DERIVATIVES OF 6-CYCLOAMINO-2,3-DIPYRIDINYLIMIDAZO[1,2-b]-PYRIDAZINE
PREPARATION AND THERAPEUTIC APPLICATION THEREOF
The present invention relates to 6-cycloamino-2,3-dihydropyridylimidazo[1,2-
b]pyridazine derivatives, to a process for preparing them and to their therapeutic use,
in the treatment or prevention of diseases involving casein kinase 1 epsilon and/or
casein kinase 1 delta.
One subject of the present invention is compounds corresponding to the general
formula (I)

in which
- R2 represents a pyridyl group optionally substituted with one or more substituents
chosen from halogen atoms and groups C1-6-alkyl;
- R3 represents a hydrogen atom or a group C1-3-alkyl;
- A represents a group C1-7-alkylene optionally substituted with one or two groups Ra;
- B represents a group C1-7-alkylene optionally substituted with a group Rb;
- L represents either a nitrogen atom optionally substituted with a group Rc or Rd, or a
carbon atom substituted with a group Re1 and a group Rd or two groups Re2;
the carbon atoms of A and B being optionally substituted with one or more groups Rf,
which may be identical to or different from each other;
Ra, Rb and Rc are defined such that:
two groups Ra may together form a group C1-6-alkylene;
Ra and Rb may together form a bond or a group C1-6-alkylene;
Ra and Rc may together form a bond or a group C1-6-alkylene;
Rb and Rc may together form a bond or a group C1-6-alkylene;
Rd represents a group chosen from a hydrogen atom and the groups C1-6-alkyl, C3.7-
cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkyloxy-C1-6-
alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl and hydroxy-C1-6-alkyl;
Re1 represents a group -NR4R5 or a cyclic monoamine optionally comprising an
oxygen atom, the cyclic monoamine being optionally substituted with one or
more substituents chosen from a fluorine atom and the groups C1-6-alkyl, C1-6-
alkyloxy and hydroxyl;
two groups Re2 form, with the carbon atom that bears them, a cyclic monoamine
optionally comprising an oxygen atom, this cyclic monoamine being optionally
substituted with one or more groups Rf, which may be identical to or different
from each other;
Rf represents a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-
alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl;
R4 and R5 represent, independently of each other, a hydrogen atom or a group C1-6
alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl;
- R7 and R8 represent, independently of each other, a hydrogen atom or a group C1-6-
alkyl.
The compounds of formula (I) may comprise one or more asymmetric carbon atoms.
They may thus exist in the form of enantiomers or diastereoisomers. These
enantiomers and diastereoisomers, and also mixtures thereof, including racemic
mixtures, form part of the invention.
The compounds of formula (I) may exist in the form of bases or of acid-addition salts.
Such addition salts form part of the invention. These salts are advantageously
prepared with pharmaceutically acceptable acids, but the salts of other acids that are
useful, for example, for purifying or isolating the compounds of formula (I) also form
part of the invention.
The compounds of formula (I) may also exist in the form of hydrates or solvates, i.e.
in the form of associations or combinations with one or more water molecules or with
a solvent. Such hydrates and solvates also form part of the invention.
In the context of the invention, the following definitions apply:
- Ct-z in which t and z may take values from 1 to 7: a carbon-based chain
possibly containing from t to z carbon atoms, for example C1-7 is a carbon-
based chain that may contain from 1 to 7 carbon atoms;
- alkyl: a linear or branched, saturated aliphatic group; for example a group C1-6-
alkyl represents a linear or branched carbon-based chain of 1 to 6 carbon
atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
pentyl or hexyl;
- alkylene: a linear or branched, saturated divalent alkyl group, for example a
group C1-6-alkylene represents a linear or branched divalent carbon-based
chain of 1 to 6 carbon atoms, for example a methylene, ethylene, 1-
methylethylene or propylene;
- cycloalkyl: a cyclic alkyl group, for example a group C3-7-cycloalkyl represents
a cyclic carbon-based group of 3 to 7 carbon atoms, for example a
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
- acyl: a group alkyl-C(O)-;
- hydroxyl: a group -OH;
- cyclic monoamine: a saturated cyclic carbon-based chain comprising 1
nitrogen atom;
- hydroxyalkyl: an alkyl group in which a hydrogen atom has been replaced with
a hydroxyl group;
- alkyloxy: a group -O-alkyl;
- alkylthio: a group -S-alkyl;
- fluoroalkyl: an alkyl group in which one or more hydrogen atoms have been
replaced with a fluorine atom;
- fluoroalkyloxy: an alkyloxy group in which one or more hydrogen atoms have
been replaced with a fluorine atom;
- a halogen atom: a fluorine, chlorine, bromine or iodine atom;
- aryl: a monocyclic or bicyclic aromatic group containing between 6 and 10
carbon atoms. Examples of aryl groups that may be mentioned include phenyl
and naphthyl groups.
As non-limiting examples of cyclic amines or diamines formed by N, A, L and B,
mention may be made especially of aziridine, azetidine, pyrrolidine, piperidine,
azepine, morpholine, thiomorpholine, homopiperidine, decahydroquinoline,
decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclononane,
azaoxobicycloheptane, azathiabicycloheptane, azaoxobicyclooctane,
azathiabicyclooctane; piperazine, homopiperazine, diazacyclooctane,
diazacyclononane, diazacyclodecane, diazacycloundecane,
octahydropyrrolopyrazine, octahydropyrrolodiazepine, octahydropyrrolopyrrole,
octahydropyrrolopyridine, decahydronaphthyridine, diazabicycloheptane,
diazabicyclooctane, diazabicyclononane, diazaspiroheptane, diazaspirooctane,
diazaspirononane, diazaspirodecane, diazaspiroundecane and
oxadiazaspiroundecane.
Among the compounds of general formula (I) that are subjects of the invention, a first
group of compounds is constituted by compounds for which:
- L represents either a nitrogen atom optionally substituted with a group Rc or Rd, or a
carbon atom substituted with a group Re1 and a group Rd;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
second group of compounds is constituted by compounds for which:
- R2 represents a pyridyl group, optionally substituted with one or more substituents
chosen from fluorine and a methyl group;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
third group of compounds is constituted by compounds for which:
- R3 represents a hydrogen atom or a methyl group;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
fourth group of compounds is constituted by compounds for which:
R7 and R8 represent a hydrogen atom or a methyl group;
the other substituents being as defined above.
Among the compounds that are subjects of the invention, a fifth group of compounds
is constituted by compounds for which:
- A represents a group C1-7-alkylene optionally substituted with one or two groups Ra;
- B represents a group C1-7-alkylene optionally substituted with a group Rb;
- L represents a nitrogen atom optionally substituted with a group Rc or Rd;
the carbon atoms of A and B being optionally substituted with one or more groups Rf,
which may be identical to or different from each other;
Ra, Rb and Rc are defined such that:
two groups Ra may together form a group C1-6-alkylene;
Ra and Rb may together form a bond or a group C1-6-alkylene;
Ra and Rc may together form a bond or a group C1-6-alkylene;
Rb and Rc may together form a bond or a group C1-6-alkylene;
Rd represents a group chosen from a hydrogen atom and groups C1-6-alkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkyloxy-C1-6-
alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl or hydroxy-C1-6-alkyl;
Rf represents a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-
alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
sixth group of compounds is constituted by compounds for which:
- A represents a group C1-7-alkylene optionally substituted with one or two groups Ra;
- B represents a group C1-7-alkylene optionally substituted with a group Rb;
- L represents a carbon atom substituted with a group Re1 and a group Rd;
the carbon atoms of A and B being optionally substituted with one or more groups Rf,
which may be identical to or different from each other;
Ra, Rb and Rc are defined such that:
two groups Ra may together form a group C1-6-alkylene;
Ra and Rb may together form a bond or a group C1-6-alkylene;
Ra and Rc may together form a bond or a group C1-6-alkylene;
Rb and Rc may together form a bond or a group C1-6-alkylene;
Rd represents a group chosen from a hydrogen atom and groups C1-6-alkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkyloxy-C1-6-
alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl or hydroxy-C1-6-alkyl;
Re1 represents a group -NR4R5 or a cyclic monoamine optionally comprising an
oxygen atom, the cyclic monoamine being optionally substituted with one or
more substituents chosen from a fluorine atom and groups C1-6-alkyl, C1-6-
alkyloxy or hydroxyl;
Rf represents a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-
alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl;
R4 and R5 represent, independently of each other, a hydrogen atom or a group C1-6-
alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
seventh group of compounds is constituted by compounds for which:
- the cyclic amine formed by -N-A-L-B- represents a piperazinyl or
hexahydropyrrolopyrrolyl group, optionally substituted with one or more groups C1-6-
alkyl;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, an
eighth group of compounds is constituted by compounds for which:
the cyclic amine formed by -N-A-L-B- represents a pyrrolidinylpiperidyl group;
- R2, R3, R7 and R8 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
ninth group of compounds is constituted by compounds for which:
- the cyclic amine formed by -N-A-L-B- represents a (3S)-3-methylpiperazin-1-yl, 3,3-
dimethylpiperazin-1-y, 4-isopropylpiperazin-1-yl, piperazin-1-yl, (3R)-3-
isopropylpiperazin-1-yl or (c/s)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl group;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a
tenth group of compounds is constituted by compounds for which:
- the cyclic amine formed by -N-A-L-B- represents a 4-pyrrolidin-1 -ylpiperidin-1 -yl
group;
the other substituents being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, an
eleventh group of compounds is constituted by compounds for which:
- the cyclic amine formed by -N-A-L-B- represents a (3S)-3-methylpiperazin-1-yl, 3,3-
dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperazin-1-yl, (3R)-3-
isopropylpiperazin-1-yl, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl or 4-
pyrrolidin-1 -ylpiperidin-1 -yl group;
- R2 represents a pyridyl group, optionally substituted with one or more substituents
chosen from fluorine and a methyl group;
- R3 represents a hydrogen atom or a methyl group;
- R7 and R8 represent a hydrogen atom or a methyl group;
in the form of the base or of an acid-addition salt.
Among the compounds that are subjects of the invention, mention may be made
especially of:
6-[(3S)-3-Methylpiperazin-1-yl]-3-(pyrid-4-yl)-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine;
6-[(3S)-3-Methylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-(pyrid-3-yl)imidazo[1,2-
b]pyridazine;
6-(3,3-Dimethylpiperazin-1-yl)-3-(pyrid-4-yl)-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine;
6-(4-lsopropylpiperazin-1-yl)-3-(pyrid-4-yl)-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine;
6-(4-lsopropylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-(pyrid-3-yl)imidazo[1,2-
b]pyridazine;
2-(5-Fluoropyrid-3-yl)-6-[(3S)-3-methylpiperazin-1-yl]-3-(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
2-(5-Fluoropyrid-3-yl)-6-[(3S)-3-methylpiperazin-1-yl]-3-(2-methylpyrid-4-
yl)imidazo[1,2-b]pyridazine;
2-(5-Fluoropyrid-3-yl)-6-(4-isopropylpiperazin-1-yl)-3-(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
6-(4-lsopropylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-(5-methylpyrid-3-yl)imidazo[1,2-
b]pyridazine;
6-Piperazin-1 -yl-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine;
6-[(3S)-3-Methylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
6-(3,3-Dimethylpiperazin-1-yl)-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine;
6-(3,3-Dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
6-(3,3-Dimethylpiperazin-1-yl)-8-methyl-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine;
6-[(3R)-3-lsopropylpiperazin-1-yl]-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine;
6-(4-lsopropylpiperazin-1-yl)-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine;
6-(4-lsopropylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-2-(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
6-[(cis)-5-Methylhexahydropyrrolo[3,4-c]pyrrol-2-yl]-2,3-bis(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
2,3-Bis(pyrid-4-yl)-6-(4-pyrrolidin-1 -ylpiperidin-1 -yl)imidazo[1,2-b]pyridazine;
2-(2-Fluoropyrid-4-yl)-6-[(3S)-3-methylpiperazin-1-yl]-3-(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
2-(2-Fluoropyrid-4-yl)-6-[(3S)-3-methylpiperazin-1-yl]-3-(2-methylpyrid-4-
yl)imidazo[1,2-b]pyridazine;
2-(2-Fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1-yl)-3-(pyrid-4-yl)imidazo[1,2-
b]pyridazine;
2-(2-Fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)imidazo[1,2-
b]pyridazine.
In accordance with the invention, the compounds of general formula (I) may be
prepared according to the general process described in Scheme 1 below.

In general and as illustrated in Scheme 1, the 6-cycloamino-2,3-di-pyridylimidazo[1,2-
b]pyridazine derivatives of general formula (I) in which R2, R3, A, L, B, R7 and R8 are
as defined above may be prepared from a 3-(pyrid-4-yl)imidazo[1,2-b]pyridazine
derivative of general formula (II), in which R2, R3, R7 and R8 are as defined above and
X6 represents a leaving group such as a halogen, by treatment with an amine of
general formula (Ila) in which A, L and B are as defined previously. This reaction may
be performed by heating the reagents in a polar solvent such as pentanol or dimethyl
sulfoxide.
The imidazo[1,2-b]pyridazine derivatives of general formula (II) may be prepared by
metal-catalysed coupling between a 3-haloimidazo[1,2-b]pyridazine derivative of
general formula (III), in which R2, X6, R7, and R8 are as defined above and X3
represents a halogen such as bromine or iodine and more particularly iodine, and a
pyridine derivative of general formula (IlIa) in which R3 is as defined above and M
represents a trialkylstannyl group, usually a tributylstannyl group or a dihydroxyboryl
or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl
group, under the Stille or Suzuki conditions.
The couplings according to the Stille method are performed, for example, by heating
in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or copper
iodide, in a solvent such as N,N-dimethylacetamide.
The couplings according to the Suzuki method are performed, for example, by
heating in the presence of a catalyst such as 1,1'-
bis(diphenylphosphino)ferrocenedichloropalladium and a mineral base such as
caesium carbonate, in a solvent mixture such as dioxane and water.
The 3-haloimidazo[1,2-b]pyridazine derivatives of general formula (III) are obtained
by regioselective bromination or iodination of an imidazo[1,2-b]pyridazine derivative
of general formula (IV), in which R2, X6, R7 and R8 are as defined above. This
reaction may be performed using N-bromo- or iodosuccinimide or iodine
monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or
chloroform.
The imidazo[1,2-b]pyridazine derivatives of general formula (IV) are known (Journal
of Heterocyclic Chemistry (2002), 39(4), 737-742) or may be prepared by analogy
with methods known to those skilled in the art.
In a second alternative, according to Scheme 2, the 6-cycloamino-2,3-
dipyridylimidazo[1,2-b]pyridazine derivatives of general formula (I) as defined above
may be prepared in two steps from an imidazo[1,2-b]pyridazine derivative of general
formula (V) in which R2, A, L, B, R7 and R8 are as defined previously.
According to a first approach, the reaction of an imidazo[1,2-b]pyridazine derivative of
general formula (V) with the mixture of a pyridine derivative of general formula (Va) in
which R3 is as defined previously, and of an alkyl chloroformate in which the alkyl
group represents a C1-6-alkyl, for example ethyl chloroformate, leads to the derivative
of general formula (VI) in which R2, A, L, B, R3, R7 and R8 are as defined above. The
derivative of general formula (VI) is then oxidized using ortho-chloranil in a solvent
such as toluene, to give the 6-cycloamino-2,3-bis-pyridylimidazo[1,2-b]pyridazine
derivatives of general formula (I).
According to a second approach, a regioselective aromatic bromination or iodination
of imidazo[1,2-b]pyridazine derivatives of general formula (V) gives the 3-bromo- or
iodoimidazo[1,2-b]pyridazine derivatives of general formula (VII) in which R2, A, L, B,
R7 and R8 are as defined above and X3 represents a halogen such as bromine or
iodine, more particularly iodine. This reaction may be performed using /V-bromo- or
iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile,
tetrahydrofuran, methanol or chloroform.
The 6-cycloamino-2,3-di-pyridylimidazo[1,2-b]pyridazine derivatives of general
formula (I) are then prepared by metal-catalysed coupling between these 3-bromo- or
iodoimidazo[1,2-b]pyridazine derivatives of general formula (VII) and a pyridine
derivative of general formula (IIIa) as defined above, under the Stille or Suzuki
conditions.
In a third alternative, according to Scheme 3, the 6-cycloamino-2,3-di-
pyridylimidazo[1,2-b]pyridazine derivatives of general formula (I) as defined above
may be prepared in three steps from a 2-bromoimidazo[1,2-b]pyridazine derivative of
general formula (VIII) in which A, L, B, R7 and R8 are as defined previously.
Regioselective aromatic iodination of imidazo[1,2-b]pyridazine derivatives of general
formula (VIII) gives the 2-bromo-3-iodoimidazo[1,2-b]pyridazine derivatives of general
formula (IX) in which A, L, B, R7 and R8 are as defined above. This reaction may be
performed using A/-iodosuccinimide or iodine monochloride in a polar solvent such as
acetonitrile, tetrahydrofuran, methanol or chloroform.
A first regioselective metal-catalysed coupling reaction between these 2-bromo-3-iodo-
imidazo[1,2-b]pyridazine of general formula (IX) and a pyridine derivative of general
formula (IIIa) as defined above, under the Stille or Suzuki conditions, leads to the 2-
bromoimidazo[1,2-b]pyridazine derivatives of general formula (X) in which A, L, B, R3, R7
and R8 are as defined above.
Finally, a second metal-catalysed coupling reaction between a 2-bromo-3-
iodoimidazo[1,2-b]pyridazine derivative of general formula (X) and a pyridine
derivative of general formula (Xa) in which R2 is as defined above and M represents a
trialkylstannyl group, usually a tributylstannyl group or a dihydroxyboryl or
dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group,
under the Stille or Suzuki conditions, leads to the 6-cycloamino-2,3-di-
pyridylimidazo[1,2-b]pyridazine derivatives of general formula (I) as defined above.
The couplings according to the Stille methods are performed, for example, by heating
in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium or copper
iodide, in a solvent such as N,N-dimethylacetamide.
Precursors
The 3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of general formula (V) as defined
above may be prepared by condensation between a pyridazin-3-ylamine derivative of
general formula (XI) in which A, L, B, R7 and R8 are as defined above and a 2-bromo,
chloro- or iodoethan-1-one derivative of general formula (Xla) in which R2 is as
defined above and X represents a bromine, chlorine or iodine atom.
The reaction may be performed by heating the reagents in a polar solvent such as
ethanol or butanol.
The pyridazin-3-ylamine derivatives of general formula (XI) are known (Journal of
Medicinal Chemistry (2008), 51(12), 3507-3525) or may be prepared by analogy with
methods known to those skilled in the art.
The 3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of general formula (V) as defined
above may also be prepared via a metal-catalysed coupling reaction between the 2-
bromoimidazo[1,2-b]pyridazine derivatives of general formula (VIII) as defined
previously and a pyridine derivative of general formula (Xa) as defined above, under
the Stille or Suzuki conditions.
The 2-bromoimidazo[1,2-b]pyridazine derivatives of general formula (VIII) may be
prepared from a 2-bromoimidazo[1,2-b]pyridazine derivative of general formula (XII),
in which R7 and R8 are as defined above and X6 represents a leaving group such as
a halogen, more particularly chlorine, by treatment with an amine of general formula
(Ila) as defined previously. This reaction may be performed by heating the reagents
in a polar solvent such as pentanol or dimethyl sulfoxide.
The 2-bromoimidazo[1,2-b]pyridazine derivatives of general formula (XII) are
obtained in two steps from a 5-halopyridazin-3-ylamine of general formula (XIV) in
which X6 represents a leaving group such as a halogen, more particularly chlorine,
and R7 and R8 are as defined previously. Thus, the 5-halopyridazin-3-ylamine
derivatives of general formula (XI) are alkylated using an alkyl 2-bromo-or 2-
chloroacetate, for example ethyl 2-bromoacetate, to give a 6-amino-3-halo-1-
(alkyloxycarbonylmethyl)pyridazin-1-ium hydrobromide or hydrochloride of general
formula (XIII) for which X6 represents a leaving group such as a halogen, more
particularly chlorine, while R7 and R8 are as defined previously. The 6-amino-3-halo-
1-(alkyloxycarbonylmethyl)pyridazin-1-ium hydrobromides or hydrochlorides of
general formula (XIII) are cyclized using phosphorus oxybromide to give the 2-bromo-
3-(pyrid-4-yl)imidazo[1,2-b]pyridazine derivatives of general formula (XII).
In the text hereinabove, the term "leaving group" means a group that can be readily
cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair.
This group may thus be readily replaced with another group during a substitution
reaction, for example. Such leaving groups are, for example, halogens or an activated
hydroxyl group such as a mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups
and references for preparing them are given in "Advances in Organic Chemistry",
J. March, 3rd Edition, Wiley Interscience, pp. 310-316.
Protecting groups
For the compounds of general formula (I) or (lla) as defined above and in the case
where the group N-A-L-B comprises a primary or secondary amine function, this
function may be optionally protected during the synthesis with a protecting group, for
example a benzyl or a t-butyloxycarbonyl.
The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, but serve merely to
illustrate the invention. The numbers of the illustrated compounds refer to those given
in Table 1 hereinbelow, which illustrate the chemical structures and physical
properties, respectively, of a number of compounds according to the invention.
Example 1 (compound 13): 6-(3,3-Dimethylpiperazin-1-yl)-3-(2-methylpyrid-4-yl)-
2-(pyrid-4-yl)imidazo[1,2-b]Pyridazine
To a solution of 24.0 g (85.3 mmol) of 3-amino-6-chloropyridazine in 1.5 L of refluxing
ethanol are added portionwise 33.2 g (256 mmol) of 2-bromo-1-(pyrid-4-yl)ethanone
hydrobromide (CAS 5469-69-2) and then 12.0 ml (85.4 mmol) of triethylamine,
dropwise over 45 minutes. The mixture is refluxed for 3 hours. After cooling, the
solvent is evaporated off under reduced pressure and the red-brown residue is taken
up in chloroform and 300 ml of 1N sodium hydroxide solution. After stirring for 15
minutes, the mixture is filtered and the solid residue is washed with chloroform. The
organic phase is separated out, washed with water and dried over sodium sulfate to
give 13 g of a brown solid, after evaporating off the solvent. The residue is purified on
a column of 500 g of silica gel, eluting with a mixture of dichloromethane, methanol
and aqueous ammonia (97/3/0.3) to give 10.1 g of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-
b]pyridazine in the form of a dark beige solid, after triturating in diisopropyl ether,
filtering off and drying under reduced pressure,
m.p. 203-205°C
1H NMR (DMSO-d6) d: 9.15 (s, 1H); 8.70 (d, 2H); 8.30 (d, 1H); 8.0 (d, 2H); 7.45 (d,
1H) ppm.
Step 1.2. 6-Chloro-3-iodo-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine

To a solution of 10.4 g (45.1 mmol) of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine
in 1 L of chloroform are added, at room temperature, 21.9 g (135 mmol) of iodine
chloride in 100 ml of methanol. After reaction for 24 hours, the mixture is poured into
saturated sodium bicarbonate solution and the resulting mixture is decolorized by
adding aqueous 5% sodium thiosulfate solution. The organic phase is separated out,
dried over sodium sulfate and concentrated under reduced pressure to give 14.4 g of
6-chloro-3-iodo-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine in the form of a beige-coloured
solid, containing about 10% of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine, after
triturating in 200 ml of acetonitrile, filtering off and drying.
1H NMR (DMSO-d6) d: 8.75 (d, 2H); 8.30 (d, 1H); 8.15 (d, 2H); 7.50 (d, 1H) ppm.
Step 1.3. 6-Chloro-3-(2-methylpyrid-4-yl)-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine

To a mixture of 2.85 g (6.39 mmol) of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine,
1.14 g (6.12 mmol) of (2-methyl-4-pyridyl)boronic acid (CAS 579476-63-4) and 6.3 g
(19 mmol) of caesium carbonate in 400 ml of a mixture of tetrahydrofuran and water
(9/1) is added, after degassing with argon, 0.47 g (0.58 mmol) of 1,1'-
bis(diphenylphosphino)ferrocenedichloropalladium (II) (CAS 72287-26-4). The
mixture is stirred at reflux for 18 hours. The mixture is concentrated under reduced
pressure and the residue is taken up in chloroform. The organic phase is washed with
water and dried over sodium sulfate, and the solvent is evaporated off under reduced
pressure. The residue is purified on a column of 110 g of silica gel, eluting with a
mixture of dichloromethane, methanol and aqueous ammonia (96/4/0.4) to give 1.35
g of 6-chloro-3-(2-methylpyrid-4-yl)-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine in the form
of a white powder, after triturating in acetonitrile, filtering off and drying.
m.p.:218-222°C
1H NMR (DMSO-d6) d: 8.60 (d, 1H); 8.55 (d, 2H); 7.95 (d, 1H); 7.50 (d, 2H); 7.35 (s,
1H); 7.25 (d, 1H); 7.15 (d, 1H); 2.60 (s, 3H) ppm.
Step 1.4. 6-(3,3-Dimethylpiperazin-1 -yl)-3-(2-methylpyrid-4-yl)-2-(pyrid-4-
yl)imidazo[1,2-b]pyridazine

A mixture of 0.500 g (1.55 mmol) of 6-chloro-3-(2-methylpyrid-4-yl)-2-(pyrid-4-
yl)imidazo[1,2-b]pyridazine and 0.52 g (4.7 mmol) of 2,2-dimethylpiperazine in 5 ml of
pentanol is refluxed for 24 hours at 150°C. The reaction medium is cooled and
poured into aqueous 2N hydrochloric acid solution. The aqueous phase is washed
with diethyl ether and then basified with aqueous 2N sodium hydroxide solution, and
the product is extracted with chloroform. The organic phase is dried over sodium
sulfate and the solvent is evaporated off under reduced pressure. The solid obtained
is purified on 35 g of silica gel, eluting with a mixture of dichloromethane, methanol
and aqueous ammonia (94/6/0.6) to give 0.17 g of 6-(3,3-dimethylpiperazin-1-yl)-3-(2-
methylpyrid-4-yl)-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine in the form of a beige-
coloured powder, after dissolving in 10 ml of acetonitrile and crystallizing by addition
of diethyl ether, filtering off and drying,
m.p.: 185-187°C
1H NMR (CDCI3) d: 8.60 (m, 3H); 7.80 (d, 1H); 7.60 (d, 2H); 7.50 (s, 1H); 7.40 (d, 2H);
6.95 (d, 1H); 3.45 (dd, 2H); 3.30 (s, 2H); 3.10 (dd, 2H); 2.65 (s, 3H); 1.2 (s, 6H) ppm.
Example 2 (compound 14): 6-(3,3-Dimethylpiperazin-1-yl)-8-methyl-2,3-
bis(pyrid-4-yl)imidazo[1,2-b]pyridazine

Step 2.1. 3-Amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methyl-
pyridazine

In an autoclave, a suspension of 50.0 g (307 mmol) of 3,6-dichloro-4-
methylpyridazine in 170 ml 30% aqueous ammonia is heated at 120°C for 18 hours.
After cooling, the mixture is poured into 200 ml of water and the solid is recovered by
filtration. After drying under reduced pressure, the mixture of products is
recrystallized from ethyl acetate to give 40 g of a mixture of 3-amino-6-chloro-4-
methylpyridazine and 3-amino-6-chloro-5-methylpyridazine (32/68).
1H NMR (CDCI3): 7.15 and 6.75 (s and s, 1H); 5.0 (broad signal, 2H); 2.35 and 2.25
(s and s, 3H).
Step 2.2. 6-Amino-3-chloro-1 -ethoxycarbonylmethyl-5-methylpyridazin-1 -ium
bromide and 6-amino-3-chloro-1 -ethoxycarbonylmethyl-4-methylpyridazin-1 -ium
bromide

To a solution of 36.0 g (251 mmol) of a mixture of 3-amino-6-chloro-4-
methylpyridazine and 3-amino-6-chloro-5-methylpyridazine (32/68) in 350 ml of
refluxing ethanol are added portionwise 30.6 ml (275 mmol) of ethyl 2-bromoacetate
and heating is continued for 24 hours. After cooling, the reaction medium is partially
concentrated under reduced pressure and then diluted with 200 ml of acetone, the
suspension is cooled to 0°C and the precipitate is separated out by filtration. The
filtrate is then partially concentrated under reduced pressure and diluted with 150 ml
of acetone, and the suspension is again cooled to 0°C. The precipitate is separated
out by filtration and combined with the first crop. After drying, 29.8 g of a mixture of 6-
amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyridazin-1-ium bromide and 6-
amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridazin-1-ium bromide (30/70) are
obtained in total.
1H NMR (MeOD): 7.90 and 7.55 (s and s, 1H); 5.30 and 5.25 (s and s, 2H); 4.35 (q,
2H); 2.50 and 2.45 (s and s, 3H); 1.35 (t, 3H).
Step 2.3. 2-Bromo-6-chloro/bromo-7-methylimidazo[1,2-b]pyridazine and 2-
bromo-6-chloro/bromo-8-methylimidazo[1,2-b]pyridazine

A mixture of 27.8 g (89.5 mmol) of 6-amino-3-chloro-1-ethoxycarbonylmethyl-4-
methylpyridazin-1 -ium, 6-amino-3-chloro-1 -ethoxycarbonylmethyl-5-methylpyridazin-
1-ium (30/70) and 82 g (286 mmol) of phosphorus oxybromide in 100 ml of toluene is
heated at 160°C for 1 hour in a sealed tube. After cooling, the solid deposited on the
walls is detached and the mixture is poured into 500 ml of water at 0°C. The aqueous
phase is then basified by addition of aqueous ammonia and, after stirring for 1 hour,
the product is dissolved in chloroform. The organic phase is separated out, dried over
sodium sulfate and concentrated under reduced pressure to give 22 g of a brown
solid. The solid is then purified by chromatography on a column of 450 g of silica gel,
eluting with dichloromethane, to give 5.0 g of 2-bromo-6-chloro-8-methylimidazo[1,2-
b]pyridazine containing 2,6-dibromo-8-methylimidazo[1,2-b]pyridazine in the form of a
white powder (41/59).
1H NMR (CDCI3): 7.80 (s, 1H); 6.85 and 7.00 (s and s, 1H); 2.55 (s, 3H).
Continuing the elution with a mixture of dichloromethane, methanol and aqueous
ammonia (90/10/1) gives 15.2 g of 2-bromo-6-chloro/bromo-7-methylimidazo[1,2-
b]pyridazine containing 2,6-dibromo-7-methylimidazo[1,2-b]pyridazine, in the form of
a pink powder.
1H NMR (CDCI3): 7.95 (s, 1H); 7.75 (s, 1H); 2.55 (s, 3H).
Step 2.4. 2-Bromo-6-(3,3-dimethylpiperazin-1-yl)-8-methylimidazo[1,2-
b]pyridazine
A mixture of 4.95 g (about 20 mmol) of 2-bromo-6-chloro-8-methylimidazo[1,2-
b]pyridazine containing 2,6-dibromo-8-methylimidazo[1,2-b]pyridazine, 2.5 g (22
mmol) of 2,2-dimethylpiperazine and 2.8 ml of triethylamine in 60 ml of pentanol is
heated at 150°C for 3 days in a sealed tube. After cooling, the reaction medium is
poured into aqueous 1N hydrochloric acid solution. The aqueous phase is washed
with ethyl acetate and then basified with aqueous ammonia solution and the product
is extracted with dichloromethane. The organic phase is dried over sodium sulfate
and the solvent is evaporated off under reduced pressure. The beige-coloured solid
obtained is purified on a column of 80 g of silica gel, eluting with a mixture of
dichloromethane, methanol and aqueous ammonia (95/65/0.5) to give 4.6 g of 2-
bromo-6-(3,3-dimethylpiperazin-1-yl)-8-methylimidazo[1,2-b]pyridazine in the form of
a white powder.
m.p.:139-141°C
1H NMR (CDCI3) d: 7.65 (s, 1H); 7.65 (s, 1H); 3.5 (m, 2H); 3.30 (s, 2H); 3.10 (m, 2H);
2.60 (s,3H); 1.25 (s, 6H) ppm.
Step 2.5. 6-(3,3-Dimethylpiperazin-1-yl)-8-methyl-2-(pyrid-4-yl)imidazo[1,2-
b]pyridazine

To a mixture of 4.64 g (14.3 mmol) of 2-bromo-6-(3,3-dimethylpiperazin-1-yl)-8-
methylimidazo[1,2-b]pyridazine and 2.5 g (17 mmol) of (4-pyridyl)boronic acid (CAS
1692-15-5) in 100 ml of a mixture of tetrahydrofuran and water (9/1), are added, after
degassing with argon, 14 g (43 mmol) of caesium carbonate and 1.05 g (1.29 mmol)
of a complex of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) and
dichloromethane (PdCI2(dppf).CH2CI2). After stirring for 8 hours at reflux, the reaction
medium is poured into aqueous 1N hydrochloric acid solution. The aqueous phase is
washed with ethyl acetate and then basified with aqueous ammonia solution and the
product is extracted with dichloromethane. The organic phase is dried over sodium
sulfate and the solvent is evaporated off under reduced pressure. The black oil
obtained is purified by chromatography on a column of 120 g of silica gel, eluting with
a mixture of dichloromethane, methanol and aqueous ammonia (95/65/0.5) to give
3.1 g of 6-(3,3-dimethylpiperazin-1-yl)-8-methyl-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine
in the form of an oil.
1H NMR (CDCI3) d: 8.70 (d, 2H); 8.15 (s, 1H); 7.85 (d, 2H); 6.70 (s, 1H); 3.55 (m, 2H);
3.30 (s, 2H); 3.15 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm.
Step 2.6. 6-(3,3-Dimethylpiperazin-1-yl)-3-iodo-8-methyl-2-(pyrid-4-yl)imidazo[1,2-
b]pyridazine

To a solution of 3.13 g (9.71 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-8-methyl-2-
(pyrid-4-yl)imidazo[1,2-b]pyridazine in 80 ml of dichloromethane are added at room
temperature 19.4 ml (19.4 mmol) of a 1M solution of iodine chloride in
dichloromethane. After reaction for 2 hours, the solution is poured into 150 ml of
water and basified by addition of sodium bicarbonate, and the resulting mixture is
decolorized by portionwise addition of sodium thiosulfate. The organic phase is
separated out, dried over sodium sulfate and concentrated under reduced pressure
to give a brown oil, which is purified by chromatography on a column of 120 g of silica
gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia
(90/10/1), to give 3.35 g of 6-(3,3-dimethylpiperazin-1-yl)-3-iodo-8-methyl-2-(pyrid-4-
yl)imidazo[1,2-b]pyridazine in the form of a beige-coloured solid,
m.p.: 153-155°C
1H NMR (CDCI3) d: 8.75 (d, 2H); 8.15 (d, 2H); 6.75 (s, 1H); 3.70 (m, 2H); 3.40 (s, 2H);
3.20 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm.
Step 2.7. 6-(3,3-Dimethylpiperazin-1 -yl)-8-methyl-2,3-bis(pyrid-4-yl)imidazo[1,2-
b]pyridazine

To a mixture of 0.40 g (0.89 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-3-iodo-8-methyl-
2-(pyrid-4-yl)imidazo[1,2-b]pyridazine and 0.155 g (1.07 mmol) of (4-pyridyl)boronic
acid (CAS 1692-15-5) in 15 ml of a mixture of tetrahydrofuran and water (9/1) are
added, after degassing with argon, 0.87 g (2.7 mmol) of caesium carbonate and
0.057 g (0.08 mmol) of a complex of 1,1'-
bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane
(PdCI2(dppf).CH2CI2 - CAS 851232-71-8). After reaction for 18 hours, the reaction
medium is poured into 150 ml of water and the product is extracted with
dichloromethane. The organic phase is dried over sodium sulfate and the solvent is
evaporated off under reduced pressure. The black oil obtained is purified by
chromatography on a column of 40 g of silica gel, eluting with a mixture of
dichloromethane, methanol and aqueous ammonia (95/65/0.5) to give 0.039 g of 6-
(3,3-dimethylpiperazin-1-yl)-8-methyl-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine in
the form of a beige-coloured powder after recrystallizing from acetonitrile, filtering off
and drying.
m.p. = 211-213°C
1H NMR (CDCI3) d: 8.70 (d, 2H); 8.60 (d, 2H); 7.60 (m, 4H); 6.75 (s, 1H); 3.45 (m,
2H); 3.25 (s, 2H); 3.05 (m, 2H); 2.70 (s, 3H); 1.20 (s, 6H) ppm.
Example 3 (compound 12): 6-(3,3-Dimethylpiperazin-1-yl)-2,3-bis(pyrid-4-
yl)imidazo[1,2-b]pyridazine

Step 3.1. 6-Chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine

A mixture of 3.80 g (28.1 mmol) of 3-amino-6-chloropyridazine and 5.00 g (17.8
mmol) of 2-bromo-1-(pyrid-4-yl)ethanone hydrobromide in 50 ml of ethanol is heated
by microwave 140°C for 50 minutes. After cooling, the solvent is evaporated off under
reduced pressure and the residue is taken up in saturated aqueous sodium hydrogen
carbonate solution. The solid is separated out by filtration, washed with water and
then chromatographed on a column of silica gel, eluting with a mixture of
dichloromethane and methanol (95/5), to give 1.97 g of 6-chloro-2-(pyrid-4-
yl)imidazo[1,2-b]pyridazine in the form of a yellow powder.
LC/MS: M+H+ = 231
1H NMR (CDCI3) d: 8.71 (dd, 2H); 8.33 (d, 1H); 7.93 (dd, 1H); 7.82 (dd, 2H); 7.11 (d,
1H).
Step 3.2. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine

A mixture of 1.95 g (8.45 mmol) of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine and
2.4 g (21 mmol) of 2,2-dimethylpiperazine is heated in a microwave oven at 150°C for
13 hours. The medium is then cooled and the solvent is evaporated off under
reduced pressure. The orange oil obtained is chromatographed on a column of silica
gel, eluting with a mixture of dichloromethane and a 1M solution of ammonia in
methanol (95/5), to give 1.63 g of 6-(3,3-dimethylpiperazin-1-yl)-2-(pyrid-4-
yl)imidazo[1,2-b]pyridazine in the form of a yellow foam.
LC/MS: M+H+ = 309
1H NMR (DMSO-d6): 8.67 (d, 1H); 8.57 (dd, 2H); 7.86 (m, 3H); 7.23 (d, 1H); 3.41 (m,
2H); 3.25 (s, 2H); 3.17 (d, 1H); 2.84 (m, 2H); 1.95 (bs, 1H); 1.07 (s, 6H).
Step 3.3. 6-(3,3-Dimethylpiperazin-1 -yl)-3-iodo-2-(pyrid-4-yl)imidazo[1,2-
b]pyridazine

To a solution of 1.37 g (4.45 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-2-(pyrid-4-
yl)imidazo[1,2-b]pyridazine in 20 ml of chloroform is added a solution of 1.80 g (11.1
mmol) of iodine monochloride in 5 ml of methanol. The suspension obtained is stirred
for 2 hours. Saturated aqueous sodium hydrogen carbonate solution is added,
followed by portionwise addition of sodium thiosulfate until the reaction medium
remains yellow. The solid is separated out by filtration and air-dried to give 1.95 g of
the product 6-(3,3-dimethylpiperazin-1-yl)-3-iodo-2-(pyrid-4-yl)imidazo[1,2-
bjpyridazine in the form of a yellow powder.
1H NMR (DMSO-d6): 9.0 (bs, 2H); 8.70 (d, 2H); 8.10 (d, 2H); 8.00 (d, 1H); 7.38 (d,
1H); 3.85 (m, 2H); 3.70 (m, 2H); 3.3 (m, 2H); 1.40 (s, 6H).
Step 3.4. 6-(3,3-Dimethylpiperazin-1 -yl)-2,3-bis(pyrid-4-yl)imidazo[1,2-
jb]pyridazine
After degassing, a mixture of 0.28 g (0.55 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-3-
iodo-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine, 0.095 g (0.77 mmol) of (pyrid-4-yl)boronic
acid, 0.89 g (2.7 mmol) of caesium carbonate and 45 mg (0.055 mmol) of a complex
of 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (II) and dichloromethane
(PdCI2(dppf).CH2CI2 - CAS 851232-71-8) in 4 ml of a mixture of 1,4-dioxane and
water (75/2) is heated in a microwave oven at 105°C for 30 minutes. After cooling,
the mixture is diluted with dichloromethane and washed with water. The organic
phase is then dried over magnesium sulfate and filtered, and the solvent is
evaporated off. The oil obtained is chromatographed on silica gel, eluting with a
mixture of a 1M solution of ammonia in a mixture of methanol and dichloromethane
(3/97), to give 0.070 g of a yellow powder.
LC/MS: M+H+ = 386
1H NMR (DMSO-d6): 8.70 (d, 2H); 8.54 (d, 2H); 7.96 (d, 1H); 7.60 (d, 2H); 7.51 (d,
2H); 7.34 (d, 1H); 3.45-3.10 (m, 4H); 2.83 (m, 2H); 1.05 (6H).
Example 4 (compound 3): 6-(3,3-Dimethylpiperazin-1-yl)-2-(pyrid-3-yl)-3-(pyrid-
4-yl)imidazo[1,2-b]pyridazine

Step 4.1. 6-Chloro-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine

A suspension of 2.80 g (11.9 mmol) of 3-amino-6-chloropyridazine, 3.69 g (13.2
mmol) of 2-bromo-1-(pyrid-3-yl)ethanone hydrobromide and 3.7 ml (26 mmol) of
triethylamine in 45 ml of ethanol is heated by microwave at 140°C for 50 minutes.
After cooling, the solvent is evaporated off under reduced pressure and the residue is
purified by chromatography on a column of 120 g of silica gel, eluting with a mixture
of dichloromethane and methanol (95/5) to give 0.77 g of product in the form of a
beige-coloured powder, after triturating in heptane, filtering off and drying under
reduced pressure.
LC/MS:M+H+ = 231
1H NMR (DMSO-d6): 9.25 (s, 1H); 9.00 (s, 1H); 8.60 (d, 1H); 8.40 (dt, 1H); 8.25 (d,
1H);7.50(dd, 1H);7.40(d, 1H).
Step 4.2. 6-(3,3-Dimethylpiperazin-1-yl)-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine

A mixture of 0.77 g (3.3 mmol) of 6-chloro-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine and
1.1 g (9.6 mmol) of 2,2-dimethylpiperazine in 7 ml of ethanol is heated in a
microwave oven at 150°C for 13 hours. The medium is then cooled and the solvent is
evaporated off under reduced pressure. The orange oil obtained is chromatographed
on a column of silica gel, eluting with a mixture of dichloromethane and a 1M solution
of ammonia in methanol (97/3), to give 0.89 g of 6-(3,3-dimethylpiperazin-1-yl)-2-
(pyrid-3-yl)imidazo[1,2-b]pyridazine in the form of a yellow powder.
LC/MS: M+H+ = 309
1H NMR (DMSO-d6): 9.14 (d, 1H); 8.56 (s, 1H); 8.48 (d, 1H); 8.23 (d, 1H); 7.85 (d,
1H); 7.45 (dd, 1H); 7.20 (d, 1H); 3.41 (t, 2H); 2.86 (t, 2H); 1.95 (bs, 2H); 1.08 (s, 6H).
Step 4.3. 6-(3,3-Dimethylpiperazin-1 -yl)-3-iodo-2-(pyrid-3-yl)imidazo[1,2-
b]pyridazine

To a solution of 0.870 g (2.82 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-2-(pyrid-3-
yl)imidazo[1,2-b]pyridazine in 10 ml of chloroform is added a solution of 0.600 g (3.70
mmol) of iodine monochloride in 4 ml of methanol. The orange-coloured suspension
is then stirred for 3 hours and the solvent is evaporated off under reduced pressure to
give a residue. Saturated aqueous sodium hydrogen carbonate solution is then
added, followed by portionwise addition of sodium thiosulfate until the reaction
mixture remains yellow. The solid is separated out by filtration and air-dried to give
0.90 g of product 6-(3,3-dimethylpiperazin-1-yl)-3-iodo-2-(pyrid-3-yl)imidazo[1,2-
6]pyridazine in the form of a beige-coloured powder.
LC/MS: M+H+ = 435
1H NMR (DMSO-d6): 9.26 (s, 1H); 8.57 (d, 1H); 8.39 (d, 1H); 7.92 (d, 1H); 7.52 (dd,
1H); 7.31 (d, 1H); 3.75-3.10 (m, 6H); 1.25 (s, 6H).
Step 4.4. 6-(3,3-Dimethylpiperazin-1 -yl)-2,3-bis(pyrid-3-yl)imidazo[1,2-
b]pyridazine

After degassing, a mixture of 0.400 g (0.92 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-3-
iodo-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine, 0.150 g (1.22 mmol) of (pyrid-4-yl)boronic
acid, 0.89 g (2.7 mmol) of caesium carbonate and 75 mg (0.092 mmol) of a complex
of 1,1'-bis(diphenylphosphinoferrocenedichloropalladium (II) and dichloromethane
(PdCl2(dppf).CH2CI2) in 6 ml of a mixture of 1,4-dioxane and water (3/1) is heated in a
microwave oven at 105°C for 30 minutes. After cooling, the mixture is diluted with
dichloromethane and washed with water. The organic phase is then dried over
magnesium sulfate and filtered, and the solvent is evaporated off to give a green oil.
The oil obtained is chromatographed on a column of 25 g of silica gel, eluting with a
mixture of a 1M solution of ammonia in methanol and dichloromethane (5/95) to give
0.170 g of 6-(3,3-dimethylpiperazin-1-yl)-2,3-bis(pyrid-3-yl)imidazo[1,2-b]pyridazine in
the form of a grey powder.
LC/MS: M+H+ = 386
1H NMR (DMSO-d6): 8.70 (d, 1H); 8.67 (d, 2H); 8.52 (d, 1H); 7.96 (d, 1H); 7.90 (d,
1H); 7.58 (d, 2H); 7.41 (dd, 1H); 7.33 (d, 1H); 3.40 (t, 2H); 3.25 (s, 2H); 2.84 (t, 2H);
1.06 (s,6H).
Example 5 (compound 22): 2-(2-Fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1-yl)-
3-(pyrid-4-yl)imidazo[1,2-b]pyridazine

Step 5.1. 6-Amino-3-chloro-1 -(ethoxycarbonylmethyl)pyridazin-1-ium bromide

A mixture of 25.6 g (198 mmol) of 3-amino-6-chloropyridazine in 230 ml of hot
ethanol is treated with 34.0 g (206 mmol) of ethyl bromoacetate. After refluxing for 24
hours, the mixture is cooled and the crystals are separated out by filtration. 36.6 g of
product are isolated after drying. A further 7.1 g are isolated by evaporating off the
solvent under reduced pressure and recrystallizing from ethanol.
1H NMR (DMSO-d6) d: 9.8 (broad signal, 1H); 9.4 (broad signal, 1H); 8.0 (d, 1H); 7.7
(d, 1H); 5.3 (s, 1H); 4.1 (d, 2H); 1.2 (t, 3H) ppm.
Step 5.2. 2-Bromo-6-chloroimidazo[1,2-b]pyridazine and 2,6-dibromoimidazo[1,2-
b]pyridazine

A mixture of 20 g (65 mmol) of 6-amino-3-chloro-1-(ethoxycarbonylmethyl)pyridazin-
1-ium bromide and 63 g of phosphorus oxybromide in 50 ml of toluene is heated at
160°C for 3 hours. The mixture is then poured onto ice (300 ml). After stirring, the
solid is separated out by filtration and then purified by chromatography on a column
of 120 g of silica gel, eluting with a mixture of 0 to 10% of methanol in
dichloromethane. 8.05 g of a mixture of the two products are thus obtained, and are
used without further purification for the rest of the synthesis.
1H NMR (CDCI3) d: 7.92 (s, 1H); 7.83 (d, 1H); 7.1 (d, 1H)
Step 5.3. 2-Bromo-6-(4-isopropylpiperazin-1 -yl)imidazo[1,2-b]pyridazine

The mixture of 3.98 g (14.4 mmol) of 2-bromo-6-chloroimidazo[1,2-b]pyridazine and
2,6-dibromoimidazo[1,2-b]pyridazine obtained in the preceding step and 3.7 g (28.5
mmol) of 1-isoproylpiperazine in 15 ml of ethanol is heated at 160°C for 8 hours in a
sealed tube in a microwave reactor. The mixture is diluted with ethanol and then
filtered to give 2.49 g of 2-bromo-6-(4-isopropylpiperazin-1-yl)imidazo[1,2-
b]pyridazine.
1H NMR (CDCl3) d: 7.62 (s, 1H); 7.60 (d, 1H); 6.9 (d, 1H); 3.5 (m, 4H); 2.73 (m, 1H);
2.64 (m,4H); 1.1 (d, 6H)
Step 5.4. 2-Bromo-3-iodo-6-(4-isopropylpiperazin-1 -yl)imidazo[1,2-b]pyridazine

A solution of 2.45 g (14.8 mmol) of iodine chloride in 2 ml of methanol is added
dropwise to a solution of 2.45 g (7.56 mmol) of 2-bromo-6-(4-isopropylpiperazin-1-
yl)imidazo[1,2-b]pyridazine in 20 ml of chloroform at 0°C. The mixture is stirred at
room temperature for 4 hours. The mixture is then triturated with sodium thiosulfate.
This mixture is concentrated under reduced pressure in the presence of 15 g of silica
gel. The residue is deposited on a column of 80 g of silica gel and is purified by
chromatography, eluting with a gradient of from 0 to 10% methanol in
dichloromethane, to give 2.07 g of 2-bromo-3-iodo-6-(4-isopropylpiperazin-1-
yl)imidazo[1,2-b]pyridazine in the form of an orange-coloured solid.
1H NMR (CDCI3) d: 7.5 (d, 1H); 6.9 (d, 1H); 3.55 (m, 4H); 3.19 (m, 4H), 3.17 (m, 1H);
1.32 (d,6H)
Step 5.5. 2-Bromo-6-(4-isopropylpiperazin-1-yl)-3-(pyrid-4-yl)imidazo[1,2-
b]pyridazine

A mixture of 0.059 g (0.12 mmol) of 2-bromo-3-iodo-6-(4-isopropylpiperazin-1-
yl)imidazo[1,2-b]pyridazine, 3 mg (0.004 mmol) of 1,1'-
bis(diphenylphosphino)ferrocenepalladium dichloride (CAS 72287-26-4), 18 mg (0.15
mmol) of pyrid-4-ylboronic acid (CAS 1692-15-5), 0.9 ml of aqueous 2M caesium
carbonate solution and 1.5 ml of 1,4-dioxane in a sealed tube is heated at 110°C for
30 minutes in a microwave oven. 1 ml of saturated sodium chloride solution and 4 ml
of ethyl acetate are added. After stirring, the mixture is percolated through a sodium
sulfate cartridge.
The solvent is evaporated off to dryness in the presence of silica gel. The absorbed
residue is deposited on a column of 4 g of silica gel and diluted with a gradient of
from 0 to 6% methanol and 1% aqueous ammonia in dichloromethane, to give 8.5 mg
of 2-bromo-6-(4-isopropylpiperazin-1 -yl)-3-(pyrid-4-yl)imidazo[1,2-jb]pyridazine.
1H NMR (CDCI3) d: 8.74 (d, 2H); 7.94 (d, 2H); 7.7 (d.1H); 6.93 (d, 1H); 3.5 (m, 4H);
2.75 (m, 1H); 2.65 (m, 4H); 1.10 (d, 6H).
Step 5.6. 2-(2-Fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1 -yl)-3-(pyrid-4-
yl)imidazo[1,2-b]pyridazine

A mixture of 2.65 g (6.6 mmol) of 2-bromo-6-(4-isopropylpiperazin-1-yl)-3-(pyrid-4-
yl)imidazo[1,2-b]pyridazine, 0.46 g (0.65 mmol) of 1,1'-
bis(diphenylphosphino)ferrocene palladium (CAS 72287-26-4), 1.12 g (9.10 mmol) of
pyridine-4-boronic acid (CAS 169215-15-5) and 15 ml of aqueous 2M caesium
carbonate solution in 25 ml of 1,4-dioxane in a sealed tube is heated at 120°C for 20
minutes. A further 0.237 g (2.7 mmol) of pyridine-4-boronic acid is added and the
reaction mixture is heated at 110°C for 30 minutes. The reaction medium is then
diluted with water and the product is extracted with ethyl acetate. The organic phase
is washed with saturated aqueous sodium chloride solution and then dried over
sodium sulfate. The solvent is stripped off under reduced pressure and the residue is
adsorbed on silica gel. The product is purified by chromatography on a column of 80
g of silica gel, eluting with a gradient of from 0 to 10% methanol in dichloromethane
to give 1.85 g of 2-(2-fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1-yl)-3-(pyrid-4-
yl)imidazo[1,2-Jb]pyridazine, after recrystallizing from isopropanol.
m.p. = 196-198°C
1H NMR (CDCI3) d: 8.74 (d, 2H); 8.15 (d, 1H); 7.80 (d, 1H); 7.56 (d, 2H); 7.39 (d, 1H);
7.25 (d, 1H); 6.98 (d, 1H); 3.50 (m, 4H); 2.76 (m, 1H); 2.62 (m, 4H); 1.08 (d, 6H).
Table 1 below illustrates the chemical structures and the physical properties of a
number of compounds according to the invention.
In this table:
- the column "m.p. °C" indicates the melting points of the products in degrees Celsius.
"N.D" means that the melting point is not determined,
- the column "[a]D" indicates the result of analysis of the optical rotation of the
compounds of the table at a wavelength of 589 nm; the solvent indicated in
parentheses corresponds to the solvent used for measuring the optical rotation, in
degrees, and the letter "c" indicates the concentration of the solvent in g/100 ml.
"N.A." means that the optical rotation measurement is not applicable,
- the column "m/z" indicates the molecular ion (M+H+) observed by analysis of the
products by mass spectrometry, either by LC-MS (liquid chromatography coupled to
Mass Spectroscopy) performed on a machine of Agilent LC-MSD Trap type in
positive ESI mode, or by direct introduction by MS (Mass Spectroscopy) on an
Autospec M (EBE) machine using the DCI-NH3 technique or using the electron
impact technique on a machine of Waters GCT type.
- "CH3-" means methyl,
- "CH3OH" means methanol,
- "DMSO" means dimethyl sulfoxide,
Biological examples
The capacity of the compounds of the invention to inhibit the phosphorylation of
casein by casein kinases 1 epsilon and delta may be evaluated according to the
procedure described in document US 2005/0 131 012.
Filter-plate assay of ATP-33P for the screening of CK1 epsilon inhibitors:
The effect of the compounds on inhibition of the phosphorylation of casein by the
enzyme casein kinase 1 epsilon (CK1 epsilon) is measured, using a casein assay via
filtration of ATP-33P in vitro.
Casein kinase 1 epsilon (0.58 mg/ml) is obtained via fermentation and purification
processes performed according to methods that are well known to those skilled in the
art, or may also be obtained from Invitrogen Corporation™ (human CK1 epsilon).
The compounds are tested at five different concentrations so as to generate IC50
values, i.e. the concentration at which a compound is capable of inhibiting the
enzymatic activity by 50%, or alternatively the percentage of inhibition at a
concentration of 10 micromolar.
"U"-bottomed Falcon plates are prepared by placing 5 µL of solutions of the
compounds according to the invention at concentrations of 10, 1, 0.1, 0.01 or 0.001
uM in different wells.
The solutions of the compounds according to the invention at these various
concentrations are prepared by diluting in a test buffer (Tris 50 mM pH 7.5, MgCI2 10
M, DTT 2 mM and EGTA 1 mM) a stock solution in DMSO at a concentration of 10
mM. Next, 5 µL of dephosphorylated casein are added to a final concentration of 0.2
µg/µL, 20 µL of CK1 epsilon to a final concentration of 3 ng/µL, and 20 µL of ATP-33P
to a final concentration of 0.02 µCi/µL mixed with cold ATP (10 µM final -
approximately 2 x 106 CPM per well). The final total test volume per well is equal to 50
µL.
The "U"-bottomed Falcon® test plate mentioned above is vortexed, and then
incubated at room temperature for 2 hours. After 2 hours the reaction is stopped by
adding an ice-cold solution of 65 µL of cold ATP (2 mM) prepared in test buffer.
100 µL of the reaction mixture are then transferred from the "U"-bottomed Falcon®
plate into Millipore® MAPH filter plates, preimpregnated with 25 µL of ice-cold 100%
TCA.
The Millipore MAPH filter plates are agitated gently and are left to stand at room
temperature for at least 30 minutes to precipitate the proteins.
After 30 minutes, the filter plates are sequentially washed and filtered with 2x150 µL
of 20% TCA, 2x150 µL of 10% TCA and 2x150 µL of 5% TCA (6 washes in total per
plate/900 µL per well).
The plates are left to dry overnight at room temperature. Next, 40 µL of Microscint-20
Packard® scintillation liquid are added per well and the plates are closed in a
leaktight manner. The radiation emitted by each well is then measured for 2 minutes
in a TopCount NXT Packard® scintillation counter, in which the values of CPM/well
are measured.
The percentage inhibition of the capacity of the enzyme to phosphorylate the
substrate (casein) is determined for each concentration of test compound. These
inhibition data expressed as percentages are used to calculate the IC50 value for
each compound compared with the controls.
The kinetic studies determined the Km value for ATP as being 21 µM in this test
system.
Table 2 below gives the IC50 values for the inhibition of phosphorylation of casein
kinase 1 epsilon for a number of compounds according to the invention.
Table 2
Under these conditions, the compounds of the invention that are the most active
have IC50 values (concentrations that inhibit 50% of the enzymatic activity of casein
kinase 1 epsilon) of between 1 nM and 2 µM.
The capacity of the compounds of the invention to inhibit the phosphorylation of
casein by the casein kinases 1 epsilon and delta may be evaluated using an FRET
(Fluorescence Resonance Energy Transfer) fluorescence test with the aid of the
"Z'Lyte™ kinase assay kit" (reference PV3670; Invitrogen Corporation™) according
to the manufacturer's instructions.
The casein kinases 1 used are obtained from Invitrogen Corporation (human CK1
epsilon PV3500 and human CK1 delta PV3665).
A peptide substrate labelled at both ends with a fluorophore-donating group
(coumarin) and a fluorophore-accepting group (fluorescein) constituting an FRET
system is dephosphorylated in the presence of ATP by casein kinase 1 epsilon or
delta in the presence of increasing concentrations of compounds of the invention.
The mixture is treated with a site-specific protease that specifically cleaves the
substrate peptide to form two fluorescent fragments having a large fluorescence
emission ratio.
The fluorescence observed is thus related to the capacity of the products of the
invention to inhibit the phosphorylation of the substrate peptide by casein kinase 1
epsilon or casein kinase 1 delta.
The compounds of the invention are dissolved at different concentrations starting
with a 10 mM stock solution in DMSO diluted in a buffer containing 50 mM HEPS, pH
7.5, 1 mM EGTA, 0.01% Brij-35, 10 mM MgCI2 for casein kinase 1 epsilon and
supplemented with Trizma Base (50 mM), pH 8.0 and NaN3 (0.01% final) for casein
kinase 1 delta.
The phosphorylation of the substrate peptide SER/THR 11 obtained from Invitrogen
Corporation™ is performed at a final concentration of 2 µM. The ATP concentration
is 4 times the Km, this value being 2 µM for casein kinase 1 epsilon and 4 µM for
casein kinase 1 delta.
The emitted fluorescence is measured at wavelengths of 445 and 520 nm (excitation
at 400 nm).
Table 3 below gives the IC50 values for the inhibition of phosphorylation of casein
kinase 1 delta for a number of compounds according to the invention.

Under these conditions, the compounds of the invention that are the most active
have IC50 values (concentration that inhibits 50% of the enzymatic activity of casein
kinase 1 delta) of between 1 nM and 2 µM.
It is thus seen that the compounds according to the invention have inhibitory activity
on the enzyme casein kinase 1 epsilon or casein kinase 1 delta.
Experimental protocols for circadian cell assay
Mper1-luc Rat-1 (P2C4) fibroblast cultures were prepared by dividing the cultures
every 3-4 days (about 10-20% of confluence) on 150 cm2 degassed polystyrene
tissue culture flasks (Falcon® # 35-5001) and maintained in growth medium [EMEM
(Cellgro #10-010-CV); 10% foetal bovine serum (FBS; Gibco #16000-044); and 50
I.U./mL of penicillin-streptomycin (Cellgro #30-001-CI)] at 37°C and under 5% CO2.
Cells obtained from Rat-1 fibroblast cultures at 30-50% of confluence as described
above were co-transfected with vectors containing the selection marker for resistance
to zeocin for a stable transfection and a luciferase reporter gene directed by the
promoter mPer-1. After 24 to 48 hours, the cultures were divided on 96-well plates
and maintained in growth medium supplemented with 50-100 µg/mL of zeocin
(Invitrogen® #45-0430) for 10-14 days. The zeocin-resistant stable transfectants
were evaluated for expression of the reporter by adding to the growth medium
luciferin 100 µM (Promega® #E1603®) and by assaying the luciferase activity on a
TopCount® scintillation counter (Packard model #C384V00). The Rat-1 cell clones
expressing both zeocin resistance and luciferase activity directed by mPer1 were
serum-shock-synchronized with 50% horse serum [HS (Gibco® #16050-122)] and
the activity of the circadian reporter was evaluated. The P2C4 clone of fibroblasts
Mper1-luc Rat-1 was selected to test the compound.
The Mper1-luc Rat-1 (P2C4) fibroblasts at 40-50% of confluence obtained according
to the protocol described above were plated out onto 96-well opaque tissue culture
plates (Perkin Elmer® #6005680). The cultures are maintained in growth medium
supplemented with 100 µg/mL of zeocin (Invitrogen #45-0430) until they reached
100% of confluence (48-72 hours). The cultures were then synchronized with 100 µL
of synchronization medium [EMEM (Cellgro #10-010-CV); 100 I.U./mL of penicillin-
streptomycin (Cellgro #30-001-C1); 50% HS (Gibco #16050-122)] for 2 hours at 37°C
and under 5% CO2. After synchronization, the cultures were rinsed with 100 µL of
EMEM (Cellgro #10-010-CV) for 10 minutes at room temperature. After rinsing, the
medium is replaced with 300 µL of CO2-independent medium [CO2I (Gibco #18045-
088); L-glutamine 2 mM (Cellgro #25-005-C1); 100 U.I./mL of penicillin-streptomycin
(Cellgro #30-001-C1); luciferin 100 µM (Promega #E 1603)]. The compounds of the
invention tested for the circadian effects were added to CO2-independent medium in
DMSO at 0.3% (final concentration). The cultures were immediately closed in a
leaktight manner with TopSeal-A® film (Packard #6005185) and transferred for the
luciferase activity measurement.
After synchronization, the test plates were maintained at 37°C in a tissue culture
oven (Forma Scientific Model #3914). The in vivo luciferase activity was estimated by
measuring the relative light emission on a TopCount scintillation counter (Packard
model #C384V00).
The period analysis was performed either by determining the interval between the
relative light emission minima over several days or by Fourier transform. The two
methods produced a virtually identical period estimation on a range of circadian
periods. The power is given in EC Delta (t+1h), which is presented as the effective
micromolar concentration that induce a 1-hour prolongation of the period. The data
were analysed by adjusting a hyperbolic curve to the data expressed as change of
period (y-axis) as a function of the concentration of the test compound (x-axis) in the
XLfit™ software and the EC Delta (t+1h) was interpolated from this curve.
Table 4 below gives the EC Delta (t+1h) for a number of compounds according to the
invention.

Under these conditions, the compounds of the invention that are the most active
have EC Delta (t+1h) values (effective micromolar concentration that induced a 1-
hour prolongation of the period) of between 1 nM and 2 µM.
By inhibiting the enzymes CKIepsilon and/or CK1 delta, the compounds that are the
subject of the invention modulate the circadian periodicity, and may be useful for
treating circadian rhythm disorders.
The compounds according to the invention may especially be used for the
preparation of a medicament for preventing or treating sleep disorders; circadian
rhythm disorders, especially such as those caused by jetlag or shift work.
Among the sleep disorders that are especially distinguished are primary sleep
disorders such as dyssomnia (for example primary insomnia), parasomnia,
hypersomnia (for example excessive somnolence), narcolepsy, sleep disorders
related to sleep apnoeia, sleep disorders related to the circadian rhythm and other
unspecified dyssomnias, sleep disorders associated with medical/psychiatric
disorders.
The compounds that are the subject of the invention also cause a circadian phase
shift and such a property may be useful in the context of a potential monotherapy or
combined therapy that is clinically effective in the case of mood disorders.
Among the mood disorders that are especially distinguished are depressive disorders
(unipolar depression), bipolar disorders, mood disorders caused by a general
medical complaint and also mood disorders induced by pharmacological substances.
Among the bipolar disorders that are especially distinguished are bipolar I disorders
and bipolar II disorders, especially including seasonal affective disorders.
The compounds that are the subject of the invention, which modulate the circadian
periodicity, may be useful in the treatment of anxiety and depressive disorders
caused in particular by an impairment in the secretion of CRF.
Among the depressive disorders that are especially distinguished are major
depressive disorders, dysthymic disorders and other unspecified depressive
disorders.
The compounds that are the subject of the invention, which modulate the circadian
periodicity, may be useful for preparing a medicament for treating diseases related to
dependency on abuse substances such as cocaine, morphine, nicotine, ethanol and
cannabis.
By inhibiting casein kinase 1 epsilon and/or casein kinase 1 delta, the compounds
according to the invention may be used for preparing medicaments, especially for
preparing a medicament for preventing or treating diseases related to
hyperphosphorylation of the tau protein, especially Alzheimer's disease.
These medicaments also find their use in therapy, especially in the treatment or
prevention of diseases caused or exacerbated by the proliferation of cells and in
particular of tumour cells.
As tumour cell proliferation inhibitors, these compounds are useful in the prevention
and treatment of liquid tumours such as leukaemias, solid tumours that are both
primary and metastatic, carcinomas and cancers, in particular: breast cancer; lung
cancer; small intestine cancer and colorectal cancer; cancer of the respiratory
pathways, of the oropharynx and of the hypopharynx; cancer of the oesophagus; liver
cancer, stomach cancer, cancer of the bile ducts, cancer of the bile vesicle,
pancreatic cancer; cancers of the urinary pathways including the kidney, urothelium
and bladder; cancers of the female genital tract, including cancer of the uterus, of the
cervix, of the ovaries, choriocarcinoma and trophoblastoma; cancers of the male
genital tract, including cancer of the prostate, of the seminal vesicles, of the testicles
and germinal cell tumours; cancers of the endocrine glands, including cancer of the
thyroid, of the pituitary and of the adrenal glands; skin cancers including
haemiangiomas, melanomas and sarcomas, including Kaposi's sarcoma; brain,
nerve, eye or meningeal tumours, including astrocytomas, gliomas, glioblastomas,
retinoblastomas, neurinomas, neuroblastomas, schwannomas and meningiomas;
malignant haematopoietic tumours; leukaemias (Acute Lymphocytic Leukaemia
(ALL), Acute Myeloid Leukaemia (AML), Chronic Myeloid Leukaemia (CML), Chronic
lymphocytic leukaemia (CLL)) chloromas, plasmocytomas, T or B cell leukaemias,
Hodgkin or non-Hodgkin lymphomas, myelomas and various malignant
haemopathies.
The compounds according to the invention may also be used for the preparation of
medicaments, especially for the preparation of a medicament for preventing or
treating inflammatory diseases especially such as inflammatory diseases of the
central nervous system, for instance multiple sclerosis, encephalitis, myelitis and
encephalomyelitis, and other inflammatory diseases, for instance vascular
pathologies, atherosclerosis, joint inflammations, arthrosis and rheumatoid arthritis.
The compounds according to the invention may thus be used for the preparation of
medicaments, in particular of medicaments for inhibiting casein kinase 1 epsilon
and/or casein kinase 1 delta.
Thus, according to another of its aspects, a subject of the invention is medicaments
comprising a compound of formula (I), or an addition salt thereof with a
pharmaceutically acceptable acid, or alternatively a hydrate or solvate of the
compounds of formula (I).
According to another of its aspects, the present invention relates to pharmaceutical
compositions comprising, as active principle, a compound according to the invention.
These pharmaceutical compositions contain an effective dose of at least one
compound according to the invention or a pharmaceutically acceptable salt, a
hydrate or solvate of the said compound, and also at least one pharmaceutically
acceptable excipient.
The said excipients are chosen, according to the pharmaceutical form and the
desired mode of administration, from the usual excipients known to those skilled in
the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active principle of formula (I) above, or the
possible salt, solvate or hydrate thereof, may be administered in unit administration
form, as a mixture with standard pharmaceutical excipients, to man and animals for
the prophylaxis or treatment of the above disorders or diseases.
The appropriate unit administration forms include oral-route forms such as tablets,
soft or hard gel capsules, powders, granules and oral solutions or suspensions,
sublingual, buccal, intratracheal, intraocular and intranasal administration forms,
inhalation forms, topical, transdermal, subcutaneous, intramuscular or intravenous
administration forms, rectal administration forms and implants. For topical
administration, the compounds according to the invention may be used in creams,
gels, ointments or lotions.
By way of example, a unit administration form of a compound according to the
invention in tablet form may comprise the following components:

Via the oral route, the dose of active principle administered per day may range from
0.1 to 20 mg/kg, in one or more dosage intakes.
There may be particular cases in which higher or lower dosages are appropriate;
such dosages are not outside the context of the invention. According to the usual
practice, the dosage that is appropriate to each patient is determined by the
practitioner according to the mode of administration and the weight and response of
the said patient.
According to another of its aspects, the present invention also relates to a method for
treating the pathologies indicated above, which comprises the administration to a
patient of an effective dose of a compound according to the invention, or a
pharmaceutically acceptable salt or hydrate or solvate thereof.
Claims
1. Compound of general formula (I)

in which:
- R2 represents a pyridyl group optionally substituted with one or more substituents
chosen from halogen atoms and groups C1-6-alkyl;
- R3 represents a hydrogen atom or a group C1-3-alkyl;
- A represents a group C1-7-alkylene optionally substituted with one or two groups Ra;
- B represents a group C1-7-alkylene optionally substituted with a group Rb;
- L represents either a nitrogen atom optionally substituted with a group Rc or Rd, or a
carbon atom substituted with a group Re1 and a group Rd or two groups Re2;
the carbon atoms of A and B being optionally substituted with one or more groups Rf,
which may be identical to or different from each other;
Ra, Rb and Rc are defined such that:
two groups Ra may together form a group C1-6-alkylene;
Ra and Rb may together form a bond or a group C1-6-alkylene;
Ra and Rc may together form a bond or a group C1-6-alkylene;
Rb and Rc may together form a bond or a group C1-6-alkylene;
Rd represents a group chosen from a hydrogen atom and groups C1-6-alkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkyloxy-C1-6-
alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl or hydroxy-C1-6-alkyl;
Re1 represents a group -NR4R5 or a cyclic monoamine optionally comprising an
oxygen atom, the cyclic monoamine being optionally substituted with one or
more substituents chosen from a fluorine atom and groups C1-6-alkyl, C1-6-
alkyloxy or hydroxy I;
two Re2 form, with the carbon atom that bears them, a cyclic monoamine optionally
comprising an oxygen atom, this cyclic monoamine being optionally substituted
with one or more groups Rf, which may be identical to or different from each
other;
Rf represents a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-
alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl;
R4 and R5 represent, independently of each other, a hydrogen atom or a group C1-6-
alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl;
R7 and R8 represent, independently of each other, a hydrogen atom or a group C1-6-
alkyl;
in the form of the base or of an acid-addition salt.
2. Compound of general formula (I) according to Claim 1, characterized in that:
- L represents either a nitrogen atom optionally substituted with a group Rc or Rd, or a
carbon atom substituted with a group Re1 and a group Rd.
3. Compound of general formula (I) according to any one of the preceding claims,
characterized in that:
- R2 represents a pyridyl group, optionally substituted with one or more substituents
chosen from fluorine and a methyl group.
4. Compound of general formula (I) according to any one of the preceding claims,
characterized in that:
R7 and R8 represent a hydrogen atom or a group C1-6-alkyl.
5. Compound of general formula (I) according to any one of the preceding claims,
characterized in that:
- A represents a group C1-7-alkylene optionally substituted with one or two groups Ra;
- B represents a group C1-7-alkylene optionally substituted with a group Rb;
- L represents a nitrogen atom optionally substituted with a group Rc or Rd;
the carbon atoms of A and B being optionally substituted with one or more groups Rf,
which may be identical to or different from each other;
Ra, Rb and Rc are defined such that:
two groups Ra may together form a group C1-6-alkylene;
Ra and Rb may together form a bond or a group C1-6-alkylene;
Ra and Rc may together form a bond or a group C1-6-alkylene;
Rb and Rc may together form a bond or a group C1-6-alkylene;
Rd represents a group chosen from a hydrogen atom and groups C1-6-alkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkyloxy-C1-6-
alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl or hydroxy-C1-6-alkyl;
Rf represents a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-
alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl.
6. Compound of general formula (I) according to any one of the preceding claims,
characterized in that:
- A represents a group C1-7-alkylene optionally substituted with one or two groups Ra;
- B represents a group C1-7-alkylene optionally substituted with a group Rb;
- L represents a carbon atom substituted with a group Re1 and a group Rd;
the carbon atoms of A and B being optionally substituted with one or more groups Rf,
which may be identical to or different from each other;
Ra, Rb and Rc are defined such that:
two groups Ra may together form a group C1-6-alkylene;
Ra and Rb may together form a bond or a group C1-6-alkylene;
Ra and Rc may together form a bond or a group C1-6-alkylene;
Rb and Rc may together form a bond or a group C1-6-alkylene;
Rd represents a group chosen from a hydrogen atom and groups C1-6-alkyl, C3-7-
cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl, C1-6-alkyloxy-C1-6-
alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl or hydroxy-C1-6-alkyl;
Re1 represents a group -NR4R5 or a cyclic monoamine optionally comprising an
oxygen atom, the cyclic monoamine being optionally substituted with one or
more substituents chosen from a fluorine atom and groups C1-6-alkyl, C1-6-
alkyloxy or hydroxyl;
Rf represents a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-
alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl;
R4 and R5 represent, independently of each other, a hydrogen atom or a group Ch-
alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl.
7. Compound of general formula (I) according to any one of the preceding claims,
characterized in that:
- the cyclic amine formed by -N-A-L-B- represents a (3S)-3-methylpiperazin-1-yl, 3,3-
dimethylpiperazin-1-y, 4-isopropylpiperazin-1-yl, piperazin-1-yl, (3R)-3-
isopropylpiperazin-1-yl, (c/s)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl or 4-
pyrrolidin-1 -ylpiperidin-1 -yl group;
- R2 represents a pyridyl group, optionally substituted with one or more substituents
chosen from fluorine and a methyl group;
- R3 represents a hydrogen atom or a methyl group;
- R7 and R8 represent a hydrogen atom or a methyl group;
in the form of the base or of an acid-addition salt.
8. Process for preparing a compound of general formula (I) according to Claim 1,
characterized in that a compound of general formula (II)

in which R2, R3, R7 and R8 are as defined in Claim 1 and X6 represents a halogen, is
reacted with an amine of general formula (III)

in which A, L and B are as defined in Claim 1.
9. Process for preparing a compound of general formula (I) according to Claim 1,
characterized in that a compound of general formula (V)

in which A, L, B, R2, R7 and R8 are defined according to Claim 1, is reacted with a
mixture of a pyridine derivative of general formula (Va)

in which R3 is defined according to Claim 1 and an alkyl chloroformate, in which the
alkyl group represents a C1-6-alkyl, to obtain a compound of general formula (VI)

in which A, L, B, R2, R3, R7 and R8 are defined according to Claim 1, the said
compound of general formula (VI) is then oxidized using ortho-chloranil.
10. Process for preparing a compound of general formula (I) according to Claim 1,
characterized in that a compound of general formula (V)

in which A, L, B, R2, R7 and R8 are defined according to Claim 1, is reacted according
to an aromatic bromination or iodination reaction, to obtain a compound of general
formula (VII)

in which A, L, B, R2, R7 and R8 are defined according to Claim 1 and X3 represents a
bromine or iodine atom,
and in that a metal-catalysed coupling is carried out between the compound of
general formula (VII) obtained and a pyridine derivative of general formula (IIIa)

in which R3 is as defined in Claim 1 and M represents a trialkylstannyl group or a
dihydroxybonyl or dialkyloxyboryl group
11. Process for preparing a compound of general formula (I) according to Claim 1,
characterized in that:
a) a compound of general formula (VIII)

in which A, L, B, R7 and R8 are defined according to Claim 1, is reacted is reacted
according to an aromatic iodination reaction to obtain a compound of general formula
(IX)

in which A, L, B, R7 and R8 are defined according to Claim 1;
b) the compound of general formula (IX) obtained in a) is reacted with a compound of
general formula (IIIa)

in which R3 is defined according to Claim 1 and M represents a trialkylstannyl group
or a dihydroxyboryl or dialkyloxyboryl group, to obtain a compound of general formula
(X)

in which A, L, B, R3, R7 and R8 are defined according to Claim 1;
c) the compound of general formula (X) obtained in b) is reacted with a compound of
general formula (Xa)
R2-M (Xa)
in which R2 is defined according to Claim 1 and M represents a trialkylstannyl group
or a dihydroxyboryl or dialkyloxyboryl group, in the presence of a catalyst.
12. Medicament, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 7, in the form of the base or of a
pharmaceutically acceptable acid-addition salt.
13. Pharmaceutical composition, characterized in that it comprises a compound of
formula (I) according to any one of Claims 1 to 7, in the form of the base or of a
pharmaceutically acceptable acid-addition salt, and also at least one
pharmaceutically acceptable excipient.
14. Use of a compound of general formula (I) according to any one of Claims 1 to 12,
for the preparation of a medicament for preventing or treating sleep disorders or
circadian rhythm disorders, mood disordes, anxiety and depressive disorders,
diseases associated with dependence on abuse substances, diseases related to
hyperphosphorylation of the tau protein, diseases caused or exacerbated by cell
proliferation or inflammatory diseases.

The invention relates to derivatives of 6-cycloamino-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2b]pyridazine
with general formula (I). The invention also relates to a method for the preparation and therapeutic application thereof, in the
treatment or prevention of illnesses involving casein kinase 1 epsilon and/or casein kinase 1 delta.