DERIVATIVES OF 6-(6-O-CYCLOALKYL- OR 6-NH-CYCLOALKYL-
TRIAZOLOPYRIDAZINE-SULFANYL) BENZOTHIAZOLES AND
BENZIMIDAZOLES, PREPARATION THEREOF, USE THEREOF AS
DRUGS, AND USE THEREOF AS MET INHIBITORS
The present invention relates to novel 6-O-cycloalkyl- or 6-NH-cycloalkyl-
triazolopyridazine-sulfanyl benzothiazole and benzimidazole derivatives, to a
process for preparing them, to the novel intermediates obtained, to their use
as medicaments, to pharmaceutical compositions containing them and to the
novel use of such 6-triazolopyridazine-sulfanyl benzothiazole and
benzimidazole derivatives.
The present invention more particularly relates to novel 6-O-cycloalkyl or 6-
NH-cycloalkyl-triazolopyridazine-sulfanyl benzothiazole and benzimidazole
derivatives with anticancer activity, via modulation of the activity of proteins, in
particular kinases.
To date, most of the commercial compounds used in chemotherapy are
cytotoxic and pose major problems of side effects and tolerance by patients.
These effects can be limited if the medicaments used act selectively on
cancer cells, to the exclusion of healthy cells. One of the solutions for limiting
the undesirable effects of a chemotherapy may thus consist in using
medicaments that act on metabolic pathways or constituent elements of these
pathways, predominantly expressed in cancer cells, and not expressed or
only sparingly expressed in healthy cells. Kinase proteins are a family of
enzymes that catalyse the phosphorylation of hydroxyl groups of specific
protein residues such as tyrosine, serine or threonine residues. Such
phosphorylations may widely modify the function of proteins: thus, kinase
proteins play an important role in regulating a wide variety of cellular
processes, especially including cell metabolism and proliferation, cellular
adhesion and motility, cell differentiation or cell survival, certain kinase
proteins playing a central role in the initiation, development and completion of
cell cycle events.
Among the various cellular functions in which the activity of a kinase protein is
involved, certain processes represent attractive targets for treating certain
diseases. Examples that may especially be mentioned include angiogenesis
and control of the cell cycle and also that of cell proliferation, in which kinase
proteins may play an essential role. These processes are especially essential
for the growth of solid tumours and also other diseases: in particular,
molecules that inhibit such kinases are capable of limiting undesired cell
proliferations such as those observed in cancers, and can intervene in the
prevention, regulation or treatment of neurodegenerative diseases such as
Alzheimer's disease or neuronal apoptosis.
One subject of the present invention is novel derivatives endowed with
inhibitory effects on kinase proteins. The products according to the present
invention may thus be used especially for preventing or treating diseases that
can be modulated by inhibiting kinase proteins.
The products according to the present invention especially show anticancer
activity, via modulation of the activity of kinases. Among the kinases for which
activity modulation is desired, MET and also mutants of the protein MET are
preferred.
The present invention also relates to the use of the said derivatives for
preparing a medicament for treating man.
Thus, one of the objects of the present invention is to propose compositions
with anticancer activity, by acting in particular on kinases. Among the kinases
for which activity modulation is desired, MET is preferred.
In the pharmacological section hereinbelow, it is shown in biochemical tests
and on cell lines that the products of the present patent application thus
especially inhibit the autophosphorylation activity of MET and the proliferation
of cells whose growth is dependent on MET or mutants forms thereof.
MET, or Hepatocyte Growth Factor Receptor, is a receptor with tyrosine
kinase activity that is expressed in particular in epithelial and endothelial cells.
HGF, Hepatocyte Growth Factor, is described as the specific ligand of MET.
HGF is secreted by mesenchymal cells and activates the MET receptor,
which homodimerizes. Consequently, the receptor becomes
autophosphorylated on tyrosines Y1230, Y1234 and Y1235 of the catalytic
domain.
Stimulation of MET with HGF induces cell proliferation, scattering (or
dispersion) and motility, resistance to apoptosis, invasion and angiogenesis.
MET and likewise HGF are found to be overexpressed in many human
tumours and a wide variety of cancers. MET is also found to be amplified in
gastric tumours and glioblastomas. Many point mutations of the MET gene
have also been described in tumours, in particular in the kinase domain, but
also in the juxtamembrane domain and the SEMA domain. Overexpression,
amplification or mutations cause constitutive activation of the receptor and
deregulation of its functions.
The present invention thus relates especially to novel inhibitors of the kinase
protein MET and mutants thereof, which may be used for anti-proliferative
and anti-metastatic treatment especially in oncology.
The present invention also relates to novel inhibitors of the kinase protein
MET and mutants thereof, which may be used for anti-angiogenic treatment,
especially in oncology.
One subject of the present invention is the products of formula (I):
in which
----- represents a single or double bond;
Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl, both
optionally substituted;
X represents S, SO or S02;
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
halogen atom or a radical cycloalkyl, 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, a cycloalkyl radical or
an alkyl radical and the other from among R1 and R2 represents a
hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an
alkyl radical optionally substituted with one or more radicals, which
may be identical or different, chosen from the following radicals:
hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl,
optionally substituted or alternatively R1 and R2 form, with the nitrogen
atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from 0, S,
N and NH, with the optional S possibly being in the form SO or S02;
this radical, including the possible NH it contains, being optionally
substituted;
with R3 and R4, which may be identical or different, representing a
hydrogen atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl
radical, a heteroaryl radical or a phenyl radical, all optionally substituted
with one or more radicals, which may be identical or different, chosen from
the following radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2,
NHAlk, N(Alk)2 or phenyl optionally substituted; or alternatively R3 and R4
form, with the nitrogen atom to which they are attached, a 3- to 10-
membered cyclic radical optionally containing one or more other
heteroatoms chosen from O, S, N and NH, with the optional S possibly
being in the form SO or S02; this radical, including the possible NH it
contains, being optionally substituted;
all the alkyl, 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, -0-C0-R5, -COOH, COOR5,
-C0NH2, C0NHR5, NH2, NHR5, NR5R5', -NH-C0-R5 and alkyl, cycloalkyl,
heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl,
heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl,
cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves
optionally substituted with one or more radicals chosen from halogen atoms
and the following radicals: hydroxyl, oxo, alkyl and alkoxy containing from 1 to
4 carbon atoms, NH2, NHalk and N(alk)2,
all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined
above being furthermore optionally substituted with a radical Si(alk)3;
it being possible for all the cycloalkyl and heterocycloalkyl radicals defined
above to be optionally substituted on one of the carbons of the ring by a
spirocycloalkyl or spiroheterocycloalkyl radical or optionally on two of the
carbons of the ring by a fused cycloalkyl or heterocycloalkyl radical;
R5 and R5', which may be identical or different, represent an alkyl or
cycloalkyl radical containing not more than 6 carbon atoms;
alk represents an alkyl radical containing not more than 4 carbon atoms;
it being understood that W does not represent H when A represents S, X
represents S, Ra represents the unsubstituted O-cyclohexyl radical or the
unsubstituted NH-cyclohexyl radical and represents a double bond,
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which
represents a single or double bond;
Ra represents a radical -O-cycloalkyl or a radical -NH-cycloalkyl optionally
substituted;
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
halogen atom or a radical cycloalkyl, 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, a cycloalkyl radical or
an alkyl radical and the other from among R1 and R2 represents a
hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an
alkyl radical optionally substituted with one or more radicals, which
may be identical or different, chosen from the following radicals:
hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl,
optionally substituted or alternatively R1 and R2 form, with the nitrogen
atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from O, S,
N and NH, with the optional S possibly being in the form SO or S02,
this radical, including the possible NH it contains, being optionally
substituted;
with R3 and R4, which may be identical or different, representing a hydrogen
atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a
heteroaryl radical or a phenyl radical, all optionally substituted with one or
more radicals, which may be identical or different, chosen from the following
radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, N(Alk)2
or phenyl, optionally substituted; or alternatively R3 and R4 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from O, S, N and
NH, with the optional S possibly being in the form SO or S02, this radical,
including the possible NH it contains, being optionally substituted;
all the alkyl, 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, -
0-CO-R5, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and
S-heteroaryl radicals, such that in the latter radicals, the alkyl,
cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are
themselves optionally substituted with one or more radicals chosen
from halogen atoms and the following radicals: hydroxyl, oxo, alkyl and
alkoxy containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;
R5 represents an alkyl or cycloalkyl radical containing not more than 6 carbon
atoms;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which ----- , Ra and X have the values
defined in any one of the other claims, and:
A represents NH or S;
W represents a hydrogen atom; an alkyl radical optionally substituted with
alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical optionally substituted with a
halogen atom or a radical cycloalkyl, NR3R4, alkoxy, hydroxyl, phenyl or
heterocycloalkyl, which are themselves optionally substituted;
- an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or
heterocycloalkyl; a radical O-phenyl or a radical 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, a heterocycloalkyl radical or an alkyl radical
optionally substituted with an alkoxy or heterocycloalkyl radical, or
NR3R4; or alternatively R1 and R2 form, with the nitrogen atom to
which they are attached, a 3- to 10-membered cyclic radical optionally
containing one or more other heteroatoms chosen from O, S, N and
NH, this radical, including the possible NH it contains, being optionally
substituted;
- with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical or a heterocycloalkyl
radical, all optionally substituted with one or more radicals, which may
be identical or different, chosen from alkoxy or heterocycloalkyl
radicals or NH2, NHAlk or 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 cycloalkyl, heterocycloalkyl and phenyl radicals, and also the cyclic
radicals that may be formed by R1 and R2 or R3 and R4 with the nitrogen
atom to which they are attached, defined above, being optionally substituted
with one or more radicals chosen from halogen atoms and the following
radicals: hydroxyl, alkoxy, NH2, NHalk, N(alk)2 and alkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that
in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals
are themselves optionally substituted with one or more radicals chosen from
halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4
carbon atoms, NH2, NHalk and N(alk)2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
As regards the cyclic radicals that can be formed by R1 and R2 or R3 and R4
with the nitrogen atom to which they are attached, these radicals optionally
containing one or more other heteroatoms chosen from O, S, N and NH, with
the optional S possibly being in the form SO or S02; these radicals, including
the optional NH they contain, may thus be optionally substituted especially
with a radical chosen from alkyl, alkoxy, cycloalkyl and heterocycloalkyl,
which are themselves optionally substituted with one or more radicals chosen
from halogen atoms and the radicals alkyl, alkoxy, NH2, NHAlk and N(Alk)2;
One subject of the present invention is the products of formula (I):
in which
----- represents a single or double bond;
Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl, both
optionally substituted;
X represents S, SO or S02;
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, a cycloalkyl radical or
an alkyl radical and the other from among R1 and R2 represents a
hydrogen atom, a cycloalkyl radical or an alkyl radical optionally
substituted with one or more radicals, which may be identical or
different, chosen from the following radicals: hydroxyl, alkoxy,
heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally substituted or
alternatively R1 and R2 form, with the nitrogen atom to which they are
attached, a 3- to 10-membered cyclic radical optionally containing one
or more other heteroatoms chosen from O, S, N and NH, this radical,
including the possible NH it contains, being optionally substituted;
with R3 and R4, which may be identical or different, representing a hydrogen
atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl
radical, all optionally substituted, or alternatively R3 and R4 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from O, S, N and
NH, this radical, including the possible NH it contains, being optionally
substituted;
all the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals
defined above, and also the cyclic radicals that may be formed by R1 and R2
or R3 and R4 with the nitrogen atom to which they are attached, being
optionally substituted with one or more radicals chosen from halogen atoms
and the following radicals: hydroxyl, oxo, alkoxy, -0-CO-R5, -COOH, COOR5,
-CONH2, CONHR5, NH2, NHR5, NR5R5', -NH-CO-R5 and alkyl, cycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and S-
heteroaryl radicals, such that in the latter radicals, the alkyl, cycloalkyl,
heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally
substituted with one or more radicals chosen from halogen atoms and the
following radicals: hydroxyl, oxo, alkyl and alkoxy containing from 1 to 4
carbon atoms, NH2, NHalk and N(alk)2,
all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined
above being furthermore optionally substituted with a radical Si(alk)3;
R5 and R5', which may be identical or different, represent an alkyl or
cycloalkyl radical containing not more than 6 carbon atoms;
alk represents an alkyl radical containing not more than 4 carbon atoms;
it being understood that W does not represent H when A represents S, X
represents S, Ra represents the unsubstituted O-cyclohexyl radical or the
unsubstituted NH-cyclohexyl radical and '"^ represents a double bond,
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which
—— represents a single or double bond;
Ra represents a radical -O-cycloalkyl or a radical -NH-cycloalkyl both
optionally substituted;
X represents S, SO or SO2;
A represents NH orS;
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, a cycloalkyl radical or
an alkyl radical and the other from among R1 and R2 represents a
hydrogen atom, a cycloalkyl radical or an alkyl radical optionally
substituted with one or more radicals, which may be identical or
different, chosen from the following radicals: hydroxyl, alkoxy,
heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally substituted or
alternatively R1 and R2 form, with the nitrogen atom to which they are
attached, a 3- to 10-membered cyclic radical optionally containing one
or more other heteroatoms chosen from O, S, N and NH, this radical,
including the possible NH it contains, being optionally substituted;
with R3 and R4, which may be identical or different, representing a hydrogen
atom, an alkyl radical, a cycloalkyl radical, a heteroaryl radical or a phenyl
radical, which is optionally substituted, or alternatively R3 and R4 form, with
the nitrogen atom to which they are attached, a 3- to 10-membered cyclic
radical optionally containing one or more other heteroatoms chosen from O,
S, N and NH, this radical, including the possible NH it contains, being
optionally substituted;
all the 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, -0-CO-R5, NH2, NHalk,
N(alk)2 and alkyl, cycloalkyl, heterocycloalkyl, CH2-heterocycloalkyl, phenyl,
CH2-phenyl, CO-phenyl, heteroaryl and S-heteroaryl radicals, such that in the
latter radicals, the alkyl, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl
radicals are themselves optionally substituted with one or more radicals
chosen from halogen atoms and the following radicals: hydroxyl, oxo, alkyl
and alkoxy containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;
R5 represents an alkyl or cycloalkyl radical containing not more than 6 carbon
atoms;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which z , Ra and X have the values
defined in any one of the other claims, and:
A represents NH orS;
W represents a hydrogen atom; an alkyl radical optionally substituted with
alkoxy, heterocycloalkyl or NR3R4; or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical optionally substituted with a
radical NR3R4, alkoxy, hydroxyl, phenyl or heterocycloalkyl, which are
themselves optionally substituted;
- an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or
heterocycloalkyl; a radical O-phenyl or a radical 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 an alkoxy or
heterocycloalkyl radical, or NR3R4; or alternatively R1 and R2 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from O, S, N and
NH, this radical, including the possible NH it contains, being optionally
substituted;
with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical or alternatively R3 and R4 form,
with the nitrogen atom to which they are attached, a 3- to 10-membered cyclic
radical optionally containing one or more other heteroatoms chosen from O,
S, N and NH, this radical, including the possible NH it contains, being
optionally substituted;
all the cycloalkyl, heterocycloalkyl and phenyl radicals, and also the cyclic
radicals that may be formed by R1 and R2 or R3 and R4 with the nitrogen
atom to which they are attached, defined above, being optionally substituted
with one or more radicals chosen from halogen atoms and the following
radicals: hydroxyl, alkoxy, NH2, NHalk, N(alk)2 and alkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that
in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals
are themselves optionally substituted with one or more radicals chosen from
halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4
carbon atoms, NH2, NHalk and N(alk)2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which----- , Ra and X have the values
defined in any one of the other claims, and:
A represents NH or S;
W represents a hydrogen atom; an alkyl radical optionally substituted with a
heterocycloalkyl radical or NR3R4; or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical optionally substituted with a
radical NR3R4, or alkoxy;
- a radical O-phenyl or 0-(CH2)n-phenyl, with phenyl optionally
substituted and n represents an integer from 1 to 2;
- or the radical NR1R2, in which R1 and R2 are such that one from
among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an
alkyl radical and the other from among R1 and R2 represents a hydrogen
atom, an alkyl radical optionally substituted with a heterocyclic radical or
NR3R4, or alternatively R1 and R2 form, with the nitrogen atom to which they
are attached, a cyclic radical optionally containing one or more other
heteroatoms chosen from O, S, N and NH, this radical, including the possible
NH it contains, being optionally substituted;
with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical or alternatively R3 and R4 form,
with the nitrogen atom to which they are attached, a cyclic radical optionally
containing one or more other heteroatoms chosen from O, S, N and NH, this
radical, including the possible NH it contains, being optionally substituted;
all the cycloalkyl, heterocyclic and phenyl radicals, and also the cyclic radicals
that may be formed by R1 and R2 or R3 and R4 with the nitrogen atom to
which they are attached, defined above, being optionally substituted with one
or more radicals chosen from halogen atoms and the following radicals:
hydroxyl, alkoxy, NH2, NHalk, N(alk)2 and alkyl and phenyl radicals, the latter
radicals themselves being optionally substituted with one or more radicals
chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing
from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which A represents NH, the
substituents 1Z-ZJL , 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).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which A represents S, the substituents zzs~ ,
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).
One subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow corresponding to formula (la) or (lb):
in which ^~ , Ra and W are chosen from the meanings indicated in any
one of the other claims,
the said products of formula (la) and (lb) being in any possible racemic,
enantiomeric or diastereoisomeric isomer form, and also the addition salts
with mineral and organic acids or with mineral and organic bases of the said
products of formulae (la) and (lb).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which ^^ represents a single bond,
corresponding to the products of formula (I'):
the substituents Ra, X, A and W having 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).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which ~ represents a double bond,
corresponding to the products of formula (I"):
in which the substituents Ra, 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).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which ----- represents a single bond,
corresponding to the products of formula (la'):
in which Ra and W are chosen from the meanings indicated in any one 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).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which ----- represents a double bond,
corresponding to the products of formula (l"a):
in which Ra 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).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which 1ZZ^ 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
ordiastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I'b).
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which represents a double bond,
corresponding to the products of formula (l"b):
in which Ra 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).
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,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radicals;
- the term heterocycloalkyl radical thus denotes a 3- to 10-membered
monocyclic or bicyclic carbocyclic radical interrupted with one or more
heteroatoms, which may be identical or different, chosen from oxygen,
nitrogen and sulfur atoms: examples that may be mentioned include
morpholinyl, thiomorpholinyl, aziridyl, azetidyl, piperazinyl, piperidyl,
homopiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl,
tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl and
oxodihydropyridazinyl radicals, or alternatively oxetanyl or thietanyl radicals,
all these radicals being optionally substituted; it may be noted that these
heterocycloalkyl radicals may comprise a bridge formed from two ring
members to form, for example, an oxa-5-azabicyclo[2.2.1]heptane or an
azaspiro[3.3]heptane radical or other azabicycloalkane or azaspiroalkane
rings.
- the terms aryl and heteroaryl denote unsaturated or partially unsaturated
monocyclic or bicyclic, carbocyclic and heterocyclic radicals, respectively,
which are not more than 12-membered, possibly containing a -C(O) ring
member, the heterocyclic radicals containing one or more heteroatoms, which
may be identical or different, chosen from O, N and S with N, where
appropriate, being optionally substituted;
- the term aryl radical thus denotes 6- to 12-membered monocyclic or bicyclic
radicals, for instance phenyl, naphthyl, biphenyl, indenyl, fluorenyl and
anthracenyl radicals, more particularly phenyl and naphthyl radicals and even
more particularly the phenyl radical. It may be noted that a carbocyclic radical
containing a -C(O) ring member is, for example, the tetralone radical;
- 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-isoxazolyI, 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, dihydrofuro pyrazolyl, 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, propionyloxymethyl, methylthiomethyl,
dimethylaminoethyl, benzyl or phenethyl groups.
The addition salts with mineral or organic acids of the products of formula (I)
may be, for example, the salts formed with hydrochloric, hydrobromic,
hydriodic, nitric, sulfuric, phosphoric, propionic, acetic, trifluoroacetic, formic,
benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic or
ascorbic acid, alkylmonosulfonic acids, for instance methanesulfonic acid,
ethanesulfonic acid, propanesulfonic acid, alkyldisulfonic acids, for instance
methanedisulfonic acid, a,(3-ethanedisulfonic acid, arylmonosulfonic acids
such as benzenesulfonic acid, and aryldisulfonic acids.
It may be recalled that stereoisomerism may be defined in its broadest sense
as isomerism of compounds having the same structural formulae, but whose
various groups are arranged differently in space, especially such as in
monosubstituted cyclohexanes in which the substituent may be in an axial or
equatorial position, and the various possible rotational conformations of
ethane derivatives. However, another type of stereoisomerism exists, due to
the various spatial arrangements of fixed substituents, either on double
bonds, or on rings, which is often referred to as geometrical isomerism or cis-
trans isomerism. The term stereoisomers is used in the present patent
application in its broadest sense and thus concerns all the compounds
indicated above.
The cyclic radicals that may be formed, on the one hand, by R1 and R2 with
the nitrogen atom to which they are attached, and, on the other hand, by R3
and R4 with the nitrogen atom to which they are attached, are optionally
substituted with one or more radicals chosen from those indicated above for
the possible substituents on the heterocycloalkyl radicals, i.e. one or more
radicals chosen from halogen atoms and the following radicals: hydroxyl, oxo,
alkoxy, NH2; NHalk, N(alk)2, and alkyl, heterocycloalkyl, CH2-
heterocycloalkyl, phenyl, CH2-phenyl, heteroaryl and CO-phenyl radicals,
such that in the latter radicals the alkyl, heterocycloalkyl and phenyl radicals
are themselves optionally substituted with one or more radicals chosen from
halogen atoms and the following radicals: hydroxyl, oxo, alkyl and alkoxy
containing from 1 to 4 carbon atoms, NH2; NHalk and N(alk)2.
The cyclic radicals that may be formed, on the one hand, by R1 and R2 with
the nitrogen atom to which they attached, and, on the other hand, by R3 and
R4 with the nitrogen atom to which they are attached, are especially
optionally substituted with one or more identical or different radicals chosen
from halogen atoms and alkyl, hydroxyl, alkoxy, CH2-pyrrolidinyl, CH2-
phenyl, heteroaryl and phenyl radicals, in which the alkyl, pyrrolidinyl and
phenyl radicals are themselves optionally substituted with one or more
identical or different radicals chosen from halogen atoms and alkyl, hydroxyl,
oxo and alkoxy radicals.
The heterocycloalkyl radicals as defined above especially represent azepanyl,
morpholinyl, pyrrolidinyl, piperidyl and piperazinyl radicals, which are
themselves optionally substituted, as defined hereinabove or hereinbelow.
When NR1R2 or NR3R4 forms a ring as defined above, such an amine ring
may be chosen especially from pyrrolidinyl, pyrazolidinyl, pyrazolinyl,
piperidyl, azepinyl, morpholinyl and piperazinyl radicals, these radicals
themselves being optionally substituted as indicated hereinabove or
hereinbelow: for example with one or more radicals, which may be identical or
different, chosen from halogen atoms and alkyl, hydroxyl, alkoxy, phenyl and
CH2-phenyl radicals, the alkyl or phenyl radicals themselves being optionally
substituted with one or more identical or different radicals chosen from
halogen atoms and alkyl, hydroxyl and alkoxy radicals.
The ring NR1R2 or NR3R4 may be chosen more particularly from pyrrolidinyl
and morpholinyl radicals optionally substituted with one or two alkyl or
piperazinyl radicals optionally substituted on the second nitrogen atom with
an alkyl, phenyl or CH2-phenyl radical, which are themselves optionally
substituted with one or more identical or different radicals chosen from
halogen atoms and alkyl, hydroxyl and alkoxy radicals.
A subject of the present invention is the products of formula (I) as defined
hereinabove or hereinbelow, in which
represents a single or double bond
Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyI optionally
substituted with a hydroxyl, alkoxy or-0-CO-R5 radical;
X represents S;
A represents S;
W represents a hydrogen atom or an alkyl radical optionally substituted with
heterocycloalkyl or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical, optionally substituted with a
radical NR3R4, or alkoxy;
- a radical O-phenyl;
- or the radical NR1R2 in which R1 and R2 are such that one represents
a hydrogen atom and the other represents an alkyl radical optionally
substituted with a heterocycloalkyl radical;
with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical;
R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon
atoms;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
Especially in the products of formula (I), the cycloalkyl radicals can represent
a cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl radical;
Especially in the products of formula (I), the heterocycloalkyl radicals can
represent a morpholinyl or pyrrolidinyl radical.
A subject of the present invention is thus the products of formula (I) as
defined hereinabove or hereinbelow, corresponding to the following formulae:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(cyclohexyloxy)[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-(cyclopentyloxy)[1,2,4]triazoIo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1 -(6-{[6-(cycloheptyloxy)[1 ^.Altriazolot^S-bfcyridazin-S-yllsulfanylH ,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyI}-1,3-
benzothiazol-2-yl)acetamide
1-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea
N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
- N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(cyclohexylamino)[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}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazo!-2-yl)acetamide
- phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)carbamate
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea
- 6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-N-[2-(pyrro-
lidin-1 -yl)ethyl]-1,3-benzothiazol-2-amine
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-methoxyacetamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,Nz-dimethylglycinamide
N-(6-{[6-(cyclohexyloxy)[1 Z4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)-3-methylbutanamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
- 6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
- 6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine
N-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
trans-4-{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}-
sulfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino}cyclohexyl
cyclopropanecarboxylate
- N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]acetamide
- 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo[4,3-
b]pyridazin-6-amine
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-dimethylglycinamide
- 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclohexyl-7,8-dihydro[1,2,4]-
triazolo[4,3-b]pyridazin-6-amine
- ethyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)carbamate
- 2-chloro-N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2-cyclopropylglycinamide
6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}[1,2,4]triazoio[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2 -amine
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-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}-1,3-
benzothiazol-2-yl)-N2,N2-diethylglycinamide
N-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[3-(morpholin-4-yl)propyl]urea
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[3-(morpholin-4-yl)propyl]urea
1 -(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1-[2-(morpholin-4-yl)ethyl]-3-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}
[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-cyclopropylacetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
rac-cis/trans-N-{4-[(3-{[2-({[2-(morpholin-4-yl)ethyl]carbamoyl}amino)-1,3-
benzothiazol-6-yl]sulfanyl}[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy]cyclohexyl}-
acetamide
- N-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
- 1-[6-({6-[(trans-4-hydroxycyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}-
sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
- 6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-amine
- 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclobutyl[1,2,4]triazolo[4,3-b]-
pyridazin-6-amine
N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)cyclobutanecarboxamide
- rac-6-({6-[(trans-2-fluorocyclohexy!)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}-
sulfanyl)-1,3-benzothiazol-2-amine
- rac-N-{6-[(6-{[(trans-2-fluorocyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
N-(6-{[6-(cyclobutylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
- rac-N2,N2-diethyl-N-[6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo[4,3-
b]pyridazin-3-yi}sulfanyl)-1,3-benzothiazol-2-yl]glycinamide
rac-2-(4-ethylpiperazin-1 -yI)-N-{6-[(6-{[trans-2-fluorocyclohexyl]oxy}[1,2,4]
triazolo[4,3-b]pyridazin-3-yl)sulfanyI]-1,3-benzothiazol-2-yl}acetamide
- rac-N-{6-[(6-{[trans-2-fluorocyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(morpholin-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide
rac-2-(4-cyclopropylpiperazin-1-yl)-N-{6-[(6-{[trans-2-fluorocyclo-
hexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-
acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(1,1 -dioxidothiomorpholin-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(1,4-oxazepan-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(3,3-difluoropiperidin-1-yl)acetamide
- rac-cis/trans-1 -{6-[(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-
3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
rac-cis/trans-N-{6-[(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
- rac-cis/trans-1-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-
3-yl}sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(piperidin-1 -yl)azetidine-1 -carboxamide
rac-cis/trans-N-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide
N-(6-{[6-(cyclohexyloxy)[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)-3-(morpholin-4-yl)azetidine-1-carboxamide
- rac-N-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
- rac-1 -{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1 ^^Jtriazolo^.S-blpyridazin-S-ynsulfanylJ-l ,3-
benzoth iazo l-2-yl)-3-methoxyazetid ine-1 -carboxam ide
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-oxetan-3-ylurea
rac-cis/trans-1 -{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
rac-cis/trans-N-{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
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, 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 1~-
represents a single or double bond, the products of formula (T) 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 may take the meanings given above
for the products of formulae (I') and (I"), substituent R5, in the compounds of
formulae (J), (1a') and (1a"), represents an alkyl radical and the substituent
R6, in the compounds of formulae (O), (1d') and (1d"), represents an alkyl
radical optionally substituted with NR3R4 (a -(CH2)n-NR3R4 radical), alkoxy,
hydroxyl, heterocycloalkyl, phenyl or -(CH2)n-phenyl, with phenyl being
optionally substituted and n representing an integer from 1 to 4. The
substituent R7 in the compounds of formulae (P) and (1e')/(1e") represents a
cycloalkyl or alkyl radical optionally substituted with an NR3R4, alkoxy,
hydroxyl, phenyl, heteroaryl or heterocycloalkyl radical, themselves optionally
substituted.
In Scheme 1 above, the groups CONR1R2, C02R6 and COR7, which
constitute W, may take the values of W as defined above for the products of
formulae (I') and (I"), when W*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, for example, by reaction of alcohols or
amines in the presence or absence of a base on the compound (S). The
reaction is performed, for example, at a temperature in the region of 20°C to
80°C.

The compounds (G) may be obtained, for example, by reacting 3-amino-4-
nitrobenzenethiol of formula (F) with the compounds of formula (E). The
compounds of formula (F) are obtained via in situ reduction of 3-amino-4-
nitrophenyl thiocyanate (Q) (commercial compound), for example, in the
presence of sodium borohydride in a solvent such as N,N-dimethylformamide,
at a temperature in the region of 20°C.

The compounds (H") such that ~ represent a double bond may be
obtained, for example, via reduction with iron (0) on 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, starting,
respectively, with a 3,4-diaminophenyl sulfide of formulae (H') and (H") and
with a pseudo thiourea of formula (J), in the presence of acetic acid and in a
protic solvent such as methanol, at a temperature in the region of 80°C.
More particularly, the benzimidazoles of general formulae (1b') and (1b") may
be prepared, respectively, by reaction of an amine NHR1R2 of formula (R)
(with R1 and R2 as defined above) with a carbamate of formulae (1a') and
(1a"), for example in the presence of an aprotic solvent such as 1-methyl-2-
pyrrolidinone. The reaction is performed, for example, at a temperature in the
region of 120°C, in a sealed tube under microwaves.
More particularly, the 2-aminobenzimidazoles of general formulae (1c') and
(1c") may be prepared, for example, by reacting cyanogen bromide with a
compound of formulae (H') and (H"), respectively, in the presence of a protic
solvent such as ethanol. The reaction is performed at a temperature in the
region of 80°C.
More particularly, the carbamates of general formulae (1d') and (1d") may be
obtained by reacting a chlorocarbonate of formula (O) (X = CI) with a
compound of general formulae (1c') and (1c"), for example in a solvent such
as tetrahydrofuran, in the presence of a base such as sodium hydrogen
carbonate, at a temperature in the region of 20°C.
More particularly, the carboxamides (1e') and (1e") may be obtained,
respectively, from the amines of general formulae (lc') and (1c")
- by reacting the amines (1c') and (1c") with an acid chloride of formula (P) (X
= CI), in the presence, for example, of a solvent such as pyridine, at a
temperature in the region of 20°C;
- by reacting the amines (1c') and (1c") with an acid anhydride of formula (P)
(X = OCOR7), in the presence, for example, of a 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 may take the meanings indicated
above for the products of formulae (I') and (I").
In Scheme 2 above, the groups CONR1R2, C02R6 and COR7, which
constitute W, may take values of W as defined above for the products of
formulae (I") and (I"), when W*H.
In Scheme 2 above, the benzothiazoles of general formulae (2a"), (2b"), (2c")
and (2d") and the reduced analogues thereof of general formulae (2a'), (2b'),
(2c') and (2d') may be prepared from 2-amino-1,3-benzothiazol-6-yl
thiocyanate (K) (commercial compound).
The carbamates of general formula (L1) may be obtained, for example, by
reacting a chlorocarbonate of formula (O) (X = CI) with 2-amino-1,3-
benzothiazol-6-yl thiocyanate (K), in a solvent such as tetrahydrofuran, in the
presence of a base such as sodium hydrogen carbonate, at a temperature in
the region of 20°C.

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
of 20°C.
The ureas (2b1) and (2b") may be obtained, for example, respectively, from
the carbamates (2a') and (2a") in which R6 = phenyl, in the same manner as
the ureas (L2) are obtained by reacting amines on the carbamates of the type
(L1).

The compounds of general formula (L3) may be obtained, for example:
- by reacting an acid chloride of formula (P) (X = CI) with 2-amino-1,3-
benzothiazol-6-yI thiocyanate (K), in the presence, for example, of a solvent
such as pyridine, at a temperature in the region of 20°C,
- by reacting an acid anhydride of formula (P) (X = OCOR7) with 2-amino-1,3-
benzothiazol-6-yl thiocyanate (K), in the presence, for example, of a solvent
such as pyridine, at a temperature in the region of 20°C,
- by coupling 2-arnino-1,3-benzothiazol-6-yl thiocyanate (K) with an acid of
formula (P) (X = OH) under the conditions described, for example, by D.D.
DesMarteau; V. Montanari (Chem. Lett., 2000 (9).1052), in the presence of 1-
hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and
in the presence of a base such as triethylamine, at a temperature in the
region of 40°C.
In the same manner that the carboxamides (L3) may be obtained via
acylation of the amine (K), the carboxamides (2c') and (2c") may be obtained,
respectively, from the amines (2d') and (2d") by coupling with an acid of
formula (P) (X = OH) under the conditions described, for example, by N. Xi
et al., Bioorg. Med. Chem. Lett. 15 (2005) 5211-5217, in the presence of O-
(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
(HATU), in a solvent such as N,N-dimethylformamide, in the presence of a
base such as diisopropylethylamine, at a temperature in the region of 20°C.
In Scheme 2bis above, the substituent R7 may take the meaning of an
aminomethyl group. These glycinamides (2c72c") may be obtained by
coupling the amines (2d') and (2d") with a glycidic acid (P') using the methods
described above for the acids (P) (X = OH).
The glycidic acids (P') may be prepared from bromoacetic acid and amines
HNR3R4 under conditions similar to those described by D. T. Witiak et a/.; J.
Med. Chem. 1985,28,1228.
Alternatively, the amines (2d') and (2d") may be treated with fluoroacetyl
chloride in the presence of a base such as pyridine, triethylamine or N-
methylmorpholine, in a solvent such as dichloromethane at a temperature in
the region of 0°C to 20°C. The a-chloroacetamides (2e72e") 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
(2c72c") 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.
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(dibenzylideneacetone)-
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 ZZJ:JL represent a double bond.
Scheme 3: Routes for synthesizing triazolopyridazine derivatives of formula
(E)
In Scheme 3 above, the substituent Ra has the meanings indicated above for
the products of formulae (I') and (I").
The substituent R8 represents a cycloalkyl radical such as defined above for
the products of formula (I).
The compounds of formula (E) may be obtained, for example, as indicated in
Scheme 3 above, from commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine
of formula (S).
More particularly, the compounds of formula (E) in which Ra represents a
radical 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 20°C to 80°C and in a
solvent such as tetrahydrofuran with an alkoxide of formula (U), which is itself
obtained by treating an alcohol (HOR8) with, for example, sodium hydride in a
solvent such as tetrahydrofuran at a temperature in the region of 0CC to 20°C.
More particularly, the compounds of formula (E) where Ra represents an
R8NH radical may be obtained by treating 3,6-dichloro[1,2,4]triazolo[4,3-b]-
pyridazine (S) with an amine of formula (R8NH2), at a temperature in the
region of 20°C to 50°C and in a solvent such as N,N-dimethylforrnamide.
Scheme 4: Synthesis of the benzothiazole derivatives of formulae (2e') and
(2e")
According to Scheme 4 above, the benzothiazoles of general formulae (2e')
and (2e") may be prepared, respectively, from the compounds of formulae
(2a') and (2a").
In Scheme 4 above, the substituent OR6 preferentially represents O-t-butyl.
The substituent R9 represents an alkyl or cycloalkyl radical optionally
substituted with an alkoxy or heterocycloalkyl radical or NR3R4 (R3 and R4
as defined above).
The carbamates of general formulae (T) and (T") may be obtained,
respectively, by reacting carbamates of general formulae (2a') and (2a") with
R6 = tBu, preferentially, for example with alkyl halides of formula (W), in a
solvent such as N,N-dimethylformamide, in the presence of sodium hydride,
at a temperature of between 20 and 90°C.
The benzothiazoles of general formulae (2e') and (2e") may also be prepared
from the compounds of formula (l_1), 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 80CC, optionally followed by an in situ treatment
with trifluoroacetic acid at 20°C, if necessary.

L4
The carbamates of general formula (L4) may be obtained by reacting
carbamates of general formula (L1), for example, with alkyl halides of formula
(W), in a solvent such as N,N-dimethylformamide, in the presence of sodium
hydride, at a temperature of between 20 and 90°C.
Scheme 5: Synthesis of the benzothiazole derivatives of formulae (2e') and
(2e")
Alternatively, according to Scheme 5 above, the benzothiazoles of general
formula (2e") may be prepared from the compounds of formulae (L6) and (E),
for example, in the presence of DL-dithiothreitol and sodium hydrogen
carbonate, in a solvent such as ethanol and at a temperature in the region of
80°C.
The benzothiazoles of general formula (2e') may be prepared from the
compounds of formula (2e") according to the methods described below for the
preparation of the compounds (I') from the compounds (I").
The compounds of formula (L6) may be prepared from the 2-
bromobenzothiazole derivative (L5) by treatment with a derivative NH2R9, for
example, in a solvent such as tetrahydrofuran, at a temperature in the region
of 20°C.
The substituent R9 represents an alkyl or cycloalkyl radical optionally
substituted with an alkoxy or heterocycloalkyl radical or NR3R4 (R3 and R4
as defined above).
The compounds of formula (L5) may be prepared from 2-amino-1,3-
benzothiazol-6-yl thiocyanate (K) (commercial compound), for example, by
treatment with an alkyl nitrite and cuprous bromide in a solvent such as
acetonitrile, at a temperature in the region of 0-20°C, according to the method
described by Jagabandhu Das etal. in J. Med. Chem. 2006, 49, 6819-6832.
Scheme 6: Other routes for synthesizing reduced derivatives of formula (I')
According to Scheme 6 above, the benzothiazoles of general formula (I') may
also be prepared from the compounds of formula (I"), via reduction, for
example, with sodium borohydride, in a solvent such as ethanol, at a
temperature in the region of 80°C, or via reduction with zinc (0) in the
presence of acetic acid, at a temperature in the region of 20°C.
Alternatively, the compounds (I') may also be prepared from the compounds
of formula (E') by coupling with compounds of the type M1, M2, M3 or N,
obtained as intermediates via reduction of the compounds L1, L2, L3 or K in
situ, as described above in Scheme 2. The compounds of the type M1, M2 or
M3 may also be isolated and used for the coupling with (E'). The compounds
(E') may be obtained from the compounds of formula (E) by reduction, for
example, with zinc (0) in the presence of acetic acid, at a temperature in the
region of 20°C.
Alternatively, the compounds (I') may also be prepared from other
compounds (I') via conversion of the group W into a group W of the same
nature as defined above for W and according to the type of reaction defined in
Scheme 2: conversion of 2d72d" into 2a72a" and into 2c72c", conversion of
2aV2a" into 2d72d" and into 2b'/2b".
In the compounds of general formula (I) as defined above, the sulfur S can be
oxidized to sulfoxide SO or sulfone S02 according to the methods known to
those skilled in the art, if necessary protecting any reactive groups with
suitable protecting groups.
Among the starting materials of formulae J, K, O, 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,
tetrahydropyranyl, benzyl or acetyl,
- amino groups may be protected, for example, with acetyl, trityl, benzyl, tert-
butoxycarbonyl, BOC, benzyloxycarbonyl or phthalimido radicals or other
radicals known in peptide chemistry.
Acid functions may be protected, for example, in the form of esters formed
with readily cleavable esters such as benzyl or tert-butyl esters or esters
known in peptide chemistry.
A list of various protecting groups that may be used will be found in the
manuals known to those skilled in the art and, for example, in patent BF 2 499
995.
It may be noted that intermediate products or products of formula (I) thus
obtained via the processes indicated above may be subjected, if desired and
if necessary, in order to obtain other intermediates or other products of
formula (I), to one or more transformation reactions known to those skilled in
the art, for instance:
a) a reaction for esterification of an acid function,
b) a reaction for saponification of an ester function to an acid function,
c) a reaction for reduction of the free or esterified carboxyl function to an
alcohol function,
d) a reaction for conversion of an alkoxy function into a hydroxyl function, or
alternatively of a hydroxyl function into an alkoxy function,
e) a reaction for removal of the protecting groups that may be borne by
protected reactive functions,
f) a salification reaction with a mineral or organic acid or with a base to obtain
the corresponding salt,
g) a reaction for resolution of racemic forms into resolved products,
the said products of formula (I) thus obtained being in any possible racemic,
enantiomeric or diastereoisomeric isomer form.
Reactions a) to g) may be performed under the usual conditions known to
those skilled in the art, for instance those indicated hereinbelow.
a) The products described above may, if desired, undergo, on the possible
carboxyl functions, esterification reactions that may be performed according
to the usual methods known to those skilled in the art.
b) The possible conversions of ester functions into an acid function of the
products described above may, if desired, be performed under the usual
conditions known to those skilled in the art, especially by acidic or alkaline
hydrolysis, for example with sodium hydroxide or potassium hydroxide in
alcoholic medium, for instance in methanol, or alternatively with hydrochloric
acid or sulfuric acid.
The saponification reaction may be performed according to the usual
methods known to those skilled in the art, for instance in a solvent such as
methanol, ethanol, dioxane or dimethoxyethane, in the presence of sodium
hydroxide or potassium hydroxide.
c) The possible free or esterified carboxyl functions of the products described
above may, if desired, be reduced to an alcohol function via the methods
known to those skilled in the art: the possible esterified carboxyl functions
may, if desired, be reduced to an alcohol function via the methods known to
those skilled in the art and especially with lithium aluminium hydride in a
solvent such as, for example, tetrahydrofuran, dioxane or ethyl ether.
The possible free carboxyl functions of the products described above may, if
desired, be reduced to an alcohol function especially with boron hydride.
d) The possible alkoxy functions, especially such as methoxy, of the products
described above may be, if desired, converted into a hydroxyl function under
the usual conditions known to those skilled in the art, for example with boron
tribromide in a solvent such as, for example, methylene chloride, with pyridine
hydrobromide or hydrochloride, or alternatively with hydrobromic acid or
hydrochloric acid in water or trifluoroacetic acid at reflux.
e) The removal of the protecting groups such as, for example, those indicated
above may be performed under the usual conditions known to those skilled in
the art, especially via acidic hydrolysis performed with an acid such as
hydrochloric acid, benzenesulfonic acid or para-toluenesulfonic acid, formic
acid ortrifluoroacetic 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
pharmaceutical^ acceptable mineral and organic acids or with
pharmaceutical^ acceptable mineral and organic bases of the said products
of formula (I).
A subject of the invention is most particularly, as medicaments, the products
corresponding to the following formulae:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(cyclohexyloxy)[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-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yI)ethyl]urea
1-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]suIfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
- N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
1 -(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea
N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
- N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxarnide
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(cyclohexylamino)[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}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
- phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)carbamate
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea
- 6-{t6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-N-[2-(pyrro-
lidin-1 -yl)ethyl]-1,3-benzothiazol-2-amine
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-methoxyacetamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-dimethylglycinamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methylbutanamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
- 6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
- 6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine
N-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
trans-4-{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}-
sulfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino}cyclohexyl
cyclo p ro pa necarboxyl ate
- N-[6-({6-[(trans-4-hydroxycyclohexyI)amino][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}suIfanyl)-1,3-benzothiazol-2-yl]acetamide
- 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo[4,3-
b]pyridazin-6-amine
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yI]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
- N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-dimethylglycinamide
- 3-[(2-amino-1 ,3-benzothiazol-6-yl)sulfanyl]-N-cyclohexyl-7,8-dihydro[1 ,2,4]-
triazolo[4,3-b]pyridazin-6-amine
- ethyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)carbamate
- 2-chloro-N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2-cyclopropylglycinamide
6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-amine
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1 ^^Itriazolo^^-blpyridazin-S-yOsulfanylJ-l ,3-
benzothiazol-2-yl)-N2,N2-diethylglycinamide
N-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[3-(morphoIin-4-yl)propyI]urea
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[3-( morphol i n-4-yl )pro pyl] urea
1 -(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
1-[2-(morpholin-4-yl)ethyl]-3-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}
[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-cyclopropylacetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
rac-cis/trans-N-{4-[(3-{[2-({[2-(morpholin-4-yl)ethyl]carbamoyl}amino)-1,3-
benzothiazol-6-yl]sulfanyl}[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy]cyclohexyl}-
acetamide
- N-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
- 1 -[6-({6-[(trans-4-hydroxycyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}-
sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
- 6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]suIfanyl}-
1,3-benzothiazol-2-amine
- 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclobutyl[1,2,4]triazolo[4,3-b]-
pyridazin-6-amine
N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)cyclobutanecarboxamide
- rac-6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}-
sulfanyl)-1,3-benzothiazol-2-amine
- rac-N-{6-[(6-{[(trans-2-fluorocyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
N-(6-{[6-(cyclobutylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)cycloprapanecarboxamide
- rac-N^N^diethyl-N-^^fe-Ktrans^-fluorocyclohexyOoxyltl^^ltriazolo^^-
b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]glycinamide
rac-2-(4-ethylpiperazin-1 -yl)-N-{6-[(6-{[trans-2-fluorocyclohexyl]oxy}[1,2,4]
triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide
- rac-N-{6-[(6-{[trans-2-fluorocyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(morpholin-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide
rac-2-(4-cyclopropylpiperazin-1-yl)-N-{6-[(6-{[trans-2-fiuorocyclo-
hexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-
acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(1,1-dioxidothiomorpholin-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(1,4-oxazepan-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(3,3-difluoropiperidin-1-yl)acetamide
- rac-cis/trans-1 -{6-[(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-
3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
rac-cis/trans-N-{6-[(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
- rac-cis/trans-1 -[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-
3-yl}sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(piperidin-1-yl)azetidine-1-carboxamide
rac-cis/trans-N-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yI}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(morpholin-4-yl)azetidine-1-carboxamide
- rac-N-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
- rac-1 -{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxyazetidine-1-carboxamide
1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-oxetan-3-ylurea
rac-cis/trans-1 -{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
rac-cis/trans-N-{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
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-benzyIamino-9-methylpurine, known as
olomoucine.
A subject of the present invention is also, as novel industrial products, the
synthetic intermediates of formulae E', M1, M2, M3 and N as defined above
and recalled hereinbelow:
in which the groups CONR1R2, C02R6 and COR7, which constitute W, may
take the values of W as defined above for the products of formula (I), when
WVH and the substituent Ra may take the meanings indicated above for the
products of formula (I).
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 10.0 and version 11
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 BrCiker
Avance DRX-400 or Bruker Avance DPX-300 spectrometer with the chemical
shifts (5 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)
- UPLC-SQD (Waters)
DAD wavelength considered A = 210-400 nm
ELSD: Sedere SEDEX 85; nebulization temperature = 35°C; nebulization
pressure = 3.7 bar
Example 1:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
a) N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide may be prepared in the
following manner:
75 mg of 6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine and 20 uL of cyclopropanecarboxylic acid chloride are
added to 2 cm3 of pyridine at 20°C. After 3 hours, a further 20 uL of
cyclopropanecarboxylic acid chloride are added and and the mixture is stirred
for 18 hours. A further 20 uL of cyclopropanecarboxylic acid chloride are
added and the mixture is left to react for a further one hour. The reaction
mixture is concentrated to dryness and the solid residue is chromatographed
by solid deposition on a Biotage Quad cartridge 12/25 (KP-SIL, 60A;
32-63 uM), eluting with a 99.5/0.5 to 90/10 gradient of
dichloromethane/methanol. The solid obtained is washed with ethyl ether. 66
mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide are thus obtained in the form of
a white powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-de) 5 ppm 0.88 - 1.01 (m, 4 H) 1.13 -
1.53 (m, 6 H) 1.52 -1.66 (m, 2 H) 1.71 -1.86 (m, 2 H) 1.92 - 2.04 (m, 1 H)
4.61 - 4.74 (m, 1 H) 7.02 (d, J = 10.0 Hz, 1 H) 7.41 (dd, J = 8.0, 2.0 Hz, 1 H)
7.67 (d, J = 8.0 Hz, 1 H) 8.05 (d, J = 2.0 Hz, 1 H) 8.28 (d, J = 10.0 Hz, 1 H)
12.67 (br.s.,1H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z = 467+; MH- = 465-.
b) 6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine may be prepared in the following manner:
A stream of argon is bubbled through a solution of 149 mg of 2-amino-1,3-
benzothiazol-6-yl thiocyanate (commercial) in 20 cm3 of ethanol for 5 minutes.
4 mg of potassium dihydrogen phosphate in 0.2 cm3 of water, 333 mg of DL-
dithiothreitol and 182 mg of 3-chloro-6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]-
pyridazine are then added. The reaction mixture is heated at 80°C for 23
hours and then concentrated to dryness under vacuum. The residue is
purified on silica by solid deposition, eluting with a gradient of from 100%
dichloromethane to 80/20 dichloromethane/(38 dichloromethane/17
methanol/2 aqueous ammonia). 130 mg of 6-{[6-(cyclohexyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine 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+ m/z = 399+; MH-= 397-
c) 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
return gradually to 20°C. The reaction medium is then 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 a Biotage Quad 12/25 cartridge (KP-SIL, 60 A;
32-63 |jM), eluting with a 95/5 to 65/35 cyclohexane/ethyl acetate gradient.
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:
1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
a) 1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyrjurea may be prepared in the
following manner:
A stream of argon is bubbled through a solution of 339 mg of 1-[2-(morpholin-
4-yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea in 20 cm3 of ethanol for
5 minutes. 5 mg of potassium dihydrogen phosphate in 0.2 cm3 of water,
463 mg of DL-dithiothreitol and 253 mg of 3-chloro-6-(cyclohexyloxy)[1,2,4]-
triazolo[4,3-b]pyridazine (1c) are then added. The reaction mixture is then
heated at 80°C for 47 hours, and the whitish solution is then evaporated to
dryness under vacuum. The residue is purified on silica by solid deposition,
eluting with a gradient of from 100% dichloromethane to 85/15
dichloromethane/(38 dichloromethane/17 methanol/2 aqueous ammonia).
246 mg of 1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea are thus obtained in the
form of a white powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-c/e) 5 ppm 1.00 - 1.55 (m, 6 H) 1.62
(m, 2 H) 1.73 -1.90 (m, 2 H) 2.29 - 2.47 (m, 6 H) 3.19 - 3.28 (m, 2 H) 3.59 (m,
4 H) 4.57 - 4.80 (m, 1 H) 6.77 (br. s., 1 H) 7.02 (d, J = 9.8 Hz, 1H) 7.36 (dd, J
= 8.5, 1.5 Hz, 1 H) 7.54 (d, J = 8.5 Hz, 1 H) 7.99 (d, J = 1.5 Hz, 1 H) 8.27 (d, J
= 9.8 Hz, 1 H) 10.90 (br. s., 1 H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z = 555+; MH- = 553-
b) 1-[2-(Morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea may
be prepared in the following manner:
A stream of argon is bubbled for 5 minutes through a mixture of 900 mg of 2-
{[(2-morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazoI-6-yl thiocyanate
and 40 cm3 of ethanol at 20°C. 11 mg of potassium dihydrogen phosphate in
0.4 cm3 of water and 1.1 g of DL-dithiothreitol are then added. The mixture is
heated at 80°C for 3.5 hours. The reaction medium is cooled to 20°C and
then poured into water. The suspension is stirred for 45 minutes while
maintaining gentle bubbling with argon. The precipitate formed is filtered off
by suction and washed with 3x10 cm3 of water and then dried under vacuum
at 20°C. 633 mg of 1-(2-morpholin-4-ylethyl)-3-(6-sulfanyl-1,3-benzothiazol-2-
yl)urea are thus obtained in the form of a white solid, the characteristics of
which are as follows:
MASS SPECTRUM: LC-MS-DAD-ELSD: MH+ m/z = 339+; (M-H)- = 337-
c) 2-{[(2-Morpholin-4-ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl
thiocyanate may be prepared in the following manner:
0.44 cm3 of 2-morpholin-4-ylethanamine is added at 20°C to a solution of 1 g
of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate in 30 cm3 of
tetrahydrofuran at 20°C. After 24 hours, the reaction mixture is evaporated to
dryness and the residue obtained is chromatographed on a Merck 70g
cartridge (solid deposition; elution with a gradient of dichloromethane and
then 90/10 dichloromethane/methanol). 902 mg of 2-{[(2-morpholin-4-
ylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl thiocyanate are thus
recovered in the form of a colourless foam, the characteristics of which are as
follows:
MASS SPECTRUM: UPLC-MS-DAD-ELSD: MH+ m/z = 364+
d) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yI)carbamate was prepared
in the following manner:
7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen
carbonate and 9.4 cm3 of water are added, at 20°C, to a solution of 2.5 g of
commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of
tetrahydrofuran. The resulting mixture is then stirred at 20°C for 20 hours and
then extracted with 2><150 cm3 of ethyl acetate. The organic phases are
combined and then washed with 3x50 cm3 of saturated aqueous sodium
hydrogen carbonate solution. The organic phase obtained is dried over
magnesium sulfate and then concentrated to dryness under reduced
pressure. The residue is taken up in 50 cm3 of water and then filtered off by
suction and dried under vacuum at 20°C. 3.45 g of phenyl (6-thiocyanato-1,3-
benzothiazol-2-yl)carbamate are thus obtained in the form of a pale yellow
solid, the characteristics of which are as follows:
MASS SPECTRUM: LC-MS-DAD-ELSD: MH+ m/z = 328+; (M-H)- =326-
Example 3:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide may be prepared in the following manner:
0.276 cm3 of acetic anhydride and 160 mg of 6-{[6-(cyclohexyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine (1 b) are
added to 2 cm3 of pyridine at 20°C. After 5 hours, a further 0.3 cm3 of acetic
anhydride is added and the mixture is left stirring for 17 hours. The reaction
mixture is concentrated to dryness under vacuum. The yellowish solid residue
is chromatographed on a Biotage Quad 12/25 cartridge (KP-SIL, 60 A; 32-63
uM), eluting with a gradient of from 100% dichloromethane to 97.5/2.5
dichloromethane/methanol. 123 mg of N-(6-{[6-(cyclohexyloxy)[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, DMSO-d6) 5ppm 1.05 -1.53 (m, 6 H) 1.52 -
1.68 (m, 2 H) 1.71 - 1.85 (m, 2 H) 2.19 (s, 3 H) 4.56 - 4.73 (m, 1 H) 7.02 (d,
J=10.0 Hz, 1 H) 7.40 (dd, J=8.5, 2.0 Hz, 1 H) 7.66 (d, J=8.5 Hz, 1 H) 8.06 (d,
J=2.0 Hz, 1 H) 8.28 (d, J=10.0 Hz, 1 H) 12.37 (br. s, 1 H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z=441+; MH- =439-
Example 4:
phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)carbamate
Phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)carbamate may be prepared in the following manner:
0.13 cm3 of phenyl chlorocarbonate is added to 200 mg of 6-{[6-(cyclo-
hexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
amine (1b) in 5 cm3 of pyridine, at 20°C. After 4 hours, the yellow suspension
is concentrated to dryness under vacuum. The residue is chromatographed
on a Biotage Quad 12/25 cartridge (KP-SIL, 60 A; 32-63 uM), eluting with a
gradient of from 100% dichloromethane to 92.5/7.5 dichloromethane/ meth-
anol. 224 mg of phenyl (6-{[6-(cyclohexyloxy)[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-c/6) 5 ppm 1.13 - 1.42 (m, 5 H) 1.43
- 1.66 (m, 3 H) 1.72 -1.85 (m, 2 H) 4.63 - 4.74 (m, 1 H) 7.03 (d, J=10.0 Hz, 1
H) 7.25 - 7.35 (m, 3 H) 7.40 - 7.50 (m, 3 H) 7.69 (d, J=9.0 Hz, 1 H) 8.07 (d,
J=2.0 Hz, 1 H) 8.28 (d, J=10.0 Hz, 1 H) 12.66 (br. s, 1 H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z=519+; MH- =517-
Example 5:
1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea
a) 1 -(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea may be prepared in the
following manner:
0.06 cm3 of 2-(pyrrolidin-1-yl)ethanamine and 0.14 cm3 of triethylamine are
added to a solution of 200 mg of phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate (4) in 5 cm3 of
tetrahydrofuran at 20°C. After 2 hours at 20°C, the reaction medium is heated
at 60°C for 3 hours. The yellow solution is evaporated to dryness under
reduced pressure. The residue is chromatographed on a Biotage Quad 12/25
cartridge (KP-SIL, 60 A; 32-63 uM), eluting with a 99/1 to 50/50
dichloromethane/methanol gradient. 171 mg of 1-(6-{[6-(cyclo-
hexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-
[2-(pyrrolidin-1-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-c/6) 6 ppm 1.08 - 1.87 (m, 14 H)
2.52 - 2.63 (masked m, 6 H) 3.32 - 3.38 (masked m, 2 H) 4.57 - 4.80 (m, 1 H)
6.82 (br. s, 1 H) 7.02 (d, J=10.0 Hz, 1 H) 7.36 (dd, J=8.5, 2.0 Hz, 1 H) 7.55 (d,
J=8.5 Hz, 1 H) 8.00 (d, J=2.0 Hz, 1 H) 8.27 (d, J=10.0 Hz, 1 H) 10.78 (s, 1 H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z=539+; MH- =537-
Example 6:
6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-N-[2-
(pyrroiidin-1 -yl)ethyl]-1,3-benzothiazol-2-amine
a) 6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-N-[2-
(pyrrolidin-1-yl)ethyl]-1,3-benzothiazol-2-amine may be prepared in the
following manner:
686 mg of 2-(pyrrolidin-1-yl)ethanamine are added to a solution of 534 mg of
2-bromo-1,3-benzothiazol-6-yl thiocyanate in 7 cm3 of tetrahydrofuran. The
reaction medium is stirred for 18 hours at 20°C, and the suspension is then
concentrated to dryness under reduced pressure. The oily brown residue
obtained is taken up in 20 cm3 of ethanol. The mixture is degassed by
sparging with argon for 5 min at 20°C, and 5 mg of potassium dihydrogen
phosphate in 0.2 cm3 of water are then added, followed by addition of 617 mg
of DL-Dithiothreitol and 253 mg of 3-chloro-6-(cyclohexyloxy)[1,2,4]triazolo-
[4,3-b]pyridazine (1c). After 23 hours at reflux, the red suspension is
concentrated to dryness under reduced pressure. The residue is purified by
dry deposition on Biotage Quad 25M (KP-SIL, 60 A; 32-63 uM), eluting with a
gradient of 95/5 to 85/15 of dichloromethane/(dichloromethane: 38/methanol:
17/aqueous ammonia: 2). The yellow solid obtained is washed with ether and
pentane. 218 mg of 6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-N-[2-(pyrrolidin-1-yl)ethyl]-1,3-benzothiazol-2-amine are thus
obtained in the form of a yellow powder, the characteristics of which are as
follows:
1H NMR SPECTRUM (400 MHz, DMSO-of6) 5 ppm 1.17 - 1.59 (m, 7 H) 1.60
-1.73 (m, 7 H) 1.79 -1.94 (m, 2 H) 2.45 (masked m, 2 H) 2.55 - 2.71 (m, 2H)
3.47 (q, J=6.0 Hz, 2 H) 4.68 - 4.81 (m, 1 H) 7.01 (d, J=10.0 Hz, 1 H) 7.24 -
7.35 (m, 2 H) 7.82 (d, J=1.5 Hz, 1 H) 8.15 (t, 1 H) 8.25 (d, J=10.0 Hz, 1
MASS SPECTRUM: UPLC-SQD: MH+ m/z=496+; MH- =494-
b) 2-Bromo-1,3-benzothiazol-6-yl thiocyanate may be prepared in the
following manner:
A solution of 6.5 g of cuprous bromide in 666 cm3 of acetonitrile is purged
with argon for 5 min. The resulting solution is cooled to 0-5°C, and 4.3 cm3 of
tert-butyl nitrite are then added. 5 g of 2-amino-1,3-benzothiazol-6-yl
thiocyanate (commercial) are then introduced portionwise, at 0°C. The
reaction mixture is stirred for 3 hours at 20°C and then concentrated to
dryness under reduced pressure. The residue is taken up in ethyl acetate and
the solution obtained is then washed with saturated sodium bicarbonate
solution. The organic phase is dried over magnesium sulfate and then
concentrated to dryness under vacuum. 5.05 g of 2-bromo-1,3-benzothiazol-
6-yl thiocyanate are thus obtained in the form of a golden-yellow powder, the
characteristics of which are as follows:
MASS SPECTRUM: UPLC-SQD: MH+ m/z=271 +
Example 7:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-methoxyacetamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-methoxyacetamide may be prepared in a manner similar
to that of Example 1a, but starting with 200 mg of 6-{[6-(cyclohexyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine (1b) in 5 cm3
of pyridine with 0.165 cm3 of methoxyacetyl chloride after reaction for
23 hours at 20°C. 196 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-2-methoxyacetamide are thus
obtained in the form of a white powder, the characteristics of which are as
follows:
1H NMR SPECTRUM (400 MHz, DMSO-of6) 5 ppm 1.09 - 1.40 (m, 5 H) 1.41
-1.65 (m, 3 H) 1.72 -1.86 (m, 2 H) 3.36 (s, 3 H) 4.19 (s, 2 H) 4.61 - 4.72 (m,
1 H) 7.02 (d, J=10.0 Hz, 1 H) 7.41 (dd, J=8.5, 2.0 Hz, 1 H) 7.68 (d, J=8.5 Hz,
1 H) 8.07 (d, J=2.0 Hz, 1 H) 8.28 (d, J=10.0 Hz, 1 H) 12.32 (br. s, 1 H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z=469+; MH- =471-
Example 8:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-dimethylglycinamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-dimethylglycinamide may be prepared in a manner
similar to that of Example 1a, but starting with 100 mg of 6-{[6-(cyclo-
hexyloxy)[1,2,4]triazolo[4,3-bJpyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
amine (1b) in 10 cm3 of dichloromethane with 300 mg of N,N-dimethylglycy!
chloride, 0.33 cm3 of triethylamine and 11 mg of 4-N,N-
dimethylaminopyridine, after reaction for 27 hours at 20°C. 75 mg of N-(6-{[6-
(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-yl)-N2,N2-dimethylglycinamide are thus obtained in the form of a yellowish
powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-af6) 6 ppm 1.10 - 1.64 (m, 8 H) 1.69
- 1.87 (m, 2 H) 2.29 (s, 6 H) 3.37 - 3.52 (m, 2 H) 4.52 - 4.75 (m, 1 H) 7.02 (d,
J=10.0 Hz, 1 H) 7.41 (dd, J=8.5, 2.0 Hz, 1 H) 7.67 (d, J=8.5 Hz, 1 H) 8.07 (d,
J=2.0 Hz, 1 H) 8.28 (d, J=10.0 Hz, 1 H) 11.92 (br. s, 1 H)
MASS SPECTRUM: Waters-ZQ: MH+ m/z=484+; MH- =482-
Example 9:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methylbutanamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methylbutanamide may be prepared in a manner similar
to that of Example 1a, but starting with 102 mg of 6-{[6-(cyclohexyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine (1b) in 5 cm3
of pyridine with 0.437 cm3 of 3-methylbutanoyi chloride after reaction for
46 hours at 20°C. 98 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-methylbutanamide are thus
obtained in the form of a white powder, the characteristics of which are as
follows:
1H NMR SPECTRUM (400 MHz, DMSO-cf6) 5 ppm 0.93 (d, J=6.8 Hz, 6 H)
1.08 - 1.63 (m, 8 H) 1.71 - 1.82 (m, 2 H) 2.03 - 2.17 (m, 1 H) 2.36 (d, J=7.1
Hz, 2 H) 4.56 - 4.69 (m, 1 H) 7.02 (d, J=9.8 Hz, 1 H) 7.40 (dd, J=8.4, 1.8 Hz,
1 H) 7.66 (d, J=8.6 Hz, 1 H) 8.07 (d, J=2.0 Hz, 1 H) 8.28 (d, J=9.8 Hz, 1 H)
12.34 (br. s, 1 H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z=483+; MH- =481-
Example 10:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide may be prepared in a manner
similar to that of Example 1a, but starting with 146 mg of 6-{[6-(cyclo-
hexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
amine (1b) in 5 cm3 of pyridine with 0.191 cm3 of 3-methoxypropanoyl
chloride after reaction for 23 hours at 20°C. 132 mg of N-(6-{[6-(cyclo-
hexyloxy)[1T2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-
methoxypropanamide are thus obtained in the form of a white powder, the
characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-cf6) 6 ppm 1.11 -1.65 (m, 8 H) 1.74
- 1.83 (m, 2 H) 2.72 (t, J=6.1 Hz, 2 H) 3.23 (s, 3 H) 3.64 (t, J=6.1 Hz, 2 H)
4.62 - 4.72 (m, 1 H) 7.02 (d, J=9.8 Hz, 1 H) 7.41 (dd, J=8.3, 2.0 Hz, 1 H) 7.66
(d, J=8.6 Hz, 1 H) 8.06 (d, J=2.0 Hz, 1 H) 8.28 (d, J=9.Q Hz, 1 H) 12.37 (br. s,
1 H)
MASS SPECTRUM: Waters-ZQ: MH+ m/z=485+; MH- =483-
Example 11:
6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-am i ne
a) 6-{[6-(Cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine may be prepared in a manner similar to that of Example
1b, but starting with 889 mg of 3-chloro-6-(cyclopentyloxy)[1,2,4]triazolo[4,3-
bjpyridazine in 30 cm3 of degassed ethanol, 17 mg of potassium dihydrogen
phosphate in 0.3 cm3 of water, 1.72 g of DL-dithiothreitol and 772 mg of 2-
amino-1,3-benzothiazol-6-yl thiocyanate after 24 hours at 80°C. 1.04 g of 6-
{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine are thus obtained in the form of a white powder, the
characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) 6 ppm 1.49 -1.76 (m, 6 H) 1.83
-1.97 (m, 2 H) 5.12 - 5.22 (m, 1 H) 6.99 (d, .7=9.8 Hz, 1 H) 7.28 (d, J=8.6 Hz,
1 H) 7.34 (dd, J=8.3, 2.0 Hz, 1 H) 7.61 (s, 2H) 7.90 (d, J=2.0 Hz, 1 H) 8.23 (d,
J=9.8 Hz, 1 H)
MASS SPECTRUM: UPLC-SQD: MH+ m/z=385+
b) 3-Chloro-6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazine may be
prepared in a manner similar to that of Example 1c, but starting with 914 mg
of cyclopentanol in 20 cm3 of tetrahydrofuran, 254mg of sodium hydride at
60% in oil and 1 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial),
after reaction for 6 hours 30 minutes. 896 mg of 3-chloro-6-
(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazine are thus obtained in the form
of a colourless oil that crystallizes, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=239+
Example 12:
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(Cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide may be prepared in a manner
similar to that of Example 1a, but starting with 300 mg of 6-{[6-
(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-amine (11a) in 5 cm3 of pyridine with 0.140 cm3 of cyclopropanecarboxylic
acid chloride, after 3 hours of reaction at 20°C. 277 mg of N-(6-{[6-
(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-yl)cyclopropanecarboxamide are thus obtained in the form of a white
powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) 6 ppm 0.84 - 1.00 (m, 4 H) 1.44
-1.71 (m, 6 H) 1.73 - 1.88 (m, 2 H) 1.92 - 2.04 (m, 1 H) 5.04 - 5.17 (m, 1 H)
7.01 (d, J=9.8 Hz, 1 H) 7.46 (dd, J=8.4, 1.8 Hz, 1 H) 7.67 (d, J=8.6 Hz, 1 H)
8.13 (d, J=2.0 Hz, 1 H) 8.26 (d, J=9.8 Hz, 1 H) 12.67 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=453+; MH- =451-
Example 13:
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
N-(6-{[6-(Cyclopentyloxy)[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 1a, but starting with 250 mg of 6-{[6-(cyclopentyloxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine 11a in 5 cm3 of
pyridine with 2.5 cm3 of acetic anhydride after reaction for 48 hours at 20°C.
255 mg of N-(6-{[6-(cyclopentyloxy)[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, DMSO-c/6) 5 ppm 1.44 -1.71 (m, 6 H) 1.71
-1.88 (m, 2 H) 2.19 (s, 3 H) 5.04 - 5.15 (m, 1 H) 7.01 (d, J=9.8 Hz, 1 H) 7.46
(dd, J=8.6, 2.0 Hz, 1 H) 7.67 (d, J=8.6 Hz, 1 H) 8.14 (d, J=2.0 Hz, 1 H) 8.26
(d, J=9.8Hz, 1 H) 12.37 (s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=427+; MH- =425-
Example 14:
1-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]suIfanyl}-1,3-
benzothiazol-2-yI)-3-[2-(morpholin-4-yl)ethyl]urea
a) 1 -(6-{[6-(Cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea may be prepared in a
manner similar to that of Example 5a, but starting with 778 mg of a mixture of
phenyl (6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)carbamate and diphenyl (6-{[6-(cyclopentyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)imidodicarbonate
in 10 cm3 of tetrahydrofuran, 0.32 cm3 of 2-(morpholin-1-yl)ethanamine and
1.04 cm3 of triethylamine at 20°C. 127 mg of 1-(6-{[6-(cyclopentyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-
yl)ethyl]urea are thus obtained in the form of a white powder, the
characteristics of which are as follows:
1H NMR SPECTRUM (500 MHz, DMSO-c/6) 6 ppm 1.48 - 1.71 (m, 6 H) 1.78
- 1.92 (m, 2 H) 2.32 - 2.46 (m, 6 H) 3.27 (q, J=5.9 Hz, 2 H) 3.54 - 3.64 (m, 4
H) 5.09 - 5.17 (m, 1 H) 6.80 (br. s, 1 H) 7.01 (d, .7=9.6 Hz, 1 H) 7.41 (dd,
J=8.5, 1.6 Hz, 1 H) 7.55 (d, J=8.5 Hz, 1 H) 8.08 (d, J=1.6 Hz, 1 H) 8.26 (d,
J=9.6 Hz, 1 H)
10.93 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=541+; MH- =539-
b) The mixture of phenyl (6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate and diphenyl (6-{[6-
(cyclopentyloxy)[1,2,4]tria2olo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-yl)imidodicarbonate may be prepared in a manner similar to that of
Example 4a, but starting with 326 mg of 6-{[6-(cyclopentyloxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine (11a) and 0.21 cm3 of
phenyl chlorocarbonate in 5 cm3 of pyridine. 892 mg of a beige-coloured
powder of a mixture of phenyl (6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)carbamate and diphenyl (6-{[6-
(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-yl)imidodicarbonate are thus obtained, which product is used without further
purification in the following step:
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=505+; MH- = 503-
Example 15:
1-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
a) 1-(6-{[6-(Cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea may be prepared in a
manner similar to that of Example 1b, but starting with 305 mg of 1-[2-
(morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea (2b), 5 cm3 of
degassed ethanol, 4 mg of potassium dihydrogen phosphate in 0.1 cm3 of
water, 347 mg of DL-dithiothreitol and 202 mg of 3-chloro-6-
(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazine. 253 mg of 1-(6-{[6-
(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-yl)-3-[2-(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white
powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) 5 ppm 1.24 - 1.40 (m, 2 H) 1.42
- 1.58 (m, 6 H) 1.58 - 1.70 (m, 2 H) 1.78 - 1.93 (m, 2 H) 2.36 - 2.45 (m, 6 H)
3.22 - 3.28 (m, 2 H) 3.59 (t, J=4.4 Hz, 4 H) 4.81 - 4.91 (m, 1 H) 6.77 (br. s, 1
H) 7.01 (d, J=10.0 Hz, 1 H) 7.36 (dd, J=8.6, 2.0 Hz, 1 H) 7.55 (d, J=8.6 Hz, 1
H) 8.00 (d, J=1.7 Hz, 1 H) 8.26 (d, J=9.8 Hz, 1 H) 10.87 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=569+; MH- =567-
b) 3-Chloro-6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazine may be
prepared in a manner similar to that of Example 1c, but starting with 1.21 g of
cycloheptanol in 15 cm3 of tetrahydrofuran, 254 mg of sodium hydride at 60%
in oil and 1 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial). 453
mg of 3-chloro-6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazine are thus
obtained in the form of a colourless oil that crystallizes, the characteristics of
which are as follows:
MASS SPECTRUM: Waters ZQ: MH+ m/z=267+
Example 16:
6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
6-{[6-(Cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine may be prepared in a manner similar to that of Example 1b,
but starting with 249 mg of 3-chloro-6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]-
pyridazine (15b) in 5 cm3 of degassed ethanol, 5 mg of potassium dihydrogen
phosphate in 0.1 cm3 of water, 432 mg of DL-dithiothreitol and 193 mg of 2-
amino-1,3-benzothiazol-6-yl thiocyanate after 24 hours at 80°C. 260 mg of 6-
{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-amine are thus obtained in the form of a white powder, the
characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) 5 ppm 1.29 - 1.74 (m, 10 H)
1.86 - 1.97 (m, 2 H) 4.87 - 4.99 (m, 1 H) 7.00 (d, J=9.8 Hz, 1 H) 7.23 - 7.31
(m, 2 H) 7.60 (s, 2 H) 7.80 - 7.85 (m, 1 H) 8.24 (d, J=9.8 Hz, 1 H)
MASS SPECTRUM: Waters ZQ: MH+ m/z=413+; MH- =411-
Example 17:
N-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
N-(6-{[6-(Cycloheptyloxy)[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 1a, but starting with 85 mg of 6-{[6-(cycloheptyloxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine (16a) in 5 cm3 of
pyridine with 0.160 cm3 of acetic anhydride after reaction for 24 hours at
20°C. 90 mg of N-(6-{[6-(cycloheptyloxy)[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
yellow powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-c/6) 6 ppm 1.20 - 1.35 (m, 2 H) 1.40
- 1.55 (m, 6 H) 1.54 - 1.66 (m, 2 H) 1.76 - 1.89 (m, 2 H) 2.19 (s, 3 H) 4.78 -
4.88 (m, 1 H) 7.01 (d, J=9.8 Hz, 1 H) 7.40 (dd, J=8.6, 2.0 Hz, 1 H) 7.67 (d,
J=8.6 Hz, 1 H) 8.06 (d, J=2.0 Hz, 1 H) 8.27 (d, J=9.8 Hz, 1 H) 12.38 (br. s,
1 H)
MASS SPECTRUM: Waters ZQ: MH+ m/z=455+; MH- =453-
Example 18:
N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
a) N-(6-{[6-(cyclohexylamino)[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 1a, but starting with 150 mg of 3-[(2-amino-1,3-benzothiazol-6-
yl)sulfanyl]-N-cyclohexyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine in 1 cm3 of
pyridine with 0.5 cm3 of acetic anhydride after reaction for 18 hours at 20°C.
65 mg of N-(6-{[6-(cyclohexylamino)[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
pale beige powder, the characteristics of which are as follows:
1H NMR SPECTRUM (300 MHz, DMSO-c/6) 6 ppm 0.95 - 1.32 (m, 5 H) 1.45
- 1.67 (m, 3 H) 1.68 - 1.84 (m, 2 H) 2.19 (s, 3 H) 3.35 - 3.45 (m, 1 H) 6.79 (d,
J=10.0 Hz, 1 H) 7.25 (d, J=7.0 Hz, 1 H) 7.38 (dd, J=8.5, 2.0 Hz, 1 H) 7.64 (d,
J=8.5 Hz, 1 H) 7.92 (d, J=10.0 Hz, 1 H) 8.05 (d, J=2.0 Hz, 1 H) 12.35 (br. s, 1
H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=440+; MH- =438-
b) 3-[(2-Amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclohexyl[1,2,4]triazolo-
[4,3-b]pyridazin-6-amine may be prepared in a manner similar to that of
Example 1b, but starting with 607 mg of 3-chloro-N-cyclohexyl[1,2,4]triazolo-
[4,3-b]pyridazin-6-amine in 10 cm3 of degassed ethanol, 12 mg of potassium
dihydrogen phosphate in 1 cm3 of water, 1.12 g of DL-dithiothreitol and
500 mg of 2-amino-1,3-benzothiazol-6-yl thiocyanate after 24 hours at 80°C.
768 mg of 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-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: MH+ m/z=398+; MH- =396-
c) 3-Ch!oro-N-cyclohexyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine may be
prepared in the following manner:
2.3 cm3 of cyclohexylamine and 3.7 cm3 of triethylamine are added to a
solution of 5 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine in
50 cm3 of N,N-dimethylformamide. The reaction is stirred at 20°C for 18
hours. A further 1.1 cm3 of cyclohexylamine and 7.5 cm3 of triethylamine are
then added and the reaction is stirred at 50°C for 4 hours. The reaction
mixture is cooled to 20°C, followed by addition of 60 cm3 of water. The white
precipitate is filtered off by suction, and then washed successively with water
and ether. 3 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. After leaving overnight, the
precipitate formed in the first filtrate, obtained above, is filtered off by suction
and washed successively with N,N-dimethylformamide, with demineralized
water and with methanol. A second crop of 1.42 g of 3-chloro-N-cyclo-
hexyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine is thus obtained in the form of a
yellow powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=252+; MH- =250-
Example 19:
1-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea
a) 1 -(6-{[6-(Cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyI}-
1,3-benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea may be prepared in a
manner similar to that of Example 1b, but starting with 300 mg of 2-{[(2-pyrro-
lidinylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yl thiocyanate in 6 cm3 of
degassed ethanol, 4 mg of potassium dihydrogen phosphate in 0.6 cm3 of
water, 400 mg of DL-dithiothreitol and 240 mg of 3-chloro-N-cyclohexyl[1,2,4]-
triazolo[4,3-b]pyridazin-6-amine (18c) after 18 hours at 80°C. 193 mg of 1-(6-
{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea are thus obtained in the form of a
pale yellow powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) 6 ppm 1.00 -1.34 (m, 6 H) 1.46
- 1.74 (m, 6 H) 1.75 - 1.86 (m, 2 H) 2.40 - 2.57 masked (m, 6 H) 3.21 - 3.28
(m, 2 H) 3.39 - 3.49 (m, 1 H) 6.79 (d, J=10.0 Hz, 1 H) 6.81 - 6.88 (m, 1 H)
7.25 (d, J=7.0 Hz, 1 H) 7.35 (dd, J=8.5, 2.0 Hz, 1 H) 7.52 (d, J=8.5 Hz, 1 H)
7.90 (d, J=10.0 Hz, 1 H) 7.98 (d, J=2.0 Hz, 1 H) 10.81 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=538+; MH- =536-
b) 2-{[(2-Pyrrolidinylethyl)carbamoyl]amino}-1,3-benzothiazol-6-yi
thiocyanate may be prepared in the following manner:
1.4 cm3 of 2-pyrrolidinylethanamine are added to a solution of 3 g of phenyl
(6-thiocyanato-1,3-benzothiazol-2-yl)carbamate in 90 cm3 of tetrahydrofuran
at 20°C. After 24 hours, the reaction mixture is concentrated to dryness under
reduced pressure. Ethyl ether is added to the oily yellow residue obtained.
The precipitate formed is filtered off by suction. 3.33 g of 2-{[(2-pyrro-
NdinylethyI)carbamoyl]amino}-1,3-benzothiazol-6-yl thiocyanate are thus
obtained in the form of a yellowish powder, the characteristics of which are as
follows:
MASS SPECTRUM: Waters ZQ: MH+ m/z=348+; MH- =346-
c) Phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate was prepared
in the following manner:
7.5 g of phenyl chlorocarbonate and then 4.05 g of sodium hydrogen
carbonate and 9.4 cm3 of water are added to a solution of 2.5 g of
commercial 2-amino-1,3-benzothiazol-6-yl thiocyanate in 94 cm3 of
tetrahydrofuran, at 20°C. The resulting mixture is then stirred at 20°C for
20 hours and then extracted with 2x150 cm3 of ethyl acetate. The organic
phases are combined and then washed with 3X50 cm3 of saturated aqueous
sodium hydrogen carbonate solution. The organic phase obtained is dried
over magnesium sulfate and then concentrated to dryness under reduced
pressure. The residue is taken up in 50 cm3 of water and then filtered off by
suction and dried under vacuum at 20°C. 3.45 g of phenyl (6-thiocyanato-1,3-
benzothiazol-2-yl)carbamate are thus obtained in the form of a pale yellow
solid, the characteristics of which are as follows:
MASS SPECTRUM: LC-MS-DAD-ELSD: MH+ m/z =328+; MH- = 326-
Example 20:
trans-4-{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}-
sulfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino}cyclohexyl
cyclopropanecarboxylate
a) trans-4-{[3-({2-[(Cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}-
sulfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino}cyclohexyl
cyclopropanecarboxylate may be prepared in a manner similar to that of
Example 1a, but starting with 300 mg of trans-4-({3-[(2-amino-1,3-benzo-
thiazol-6-yl)sulfanyl][1,2,4]triazolo[4,3-b]pyridazin-6-yI}amino)cyclohexanol in
2.1 cm3 of pyridine with 0.133 cm3 of cyclopropanecarboxylic acid chloride
after reaction for 18 hours at 20°C. 303 mg of trans-4-{[3-({2-[(cyclo-
propylcarbonyl)amino]-1,3-benzothiazol-6-yl}sulfanyl)[1,2,4]triazolo[4,3-b]-
pyridazin-6-yl]amino}cyclohexyl cyclopropanecarboxylate are thus obtained in
the form of a white powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-c/6) 6 ppm 0.76 - 1.01 (m, 8 H) 1.06
- 1.32 (m, 4 H) 1.51 - 1.65 (m, 1 H) 1.67 - 1.81 (m, 4 H) 1.93 - 2.05 (m, 1 H)
3.30 - 3.38 (m, 1 H) 4.44 - 4.61 (m, 1 H) 6.78 (d, J=9.8 Hz, 1 H) 7.20 - 7.34
(m, 2 H) 7.62 (d, J=8.6 Hz, 1 H) 7.93 (d, J=9.8 Hz, 1 H) 8.05 (d, J=2.0 Hz, 1
H) 12.64 (br.s,1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=550+; MH- =548-
b) trans-4-({3-[(2-Amino-1,3-benzothiazol-6-yl)sulfanyl][1,2,4]triazolo[4,3-
b]pyridazin-6-yl}amino)cyclohexanol may be prepared in a manner similar to
that of Example 1b, but starting with 1 g of 2-amino-1,3-benzothiazol-6-yl
thiocyanate in 20 cm3 of degassed ethanol, 23 mg of potassium dihydrogen
phosphate in 2 cm3 of water, 2.32 g of DL-dithiothreitol and 1.29 g of trans-4-
[(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)amino]cyclohexanol after
18 hours at 80°C. 1.8 g of trans-4-({3-[(2-amino-1,3-benzothiazol-6-
yl)sulfanyl][1,2,4]triazolo[4,3-b]pyridazin-6-yl}amino)cyclohexanol are thus
obtained in the form of a cream-white powder, the characteristics of which are
as follows:
MASS SPECTRUM: Waters ZQ: MH+ m/z=414+; MH- =412-
c) trans-4-[(3-Chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-
aminojcyclohexanol may be prepared in a manner similar to that of
Example 18c, but starting with 5 g of commercial 3,6-dichloro[1,2,4]triazolo-
[4,3-b]pyridazine in 50 cm3 of N,N-dimethylformamide, 6 g of trans-4-
aminocyclohexanol hydrochloride and 17 cm3 of triethylamine after 48 hours
at 20°C and 4 hours at 50°C. 3.5 g of trans-4-[(3-chloro[1,2,4]triazolo[4,3-b]-
pyridazin-6-yl)amino]cyclohexanol are thus obtained in the form of a white
powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=268+; MH- =266-
Example 21:
N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(Cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide may be prepared in a manner
similar to that of Example 1a, but starting with 300 mg of 3-[(2-amino-1,3-
benzothiazol-6-yl)sulfanyl]-N-cyclohexyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine
(18b) in 2.1 cm3 of pyridine with 0.14 cm3 of cyclopropanecarboxylic acid
chloride, after reaction for 18 hours at 20°C. 268 mg of N-(6-{[6-(cyclo-
hexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-
cyclopropanecarboxamide are thus obtained in the form of a cream-white
powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-c/6) 6 ppm 0.86 - 1.00 (m, 4 H) 1.01
-1.28(m, 5 H) 1.48-1.66 (m, 3 H) 1.70 - 1.83 (m, 2 H) 1.92 - 2.04 (m, 1 H)
3.36 - 3.45 (m, 1 H) 6.79 (d, J=9.8 Hz, 1 H) 7.25 (d, J=7.1 Hz, 1 H) 7.39 (d,
J=8.6 Hz, 1 H) 7.65 (d, J=8.3 Hz, 1 H) 7.91 (d, J=9.8 Hz, 1 H) 8.03 (s, 1 H)
12.65 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=466+; MH- =464-
Example 22:
N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]acetamide
a) N-[6-({6-[(trans-4-Hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]acetamide may be prepared in the
following manner:
0.08 cm3 of acetyl chloride and 0.16 cm3 of triethylamine are added to a
solution of 114 mg of trans-4-({3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-
[1,2,4]triazolo[4,3-b]pyridazin-6-yl}amino)cyclohexanol (20b) in 2 cm3 of
dichloromethane. After 18 hours, the reaction medium is concentrated to
dryness under reduced pressure. The residue is taken up in water. The
yellow-white precipitate formed is filtered off by suction and washed with
water and is then purified by dry deposition on Biotage Quad 25M (KP-SIL,
60 A; 32-63 uM), eluting with a gradient of 95/5 to 70/30 of
dichloromethane/(dichloromethane: 38/methanol: 17/aqueous ammonia: 2).
46 mg of N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][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 beige-coloured powder, the characteristics of which are as
follows:
1H NMR SPECTRUM (400 MHz, DMSO-of6) 6 ppm 1.01 - 1.27 (m, 4 H) 1.68
-1.86 (m, 4 H) 2.19 (s, 3 H) 3.35 - 3.44 (m, 2 H) 4.51 (d, J=4.6 Hz, 1 H) 6.77
(d, J=9.8 Hz, 1 H) 7.25 (d, J=6.8 Hz, 1 H) 7.42 (dd, J=8.4, 1.8 Hz, 1 H) 7.65
(d, J=8.3 Hz, 1 H) 7.92 (d, J=9.8 Hz, 1 H) 8.01 (d, J=1.7 Hz, 1 H) 12.34 (br. s,
1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=456+; MH- =454-
Example 23:
N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
N-[6-({6-[(trans-4-Hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyridazin-3-
yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide may be prepared
in a manner similar to that of Example 1a, but starting with 300 mg of trans-4-
({3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl][1,2,4]triazolo[4,3-b]pyridazin-6-
yl}amino)cyclohexanol (20b) in 3 cm3 of pyridine with 0.235 cm3 of
cyclopropanecarboxylic acid chloride, after reaction for 16 hours at 20°C. 51
mg of N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide are thus
obtained in the form of a beige-coloured powder, the characteristics of which
are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-of6) 6 ppm 0.89 - 0.99 (m, 4 H) 1.02
- 1.27 (m, 4 H) 1.68 - 1.87 (m, 4 H) 1.92 - 2.03 (m, 1 H) 3.31 - 3.45 (m, 2 H)
4.51 (d, J=4A Hz, 1 H) 6.77 (d, J=9.8 Hz, 1 H) 7.25 (d, J=7.1 Hz, 1 H) 7.43
(dd, J=8.6, 2.0 Hz, 1 H) 7.65 (d, ^=8.6 Hz, 1 H) 7.91 (d, J=9.8 Hz, 1 H) 8.00
(d, J=1.7Hz,1 H) 12.64 (br. 3,1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=482+; MH- =480-
Example 24:
3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo-
[4,3-b]pyridazin-6-amine
a) 3-[(2-Amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]-
triazolo[4,3-b]pyridazin-6-amine may be prepared in a manner similar to that
of Example 1b, but starting with 1.4 g of 2-amino-1,3-benzothiazol-6-yl
thiocyanate in 41 cm3 of degassed ethanol, 32 mg of potassium dihydrogen
phosphate in 4 cm3 of water, 3.13 g of DL-dithiothreitol and 1.42 g of 3-chloro-
N-cyclopropyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine after 18 hours at 80°C.
1.22 g of 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]-
triazolo[4,3-b]pyridazin-6-amine 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) 5 ppm 0.41 - 0.48 (m, 2 H) 0.71
- 0.79 (m, 2 H) 2.56 - 2.65 (m, 1 H) 6.76 (d, J=9.8 Hz, 1 H) 7.27 (d, J=8.3 Hz,
1 H) 7.42 (dd, J=8.3, 2.0 Hz, 1 H) 7.67 (br. s, 3 H) 7.92 (d, J=9.8 Hz, 1 H)
7.95 (d, J=1.7Hz, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=356+; MH- =354-
b) 3-Chloro-N-cyclopropyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine
DPN1.150 may be prepared in a manner similar to that of Example 18c, but
starting with 2 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine in
20 cm3 of N,N-dimethylformamide, 1.1 cm3 of cyclopropylamine and 3 cm3 of
triethylamine, after 18 hours at 20°C and 3 hours at 50°C. 1.53 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 2Q: MH+ m/z=210+; MH- =208-
Example 25:
N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
a) N-(6-{[6-(Cyclopropylamino)[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 1a, but starting with 300 mg of 3-[(2-amino-1,3-
benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo[4,3-b]pyridazin-6-
amine (24a) in 2.1 cm3 of pyridine with 1.04 cm3 of acetic anhydride after
reaction for 18 hours at 20°C. 100 mg of N-(6-{[6-(cyclopropylamino)[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, DMSO-d6) 6 ppm 0.34 - 0.45 (m, 2 H) 0.61
- 0.74 (m, 2 H) 2.19 (s, 3 H) 2.53 - 2.58 (m, 1 H) 6.77 (d, J=9.5 Hz, 1 H) 7.53
(d, J=8.3 Hz, 1 H) 7.62 - 7.73 (m, 2 H) 7.94 (d, J=9.8 Hz, 1 H) 8.19 (s, 1 H)
12.38 (br.s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=398+; MH- =396-
Example 26:
N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
a) N-(6-{[6-(Cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yI]-
sulfanyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide may be prepared in
a manner similar to that of Example 1a, but starting with 300 mg of 3-[(2-
amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo[4,3-b]pyrid-
azin-6-amine (24a) in 3 cm3 of pyridine with 0,16 cm3 of cyclopropane-
carboxylic acid chloride, after reaction for 18 hours at 20°C. 208 mg of N-(6-
{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-yl)cyclopropanecarboxamide are thus obtained in the form of a white
powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-cf6) 5 ppm 0.34 - 0.44 (m, 2 H) 0.62
- 0.73 (m, 2 H) 0.89 -1.01 (m, 4 H) 1.93 - 2.03 (m, 1 H) 2.52 - 2.61 (m, 1 H)
6.77 (d, J=9.8 Hz, 1 H) 7.53 (dd, J=8.6, 1.7 Hz, 1 H) 7.61 - 7.71 (m, 2 H) 7.94
(d, J=9.8 Hz, 1 H) 8.19 (d, J=1.5 Hz, 1 H) 12.66 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=424+; MH- =422-
Example 27:
1-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyI}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
a) 1 -(6-{[6-(Cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea may be prepared in a
manner similar to that of Example 1b, but starting with 300 mg of 1-[2-
(morpholin-4-yl)ethyl]-3-(6-suifanyl-1,3-benzothiazol-2-yl)urea (2b), 7.5 cm3 of
degassed ethanol, 6 mg of potassium dihydrogen phosphate in 0.7 cm3 of
water, 552 mg of DL-dithiothreitol and 403 mg of 3-chloro-N-cyclohexyl[1,2,4]-
triazolo[4,3-b]pyridazin-6-amine (18c). 370 mg of 1-(6-{[6-(cyclohexylamino)-
[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-[2-
(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white powder, the
characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-dB) 6 ppm 1.08 - 1.30 (m, 5 H) 1.47
- 1.70 (m, 3 H) 1.71 - 1.89 (m, 2 H) 2.32 - 2.46 (m, 6 H) 3.22 - 3.28 (masked
m, 2 H) 3.36 - 3.52 (m, 1 H) 3.59 (t, J=4.3 Hz, 4 H) 6.69 - 6.93 (m, 2 H) 7.25
(d, J=7.1 Hz, 1 H) 7.35 (dd, J=8.3, 2.0 Hz, 1 H) 7.52 (d, J=8.3 Hz, 1 H) 7.90
(d, J=10.0 Hz, 1 H) 7.98 (d, J=1.7 Hz, 1 H) 10.90 (br. s, 1 H)
MASS SPECTRUM: Waters ZQ: MH+ m/z=554+; MH- =552-
Example 28:
N-(6-{t6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-methoxypropanamide
a) N-(6-{[6-(Cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yI]-
sulfanyl}-1,3-benzothiazol-2-yl)-3-methoxypropanamide may be prepared in a
manner similar to that of Example 1a, but starting with 220 mg of 3-[(2-amino-
1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo[4,3-b]pyridazin-6-
amine (24a) in 7 cm3 of pyridine with 0.2 cm3 of 3-methoxypropanoyl chloride,
after reaction for 18 hours at 20°C. 81 mg of N-(6-{[6-(cyclo-
propylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
yl)-3-methoxypropanamide are thus obtained in the form of a pale beige
powder, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6) 5 ppm 0.33 - 0.43 (m, 2 H) 0.62
- 0.73 (m, 2 H) 2.53 - 2.59 (m, 1 H) 2.73 (t, J=6A Hz, 2 H) 3.24 (s, 3 H) 3.64
(t, J=6.0 Hz, 2 H) 6.77 (d, J=9.5 Hz, 1 H) 7.53 (dd, J=8.4, 1.6 Hz, 1 H) 7.68 (d,
J=8.6 Hz, 1 H) 7.72 (d, J=2.7 Hz, 1 H) 7.96 (d, J=9.8 Hz, 1 H) 8.22 (d, J=1.5
Hz, 1 H) 12.46 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=442+
Example 29:
1-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
a) 1-(6-{[6-(Cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea may be prepared in a
manner similar to that of Example 1b, but starting with 300 mg of 1-[2-
(morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea (2b), 12 cm3 of
degassed ethanol, 5 mg of potassium dihydrogen phosphate in 1.2 cm3 of
water, 410 mg of DL-dithiothreitol and 187 mg of 3-chloro-N-cyclo-
propyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine (24b), after 18 hours at 80°C.
133 mg of 1-(6-{[6-(cyclopropylamino)[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 cream-white powder, the characteristics of which are
as follows:
1H NMR SPECTRUM (400 MHz, DMSO-c/6 CD3COOD) 5 ppm 0.36 - 0.49 (m,
2 H) 0.65 - 0.82 (m, 2 H) 2.57 - 2.65 (m, 1 H) 2.96 - 3.16 (m, 6 H) 3.50 (t,
J=5.7 Hz, 4H) 3.79 (br. s, 2 H) 6.79 (d, J=9.8 Hz, 1 H) 6.90 - 7.05 (m, 1 H)
7.48 - 7.63 (m, 2 H) 7.66 (br. s, 1 H) 7.91 (d, J=9.8 Hz, 1 H) 8.16 (s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=512+; MH- =510-
Example 30:
N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-N2,N2-dimethylglycinamide
a) N-(6-{[6-(Cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yI)-N2,N2-dimethylglycinamide may be prepared
in a manner similar to that of Example 1a, but starting with 220 mg of 3-[(2-
amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo[4,3-b]pyrid-
azin-6-amine (24a) in 8 cm3 of dichloromethane with 197 mg of N,N-dimethyl-
glycyl chloride hydrochloride and 0.26 cm3 of triethylamine, after reaction for
18 hours at 20°C. 167 mg of N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-N2,Nz-dimethylglycinamide are
thus obtained in the form of a pale beige powder, the characteristics of which
are as follows:
1H NMR SPECTRUM (500 MHz, DMSO-c/6) 6 ppm 0.39 (br. s, 2 H) 0.69 (d,
J=5.2 Hz, 2 H) 2.29 (s, 6 H) 2.52 - 2.59 (m, 1 H) 3.10 - 3.25 (masked m, 2 H)
6.77 (d, J=9.6 Hz, 1 H) 7.53 (d, J=8.2 Hz, 1 H) 7.61 - 7.74 (m, 2 H) 7.95 (d,
J=9.6 Hz, 1 H) 8.20 (s, 1 H) 12.06 (br. s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=441+; MH- =439-
Example 31:
3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclohexyl-7,8-
dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-amine
a) 3-[(2-Amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclohexyl-7,8-
dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-amine may be prepared in a manner
similar to that of Example 1b, but starting with 250 mg of 2-amino-1,3-benzo-
thiazol-6-yl thiocyanate, 8 cm3 of degassed ethanol, 6 mg of potassium
dihydrogen phosphate in 0.8 cm3 of water, 660 mg of DL-dithiothreitol and
306 mg of 3-chloro-N-cyclohexyl[1,2,4]triazolo[4,3-b]pyridazin-6-amine. 202
mg of 3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclohexyl-7,8-dihydro-
[1,2,4]triazolo[4,3-b]pyridazin-6-amine 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) 6 ppm 1.00 -1.35 (m, 5 H) 1.48
-1.74 (m, 3 H) 1.78 -1.90 (m, 2 H) 2.56 (t, J=7.7 Hz, 2 H) 2.96 (t, J=7.7 Hz, 2
H) 3.45 - 3.55 (m, 1 H) 7.08 (d, J=7.6 Hz, 1 H) 7.16 - 7.37 (m, 2 H) 7.66 (br. s,
2 H) 7.81 (s, 1 H)
MASS SPECTRUM: Waters UPLC-SQD: MH+ m/z=400+; MH- =398-
b) 3-Chloro-N-cyclohexyl-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-
amine may be prepared in the following manner:
1.3 g of zinc powder are added to 500 mg of 3-chloro-N-cyclohexyl[1,2,4]-
triazolo[4,3-b]pyridazin-6-amine (18c) in 16 cm3 of glacial acetic acid at 20°C.
After stirring for 2 hours, the suspension is filtered through filter paper and the
filtrate is concentrated to dryness under reduced pressure. The solid residue
obtained is purified by chromatography on silica, by dry deposition on a
Biotage Quad 12/25 cartridge (KP-SIL, 60 A; 32-63 uM), eluting with a 95/5 to
90/10 gradient of dichloromethane/methanol. 317 mg of 3-chloro-N-cyclo-
hexyl-7,8-dihydro[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: MH+ m/z=254+; MH- =252-
Example 32:
ethyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)carbamate
a) Ethyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)carbamate may be prepared in the following manner:
320 mg of 2-[(morpholin-4-ylcarbonyl)amino]-1,3-benzothiazol-6-yl
thiocyanate (32b) in 7 cm3 of ethanol are placed in a 10 cm3 microwave vial
equipped with a stirrer, at 20°C. A stream of argon is bubbled through the
mixture for 5 minutes, followed by adding 408 mg of potassium dihydrogen
phosphate in 0.25 cm3 of water, 463 mg of DL-dithiothreitol and 252 mg of 3-
chloro-6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazine (1c). The mixture is
stirred in a microwave oven for 1 hour at 120°C. The reaction mixture is then
concentrated to dryness under vacuum and the solid residue is then purified
by two successive chromatographies on a Merck silica cartridge by solid
deposition, eluting with a 99/1 to 97/3 gradient of dichloromethane/methanol.
77 mg of ethyl (6-{[6-(cyclohexyloxy)[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 solid, the characteristics of which are as follows:
MASS SPECTRUM: LC/MS Electrospray on WATERS UPLC - SQD:
Retention time Rt (min) = 1.06; [M+H]+: m/z 471; [M-H]-: m/z 469
1H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.15 to 1.40 (m, 8 H);
1.42 to 1.64 (m, 3 H); 1.79 (d, J=13.2 Hz, 2 H); 4.24 (q, J=7.1 Hz, 2 H); 4.67
(m, 1 H); 7.02 (d, J=9.8 Hz, 1 H); 7.39 (dd, J=1.8 and 8.2 Hz, 1 H); 7.62 (d,
J=8.6 Hz, 1 H); 8.05 (s, 1 H); 8.28 (d, J=9.8 Hz, 1 H); 12.06 (broad s, 1 H)
b) 2-[(Morpholin-4-ylcarbonyl)amino]-1,3-benzothiazol-6-yl thiocyanate
may be prepared in a manner similar to that of Example 2c, but starting with
2.29 g of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate (2d) in a
mixture of 70 cm3 of tetrahydrofuran and 0.602 cm3 of morpholine at 50°C for
26 hours. 2.12 g of 2-[(morpholin-4-ylcarbonyl)amino]-1,3-benzothiazol-6-yl
thiocyanate are thus obtained in the form of a white solid, the characteristics
of which are as follows:
MASS SPECTRUM: Waters UPLC-SQD:
Retention time Rt (min) = 0.73; [M+H]+: m/z 321; [M-H]-: m/z 319
Example 33:
2-chloro-N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)acetamide
a) 2-Chloro-N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)acetamide may be prepared in the following
manner:
0.1 cm3 of chloroacetyl chloride is added dropwise to 200 mg of 6-{[6-(cyclo-
hexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
amine (1b) in 2 cm3 of dichloromethane and 0.5 cm3 of pyridine at 0-5°C. The
resulting solution is stirred for 30 minutes at 20°C, and the medium is then
evaporated to dryness under argon at 20°C. The residue is purified by
chromatography on a Merck silica cartridge by solid deposition, eluting with a
gradient of from 100% dichloromethane to 92/8
dichloromethane/(dichloromethane: 38/methanol: 17/aqueous ammonia: 2).
After slurrying in ether and drying under vacuum, 102 mg of 2-chloro-N-(6-{[6-
(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-
2-yl)acetamide are obtained in the form of a white solid, the characteristics of
which are as follows:
MASS SPECTRUM: Waters UPLC-SQD:
Retention time Rt (min) = 1.03; [M+H]+: m/z 475; [M-H]-: m/z 473
1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d6): 1.10 to 1.38 (m, 5 H);
1.41 to 1.65 (m, 3 H); 1.77 (m, J=12.2 Hz, 2 H); 4.44 (s, 2 H); 4.66 (m, 1 H);
7.03 (d, J=9.8 Hz, 1 H); 7.42 (dd, J=2.0 and 8.6 Hz, 1 H); 7.70 (d, J=8.6 Hz, 1
H); 8.08 (d, J=2.0 Hz, 1 H); 8.29 (d, J=10.0 Hz, 1 H); 12.75 (broad s, 1 H)
Example 34:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2-cyclopropylglycinamide
a) N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-N2-cyclopropylglycinamide may be prepared in the
following manner:
0.35 cm3 of cyclopropylamine is added to 280 mg of 2-chloro-N-(6-{[6-(cyclo-
hexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-
acetamide (33) in 4 cm3 of pyridine at 20°C. After stirring for 5 hours, the
reaction medium is evaporated to dryness at 20°C. The residue is purified by
chromatography on a Merck silica cartridge by solid deposition, eluting with a
gradient of from 100% de dichloromethane to 97/3
dichloromethane/methanol. 110 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-N2-cyclopropylglycin-
amide are thus obtained in the form of a yellow solid, the characteristics of
which are as follows:
MASS SPECTRUM: Waters UPLC-SQD:
Retention time Rt (min) = 0.74; [M+H]+: m/z 496; [M-H]-: m/z 494
1H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d6): 0.19 to 0.40 (m, 4 H);
1.14 to 1.26 (m, 3 H); 1.33 (m, 2 H); 1.41 to 1.66 (m, 3 H); 1.78 (m, 2 H); 2.17
(m, 1 H); 3.51 (s, 2 H); 4.60 to 4.72 (m, 1 H); 7.03 (d, J=9.8 Hz, 1 H); 7.41
(dd, J=1.5 and 8.3 Hz, 1 H); 7.68 (d, J=8.8 Hz, 1 H); 8.08 (s, 1 H); 8.28 (d,
J=9.8 Hz, 1 H)
Example 35:
6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]suIfanyl}-1,3-
benzothiazol-2-amine
a) 6-{[6-(Cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine may be prepared in a manner similar to that of Example
1b, but starting with 1.07 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate,
15 cm3 of degassed ethanol, 20 mg of potassium dihydrogen phosphate in
0.1 cm3 of water, 1.99 g of DL-dithiothreitol and 964 mg of 3-chloro-6-(cyclo-
butyloxy)[1,2,4]triazolo[4,3-b]pyridazine. 1.1 g of 6-{[6-(cyclobutyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-amine are thus
obtained in the form of a whitish powder, the characteristics of which are as
follows:
MASS SPECTRUM: Waters ZQ:
Retention time Rt (min) = 3.39; [M+H]+: m/z 371; [M-H]-: m/z 369
1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d6): 1.66 (m, 1 H); 1.80 (m,
1 H); 2.01 to 2.13 (m, 2 H); 2.31 to 2.40 (m, 2 H); 4.96 (qd, J=7.1 and 7.3 Hz,
1 H); 7.04 (d, J=9.8 Hz, 1 H); 7.29 (d, J=8.3 Hz, 1 H); 7.34 (dd, J=2.0 and 8.6
Hz, 1 H); 7.62 (s, 2 H); 7.88 (d, J=1.7 Hz, 1 H); 8.26 (d, J=9.8 Hz, 1 H)
b) 3-Chloro-6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazine may be
prepared in a manner similar to that of Example 1c, but starting with 954 mg
of cyclobutanol in 10 cm3 of tetrahydrofuran, 317 mg of sodium hydride at
60% in oil and 1 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial).
1.03 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, 5 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 36:
N-(6-{[6-(cyclobutyloxy)[1,2,4]tria2olo[4,3-b]pyridazin-3-yl]sulfanyl}-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}-1,3-
benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide may be prepared in the
following manner:
A mixture of 273 mg of (4-ethylpiperazin-1-yl)acetic acid (commercial),
0.28 cm3 of diisopropylethylamine and 411 mg of 0-(7-azabenzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) in 3 cm3 of N,N-
dimethylformamide at 20°C is stirred for 1 hour at 20°C. 200 mg of 6-{[6-
(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-
amine (35a) are added to the reaction medium. After 18 hours, the solution is
poured into ice-water and the precipitate is filtered off. The yellow paste
isolated is taken up in a 90/10 ethyl acetate/methanol mixture. The solution
obtained is dried over magnesium sulfate, filtered and then concentrated to
dryness under vacuum. The oily residue is purified on SPOT II by
chromatography on a silica cartridge (SVF D26 Si60; 15-40 uM; 25 g), eluting
with a gradient of from 96/4 dichloromethane/methanol to 100% methanol.
127 mg of N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide are thus obtained in
the form of a yellow powder, the characteristics of which are as follows:
MASS SPECTRUM: Waters ZQ
Retention time Rt (min) = 3.10; [M+H]+: m/z 525; [M-H]-: m/z 523
1H NMR Spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.00 (t, J=7.2 Hz, 3 H);
1.59 (m, 1 H); 1.73 (m, 1 H); 1.94 to 2.09 (m, 2 H); 2.20 to 2.31 (m, 2 H); 2.32
to 2.58 (partially masked m, 10 H); 3.34 (s, 2 H); 4.90 (m, 1 H); 7.06 (d, J=9.8
Hz, 1 H); 7.48 (dd, J=1.8 and 8.6 Hz, 1 H); 7.71 (d, J=8.6 Hz, 1 H); 8.14 (d,
J=1.8 Hz, 1 H); 8.30 (d, J=9.8 Hz, 1 H); 12.12 (very broad m, 1 H)
Example 37:
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-diethylglycinamide
a) N-(6-{[6-(Cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-diethylglycinamide may be prepared in the following
manner:
A mixture of 827 mg of sodium (diethylamino)acetate (commercial) in 5.5 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. 8 cm3 of
pyridine, 200 mg of 6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-amine (35a) and 1.03 g of N-(3-
dimethylaminopropyl)N'-ethylcarbodiimide hydrochloride are added to the
white residue obtained, at 20°C. After 5 hours, the brown reaction medium is
evaporated to dryness. The residue is taken up in toluene and the mixture is
again evaporated to dryness under vacuum. The residue is taken up in water
and the mixture is extracted with ethyl acetate and then evaporated to
dryness. The residue is purified by dry deposition on silica and
chromatographed on a Biotage Quad 12/25 cartridge (KP-SIL, 60 A; 32-63
uM), eluting with a 100/0 to 98/2 gradient of dichloromethane/methanol. 135
mg of N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-diethylglycinamide 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 Rt (min) = 0.72; [M+H]+: m/z 484; [M+2HJ2+: m/z 242.5 (base
peak); [M-H]-: m/z 482
1H NMR Spectrum (400 MHz, 6 in ppm, DMSO-d6): 1,00 (t, J=7.2 Hz, 6 H);
1.52 to 1.66 (m, 1 H); 1.68 to 1.80 (m, 1 H); 1.95 to 2.09 (m, 2 H); 2.20 to 2.31
(m, 2 H); 2.62 (q, J=7.2 Hz, 4 H); 3.40 (s, 2 H); 4.90 (m, 1 H); 7.06 (d, J=9.8
Hz, 1 H); 7.47 (dd, J=1.9 and 8.5 Hz, 1 H); 7.69 (d, J=8.5 Hz, 1 H); 8.13 (d,
J=1.9 Hz, 1 H); 8.29 (d, J=9.8 Hz, 1 H); 11.54 (very broad m, 1 H)
Other examples and intermediates thereof prepared by analogy with the
above examples are described in the table below:
xample 65:
ac-1-{6-[(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morphoiin-4-yl)ethyl]urea, 15/85
lixture of the cis and trans isomers (major)
) 1 -{6-[(6-{[3-Methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea may be
repared in a manner similar to that described for Example 2a, but with
.240 g of a 1/1 mixture of racemic cis- and trans-3-chloro-6-{[3-methylcyclo-
exyI]oxy}[1,2,4]triazolo[4,3-b]pyridazine, dissolved in 12 cm3 of ethanol,
illowed by addition, at a temperature in the region of 20°C, of 0.457 g of 1-
!-(morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea (2b), 0.416 g
f DL- dithiothreitol, and a solution of 0.061 g of potassium dihydrogen
hosphate in 0.600 cm3 of distilled water. After stirring at reflux for 8 hours,
le reaction medium is concentrated to dryness under reduced pressure
1.7 kPa). The residue is taken up in 40 cm3 of dichloromethane and the
lixture obtained is washed successively with twice 30 cm3 of distilled water
nd 15 cm3 of saturated sodium chloride solution, and is then dried over
nhydrous magnesium sulfate, filtered and concentrated to dryness under
sduced pressure (2.7 kPa) to give 0.370 g of an orange-coloured foam. This
range foam is purified by flash chromatography on silica [eluent:
ichloromethane/methanol/acetonitrile (90/5/5 by volume + 0.1 % 7V of 20%
queous ammonia solution)]. After concentrating the fractions under reduced
ressure, 0.121 g of a 15/85 mixture of racemic cis- and trans-1-{6-[(6-{[3-
iethylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo-
Yiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea is obtained in the form of a white
olid melting at 197.6°C, the characteristics of which are as follows:
1H NMR spectrum (400 MHz, 6 in ppm, DMSO-d6) mixture of isomers 85%
H1-ax 15% H1-eq with 0.71 (d, J=6.3 Hz, 0.45 H); 0.81 (d, J=6.6 Hz, 2.55 H);
0.72 to 1.80 (m, 7 H); 1.85 to 1.94 (m, 2 H); 2.36 to 2.44 (m, 6 H); 3.26
(partially masked m, 2 H); 3.59 (m, 4H); 4.64 (m, 0.85 H); 5.07 (m, 0.15 H);
6.78 (broad t, J=6.1 Hz, 1 H); 7.01 (d, J=10.0 Hz, 0.85 H); 7.03 (d, J=10.0 Hz,
0.15 H); 7.34 (dd, J=2.0 and 8.6 Hz, 0.85 H); 7.37 (dd, J=2.0 and 8.6 Hz, 0.15
H); 7.54 (d, J=8.6 Hz, 1 H); 7.96 (d, J=2.0 Hz, 0.85 H); 8.03 (d, J=2.0 Hz, 0.15
H); 8.25 (d, J=10.0 Hz, 0.15 H); 8.27 (d, J=10.0 Hz, 0.85 H); 10.90 (broad m,
1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z 569; [M-H]-: m/z 567.
b) The 1/1 mixture of racemic cis- and trans-3-chloro-6-{[3-methylcyclo-
hexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazine may be prepared in a manner similar
to that described in Example 1c, but starting with 0.628 g of a 1/1 mixture of
racemic cis- and trans-3-methyl-cyclohexanol dissolved in 6 cm3 of
tetrahydrofuran under a stream of argon, to which is added, at a temperature
in the region of 0°C, 0.220 g of sodium hydride at 60% in oil. The reaction
medium is maintained at a temperature in the region of 0°C for 15 minutes,
followed by addition of 0.650 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine.
After stirring at a temperature in the region of 20°C for 24 hours, 10 cm3 of
saturated aqueous ammonium chloride solution and 20 cm3 of ethyl acetate
are added. After separating the two phases, the organic phase is washed
successively with twice 10 cm3 of distilled water and 15 cm3 of saturated
sodium chloride solution and is then dried over anhydrous magnesium
sulfate, filtered and concentrated to dryness under reduced pressure
(2.7 kPa) to give 0.950 g of a 1/1 mixture of racemic cis- and trans-3-chloro-6-
{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazine in the form of a
brown oil, the characteristics of which are as follows:
MASS SPECTRUM ES+: [M+H]+: m/z 267.
Example 66:
Rac-N-{6-[(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide, 15/85
mixture of the cis and trans isomers (major)
a) The 15/85 mixture of the cis and trans isomers of racemic N-{6-[(6-{[3-
methylcyclohexyI]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo-
thiazol-2-yl}cyclopropanecarboxamide may be prepared in a manner similar
to that described for Example 2a, but starting with 0.500 g of N-(6-sulfanyl-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide, 0.616 g of DL-dithiothreitol,
a solution of 0.090 g of potassium dihydrogen phosphate in 1 cm3 of distilled
water, 0.355 g of a 1/1 mixture of racemic cis- and trans-3-chloro-6-{[3-
methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazine (65b) and 18 cm3 of
ethanol. After stirring at reflux for 8 hours, followed by work-up and
purification by flash chromatography on silica [eluent:
dichloromethane/methanol/acetonitrile (90/5/5 by volume)], 0.198 g of a 15/85
mixture of the cis and trans isomers of racemic N-{6-[(6-{[3-methylcyclo-
hexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-
yljcyclopropanecarboxamide is obtained in the form of a white solid melting at
216.5°C, the characteristics of which are as follows:
1H NMR spectrum (400 MHz, 6 in ppm, DMSO-d6) mixture of isomers 85%
H1-ax - 15% H1-eq with 0.70 (d, J=6.4 Hz, 0.45 H); 0.78 (d, J=6.4 Hz, 2.55
H); 0.72 to 1.78 (m, 11 H); 1.85 (m, 2 H); 1.97 (m, 1 H); 4.62 (m, 0.85 H); 5.03
(m, 0.15 H); 7.01 (d, J=9.8 Hz, 0.85 H); 7.03 (d, J=9.8 Hz, 0.15 H); 7.39 (dd,
J=2.0 and 8.6 Hz, 0.85 H); 7.41 (dd, J=2.0 and 8.6 Hz, 0.15 H); 7.66 (d, J=8.6
Hz, 1 H); 8.02 (d, J=2.0 Hz, 0.85 H); 8.09 (d, J=2.0 Hz, 0.15 H); 8.26 (d, J=9.8
Hz, 0.15 H); 8.28 (d, J=9.8 Hz, 0.85 H); 12.67 (broad m, 1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z 481; [M-H]-: m/z 479.
b) N-(6-Sulfanyl-1,3-benzothiazol-2-yl)cyclopropanecarboxamide may be
prepared in a manner similar to that described in Example 2b, but starting
with 14.0 g of 2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl
thiocyanate, 22.44 g of DL-dithiothreitol, a solution of 0.235 g of potassium
dihydrogen phosphate in 60 cm3 of distilled water and 450 cm3 of ethanol.
After stirring at reflux for 5 hours, the reaction medium is poured into 700 cm3
of ice-water under a stream of argon. The yellow solid formed is filtered off on
VF3, washed with twice 70 cm3 of ice-water and then oven-dried under
reduced pressure (2.7 kPa) at 40°C for 24 hours, to give 12.74 g of N-(6-
sulfanyl-1,3-benzothiazol-2-yl)cyclopropanecarboxamide in the form of a
yellow solid, the characteristics of which are as follows:
MASS SPECTRUM ES+/-: [M+H]+: m/z 251; [M-H]-: m/z249.
c) 2-[(Cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl thiocyanate may
be prepared in a manner similar to that described in Example 1a, but starting
with 15.0 g of 2-amino-1,3-benzothiazol-6-yl thiocyanate, 7.88 cm3 of
cyclopropanecarboxylic acid chloride and 150 cm3 of pyridine. After stirring for
5 hours at a temperature in the region of 20°C, the reaction medium is poured
into 500 cm3 of ice-water. The solid formed is filtered off on a VF3 filter and
then washed with 5 times 70 cm3 of ice-water, followed by oven-drying under
reduced pressure (2.7 kPa) at 40°C for 10 hours, to give 19 g of 2-[(cyclo-
propylcarbonyl)amino]-1,3-benzothiazol-6-yl thiocyanate in the form of a pink
solid, the characteristics of which are as follows:
MASS SPECTRUM ES+/-: [M+H]+: m/z 276; [M-H]-: m/z 274.
Example 67:
1-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}-
sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea, 15/85
mixture of the cis and trans isomers (major)
a) The 15/85 mixture of cis- and trans-1-[6-({6-[(4-methylcyclohexyl)oxy]-
[1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-
(morpholin-4-yI)ethyl]urea may be prepared in a manner similar to that
described for Example 2a, but starting with 0.876 g of 1-[2-(morpholin-4-yl)-
ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-yl)urea (2b), 0.798 g of DL-
dithiothreitol, a solution of 0.117 g of potassium dihydrogen phosphate in 1.15
cm3 of distilled water, 0.460 g of a 1/1 mixture of cis- and trans-3-chloro-6-(4-
methylcyclohexyloxy)-1,2,4-triazolo[4,3-b]pyridazine and 23 cm3 of ethanol.
After stirring at reflux for 16 hours, followed by work-up and purification by
flash chromatography on silica [eluent: dichloromethane/methanol/acetonitrile
(90/5/5 by volume + 0.1 % v/v of 20% aqueous ammonia solution)], 0.261g of
a 15/85 mixture of racemic cis- and trans-1-[6-({6-[(4-methylcyclohexyl)oxy]-
[1,2,4]triazolo[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-
(morpholin-4-yl)ethyl]urea is obtained in the form of a white solid melting at
155.9°C, the characteristics of which are as follows:
1H NMR spectrum (400 MHz, 6 in ppm, DMSO-d6) mixture of isomers 85%
H1-ax - 15% H1-eq with: 0.86 (d, J=6.4 Hz, 3 H); 0.88 to 0.93 (m, 2 H); 1.17
to 1.63 (m, 5 H); 1.76 to 1.93 (m, 2 H); 2.35 to 2.45 (m, 6 H); 3.26 (partially
masked m, 2 H); 3.59 (m, 4 H); 4.40 to 4.57 (m, 1 H); 6.78 (broad m, 1 H);
7.00 (d, J=9.8 Hz, 0.85 H); 7.04 (d, J=9.8 Hz, 0.15 H); 7.31 (dd, J=2.0 and 8.6
Hz, 0.85 H); 7.40 (dd, J=2.0 and 8.6 Hz, 0.15 H); 7.53 (d, J=8.6 Hz, 0.85 H);
7.55 (d, J=8.6 Hz, 0.15 H); 8.00 (d, J=2.0 Hz, 0.85 H); 8.04 (d, J=2.0 Hz, 0.15
H); 8.25 (d, J=9.8 Hz, 0.15 H); 8.27 (d, J=9.8 Hz, 0.85 H); 10.91 (broad m,
1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z 569; [M-H]-: m/z 567.
b) The 1/1 mixture of cis- and trans-3-chloro-6-(4-methylcyclohexyloxy)-
1,2,4-triazolo[4,3-b]pyridazine may be prepared in a manner similar to that
described in Example 1c, but starting with 0.628 g of a 1/1 mixture of racemic
cis- and trans-4-methyl cyclohexanol, 6 cm3 of tetrahydrofuran, 0.220 g of
sodium hydride at 60% in oil and 0.650 g of 3,6-dichloro[1,2,4]triazolo[4,3-b]-
pyridazine. After stirring at a temperature in the region of 20°C for 24 hours,
followed by work-up, 0.880 g of a 1/1 mixture of cis- and trans-3-chloro-6-(4-
methyl-cyclohexyloxy)-1,2,4-triazolo[4,3-b]pyridazine is obtained in the form
of a brown oil that solidifies, the characteristics of which are as follows:
MASS SPECTRUM ES+: [M+H]+: m/z 267.
Example 68:
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(piperidin-1-yl)azetidine-1-carboxamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(piperidin-1-yl)azetidine-1-carboxamide may be prepared
in a manner similar to that of Example 5, but starting with 185 mg of phenyl
(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzo-
thiazol-2-yl)carbamate (4) in 10 cm3 of THF and 10 cm3 of DMF with 75 mg of
1-(azetidin-3-yl)piperidine dihydrochloride and 0.160 cm3 of triethylamine
after reaction for 66 hours at 20°C. 155 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]-
triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(piperidin-1-
yl)azetidine-1-carboxamide are thus obtained in the form of a pale yellow
solid, the characteristics of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6, 5ppm): 1.13 to 1.67 (m, 14 H);
1.81 (m, 2 H); 2.24 (broad m, 4 H); 2.99 to 3.20 (broad m, 1 H); 3.70 to 4.15
(broad m, 4 H); 4.64 to 4.74 (m, 1 H); 7.01 (d, J=9.8 Hz, 1 H); 7.37 (dd, J=2.0
and 8.3 Hz, 1 H); 7.55 (d, J=8.3 Hz, 1 H); 8.00 (broad s, 1 H); 8.27 (d, J=9.8
Hz, 1 H); 11.32 (broad m, 1 H).
MASS SPECTRUM (Electrospray on WATERS UPLC - SQD):
[M+H]+: m/z 565; [M-HJ-: m/z 563.
Example 69:
N-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-3-yl}-
sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide, 15/85 mixture
> of the cis and trans isomers (major)
The 85/15 mixture of cis- and trans-N-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]-
triazolo[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropane-
carboxamide may be prepared in a manner similar to that described for
Example 2a, but starting with 0.592 g of N-(6-sulfanyl-1,3-benzothiazol-2-yI)-
) cyclopropanecarboxamide (66b), 0.729 g of DL-dithiothreitol, a solution of
0.107 g of potassium dihydrogen phosphate in 1.05 cm3 of distilled water,
0.420 g of a 1/1 mixture of 3-chloro-6-(4-methyl-cyclohexyloxy)-1,2,4-triazolo-
[4,3-bJpyridazine (67b) and 20 cm3 of ethanol. After stirring at reflux for
16 hours, followed by work-up and purification by flash chromatography on
silica [eluent: dichloromethane/methanol/acetonitrile (90/5/5 by volume)],
0.336 g of a 15/85 mixture of the cis and trans isomers of N-[6-({6-[(4-
methylcyclohexyl)oxy][1,2,4]tria2olo[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzo-
thiazol-2-yrjcyclopropanecarboxamide is obtained in the form of a white solid
melting at 230°C, the characteristics of which are as follows:
1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6) mixture of isomers 85%
H1-ax - 15% H1-eq with: 0.72 to 0.99 (m, 6 H); 0.82 (d, J=6.6 Hz, 2.55 H);
0.88 (d, J=6.6 Hz, 0.45 H); 1.06 to 1.59 (m, 5 H); 1.82 (d, J=9.0 Hz, 2 H); 1.94
to 2.04 (m, 1 H); 4.35 to 4.51 (m, 1 H); 7.00 (d, J=9.8 Hz, 0.85 H); 7.04 (d,
J=9.8 Hz, 0.15 H); 7.35 (dd, J=2.0 and 8.6 Hz, 0.85 H); 7.45 (dd, ^=2.0 and
8.6 Hz, 0.15 H); 7.66 (d, J=8.6 Hz, 0.85 H); 7.68 (d, J=8.6 Hz, 0.15 H); 8.06
(d, J=2.0 Hz, 0.85 H); 8.11 (d, J=2.0 Hz, 0.15 H); 8.26 (d, J=9.8 Hz, 0.15 H);
8.28 (d, J=9.8 Hz, 0.85 H); 12.68 (broad m, 1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z 481; [M-H]-: m/z 479.
Example 70:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide may be
prepared in a manner similar to that described in Example 5, but starting with
150 mg of phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)carbamate (4), 65 mg of 2-oxa-6-aza-
spiro[3.3]heptane monooxalate, 0.144 cm3 of triethylamine and 10 cm3 of
tetrahydrofuran. After stirring for 15 hours at a temperature in the region of
20°C, followed by work-up, 0.056 g of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-2-oxa-6-azaspiro[3.3]-
heptane-6-carboxamide are obtained in the form of a white solid, the
characteristics of which are as follows:
MASS SPECTRUM ES+/-: [M+H]+: m/z 524; [M-H]-: m/z 522.
1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 1.15 to 1.42 (m, 5 H); 1.49
(m, 1 H); 1.61 (m, 2 H); 1.81 (m, 2 H); 4.20 (broad s, 4 H); 4.66 (s, 4 H); 4.68
to 4.74 (m, 1 H); 7.01 (d, J=9.8 Hz, 1 H); 7.37 (dd, J=2.0 and 8.6 Hz, 1 H);
7.55 (broad d, J=8.6 Hz, 1 H); 8.00 (d, J=2.0 Hz, 1 H); 8.27 (d, J=9.8 Hz, 1 H);
11.36 (broad m, 1 H).
2-Oxa-6-azaspiro[3.3]heptane monooxalate may be prepared as described by
Georg Wuitschik, Mark Rogers-Evans, Andreas Buckl, Maurizio Bernasconi,
Moritz Marki, Thierry Godel, Holger Fischer, Bjom Wagner, Isabelle Parrilla,
Franz Schuler, Josef Schneider, Andre Alker, W. Bernd Schweizer, Klaus
Miiller, and Erick M. Carreira, Angew. Chem. Int. Ed. 2008, 47, 4512 -4515.
Example 71:
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(morpholin-4-yl)azetidine-1-carboxamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolot4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(morpholin-4-yl)azetidine-1 -carboxamide may be
prepared in a manner similar to that of Example 5, but starting with 182 mg of
phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)carbamate (4) in 10 cm3 of THF, 106 mg of 4-(azetidin-3-
yl)morpholine dihydrochloride and 0.167 cm3 of triethylamine, after reaction
for 22 hours at 20°C. 60 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-(morpholin-4-yl)azetidine-1-
carboxamide are thus obtained in the form of a white solid, the characteristics
of which are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6, 5ppm): 1.11 to 1.42 (m, 5 H);
1.50 (m, 1 H); 1.62 (m, 2 H);1.82 (m, 2 H); 2.31 (m, 4 H); 3.09 to 3.19 (m,
1 H); 3.59 (m, 4 H); 3.85 (m, 2 H); 4.04 (m, 2 H); 4.63 to4.78 (m, 1 H); 7.01 (d,
J=9.8 Hz, 1 H); 7.36 (dd, J=2.0 and 8.6 Hz, 1 H); 7.52 (broad d, J=8.6 Hz,
1 H);7.98 (d, J=2.0 Hz, 1 H); 8.26 (d, J=9.8 Hz, 1 H); 11.38 (broad m, 1 H).
MASS SPECTRUM (Electrospray WATERS ZQ):
[M+H]+: m/z 567; [M-H]-: m/z 565.
Example 72:
Rac-N-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
a) rac-N-{6-[(6-{[trans-2-Methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide may be
prepared in a manner similar to that described for Example 2a, but starting
with 0.636 g of N-(6-sulfanyl-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
(66b), 0.784 g of DL-dithiothreitol, a solution of 0.115 g of potassium
dihydrogen phosphate in 1.27 cm3 of distilled water, 0.428 g of a 1/1 mixture
of racemic cis- and trans-3-chloro-6-(2-methyl-cyclopentyloxy)-1,2,4-triazolo-
[4,3-b]pyridazine and 23 cm3 of ethanol. After stirring at reflux for 16 hours,
followed by work-up and purification by flash chromatography on silica
[eluent: dichloromethane/methanol/acetonitrile (90/5/5 by volume)], 0.260 g of
rac-N-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide is obtained in the
form of a white solid melting at 197.7°C, the characteristics of which are as
follows:
1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 0.89 (d, J=7.1 Hz, 3 H);
0.92 to 1.00 (m, 4 H); 1.06 to 1.21 (m, 1 H); 1.46 to 1.69 (m, 3 H); 1.78 to 2.12
(m, 4 H); 4.45 to 4.56 (m, 1 H); 7.03 (d, J=9.8 Hz, 1 H); 7.43 (dd, J=2.0 and
8.6 Hz, 1 H); 7.68 (d, J=8.6 Hz, 1 H); 8.09 (d, J=2.0 Hz, 1 H); 8.27 (d, J=9.8
Hz, 1 H); 12.67 (broad m, 1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z 467; [M-H]-: m/z 465.
b) The 1/1 mixture of racemic cis- and trans-3-chloro-6-(2-
methylcyclopentyloxy)-1,2,4-triazolo[4,3-b]pyridazine may be prepared in a
manner similar to that described in Example 1c, but starting with 0.678 g of a
1/1 mixture of cis- and trans- 2-methylcyclopentanol, 10 cm3 de
tetrahydrofuran, 0.271 g of sodium hydride at 60% in oil, and 0.800 g of 3,6-
dichloro[1,2,4]triazolo[4,3-b]pyridazine. After stirring at a temperature in the
region of 20°C for 24 hours, followed by work-up, 1.033 g of a 1/1 mixture of
racemic cis- and trans-de 3-chloro-6-(2-methyl-cyclopentyloxy)-1,2,4-triazolo-
[4,3-b]pyridazine are obtained in the form of a brown oil, the characteristics of
which are as follows:
MASS SPECTRUM ES+: [M+H]+: m/z 253.
Example 73:
Rac-1-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
rac-1-{6-[(6-{[trans-2-Methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea may be
prepared in a manner similar to that described for Example 2a, but starting
with 0.609 g of 1-[2-(morpholin-4-yl)ethyl]-3-(6-sulfanyl-1,3-benzothiazol-2-
yl)urea (2b), 0.555 g of DL-dithiothreitol, a solution of 0.081 g of potassium
dihydrogen phosphate in 0.85 cm3 of distilled water, 0.303 g of a 1/1 mixture
of racemic cis- and trans-3-chloro-6-(2-methyl-cyclopentyloxy)-1,2,4-triazolo-
[4,3-b]pyridazine (72b) and 17 cm3 of ethanol. After stirring at reflux for 16
hours, followed by work-up and purification by flash chromatography on silica
[eluent: dichloromethane/ methanol/acetonitrile (90/5/5 by volume + 0.1 % v/v
of 20% aqueous ammonia solution)], 0.223 g of rac-1-{6-[(6-{[trans-2-
methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo-
thiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea is obtained in the form of a pale
yellow solid melting at 203.3°C, the characteristics of which are as follows:
1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6): 0.92 (d, J=7.1 Hz, 3 H);
1.16 (m, 1 H); 1.50 to 1.69 (m, 3 H); 1.79 to 2.12 (m, 3 H); 2.37 to 2.44 (m, 6
H); 3.26 (partially masked m, 2 H); 3.59 (m, 4 H); 4.52 to 4.60 (m, 1 H); 6.79
(broad m, 1 H); 7.03 (d, J=9.8 Hz, 1 H); 7.37 (dd, J=2.0 and 8.5 Hz, 1 H); 7.55
(d, J=8.5 Hz, 1 H); 8.03 (d, J=2.0 Hz, 1 H); 8.26 (d, J=9.8 Hz, 1 H); 10.90
(broad m, 1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z 555; [M-H]-: m/z 553.
Example 74:
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxyazetidine-1-carboxamide
N-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxyazetidine-1-carboxamide may be prepared in a
manner similar to that of Example 5, but starting with 192 mg of phenyl (6-{[6-
(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yi]sulfanyl}-1,3-benzothiazol-
2-yl)carbamate (4) in 5 cm3 of dimethylformamide, 69 mg of 3-methoxy-
azetidine hydrochloride and 0.078 cm3 of triethylamine, after reaction for 20
hours at 20°C. 120 mg of N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-methoxyazetidine-1-carboxamide
are thus obtained in the form of an off-white solid, the characteristics of which
are as follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6, 5 ppm): 1.14 to 1.42 (m, 5 H);
1.44 to 1.53 (m, 1 H); 1.61 (m, 2 H); 1.81 (m, 2 H); 3.21 (s, 3 H); 3.83 (m, 2
H); 4.13 to 4.30 (m, 3 H); 4.64 to 4.74 (m, 1 H); 7.02 (d, J=9.8 Hz, 1 H); 7.37
(dd, J=2.0 and 8.6 Hz, 1 H); 7.54 (broad d, J=8.6 Hz, 1 H); 8.00 (d, J=2.0 Hz,
1 H); 8.27 (d, J=9.8 Hz, 1 H); 11.36 (broad m, 1 H).
MASS SPECTRUM (Electrospray WATERS ZQ):
[M+H]+: m/z 512; [M-H]-: m/z 510.
Example 75:
1-(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-oxetan-3-ylurea
1 -(6-{[6-(Cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-oxetan-3-ylurea may be prepared in a manner similar to
that of Example 5, but starting with 191 mg of phenyl (6-{[6-(cyclo-
hexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-
carbamate (4) in 3 cm3 of dimethylformamide, 40 mg of oxetan-3-amine, after
reaction for 20 hours at 20°C. 95 mg of 1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo-
[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-benzothiazol-2-yl)-3-oxetan-3-ylurea are
thus obtained in the form of a white solid, the characteristics of which are as
follows:
1H NMR SPECTRUM (400 MHz, DMSO-d6, 5ppm): 1.12 to 1.43 (m, 5 H);
1.47 to 1.54 (m, 1 H); 1.62 (m, 2 H); 1.83 (m, 2 H); 4.47 (t, J=6.4 Hz, 2 H);
4.67 to 4.76 (m, 3 H); 4.77 to 4.86 (m, 1 H); 7.01 (d, J=9.8Hz, 1 H); 7.35 (dd,
J=1.8 and 8.4 Hz, 1 H); 7.52 (broad m, 2 H); 7.97 (broad s, 1 H); 8.26 (d,
J=9.8 Hz, 1 H); 10.99 (broad m, 1 H).
MASS SPECTRUM (Electrospray on WATERS UPLC - SQD):
[M+H]+: m/z 498; [M-H]-: m/z 496.
Example 76:
Rac-1-{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea, 2/3
mixture of the racemic cis and trans isomers (major)
a) The 2/3 mixture of the racemic cis and trans isomers of 1-{6-[(6-{[3-
methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo-
thiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea may be prepared in a manner
similar to that described for Example 2a, but starting with 0.643 g of 1-(6-
mercapto-benzothiazol-2-yl)-3-(2-morpholin-4-yl-ethyl)-urea (2b), 0.586 g of
DL-dithiothreitol, a solution of 0.086 g of potassium dihydrogen phosphate in
0.95 cm3 of distilled water, 0.320 g of a 1/1 mixture of the racemic cis and
trans isomers of 3-chloro-6-(3-methyl-cyclopentyloxy)-1,2,4-triazolo[4,3-b]-
pyridazine and 19 cm3 of ethanol. After stirring at reflux for 16 hours, followed
by work-up and purification by flash chromatography on silica [eluent:
dichloromethane/methanol/acetonitrile (90/5/5 by volume with 0.1% v/v of 20%
aqueous ammonia solution)], 0.065 g of a 2/3 mixture of the racemic cis and
trans isomers of 1-{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea is
obtained in the form of a white solid melting at 174.7°C, the characteristics of
which are as follows:
1H NMR spectrum (400 MHz, 5 in ppm, DMSO-d6) 2/3 - 1/3 mixture of
isomers, with: 0.90 (d, J=6.8 Hz, 1 H); 0.94 (d, J=6.6 Hz, 2 H); 1.00 to 1.35
(m, 2 H); 1.57 to 2.16 (m, 5 H); 2.36 to 2.44 (m, 6 H); 3.26 (partially masked
m, 2 H); 3.59 (m, 4 H); 5.05 (m, 0.66 H); 5.11 (m, 0.34 H); 6.79 (broad m, 1
H); 7.00 (d, J=9.8 Hz, 0.34 H); 7.02 (d, J=9.8 Hz, 0.66 H); 7.38 (split dd, J=2.0
and 8.6 Hz, 1 H); 7.54 (d, J=8.6 Hz, 1 H); 8.04 (d, J=2.0 Hz, 1 H); 8.25 (split
d, J=9.8 Hz, 1 H); 10.92 (broad m, 1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z 555; [M-H]-: m/z 553.
b) The 1/1 mixture of the racemic cis and trans isomers of 3-chloro-6-(3-
methyl-cyclopentyloxy)-1,2,4-triazolo[4,3-b]pyridazine may be prepared in a
manner similar to that described in Example 1c, but starting with 0.678 g of a
1/1 mixture of racemic cis and trans-3-methylcyclopentanol isomers, 10 cm3
of tetrahydrofuran, 0.271 g of sodium hydride at 60% in oil and 0.800 g of
3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine. After stirring at a temperature in
the region of 20°C for 24 hours followed by work-up, 0.860g of a 1/1 mixture
of the racemic cis and trans isomers of 3-chloro-6-(3-methyl-cyclopentyloxy)-
1,2,4-triazolo[4,3-b]pyridazine is obtained in the form of a brown oil, the
characteristics of which are as follows:
MASS SPECTRUM ES+/-: [M+H]+: m/z 253.
Example 77:
Rac-N-{6-[(6-{[3-methylcyclopentyl]oxy}t1,2,4]triazolo[4,3-b]pyridazin-3-
yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide, 2/3 mixture
of the racemic cis and trans isomers (major)
The 2/3 mixture of the racemic cis and trans isomers of N-{6-[(6-{[3-
methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzo-
thiazol-2-y!}cyclopropanecarboxamide may be prepared in a manner
similar to that described for Example 2a, but starting with 0.505 g of N-(6-
sulfanyl-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (66b), 0.622 g of
DL-dithiothreitol, a solution of 0.091 g of potassium dihydrogen phosphate in
1.01 cm3 of distilled water, 0.340 g of a 1/1 mixture of the racemic cis and
trans isomers of 3-chloro-6-(3-methyl-cyclopentyloxy)-1,2,4-triazolo[4,3-b]-
pyridazine (76b) and 23 cm3 of ethanol. After stirring at reflux for 16 hours,
followed by work-up and purification by flash chromatography on silica
[eluent: dichloromethane/methanol/acetonitrile (90/5/5 by volume)], 0.172 g of
a 2/3 mixture of the racemic cis and trans isomers of N-{6-[(6-{[3-methylcyclo-
pentyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-
yl}cyclopropanecarboxamide is obtained in the form of a white solid melting at
98°C, the characteristics of which are as follows:
1H NMR spectrum (400 MHz, 6 in ppm, DMSO-d6) 2/3 - 1/3 mixture of
isomers, with: 0.84 to 0.97 (m, 7 H); 0.99 to 1.30 (m, 2 H); 1.54 to 2.14 (m,
6 H); 5.03 (m, 0.66 H); 5.10 (m, 0.34 H); 7.00 (d, J=9.8 Hz,
0.34 H); 7.02 (d, J=9.8 Hz, 0.66 H); 7.41 (split dd, J=2.0 and 8.6 Hz, 1 H);
7.65 (broad d, J=8.6 Hz, 1 H); 8.08 (broad s, 1 H); 8.26 (split d, J=9.8 Hz, 1
H); 12.64 (broad m, 1 H).
MASS SPECTRUM ES+/-: [M+H]+: m/z467; [M-H]-: m/z465.
Example 78: 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 79: Pharmaceutical composition
Tablets corresponding to the following formula were prepared:
Product of Example 4.......................0.2 g
Excipient for a finished tablet weighing..........1 g
(details of the excipient: lactose, talc, starch, magnesium stearate).
Examples 1 and 4 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 I MAC 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, MgCb
2 mM, and Na3V04 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 + Na3V04 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 ul of enzymatic reaction, MET 5 nM final is incubated
in the presence of the test molecule (for a final concentration range of
0.17 nM to 10 uM, DMSO 3% final) in MOPS 10 mM pH 7.4, DTT 1 mM,
0.01% Tween 20 buffer. The reaction is initiated with the substrate solution to
obtain final concentrations of poly-(GAT) 1 ug/ml, ATP 10 uM and MgCI2
5 mM. After incubation for 10 minutes at room temperature, the reaction is
stopped with a mix of 30 ul to obtain a final solution of Hepes 50 mM pH 7.5,
potassium fluoride 500 mM, 0.1% BSA and EDTA 133 mM in the presence of
80 ng of streptavidin 61SAXLB Cis-Bio Int. and 18 ng of anti-phosphotyrosine
Mab PT66-Europium Cryptate per well. After incubation for 2 hours at room
temperature, the reading is taken at two wavelengths, 620 nm and 665 nm,
on a reader for the TRACE / HTRF technique and the percentage of inhibition
is calculated from the 665/620 ratios.
The results obtained via this test A for the products of formula (I) illustrated in
the experimental section are such that the IC50 is less than 500 nM and
especially less than 100 nM.
B) Test B: Inhibition of autophosphorylation of MET; ELISA technique
(pppY1230,1234,1235)
a) Cell lysates: Inoculated MKN45 cells in 96-well plates (Cell coat BD
polylysine) to a rate of 20 000 cells/well in 200 ul 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 uM
with an increment of 3 in pure DMSO - Intermediate 50-fold dilutions in the
culture medium, followed by removal of 10 ul added directly to the cells
(200 pi): final range from 10 000 to 30 nM.
At the end of incubation, delicately remove the supernatant and rinse with
200 pi of PBS. Next, place 100 pi 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 Na3V04, 1 mM PMSF and anti-
protease cocktail.
The 100 pi 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 pi of kit dilution buffer + 30 pL of cell lysates or 30 pi 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 ul of kit washing buffer. Incubate with
100 ul of anti-phospho MET antibody for 1 hour at room temperature.
Rinse the wells four times with 400 uL of kit washing buffer. Incubate with
100 ul 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 pi of kit washing buffer. Introduce 100 pi
of chromogen and incubate for 30 minutes in the dark at room temperature.
Stop the reaction with 100 pi 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 pi for 4 hours at
37°C and 5% C02: HCT116 cells at a rate of 2500 cells per well in DMEM
medium + 10% foetal calf serum + 1 % L-Glutamine and MKN45 cells at a rate
of 7500 cells per well in RPMI medium + 10% foetal calf serum + 1% L-
Glutamine. After these 4 hours of incubation, the products are added in 10 pi
as a 20-fold concentrated solution according to the dilution method cited for
ELISA. The products are tested at 10 concentrations in duplicate from
10 000 nM to 0.3 nM with an increment of 3.
After 72 hours of treatment, add 10 ul of 14C-thymidine at 10 uCi/ml to obtain
0.1 uCi 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 orTECAN stations.
The results obtained via this test B for the products of formula (I) illustrated in
the experimental section are such that the IC50 is less than 10 uM and
especially less than 1 uM.
The results obtained for the products illustrated in the experimental section
are given in the table of pharmacological results hereinbelow, as follows:
for test A, the + sign corresponds to less than 500 nM and the ++ sign
corresponds to less than 100 nM,
for test B, the + sign corresponds to less than 500 nM and the ++ sign
corresponds to less than 100 nM,
for test C, the + sign corresponds to less than 10 uM and the ++ sign
corresponds to less than 1 uM.
CLAIMS
1- Products of formula (I):
in which
----- represents a single or double bond;
Ra represents a radical -O-cycloalkyl, or a radical -NH- cycloalkyl, both
optionally substituted;
X represents S, SO or S02;
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
halogen atom or a radical cycloalkyl, 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, a cycloalkyl radical, a
heterocycloalkyl radical or an alkyl radical and the other from among
R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl
radical optionally substituted with one or more radicals, which may be
identical or different, chosen from the following radicals: hydroxyl,
alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl, optionally
substituted or alternatively R1 and R2 form, with the nitrogen atom to
which they are attached, a 3- to 10-membered cyclic radical optionally
containing one or more other heteroatoms chosen from O, S, N and
NH, with the optional S possibly being in the form SO or S02; this
radical, including the possible NH it contains, being optionally
substituted;
with R3 and R4, which may be identical or different, representing a hydrogen
atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a
heteroaryl radical or a phenyl radical, all optionally substituted with one or
more radicals, which may be identical or different, chosen from the following
radicals: optionally substituted hydroxyl, alkoxy, heteroaryl, heterocycloalkyl,
NH2, NHAlk, N(Alk)2 or phenyl; or alternatively R3 and R4 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from O, S, N and
NH, with the optional S possibly being in the form SO or S02; 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, -0-CO-R5, -COOH, COOR5,
-CONH2, CONHR5, NH2, NHR5, NR5R5', -NH-CO-R5 and alkyl, cycloalkyl,
heterocycloalkyl, CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl,
heteroaryl and S-heteroaryl radicals, such that in the latter radicals, the alkyl,
cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are themselves
optionally substituted with one or more radicals chosen from halogen atoms
and the following radicals: hydroxyl, oxo, alkyl and alkoxy containing from 1 to
4 carbon atoms, NH2, NHalk and N(alk)2,
all the cycloalkyl, heterocycloalkyl, heteroaryl and phenyl radicals defined
above being furthermore optionally substituted with a radical Si(alk)3;
it being possible for all the cycloalkyl and heterocycloalkyl radicals defined
above to be optionally substituted on one of the carbons of the ring by a
spirocycloalkyl or spiroheterocycloalkyl radical or optionally on two of the
carbons of the ring by a fused cycloalkyl or heterocycloalkyl radical;
R5 and R5', which may be identical or different, represent an alkyl or
cycloalkyl radical containing not more than 6 carbon atoms;
alk represents an alkyl radical containing not more than 4 carbon atoms;
it being understood that W does not represent H when A represents S, X
represents S, Ra represents the unsubstituted O-cyclohexyl radical or the
unsubstituted NH-cyciohexyl radical and —~ represents a double bond,
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 Claim 1, in which
----- represents a single or double bond;
Ra represents a radical -O-cycloalkyl or a radical -NH-cycloalkyl optionally
substituted;
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
halogen atom or a radical cycloalkyl, 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, a cycloalkyl radical or
an alkyl radical and the other from among R1 and R2 represents a
hydrogen atom, a cycloalkyl radical, a heterocycloalkyl radical or an
alkyl radical optionally substituted with one or more radicals, which
may be identical or different, chosen from the following radicals:
hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NR3R4, phenyl,
optionally substituted or alternatively R1 and R2 form, with the nitrogen
atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from O, S,
N and NH, with the optional S possibly being in the form SO or S02,
this radical, including the possible NH it contains, being optionally
substituted;
with R3 and R4, which may be identical or different, representing a hydrogen
atom, an alkyl radical, a cycloalkyl radical, a heterocycloalkyl radical, a
heteroaryl radical or a phenyl radical, all optionally substituted with one or
more radicals, which may be identical or different, chosen from the following
radicals: hydroxyl, alkoxy, heteroaryl, heterocycloalkyl, NH2, NHAlk, N(Alk)2
or phenyl, optionally substituted; or alternatively R3 and R4 form, with the
nitrogen atom to which they are attached, a 3- to 10-membered cyclic radical
optionally containing one or more other heteroatoms chosen from O, S, N and
NH, with the optional S possibly being in the form SO or S02, this radical,
including the possible NH it contains, being optionally substituted;
all the alkyl, 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,
-0-CO-R5, NH2, NHalk, N(alk)2 and alkyl, cycloalkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl, CO-phenyl, heteroaryl and
S-heteroaryl radicals, such that in the latter radicals, the alkyl,
cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals are
themselves optionally substituted with one or more radicals chosen
from halogen atoms and the following radicals: hydroxyl, oxo, alkyl and
alkoxy containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;
R5 represents an alkyl or cycloalkyl radical containing not more than 6 carbon
atoms;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
3- Products of formula (I) as defined in any one of the claims, in which zzzs~ ,
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; 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
halogen atom or a radical cycloalkyl, NR3R4, alkoxy, hydroxyl, phenyl or
heterocycloalkyl, which are themselves optionally substituted;
- an alkoxy radical optionally substituted with NR3R4, alkoxy, hydroxyl or
heterocycloalkyl; a radical O-phenyl or a radical 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, a heterocycloalkyl radical or an alkyl radical optionally
substituted with an alkoxy or heterocycloalkyl radical, or NR3R4; or
alternatively R1 and R2 form, with the nitrogen atom to which they are
attached, a 3- to 10-membered cyclic radical optionally containing one
or more other heteroatoms chosen from O, S, N and NH, this radical,
including the possible NH it contains, being optionally substituted;
- with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical or a heterocycloalkyl
radical, all optionally substituted with one or more radicals, which may
be identical or different, chosen from alkoxy or heterocycloalkyl radicals
or NH2, NHAlk or 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 cycloalkyl, heterocycloalkyl and phenyl radicals, and also the cyclic
radicals that may be formed by R1 and R2 or R3 and R4 with the nitrogen
atom to which they are attached, defined above, being optionally substituted
with one or more radicals chosen from halogen atoms and the following
radicals: hydroxyl, alkoxy, NH2, NHalk, N(alk)2 and alkyl, heterocycloalkyl,
CH2-heterocycloalkyl, phenyl, CH2-phenyl and heteroaryl radicals, such that
in the latter radicals, the alkyl, heterocycloalkyl, phenyl and heteroaryl radicals
are themselves optionally substituted with one or more radicals chosen from
halogen atoms and hydroxyl, alkyl and alkoxy radicals containing from 1 to 4
carbon atoms, NH2, NHalk and N(alk)2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
4- Products of formula (I) as defined in any one of the other claims, in which
, Ra and X have the values defined in any one of the other claims, and:
A represents NHorS;
W represents a hydrogen atom; an alkyl radical optionally substituted with a
heterocycloalkyl radical or NR3R4; or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical optionally substituted with a
radical NR3R4, or alkoxy;
- a radical O-phenyl or 0-(CH2)n-phenyl, with phenyl optionally
substituted and n represents an integer from 1 to 2;
- or the radical NR1R2, in which R1 and R2 are such that one from
among R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an
alkyl radical and the other from among R1 and R2 represents a hydrogen
atom, an alkyl radical optionally substituted with a heterocyclic radical or
NR3R4, or alternatively R1 and R2 form, with the nitrogen atom to which they
are attached, a cyclic radical optionally containing one or more other
heteroatoms chosen from O, S, N and NH, this radical, including the possible
NH it contains, being optionally substituted;
with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical or alternatively R3 and R4 form,
with the nitrogen atom to which they are attached, a cyclic radical optionally
containing one or more other heteroatoms chosen from O, S, N and NH, this
radical, including the possible NH it contains, being optionally substituted;
all the cycloalkyl, heterocyclic and phenyl radicals, and also the cyclic radicals
that may be formed by R1 and R2 or R3 and R4 with the nitrogen atom to
which they are attached, defined above, being optionally substituted with one
or more radicals chosen from halogen atoms and the following radicals:
hydroxyl, alkoxy, NH2, NHalk, N(alk)2 and alkyl and phenyl radicals, the latter
radicals themselves being optionally substituted with one or more radicals
chosen from halogen atoms and hydroxyl, alkyl and alkoxy radicals containing
from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
5- Products of formula (I) as defined in any one of the 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).
6- 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).
7- 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).
8- 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
(I"):

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).
9- 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).
10- 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).
11- Products of formula (I) as defined in any one of the preceding claims, in
which
----- represents a single or double bond
Ra represents a radical -O-cycloalkyl, or a radical -NH-cycloalkyl; optionally
substituted with a hydroxyl, alkoxy or -0-CO-R5 radical;
X represents S;
A represents S;
W represents a hydrogen atom or an alkyl radical optionally substituted with
heterocycloalkyl or the radical COR in which R represents:
- a cycloalkyl radical or an alkyl radical, optionally substituted with a
radical NR3R4, or alkoxy;
- a radical O-phenyl;
- or the radical NR1R2 in which R1 and R2 are such that one represents
a hydrogen atom and the other represents an alkyl radical optionally
substituted with a heterocycloalkyl radical;
with NR3R4 such that R3 and R4, which may be identical or different,
represent a hydrogen atom or an alkyl radical;
R5 represents an alkyl or cycloalkyl radical containing at most 6 carbon
atoms;
the said products of formula (I) being in any possible racemic, enantiomeric or
diastereoisomeric isomer form, and also the addition salts with mineral and
organic acids or with mineral and organic bases of the said products of
formula (I).
12- Products of formula (I) as defined in any one of the other claims,
corresponding to the following formulae:
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
1-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzoth iazol-2-yl)-3-[2-( morpholin-4-yl )ethyl] urea
1 -(6-{[6-(cyclopentyloxy)[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-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexylamino)[1,2,4]triazoIo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
1 -(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(pyrrolidin-1 -yl)ethyl]urea
N-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
1 -(6-{[6-(cyclohexylamino)[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-y!]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)acetamide
phenyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)carbamate
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4, 3-b]pyridazin-3-yl]sulfanyl}-1 ,3-
benzothiazol-2-yl)-3-[2-(pyrrolidin-1-yl)ethyl]urea
6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-N-[2-
(pyrrolidin-1 -yl)ethyl]-1,3-benzothiazol-2-amine
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-methoxyacetamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-dimethylglycinamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methylbutanamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(cyclopentyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-amine
N-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
trans-4-{[3-({2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazol-6-yl}-
sulfanyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]amino}cyclohexyl
cyclopropanecarboxylate
N-[6-({6-[(trans-4-hydroxycyclohexyl)amino][1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]acetamide
3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclopropyl[1,2,4]triazolo-
[4,3-b]pyridazin-6-amine
N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)acetamide
N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-methoxypropanamide
N-(6-{[6-(cyclopropylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-N2,N2-dimethylglycinamide
3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclohexyl-7,8-dihydro-
[1,2,4]triazolo[4,3-b]pyridazin-6-amine
ethyl (6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)carbamate
2-chloro-N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yI)acetamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-N2-cyclopropylglycinamide
6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyridazin-
3-yl)sulfanyl]-1,3-benzothiazol-2-amine
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(4-ethylpiperazin-1-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yi]sulfanyl}-1,3-
benzothiazol-2-yl)-N2,N2-diethylglycinamide
N-(6-{[6-(cycloheptyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
1-(6-{[6-(cyclohexylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)-3-[3-(morpholin-4-yl)propyl]urea
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[3-(morpholin-4-yl)propyl]urea
1 -(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyI]urea
1-[2-(morpholin-4-yl)ethyl]-3-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}
[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-cyclopropylacetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)cyclopropanecarboxamide
rac-cis/trans-N-{4-[(3-{[2-({[2-(morpholin-4-yl)ethyl]carbamoyl}amino)-
1,3-benzothiazol-6-yl]sulfanyl}[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy]cyclo-
hexyl}acetamide
N-{6-[(6-{[4-(trifluoromethyl)cyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
1-[6-({6-[trans-4-hydroxycyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-
3-yl}sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-amine
3-[(2-amino-1,3-benzothiazol-6-yl)sulfanyl]-N-cyclobutyl[1,2,4]triazolo-
[4,3-b]pyridazin-6-amine
N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)cyclobutanecarboxamide
rac-6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo[4,3-b]pyridazin-
3-yl}sulfanyl)-1,3-benzothiazol-2-amine
rac-N-{6-[(6-{[(trans-2-fluorocycIohexyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
N-(6-{[6-(cyclobutylamino)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-
1,3-benzothiazol-2-yl)cyclopropanecarboxamide
N-(6-{[6-(bicyclo[3.1.0]hex-3-yloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-
sulfanyl}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide
rac-N2,N2-diethyl-N-[6-({6-[(trans-2-fluorocyclohexyl)oxy][1,2,4]triazolo-
[4,3-b]pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]glycinamide
rac-2-(4-ethylpiperazin-1-yl)-N-{6-[(6-{[trans-2-fluorocyclohexyl]oxy}-
[1,2,4] triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acetamide
rac-N-{6-[(6-{[trans-2-fiuorocyclohexyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-2-(morpholin-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(morpholin-4-yl)acetamide
rac-2-(4-cyclopropylpiperazin-1-yl)-N-{6-[(6-{[trans-2-fluorocyclohexyl]-
oxy}[1,2,4]triazolo[4,3-b]pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}acet-
amide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(4-cyclopropylpiperazin-1-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(1,1 -dioxidothiomorpholin-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(1,4-oxazepan-4-yl)acetamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxypropanamide
N-(6-{[6-(cyclobutyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-(3,3-difluoropiperidin-1-yl)acetamide
rac-cis/trans-1 -{6-[(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyI]urea
rac-cis/trans-N-{6-t(6-{[3-methylcyclohexyl]oxy}[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
rac-cis/trans-1 -[6-({6-[(4-methyicyclohexyl)oxy][1,2,4]triazolo[4,3-b]-
pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(piperidin-1-yl)azetidine-1-carboxamide
rac-cis/trans-N-[6-({6-[(4-methylcyclohexyl)oxy][1,2,4]triazolo[4,3-b]-
pyridazin-3-yl}sulfanyl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-(morpholin-4-yl)azetidine-1-carboxamide
rac-N-{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
rac-1 -{6-[(6-{[trans-2-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]pyrid-
azin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
N-(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yI]sulfanyl}-1,3-
benzothiazol-2-yl)-3-methoxyazetidine-1-carboxamide
1 -(6-{[6-(cyclohexyloxy)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulfanyl}-1,3-
benzothiazol-2-yl)-3-oxetan-3-ylurea
rac-cis/trans-1 -{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea
rac-cis/trans-N-{6-[(6-{[3-methylcyclopentyl]oxy}[1,2,4]triazolo[4,3-b]-
pyridazin-3-yl)sulfanyl]-1,3-benzothiazol-2-yl}cyclopropanecarboxamide
and also the addition salts with mineral and organic acids or with mineral and
organic bases of the said products of formula (I).
13- Process for preparing the products of formula (I) as defined in any one of
the other claims.
14- Process for preparing the products of formula (I) as defined in any one of
the other claims, in which A represents NH.
15- Process for preparing the products of formula (I) as defined in any one of
the other claims, in which A represents S.
16- As medicaments, the products of formula (I) as defined in any one of
Claims 1 to 12, and also the addition salts with pharmaceutical^ acceptable
mineral and organic acids or with pharmaceutically acceptable mineral and
organic bases of the said products of formula (I).
17- As medicaments, the products of formula (I) as defined in Claim 12, and
also the addition salts with pharmaceutically acceptable mineral and organic
acids or with pharmaceutically acceptable mineral and organic bases of the
said products of formula (I).
18- Pharmaceutical compositions containing, as active principle, at least one
of the products of formula (I) as defined in any one of Claims 1 to 12, or a
pharmaceutically acceptable salt of this product or a prodrug of this product
and a pharmaceutically acceptable support.
19- Use of the products of formula (I) as defined in any one of Claims 1 to 12,
or of pharmaceutically acceptable salts of these products, for the preparation
of a medicament for inhibiting the activity of the kinase protein MET and
mutant forms thereof.
20- Use as defined in Claim 19, in which the kinase protein is in a cell culture.
21- Use as defined in Claim 19 or 20, in which the kinase protein is in a
mammal.
22- Use of a product of formula (I) as defined in any one of Claims 1 to 12, for
the preparation of a medicament for treating or preventing a disease chosen
from the following group: blood vessel proliferation disorders, fibrotic
disorders, "mesangial" cell proliferation disorders, metabolic disorders,
allergies, asthmas, thromboses, nervous system diseases, retinopathy,
psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.
23- Use of a product of formula (I) as defined in any one of Claims 1 to 12, for
the preparation of a medicament for treating cancers.
24- Use according to 23, for treating solid or liquid tumours.
25- Use according to 23 or 24, for treating cancers that are resistant to
cytotoxic agents.
26- Use according to one or more of Claims 23 and 24, for treating primary
tumours and/or metastases, in particular in stomach, liver, kidney, ovarian,
bowel or prostate cancer, lung cancer (NSCLC and SCLC), glioblastomas,
thyroid, bladder or breast cancers, melanomas, lymphoid or myeloid
haematopoietic tumours, sarcomas, brain cancers, cancer of the larynx,
cancer of the lymphatic system, bone cancers and pancreatic cancers.
27- Use of the products of formula (I) as defined in Claims 1 to 12, for the
preparation of medicaments for cancer chemotherapy.
28- Use of the products of formula (I) as defined in Claims 1 to 12, for the
preparation of medicaments for cancer chemotherapy, alone or in
combination.
29- Products of formula (I) as defined in any one of Claims 1 to 12, as kinase
inhibitors.
30- Products of formula (I) as defined in any one of Claims 1 to 12, as MET
inhibitors.
31- As novel industrial products, the synthetic intermediates of formulae E',
M1,M2, M3 and N:
in which R6 represents an alkyl radical optionally substituted with an NR3R4
(a -(CH2)n-NR3R4 radical), alkoxy, hydroxyl, heterocycloalkyl, phenyl or
-(CH2)n-phenyl group, with phenyl being optionally substituted and n
representing an integer from 1 to 4, such that OR6 represents the
corresponding values of R as defined above; R7 represents a cycloalkyl or
alkyl radical optionally substituted with an NR3R4, alkoxy or hydroxyl radical
or a phenyl, heteroaryl or heterocycloalkyl radical, 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: - - - - is a single or double bond; Ra is -O-
cycloalkyl or -NH-cycloalkyl; X is S, SO or SO2, A is NH or S; W is H, alkyl or COR with R being cycloalkyl; alkyl; alkoxy; O-
phenyl; -O-(CH2)n-phenyl with n = 1 to 4; or NR1R2 with R1 is H or alk and R2 is H, cycloalkyl, heterocycloalkyl, or alkyl; or
R1, R2 form a cycle with N optionally containing O, S, N and/or NH; wherein all of said radicals are optionally substituted; and
wherein said products are in any isomer or salt form and can be used as drugs, in particular as MET inhibitors.