bromine or fluorine atom.

WO 2010/089507 PCTIFR2010/050178 22 - the term cycloalkyl radical denotes a saturated carbocyclic radical containing 3 to 10 carbon atoms and thus especially denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals and most particularly cyclopropyl, cyclopentyl and cyclohexyl radicals; 5 - the term heterocycloalkyl radical thus denotes a 3- to 10-membered monocyclic or bicyclic carbocyclic radical interrupted with one or more heteroatoms, which may be identical or different, chosen from oxygen, nitrogen and sulfur atoms: examples that may be mentioned include morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl, 10 homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahyd roth ienyl, tetra hydropyra nyl, tetrahydrothiopyranyl and oxodihydropyridazinyl radicals, or alternatively oxetanyl or thietanyl radicals, all these radicals being optionally substituted; it may be noted that these heterocycloalkyl radicals may comprise a bridge formed from two ring 15 members to form, for example, an oxa-5-azabicyclo[2.2.1]heptane or an azaspiro[3.3]heptane radical or other azabicycloalkane or azaspiroalkane rings. - the terms aryl and heteroaryl denote unsaturated or partially unsaturated monocyclic or bicyclic, carbocyclic and heterocyclic radicals, respectively, 20 which are not more than 12-membered, possibly containing a -C(O) ring member, the heterocyclic radicals containing one or more heteroatoms, which may be identical or different, chosen from 0, N and S with N, where appropriate, being optionally substituted; - the term aryl radical thus denotes 6- to 12-membered monocyclic or bicyclic 25 radicals, for instance phenyl, naphthyl, biphenyl, indenyl, fluorenyl and anthracenyl radicals, more particularly phenyl and naphthyl radicals and even more particularly the phenyl radical. It may be noted that a carbocyclic radical containing a -C(O) ring member is, for example, the tetralone radical; it may also be noted that the aryl radical such as phenyl may be optionally 30 substituted, for example, with two alkoxy radicals to form a benzodioxolyl radical, which is itself optionally substituted as indicated for the aryl radical; WO 20101089507 PCT/FR2010/050178 23 - the term heteroaryl radical thus denotes 5- to 12-membered monocyclic or bicyclic radicals: monocyclic heteroaryl radicals, for instance 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 5 and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such as 3- or 4-isoxazolyl, furazanyl, free or salified tetrazolyl, all these radicals being optionally substituted, among which more particularly are thienyl radicals such as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl, 10 imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridyl and pyridazinyl, these radicals being optionally substituted; bicyclic heteroaryl radicals, for instance benzothienyl radicals such as 3-benzothienyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, quinolone, tetralone, adamantyl, benzofuryl, isobenzofuryl, dihydrobenzofuryl, ethylenedioxyphenyl, thianthrenyl, 15 benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl, azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydro cyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydro pyridinopyrazolyl or oxodihydropyridinopyrazolyl, all these radicals being 20 optionally substituted. As examples of heteroaryl or bicyclic radicals, mention may be made more particularly of pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyl radicals, optionally substituted with one or more identical or different 25 substituents as indicated above. It may be noted that two substituents on the cycloalkyl, heterocycloalkyl, heteroaryl, aryl and phenyl radicals, and also on the cyclic radicals that may be formed by RI and R2 or R3 and R4, respectively, with the nitrogen atom to 30 which they are attached, may optionally form a ring of cycloalkyl or WO 2010/089507 PCT/FR2010/050178 24 heterocycloalkyl type, depending on the case and the usual techniques known to those skilled in the art. The carboxyl radical(s) of the products of formula (1) may be salified or 5 esterified with various groups known to those skilled in the art, among which examples that may be mentioned include: - among the salification compounds, mineral bases such as, for example, one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium, or organic bases, for instance methylamine, propylamine, trimethylamine, 10 diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methyl glucamine, - among the esterification compounds, alkyl radicals to form alkoxycarbonyl 15 groups, for instance methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals possibly being substituted with radicals chosen, for example, from halogen atoms and hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino and aryl radicals, for instance in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxym ethyl, methylthiomethyl, 20 dimethylaminoethyl, benzyl or phenethyl groups. The addition salts with mineral or organic acids of the products of formula (1) may be, for example, the salts formed with hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic, 25 benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic or ascorbic acid, alkylmonosulfonic acids, for instance methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, alkyldisulfonic acids, for instance methanedisulfonic acid, a,0-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid, and aryldisulfonic acids. 30 WO 20101089507 PCT/FR2010/050178 25 It may be recalled that stereoisomerism may be defined in its broadest sense as isomerism of compounds having the same structural formulae, but whose various groups are arranged differently in space, especially such as in monosubstituted cyclohexanes in which the substituent may be in an axial or 5 equatorial position, and the various possible rotational conformations of ethane derivatives. However, another type of stereoisomerism exists, due to the various spatial arrangements of fixed substituents, either on double bonds, or on rings, which is often referred to as geometrical isomerism or cis trans isomerism. The term stereoisomers is used in the present patent 10 application in its broadest sense and thus concerns all the compounds indicated above. The cyclic radicals that may be formed, on the one hand, by RI and R2 with the nitrogen atom to which they are attached, and, on the other hand, by R3 15 and R4 with the nitrogen atom to which they are attached, are optionally substituted with one or more radicals chosen from those indicated above for the possible substituents on the heterocycloalkyl radicals, i.e. one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, NH2; NHalk, N(alk)2, and alkyl, heterocycloalkyl, CH2 20 heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl and CO-phenyl radicals, such that in the latter radicals the alkyl, heterocycloalkyl and phenyl radicals are themselves optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4 carbon atoms, NH2; NHalk and N(alk)2. 25 The cyclic radicals that may be formed, on the one hand, by R1 and R2 with the nitrogen atom to which they attached, and, on the other hand, by R3 and R4 with the nitrogen atom to which they are attached, are especially optionally substituted with one or more identical or different radicals chosen 30 from halogen atoms and alkyl, hydroxyl, alkoxy, CH2-pyrrolidinyl, CH2 phenyl, heteroaryl and phenyl radicals, in which the alkyl, pyrrolidinyl and WO 2010/089507 PCT/FR2010/050178 26 phenyl radicals are themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl, oxo and alkoxy radicals. 5 The heterocycloalkyl radicals as defined above especially represent azepanyl, morpholinyl, pyrrolidinyl, piperidyl and piperazinyl radicals, which are themselves optionally substituted, as defined hereinabove or hereinbelow. When NR1R2 or NR3R4 forms a ring as defined above, such an amine ring 10 may be chosen especially from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholinyl and piperazinyl radicals, these radicals themselves being optionally substituted as indicated hereinabove or hereinbelow: for example with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and 15 CH2-phenyl radicals, the alkyl or phenyl radicals themselves being optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals. The ring NR1R2 or NR3R4 may be chosen more particularly from pyrrolidinyl 20 and morpholinyl radicals optionally substituted with one or two alkyl or piperazinyl radicals optionally substituted on the second nitrogen atom with an alkyl, phenyl or CH2-phenyl radical, which are themselves optionally substituted with one or more identical or different radicals chosen from halogen atoms and alkyl, hydroxyl and alkoxy radicals. 25 A subject of the present invention is especially the products of formula (1) as defined hereinabove or hereinbelow in which Rb represents a fluorine atom, the other substituents of the said products of formula (1) having any one of the definitions indicated hereinabove or hereinbelow. 30 WO 2010/089507 PCT/FR2010/050178 27 A subject of the present invention is especially the products of formula (1) as defined hereinabove or hereinbelow, in which Ra represents a radical -0 phenyl optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, alkoxy, 0-cycloalkyl, alkyl and 5 CF3, the other substituents of the said products of formula (1) having any one of the definitions indicated hereinabove or hereinbelow. A subject of the present invention is the products of formula (I) as defined hereinabove or hereinbelow, in which 10 represents a single or double bond Ra represents a radical -0-phenyl optionally substituted with one or more halogen atoms; Rb represents a hydrogen atom; X represents S; 15 A represents S; W represents a hydrogen atom; or the radical COR in which R represents: - a cycloalkyl radical or an alkyl radical; or the radical NR1 R2 in which R1 and R2 are such that one from among R1 and R2 represents a hydrogen atom, and the other from among R1 and R2 20 represents an alkyl radical optionally substituted with a heterocycloalkyl radical; the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of 25 formula (I). A subject of the present invention is thus the products of formula (1) as defined hereinabove or hereinbelow, corresponding to the following formulae: - 6-[(6-phenoxy[1,2,4ltriazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2 30 amine Wa 2010/089507 PCT/FR2O1 0/050178 28 - N-{6-[(6-phenoxy[1 ,2 ,4]triazolo[4 ,3-b]pyridazin-3-yI)sulfanyl]- 1,3-benzo th iazol-2-yIlcyclopropaneca rboxam ide - N-{6-[(6-phenoxy[1 ,2 ,4jtriazolo[4 ,3-b]pyridazin-3-yI)sulfanyl]-1I,3-benzo th jazo l-2-yIlacetam ide 5 - I -[2-(morpholi n-.4-yI)ethyl]-3-{6-[(6-phenoxy[1 ,2 ,4] triazolo[4 ,3-b] pyridazin-3 yi)sulfanyl]-1 ,3-benzothiazol-2-yllurea - I -(6-{[6-(3-fluorop henoxy)[1 ,2 ,4]triazolo[4 ,3-b] pyridazin-3-yI]sulfanyl}- 1,3 benzoth iazoi-2-yI)-3-[2-(morpholn.4-y)ethyl] urea -6-{[6-(3-fluorophenoxy)[1 ,2 ,4]triazolo[4 ,3-blpyridazi n-3-yl]sulfa nyl}-1 ,3 10 benzothiazol-2-amjne - N-(6-{ [6-(3-fluorophenoxy)[1,2 ,4]triazoloj4 ,3-b] pyridazin-3-yljsu Itanyl}- 1,3 benzoth iazol-2-yI )- 2

-(

2 -methoxyethoxy)acetamide - N 2 , N 2 -d iethyl-N-(6-{[6-(3-fl uorophenoxy)[1 ,2 ,4ltriazolo[4,3-bjpyridazi n-3-yJ s uIfanyl)- 1,3-benzoth iazol-2-yI)glycinam ide 15 - N 2 -cYclopropyr-N-(6d[6-(3-fluorophenoy)L 1,2,A]triazolo[4 ,3-b] pyridazi n-3-yI] sulfa nyl}- 1, 3- ben zoth iazol1-2 -yI)giycina m ide - N-[ 6 -({6-[3-(morphoin..4..ymethyI)phenoxw][1 ,2,4]triazo io[4 1 3-b]pyridazin-3 yI~su Ifanyl )-1 ,3-benzoth iazoI- 2 -yIjcyclopropanecarboxam ide - N-(6-{[6-(3-fluorophenoxy)[1,2 ,4jtriazolo[4 ,3-b]pyridazin-3-yI]su Ifanyl}-1A3 20 benzothiazol-2-yqacetamide - N-(6-{[6-(3-fl uorophenoxy)[1 ,2 1 4]triazolo[4 7 3-b]pyridazin-3-yI]sulfa nyl}- 1,3 benzothiazol-2-yI)cyclopropaneca rboxamide - I -(6-{[8-(4-fluoroph enoxy)[1 ,2 ,4]triazolo[4, 3-b]pyridazin-3-yljsu Ifanyl}-1,3 benzothiazol-2-yI )-3-[2-(morphoIi n-4-yI )ethyl] urea 25 - I -(6-{L6-(3-fluoro-4-methylph enoxy)[1 ,2 ,4]triazolo[4 ,3-b] pyridazin-3-yIlsu If anyl}- , 3-benzothiazol-2-yI

)-

3

-[

2 -(morpholin-4-yI)ethyl]urea - 6-{[6-(tetra hydro-2H-pyran-4-yloxy)[1 ,2 ,4]triazolo[4,3-b] pyridazin-3-yI]sulf anyl}-1 ,3-benzothiazol-2-amine

-

6 -{[6-(4-fluorophenoxyfll ,2,4]triazolo[4 ,3-b]pyridazin-3-yijsulfa nyl}- ,3 30 benzothiazol-2-amine Wa 2010/089507 PCT/FR2O1 0/050178 29 - 1 -[2-(morphol in- 4 -yI)ethyl]-3-(6-{[6-(tetrahyd ro-2 H-pyra n-4-yloxy)(1 ,2,A] triazolo[4 ,3-b] pyridazi n-3-yI]su Ifanyl}-1 ,3-benzoth iazol-2-yl )urea - 1 -[6-({6-[(1 1-ethyl pi perid in-4-yl)oxy][1, 2 ,4]triazolo [4 1 3-b]pyridazin-3-yI}su If -anyl)-1, 3-benzoth iazoI-2-yI]-3-[2-(m orphol in-4-yI )ethyljurea 5 - N-(6-{[6-(tetra hydro-2 H-pyran-4-yloxy)[1 ,2 ,4]triazolo[4, 3-b] pyridazin-3-yIls uIf anyl-1 ,3-benzoth iazol-2-yi)cyclopropanecarboxam ide - N-(6-{[6-(4-fluorophenoxy)[1, 2,4]triazolo[4 ,3-b]pyridazi n-3-yI]su Ifanyl}- 1,3 benzoth iazol-2-yI)cyclopropa necarboxam ide - N-( 6 -{[6-(3-fluoro-4-methylphenoxy)[1 ,2 ,4]triazolo[4,3-b] pyridazin-3-yI]su If 10 a nyl}-1 ,3-benzoth iazol-2-yI)cyclo pro panecarboxa m ide - N-[6-({6-[( I -ethyip iperid in-4-yI)oxy] [1,2 ,4]triazo Io[4, 3-blpyridazin-3-yI~su If anyl)- 1, 3-benzoth iazol-2-yIlcyclopropa nec~arboxamide - 1 -[2-(morphol in- 4 -Y)ethYl]-3-(6-{[6-(tetrahydrofuran-3yloxy)[1 2 ,4]triazolo [4,3-b] pyridazin-3-yq~su Ifanyl}-1 ,3-benzoth iazot-2-yI)urea 15 - I -(6-{[6-( 1, 3-benzodioxol--yloxy)[1 ,2 , 4 ]triazolo[4,3-blpyridazi n-3-yljsulf anyl}-1, 3-benzoth iazol-2-yI)-3-[2-(morphol in-4-yI)ethyl] urea - I -(6-{[6-(3 ,4-d ich Iorophenoxy)[1 ,2 ,4]triazolo[4 ,3-b] pyridazin-3-yljsu Ifanyl}

I

1 3-benzothiazol-2-yI )-3-[2-(morphol in-4-yI)ethyl] urea - 6-{[6-(3 1 4-d ich Iorophenoxy)[1, 2,4]triazolo[4 ,3-b]pyridazin-3-yI]su Ifa nyl)- 1,3 20 benzothiazol-2-amine - 6-{[6-(tetrahyd rofura n-3-yloxy)[1 ,2 ,4 triazo 10(4,3-b] pyridazin-3-yI]su Ifa nyl) I ,3-benzothiazol-2-amine - 1 -(6-{[G-(l1 H-i ndol-6-yloxy)[1 ,2 ,4]triazo lo[4 1 3-b]pyridazin-3-yl]sulfanyly-l,3 ben zoth i azolI-2-yI)-3-[2-(mo rp hol in-4-yI)ethylj u rea 25 - N-(6-{[6-(tetrahyd rofuran-3-yloxyfl , 2 ,4jtriazolo[4, 3-blpyridazin-3-yllsu Ifanyl} I ,3-benzoth iazol-2-yI )cyclopropan ecarboxam ide - N-(6-{[6-(1 5 3-benzodioxol-5-yloxy)[1 ,2 ,4]triazolo[4, 3-b]pyridazin-3-yllsulf a nyl}-1 , 3 -benzothiazoI-2-yI)cycopropanecarboxam ide - N-(6-{[6-(3 ,4-d ich Iorophenoxy)[1 ,2 ,4]triazolo[4 ,3-bjpyridazi n-3-yI]su Ifanyl} 30 1 ,3-benzoth iazol-2-yI )cyclopropa necarboxam ide WO 20 10/089507 PCT/FR2O1 01050178 30 - N-(8-{[6-( I H-i ndol-6-yloxy)[1 ,2 , 4 ]triazolo[4,3-bjpyridazi n-3-yI]su Ifanyl}-1 ,3 benzothiazo

I-

2 -y)cyclopropanecarboxam ide - N-(6-{[6-(3-fluoroph enoxy)[1 ,2 ,4]triazolo[4, 3-b]pyridaziri-3-yIJsu Ifa nyl)- ,3 benzoth iazol-2-ylcyclobutanecarboxam ide 5 - N-(6-{[6-(3-fl uorophenoxy)[1,2 ,4]triazolo[4 ,3-blpyridazi n-3-yI]sultanylyi ,3 benzothiazol-2-yI

)-N

2 , N 2 -dimethyiglycina mide

-

2 -ethoxy-N-(6-{[6-(3-fluorophenoxy)[1I,2 ,4]triazolo[4 ,3-b]pyridazi n-3-yllsu If anyl}-1 3 -benzothiazoI-2-yI)acetamide - 2-(cyciohexyloxy)-N-(6-[6-(3-fl uorophenoxy)[1 ,2,4jtriazolo[4 ,3-b] pyridazi n-3 10 yI]su Ifanyl}-1 ,3-benzoth iazol-2-yI )acetam ide - 6-{[6-(pyridin-3-yloxy)[ 1,2 1 4 ]triazolo[4,3-b]pyridazin-3-y1]sulfa nyl}-1I,3-benzo thiazol-2-amine

-

6

-({

6 -L3-(tifluoromethoxy)phenoxy] [1,2 ,4]triazo Io[4 1 3-blpyridazin-3-yI~sulf anyl)-1 ,3-benzothiazol-2-amine 15 - 2-methylpropan-2-y [3-({3-[(2-amino-1 ,3-benzoth iazol-6-yI )su Ifanyl] [1,2 ,4]triazolo[4, 3 -blpyridazin-6-yIloxy)phenyl]carbam ate - N-(8-{[6-(pyridi n-3-yloxy)[1 ,2,4]triazolo[4, 3-b]pyridazin-3-yJsu Ifanyl}-1 ,3 benzoth iazol-2-yI)cyclobutanecarboxamide - N-(6-{[6-(3-fl uorophenoxy)[1 ,2 ,4]triazoio[4,3-bjpyridazi n-3-yl]sulfany}- ,3 20 benzoth iazol-2-yI )- 2 -(morpholin-4-yI)acetamide - N 2 -c-yclohexyl-N -(G-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4, 3-b]pyridazin-3-y] su Ifanyl}- 1, 3-benzoth jazo r-2-yI)glyci nam ide - N-(6-{[6-(3-fl uorophenoxy)[1 ,2 ,4]triazolo[4 ,3-b~pyridazin-3-yI]su Ifanyl}-1 ,3 benzoth iazol-2-yI )-N 2 -methyl-N 2 -[2-(morphol in- 4 -yI)ethyl]glycinam ide 25 - 2-(4-ethyl piperazin-1 -yI )- N-(6-{[6- (3-fluo rop hen oxy)[1, 2 ,4] tri azo Io[4 ,3-b] pyrid azin-3-yI]su Ifanyl}-1 ,3-benzoth iazol-2-yI)acetam ide - 6-{[6-(3,5-d ifluorophenoxyfll ,2 ,4]triazoo[4,3-b]pyridazin3yl]su Ifa nyl}-1, 3 benzoth iazol-2-amin a -6-{[6-(3-am inophenoxy)[1 ,2 ,4jtriazolo[4 ,3-b]pyridazi n-3-yl]sulfanyl}- 1,3 30 benzothiazol-2-amine WO 20101089507 PCT/FR2O1 0/050178 31 - N-(6-{[6-(3-fluorophenoxy)[1 ,2 ,4]triazolo[4 ,-bpyridazin-3-ylsulfanylp l,3 benzoth iazol-2-yl )-N-'2---(tetrahyd ro-2 H-pyran-4-yl )g lycina mide - N-[G-(6-[4-(trifluoromethyl)phenow][1 ,2 ,4]triazolo[4 ,3-blpyridazin-3-yl~su It anyl)-1 ,3-benzoth iazol-2-yi]cyclopro pan ecarboxamide 5 - N -IG-( 6

-[

3 -(trifluoromethoxy)phenoxy[1 ,2 ,4]triazolo[4,3-b] pyridazin-3-y~su If a nyl )- 1, 3-benzoth iazol- 2 -yI]cyclo pro panecarboxa m ide - N-[6-({6-[(2-methylpyridin.3.y)oxy] [1,2 ,4]triazolo[4 ,3-bJ pyridazi n-3-yl}su If any.I 1 3 -benzothiazol-2-yllcyclopropanecarboxam ide - N-(6-{ [6-(3, 5-d luorophen oxy)[1 ,2,4]triazolo[4 ,3-b] pyridazin-3-yllsu Ifa nyl} 10 1 ,3-benzoth iazol-2-yI )cyclopropanecarboxamide - 2-[(6-{[6-(3-fl uorophenoxy)[1 ,2 ,4]triazolo[4 p3-b] pyridazin-3-ylsufanyl.1 ,3 benzothiazol-2-yl)amino]-2..oxoethy acetate - N-[6-({6-[(6-methylpyrid in-3-yI)oxy][1 ,2 ,4ltriazolo[4 ,3-b]pyridazin-3-yl}su if an yQ- 1, 3-benzoth iazol-2-yI]cyclo pro paneca rboxam ide 15 - N-[6-({6-[4-(morphol in-4-yI methyl )phenoxy[1 ,2,4]triazolo[4,3-blpyridazin-3 yIlsulfanyl)-1 ,3-benzoth iazoI- 2 -y]cyclopropanecarboxamide - 2-methylpropan-2-y

(

3

-{[

3

-({

2 -[(cyclopropylcarbo nyl)am ino]-1 ,3-benzo th iazol1-6-yllsu iea nyl)[i ,2 .4]triazolo[4 .3-b] pyridazi n-G-y]oxyph enyl)carbam ate - N-(6-{[6-(pyridin-3-yloxy)[1 ,2 ,4]triazolo[4, 3-bjpyridazi n-3-yIlsu Ifanyl)- 1,3 20 benzothiazol-2-yl)cyclopropanecarboxamjde - N-{6-[(6-{3-[( I S .

4 S)-2-oxa-5-azabicyolo[2 ,2, 1 ]hept-5-ylmethyllphenoxyp [1,2 ,4]triazolo[4 .3-b] pyridazin-3-yI)sulfanyl]-1, 3 -benzothiazol-2-yllcyclopro panecarboxamide - N-{6-[(6-{3-[(d iethylam ino)methyl] phenoxy}[1 ,2 ,4]triazolo[4, 3-b]pyridazin-3 25 yI)su Ifanyi]-1 ,3-benzoth iazol- 2 -yllcyclopropanecarboxam ide - N-(6-{[6-(3 ,5-dflluorophenoxy)[1 ,2 ,4]triazolo[4 ,3-b] pyridazin-3-yI]su Ifanyl) I ,3-benzoth iazo-2-yl)-N 2 N 2 -d iethylglycinamide - N-(6-{[6-(3-fluorophenoxy)[1.2 ,4]triazolo[4, 3-b]pyridazin-3-yl]sulfanyl} 1,3 bonzothiazol-2-yI}..2-.hyd roxyacetam ide 30 - 2

-(

4 -cyclopropylpiperazin- 1 -Yi-N-(6-{[6-(3-fluorophenoxy)[1 ,2 ,4]triazolo[4 ,3 bipyridazi n-3-yl]sulfa nyl}-1 .

3 -benzothiazol-2-yI)acetam ide WO 2010/089507 PCT/FR2010/050178 32 - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl} 1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1 -yl)acetamide

-

2 -(4-cyclopropylpiperazin-1-yl)-N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo [4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide 5 - 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-[(diethylam ino)methyl] phenoxy}[1,2,4]triazolo[4,3-b] pyridazin-3 yl)sulfanyl]-1, 3 -benzothiazol-2-yI}-2-methoxyacetamide - 2-methoxy-N-{6-[(6-{3-[(1

S,

4 S)-2-oxa-5-azabicyclo[2,2,1 ] hept-5-ylm ethyl] 10 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-benzo thiazol-2-amine - 2-(morpholin- 4 -yI)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b] 15 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-y)- 2 -(morpholin-4-yl)acetamide - N 2 , N 2 -d iethyl-N-(6-{[6-(tetrahydrofu ra n-3-yloxy)[1,2,4]triazolo[4,3-blpyridazin 3-yl]sulfanyl}-1, 3-benzoth iazol-2-yl)g lyci nam ide 20 - 2-(4-ethylpiperazin-1-yi)-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-yI)-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 25 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-yf)acetamide 30 and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (1).

WO 2010/089507 PCT/FR2010/050178 33 A subject of the present invention is also any process for preparing the products of formula (1) as defined above. 5 A subject of the present invention is thus any process for preparing the products of formula (1) as defined above, in which A represents NH. A subject of the present invention is thus any process for preparing the products of formula (1) as defined above, in which A represents S. 10 The products according to the invention may be prepared from conventional methods of organic chemistry. Schemes 1, 2, 2bis, 3, 4, 5 and 6 hereinbelow illustrate methods used for the preparation of the products of formula (1). In this respect, they shall not constitute a limitation of the scope of the invention, 15 as regards the methods for preparing the claimed compounds. The products of formula (1) as defined above according to the present invention may thus especially be prepared according to the processes described in Schemes 1, 2, 2bis, 3, 4, 5 and 6 hereinbelow. 20 A subject of the present invention is thus also the process for preparing products of formula (1) according to Scheme 1 as defined below. A subject of the present invention is thus also the process for preparing 25 products of formula (1) according to Scheme 2 as defined below. A subject of the present invention is thus also the process for preparing products of formula (1) according to Scheme 2bis as defined below. 30 A subject of the present invention is thus also the process for preparing products of formula (1) according to Scheme 3 as defined below.

WO 2010/089507 PCT/FR2010/050178 34 A subject of the present invention is thus also the process for preparing products of formula (1) according to Scheme 4 as defined below. 5 A subject of the present invention is thus also the process for preparing products of formula (1) according to Scheme 5 as defined below. A subject of the present invention is thus also the process for preparing products of formula (1) according to Scheme 6 as defined below. 10 Similarly, among the products of formula (1) as defined above in which represents a single or double bond, the products of formula (I') are defined, which represent products of formula (1) in which : represents a single bond and products of formula (I") which represent products of formula (1) in 15 which represents a double bond, and similarly, for the synthetic intermediates as defined below of formulae (a), (b), (c), (d), (e) and (f) in which represents a single or double bond, the compounds of formulae (a'), (b'), (c'), (d'), (e') and (f') are defined, in which represents a single bond, and the compounds of formulae (a"), (b"), 20 (c"), (d"), (e") and (f") in which represents a double bond. Scheme 1: synthesis of benzimidazole derivatives of formulae (la"), (1b"), (1 "c), (1 d"), (1 e"), (1 a'), (1b'), (1 c'), (1 d') and (1 e') WO 2010/089507 PCT/FR2010/050178 35 NC-S NH 2 reduction HS NH2f . OyS yNH2 K+ s- F NH 2 Rb NO 2 when RbF NO 2 when F D NO C FN Q Rb=H F 2Rb=F LD 2 C Q commercial CI Ra- CI NH N NH2 N -- N (F) Rb NO 2 According to com rl Scheme 3 Ra R commercial to RaL.-~~c~2 H EI N H reductionn S.>%N S H I+C0 2

R

5 N ,S NH N H (R N H RW'%''5 b b aR O-N S NH 2 SBrCN R NH2b Ra id'/Id" Rn 1cy/1c" RCOX (P) i> N R0) Ra 1e'/e" In Scheme 1 above, the substituents, Ra and Rb, have the meanings given above for the products of formulae (I') and (l"). Substituent R5, in the 5 compounds of formulae (J), (Ia') and (1a"), represents an alkyl radical. In Scheme I above, the groups CONRI1R2, C02R6 and COR7, which constitute W, may take the values of W as defined above for the products of formulae (I') and (l"), when W;4- WO 2010/089507 PCT/FR2010/050178 36 In the above Scheme 1, the benzimidazoles of general formulae (1a"), (1b"), (1c"), (Id") and (1e") and also the reduced analogues thereof of general formulae (la'), (1b'), (1c'), (1d') and (le') may be prepared from commercial 5 3,6-dichloro[1,2, 4 ]triazolo[4,3-b]pyridazine of formula (S). tc5 N E Ra The compounds (E) may be obtained, for example, by reaction of phenols or alcohols in the presence of a base on the compound (S). The reaction is 10 performed, for example, at a temperature in the region of 200C. HS NH2 F Rb NO 2 NNHG Rb NO 2 Ra 15 The compounds (G), with Rb = H, may be obtained, for example, by reacting 3 -amino-4-nitrobenzenethiol of formula (F) with the compounds of formula (E), in the presence of a base such as sodium hydride, in a solvent such as N,N-dimethylformamide, at a temperature in the region of 20*C. The compounds of formula (F) are obtained via in situ reduction of 3-amino-4 20 nitrophenyl thiocyanate (Q) (commercial compound), for example, in the presence of sodium borohydride in a solvent such as N,N-dimethylformamide, at a temperature in the region of 200C. The compounds (G), with Rb = F, may be obtained, for example, by reacting 25 2 -fluoro-5-amino-4-nitrobenzenethio of formula (F) with the compounds of WO 2010/089507 PCT/FR2010/050178 37 formula (E), in the presence of a base such as sodium hydride, in a solvent such as N,N-dimethylformamide, at a temperature in the region of 20 0 C. The compounds of formula (F), with Rb = F, are obtained by reacting 2-nitro-4,5 difluoroaniline (Q') (commercial compound), for example, in the presence of 5 potassium thioacetate (C) in a solvent such as N,N-dimethylformamide, at a temperature in the region of 20"C. 4e N "rS NH 2 H'IH" The compounds (H") such that represent a double bond may be obtained, for example, via reduction with iron (0) of the compounds of formula 10 (G), in a solvent such as methanol, in the presence of acetic acid, at a temperature in the region of 70"C. The compounds (H') such that - represent a single bond may be obtained, for example, via reduction with zinc (0) of the compounds of formula 15 (G), in the presence of acetic acid, at a temperature in the region of 20"C. More particularly, the carbamates of general formulae (1a') and (1a") may especially be prepared as described in patent WO 03/028721 A2, but starting, respectively, with a 3,4-diaminophenyl sulfide of formulae (H') and (H") and 20 with a pseudo thiourea of formula (J), in the presence of acetic acid and in a protic solvent such as methanol, at a temperature in the region of 80*C. More particularly, the benzimidazoles of general formulae (I b') and (1 b) may be prepared, respectively, by reaction of an amine NHR1 R2 of formula (R) 25 (with R1 and R2 as defined above) with a carbamate of formulae (1a') and (la"), for example in the presence of an aprotic solvent such as 1-methyl-2 pyrrolidinone. The reaction is performed, for example, at a temperature in the region of 120"C, in a sealed tube under microwaves.

WO 2010/089507 PCT/FR2010/050178 38 More particularly, the 2-aminobenzimidazoles of general formulae (1c') and (1c") may be prepared, for example, by reacting cyanogen bromide with a compound of formulae (H') and (H"), respectively, in the presence of a protic 5 solvent such as ethanol. The reaction is performed at a temperature in the region of 80*C. More particularly, the carbamates of general formulae (1d') and (Id") may be obtained by reacting a chlorocarbonate of formula (0) (X = Cl) with a 10 compound of general formulae (Ic') and (1c"), for example in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogen carbonate, at a temperature in the region of 20"C. More particularly, the carboxamides (le') and (le") may be obtained, 15 respectively, from the amines of general formulae (Ic') and (1 c") - by reacting the amines (1c') and (1c") with an acid chloride of formula (P) (X = Cl), in the presence, for example, of a solvent such as pyridine, at a temperature in the region of 20"C; - by reacting the amines (1c') and (1c") with an acid anhydride of formula (P) 20 (X = OCOR7), in the presence, for example, of pyridine at a temperature in the region of 20"C; - by coupling the amines (1c') and (Ic") with an acid of formula (P) (X = OH) under the conditions described, for example, by D.D. DesMarteau; V. Montanari (Chem. Lett., 2000 (9). 1052), in the presence of 1 25 hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and in the presence of a base such as triethylamine, at a temperature in the region of 40*C. Scheme 2: Synthesis of benzothiazole derivatives of formulae (2a'), (2b'), 30 (2c'), (2d'), (2a)', (2b'), (2c') and (2d') WO 2010/089507 PCT/FR2010/050178 39 SSCI R~b N NCA L2/reduction Ra E , L2 R 2 RN N N M2 0 R

NHRR

2 (R) 1 iC NC K NH reduction N Ra E Rb N RCOX (P) IN N NC N R reduction N R Ra E/>S H

NCJI-NH

2 />_ EL'2 6 M ZXN Rba RbrCCN J K N Zd'12d" RJCOX N($VCI NC:)aVlSreduction HS 8 Ra E N RbAk'% Nt R 7 Rb:C tR 7 tN Rb CN R 7 L3 M3 2c'2c" Ra In Scheme 2 above, the substituents Ra and Rb have the meanings indicated above for the products of formulae (I') and (i"). Similarly, the groups 5 CONR1 R2, C02R6 and COR7, which constitute W, may take values of W as defined above for the products of formulae (I') and (I"), when WM. In Scheme 2 above, the benzothiazoles of general formulae (2a"), (2b"), (2c") and (2d") and the reduced analogues thereof of general formulae (2a'), (2b'), 10 (2c') and (2d') with Rb = H may be prepared from 2-amino-1,3-benzothiazol 6-yl thiocyanate (K) (commercial compound). NC NC O R Rb'Ie cII>zNH 2 /N0 RB N K Rb~a WO 2010/089507 PCT/FR2010/050178 40 The carbamates of general formula (L1) may be obtained, for example, by reacting a chlorocarbonate of formula (0) (X = CI) with 2-amino-1,3 benzothiazol-6-y thiocyanate (K), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogen carbonate, at a temperature in 5 the region of 20*C. KSCN 7N F NH2 Br 2 /iNHl2 commercial AcoH F N K In Scheme 2 above, the benzothiazoles of general formulae (2a"), (2b"), (2c") and (2d") and the reduced analogues thereof of general formulae (2a'), (2b'), (2c') and (2d') with Rb = F may be prepared from 2-amino-5-fluoro-1,3 10 benzothiazol-6-yI thiocyanate. 2-Amino-5-fluoro-1,3-benzothiazol-6-y thiocyanate (K) may be prepared from 3-fluoroaniline in the manner described by K. Papke and R. Pohloudek-Fabini in Pharmazie; GE; 22, 5 1967, P229 233, by reacting potassium thiocyanate and 3-fluoroaniline in the presence of bromine in acetic acid. NC N L2 15 Rb The compounds of general formula (L2) may be obtained, for example, by reacting the carbamates of formula (L1) in which R6 = phenyl with amines NHR1R2 of formula (R) (with Rb, R1 and R2 as defined above), in the presence of an aprotic solvent such as tetrahydrofuran, at a temperature in 20 the region of 200C. The ureas (2b') and (2b") may be obtained, for example, respectively, from the carbamates (2a') and (2a") in which R6 = phenyl, in the same manner as the ureas (L2) are obtained by reacting amines on the carbamates of the type 25 (L1).

WO 2010/089507 PCT/FR2010/050178 41 NC N R Rb 0 The compounds of general formula (L3) may be obtained, for example: - by reacting an acid chloride of formula (P) (X = C) with 2-amino-1,3 benzothiazol-6-yl thiocyanate (K), in the presence, for example, of a solvent 5 such as pyridine, at a temperature in the region of 200C, - by reacting an acid anhydride of formula (P) (X = OCOR7) with 2-amino-1,3 benzothiazol-6-yl thiocyanate (K), in the presence, for example, of a solvent such as pyridine, at a temperature in the region of 20*C, - by coupling 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) with an acid of 10 formula (P) (X = OH) under the conditions described, for example, by D.D. DesMarteau; V. Montanari (Chem. Left., 2000 (9).1052), in the presence of 1 hydroxybenzotriazole and I -(3-dimethylam inopropyl)-3-ethylcarbod iim ide and in the presence of a base such as triethylamine, at a temperature in the region of 40"C. 15 In the same manner that the carboxamides (L3) may be obtained via acylation of the amine (K), the carboxamides (2c') and (2c") may be obtained, respectively, from the amines (2d') and (2d") by coupling with an acid of formula (P) (X = OH) under the conditions described, for example, by N. Xi 20 et al., Bioorg. Med. Chem. Left. 15 (2005) 5211-5217, in the presence of 0 (7-aza benzotriazol- 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 diisopropylethylamine, at a temperature in the region of 20*C.

WO 2010/089507 PCT/FR2010/050178 42 Scheme 2bis: Routes for synthesizing the glycinamide derivatives (2c') and (2c") HO S >-NH2 O>/ NRR 4 N Ra 2d'12d" 2c'2c" 0 Ra R7=CH2-NR3R4 cH /NR3R4 Ra 2o'2e" 5 In Scheme 2bis above, the substituent R7 may take the meaning of an aminomethyl group. These glycinamides (2c'/2c") may be obtained by coupling the amines (2d') and (2d") with a glycidic acid (P') using the methods described above for the acids (P) (X = OH). 10 The glycidic acids (P') may be prepared from bromoacetic acid and amines HNR3R4 under conditions similar to those described by D. T. Witiak et al; J. Med. Chem. 1985, 28,1228. Alternatively, the amines (2d') and (2d") may be treated with fluoroacetyl 15 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 200C. The a-chloroacetamides (2e'/2e") thus formed can react with amines of the type HNR3R4, as defined above, in a solvent such as pyridine at a temperature in the region of 200C, to give the derivatives 20 (2c'/2c") as defined in Scheme 2bis above. The compounds of general formulae (Ml), (M2) and (M3) may be obtained, for example, by reduction of compounds of general formula (L1), (L2) or (L3) WO 2010/089507 PCT/FR2010/050178 43 with DL-dithiothreitol, in the presence of sodium hydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 80*C. The compound of general formula (N) may be prepared in situ by reduction of 5 the compound of formula (K), for example with sodium borohydride in a solvent such as N,N-dimethylformamide, in the presence of a base such as triethylamine and at a temperature in the region of 95"C or between 20*C and 95 0 C. 10 The above arylthiol intermediates may exist in the form of free thiols or in the form of disulfides or a mixture of the two forms that may be employed without preference in the rest of the reactions. More particularly, the benzothiazoles of general formulae (2d') and (2d") may 15 also be prepared, respectively, from carbamates of formulae (2a') and (2a") in which R6 = t-butyl, by reaction, for example, with trifluoroacetic acid in a solvent such as dichloromethane, at a temperature in the region of 20*C. Reciprocally, the benzothiazoles of general formulae (2a') and (2a") may also 20 be prepared from benzothiazoles of formulae (2d') and (2d"), respectively, for example, by reaction with a chlorocarbonate of formula (0) (X = Cl), in a solvent such as tetrahydrofuran, in the presence of a base such as sodium hydrogen carbonate, at a temperature in the region of 20"C. 25 More particularly, the benzothiazoles of general formulae (2a"), (2b"), (2c") and (2d") and the reduced analogues thereof of general formulae (2a'), (2b'), (2c') and (2d') may be prepared, for example: 1) either 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), WO 2010/089507 PCT/FR2010/050178 44 (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 in the region of 950C or between 500C and 95*C; 2) or by coupling the isolated derivatives (M1), (M2) and (M3) and a 5 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 in the region of 95"C; 3) or by coupling a compound of formula (E) with derivatives (M1), (M2) and (M3) and (N) generated in situ by reduction of the derivatives (L1), (L2), (L3) 10 and (K) in the presence of DL-dithiothreitol and sodium hydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 80"C. The reductive conditions 1) and 2) may give products of formulae (2a), (2b), (2c) and (2d) such that - represent a single or double bond, whereas 15 conditions 3) and 4) give products of formulae (2a), (2b), (2c) and (2d) such that represent a double bond. Scheme 3: Routes for synthesizing triazolopyridazine derivatives of formula (E) Rc-Z-O- C (U)E N N 20 ClS R a Ra = O-Z-Rc 20 Ci S R a In Scheme 3 above, the substituents Ra, Z and Rc have the meanings indicated above for the products of formulae (I') and (I"). The compounds of formula (E) may be obtained, for example, as indicated in 25 Scheme 3 above, from commercial 3,6-dichloro[1,2, 4 ]triazolo[4,3-b]pyridazine of formula (S).

WO 2010/089507 PCT/FR2010/050178 45 More particularly, the compounds of formula (E) in which Ra represents a radical O-Z-Rc may be obtained by treating 3,6-dichloro[1,2,4]triazolo[4,3 bjpyridazine (S) at a temperature in the region of 20*C in a solvent such as tetrahydrofuran with an alkoxide of formula (U), which is itself obtained by 5 treating the corresponding alcohol with a base such as sodium hydride at a temperature in the region of 0*C to 200C. Scheme 4: Synthesis of the benzothiazole derivatives of formulae (2e') and (2e") N S

R

9 X N deprotection aX Ra 2a/ 2a" Ra 207 2e" reductive conditions E NC (W) NC E N 0Rb N t Rb 0 1 R,0 R P via T" 10 Li Ra 2a" According to Scheme 4 above, the benzothiazoles of general formulae (2e') and (2e") may be prepared, respectively, from the compounds of formulae (2a') and (2a"). 15 In Scheme 4 above, the substituent OR6 preferentially represents O-t-butyl. The substituent R9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy or heterocycloalkyl radical or NR3R4 (R3 and R4 as defined above).

WO 2010/089507 PCT/FR2010/050178 46 N Rb N -/- R O R 1 Ra T'/ T" The carbamates of general formulae (T') and (T") may be obtained, respectively, by reacting carbamates of general formulae (2a') and (2a") with R6 = tBu, preferentially, for example with alkyl halides of formula (W), in a 5 solvent such as N,N-dimethylformamide, in the presence of sodium hydride, at a temperature of between 20 and 90*C. The benzothiazoles of general formulae (2e') and (2e") may also be prepared from the compounds of formula (L1), with, preferably, R6 = tBu, via the 10 compounds of formulae (T') and (T"). More particularly, the compounds of general formulae (2e') and (2e") may be obtained, respectively, by treating the isolated compounds (T') and (T"), for example, with trifluoroacetic acid, in a solvent such as dichloromethane, at a 15 temperature in the region of 20"C. Alternatively, the compounds of general formula (2e") may be obtained directly by reacting the compounds of formulae (L4) and (E), via compound (T") formed in situ, for example in the presence of DL-dithiothreitol and 20 sodium hydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 80*C, optionally followed by an in situ treatment with trifluoroacetic acid at 20"C, if necessary. NCIIN Rbr:CN> 0 R 6 L4 The carbamates of general formula (L4) may be obtained by reacting 25 carbamates of general formula (L1), for example, with alkyl halides of formula WO 2010/089507 PCT/FR2010/050178 47 (W), in a solvent such as N,N-dimethylformamide, in the presence of sodium hydride, at a temperature of between 20 and 90 0 C. Scheme 5: Synthesis of the benzothiazole derivatives of formulae (2e') and 5 (2e") diazotation ENH E 2 RN bromination s Br R SH 'I />-NH, ->B H Ra N O N CuBr 2 RVS.N N b K NN 2 Rb): R N 2.. LS L6 Ra ,Ny~N Rb 2e' Ra Alternatively, according to Scheme 5 above, the benzothiazoles of general formula (2e") may be prepared from the compounds of formulae (L6) and (E), 10 for example, in the presence of DL-dithiothreitol and sodium hydrogen carbonate, in a solvent such as ethanol and at a temperature in the region of 80*C. The benzothiazoles of general formula (2e') may be prepared from the 15 compounds of formula (2e") according to the methods described below for the preparation of the compounds (I') from the compounds (I"). The compounds of formula (L6) may be prepared from the 2 bromobenzothiazole derivative (L5) by treatment with a derivative NH2R9, for 20 example, in a solvent such as tetrahydrofuran, at a temperature in the region of 20CC.

WO 2010/089507 PCT/FR2010/050178 48 The substituent R9 represents an alkyl or cycloalkyl radical optionally substituted with an alkoxy or heterocycloalkyl radical or NR3R4 (R3 and R4 as defined above). 5 The compounds of formula (L5) may be prepared from 2-amino-1,3 benzothiazol-6-yl thiocyanate (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 et al. in J. Med. Chem. 2006, 49, 6819-6832. 10 Scheme 6: Other routes for synthesizing reduced derivatives of formula (I') RHb reaction N S aW >H onr wthe A> -N reucio g-N, group 1XWi -I Ra ( Ra ()) a coupling Mior M2 or M3 or N CI reduction A Ci N E Ra E' Re According to Scheme 6 above, the benzothiazoles of general formula (I') may 15 also be prepared from the compounds of formula (I"), via reduction, for example, with sodium borohydride, in a solvent such as ethanol, at a temperature in the region of 80*C, or via reduction with zinc (0) in the presence of acetic acid, at a temperature in the region of 20*C. 20 Alternatively, the compounds (I') may also be prepared from the compounds of formula (E') by coupling with compounds of the type MI, M2, M3 or N, obtained as intermediates via reduction of the compounds L1, L2, L3 or K in situ, as described above in Scheme 2. The compounds of the type M1, M2 or WO 2010/089507 PCT/FR2010/050178 49 M3 may also be isolated and used for the coupling with (E'). The compounds (E') may be obtained from the compounds of formula (E) by reduction, for example, with zinc (0) in the presence of acetic acid, at a temperature in the region of 20 0 C. 5 Alternatively, the compounds (l') may also be prepared from other compounds (') via conversion of the group W into a group W' of the same nature as defined above for W and according to the type of reaction defined in Scheme 2: conversion of 2d'/2d" into 2a'/2a" and into 2c'2c", conversion of 10 2a'/2a" into 2d'/2d" and into 2b'/2b". In the compounds of general formula (1) as defined above, the sulfur S can be oxidized to sulfoxide SO or sulfone S02 according to the methods known to those skilled in the art, if necessary protecting any reactive groups with 15 suitable protecting groups. Among the starting materials of formulae J, K, 0, P, P', Q, Q', R, S, U and W, some are known and may be obtained either commercially or according to the usual methods known to those skilled in the art, for example from commercial 20 products. It is understood by those skilled in the art that, to implement the processes according to the invention described previously, it may be necessary to introduce protecting groups for the amino, carboxyl and alcohol functions in 25 order to avoid side reactions. The following non-exhaustive list of examples of protection of reactive functions may be mentioned: - hydroxyl groups may be protected, for example, with alkyl radicals such as 30 tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl, WO 2010/089507 PCT/FR2010/050178 50 - amino groups may be protected, for example, with acetyl, trity, benzyl, tert butoxycarbonyl, BOC, benzyloxycarbonyl or phthalimido radicals or other radicals known in peptide chemistry. 5 Acid functions may be protected, for example, in the form of esters formed with readily cleavable esters such as benzyl or tert-butyl esters or esters known in peptide chemistry. A list of various protecting groups that may be used will be found in the 10 manuals known to those skilled in the art and, for example, in- patent BF 2 499 995. It may be noted that intermediate products or products of formula (I) thus obtained via the processes indicated above may be subjected, if desired and 15 if necessary, in order to obtain other intermediates or other products of formula (1), to one or more transformation reactions known to those skilled in the art, for instance: a) a reaction for esterification of an acid function, b) a reaction for saponification of an ester function to an acid function, 20 c) a reaction for reduction of the free or esterified carboxyl function to an alcohol function, d) a reaction for conversion of an alkoxy function into a hydroxyl function, or alternatively of a hydroxyl function into an alkoxy function, e) a reaction for removal of the protecting groups that may be borne by 25 protected reactive functions, f) a salification reaction with a mineral or organic acid or with a base to obtain the corresponding salt, g) a reaction for resolution of racemic forms into resolved products, the said products of formula (I) thus obtained being in any possible racemic, 30 enantiomeric or diastereoisomeric isomer form.

WO 2010/089507 PCT/FR2010/050178 51 Reactions a) to g) may be performed under the usual conditions known to those skilled in the art, for instance those indicated hereinbelow. a) The products described above may, if desired, undergo, on the possible 5 carboxyl functions, esterification reactions that may be performed according to the usual methods known to those skilled in the art. b) The possible conversions of ester functions into an acid function of the products described above may, if desired, be performed under the usual 10 conditions known to those skilled in the art, especially by acidic or alkaline hydrolysis, for example with sodium hydroxide or potassium hydroxide in alcoholic medium, for instance in methanol, or alternatively with hydrochloric acid or sulfuric acid. 15 The saponification reaction may be performed according to the usual methods known to those skilled in the art, for instance in a solvent such as methanol, ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide. 20 c) The possible free or esterified carboxyl functions of the products described above may, if desired, be reduced to an alcohol function via the methods known to those skilled in the art: the possible esterified carboxyl functions may, if desired, be reduced to an alcohol function via the methods known to those skilled in the art and especially with lithium aluminium hydride in a 25 solvent such as, for example, tetrahydrofuran, dioxane or ethyl ether. The possible free carboxyl functions of the products described above may, if desired, be reduced to an alcohol function especially with boron hydride. 30 d) The possible alkoxy functions, especially such as methoxy, of the products described above may be, if desired, converted into a hydroxyl function under WO 2010/089507 PCT/FR2010/050178 52 the usual conditions known to those skilled in the art, for example with boron tribromide in a solvent such as, for example, methylene chloride, with pyridine hydrobromide or hydrochloride, or alternatively with hydrobromic acid or hydrochloric acid in water or trifluoroacetic acid at reflux. 5 e) The removal of the protecting groups such as, for example, those indicated above may be performed under the usual conditions known to those skilled in the art, especially via acidic hydrolysis performed with an acid such as hydrochloric acid, benzenesulfonic acid or para-toluenesulfonic acid, formic 10 acid or trifluoroacetic acid, or alternatively via catalytic hydrogenation. The phthalimido group may be removed with hydrazine. f) The products described above may, if desired, undergo salification 15 reactions, for example with a mineral or organic acid or with a mineral or organic base according to the usual methods known to those skilled in the art: such a salification reaction may be performed, for example, in the presence of hydrochloric acid, for example, or tartaric acid, citric acid or methanesulfonic acid, in an alcohol, for instance ethanol or methanol. 20 g) The possible optically active forms of the products described above may be prepared by resolving racemic mixtures according to the usual methods known to those skilled in the art. 25 The products of formula (1) as defined above and the acid-addition salts thereof have advantageous pharmacological properties especially on account of their kinase-inhibiting properties as indicated above. The products of the present invention are especially useful for treating 30 tumours.

WO 2010/089507 PCT/FR2010/050178 53 The products of the invention may thus also increase the therapeutic effects of commonly used antitumour agents. These properties justify their therapeutic use, and a subject of the invention is 5 particularly, as medicaments, the products of formula (1) as defined above, the said products of formula (1) being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition salts with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of the said products 10 of formula (1). A subject of the invention is most particularly, as medicaments, the products corresponding to the following formulae: - 6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2 15 amine - N-{6-[(6-phenoxy[1,2,4]triazolo[4,3-blpyridazin-3-yl)sulfanylJ-1,3-benzo thiazol- 2 -yl}cyclopropanecarboxamide - N-{6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo thiazol-2-yl}acetamide 20 - 1-[ 2 -(morpholin-4-yl)ethyl]-3-{6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3 yl)sulfanyl]-1,3-benzothiazol-2-yl}urea - 1-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3 benzoth iazol- 2 -yl)-3-[2-(morpholin-4-yl)ethyl] urea

-

6 -{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b] pyridazin-3-yl]su lfanyl)-1, 3 25 benzothiazol-2-amine - N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-blpyridazin-3-yl]sulfanyl)-1,3 benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide - N 2 , N 2 -diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl] sulfanyl}-1,3-benzothiazol-2-yl)glycinamide 30 - N 2 -cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-bipyridazin-3-yl] sulfanyl}-1,3-benzothiazol-2-yl)glycinamide WO 2010/089507 PCT/FR2010/050178 54 - N-[6-({6-[3-(morpholi n-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b] pyridazin-3 yl}su lfanyl)- 1,3-be nzoth iazo -2-yl]cyclopro panecarboxamide - N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3 benzothiazol-2-yl)acetamide 5 - N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b] pyridazin-3-yI]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]sulf 10 anyl}-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-blpyridazin-3-yllsulf any}-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 15 - 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-yI}sulf anyl)-1,3-benzothiazol- 2 -yl]-3-[2-(morpholin-4-yl)ethyl]urea - N-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yI]sulf 20 a nyl}- 1,3-benzoth iazol-2-yl)cyclo pro panecarboxam ide - N-( 6 -{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1,3 benzoth iazo -2-yl)cyclopropaneca rboxamide - N-(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yiqsulf anyl}- 1, 3-benzoth iazol-2-yl)cyclopropanecarboxamide 25 - N-[6-({6-[(1 -ethylp iperid in-4-yl)oxy] [1,2,4]triazolo[4,3-b]pyridazi n-3-yl}sulf anyl)-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]sulf 30 anyl}-1,3-benzothiazol-2-yI)-3-[2-(morpholin-4-yl)ethyl]urea WO 2010/089507. PCT/FR2O1 0/050178 55 - I -(6-{[6-(3 ,4-d ich Iarophenoxy)(1 ,2,4]triazo Io[4 1 3-bjpyridazi n-3-yI]su Ifanyl) 1, 3-benzoth iazol-2-yl )- 3 -[2-(morpholin-4-yI)ethyl] urea - 6-{[6-(3 ,4-d ichlorophenoxyfl 1,2 ,4jtriazolo[4 ,3-b]pyridazin-3-yI]su Itanyl}- ,3 benzoth iazol-2-am in e 5 - G-[6-(tetrahydrofura n-3-yloxy)[1, 2,4]triazoro[4,3-bjpyridazi n-3-yIlsu Ifanyl}

I

1 3-benzothiazol-2-amine - 1 -(6-{[6-( I H-indol-6-yloxy)[1 ,2 ,4]triazo [o[4 1 3-bjpyridazin-3-yljsu Ifanyl}- 1,3 benzoth iazol-2-yI)-3-[2-(morphoin.4-y)ethyl] urea - N-(6-{[6-(tetrahydrofura n-3-yloxy)[1 ,2,4]triazolo[4 ,3-b] pyridazin-3-yljsu Ifanyl) 10 1, 3-benzothiazol-2-yI )cyclopropanecarboxam ide - N-(6-{[8-(1 1 3-benzod ioxol-5-yloxyfll ,2 ,4]triazo Io[4 ,3-b] pyridazi n-3-yI]sulf anyl)- 1, ,3-benzoth iazol-2-yI )cyc lo pro panecarboxam id e - N-(6-{[6-(3 ,4-dichlorophenoxy)[1, 2,4]triazolo[4 ,3-b] pyridazin-3-yI]su Ifanyl) 1, 3-benzoth iazoI- 2 -y)cycopropanecarboxam ide 15 - N-(6-{[6-(1 H-indol-6-yloxyfll t 2 t 4 ]triazolo[4,3-b]pyridazin-3-yI]sulfanyly1 ,3 benzothiazol-2-yI)cyclopropanecarboxam ide - N-(6-{[6-(3-fluorophenoxy)[1

,

2

,

4 ]triazolo[4 5 3-b~pyridazin.3..yIjsulfanyI-1 , 3 benzothiazor-2-yI)oycobutanecarboxam ide - N-(6-{[6-(3-fluorophenoxy)[1 ,2 ,4]triazolo[4 ,3-b]pyridazin-3-yI]s u fa nyl}- 1,3 20 benzoth iazol-2-yI)-N 2 , N 2 -dimethylglycinam ide - 2-ethoxy- N-(6-{[6-(3-fluorophenoxy)[1 ,2 , 4 ]triazoo[4,3-bpyridazin3-y]su If anyl)- 1,3-benzoth iazol-2-yI)acetamide

-

2 -(CYCOhexyoxy)- N-(6- [6-(34Iluo rop hen oxy)[, ,2,4]triazo lo[4 ,3-b] pyrid azin-3 yI]su Ifanyl}- 1, 3-benzothiazol-2-yi)acetam ide 25 - 6-{[6-(pyridi n-3-yloxy)[1 ,2 ,4]triazo Io[4 ,3-bjpyridazi n-3-yilsuifanyl}- 1, 3-benzo thiazol-2-amine - G-({6-[3-(trifluorometh oxy)phenoxy][1 ,2 ,4]triazolo[4 1 3 -bjpyridazin-3-ylysu If anyl)- 1, 3-benzothiazol-2-am ine - 2-methyipropa n-2-yI [3-({3-[(2-amino-I, 3-benzoth iazol-6-yI)su Ifa nyl][1I,2 ,4] 30 triazolo[4, 3-blpyridazin-6-yI}oxy)ph enyi]carbamate WO 2010/089507 PCT/FR2010/050178 56 - 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]suifanyl}-1,3 benzothiazol-2-y)- 2 -(morpholin-4-yi)acetamide 5 - 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-N[2-(morpholin-4-yl)ethyl]glycinamide - 2-(4-ethylpiperazin-1-yl)-N-(6-f[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b] 10 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-am inophenoxy)[ 1,2,4]triazolo[4,3-b] pyridazin-3-yl]su Ifanyl)-1, 3 benzothiazol-2-amine 15 - N-(6-{{6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3 benzothiazol-2-yI)-N-2~-(tetrahydro-2H-pyran-4-yl)glycinamide - N-[6-({6-[4-(trifluorom ethyl)phenoxy] [1,2, 4 ]triazolo[4,3-b]pyridazin-3-yl}sulf anyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide - N-[6-({6-[3-(trifluoromethoxy)phenoxy][1,2, 4 ]triazolo[4,3-bjpyridazin-3-yI)sulf 20 anyl)-1,3-benzothiazol- 2 -yi]cyclopropanecarboxamide - N-[6-({6-[(2-methylpyridin-3-yl)oxy][1,2,4]triazoIo[4,3-b]pyridazin-3-yl}sulf anyl)- 1, 3-benzoth iazol- 2 -yl]cyclopropanecarboxamide - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl} 1, 3-benzoth iazol-2-yl)cyclopropanecarboxam ide 25 - 2-[(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3 benzothiazol-2-yl)amino]-2-oxoethyl acetate - N-[6-({6-[(6-methylpyridin-3-yl)oxy][1,2,4]triazolo[4, 3 -blpyridazin-3-yl)sulf anyl)-1,3-benzothiazol- 2 -yl]cyclopropanecarboxamide - N-[6-({6-[4-(morpholin-4-ylmethyl)phenoxy][1,2, 4 ]triazolo[4,3-b]pyridazin-3 30 yl}sulfanyl)-1, 3 -benzothiazol-2-yl]cyclopropanecarboxamide WO 2010/089507 PCT/FR2OI 0/050178 57 - 2-methylpropan-2-y

(

3

-{[S-({

2 -[(cyclopropyloarbonyl)am inol-1 ,3-benzo th iazol-6-yI~sulfanyl)[i ,2,4]triazolo[4 ,3-b] pyridazin-6-yI]oxylphenyl)carbam ate - N-(6-{[6-(pyridin-3-yloxy)[1 ,2,4]triazolo[4 ,3-b] pyridazin-3-yllsu Ifanyl}-1 ,3 be nzoth iazol-2-yi )cyclopropan ecarboxam ide 5 - N-{6-[(6-{3-[( I S 1 4S)-2-oxa-5-azabicycro[2 ,2, 1 ]hept-5-ylmethyl] phenoxy} [1,2 ,4]triazoro[4, 3-b] pyridazi n-3-yI)suifanyl]-1I,3-berizoth lazo i-2-yIlcyclo propanecarboxam ide - N-{6-[(6-{3-[(diethylam ino)methyl]phenoxy[1 ,2 ,4]triazolo[4 ,3-blpyridazin-3 yI )su Ifa nyl]- 1, 3-benzoth iazol-2-yllcyclopropa necarboxam ide 10 - N-(6-{[6-(3 ,5-d ifi uorophenoxy)[1 ,2 ,4]triazolo[4,3-bjpyridazi n-3-yI]su Ifanyl} 1, 3-benzoth iazol-2-yI )-N 2 , N 2 d iethylglycinam ide - N-(6-{[6-(3-fluorophenori)[1,2 ,4]triazolo[4 ,3-b] pyridazin-3-yI]su Itanyl}- ,3 benzoth iazol-2-yI)-2-hydroxyacetamide - 2-(4-cyclo pro pyl pi perazi n-I1 -YI)- N-(6-{[6-(3-fl uorop hen oxy)[1, 2 ,4] triazo lo[4, 3 15 b]pyridazin-3-yI]sulfa nyl)-1I,3-benzoth iazol-2-yi)acetamide - N-(6-{[6-(3 ,5-difluorophen oxy)[1 ,2,4jtriazolo[4 ,3-blpyridazin-3-yI]s u fanyl) I ,3-benzoth iazol-2-yI )-2-(4-ethylpiperazin-1 -yI)acetam ide

-

2

-(

4 -cyciopropylpiperazin-1 I-yl )-N-(6-{[6-(3 ,5-dif luoro phenoxy)[I ,2 ,4]triazolo [4, 3-b]pyridazin-3-yI]su Ifa nyl}-I 1 3-benzothiazol-2-yI )acetam ide 20 - N-{6-[(6-{3-[(d iethylamino)methyl] phenoxy}[I, 2,4]triazolo[4 ,3-b]pyridazin-3 yI)su Ifanyl]-I ,3-benzoth iazol-2-yI~acetamide - N-{6-[(6-{3-[(diethylam ino)methyl]phenoxy[1 ,2 , 4 ]triazolo[4,3-blpyridazin-3 yI )sulfa nylf- 1 ,3-benzoth iazol- 2 -yI-2-methoxyacetam ide - 2-methoxy-N-{6-[(6-{3..gI S , 4 S)2-oxa-5-azabicyclo[2 ,2,I11 hept-5-ylm ethyl] 25 ph enoxy}[1 ,2 ,4]triazo Io[ 4

,

3 -b]pyridazin-3..y)sulfanyljp 3-benzoth iazol-2-y} acetamide - S-{[ 6 -(oxetan-3-yloxy)[ 1,2 1 4]triazolo[4,3-blpyridazi n-3-yllsu Ifa nyl}- 1,3-benzo thiazol-2-amine - 2-(morphoin- 4 -yl)-N-( 6 -{L6-(tetrahydrofuran.3-y 0 ,)[1 ,2 ,4]triazolo [4,3-b] 30 pyridazin-3-yqjsu Ifanyl}-I 5 3 -benzothiazol-2-yI)acetam ide WO 2010/089507 PCT/FR2010/050178 58 - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl} 1,3-benzothiazol-2-yI)-2-(morpholin-4-yl)acetamide - N 2

,N

2 -diethyl-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-bjpyridazin 3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide 5 - 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]sulfa nyl}- 1,3 10 benzoth iazol- 2 -yl)cyclopropanecarboxamide

-

2 -(4-ethylpiperazin-1-yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyrid azin-3-yl]sulfa nyl}-1,3-benzoth iazol-2-yl)acetam ide

-

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 15 and also the addition salts with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of the said products of formula (1). The invention also relates to pharmaceutical compositions containing, as 20 active principle, at least one of the products of formula (1) as defined above or a pharmaceutically acceptable salt of this product or a prodrug of this product and, where appropriate, a pharmaceutically acceptable support. The invention thus covers pharmaceutical compositions containing, as active 25 principle, at least one of the medicaments as defined above. Such pharmaceutical compositions of the present invention may also, where appropriate, contain active principles of other antimitotic medicaments, especially such as those based on taxol, cisplatin, DNA-intercalating agents 30 and the like.

WO 2010/089507 PCT/FR2010/050178 59 These pharmaceutical compositions may be administered orally, parenterally or locally as a topical application to the skin and mucous membranes or via intravenous or intramuscular injection. 5 These compositions may be solid or liquid and may be in any pharmaceutical form commonly used in human medicine, for instance simple or sugar-coated tablets, pills, lozenges, gel capsules, drops, granules, injectable preparations, ointments, creams or gels; they are prepared according to the usual methods. The active principle may be incorporated therein with excipients usually used 10 in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or plant origin, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers, and preserving agents. 15 The usual dosage, which is variable according to the products used, the patient treated and the complaint under consideration, may be, for example, from 0.05 to 5 g per day or preferably from 0.1 to 2 g per day for an adult. A subject of the present invention is also the use of the products of formula (1) 20 as defined above or of pharmaceutically acceptable salts of these products for the preparation of a medicament for inhibiting the activity of a kinase protein. A subject of the present invention is also the use of products of formula (1) as 25 defined above for the preparation of a medicament for treating or preventing a disease characterized by deregulation of the activity of a kinase protein. Such a medicament may especially be intended for treating or preventing a disease in a mammal. 30 WO 2010/089507 PCT/FR2010/050178 60 A subject of the present invention is also the use defined above, in which the kinase protein is a tyrosine kinase protein. A subject of the present invention is also the use defined above, in which the 5 tyrosine kinase protein is MET or mutant forms thereof. A subject of the present invention is also the use defined above, in which the kinase protein is in a cell culture. 10 A subject of the present invention is also the use defined above, in which the kinase protein is in a mammal. A subject of the present invention is especially the use of a product of formula (1) as defined above for the preparation of a medicament for preventing or 15 treating diseases associated with an uncontrolled proliferation. A subject of the present invention is particularly the use of a product of formula (1) as defined above for the preparation of a medicament for treating or preventing a disease chosen from the following group: blood vessel 20 proliferation disorders, fibrotic disorders, "mesangial" cell proliferation disorders, metabolic disorders, allergies, asthmas, thromboses, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers. 25 A subject of the present invention is thus most particularly the use of a product of formula (I) as defined above for the preparation of a medicament for treating or preventing oncology diseases and especially for treating cancers. 30 Among these cancers, attention is focused on the treatment of solid or liquid tumours and the treatment of cancers that are resistant to cytotoxic agents.

WO 2010/089507 PCT/FR2010/050178 61 The cited products of the present invention may be used especially for treating primary tumours and/or metastases, in particular in stomach, liver, kidney, ovarian, bowel or prostate cancer, lung cancer (NSCLC and SCLC), 5 glioblastomas, thyroid, bladder or breast cancers, melanomas, lymphoid or myeloid haematopoietic tumours, sarcomas, brain cancers, cancer of the larynx, cancer of the lymphatic system, bone cancers and pancreatic cancers. A subject of the present invention is also the use of the products of formula (1) 10 as defined above for the preparation of medicaments intended for cancer chemotherapy. Such medicaments intended for cancer chemotherapy may be used alone or in combination. 15 The products of the present patent application may especially be administered alone or in combination with chemotherapy or radiotherapy or alternatively in combination, for example, with other therapeutic agents. 20 Such therapeutic agents may be commonly used antitumour agents. Kinase inhibitors that may be mentioned include butyrolactone, flavopiridol and 2-(2-hydroxyethylam ino)-6-benzylamino-9-methyl purine, known as olomoucine. 25 A subject of the present invention is also, as novel industrial products, the synthetic intermediates of formulae M1, M2, M3 and N with Rb representing a fluorine atom F, as defined above and recalled hereinbelow: WO 2010/089507 PCT/FR2010/050178 62 />-N S H (N /-N OR, Rb N O M1 M2 0 R 2 HSS>N HS Rb/ N2 NM3 Rb N N N in which the groups CONR1 R2, C02R6 and COR7, which constitute W, may take the values of W as defined above for the products of formulae (I') and (I"), when WM1. 5 The examples that follow, which are products of formula (1), illustrate the invention without, however, limiting it. Experimental section 10 The nomenclature of the compounds of the present invention was produced with the ACDLABS software version 11.0. Microwave oven used: 15 Biotage, Initiator EXP-EU, 300 W max, 2450 MHz The 400 MHz and 300 MHz 1 H NMR spectra were acquired using a Brtlker Avance DRX-400 or BrOker Avance DPX-300 spectrometer with the chemical 20 shifts (6 in ppm) in the solvent dimethyl sulfoxide-d 6 (DMSO-d 6 ) referenced to 2.5 ppm, at a temperature of 303 K. The Mass spectra were acquired either by analysis: - LC-MS-DAD-ELSD (MS = Waters ZQ ) WO 2010/089507 PCT/FR2010/050178 63 - LC-MS-DAD-ELSD (MS = Platform II Waters Micromass) - UPLC-MS-DAD-ELSD (MS = Quattro Premier XE Waters) DAD wavelength considered A = 210-400 nm ELSD: Sedere SEDEX 85; nebulization temperature = 35"C; nebulization 5 pressure = 3.7 bar Example 1: 6-[(6-phenoxy[1,2, 4 ]triazoIo[4,3-blpyridazin-3-yl)sulfanyl]-1,3-benzo thiazol-2-amine 10 a) 6-[(6-Phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo thiazol-2-amine may be prepared in the following manner: A stream of argon is bubbled through a solution of 622 mg of 2-amino-1,3 benzothiazol-6-yl thiocyanate (commercial) in 30 cm 3 of ethanol, for 5 minutes. 14 mg of potassium dihydrogen phosphate in 0.3 cm 3 of water, 15 1.39 g of DL-dithiothreitol and 740 mg of 3-chloro-6-phenoxy[1,2,4]triazolo [4,3-bipyridazine are then added. The reaction mixture is heated at 80 0 C for 24 hours, and then concentrated to dryness under reduced pressure. The residue is purified on silica by deposition of the solid, eluting with a 95/05 to 80/20 dichloromethane/(38 dichloromethane/1 7 methanol/2 aqueous 20 ammonia) gradient. 717 mg of 6-[(6-phenoxy[1,2, 4 ]triazolo[4,3-bjpyridazin-3 yl)sulfanyl]-1,3-benzothiazol-2-amine are thus obtained in the form of a white powder whose characteristics are as follows: 1H NMR SPECTRUM (400 MHz, DMSO-d6) 5 ppm 7.13 (dd, J = 8.3, 2.0 Hz, 1 H) 7.21 (d, J = 8.3 Hz, 1 H) 7.25 - 7.32 (m, 2 H) 7.32 - 7.39 (m, 2 H) 7.50 (t, 25 J = 7.8 Hz, 2 H) 7.61 (d, J = 1.5 Hz, 1 H) 7.64 (s, 2 H) 8.43 (d, J = 9.8 Hz, 1 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 may be prepared in the following manner: 30 254 mg of sodium hydride at 60% in oil are added to a solution of 996 mg of phenol in 20 cm 3 of tetrahydrofuran, at O'C under argon. After stirring for WO 2010/089507 PCT/FR2010/050178 64 15 minutes, 1 g of 3,6-dichloro[1, 2

,

4 ]triazolo[4,3-b]pyridazine (commercial) is added. The reaction medium is stirred while allowing it to warm gradually to 20"C over 23 hours. The reaction mixture is poured into water and the mixture obtained is extracted with ethyl acetate. The organic phase is concentrated to 5 dryness under vacuum. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60A; 32-63 pM), eluting with a 95/5 to 50/50 cyclohexane/ethyl acetate gradient. 1.07 g of 3-chloro-6-phenoxy[1, 2

,

4 ]triazolo[4,3-b]pyridazine are thus obtained in the form of a white powder, the characteristics of which are as follows: 10 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-benzo thiazol- 2 -yl}cyclopropanecarboxamide 15 a) N-{6-[(6-Phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3 benzothiazol-2-yl}cyclopropanecarboxamide may be prepared in the following manner: 0.120 cm 3 of cyclopropanecarboxylic acid chloride is added to a mixture of 250 mg of 6-[(6-phenoxyf[,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3 20 benzothiazol-2-amine (1a) in 5 cm 3 of pyridine at 20*C. After 2 hours 30 minutes, the reaction mixture is concentrated to dryness and the solid residue is chromatographed by solid deposition on Biotage Quad 12/25 (KP SIL, 60A; 32-63 pM), eluting with a gradient of from 100% dichloromethane to 96/4 dichloromethane/methanol. 221 mg of N-{6-[(6-phenoxy[1,2,4]triazolo 25 [ 4 ,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-y}cyclopropanecarboxamide are thus obtained in the form of a white powder, the characteristics of which are as follows: I H NMR SPECTRUM (400 MHz, DMSO-de) 5 ppm 0.93 - 0.98 (m, 4 H) 1.99 (quint, J = 6.2 Hz, 1 H) 7.20 - 7.45 (m, 7 H) 7.60 (d, J = 8.3 Hz, 1 H) 7.86 (d, J 30 = 1.7 Hz, 1 H) 8.46 (d, J = 10.0 Hz, 1 H) 12.67 (br. s., 1 H) MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 461+; MH- = 459- WO 20101089507 PCT/FR2010/050178 65 Example 3: N-{6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo thiazol-2-yI}acetamide 5 N-{6-[(6-Phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol 2-yI}acetamide may be prepared in a manner similar to that of Example 2a, but starting with 302 mg of 6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3 yl)sulfanyl]-1,3-benzothiazol-2-amine (1a) in 10 cm 3 of pyridine with 0.220 cm 3 of acetyl chloride after 24 hours of reaction at 20*C. 280 mg of N-{6-[(6 10 phenoxy[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)su Ifanylj-1 ,3-benzoth iazol-2-yl} acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows: 1H NMR SPECTRUM (400 MHz, DMSO--ds) 5 ppm 2.20 (s, 3 H) 7.23 (d, J = 7.6 Hz, 2 H) 7.26 - 7.33 (m, 2 H) 7.34 - 7.44 (m, 3 H) 7.61 (d, J = 8.6 Hz, 1 H) 15 7.87 (d, J = 1.7 Hz, 1 H) 8.46 (d, J = 9.8 Hz, 1 H) 12.39 (br. s., 1 H) 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]pyrid 20 azin-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] pyrid azin-3-yl)sulfanyl]-1, 3 -benzothiazol-2-yl}urea may be prepared in a manner similar to that of Example la, but starting with 533 mg of 1-[2-(morpholin-4 yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea, 10 cm 3 of degassed ethanol, 25 6 mg of potassium dihydrogen phosphate in 0.1 cm 3 of water, 606 mg of DL dithiothreitol and 324 mg of 3-chloro-6-phenoxy[1,2, 4 ]triazolo[4,3-b]pyridazine (1 b), after 32 hours at 80*C. 320 mg of 1-[2-(morpholin-4-yl)ethyl]-3-{6-[(6 ph enoxy[ 1, 2,4]triazolo[4,3-bipyridazi n-3-yl)su Ifa nyl]- 1,3-benzoth iazol-2-yl} urea are thus obtained in the form of a white powder, the characteristics of 30 which are as follows: WO 2010/089507 PCT/FR2010/050178 66 1 H NMR SPECTRUM (400 MHz, DMSO-de) 6 ppm 2.36 - 2.46 (m, 6 H) 3.24 3.29 (m, 2 H) 3.59 (t, J = 4.4 Hz, 4 H) 6.80 (t, J = 5.7 Hz, 1 H) 7.20 - 7.28 (m, 3 H) 7.29 - 7.34 (m, 1 H) 7.36 (d, J = 9.8 Hz, I H) 7.44 (t, J = 7.8 Hz, 2 H) 7.49 (d, J = 8.6 Hz, 1 H) 7.80 (d, J= 1.7 Hz, 1 H) 8.45 (d, J = 9.8 Hz, 1 H) 5 10.93 (br. s., 1 H) MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 549+; MH- = 547 b) 1 -(2-Morpholin-4-ylethyl)-3-(6-su Ifanyl- 1,3-benzoth iazol-2-yl)urea may be prepared in the following manner: A stream of argon is bubbled for 5 minutes through a mixture of 900 mg of 2 10 {[(2-morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl thiocyanate and 40 cm 3 of ethanol at 20*C. 11 mg of potassium dihydrogen phosphate in 0.4 cm 3 of water and 1.1 g of DL-dithiothreitol are then added. The mixture is heated at 80"C for 3.5 hours. The reaction mixture is cooled to 200C and then poured into water. The suspension is stirred for 45 minutes while maintaining 15 gentle bubbling with argon. The precipitate formed is filtered off by suction and washed with 3x10 cm3 of water and then dried under vacuum at 20*C. 633 mg of 1-(2-morpholin-4-yIethyl)-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a white solid, the characteristics of which are as follows: 20 MASS SPECTRUM: LC-MS-DAD-ELSD: MI+ m/z = 339+; (M-H)- = 337 c) 2-{[(2-Morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yI thiocyanate may be prepared in the following manner: 0.44 cm 3 of 2 -morpholin-4-ylethanamine is added at 20'C to a solution of 1 g of phenyl (6-thiocyanato-1, 3 -benzothiazol-2-yl)carbaimate in 30 cm 3 of 25 tetrahydrofuran at 200C. After 24 hours, the reaction mixture is evaporated to dryness and the residue obtained is chromatographed on a Merck 70g cartridge (solid deposition; elution with a gradient of dichloromethane and then 90/10 dichloromethane/methanol). 902 mg of 2-([(2-morpholin-4 ylethyl)carbamoyljamino}-1,3-benzothiazol-6-yI thiocyanate are thus 30 recovered in the form of a colourless foam, the characteristics of which are as follows: WO 2010/089507 PCT/FR2010/050178 67 MASS SPECTRUM: UPLC-MS-DAD-ELSD: MH+ m/z = 364+ d) Phenyl (6-th iocyanato- 1,3-benzothiazo l-2-yl)carbamate was prepared in the following manner: 7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen 5 carbonate and 9.4 cm 3 of water are added, at 20"C, to a solution of 2.5 g of commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm 3 of tetrahydrofuran. The resulting mixture is then stirred at 20 0 C for 20 hours and then extracted with 2x150 cm 3 of ethyl acetate. The organic phases are combined and then washed with 3x5Q cm 3 of saturated aqueous sodium 10 hydrogen carbonate solution. The organic phase obtained is dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is taken up in 50 cm 3 of water and then filtered off by suction and dried under vacuum at 20*C. 3.45 g of phenyl (6-thiocyanato-1,3 benzothiazol-2-yl)carbamate are thus obtained in the form of a pale yellow 15 solid, the characteristics of which are as follows: MASS SPECTRUM: LC-MS-DAD-ELSD: MH+ m/z = 328+; (M-H)- =326 Example 5: 1-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl} 20 1, 3 -benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea a) 1 -(6-{[6-(3-Fl uorop henoxy)[1,2,4]triazolo[4,3-b] pyridazin-3-yl]su Ifa nyl} 1, 3 -benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethylJurea may be prepared in a manner similar to that of Example 1a, but starting with 305 mg of 1-[2 (morpholin-4-yl)ethyl]-3-(6-sulfanyl-1, 3 -benzothiazol-2-yl)urea (4b), 5 cm 3 of 25 degassed ethanol, 4 mg of potassium dihydrogen phosphate in 0.1 cm 3 of degassed ethanol, 347 mg of DL-dithiothreitol and 202 mg of 3-chloro-6-(3 fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazine. 253 mg of 1-(6-{[6-(3 fluorophe noxy)[1, 2,4]triazolo[4,3-b] pyridazin-3-yl]su lfanyl}- 1, 3-benzoth iazol-2 yl)- 3

-[

2 -(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white 30 powder, the characteristics of which are as follows: WO 2010/089507 PCT/FR2010/050178 68 1H NMR SPECTRUM (400 MHz, DMSO-d) 5 ppm 2.36 - 2.45 (m, 6 H) 3.25 - 3.28 (m, 2 H) 3.59 (t, J = 4.3 Hz, 4 H) 6.78 (br. s., 1 H) 7.14 (dd, J = 8.3, 1.7 Hz, 1 H) 7.18 (td, J = 8.5, 2.3 Hz, I H) 7.23 - 7.31 (m, 2 H) 7.38 (d, J = 9.8 Hz, 1 H) 7.42 - 7.51 (m, 2 H) 7.84 (d, J = 1.7 Hz, I H) 8.47 (d, J = 9.8 Hz, 5 1 H) 10.89 (br. s., 1 H) 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 that of Example 1 b, but starting with 1.19 g of 3-fluorophenol in 15 cm 3 of tetrahydrofuran, 254 mg of sodium hydride at 60% 10 in oil and 1 g of 3,6-dichloro[1, 2

,

4 ]triazolo[4,3-blpyridazine (commercial). 837 mg of 3-chloro-6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a white powder, the characteristics of which are as follows: MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 265+ 15 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-benzo 20 thiazol-2-amine may be prepared in a manner similar to that of Example 1a, but starting with 529 mg of 3 -chloro-6-(3-fluorophenoxy)[1,2,4]triazolo[4,3 b]pyridazine (5b), 10 mg of potassium dihydrogen phosphate in 0.1 cm 3 of degassed ethanol, 926 mg of DL-dithiothreitol and 414 mg of 2-amino-1,3 benzothiazol-6-y thiocyanate (commercial) in 10 cm 3 of ethanol. 587 mg of 6 25 {[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo thiazol-2-amine are thus obtained in the form of a white powder, the characteristics of which are as follows: 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 7.11 to 7.25 (m, 4 H); 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 30 and 8.3 Hz, 1 H); 7.63 (broad s, 2 H); 7.65 (d, J = 2.0 Hz, 1 H); 8.45 (d, J = 9.8 Hz, 1 H) WO 2010/089507 PCT/FR2010/050178 69 MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 411; [M-H]-: m/z 409 Example 7: N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl) 5 1,3-benzothiazol-2-yI)- 2 -(2-methoxyethoxy)acetamide a) N-(6-{[6-(3-Fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl} 1,3-benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide may be prepared in the following manner: A mixture of 131 mg of ( 2 -methoxyethoxy)acetic acid (commercial), 0.17 cm 3 10 of diisopropylethylamine and 371 mg of O-(7-azabenzotriazol-1-yl)-N,NN',N' tetramethyluronium hexafluorophosphate (HATU) in 3 cm 3 of N,N dimethylformamide at 20 0 C is stirred for 1 hour at 20 0 C. 200 mg of 6-{[6-(3 fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl)-1,3-benzothiazol-2 amine (6) are added to the reaction medium. After 18 hours, the brown 15 solution is poured into ice-water and the precipitate is filtered off. After drying the precipitate, 219 mg of N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3 b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2 -yl)- 2 -(2-methoxyethoxy)acet amide are obtained in the form of a white powder, the characteristics of which are as follows: 20 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 3.29 (partially masked s, 3 H); 3.48 to 3.54 (m, 2 H); 3.66 to 3.71 (m, 2 H); 4.29 (s, 2 H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.2 and 8.3 Hz, I H); 7.24 (td, J = 2.2 and 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, IH); 7.42 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.63 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 25 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.20 (broad m, 1 H) MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 527; [M-H]-: m/z 525 Example 8:

N

2 , N 2 -diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3 30 yl]sulfanyl}-1, 3 -benzothiazol-2-yl)glycinamide WO 2010/089507 PCT/FR2010/050178 70 a) N 2 , N 2 -Diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-bjpyridazin 3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide may be prepared in the following manner: A mixture of 373 mg of sodium N,N-diethylglycinate (commercial) in 2.4 cm 3 of 5 a 2N solution of hydrogen chloride in ether is stirred for 1 hour at 200C. The resulting suspension is evaporated to dryness under vacuum. 4 cm 3 of pyridine, 100 mg of 6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-y] sulfanyl}-1,3-benzothiazol-2-amine (6) and 467 mg N-(3-dimethylamino propyl)-N'-ethylcarbodiimide hydrochloride are added, at 20*C, to the white 10 residue obtained. After 4 hours 30 minutes, the brown reaction medium is evaporated to dryness. The residue is taken up in water and the mixture is then extracted with ethyl acetate. The organic phase is evaporated to dryness. The oily brown residue is taken up in ether and the precipitate is filtered off by suction. 76 mg of N 2

,N

2 -diethyl-N-(6-{[6-(3-fluorophenoxy) 15 [1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1, 3 -benzothiazol-2-yl)glycinamide are thus obtained in the form of a beige-coloured powder, the characteristics of which are as follows: 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): for this crop, all the signals are broad, with: 1.00 (t, J = 6.9 Hz, 6 H); 2.63 (q, J = 6.9 Hz, 4 H); 20 3.41 (s, 2 H); 7.06 to 7.20 (m, 2 H); 7.24 (d, J = 9.5 Hz, I H); 7.31 (d, J = 8.3 Hz, 1 H); 7.35 to 7.47 (m, 2 H); 7.61 (d, J = 8.3 Hz, 1 H); 7.92 (s, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 9.44 to 14.07 (very broad m, 1 H) MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 524; [M-H]-: m/z 522 25 Example 9:

N

2 -cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin 3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide a) N 2 -Cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyrid azin-3-yl]suifanyl}-1

,

3 -benzothiazol-2-yl)glycinamide may be prepared in the 30 following manner: WO 2010/089507 PCT/FR2010/050178 71 0.13 cm 3 of cyclopropylamine is added to 137 mg of 2-chloro-N-(6-{[6-(3 fluorophenoxy)[1,2, 4 ]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2 yl)acetamide (9b) in 1.5 cm 3 of pyridine at 20 0 C. After stirring for 5 hours, the reaction medium is evaporated to dryness at 20*C. The residue is purified by 5 chromatography on a Merck silica cartridge by solid deposition, eluting with a gradient of from 100% dichloromethane to 97/3 dichloromethane/methanol. 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-2-yl)glycinamide are thus obtained in the form of a white solid, the characteristics of which are as follows: 10 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.19 to 0.42 (m, 4 H); 2.18 (m, 1 H); 3.52 (s, 2 H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1 H); 7.16 (ddt, J = 1.0 and 2.3 and 8.3 Hz, 1 H); 7.25 (td, J = 2.3 and 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.45 (dt, J = 6.9 and 8.3 Hz, 1H); 7.45 (broad m, 1 H); 7.60 (d, J = 8.3 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H); 15 8.49 (d, J = 9.8 Hz, 1 H) MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 508; [M-H]-: m/z 506 b) 2-Chloro-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-blpyridazin-3-y] sulfanyl}-1, 3 -benzothiazol-2-yl)acetamide may be prepared in the following manner: 20 0.06 cm 3 of chloroacetyl chloride is added dropwise to 205 mg of 6-{[6-(3 fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-y]su lfanyl}- 1, 3-benzoth iazol-2 amine (6) in 2 cm 3 of dichloromethane and 0.5 cm 3 of pyridine at 0-5*C. The resulting white suspension is stirred for 30 minutes at 20"C. 0.03 cm 3 of chloroacetyl chloride is added and the mixture is stirred for a further 30 25 minutes. A small amount of methanol is added to the mixture, and the medium is then evaporated to dryness under argon at 20"C. The residue is purified by chromatography on a Merck silica cartridge by solid deposition, eluting with a gradient of from 100% dichloromethane to 92/8 dichloromethane/(dichloromethane: 38/methanol: 17/aqueous ammonia: 2). 30 137 mg of 2-chloro-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3- WO 2010/089507 PCT/FR2010/050178 72 yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide are thus obtained in the form of a white solid, the characteristics of which are as follows: MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 487; [M-H]-: m/z 485 5 Example 10: N-[6-({6-[ 3 (morpholin-4-ylmethyl)phenoxy][1, 2 ,4]triazolo[4,3-b]pyrid azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide a) N-[6-({6-[3-(Morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyrid azin-3-yl}sulfanyl)-1,3-benzothiazol-2 -yllcyclopropanecarboxamide may be 10 prepared in a manner similar to that of Example 2a, but starting with 85 mg of 6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-blpyridazin-3-yl} sulfanyl)-1,3-benzothiazol-2-amine (1Ob) in 5 cm 3 of pyridine with 0.124 cm 3 of cyclopropanecarbonyl chloride after 3 hours 30 minutes of reaction at 50 0 C. 57.3 mg of N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo 15 [4,3-b]pyridazin-3-y}su Ifa nyl)-1,3-benzoth iazol- 2 -yl]cyclopropanecarboxam ide are thus obtained in the form of a white powder, the characteristics of which are as follows: 1 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 0.88 to 1.00 (m, 4 H); 1.92 to 2.04 (m, 1 H); 2.30 to 2.35 (m, 4 H); 3.39 (s, 2 H); 3.51 to 3.57 (m, 20 4 H); 7.09 to 7.14 (m, I H); 7.20 to 7.25 (m, 2 H); 7.28 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.31 to 7.39 (m, 2 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.83 (d, J = 2.0 Hz, 1 H); 8.47 (d, J = 9.8 Hz, 1H ); 12.68 (broad m, 1 H) MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 560; [M-H]-: m/z 558 b) 6-({6-[3-(Morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin 25 3-yl}sulfanyl)-1, 3 -benzothiazol-2-amine (10b) may be prepared in a manner similar to that of Example ia, but starting with 133 mg of 3-chloro-6-[3 (morpholin-4-ylmethyl)phenoxy][1, 2, 4 ]triazolo[4,3-b]pyridazine (10c), 3 mg of potassium dihydrogen phosphate in 0.1 cm 3 of degassed ethanol, 176 mg of DL-dithiothreitol and 79 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate 30 (commercial), in 5 cm 3 of ethanol. 111 mg of 6 -({6-[3-(morpholin-4 ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzo- WO 2010/089507 PCT/FR2010/050178 73 thiazol-2-amine are thus obtained in the form of a colourless oil, the characteristics of which are as follows: MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 492; [M+2H]2+: m/z 246.5 (base peak); [M-H]-: m/z 490 5 c) 3-Chloro-6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b] pyridazine (10c) may be prepared in a manner similar to that of Example lb, but starting with 310 mg of 3 -(morpholin-4-ylmethyl)phenol (1Od) in 5 cm 3 of tetrahydrofuran, 76 mg of sodium hydride at 60% in oil and 275 mg of 3,6 dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial). 138 mg of 3-chloro-6-[3 10 (morpholin-4-ylmethyl)phenoxy][ 1,2, 4 ]triazolo[4,3-b]pyridazine are thus obtained in the form of a brown oil, the characteristics of which are as follows: MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 346 d) 3 -(Morpholin-4-ylmethyl)phenol (10d) may be prepared in the following manner: 15 438 mg of morpholine are added to a solution of 188 mg of 3 (bromomethyl)phenol (10e) in 5 cm 3 of THF at 20"C. After twenty-four hours, the white suspension is concentrated to dryness under reduced pressure. The residue is taken up in water and then extracted with dichloromethane. The organic phase is evaporated to dryness to give a colourless oil that gradually 20 crystallizes. 182 mg of 3 -(morpholin-4-ylmethyl)phenol are thus obtained, the characteristics of which are as follows: MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 194 e) 3-(Bromomethyl)phenol (10e) may be prepared in the following manner: 25 3.19 cm 3 of a 1M solution of boron tribromide in dichloromethane are added to a solution of 500 mg of 1 -(chloromethyl)-3-methoxybenzene (commercial) in 5 cm 3 of dichloromethane at 20*C. After 19 hours, the resolution is poured into ice-water and then extracted with dichloromethane. The organic phase is evaporated to dryness under vacuum to give a violet-coloured oil that 30 crystallizes. This residue is purified by chromatography on a SPOT 11 machine equipped with an SVF D26 15-40 pM silica cartridge, after solid deposition, WO 2010/089507 PCT/FR2010/050178 74 eluting with a gradient of from 100% dichloromethane to 100% methanol. 328 mg of 3 -(bromomethyl)phenol are thus obtained in the form of pink crystals, the characteristics of which are as follows: MASS SPECTRUM: Waters ZQ: [M-H]-: mlz 185 5 Other examples and intermediates thereof prepared by analogy with the above examples are described in the table below: Ex. Name A E Starting with: AmOut isolated a. N-(6-{[6-(3-21mgo -[(3 fluorophenoxy)[1 ,2,4]triazolo| 212 mg of 6-{[6-(3 11 4 3 -blpyridazin-3-yl]sulfanyl} 3 fluorophenoxy)[1,2,4]triazolo[4,3 1,3-benzothiazol-2- b]pyridazin-3-yl]sulfanyl)-1,3-benzothiazol- 201 mg yI)acetamide 2-amine (6) and 41mg of acetyl chloride N-(6-{ [6-(3- 205 mg of 6-{[6-(3 fluorophenoxy)[1,2,4]triazolo[ fluorophenoxy)[1,2,4]triazolo[4,3 12 4,3-b]pyridazin-3-yl]sulfanyl}- 3 blpyridazin-3-yl]sulfanyl}-1,3-benzothiazol- 194 mg 1,3-benzothiazol-2- 2-amine (6) and 104 mg of yl)cyclopropanecarboxamide cyclopropanecarbony chloride 1-(6-{[6-(4- 200 mg of 3-chloro-6-(4 fluorophenoxy)[1,2,4]triazolo[ fluorophenoxy)[1,2,4]triazolo[4,3 13 4

,

3 -b]pyridazin-3-yl]sulfanyl}- 5a b]pyridazine (13b) and 358 mg of 1-[2- 133 mg 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- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 13b fluorophenoxy)[1,2,4]triazolol lb b]pyridazine (commercial) and 1.46 g of 4- 1.11 g 4,3-b]pyridazine fluorophenol 1 -(6-{[6-(3-fluoro-4 methylphenoxy)[1,2,4]triazol 200 mg of 3-chloro-6-(3-fluoro-4 o[4,3-b]pyridazin-3-ylsuIlf- methylphenoxy)[1,2,4]triazolo[4,3 anyl}- ,3-benzothiazol-2-y)- 5a bipyridazine (14b) and 340 mg of 1-[2- 202 mg 3-[2-(morphoiin-4- (morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3 yf)ethyl]urea benzothiazol-2-yl)urea (4b) 3-chloro-6-(3-fluoro-4- 1 g of 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-bipyridazine fluoro-4-methylphenol 6-{[6-(tetrahydro-2H-pyran-4- 500 mg of 3 -chloro-6-(tetrahydro-2H-pyran 15~ yloxy)[1,2,4]triazolo[4,3- 1a 4-yloxy)[1 2, 4 ]triazolo[4,3-b]pyridazine 416 mg b]pyridazin-3-yljsulfanyl}-1,3- (1 5b) and 407 mg of 2-amino-i ,3-benzo- WO 2010/089507 PCT/FR2010/050178 75 benzothiazol-2-amine thiazol-6-y thiocyanate (commercial) 3-chloro-6-(tetrahydro-2H- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 15b pyran-4-yloxy)[1,2,4]triazolo- lb b]pyridazine (commercial) and 1.35 g of 929 mg [4,3-b]pyridazine tetrahydro-2H-pyran-4-ol 6-{[6-(4- - 350 mg of 3-chloro-6-(4 16 fluorophenoxy)[1,2,4]triazolo fluorophenoxy)[1,2,4]triazolo[4,3 4,3-b]pyridazin-3-yl]sulfanyl}- Ia bipyridazine (13b) and 274 mg of 2-amino- 246 mg 1,3-benzothiazol-2-amine 1,3-benzothiazol-6-yi thiocyanate (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 17 4 -yloxy)[1,2,4]triazolo[4,3- Sa (15b) and 372 mg of 1-[2-(morpholin-4- 179 mg b]pyridazin-3-yl]sulfanyl)-1,3- yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2 benzothiazol-2-yl)urea yl)urea (4b) -[6-({6-[(1-ethylpiperidin-4- 200 mg of 3-chloro-6-[(1 -ethylpiperidin-4 18 b]pyridazin-3-yl}sulfany)-1,3- Sa yl)oxy][1, 2

,

4 ]triazolo[4,3-blpyridazine (18b) benzothiazo-2-y]-3-[2 - and 336 mg of 1-[2-(morpholin4-yl)ethyl]-3- 153 mg (morpholin-4-yl)ethyl]urea (6-sulfanyl-1, 3 -benzothiazol-2-yl)urea (4b) 3 -chloro-6-[1-ethylpiperidin- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 18b 4-y)oxy][1,2,4jtriazolo[4,3- lb b]pyridazine (commercial) and 168 g of 1- 758 mg b]pyridazine ethylpiperidin-4-ol N-(6-{[6-(tetrahydro-2H- 354 mg of 6 -{[6-(tetrahydro-2H-pyran-4 pyran-4-yloxy)[1,2,4]triazolo- yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3 19 [4,3-blpyridazin-3-yl]sulf- 3 yl]sulfanyl}-1,3-benzothiazol-2-amine (15) 198 mg anyl}-1,3-benzothiazol-2- and 0.162 cm 3 of cyclopropanecarbonyl yl)cyclopropanecarboxamide chloride N-(6-{[6-(4- 210 mg of 6-{[6-(4 fluorophenoxy)[1,2,4]triazolo[ fluorophenoxy)[1,2,4]triazolo[4,3 20 4

,

3 -b]pyridazin-3-yr]sulfanyl}- 3 b]pyridazin-3-yllsulfanyl}-1,3-benzothiazol- 149 mg 1,3-benzothiazol-2- 2-amine (16) and 0.094 cm 3 of yl)cyclopropanecarboxamide cyclopropanecarbonyl chloride N-(6-{[6-(3-fluoro-4- 560 mg of 6-{[6-(3-fluoro-4 methylphenoxy)[1,2,4]triazol methylphenoxy)[1,2,4]triazolo[4,3 21 o[ 4 ,3-b]pyridazin-3-yl]sulf- 3 b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol- 326 mg anyl}-1,3-benzothiazol-2- 2-amine (21 b) and 0.241 cm 3 of yl)cyclopropanecarboxamide cyclopropanecarbonyl chloride 6-{[6-(3-fluoro-4- 500 mg of 3-chloro-6-(3-fluoro-4 methylphenoxy)[1,2,4]triazol methylphenoxy)[1, 2,4]triazolo[4,3 21b o[ 4 ,3-b]pyridazin-3-y]sulf- Ia bipyridazine (14b) and 372 mg of 2-amino- 360 mg anyl)-1,3-benzothiazol-2- 1,3-benzothiazol-6-yi thiocyanate amine (commercial) N-[6-({6-[(1-ethylpiperidin-4- 235 mg of 6-({6-[(1-ethylpiperidin-4 22 yJ)oxy][1,2,4]triazolo[4,3- 3 yl)oxy][1,2, 4 ]triazolo[4,3-b]pyridazin-3- 155 mg b]pyridazin-3-yl}sulfanyl)-1,3- _ yulfanyl)-1, 3 -benzothiazol-2-amine (22b) WO 2010/089507 PCT/FR2010/050178 76 benzothiazol-2- and 0.101 cm 4 of cyclopropanecarbonyl yl]cyclopropanecarboxamide chloride 6-({6-[(1-ethylpiperidin-4- 500 mg of 3-chloro-6-(3-fluoro-4 22b yl)oxy][1,2,4]triazolo[4,3- methylphenoxy)[1,2,4]triazolo[4,3 b]pyridazin-3-yl)sulfanyl)-1,3- Ia b]pyridazine (14b) and 368 mg of 2-amino- 286 mg benzothiazol-2-amine 1,3-benzothiazol-6-yi thiocyanate (commercial) rac-1-[2-(morphon-4- 200 mg of rac-3-chloro-6-(tetrahydrofuran 23 (tetrahydrofuran-3- 3-yloxy)[1,2, 4 ]triazolo[4,3-blpyridazine yloxy)[1,2,4]triazolo[4,3- 5a (23b) and 394 mg of 1-[2-(morpholin-4- 173 mg b]pyridazin-3-yI]suIfanyl-1,3- yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2 benzothiazol-2-yl)urea yI)urea (4b) rac-3-chloro-6- 1 g of 3,6-dichloro(1,2,4]triazolo[4,3 23b (tetrahydrofuran-3- Ilb b]pyridazine (commercial) and 954 mg of 410 mg yloxy)[ 1 2,4]triazolo[4,3- rac-tetrahydrofuran-3-ol b~pyridazineI 1-(6-{[6-(1,3-benzodioxol-5- 200 mg of 6-(1,3-benzodioxol-5-yloxy)-3 24 b]pyridazin-3-y]sulranyl-11,3- 5a chloro[1,2,4]triazolo[4,3-b]pyridazine (24b) benzothiazol-2-yl)-3-[2- and 327 mg of 1-[2-(morpholin-4-yl)ethyl-3- 174 mg (morphoiin-4-yi)ethyl]urea (6-sulfanyl-1, 3 -benzothiazol-2-yl)urea (4b) 6-(1,3-benzodioxol-5- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 chloro[1 ,2,4]triazolo[4,3- lb bpyridazine (commercial) and 1.8 g of 1,3- 1.07 g b]pyridazine benzodioxol-5-ol I1-(6-{[6-(3,4 dichlorophenoxy)[1,2,4]triazo 200 mg of 3-chloro-6-(3,4 25 lol 4 ,3-b]pridazin-3-yflsulIf- dichlorophenoxy)[1,2,4]triazolo[4,3 anyl}-I,3-benzothiazol-2-yl)- 5a bipyridazine (25b) and 300 mg of 1-[2- 90 mg 3-[2-(morpholin-4- (morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3 yl)ethylj urea benzothiazol-2-yl)urea (4b) 3-chloro-6-(3,4- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 25b dichlorophenoxy)[1,2,4]triazo lb b]pyridazine (commercial) and 2.12 g of 680 mg lo[4,3-b]pyridazine 3.4-dichlorophenol 6-{[6-(3,4- 500 mg 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-y]sulf- Ia b]pyridazine (25b) and 328 mg of 2-amino- 155 mg anyl)-1,3-benzothiazol-2- 1,3-benzothiazol-6-yl thiocyanate amine (commercial) rac-6-{[6-(tetrahydrofuran-3- 500 mg of rac-3-chloro-6-(tetrahydrofuran 27 yloxy)[1,2,4]triazolo[4,3- 1a 3-yloxy)[1 2,4 1 triazolo[4,3-bpyridazine b]pyridazin-3-yJ]sulfanyl}- ,3- (23b) and 431 mg of 2-amino-1,3-benzo- 297 mg benzothiazol-2-amine thiazol-6-yl thiocyanate (commercial) WO 2010/089507 PCT/FR2010/050178 77 1-(6-{[6-(1 H-indol-6 yloxy)[1,2,4]triazolo[4,3- 250 mg of 3-chloro-6-(1 H-indol-6 28 b]pyridazin-3-ylsulfanyl}-1,3- 5a yloxy) , 2 4 ]triazolo[4,3-bpyridazine (28b) 298 benzothiazol-2-yl)-3-[2- and 355 mg of 1-[2-(morpholin-4-yl)ethyl]-3 mg (morpholin-4-y)ethyl]urea (6-sulfanyl-1,3-benzothiazol-2-yl)urea (4b) 3-chloro-6-(1 H-indol-6- I g of 3,6-dichloro[12,4]triazolo[4,3 28b yloxy)[1,2,4]triazolo[4,3- lb b]pyridazine (commercial) and 1.73 g of I H- 1.01 g b]pyridazine indol-6-ol rac-N-(6-{[6 (tetrahydrofuran-3- 228mg of rac-6-{[6-(tetrahydrofuran-3 yloxy1,2,4]iazo3- yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3 b]pyridazin-3-ylsulfanyl-1,3- 3 yl]sulfanyl)-1,3-benzothiazol-2-amine (27) 164 mg benzothiazol-2- and 0.108 cm 3 of cyclopropanecarbonyl yl)cycopropanecarboxamide chloride N-(6-{[6-(1,3-benzodioxol-5- 300 mg of 6-{[6-(1,3-benzodioxol-5 yloxy)[1,2,4]triazolo[4,3- yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3 30 b]pyridazin-3-yl]sulfanyl}-1,3- 3 yl]sulfanyl)-1, 3 -benzothiazol-2-amine (30b) 202 mg benzothiazol-2- and 0.127 cm 3 of cyclopropanecarbonyl yl)cyclopropanecarboxamide chloride 6-{[6-(1,3-benzodioxol-5- 360 mg of 6-(1,3-benzodioxol-5-yloxy)-3 30b yloxy)[1,2,4]triazolo[4,3- 1la chloro[1,2, 4 ]triazolo[4,3-b]pyridazine (24b) 679 mg b]pyridazin-3-yl]sulfanyl}-1,3- and 357 mg of 2-amino-1,3-benzothiazol benzothiazol-2-amine 6yi thiocyanate (commercial) N-(6-{[6-(3,4- 115 mg of 6-{[6-(3,4 dichlorophenoxy)[1,2,4]triazo dichlorophenoxy)[1,2,4]triazolo{4,3 31 Io[4,3-b]pyridazin-3-yl]sulf- 3 blpyridazin-3-y]sulfanyl}-1,3-benzothiazol- 75 mg anyl}-1,3-benzothiazol-2- 2-amine (26) and 0.046 cm 3 of yl)cyclopropanecarboxamide cyclopropanecarbonyl chloride N-(6-{[6-(1 H-indol-6- 345 mg of 6-{[6-(1 H-indol-6 yioxy)[1,2,4Itriazolo[4,3- yloxy)[1,2, 4 ]triazolo[4,3-b]pyridazin-3 32 b]pyridazin-3-yl]sulfany)-1,3- 3 yl]sulfanyl}-1,3-benzothiazol-2-amine (32b) 396 mg benzothiazol-2- and 0.147 cm 3 of cyclopropanecarbonyl yl)cyclopropanecarboxamide chloride 6-{[6-(1 H-indol-6- 500 mg of 3-chloro-6-(1 H-indol-6 32b yloxy)[1,2,4]triazolo[4,3- 1a yloxy)[1,2,4]triazolo[4,3-b]pyridazine (28b) 396 mg b]pyridazin-3-yl]sulfanyl}-1,3- and 363 mg of 2-amino-1,3-benzothiazol-6 benzothiazol-2-amine yl thiocyanate (commercial) N-(6-{ [6-(3- 200 mg of 6-{[6-(3 fluorophenoxy)[1,2,4]triazolol fluorophenoxy)[1,2,4]triazolo[4,3 33 4 ,3-b]pyridazin-3-yllsulfanyl}- 3 b]pyridazin-3-yl]sulfanyll-1 ,3-benzothiazol- 170 mg 1,3-benzothiazol-2- 2-amine (6) and 0.111 cm 3 of yl)cyclobutanecarboxamide cyclobutanecarbony chloride N-(6-{[6-(3- 200 mg of 6-{[6-(3 34 fluorophenoxy)[1,2,4]triazolo 3 fluorophenoxy)[1,2,4]triazolo[4,3- 129 mg 4,3-bpyridazin-3-yl]sulfanyl} __ bipyridazin-3-yI]sulfanyl}-1,3-benzothiazol- WO 2010/089507 PCT/FR2010/050178 78 1,3-benzothiazol-2-yl)-N2,N2_ 2-amine (6) and 116 mg of N,N dimethylglycinamide dimethylglycyl chloride hydrochloride in refluxing dichloromethane 2-ethoxy-N-(6-{[6-(3- 200 mg of 6-{[6-(3 fluorophenoxy)[1,2,4]triazolol fluorophenoxy)[1,2,4]triazolo[4,3 35 4 ,3-bpyrdazin-3-yl]sulfanyl}- 7 b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol- - 223 mg 1,3-benzothiazol-2- 2-amine (6) and 101 mg of ethoxyacetic yl)acetamide acid and 371 mg of HATU 2-(cyclohexyloxy)-N-(6-{[6- 200 mg of 6-{[6-(3 (3- fiuorophenoxy)[1,2,4]triazolo{4,3 36 fluorophenoxy)[1,2,4]triazolol 7 b]pyridazin-3-ylsulfanyl}-1,3-benzothiazol- 130 mg 4, 3 -b]pyridazin-3-yl]sulfany}- 2-amine (6) and 154 mg of 1,3-benzothiazol-2- (cyclohexyloxy)acetic acid and 371 mg of yl)acetamide HATU 6-{[6-(pyridin-3- 460 mg of 3-chloro-6-(pyridin-3 37 yoxy)[1,2,4jtriazolo[4,3- 1l yloxy)[1,2 ,4 ]triazolo[4,3-b]pyridazine (37b) 400 b]pyridazin-3-yl]sulfanyl}-1,3- and 347 mg of 2-amino-1,3-benzothiazol-6- m benzothiazol-2-amine yl thiocyanate (commercial) 3-chloro-6-(pyridin-3- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 37b yloxy)[1,2,4]triazolo[4,3- Ib b]pyridazine (commercial) and 1.01 g of 408 mg bjpyridazine pyridine-3-ol 6-({6-[3- 200 mg of 3-chloro-6-[3 (trifluoromethoxy)phenoxy][1 (trifluoromethoxy)phenoxy][1,2,4]triazolo 38 , 2

,

4 ]triazolo[4,3-b]pyridazin- 1a [4,3-b]pyridazine (38b) and 126 mg of 2- 111 mg 3-yl}sulfanyl)-1,3-benzo- amino-1,3-benzothiazol-6-y thiocyanate thiazol-2-amine (commercial) 3-chloro-6-[3- 500 mg of 3,6-dichloro[1,2,4]triazolo[4,3 38b (trifluoromethoxy)phenoxy][1 lb b]pyridazine (commercial) and 950 mg of 3- 216 mg ,2, 4 ]triazolo[4,3-b]pyridazine (trifluoromethoxy)phenol 2-methylpropan-2-y [3-({3- 550 mg of 2-methylpropan-2-yl {3-[(3 [(2-amino-1,3-benzothiazol- chloro[1,2, 4 ]triazolo[4,3-b]pyridazin-6 39 6-yl)sulfanyl][1,2,4]triazolo- Ia yl)oxylphenyl}carbamate (39b) and 315 mg 131 mg [4,3-b]pyridazin-6- of 2-amino-1,3-benzothiazo-6-y ylIoxy)phenyl]carbamate thiocyanate (commercial) 2-methylpropan-2-yi (3-[(3- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 39b chloro[1,2,4]triazolo[4,3- lb b]pyridazine (commercial) and 2.21 g of 2- 1.43 g b]pyridazin-6- methylpropan-2-yl (3 yl)oxy]phenyl}carbamate hydroxyphenyl)carba mate N-(6-{[6-(pyridin-3- 330 mg of 6-{{6-(pyridin-3 yloxy)[1,2,4]triazolo[4,3- yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3 40 b]pyridazin-3-y]sulfany}-1,3- 3 yl]sulfanyl}-1,3-benzothiazol-2-amine (37) 262 mg benzothiazol-2- and 0.091 cm 3 of cyclobutanecarbony yl)cyclobutanecarboxamide chloride 41 N-(6-{[6-(3- g 225 mg of 2-chloro-N-(6-{[6-(3 fluorophenoxy)[1,2,4]triazolol fluorophenoxy)[1,2,4]triazolo[4,3- 184 mg WO 2010/089507 PCT/FR2010/050178 79 4,3-b]pyridazin-3-yl]sulfanyl}- b]pyridazin-3-yl]sulfanyl)-1,3-benzothiazol 1,3-benzothiazol-2-yl)-2- 2-yl)acetamide (9b) and 0.40 cm 3 of (morpholin-4-yi)acetamide morpholine

N

2 -cyclohexyl-N-(6-{[6-(3- 225 mg of 2-chloro-N-(6-{[6-(3 fluorophenoxy)[1,2,4]triazolol fluorophenoxy)[1,2,4]triazolo[4,3 42 4 ,3-b]pyridazin-3-yl]sulfanyl}- 9 b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol- 65 mg 1,3-benzothiazol-2- 2-yl)acetamide (9b) and 0.40 cm 3 of yl)glycinamide cyclohexylamine fluorophenoxy)[1,2,4]triazolo 243 mg of 2-chioro-N-(6-{[6-(3 4,3-bpridazin-y)1.]ulfanyl} fluorophenoxy)[1,2,4]triazolo[4,3 43 ,3-bLnohiazI--yljuIfany)- 9 b]pyridazin-3-yl]suifanyl}-1,3-benzothiazol- 149 mg methyi-N[2-(morpholin-4- 2-yl)acetamide (9b) and 425 mg of N yl)ethyl]glycinamide methyl-2-(morpholin-4-yl)ethanamine 2 -(4-ethylpiperazin-1 -yl)-N- 200 mg of 6-{[6-(3 (6-{[6-(3- fluorophenoxy)[1,2,4]triazolo[4,3 fluorophenoxy)[1,2,4]triazolo| 7 bjpyridazin-3-yl]sulfanyl}-1,3-benzothiazol 4,3-b]pyridazin-3-yl]sulfanyl}- 2-amine (6) and 247mg of (4 1,3-benzothiazol-2- ethylpiperazin-1 -yl)acetic acid yl)acetamide hydrobromide and 371 mg of HATU 6-{ [6-(3,5- 350 mg of 3-chloro-6-(3,5 difluorophenoxy)[1,2,4]triazol d ifluorophenoxy)[1,2,4]triazolo[4,3 45 o[4,3-blpyridazin-3-yl]sulf- 1a b]pyridazine (45b) and 257 mg of 2-amino- 85 mg anyl}-1,3-benzothiazol-2- 1,3-benzothiazol-6-y thiocyanate amine (commercial) 3-chloro-6-(3,5- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 45b difluorophenoxy)[1,2,4]triazol lb b]pyridazine (commercial) and 1.38 g of 363 mg o[4,3-b]pyridazine 3,5-difluorophenol 550 mg of 2-methylpropan-2-y (3-[(3 6-{[6-(3- chloro[1, 2 ,4]triazolo[4,3-bjpyridazin-6 aminophenoxy)[1,2,4]triazolo yl)oxy]phenyl}carbamate (39b) and 315 mg 46 [4,3-b]pyridazin-3-yl]sulf- I a of 2-amino-1,3-benzothiazol-6-y 137 mg anyl}-1,3-benzothiazol-2- thiocyanate (commercial) note: 2 amine methylpropan-2-yl carbamate is cleaved in these operating conditions. N-(6-{[6-(3-24mgo -hooN([6(3 fluorophenoxy)[1,2,4]triazolo| 243 mg of 2-chloro-N-(6-[6-(a3 47 4,3-bjpyridazi n-3-yl]sulfanyl}- ftuorophenoxy)[1 ,2 ,4]triazolo[4,3 1 ,3-benzothiazor-2-yl)-N~2- 9 b]pyridazin-3-yl]sulfanyl}.1,3-benzothiazol- 81 mg (tetrahydro-2H-pyran-4- 2-yl)acetamide (9b) and 400 mg of yI)glycinam ide tetrahydro-2 H-pyran-4-amine N-[6-({6-[4-(trifluoromethyl)- 85 mg of 6-({6-[4 phenoxy][1,2,4]triazolo[4,3- (trifluoromethy)phenoxy][1,2,4]triazolo[4 ,3 48 b]pyridazin-3-yl}sulfanyl}-1,3- 3 blpyridazin-3-yl}sulfanyl)-1,3-benzothiazol- 58 mg benzothiazol-2-yljcyclo- 2-amine (48b) and 0.034 cm 3 of propanecarboxamide cyclopropanecarbonyl chloride WO 2010/089507 PCT/FR2010/050178 80 6-({6-[4- 350 mg of 3-chloro-6-[4 (trifluoromethyl)phenoxy][1,2 (trifluoromethyi)phenoxy][1,2,4]triazolo[4,3 48b ,4]triazolo[4,3-b]pyridazin-3- 1a bipyridazine (45b) and 231 mg of 2-amino- 109 mg yi}sulfany)-1.,3-benzothiazol- 1,3-benzothiazol-6-y thiocyanate 2-amine (commercial) 3-chloro-6-[4-(trifluoro- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 48c methyl)phenoxy][1,2,4]- lb b]pyridazine (commercial) and 1.29 g of 4- 356 mg triazolo[4,3-b]pyridazine (trifluoromethyl)phenol N-[6-({6-[3-14mgo (6[3 (trifluoromethoxy)phenoxy][1 144 mg of 6-({6-[3 ,2, 4 ]triazolo[4,3-blpyridazin- (trifluoromethoxy)phenoxy][1,2,4]triazolo 3-y2,4sulfanl),3-be n- 3 [ 4 ,3-b]pyridazin-3-yl)sulfanyl)-1,3-benzo- 61 mg 3-ylsulfanyl)-1 ,3-benzo- thiazol-2-amine (38) and 0.055 cm 3 of thiazol-2- ylpoaeabn cord yl]cyclopropanecarboxamide cyclopropanecarbonyl chloride N-[6-({6-[(2-methylpyridin-3- 84 mg of 6 -({6-[(2-methylpyridin-3 yl)oxy][1,2,4]triazolo{4,3- yl)oxy][1,2,4]triazolo[4,3-bjpyridazin-3 50 b]pyridazin-3-y)sulfanyl)-1,3- 3 yl}sulfanyl)-1,3-benzothiazol-2-amine (50b) 71 mg benzothiazol-2- and 0.040 cm 3 of cyclopropanecarbonyl yl]cyclopropanecarboxamide chloride 6 -({6-[(2-methylpyridin-3- 550 mg of 3 -chloro-6-[(2-methylpyridin-3 50b yI)oxy][1,2,4]triazolo[4,3- 1a yI)oxy][1,2, 4 ]triazolo[4,3-b]pyridazine (soc) 84 mg bJpyridazin-3-yl}sulfanyl)-1,3- and 436 mg of 2 -amino-1,3-benzothiazol-6 benzothiazol-2-amine yl thiocyanate (commercial) 3 -chloro-6-[(2-methylpyridin- I g of 3,6-dichloro[1,2,4]triazolo[4,3 50c 3-yl)oxy][1,2,4]triazolo[4,3- lb b]pyridazine (commercial) and 1.16 g of 2- 734 mg b]pyridazine methylpyridin-3-ol N-(6-{[6-(3,5- 75 mg of 6-{{6-(3,5 difluorophenoxy)[1,2,4]triazol difluorophenoxy){1,2,4]triazolo[4,3 51 o[4,3-b]pyridazin-3-yl]sulf- 3 blpyridazin-3-yljsulfanyl)-1,3-benzothiazol- 37 mg anyl}-1,3-benzothiazol-2- 2-amine (45) and 0.033 cm 3 of yl)cyclopropanecarboxamide cyclopropanecarbonyl chloride 2-[(6-{[6-(3- 112 mg of 6-{[6-(3 fluorophenoxy)[1,2,4]triazolo| fluorophenoxy)[1,2,4]triazolo[4,3 52 4

,

3 -b]pyridazin-3-yl]sulfanyi}- 3 blpyridazin-3-yi]sulfanyl)-1 ,3-benzothiazol- 62 mg 1,3-benzothjazol-2- 2-amine (6) and 0.107 cm 3 of 2-chloro-2 yl)amino]-2-oxoethyl acetate oxoethyl acetate N-[6-({6-[(6-methylpyridin-3- 69 mg of 6 -({6-[(6-methylpyridin-3 yl)oxy][1,2,4]triazolo[4,3- yl)oxy][1,2, 4 ]triazolo[4,3-b]pyridazin-3 53 blpyridazin-3-ylsulfanyl)-1,3- 3 yl}sulfanyl)-1, 3 -benzothiazol-2-amine (53b) 45 mg benzothiazol-2- and 0.031 cm 3 of cyclopropanecarbonyl yl]cyclopropanecarboxamide chloride 6 -({6-[(6-methylpyridin-3- 255 mg of 3 -chloro-6-[(6-methylpyridin-3 53b yl)oxy][1,2,4]triazoio[4,3- 1a yl)oxy][1,2, 4 ]triazolo[4,3-b]pyridazine (53c) 69 mg b]pyridazin-3-yl}sulfanyl)-1,3- and 202 mg of 2-amino-1,3-benzothiazol-6 benzothiazol-2-amine yl thiocyanate (commercial) WO 2010/089507 PCT/FR2010/050178 81 3-chloro-6-[(6-methylpyridin- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3 53c 3-yl)oxy][1,2,4]triazolo[4,3- 1b b]pyridazine (commercial) and 1.16 g of 6- 260 mg b]pyridazine methylpyridin-3-ol N-[6-({6-[4-(morpholin-4- 87 mg of 6 -({6-[4-(morpholin-4 ylmethyl)phenoxy][1,2,4]triaz ylmethyl)phenoxy][1,2,4]triazolo[4,3 54 olo[4,3-b]pyridazin-3-yl}sulf- 3 b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol- 86 mg anyl)-1,3-benzothiazol-2- 2-amine (54b) and 0.024 cm 3 of yllcyclopropanecarboxamide cyclopropanecarbonyl chloride 6-({6-[4-(morpholin-4- 155 mg of 3-chloro-6-[4-(morpholin-4 ylmethyl)phenoxy][1,2,4]triaz ylmethyl)phenoxy][1,2,4]triazolo[4,3 54b olo[4,3-b]pyridazin-3-yl}sulf- Ia b]pyridazine (54c) and 93 mg of 2-amino- 91 mg anyl)-1,3-benzothiazol-2- 1,3-benzothiazol-6-yl thiocyanate amine (commercial) 3-chloro-6-(4-(morpholin-4- 189 mg of 3,6-dichloro[1,2,4]triazolo[4,3 54c ylmethyl)phenoxy][1, 2,4]triaz lb b]pyridazine (commercial) and 207 mg of 4- 158 mg olo[4,3-b]pyridazine (morpholin-4-ylmethyl)phenol (54d) 54d 4-(morpholin-4- 10d 185mg of 4-(chloromethyl)phenyl acetate 207 mg ylmethyl)phenol and 436 mg of morpholine 2-methylpropan-2-yl ( 84 mg of 2-methylpropan-2-y [3-(33--(2

((

2 - 13cy-lopropylcarbonyl)- amino-1,3-benzothiazol-6-yl)sulf yl}su Ifanyl)1,2,4]triazolo[4,3- 3 anyl][1,2,4]triazolo[4,3-b]pyridazin-6- 59 mg b]pyridazin-6-yl]oxy}- ylloxy)phenyl]carbamate (39) and phenyl)carbamate 0.031 cm 3 of cyclopropanecarbonyl chloride N-(6-{[6-(pyrid in-3 yloxy){1,2,4]triazolo[4,3- 150 mg of 6-[6-(pyridin-3-yloxy) 56 blpyridazin-3-yl]sulfanyl}-1,3- 3 [1,2 ,4 ]triazolo[4,3-b]pyridazin-3-yl]sufanyl} benzothiazol-2- 1,3-benzothiazol-2-amine (37) and 143 mg yl)cyclopropanecarboxamide 0.070 cm 3 of cyclopropanecarbonyl chloride N-[(6-{3-[(1S,4S)-2-oxa-5- 46 mg of 6-[ 6 -({3-[(lS,4S)-2-oxa-5-aza azabicyclo[2,2, 1 ]hept-5- bicyclo[2,2,I]hept-5-ylmethyl]phenoxy} 57 ylmethyl]phenoxy}[1,2,4]triaz 3 [1,2, 4 ]triazolo[4,3-b]pyridazin-3-yl)surfanyl]- 31 mg olo[4,3-b]pyridazin-3-yl)sulf- 1,3-benzothiazol-2-amine (57b) and anylJ-1,3-benzothiazol-2- 0.105 cm 3 of cyclopropanecarbonyl chloride yl}cyclopropanecarboxamide for 4 hours at 50 0 C -[(-{3-(ilS,4S)-2-oxa-5- 103 mg of 3-chloro-6-{3-(1lS,4S)-2-oxa-5 57b ylmethyl]phenoxy)[ ,2,4]triaz azabicyclo[2,2, I]hept-5-ylmethyl]phenoxy} olo[4,3-b]pyridazin-3-yl)sulf- Ia [1,2, 4 ]triazolo[4,3-b]pyridazine (57c) and 60 51 mg anyl]-1,3-benzothiazol-2- mg of 2-amino-1,3-benzothiazol-6-y amine thiocyanate (commercial) 3-chloro-6-{3-[(1 S,4S)-2-oxa- 85 mg of 3,6-dichloro[1,2,4]triazolo[4,3 57c 5-azabicyclo[2,2,1]hept-5 b b]pyridazine (commercial) and 110 mg of 3 ylmethyl]phenoxy)[1,2,4]triaz [(1S, 4 S)-2-oxa-5-azabicyco[2,2,1 ]hept-5 olo[4,3-b]pyridazine ylmethyljphenol (57d) WO 2010/089507 PCT/FR2010/050178 82 3-[(1S,4S)-2-oxa-5- 188 mg of 3-(bromomethyl)phenol (10e) 57d azabicyclo[2,2,1]hept-5- 10d and 163 mg of (1S,4S)-2-oxa-5 ylmethyljphenol azabicyclo[2,2,1]heptane hydrochloride 111 mg (commercial) N-{6-[(6-{3- 4 go +-3 {(diethylamino)methyljpheno 46 mg of 6-[6-{3 58 xy}[1,2,4]triazolo[4,3.. [(diethylamino)methylphenoxy[1,2,4]triazol b] pyridazin-3-yl)sulfanyl]-1 3 o[4,3-blpyridazin-3-yl)sulfanyl]-1,3-benzo- 30 mg benzothiazol-2- thiazol-2-amine (58b) and 0.013 cm 3 Of yl}cyclopropanecarboxamide cyclopropanecarbonyl chloride 6-[(6-{3- 160 mg of N-{3-[(3-chloro[1,2,4]triazolo[4,3 [(diethylamino)methyl]pheno bjpyridazin-6-yl)oxyjbenzyl}N 58b xy}[1,2,4]triazolo[4,3- 1a ethylethanamine (58c) and 120 mg of 2- 157 mg b]pyridazin-3-yl)sulfanyl]-1,3- amino-1,3-benzothiazol-6-y thiocyanate benzothiazol-2-amine (commercial) N-3-[(3-ohloro[1,24]triazolo- 148 mg of 3,6-dichloro[1,2,4]triazolo[4,3 58c y43-bpyridain-6- lb b]pyridazine (commercial) and 169 mg of 3- 163 mg yl)oxy]benzyl-N- [(diethylamino)methyl]phenol (58d) ethylethanamine 58d 3- 1d 375 mg of 3-(bromomethyl)phenol (10e) 188 mg [(diethylamino)methyl]phenol and 731 mg of diethylamine N-(6-{[6-(3,5- 200 mg of 6-{[6-(3,5 difluorophenoxy)[1,2,4]triazol difluorophenoxy)[1,2,4]triazolo[4,3 59 o[4,3-b]pyridazin-3-yl]sulf- 8 b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol- 127 mg anyl}-1,3-benzothiazol-2-y)- 2-amine (45) and 715 mg of the sodium salt

N

2

,N

2 -diethylglycinamide of NN-diethylglycine 510 mg 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]sulfany}-1,3-benzothiazol 60 4 ,3-b]pyridazin-3-yl]sulfanyl}- 2 -yl)amino]-2-oxoethyl acetate (52) and 1,3-benzothiazol-2-yl)-2- 42mg of lithium hydroxide hydrate under 262 mg hydroxyacetamide conditions similar to those described by T. G. Murali Dhar et a. in J. Med. Chem. 2002, 45, 2127-2130 2

-(

4 -cyclopropylpiperazin-1- 243 mg of 2-chloro-N-(6-{[6-(3 yl)-N-(6-{[6-(3- fluorophenoxy)[1,2,4]triazolo{4,3 61 fluorophenoxy)[1,2,4]triazolo[ b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol 4,3-b]pyridazin-3-yl]sufanyl}- 9 2-yl)acetamide (9b) and 200 mg of 1- 242 mg 1,3-benzothiazol-2- cyclopropylpiperazine dihydrochloride yl)acetamide (commercial) with triethylamine in N,N dimethylformamide N-(6-{[6-(3,5- 200 mg of 6-{[6-(3,5 difluorophenoxy)[1,2,4]triazol difluorophenoxy)[1,2,4]triazolo[4,3 62 o[4,3-b]pyridazin-3-y]suf- 8 b]pyridazin-3-yljsulfanyl}-1,3-benzothiazol- 144 mg anyl}-1,3-benzothiazol-2-yf)- 2-amine (45) and 1.19 g of (4 2-(4-ethylpperazin- ethylpiperazin-1-yl)acetic acid; WO 2010/089507 PCT/FR2010/050178 83 yl)acetamide (commercial) 2

-(

4 -cyclopropylpiperazin-1- 142 mg of 6-{[6-(3,5 yl)-N-(6-[6-(3,5- difluorophenoxy)[1,2,4]triazolo[4,3 63 difluorophenoxy)[1,2,4]triazol 8 b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol o[4,3-bJpyridazin-3-y]]sulf- 2-amine (45) and 683 mg of the potassium 65 mg anyl}-1,3-benzothiazol-2- salt of ( 4 -cyclopropylpiperazin-1-y])acetic yl)acetamide acid (63b)(or commercial) 2.1 g of bromoacetic acid and 3 g of 4 potassium salt of (4- cyclopropylpiperazine hydrochloride § 63b cyclopropylpiperazin-1- § under conditions similar to those described 2.66 g yl)acetic acid by D. T. Witiak et at; J. Med. Chem. 1985, 28, 1228 [diethylamino)methyl]pheno 120 mg of 6-[( 6 -{3-[(diethylamino)methyl] 64 xy)1l,2,4]triazolo[4,3- 3 phenoxy}[1,2, 4 ]triazolo[4,3-b]pyridazin-3 b]pyridazin-3-yl)sulfany]1,3 yI)su lfanyl]- 1, 3 -benzothiazol-2-amine (58b) 84 mg benzothiazoi-2-yl}acetamide and 20 mg of acetyl chloride N-{6-[(6-{3 [(diethylam ino)methyl]pheno 120 mg of 6-[( 6 -{3-[(diethylamino)methyl] 65 xy}[1,2,4]triazolo[4,3- 3 phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3 b]pyridazin-3-yl)sulfanyl]-1,3- yl)sulfanyl]-1 ,3-benzothiazol-2-amine (58b) 76 mg benzothiazol-2-yl}-2- and 33 mg of 2-methoxyacetyl chloride methoxyacetamide 2-methoxy-N-{6-[(6-{3 [(1 S,4S)-2-oxa-5- 135 mg of 6-[(6-{3-[(1 S,4S)-2-oxa-5 azabicyclo[2,2, I]hept-5- azabicyclo[2,2,1]hept-5-ylmethyl] 66 ylmethyl]phenoxy}[1,2,4]triaz 3 phenoxy}[1, 2

,

4 ]triazolo[4,3-bjpyridazin-3- 109 mg olo[4,3-b]pyridazin-3-yl)suf- yl)sulfanyl]-1,3-benzothiazol-2-amine (57b) anyl]-1,3-benzothiazol-2- and 35 mg of 2-methoxyacetyl chloride yl}acetamide 6-{[6-(oxetan-3- 1.02 g of 3 -chloro-6-(oxetan-3-yloxy)(1,2 ,4] 67 yloxy)[1,2,4]triazolo[4,3- 1a triazolo[4,3-b]pyridazine (67b) and 1.12 g of 383 mg b]pyridazin-3-yljsulfanyl- 1,3- 2-amino-1 3-benzothiazol-6-yl thiocyanate benzothiazol-2-amine (commercial) 3-chloro-6-(oxetan-3- 2 g of 3,6-dichloro[1,2,4]triazolo[4,3 67b yloxy)[1 ,2,4]triazolo[4,3- 1b bipyridazine (commercial) and 1.96 g of 1.01 g b]pyridazine oxetan-3-ol rac-2-(morpholin-4-yl)-N-(6- 250 mg of rac-6-{[6-(tetrahydrofuran-3 {[6-(tetrahydrofuran-3- yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3 68 yloxy)[1,2,4]triazolo[4,3- 8 yllsulfanyl}-1,3-benzothiazol-2-amine (27) 86 mg b]pyridazin-3-yl]sulfanyl}1 ,3- and 939 mg of morphoin-4-ylacetic acid benzothiazol-2-yl)acetamide (commercial) N-(6-{[6-(3,5- 150 mg of 6-{[6-(3,5 69 difluorophenoxy)[1,2,4]triazol 8 difluorophenoxy)[1,2,4]triazolo[4,3- Ill mg o[4,3-blpyridazin-3-yl]sulf- bjpyridazin-3-yl]sulfanyl}-1,3-benzothiazol anyl}-11,3-benzothiazol-2-yl)- 2-amine (45) and 508 mg of morpholin-4- WO 2010/089507 PCT/FR2010/050178 84 2 -(morpholin-4-yl)acetamide yiacetic acid (commercial) rac-N 2

N

2 -diethyl-N-(.{[6- 250 mg of rac-6-{[6-(tetrahydrofuran-3 70 yloxy)[1,2,4]triazolo[4,3- yloxy)[1,2, 4 ]triazolo[4,3-bjpyridazin-3 b]pyridazin-3-y]sulfanyl}1,3- 8 yl]sulfanyl}-1,3-benzothiazol-2-amine (27) 48 mg benzothiazol-32-. and 991mg of the sodium salt of N,N yI)g lycinamide diethylglycine (commercial) rac-2-(4-ethylpiperazin-1-yl)- 250 mg of rac-6-{[6-(tetrahydrofuran-3 N-(6-{[6-(tetrahydrofuran-3- yloxy)[1,2, 4 ]triazolo[4,3-b]pyridazin-3 71 yloxy)[1,2,4]triazolo[4,3- 8 yllsulfanyl}-1,3-benzothiazol-2-amine (27) 50 mg b]pyridazin-3-yl]sulfanyl)-1,3- and 655 mg of ( 4 -ethylpiperazin-1-yl)acetic benzothiazol-2-yl)acetamide acid (commercial) rac-2-(4- 198 mg of rac-6-{[6-(tetrahydrofuran-3 cyclopropylpiperazin-1-yl)-N- yloxy)[1,2,4]triazoio[4,3-blpyridazin-3 (6-{[6-(tetrahydrofuran-3- 8 yllsulfanyl}-1,3-benzothiazol-2-amine (27) yloxy)[1,2,4]triazolo[4,3- and 619 mg of the potassium salt of (4- 83 mg b]pyridazin-3-yl]sulfanyl}- 1,3- cyclopropylpiperazin-1-yl)acetic acid (63b) benzothiazol-2-yI)acetamide (or commercial) N-(6-{[6-(oxetan-3- 60 mg of 6-([6-(oxetan-3 yloxy)(1,2,4]triazolo[4,3- yloxy)[1,2, 4 ]triazolo[4,3-bjpyridazin-3 73 b]pyridazin-3-yl]sulfanyl}-1,3- 3 yisulfanyl}-1,3-benzothiazol-2-amine (67) 42 mg benzothiazol-2- and 0.022 cm 3 of cyclopropanecarbonyl yl)cyclopropanecarboxamide chloride 2 -(4-ethylpiperazin-1 -yl)-N- 150 mg 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- 8 yljsulfanyl}-1, 3 -benzothiazol-2-amine (67) 123 mg b]pyridazin-3-yl]sulfanyl}-1,3- and 357 mg of (4-ethylpiperazin-1-yl)acetic benzothiazol-2-yl)acetamide acid (commercial) 2

-(

4 -cyclopropylpiperazin-1 - 143 mg of 6-{[6-(oxetan-3 yl)-N-(6-{[6-(oxetan-3- yloxy)[1, 2

,

4 ]triazolo[4,3-b]pyridazin-3 75 yloxy)[1,2,4]triazolo[4,3- 8 yl]sulfanyl)-1,3-benzothiazol-2-amine (67) 90 mg b]pyridazin-3-yl]sulfanyl}-1,3- and 427 mg of the potassium salt of (4 benzothiazol-2-yl)acetamide cyclopropylpiperazin-1-yI)acetic acid (63b) (or commercial) The characteristics of the products of the above table are as follows: Ex- MS NMR H NMR Spectrum (400 MHz, 6 in ppm, DMSO-drs): 2.20 (s, 3 H); 7.11 (broad dd, J = 2.2 and 8.5 Hz, 1 H); 7.16 (ddt, J = 1.0 and 2.2 1 [M+H]+: m/z 453; [M- and 8.5 Hz, 1 H); 7.25 (td, J = 2.2 and 10.0 Hz, 1 H); 7.30 (dd, J = HJ-: m/z 451 1.9 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.43 (dt, J = 7.1 and 8.6 Hz, 1 H); 7.60 (d, J = 8.6 Hz, I H); 7.91 (d, J = 1.9 Hz, 1 H); 8.49 (d, J = 9.8 Hz, I H); 12.39 (broad m, I H) 12_[M+H]+:m/z 479;_[M- _H NMR Spectrum (400 MHz, in ppm, DMS-d): 0.92 to 1.00 (n, WO 2010/089507 PCT/FR2010/050178 85 H]-: m/z 477 4 H); 1.94 to 2.04 (m, 1 H); 7.12 (broad dd, J = 2.3 and 8.3 Hz, 1 H); 7.16 (ddt, J = 1.0 and 2.3 and 8.3 Hz, 1 H); 7.25 (td, J = 2.3 and 10.0 Hz, I H); 7.31 (dd, J = 1.9 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.43 (dt, J = 6.8 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, I H); 7.90 (d, J = 1.9 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.69 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 2.36 to 2.46 (m, [M+H]+: m/z 567; [M- 6 H); 3.26 to 3.34 (partially masked m, 2 H); 3.59 (m, 4 H); 6.78 13 H]-: m/z 565 (broad m, 1 H); 7.18 to 7.26 (m, 3 H); 7.26 to 7.32 (m, 2 H); 7.36 (d, J = 9.8 Hz, 1 H); 7.50 (d, J = 8.6 Hz, 1 H); 7.82 (d, J = 1.9 Hz, 1 H); 8.46 (d, J = 9.8 Hz, I H); 10.89 (broad m, 1 H) Retention time Tr 13b (min) = 0.78; [M+H]+: m/z 265; 1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 8 ): 2.27 (s, 3 H); 2.41 (m, 6 H); 3.25 to 3.35 (partially masked m, 2 H); 3.60 (m, 4 H); 14 [M+H]+: m/z 581; [M- 6.78 (broad m, I H); 7.00 (broad d, J = 8.3 Hz, 1 H); 7.19 (broad d, HJ-: m/z 579 J = 10.3 Hz, 1 H); 7.23 to 7.31 (m, 2 H); 7.35 (d, J = 9.8 Hz, 1 H); 7.48 (d, J = 8.6 Hz, 1 H); 7.84 (d, J = 1.9 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 10.89 (broad m, 1 H) Retention time Tr 14b (min) = 0.88; [M+H]+: m/z 279; 1 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 1.55 (m, 2 H); 15 [M+H]+: m/z 399; [M- 1.87 (m, 2 H); 3.41 (m, 2 H); 3.72 to 3.80 (m, 2 H); 4.91 (m, 1 H); H]-: m/z 401 7.04 (d, J = 9.8 Hz, I H); 7.22 to 7.30 (m, 2 H); 7.61 (s, 2 H); 7.82 (d, J = 1.0 Hz, 1 H); 8.28 (d, J = 9.8 Hz, 1 H) Retention time Tr 15b (min) = 2.74; [M+H]+: m/z 255; IH NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 8 ): 7.12 (dd, J = 16 [M+H]+: m/z 411; [M- 1.9 and 8.4 Hz, 1 H); 7.22 (d, J = 8.4 Hz, 1 H); 7.24 to 7.38 (m, H]-: m/z 409 5 H); 7.62 (d, J = 1.9 Hz, I H); 7.64 (broad s, 2 H); 8.44 (d, J = 9.8 Hz, 1 H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 1.52 (m, 2 H); 1.81 (m, 2 H); 2.35 to 2.45 (m, 6 H); 3.23 to 3.27 (masked m, 2 H); 17 [M+H]+: m/z 557; [M- 3.32 to 3.39 (masked m, 2 H); 3.59 (t, J = 4.6 Hz, 4 H); 3.71 (m, H]-: m/z 555 2 H); 4.86 ( m, 1 H); 6.79 (broad s, 1 H); 7.05 (d, J = 9.8 Hz, 1 H); 7.33 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.55 (d, J = 8.6 Hz, 1 H); 8.01 (d, J = 2.0 Hz, 1 H); 8.30 (d, J = 9.8 Hz, 1 H); 10.91 (broad s, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.96 (t, J = 7.2 Hz, 3 H); 1.49 (m, 2 H); 1.76 (m, 2 H); 1.93 (t, J = 9.5 Hz, 2 H); 18 [M+H]+: m/z 584 2.28 (q, J = 7.1 Hz, 2 H); 2.41 (m, 6 H); 2.51 to 2.59 (m, 2 H); 3.24 to 3.28 (masked m, 2 H); 3.59 (t, J = 4.6 Hz, 4 H);4.61 (m, I H); 6.77 (broad s, 1 H); 7.03 (d, J = 9.8 Hz, 1 H); 7.28 (dd, J = 2.1 and 8.4Hz, 1 H;7.53 (d, J = 8.6 Hz, I H); 8.02 (d, J = 2.0 Hz, 1 H); WO 2010/089507 PCT/FR2010/050178 86 8.28 (d, J = 9.8 Hz, 1 H); 10.89 (broad s, 1 H) 1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 1.01 (t, J= 7.2 Hz, 3 H); 1.67 to 1.86 (m, 2 H); 2.03 to 2.12 (m, 2 H); 2.21 to 18b 2.28 (m, 2 H); 2.35 (q, J = 7.2 Hz, 2 H); 2.61 to 2.75 (m, 2 H); 5.01 (tt, J = 4.1 and 8.2 Hz, 1 H); 7.10 (d, J = 10.0 Hz, 1 H); 8.27 (d, J = 10.0 Hz, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 8 ): 0.90 to 0.98 (m, 4 H); 1.51 (m, 2 H); 1.78 (m, 2 H); 1.97(m, I H); 3.31 to 3.36 19 [M+HJ+: m/z 469; [M- (masked m, 2 H); 3.70 (m, 2 H); 4.84 (m, I H); 7.05 (d, J = 9.8 Hz, H]-: m/z 467 1 H); 7.38 (dd, J = 2.0 and 8.8 Hz, 1 H); 7.66 (d, J = 8.6 Hz, I H); 8.06 (d, J = 1.2 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 12.68 (broad s, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d6): 0.92 to 1.00 (m, 20 [M+H]+: m/z 479; [M- 4 H); 1.96 to 2.04 (m, 1 H); 7.18 (t, J = 8.3 Hz, 2 H); 7.22 to 7.32 (m, H]-: m/z 477 3 H); 7.37 (d, J = 10.0 Hz, 1 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.87 (d, J = 1.9 Hz, 1 H); 8.47 (d, J = 10.0 Hz, 1 H): 12.70 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.92 to 1.00 (m, 4 H); 1.96 to 2.03 (m, 1 H); 2.25 (d, J = 1.5 Hz, 3 H); 6.97 (dd, J = 21 [M+H]+: m/z 493; [M- 2.3 and 8.6 Hz, 1 H); 7.16 (dd, J = 2.3 and 10.6 Hz, 1 H); 7.24 H]-: m/z 491 (broad t, J = 8.6 Hz, 1 H); 7.30 (dd, J = 1.9 and 8.6 Hz, 1 H); 7.36 (d, J = 9.8 Hz, 1 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.89 (d, J = 1.9 Hz, I H); 8.47 (d, J = 9.8 Hz, I H); 12.69 (broad m, I H) Retention time Tr 21 b (min) = 0,82; [M+H]+: m/z 425; [M-H]-: m/z 423 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.89 (d, J= 6.1 Hz, 4 H); 0.94 (t, J = 7.1 Hz, 3 H); 1.48 (m, 2 H); 1.75 (m, 2 H); 22 [M+H]+: m/z 496; [M- 1.84 to 1.95 (m, 3 H); 2.26 (q, J = 7.1 Hz, 2 H); 2.52 to 2.57 HJ-: m/z 494 (masked m, 2 H); 4.58 (m, 1 H); 7.02 (d, J = 9.8 Hz, I H); 7.29 (dd, J = 1.8 and 8.4 Hz, 1 H); 7.58 (d, J = 8.3 Hz, 1 H); 8.03 (d, J = 1.2 Hz, 1 H); 8.28 (d, J = 9.8 Hz, I H); 12.62 (s, 1 H) Retention time Tr (min) = 0.36; [M+H]+: 22b m/z 428; M+2H]2+: m/z 214.5 (base peak); [M-H}-: m/z 426 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 1.98 (m, 1 H); 2.17 (m, I H); 2.35 to 2.45 (m, 6 H); 3.22 to 3.28 (masked m, 2 H); 23 [M+H]+: m/z 543; [M- 3.59 (t, J = 4.6 Hz, 4 H); 3.66 to 3.85 (m, 4 H); 5.32 (m, 1 H); 6.78 H]-: m/z 541 (t, J = 5.9 Hz, 1 H); 7.07 (d, J = 9.8 Hz, 1 H); 7.42 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.57 (d, J = 8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, 1 H); 8.30 (d, J = 9.8 Hz, 1 H); 10.88 (broad s, 1 H) 23b Retention time Tr 1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 2.05 to 2.18 (m, ( 0 [ 1 H); 2.25 to 2.39 (m, I H); 3.78 (m, 1 H); 3.88 (m, 1 H); 3.94 (m, 2 H); 5.52 (m, 1 H); 7.12 (d, J = 9.8 Hz, 1 H); 8.29 d, J = 9.8 Hz, WO 2010/089507 PCT/FR2010/050178 87 m/z 241 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 2.36 to 2.45 (m, 6 H); 3.25 to 3.32 (partially masked m, 2 H); 3.59 (m, 4 H); 6.12 (s, 24 [M+H]+: mlz 593; [M- 2 H); 6.72 (dd, J = 2.4 and 8.6 Hz, 1 H); 6.79 (broad m, 1 H); 6.93 H]-: m/z 591 (d, J = 8.6 Hz, 1 H); 6.95 (d, J = 2.4 Hz, 1 H); 7.27 to 7.33 (m, 2 H); 7.50 (d, J = 8.6 Hz, 1 H); 7.87 (d, J = 1.9 Hz, 1 H); 8.42 (d, J 9.8 Hz, 1 H); 10.90 (broad m, 1 H) Retention time Tr 24b (min) = 0.73; [M+H]+: m/z 291 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 2.37 to 2.45 (m, 6 H); 3.24 to 3.33 (partially masked in, 2 H); 3.59 (m, 4 H); 6.78 25 [M+H]+: m/z 617; {M- (broad m, I H); 7.24 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.30 (dd, J = 2.7 H]-: mfz 615 and 8.8 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.48 (d, J = 8.3 Hz, 1 H); 7.62 (d, J = 8.8 Hz, I H); 7.74 (d, J = 2.7 Hz, 1 H); 7.84 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 10.92 (broad m, 1 H) Retention time Tr 25b (min) = 0.98; [M+HJ+: m/z 315 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 7.13 (dd, J = [M+H]+: m/z 461; [M- 2.0 and 8.4 Hz, 1 H); 7.20 (d, J = 8.4 Hz, 1 H); 7.34 (dd, J = 2.7 and 26 H]-: m/z 459 8.8 Hz, 1 H); 7.38 (d, J = 9.8 Hz, I H); 7.64 (s, 2 H); 7.66 (d, J = 2.0 Hz, I H); 7.71 (d, J = 8.8 Hz, 1 H); 7.79 (d, J = 2.7 Hz, 1 H); 8.47 (d, J = 9.8 Hz, I H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-de): 2.02 (m, 1 H); [M+H]+: m/z 387; [M- 2.22 (m, 1 H); 3.69 to 3.86 (m, 4 H); 5.35 (m, 1 H); 7.06 (d, J = 27 H]-: m/z 385 10.0 Hz, 1 H); 7.29 (d, J = 8.6 Hz, 1 H); 7.34 (dd, J = 2.0 and 6.6 Hz, I H); 7.62 (s, 2 H); 7.88 (d, J = 2.0 Hz, I H); 8.28 (d, J = 9.8 Hz, I H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 2.38 to 2.45 (m, 6 H); 3.22 to 3.35 (partially masked m, 2 H); 3.60 (m, 4 H); 6.51 (m, [M+H]+: miz 588; [M- I H); 6.77 (broad m, 1 H); 6.91 (dd, J = 2.3 and 8.6 Hz, 1 H); 7.21 28 HJ-: m/z 586 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.33 (d, J = 10.0 Hz, 1 H); 7.34 to 7.37 (m, 2 H): 7.42 (dd, J = 2.3 and 3.0 Hz, 1 H); 7.58 (d, J = 8.6 Hz, I H); 7.88 (d, J = 2.0 Hz, I H); 8.41 (d, J = 10.0 Hz, I H); 10.89 (broad m, 1 H); 11.25 (broad m, 1 H) Retention time Tr 28b (min) = 0.76; [M+H]+: m/z 286; [M-H]-: m/z 284 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.95 (m, 4 H) [M+H]+: m/z 455; [M- 1.97 (m, 2 H); 2.15 (m, 1 H); 3.63 to 3.73 (m, 3 H); 3.78 (q, J = 9 H]-: m/z 453 7.7 Hz, I H); 5.33 (m, 1 H); 7.08 (d, J = 10.0 Hz, 1 H); 7.46 (dd, J 2.1 and 8.4 Hz, I H); 7.69 (d, J = 8.3 Hz, 1 H); 8.11 (d, J = 2.0 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 12.67 (broad s, 1 H) WO 2010/089507 PCT/FR2010/050178 88 'H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.90 to 1.00 (m, 4 H); 1.92 to 2.05 (m, 1 H); 6.09 (s, 2 H); 6.70 (dd, J = 2.3 and 30 [M+H]+: m/z 505; [M- 8.4 Hz, I H); 6.89 (d, J = 8.4 Hz, 1 H); 6.92 (d, J = 2.3 Hz, 1 H); H]-: m/z 503 7.32 (d, J = 9.8 Hz, 1 H); 7.35 (dd, J = 2.0 and 8.6 Hz, I H); 7.62 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 H); 8.43 (d, J = 9.8 Hz, 1 H); 12.68 (broad m, 1 H) Retention time Tr 30b (min) = 0.70; [M+H]+:m/z 437; [M H]-:m/z 435 'H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 0.90 to 0.99 (m, 31 [M+H]+: m/z 529; [M- 4 H); 1.94 to 2.05 (m, 1 H); 7.24 to 7.30 (m, 2 H); 7.40 (d, J = H]-: m/z 527 9.8 Hz, I H); 7.55 to 7.61 (m, 2 H); 7.71 (d, J = 2.7 Hz, I H); 7.89 (d, J = 2.0 Hz, 1 H); 8.50 (d, J = 9.8 Hz, 1 H); 12.70 (broad m, I H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 8 ): 0.86 to 1.03 (m, 4 H); 1.94 to 2.06 (m, 1 H); 6.50 (t, J = 2.2 Hz, 1 H); 6.90 (dd, J = 32 [M+H]+: m/z 500; [M- 2.2 and 8.6 Hz, I H); 7.25 (dd, J = 1.9 and 8.6 Hz, 1 H); 7.30 to H]-: m/z 499 7.36 (m, 2 H); 7.40 to 7.46 (m, 2 H); 7.55 (d, J = 8.6 Hz, 1 H); 7.94 (d, J = 1.9 Hz, 1 H); 8.41 (d, J = 9.8 Hz, I H); 11.24 (broad s, 1 H); 12.69 (broad m, 1 H) Retention time Tr 32b (min) = 3.32; [M+H]+: m/z 432; [M-H]-: m/z 430 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 1.76 to 1.89 (m, I H); 1.89 to 2.04 (m, 1 H); 2.07 to 2.33 (m, 4 H); 3.34 to 3.45 (m, [M+H]+: mfz 493; [M- 1 H); 7.12 (dd, J = 2.3 and 8.4 Hz, I H); 7.17 (broad dt, J = 2.3 and H: m/z 491 8.4 Hz, 1 H); 7.25 (td, J = 2.3 and 10.0 Hz, I H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.43 (dt, J = 6.9 and 8.4 Hz, 1 H); 7.59 (d, J = 8.6 Hz, I H); 7.91 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.25 (broad m, 1 H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 2.30 (s, 6 H); 3.22 to 3.42 (partially masked m, 2 H); 7.11 (dd, J = 2.3 and 8.3 Hz [M+H]+: mfz 496; [M- 1 H); 7.16 (dt, J = 2.3 and 8.3 Hz, 1 H); 7.24 (td, J = 2.3 and 9.9 Hz, 4 HF-: mn/z 494 1 H); 7.31 (dd, J 1.9 and 8.6 Hz, 1 H); 7.39 (d, J = 10.0 Hz, 1 H); 7.42 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.91 (d, J = 1.9 Hz, 1 H); 8.49 (d, J = 10.0 Hz, 1 H); 11.93 (very broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-de): 1.17 (t, J = 7.1 Hz, 3 H); 3.56 (q, J = 7.1 Hz, 2 H); 4.24 (s, 2 H); 7.11 (dd, J 35 [M+H]+: mfz 497; [M- 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.2 and 8.3 Hz, I H); 7.24 (td, J = HI-: m/z 495 2.2 and 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.36 to 7.46 (m, 2 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.29 (broad m, I H) 36 [M+H]+: m/z 551; {M- 1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-de): 1.11 to 1.36 (m, H]-: m/z 549 5 H); 1.42 to 1.53 (m, 1 H); 1.68 (m, 2 H); 1.88 (m, 2 H); 3.36 to WO 2010/089507 PCT/FR2010/050178 89 3.44 (m, 1 H); 4.26 (s, 2 H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.2 and 8.3 Hz, I H); 7.24 (td, J = 2.2 and 10.0 Hz, I H); 7.31 (dd, J = 2.0 and 8.6 Hz, I H); 7.37 to 7,46 (m, 2 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.19 (broad m, 1 H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-ds): 7.10 (dd, J = [M+H]+: m/z 394; [M-. 1.8 and 8.4 Hz, 1 H); 7.21 (d, J = 8.3 Hz, 1 H); 7.42 (d, J = 9.8 Hz, 37 H]-: m lz 392 1 H); 7.53 (dd, J = 4.8 and 8.4 Hz, 1 H); 7.61 (d, J = 2.0 Hz, 1 H); 7.64 (s, 2 H); 7.76 to 7.81 (m, 1 H); 8.47 (d, J = 9.8 Hz, 1 H); 8.59 (dd, J = 1.2 and 4.6 Hz, 1 H); 8.63 (d, J = 2.9 Hz, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 7.46 (d, J = 37b 10.0 Hz, 1 H); 7.58 (ddd, J = 0.5 and 4.7 and 8.3 Hz, 1 H); 7.90 (ddd, J = 1.2 and 2.7 and 8.3 Hz, 1 H); 8.49 (d, J = 10.0 Hz, 1 H); 8.56 (dd, J = 1.2 and 4.7 Hz, 1 H); 8.68 (broad d, J = 2.7 Hz, 1 H) 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 7.19 (dd, J = 38 [M+H]+: m/z 477; [M- 1.9 and 8.5 Hz, 1 H); 7.24 (d, J = 8.5 Hz, 1 H); 7.37 to 7.46 (m, H]-: m/z 475 3 H); 7.58 (broad s, 1 H); 7.63 to 7.75 (m, 4 H); 8.52 (d, J = 9.8 Hz, 1 H) Retention time Tr 38b (min) = 4.12; [M+H]+: m/z 331 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 1.48 (s, 9 H); [M+H]+: m/z 508; [M- 6.86 (broad d, J = 7.8 Hz, 1 H); 7.17 (dd, J = 1.8 and 8.5 Hz, 1 H); 39 H]-: mfz 506 7.22 (d, J = 8.5 Hz, I H); 7.28 to 7.40 (m, 3 H); 7.51 (broad s, 1 H); 7.62 (broad s, 2 H); 7.71 (d, J = 1.8 Hz, I H); 8.42 (d, J = 9.8 Hz, 1 H); 9.59 (broad s, 1 H) 39b [M+H]+: m/z 362; [M H]-: m/z 360 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 1.78 to 2.04 (m, [M+H]+: m/z 476; [M- 2 H); 2.11 to 2.34 (m, 4 H); 3.41 (m, I H); 7.27 (dd, J = 2.0 and 40 H]-: m/z 474 8.3 Hz, 1 H); 7.38 to 7.46 (m, 2 H); 7.60 (d, J = 8.3 Hz, I H); 7.72 (dd, J = 3.9 and 8.3 Hz, 1 H); 7.89 (d, J = 2.0 Hz, 1 H); 8.47 to 8.55 (m, 2 H); 8.58 (d, J = 2.9 Hz, 1 H); 12.27 (broad s, 1 H) H NMR Spectrum (400 MHz, & in ppm, DMSO-d): 2.54 (m, 4 H); 3.34 (s, 2 H); 3.62 (m, 4 H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1 H); 7.16 41 [M+H]+: m/z 538; [M- (ddt, J = 0.9 and 2.3 and 8.3 Hz, 1 H); 7.25 (td, J = 2.3 and 10.0 Hz, H]-: m/z 536 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, I H); 7.43 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.91 (d, J = 2.0 Hz, I H); 8.49 (d, J = 9.8 Hz, 1 H); 12.21 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 8 ): 1.00 to 1.29 (m, 5 H); 1.50 to 1.57 (m, 1 H); 1.61 to 1.72 (m, 2 H); 1.83 (m, 2 H); 42 [M+H]+: m/z 550; [M- 2.46 (partially masked m, I H); 3.52 (s, 2 H); 7.09 to 7.20 (m, 2 H); H]-: m/z 548 7.23 to 7.30 (m, 2 H); 7.38 (d, J = 9.8 Hz, 1 H); 7.44 (dt, J = 6.9 and 8.3 Hz, I H); 7.57 (d, J = 8.3 Hz, I H); 7.88 (d, J = 2.0 Hz, 1 H); 8.48 (d, J = 9.8 Hz, 1 H) WO 2010/089507 PCT/FR2010/050178 90 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 2.35 to 2.46 (m, 9 H); 2.65 (t, J = 6.1 Hz, 2 H); 3.39 (s,.2 H); 3.64 (m, 4 H); 7.11 (dd, 43 [M+H]+: m/z 595; [M- J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.2 and 8.3 Hz, I H); 7.25 (td, H]-: m/z 593 J = 2.2 and 10.0 Hz, 1 H); 7.31 (dd, J = 1.7 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.42 (m, 1 H); 7.59 (d, J = 8.6 Hz, I H); 7.91 (d, J = 1.7 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.01 (broad m, 1 H) 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-de): 1.00 (broad t, J [M+H]+: m/z 565. = 6.8 Hz, 3 H); 2.30 to 2.62 (partially masked m, 10 H); 3.34 (s, [M+2H]2+: m/z 283 2 H); 7.11 (dd, J = 2.3 and 8.3 Hz, I H); 7.16 (dt, J = 2.3 and 4(base peak); [M-H]-: 8.3 Hz, I H); 7.24 (td, J = 2.3 and 10.0 Hz, I H); 7.32 (dd, J = 2.0 m/z 563 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.43 (m, 1 H); 7.62 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, I H); 12.11 (broad m, 1 H) [M+H]+: m/z 429; [M- 1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 7.19 (broad s, 45 H] m/z 42 2 H); 7.21 to 7.33 (m, 3 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.64 (broad s, H]-: m/z 427 2 H); 7.69 (broad s, I H); 8.48 (d, J = 9.8 Hz, 1 H) Retention time Tr 45b (min) = 0.83; [M+H)+: m/z 283 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d): 5.36 (broad s, [M+H]+: m/z 408; [M- 2 H); 6.36 (dd, J = 2.0 and 8.1 Hz, 1 H); 6.45 (t, J = 2.0 Hz, 1 H); 6H]-: m/z 406 6.54 (dd, J = 2.0 and 8.1 Hz, I H); 7.11 (t, J = 8.1 Hz, 1 H); 7.20 to 7.33 (m, 3 H); 7.63 (broad s, 2 H); 7.74 (d, J = 1.8 Hz, I H); 8.39 (d, J = 9.8 Hz, 1 H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 1.22 to 1.34 (m, 2 H); 1.76 (m, 2 H); 2.68 (m, 1 H); 3.30 (m, 2 H); 3.52 (s, 2 H); 3.81 [M+H]+: m/z 552; [M- (m, 2 H); 7.12 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.0 and 7 H]-: m/z 550 8.3 Hz, 1 H); 7.25 (td, J = 2.0 and 10.0 Hz, I H); 7.30 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.44 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.59 (d, J = 8.3 Hz, 1 H); 7.90 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, I H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.89 to 1.01 (m, 48 [M+H]+: m/z 529; [M- 4 H); 2.01 (m, 1 H); 7.25 (dd, J = 1.8 and 8.7 Hz, 1 H); 7.37 to 7.47 H]-: m/z 527 (m, 3 H); 7.58 (d, J = 8.7 Hz, I H); 7.66 (d, J = 8.6 Hz, 2 H); 7.83 (d, J = 1.8 Hz, 1 H); 8.53 (d, J = 9.8 Hz, 1 H); 12.69 (broad s, 1 H) 48b [M+H]+: m/z 461; [M H]-: m/z 459 Retention time Tr 48c (min) = 0.93; [M+HJ+: mfz 315 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.86 to 1.01 (m, [M+H]+: m/z 545; [M- 4 H); 1.99 (m, I H); 7.24 to 7.35 (m, 3 H); 7.40 (d, J = 9.8 Hz, 1 H); HJ-: m/z 543 7.46 (broad s, I H); 7.52 (t, J = 8.3 Hz, 1 H); 7.59 (d, J = 8.3 Hz, 1 H); 7.89 (broad s, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.67 (broad m, 1 H) WO 2010/089507 PCT/FR2010/050178 91 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.96 (m, 4 H); 1.98 (m, I H); 2.23 (s, 3 H); 7.17 (dd, J = 2.0 and 8.6 Hz, I H); 7.25 50 {M+H]+: m/z 476; [M- (dd, J = 5.1 and 8.1 Hz, 1 H); 7.45 (d, J = 9.8 Hz, 1 H); 7.57 (d, J = H]-: m/z 474 8.6 Hz, 1 H); 7.61 (dd, J = 1.6 and 8.2 Hz, 1 H); 7.79 (d, J = 2.0 Hz, I H); 8.42 (dd, J = 1.7 and 4.6 Hz, 1 H); 8.50 (d, J = 9.8 Hz, I H); 12.67 (broad s, 1 H) Retention time Tr 50b (min) = 0.48; [M+H]+: mlz 408; [M-H]-: m/z 406 Retention time Tr SOc (min) = 0.37; [M+H]+: m/z 262 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d): 0.91 to 1.00 (m, [M+H]+: m/z 497; [M- 4 H); 1.94 to 2.03 (m, 1 H); 7.11 to 7.25 (m, 3 H); 7.33 (d d, J = 2.0 51 H]-: mfz 495 and 8.6 Hz, 1 H); 7.40 (d, J = 10.0 Hz, I H); 7.59 (d, J = 8.6 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H); 8.51. (d, J = 10.0 Hz, 1 H); 12.67 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 2.14 (s, 3 H); 4.83 (s, 2 H); 7.11 (dd, J = 2.1 and 8.5 Hz, I H); 7.15 (dt, J = 2.1 52 [M+H]+: m/z 511; [M- and 8.5 Hz, I H); 7.24 (td, J = 2.1 and 10.0 Hz, 1 H); 7.32 (dd, J = H]-: m/z 509 2.0 and 8.6 Hz, I H); 7.36 to 7.46 (m, 2 H); 7.64 (d, J = 8.6 Hz, I H); 7.93 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.64 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.96 (m, 4 H); 1.99 (m, 1 H); 2.51 (masked, 3 H); 7.20 (d, J = 8.6 Hz, 1 H); 7.26 53 [M+H]+: m/z 476; [M- (dd, J = 2.0 and 8.3 Hz, I H); 7.41 (d, J = 10.0 Hz, I H); 7.55 (dd, J H-: m/z 474 = 2.8 and 8.4 Hz, I H); 7.60 (d, J = 8.6 Hz, 1 H); 7.86 (d, J = 2.0 Hz, 1 H); 8.40 (d, J = 2.9 Hz, 1 H); 8.48 (d, J = 9.8 Hz, 1 H); 12.68 (broad s, I H) Retention time Tr 53b (min) = 0.51; [M+H]+: m/z 408; [M-H]-: mfz 406 Retention time Tr 53c (min) = 0.40; [M+H]+: m/z 262 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 0.89 to 1.00 (M, 5 [M+H]+: m/z 560; [M- 4 H); 1.93 to 2.06 (m, 1 H); 2.33 (m, 4 H); 3.45 (s, 2 H); 3.52 to 3.59 H]-: m/z 558 (m, 4 H); 7.11 (d, J = 8.6 Hz, 2 H); 7.17 to 7.26 (m, 3 H); 7.36 (d, J = 9.8 Hz, 1 H); 7.60 (d, J = 8.6 Hz, 1 H); 7.83 (d, J = 2.0 Hz, I H); 8.46 (d, J = 9.8 Hz, 1 H); 2.70 (broad m, 1 H) Retention time Tr 54b (min) = 0.42; [M+H]+: _m/z 492;[M-H]-: mlz I WO 2010/089507 PCT/FR2010/050178 92 490 Retention time Tr 54c (min) = 0.32; [M+H]+: m/z 346 - Retention time Tr 54d (min) = 0.3; [M+H]+: m/z 194; [M-H]-: m/z 192 'H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 8 ): 0.95 (m, 4 H); [M+H]+: m/z 576; [M- 1.44 (s, 9 H); 1.99 (m, I H); 6.81 (d, J = 8.3 Hz, 1 H); 7.23 (t, J= 55H]-: mz 574 8.3 Hz, I H); 7.33 (d, J = 9.8 Hz, 3 H); 7.49 (s, 1 H); 7.61 (d, J = 8.3 Hz, 1 H); 7.95 (s, I H); 8.44 (d, J = 9.8 Hz, 1 H); 9.56 (s, 1 H); 12.52 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.96 (m, 4 H); [M+H]+: m/z 462; [M- 2.00 (m, I H); 7.27 (dd, J = 1.7 and 8.6 Hz, 1 H); 7.39 to 7.47 (m, 6 H]-: m/z 460 2 H); 7.62 (d, J = 8.3 Hz, 1 H); 7.72 (dt, J = 2.0 and 8.3 Hz, 1 H); 7.87 (d, J = 2.0 Hz, I H); 8.50 (d, J = 9.8 Hz, 1 H); 8.53 (d, J = 4.9 Hz, I H); 8.58 (d, J = 2.9 Hz, 1 H); 12.69 (, 1 H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 0.90 to 0.99 (m, 4 H); 1.55 (broad d, J = 9.8 Hz, I H); 1.73 (broad d, J = 9.8 Hz, I H); 1.94 to 2.05 (m, 1 H); 2.39 (broad d, J = 9.8 Hz, 1 H); 2.70 [M+H]+: m/z 572; [M- (broad d, =9.8 Hz, I H); 3.41 (broad s, 1 H); 3.49 (dd, J = 1.5 and 57 H]-: mfz 570 7.6 Hz, 1 H); 3.61 (d, J = 14.0 Hz, 1 H); 3.67 (d, J = 14.0 Hz, 1 H); 3.87 (d, J = 7.6 Hz, 1 H); 4.29 (s, 1 H); 7.10 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.21 to 7.30 (m, 3 H); 7.31 to 7.39 (m, 2 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.84 (d, J = 2.0 Hz, I H); 8.46 (d, J 9.8 Hz, 1 H); 12.68 (broad m, 1 H) Retention time Tr 57b (min) = 0.43; [M+H]+: m/z 504; [M-H]-: m/z 502 Retention time Tr 57c (min) = 0.34; [M+H]+: m/z 358 Retention time Tr 57d (min) = 0.16; [M+H]+: m/z 206 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 0.93 (t, J = 7.2 Hz, 6 H); 0.95 (m, 4 H); 1.97 to 2.04 (m, 1 H); 2.42 (q, J = [M+H]+: m/z 546; [M- 7.2 Hz, 4 H); 3.45 (s, 2 H); 7.08 (broad dd, J = 2.0 and 8.2 Hz, 1 H); 58 H]-: m/z 544 7.19 to 7.26 (m, 2 H); 7.28 (dd, J = 2.0 and .6 Hz, 1 H); 7.33 (t, J 8.2 Hz, 1 H); 7.36 (d, J = 9.8 Hz, 1 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.84 (d, J = 2.0 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.68 (broad m, 1 H) WO 2010/089507 PCT/FR2010/050178 93 Retention time Tr (min) = 0.46; [M+H]+: 58b m/z 478; [M+2H]2+: m/z 239.5 (base peak); [M-H]-: m/z 476 Retention time Tr 58c (min) = 0.40; [M+H]+: m/z 332 Retention time Tr 58d (min) = 0.22; [M+H]+: m/z 180 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 1.00 (t, J = 59 [M+H]+: m/z 542; [M- 7.2 Hz, 6 H); 2.62 (q, J = 7.2 Hz, 4 H); 3.40 (s, 2 H); 7.09 to 7.25 H]-: m/z 540 (m, 3 H); 7.33 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.41 (d, J = 9.8 Hz, 1 H); 7.60 (d, J = 8.6 Hz, 1 H); 7.93 (d, J = 2.0 Hz, I H); 8.52 (d, J = 9.8 Hz, 1 H); 11.79 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 4.19 (broad s, 2 H); 5.49 (broad s, I H); 7.11 (broad dd, J = 2.2 and 8.3 Hz, I H); [M+H]+: m/z 469; [M- 7.16 (, J = 1.0 and 2.2 and 8.3 Hz, 1 H); 7.25 (td, J = 2.2 and 60 H]-: m/z 467 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7,39 (d, J = 9.8 Hz, I H); 7.42 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, I H); 12.09 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.26 (m, 2 H); 0.39 (m, 2 H); 1.61 (m, 1 H); 2.43 to 2.60 (partially masked m, 8 H); [M+H]+: m/z 577; [M- 3.31 (broad s, 2 H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 61 H]-: mlz 575 2.2 and 8.3 Hz, 1 H); 7.25 (td, J = 2.2 and 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, I H); 7.39 (d, J = 9.8 Hz, 1 H); 7.43 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, I H); 12.07 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 1.00 (t, J = [M+H]+: mfz 583; [M- 6.8 Hz, 3 H); 2.28 to 2.62 (partially masked m, 10 H); 3.34 (s, 2 H); 62 H]-: m/z 581 7.10 to 7.26 (m, 3 H); 7.34 (dd, J = 2.0 and 8.6 Hz, I H); 7.41 (d, J = 9.8 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.94 (d, J = 2.0 Hz, I H); 8.52 (d, J = 9.8 Hz, 1 H); 11.88 (broad m, 1 H) 1H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 0.23 to 0.30 (m, [M+H]+: m/z 595; 2 H); 0.35 to 0.44 (m, 2 H); 1.61 (m, 1 H); 2.40 to 2.60 (partially 63 [M+2H]2+: m/z 298 masked m, 8 H); 3.31 (s, 2 H); 7.08 to 7.24 (m, 3 H); 7.33 (dd, j = (base peak); [M-H]-: 1.7 and 8.6 Hz, 1 H); 7.41 (d, J = 9.8 Hz, I H); 7.61 (d, J = 8.6 Hz, m/z 593 1 H); 7.94 (d, J = 1.7 Hz, 1 H); 8.52 (d, J = 9.8 Hz, 1 H); 12.10 (broad m, 1 H) Retention time Tr 63b (min) = 0.1; [M+H]+: m/z 185 64 [M+H]+:mz520;[M- 1 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 0.93 (t, J= WO 2010/089507 PCT/FR2010/050178 94 H]-: m/z 518 7.1 Hz, 6 H); 2.19 (s, 3 H); 2.43 (q, J = 7.0 Hz, 4 H); 3.46 (s, 2 H); 7.08 (dd, J = 1.7 and 8.1 Hz, 1 H); 7.21 to 7.38 (m, 5 H); 7.58 (d, J = 8.3 Hz, 1 H); 7.86 (d, J = 1.7 Hz, I H); 8.46 (d, J = 9.8 Hz, 1 H); 12.37 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.93 (t, J J [M+H]+: m/z 550; [M- 7.1 Hz, 6 H); 2.43 (q, J = 7.1 Hz, 4 H); 3.37 (s, 3 H); 3.46 (s, 2 H)1 65 H]-: m/z 548 4.19 (s, 2 H); 7.03 to 7.10 (m, 1 H); 7.21 to 7.34 (m, 4 H); 7.36 (d, J = 9.8 H H); 7.60 (d, J = 8.6 Hz, 1 H); 76); 7.87 (d, J = 1.7 Hz, 1 H) 8.46 (d, J = 9.8 Hz, I H); 12.34 (broad m, 1 H) H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 1.55 (broad d, J = 9.3 Hz, 1 H); 1.73 (dd, J = 2.0 and 9.3 Hz, 1 H); 2.39 (d, J = 9.9 Hz, 1 H); 2.70 (dd, J = 1.7 and 9.9 Hz, 1 H); 3.37 (s, 3 H); 3.41 66 [M+H]+: m/z 576; [M- (broad s, 1 H); 3.49 (dd, J = 1.7 and 7.6 Hz, 1 H); 3.61 (d J = H]-: m/z 574 14.0 Hz, 1 H); 3.67 (d, J = 14.0 Hz, 1 H); 3.87 (d, J = 7.6 Hz, 1 H) 4.20 (s, 2 H); 4.29 (broad s, H); 7.03 to 7.13 (m, I H); 7.22 to 74 (m, 4 H); 7.36 (d, J = 9.8 Hz, 1 H); 7.87 (d J = 1.7 Hz, I H); 8.46 (d, J = 9.8 Hz, 1 H); 12.38 (broad m, M H) 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 4.53 (m 2 H) 67 [M+H]+: m/z 373; [M- 4.81 (m, 2 H); 5.40 to 5.55 (m, 1 H); 7.17 (d, J = 10.3 Hz, 1 H); 7.2 H]-: m/z 371 to 7.36 (m, 2 H); 7.61 (broad s, 2 H); 7.82 (broad s, 1 H); 8.34 (d, J 8= 9.8 Hz, H) Retention time Tr 67b (min) = 0.41; [M+H]+: m/z 227 H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d 6 ): 1.91 to 2.05 (m 1 H); 2.08 to 2.20 (m, 1 H); 2.53 (m, 4 H); 3.34 (s, 2 H); 3.58 to 3.63 68 [M+H]+: mfz 514; [M- (m, 4 H); 3.65 to 3.82 (m, 4 H); 5.30 (m, 1 H); 7.08 (d, J = 9.8 Hz, H]-: m/z 512 1 H); 7.47 (dd, J = 2.1 and 8.6 Hz, 1 H); 7.70 (d, J = 8.6 Hz, 1 H) H.12 (d, J = 2.1 Hz, H); 8.31 (d, J = 9.8 Hz, 1 H) 12.16 (broad m, 1 H) 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d): 2.53 (m, 4 H) 70 [M+H]+: n/z 556; [M-- 3.32 (s, 2 H); 3.56 to 3.63 (m, 4 H); 7.12 to 7.24 (m, 3 H); 7.32 (dd 97H]-: m/z 554 J = 2.0 and 8.6 Hz, 1 H); 7.41 (d, J = 9.8 Hz, 1 H); 7.58 (d, J = 8.6 Hz, I H); 7.92 (d, J = 2.0 Hz, I H); 8.51 (d, J = 9.8 Hz, I H); 10.47 to 13.46 (very broad m, 1 H) 'H NMR Spectrum (400 MHz, 6 in ppm, DMSO-de): 1.00 (t, J = 7.1 Hz, 6 H); 1.90 to 2.03 (m, 1 H); 2.07 to 2.22 (m, 1 H); 2.62 (q, J 70 [M+H]+: m/z 500 = 7.1 Hz, 4 H); 3.40 (s, 2 H); 3.63 to 3.84 (m, 4 H); 5.29 (m, 1 H); 7.08 (d, J = 9.8 Hz, 1 H); 7.47 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.69 (d, J = 8.3 Hz, 1 H); 8.12 (d, J = 2.0 Hz, I H); 8.31 (d, J = 9.8 Hz, I H); 12.11 (broad m, 1 H) [M+H]: m/z541- H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d6): 0.98 (t, J= [M+2H]+: m/z 21; 71 Hz, 3 H); 1.92 to 2.03 (m, 1 H); 2.10 to 2.22 (m, 1 H); 2.31 (q, J 71 (base+ peak) [M-H] - 7.1 Hz, 2 H); 2.22 to 2.48 (partially masked broad m, 8 H); 3.30 m/zs 539 ) [ -H- (partially masked s, 2 H); 3.64 to 3.84 (m, 4 H); 5.30 (m, 1 H); 7.08 rn/z539(d, J = 9.8 Hz, 1 H); 7.47 (dd, J = 2.0 and 8.6 Hz, I H); 7.69 (d, J= 8. z,1H; .2(d, J = 2. 0 H z, 1 H'); 8.31 ( d, J = 9.8 H z, 1 H); WO 2010/089507 PCT/FR2010/050178 95 11.96 (broad m, I H) 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-de): 0.22 to 0.30 (m, [M+H]+: m/z 553; 2 H); 0.36 to 0.43 (m, 2 H); 1.54 to 1.64 (m, 1 H); 1.90 to 2.03 (m, [M+2H]2+: m/z 277 1 H); 2.06 to 2.19 (m, 1 H); 2.40 to 2.60 (partially masked broad rn, 72(base peak); [M-H-: 8 H); 3.36 (partially masked m, 2 H); 3.64 to 3.83 (m, 4 H); 5.30 (m, m/zse 5 ) 1 H) 7.08 (d, J = 9.8 Hz, 1 H); 7.47. (dd, J = 2.0 and 8.6 Hz, 1 H); mlz 551 7.69 (d, J = 8.6 Hz, 1 H); 8.12 (d, J = 2.0 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 10.51 to 13.65 (very broad m, 1 H) 1 H NMR Spectrum (400 MHz, 6 in ppm, DMSO-de): 0.90 to 0.98 (m, [M+H]+: m/z 441; [M- 4 H); 1.94 to 2.04 (m, 1 H); 4.47 (m, 2 H); 4.71 (m, 2 H); 5.39 to 73 H]-: m/z 439 5.48 (m, I H); 7.19 (d, J = 9.8 Hz, I H); 7.44 (dd, J = 2.0 and 8.6 Hz, I H); 7.69 (d, J = 8.6 Hz, I H); 8.05 (d, J = 2.0 Hz, I H); 8.37 (d, J = 9.8 Hz, 1 H); 12.68 (broad m, 1 H) 'H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d 6 ): 0.97 (t, J = [M+H]+: m/z 527; 7.1 Hz, 3 H); 2.30 (q, J = 7.1 Hz, 2 H); 2.32 to 2.57 (partially 74 [M+2H]2+: m/z 264 masked broad m, 8 H); 3.31 (s, 2 H); 4.46 (m, 2 H); 4.70 (m, 2 H); (base peak); [M-H]-: 5.42 (m, 1 H); 7.20 (d, J = 9.8 Hz, 1 H); 7.44 (dd, J = 2.0 and m/z 525 8.6 Hz, 1 H); 7.70 (d, J = 8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, I H); 8.38 (d, J = 9.8 Hz, 1 H); 12.03 (broad m, 1 H) H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d): 0.23 to 0.29 (m, [M+H]+: m/z 539; 2 H); 0.35 to 0.42 (m, 2 H); 1.60 (m, 1 H); 2.40 to 2.60 (partially 75 [M+2H]2+: m/z 270 masked broad m, 8 H); 3.31 (s, 2 H); 4.46 (m, 2 H); 4.70 (m, 2 H); (base peak); [M-H]-: 5.42 (m, I H); 7.20 (d, J = 9.8 Hz, I H); 7.44 (dd, J = 2.0 and m/z 537 8.6 Hz, I H); 7.70 (d, J = 8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, I H); 8.38 (d, J = 9.8 Hz, 1 H); 12.09 (broad m, 1 H) Example 76: Pharmaceutical composition Tablets corresponding to the following formula were prepared: Product of Example 2....................... 0.2 g 5 Excipient for a finished tablet weighing ..... 1 g (details of the excipient: lactose, talc, starch, magnesium stearate). Example 77: Pharmaceutical composition 10 Tablets corresponding to the following formula were prepared: Product of Example 5 ....................... 0.2 g Excipient for a finished tablet weighing ..... 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

WO 2010/089507 PCT/FR2010/050178 96 Examples 2 and 5 are taken as examples of pharmaceutical preparation, this preparation possibly being performed, if desired, with other products illustrated in the present patent application. 5 Pharmacological section: Experimental protocols 1) Expression and Purification of MET, cytoplasmic domain Expression as Baculovirus: The recombinant DNA His-Tev-MET (956-1390) in pFastBac (Invitrogen) is 10 transfected into insect cells and, after several viral amplification steps, the final baculovirus stock is tested for expression of the protein of interest. After infection for 72 hours at 27*C with the recombinant virus, the SF21 cell cultures are harvested by centrifugation and the cell pellets are stored at 15 -80*C. Purification: The cell pellets are resuspended in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCI, Glycerol 10%, TECP 1 mM J; + Roche Diagnostics

EDTA

20 free protease inhibitor cocktail, ref. 1873580), stirred at 4*C until homogeneous, and then mechanically lysed using a "Dounce" machine. After centrifugation, the lysis supernatant is incubated for 2 hours at 4 0 C with nickel chelate resin (His-Trap 6 Fast Flow TM, GE HealthCare). After washing 25 with 20 volumes of buffer A, the suspension is packed into a column, and the proteins are eluted with a gradient of buffer B (buffer A + 290 mM imidazole). The fractions containing the protein of interest in the light of the electrophoretic analysis (SDS PAGE) are pooled, concentrated by 30 ultrafiltration (10 kDa cut-off) and injected onto an exclusion chromatography column (Superdex T m 200, GE HealthCare) equilibrated with buffer A.

WO 2010/089507 PCT/FR2010/050178 97 After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast Flow TM, GE HealthCare) equilibrated with buffer A. The fractions eluted with a 5 gradient of buffer B and containing the protein of interest after electrophoresis (SDS PAGE) are finally pooled and stored at -80 0 C. For the production of autophosphorylated protein, the preceding fractions are incubated for 1 hour at room temperature after addition of ATP 2 mM, MgCl 2 10 2 mM, and Na 3

VO

4 4 mM. After stopping the reaction with 5 mM of EDTA, the reaction mixture is injected onto a HiPrep desalting column (GE HealthCare) pre-equilibrated with buffer A + Na 3

VO

4 4 mM, and the fractions containing the protein of interest (SDS PAGE analysis) are pooled and stored at -80"C. The degree of phosphorylation is checked by mass spectrometry (LC-MS) 15 and by peptide mapping. II) Tests A and B and C A) Test A: HTRF MET test in 96-well format In a final volume of 50 pl of enzymatic reaction, MET 5 nM final is incubated 20 in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 pM, DMSO 3% final) in MOPS 10 mM pH 7.4, DTT 1 mM, 0.01 % Tween 20 buffer. The reaction is initiated with the substrate solution to obtain final concentrations of poly-(GAT) 1 pg/ml, ATP 10 pM and MgCl 2 5 mM. After incubation for 10 minutes at room temperature, the reaction is 25 stopped with a mix of 30 pl to obtain a final solution of Hepes 50 mM pH 7.5, potassium fluoride 500 mM, 0.1% BSA and EDTA 133 mM in the presence of 80 ng of streptavidin 61SAXLB Cis-Bio Int. and 18 ng of anti-phosphotyrosine Mab PT66-Europium Cryptate per well. After incubation for 2 hours at room temperature, the reading is taken at two wavelengths, 620 nm and 665 nm, 30 on a reader for the TRACE / HTRF technique and the percentage of inhibition is calculated from the 665/620 ratios.

WO 2010/089507 PCT/FR2010/050178 98 The results obtained via this test A for the products of formula (1) illustrated in the experimental section are such that the IC50 is less than 500 nM and especially less than 100 nM. 5 B) Test B: Inhibition of autophosphorylation of MET; ELISA technique (pppYl 230,1234,1235) a) Cell lysates: Inoculated MKN45 cells in 96-well plates (Cell coat BD 10 polylysine) to a rate of 20 000 cells/well in 200 pl in RPMI medium + 10% FCS + 1% L-glutamine. Leave to adhere for 24 hours in an incubator. The cells are treated the day after inoculation with the products at six concentrations in duplicate for 1 hour. At least three control wells are treated 15 with the same amount of final DMSO. Product dilution: Stock at 10 mM in pure DMSO - range from 10 mM to 30 pM with an increment of 3 in pure DMSO - Intermediate 50-fold dilutions in the culture medium, followed by removal of 10 pl added directly to the cells 20 (200 pl): final range from 10 000 to 30 nM. At the end of incubation, delicately remove the supernatant and rinse with 200 pl of PBS. Next, place 100 pl of lysis buffer directly in the wells on ice and incubate at 4"C for 30 minutes. Lysis buffer: 10 mM Tris-HCI pH 7.4, 100 mM 25 NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20 mM NaF, 2 mM Na 3

VO

4 , 1 mM PMSF and anti protease cocktail. The 100 pl of lysates are transferred into a V-bottomed polypropylene plate 30 and ELISA is performed directly or the plate is frozen at -80*C.

WO 2010/089507 PCT/FR2010/050178 99 b) ELISA PhosphoMET BioSource Kit KH00281 Add 70 pl of kit dilution buffer + 30 pL of cell lysates or 30 pl of lysis buffer for the blanks to each well of the kit plate. Incubate for 2 hours with gentle 5 rocking at room temperature. Rinse the wells four times with 400 pl of kit washing buffer. Incubate with 100 pl of anti-phospho MET antibody for 1 hour at room temperature. 10 Rinse the wells four times with 400 pL of kit washing buffer. Incubate with 100 pl of anti-rabbit HRP antibody for 30 minutes at room temperature (except for the wells with chromogen alone). Rinse the wells four times with 400 pl of kit washing buffer. Introduce 100 pl 15 of chromogen and incubate for 30 minutes in the dark at room temperature. Stop the reaction with 100 pl of stop solution. Take the reading without delay, at 450 nM 0.1 second on a Wallac Victor plate reader. 20 C) Test C: Measurement of the cell proliferation via a 14C-thymidine pulse The cells are inoculated in Cytostar 96-well plates in 180 pl for 4 hours at 37"C and 5% C0 2 : HCT1 16 cells at a rate of 2500 cells per well in DMEM medium + 10% foetal calf serum + 1% L-Glutamine and MKN45 cells at a rate 25 of 7500 cells per well in RPMI medium + 10% foetal calf serum + 1% L Glutamine. After these 4 hours of incubation, the products are added in 10 pl as a 20-fold concentrated solution according to the dilution method cited for ELISA. The products are tested at 10 concentrations in duplicate from 10 000 nM to 0.3 nM with an increment of 3. 30 WO 2010/089507 PCT/FR2010/050178 100 After 72 hours of treatment, add 10 pl of 14C-thymidine at 10 pCi/ml to obtain 0.1 pCi per well. The incorporation of 14C-thymidine is measured on a Micro Beta machine (Perkin-Elmer) after 24 hours of pulse and 96 hours of treatment. 5 All the test steps are automated on BIOMEK 2000 or TECAN stations. The results obtained via this test B for the products of formula (1) illustrated in the experimental section are such that the IC50 is less than 10 pM and 10 especially less than 1 pM. The results obtained for the products illustrated in the experimental section are given in the table of pharmacological results hereinbelow, as follows: for test A, the + sign corresponds to less than 500 nM and the ++ sign 15 corresponds to less than 100 nM, for test B, the + sign corresponds to less than 500 nM and the ++ sign corresponds to less than 100 nM, for test C, the + sign corresponds to less than 10 pM and the ++ sign corresponds to less than 1 pM. 20 Table of pharmacological results: Ex. number test A test B test C S++ ++ + 2 ++ ++ ++ 3 ++ ++ 4 ++ ++ ++ 5 ++ ++ ++ 6 -H- ++ + 7 ++ ++ ++ 8 ++

+-

WO 2010/089507 PCT/FR2010/050178 101 9 ++ ++ ++ 10 ++ ++ ++ 11 ++ ++ ++4 12 ++ ++

++

13 ++ ++ ++ 14 ++ ++ ++ 15 + ++ 16 ++ + ++ 17 ++ ++ ++ 18 ++ + 19 ++ ++ ++ 20 ++ ++ ++ 21 ++ ++ ++ 22 ++ ++ ++ 23 ++ ++ ++ 24 ++ ++ ++ 25 ++ ++ ++ 26 ++ + ++ 27 + ++ 28 ++ + ++ 29 ++ ++ ++ 30 ++ ++ ++ 31 ++ ++ ++ 32 ++ ++ ++ 33 ++ ++ ++ 34 ++ ++ ++ 35 ++ ++ ++ 36 ++ ++ 37 ++ ++ 38 ++ +

++

WO 2010/089507 PCT/FR2010/050178 102 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 ++ +

++

WO 2010/089507 103 PCT/FR2010/050178 69 ++ ++ +4 70 + + ++ 71 + + 72 ++ +++ 73 ++ +++ 74 + ++ 75 +

Claims

3-benzodioxol-5-yloxy)[1 ,2 ,4]triazolo[4 1 3-blpyridazin-3-yl su If any}-1 1 3-be nzoth iazol- 2 -yI)cyclopropanecarboxamide - N-(6-{[6-(3 ,4-d ich Iorophenoxy)[1 ,2 ,4]triazolo[4,3-b] pyridazi n-3-yI]su Ifanyl} 1, 3-be nzoth i azol1-2-yI )cyclo pro panecarboxa m id e 5 - N -(6-{[6-( I H-indol-6-yloxy)[I ,2,4]triazolo[4,3-b]pyridazi n-3-yI]su Ifanyl}-I ,3 ben zoth i azol1-2 -yI)cycl opropanecarboxam ide - N-(6-{[6-(3-fiuorophenoxy)[1 ,2 ,4]triazolo[4 ,3-b] pyridazin-3-yI]suifa nyl}-1 ,3 benzoth iazol-2-yI)cyclobutaneca rboxam ide - N-(6-{[6-(3-fluorophenoxy)[1,2 ,4]triazolo[4 ,3-blpyridazin-3-yllsu Itanyl}- 1,3 10 benzothiazo-2-y)-N 2, N 2 -di methyiglycinam ide - 2-ethoxy- N-(6-{[6-(3-fluorophenoxy)[1 ,2 ,4]triazolo[4 ,3-b] pyridazin-3-yI]su If a nyl}- 1,3-be nzoth iazol-2-yl )acetam ide - 2 -(CYlohexyoxy)-N-(64[6-(3-fluorophenoxy)[ , 2 ,4]triazolo[4 ,3-b] pyridazin-3 yIlsu Ifanyl}-1I,3-bnzoth iazol-2-yI )acetam ide 15 - 6-{[6-(pyridin-3-yloxy[l, 2 ,4]triazolo[4 ,3-b] pyridazin-3-yIlsu Ifanyl}- 1, 3-benzo thiazol-2-amine - G-({ 6 -[ 3 -(trifluoromethoxy)phenoxy] [1,2 ,4]triazolo[4, 3-b] pyridazin-a-y}sulf anyl)-1I,3-benzoth iazol-2-am Ine - 2-methyipro pan-2-yI [3-({3-[(2-ami no-I, 3-benzoth iazo I-6-yI)su If 20 anyl] [1,2 ,4]triazolo[4 ,3-b] pyridazin-6-yIloxy)phenyl]carba mate - N-(6-{[6-(pyrid in-3-yloxy)[1, 2,4]triazolo[4, 3 -b]pyridazin-3-yl]sulfanylp 1,3 benzoth iazol-2-yI)cyclo butanecarboxamide - N-(6-{[6-(3-fluorophenoxw)rI ,2 1 4]triazolo[4,3-b]pyridazin-3.yI]su Ifanyl}-1 ,3 benzoth iazol-2-yI)-2-(m orphol in-4-yI)acetam ide 25 - N 2 -cycloh exyl-N -(G-{[6-(3-fluorophenoxy)[I ,2 ,4]triazolo[4 ,3-b]pyridazi n-3-yI] su Ifanyl}-1 1 3-benzoth iazol-2-yI)glyci nam ide - N-(6-{[6-(3-fluorophenoxy)[I ,2 ,4]triazolo[4 ,3-b] pyridazin-3-yg~sulfa nyl}- 1,3 benzothiazo-2-yi)-N 2_methyl-.N2[2..(morpholIin-4-yl)ethyl]g lyci nam ide - 2-(4-ethyl pi perazi n-I -yI )-N-(6-{[6-(3-fluorophe noxy)[1 ,2 ,4]triazolo[4 ,3-b] 30 pyridazin-3-yI]su Ifanyl}-1I,3-benzoth iazol-2-yI )acetamide WO 2010/089507 PCT/FR2010/050178 117 - 6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl)-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 5 - N-(6-{[6-(3-fluorophenoxy)[1,2, 4 ]triazolo[4,3-blpyridazin-3-yl]sulfanyl}-1,3 benzothiazol-2-yI)-N -2--(tetrahyd ro-2 H-pyran-4-yl)g lycinam ide - N-[6-({6-[4-(trifl u oromethyl)p henoxy][1,2,4]triazolo[4,3-b] pyridazi n-3-yl}s u If anyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide - N-[ 6 -({6-[3-(trifluoromethoxy)phenoxy][1,2,4]triazolo[4,3-blpyridazin-3-yl}sulf 10 anyl)-1,3-benzothiazol- 2 -yl]cyclopropanecarboxamide - N-[6-({6-[(2-methylpyridin-3-yl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf anyl)-1, 3 -benzothiazol-2-ylJcyclopropanecarboxamide - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl} 1,3-benzothiazol- 2 -yl)cyclopropanecarboxamide 15 - 2-[(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3 -b]pyridazin-3-yl]sulfanyl}-1,3 benzothiazol-2-yl)amino]-2-oxoethy acetate - N-[6-({6-[(6-methylpyridin-3-yl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf anyl)-1,3-benzothiazol-2-ylcyclopropanecarboxamide - N-[6-({6-[4-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3 20 yl}sulfanyl)-1,3-benzothiazol- 2 -yl]cyclopropanecarboxamide - 2-methylpropan-2-y ( 3 -{[ 3 -({ 2 -[(cyclopropylcarbony)am ino]- 1, 3-benzo thiazol-6-yi}sulfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]oxy}phenyl)carbamate - N-(6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-bipyridazin-3-yl]sulfanyl}-1,3 benzothiazol-2-yl)cyclopropanecarboxamide 25 - N-{6-[(6-{3-[(1 S,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}cyclopro panecarboxamide - N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3 yl)su Ifanyl]- 1,3-benzoth iazol-2-yl}cyclopro panecarboxam ide 30 - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl} 1,3-benzothiazol-2-yl)-N2,N2-diethylglycinamide WO 2010/089507 PCT/FR2010/050178 118 - N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-blpyridazin-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 5 - N-(6-{[6-(3,5-d ifluorop hen oxy)[1,2,4]triazolo[4,3-blpyridazin-3-yl]su Ifa nyl} 1,3-benzothiazol-2-yI)- 2 -(4-ethylpiperazin-I -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 10 yl)sulfanyl]-1, 3 -benzothiazol-2-yl}acetamide - N-{6-[(6-{3-[(d iethylami no)methyl] phenoxy}[1, 2,4]triazolo[4,3-b]pyrid azi n-3 yl)sulfanyl]-1,3-benzothiazol-2-yI}-2-methoxyacetamide - 2-methoxy-N-{6-[(6-{3-[(1 S, 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-y} 15 acetamide - 6 -{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo thiazol-2-amine - 2 -(morpholin-4-y)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b] pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide 20 - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl} 1,3-benzothiazol-2-yI)-2-(morpholin-4-yl)acetamide -N 2 , N 2 -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-yI)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3 25 b]pyridazin-3-yl]sulfanyl}-1, 3 -benzothiazol-2-yl)acetamide - 2 -( 4 -cyclopropylpiperazin-1 -yI)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4] triazolo[4,3-bjpyridazin-3-yllsulfanyl}-1,3-benzothiazol-2-yl)acetamide - N-(6-{[6-(oxetan-3-yloxy)[1,2,4]t riazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3 benzoth iazol-2-yl)cyclopropan ecarboxamide 30 - 2-(4-ethylpiperazin-i -yI)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b] pyridazin-3-yl]sulfanyI}-1,3-benzothiazol-2-yl)acetamide WO 2010/089507 PCT/FR2010/050178 119 - 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3 b]pyridazin-3-yllsulfanyl}-1,3-benzothiazol-2-yl)acetamide and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I). 5 13) Process for preparing the products of formula (1) as defined in any one of the other claims. 14) Process for preparing the products of formula (1) as defined in any one of the other claims, in which A represents NH. 15) Process for preparing the products of formula (1) as defined in any one of 10 the other claims, in which A represents S. 16) As medicaments, the products of formula (1) as defined in any one of Claims 1 to 12, and also the addition salts with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of the said products of formula (1). 15 17) As medicaments, the products of formula (1) as defined in Claim 12, and also the addition salts with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of the said products of formula (1). 18) Pharmaceutical compositions containing, as active principle, at least one 20 of the products of formula (I) as defined in any one of Claims I to 12, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable support. 19) Use of the products of formula (1) as defined in any one of Claims 1 to 12, or of pharmaceutically acceptable salts of these products, for the preparation 25 of a medicament for inhibiting the activity of the kinase protein MET and mutant forms thereof. 20) Use as defined in Claim 19, in which the kinase protein is in a cell culture. 21) Use as defined in Claim 19 or 20, in which the kinase protein is in a mammal. 30 22) Use of a product of formula (1) as defined in any one of Claims 1 to 12, for the preparation of a medicament for treating or preventing a disease chosen WO 2010/089507 PCT/FR2010/050178 120 from the following group: blood vessel proliferation disorders, fibrotic disorders, "mesangial" cell proliferation disorders, metabolic disorders, allergies, asthmas, thromboses, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers. 5 23) Use of a product of formula (1) as defined in any one of Claims 1 to 12, for the preparation of a medicament for treating cancers. 24) Use according to 23, for treating solid or liquid tumours. 25) Use according to 23 or 24, for treating cancers that are resistant to cytotoxic agents. 10 26) Use according to one or more of Claims 23 and 24, for treating primary tumours and/or metastases, in particular in stomach, liver, kidney, ovarian, bowel or prostate cancer, lung cancer (NSCLC and SCLC), glioblastomas, thyroid, bladder or breast cancers, melanomas, lymphoid or myeloid haematopoietic tumours, sarcomas, brain cancers, cancer of the larynx, 15 cancer of the lymphatic system, bone cancers and pancreatic cancers. 27) Use of the products of formula (1) as defined in Claims 1 to 12, for the preparation of medicaments for cancer chemotherapy. 28) Use of the products of formula (1) as defined in Claims I to 12, for the preparation of medicaments for cancer chemotherapy, alone or in 20 combination. 29) Products of formula (1) as defined in any one of Claims 1 to 12, as kinase inhibitors. 30) Products of formula (1) as defined in any one of Claims 1 to 12, as MET inhibitors. 25 31) As novel industrial products, the synthetic intermediates of formulae M1, M2, M3 and N with Rb representing a fluorine atom F, as defined hereinbelow: WO 2010/089507 PCT/FR2010/050178 121 H1 y~ H H>< Rb N R6 Rb N N, M1 M2 HS~ H S />-N xS M3 0 Rb N NH N in which the groups CONR1 R2, C02R6 and COR7, which constitute W, may take the values of W as defined in any one of Claims 1 to 11 for the products of formulae (I') and (I"), when W 4.