DERIVATIVES OF 6-(6-O-SUBSTITUTED-TRIAZOLOPYRIDAZINE-SULFANYL)
BENZOTHIAZOLES AND BENZIMIDAZOLES, PREPARATION THEREOF, USE
THEREOF AS DRUGS, AND USE THEREOF AS MET INHIBITORS
The present invention relates to novel 6-(6-O-substituted triazolopyridazine-
sulfanyl) benzothiazole and benzimidazole derivatives, to a process for
preparing them, to the novel intermediates obtained, to their use as
medicaments, to pharmaceutical compositions containing them and to the
novel use of such 6-triazolopyridazine-sulfanyl benzothiazole and
benzimidazole derivatives.
The present invention more particularly relates to novel 6-(6-0-substituted
triazolopyridazine-sulfanyl) benzothiazole and benzimidazole derivatives with
anticancer activity, via modulation of the activity of proteins, in particular
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 attractive targets for treating certain
diseases. Examples that may especially be mentioned include angiogenesis
and control of the cell cycle and also that of cell proliferation, in which kinase
proteins may play an essential role. These processes are especially essential
for the growth of solid tumours and also other diseases: in particular,
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 receptor,
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
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):

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 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 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 0, 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, NHAlk, N(Alk)2 and phenyl, which is
itself optionally substituted; or alternatively R3 and R4 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic
radical optionally containing one or more other heteroatoms chosen
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, 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, COOR5, -CONH2, CONHR5, NH2, NHR5,
NR5R5', -NH-CO-R5, -NHCOOR5 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 R5', which may be identical or different, represent an alkyl or
cycloalkyl radical containing not more than 6 carbon atoms;
alk represents an alkyl radical containing not more than 4 carbon atoms;
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 (I).
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 Rc
represents optionally substituted aryl;
Rb represents a hydrogen or fluorine atom;
X represents S, SO or SO2;
A represents NH or S;
W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally
substituted with alkoxy, heterocycloalkyl or NR3R4; 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, NHAlk, N(Alk)2
or phenyl, optionally substituted; or alternatively R3 and R4 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from 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,
-O-CO-R5, -OR5, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-
heteroaryl radicals, such that in the latter radicals, the alkyl, cycloalkyl,
heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally
substituted with one or more radicals chosen from halogen atoms and the
following radicals: hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4
carbon atoms, NH2, NHalk and N(alk)2;
R5 represents an alkyl or cycloalkyl radical containing not more than 6 carbon
atoms;
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
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
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 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,
NHAlk, N(Alk)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 0, 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 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).
As regards the cyclic radicals that can be formed by R1 and R2 or R3 and R4
with the nitrogen atom to which they are attached, these radicals optionally
containing one or more other heteroatoms chosen from 0, S, N and NH, with
the optional S possibly being in the form SO or S02; these radicals, including
the optional NH they contain, may thus be optionally substituted especially
with a radical chosen from alkyl, alkoxy, cycloalkyl and heterocycloalkyl,
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 (I):

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 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, 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,
COOR5, -CONH2, CONHR5, NH2, NHR5, NR5R5', -NH-CO-R5 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,
all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined
above being furthermore optionally substituted with a radical Si(alk)3;
R5 and R5', which may be identical or different, represent an alkyl or
cycloalkyl radical containing not more than 6 carbon atoms;
alk represents an alkyl radical containing not more than 4 carbon atoms;
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 (I).
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 Rc
represents optionally substituted aryl;
Rb represents a hydrogen or fluorine atom;
X represents S, SO or SO2;

A represents NH or S;
W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally
substituted with alkoxy, heterocycloalkyl or NR3R4; 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 0, S, N and NH, this radical,
including the possible NH it contains, being optionally substituted;
with R3 and R4, which may be identical or different, representing a hydrogen
atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl
radical, 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, -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;
R5 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 (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
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;

- 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 or an alkyl radical or alternatively R3 and R4 form,
with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic
radical optionally containing one or more other heteroatoms chosen from 0,
S, N and NH, this radical, including the possible NH it contains, being
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
NR3R4, or alternatively R1 and R2 form, with the nitrogen atom to which they
are attached, a cyclic radical optionally containing one or more other
heteroatoms chosen from 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
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 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 (I).
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 (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).
One subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow corresponding to formula (la) or (lb):



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 (lb) being in any possible racemic,
enantiomeric or diastereoisomeric isomer form, and also the addition salts
with mineral and organic acids or with mineral and organic bases of the said
products of formulae (la) and (lb).
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'):

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 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 represents a double bond,
corresponding to the products of formula (I"):


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 (I).
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 (la'):

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 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).

A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which represents a double bond,
corresponding to the products of formula (l"a):

in which Ra, Rb and W are chosen from any one of the meanings indicated
hereinabove or hereinbelow,
the said products of formula (l"a) being in any possible racemic, enantiomeric
or diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (l"a).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which represents a single bond,
corresponding to the products of formula (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 (l"b):

in which Ra, Rb and W are chosen from any one of the meanings indicated
hereinabove or hereinbelow,
the said products of formula (l"b) being in any possible racemic, enantiomeric
or diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (l"b).
In the products of formula (I) 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, isohexyl and also heptyl, octyl, nonyl and decyl
radicals, and also the linear or branched positional isomers thereof: alkyl
radicals containing from 1 to 6 carbon atoms and more particularly alkyl
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;
- 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,
tetrahydrothienyl, 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(O) 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, pyrrolyl,
pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, pyridyl such as 2-pyridyl, 3-pyridyl
and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl,
isothiazolyl, diazolyl, thiadiazolyl, thiatriazolyl, oxadiazolyl, isoxazolyl such as
3- or 4-isoxazolyl, furazanyl, free or salified tetrazolyl, all these radicals being
optionally substituted, among which more particularly are thienyl radicals such
as 2-thienyl and 3-thienyl, furyl such as 2-furyl, pyrrolyl, pyrrolinyl, pyrazolinyl,
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, benzoxazolyl, thionaphthyl, indolyl, 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 pyrazolyl
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 salification compounds, mineral bases such as, for example, one
equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium,
or organic bases, for instance methylamine, propylamine, trimethylamine,
diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)-
aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine,
morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methyl-
glucamine,
- among the esterification compounds, alkyl radicals to form alkoxycarbonyl
groups, for instance methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or
benzyloxycarbonyl, these alkyl radicals possibly being substituted with
radicals chosen, for example, from halogen atoms and hydroxyl, alkoxy, acyl,
acyloxy, alkylthio, amino and aryl radicals, for instance in chloromethyl,
hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl,
dimethylaminoethyl, benzyl or phenethyl groups.
The addition salts with mineral or organic acids of the products of formula (I)
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, α,β-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 cyclohexanes 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 stereoisomerism exists, due to
the various spatial arrangements of fixed substituents, either on double
bonds, or on rings, which is often referred to as geometrical isomerism or cis-
trans isomerism. The term stereoisomers is used in the present patent
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 heterocycloalkyl radicals, i.e. one or more
radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo,
alkoxy, NH2; NHalk, N(alk)2, and alkyl, heterocycloalkyl, CH2-
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 azepanyl,
morpholinyl, pyrrolidinyl, piperidyl and piperazinyl radicals, which are
themselves optionally substituted, as defined hereinabove or hereinbelow.
When NR1R2 or NR3R4 forms a ring as defined above, such an amine ring
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 (I) 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.

A subject of the present invention is especially the products of formula (I) 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
CF3, 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 (I) 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;
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 (I).
A subject of the present invention is thus the products of formula (I) 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-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
N-(6-{[6-(3-fIuorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide
- N2,N2-diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
- N2-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
- N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
- N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- 1 -(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]ltriazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-amine
6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine

1 -[2-(morpholin-4-yl)ethyl]-3-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)urea
1 -[6-({6-[(1 -ethylpiperidin-4-yl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf-
anyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
-N-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
- N-(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]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-yl]sulfanyl}-1,3-benzothiazol-2-yl)urea
1 -(6-{[6-(1,3-benzodioxol-5-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1 -(6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- 6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
6-{[6-(tetrahydrofuran-3-yloxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-amine
1 -(6-{[6-(1 H-indol-6-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(1,3-benzodioxol-5-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide

- N-(6-{[6-(1 H-indol-6-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclobutanecarboxamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-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-
yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- 6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-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-yl}oxy)phenyl]carbamate
N-(6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclobutanecarboxamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide
- N2-cyclohexyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2-methyl-N2-[2-(morpholin-4-yl)ethyl]glycinamide
2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- 6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
6-{[6-(3-aminophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-am ine

N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)-N~2~-(tetrahydro-2H-pyran-4-yl)glycinamide
- N-[6-({6-[4-(trifluoromethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf-
anyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
- 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-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
- 2-[(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)amino]-2-oxoethyl acetate
N-[6-({6-[(6-methylpyridin-3-yl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf-
anyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
- N-[6-({6-[4-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
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-yl]oxy}phenyl)carbamate
N-(6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-{6-[(6-{3-[(1 S,4S)-2-oxa-5-azabicyclo[2,2,1 ]hept-5-ylmethyl]phenoxy}-
[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopro-
panecarboxamide
- N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-N2,N2-diethylglycinamide
N-(6-{[6-(3-fIuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-hydroxyacetamide
- 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-
b] pyridazin-3-yl]su Ifanyl}-1,3-benzoth iazol-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 -yl)-N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- N-{6-{(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide
- N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-methoxyacetamide
- 2-methoxy-N-{6-[(6-{3-[(1S,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-ylmethyl]-
phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-
acetamide
- 6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-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-yl)acetamide
N-(6-{[6-(3,5-difiuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide
-N2,N2-diethyl-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-
3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
- 2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
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 (I) as defined above.
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 (I) 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 (I). 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.
A subject of the present invention is thus also the process for preparing
products of formula (I) according to Scheme 5 as defined below.
A subject of the present invention is thus also the process for preparing
products of formula (I) according to Scheme 6 as defined below.
Similarly, among the products of formula (I) as defined above in which
represents a single or double bond, the products of formula (I') are defined,
which represent products of formula (I) in which represents a single
bond and products of formula (I") which represent products of formula (I) 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 (a'), (b'), (C), (d'), (e') and (f) are defined, in which
represents a single bond, and the compounds of formulae (a"), (b"),
(c"), (d"), (e") and (f') in which represents a double bond.
Scheme 1: synthesis of benzimidazole derivatives of formulae (1a"), (1b"),
(1"c), (1d"), (1e"), (1a'), (1b'), (1c'), (1d') and (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

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 (1a'), (1b'), (1c'), (1d') and (1e') may be prepared from commercial
3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine of formula (S).

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.

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-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), 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-dimethylformamide, at a
temperature in the region of 20°C.

The compounds (H") such that represent a double bond may be
obtained, for example, via reduction with iron (0) of the compounds of formula
(G), in a solvent such as methanol, in the presence of acetic acid, at a
temperature in the region of 70°C.
The compounds (H') such that 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 (1a') and (1a") may
especially be prepared as described in patent WO 03/028721 A2, but starting,
respectively, with a 3,4-diaminophenyl sulfide of formulae (H') and (H") and
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 (1b') 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
(1c") may be prepared, for example, by reacting cyanogen bromide with a
compound of formulae (H') and (H"), respectively, in the presence of a protic
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 (O) (X = CI) with a
compound of general formulae (1c') and (1c"), for example in a solvent such
as tetrahydrofuran, in the presence of a base such as sodium hydrogen
carbonate, at a temperature in the region of 20°C.
More particularly, the carboxamides (1e') and (1e") may be obtained,
respectively, from the amines of general formulae (lc') and (1c")
- by reacting the amines (1c') and (1c") with an acid chloride of formula (P) (X
= CI), in the presence, for example, of a solvent such as pyridine, at a
temperature in the region of 20oC;
- by reacting the amines (1c') and (1c") with an acid anhydride of formula (P)
(X = OCOR7), in the presence, for example, of pyridine at a temperature in
the region of 20°C;
- by coupling the amines (1c') and (1c") 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.
Scheme 2: Synthesis of benzothiazole derivatives of formulae (2a'), (2b'),
(2c'), (2d'), (2a)', (2b'), (2c') and (2d')


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, C02R6 and COR7, which constitute W, may take values of W as
defined above for the products of formulae (I') and (I"), when W-H.
In Scheme 2 above, the benzothiazoles of general formulae (2a"), (2b"), (2c")
and (2d") and the reduced analogues thereof of general formulae (2a'), (2b'),
(2c') and (2d') with Rb = H may be prepared from 2-amino-1,3-benzothiazol-
6-yl thiocyanate (K) (commercial compound).


The carbamates of general formula (L1) may be obtained, for example, by
reacting a chlorocarbonate of formula (O) (X = CI) 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.

In Scheme 2 above, the benzothiazoles of general formulae (2a"), (2b"), (2c")
and (2d") and the reduced analogues thereof of general formulae (2a'), (2b'),
(2c') and (2d') with Rb = F may be prepared from 2-amino-5-fluoro-1,3-
benzothiazol-6-yl 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.

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).


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 = OCOR7) with 2-amino-1,3-
benzothiazol-6-yl thiocyanate (K), in the presence, for example, of a solvent
such as pyridine, at a temperature in the region of 20°C,
- by coupling 2-amino-1,3-benzothiazol-6-yl thiocyanate (K) with an acid of
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 (2c') and (2c") may be obtained,
respectively, from the amines (2d') and (2d") by coupling with an acid of
formula (P) (X = OH) under the conditions described, for example, by N. Xi
et al., Bioorg. Med. Chem. Lett. 15 (2005) 5211-5217, in the presence of O-
(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
(HATU), in a solvent such as N,N-dimethylformamide, in the presence of a
base such as diisopropylethylamine, at a temperature in the region of 20°C.


In Scheme 2bis above, the substituent R7 may take the meaning of an
aminomethyl group. These glycinamides (2c72c") 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 et a/.; 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 type HNR3R4, as defined above, in a solvent such
as pyridine at a temperature in the region of 20°C, to give the derivatives
(2c'/2c") 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.

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 (2a') and (2a") may also
be prepared from benzothiazoles of formulae (2d') and (2d"), respectively, for
example, by reaction with a chlorocarbonate of formula (O) (X = CI), 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'),
(2c') and (2d') may be prepared, for example:
1) either by coupling a compound of formula (E) with derivatives (M1), (M2)
and (M3) and (N) generated in situ by reduction of the derivatives (L1), (L2),

(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
compound of formula (E), in the presence of sodium borohydride in a solvent
such as N,N-dimethylformamide and in the presence of a base such as
triethylamine, at a temperature in the region of 95°C;
3) or by coupling a compound of formula (E) with derivatives (M1), (M2) and
(M3) and (N) generated in situ by reduction of the derivatives (L1), (L2), (L3)
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 triazolopyridazine derivatives of formula
(E)

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-dichloro[1,2,4]triazolo[4,3-b]pyridazine
of formula (S).

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-
b]pyridazine (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 (2e') and
(2e")

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).


The carbamates of general formulae (T) and (T") may be obtained,
respectively, by reacting carbamates of general formulae (2a') and (2a") with
R6 = tBu, preferentially, for example with alkyl halides of formula (W), in a
solvent such as N,N-dimethylformamide, in the presence of sodium hydride,
at a temperature of between 20 and 90°C.
The benzothiazoles of general formulae (2e') and (2e") may also be prepared
from the compounds of formula (L1), with, preferably, R6 = tBu, via the
compounds of formulae (T) and (T").
More particularly, the compounds of general formulae (2e') and (2e") may be
obtained, respectively, by treating the isolated compounds (T) and (T"), for
example, with trifluoroacetic acid, in a solvent such as dichloromethane, at a
temperature in the region of 20°C.
Alternatively, the compounds of general formula (2e") may be obtained
directly by reacting the compounds of formulae (L4) and (E), via compound
(T) formed in situ, for example in the presence of DL-dithiothreitol and
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.

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 (2e') and
(2e")

Alternatively, according to Scheme 5 above, the benzothiazoles of general
formula (2e") 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 (2e') 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 substituent R9 represents an alkyl or cycloalkyl radical optionally
substituted with an alkoxy or heterocycloalkyl radical or NR3R4 (R3 and R4
as defined above).
The compounds of formula (L5) may be prepared from 2-amino-1,3-
benzothiazol-6-yl thiocyanate (K) (commercial compound), for example, by
treatment with an alkyl nitrite and cuprous bromide in a solvent such as
acetonitrile, at a temperature in the region of 0-20°C, according to the method
described by Jagabandhu Das et al. in J. Med. Chem. 2006,49, 6819-6832.
Scheme 6: Other routes for synthesizing reduced derivatives of formula (I')

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.
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 2d72d" into 2a72a" and into 2c72c", conversion of
2a72a" into 2d72d" and into 2b72b".
In the compounds of general formula (I) 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', Q, Q', R, S, U and W,
some are known and may be obtained either commercially or according to the
usual methods known to those skilled in the art, for example from commercial
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 hydroxyl function, or
alternatively of a hydroxyl function into an alkoxy function,
e) a reaction for removal of the protecting groups that may be borne by
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 to those skilled in the art, especially by acidic or alkaline
hydrolysis, for example with sodium hydroxide or potassium hydroxide in
alcoholic medium, for instance in methanol, or alternatively with hydrochloric
acid or sulfuric acid.
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 carboxyl 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 (I) 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 (I).
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-benzothiazoI-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-b3pyridazin-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-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
- N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide
- N2,N2-diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
- N2-cycIopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yI)glycinamide

- N-[6-({6-[3-(morpholin-4-yimethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyI)-1,3-benzothiazoI-2-yI]cyclopropanecarboxamide
- N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
N-(6-{[6-(3-fIuorophenoxy)[1,2,4]triazoio[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazoI-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- 1 -(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazoI-2-yl)-3-[2-(morphoIin-4-yl)ethyI]urea
6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-amine
6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
1 -[2-(morpholin-4-yl)ethyI]-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-
anyI)-1,3-benzothiazoI-2-yl]-3-[2-(morpholin-4-yI)ethyl]urea
-N-(6-{[6-(tetrahydro-2H-pyran-4-yIoxy)[1,2,4]triazolo[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-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cycIopropanecarboxamide
- N-(6-{[6-(3-fIuoro-4-methyIphenoxy)[1,2,4]triazo!o[4,3-b]pyridazin-3-yl3sulf-
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-yi3cyclopropanecarboxamide
- 1 -[2-{morpho!in-4-yl)ethyl]-3-(6-{[6-(tetrahydrofuran-3-yioxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazoI-2-yI)urea
1 -(6-{[6-(1,3-benzodioxol-5-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea

1 -(6-{[6-(3,4-dich!orophenoxy)[1 ,2,43triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morphoIin-4-yI)ethyl]urea
- 6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazoI-2-amine
- 1 -{6-{[6-(1 H-indol-6-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yI)cycIopropanecarboxamide
N-(6-{[6-{1,3-benzodioxol-5-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]suIf-
anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
- N-(6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yI)eyclopropanecarboxamide
- N-(6-{[6-(1H-indol-6-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclobutanecarboxamide
- N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazoIo[4,3-b]pyridazin-3-yl]suifanyl}-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-(cyclohexyioxy)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazoIo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- 6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine
6-{{6-[3-(trifIuoromethoxy)phenoxy][1,2,4]triazoIo[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]-
triazoIo[4,3-b]pyridazin-6-yl}oxy)phenyl]carbamate

N-(6-{[6-(pyridin-3-yioxy)[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]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide
- N2-cyclohexyl-N-(6-{[6-(3-fiuorophenoxy)[1,2,4]triazoIo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazoI-2-yI)gIycinamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazo[o[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2-methyl-N2-[2-(morpholin-4-yl)ethyl]glycinamide
2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazoI-2-yl)acetamide
- 6-{[6-(3,5-difluorophenoxy)[1 ,2,4]triazoio[4,3-b]pyridazin-3-yl]suIfanyI}-1 ,3-
benzothiazol-2-amine
6-{[6-(3-aminophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazoI-2-amine
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazoIo[4,3-b]pyridazin-3-yI]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-yl}sulf-
anyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
- N-[6-({6-[3-(trifluoromethoxy)phenoxy][1,2,43triazolo[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-yl]suIfanyl}-
1,3-benzothiazol-2-yl)cycIopropanecarboxamide
- 2-[(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazoI-2-yi)amino]-2-oxoethyl acetate
N-[6-({6-[(6-methylpyridin-3-yl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf-
anyI)-1,3-benzothiazoI-2-yl]cyclopropanecarboxamide
- N-[6-({6-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide

2-methyIpropan-2-yl (3-{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzo-
thiazol-6-yi}suIfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yI]oxy}phenyl)carbamate
N-(6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-{6-[(6-{3-[(1S,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-ylmethyl]phenoxy}-
[1,2,4]triazolo[4,3-b]pyridazin-3-yl)suIfanyl]-1,3-benzothiazoI-2-yl}cycIo-
propanecarboxamide
- N-{6-[(6-{3-[(diethyiamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yi)sulfanyl3-1,3-benzothiazol-2-yl}cyciopropanecarboxamide
N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-N2,N2-diethylglycinamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazoI-2-yl)-2-hydroxyacetamide
- 2-(4-cycIopropyIpiperazin-1 -yl)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyI}-1,3-benzothiazoI-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 -yl)-N-{6-{[6-(3,5-difluorophenoxy)[1,2,4Jtriazolo-
[4,3-b]pyridazin-3-yI]sulfanyI}-1,3-benzothiazoI-2-yI)acetamide
- N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide
- N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yI)suIfanyl]-1,3-benzothiazoI-2-yI}-2-methoxyacetamide
- 2-methoxy-N-{6-[(6-{3-[(1S,4S)-oxa-5-azabtcyclo[2,2,1 ]hept-5-ylmethyl]-
phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-
acetamide
- 6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]suIfanyl}-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-yl)acetamide

N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazoI-2-yl)-2-(morphoIin-4-yl)acetamide
-N2,N2-diethyl-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazoIo[4,3-b]pyridazin-
3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
- 2-(4-ethyipiperazin-1 -yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yI]sulfanyl}-1,3-benzothiazoI-2-yI)acetamide
2-(4-cyclopropylpiperazin-1 -yl)-N-{6-{[6-{tetrahydrofuran-3-yIoxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
- 2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazoIo[4,3-b]pyrid-
azin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]suIfanyl}-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 (I) 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
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.
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 (I)
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 (I) 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
(I) 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 (I) 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 (I)
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, flavopiridol
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:


in which the groups CONR1R2, C02R6 and COR7, which constitute W, may
take the values of W as defined above for the products of formulae (I') and
(I"), when W-.
The examples that follow, which are products of formula (I), 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 Bruker Avance DPX-300 spectrometer with the chemical
shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (DMSO-d6) 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 II Waters Micromass)
- UPLC-MS-DAD-ELSD (MS = Quattro Premier XE Waters)
DAD wavelength considered A = 210-400 nm
ELSD: Sedere SEDEX 85; nebulization temperature = 35°C; nebulization
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 30 cm3 of ethanol, for
5 minutes. 14 mg of potassium dihydrogen phosphate in 0.3 cm3 of water,
1.39 g of DL-dithiothreitol and 740 mg of 3-chloro-6-phenoxy[1,2,4]triazolo-
[4,3-b]pyridazine 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 dichloromethane/(38 dichloromethane/17 methanol/2 aqueous
ammonia) gradient. 717 mg of 6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-amine are thus obtained in the form of a white
powder whose characteristics are as follows :
1H NMR SPECTRUM (400 MHz, DMSO-d6) δ ppm 7.13 (dd, J = 8.3, 2.0 Hz,
1 H) 7.21 (d, J = 8.3 Hz, 1 H) 7.25 - 7.32 (m, 2 H) 7.32 - 7.39 (m, 2 H) 7.50 (t,
J = 7.8 Hz, 2 H) 7.61 (d, J = 1.5 Hz, 1 H) 7.64 (s, 2 H) 8.43 (d, J = 9.8 Hz,
1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 393+; MH- = 391-
b) 3-Chloro-6-phenoxy[1,2,4]triazolo[4,3-b]pyridazine may be prepared in
the following manner:
254 mg of sodium hydride at 60% in oil are added to a solution of 996 mg of
phenol in 20 cm3 of tetrahydrofuran, at 0°C under argon. After stirring for

15 minutes, 1 g of 3,6-dichioro[1,2,4]triazolo[4,3-bjpyridazine (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 µM), 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:
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 247+
Example 2:
N-{6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yI)sulfanyl]-1,3-benzo-
thiazol-2-yI}cyclopropanecarboxamide
a) N-{6-[(6-Phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-
benzothiazol-2-yl}cyclopropanecarboxamide may be prepared in the following
manner:
0.120 cm3 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 (1a) in 5 cm3 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 µM), 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-d6) δ ppm 0.93 - 0.98 (m, 4 H) 1.99
(quint, J = 6.2 Hz, 1 H) 7.20 - 7.45 (m, 7 H) 7.60 (d, J = 8.3 Hz, 1 H) 7.86 (d, J
= 1.7 Hz, 1 H) 8.46 (d, J = 10.0 Hz, 1 H) 12.67 (br. s., 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 461 +; MH- = 459-

Example 3:
N-{6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)suIfanyl]-1,3-benzo-
thiazol-2-yl}acetamide
N-{6-[(6-Phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-
2-yI}acetamide may be prepared in a manner similar to that of Example 2a,
but starting with 302 mg of 6-[(6-phenoxy[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-amine (1a) in 10 cm3 of pyridine with 0.220 cm3
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-yI)sulfanyl]-1,3-benzothiazoI-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-d6) δ ppm 2.20 (s, 3 H) 7.23 (d, J =
7.6 Hz, 2 H) 7.26 - 7.33 (m, 2 H) 7.34 - 7.44 (m, 3 H) 7.61 (d, J = 8.6 Hz, 1 H)
7.87 (d, J = 1.7 Hz, 1 H) 8.46 (d, J = 9.8 Hz, 1 H) 12.39 (br. s., 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 435+; MH- = 433-
Example 4:
1-[2-(morpholin-4-yl)ethyl3-3-{6-[(6-phenoxy[1,2,4]triazoIo[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-yl}urea may be prepared in a manner
similar to that of Example 1a, but starting with 533 mg of 1-[2-(morpholin-4-
yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea, 10 cm3 of degassed ethanol,
6 mg of potassium dihydrogen phosphate in 0.1 cm3 of water, 606 mg of DL-
dithiothreitol and 324 mg of 3-chloro-6-phenoxy[1,2,4]triazolo[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)sulfanyl]-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-d6) δ ppm 2.36 - 2.46 (m, 6 H) 3.24 -
3.29 (m, 2 H) 3.59 (t, J = 4.4 Hz, 4 H) 6.80 (t, J = 5.7 Hz, 1 H) 7.20 - 7.28 (m,
3 H) 7.29 - 7.34 (m, 1 H) 7.36 (d, J = 9.8 Hz, 1 H) 7.44 (t, J = 7.8 Hz, 2 H)
7.49 (d, J = 8.6 Hz, 1 H) 7.80 (d, J = 1.7 Hz, 1 H) 8.45 (d, J = 9.8 Hz, 1 H)
10.93 (br.s.,1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 549+; MH- = 547-
b) 1-(2-Morpholin-4-ylethyl)-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea may
be prepared in the following manner:
A stream of argon is bubbled for 5 minutes through a mixture of 900 mg of 2-
{[(2-morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl thiocyanate
and 40 cm3 of ethanol at 20°C. 11 mg of potassium dihydrogen phosphate in
0.4 cm3 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 cm3 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)carbamoyl]amino}-1,3-benzothiazol-6-yl
thiocyanate may be prepared in the following manner:
0.44 cm3 of 2-morpholin-4-ylethanamine is added at 20°C to a solution of 1 g
of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate in 30 cm3 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)carbamoyl]amino}-1,3-benzothiazol-6-yl 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 cm3 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 cm3 of
tetrahydrofuran. The resulting mixture is then stirred at 20°C for 20 hours and
then extracted with 2×150 cm3 of ethyl acetate. The organic phases are
combined and then washed with 3×50 cm3 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 cm3 of water and then filtered off by
suction and dried under vacuum at 20°C. 3.45 g of phenyl (6-thiocyanato-1,3-
benzothiazo!-2-yl)carbamate are thus obtained in the form of a pale yellow
solid, the characteristics of which are as follows:
MASS SPECTRUM: LC-MS-DAD-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-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea may be prepared in a
manner similar to that of Example 1a, but starting with 305 mg of 1-[2-
(morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea (4b), 5 cm3 of
degassed ethanol, 4 mg of potassium dihydrogen phosphate in 0.1 cm3 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)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
yl)-3-[2-(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white
powder, the characteristics of which are as follows:

1H NMR SPECTRUM (400 MHz, DMSO-d6) δ ppm 2.36 - 2.45 (m, 6 H) 3.25
- 3.28 (m, 2 H) 3.59 (t, J = 4.3 Hz, 4 H) 6.78 (br. s., 1 H) 7.14 (dd, J = 8.3,
1.7 Hz, 1 H) 7.18 (td, J = 8.5, 2.3 Hz, 1 H) 7.23 - 7.31 (m, 2 H) 7.38 (d, J =
9.7 Hz, 1 H) 7.42 - 7.51 (m, 2 H) 7.84 (d, J = 1.7 Hz, 1 H) 8.47 (d, J = 9.8 Hz,
1 H) 10.89 (br. s., 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 567+; MH- = 565-
b) 3-Chloro-6-(3-fIuorophenoxy)[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 cm3 of tetrahydrofuran, 254 mg of sodium hydride at 60%
in oil and 1 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial).
837 mg of 3-chloro-6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazine are
thus obtained in the form of a white powder, the characteristics of which are
as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z = 265+
Example 6:
6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
6-{[6-(3-Fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
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-
bjpyridazine (5b), 10 mg of potassium dihydrogen phosphate in 0.1 cm3 of
degassed ethanol, 926 mg of DL-dithiothreitol and 414 mg of 2-amino-1,3-
benzothiazol-6-yl thiocyanate (commercial) in 10 cm3 of ethanol. 587 mg of 6-
{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine are thus obtained in the form of a white powder, the
characteristics of which are as follows:
1H NMR Spectrum (400 MHz, δ in ppm, DMSO-d6): 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 8.3 Hz, 1 H); 7.63 (broad s, 2 H); 7.65 (d, J = 2.0 Hz, 1 H); 8.45 (d, J =
9.8 Hz, 1 H)

MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z411; [M-H]-: m/z 409
Example 7:
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-y]sulfanyl}-
1,3-benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide
a) N-(6-{[6-(3-Fiuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyI}-
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 cm3
of diisopropylethylamine and 371 mg of 0-(7-azabenzotriazoI-1-yI)-N,N,N',N'-
tetramethyluronium hexafluorophosphate (HATU) in 3 cm3 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-yl]sulfanyl}-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, 219 mg of N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-2-(2-methoxyethoxy)acet-
amide are obtained in the form of a white powder, the characteristics of which
are as follows:
1H NMR Spectrum (400 MHz, δ in ppm, DMSO-d6): 3.29 (partially masked s,
3 H); 3.48 to 3.54 (m, 2 H); 3.66 to 3.71 (m, 2 H); 4.29 (s, 2 H); 7.11 (dd, J =
2.2 and 8.3 Hz, 1 H); 7.16 (dt, J = 2.2 and 8.3 Hz, 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); 7.39 (d, J = 9.8 Hz, 1H);
7.42 (dt, J = 6.9 and 8.3 Hz, 1 H); 7.63 (d, J = 8.6 Hz, 1 H); 7.93 (d, J =
2.0 Hz, 1 H); 8.49 (d, J = 9.8 Hz, 1 H); 12.20 (broad m, 1 H)
MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 527; [M-H]-: m/z 525
Example 8:
N2,N2-diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide

a) N2,N2-Diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-
3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide may be prepared in the
following manner:
A mixture of 373 mg of sodium N,N-diethylglycinate (commercial) in 2.4 cm3 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 cm3 of
pyridine, 100 mg of 6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-amine (6) and 467 mg 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 N2,N2-diethyl-N-(6-{[6-(3-fluorophenoxy)-
[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
are thus obtained in the form of a beige-coloured powder, the characteristics
of which are as follows:
1H NMR Spectrum (400 MHz, δ in ppm, DMSO-d6): for this crop, all the
signals are broad, with: 1.00 (t, J = 6.9 Hz, 6 H); 2.63 (q, J = 6.9 Hz, 4 H);
3.41 (s, 2 H); 7.06 to 7.20 (m, 2 H); 7.24 (d, J = 9.5 Hz, 1 H); 7.31 (d, J =
8.3 Hz, 1 H); 7.35 to 7.47 (m, 2 H); 7.61 (d, J = 8.3 Hz, 1 H); 7.92 (s, 1 H);
8.49 (d, J = 9.8 Hz, 1 H); 9.44 to 14.07 (very broad m, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 524; [M-H]-: m/z 522
Example 9:
N2-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-
3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
a) N2-Cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide may be prepared in the
following manner:

0.13 cm3 of cyclopropylamine is added to 137 mg of 2-chloro-N-(6-{[6-(3-
fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothia2ol-2-
yl)acetamide (9b) in 1.5 cm3 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.
52 mg of N2-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide are thus obtained in
the form of a white solid, the characteristics of which are as follows:
1H NMR Spectrum (400 MHz, δ in ppm, DMSO-d6): 0.19 to 0.42 (m, 4 H);
2.18 (m, 1 H); 3.52 (s, 2 H); 7.11 (dd, J = 2.3 and 8.3 Hz, 1 H); 7.16 (ddt, J =
1.0 and 2.3 and 8.3 Hz, 1 H); 7.25 (td, J = 2.3 and 10.0 Hz, 1 H); 7.31 (dd, J =
2.0 and 8.3 Hz, 1 H); 7.39 (d, J = 9.8 Hz, 1 H); 7.45 (dt, J = 6.9 and 8.3 Hz,
1H); 7.45 (broad m, 1 H); 7.60 (d, J = 8.3 Hz, 1 H); 7.91 (d, J = 2.0 Hz, 1 H);
8.49 (d, J = 9.8 Hz, 1 H)
MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 508; [M-H]-: m/z 506
b) 2-Chloro-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)acetamide may be prepared in the following
manner:
0.06 cm3 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 cm3 of dichloromethane and 0.5 cm3 of pyridine at 0-5°C. The
resulting white suspension is stirred for 30 minutes at 20°C. 0.03 cm3 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
dichloromethane/(dichloromethane: 38/methanol: 17/aqueous ammonia: 2).
137 mg of 2-chloro-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-

yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide are thus obtained in the form of a
white solid, the characteristics of which are as follows:
MASS SPECTRUM: Waters ZQ: [M+H]+: m/z487; [M-H]-: m/z485
Example 10:
N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
a) N-[6-({6-[3-(Morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide 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}-
sulfanyl)-1,3-benzothiazol-2-amine (10b) in 5 cm3 of pyridine with 0.124 cm3
of cyclopropanecarbonyl chloride after 3 hours 30 minutes of reaction at
50°C. 57.3 mg of N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo-
[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
are thus obtained in the form of a white powder, the characteristics of which
are as follows:
1H NMR Spectrum (400 MHz, δ in ppm, DMSO-d6): 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,
4 H); 7.09 to 7.14 (m, 1 H); 7.20 to 7.25 (m, 2 H); 7.28 (dd, J = 2.0 and
8.6 Hz, 1 H); 7.31 to 7.39 (m, 2 H); 7.59 (d, J = 8.6 Hz, 1 H); 7.83 (d, J =
2.0 Hz, 1 H); 8.47 (d, J = 9.8 Hz, 1H ); 12.68 (broad m, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 560; [M-H]-: m/z 558
b) 6-({6-[3-(Morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-
3-yl}sulfanyl)-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-chloro-6-[3-
(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazine (10c), 3 mg of
potassium dihydrogen phosphate in 0.1 cm3 of degassed ethanol, 176 mg of
DL-dithiothreitol and 79 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate
(commercial), in 5 cm3 of ethanol. 111 mg of 6-({6-[3-(morpholin-4-
ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzo-

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
c) 3-Chloro-6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]-
pyridazine (10c) may be prepared in a manner similar to that of Example 1b,
but starting with 310 mg of 3-(morpholin-4-ylmethyl)phenol (10d) in 5 cm3 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-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazine are thus
obtained in the form of a brown oil, the characteristics of which are as follows:
MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 346
d) 3-(Morpholin-4-ylmethyl)phenol (10d) may be prepared in the following
manner:
438 mg of morpholine are added to a solution of 188 mg of 3-
(bromomethyl)phenol (10e) in 5 cm3 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 cm3 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 cm3 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 II machine
equipped with an SVF D26 15-40 µM 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

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:
Experimental protocols
\) 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 NaCI, Glycerol 10%, TECP 1 mM ]; + Roche Diagnostics EDTA-
free protease inhibitor cocktail, ref. 1873580), stirred at 4°C until
homogeneous, and then mechanically lysed using a "Dounce" machine.
After centrifugation, the lysis supernatant is incubated for 2 hours at 4°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, MgCI2
2 mM, and Na3VO4 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 + Na3VO4 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.
II) Tests A and B and C
A) Test A: HTRF MET test in 96-well format
In a final volume of 50 ul 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 µM, 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 µg/ml, ATP 10 uM and MgCI2
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 a reader 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 (I) illustrated in
the experimental section are such that the IC50 is less than 500 nM and
especially less than 100 nM.
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 µl 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 µM
with an increment of 3 in pure DMSO - Intermediate 50-fold dilutions in the
culture medium, followed by removal of 10 µl added directly to the cells
(200 µl): final range from 10 000 to 30 nM.
At the end of incubation, delicately remove the supernatant and rinse with
200 µl of PBS. Next, place 100 µl 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
NaCI, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 10% glycerol, 0.1% SDS,
0.5% deoxycholate, 20 mM NaF, 2 mM Na3VO4, 1 mM PMSF and anti-
protease cocktail.
The 100 µl 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 µl of kit dilution buffer + 30 µL of cell lysates or 30 µl 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 µl of kit washing buffer. Incubate with
100 µl of anti-phospho MET antibody for 1 hour at room temperature.
Rinse the wells four times with 400 µL of kit washing buffer. Incubate with
100 µl 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 µl of kit washing buffer. Introduce 100 µl
of chromogen and incubate for 30 minutes in the dark at room temperature.
Stop the reaction with 100 µl 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 µl for 4 hours at
37°C and 5% CO2: 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 µl of 14C-thymidine at 10 µCi/ml to obtain
0.1 µCi 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 (I) illustrated in
the experimental section are such that the IC50 is less than 10 uM and
especially less than 1 µM.
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 µM.

CLAIMS
1) Products of formula (I):

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 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 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: hydroxy!, 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: optionally substituted
hydroxy!, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, 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, COOR5, -CONH2, CONHR5, NH2, NHR5,
NR5R5', -NH-CO-R5, -NHCOOR5 and alkyl, heterocycloalkylalkyl, cycloalkyl,

heterocycloaikyl, 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, heterocycloaikyl, heteroaryl and phenyl radicals defined
above being furthermore optionally substituted with a radical Si(alk)3;
R5 and R5', which may be identical or different, represent an alkyl or
cycloalkyl radical containing not more than 6 carbon atoms;
alk represents an alkyl radical containing not more than 4 carbon atoms;
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
heterocycloaikyl radical;
the said products of formula (l) 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).
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 SO2;
A represents NH or S;
W represents a hydrogen atom; an alkyl or cycloalkyl radical optionally
substituted with alkoxy, heterocycloaikyl 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-phenyi 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, NHAlk, N(Alk)2
or phenyl, optionally substituted; or alternatively R3 and R4 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from 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-cycIoalkyl, 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, 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;
R5 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 (I).
3} 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
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-cycloalkyI, -OCO-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 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,
NHAlk, N(Alk)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 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 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
NR3R4, or alternatively R1 and R2 form, with the nitrogen atom to which they
are attached, a cyclic radical optionally containing one or more other
heteroatoms chosen from 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
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).
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 (I).
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 (I).
7) Products of formula (I) as defined in any one of the claims, corresponding
to formula (la) or (lb):


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 (lb) 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 (lb).
8) Products of formula (I) as defined in any one of the claims, in which
represents a double bond, corresponding to the products of formula (I"):

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 (I).
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 (I"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 diastereoisomeric isomer form, and also the addition salts with mineral and

organic acids or with mineral and organic bases of the said products of
formula (l"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 (l"b);

in which Ra, Rb and W are chosen from any one of the meanings indicated
hereinabove or hereinbelow,
the said products of formula (l"b) being in any possible racemic, enantiomeric
or diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (l"b).
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 (I).

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)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-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(2-methoxyethoxy)acetamide
N2,N2-diethyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
N2-cyclopropyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
- N-[6-({6-[3-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)acetamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1-(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea

6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-amine
6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
1 -[2-(morpholin-4-yl)ethyl]-3-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)urea
1 -[6-({6-[(1 -ethylpiperidin-4-yl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf-
anyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
-N-(6-{[6-(tetrahydro-2H-pyran-4-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(4-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
- N-(6-{[6-(3-fluoro-4-methylphenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]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-yl]sulfanyl}-1,3-benzothiazol-2-yl)urea
1 -(6-{[6-(1,3-benzodioxol-5-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1 -(6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- 6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-amine
1 -(6-{[6-(1 H-indol-6-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide

N-(6-{[6-(1,3-benzodioxol-5-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
- N-(6-{[6-(3,4-dichlorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
- N-(6-{[6-(1 H-indol-6-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclobutanecarboxamide
N-(6-{[6-(3-fiuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-dimethylglycinamide
- 2-ethoxy-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulf-
anyl}-1,3-benzothiazol-2-yl)acetamide
- 2-(cyclohexyloxy)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- 6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-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)sulf-
anyl][1,2,4]triazolo[4,3-b]pyridazin-6-yl}oxy)phenyl]carbamate
N-(6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-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
- N2-cyclohexyl-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
N-(6-{[6-(3-fIuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2-methyl-N2-[2-(morpholin-4-yl)ethyl]glycinamide
2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide

- 6-{[6-(3,5-difIuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
6-{[6-(3-aminophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl]-1 ,3-
benzothiazol-2-amine
N-(6-{[6-(3-fiuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N~2~-(tetrahydro-2H-pyran-4-yl)glycinamide
- N-[6-({6-[4-(trifluoromethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf-
anyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
- N-[6-({6-[3-(trifIuoromethoxy)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-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
- 2-[(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)amino]-2-oxoethyl acetate
N-[6-({6-[(6-methylpyridin-3-yl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulf-
anyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
- N-[6-({6-[4-(morpholin-4-ylmethyl)phenoxy][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
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-yl]oxy}phenyl)carbamate
N-(6-{[6-(pyridin-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-{6-[(6-{3-[(1 S,4S)-2-oxa-5-azabicyclo[2,2,1 ]hept-5-ylmethyl]phenoxy}-
[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopro-
panecarboxamide
- N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
N-(6-{[6-(3,5-difIuorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-N2,N2-diethylglycinamide

N-(6-{[6-(3-fluorophenoxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)-2-hydroxyacetamide
- 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(3-fluorophenoxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1 -yl)acetamide
- 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
- N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide
- N-{6-[(6-{3-[(diethylamino)methyl]phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-methoxyacetamide
- 2-methoxy-N-{6-[(6-{3-[(1S,4S)-2-oxa-5-azabicyclo[2,2,1]hept-5-ylmethyl]-
phenoxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-
acetamide
- 6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-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-yl)acetamide
N-(6-{[6-(3,5-difluorophenoxy)[1,2,4]triazolo[4,3-b]pyridazin-S-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide
-N2,N2-diethyl-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-
3-yl]sulfanyl}-1,3-benzothiazol-2-yl)glycinamide
- 2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]suifanyl}-1,3-benzothiazol-2-yl)acetamide
2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(tetrahydrofuran-3-yloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
2-(4-ethylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide

- 2-(4-cyclopropylpiperazin-1 -yl)-N-(6-{[6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)acetamide
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 (I) as defined in any one of
the other claims.
14) Process for preparing the products of formula (I) as defined in any one of
the other claims, in which A represents NH.
15) Process for preparing the products of formula (I) as defined in any one of
the other claims, in which A represents S.
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 (I).
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 (I).
18) Pharmaceutical compositions containing, as active principle, at least one
of the products of formula (I) as defined in any one of Claims 1 to 12, or a
pharmaceutically acceptable salt of this product or a prodrug of this product
and a pharmaceutically acceptable 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
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 (I) 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 (I) as defined in Claims 1 to 12, for the
preparation of medicaments for cancer chemotherapy.
28) Use of the products of formula (I) 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 (I) 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:


in which the groups CONR1R2, C02R6 and COR7, which constitute W, may
take the values of W as defined in any one of Claims 1 to 11 for the products
of formulae (I') and (I"), when W=H.

The invention relates to novel products of the formula (I) where: (II) is a single double bond; Ra is -O-Z-Rc with
Z being a single bond or optionally substituted alkylene and Rc being optionally substituted cycloalkyl, heterocycloalkyl, aryl or
heteroaryl; Rb is H or F; if Rb is H, then Rc is not cycloalkyl when Z is a single bond, and Rc is not heterocycloalkyl when Z is
alkylene; X is S, SO or SO2, A is NH or S; W is H, alkyl, cycloalkyl or COR with R being cycloalkyl; alkyl; alkoxy; O- phenyl;
-O-(CH2)n-phenyl with n = 1 to 4; or NR1 R2 with R1 is H or alk and R2 is H, cycloalkyl or alkyl; or R1, R2 form a cycle with N
optionally containing O, S, N and/or NH; wherein all of these radicals are optionally substituted, and said products are in any
isomer or salt form and can be used as drugs, in particular as MET inhibitors.