DERIVATIVES OF 6-(6-SUBSTITUTED TRIAZOLOPYRIDAZINE-SULFANYL) 5-
FLUOROBENZOTHIAZOLES AND 5-FLUOROBENZIMIDAZOLES,
PREPARATION THEREOF, USE THEREOF AS DRUGS, AND USE THEREOF AS
MET INHIBITORS
The present invention relates to novel 6-(6-substituted triazolopyridazine-sulf-
anyl) 5-fluorobenzothiazole and 5-fluorobenzimidazole 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-(6-substituted triazolopyridazine-sulfanyl) 5-fluorobenzo-
thiazole and 5-fluorobenzimidazole derivatives.
The present invention more particularly relates to novel 6-(6-substituted
triazolopyridazine-sulfanyl) 5-fluorobenzothiazole and 5-fluorobenzimidazole
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;
Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally
substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl
radical, which is itself optionally substituted; a radical -O-cycloalkyl,
-O-heterocycloalkyl; -NH-cycloalkyl and -NH-heterocycloalkyl, all optionally
substituted; an optionally substituted heteroaryl radical; an optionally
substituted phenyl radical; a radical NHCOalkyl or NHCOcycloalkyl; or a
radical NR1R2 as defined below;
X represents S, SO or SO2;
A represents NH or S;
W represents a hydrogen atom; an alkyl, cycloalkyl or heterocycloalkyl 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 0-(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 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, 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 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, this radical, including the
possible NH it contains, being optionally substituted;
all the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl 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, NH2, NHalk, N(alk)2 and
alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycioalkyl, phenyl, CH2-phenyl,
heteroaryl, CO-phenyl and S-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 the following radicals: hydroxyl, oxo, alkyl and alkoxy
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).
In the products of formula (I), F represents a fluorine atom.
The present invention relates especially to the products of formula (I) in which
Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally
substituted with a heterocycloalkyl radical, which is itself optionally
substituted; an optionally substituted heteroaryl radical; an optionally
substituted phenyl radical; an optionally substituted radical -O-cycloalkyl;
optionally substituted O-heterocycloalkyl; optionally substituted -NH-cycio-
alkyl; optionally substituted -NH-heterocycloalkyl; a radical -NHCOalkyl or
-NHCOcycloalkyl; or a radical NR1R2 as defined hereinabove or hereinbelow,
the other substituents on the said products of formula (I) having any of the
meanings indicated hereinabove or hereinbelow.
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which , X and A have the meanings
given hereinabove or hereinbelow,
Ra represents an alkoxy radical optionally substituted with a chlorine atom, a
hydroxyl radical or a heterocycloalkyl radical, which is itself optionally
substituted; a radical -O-cycloalkyl; a radical -NHCOalk; or a radical
-NR1aR2a; such that R1a and R2a represent 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 hydroxyl, alkoxy, heteroaryl,
heterocycloalkyl, NR3R4 and phenyl radicals, optionally substituted;

and 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, 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 0-(CH2)n-phenyl,
with phenyl optionally substituted and n represents an integer from 1 to
- or the radical NR1R2 in which R1 and R2 are such that one from
among R1 and R2 represents a hydrogen atom 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 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, this radical,
including the possible NH it contains, being optionally substituted;

all the heterocycloalkyl, heteroaryl 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, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl,
heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl,
CO-phenyl and S-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 the
following radicals: hydroxyl, oxo, alkyl and alkoxy 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 , X and A have the meanings
given hereinabove or hereinbelow;
Ra represents an alkoxy radical optionally substituted with a heterocycloalkyl
radical, which is itself optionally substituted; a radical NHCOalk or a radical
NR1aR2a; such that R1a and R2a represent 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 hydroxyl, alkoxy, heteroaryl,
heterocycloalkyl, NR3R4 and phenyl radicals, optionally substituted;
and 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, 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 or an alkyl radical and the
other from among R1 and R2 represents a hydrogen atom or an alkyl radical
optionally substituted with one or more radicals, which may be identical or
different, chosen from hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4
and phenyl radicals, 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, represent a hydrogen
atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl
radical, all optionally substituted with one or more radicals, which may be
identical or different, chosen from hydroxyl, 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 heterocycloalkyl, heteroaryl 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, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl,
heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, CO-

phenyl and S-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, oxo, 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).
One subject of the present invention is the products of formula (I) as defined
above in which
represents a single or double bond;
Ra represents a hydrogen atom; a halogen atom, an alkoxy radical optionally
substituted with a heterocycloalkyl radical, which is itself optionally
substituted; an optionally substituted heteroaryl radical; an optionally
substituted phenyl radical; a radical NHCOalkyl or NHCOcycloalkyl; or a
radical NR1R2 as defined hereinbelow;
X represents S, SO or SO2;
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, 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 0-(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 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 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 hydroxyl,
alkoxy, heteroaryl, heterocycloalkyl, NH2, NHalk, N(alk)2 and phenyl radicals,
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 heterocycloalkyl, heteroaryl 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, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl,
heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl,
CO-phenyl and S-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 the
following radicals: hydroxyl, oxo, alkyl and alkoxy 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).
The present invention, which thus concerns the products of formula (I) as
defined above, in which represents a single or double bond, thus
precisely concerns the products of formula (I') which represent the products of
formula (I) in which represents a single bond and the products of
formula (I") which represent the products of formula (I) in
which represents a double bond.
Thus, all the products of formula (I) as defined hereinabove or hereinbelow
particularly represent products of formula (I') in which represents a
single bond.
The products of formula (I) as defined hereinabove or hereinbelow also
represent products of formula (I") in which represents a double bond.
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which , Ra and X have the values
defined hereinabove or hereinbelow, and:
A represents NH or S;
W represents a hydrogen atom; an alkyl radical optionally substituted with
alkoxy or heterocycloalkyl; 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 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 NR3R4 or alkoxy; 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 O,
S, N and NH, this radical, including the possible NH it contains, being
optionally substituted;
all the heterocycloalkyl, heteroaryl 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, NH2, NHalk, N(alk)2 and alkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, CO-phenyl and
S-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).

One subject of the present invention is thus the products of formula (I) as
defined above, in which ' , Ra, X, A and W have any of the values defined
hereinabove or hereinbelow, and the radical NR1R2 is 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 or an alkyl radical
optionally substituted with NR3R4 or with alkoxy, 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 optional NH it contains, being
optionally substituted;
all the other substituents having the definitions given hereinabove;
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 hydrogen atom or a halogen atom, or alternatively an
optionally substituted phenyl radical,
X represents S, SO or SO2
A represents NH or S;
W represents a hydrogen atom or a radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical optionally substituted with a
phenyl, heteroaryl, NR3R4 or heterocycloalkyl radical, which are
themselves optionally substituted;

- an alkoxy radical optionally substituted with NR3R4, i.e. a radical
O-(CH2)n-NR3R4; a radical O-phenyl or a radical O-(CH2)n-phenyl,
with phenyl optionally substituted and n representing 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 cycloalkyl radical or an
alkyl radical optionally substituted with one or more radicals, which
may be identical or different, chosen from hydroxyl, alkoxy, heteroaryl,
heterocycloalkyl, NR3R4 or phenyl radicals, optionally substituted, 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
optional 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, optionally substituted, 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 optional NH it contains, being optionally substituted;
all the heterocycloalkyl, heteroaryl 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, hydroxyl, oxo, alkoxy, NH2,
NHalk and N(alk)2 radicals and alkyl, cycloalkyl, CH2-heterocycloalkyl,
CH2-phenyl, CO-phenyl and S-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, oxo, 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).
Products of formula (I) as defined hereinabove or hereinbelow, in which
, Ra and X have the values defined hereinabove or hereinbelow, and:
A represents NH or S;
W represents a hydrogen atom or an alkyl radical or the radical COR in which
R represents:
- an alkyl radical optionally substituted with OCH3 or NR3R4;
- a cycloalkyl radical
- an alkoxy radical optionally substituted with OCH3 or NR3R4, i.e. a
radical O-(CH2)n-OCH3 or a radical O-(CH2)n-NR3R4, a radcial 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 an alkyl radical
optionally substituted with 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;
the 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, NH2, NHalk,
N(alk)2 and alkyl, CH2-heterocycloalkyl, CH2-phenyl, CO-phenyl and
S-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).
One subject of the present invention is thus the products of formula (I) as
defined above, in which , Ra and X have any one of the values defined
hereinabove or hereinbelow,
A represents NH or S;
W represents a hydrogen atom or the radical COR in which R represents:
an alkyl radical optionally substituted with NR3R4;
an alkoxy radical optionally substituted with NR3R4, i.e. a radical
O-(CH2)n-NR3R4, a radical O-phenyl or O-(CH2)n-phenyl, with phenyl
optionally substituted and n representing 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 or an alkyl radical and the
other from among R1 and R2 represents an alkyl radical optionally substituted
with 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 optional
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 optional NH it contains, being optionally
substituted;
the phenyl radicals and 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 hydroxyl, alkoxy, NH2, NHalk, N(alk)2 radicals and alkyl,
CH2-heterocycloalkyl, CH2-phenyl, CO-phenyl and S-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).
One subject of the present invention is thus the products of formula (I) as
defined above, in which , X, A and W have the meanings given
hereinabove or hereinbelow, Ra represents a hydrogen atom or a chlorine
atom, or the radical:

with Rb representing a halogen atom or a radical S-heteroaryl optionally
substituted with a radical 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 may 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 O, S, N and NH, with
the optional S possibly being in the form SO or SO2; 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 alkyl, alkoxy, NH2, NHalk or N(alk)2 radicals.
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 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;
- 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.
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, propionyioxymethyl, 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, morpholino 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 morpholino 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) in
which A represents NH, the substituents Ra, X and W being chosen from all
the values defined for these radicals 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 especially the products of formula (I) in
which A represents S, the substituents Ra, X and W being chosen from all the
values defined for these radicals 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).
In particular, the present invention relates to the products of formula (I)
corresponding to formula (la) or (lb):


in which , Ra and W are chosen from all the meanings indicated
hereinabove or hereinbelow,
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).
The present invention thus particularly relates to 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, X, A and W are chosen from all 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').

The present invention thus particularly relates to 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, X, A and W are chosen from all 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").
The present invention thus particularly relates to the products of formula (la)
as defined hereinabove or hereinbelow, in which represents a single
bond, corresponding to the products of formula (la'):

in which Ra and W are chosen from all 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).

The present invention thus particularly relates to the products of formula (la)
as defined hereinabove or hereinbelow, in which represents a double
bond, corresponding to the products of formula (l"a):

in which Ra and W are chosen from all 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).
The present invention thus particularly relates to the products of formula (lb)
as defined hereinabove or hereinbelow, in which represents a single
bond, corresponding to the products of formula (I'b):

in which Ra and W are chosen from all 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).

The present invention thus particularly relates to the products of formula (lb)
as defined hereinabove or hereinbelow, in which represents a double
bond, corresponding to the products of formula (l"b):

in which Ra and W are chosen from all 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).
When, in the products of formula (I), Ra represents the radical:

Rb is especially in the para position.
When Rb defined above represents a halogen atom, Rb especially represents
fluorine.
A subject of the present invention is most particularly the products of formula
(I) as defined above, corresponding to the following formulae:
-1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-fluoro-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- 2-methylpropan-2-yl (5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate

- 5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-amine
-1 -(5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
-1 -(6-{[6-(cyclopropylamino)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
-1 -(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- 2-(4-cyclopropylpiperazin-1 -yl)-N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-
3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}acetamide
- N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-fluoro-
1,3-benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide
- N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-
benzothiazol-2-yl}-2-(4-ethylpiperazin-1-yl)acetamide
-N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-fluoro-
1,3-benzothiazol-2-yl)-2-(4-ethyipiperazin-1 -yl)acetamide
- 2-(4-cyclopropylpiperazin-1 -yl)-N-(5-fluoro-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-(5-fluoro-6-{[6-(tetrahydrofuran-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 substituent Ra has the meanings given above for the
products of formulae (I') and (I") and the groups CONR1R2, COR6 and
COR7, which constitute W, may take the values of W as defined above for the
products of formulae (I') and (I"), when W≠H
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 by the routes described in Scheme 3
below

The compounds (G) may be obtained, for example, by reacting 2-fluoro-4-
nitro-5-aminobenzenethiol of formula (F) with the compounds of formula (E).
The compound of formula (F) may be obtained by introducing the thiol
function onto the derivative 2-nitro-4,5-difluoroaniline (Q) (commercial
compound), for example, in the presence of potassium thioacetate 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 2-fluoro-4,5-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 20°C;
- by reacting the amines (1c') and (1c") with an acid anhydride of formula (P)
(X = OCOR7), in the presence, for example, of solvent such as 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 substituent Ra has the meanings indicated above for
the products of formulae (I') and (I") and the groups CONR1R2, COR6 and
COR7, which constitute W, may take values of W as defined above for the
products of formulae (I') and (I"), when WVH.
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') may be prepared from 2-amino-5-fluoro-1,3-benzothiazol-6-yl
thiocyanate (K).


In Scheme 2 above, 2-amino-5-fiuoro-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

The carbamates of general formula (L1) may be obtained, for example, by
reacting a chlorocarbonate of formula (0) (X = CI) with 2-amino-5-fluoro-1,3-
benzothiazol-6-yi 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.

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 R1 and R2 as defined above), in the presence
of an aprotic solvent such as tetrahydrofuran, at a temperature in the region
of20°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-5-fluoro-
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-5-
fiuoro-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-5-fluoro-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").
Scheme 2bis: Routes for synthesizing the glycinamide derivatives (2c') and
(2c")

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 (2e72en) 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, or, alternatively, for example, with DL-dithiotreitol, in the presence of
sodium hydrogen carbonate, in a solvent such as ethanol, and at a
temperature in the region of 80°C.
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 the isolated derivatives (M1), (M2) and (M3) and a
compound of formula (E) under the conditions described, for example, by
U. Schopfer et al. (Tetrahedron, 2001, 57, 3069) in the presence of
n-tributylphosphine, potassium tert-butoxide, tris(dibenzylidene-
acetone)dipalladium(O) and bis(2-diphenylphosphinophenyl) ether, in a
solvent such as toluene at a temperature in the region of 110°C;
4) 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, R1 and R2 have the meanings given
hereinabove for the products of formulae (I') and (I"). The substituent R7
represents an alkyl or cycloalkyl radical.
The substituent R8 represents:
- either an alkyl radical optionally substituted with a chlorine atom, a hydroxyl
radical or a heterocycloalkyl radical, which is itself optionally substituted,
- or a cycloalkyl radical.

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 OR8 may be obtained by treating 3,6-dichloro[1,2,4]triazolo[4,3-
b]pyridazine (S) at a temperature in the region of 80°C and in a solvent such
as N,N-dimethyiformamide 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.
More particularly, the compounds of formula (E) in which Ra represents a
radical NR1R2 may be obtained by treating 3,6-dichloro[1,2,4]triazoIo[4,3-b]-
pyridazine (S) with an amine of formula (R), at a temperature in the region of
20°C and in a solvent such as N,N-dimethylformamide, or, when NR1R2 is
NH2, with aqueous ammonia, in a solvent such as dioxane, in a sealed tube,
at a temperature between 70°C and 90°C.
More particularly, the compounds of formula (E) in which Ra represents a
radical NHCOR7 may be obtained by reacting a compound of general formula
(E) with Ra = NH2 with a compound of formula (P) as described for the
compounds of general formulae (L3), (1e') and (1e").
More particularly, the compounds of formula (E) in which Ra represents an
aryl or heteroaryl radical may be obtained, for example:
- from the boronic acids of formula (B), in the presence of barium
hydroxide octahydrate and (1,1'-bis{diphenylphosphino)ferrocene)di-
chloropalladium(II) in a solvent such as, for example, N,N-dimethyl-
formamide, at a temperature in the region of 80°C,
- or alternatively, from the boronic esters of formula (V), in the
presence of dichlorobis(triphenylphosphine)palladium in a solvent such

as, for example, 1,2-dimethoxyethane, in the presence of a base such
as 1N sodium hydroxide, at a temperature in the region of 80°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, cycloalkyl or heterocycloalkyl 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 (Y) 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-5-fluoro-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 2a'/2a" and into 2c/2c", conversion of
2a72a" into 2d'/2d" 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 B, D, J, K, O, P, P', Q, R, S, U, V
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, tetra-
hydropyranyl, 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
of formula (I) as defined above, corresponding to the following formulae:
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
2-methylpropan-2-yl (5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate
5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-amine
1-(5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1 -(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
5-fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1 -(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
2-(4-cyclopropylpiperazin-1 -yl)-N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-
b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide

N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-
benzothiazol-2-yl}-2-(4-ethylpiperazin-1 -yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide
2-(4-cyclopropylpiperazin-1 -yl)-N-(5-fluoro-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-(5-fluoro-6-{[6-(tetrahydrofuran-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 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, COR6 and COR7, which constitute W, may
take the values of W as defined above for the products of formulae (I') and
(I"), when W≠H.
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 Briiker 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 λ = 210-400 nm
ELSD: Sedere SEDEX 85; nebulization temperature = 35°C; nebulization
pressure = 3.7 bar
Example 1:
1-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
a) 1 -(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea may be prepared
in the following manner
a stream of argon is bubbled for 5 minutes through a mixture of 230 mg of
N,N"-[disulfanediylbis(5-fluoro-1,3-benzothiazole-6,2-diyl)]bis{3-[2-(morpholin-
4-yl)ethyl]urea} in 15 cm3 of ethanol. 3 mg of potassium dihydrogen
phosphate in 0.1 cm3 of water, 310 mg of DL-dithiothreitol and 170 mg of
3-chloro-6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazine (1e) are then added.
The reaction mixture is heated at 80°C for 44 hours and then concentrated to
dryness under reduced pressure. The residue is taken up in water containing
sodium bicarbonate, and extracted with ethyl acetate. The organic phase is
concentrated under reduced pressure. The white solid obtained is purified on
silica by solid deposition, eluting with a 95/5 to 75/25 gradient of
dichloromethane/(38 dichloromethane/17 methanol/2 aqueous ammonia).
253 mg of 1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
5-fluoro-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 1.12 -1.31 (m, 3 H) 1.32 -
1.44 (m, 2 H) 1.44-1.55 (m, 1 H) 1.56 -1.67 (m, 2 H) 1.73 -1.88 (m, 2 H)
2.35 - 2.45 (m, 6 H) 3.21 - 3.27 (m, 2 H) 3.59 (t, J=4.4 Hz, 4 H) 4.57 - 4.77 (m,

1 H) 6.75 (t, v7=4.9 Hz, 1 H) 7.01 (d, J=9.8 Hz, 1 H) 7.53 (d, J=10.3 Hz, 1 H)
8.00 (d, J=7.3 Hz, 1 H) 8.27 (d, J=9.8 Hz, 1 H) 10.99 (br. s., 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=573+; MH- =571-
b) N,N"-[Disulfanediylbis(5-fluoro-1,3-benzothiazole-6,2-diyl)]bis{3-[2-
(morpholin-4-yl)ethyl]urea} may be prepared in the following manner
0.24 cm3 of 2-(morpholin-1-yl)ethanamine and 0.39 cm3 of triethylamine are
added to 322 mg of phenyl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-
yl)carbamate in 10 cm3 of tetrahydrofuran at 20°C. The reaction medium is
heated at 60°C for 5 hours. The clear brown solution obtained is evaporated
to dryness under reduced pressure. The residue is chromatographed on
Biotage Isolera Four 12/25 (KP-SIL, 60A; 32-63 uM), eluting with a 99/1 to
75/25 gradient of dichloromethane/(38 dichloromethane/17 methanol/2
aqueous ammonia). 231 mg of N,N"-[disulfanediylbis(5-fluoro-1,3-
benzothiazole-6,2-diyl)]bis{3-[2-(morpholin-4-yl)ethyl]urea} are thus obtained
in the form of a whitish powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=711+; MH- =709-
c) Phenyl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl)carbamate may
be prepared in the following manner:
0.75 cm3 of phenyl chlorocarbonate is added to 451 mg of 2-amino-5-fluoro-
1,3-benzothiazol-6-yl thiocyanate in 5 cm3 of pyridine at 20°C. After 5 hours
30 minutes, the yellow suspension is concentrated to dryness under reduced
pressure. The residue is chromatographed on Biotage Quad 12/25 (KP-SIL,
60A; 32-63 uM), eluting with a gradient of from 100% dichloromethane to
90/10 dichloromethane/methanol. 570 mg of phenyl (5-fluoro-6-thiocyanato-
1,3-benzothiazol-2-yl)carbamate are thus obtained in the form of a beige-
coloured powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters ZQ: MH+ m/z=346+
d) 2-Amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate may be prepared
in the manner described by K. Papke and R. Pohloudek-Fabini in Pharmazie;
GE; 22, 5 1967, pp. 229-233.

e) 3-Chloro-6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazine may be
prepared in the following manner
762 mg of sodium hydride at 60% in oil are added to a solution of 3.18 g of
cyclohexanol in 30 cm3 of tetrahydrofuran, at 0°C under argon. After stirring
for 15 minutes, 3 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial)
are added. The brown suspension is stirred for 22 hours while allowing it to
warm gradually to 20°C. The reaction mixture is poured into ice-water and the
mixture is extracted with ethyl acetate. After concentrating the organic phase
to dryness under vacuum, a brown oil is obtained. The oily residue is
chromatographed on Biotage Quad 12/25 (KP-SIL, 60A; 32-63 uM), eluting
with a 95/5 to 65/35 gradient of cyclohexane/ethyl acetate. 2.7 g of 3-Chloro-
6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form
of a yellowish powder, the characteristics of which are as follows:
MASS SPECTRUM: LC/MS Electrospray on WATERS UPLC - SQD:
MH+ = 253+
Example 2:
2-Methylpropan-2-yl (5-fluoro-6-{[6-(4-fluorophenyI)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate
a) 2-Methylpropan-2-yl (5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate may be prepared in
a manner similar to that of Example 1a, but starting with 131 mg of
2-methylpropan-2-yl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl)carbamate,
10 cm3 of degassed ethanol, 4 mg of potassium dihydrogen phosphate in
0.2 cm3 of water, 186 mg of DL-dithiothreitol and 100 mg of 3-chloro-6-(4-
fiuorophenyl)-1,2,4-triazolo[4,3-b]pyridazine, after 42 hours at 80°C. 33 mg of
2-methylpropan-2-yl (5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate 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 1.50 (s, 9 H) 7.40 (t,
J=8.8 Hz, 2 H) 7.65 (d, J=10.3 Hz, 1 H) 8.02 (d, J=9.8 Hz, 1 H) 8.10 (dd,

J=8.8, 5.4 Hz, 2 H) 8.26 (d, J=7.1 Hz, 1 H) 8.50 (d, J=9.8 Hz, 1 H) 11.97 (br.
s., 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=513+; MH- =511-
b) 2-Methylpropan-2-yl (5-fluoro-6-thiocyanato-1,3-benzothiazol-2-yl)-
carbamate may be prepared in the following manner:
41 mg of dimethylamino pyridine and 348 mg of di-tert-butyl dicarbonate are
added to 300 mg of 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate in
5 cm3 of dichloromethane and 0.45 cm3 of triethylamine, at 20°C. After 3
hours at 20°C, the reaction mixture is poured into water, the dichloromethane
is separated out by settling and the aqueous phase is extracted with ethyl
acetate. The combined organic phases are concentrated under reduced
pressure. The solid yellow residue is washed with ether and dried under
vacuum. 343 mg of 2-methylpropan-2-yl (5-fluoro-6-thiocyanato-1,3-
benzothiazol-2-yl)carbamate are thus obtained in the form of a yellow powder,
the characteristics of which are as follows:
MASS SPECTRUM: LC/MS Electrospray on WATERS UPLC - SQD:
MH+ = 324+
c) 3-Chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine may be
prepared in the following manner:
A mixture of 4.16 g of 4-fluorophenylboronic acid, 9.37 g of barium hydroxide
octahydrate, 2.20 g of [1,1'-bis(diphenylphosphino)ferrocene]dichloro-
palladium(ll) as a complex with dichloromethane (1:1) and 5.1 g of
commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine in 40 cm3 of
N,N-dimethylformamide containing 10 cm3 of water is heated in a bath at
80°C for 1.5 hours. The beige-brown suspension obtained is cooled to 20°C
and then poured into about 200 cm3 of water. The insoluble material is filtered
off by suction and washed successively with water and ether, and then dried
under vacuum at 20°C. The resulting beige-coloured solid is slurried in
dichloromethane, filtered off by suction and dried under vacuum at 20°C.
1.24 g of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine are thus
obtained. 30 g of silica are added to the combined mother liquors and the

mixture is evaporated to dryness under vacuum. This residue is deposited on
a bed of 10 g of silica in a sinter funnel, and eluted with dichloromethane. An
additional 1.60 g of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine
are thus recovered, the characteristics of which are as follows:
MASS SPECTRUM: LC-MS-DAD-ELSD: MH+ m/z=249+
Example 3:
5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-amine
5-Fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine may be prepared in the following manner:
0.9 cm3 of trifluoroacetic acid (containing 10% anisole) are gradually added
over 24 hours to a mixture of 157 mg of 2-methylpropan-2-yl (5-fluoro-6-{[6-
(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-yl)carbamate in 5 cm3 of dichloromethane at 20°C, until the starting material
has disappeared. The reaction mixture is concentrated under reduced
pressure. The residue is purified by chromatography on Biotage Quad 12/25
(KP-SIL, 60A; 32-63 urn), eluting with a 100/0 to 50/50 gradient of
dichloromethane/(dichloromethane:38/methanol:17/aqueous ammonia:2).
67 mg of 5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-amine are thus obtained in the form of a beige-
coloured powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) δ  ppm 7.26 (d, J=10.3 Hz, 1 H)
7.41 (t, J=8.8 Hz, 2 H) 7.84 (s, 2 H) 7.94 - 8.06 (m, 2 H) 8.11 (dd, J=8.8, 5.4
Hz, 2 H) 8.48 (d, J=9.8 Hz, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=413+; MH- =411-
Example 4:
1 -(5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-
yI]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea

a) 1 -(5-Fluoro-6-{[6-(4-fluorophenyl)[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 the following manner:
a stream of argon is bubbled through a solution of 217 mg of N,N"-[disulfane-
diylbis(5-fluoro-1,3-benzothiazole-6,2-diyl)]bis{3-[2-(morpholin-4-yl)ethyl]urea}
(1b) in 10 cm3 of ethanol, for 5 minutes. 3 mg of potassium dihydrogen
phosphate in 0.1 cm3 of water, 282 mg of DL-dithiothreitol and 152 mg of
3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine are then added.
The reaction medium is heated at 80°C for 40 hours and then concentrated to
dryness under reduced pressure. The residue is purified on silica by solid
deposition, eluting with a gradient of from 100% dichloromethane to 75/25
dichloromethane/(38 dichloromethane/17 methanol/2 aqueous ammonia).
104 mg of 1-(5-fluoro-6-{[6-(4-fluorophenyl)[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 beige-coloured powder, the characteristics of which
are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) δ ppm 2.28 - 2.47 (m, 6 H)
3.30 (masked m, 2 H) 3.50 - 3.67 (m, 4 H) 6.76 (br. s., 1 H) 7.40 (t, J=8.8 Hz,
2 H) 7.57 (d, J=10.0 Hz, 1 H) 8.02 (d, J=9.8 Hz, 1 H) 8.10 (dd, J=8.9,
5.3 Hz, 2 H) 8.21 (d, J=7.3 Hz, 1 H) 8.50 (d, J=9.5 Hz, 1 H) 11.01 (s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=569+; MH- =567-
Example 5:
1-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
5-fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
a) 1 -(6-{[6-(Cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
5-fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea may be
prepared in a manner similar to that of Example 1 a, but starting with 203 mg
of N,N"-[disulfanediylbis(5-fluoro-1,3-benzothiazole-6,2-diyl)]bis{3-[2-
(morpholin-4-yl)ethyI]urea} (1b) in 5 cm3 of degassed ethanol, 5 mg of
potassium dihydrogen phosphate in 0.5 cm3 of water, 265 mg of

DL-dithiothreitol and 120 mg of 3-chloro-N-cyclopropyl[1,2,4]triazolo[4,3-b]-
pyridazin-6-amine, after 18 hours at 80°C. The reaction medium is cooled to
20°C and the precipitate is filtered off by suction and then washed with
ethanol. 198 mg of 1-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-
3-yl]sulfanyl}-5-fluoro-1,3-benzothiazol-2-yl)-3-[2-(morphoiin-4-yl)ethyl]urea
are thus obtained in the form of a cream-white powder, the characteristics of
which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) δ ppm 0.32 - 0.45 (m, 2 H)
0.59 - 0.73 (m, 2 H) 2.51 - 2.56 (masked m, 1 H) 3.11 (br. s., 2 H) 3.19 - 3.29
(masked m, 2 H) 3.43 - 3.62 (m, 4 H) 3.64 - 3.81 (m, 2 H) 3.98 (m, J=10.5 Hz,
2 H) 6.77 (d, J=9.8 Hz, 1 H) 7.22 (br. s., 1 H) 7.55 (d, J=10.3 Hz, 1 H) 7.70 (d,
J=2.7 Hz, 1 H) 7.93 (d, J=9.8 Hz, 1 H) 8.14 (d, J=7.3 Hz, 1 H) 10.12 (br. s., 1
H) 11.39 (br. s., 1 H)
MASS SPECTRUM: Waters ZQ: MH+ m/z=530+; MH- =528-
b) 3-Chloro-N-cyclopropyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine may be
prepared in a manner similar to that of Example 1e, but starting with 1 cm3 of
cyclopropylamine and 2 g of 3,6-dichloro[1,2,4]triazoio[4,3-b]pyridazine
(commercial) in 20 cm3 of N,N-dimethylformamide containing 2.5 cm3 of
triethylamine, at 20°C for 18 hours. 1.83 g of 3-chloro-N-
cyclopropyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine are thus obtained in the
form of a white powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters ZQ: Retention time Tr (min) = 2.66; MH+
m/z=210+;MH-=208-
Example 6:
1-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]suIfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morphoiin-4-yl)ethyl]urea
a) 1 -(6-{[6-(Cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
5-fluoro-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 226 mg
of N,N"-[disulfanediylbis(5-fluoro-1,3-benzothiazole-6,2-diyl)]bis{3-[2-

(morpholin-4-yl)ethyl]urea} (1b) in 5 cm3 of degassed ethanol, 5 mg of
potassium dihydrogen phosphate in 0.5 cm3 of water, 265 mg of
DL-dithiothreitol and 160 mg of 3-chloro-N-cyclohexyl[1,2,4]triazolo[4,3-b]-
pyridazin-6-amine, after 18 hours at 80°C. The reaction medium is cooled to.
20°C and the precipitate is filtered off by suction and then washed with
ethanol. 189 mg of 1-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-5-fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea are
thus obtained in the form of a cream-white powder, the characteristics of
which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) δ ppm 1.00 -1.32 (m, 5 H)
1.47-1.69 (m, 3 H) 1.79 (d, J=11.5 Hz, 2 H) 2.36 - 2.46 (m, 6 H) 3.22 - 3.28
(m, 2 H) 3.32 - 3.42 (m, 1 H) 3.59 (t, J=4.4 Hz, 4 H) 6.75 (br. s., 1 H) 6.78 (d,
J=10.0 Hz, 1 H) 7.25 (d, J=7.1 Hz, 1 H) 7.50 (d, J=10.3 Hz, 1 H) 7.90 (d,
J=9.8 Hz, 1 H) 7.95 (d, J=7.3 Hz, 1 H) 10.97 (br. s., 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=572+; MH- =570-
b) 3-Chloro-N-cyclohexyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine may be
prepared in a manner similar to that of Example 1e, but starting with 3.4 cm3
of cyclohexylamine and 5 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine
(commercial) in 50 cm3 of N,N-dimethylformamide containing 11.2 cm3 of
triethylamine, at 20°C for 18 hours and then at 50°C for 4 hours. 4.45 g of
3-chloro-N-cyclohexyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine are thus obtained
in the form of a white powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.86; MH+
m/z=252+; MH- =250-
Example 7:
2-(4-cyclopropylpiperazin-1-yl)-N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-
b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}acetamide
a) 2-(4-Cyclopropylpiperazin-1 -yl)-N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-
b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}acetamide may be
prepared in a manner similar to that of Example 2a, but starting with 189 mg

of 2-{[(4-cyclopropylpiperazin-1 -yl)acetyl]amino}-5-fluoro-1,3-benzothiazol-6-yl
thiocyanate (7b), 5 cm3 of degassed ethanol, 5 mg of potassium dihydrogen
phosphate in 0.1 cm3 of water, 222 mg of DL-dithiothreitol and 96 mg of
3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine (7c), after 21 hours 30
minutes at 90°C. 114 mg of 2-(4-cyclopropyipiperazin-1-yl)-N-{6-[(6-
ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyi]-5-fluoro-1,3-benzothiazol-2-
yljacetamide 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): 0.27 (m, 2 H); 0.39 (m,
2 H); 1.27 (t, J=7.1 Hz, 3 H); 1.61 (m, 1 H); 2.42 to 2.58 (partially masked m,
8 H); 3.32 (s, 2 H); 4.24 (q, J=7.1 Hz, 2 H); 7.06 (d, J=9.8 Hz, 1 H); 7.68 (d,
J=10.0 Hz, 1 H); 8.22 (d, J=7.1 Hz, 1 H); 8,28 (d, J=9.8 Hz, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 529; [M-H]-: m/z 527
b) 2-{[(4-Cyclopropylpiperazin-1 -yl)acetyl]amino}-5-fluoro-1,3-benzo-
thiazol-6-yl thiocyanate may be prepared in the following manner:
a mixture of 1.34 g of the potassium salt of (4-cyclopropylpiperazin-1-yl)acetic
acid (7d) in 10 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. 15 cm3 of pyridine, 226 mg of 2-amino-5-fluoro-1,3-benzothiazol-6-yl
thiocyanate (1d) and 1.92 g of N-(3-dimethylaminopropyl)-N'-ethyl-
carbodiimide hydrochloride are added, at 20°C, to the white residue obtained.
After 2 hours 30 minutes, the brown reaction medium is evaporated to
dryness. The oily residue is taken up in water. The precipitate formed is
filtered off and the aqueous filtrate is then extracted with a 90/10 mixture of
ethyl acetate and methanol. The filtered precipitate is taken up in ethyl
acetate and then combined with the organic phase. The resulting solution is
dried over magnesium sulfate, filtered and then evaporated to dryness under
vacuum. The brown residue is purified on SPOT II by chromatography on a
silica cartridge (SVF D26 Si60; 15-40 uM; 25 g) eluting with a 97.4/2.6 to
90/10 gradient of dichloromethane/methanol. 191 mg of 2-{[(4-cyclopropyl-
piperazin-1-yl)acetyl]amino}-5-fluoro-1,3-benzothiazol-6-yl thiocyanate are

thus obtained in the form of a yellow powder, the characteristics of which are
as follows:
MASS SPECTRUM: Waters ZQ: Retention time Tr (min) = 2.75;
[M+H]+: m/z 392; [M-H]-: m/z 390
c) 3-Chioro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine may be prepared in a
manner similar to that of Example 1e, but starting with 19.7 g of a solution of
sodium ethoxide at 21% in ethanol and 10 g of 3,6-dichloro[1,2,4]triazolo[4,3-
bjpyridazine (commercial) in 100 cm3 of dioxane, after refluxing for 7 hours.
9.6 g of 3-chloro-6-ethoxy[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in
the form of a beige-coloured powder, the characteristics of which are as
follows:
MASS SPECTRUM: Waters ZQ: Retention time Tr (min) = 2.89; [M+H]+: m/z
199
d) The potassium salt of (4-cyclopropylpiperazin-1-yl)acetic acid may be
prepared in a manner similar to the conditions described by D.T. Witiak et al.;
J. Med. Chem. 1985, 28, 1228, but with 1 g of bromoacetic acid and 3g of
4-cyclopropylpiperazine hydrochloride. 2.66 g of the potassium salt of
(4-cyclopropylpiperazin-1-yl)acetic acid are thus obtained in the form of a
beige-coloured powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.10;
[M+H]+:m/z 185
Example 8:
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yI]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide
a) N-(6-{[6-(Cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide may be
prepared in a manner similar to that of Example 2a, but starting with 266 mg
of 2-{[(4-cyclopropylpiperazin-1 -yl)acetyl]amino}-5-fluoro-1,3-benzothiazol-6-yl
thiocyanate (7b), 5 cm3 of degassed ethanol, 5 mg of potassium dihydrogen
phosphate in 0.1 cm3 of water, 315 mg of DL-dithiothreitol and 153 mg of

3-chloro-6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazine (8b), after 24 hours
at 90°C. 180 mg of N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-5-fluoro-1,3-benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-
yl)acetamide 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): 0.22 to 0.30 (m, 2 H);
0.36 to 0.44 (m, 2 H); 1.52 to 1.65 (m, 2 H); 1.69 to 1.81 (m, 1 H); 1.95 to 2.11
(m, 2 H); 2.19 to 2.30 (m, 2 H); 2.43 to 2.58 (partially masked m, 8 H); 3.32 (s,
2 H); 4.86 (m, 1 H); 7.05 (d, J=9.8 Hz, 1 H); 7.70 (d, J=10.3 Hz, 1 H); 8.15 (d,
J=7.3 Hz, 1 H); 8.29 (d, J=10.0 Hz, 1 H); 10.15 to 14.69 (very broad m, 1 H)
MASS SPECTRUM: Waters ZQ: [M+H]+: m/z 555; [M-H]-: m/z 553
b) 3-Chloro-6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazine may be
prepared in a manner similar to that of Example 1e, but starting with 10.4 cm3
of cyclobutanol, 3.17 g of sodium hydride at 60% in oil, and 10 g of
3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial) in 100 cm3 of
tetrahydrofuran. 9 g of 3-chloro-6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]-
pyridazine 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): 1.63 to 1.96 (m, 2 H);
2.07 to 2.24 (m, 2 H); 2.41 to 2.52 (partially masked m, 2 H); 4.95 to 5.34 (m,
1 H); 7.10 (d, J=9.8 Hz, 1 H); 8.28 (d, J=9.8 Hz, 1 H)
Example 9:
N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-
benzothiazol-2-yl}-2-(4-ethylpiperazin-1 -yl)acetamide
a) N-{6-[(6-Ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-
benzothiazol-2-yl}-2-(4-ethylpiperazin-1-yl)acetamide may be prepared in a
manner similar to that of Example 2a, but starting with 353 mg of 2-{[(4-ethyl-
piperazin-1-yl)acetyl]amino}-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (9b),
10 cm3 of degassed ethanol, 5 mg of potassium dihydrogen phosphate in
0.1 cm3 of water, 430 mg of DL-dithiothreitol and 185 mg of 3-chloro-6-

ethoxy[1,2,4]triazolo[4,3-b]pyridazine (7c), after 21 hours at 90°C. 259 mg of
N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-
benzothiazol-2-yl}-2-(4-ethylpiperazin-1-yl)acetamide are thus obtained in the
form of a whitish powder, the characteristics of which are as follows:
1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 0.98 (t, J=7.1 Hz, 3 H);
1.27 (t, J=7.1 Hz, 3 H); 2.31 (q, J=7.1 Hz, 2 H); 2.35 to 2.44 (m, 4 H); 2.48 to
2.58 (partially masked m, 4 H); 3.33 (s, 2 H); 4.24 (q, J=7.1 Hz, 2 H); 7.06 (d,
J=9.8 Hz, 1 H); 7.69 (d, J=10.3 Hz, 1 H); 8.23 (d, J=7.3 Hz, 1 H); 8.28 (d,
J=9.8 Hz, 1 H); 12.16 (broad m, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 517; [M+2H]2+: m/z
259 (base peak); [M-H]-: m/z 515
b) 2-{[(4-Ethylpiperazin-1 -yl)acetyl]amino}-5-fluoro-1,3-benzothiazol-6-yl
thiocyanate may be prepared in a manner similar to that of Example 7b, but
starting with 4.6 g of (4-ethylpiperazin-1-yl)acetic acid (commercial or the
potassium salt of (4-ethylpiperazin-1 -yl)acetic acid may also be prepared in a
manner similar to the conditions described by D.T. Witiak et al. in Example
7d), 1 g of 2-amino-5-fluoro-1,3-benzothiazol-6-yl thiocyanate (1d) and 8.51 g
of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 50 cm3 of
pyridine. 714 mg of 2-{[(4-ethylpiperazin-1-yl)acetyl]amino}-5-fluoro-1,3-
benzothiazol-6-yl thiocyanate are thus obtained in the form of a yellow
powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.59;
[M+H]+: m/z 380; [M-H]-: m/z 378
Example 10:
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide
a) N-(6-{[6-(Cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide may be
prepared in a manner similar to that of Example 2a, but starting with 355 mg
of 2-{[(4-ethylpiperazin-1-yl)acetyl]amino}-5-fluoro-1,3-benzothiazol-6-yl (5-

fluoro-6-thiocyanato thiocyanate (9b), 10 cm3 of degassed ethanol, 5 mg of
potassium dihydrogen phosphate in 0.1 cm3 of water, 430 mg of DL-
dithiothreitol and 210 mg of 3-chloro-6-(cyclobutyloxy)[1,2,4]triazolo[4,3-
bjpyridazine (8b), after 21 hours at 90°C. 232 mg of N-(6-{[6-
(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-fluoro-1,3-
benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide 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): 0.98 (t, J=7.1 Hz, 3 H);
1.51 to 1.66 (m, 1 H); 1.74 (m, 1 H); 1.95 to 2.10 (m, 2 H); 2.19 to 2.27 (m, 2
H); 2.31 (q, J=7.1 Hz, 2 H); 2.39 (m, 4 H); 2.54 (m, 4 H); 3.33 (s, 2 H); 4.86
(m, 1 H); 7.05 (d, J=9.8 Hz, 1 H); 7.70 (d, J=10.3 Hz, 1 H); 8.15 (d, J=7.2 Hz,
1 H); 8.29 (d, J=9.8 Hz, 1 H); 12.20 (broad m, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 543; [M+2H]2+: m/z
272 (base peak); [M-H]-: m/z 541
Example 11:
2-(4-cyclopropylpiperazin-1-yl)-N-(5-fluoro-6-{[6-(oxetan-3-yl-
oxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
yl)acetamide
a) 2-(4-Cyclopropylpiperazin-1 -yl)-N-(5-fluoro-6-{[6-(oxetan-3-
yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
yl)acetamide may be prepared in a manner similar to that of Example 2a, but
starting with 346 mg of 2-{[(4-cyclopropylpiperazin-1-yl)acetyl]amino}-5-fluoro-
1,3-benzothiazol-6-yl thiocyanate (7b), 10 cm3 of degassed ethanol, 5 mg of
potassium dihydrogen phosphate in 0.1 cm3 of water, 407 mg of
DL-dithiothreitol and 200 mg of 3-chloro-6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazine (11b), after 22 hours at 90°C. 238 mg of 2-(4-cyclopropyl-
piperazin-1-yl)-N-(5-fluoro-6-{[6-(oxetan-3-yloxy)[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 powder, the characteristics of which are as follows:

1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 0.22 to 0.29 (m, 2 H);
0.36 to 0.42 (m, 2 H); 1.60 (m, 1 H); 2.43 to 2.60 (partially masked m, 8 H);
3.32 (s, 2 H); 4.48 (m, 2 H); 4.71 (m, 2 H); 5.36 to 5.46 (m, 1 H); 7.20 (d,
J=9.8 Hz, 1 H); 7.71. (d, J=10.3 Hz, 1 H); 8.06 (d, J=7.3 Hz, 1 H) 8.38 (d,
J=9.8 Hz, 1 H); 12.15 (broad m, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 557; [M+2H]2+: m/z
279 (base peak); [M-H]-: m/z 555
b) 3-Chloro-6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazine may be
prepared in a manner similar to that of Example 1e, but starting with 1.96 g of
oxetan-3-ol, 634 mg of sodium hydride at 60% in oil and 2 g of
3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial) in 20 cm3 of
tetrahydrofuran. 2.04 g of 3-chloro-6-(oxetan-3-yloxy)[1,2,4]triazolo[4,3-
b]pyridazine are thus obtained in the form of a whitish powder, the
characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.41;
[M+H]+: m/z 227
Example 12:
Rac-2-(4-cyclopropylpiperazin-1-yl)-N-(5-fluoro-6-{[6-(tetrahydrofuran-3-
yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothlazol-2-
yl)acetamide
a) rac-2-(4-Cyclopropylpiperazin-1-yl)-N-(5-fluoro-6-{[6-(tetrahydrofuran-
3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-
acetamide may be prepared in a manner similar to that of Example 2a, but
starting with 325 mg of 2-{[(4-cyclopropylpiperazin-1-yl)acetyl]amino}-5-fluoro-
1,3-benzothiazol-6-yl thiocyanate (7b), 10 cm3 of degassed ethanol, 5 mg of
potassium dihydrogen phosphate in 0.1 cm3 of water, 385 mg of
DL-dithiothreitol and 200 mg of rac-3-chloro-6-(tetrahydrofuran-3-
yloxy)[1,2,4]triazolo[4,3-b]pyridazine (12b), after 18 hours at 90°C. 206 mg of
rac-2-(4-cyclopropylpiperazin-1-yl)-N-(5-fluoro-6-{[6-(tetrahydrofuran-3-
yloxy)[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 powder, the
characteristics of which are as follows:
1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 0.19 to 0.30 (m, 2 H);
0.36 to 0.43 (m, 2 H); 1.60 (m, 1 H); 1.94 to 2.02 (m, 1 H); 2.07 to 2.22 (m, 1
H); 2.42 to 2.60 (partially masked m, 8 H); 3.32 (s, 2 H); 3.60 to 3.84 (m, 4 H);
5.27 (m, 1 H); 7.08 (d, J=9.8 Hz, 1 H); 7.70 (d, J=10.0 Hz, 1 H); 8.14 (d, J=7.3
Hz, 1 H); 8.31 (d, J=9.8 Hz, 1 H); 12.17 (broad m, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: [M+H]+: m/z 571; [M-H]-: m/z 569
b) rac-3-Chloro-6-(tetrahydrofuran-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazine
may be prepared in a manner similar to that of Example 1e, but starting with
2.33 g of rac-tetrahydrofuran-3-ol, 634 mg of sodium hydride at 60% in oil and
2 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial) in 20 cm3 of
tetrahydrofuran. 2.09 g of rac-3-chloro-6-(tetrahydrofuran-3-yl-
oxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form of a beige-
coloured powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: Retention time Tr (min) = 0.49;
[M+H]+: m/z 241
Example 13: Pharmaceutical composition
Tablets corresponding to the following formula were prepared:
Product of Example 1 0.2 g
Excipient for a finished tablet weighing 1 g
(details of the excipient: lactose, talc, starch,
magnesium stearate).
Example 14: Pharmaceutical composition
Tablets corresponding to the following formula were prepared:
Product of Example 6 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
I) Expression and Purification of MET, cytoplasmic domain
Expression as Baculovirus:
The recombinant DNA His-Tev-MET (956-1390) in pFastBac (Invitrogen) is
transfected into insect cells and, after several viral amplification steps, the
final baculovirus stock is tested for expression of the protein of interest.
After infection for 72 hours at 27°C with the recombinant virus, the SF21 cell
cultures are harvested by centrifugation and the cell pellets are stored at
-80°C.
Purification:
The cell pellets are resuspended in lysis buffer (buffer A [50 mM HEPES, pH
7.5, 250 mM 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
A) Test A: HTRF MET test in 96-well format
In a final volume of 50 µl 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 µM and MgCI2
5 mM. After incubation for 10 minutes at room temperature, the reaction is
stopped with a mix of 30 µl 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 µM 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;
Ra represents a hydrogen atom; a halogen atom; an alkoxy radical optionally
substituted with a chlorine atom, a hydroxyl radical or a heterocycloalkyl
radical, which is itself optionally substituted; a radical -O-cycloalkyl, -O-
heterocycloalkyl; -NH-cycloalkyl and -NH-heterocycloalkyl, all optionally
substituted; an optionally substituted heteroaryl radical; an optionally
substituted phenyl radical; a radical NHCOalkyl or NHCOcycloalkyl; or a
radical NR1R2 as defined below;
X represents S, SO or SO2;
A represents NH or S;
W represents a hydrogen atom; an alkyl, cycloalkyl or heterocycloalkyl 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 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 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, 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, this
radical, including the possible NH it contains, being optionally
substituted;
all the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl 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, NH2, NHalk, N(alk)2 and
alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl,
heteroaryl, CO-phenyl and S-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 the following radicals: hydroxyl, oxo, alkyland alkoxy
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).
2) Products of formula (I) as defined in the preceding claim, in which , X
and A have the meanings given in the preceding claim,
Ra represents an alkoxy radical optionally substituted with a chlorine atom, a
hydroxyl radical or a heterocycloalkyl radical, which is itself optionally
substituted; a radical O-cycloalkyl; a radical NHCOalk; or a radical
NR1aR2a such that R1a and R2a represent 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 hydroxyl, alkoxy, heteroaryl,
heterocycloalkyl, NR3R4 and phenyl radicals, optionally substituted;
and 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, hydroxy, 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 representing 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 one or
more radicals, which may be identical or different, chosen from
hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4 or phenyl

radicals, 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 optional 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 with one or more radicals, which may be
identical or different, chosen from hydroxyl, alkoxy, heteroaryl,
heterocycloalkyl, NH2, NHalk, N(alk)2 or phenyl radicals, 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 optional NH it contains, being optionally substituted;
all the heterocycloalkyl, heteroaryl 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, hydroxyl, oxo, alkoxy, NH2,
NHalk, N(alk)2 radicals and alkyl, cycloalkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl, CO-phenyl and
S-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, oxo, 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).

3) Products of formula (I) as defined in either of the preceding claims, in
which , Ra and X have the values defined in either of the preceding
claims, and:
A represents NH or S;
W represents a hydrogen atom; an alkyl radical optionally substituted with
alkoxy or heterocycloalkyl; or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical optionally substituted with a
radical NR3R4, alkoxy, hydroxy, 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 representing 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 NR3R4 or with alkoxy, 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 optional NH it contains, being optionally substituted;
with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical, or alternatively R3 and R4
form, with the nitrogen atom to which they are attached, a 3- to 10-membered
cyclic radical optionally containing one or more other heteroatoms chosen
from O, S, N and NH, this radical, including the optional NH it contains, being
optionally substituted;
the heterocycloalkyl, heteroaryl 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, hydroxyl, alkoxy, NH2,
NHalk, N(alk)2 radicals and alkyl, heterocycloalkyl, CH2-heterocycloalkyl,
phenyl, CH2-phenyl, heteroaryl, CO-phenyl and S-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
and 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 other claims, in which
represents a single or double bond;
Ra represents a hydrogen atom or a halogen atom, or alternatively an
optionally substituted phenyl radical;
X represents S, SO or SO2;
A represents NH or S;
W represents a hydrogen atom or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical, optionally substituted with a
radical phenyl, heteroaryl, NR3R4 or heterocycloalkyl, which are
themselves optionally substituted;
- an alkoxy radical optionally substituted with NR3R4, i.e. a radical
O-(CH2)n-NR3R4, a radical O-phenyl or 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 cycloaJkyl 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 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, optionally substituted 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 heterocycloalkyl, heteroaryl 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, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl, CH2-hetero-
cycloalkyl, CH2-phenyl, CO-phenyl and S-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 the following radicals: hydroxyl, oxo, alkyl and alkoxy
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 other claims, in which
, Ra and X have the values defined in any one of the other claims, and:
A represents NH or S;
W represents a hydrogen atom or an alkyl radical or the radical COR in which
R represents:

- an alkyl radical optionally substituted with OCH3 or NR3R4;
- a cycloalkyl radical;
- an alkoxy radical optionally substituted with OCH3 or NR3R4, i.e. a
radical O-(CH2)n-OCH3 or a radical O-(CH2)n-NR3R4, 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 an alkyl radical
optionally substituted with 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;
the 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, NH2, NHalk,
N(alk)2 and alkyl, CH2-heterocycloalkyl, CH2-phenyl, CO-phenyl and
S-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).
6) Products of formula (I) as defined in any one of the other claims, in which
, Ra and X have the values defined in any one of the other claims, and:
A represents NH or S;
W represents a hydrogen atom or the radical COR in which R represents:
- an alkyl radical optionally substituted with NR3R4;
- an alkoxy radical optionally substituted with NR3R4, i.e. a radical
O-(CH2)n-NR3R4, a radical O-phenyl or O-(CH2)n-phenyl, with phenyl
optionally substituted and n representing 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 or an alkyl radical and the
other from among R1 and R2 represents an alkyl radical optionally substituted
with 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;
the 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, NH2, NHalk,
N(alk)2 and alkyl, CH2-heterocycloalkyl, CH2-phenyl, CO-phenyl and
S-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).
7) Products of formula (I) as defined in any one of the preceding claims, in
which , X, A and W have the meanings indicated in any one of the other
claims, Ra represents a hydrogen atom or a chlorine atom, or the radical:

with Rb representing a halogen atom or a radical S-heteroaryl optionally
substituted with a radical 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).
8) Products of formula (I) as defined in any one of the other claims, in which A
represents NH, the substituents , Ra, 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).
9) Products of formula (I) as defined in any one of the other claims, in which A
represents S, the substituents , Ra, 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).
10) Products of formula (I) as defined in any one of the other claims,
corresponding to formula (la) or (lb):

in which , Ra 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).
11) Products of formula (I) as defined in any one of the preceding claims, in
which represents a single bond, corresponding to the products of
formula (I'):

the substituents Ra, X, A and W having the meanings given in any 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).
12) Products of formula (I) as defined in any one of the other claims, in which
represents a double bond, corresponding to the products of formula

in which the substituents Ra, X, A and W have the meanings indicated 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).
13) Products of formula (la) as defined in any one of the preceding claims, in
which represents a single bond, corresponding to the products of
formula (la'):

in which Ra and W are chosen from the meanings given in any of the other
claims,
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).

14) Products of formula (la) as defined in any one of the other claims, in
which represents a double bond, corresponding to the products of
formula (l"a):

in which Ra and W are chosen from the meanings indicated in any one of the
other claims,
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).
15) Products of formula (lb) as defined in any one of the preceding claims, in
which represents a single bond, corresponding to the products of
formula (I'b):

in which Ra and W are chosen from the meanings indicated in any one of the
other claims,
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).
16) Products of formula (lb) as defined in any one of the other claims, in
which represents a double bond, corresponding to the products of
formula (l"b):


in which Ra and W are chosen from the meanings indicated in any one of the
other claims,
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).
17) Products of formula (I) as defined in any one of the other claims,
corresponding to the following formulae:
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
2-methylpropan-2-yl (5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-
b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate
5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-amine
1 -(5-fluoro-6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-
yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1 -(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
5-fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1 -(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
2-(4-cyclopropylpiperazin-1 -yl)-N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-
b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-benzothiazol-2-yl}acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1 -yl)acetamide

N-{6-[(6-ethoxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-5-fluoro-1,3-
benzothiazol-2-yl}-2-(4-ethylpiperazin-1 -yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-5-
fluoro-1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide
2-(4-cyclopropylpiperazin-1 -yl)-N-(5-fiuoro-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-(5-fluoro-6-{[6-(tetrahydrofuran-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).
18) Process for preparing the products of formula (I) as defined in any one of
the other claims.
19) Process for preparing the products of formula (I) as defined in any one of
the other claims, in which A represents NH.
20) Process for preparing the products of formula (I) as defined in any one of
the other claims, in which A represents S.
21) As medicaments, the products of formula (I) as defined in any one of
Claims 1 to 17, 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).
22) As medicaments, the products of formula (I) as defined in Claim 17, 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).
23) Pharmaceutical compositions containing, as active principle, at least one
of the products of formula (I) as defined in any one of Claims 1 to 17, or a
pharmaceutically acceptable salt of this product or a prodrug of this product
and a pharmaceutically acceptable support.

24) Use of the products of formula (I) as defined in any one of Claims 1 to 17,
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.
25) Use as defined in Claim 24, in which the kinase protein is in a cell culture.
26) Use as defined in Claim 24 or 25, in which the kinase protein is in a
mammal.
27) Use of a product of formula (I) as defined in any one of Claims 1 to 17, 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.
28) Use of a product of formula (I) as defined in any one of Claims 1 to 17, for
the preparation of a medicament for treating cancers.
29) Use according to Claim 28, for treating solid or liquid tumours.
30) Use according to Claims 28 or 29, for treating cancers that are resistant to
cytotoxic agents.
31) Use according to one or more of Claims 28 to 30, 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.
32) Use of the products of formula (I) as defined in Claims 1 to 17, for the
preparation of medicaments for cancer chemotherapy.
33) Use of the products of formula (I) as defined in Claims 1 to 17, for the
preparation of medicaments for cancer chemotherapy, alone or in
combination.
34) Products of formula (I) as defined in any one of Claims 1 to 17, as kinase
inhibitors.

35) Products of formula (I) as defined in any one of Claims 1 to 17, as MET
inhibitors.
36) As novel industrial products, the synthetic intermediates of formulae M1,
M2, M3 and N:

in which R6 represents an alkyl radical optionally substituted with a group
NR3R4 (a radical -(CH2)n-NR3R4), alkoxy, hydroxyl, heterocycloalkyl, phenyl
or -(CH2)n-phenyl, with phenyl optionally substituted and n representing an
integer from 1 to 4, such that OR6 represent the corresponding values of R as
defined above; R7 represents a cycloalkyl or alkyl radical optionally
substituted with a radical NR3R4, alkoxy or hydroxyl or a phenyl, heteroaryl or
heterocycloalkyl radical, which are themselves optionally substituted as
indicated in Claim 1; and Ra, R1, R2, R3 and R4 have the meanings
indicated in Claim 1.

The invention relates to novel products of the formula (I) where: (II) is a single or double bond; F is a fluorine
atom, Ra is H, HaI, alkoxy, O-cycloalkyl, -O- heterocycloalkyl; -NH-cycloalkyl, -NH-heterocycloalkyl, heteroaryl, phenyl,
NHCOaIk, NHCOcycloalk or NR1 R2; X is S, SO or SO2, A is NH or S; W is H, alkyl, or COR with R being cycloalkyl; alkyl
optionally substituted by NR3R4, alkoxy, hydroxy, phenyl, heteroaryl, or heterocycloalkyl; alkoxy optionally substituted by
NR3R4, i.e. a O-(CH2)n-NR3R4 radical, an O-phenyl or an O-(CH2)n-phenyl radical, with phenyl optionally substituted and n =
1 to 4; or the NR1 R2 radical; R1 is H or alk and R2 is H, cycloalkyl or alkyl; R3 and R4 are H, alk, cycloalkyl, heteroaryl or
phenyl; R1, R2 and/or R3,R4 form a cycle together with N optionally containing O, S, N and/or NH; heterocycloalkyl, heteroaryl
and phenyl and cycles all being optionally substituted; wherein said products can be in any isomer or salt form, and can be used as
drugs, in particular as MET inhibitors.