SG173559A1

SG173559A1 - 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: SG173559A1
Application number: SG2011056488A
Authority: SG
Inventors: Conception Nemececk; Antonio Ugolini; Sylvie Wentzler; Eric Bacque; Gilles Barbalat
Original assignee: Sanofi Sa
Priority date: 2009-02-06
Filing date: 2010-02-04
Publication date: 2011-09-29
Also published as: FR2941950A1; EA201171011A1; FR2941950B1; TW201031670A; KR20110132560A; WO2010089507A1; MX2011008319A; AU2010212232A1; MA33107B1; CL2011001879A1; IL214406A0; CN102378759A; UY32420A; JP2012517408A; BRPI1008232A2; CO6400223A2; AR075249A1; CA2750875A1; EP2393791A1

Description

DERIVATIVES OF 6-(6-0-SUBSTITUTED-TRIAZOLOPYRIDAZINE-SULFANYL)

BENZOTHIAZOLES AND BENZIMIDAZOLES, PREPARATION THEREOF, USE

THEREOF AS DRUGS, AND USE THEREOF AS MET INHIBITORS 9 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, fo pharmaceutical compositions containing them and to the novel use of such 6-triazolopyridazine-sulfanyl benzothiazole and benzimidazole derivatives.

The present invention more particularly relates to novel 6-(6-O-substituted triazolopyridazine-sulfanyl) benzothiazole and benzimidazole derivatives with anticancer activity, via modulation of the activity of proteins, in particular 16 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 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 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 adhesion and motility, cell differentiation or cell survival, certain kinase 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 involved, certain processes represent aftractive 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, 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.

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. :

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.

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 for which activity modulation is desired, MET is preferred.

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.

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 recepior, 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 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.

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

MET and mutants thereof, which may be used for anti-angiogenic treatment, especially in oncology.

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

AX A

4 TO [ w Rb N WwW \

Ra 0 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 from 1 to 6 carbon atoms and optionally substituted with an alkyl group or a halogen atom;

Re represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical;

X represents S, SO or SO2;

A represents NH or S;

W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: - a cycloalkyl radical or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -O-CO-R5, hydroxyl, phenyl, heteroaryl or heterocycioalkyl, which are themselves optionally “substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyl; a radical O-phenyl or a radical O-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 4; - 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, 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 attached, a 3- to 10-membered cyclic radical optionally containing one : or more other heteroatoms chosen from O, S, N and NH, with the optional S possibly being in the form SO or SO2; 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 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 radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIk, 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 from O, 8, N and NH, with the optional S$ possibly being in the form SO or SO2; this radical, including the possible NH it contains, being optionally substituted; all the alkyl, alkoxy, -O-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 chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, -0-CO-R5, -ORS5 -COOH, COORS5, -CONH2, CONHR5, NH2, NHRS5,

NRS5RS%', -NH-CO-RS, -NHCOORS and alkyl, heterocycloalkylalkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl,

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 1 to 4 carbon atoms, NH2, NHalk and N(alk)2; B all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined above being furthermore optionally substituted with a radical Si(alk)3;

R5 and RS, 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; 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; | 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 (1).

A subject of the present invention is the products of formula (I) 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 Re represents optionally substituted aryl;

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, heterocycloalkyli or NR3R4; or the radical COR in which R represents:

- a cycloalkyl radical or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -O-CO-R5, hydroxyl, phenyl, : heteroaryl or heterocycloalkyl, which are themselves optionally substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyl; a radical O-phenyl or a radical O-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 4; - 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, 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 attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, with the optional 8 possibly being in the form SO or SO2; 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 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 radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIk, 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, including the possible NH it contains, being optionally substituted;

all the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyi, 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 chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, -0-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 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;

RS represents an alkyl or cycloalkyl radical containing not more than 6 carbon atoms; 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 (1).

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 alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: - a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -O-CO-R5, hydroxyl, phenyl or heterocycloalkyl, which are themselves optionally substituted; - an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyi; a radical O-phenyl or a radical O-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 4;

- 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 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 O, S, N and

NH, this radical, including the possible NH it contains, being optionally substituted; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom, 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,

NHAIk, N(AIk)2, 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 O, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; all the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl and phenyl radicals, 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, defined above, being optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, alkoxy, O-cycloalkyl, NH2, NHalk,

N(alk)2 and alkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that in the latter radicals, the alkyi, 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 (!) 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). :

As regards the cyclic radicals that can be formed by R1 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 O, 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):

PAN X A dg T0 { W Rb N Ww \_/ ka (0) 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:

Rc represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical;

X represents S, SO or S02;

Arepresents 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: = 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 O-phenyl or a radical O-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to : 4; - 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, 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 attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; with 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 nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and

NH, this radical, including the possible NH it contains, being optionally substituted; all the alkyl, 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 and the following radicals: hydroxyl, oxo, alkoxy, -O-CO-R5, -OR5, -COOH,

COORS5, -CONH2, CONHRS, NH2, NHR5, NR5RS’, -NH-CO-R5 and alkyl, cycloalkyl, heterocycioalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO- phenyi, 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, all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined above being furthermore optionally substituted with a radical Si(alk)3;

R5 and RY, 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; 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).

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-R¢ in which Z represents a single bond and Rc represents optionally substituted aryl;

Rb represents a hydrogen or fluorine atom;

Xrepresents S, SO or SO2;

A represents NH or S;

W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally substituted with alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents: - 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 O-phenyl or a radical O-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 4, - 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, 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 attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; with 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, 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 O,

S, N and NH, this radical, including the possible NH it contains, being optionally substituted;

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 and the following radicals: hydroxyl, oxo, alkoxy, -O-CO-R5, -ORS5, 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 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;

RS represents an alkyl or cycloalkyl radical containing not more than 6 carbon atoms; the said products of formula (I} being in any possible racemic, enantiomeric or diasterecisomeric 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 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 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 heterocycloalkyl; a radical O-phenyl or a radical O-(CH2)n-phenyl, with phenyl optionally substituted and n represents an integer from 1 to 4:

NH, this radical, including the possible NH it contains, being optionally substituted; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or 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 O,

S, N and NH, this radical, including the possible NH it contains, being optionally substituted; : all the cycloalkyl, heterocycloalkyl and phenyl radicals, 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, defined above, being optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, alkoxy, O-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 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 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).

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 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 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

NRB3R4, 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 O, S, N and NH, this radical, including the possibie

NH it contains, being optionally substituted; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or 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 O, 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 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, O-cycloakyl, NH2, NHalk, N(alk)2 and alkyl and phenyl radicals, the latter radicals themselves being 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 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 (I) 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 (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 (1).

A subject of the present invention is the products of formula (I) as defined 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 diastereocisomeric 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).

One subject of the present invention is the products of formula (1) as defined hereinabove or hereinbelow corresponding to formula (la) or (Ib):

AN S N H oh TA { WN Rb N w \ J

Ra (la)

Nas H

NY NN

\ )—N \ N Ww \ N Rb \ J

Ra (Ib) in which = , Ra, Rb and W are chosen from the meanings indicated in any one of the other claims, 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 (1a) and (Ib).

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): x AM mn oN

N Rb w /

Ra r) the substituents Ra, Rb, X, A and W having any one of the meanings indicated hereinabove or hereinbelow, the said products of formula (I} being in any possible racemic, enantiomeric or diastereoisomeric isomer form, and also the addition saits 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 (I) as defined hereinabove or hereinbelow, in which = represents a double bond, corresponding to the products of formula (I):

"a A H y TC )— N \ Rb N w \/ = a 1") 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 (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 (1).

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 (1a’): "Oa N Ho . ToL )— No \y Rb N ~~ w /

Ra (a) in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, the said products of formula (I'a) being in any possible racemic, enantiomeric or diasterecisomeric 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'a).

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"a): .- _N

Ne Ns N A

N TU / \

N Rb N w \ 7 "a 2 a (1"a) in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, the said products of formula (1”a) being in any possible racemic, enantiomeric or diastereocisomeric 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"a).

A subject of the present invention is the products of formula (I) as defined hereinabove or hereinbelow, in which —— represents a single bond, corresponding to the products of formula (I'b):

N

YY

N : / N \y Rb N w /

Ra {I'b) in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, 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).

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

TS

N

\ 7

N Rb N Ww \_/ in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, : the said products of formula (I"b) being in any possible racemic, enantiomeric or diasterecisomeric 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).

In the products of formula (1) and in the text hereinbelow: - 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, ischexyl 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 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 preferred; - the term halogen atom denotes a chlorine, bromine, iodine or fluorine atom and preferably the chlorine, bromine or fluorine atom.

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

9 - 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,

homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyt, tetrahydropyranyl, 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 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,

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 O, N and S with N, where appropriate, being optionally substituted:

- the term aryl radical thus denotes 6- to 12-membered monocyclic or bicyclic 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(Q) ring member is, for example, the tetralone radical; it may also be noted that the aryl radical such as phenyl may be optionally substituted, for example, with two alkoxy radicals to form a benzodioxolyl radical, which is itself optionally substituted as indicated for the aryl radical;

- 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, pyrrolyi, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl 9 and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyt, 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, pyrazolinyt, 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, benzopyrrolyl, benzimidazolyl, benzoxazolyt, thionaphthyl, indoly!, azaindolyl, indazolyl, purinyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydro- cyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetrahydro- pyridinopyrazolyl or oxodihydropyridinopyrazolyl, all these radicals being optionally substituted.

As examples of heteroaryl or bicyclic radicals, mention may be made more particularly of pyrimidinyl, pyridyl, pyrrolyl, azaindolyl, indazolyl or pyrazolyi radicals, optionally substituted with one or more identical or different 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 R1 and R2 or R3 and R4, respectively, with the nitrogen atom to which they are attached, may optionally form a ring of cycloalkyl or 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 (I) may be salified or esterified with various groups known to those skilled in the art, among which examples that may be mentioned include: - among the sallification compounds, mineral bases such as, for example, che equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium, or organic bases, for instance methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)- aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methyi- glucamine, - among the esterification compounds, alkyl radicals to form alkoxycarbonyl groups, for instance methoxycarbonyi, 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, propionyloxymethyl, methylthiomethyl, 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, 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,B-ethanedisulfonic acid, arylmonosulfonic acids : such as benzenesulfonic acid, and aryldisulfonic acids.

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 cyciohexanes in which the substituent may be in an axial or equatorial position, and the various possible rotational conformations of ethane derivatives. However, another type of sterecisomerism 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 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 R1 and R2 with the nitrogen atom to which they are attached, and, on the other hand, by R3 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 heterocycloalky! radicals, i.e. one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, NH2; NHalk, N(akk)2, and alkyl, heterocycloalkyl, CH2- 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.

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 from halogen atoms and alkyl, hydroxyl, alkoxy, CH2-pyrrolidinyl, CH2- phenyl, heteroaryl and phenyl radicals, in which the alkyl, pyrrolidinyl and 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.

The heterocycloalkyl radicals as defined above especially represent azepanyil, 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 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

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 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.

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 (I) having any one of the definitions indicated hereinabove or hereinbelow.

‘WO 2010/089507 or PCT/FR2010/050178

A subject of the present invention is especially the products of formula (1) as defined hereinabove or hereinbelow, in which Ra represents a radical -O- phenyl optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, alkoxy, O-cycloalkyl, alkyl and

CFS, the other substituents of the said products of formula (I) having any one : of the definitions indicated hereinabove or hereinbelow.

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-phenyl optionally substituted with one or more halogen atoms;

Rb represents a hydrogen atom;

X represents S;

Avrepresents S;

W represents a hydrogen atom; or the radical COR in which R represents: - a cycloalkyl radical or an alkyl radical; or the radical NR1R2 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 represents an alkyl radical optionally substituted with a heterocycloalkyl radical; 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 (1). : A subject of the present invention is thus the products of formula (Hh) as defined hereinabove or hereinbelow, corresponding to the following formulae: - 6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2- amine

- N-{6-[(6-phenoxy[1,2 4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-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 : - 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-ylsulfanyl}-1,3- benzothiazol-2-yl)-3-[2-(morpholin-4-yhethyljurea - 6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b] pyridazin-3-ylfsulfanyl(}-1,3- : 10 benzothiazol-2-amine :

- N-~(6-{[6-(3-flucrophenoxy)[1 ,2,4]triazolof4,3-b]pyridazin-3-yllsulfanyi}-1,3- benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide - N2,N2-diethyl-N-(6-{[6-(3-fluorophenoxy)[1 2 ,4triazolo[4,3-b]pyridazin-3-yl]- sulfanyl}-1,3-benzothiazol-2-yl)glycinamide

156 - N2-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1 .2.,4]triazolo[4,3-b]pyridazin-3-yl]- suifanyi}-1,3-benzothiazol-2-yl)glycinamide - N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4ltriazolof4,3-b]pyridazin-3- yl}sulfanyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide - N-(6-{[6-(3-fluorophenoxy)[1 2,4]triazolof4,3-b]pyridazin-3-yl]sulfanyl}-1,3-

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

benzothiazol-2-yl)cyclopropanecarboxamide

- 1-(6-{[6-(4-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}-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- anyl}-1,3-benzothiazol-2-yi)-3-[2-(morpholin-4-yl)ethyllurea - 6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-ylisulf- anyl}-1,3-benzothiazol-2-amine - 6-{[6-(4-fluorophenoxy){1 ,2,4]triazolo[4,3-b]pyridazin-3-yflsulfanyl}-1,3-

benzothiazol-2-amine

- 1 -[2-(morpholin-4-yl)ethyl}-3-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1 2,4]- triazolo[4,3-b]pyridazin-3-yl[sulfanyl}-1 ,3-benzothiazol-2-yl)urea - 1-[6-({6-[(1-ethylpiperidin-4-yl)oxy][1 ,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- ..anyl}1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyllurea 3 - N-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1 ,2,4]triazolo[4,3-bjpyridazin-3-yl]sulf- anyli}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(4-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4]triazolo[4,3-bipyridazin-3-yl]sulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-[6-({6-[(1-ethylpiperidin-4-yl)oxy][1 2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- anyl)-1,3-benzothiazol-2-yl|cyclopropanecarboxamide : - 1-[2-(morpholin-4-yl)ethyl]-3-(6-{[6-(tetrahydrofu ran-3-yloxy})[1,2,41triazolo- [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-yljsulf- anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyllurea - 1-(8-{[6-(3.4-dichlorophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}- 1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-ylethyllurea - 6-{[6-(3,4-dichlorophenoxy)[1 2 ,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1 ,3- benzothiazol-2-amine - 6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}- 1,3-benzothiazol-2-amine - 1-(6-{[6-(1 H-indol-6-yloxy)[1 2 ,4]triazolof4,3-b]pyridazin-3-yljsulfanyl}-1 '3- benzothiazol-2-y1)-3-[2-(morpholin-4-yi)ethyljurea - N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 2 Altriazolo[4,3-b]pyridazin-3-ylsulfanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(1,3-benzodioxol-5-yloxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yllsulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3,4-dichiorophenoxy)[1 2.4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide

- N-(6-{[6-(1H-indol-6-yloxy)[1 2,4]triazolo[4,3-b}pyridazin-3-ylJsulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide : - N-(8-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3- benzothiazol-2-yl)cyciobutanecarboxamide = N-(6-{[6-(3-fluorophenoxy)[1 .2,4]triazolof4,3-b]pyridazin-3-yljsulfanyl}-1,3- benzothiazol-2-yl)-N2,N2-dimethylglycinamide - 2-ethoxy-N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]suif- anyl}-1,3-benzothiazol-2-yl)acetamide - 2-(cyclohexyloxy)-N-(6-{[6-(3-fluorophenoxy)[1 ,2.4]triazolo[4,3-b]pyridazin-3- vylisulfanyl}-1,3-benzothiazol-2-yl)acetamide - 6-{[6-(pyridin-3-yloxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3-benzo- thiazol-2-amine - 6-({6-[3-(trifluoromethoxy)phenoxy][1 2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- anyl)-1,3-benzothiazol-2-amine - 2-methylpropan-2-yl [3-({3-{(2-amino-1,3-benzothiazol-6-yl)sulfanyl]- [1,2,4]triazolo[4,3-b]pyridazin-6-yljoxy)phenyl]carbamate - N-(6-{[6-{pyridin-3-yloxy)[1 2,4}triazolo[4,3-blpyridazin-3-ylsulfanyl}-1,3- benzothiazol-2-yl)cyclobutanecarboxamide - N-(6-{[6-(3-fluorophenoxy)[1 .2,4]triazolo[4,3-blpyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide - N2-cyclohexyl-N-(6-{[6-(3-fluorophenoxy)[1 ,2,4triazolof4,3-b]pyridazin-3-yl]- sulfanyl}-1,3-benzothiazol-2-yl)glycinamide - N-(6-{[6-(3-flucrophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}-1,3- benzothiazol-2-yl)-N*-methyl-N*[2-(morpholin-4-yl)ethyl]glycinamide - 2-(4-ethylpiperazin-1-yl)-N~(6-{[6-(3-fluorophenoxy)[1 ,2,4ltriazolo[4,3-b]- pyridazin-3-yllsulfanyl}-1,3-benzothiazol-2-yl)acetamide - 6-{[6-(3,5-diflucrophenoxy)[1 ,2,4]triazolof4,3-blpyridazin-3-ylsuifanyl}-1,3- benzothiazol-2-amine - 6-{[6-(3-aminophenoxy)[1,2 4ltriazolo[4,3-b]pyridazin-3-yl]sulfa nyl}-1,3- benzothiazol-2-amine

- N-(6-{[6-(3-fluorophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}-1,3- benzothiazol-2-yl)}-N~2~-(tetrahydro-2H-pyran-4-yh)glycinamide - N-[6-({6-[4-(trifluoromethyl)phenoxy][1 .2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- anyl)-1 .3-benzothiazol-2-ylcyclopropanecarboxamide 2 = N-[6-({6-[3-(trifluoromethoxy)phenoxy][1 2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- 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-yl]cyclopropanecarboxamide - N-(6-{[6-(3,5-difluorophenoxy){1,2,4ltriazolo[4,3-b]pyridazin-3-yllsuifanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide - 2-[(6-{[6-(3-fluorophenoxy)[1 ,2,4ltriazolo[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-b]pyridazin-3-yl}sulf- anyl)-1,3-benzothiazol-2-yljcyclopropanecarboxamide - N-[6-({6-[4-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3- yl}sulfanyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide - 2-methylpropan-2-yl (3-{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzo- thiazol-6-yl}sulfanyl)[1 .2,4ltriazolo[4,3-b]pyridazin-6-ylJoxy}phenyl)carbamate - N-(6-{[6-(pyridin-3-yloxy)[1,2 4]triazolo[4,3-b]pyridazin-3-yl|sulfa nyi}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - N-{6-[(6-{3-[(1S,4S}-2-0xa-5-azabicyclo[2,2,1 ]hept-5-yimethyllphenoxy}- [1 2 4ltriazolo[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)sulfanyl}-1,3-benzothiazol-2-yl}cyclopropanecarboxamide - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}- 1,3-benzothiazol-2-yl)-N2, N-diethylglycinamide - N-(6-{[6-(3-fluorophenoxy)[1 ,2,4}triazolo[4,3-b]pyridazin-3-ylJsulfanyi}-1,3- benzothiazol-2-yl)-2-hydroxyacetamide - 2-(4-cyclopropylpiperazin-1-yl)-N-(6-{[6-(3-flucrophenoxy)[1,2 4]triazolo[4,3- b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide

- N-(6-{[6-(3 5-difluorophenoxy)[1,2 4ltriazolof4,3-blpyridazin-3-yllsulfanyl}- : 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-blpyridazin-3-yllsulfanyl}-1 +3-benzothiazol-2-yl)acetamide - N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1 ,2,4]triazolo[4,3-b]pyridazin-3- yhsulfanyl]-1,3-benzothiazol-2-yl}acetamide - N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1 .2,4]triazolo[4,3-b]pyridazin-3- yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-methoxyacetamide - 2-methoxy-N-{6-[(6-{3-[(1S,4S)-2-oxa-5-azabicyclo[2,2, 1 Jhept-5-yimethyl]- phenoxy}1 .2,4]triazolo[4,3-b]pyridazin-3-yl)suifanyl]-1 .3-benzothiazol-2-yl}- acetamide - 6-{[6-(oxetan-3-yloxy)[1 2 ,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3-benzo- thiazol-2-amine - 2-(morpholin-4-yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 .2,4]triazolo[4,3-b]- 16 pyridazin-3-ylJsulfanyl}-1,3-benzothiazol-2-yl)acetamide - N-(6-{[6-(3,5-difluorophenoxy)[1,2 4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)- 1,3-benzothiazol-2-yl)-2-(morpholin-4-yhacetamide - N2,N*-diethyl-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 2 4ltriazolo[4,3-b]pyridazin- 3-yllsulfanyl}-1,3-benzothiazol-2-yl)glycinamide - 2-(4-ethylpiperazin-1-yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4, 3- blpyridazin-3-yllsulfanyl}-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-ylacetamide - N-(6-{[6-(oxetan-3-yloxy)[1,2 4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - 2-(4-ethylpiperazin-1-yl)-N-(6-{[6-(oxetan-3-yloxy)[1 ,2,4]triazolo[4,3-b]- pyridazin-3-yljsulfanyl}-1,3-benzothiazol-2-yl)acetamide - 2-(4-cyclopropylpiperazin-1 -yI)-N-(6-{[6-(oxetan-3-yloxy)[1,2 4ltriazolo[4,3- b]pyridazin-3-yl]sulfanyl}-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).

A ‘subject of the present invention is also any process for preparing the products of formula (1) as defined above. 9 A subject of the present invention is thus any process for preparing the products of formula (I) 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.

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 N. In this respect, they shall not constitute a limitation of the scope of the invention, as regards the methods for preparing the claimed compounds.

The products of formula (I) 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.

A subject of the present invention is thus also the process for preparing products of formula (I) according to Scheme 1 as defined below.

A subject of the present invention is thus also the process for preparing products of formula (I) according to Scheme 2 as defined below.

A subject of the present invention is thus also the process for preparing products of formula (I) according to Scheme 2bis as defined below.

A subject of the present invention is thus also the process for preparing products of formula (I) according to Scheme 3 as defined below.

A subject of the present invention is thus also the process for preparing - products of formula (I) according to Scheme 4 as defined below. 9 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.

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 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 (2°), (b), (¢), (d), (€') and (f') are defined, in which — represents a single bond, and the compounds of formulae (a), (b™), (c”), (d"), (e") and (’) in which = represents a double bond.

Scheme 1: synthesis of benzimidazole derivatives of formulae (1a”), (1 b”), (17c), (1d™), (1e”), (12’), (1b’), (1c’), (1d") and (1e')

: WO 2010/089507 PCT/FR2010/050178 35

NC—$ NH, ‘(eduction HS NH, Yoo K+ Ao or

THe when WH when F NO, Cc F NO,

Q " Rb=H E Rb=F D Q commercial

N- —N N : 3 HS. NH Nes NH (3a ye reno, J XX

ZN Rat _ _N _ A Yy Rb NO, s according to Z G cl Scheme 3 Ra Ra commercial E reduction

Ri NCOR, pn NH i" Ns AN Mes{ oR Ne ys 2

Ns N NT —N Ho20 SN

N ¥ H (R) N 4 W) Nn Rb NH, oN NRT re SN 0, \ 7 \'Rb N Pu \ 4 0 Rj 3 MN 0 R, : Ra Ra HY H™

Ra 10710 fata” | BrCN

H

MN _s H R0COX | Ng H

NT Xr rh o [NT XI pa \ N 0 -— W Rb » Rb 0 R, \ 4

Ra 4gy4qn Ra ore

R,COX {P)

Nos H

NT >—N "\ Rb NR \ A 0

Ra 1e 1e"

In Scheme 1 above, the substituents, Ra and Rb, have the meanings given above for the products of formulae (I'} and (I"). Substituent R5, in the compounds of formulae (J), (1a) and (1a”}, represents an alkyl radical.

In Scheme 1 above, the groups CONR1R2, CO2R6 and COR7, which constitute W, may take the values of W as defined above for the products of formulae (I') and (I), when W 21

“WO 2010/089507 PCT/FR2010/050178

In the above Scheme 1, the benzimidazoles of general formulae (1a™), (1b"), (1c”), (1d”) and (1e”) and also the reduced analogues thereof of general formulae (12), (10°), (1c), (1d’) and (1e’) may be prepared from commercial 9 3,6-dichioro[1,2,4]triazolo{4,3-b]pyridazine of formula (8).

A 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 performed, for example, at a temperature in the region of 20°C.

HS NH,

XL,

Rb NO,

SCO .

N Rb NO,

Ra

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- 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 20°C.

The compounds (G), with Rb = F, may be obtained, for example, by reacting 2-fluoro-5-amino-4-nifrobenzenethiol 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), with Rb = F, are obtained by reacting 2-nitro-4,5- difluoroaniline (Q') (commercial compound), for example, in the presence of potassium thioacetate (C) in a solvent such as N,N-dimethyliformamide, at a temperature in the region of 20°C.

HRC, HH" . \ Rb NH, a,

Ra

The compounds (H”) such that = represent a double bond may be obtained, for example, via reduction with iron (0) of the compounds of formula (BG). 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 (G), in the presence of acetic acid, at a temperature in the region of 20°C.

More particularly, the carbamates of general formulae (12’) and (12") 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 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 (1 b’) and (1b”) may be prepared, respectively, by reaction of an amine NHR1R2 of formula (R) (with R1 and R2 as defined above) with a carbamate of formulae (1a’) and (1a”), 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.

More particularly, the 2-aminobenzimidazoles of general formulae (1c’) and (1¢”} may be prepared, for example, by reacting cyanogen bromide with a .. compound of formulae (H') and (H”), respectively, in the presence of a protic 9 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 (1d”) may be obtained by reacting a chlorocarbonate of formula (0) (X = Cl) with a compound of general formulae (1¢’) and (1¢”), 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 (1e’) and (1¢”) may be obtained, respectively, from the amines of general formulae (Ic’) and (1 c’) - by reacting the amines (1c) and (1¢”) 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 (1¢’) and (1¢”) with an acid anhydride of formula (P) (X= OCORY7), in the presence, for example, of pyridine at a temperature in the region of 20°C; - by coupling the amines (1c’) and (1¢”) with an acid of formula (P) (X= 0H) under the conditions described, for example, by D.D. DesMarteau; V.

Montanari (Chem. Lett, 2000 (9). 1052), in the presence of 1- hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and in the presence of a base such as triethylamine, at a temperature in the region of 40°C.

Scheme 2: Synthesis of benzothiazole derivatives of formulae (2a’), (2b), (2c), (2d), (2a), (2b), (2c) and (2d")

- Ne 8 s

Fe 0 8 SH HS s Ww i:

NC : H E “XX I { reduction XH _g Ra a abl 25 2 O77 Re Te dR

NHR, Ne oR ®R | Ch Cl . LX i

ZN 4

AS S H HS SH Ra E N Rb N Jo,

NC x JN reduction TX rN NA CQ Rg

Rb N ro, "Rb N Jo. a 2a 2a" 1 9 Re wm oe

R.0COX - © | Se 2N NS 8 #3 S reduction [HS Ss Ra E \ N YI- NH,

Le = 00] | eR

Rb oO Rb \ N os 202d"

R,COX Ng ®) CN ; No _-8 reduction HS Ss Ra E 2 S

I — GH 2 NT XA

Rb N JR, Rb N d R, N Rb N 4 R; i © M3 2cY2¢" . 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

CONR1R2, CO2R6 and COR7, which constitute W, may take values of W as defined above for the products of formulae (I') and (I), when WH.

In Scheme 2 above, the benzothiazoles of general formulae (2a), (2b™), (2¢”) and (2d”) and the reduced analogues thereof of general formulae (22’), (2b"), (2c) and (2d’) with Rb = H may be prepared from 2-amino-1,3-benzothiazol- 6-yl thiocyanate (K) (commercial compound).

S S 5 5 rd

NC NC i L peas 0H,

Rb N K Re d Re

The carbamates of general formula (L1) may be obtained, for example, by reacting a chlorocarbonate of formula (0) (X = Cl) with 2-amino-1,3- benzothiazol-6-yl thiocyanate (K), 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.

CN

KSCN i s commercial K

In Scheme 2 above, the benzothiazoles of general formulae (2a”), (2b™), (2¢”) 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- benzothiazol-6-yi thiocyanate. 2-Amino-5-fluoro-1,3-benzothiazol-6-yl 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. 5 S " XI) \ £2

Rb N rr ™ ° RR

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 the region of 20°C.

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 (L1).

AS Ss

Ne XI 7 3

Rb 4

The compounds of general formula (L3) may be obtained, for example: - by reacting an acid chloride of formula (P) (X = CI) 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 reacting an acid anhydride of formula (P) (X = OCOR?7) 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 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- 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.

In the same manner that the carboxamides (L3) may be obtained via acylation of the amine (K), the carboxamides (2¢’) and (2¢”) 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 etal, Bioorg. Med. Chem. Lett. 15 (2005) 5211-5217, in the presence of O- (7-azabenzotriazol-1-yl)-N,N,N’,N'-tetramethyluronium hexafluorophosphate (HATU), in a solvent such as N,N-dimethylformamide, in the presence of a base such as diisopropylethylamine, at a temperature in the region of 20°C. -_————

Scheme 2bis: Routes for synthesizing the glycinamide derivatives (2¢’) and (2¢7)

HO,

N S S

NY Xr )—NH, I rr, My S, H

N, N *) S PN

CY — ST oa 2d'/2d" 4 2c2e ©

Ra R7=CH2-NR3R4

Ny 8. S aN N Ng Tx > po o cl » da : 2¢'[2e" .

Ra

In Scheme 2bis above, the substituent R7 may take the meaning of an aminomethyl group. These glycinamides (2¢/2¢”) 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).

The glycidic acids (P’) may be prepared from bromoacetic acid and amines

HNR3R4 under conditions similar to those described by D. T. Witiak ef al.; J.

Med. Chem. 1985, 28, 1228.

Alternatively, the amines (2d’) and (2d") may be treated with fluoroacetyl chloride in the presence of a base such as pyridine, triethylamine or N- methylmorpholine, in a solvent such as dichloromethane at a temperature in the region of 0°C to 20°C. The a-chloroacetamides (2e’/2e”) thus formed can react with amines of the fype HNR3R4, as defined above, in a solvent such as pyridine at a temperature in the region of 20°C, to give the derivatives (2c'f2c”) as defined in Scheme 2bis above.

The compounds of general formulae (M1), (M2) and (M3) may be obtained, for example, by reduction of compounds of general formula (L1), (L2) or (L3)

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 the compound of formula (K), for example with sodium borohydride in a solvent such as N,N-dimethylformamide, in the presence of a base such as triethylamine and at a temperature in the region of 95°C or between 20°C and 95°C.

HS S. H S S. NH

To XH

Rb N x . N 2

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 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 (22°) and (2a") may also be prepared from benzothiazoles of formulae (2d’) and (2d"), respectively, for example, by reaction with a chlorocarbonate of formula O)y(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.

More particularly, the benzothiazoles of general formulae (2a"), (2b"), (2c) and (2d”) and the reduced analogues thereof of general formulae (2a), (2b), (2¢’) 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),

(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 95°C or between 50°C and 95°C: 2) or by coupling the isolated derivatives (M1), (M2) and (M3) and a 9 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 sifu by reduction of the derivatives (L1), (L2), (L3) 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 conditions 3) and 4) give products of formulae (2a), (2b), (2c) and (2d) such that = represent a double bond.

Scheme 3: Routes for synthesizing friazolopyridazine derivatives of formula (E)

N—N i Ne [ Dc Rezo A Da ff X u) | 0 E

ZN =N

Ra = 0-ZRc © 8 Ra

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

Scheme 3 above, from commercial 3,6-dichioro[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- blpyridazine (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 treating the corresponding alcohol with a base such as sodium hydride at a temperature in the region of 0°C to 20°C.

Scheme 4: Synthesis of the benzothiazole derivatives of formulae (2¢’) and (27)

N

RX NN NYS SH

Ms Ss. nu , ys s. Ro deprotection i) N Tr PN

Ww \ N \ A, — SI { / = h 8 4 0 R, NZ Tr 9 Re Ra

Ra 2a’ 2a" Ra 2e'f 2e" conditions

Rox s s. R a H

Nes SH WwW) Nc” —N E N pe,

XG, SL Yo Co Co Ro Ro 4 R, 0 Ry viaT ha . 1 L4 2¢

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").

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).

Sa 5s. Re

HR)

NW, © R,

TT

The carbamates of general formulae (T) and (T") may be obtained, respectively, by reacting carbamates of general formulae (2a’) and (2a) with

R6 = Bu, preferentially, for example with alkyl halides of formula (W), in a solvent such as N,N-dimethylformamide, in the presence of sodium hydride, at a temperature of between 20 and 90°C. ~The benzothiazoles of general formulae (2¢’) and (2e”) may also be prepared from the compounds of formula (L1), with, preferably, R6 = tBu, via the compounds of formulae (T') and (T™).

More particularly, the compounds of general formulae (2¢’) 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 (2¢”) 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 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.

Ne-S s, Rg

XC, 0 R,

L4

The carbamates of general formula (L4) may be obtained by reacting carbamates of general formula (L1), for example, with alkyl halides of formula

(W), in a solvent such as N,N-dimethylformamide, in the presence of sodium hydride, at a temperature of between 20 and 90°C.

Scheme 5: Synthesis of the benzothiazole derivatives of formulae (2¢’) and (2&7) , wr a N E { ; ! S$ bromination ! Ss Ry-NH, ! s \_4 g OH

TL CuBr = XI A. OL NR,

Rb K NaNO, Rb Rb N Ro \¢ 2e" : Ls L6 Ra

N.S seers

ES Rb I { 2¢"

Ra

Alternatively, according to Scheme 5 above, the benzothiazoles of general formula (2€”) may be prepared from the compounds of formulae (L6) and (E), 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 (2¢’) may be prepared from the 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 example, in a solvent such as tetrahydrofuran, at a temperature in the region of 20°C. :

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. 2008, 49, 6819-6832. :

Scheme 6: Other routes for synthesizing reduced derivatives of formula ("

N reaction

CO = {ey oh tm

Rb N wo. \ Rb N Ww | \ Rb N w

Gri 3

Ra (I) Ra ) Ra 1 } coupling | Mor

Ce \_/ 7

E Ra E Ra

According to Scheme 6 above, the benzothiazoles of general formula (I') may 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.

Alternatively, the compounds (I') may also be prepared from the compounds of formula (E’) by coupling with compounds of the type M1, 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

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°C. B

Alternatively, the compounds (I) may also be prepared from other compounds (I) 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 2¢'/2¢”, conversion of 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 SO2 according to the methods known to those skilled in the art, if necessary protecting any reactive groups with suitable protecting groups.

Among the starting materials of formulae J, K, O, P, P, QQ,R,S,Uandw, 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 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 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 tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,

- amino groups may be protected, for example, with acetyl, trityl, benzyl, tert- : butoxycarbonyl, BOC, benzyloxycarbonyl or phthalimido radicals or other radicals known in peptide chemistry.

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 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 if necessary, in order to obtain other intermediates or other products of formula (I), 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, 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 hydroxy! function, or alternatively of a hydroxyl function into an aikoxy function, e) a reaction for removal of the protecting groups that may be borne by 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, enantiomeric or diastereoisomeric isomer form.

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 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 conditions known fo 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.

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. 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 solvent such as, for example, tetrahydrofuran, dioxane or ethyl ether.

The possible free carboxy! functions of the products described above may, if desired, be reduced to an alcohol function especially with boron hydride. d) The possible alkoxy functions, especially such as methoxy, of the products described above may be, if desired, converted into a hydroxyl function under 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. 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 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 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. 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.

The products of formula (I) 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 tumours.

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 particularly, as medicaments, the products of formula (1) as defined above, the said products of formula (I) 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 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- amine - N-{6-[(6-phenoxy[1 2 Altriazolo[4,3-b]pyridazin-3-yhsulfanyl}-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 - 1-[2-(morpholin-4-yl)ethyl]-3-{6-[(6-phenoxy[1 ,2,4]triazolo[4,3-b]pyridazin-3- yh)sulfanyl]-1,3-benzothiazol-2-yljurea - 1-(6-{[6-(3-fluorophenoxy)[1 2, 4ltriazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea - 6-{[6-(3-fluorophenoxy)[1,2 4ltriazolo[4,3-b]pyridazin-3-yisulfa nyl}-1,3- benzothiazol-2-amine - N-(6-{[6-(3-fluorophenoxy){1 2,41triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide - NZ, N2-diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]- sulfanyl}-1,3-benzothiazol-2-yl)glycinamide - N*-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4ltriazolo[4,3-b]pyridazin-3-yl]- suifanyl}-1,3-benzothiazol-2-yi)glycinamide

- N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3- yl}sulfanyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide - N-(6-{[6-(3-flucrophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}-1,3- benzothiazol-2-yl)acetamide - N-(6-{[6-(3-fluorophenoxy)[1,24}triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - 1-(6-{[6-(4-flucrophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyi}-1,3- benzothiazol-2-yf)-3-[2-(morpholin-4-yl)ethyl]urea - 1-(6-{[6-(3-fluoro-4-methylphenoxy)[1 ,2,4ltriazolof4,3-b]pyridazin-3-yl]sulf- anyl}-1,3-benzothiazol-2-yf)-3-[2-(morpholin-4-yl)ethyljurea - 6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2 4]triazolo[4, 3-b]pyridazin-3-yljsulf- anyi}-1,3-benzothiazol-2-amine : - 6-{[6-(4-fluorophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyi}-1,3- benzothiazol-2-amine - 1-[2-(morpholin-4-yl)ethy[l-3-(6-{[6- tetrahydro-2H-pyran-4-yloxy)[1 2,4) triazolof4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-benzothiazol-2-yl)urea - 1-[6-({6-[(1-ethylpiperidin-4-yl)oxy][1 2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- anyl}-1 3-benzothiazol-2-yl}-3-[2-(morpholin-4-yljethyiju rea - N-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1 .2,4triazolo[4,3-b]pyridazin-3-yljsulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-{4-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4ltriazolo[4,3-b]pyridazin-3-yljsulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-[6-({6-[(1-ethylpiperidin-4-yljoxy][1,2.4ltriazolo[4 3-blpyridazin-3-yljsulf- anyl)-1,3-benzothiazol-2-yljcyclopropanecarboxamide - 1-[2«{morpholin-4-yl)ethyl]-3-(6-{[6-(tetrahyd rofuran-3-yloxy)[1,2 4]triazolo- [4,3-b]pyridazin-3-yllsulfanyl}-1,3-benzothiazol-2-yl)urea - 1-(6-{[6-(1,3-benzodioxal-5-yloxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yljsuif- anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyilurea

- 1-(6-{{6-(3,4-dichlorophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}- 1,3-benzothiazol-2-y)-3-[2-(morpholin-4-yl)ethyljurea : - 6-{[6-(3.4-dichlorophenoxy)[1 2,41triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1 ,3- benzothiazol-2-amine - 6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl)- 1,3-benzothiazol-2-amine - 1-(6-{[6-(1H-indol-6-yloxy)[1 :2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyi}-1 3- benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyljurea - N-~(6-{[6-(tetrahydrofuran-3-yloxy)[1 2. 4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}- : 10 1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(1,3-benzodioxol-5-yloxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yl]sulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3,4-dichlorophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(1H-indol-6-yloxy)[1 2,4ltriazolo[4,3-blpyridazin-3-yljsulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3-fluorophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}-1 ,3- benzothiazol-2-yl)cyclobutanecarboxamide - N-(6-{[6-(3-flucrophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1,3- benzothiazol-2-yl)-N2 N2-dimethylglycinamide - 2-ethoxy-N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf- anyl}-1,3-benzothiazol-2-yl)acetamide - 2-(cyclohexyloxy)-N-(6-{[6-(3-fluorophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3- yllsulfanyl}-1,3-benzothiazol-2-yl)acetamide - 6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3-benzo- thiazol-2-amine - 6-({6-[3-(trifluoromethoxy)phenoxy][1,2,4]iriazolo[4,3-b]pyridazin-3-yl}sulf- anyl}-1,3-benzothiazol-2-amine - 2-methylpropan-2-yl [3-({3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl][1,2,4]- triazolo[4,3-b]pyridazin-6-yljoxy)phenyl]carbamate

- N-(6-{[6-(pyridin-3-yloxy)[1 2 ,41triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1 3- benzothiazol-2-yl)cyclobutanecarboxamide - N+(6-{[6-(3-flucrophenoxy)[1 2,4]triazolof4,3-b]pyridazin-3-yljsulfanyl}-1,3- __ benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide =~ N-cyclohexyl-N-(6-{[6-(3-fluorophenoxy){1,2,4]triazolo[4,3-b]pyridazin-3-yi]- sulfanyl}-1,3-benzothiazol-2-yl)glycinamide - N-(6-{[6-(3-fluorophenoxy)[1 2,4]triazolo[4,3-blpyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl}-N*-methyl-N-[2-(morpholin-4-yi)ethyflglycinamide - 2-(4-ethylpiperazin-1-yl)-N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]- pyridazin-3-yllsulfanyl}-1,3-benzothiazol-2-yl)acetamide - 6-{[6+(3,5-difluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yi]sulfanyl}-1,3- benzothiazol-2-amine - 6-{[6-(3-aminophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 KE benzothiazol-2-amine - N-(6-{[6-(3-fluorophenoxy)[1,2 4ltriazolo[4,3-b]pyridazin-3-yl]sulfanyi}-1,3- benzothiazol-2-yl)-N-2~-(tetrahydro-2H-pyran-4-yl)glycinamide - N-[6-({6-[4-(trifluoromethyl)phenoxy][1 2 ,4]triazolo[4,3-b]pyridazin-3-ylisulf- - anyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide ~~ - N-{6-({6-[3-(trifluoromethoxy)phenoxy][1 2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- anyl)-1,3-benzothiazol-2-yl[cyclopropanecarboxamide - N-[6-({6-[(2-methylpyridin-3-yl)oxy][1 .2,4]triazolo[4,3-b]pyridazin-3-yi}sulf- anyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide - N-(6-{[6-(3,5-difluorophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide - 2-[(6-{[6-(3-fluorophenoxy)[1,2,4]triazolof4,3-b]pyridazin-3-yl]sulfanyf}-1,3- benzothiazol-2-yl)amino]-2-oxoethyl acetate - N-[6-({6-[(6-methylpyridin-3-yl)oxy][1 ,2,4]triazolo[4,3-bjpyridazin-3-yl}sulf- anyl)-1,3-benzothiazol-2-yl[cyclopropanecarboxamide - N-[6-({6-[4-(morpholin-4-yimethyl)phenoxy][1 2.4]triazolo[4,3-b]pyridazin-3- yl}isulfanyl)-1,3-benzothiazol-2-ylJcyclopropanecarboxamide

- 2-methylpropan-2-yl (3{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzo- thiazol-6-yl}sulfanyi)[1 2,4]triazolo[4,3-b]pyridazin-6-yfJoxy}phenyl)carbamate - N-(6-{[6-(pyridin-3-yloxy)[1,2,4]triazolof4,3-b] pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - N-{6-[(6-{3-[(1S,48)-2-oxa-5-azabicyclo[2,2,1 Ihept-5-yimethyl]phenoxy}- [1.2,4]triazolo[4,3-b]pyridazin-3-yi)sulfanyf]-1 ,3-benzothiazol-2-yl}cyclo- propanecarboxamide - N-{6-[(6-{3-[(diethylamino)methyllphenoxy}[1,2,4ltriazolo[4,3-b]pyridazin-3- yhsulfanyi]-1,3-benzothiazol-2-ylicyclopropanecarboxamide - N-(6-{[6-(3,5-difluorophenoxy)[1,2 4ltriazolo[4,3-b]pyridazin-3-yljsulfanyl)- 1,3-benzothiazol-2-yl)-N2,N2-diethylglycinamide - N-(8-{[6~(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)-2-hydroxyacetamide - 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3- blpyridazin-3-ylsulfanyl}-1,3-benzothiazol-2-yl)acetamide - N-(6-{[6~(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}- 1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide - 2-(4-cyclopropylpiperazin-1 -yi)-N-(6-{[6-(3,5-difluorophenoxy)[1 ,2,4]triazolo- [4,3-b]pyridazin-3-yljsulfanyl}-1 3-benzothiazol-2-yl)acetamide - N-{6-[(6-{3-[(diethylamino)methyllphenoxy}[1,2,4]triazolo[4,3-blpyridazin-3- yl)sulfanyl}-1,3-benzothiazol-2-yi}acetamide - N-{6-[(6{3-[(diethylamino)methyl]phenoxy}[1,2 4]triazolof4,3-b]pyridazin-3- yhsulfanyi]-1,3-benzothiazol-2-yl}-2-methoxyacetamide - 2-methoxy-N-{6-[(6-{3-[(1 S,48)-2-oxa-5-azabicyclo[2,2, 1 Ihept-5-yimethyl]- phenoxy}[1,2,4ltriazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1 ,3-benzothiazol-2-yl}- acetamide - B-{[6-(oxetan-3-yloxy)[1 2 4]triazolof4,3-b]pyridazin-3-yllsulfanyi}-1,3-benzo- thiazol-2-amine - 2-(morpholin-4-yl}-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 .2,4]triazolo[4,3-b]- pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yhacetamide

- N-(6-{[6-(3,5-difluorophenoxy)[1 2 4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}- 1,3-benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide - N?,N2-diethyl-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 ,2,4]triazolo[4,3-b]pyridazin- 3-ylisulfanyl}-1 .3-benzothiazol-2-yl)glycinamide - 2-(4-ethylpiperazin-1-yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 2 4ltriazolo[4,3- b]pyridazin-3-yllsulfanyl}-1,3-benzothiazol-2-ylacetamide - 2-(4-cyclopropylpiperazin-1 -¥1)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]- triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1 ,3-benzothiazol-2-y|)acetamide - N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b] pyridazin-3-yl]sulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - 2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1 ,2,4ltriazolo[4,3-b]pyrid- azin-3-ylJsulfanyl}-1,3-benzothiazol-2-yl)acetamide - 2-(4-cyclopropylpiperazin-1 -y1)-N-(6-{[6-(oxetan-3-yloxy)[1 ,2,4triazolo[4,3- b]pyridazin-3-yljsulfanyl}-1,3-benzothiazol-2-yl)acetamide 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 (I).

The invention also relates to pharmaceutical compositions containing, as 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 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 and the like.

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.

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. 156 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) 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 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.

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 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.

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 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 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.

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.

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.

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), 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) 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.

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.

Such therapeutic agents may be commonly used antitumour agents.

Kinase inhibitors that may be mentioned include butyrolactone, flavopirido! and 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine, known as olomoucine.

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:

HS S. H HS S

H

IH 0A

Rb N J ° Rb NN i M1 6 M2 0 R,

IG rN HS Ss

Rb NR, Tr J—NH,

M3

N in which the groups CONR1R2, CO2R6 and COR?7, which constitute W, may take the values of W as defined above for the products of formulae (I'y and (I'"), when W si.

The examples that follow, which are products of formula (1), illustrate the invention without, however, limiting it.

Experimental section

The nomenclature of the compounds of the present invention was produced with the ACDLABS software version 11.0.

Microwave oven used:

Biotage, Initiator EXP-EU, 300 W max, 2450 MHz

The 400 MHz and 300 MHz 1H NMR spectra were acquired using a Briiker

Avance DRX-400 or Briiker Avance DPX-300 spectrometer with the chemical shifts (5 in ppm) in the solvent dimethyl sulfoxide-ds (DMSO-dg) 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 )

- LC-MS-DAD-ELSD (MS = Platform ll 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 pressure = 3.7 bar

Example 1: 6-[(6-phenoxy[1 2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo- thiazol-2-amine 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 30cm® of ethanol, for 5 minutes. 14 mg of potassium dihydrogen phosphate in 0.3 cm® of water, 1.39 g of DL-dithiothreitol and 740 mg of 3-chloro-6-phenoxy[1,2,4]triazolo- [4,3-b]pyridazine are then added. The reaction mixture is heated at 80°C for 24 hours, and then concentrated to dryness under reduced pressure. The residue is purified on silica by deposition of the solid, eluting with a 95/05 to 80/20 dichioromethane/(38 dichloromethane/17 methanol/2 aqueous ammonia) gradient. 717 mg of 6-[(6-phenoxy[1 2, 4}triazolo[4,3-b]pyridazin-3- ylsulfanyl]-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-ds) & ppm 7.13 (dd, J = 8.3, 2.0 Hz,

TH)7.21(d, J=8.3 Hz, 1H) 7.25-7.32 (m, 2H) 7.32 - 7.39 (m, 2H) 7.50 (t,

J=78Hz 2H) 7.61(d, J=15Hz 1H) 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: 254 mg of sodium hydride at 60% in oil are added to a solution of 996 mg of phenol in 20cm? of tetrahydrofuran, at 0°C under argon. After stirring for

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 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+ :

N-{6-[(6-phenoxy[1 »2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo- thiazol-2-yl}cyclopropanecarboxamide a) N-{6-[(6-Phenoxy[1 ,2,4triazolof4,3-blpyridazin-3-yl)sulfanyl]-1 ,3- benzothiazol-2-yi}cyclopropanecarboxamide may be prepared in the following manner: : 0.120 cm? of cyclopropanecarboxylic acid chloride is added to a mixture of 250 mg of 6-[(6-phenoxy{1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3- benzothiazol-2-amine (fa) in 5cm® 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- [4,3-b]pyridazin-3-yl)sulfanyl}-1,3-benzothiazol-2-yl}cyclopropanecarboxamide are thus obtained in the form of a white powder, the characteristics of which are as follows: 1H NMR SPECTRUM (400 MHz, DMSO-ds) & ppm 0.93 - 0.98 (m4H)1.99 oo (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 =1.7Hz 1H)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- = 450-

Example 3:

N-{6-[(6-phenoxy[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo- __ thiazol-2-yl}acetamide

N-{6-[(6-Phenoxy[1 .2,4]triazolo[4,3-b]pyridazin-3-yhsulfanyl]-1,3-benzothiazol- 2-yllacetamide 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® of pyridine with 0.220 cm?® of acetyl chloride after 24 hours of reaction at 20°C. 280 mg of N-{6-{(6- phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1 ,3-benzothiazol-2-yi}- 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) & ppm 2.20 (s, 3 H) 723d, J= 76Hz,2H)7.26-7.33(m, 2H) 7.34-7.44 (m,3H)7.61(d, J=8.6 Hz, 1 H) 7.87(d, J=1.7Hz, 1H) 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- 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-yljurea may be prepared in a manner similar to that of Example 1a, but starting with 533 mg of 1-[2-(morpholin-4- yhethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea, 10 cm? of degassed ethanol, 6 mg of potassium dihydrogen phosphate in 0.1 cm?® of water, 606 mg of DL- dithiothreitol and 324 mg of 3-chloro-6-phenoxy[1,2 4ltriazolo[4,3-b]pyridazine (1b), after 32 hours at 80°C. 320 mg of 1-{2-(morpholin-4-yl)ethyl}-3-{6-[(6- phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyf]-1 .3-benzothiazol-2-yl}- urea are thus obtained in the form of a white powder, the characteristics of which are as follows:

1H NMR SPECTRUM (400 MHz, DMSO-des) 8 ppm 2.36 - 2.46 (m, 6 H) 3.24 - 3.29 (m, 2H) 3.59 (t, J=4.4 Hz, 4 H) 6.80 (t, J = 5.7 Hz, 1 H) 7.20 - 7.28 (m, 3H) 7.29 -734 (m, 1H) 7.36 (d, J=9.8Hz, 1H) 7.44 (t, J =7.8Hz 2H) 749 (d, J=86Hz 1H) 7.80 (d, J=1.7 Hz, 1H) 8.45 (d, J = 9.8 Hz, 1H) 10.93 (br.s., 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 549+; MH- = 547- b) 1-(2-Morpholin-4-ylethyl)-3-(6-sulfanyl-1 ,3-benzothiazol-2-yl)Jurea may be prepared in the following manner:

A stream of argon is bubbled for 5 minutes through a mixture of 900 mg of 2- {{(2-morpholin-4-ylethyl)carbamoyl]lamino}-1,3-benzothiazol-6-yl thiocyanate and 40 cm® of ethanol at 20°C. 11 mg of potassium dihydrogen phosphate in 0.4 cm?® 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 20°C and then poured into water. The suspension is stirred for 45 minutes while maintaining gentle bubbling with argon. The precipitate formed is filtered off by suction and washed with 3x10 cm® of water and then dried under vacuum at 20°C. 633 mg of 1-(2-morpholin-4-ylethyl)-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a white solid, the characteristics of which are as follows:

MASS SPECTRUM: LC-MS-DAD-ELSD: MH+ m/z = 339+ (M-H)- = 337- c) 2-{[(2-Morpholin-4-ylethyl)carbamoyljamino}-1 ,3-benzothiazol-6-yl thiocyanate may be prepared in the following manner: 0.44 cm® of 2-morpholin-4-ylethanamine is added at 20°C to a solution of 1 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yi)carbamate in 30cm? of tetrahydrofuran at 20°C. 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)carbamoyilamino}-1,3-benzothiazol-6-yi thiocyanate are thus recovered in the form of a colourless foam, the characteristics of which are as follows:

MASS SPECTRUM: UPLC-MS-DAD-ELSD: MH+ m/z = 364+ d) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate was prepared in the following manner: 7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen carbonate and 9.4 cm® 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® of tetrahydrofuran. The resulting mixture is then stirred at 20°C for 20 hours and then extracted with 2x150 cm?® of ethyl acetate. The organic phases are combined and then washed with 3x50 cm® of saturated aqueous sodium 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? 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 solid, the characteristics of which are as follows:

MASS SPECTRUM: [.C-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}- 1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea a) 1-(6-{[6-(3-Fluorophenoxy)[1 2.,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}- 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)ethyi]-3-(6-sulfanyl-1,3-benzothiazol-2-ylurea (4b), 5 cm? of degassed ethanol, 4 mg of potassium dihydrogen phosphate in 0.1 cm® 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- fluorophenoxy)[1,2 /Altriazolo[4,3-b]pyridazin-3-yljsulfanyl}-1,3-benzothiazol-2- yl}-3-[2-(morpholin-4-yl)ethyllurea are thus obtained in the form of a white powder, the characteristics of which are as follows:

1H NMR SPECTRUM (400 MHz, DMSO-d) 8 ppm 2.36 - 2.45 (m, 6 H) 3.25 : -3.28 (m, 2H) 3.59 (t, J =4.3Hz, 4H) 6.78 (br. s., 1 H) 7.14 (dd, J = 8.3, 1.7Hz, TH) 7.18 (id, J = 8.5, 23 Hz, 1H) 7.23 - 7.31 (m, 2 H)7.38(d, J= 9.8Hz, 1H)742-751 (m,2H)784(d, J=1.7 Hz, 1 H} 8.47 (d, J=9.8 Hz, 1H)10.89 (br. s., 1H)

MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 567+; MH- = 565- b) 3-Chloro-6-(3-fluorophenoxy)[1 .2,4]triazolo[4,3-b]pyridazine may be prepared in a manner similar to that of Example 1b, but starting with 1.19 g of 3-fluorophenol in 15 cm? 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-b]pyridazine (commercial). 837mg 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+ :

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-yllsulfanyl}-1,3-benzo- 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- blpyridazine (Sb), 10 mg of potassium dihydrogen phosphate in 0.1 cm? of degassed ethanol, 926 mg of DL-dithiothreito! and 414 mg of 2-amino-1,3- benzothiazol-6-yl thiocyanate (commercial) in 10 cm? of ethanol. 587 mg of 6- {[6-(3-fluorophenoxy)[1 .2,4]triazolo[4,3-bpyridazin-3-yllsulfanyl}-1,3-benzo- thiazol-2-amine are thus obtained in the form of a white powder, the characteristics of which are as follows: 'H NMR Spectrum (400 MHz, 0 in ppm, DMSO-dg): 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 and 8.3Hz, 1H); 7.63 (broad s, 2H); 7.65 (d, J = 2.0 Hz, 1 H); 8.45 (d, J = 9.8 Hz, 1 H)

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]sulfany}- 1,3-benzothiazol-2-yl}-2-(2-methoxyethoxy)acetamide a) N-(6-{[6-(3-Fluorophenoxy)[1,2,4]triazolo[4,3-b] pyridazin-3-yllsulfanyi}- 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?® of diisopropylethylamine and 371 mg of O-(7-azabenzotriazol-1-y1)-N,N,N’ N’- - tetramethyluronium hexafluorophosphate (HATU) in 3cm® of N,N- dimethylformamide at 20°C is stirred for 1 hour at 20°C. 200 mg of 6-{[6-(3- fluorophenoxy)[1 ,2,4}triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3-benzothiazol-2- amine (6) are added to the reaction medium. After 18 hours, the brown solution is poured into ice-water and the precipitate is filtered off. After drying the precipitate, 219mg of N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3- blpyridazin-3-yljsulfanyi}-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: "H NMR Spectrum (400 MHz, & in ppm, DMSO-ds): 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 = 2.2and 8.3 Hz, 1H); 7.16 (dt, J =2.2 and 8.3 Hz, 1 H); 7.24 (td, J = 2.2 and 10.0Hz, 1H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1H); 7.42 (dt, J = 6.9 and 8.3 Hz, 1H); 7.63 (d, J = 8.6 Hz, 1 H), 793 (d, J = 2.0Hz, 1H); 849 (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?,N*-diethyl-N~(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3- yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide :

a) N?,N2-Diethyl-N-(6-{[6-(3-fluorophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin- 3-yllsulfanyl}-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? of a 2N solution of hydrogen chloride in ether is stirred for 1 hour at 20°C. The resulting suspension is evaporated to dryness under vacuum. 4 cm® of pyridine, 100 mg of 6-{[6-(3-fluorophenoxy)[1 .2,4]triazolof4,3-b]pyridazin-3-yi]- 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 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 NZ N2-diethyl-N-(6-{[6~(3-fluorophenoxy)- [1,2 4liriazolo[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: 'H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): for this crop, all the signals are broad, with: 1.00 (t, J = 6.9 Hz, 6 H); 2.63 (qQ, J = 6.9 Hz, 4 H); 3.41 (s, 2H), 7.06 to 7.20 (m, 2H); 7.24 (d, J = 9.5 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1H); 7.35 to 7.47 (m, 2H); 7.61 (d, J = 8.3 Hz, 1 H); 7.92 (s, 1H) 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

Example 9:

N*-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin- 3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide a) N2-Cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyrid- azin-3-ylJsulfanyl}-1,3-benzothiazol-2-yl)glycinamide may be prepared in the following manner:

0.13 cm? of cyclopropylamine is added to 137 mg of 2-chloro-N-(6-{[6-(3- fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1,3-benzothiazol-2- yhacetamide (9b) in 1.5 cm? of pyridine at 20°C. After stirring for 5 hours, the reaction medium is evaporated to dryness 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 97/3 dichloromethane/methanol. 52mg of N*-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b}- pyridazin-3-ylisulfanyl}-1,3-benzothiazol-2-yl)glycinamide are thus obtained in the form of a white solid, the characteristics of which are as follows: 'H NMR Spectrum (400 MHz, 6 in ppm, DMSO-dg): 0.19 to 0.42 (m, 4 HY; 2.18 (m, 1H); 3.52 (s, 2H); 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 (id, 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,

TH); 7.45 (broad m, 1 H); 7.60 (d, J = 8.3 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H); 8.49(d,J=9.8Hz, 1H) :

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-b]pyridazin-3-yi]- ~ sulfanyl}-1,3-benzothiazol-2-yl)acetamide may be prepared in the following manner: 0.06 cm® of chloroacetyl chloride is added dropwise to 205 mg of 6-{[6-(3- fluorophenoxy)[1,2.4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2- amine (6) in 2 cm® of dichloromethane and 0.5 cm? of pyridine at 0-5°C. The resulting white suspension is stirred for 30 minutes at 20°C. 0.03 cm?® of chloroacetyl chloride is added and the mixture is stirred for a further 30 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 dichioromethane/(dichloromethane: 38/methanol: 17/aqueous ammonia: 2). 137 mg of 2-chloro-N-(6-{[6-(3-flucrophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-

ylfsulfanyt}-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

Example 10:

N-[6-({6-[3-(morpholin-4-yimethyl)phenoxy][1 ,2,4]triazolo[4,3-b]pyrid- azin-3-yi}sulfanyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide a) N-[6-({6-[3-(Morpholin-4-yimethyl)phenoxy][1,2,4]triazolo[4,3-b]pyrid- azin-3-ylsulfanyl)-1,3-benzothiazol-2-yilcyclopropanecarboxamide may be 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-b] pyridazin-3-yl}- sulfany)-1,3-benzothiazol-2-amine (10b) in 5 cm® of pyridine with 0.124 cm?® of cyclopropanecarbonyl chloride after 3 hours 30 minutes of reaction at 50°C. 567.3 mg of N-[6-({6-[3-(morpholin-4-yimethyl)phenoxy][1,2,4]triazolo- [4,3-blpyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide : are thus obtained in the form of a white powder, the characteristics of which are as follows: 'H NMR Spectrum (400 MHz, & in ppm, DMSO-ds): 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, 4H) 7.09 to 7.14 (m, 1H); 7.20 to 7.25 (m, 2 H); 7.28 (dd, J = 2.0 and 8.6 Hz, 1H); 7.31 to 7.39 (m, 2H), 7.59 (d, J = 8.6 Hz, 1H); 7.83 (d, J = 2.0 Hz, 1H); 8.47 (d, J=9.8 Hz, 1H ); 12.68 (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- 3-yllsulfanyl)-1,3-benzothiazol-2-amine (10b) may be prepared in a manner similar to that of Example 1a, but starting with 133 mg of 3-chioro-6-[3- (morpholin-4-ylmethyl)phenoxy][1,2 4ltriazolo[4,3-b]pyridazine (10¢), 3 mg of potassium dihydrogen phosphate in 0.1 cm® of degassed ethanol, 176 mg of

DL-dithiothreitol and 79mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate (commercial), in 5cm® of ethanol. 111 mg of 6-({6-[3-(morpholin-4- ylmethyl)phenoxy][1,2 4]triazolo[4,3-b]pyridazin-3-yi}sulfanyl)-1,3-benzo-

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 ¢) 3-Chloro-6-[3-(morpholin-4-ylmethyl)phenoxy]j1 ,2,4]triazolo[4,3-b]- pyridazine (10¢) may be prepared in a manner similar to that of Example 1b, but starting with 310 mg of 3-(morpholin-4-ylmethyl)pheno! (10d) in 5 cm? 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- (morpholin-4-yimethyl)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: 438 mg of morpholine are added to a solution of 188 mg of 3- (bromomethyl)phenol (10e) in 5 cm® 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 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: 3.19 cm® 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? 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 crystallizes. This residue is purified by chromatography on a SPOT Il machine equipped with an SVF D26 15-40 uM silica cartridge, after solid deposition,

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]-: m/z 185

Other examples and intermediates thereof prepared by analogy with the above examples are described in the table below: c= : 2249

SF 8 — Amount

Name SE 5 Starting with: isolated a ® 1

N-(6-{[6-(3- 212m : g of 6-{[6-(3-

DL a] fluorophenoxy)[1,2,4]triazolo[4,3- 201m 13 berths: blpyridazin-3-ylJsulfanyl}-1,3-benzothiazol- J yacetamide 2-amine (6) and 41mg of acetyl chloride

N-(6-{[6-(3~ 205 mg of 6-{[6-(3- fluorcphenoxy)[1,2,4]triazolo]] fluorophenoxy)[1,2,4]triazolo[4,3- 4,3-b]pyridazin-3-yljsulfanyl}- blpyridazin-3-yljsulfanyl}-1,3-benzothiazol- 184 mg 1,3-benzothiazol-2- 2-amine (6) and 104 mg of ylicyclopropanecarboxamide cyclopropanecarbonyl chloride 1-(6-{[6-(4- 200 mg of 3-chloro-6-(4- . fluorophenoxy)[1,2,4]triazolo] fluorophenoxy)[1,2,4}triazolof4,3- : 4,3-b]pyridazin-3-yi]sulfanyl}- blpyridazine (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)ethyllurea benzothiazol-2-yl)urea (4b) 3-chloro-6-(4- 1 g of 3,6-dichloro[1,2,4}triazolo[4,3- fluorophenoxy)[1,2,4]triazolo]] blpyridazine (commercial) and 1.46 g of 4- 111g 4,3-blpyridazine fluorophenol 1-{6-{[6-(3-fluoro-4- ] Af } methylphenoxy)[1,2,4]triazol 200 mg of 3-chioro-6 (3-fluoro-4 04, 3-blpyridazin-3-yilsulf- methylphenoxy)[1,2,4}triazolo[4,3- anyi)1 3 benzothiazoh2-yi) blpyridazine (14b) and 340 mg of 1-[2- 202 mg ap morphoing. (morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3- y)ethyflurea benzothiazol-2-yl)urea (4b) 3-chloro-6-(3-fluoro-4- 1 g of 3,6-dichloro[1,2 4]triazolo[4,3- methylphenoxy)[1,2,4]triazol b]pyridazine (commercial) and 1.64 g of 3- 115¢ of4,3-b]pyridazine fluoro-4-methylphenol 6-{[6-(tetrahydro-2H-pyran-4 900 mg of 3-chloro-8-(tetrahydro-2H-pyran- yloxy)[1,2,4]triazolo}4,3- 4-yloxy)[1,2,4]triazolo[4,3-b]pyridazine 418 mg blpyridazin-3-yilsulfanyl}-1,3- 15b) and 407 mg of 2-amino-1,3-henzo-

3-chloro-6-(tetrahydro-2H- 1 g of 3,6-dichloro[1,2,4}triazolo[4,3- pyran-4-yloxy)[1,2,4]triazolo- blpyridazine (commercial) and 1.35 g of 929 mg [4,3-b]pyridazine tetrahydro-2H-pyran-4-ol . 6-{[6-(4 “- 350 mg of 3-chioro-6-(4-

TUM : . fluorophenoxy){1,2,4]triazolof4,3- fluorophenoxy)[1 2.4]triazolo blpyridazine (13b) and 274 mg of 2-amino- | 246 mg 4,3-b]pyridazin-3-yl]suifanyl}- . , 1.3-benzothiazol-2-amine 1,3-benzothiazol-6-yl thiocyanate ’ 0 (commercial) 1-[2-{(morpholin-4-yl)ethyl}-3- 200 mg of 3-chloro-6-(tetrahydro-2M-pyran- (6-{[6-(tetrahydro-2H-pyran- 4-yloxy)[1,2 4ltriazolo[4,3-b]pyridazine 17 | 4-yloxy)[1,2 4]triazoio[4,3- (15b) and 372 mg of 1-[2-(morpholin-4- 179 mg b]pyridazin-3-yljsulfanyl}-1,3- yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2- benzothiazol-2-ylyurea - ylurea (4b) my prrbasning 200 mg of 3-chioro-6-[(1-ethylpiperidin-4- bi Re dain 13 yloxyl[1,2 4triazolo[4,3-blpyridazine (18b) 153m benzothiazol Syl [2 . and 336 mg of 4-[2{morpholin-4-yl)ethyi-3- a (morpholin-4-yljethyl]urea (6-sulfanyl-1,3-benzothiazol-2-yl)urea (4b) 3-chioro-6-[(1-ethylpiperidin- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3- 18b | 4-ylioxyl[1,2,41triazolo[4,3- b]pyridazine (commercial) and 168 g of 1- 758 mg blpyridazine 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- yllsulfanyl}-1,3-benzothiazol-2-amine (15) 198 mg anyl}-1,3-benzothiazol-2- and 0.162 cm® 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- 4,3-b]pyridazin-3-yllsulfanyl}- b]pyridazin-3-yiJsulfanyl}-1,3-benzothiazol- 149 mg 1,3-benzothiazol-2- 2-amine (16) and 0.094 cm® of ylicyclopropanecarboxamide cyclopropanecarbonyi chloride

N-(6-{[6-(3-flucro-4- 560 mg of 6-{[6-(3-fluoro-4- methylphenoxy)[1,2,4]triazol methylphenoxy)[1,2,4}triazolo[4,3- of4,3-b]pyridazin-3-yl]sulf- blpyridazin-3-yllsulfanyl}-1,3-benzothiazol- 326' mg anyl}-1,3-benzothiazol-2- 2-amine (21b) and 0.241 cm’ of yl)cyclopropanecarboxamide cyclopropanecarbonyl chioride 6-{[6-(3-fluoro-4- 500 mg of 3-chloro-6-(3-fluoro-4- methylphenoxy)[1,2,41triazol methyiphenoxy)[1,2,4]triazolo[4,3- o[4,3-b]pyridazin-3-yl]sulf- 1a | blpyridazine (14b) and 372 mg of 2-amino- | 360 mg anyi}-1,3-benzothiazol-2- 1,3-benzothiazol-6-yl thiocyanate amine (commercial)

N-[6-({6-[(1-ethylpiperidin-4- 235 mg of 6-({6-{(1-ethyipiperidin-4- yloxy][1,2.4]triazolo[4,3- vl)oxyl[1,2,4)triazolo[4,3-b]pyridazin-3- 155 mg bipyridazin-3-yl}sulfanyl}-1,3 I}sulfanyl)-1,3-benzothiazol-2-amine (22b benzothiazol-2- and 0.101 cm” of cyclopropanecarbonyl yllcyclopropanecarboxamide chloride

Ce 500 mg of 3-chloro-6-(3-flucro-4-

ALI Yh methyiphenoxy)[1,2 Aliiazolold,3- blpyri dazin-3-ylsulfanyl)- 13 bpyridazine (14b) and 368 mg of 2-amino- | 286 mg benzothiazol-2-amine ’ 1,3-benzothiazol-6-yt thiocyanate (commercial)

So alf3- 200 mg of rac-3-chloro-6-{tetrahydrofuran-

Yetrahy Srofuran-a- 3-yloxy)[1,2,4ltriazolo[4,3-b]pyridazine yloxy)[1,2,4]iriazolo[4,3- {23b) and 394 mg of 1-4{2-(morpholin-4- 173 mg : bpyri dazin-3-yljsulfanyl}-1 3. ylethyl]-3-(6-sulfanyl-1,3-benzothiazol-2- benzothiazol-2-yl)urea Yhurea (4b) freeing 1g of 3,6-dichioro[1,2 4ltriazolo[4, 3- 23b lox $4 2 4]triazolof4,3- blpyridazine (commercial) and 954 mg of 410 mg

Vow dazin o ! rac-tetrahydrofuran-3-ol

Joie pS 200 mg of 6~(1 ,3-benzodioxol-5-yloxy)-3- blov dazin-3-yllsulfanyl}-1 3. chlorof1 2 4]triazolo[4,3-b]pyridazine (24b) 174 mg benzothiazol-2-yl)-3-[2- ! and 327 mg of 1-[2-(morpholin-4-yl)ethyl}-3- (morpholin-4-yljethyijurea (6-sulfanyl-1,3-benzothiazol-2-yljurea (4b) oye odtioxols- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3- - ] b]pyridazine (commercial) and 1.8 gof 1,3- | 1.07 g

Door 2 lriazolof4,3 benzodioxol-5-0l 1-(6-{[6~(3,4- 200m . . g of 3-chloro-6-(3,4-

M2 az dichlorophenoxy)[1,2,4]triazolof4,3- : any bonaofiiomot a. i) blpyridazine (25b) and 300 mg of 1-[2- 90 mg 3 [mor id y (morpholin-4-yl)ethyl]-3-(6-sulfanyi-1,3-

Yisthyllurea : benzothiazol-2-yl)urea (4b) 3-chloro-6-(3,4- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3- dichlorophenoxy)[1,2,4]triazo blpyridazine (commercial) and 2.12 g of 680 mg lo[4,3-bipyridazine 3.4-dichloraphenol 6-{[6-(3,4- 500 mg of 3-chloro-6-(3,4- dichlorophenoxy)[1,2,4]triazo dichlorophenoxy)[1,2,4]triazolo[4,3- lo[4,3-blpyridazin-3-yi]sulf- blpyridazine (25b) and 328 mg of 2-amino- | 155 m g anyl}-1,3-benzothiazol-2- 1,3-benzothiazol-6-yl thiocyanate amine (commercial) rac-8-{[6-(tetrahydrofuran-3- 500 mg of rac-3-chloro-6-{tetrahydrofuran- 27 yioxy)[1,2,4]triazolo[4,3- 3-yloxy)[1,2,4}triazolo[4,3-b]pyridazine 297 m blpyridazin-3-yllsulfanyl}-1,3- (23b) and 431 mg of 2-amino-1,3-benzo- g benzothiazol-2-amine thiazol-6-yl thiocyanate (commercial)

I a aso] 4a 250 mg of 3-chloro-6-(1H-indok6- : He : dazin3- ilsulfanyl)- 13 yloxy)[1,2 4]triazolo[4,3-b]pyridazine (28b) 298 m benzothiazol 51) 3.12. ! and 355 mg of 1-[2-(morpholin-4-yl)ethyl}-3- g (morpholin-d-yljethylurea (6-sulfanyl-1,3-benzothiazol-2-yl)urea (4b) 3-chloro-6-(1H-indol-6- 1 g of 3,6-dichioro[1,2,4]iriazolo}4,3- yloxy)[1,2,4]triazolo[4,3- b]pyridazine (commercial) and 1.73 g of 1H- | 1.01 g blpyridazine indol-6-ol

Er tle 228mg of rac-6-{[6-(tetrahydrofuran-3- yloxy)[1,2,4]triazolo[4,3- yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3- blovrid ’ ina. [sulfan }-1,3- yllsulfanyl}-1,3-benzothiazol-2-amine (27) 164 mg lpr az y irl and 0.108 cm? of cyclopropanecarbonyl enzothiazol-2- ; . chloride yl)cyclopropanecarboxamide

N-(6-{[6-(1,3-benzodioxal-5- 300 mg of 8-{[6-(1,3-benzodioxol-5- yloxy)[1,2,4]triazolo[4,3- yloxy){1,2,4triazolo[4,3-b]pyridazin-3- blpyridazin-3-yljsulfanyi}-1,3- yllsulfanyl}-1,3-benzothiazol-2-amine (30b) | 202 mg benzothiazol-2- and 0.127 ecm® of cyclopropanecarbonyl yl)cyclopropanecarboxamide chloride 6-{[6-(1,3-benzodioxol-5- 360 mg of 6-(1,3-benzodioxol-5-yloxy)-3- yloxy)[1,2,4]triazolo[4,3- chloro[1,2,4]triazolo[4,3-b]pyridazine (24b) 679m blpyridazin-3-ylJsulfanyl}-1,3- and 357 mg of 2-amino-1,3-benzothiazol- g benzothiazol-2-amine By! thiocyanate (commercial)

N-{6-{[6-(3,4- 115 mg of 6-{[6-(3,4- dichiorophenoxy)[1,2,41triazo dichlorophenoxy){1,2,4}triazolo[4,3- 31 | lo[4,3-blpyridazin-3-yl]sulf- b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol- 75 my anyl}-1,3-benzothiazol-2- 2-amine (26) and 0.046 cm® of ylicyclopropanecarboxamide cyclopropanecarbonyl chloride

N-{6-{[6-(1H-indol-6- 345 mg of 6-{[6-(1H-indol-6- yioxy)[1,2,4]triazolo{4,3- yloxy)[1,2 4}triazolo[4,3-b]pyridazin-3- b]pyridazin-3-yl]sulfaryl}-1,3- yllsulfanyl}-1,3-benzothiazol-2-amine (32b) | 396 mg benzothiazol-2- and 0.147 cm® of cyclopropanecarbonyl yl)cyclopropanecarboxamide chloride 6-{[6-(1H-indol-6- 500 mg of 3-chloro-6-(1H-indol-6- yloxy){1,2 4]triazolo[4,3- yloxy){1,2,4]triazolo[4,3-b]pyridazine (28h) 396 m b]pyridazin-3-yllsulfanyl}-1,3- and 363 mg of 2-amino-1,3-benzothiazol-6- 9 benzothiazol-2-amine yl thiocyanate (commercial)

N-(6-{[6-(3- 200 mg of 6-{[6-(3- fluorophenoxy)[1,2,41triazolo]] fluorophenoxy)(1,2,4]triazolo[4,3- : 4,3-b]pyridazin-3-yllsulfanyl}- blpyridazin-3-yljsulfanyl}-1,3-benzothiazol- 170 mg 1,3-benzothiazol-2- 2-amine (6) and 0.111 cm” of ylcyclobutanecarboxamide cyclobutanecarbonyl chicride

N-(6-{[6-(3- 200 mg of 6-{[6-(3-

B fluorophenoxy)[1,2,4]triazolo a fluorophenoxy)[1,2 4]triazolo[4,3- 4,3-b)pyridazin-3-ylisulfanyl}- blpyridazin-3-yiJsulfanyl}-1,3-benzothiazol-

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)[1,2,41triazolo] fluorophenoxy)|1,2,4]triazolo[4,3- 4,3-blpyridazin-3-yilsulfanyl}4 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- fluorophenoxy)[1,2,4]triazolof4,3- fluorophenoxy){1,2,4]triazolo]] 7 b]pyridazin-3-yllsulfanyl}-1,3-benzothiazol- 130 4,3-bipyridazin-3-ylJsulfanyl}- 2-amine (6) and 154 mg of mg 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 yloxy)[1,2.4]triazolo[4,3- yloxy)[1,2 4]triazolof4,3-bjpyridazine (37b) 400 m b]pyridazin-3-yl]sulfanyi}-1,3- and 347 mg of 2-amino-1,3-benzothiazol-6- 9 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- b]pyridazine (commercial) and 1.01 g of 408 mg bipyridazine pyriding-3-ol 6-({6-[3- 200 mg of 3-chioro-6-[3- {trifluoromethoxy)phenoxy][1 (trifluoromethoxy)phenoxy][1,2,4ltriazolo- 2 4ltriazolo[4,3-b]pyridazin- [4,3-b]pyridazine (38b) and 126 mg of 2- 111 mg 3-yl}sulfanyl)-1,3-benzo- amino-1,3-benzothiazol-6-yl thiocyanate thiazol-2-amine {commercial) 3-chloro-6-[3- 500 mg of 3,6-dichloro[1,2,4]triazolo[4,3- (triflucromethoxy)phenoxy][1 b]pyridazine (commercial) and 950 mg of 3- | 216 mg 2 4)triazolo[4,3-b]pyridazine (triftuoromethoxy)phenol 2-methylpropan-2-yi [3-({3- 550 mg of 2-methylpropan-2-yl {3-[(3- [(2-amino-1,3-henzothiazol- chloro[1,2,4ltriazolo[4,3-b]pyridazin-6- 6-yl)sulfanyfl{1,2,4]triazolo- yl)oxylphenyljcarbamate (39b) and 315 mg | 131mg [4,3-b]pyridazin-6- of 2-amino-1,3-benzothiazol-6-yl yiloxy)phenyljcarbamate thiocyanate (commercial) 2-methylpropan-2-yl {3-[(3- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3- chloro[1,2 4]triazolo[4,3- blpyridazine (commercial) and 2.21 g of 2- 1.43 b]pyridazin-6- methylpropan-2-yi (3- 429 yl)oxy]phenyl}carbamate hydroxyphenylicarbamate

N-(B-{[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- bipyridazin-3-yf]sulfanyi}-1,3- yllsulfanyi}-1,3-benzothiazol-2-amine (37) 262 mg benzothiazol-2- and 0.091 cm® of cyclobutanecarbonyl ylieyclobutanecarboxamide chloride a N-{(6-{[6-(3- Co | 225 mg of 2-chloro-N-(6-{[6-(3- fluorophenoxy)[1,2 4]triazolo] fluorophenoxy)[1,2 4]triazolo[4,3-

4,3-blpyridazin-3-yljsulfanyi}- blpyridazin-3-yl]sulfanyl}-1,3-benzothiazoi- 1,3-benzothiazol-2-yl)-2- 2-yl)acetamide (9b) and 0.40 cm® of (morpholin-4-yl)acetamide morpholine

N2-cyclohexyl-N-(6-{[6-(3- 225 mg of 2-chloro-N-(6-{[6-(3- fluorophenoxy)[1,2,4]triazolo]] fluorophenoxy)[1,2,4]triazolo[4,3- 4,3-b]pyridazin-3-ylJsulfanyl}- b]pyridazin-3-yllsulfanyl}-1,3-benzothiazol- 65 my . 1,3-benzothiazol-2- 2-ylyacetamide (9b) and 0.40 cm? of yhglycinamide cyclohexylamine

N-(6-{[6-(3- fluorophenoxy)[1,2,4]triazolo]] 243 mg of 2-chioro-N-(6-{[6-(3- 4,3-bipyridazin-3-yilsulfanyl} fluorophenoxy)[1,2,4}triazolof4, 3- 1,3-benzothiazol-2-yl)-Ne- blpyridazin-3-yi]suifanyl}-1,3-benzothiazol- 149 mg methyl-Nz-[2- (morpholin-4- 2-ylyacetamide (9b) and 425 mg of N- y)ethyllglycinamide methyl-2-(morpholin-4-yl)ethanamine 2-(4-ethylpiperazin-1-y!)-N- 200 mg of 6-{[6-(3- (6-{[6-(3- fluorophenoxy)[1,2 4]triazolo[4,3- fluorophenoxy)[1,2,4]triazolo]] 7 blpyridazin-3-yllsulfanyl}-1,3-benzothiazol- 154 m 4,3-blpyridazin-3-yiJsuifany}- 2-amine (6) and 247mg of (4- g 1,3-benzothiazol-2- ethylpiperazin-1-yl)acetic acid yijacetamide hydrobromide and 371 mg of HATU 6-{[6-(3,5- 350 mg of 3-chloro-6-(3,5- diffuorophenoxy)[1,2,4]triazo} difluorophenoxy){1,2,4]triazolo[4,3- o[4,3-b]pyridazin-3-yljsulf- blpyridazine (45b} and 257 mg of 2-amino- 85 mg anyl}-1,3-benzothiazol-2- 1,3-benzothiazol-6-yl thiocyanate amine (commercial) 3-chloro-6-(3,5- 1 g of 3,8-dichioro[1,2 4]triazolo[4,3- difluorophenoxy)[1,2,4ltriazol] 1b | blpyridazine (commercial) and 1.38 g of 363 mg o[4,3-b]pyridazine 3,5-difluorophenol 850 mg of 2-methylpropan-2-yl {3-[(3- 6-{[6-(3- chloro[1,2,4}triazolo[4,3-b]pyridazin-6- aminophenoxy)[1,2 4]triazolo yl)oxylphenyi}carbamate (39b) and 315 mg [4,3-b]pyridazin-3-yi]sulf- 1a | of 2-amino-1,3-benzothiazol-6-yl 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- fluorophenoxy)[1,2,4}triazolo] 243 mg of 2-chloro-N-(B-{[6~(3- 4,3-blpyridazin-3-ylJsulfanyl)- fluorophenoxy)[1,2,4]triazolo[4,3- 47 | 350 pyrigazin-c-y yi blpyridazin-3-yi]sulfanyl}-1,3-benzothiazol- 3-benzothiazol-2-yl}-N~2~- : (tetrahydro-2H-pyran-4- 2-yhacetamide (9b) and 400 mg of yiglycinamide tetrahydro-2H-pyran-4-amine

N-[6-({6-[4-(trifluoromethy!)- 85 mg of 8-({6-[4- phenoxy][1,2,4]triazolo[4,3- (trifluoromethyl}phenoxy][1 2 4]triazolof4,3- b]pyridazin-3-yl}sulfanyi)-1,3 b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol- benzothiazol-2-ylleyclo- 2-amine (48b) and 0.034 cm® of propanecarboxamide cyclopropanecarbonyl chloride

6-({6-[4- 350 mg of 3-chloro-6-[4- (trifluoromethyl)phenoxy][1,2 (trifluoromethyl)phenoxy][1,2,4]triazolo[4,3- 48b | 4ltriazolo[4,3-b]pyridazin-3- b]pyridazine (45b) and 231 mg of 2-amino- | 109 mg yilsulfanyl}-1,3-benzothiazol- 1,3-benzothiazol-6-yl thiocyanate 2-amine (commercial) 3-chioro-6-[4-(trifluoro- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3- methyl)phenoxyl[1,2,4]- blpyridazine (commercial) and 1.29 g of 4- 356 mg triazolo[4,3-blpyridazine (triflucromethyl)phenol

N-[6-({6-[3- 144 mg of 6-({6-[3- (ifuoromethoxy)phen oxy][1 (trifluoromethoxy)phenoxyl[1,2,4]triazolo- ,2:4ltriazolol4,3-blpyridazin- 4,3-blpyridazin-3-yllsuffanyl)-1,3-benzo- | 61 3-yl}sulfanyl)-1,3-benzo- [ r>-olpyrida: yusuiany)-1. 20 mg thiazol-2- thiazol-2-amine (38) and 0.055 cm” of ylleyclopropanecarboxamide cyclopropanecarbonyl chloride

N-{6-({6-[(2-rethylpyridin-3- 84 mg of 6-({6-[(2-methylpyridin-3- yloxyl[1,2,4)triazolic[4,3- yhoxyl[1,2,4]triazolo[4,3-b]pyridazin-3- blpyridazin-3-yl}sulfanyi)-1,3 yl}sulfanyt)-1,3-benzothiazol-2-amine (50b) 71mg benzothiazol-2- and 0.040 cm?® of cyclopropanecarbonyl ylleyclopropanecarboxamide chloride 6-({6-[(2-methylpyridin-3- 950 mg of 3-chloro-6-[(2-methylpyridin-3- yl)oxy][1,2,4]triazolo[4,3- ylyoxy][1,2,4}triazolo[4,3-b]pyridazine (50¢) 84 blpyridazin-3-yi}sulfanyl)-1,3 and 436 mg of 2-amino-1,3-benzothiazol-6- mg benzothiazol-2-amine yi thiocyanate (commercial) 3-chloro-6-[{2-methyipyridin- 1 g of 3,6-dichloro[1,2,4]triazolo[4,3- 3-yhoxy|[1,2,4]triazolo[4,3- blpyridazine (commercial) and 1.16 g of 2- 734 my blpyridazine methylpyridin-3-ol

N-{6-{[6-(3,5- 75 mg of 6-{[6-(3,5- difluorophenoxy)[1,2,4itriazol difluorophenoxy)[1,2,4]triazolo[4,3- of4,3-blpyridazin-3-yl]sulf- blpyridazin-3-ylJsulfanyl}-1,3-benzothiazol- 37 mg anyl}-1,3-benzothiazol-2- 2-amine (45) and 0.033 cm? of ylicyclopropanecarboxamide cyclopropanecarbonyi chloride 2-[(6-{[6-(3- 112 mg of 6-{[6-(3- fluorophenoxy)]1,2,4%riazolo] fiuorophenoxy)[1,2,4ltriazolo[4,3- 4,3-blpyridazin-3-yljsuifanyl}- blpyridazin-3-yllsuifanyl}-1,3-benzothiazol- 1,3-benzothiazol-2- 2-amine (6) and 0.107 cm® of 2-chioro-2- yl)amino}-2-oxoethyl acetate oxoethy! acetate

N-[6-({6-[(6-methylpyridin-3- 69 mg of 6-({6-[(6-methylpyridin-3- yiyoxy][1,2,41triazolo[4,3- ylhoxy][1,2,4]triazolo[4,3-b]pyridazin-3- bjpyridazin-3-yl}sulfanyl)-1,3 yl}sulfanyl}-1,3-benzothiazol-2-amine (53b) | 45mg benzothiazol-2- and 0.031 cm® of cyclopropanecarbonyl ylleyclopropanecarboxamide chloride 6-({6-{{6-methylpyridin-3- 255 mg of 3-chioro-8-[(6-methylpyridin-3- yhoxy][1,2 4]triazolo[4,3- yl)oxy][1,2,4]triazolof4,3-blpyridazine (53c)- 69 m blpyridazin-3-yi}sulfanyl)-1,3 and 202 mg of 2-amino-1,3-benzothiazol-6- 9 benzothiazol-2-amine yl thiocyanate (commercial)

3-chioro-8-{{6-methylpyridin- 1 g of 3,6-dichloro[1,2,4]triazolo[4, 3- 3-yhoxyl[1,2,4]triazolof4,3- blpyridazine (commercial) and 1.16 g of 6- 260 mg blpyridazine methylpyridin-3-ol

N-[6-({8-[4-(morpholin-4- 87 mg of 6-({6-[4-(morpholin-4- yimethyl)phenoxy][1,2 4]triaz yimethyl)phenoxy][1,2,4}triazolo[4,3- olo[4,3-b]pyridazin-3-yi}sulf- blpyridazin-3-yl}sulfanyl}-1,3-benzothiazol- 86 mg anyl)-1,3-benzothiazol-2- 2-amine (54b) and 0.024 cm® of yllcyclopropanecarboxamide cyclopropanecarbonyl chloride 6-({6-[4-(morpholin-4- 155 mg of 3-chloro-8-[4-(morpholin-4- ylmethyl)phenoxyl[1,2,4]triaz ylmethyl)phenoxy][1,2 4]triazolo[4,3- olo[4,3-b]pyridazin-3-yl}suif- blpyridazine (54¢) 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 2,4ltriazolo[4,3- yimethyl)phenoxy][1,2,4]triaz bipyridazine (commercial) and 207 mg of 4- | 158 mg olo[4,3-b]pyridazine (morpholin-4-yimethyt)phenol (54d) 4-(moarpholin-4- 185mg of 4-(chloromethyl)pheny! acetate 207 m yimethyl)phenol and 436 mg of morpholine 9 2-methylpropan-2-yl (3-{[3- a. Ad [RIA {{2-[(cyclopropylcarbonyl)- 34 mg §f 2-methyiprop oe 2 Is {3-2 amino]-1,3-benzothiazol-6- no-1,5-benzothiazol-6-yl)sulf- sulfan At 2 Altriazolo[4,3- anyl][1.2,41trlazolo[4,3-b]pyridazin-6- 59 mg

Yio dain 6oylloxyh ’ yloxy)phenyljcarbamate (39) and phenyljcarbamate 0.031 cm” of cyclopropanecarbonyl chloride

N-(6-{[6-(pyridin-3- eri 2 !

Ee 4 a [12 4a i sua 143 bipyridazin 3-ys its 1,3-benzothiazol-2-amine (37) and m3 vl)eyclopropanecarboxamide 0.070 cm” of cyclopropanecarbonyl chloride

N-{6-[(6-{3-[(1S,48)-2-0xa-5- 46 mg of 6-[(6-{3-[(1S,48)-2-0xa-5-aza- azabicyclo[2,2,1]hept-5- bicyclo[2,2,1]hept-5-yimethyllphenoxy}- 57 yimethyllphenoxy}[1,2,4]triaz [1.2.4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl)- 31m olo[4,3-b]pyridazin-3-yi)sulf- 1,3-benzothiazol-2-amine (57b) and 9 anyl]-1,3-benzothiazol-2- 0.105 cm® of cyclopropanecarbonyl chloride yileyclopropanecarboxamide for 4 hours at 20°C eB poor 103 mg of 3-chioro-6-{3-{(1S,4S)-2-0xa-5- imethy] henox 1.2 4]triaz azabicyclio[2,2,1}hept-5-yimethyllphenoxy}- 57h | YMetyiphenoxyl1,z, [1,2,4]triazolof4,3-bJpyridazine (57¢) and 60 | 51 mg olo{4,3-b]pyridazin-3-yl)sulf- f 2-amino-1.3-b thiazol-6-vi anyl}-1,3-benzothiazol-2- he o ii ~ eh 'azol-6-y amine iocyanate (commercial) 3-chloro-6-{3-[(15,45)-2-0xa 85 mg of 3,6-dichloro[1,2 4triazolo[4,3- 57 5-azabicyclo[2,2, 1]hept-5- blpyridazine (commercial) and 110 mg of 3- 108 m ¢ yimethyllphenoxy}{1,2,4}triaz [(18,48)-2-oxa-5-azabicyclof2,2,1]hept-5- 9 olo[4,3-b]pyridazine ylmethyllphenol (57d)

188 mg of 3-(bromomethyi)phenol (10e) 57d oe 5. and 163 mg of (1S,4S)-2-0xa-5- Hm azabicyclo[2,2, tihep azabicyclo[2,2,1]heptane hydrochloride 9 yimethytjphenol (commercial)

N-{6-[(6~{3- 6m : . g of 6-[(6-{3- ae er ylipheno [(diethylarmino)methyllphenoxy}{1,2 4]triazol x : J I wy If 1-1.3- of4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo- 30mg

Dlpyridazin 3 yljsulfanll-1, thiazol-2-amine (58b) and 0.013 cm’ of yllcyclopropanecarboxamide cyclopropanecarbony! chloride 6-[(6-{3- 160 mg of N-{3-[(3~-chloro[1,2 4]triazolo[4,3- [(diethylamino)meathyljpheno b]pyridazin-6-yl)oxy]benzyl}-N- xy} 1,2 4]triazolo[4,3- 1a | ethylethanamine (58¢) and 120 mg of 2- 157 mg blpyridazin-3-yi)sulfanyl]-1,3- amino-1,3-benzothiazol-6-yi thiocyanate benzothiazol-2-amine (commercial) : 3 113 chloral 2 4]riazolo- 148 mg of 3,6-dichloro[1,2,4]triazolo[4,3-

Do - blpyridazine (commercial) and 169 mg of 3- | 163 mg ethylethanamine [(diethylamino)methyl}phenol (58d) 3- 375 mg of 3-(bromomethyl)phenol {10e) 188 m [(diethylamino)methyl]phenol and 731 mg of diethylamine 9

N-(6-{[6-(3,5- 200 mg of 6-{[6-(3,5- difluorophenoxy){1,2 4]triazol difluorophenoxy)[1,2,4]triazolo}4,3- o[4,3-b]pyridazin-3-yl]sulf- blpyridazin-3-yl]sulfanyl}-1,3-benzothiazoi- 127 mg anyl}-1,3-benzothiazol-2-yl)- 2-amine (45) and 715 mg of the sodium salt

N2,N2-diethylglycinamide of N,N-diethylglycine 510 mg of 2-[(6-{[6-(3-

N-(6-(6-(3 fluorophenoxy)[1,2,4]triazolo[4,3-

SEALS , blpyridazin-3-yl}sulfanyl}-1,3-benzothiazol- maya 2-yl)amino}-2-oxoethyl acetate (52) and 262

S olpyidazin: oy y 42mg of lithium hydroxide hydrate under mg hud enz or Y conditions simitar to those described by T. ydroxyacetamide G. Murali Dhar ef al. in J. Med. Chem. 2002, 45, 2127-2130 . 243 mg of 2-chloro-N-(6-{[6-(3- 218 cyslopropyipiparazin- - flucrophenoxy)[1,2,4]triazolo[4, 3- y- ~( H] (3 [1.2 4]triazolol] blpyridazin-3-yljsulfanyl}-1,3-benzothiazol- rt or srioxy) 3 i riaz i- 2-yl)acetamide (9b) and 200 mg of 1- 242mg 3.5 ojo hia Th s y cyclopropyipiperazine dihydrochloride ; - i q lazol- (commercial) with triethylamine in N,N-

Wjacetamide dimethylformamide

N-(6-{[6-(3,5- 200 mg of 6-{[6~(3,5- difluorophenoxy)[1,2,4}triazo} difluorophenoxy)[1,2,4]triazolo[4,3- o[4,3-b]pyridazin-3-yljsulf- blpyridazin-3-ylsulfanyl}-1,3-benzothiazol- | 144 mg anyl}-1,3-benzothiazol-2-yl}- 2-amine (45) and 1.19 g of (4- 2-(4-ethylpiperazin-1- ethylpiperazin-1-yl)acetic acid:

[esi Teommens) 2-{4-cyclopropyipiperazin-1- 142 mg of 6-{[6-(3,5- yl)-N-(8-{[6-(3,5~ difluorophenoxy)[1,2,4]triazolo[4,3- difluorophenoxy)[1,2,41triazol b]pyridazin-3-yljsulfanyl}-1,3-benzothiazol- of4,3-b]pyridazin-3-ylJsulf- 2-amine (45) and 683 mg of the potassium . anyl}-1,3-benzothiazol-2- salt of (4-cyclopropylpiperazin-1-yl)acetic yl)acetarnide acid (63b){or commercial) 2.1 g of bromoagcetic acid and 3 g of 4- potassium salt of (4- cyclopropylpiperazine hydrochloride § cyclopropylpiperazin-1- under conditions similar to those described 266g yhacetic acid by D. T. Witiak ef al.; J. Med. Chem. 1985, 28, 1228 oS ymethylloheno 120 mg of 6-1(6-{3-[(diethylamino)methyl]- xy}[1,2 4]triazolo[4,3- phenoxy}{1,2,4]triazoto[4,3-b]pyridazin-3- 84m 4 yl)sulfanyi]-1,3-benzothiazol-2-amine (58b) 9 blpyridazin-3-yl)suifanyl]-1,3- and 20 mg of acetyl chioride benzothiazol-2-yllacetamide 9

N-{6-[(6-{3- [(diethylamino)methyl]pheno 120 mg of 6-[(6-{3-{(diethylamino)methyl]- :

Xy}[1,2,41triazolof4,3- phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3- 76m blpyridazin-3-yl)sulfanyl]-1,3- yhsulfanyl]-1,3-benzothiazol-2-amine (58b) g benzothiazolh-2-yl}-2- and 33 mg of 2-methoxyacetyl chloride methoxyacetamide 2-methoxy-N-{6-[(6-{3- [(1S,48)-2-0xa-5- 135 mg of 6-[(6-{3-[(1S,48)-2-0xa-5- azabicyclof2,2,1]hept-5- azabicyclo2,2, 1Jhept-5-yimethyl]- yimethyllphenoxy}[1,2,4]triaz phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3- 109 mg olo[4,3-b]pyridazin-3-yl)sulf- yl)sulfanyl]-1,3-benzothiazol-2-amine (57b) anyl]-1,3-benzothiazol-2- and 35 mg of 2-methoxyacetyl chloride yllacetamide : 8-{[6-(oxetan-3- 1.02 g of 3-chloro-6-(oxetan-3-yloxy)[1,2,4]- 67 yloxy)[1,2,4]triazolo[4,3- triazolof4,3-b]pyridazine (67b) and 1.12 g of 383 m blpyridazin-3-yl]sulfanyl}-1,3- 2-amino-1,3-benzothiazol-6-y! thiocyanate 9 benzothiazol-2-amine (commercial) 3-chloro-6-{oxetan-3- 2 g of 3,6-dichloro[1,2,4]triazolo[4,3- 67b | yioxy)[1,2,4]triazolo[4,3- bipyridazine (commercial) and 1.96 g of 1.01¢ blpyridazine oxetan-3-ol rac-2-(morpholin-4-y1)-N-(6- 250 mg of rac-8-{[6-(tetrahydrofuran-3- {[6~(tetrahydrofuran-3- yloxy)[1,2 4ltriazolo{4,3-b]pyridazin-3- yioxy)[1,2,4]triazolo[4,3- yllsulfanyl}-1,3-benzothiazol-2-amine (27) 86 mg blpyridazin-3-yl]suifanyl}-1,3- and 939 mg of morpholin-4-ylacetic acid benzothiazol-2-yl)acetamide (commercial)

N-(6-{[6-(3.5- 150 mg of 6-{[6-(3,5- difluorophenoxy){1,2,4}triazol difluorophenoxy)[1,2,4ltriazolof4,3- 111 mg of4,3-blpyridazin-3-yljsulf- blpyridazin-3-ylsulfanyl}-1,3-benzothiazol- anyl}-1,3-benzothiazol-2-yl)- 2-amine (45) and 508 mg of morpholin-4-

IN 2-(morpholin-4-yl)acetamide IN ylacetic acid (commercial) Co] er] 2_ i - | po j— rare. (6-{[6 250 mg of rac-6-{[6-(tetrahydrofuran-3- ox 2 4lriazon[4.3- yloxy)[1,2 4ltriazolo[4,3-blpyridazin-3- 70 bo : dazin-3- flsulfan 1-1,3- yllsulfanyl}-1,3-benzothiazol-2-amine (27) 48 mg aa, yi-1s and 991mg of the sodium salt of N,N- yglycinamide - 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]iriazolo[4,3-b]pyridazin-3- 71 | yioxy)[1,2,4ltriazolo[4,3- ylisulfanyl}-1,3-benzothiazol-2-amine (27) 50 mg blpyridazin-3-yi]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]triazolof4,3-b]pyridazin-3- 72 (6-{[6-(tetrahydrofuran-3- yllsuifanyl}-1,3-benzothiazol-2-amine (27) 83 mg yloxyY[1,2 4]triazolo[4,3- and 619 mg of the potassium salt of (4- blpyridazin-3-yl]sulfanyi}-1,3- cyclopropylpiperazin-1-yl)acetic acid (63b) benzothiazol-2-yl)acetamide {or commercial)

N-{6-{[6-(oxetan-3- 60 mg of 6-{[6-(oxetan-3- yioxy){1,2,4]triazolo[4,3- yloxy)[1,2 4]triazolo[4,3-bjpyridazin-3- 73 | blpyridazin-3-yljsulfanyl}-1,3- ylsulfanyl}-1,3-benzothiazol-2-amine (67) 42 mg benzothiazo!-2- and 0.022 cm® of cyclopropanecarbonyl yljcyclopropanecarboxamide chloride 2-(4-ethylpiperazin-1-yl)-N- 150 mg of 6-{[6-(oxetan-3- (6-{[6-(oxetan-3- yloxy)[1,2,4]triazolof4,3-b]pyridazin-3- 74 | yloxy)[t,2 4]triazolo[4,3- yllsulfanyl}-1,3-benzothiazol-2-amine (67) 123 mg bipyridazin-3-yljsulfanyl}-1,3- and 357 mg of (4-ethylpiperazin-1-yl)acetic benzothiazol-2-yl)acetamide acid (commercial) , py 143 mg of 6-{[6-(oxetan-3- 2-(4-cyclopropylpiperazin-1 yioxy)[1,2,4]triazolo[4,3-bjpyridazin--

YI)-N-(6-{[6-(oxetan-3- yllsulfanyl}-1,3-benzothiazol-2-amine (67) 75 | yloxy)[1,2,4]triazolo[4,3- ; : 90 mg blpyridazin-a-yllsuifanyi}-1,3- and 427 mg of the potassium salt of (4- : $ cyclopropylpiperazin-1-yl)acetic acid (63b) benzothiazol-2-yl)acetamide (or commercial)

The characteristics of the products of the above table are as follows: lw [em 'H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 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 [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 =

HI-- 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, 1H), 7.60 (d, J =8.6 Hz, 1 H); 7.91 (d, J = 1.9 Hz, 1 H); 8.42 (d, J =9.8 Hz, 1 H}; 12.39 (broad m, 1 H) 12 | M+H]+: m/z 479; [M- | '"H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 0.92 to 1.00 (m,

H]-: m/z 477 4 H); 1.9410 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, 1 H); 7.31 (dd, J=1.9 and 8.6 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1H); 7.43 (dt, J =6.8 and 8.3 Hz, 1 H); 7.61 (d, J =8.6 Hz, 1H); 7.90 (d, J=1.9 Hz, 1 H); 8.49 (d, J =9.8 Hz, 1 H); 12.69 {broad m, 1 H) "HNMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 2.36 to 2.46 {m, . . 6 H); 3.26 to 3.34 (partially masked m, 2 H); 3.59 (m, 4 H); 6.78 [pr mz S87: IM | (broad m, 1 HY; 7.18 10 7.26 (m, 3 H); 7.26 to 7.32 (m, 2 H): 7.36 (d,

J wiz J=9.8Hz, 1H); 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, 1 M); 10.89 (broad m, 1 H)

Retention time Tr (min) = 0.78; [M+M]+: m/z 265;

HNMR Spectrum (400 MHz, & in ppm, DMSO-dg): 2.27 (s, 3 H); 2.41 (m, 6 H); 3.25 fo 3.35 (partially masked m, 2 H); 3.60 (m, 4 HY; [M+H]+: m/z 581; [M- | 6.78 (broad m, 1 H); 7.00 (broad d, J = 8.3 Hz, 1 H); 7.19 (broad d,

H]-: m/z 579 J=10.3 Hz, 1 H); 7.2310 7.31 (m, 2H); 7.35 (d, J = 9.8 Hz, 1 H); 748(d,J=86Hz,1H),7.84(d, J=1.9Hz, 1H); 846 (d, J = 9.8 Hz, 1 H); 10.89 (broad m, 1 H)

Retention time Tr : (min) = 0.88; [M+H]+: mfz 279; "H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 1.55 (m, 2 H); [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, 1 H); 7.22 t0 7.30 {m, 2 H); 7.61 (s, 2 H); 7.82 (d,J=1.0Hz, 1H); 8.28 (d, J =9.8 Hz, 1 H)

Retention time Tr {min) = 2.74; [M+H]+: m/z 255;

HNMR Spectrum (400 MHz, 8 in ppm, DMSO-d): 7.12 (dd, J = [M+H]+: m/z 411; {M- | 1.9 and 8.4 Hz, 1H); 7.22 (d, J =8.4 Hz, 1 H); 7.24 0 7.38 {m,

H}-: m/z 409 SH) 7.62 (d, J= 1.9 Hz, 1 H); 7.64 (broad s, 2 H); 8.44 {d, J= 9.8 Hz, 1H) 'H NMR Spectrum (400 MHz, & in ppm, DMSO-d): 1.52 {m, 2 HY; 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 RH); 3.59 (t, J = 4.6 Hz, 4 H); 3.71 (mn,

H]-: m/z 555 2H), 4.86 (m, 1H); 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=2.0Hz, 1H); 8.30 (d, J =9.8 Hz, 1 H); 10.91 (broad s, 1 H) 'H NMR Spectrum (400 MHz, § in ppm, DMSO-dg): 0.96 (t, J = 7.2 Hz, 3H); 1.49 (m, 2 H); 1.76 (m, 2 H); 1.93 (t, J = 9.5 Hz, 2 H); 18 | [M+H]+: miz 584 2.28 (q, J =7.1 Hz, 2 H); 2.41 (m, 6 H); 2.51 t0 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, 1 H); 6.77 (broad s, 1 H); 7.03 (d, J =9.8 Hz, 1 H); 7.28 (dd, J = 2.1 and 8.4 Hz, 1H); 7.53 (d, J =8.6 Hz, 1 H); 8.02 (d, J =2.0 Hz, 1 H):

CC 8.28 (d, J =9.8 Hz, 1 H); 10.89 (broad s, 1 H) : "H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 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 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=4.1and 8.2 Hz, 1H); 7.10 (d, J =10.0 Hz, 1 H); 8.27 (d, J = 10.0 Hz, 1 H) a. *H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 0.90 to 0.98 (m, 4 H); 1.51 (m, 2 H); 1.78 (m, 2 H); 1.97(m, 1 H); 3.31 to 3.36 [M+H]+: m/z 469; [M- | (masked m, 2 H); 3.70 (m, 2 H); 4.84 (m, 1 H); 7.05 (d, J = 9.8 Hz, 19 HF: m/z 467 1H); 7.38 (dd, J=2.0 and 8.8 Hz, 1 H); 7.66 (d, J = 8.6 Hz, 1 H); 8.06 (d, /=1.2 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 12.68 (broad s, 1H) *H NMR Spectrum (400 MHz, 8 in ppm, DMSO-dg): 0.92 to 1.00 (m, : [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,

Hl: m/z 477 3H); 7.37 (d, J=10.0 Hz, 1H); 7.62 (d, J = 8.6 Hz, 1 H); 7.87 (d, J = 1.8 Hz, 1 H); 8.47 (d, J =10.0 Hz, 1 H); 12.70 (broad m, 1 H)

HNMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 0.92 to 1.00 (m, 4H); 1.96 10 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

HI-: 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=9.8Hz 1H);7.59(d, J=8.6 Hz, 1 H); 7.89 (d, J = 1.9 Hz, 1H), 8.47 (d, J = 9.8 Hz, 1 H); 12.69 (broad m, 1 H)

Retention time Tr {min} = 0.82; [M+H]+: m/z 425; [M-H]-: m/z 423 'H NMR Spectrum (400 MHz, § in ppm, DMSO-dg): 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); [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

H]-: miz 494 (masked m, 2 H); 4.58 (m, 1 H); 7.02 (d, J =9.8 Hz, 1 H); 7.29 (dd,

J=1.8and 84 Hz, 1H); 7.58 (d, J=8.3 Hz 1 H);8.03(d, J= 1.2 Hz, 1H); 8.28 (d, J = 9.8 Hz, 1 H); 12.62 (s, 1 H)

Retention time Tr {min) = 0.36; [M+H]+: mfiz 428; M+2H]2+: m/z 214.5 (base peak); [M-H]-: m/z 426 "MH NMR Spectrum (400 MHz, in ppm, DMSO-d): 1.98 (m, 1 H); 2.17 (m, 1H); 2.35 to 2.45 (m, 6 H); 3.22 to 3.28 (masked m, 2 H); [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

Hl-: m/z 541 {t, J=5.2Hz 1H),7.07(d, J=9.8 Hz, 1 H); 7.42 (dd, J =2.0 and 8.8 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) iL "HNMR Spectrum (400 MHz, & in ppm, DMSO-dg): 2.05 to 2.18 (m,

Retention time ie + | 1H) 2.25102.39 (m, 1 H); 3.78 (m, 1 H); 3.88 (m, 1 H); 3.94 (m, (min) = 0.49; MHI: | 5 4): 5:52 (m, 1 H); 7.42 (d, J = 9.8 Hz, 1 H): 8.20'(d, / = 9.8 He

I

HNMR Spectrum (400 MHz, 5 in ppm, DMSO-d): 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, [M+H}+: m/z 593; [M- | 2 H); 6.72 (dd, J = 2.4 and 8.6 Hz, 1 H); 6.79 (broad m, 1 H); 6.93

HJ-: m/z 591 (d, J=8.6Hz, 1H), 6.95(d, J=24 Hz, 1H); 7.27 t0 7.33 (m, 2 H); 7.50 (d, J=8.6 Hz, 1H); 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 {min} = 0.73; [M+H]+: miz 291

HM NMR Spectrum {400 MHz, § in ppm, DMSO-dg): 2.37 to 2.45 (m, 6 H); 3.24 to 3.33 (partially masked m, 2 H); 3.59 {m, 4 H); 6.78 [M+H]+: m/z 617; [M- | (broad m, 1 H); 7.24 (dd, J =2.0 and 8.3 Hz, 1 H); 7.30 (dd, J=2.7

H]-: m/z 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=88Hz 1H); 7.74 (d, J=2.7 Hz, 1 H); 7.84 {d,J= 2.0 Hz, 1H); 8.49 (d, J = 9.8 Hz, 1 H); 10.92 (broad m, 1 H)

Retention time Tr (min) = 0.98; [M+H]+: m/z 315 'H NMR Spectrum (400 MHz, 8 in ppm, DMSO-dg): 7.13 (dd, J = 2.0 and 8.4 Hz, 1H); 7.20 (d, J = 8.4 Hz, 1 H); 7.34 (dd, J = 2.7 and

Pi Js 401 IM- | 8.8 Hz, 1H); 7:38 (d, J = 9.8 Hz, 1 H); 7.64 (5. 2 H); 7.66 (d, J =

I miz 2.0 Hz, 1H), 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, 1 H) 'H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 2.02 (m, 1 H); 2.22 (m, 1H); 3.69 to 3.86 (m, 4 H); 5.35 (m, 1 H); 7.06 (d, J = 27 pT me 387: M- | 10.0 Hz, 1 Hy. 7.29 (d, J = 8.6 Hz, 1 H); 7.34 (dd, J = 2.0 and

Fiz 6.6 Hz, 1H); 7.62 (s, 2 H); 7.88 (d, J =2.0 Hz, 1 H); 8.28 (d, J = . | 9.8Hz, 1H) 'H NMR Spectrum (400 Miz, & in ppm, DMSO-dg): 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, . ] 1H); 6.77 (broad m, 1 H); 6.91 (dd, J = 2.3 and 8.6 Hz, 1 Hj; 7.21

NI mz P88; IM | (4d, J =2.0 and 8.6 Hz, 1 H); 7.33 (d, J = 10.0 Hz, 4 Hy; 7.34 to

I miz 7.37 (m, 2H); 7.42 (dd, J=2.3 and 3.0 Hz, 1 H); 7.58 (d, J = 8.6 Hz, 1H); 7.88 (d, J = 2.0 Hz, 1 H); 8.41 (d, J = 10.0 Hz, 1 H); 10.89 (broad m, 1 H); 11.25 (broad m, 1 H)

Retention time Tr {min) = 0.76; [M+H]+: m/z 286; [M-H]-: m/z 284 'H NMR Spectrum (400 MHz, 3 in ppm, DMSO-d): 0.95 {m, 4 H); . . 1.97 (m, 2H); 2.15 (m, 1H); 3.6310 3.73 (m, 3H); 3.78 (q, J = [ore ovz 455: IM | 7.7 Hz, 1 H); 5.33 (m, 1 H): 7.08 (d, J = 10.0 Hz, 1 H); 7.46 (dd, J =

I: miz 2.1 and 8.4 Hz, 1 H); 7.69 (d, J = 8.3 Hz, 1 H); 8.11 (d, J = 2.0 Hz, 1H); 8.31 (d, J=9.8 Hz, 1 H); 12.67 (broad s, 1 H)

'H NMR Spectrum (400 MHz, 3 in ppm, DMSO-dg): 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 [M+H]+: m/z 505; [M- | 8.4 Hz, 1H); 6.89 (d, J = 8.4 Hz, 1 H); 6.92 (d, J = 2.3 Hz, 1 H);

HJ-: m/z 503 7.32 (d, J=9.8 Hz, 1H); 7.35 (dd, J = 2.0 and 8.6 Hz, 1 H); 7.62 (d,

J=8.8 Hz, 1H); 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 {min} = 0.70; [M+H]+:m/z 437; [M-

Hj-:m/z 435 "H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 0.90 to 0.99 (m, [M+H]+: m/z 529; [M- | 4 H); 1.94 0 2.05 (m, 1 H); 7.24 to 7.30 (m, 2 H); 7.40 (d, J =

H}- miz 527 9.8 Hz, 1H), 7.5510 7.61 (m, 2 H); 7.71 (d, J =2.7 Hz, 1 H); 7.89 (d, J =2.0 Hz, 1H); 8.50 (d, J = 9.8 Hz, 1 H); 12.70 (broad m, 1 H) "H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 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 = [M+H]+: m/z 500; [M- | 2.2 and 8.6 Hz, 1 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=1.9Hz, 1H); 841(d, J=9.8 Hz, 1 H). 11.24 (broad s, 1 H); 12.69 (broad m, 1 H)

Retention time Tr (min) = 3.32; [M+H]+: mfz 432; [M-H]-: m/z 430 'H NMR Spectrum (400 MHz, 8 in ppm, DMSO-d): 1.76 to 1.89 (m, 1H); 1.89 to 2.04 (m, 1 H); 2.07 to 2.33 (m, 4 H); 3.34 to 3.45 (m, } } 1H); 7.12 (dd, J = 2.3 and 8.4 Hz, 1 H); 7.17 (broad dt, J = 2.3 and [Hi mz 49% IM | 8.4 Fiz, 1 Hy: 7.25 (td, J = 2.3 and 10.0 Hz, 1 H): 7.31 (dd, J = 2.0

I wiz 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, 1H); 7.59 (d, J = 8.6 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H); 8.49 (d, J =9.8 Hz, 1H); 12.25 (broad m, 1 H) 'H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d): 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, 1H); 7.16 (dt, J=2.3 and 8.3 Hz, 1 H); 7.24 (td, J = 2.3 and 9.9 Hz, [eHl>: 0/2 496: IM- | 1H); 7.31 (ad, v= 1.9 and 8.6 Hz, 1H}; 7.39 (d, J = 10.0 Hz, 1 H)

H]- m/z 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=1.9Hz, 1H); 8.49 (d, J = 10.0 Hz, 1 H); 11.93 (very broad m, 1 H) 'H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 1.17 {t, J = 7.1 Hz, 3H); 3.56 (q, J =7.1 Hz, 2 H); 4.24 (s, 2 H); 7.11 (dd, J = [M+H]+: m/z 497; [M- | 2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.2 and 8.3 Hz, 1 H); 7.24 (td, J =

H]-: 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, 2H); 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 HY; 12.29 (broad m, 1 H) [M+H]+ m/z 551; {M- | "4 NMR Spectrum (400 MHz, 5 in ppm, DMSO-d): 1.11 to 1.36 (m,

H}-: m/z 549 5H); 1.4210 1.53 (m, 1 H); 1.68 (m, 2 H); 1.88 (m, 2 H); 3.36 to

3.44 (m, 1H); 4.26 (s, 2H); 7.11 (dd, J = 2.2 and 8.3 Hz, 1 HY; 7.16 (dt, J=2.2 and 8.3 Hz, 1 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); 7.37 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, & in ppm, DMSO-dg): 7.10 (dd, J = 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 | [HE 239% IM | 111), 7.53 (dd, J = 4.8 and 8.4 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1 H);

I mz 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, 8 in ppm, DMSO-dg): 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) 'H NMR Spectrum (400 MHz, § in ppm, DMSO-d): 7.19 (dd, J = [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]-: miz 475 3H); 7.58 (broad s, 1 H); 7.63 to 7.75 (m, 4 H); 8.52 (d, J = 9.8 Hz, 1H)

Retention time Tr (min) = 4.12; [M+H]+: miz 331 "H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 1.48 (s, 9 H): 6.86 (broad d, J =7.8 Hz, 1 H); 7.17 (dd, J = 1.8 and 8.5 Hz, 1 H); [rel ov S08: IM | 722 (d, J = 85 Hz, 1 H); 7.28 0 7.40 (m, 3 H); 7.641 (broad 5, 1 H)

I: miz 7.62 (broad s, 2 HY, 7.71 (d, J = 1.8 Hz, 1 H); 8.42 (d, J =9.8 Hz, 1 H); 9.59 (broad s, 1 H) [M+H}+: miz 362; [M-

HJ: m/z 360 'H NMR Spectrum (400 MHz, 3 in ppm, DMSO-dg): 1.78 to 2.04 {m, 2 H); 2.1110 2.34 (m, 4 H); 3.41 (m, 1 H); 7.27 (dd, J = 2.0 and

AR mz 476: IM- | 8.3 Hz, 1 H): 7.38 to 7.46 (m, 2 H); 7.60 (d, J = 8.3 Hz, 1 H): 7.72

J: mz (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) "HNMR Spectrum (400 MHz, 8 in ppm, DMSO-dg): 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 [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 1H); 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 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1 H); 7.91 (d,

J =2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.21 (broad m, 1 H) "H NMR Spectrum (400 MHz, § in ppm, DMSO-dg): 1.00 fo 1.29 (m, 5H); 1.50 to 1.57 (m, 1 H); 1.61 to 1.72 (m, 2 HY; 1.83 (m, 2 H); [M+H]+: m/z 550; [M- | 2.46 (partially masked m, 1 H); 3.52 (s, 2 H); 7.09 to 7.20 (m, 2 H);

H]-: m/z 548 7.23 107.30 (m, 2 H); 7.38 (d, J = 9.8 Hz, 1 H); 7.44 (dt, J = 6.9 and 8.3Hz, 1H); 7.57 (d, J=8.3 Hz, 1H); 7.88 (d, J =2.0 Hz, 1H }; 8.48 (d, J =9.8 Hz, 1 H)

~~ WO 2010/089507 PCT/FR2010/050178 90 ‘HNMR Spectrum (400 MHz, & in ppm, DMSO-dg): 2.35 to 2.46 (m, 9H); 2.65 (t, J =6.1 Hz, 2 H); 3.39 (5, 2 H); 3.64 (m, 4 H); 7.11 (dd, [M+H]+: m/z 595; [M- | J =2.2and 8.3 Hz, 1 H); 7.16 (dt, J =2.2 and 8.3 Hz, 1 H); 7.25 (id,

Hl: 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, 1 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) *H NMR Spectrum (400 MHz, 8 in ppm, DMSO-d): 1.00 (broad t, J } A =6.8 Hz, 3 H); 2.30 to 2.62 (partially masked m, 10 H); 3.34 {s, mz oo 2 HY; 7.11 (dd, J = 2.3 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.3 and

Y l a ~ i: | 8:3 Hz, 1H); 7.24 (td, J = 2.3 and 10.0 Hz, 1 H); 7.32 (dd, J = 2.0 ( aso boa IMR ang 8.6 Hz, 1H); 7.39 (d, J = 9.8 Hz, 1 Hy, 7.43 (m, 1 HY; 7.62 (d, J mz =8.6 Hz, 1H); 7.92 (d, J = 2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H): 12.11 (broad m, 1 H) 1 . } A H NMR Spectrum (400 MHz, 8 in ppm, DMSO-dg): 7.19 (broad s, as | [HI MZ 429 IM) 5 Hy: 7.21 107.33 (m, 3 H); 7.39 (d, J = 0.8 Hz, 1 1); 7.64 (broad &,

I miz 2H); 7.69 (broad's, 1 H); 8.48 (d, J = 9.8 Hz, 1 H)

Retention time Tr (min) = 0.83; [M+H]+: m/z 283 'H NMR Spectrum (400 MHz, 3 in ppm, DMSO-d): 5.36 (broad s, 2 H); 6.36 (dd, J =2.0 and 8.1 Hz, 1 H); 6.45 (t, J = 2.0 Hz, 1 H); [A Je 408: IM- | 6.54'(ad, J =2.0 and 8.1 Hz, 1 H): 7.11 (1, J = 8.1 Hz, 1 Hy: 7.20 to

I miz 7.33 (m, 3H); 7.63 (broad s, 2 H); 7.74 (d, J = 1.8 Hz, 1 H); 8.38 (d,

J=9.8Hz, 1H) "H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 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, 2H); 7.12 (dd, J = 2.0 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.0 and 47 [Pepe mz P92 IM | 83 Hz, 1 HY, 7.25 (td, J = 2.0 and 10.0 Hz, 1 H); 7.30 (dd. J = 2.0

I m/z and 8.3 Hz, 1H); 7.39 (d, J =9.8 Hz, 1 H); 7.44 (dt, J = 6.9 and 8.3 Hz, 1H); 7.69 (d, J =8.3 Hz, 1 H); 7.90 (d, J = 2.0 Hz, 1 M); 8.49 (d, J =9.8 Hz, 1 H) 'H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 0.89 to 1.01 (m, 48 | M#HI+: miz 529; [M- | 4 H); 2.01 (m, 1H); 7.25 (dd, J = 1.8 and 8.7 Hz, 1 H); 7.37 to 7.47

MH} m/z 527 (m. 3H); 7.58 (d, J =8.7 Hz, 1 H); 7.66 (d, J = 8.6 Hz, 2 H); 7.83 (d,

J=1.8Hz, 1H); 853 (d, J =9.8 Hz, 1 H); 12.69 (broad s, 1 H) fM+H]+: miz 461; [M- 48b | 11 iz 459

Retention time Tr : 48c | (min) = 0.93; [M+H]+: m/z 315 'H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 0.86 to 1.01 (m, 4 H); 1.99 (m, 1 H); 7.24 to 7.35 (m, 3 H); 7.40 (d, J = 9.8 Hz, 1 H);

Iie vz 545: M- | 7 46 (broad s, 1 H): 7.52 (t, J = 8.3 Hz, 1 H); 7.59 (d, J = 8.3 Hz,

J wiz 1H); 7.89 (broad s, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.67 (broad m, 1 H)

"H NMR Spectrum {400 MHz, & in ppm, DMSO-dg): 0.96 (m, 4 H); 1.98 (m, 1H); 2.23 (s, 3H); 7.17 (dd, J =2.0 and 8.6 Hz, 1 H); 7.25 [MeH]+: 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, d= :

Hl 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 Mz, 1H); 8.42 (dd, J =1.7 and 4.6 Hz, 1 H); 8.50 (d, J = 9.8 Hz, 1 H); 12.67 (broad s, 1 H)

Retention time Tr (min} = 0.48; [M+H]+: m/z 408; [M-H]-: m/z 406

Retention time Tr (min} = 0.37; [M+H]+: m/z 262 'H NMR Spectrum (400 MHz, 3 in ppm, DMSO-dg): 0.91 to 1.00 (m, } 4H); 1.9410 2.03 (m, 1 H); 7.11 10 7.25 (m, 3 H); 7.33 (dd, J = 2.0 [eri me 497: IM | and 8.6 Hz, 1H); 7.40 (d, J = 10.0 Hz, 1 Hy: 7.59 (d. J = 8.6 Hz.

I m/z 1H); 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, in ppm, DMSO-dg): 2.14 (s, 3 H); 4.83 (s, 2H); 7.11 (dd, J =2.1 and 8.5 Hz, 1 H); 7.15 (dt, J = 2.1 [M+H}+: m/z 511; [M- | and 8.5 Hz, 1 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, 1 H); 7.36 to 7.46 (m, 2 H); 7.64 (d, J = 8.6 Hz, 1H), 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, & in ppm, DMSO-dg): 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 [MEH]+: m/z 476; [M- | (dd, J =2.0 and 8.3 Hz, 1 H); 7.41 (d, J = 10.0 Hz, 1 H); 7.55 (dd, J

H]-: m/z 474 =2.8and 8.4 Hz, 1 H); 7.60 (d, J = 8.6 Hz, 1 H); 7.86 (d, J = 2.0 Hz, 1H), 8.40 (d, J=29 Hz, 1 H); 8.48 (d, J =9.8 Hz, 1 H); 12.68 (broad s, 1 H)

Retention time Tr (min) = 0.51; [M+H]+: mfz 408; [M-H}-: m/z 406

Retention time Tr (min) = 0.40; [M+H]}+: m/z 262 "H NMR Spectrum (400 MHz, 3 in ppm, DMSO-d): 0.89 to 1.00 (m, . 4H); 1.9310 2.06 (m, 1 H); 2.33 (m, 4 H); 3.45 (s, 2 H); 3.52 to 3.59 54 [eri me O80: IM | (mm, 4 H); 7.11 (d, J = 8.6 Hz, 2 H); 7.17 to 7.26 (m, 3 HY: 7.36 (d. J

I miz =9.8 Hz, 1H); 7.60 (d, J=8.6 Hz, 1 H); 7.83 (d, / = 2.0 Hz, 1 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 432; IM-H]-: m/z

I

Retention time Tr (min) = 0.32; [M+H]+: m/z 346 -- Retention time Tr (min) = 0.3; [M+H]+: 94d m/z 194; [M-M]-: m/z 102

HNMR Spectrum (400 MHz, & in ppm, DMSO-d): 0.95 (m, 4 H}; . . 1.44 (s, 9H); 1.99 (m, 1H), 6.81 (d, J=8.3 Hz, 1 H); 7.23 (t, J = [pais mz S70: IM | 8.3 Hz, 1H); 7.33 (d, J = 9.8 Hz, 3 H); 7.49 (5, 1 HY; 7.61 (d, J =

J mz 8.3 Hz, 1H); 7.95 (s, 1H); 8.44 (d, J = 9.8 Hz, 1 HY; 9.56 (s, 1 H); 12.52 (broad m, 1 H) "HNMR Spectrum (400 MHz, 3 in ppm, DMSO-dg): 0.96 (m, 4 H); . 2.00 (m, 1 H); 7.27 (dd, J = 1.7 and 8.6 Hz, 1 H); 7.39 to 7.47 (m, [eile mz 402 IM- 1 21), 7.62 (d, y= 8.3 Hz, 1 H); 7.72 (dt, J = 2.0 and 8.3 Hz, 1 H),

I miz 7.87 (d, J =2.0 Hz, 1H); 8.50 (d, J = 9.8 Hz, 1 H); 8.53 (d, J = 4.9 Hz, 1H); 8.58 (d, J = 2.9 Hz, 1 H); 12.69 (, 1 H) 'H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 0.90 to 0.99 {m, 4H); 1.55 (broad d, J=9.8 Hz, 1 H); 1.73 (broad d, J = 9.8 Hz, 1H); 1.94 t0 2.05 (m, 1 H); 2.39 (broad d, J = 9.8 Hz, 1 H); 2.70 } ] (broad d, =9.8 Hz, 1 H); 3.41 (broad 5, 1 H); 3.49 (dd, J=15and 57 [Ws ove S72 M- | 76 Hz, 1 Hy; 3.61(d, J = 14.0 Hz, 1 H); 3.67 (4, J = 14.0 Hz. 1 H);

I miz 3.87 (d,J=7.6 Hz, 1H); 4.29 (s, 1 H); 7.10 (dd, J = 2.0 and 8.3 Hz, 1H); 7.2110 7.30 (m, 3 H); 7.31 10 7.39 (m, 2 H); 7.59 (d, J = 8.6 Hz, 1H); 7.84 (d, J=2.0 Hz, 1 H); 8.46 (d, J =9.8 Hz, 1 H); 12.68 (broad m, 1 H)

Retention time Tr (min) = 0.43; [M+H]+: 57b m/z 504; [M-H}-: m/z 502

Retention time Tr 57¢ | (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, 3 in ppm, DMSO-dg): 0.93 tJ = 7.2 Hz, 6 H); 0.95 (m, 4 H); 1.97 f0 2.04 (m, 1 H); 2.42 (q, J = i 7.2 Hz, 4H); 3.45 (s, 2 H); 7.08 (broad dd, J = 2.0 and 8.2 Hz, 1 H); [Hl Hi 240 IM | 7719 167.26 (m, 2 H); 7.28 (dd, J = 2.0 and 6 Hz, 1 H); 7.83 (, J =

I m/z 8.2 Hz, 1H); 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, 1H); 8.46 (d, J = 9.8 Hz, 1 H); 12.68 {broad m, 1H)

- WO 2010/089507 ~~. PCT/FR2010/050178 93

Retention time Tr (min) = 0.46; {M+H]+: mfz 478; [M+2H]2+: m/z 232.5 (base peak}; [M-H}-: m/z 476

Retention time Tr (min) = 0.40; {IM+H]+: m/z 332

Retenticn time Tr (min) = 0.22; {M+H]+: m/z 180 'H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 1.00 (t, J = . } | 7.2Hz, 6H); 2.62 (q, J =7.2 Hz, 4 H); 3.40 (s, 2 H); 7.09 to 7.25 [ip mz S42: 1 (m, 3H); 7.33 (dd, J =2.0 and 8.6 Hz, 1 HY; 7.41 (d. J = 0.8 He,

I miz 1H): 7.60(d, J=8.6Hz 1H); 793(d, J=2.0Hz, 1 H); 8.52 (d, J = 9.8 Hz, 1 H); 11.79 (broad m, 1 H) 'H NMR Spectrum (400 MHz, & in ppm, DMSO-d): 4.19 (broad s, 2H); 5.49 (broad s, 1 H); 7.11 (broad dd, J = 2.2 and 8.3 Hz, 1 Hy; . . 7.16 (,J=1.0 and 2.2 and 8.3 Hz, 1 H); 7.25 (td, J = 2.2 and per Jc 40% IM | 10.0 Hz, 1 H); 7.31 (dd, J = 2.0 and 8.6 Hz, 1 H): 7.39 (d, J =

I miz 9.8 Hz, 1 H); 7.42 (dt, J =6.9 and 8.3 Hz, 1 H); 7.61 (d, J = 8.6 Hz, 1H); 7.92 (d, J=2.0 Mz, 1 H); 8.49 (d, J =9.8 Hz, 1 H); 12.09 (broad m, 1 H) : 'H NMR Spectrum (400 MHz, 6 in ppm, DMSO-dg): 0.26 (m, 2 H); 0.39 (m, 2 H); 1.61 (m, 1 H); 2.43 to 2.60 (partially masked m, 8 HY); i . 3.31 (broad s, 2 H); 7.11 (dd, J =2.2 and 8.3 Hz, 1 H); 7.16 (df, J = [eT vz O75 IM | 92 and 8.3 Hz, 1H); 7.25 (td, J = 2.2 and 10.0 Hz, 1 H); 7.31 (dd, J

I: mz =2.0and 8.6 Hz, 1H); 7.39 (d, J=9.8 Hz, 1 H); 7.43 (dt, J = 6.9 and 8.3 Hz, 1H), 7.61(d, J=8.6 Hz, 1 H); 7.92 (d, J = 2.0 Hz, 1 HY: 8.49 (d, J =9.8 Hz, 1 H); 12.07 (broad m, 1 H) "H NMR Spectrum (400 MHz, § in ppm, DMSO-d): 1.00 (t, J = . . 6.8 Hz, 3 H); 2.28 to 2.62 (partially masked m, 10 H); 3.34 (s, 2 HY; [rat oe S83: IM | 7110 t0 7.26 (m, 3 H); 7.34 (dd, J = 2.0 and 8.6 Hz, 1 1); 7.41 d, J

J: m/z =9.8Hz, 1H), 7.61 (d, J=8.6 Hz, 1 H); 7.94 (d, J = 2.0 Hz, 1 H); 8.52 (d, J=9.8 Hz, 1 H); 11.88 (broad m, 1 H) 'H NMR Spectrum (400 MHz, & in ppm, DMSO-d): 0.23 to 0.30 (m, [M+H]+: m/z 595; 2H), 0.35 to 0.44 (m, 2 HY; 1.61 (m, 1 H); 2.40 to 2.60 (partially [M+2H]2+: m/z 298 masked m, 8 H); 3.31 (s, 2H); 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, 1 H); 7.61 (d, J = 8.6 Hz, m/z 593 1H) 7.94 (d, J=1.7 Hz, 1H); 8.52 (d, J =9.8 Hz, 1 H); 12.10 {broad m, 1 H) :

Retention time Tr {min} = 0.1; [M+H]+: m/z 185 64 | M+H]+: m/z 520; [M- | 'H NMR Spectrum (400 MHz, § in ppm, DMSO-dg): 0.93 (t, J =

H]-: m/z 518 7.1 Hz, 6H); 2.19 (s, 3H), 2.43 (gq, J =7.0 Hz, 4 H); 3.46 (s, 2H); 7.08 (dd, J =1.7 and 8.1 Hz, 1 H); 7.21 to 7.38 (m, 5 H); 7.58 (d, J =8.3Hz, 1H); 7.86 (d, J = 1.7 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.37 (broad m, 1 H) "HNMR Spectrum (400 MHz, & in ppm, DMS0O-dg): 0.93 tJ= 7.1 Hz, 6 H); 2.43 (q, J =7.1 Hz, 4 H); 3.37 (s, 3 H); 3.46 (s, 2 H); [eH mz S90: IM | 419 (s, 2 HY: 7.0310 7.10 (m, 1 H); 7.21 10 7.34 (m. 4 HY: 7.36 d. J m/z =9.8 Hz, 1 H); 7.60 (d, J = 8.6 Hz, 1 H); 7.87 (d, J = 1.7 Hz, 1 H); 8.46 (d, J = 9.8 Hz, 1 H); 12.34 (broad m, 1 H) "H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 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, 1H); 2.70 (dd, J =1.7 and 9.9 Hz, 1 H); 3.37 (s, 3 H); 3.41 [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, 1 H); 7.03 to 7.13 (m, 1 H); 7.22 to 7.34 (m, 4 H); 7.36 (d, J =9.8 Hz, 1 H); 7.61 (d, J = 8.3 Hz, 1 H); 7.87 (d,

J=1.7 Hz, 1H); 8.46 (d, J = 9.8 Hz, 1 H); 12.38 (broad m, 1 H) 'H NMR Spectrum (400 MHz, 3 in ppm, DMSQ-ds): 4.53 (m, 2 H); 67 | M*HI*: 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); 7.22

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 =0.8Hz, 1 H)

Retention time Tr 67b | (min) = 0.41; [M+H]+: m/z 227 'H NMR Spectrum (400 MHz, & in ppm, DMSO-d): 1.91 to 2.05 (m, 1H); 2.08 10 2.20 (m, 1 H); 2.53 (m, 4 H); 3.34 (s, 2 H); 3.58 to 3.63

IM+H]+: m/z 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 1H), 7.47 (dd, J =2.1 and 8.6 Hz, 1 H); 7.70 (d, J = 8.6 Hz, 1 H); 8.12(d, J=2.1 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 12.16 (broad m, 1 H) "H NMR Spectrum (400 MHz, & in ppm, DMSO-de): 2.53 (m, 4 H) 3.32 (s, 2H); 3.56 t0 3.63 (m, 4 H), 7.12 to 7.24 (m, 3 H); 7.32 (dd, [ir a 596: IM- | J'=2.0'and 8.6 Hz, 1 H), 7.41 (d, J = 90.8 Hz, 1 Hy; 7.58 (d, J =

J miz 8.6 Hz, 1H); 7.92 (d, J =2.0 Hz, 1 H); 8.51 (d, J = 9.8 Mz, 1 H); 10.47 to 13.46 (very broad m, 1 H) 'H NMR Spectrum (400 MHz, 3 in ppm, DMSO-dg): 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 . =7.1 Hz, 4 H), 3.40 (s, 2 H); 3.63 fo 3.84 (m, 4 H); 5.29 (m, 1 H); 70 | [M+H]+: m/z 500 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=8.3Hz, 1H); 812(d, J=2.0Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H); 12.11 (broad m, 1 H) "H NMR Spectrum (400 MHz, 5 in ppm, DMSO-dg): 0.98 (i, J = [M+H]+: m/z 541; 7.1 Hz, 3H); 1.9210 2.03 (m, 1 HY, 2.10 to 2.22 (m, 1 H); 2.31 (q, J 71 | M2HIZ#: m/z 271 | 27 4 Bz, 2 HY; 2.22 to 2.48 (partially masked broad m, 8 H); 3.30 (base peak); IM-HI-: | (partially masked s, 2 H); 3.64 to 3.84 (m, 4 HY; 5.30 (m, 1 H); 7.08 m/z 539 (d, J=9.8Hz, 1H); 7.47 (dd, J=2.0 and 8.6 Hz, 1 H); 7.69 (d, J = 8.6 Hz, 1H); 8.12 (d, J = 2.0 Hz, 1 H); 8.31 (d, J = 9.8 Hz, 1 H):

[Tween : "H NMR Spectrum (400 MHz, 8 in ppm, DMSO-dg): 0.22 to 0.30 (m, } 2H); 0.36 10 0.43 (m, 2 H); 1.54 to 1.64 (m, 1 H); 1.90 to 2.03 (m,

Mepis roa 1H); 2.06 t0 2.19 (m, 1 H); 2.40 to 2.60 (partially masked broad m, 72 ba e Kk): M-H]-: 8 H); 3.36 (partially masked m, 2 H); 3.64 to 3.83 (m, 4 H); 5.30 (m, ( oak: IMF 1 H)7.08 (d, J = 9.8 Hz, 1 H); 7.47. (dd, J = 2.0 and 8.6 Ha, 4 HY; m 7.69 (d, J=8.6Hz, 1H);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) 'H NMR Spectrum (400 MHz, § in ppm, DMSO-ds): 0.90 to 0.98 (m, } im. | 4H): 1.94 102.04 (m, 1 H); 4.47 (m, 2 H); 4.71 (m, 2 H): 5.39 to 73 [ae Ie he 44% IM 5.48 (m, 1 Hy, 7.19 (d, J = 9.8 Hz, 1 Hy; 7.44 (dd, J = 2.0 and miz 8.6 Hz, 1H). 7.69 (d, J = 8.6 Hz, 1 MH); 8.05 (d, J =2.0 Hz, 1 H); 8.37 (d, J = 9.8 Hz, 1H); 12.68 (broad m, 1 H) : "H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 0.97 {t, J = [M+H]+: m/z 527; 7.1Hz, 3H), 2.30 (q, J =7.1 Hz, 2 H); 2.32 t0 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 HY); (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, 1H); 7.70 (d, J = 8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, 1 H); 8.38 (d, J = 9.8 Hz, 1 H); 12.03 (broad m, 1 H)

H NMR Spectrum (400 MHz, & in ppm, DMSO-dg): 0.23 to 0.29 (m, [M+H]+: m/z 539; 2H); 0.35 10 0.42 (m, 2 H); 1.60 (m, 1 H); 2.40 to 2.60 (partially 75 IM+2H]2+: m/z 270 masked broad m, 8 H); 3.31 (s, 2 H); 4.46 (m, 2 H); 4.70 (m, 2 HY; (base peak); [M-H]-: | 5.42 (m, 1H); 7.20 (d, J = 9.8 Hz, 1 H); 7.44 (dd, J =2.0 and m/z 537 8.6 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1 H); 8.06 (d, J = 2.0 Hz, 1 H); 8.38 (d, J = 9.8 Hz, 1H); 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 Excipient for a finished tablet weighing .......... 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

Example 77: Pharmaceutical composition

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).

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.

Pharmacological section: Te

Experimental protocols

I) Expression and Purification of MET, cytoplasmic domain :

Expression as Baculovirus:

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

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

Purification:

The cell pellets are resuspended in lysis buffer (buffer A [50 mM HEPES, pH 7.5, 250 mM NaCl, Glycerol 10%, TECP 1 mM ]; + Roche Diagnostics EDTA- free protease inhibitor cocktail, ref. 1873580), stired 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°C with nickel chelate resin (His-Trap 6 Fast Flow ™, GE HealthCare). After washing 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 ultrafiltration (10 kDa cut-off) and injected onto an exclusion chromatography column (Superdex ™ 200, GE HealthCare) equilibrated with buffer A.

After enzymatic cleavage of the Histidine tag, the protein is reinjected onto a new IMAC Nickel Chelate chromatography column (His-Trap 6 Fast Flow ™

GE HealthCare) equilibrated with buffer A. The fractions eluted with a gradient of buffer B and containing the protein of interest after electrophoresis (SDS PAGE) are finally pooled and stored at -80°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 mM, and NazVO, 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 + NazVO4 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) and by peptide mapping. : il) Tests Aand Band C

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

In a final volume of 50 pi of enzymatic reaction, MET 5 nM final is incubated in the presence of the test molecule (for a final concentration range of 0.17 nM to 10 uM, 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 uM and MgCl, 5 mM. After incubation for 10 minutes at room temperature, the reaction is stopped with a mix of 30 ul 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, on areader for the TRACE / HTRF technique and the percentage of inhibition is calculated from the 665/620 ratios.

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 (pppY1230,1234,1235) a) Cell lysates: Inoculated MKN45 cells in 96-well plates (Cell coat BD polylysine) to a rate of 20 000 cells/well in 200 yl 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 with the same amount of final DMSO.

Product dilution: Stock at 10 mM in pure DMSO - range from 10 mM to 30 MM “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 (200 pi): final range from 10 000 to 30 ni.

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

NaCl, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS, 0.5% deoxycholate, 20 mM NaF, 2 mM NazVO,;, 1 mM PMSF and anti protease cocktail.

The 100 pl of lysates are transferred into a V-bottomed polypropylene plate and ELISA is performed directly or the plate is frozen at —-80°C.

b) ELISA PhosphoMET BioSource Kit KHO0281

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 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.

Rinse the wells four times with 400 HL 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 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. 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% COj: HCT116 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 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 pi 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.

After 72 hours of treatment, add 10 ul 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.

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 uM and : 10 especially less than 1 uM. :

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 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 uM and the ++ sign corresponds to less than 1 uM.

Table of pharmacological results:

Eemumber [eeA [Ge Jwwo °c. = se = cm IE - er eT

FT ee ve oI TET er wT

©

Claims

CLAIMS 1) Products of formula (I): Nx A ] HL \ N Rb " \ \ w (I) Ra in which ~~ represents a single or double bond: : Rb represents a hydrogen atom or a fluorine atom: Ra represents a radical -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 halogen atom;

Rc represents an optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl radical;

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 which R represents:

- a cycloalkyl radical or an alkyl radical, optionally substituted with a

: ~ radical NR3R4, alkoxy, -O-cycioalkyl, -O-CO-R5, hydroxyl, phenyl,

heteroaryl or heterocycloalkyl, which are themselves optionally substituted;

- an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxy!

or heterocycloalkyl; a radical O-phenyl or a radical O-(CH2)n-phenyl,

with phenyl optionally substituted and n represents an integer from 1 to

- 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, 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 attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from O, 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;

- 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 radicals: optionally substituted hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIk, N(Alk)2, phenyl; 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 O, S, N and

NH, with the optional S possibly being in the form SO or SO2: this radical, including the possible NH it contains, being optionally substituted;

all the alkyl, alkoxy, -O-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 chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy,

-O-CO-R5, -OR5 -COOH, COORS5, -CONH2, CONHRS5, NH2, NHRS5, NRS5RS’, -NH-CO-R5, -NHCOORS and alkyl, heterocycloalkylalkyl, cycloalkyl,

heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl, 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 1 to : 4 carbon atoms, NH2, NHalk and N(alk)2; all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined above being furthermore optionally substituted with a radical Si(alk)3; R5 and R®’, 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:

. it being understood that: i) when Rb represents hydrogen and Z represents a single bond, then Re 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; 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 (1).
2) Products of formula (I) as defined in Claim 1, 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; 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 which R represents:

- a cycloalkyl radical or an alkyl radical, optionally substituted with a radical NR3R4, alkoxy, -O-cycloalkyl, -O-CO-R5, hydroxyl, phenyl, heteroaryl or heterocycloalkyl, which are themselves optionally substituted;

- an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or heterocycloalkyl; a radical O-phenyl or a radical O-(CH2)n-phenyl, with phenyl! optionally substituted and n represents an integer from 1 to

4: - 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, 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 attached, a 3- to 10-membered cyclic radical optionally containing one or more other heteroatoms chosen from O, 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; 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 radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAIK, 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 O, 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, -O-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 chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkoxy, -0-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 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;

RS represents an alkyl or cycloalkyl radical containing not more than 6 carbon atoms;

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).
3) Products of formula (1) as defined in any one of the claims, 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 alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:

- a cycloalkyl radical or an alkyl radical optionally substituted with a radical NR3R4, alkoxy, -O-cycioalkyl, -O-CO-R5, hydroxyl, phenyl or heterocycloalkyl, which are themselves optionally substituted;

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

- 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 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; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom, an alkyl radical or a heterocycloalkyl radical, : 10 optionally substituted with one or more radicals, which may be identical or different, chosen from alkoxy, heteroaryl or heterocycloalkyl radicals or NH2, NHAIk, N(AIk)2, 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 O, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; all the alkyl, alkoxy, -O-cycloalkyl, cycloalkyl, heterocycloalkyl and phenyi radicals, 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, defined above, being optionally substituted with one or more radicals chosen from halogen atoms and the following radicals: hydroxyl, alkoxy, O-cycloalkyl, NH2, NHalk, N(alk)2 and alkyl, heterocycioalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyi 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 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 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).
4) Products of formula (I) as defined in any one of the claims, 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 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 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 cycloalky] 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 NR3R4, or alternatively R1 and R2 form, with the nitrogen atom to which they are aftached, a cyclic radical optionally containing one or more other heteroatoms chosen from O, S, N and NH, this radical, including the possible NH it contains, being optionally substituted; with NR3R4 such that R3 and R4, which may be identical or different, represent a hydrogen atom or an alkyl radical or 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 O, 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 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, -O-cycloalkyl, NH2, NHalk, N(alk)2 and alkyl and phenyl radicals, the latter radicals themselves being 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 diasterecisomeric 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). N
5) Products of formula (I) as defined in any one of the claims, 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 (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 (1).
6) Products of formula (I) as defined in any one of the claims, 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 (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 (1). oo
7) Products of formula (1) as defined in any one of the claims, corresponding to formula (la) or (Ib): a N H 3 JOG, \ NRE Ra (Ia) SS S A O T, \ MN Rb 5 (Ib) Ra in which = , Ra, Rb and W are chosen from the meanings indicated in any one of the other claims, 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 formula (la) and (Ib).
8) Products of formula (1) as defined in any one of the claims, in which —— represents a double bond, corresponding to the products of formula (I): NX AH ® JC N Rb N w \ a) 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 (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 (1).
9) Products of formula (i) as defined in any one of the claims, in which =~ represents a double bond, corresponding to the products of formula (17a): NS N H ! N To NN Rb (I"a) Ra in which Ra, Rb and W are chosen from any one of the meanings indicated hereinabove or hereinbelow, the said products of formula (Ia) 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”a).
10) Products of formula (I) as defined in any one of the claims, in which — represents a double bond, corresponding to the products of formula (Ib): Ne SS Ss H "\ I To - N Cpe " (i"b) Ra in which Ra, Rb and W are chosen from any one of the meanings indicated : hereinabove or hereinbelow, : 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 (Ib).
11) Products of formula (I) as defined in any one of the claims, in which — represents a single or double bond Ra represents a radical -O-phenyl optionally substituted with one or more halogen atoms; Rb represents a hydrogen atom; X represents S; 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 NR1R2 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 represents an alkyl radical optionally substituted with a heterocycloalkyl radical; | : 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 (1).
12) Products of formula (I) as defined in any one of the claims, corresponding - to the following formulae: - 6-[(6-phenoxy[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyi}-1 ,3-benzothiazol-2- amine N - N-{6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo- thiazol-2-yl}cyclopropanecarboxamide - N-{6-[(6-phenoxy[1,2,4]iriazolo[4,3-b]pyridazin-3-yl)sulfanyl}-1,3-benzo- thiazol-2-yllacetamide - 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-yljsulfanyl}-1,3- benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyllurea - 6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl}-1,3- benzothiazol-2-amine - N-(6-{[6-(3-fluorophenoxy)[1,2,4ltriazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3- benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide - N2,N2-diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4ltriazolo[4,3-b]pyridazin-3- ylJsulfanyi}-1,3-benzothiazol-2-yl)glycinamide - N2-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2 4ltriazolo[4,3-b]pyridazin-3- yllsulfanyl}-1,3-benzothiazol-2-yl)glycinamide - N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,41triazolo[4,3-b]pyridazin-3- yl}sulfanyf)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide - N-(6-{[6-(3-fluorophenoxy)[1 ,2,4ltriazolof4,3-b]pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)acetamide - N-(6-{[6-(3-fluorophenoxy)[1.2 4ltriazolo[4,3-b]pyridazin-3-yljsuifany(}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - 1-(6-{[6-(4-fluorophenoxy)[1 ,2,4]triazolof4,3-b]pyridazin-3-ylJsulfanyl}-1,3- benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethylJurea - 1-(6-{[6-(3-flucro-4-methylphenoxy)[1 2 4]triazolof4,3-b]pyridazin-3-yl]sulf- anyl}-1,3-benzothiazol-2-yl)-3-[2-(morphoiin-4-yl)ethyljurea

- 6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-yiJsulf- anyl}-1,3-benzothiazol-2-amine - 6-{[6-(4-fluorophenoxy)[1 2,4ltriazolo[4,3-blpyridazin-3-ylsulfanyl}-1,3- benzothiazol-2-amine © 5 1-[2-(morpholin-4-yl)ethyi]-3-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1 2,4] - triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1,3-benzothiazol-2-yhurea - 1-[6-({8-[(1-ethylpiperidin-4-yl)oxy][1 2,4triazolo[4,3-b]pyridazin-3-yl}sulf- anyl)-1,3-benzothiazol-2-yi]-3-[2-(morpholin-4-yl)ethyl]urea - N-(8-{[6-(tetrahydro-2H-pyran-4-yloxy)[1 ,2,4ltriazolo[4,3-b]pyridazin-3-yl]sulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(4-fluorophenoxy)[1 ,2,4]triazolo[4,3-blpyridazin-3-ylJsulfanyl}-1,3-

. benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3-fluoro-4-methylphenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yl]sulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-[6-({6-[(1-ethylpiperidin-4-yl)oxy][1,2,4]triazolo[4,3-b] pyridazin-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-yllsulfanyl}-1,3-benzothiazol-2-yl)urea - 1-(6-{[6-(1,3-benzodioxol-5-yloxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yiJsulf- anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyllurea - 1-(6-{[6-(3,4-dichlorophenoxy)[1 .2,4]triazolo[4,3-b]pyridazin-3-y{lsulfanyl}- 1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yhethyllurea - 6-{[6-(3,4-dichlorophenoxy)[1 2 4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-amine - 6-{[6-(tetrahydrofuran-3-yloxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}- 1,3-benzothiazol-2-amine - 1-(6-{[6-(1H-indol-6-yloxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyi}-1,3- benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea - N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 ,2,4}triazolo[4,3-b]pyridazin-3-yisulfanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide

- N-(6-{[6-(1,3-benzodioxol-5-yloxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yljsulf- anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yllsulfanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(1 H-indol-6-yloxy)[1,2 4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3- benzothiazol-2-yl)cyclopropanecarboxamide - N-(6-{[6-(3-flucrophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}-1,3- benzothiazol-2-yl)cyclobutanecarboxamide - N-(6-{[6-(3-fluorophenoxy)[1 2 4triazolo[4,3-b]pyridazin-3-yllsulfanyl}-1,3- benzothiazol-2-yl)-N2 N2-dimethylglycinamide - 2-ethoxy-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolof4,3-b]pyridazin-3-ylJsulf- anyl}-1,3-benzothiazol-2-yl)acetamide - 2-(cyclohexyloxy)-N-(6-{[6-(3-fluocrophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3- yllsuifanyl}-1,3-benzothiazol-2-yl)acetamide - 6-{[6-(pyridin-3-yloxy)[1 2 ,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo- thiazol-2-amine - 6-({6-[3-(triflucromethoxy)phenoxy][1,2,4ltriazolo[4, 3-b]pyridazin-3-yl}sulf- ‘anyl}-1,3-benzothiazol-2-amine : - 2-methylpropan-2-yl [3~({3-[(2-amino-1,3-benzothiazol-6-yl)sulf- anyll[1,2,4]triazolo[4,3-b]pyridazin-6-yl}oxy)phenyllcarbamate - N-(6-{[6-(pyridin-3-yloxy)[1 2 ,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3- benzothiazol-2-yl)cyclobutanecarboxamide - N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo{4,3-b]pyridazin-3-yl]sulfanyl}-1,3- benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide - Ncyclohexyl-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)[t 2,4]triazolo[4,3-b]pyridazin-3-yl}sulfanyi}-1,3- : benzothiazol-2-yl)-N*methyl-N2-[2-(morpholin-4-yi)ethyllglycinamide - 2-(4-ethylpiperazin-1-yl)-N-(6-{[6-(3-fluorophenoxy)[1 .2,4]triazolo[4,3-b]- pyridazin-3-yllsulfanyl}-1,3-benzothiazol-2-yl)acetamide

- 6-{[6-(3,5-difluorophenoxy)[1 .2,4]triazolo[4,3-blpyridazin-3-yiisulfanyl}-1,3- benzothiazol-2-amine - 6-{[6-(3-aminophenoxy)[1 2 ,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1,3- benzothiazol-2-amine - N-(6-{[6-(3-fluorophenoxy)[1 2,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1,3- benzothiazol-2-yl)-N~2~-(tetrahydro-2H-pyran-4-yl)glycinamide - N-[6-({6-[4-(trifluoromethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- anyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide - N-[6-({6-[3-(trifluoromethoxy)phenoxy][1 ,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf- 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-yl]cyclopropanecarboxamide : - N-(6-{[6-(3,5-difluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-y{sulfanyl}- 1,3-benzothiazol-2-yl)cyclopropanecarboxamide - 2-[(6-{[6-(3-fluorophenoxy)[1,2,4ltriazolo[4,3-b]pyridazin-3-ylisulfanyl}-1 3- benzothiazol-2-ylJamino}-2-oxoethyl 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-yljcyclopropanecarboxamide - N-[6-({6-[4-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3- ylsulfanyl)-1,3-benzothiazol-2-yllcyclopropanecarboxamide - 2-methylpropan-2-yl ~~ (3-{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzo- thiazol-6-yl}sulfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-ylloxy}phenyl)carbamate - N-(6-{[6-(pyridin-3-yloxy)[1 .2,4}triazolo[4,3-b]pyridazin-3-yljsulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - N-{6-[(6-{3-[(1S,4S)-2-0oxa-5-azabicyclo[2,2,1 Ihept-5-yimethyl]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)sulfanyf]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide - N-(6-{[6-(3,5-diflucrophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yljsulfanyl}- 1,3-benzothiazol-2-yl)-N2,N2-diethylglycinamide :

- N-(6-{[6-(3-fluorophenoxy)[1 2 ,4]triazolo[4,3-b]pyridazin-3-ylJsulfanyl}-1 3- benzothiazol-2-yl}-2-hydroxyacetamide : - 2-(4-cyclopropylpiperazin-1 -y1)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4, 3- blpyridazin-3-yllsulfanyf}-1,3-benzothiazol-2-yl)acetamide - N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}- 1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide - 2-(4-cyclopropylpiperazin-1 -yI}-N-(6-{[6-(3,5-diflucrophenoxy)[1,2 4]triazolo-

[4.3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide - N-{6-{(6-{3-[(diethylamino)methyllphenoxy}[1 2,4]triazolo[4,3-b]pyridazin-3- : 10 yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide - N-{6-[(6-{3-[(diethylamino)methylphenoxy}[1 2,4]triazolo[4,3-b]pyridazin-3- yh)sulfanylj-1,3-benzothiazol-2-yl}-2-methoxyacetamide - 2-methoxy-N-{6-[(6-{3-[(1 S,48)-2-0xa-5-azabicyclo[2,2, 1]hept-5-yimethyl]- 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-yljsulfanyl}-1,3-benzo- thiazol-2-amine : - 2-(morpholin-4-yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1 2 4]triazolo[4,3-b]- pyridazin-3-yljsulfanyl}-1,3-benzothiazol-2-yl)acetamide - N-+(6-{[6-(3,5-difluorophenoxy)[1 .2,4]triazolof4,3-b]pyridazin-3-yllsulfanyl}- 1,3-benzothiazol-2-yl)-2-(morpholin-4-ylacetamide - NZ N2-diethyl-N-(6~{[6-(tetrahydrofuran-3-yloxy)[1 .2,4]triazolo[4,3-b]pyridazin- 3-yllsulfanyl}-1,3-benzothiazol-2-yl)glycinamide - 2-(4-ethylpiperazin-1-yl)-N-(6-{[6-(tetrahydrofura n-3-yloxy)[1,2,41triazolo[4,3- b]pyridazin-3-ylJsulfanyl}-1,3-benzothiazol-2-yl)acetamide - 2-(4-cyclopropylpiperazin-1-yl)-N-(6-{[6-(tetrahydrofu ran-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-ylsulfanyl}-1,3- benzothiazol-2-yl)cyclopropanecarboxamide - 2-(4-ethylpiperazin-1-yl)-N~(6-{[6-(oxetan-3-yloxy)[1 ,2,4]triazolo[4,3-b]- pyridazin-3-yljsulfanyl}-1,3-benzothiazol-2-yl)acetamide

- 2~(4-cyclopropylpiperazin-1-yl)-N-(6-{[6-(oxetan-3-yloxy)[1 2 4ltriazolo[4,3- blpyridazin-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).
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 the other claims, in which A represents S.
16) As medicaments, the products of formula (I) 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).
17) As medicaments, the products of formula (I) 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 of the products of formula (1) as defined in any one of Claims 1 to 12, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable support.
19} Use of the products of formula (I} 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.
22) Use of a product of formula (I) as defined in any one of Claims 1 to 12, for the preparation of a medicament for treating or preventing a disease chosen 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.
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.
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,

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 1 to 12, for the preparation of medicaments for cancer chemotherapy, alone or in combination.
29) Products of formula (I} 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.
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:

HS S, H HS S H LH 0A 5 Rb N J ° Rb N rN " 6 m2 © R HS S.

H XE ype m3 © Rb N N in which the groups CONR1R2, CO2R6 and COR?7, 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 WH.