6-CYCLOAMINO-3-(1H-PYRROLO[2,3-b]PYRIDIN-4-YL)IMIDAZO[1,2-b]PYRiDA2INE
DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
The present invention relates to 6-cycloamino-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine derivatives, to the preparation thereof and to the therapeutic use thereof, 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 the compounds corresponding to the general
formula (I):

in which:
- R2 represents an aryl group optionally substituted with one or more substituents chosen
from halogen atoms and C1-6-alkyl, C1-6alkyloxy, C1-6-alkylthio, C1-6-fluoroalkyl, C1-6-
fiuoroalkyloxy and -CN groups or R2 represents a C1-6-alkyl, C1-6-fluoroalkyl, C1-6-cycloalkyl
or C3-7-cycloalkyl-C1-6-alkyl group;
- A represents a C1-6-alkylene group optionally substituted with one or two Ra groups;
- B represents a C1-6-alkylene group optionally substituted with an Rb group;
- L represents either a nitrogen atom optionally substituted with an Rc or Rd group, or a
carbon atom substituted with an Re1 group and an Rd group or two Re2 groups;
the carbon atoms of A and B being optionally substituted with one or more Rf groups, which
may be identical to or different from one another;
- Ra, Rb and Rc are defined such that:
two Ra groups may together form a C1-6-alkylene group;
Ra and Rb may together form a bond or a C1-6-alkylene group;
Ra and Re may together form a bond or a C1-6alkylene group;
Rb and Rc may together form a bond or a C1-6-alkylene group;
- Rd represents a group chosen from a hydrogen atom and C1-6-alkyl, C3-7-cycloalkyl, C3-7-
cycloalkyl-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylthio-C1-6-
alkyl, C1-6-fiuoroalkyl or benzyl groups;
- Re1 represents an -NR4R5 group 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 C1-6-alkyl, C1-6-alkyloxy and hydroxy!
groups;
- two Re2 groups form, with the carbon atom that bears them, a cyclic monoamine optionally
comprising an oxygen atom, the cyclic monoamine being optionally substituted with
one or more Rf groups, which may be identical to or different from one another;
- Rf represents a 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, phenyl or benzyl group;
- R4 and R5 represent, independently of one another, a hydrogen atom or a C1-6-alkyl, C3-7-
cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl group; and
- R7 and R8 represent, independently of one another, a hydrogen atom or a C1-6-alkyl group.
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 addition salts with acids.
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 and isolating 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 molecules of water 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 C1-6-alkyl group
represents a linear or branched carbon-based chain of 1 to 7 carbon atoms, for example
a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or heptyl;
- alkylene, a linear or branched, saturated divalent alkyl group, for example a C-i^-
alkylene group represents a linear or branched divalent carbon-based chain of 1 to 6
carbon atoms, for example a methylene, ethylene, 1-methylethylene propylene or
butylene;
- cycloalkyl, a cyclic alkyl group, for example a C3-7-cycloalkyl group represents a cyclic
carbon-based group of 3 to 7 carbon atoms, for example a cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
- hydroxyl, an -OH group;
- -CN, a nitrite group;
- cyclic monoamine, a saturated cyclic or polycyclic carbon-based chain, optionally
bridged or condensed, comprising one nitrogen atom;
By way of example of a cyclic monoamine formed by N, A, L and B optionally
comprising an oxygen atom, mention may in particular be made of aziridine, azetidine,
pyrrolidine, piperidine, azepine, morpholine, homopiperidine, decahydroquinoline,
decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclononane,
azaoxobicycloheptane and azaoxobicyclooctane;
- hydroxyalkyl, an alkyl group in which one hydrogen atom has been substituted with a
hydroxyl group;
- alkyloxy, an -O-alkyl group;
- alkylthio, an -S-alkyl group;
fluoroalkyl, an alkyl group in which one or more hydrogen atoms have been substituted
with a fluorine atom;
fluoroalkyloxy, an alkyioxy group in which one or more hydrogen atoms have been
substituted 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. By way of example of an aryl group, mention may be made of phenyl or naphthyl
groups.
Among the compounds of general formula (I) that are subjects of the invention, a first group
of compounds is constituted by the compounds for which R2 represents a phenyl optionally
substituted with one or more halogen atoms or C1-6-alkyl or C1-6-fluoroalkyl groups;
A, L, B, R7 and R8 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 the compounds for which R2 represents a phenyl
optionally substituted with one or more fluorine atoms;
A, L, B, R7 and R8 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 the compounds for which R2 represents a 3-
fluorophenyl or 4-fluorophenyl;
A, L, B, R7 and R8 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 the compounds for which R2 represents a C1-6-alkyl,
C1-6-fluoroalkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl group;
A, L, B, R7 and R8 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a fifth group
of compounds is constituted by the compounds for which R2 represents a methyl group;
A, L, B, R7 and R8 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 the compounds for which R7 and R8 represent,
independently of each other, a hydrogen atom or a methyl group;
A, L, B, and R2 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 the compounds for which:
- A represents a C1-7-alkylene group optionally substituted with one or two Ra groups;
- B represents a C1-6-alkylene group optionally substituted with an Rb group;
- L represents a nitrogen atom optionally substituted with an Rc or Rd group;
the carbon atoms of A and of B being optionally substituted with one or more Rf groups,
which may be identical to or different from each other;
- two Ra groups may together form a C1-6-alkylene group;
- Ra and Rb may together form a bond or a C1-6-alkylene group;
- Ra and Rc may together form a bond or a C1-6-alkylene group;
- Rb and Rc may together form a bond or a C1-6-alkylene group;
- Rd represents a group chosen from a hydrogen atom and C1-6-alkyl, C3-7-cycloalkyl, C3-7-
cycloalkyl-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl,
C1-6-fluoroalkyl or benzyl groups; and
- Rf represents a C1-6-alkyl, C1-6-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl,
hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or phenyl group;
- Ra, Rb, Rc, R2, R7 and R8 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 the compounds for which:
- the cyclic amine formed by -N-A-L-B- represents a piperazinyl, diazabicycloheptyl,
hexahydropyrrolopyrrolyl or octahydropyrrolopyridinyl group optionally substituted with one
or more methyl, isopropyl, butylene, phenyl, benzyl, hydroxymethyl, hydroxyethyl,
hydroxypropyl, hydroxymethylpropyl or hydroxymethylbutyl groups;
- R2, 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 the compounds for which:
- the cyclic amine formed by -N-A-L-B- represents an (R)-3-methylpiperazin-1-yl, 3,3-
dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 6,9-
diazaspiro[4.5]dec-9-yl, 3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 3-
hydroxymethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, (R)-4-(2-hydroxypropyl)-
piperazin-1 -yl, (S)-4-(2-hydroxypropyl)piperazin-1 -yl, 4-(1-hydroxy-2-methylpropan-2-yl)-
piperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, 4-(3-hydroxy-3-methylbutyl)-
piperazin-1-yl, (R)-3-phenylpiperazin-1-yl, (S)-3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-
yl, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl, (cis)-5-(2-hydroxyethyl)hexahydro-
pyrrolo[3,4-c]pyrrol-2(1 H)-yl, (4aR, 7aR)-1 -methyloctahydro-6H-pyrroio[3,4-b]pyridin-6-yl,
(4aS, 7aS)-1 -methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, or (1S,4S)-5-methyl-2,5-diaza-
bicyclo[2.2.1]hept-2-yl group;
- R2, R7 and R8 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 the compounds for which:
- A represents a C1-7-alkylene group optionally substituted with one or two Ra groups;
- B represents a C1-7-alkylene group optionally substituted with an Rb group;
- L represents a carbon atom optionally substituted with two Re2 groups;
the carbon atoms of A and of B being optionally substituted with one or more Rf groups,
which may be identical to or different from each other;
- two Re2 groups 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 Rf groups, which may be identical to or different from one another; and
- Rf represents a C1-6-alkyl group;
- Ra, Rb, R2, R7 and R8 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 the compounds for which:
the cyclic amine formed by -N-A-L-B- represents a diazaspiroundecyl group;
R2, R7 and R8 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a twelfth
group of compounds is constituted by the compounds for which:
the cyclic amine formed by -N-A-L-B- represents a 2,9-diazaspiro[5.5]undec-9-yl group;
R2, R7 and R8 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a thirteenth
group of compounds is constituted by the compounds for which:
- A represents a C1-7-alkylene group;
- B represents a C1-7-alkylene group;
- L represents a carbon atom substituted with an Re1 group and an Rd group;
- Rd represents a hydrogen atom;
- Re1 represents an -NR4R5 group or a cyclic monoamine optionally comprising an oxygen
atom, the cyclic monoamine being optionally substituted with one or more Rf groups, which
may be identical to or different from one another; and
- Rf represents a C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6_alkyl group;
- R2, R7 and R8 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a fourteenth
group of compounds is constituted by the compounds for which:
- A represents a -C2H4- group;
- B represents a -C2H4- group;
- L represents a carbon atom substituted with an Re1 group and an Rd group;
- Rd represents a hydrogen atom; and
- Re1 represents a pyrrolidinyl group;
- R2, R7 and R8 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a fifteenth
group of compounds is constituted by the compounds for which:
- the cyclic amine formed by -N-A-L-B- represents a 4-(pyrrolidin-1-yl)piperidin-1-yl;
- R2, R7 and R8 being as defined above.
Among the compounds of general formula (I) that are subjects of the invention, a sixteenth
group of compounds is constituted by the compounds for which:
- R2 represents a methyl group;
- the cyclic amine formed by -N-A-L-B- represents a (3R)-3-methylpiperazin-1-yl, 3,3-
dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl or (cis)-5-
methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl group; and
- R7 and R8 represent a hydrogen atom.
Among the compounds of general formula (I) that are subjects of the invention, a
seventeenth group of compounds is constituted by the compounds for which:
- R2 represents a 3-fluorophenyl or a 4-fluorophenyl group;
- the cyclic amine formed by -N-A-L-B- represents an (R)-3-methylpiperazin-1-yl, 3,3-
dimethy!piperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 6,9-
diazaspiro[4.5]dec-9-yl, 3-phenyipiperazin-1-yl, 4-benzylpiperazin-1-yl, 3-
hydroxymethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, (R)-4-(2-hydroxypropyl)-
piperazin-1 -yl, (S)-4-(2-hydroxypropyl)piperazin-1 -yl, 4-(1 -hydroxy-2-methylpropan-2-yl)-
piperazin-1 -yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1 -yl, 4-(3-hydroxy-3-methylbutyl)-
piperazin-1-yl, (R)-3-phenylpiperazin-1-yl, (S)-3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-
yl, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl, (cis)-5-(2-hydroxyethyl)hexahydro-
pyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR, 7aR)-1 -methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,
(4aS, 7aS)-1 -methyloctahydro-6H-pyrrolo[3,4-6]pyridin-6-yl, or (1 S,4S)-5-methyl-2,5-diaza-
bicyclo[2.2.1]hept-2-yl group; and
- R7 and R8 represent, independently of each other, a hydrogen atom or a methyl group.
Among the compounds of general formula (I) that are subjects of the invention, an
eighteenth group of compounds is constituted by the compounds for which:
- R2 represents a 4-fluorophenyl group;
- the cyclic amine formed by -N-A-L-B- represents a 2,9-diazaspiro[5.5]undec-9-yl group;
and
- R7 and R8 represent a hydrogen atom.
Among the compounds of general formula (I) that are subjects of the invention, a
nineteenth group of compounds is constituted by the compounds for which:
- R2 represents a 4-fluorophenyl group;
- the cyclic amine formed by -N-A-L-B- represents a 4-(pyrrolidin-1-yl)-piperidin-1-yl group;
- R7 and R8 represent a hydrogen atom.
Among the compounds of general formula (I) that are subjects of the invention, mention
may especially be made of the following compounds:
1. 2-Methyl-6-[(R)-3-methylpiperazin-1 -yl]-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine;
2. 6-(3,3-Dimethylpiperazin-1-yl)-2-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
6]pyridazine and the trihydrochloride thereof;
3. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine and the trihydrochloride thereof;
4. 6-(4-lsopropylpiperazin-1 -yl)-2-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine and the trihydrochloride thereof;
5. 2-Methyl-6-[(cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(1H-pyrrolo[2,3-
6]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;
6. 2-(4-Fluorophenyl)-6-[(R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine;
7. {4-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-
piperazin-2-yl}methanol;
8. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(4-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine;
9. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(3-fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
10. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(4-fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
11. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine;
12. 2-{4-[2-(3-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}ethanol;
13. 2-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1 -yl}ethanol;
14. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine;
15. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-8-methyl-3-(1H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
16. (R)-1 -{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;
17. (S)-1 -{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;
18. 6-(6,9-Diazaspiro[4.5]dec-9-yl)-2-(4-fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
19. 2-{4-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-
yl]piperazin-1-yl}-2-methylpropan-1-ol;
20.1 -{4-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-
yl]piperazin-1 -yl}-2-methylpropan-2-ol;
21.1 -{4-[2-(3-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;
22.1 -{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;
23.4-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-
yl]piperazin-1-yl}-2-methylbutan-2-ol;
24. (R)-2-(4-Fluorophenyl)-6-[3-phenylpiperazin-1 -yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine and the trihydrochloride thereof;
25. (S)-2-(4-Fluorophenyl)-6-[3-phenylpiperazin-1 -yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine and the trihydrochloride thereof;
26. 2-(4-Fluorophenyl)-8-methyl-6-[3-phenylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine;
27. 6-(4-Benzylpiperazin-1 -yl)-2-(4-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine;
28. (cis)-2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)-3-(1 H-
pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
29. (cis)-2-(4-Fluorophenyl)-8-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-
yl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
30. (cis)-2-{5-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;
31. (cis)-2-{5-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;
32.2-(4-Fluorophenyl)-8-methyl-6-((4aR, 7aR)-1 -methyloctahydro-6H-pyrrolo[3,4-
6]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-d]pyridazine;
33.2-(4-Fluorophenyl)-8-rnethyl-6-((4aS, 7aS)-1 -methyloctahydro-6H-pyrrolo[3,4-
6]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
34. 2-(4-Fluorophenyl)-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(1 H-
pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
35. 9-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-
2,9-diazaspiro[5.5]undecane;
36. 2-(4-Fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine.
Another subject of the invention is a process for preparing compounds of the invention of
formula (I).
In accordance with the invention, it is possible to prepare the compounds of general
formula (I) according to the general process described in Scheme 1 below.
Generally, and as illustrated in Scheme 1, the 6-cycloamino-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine derivatives of general formula (I) in which R2, A, L, B, R7 and R8
are as defined above may be prepared from a (1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine derivative of general formula (II), in which R2, R7 and R8 are as defined above
and X6 represents a leaving group such as a halogen, by treatment using an amine of
general formula (III) in which A, L and B are as defined previously. This reaction may be
carried out by heating the reactants in a polar solvent such as pentanol or
dimethylsulphoxide.
The (1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine derivatives of general formula
(II) as defined above may be obtained from derivatives of general formula (IV) in which R2,
X6, R7 and R8 are as defined above and PG represents a protecting group for protecting an
amine function such as a sulphonate, for example tosylate or any other group normally
used for the protection of imidazole, pyrrole or indole (" Protective groups in organic
chemistry", T. W. Greene and P. G. M. Wuts, 2nd Edition, Wiley Interscience, p. 385-397).
The conversion of the derivatives of general formula (IV) is then carried out via a
deprotection reaction, for example by treatment using a base such as sodium hydroxide
when PG represents a benzene or toluenesulphonyl group.
Alternatively, the 6-cycloamino-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine
derivatives of general formula (I) may also be prepared by deprotecting a (1H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine derivative of general formula (V) in which R2, A, L, B,
R7, R8 and PG are as defined above. The conversion of the derivatives of general formula
(V) is then carried out via a deprotection reaction, for example by treatment using a base
such as sodium hydroxide when PG represents a benzene or toluenesulphonyl group.
The derivatives of general formula (V) may be prepared from derivatives of general formula
(IV) as defined above by treatment using an amine of general formula (III) in which A, L and
B are as defined previously. This reaction may be carried out by heating the reactants in a
polar solvent such as pentanol or dimethylsulphoxide.
The (1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine derivatives of general formula
(IV), in which R2, X6, R7, R8 and PG are as defined above, may be prepared by metal-
catalysed coupling according to Suzuki conditions between a 3-haloimidazo[1,2-
b]pyridazine derivative of general formula (VI) in which R2, X6, R7 and R8 are as defined
above whilst X3 represents a bromine or iodine atom and a 1H-pyrrolo[2,3-b]pyridine
derivative of general formula (VII) in which PG is as defined above and M represents a
dihydroxyboryl or dialkyloxyboryl group, most often a 4,4,5,5-tetramethyl-1,3,3,2-
dioxaborolan-2-yl group.
The couplings according to the Suzuki method are, for example, carried out by heating in
the presence of a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
and of a mineral base such as caesium carbonate, in a mixture of solvents such as dioxane
and water.
The 3-halo-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine derivatives of general
formula (VI) and the 1H-pyrrolo[2,3-b]pyridine derivatives of general formula (VII) as
defined above are known or may be prepared according to methods known to a person
skilled in the art.
In certain cases, the 6-cycloamino-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine
derivatives of general formula (I) for which the amine formed by N, L, A and B comprises a
second secondary or tertiary amine may be prepared respectively from the corresponding
primary or secondary amine by alkylation or reductive amination according to methods
customary for a person skilled in the art.
Protecting groups
In certain cases, the derivatives of general formulae (I) or (V) as defined above with an N-
A-L-B group comprising a primary or secondary amine function, may be protected during
the synthesis at this primary or secondary amine function by a protecting group, for
example a benzyl or a t-butyloxycarbonyl.
The products of general structure (I) as defined above are then obtained according to the
processes described, after a supplementary step of deprotection of the protecting group
according to the usual conditions known to the person skilled in the art.
Leaving groups
In the foregoing, the expression "leaving group" is understood to mean a group which may
be easily cleaved from a molecule by breaking a heterolysis bond, with the departure of a
pair of electrons. This group may, for example, thus be readily replaced with another group
during a substitution reaction. 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 also references for the preparation thereof are given in "Advances in Organic
Chemistry", J. March, 3rd Edition, Wiley Interscience, p. 310-316.
The following examples describe the preparation of certain compounds in accordance with
the invention. These examples are not limiting and serve only to illustrate the invention. The
numbers of the compounds exemplified refer to those given in Table 1, hereinafter, which
illustrates the chemical structures and the physical properties, respectively, of a number of
compounds according to the invention.
Example 1 (compound No. 29): (cis)-2-(4-fluorophenyl)-8-methyl-6-(5-methyl-
hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine

Step 1.1 6-Chloro-4-methylpyridazin-3-yIamine and 6-chloro-5-methylpyridazin-3-
ylamine

A mixture of 50.0 g (307 mmol) of 3,6-dichloro-4-methylpyridazine in 170 ml of aqueous
ammonia (30%) is heated at 120°C for 16 h in a steel reactor at an internal pressure of
10 bar.
The reactor is cooled and the reaction mixture is poured into 200 ml of water. The solid
formed is isolated by filtration and dried under vacuum to give 38.7 g of a mixture
containing around 45% of 6-chloro-4-methylpyridazin-3-ylamine (CAS 64068-00-4) and
55% of 6-chloro-5-methylpyridazin-3-ylamine (CAS 66346-87-0).
1H NMR (CDCI3) d: 7.20 and 6.75 (2s, 1H); (d, 0.55H); 4.9 (sl, 2H); 2.40 and 2.25 (2s,
3H) ppm.
Step 1.2 6-Chloro-2-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine and 6-chloro-
2-(4-fluorophenyl)-7-methylimidazo[1,2-b]pyridazine

The mixture of 76 g (350 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone (CAS 403-29-2)
with 38.7 g (269 mmol) of the mixture of 6-chloro-4-methylpyridazin-3-ylamine and of 6-
chloro-5-methylpyridazin-3-ylamine obtained in step 1.1 in 500 ml of n-butanol is heated at
120°C for 18 hours.
The solvent is removed by evaporation under reduced pressure and the solid is triturated in
acetone. After chilling, the solid is separated by filtration. The filtrate is concentrated under
reduced pressure and the residue is triturated in diethyl ether. After chilling, the solvent is
again separated by filtration. The two batches of solid (75 g) are combined and dissolved in
1 I of water. The solution is basified by addition of aqueous ammonia and the product is
extracted with chloroform. The organic phase is dried over sodium sulphate and the solvent
is evaporated under reduced pressure to give a red-brown solid. The separation of the two
isomers is carried out by chromatography on a silica gel column (2 x 800 g) by eluting with
dichloromethane. 21.9 g of 6-chloro-2-(4-fluorophenyl)-8-methylimidazo[1,2-b]pyridazine
are obtained in the form of a beige solid after trituration in isopropyl ether, chilling, filtration
and drying.
MP:210-212°C
1H NMR (CDCI3) d: 8.20 (s, 1H); 8.00 (dd, 2H); 7.25 (pt, 2H); 6.95 (s, 1H); 2.75 (s,
3H) ppm.
Continuing the elution with a mixture of 2% methanol in dichloromethane gives 22.0 g of 6-
chloro-2-(4-fluorophenyl)-7-methylimidazo[1,2-b]pyridazine in the form of a beige solid after
trituration in isopropyl ether, chilling, filtration and drying.
MP: 196-198°C
1H NMR (CDCI3) d: 8.15 (s, 1H); 8.00 (dd, 2H); 7.80 (s, 1H); 7.20 (pt, 2H); 2.55 (s,
3H) ppm.
Step 1.3 6-Chloro-2-(4-fluorophenyl)-3-iodo-8-methylimidazo[1,2-b]pyridazine

Added to a suspension of 21.9 g (83.7 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-
imidazo[1,2-b]pyridazine in 500 ml of chloroform are 20.4 g (126 mmol) of iodine
monochloride in solution in 40 to 50 ml of methanol. After stirring for 2 hours at ambient
temperature, 5.0 g (31 mmol) of iodine monochloride in solution in around 10 ml of
methanol are again added.
After stirring for a further 2 hours, the solution is poured over 500 ml of an aqueous solution
of sodium hydrogen carbonate and the mixture is treated, with vigorous stirring, with
sodium thiosulphate which is added in portions until the mixture is decoloured (red to
yellow).
The organic phase is separated, dried over sodium sulphate and the solvent removed by
evaporation under reduced pressure. The solid obtained is then triturated in acetonitrile, the
suspension is chilled and the solid is isolated by filtration to give 30.7 g of 6-chloro-2-(4-
fluorophenyl)-3-iodo-8-methylimidazo[1,2-b]pyridazine in the form of a beige powder.
MP:190-192°C
1H NMR (CDCI3) d: 8.05 (dd, 2H); 7.10 (pt, 2H); 6.90 (s, 1H); 2.65 (s, 3H) ppm.
Step 1.4 6-Chloro-2-(4-fluorophenyl)-8-methyl-3-[1-(phenylsulphonyl)-1 H-pyrrolo[2,3-
b]pyridin-4-yl]imidazo[1,2-b]pyridazine

Added to a mixture, which has been previously degassed and is under argon, of 5.00 g
(12.9 mmol) of 6-chloro-2-(4-fluorophenyl)-3-iodo-8-methylimidazo[1,2-b]pyridazine, 5.95 g
(15.5 mmol) of 1-(phenylsulphonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrrolo[2,3-b]pyridine (CAS 942919-24-6) and 12.6 g (38.7 mmol) of caesium carbonate in
50 ml of a mixture of tetrahydrofuran and water (9/1) are 0.95 g (1.2 mmol) of a complex of
[1,1'-bis(diphenylphosphino)ferrocene]palladium(ll) and dichioromethane.
The mixture is heated under reflux for 18 hours, then poured over 300 ml of water. The
product is extracted with dichioromethane. The organic phase is separated, dried over
sodium sulphate and the solvent is removed by evaporation under reduced pressure. The
chestnut brown solid obtained is then chromatographed over a silica gel column (200 g) by
eluting with a mixture of dichloromethane, methanol and aqueous ammonia (97/3/0.3) in
order to give 5.99 g of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-[1-(phenylsulphonyl)-1H-
pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine in the form of a yellow powder after
trituration in isopropyl ether, chilling, filtration and drying.
MP: 226-228°C
1H NMR (CDCI3) d: 8.65 (d, 1H); 8.30 (d, 2H); 7.6 (m, 7H); 7.05 (m, 3H); 6.10 (d, 1H); 2.80
(s, 3H) ppm.
Step 1.5 6-Chloro-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-d]pyridin-4-
yl)imidazo[1,2nb]pyridazine

Added to a suspension of 0.50 g (0.97 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-[1-
(phenylsulphonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine in 10 ml of a
mixture of methanol and a few ml of tetrahydrofuran is 0.32 ml (1.9 mmol) of a 6N aqueous
solution of sodium hydroxide. The mixture gradually become homogeneous and the
reaction is stirred for 30 minutes. The reaction medium is diluted with 100 ml of water and
the product is extracted with dichloromethane. The organic phase is separated, dried over
sodium sulphate and the solvent is removed by evaporation under reduced pressure. The
orange solid obtained is then chromatographed over a silica gel column (35 g) by eluting
with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to
give 0.293 g of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine in the form of a yellow powder after trituration in isopropyl ether,
chilling, filtration and drying.
MP: 226-228°C
1H NMR (CDCI3) d: 9.5 (sl, 1H); 8.40 (d, 1H); 7.55 (d, 2H); 7.30 (d, 1H); 7.2 (m, 1H); 6.9 (m,
3H); 5.90 (m, 1H); 2.70 (s, 3H) ppm.
Step 1.6 (cis)-2-(4-Fluorophenyl)-8-methyl-6-[(cis)-5-methyihexahydropyrroio[3,4-
c]pyrrol-2(1 H)-yl]-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine

In a sealed tube the mixture of 0.29 g (0.77 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-
3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine, 0.12 g (0.92 mmol) of (cis)-
octahydro-6H-2-methylpyrrolo[3,4-c]pyrrole (CAS 172739-03-6) and 0.11 ml (0.77 mmol) of
triethylamine in 4 ml of pentanol is heated at 150°C for 26 hours.
After cooling, the reaction mixture is poured into 60 ml of a 1N aqueous solution of
hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then
basified by addition of aqueous ammonia and the product is extracted with
dichloromethane. The organic phase is separated, dried over sodium sulphate and the
solvent is removed by evaporation under reduced pressure. The chestnut brown oil
obtained is then chromatographed over a silica gel column (35 g) by eluting with a mixture
of dichloromethane, methanol and aqueous ammonia (90/10/1) in order to give 0.101 g of
2-(4-fluorophenyl)-8-methyl-6-[(cis)-5-methyihexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(1H-
pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine in the form of a beige powder after
trituration in diethyl ether, chilling, filtration and drying.
MP: 255°C (decomposition)
1H NMR (DMSO-d6) d: 11.7 (s, 1H); 8.35 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H); 7.30 (d, 1H);
7.1 (pt, 2H); 6.90 (m, 1H); 5.90 (d, 1H); 3.50 (m, 2H); 3.20 (dd, 2H); 2.85 (m, 2H); 2.60 (s,
3H); 2.45 (m, 2H); 2.40 (m, 2H); 2.20 (s, 3H) ppm.
Example 2 (compound No. 1): 2-Methyl-6-[(R)-3-methylpiperazin-1-yl]-3-(1H-
pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine

Step 2.1. 6-Chloro-3-iodo-2-methylimidazo[1,2-b]pyridazine

Added to a solution of 7.00 g (41.8 mmol) of 6-chloro-2-methylimidazo[1,2-b]pyridazine
(CAS 14793-00-1) in 300 ml of chloroform, cooled to 0°C, are 10.2 g (62.7 mmol) of iodine
monochloride in solution in 20 ml of methanol. The reaction is then left at ambient
temperature for 16 hours then poured over a mixture of a 5% sodium thiosulphate solution
and of sodium hydrogen carbonate. The product is extracted with dichloromethane, the
organic phase is dried over sodium sulphate and the solvent is evaporated under reduced
pressure.
The solid residue is triturated with acetonitrile, then isolated by filtration in order to give,
after drying, 8.5 g of 6-chloro-3-iodo-2-methylimidazo[1,2-b]pyridazine in the form of a
yellow solid.
1H NMR (CDCI3) d: 7.80 (d, 1H); 7.10 (d, 1H); 2.55 (s, 3H) ppm.
Step 2.2. 6-Chloro-2-methyl-3-{1 -[(4-methylphenyl)sulphonyl]-1 H-pyrrolo[2,3-b]pyridin-
4-yl}imidazo[1,2-b]pyridazine

Added to a mixture, which has been previously degassed and is under argon, of 0.470 g
(1.60 mmol) of 6-chloro-3-iodo-2-methylimidazo[1,2-b]pyridazine, 0.765 g (1.92 mmol) of 1-
[(4-methylphenyl)sulphonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-
b]pyridine (CAS 916176-50-6) and 1.56 g (4.80 mmol) of caesium carbonate in 10 ml of a
mixture of tetrahydrofuran and water (9/1), is 0.12 g (0.14 mmol) of a complex of [1,1-
bis(diphenylphosphino)ferrocene]palladium(ll) dichloride and of dichloromethane. The
mixture is heated under reflux for 18 hours, then poured into 100 ml of water. The product
is extracted with dichloromethane. The organic phase is separated, dried over sodium
sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut
brown solid obtained is then chromatographed over an aminopropyl-grafted silica gel
column (SiNH2; 30 g) by eluting with a mixture of dichloromethane and petroleum ether
(70/30) in order to give 0.42 g of 6-chloro-2-methyl-3-{1-[(4-methylphenyl)sulphonyl]-1H-
pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a white powder.
MP: 138-140°C
1H NMR (CDCI3) d: 8.50 (d, 1H); 8.10 (d, 2H); 7.85 (d, 1H); 7.75 (d, 1H); 7.25 (d, 2H); 7.05
(d, 1H); 6.30 (d, 1H); 2.45 (s, 3H); 2.35 (s, 3H) ppm.
Step 2.3. 2-Methyl-6-[(R)-3-methylpiperazin-1 -yl]-3-{1 -[(4-methylphenyl)sulphonyl]-1 H-
pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine

A mixture of 0.325 g (0.97 mmol) of 6-chloro-2-methyl-3-{1-[(4-methylphenyl)sulphonyl]-1H-
pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine, 0.15 g (1.5 mmol) of {2R)-2-
methylpiperazine and 0.10 ml (0.74 mmol) of triethylamine in 5 ml of pentanol is heated
under reflux for 3 days at 150°C. The reaction medium is diluted with 100 ml of a 1N
aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The
aqueous phase is then basified by addition of aqueous ammonia and the product is
extracted with dichloromethane. The organic phase is separated, dried over sodium
sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut
brown oil obtained is then chromatographed over a silica gel column (35 g) by eluting with a
mixture of dichloromethane, methanol and aqueous ammonia (90/10/1) in order to give
0.293 g of 2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-
pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a yellow oil after drying.
1H NMR (CDCl3) d: 8.60 (d, 1H); 8.20 (d, 2H); 7.80 ( d, 1H); 7.75 (d, 1H); 7.40 (s, 1H); 7.35
(d, 2H); 6.90 (d, 1H); 6.55 (d, 1H); 3.8 (m, 2H); 2.9 (m, 1H); 2.7 (m, 3H); 2.40 (s, 3H); 2.35
(m, 1H); 2.25 (si, 1H); 0.95 (d, 3H) ppm.
Step 2.4. 2-Methyl-6-[(R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine

Added to a solution of 0.300 g (0.60 mmol) of 2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-
[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in 5 ml of
methanol is 0.20 ml (1.6 mmol) of a 6N aqueous solution of sodium hydroxide.
The mixture is heated at 60°C for 1 hour then poured into 100 ml of water. The product is
extracted with dichloromethane. The organic phase is separated, dried over sodium
sulphate and the solvent is removed by evaporation under reduced pressure. The residue
obtained is then chromatographed over a silica gel column (15 g) by eluting with a mixture
of dichloromethane, methanol and aqueous ammonia (90/10/1) in order to give 0.195 g of
2-methyl-6-[(3R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine after trituration in diisopropyl ether, chilling, filtration and drying.
MP: 202-204°C
[alpha]D = + 29.0° (CH3OH, c= 0.683 g/100ml)
1H NMR (CDCI3) d: 8.35 (d, 1H); 7.80 (d, 1H); 7.50 (d, 1H); 7.30 (d, 1H); 7.20 (d, 1H); 6.30
(d, 1H); 3.85 (m, 2H); 2.9 (m, 1H); 2.7 (m, 3H); 2.40 (s, 3H); 2.35 (m, 1H); 2.2 (si, 1H); 0.95
(d, 3H) ppm.
Example 3 (compound No. 6): 2-(4-Fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-
(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine

Step 3.1. 6-Chloro-2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazine

A solution of 6.61 g (40.9 mmol) of iodine monochloride in 40 ml of chloroform is added in a
rapid dropwise manner to a solution, cooled to 0°C, of 5.20 g (21.0 mmol) of 6-chloro-2-(4-
fluorophenyl)imidazo[1,2-b]pyridazine (CAS number: 244081-70-7) in 130 ml of chloroform.
After returning to ambient temperature and after stirring for 4 hours, the mixture is treated
with a 5% aqueous solution of sodium thiosulphate. The product is extracted with
dichloromethane, the organic phase is dried by filtration over a hydrophobic filtration
cartridge and concentrated under reduced pressure. The residue is triturated in acetonitrile,
the solid is isolated after filtration and rinsing with diisopropyl ether. 5.7 g of beige powder
are isolated after drying under vacuum.
MP:215°C
1H NMR (DMSO-d6) d: 8.20 (m; 3H), 7.40 (m, 3H) ppm.
Step 3.2. 6-Chloro-2-(4-fluorophenyl)-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-
b]pyridin-4-yl}imidazo[1,2-b]pyridazine

Added to a mixture, which has been previously degassed and is under argon, of 0.782 g
(2.09 mmol) of 6-chloro-2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazine, 1.00 g
(2.51 mmol) of 1-[(4-methylphenyl)sulphonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1H-pyrrolo[2,3-b]pyridine (CAS 916176-50-6) and 2.05 g (6.28 mmol) of caesium
carbonate in 15 ml of a mixture of tetrahydrofuran and water (9/1) is 0.15 g (0.19 mmol) of
a complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride and of
dichloromethane. The mixture is heated under reflux for 18 hours, then poured into 100 ml
of water. The product is extracted with dichloromethane. The organic phase is separated,
dried over sodium sulphate and the solvent is removed by evaporation under reduced
pressure. The chestnut brown solid obtained is then chromatographed over an
aminopropyl-grafted silica gel column (SiNH2; 30 g) by eluting with a mixture of
dichloromethane and petroleum ether (70/30) in order to give 0.62 g of 6-chloro-2-(4-
fluorophenyl)-3-{1 -[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-
b]pyridazine in the form of a white powder.
MP: 244-246°C
1H NMR (CDCI3) d: 8.50 (d, 1H); 8.05 (d, 2H); 7.95 ( d, 1H); 7.55 (d, 1H); 7.4 (m, 3H); 7.25
(m, 2H); 7.10 (d, 1H); 6.30 (t, 2H); 5.95 (d, 1H); 2.35 (s, 3H) ppm.
Step 3.3. 2-(4-Fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-
methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine

A mixture of 0.330 g (0.58 mmol) of 6-chloro-2-(4-fluorophenyl)-3-{1-[(4-
methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-y!}imidazo[1,2-b]pyridazine, 0.116 g
(1.16 mmol) of (2R)-2-methylpiperazine and 0.08 ml (0.6 mmol) of triethylamine in 5 ml of
pentanol is heated under reflux for 24 hours. The reaction medium is diluted with 100 ml of
an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The
aqueous phase is then basified by addition of aqueous ammonia and the product is
extracted with dichloromethane. The organic phase is separated, dried over sodium
sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut
brown solid obtained is then purified by chromatography on a silica gel column (35 g) by
eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in
order to give 0.232 g of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-
methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form
of a yellow powder after drying.
MP: 253-256°C
1H NMR (CDCI3) d: 8.85 (d, 1H); 8.20 (d, 2H); 7.85 ( d, 1H); 7.65 (d, 1H); 7.5 (m, 3H); 7.35
(m, 2H); 7.0 (m, 3H); 6.20 (d, 1H); 3.9 (m, 2H); 3.1 (m, 1H); 2.9 (m, 3H); 2.55 (m, 1H); 2.50
(s, 3H); 1.8 (si); 1.10 (d, 3H) ppm.
Step 3.4. 2-(4-Fluorophenyl)-6-[(3R)-3-methylpiperazin-1 -yl]-3-(1H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2nb]pyridazine

Added to a solution of 0.230 g (0.40 mmol) of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-
1 -yl]-3-{1 -[(4-methylphenyl)sulphonyl]-1 H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine
obtained in step 3.3, in 5 ml of methanol, is 0.13 ml (0.76 mmol) of a 6N aqueous solution
of sodium hydroxide. The mixture is heated at 60°C for 30 minutes then poured into 100 ml
of water. The product is extracted with dichloromethane. The organic phase is separated,
dried over sodium sulphate and the solvent is removed by evaporation under reduced
pressure. The residue obtained is recrystallized in acetonitrile in order to give 0.156 g of 2-
(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine after drying.
MP: 285-287°C
[alpha]D = + 4.8° (dichloromethane, c = 0.998 g/100ml)
1H NMR (CDCI3) d: 9.3 (si, 1H); 8.35 (d, 1H); 7.85 (d, 1H); 7.50 (m, 2H); 7.30 (d, 1H); 7.15
(d, 1H); 6.085 (m, 4H); 6.0 (s, 1H); 3.80 (m, 2H); 3.45 (s, 1H); 2.95 (s, 1H); 2.80 (m, 3H);
2.40 (m,2H); 1.00 (d, 3H) ppm.
Example 4 (compound No. 13): 2-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol

Step 4.1. 2-{4-[2-(4-Fluorophenyl)-8-methyl-3-{1-[phenylsulphonyl]-1H-pyrrolo[2,3-
b)]pyridin-4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol
A mixture of 0.530 g (1.02 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-[1-
(phenylsulphonyl)-l H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2nb]pyridazine, prepared
according to the method described in step 1.4 from Example 1, 0.266 g (2.05 mmol) of 1-
(2-hydroxyethyl)piperazine (CAS 103-76-4) and 0.14 ml (1.0 mmol) of triethylamine in 5 ml
of pentanol is stirred for 2 days at 150°C. The reaction medium is diluted with 20 ml of an
aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The
aqueous phase is then basified by addition of aqueous ammonia and the product is
extracted with dichloromethane. The organic phase is separated, dried over sodium
sulphate and the solvent is removed by evaporation under reduced pressure. The brown oil
obtained is then purified by chromatography on a silica gel column (40 g) by eluting with a
mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give
0.220 g of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-{1-[phenylsulphonyl]-1H-pyrrolo[2,3-fa]pyridin-
4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol in the form of an amorphous powder
which is used in the following step.
1H NMR (CDCI3) d: 8.40 (d, 1H); 8.15 (d, 2H); 7.6-7.3 (m, 7H); 6.85 (pt, 2H); 6.65 (s, 1H);
6.05 (d, 1H); 3.6 (m, 2H); 3.3 (m, 4H); 2.6 (s, 3H); 2.5 (m, 6H) ppm.
Step 4.2. 2-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-/b]pyridin-4-
yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1 -yl}ethanol

Added to a solution of 0.22 g (0.36 mmol) of 2-{4-[2-(4-fluorophenyl)-8-methyl-3-{1-
[phenylsulphonyl]-1 H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazin-6-yl]piperazin-1 -
yl}ethanol in 5 ml of a mixture of tetrahydrofuran and methanol (1/1), is 0.12 ml (0.72 mmol)
of a 6N aqueous solution of sodium hydroxide. The mixture is heated at 50°C for 1 hour,
then poured into 20 ml of water. The product is extracted with dichloromethane. The
organic phase is separated, dried over sodium sulphate and the solvent is removed by
evaporation under reduced pressure. The yellowish residue obtained is then purified by
chromatography on a silica gel column (40 g) by eluting with a mixture of dichloromethane,
methanol and aqueous ammonia (95/5/0.5) in order to give 0.110 g of 2-{4-[2-(4-
fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b)]pyridin-4-yl)imidazo[2,3-b)pyridazin-6-
yl]piperazin-1-yl}ethanol after crystallization in 10 ml of acetonitrile, filtration and drying.
MP: 239-242°C
1H NMR (CDCI3) 5: 8.35 (d, 1H); 7.55 (2d, 2H); 7.40 (d, 1H); 7.30 (d, 1H); 7.20 ( s, 1H);
7.10 (pt, 2H); 5.90 (d, 1H); 4.40 (t, 1H); 3.50 (m, 2H); 3.3 (m, 4H); 2.60 (s, 3H); 2.50 (m,
4H); 2.40 (t, 2H) ppm.
Example 5 (compound No. 35): 9-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-Z>]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane

Step 5.1. Tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsuiphonyl)-1H-
pyrrolo[2,3-l)]pyridin-4-yl]imidazo[1,2-t)]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-
carboxylate

A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-
methylphenylsulphonyl)-1 H-pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared
according to the method described in step 3.2 of Example 3, 0.337 g (1.15 mmol) of tert-
butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate hydrochloride (1:1) (CAS 1023301-88-3)
and 0.224 g (1.7 mmol) of diisopropylethylamine in 2 ml of pentanol is heated under reflux
for 40 hours at 140°C. The solvent is then evaporated under reduced pressure and the
residue is purified by chromatography on a silica gel column by eluting with a gradient of
dichloromethane, methanol and aqueous ammonia (of 100/0/0 to 90/10/1) in order to give
0.190 mg of tert-butyl 9-{2-(4-fluorophenyl)-3-[1-(4-methylphenylsulphonyl)-1H-pyrrolo[2,3-
b]pyridin-4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate after
crystallization in methanol.
Step 5.2. Tert-butyl 9-[2-(4-fluorophenyl)-3-(1/-/-pyrrolo[2,3-f)]pyridin-4-yl)imidazo[1,2-
6]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane-2-carboxylate

The tert-butyl 9-{2-(4-fluorophenyl)-3-[1 -(4-methylphenylsulphonyl)-1 H-pyrrolo[2,3-b]pyridin-
4-yl]imidazo[1,2-b]pyridazin-6-yl}-2,9-diazaspiro[5.5]undecane-2-carboxylate obtained in
step 5.1 is dissolved in 3 ml of a mixture of methanol and tetrahydrofuran (2/1) and is
treated using 0.09 ml (0.54 mmol) of a 6N aqueous solution of sodium hydroxide at 60°C
for 1 and a half hours. The solvent is evaporated under reduced pressure and the residue
taken up in 3 ml of water. The product is extracted 2 times with 3 ml of dichioromethane.
The organic phase is dried over sodium sulphate and the solvent is removed by
evaporation under reduced pressure. The residue obtained is then purified by
chromatography on a silica gel column (4 g) by eluting with a gradient of dichioromethane,
methanol and aqueous ammonia (of 95/5/05 to 90/10/1) in order to give 0.06 g of tert-butyl
9-[2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-
diazaspiro[5.5]undecane-2-carboxylate after crystallization in 10 ml of acetonitrile, filtration
and drying.
MP:192-193°C
M+H = 582
1H NMR (DMSO-d6) d: 8.35 (d, 1H); 7.95 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H); 7.30 (m, 2H);
7.10 (pt, 2H); 5.85 (d, 1H); 3.55 (si); 3.40-3.10 (m); 1.2-15 (m) ppm.
Step 5.3. 9-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane

0.20 mg (0.34 mmol) of tert-butyl 9-[2-(4-fiuorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane-2-carboxylate are treated with
5 ml of aqueous 3N hydrochloric acid over 18 hours at ambient temperature. The reaction
medium is poured into 20 ml of water and is neutralized by addition of concentrated sodium
hydroxide. The product is then extracted with dichioromethane, then the organic phase is
dried over sodium sulphate and the solvent is removed by evaporation under reduced
pressure.
The residue obtained is then purified by chromatography on a silica gel column by eluting
with a mixture of dichioromethane, methanol and aqueous ammonia (90/10/1) in order to
give 0.07 g of 9-[2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-ib]pyridazin-
6-yl]-2,9-diazaspiro[5.5]undecane.
MP: 279-280°C
1H NMR (DMSO-dg) 5: 11.7 (s, 1H); 8.35 (d, 1H); 7.95 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H);
7.30 (m, 2H); 7,10 (pt, 2H); 5.90 (d, 1H); 3.4-3.25 (2m, 4H); 2.6 (m, 4H); 1.6-1.35 (2m, 8H)
ppm.
Example 6 (compound No. 36): 2-(4-Fluorophenyl)-6-(4-pyrrolidin-1 -ylpiperidin-1 -yl)-
3-(1 W-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-fc]pyridazine

Step 6.1. 2-(4-Fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-[1-(4-
methylphenylsulphonyl)-1H-pyrroio[2,3-b]pyridin-4-yl]imidazo[1,2-d]pyridazine

A mixture of 0.15 g (0.29 mmol) of 6-chloro-2-(4-fluorophenyl)-3-[1-(4-
methylphenylsulphonyl)-1 H-pyrrolo[2,3-fa]pyridin-4-yl]imidazo[1,2-b]pyridazine, prepared
according to the method described in step 3.2 of Example 3, and 0.179 g (1.16 mmol) of 4-
pyrrolidin-1-ylpiperidine is heated under reflux for 40 hours at 140°C. The reaction medium
is cooled. The crystalline solid which forms on cooling is triturated in 1 ml of diisopropyl
ether and is isolated by centrifugation and removal of the supernatant in order to give
0.144 g of 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-[1-(4-
methylphenylsulphonyl)-1H-pyrrolo[2,3-/b]pyridin-4-yl]imidazo[1,2-b]pyridazine, used without
additional purification in the remainder of the synthesis.
M+H = 636
Step 6.2. 2-(4-Fluorophenyl)-6-(4-pyrrolidin-1 -ylpiperidin-1 -yl)-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine

The 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-[1-(4-methyiphenylsulphonyl)-1H-
pyrrolo[2,3-b]pyridin-4-yl]imidazo[1,2-b]pyridazine obtained in step 6.1 is dissolved in 3 ml
of a mixture of methanol and tetrahydrofuran (2/1), then treated using 0.09 ml (0.54 mmol)
of a 6N aqueous solution of sodium hydroxide at 60°C for 1 and a half hours. The solvent is
evaporated and the residue taken up in 3 ml of water. The product is extracted 2 times with
3 ml of dichloromethane. The organic phase is dried over sodium sulphate and the solvent
is removed by evaporation under reduced pressure. The residue obtained is then purified
by chromatography over a silica gel column (4 g) by eluting with a gradient of
dichloromethane, methanol and aqueous ammonia (of 95/5/05 to 90/10/1) in order to give
0.064 g of 2-(4-fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-(1H-pyrrolo[2,3-fa]pyridin-4-
yl)imidazo[1,2-b]pyridazine after crystallization in 10 ml of acetonitrile, filtration and drying.
MP:261-264°C
M+H = 582
1H NMR (DMSO-d6) d: 11.7 (s, 1H); 8.35 (d, 1H); 7.95 (d, 1H); 7.50 (m, 2H); 7.40 (d, 1H);
7.30 (m, 2H); 7.10 (pt, 2H); 5.85 (d, 1H); 2.9 (m, 2H); 2.45 (m, 4H); 2.15 (m, 1H); 1.85 ( m,
2H); 1.7 (m, 4H), 1.4 (m, 2H) ppm.
Example 7 (compound No. 16): (R)-1 -{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-
pyrrolo[2,3-fa]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol

Step 7.1. (R)-1-(4-Benzylpiperazin-1-yl)-2-hydroxypropan-1-one

A mixture of 10.3 g (87.2 mmol) of ethyl (R)-lactate (CAS 7699-00-5) and 15.3 g of
benzylpiperazine (CAS 2759-28-6) is heated at 150°C in a microwave oven for 2 hours.
The reaction medium is cooled and is chromatographed over a silica gel cartridge by
eluting with a mixture of ethyl acetate and methanol (99/1 then 98/2) in order to lead to 10 g
of (R)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one in the form of a brown oil.
[alpha]D = +2.4° (methanol, c = 1 g/100 ml)
1H NMR (DMSO-d6) 5: 7.35 (m, 5H); 4.45 (m, 1H); 3.85 (m, 1H); 3.7 (m, 2H); 3.55 (s, 2H);
3.45 (m, 2H); 2.5 (m, 4H); 1.35 (d, 3H) ppm.
Step 7.2. (R)-1-(4-Benzylpiperazin-1-yl)propan-2-ol

Added dropwise, over 20 minutes, to a suspension of 3.9 g (103 mmol) of lithium aluminium
hydride in 200 ml of tetrahydrofuran, at 20°C and with stirring, are 12.8 g (51.7 mmol) of
(R)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one in solution in 100 ml of
tetrahydrofuran. An increase in the temperature of the reaction medium was observed up to
35°C and the temperature of the reaction was left to drop back down to ambient
temperature. After 30 minutes, the excess of hydride is hydrolysed by addition of hydrated
sodium sulphate, the mixture is then filtered and the solid residue is washed with
tetrahydrofuran. The filtrate is concentrated under reduced pressure in order to give 11 g of
a yellow oil which is chromatographed over a silica gel cartridge by eluting with a mixture of
ethyl acetate, methanol and aqueous ammonia (95/5/0.5) in order to result in 6.4 g of (R)-1-
(4-benzylpiperazin-1-yl)propan-2-ol in the form of a yellow oil.
[alpha]D = -20.5° (methanol, c = 0.1 g/100 ml)
1H NMR (CDCI3) d: 7.25 (m, 5H); 4.20 (d, 1H); 3.70 (m, 1H); 3.45 (s, 2H); 2.4 and 2.2 (m,
10 H); 1.0 (d, 3H)ppm.
Step 7.3. (R)-1-(piperazin-1-yl)propan-2-ol dihydrochloride

A solution of 6.2 g (26.5 mmol) of (R)-1-(4-benzylpiperazin-1-yl)propan-2-ol in 60 ml of
methanol is hydrogenated under a hydrogen pressure of 60 psi at ambient temperature for
2 hours in the presence of 2.95 g of palladium hydroxide-on-carbon (CAS 12135-22-7). The
mixture is then filtered through a Buchner funnel and the filtrate is concentrated under a
reduced pressure to give 3.8 g of yellow oil. The oil is diluted in around 60 ml of
isopropanol and the solution is acidified by addition of 5-6N hydrochloric acid in solution in
isopropanol. The precipitate is stirred for 15 minutes and is isolated by filtration in order to
give, after drying, 4.97 g of (R)-1-(piperazin-1-yl)propan-2-ol dihydrochloride in the form of
a white powder.
MP: 222-224°C
[alpha]D = -29.2° (methanol, c = 1 g/100 ml)
1H NMR (CDCI3) d: 3.8 (m, 1H); 2.9 (m, 3H); 2.65 (m, 4H); 2.35 and 2.2 (m and m, 3H);
1.15 (d, 3H)ppm.
Step 7.4. (R)-1 -{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazin-6-yl]piperazin-1 -yl}propan-2-ol
I
A solution of 0.450 g (1.19 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine, prepared according to the method described in step
1.5 of Example 1, 0.517 g (2.38 mmol) of (R)-1-(piperazin-1-yl)propan-2-ol dihydrochloride
and 0.98 ml of diisopropylethylamine in 5 ml of dimethylsulphoxide is heated at 85°C for 7
days. After cooling, the reaction mixture is poured into water and the product is extracted
with ethyl acetate. The organic phase is then dried over sodium sulphate, then
concentrated under reduced pressure. The brown residue obtained is then purified by
chromatography over silica gel by eluting with a mixture of dichloromethane, methanol and
aqueous ammonia (95/5/0.5) in order to result in 0.04 g of (R)-1-{4-[2-(4-fluorophenyl)-8-
methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-
ol after recrystallization in 40 ml of acetonitrile, filtration and drying.
MP: >350°C
[alpha]D = -12.6° (methanol, c = 0.09 g/100 ml)
1H NMR (DMSO-de) 5: 11.7 (broad s, 1 H); 8.35 (d, 1H); 7.50 (m, 2H); 7.40 (m, 1H); 7.30
(dd, 1H); 7.20 (s, 1H); 7.10 (m, 2H); 5.85 (m, 1H); 4.30 (m, 1H); 3.80 (m, 1H); 3.35 (m,
4H+H20); 2.60 (s, 3H); 2.40 (m, 4H+DMSOd5); 2.25 (m, 2H); 1.05 (d, 3H).
Example 8 (compound No. 17): (S)-1 -{4-[2-{4-Fluorophenyl)-8-methyl-3-(1 H-
pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-fe]pyridazin-6-yl]piperazin-1-yl}propan-2-ol
I
Step 8.1. (S)-1 -(4-Benzylpiperazin-1 -yl)-2-hydroxypropan-1 -one

A mixture of 6.00 g (50.8 mmol) of ethyl (S)-lactate (CAS 687-47-8) and 9.85 g
(50.8 mmol) of benzylpiperazine (CAS 2759-28-6) is heated at 140°C in a microwave oven
(300W) for 1 hour. The reaction medium is cooled, then it is chromatographed over a silica
gel cartridge by eluting with a mixture of dichloromethane, methanol and aqueous ammonia
(95/5/0.5) in order to give 7 g of yellow oil. This oil is diluted in acetone and the (S)-1-(4-
benzylpiperazin-1-yl)-2-hydroxypropan-1-one hydrochloride is formed by addition of a
solution of hydrochloric acid in isopropanol. The white precipitate formed is isolated by
filtration, then it is taken up in water and treated using aqueous ammonia. The product is
then extracted using dichloromethane, the solution is dried over sodium sulphate and the
solvent evaporated under reduced pressure in order to result in 3.7 g of (S)-1-(4-benzyl-
piperazin-1-yl)-2-hydroxypropan-1-one in the form of a colourless oil.
[alpha]D = -2.2° (methanol, c = 1.56 g/100 ml)
1H NMR (CDCI3) d: 7.25 (m, 5H); 4.35 (m, 1H); 3.75 (m, 1H); 3.6 (m, 2H); 3.45 (s, 2H); 3.35
(m, 2H); 2.4 (m, 4H); 1.25 (d, 3H) ppm.
Step 8.2. (S)-1-(4-Benzylpiperazin-1-yl)propan-2-ol

Added dropwise to a suspension of 1.13 g (29.8 mmol) of lithiumaluminium hydride in 20 ml
of tetrahydrofuran, at 20°C and with stirring, are 3.70 g (14.9 mmol) of (S)-1-(4-benzyl-
piperazin-1-yl)-2-hydroxypropan-1-one in solution in 100 ml of tetrahydrofuran. The
temperature of the reaction is left to drop back down to ambient temperature. After 2 hours,
the excess hydride is hydrolysed by addition of hydrated sodium sulphate, then the mixture
is then filtered and the filtrate is concentrated under reduced pressure. The oil obtained is
chromatographed over a silica gel cartridge by eluting with a mixture of methanol and
aqueous ammonia in dichloromethane (100/0/0 to 95/5/0.5) in order to result in 1.2 g of
(S)-1-(4-benzy-piperazin-1-yl)propan-2-ol in the form of a yellow oil.
[alpha]D = +23.2° (methanol, c = 1 g/100 ml)
1H NMR (CDCI3) d: 7.3 (m, 5H); 3.85 (m, 1H); 3.65 (s, 2H); 2.8-2.2 (m, 10H) 1.15 (d, 3H)
ppm.
Step 8.3. (S)-1-(piperazin-1-yl)propan-2-ol

A solution of 1.2 g (5.1 mmol) of (S)-1-(4-benzylpiperazin-1-yl)propan-2-ol in 50 ml of
methanol is hydrogenated under a hydrogen pressure of 50 psi at ambient temperature for
2 hours in the presence of 0.6 g of palladium hydroxide. The mixture is then filtered through
a Buchner funnel and the filtrate is concentrated under reduced pressure to give 0.5 g of
yellow oil.
[alpha]D = +30.5° (methanol, c = 1 g/100 ml)
1H NMR (CDCI3) d: 3.8 (m, 1H); 2.8 (m, 4H); 2.65 -2.05 (m, 8H); 1.05 (d, 3H) ppm.
Step 8.4. (S)-1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol

A solution of 0.300 g (0.79 mmol) of 6-chloro-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine, prepared according to the method described in step
1.5 of Example 1, 0.345 g (1.59 mmol) of (S)-1-(piperazin-1-yl)propan-2-ol and 0.45 ml
(3.18 mmol) of diisopropylethylamine in 5 ml of pentanol is heated at 150°C for 8 days.
After cooling, the reaction mixture is poured into a 1N aqueous solution of hydrochloric acid
and the aqueous phase is washed with ethyl acetate. The aqueous phase is then basified
using an aqueous solution of ammonia and the product is extracted with dichloromethane.
The organic phase is then dried over sodium sulphate, then concentrated under reduced
pressure. The brown residue obtained is then purified by chromatography over a silica gel
cartridge by eluting with a mixture of dichloromethane, methanol and aqueous ammonia
(95/5/0.5) in order to result in 0.05 g of (S)-1-{4-[2-(4-fluorophenyl)-8-methyl-3-(1H-
pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol after
recrystallization in acetonitrile, filtration and drying.
MP: >350°C
[Alpha]D = +13.9° (methanol, c = 0.2 g/100 ml)
1H NMR (DMSO-d6) d: 11.7 (broad s, 1H); 8.35 (d, 1H); 7.50 (m, 2H); 7.40 (m, 1H); 7.30
(dd, 1H); 7.20 (s, 1H); 7.10 (m, 2H); 5.85 (m, 1H); 4.30 (m, 1H); 3.80 (m, 1H); 3.35 (m, 4H);
2.60 (s, 3H); 2.40 (m , 4H); 2.25 (m, 2H); 1.05 (d, 3H).
Table 1 which follows illustrates the chemical structures and the physical properties of a
number of compounds according to the invention.
In this table:
- in the column "Salt","-" represents a compound in free base form, whereas "HCI"
represents a compound in the hydrochloride form and the ratio between parentheses is the
acid:base ratio;
- the column "MP°C" reports the melting points of the products in degrees Celsius. "N.D"
means that the melting point is not determined;
- the column [a] D reports the result of the analysis of the optical rotation of the compounds
from the table at a wavelength of 589 nm; the solvent indicated between parentheses
corresponds to the solvent used to carry out the measurement of the optical rotation in
degrees and the letter "c" indicates the concentration of the solvent in g/100 ml. "N.A."
signifies that the optical rotation measurement is not applicable,
- the column "m/z" reports the molecular ion (M+H+) or (M+) observed by analysis of the
products by mass spectrometry, either by LC-MS (Liquid Chromatography coupled to Mass
Spectroscopy) carried out on an Agilent LC-MSD Trap instrument in positive ESI mode, or
by direct introduction by MS (Mass Spectroscopy) into an Autospec M (EBE) instrument
using the DCI-NH3 technique or by using the electron impact technique on a Waters GCT
instrument. The values that have an asterisk "*" correspond to the detection of the ion (M+);
- "CH3-" stands for methyl;
- "CH3OH" stands for methanol;
- "CH2CI2" stands for dichloromethane; and
- "DMSO" stands for dimethylsulphoxide.
Biological examples
The capacity of the compounds of the invention to inhibit the phosphorylation of casein by
casein kinase 1 epsilon and delta may be evaluated according to the procedure described
in US 2005/0131012.
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 with 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 various
wells. The solutions of the compounds according to the invention at these various
concentrations are prepared by diluting in a test buffer (50 mM Tris, pH 7.5, 10 M MgCI2,
2 mM DTT and 1 mM EGTA) 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
ambient temperature for 2 hours. After 2 hours, the reaction is stopped by adding an ice-
cold solution of 65 pi of ATP (2 mM) prepared in test buffer.
100 pi of the reaction mixture are then transferred from the "U"-bottomed Falcon® plate into
Millipore® MAPH filter plates, preimpregnated with 25 pi of ice-cold 100% TCA.
The Millipore MAPH filter plates are agitated gently and are left to stand at ambient
temperature for at least 30 minutes to precipitate the proteins.
After 30 minutes, the filter plates are sequentially washed and filtered with 2 x 150 µl of
20% TCA, 2 x 150 µl of 10% TCA and 2 * 150 pi of 5% TCA (6 washes in total per
plate/900 pi per well).
The plates are left to dry overnight at ambient temperature. Next, 40 pi 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 Packard®
Topcount NXT 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 compound tested. 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 uM 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 most active compounds of the invention show ICso values
(concentration which inhibits 50% of the enzymatic activity of casein kinase 1 epsilon) of
between 1 nM and 2 uM.
The capacity of the compounds of the invention to inhibit the phosphorylation of casein by
casein kinase 1 epsilon and delta may be evaluated using a 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 fluorophor donor group (coumarin) and a
fluorophor acceptor group (fluorescein) constituting a FRET system is phosphorylated 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 peptide
substrate 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 peptide substrate 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 m
MEGTA, 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 peptide substrate 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 uM for casein kinase 1 epsilon and 4 uM 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 uM.
It is thus seen that the compounds according to the invention have an inhibitory activity on
the casein kinase 1 epsilon or casein kinase 1 delta enzyme.
Experimental protocols for circadian cell assay
Mper1-luc Rat-1 (P2C4) fibroblast cultures were prepared by dividing the cultures every
3-4 days (approximately 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 controlled by the mPer-1 promoter.
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 the expression of the reporter
by adding 100 uM luciferin (Promega® # E1603®) to the growth medium and by assaying
the luciferase activity on a TopCount® scintillation counter (Packard Model # C384V00).
The Rat-1 cell clones expressing both zeocin resistance and lucerifase activity controlled
by mPerl 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 Mper1-luc
Rat-1 fibroblasts was selected to test the compound.
Mpefl-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 reach 100% of confluence (48-72 h).
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 ambient
temperature. After rinsing, the medium was replaced with 300 µl of CO2-independent
medium [CO2l (Gibco #18045-088); 2mM L-glutamine (Cellgro #25-005-C1); 100U.I./ml
of penicillin-streptomycin (Cellgro # 30-001-C1); 100 pM luciferin (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 incubator
(Forma Scientific Model # 3914). The in vivo lucerifase 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 reported in CE Delta (t+1h), which is presented as the effective micromolar concentration
that induced 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 CE Delta (t+1h)
was interpolated from this curve.
Table 4 below gives the CE 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 CE
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
subjects of the invention modulate the circadian periodicity, and may be useful for treating
circadian rhythm disorders.
The compounds according to the invention may in particular be used for the preparation of
a medicament for preventing or treating sleep disorders: circadian rhythm disorders, such
as, in particular, 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 apnoea, sleep
disorders related to the circadian rhythm and otherwise unspecified dyssomnias, sleep
disorders associated with medical/psychiatric disorders.
The compounds that are the subjects 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, including in particular seasonal affective disorders.
The compounds that are the subjects 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 otherwise unspecified depressive disorders.
The compounds that are the subjects 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 or
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, in particular for
preparing a medicament for preventing or treating diseases related to hyperphosphorylation
of the tau protein, in particular Alzheimer's disease.
These medicaments also find their use in therapy, in particular in the treatment or
prevention of diseases caused or exacerbated by the proliferation of cells, in particular
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, colorectal cancer; cancer of the respiratory pathways, of the oropharynx
and of the hypopharynx; oesophageal cancer; liver cancer, stomach cancer, cancer of the
bile ducts, cancer of the gall bladder, pancreatic cancer; cancer of the urinary tracts,
including kidney, urothelium and bladder; cancers of the female genital tract, including
cancer of the uterus, cervical cancer, ovarian cancer, chloriocarcinoma and
trophoblastoma; cancers of the male genital tract, including prostate cancer, cancer of the
seminal vesicles, testicular cancer and germinal cell tumours; cancers of the endocrine
glands, including thyroid cancer, pituitary cancer and cancer of the adrenal glands; skin
cancers, including haemangiomas, melanomas and sarcomas, including Kaposi's sarcoma;
brain, nerve, eye or meninges 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 intended for preventing or
treating inflammatory diseases, such as, in particular, 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 which
comprise a compound of formula (I), or an addition salt thereof with a pharmaceutically
acceptable acid, or alternatively a hydrate or a solvate of the compound 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 a solvate of
said compound, and also at least one pharmaceutically acceptable excipient.
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 humans 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 application, 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 reach 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 do not depart from 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 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 an aryl group optionally substituted with one or more substituents chosen
from halogen atoms and C1-6-alkyl, C1-6-alkyloxy, C1-6-alkylthio, C1-6-fluoroalkyl, C1-6-
fluoroalkyloxy and -CN groups or R2 represents a C1-6-alkyl, C1-6-fluoroalkyl, C1-6-cycloalkyl
or C3-7-cycloalkyl-C1-6-alkyl group;
- A represents a C1-6-alkylene group optionally substituted with one or two Ra groups;
- B represents a C1-7-alkylene group optionally substituted with an Rb group;
- L represents either a nitrogen atom optionally substituted with an Rc or Rd group, or a
carbon atom substituted with an Re1 group and an Rd group or two Re2 groups;
the carbon atoms of A and B being optionally substituted with one or more Rf groups, which
may be identical to or different from one another;
- Ra, Rb and Rc are defined such that:
two Ra groups may together form a C1-6-alkylene group;
Ra and Rb may together form a bond or a C1-6-alkylene group;
Ra and Rc may together form a bond or a C1-6-alkylene group;
Rb and Rc may together form a bond or a C1-6-alkylene group;
- Rd represents a group chosen from a hydrogen atom and C1-6-alkyl, C1-6-cycloalkyl, C1-6-
cycloalkyl-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylthio-C1-6-
alkyl, C1-66-fluoroalkyl or benzyl groups;
- Re1 represents an -NR4R5 group 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 C1-6-alkyl, C1-6-alkyloxy and hydroxyl
groups;
- two Re2 groups form, with the carbon atom that bears them, a cyclic monoamine optionally
comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or
more Rf groups, which may be identical to or different from one another;
- Rf represents a C1-6-alkyl, C1-6rcycloalkyl, C3-7cycloalkyl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl,
hydroxy-C1-6-alkyl, C1-6-fluoroalkyl, phenyl or benzyl group;
- R4 and R5 represent, independently of one another, a hydrogen atom or a C1-6-alkyl, C1-6r
cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl group; and
- R7 and R8 represent, independently of one another, a hydrogen atom or a C1-6-alkyl group;
in the form of a base or of an addition salt with an acid.
2. Compound of general formula (I) according to Claim 1, characterized in that:
- R2 represents a phenyl optionally substituted with one or more halogen atoms or C1-6-alkyl
or C1-6-fluoroalkyl groups.
3. Compound of general formula (I) according to Claim 1, characterized in that:
- R2 represents a group chosen from C1-6-alkyl, C1-6-fluoroalkyl, C3-7-cycloalkyl or C3-7-
cycloalkyl-C1-6-alkyl groups.
4. Compound of general formula (I) according to any one of Claims 1 to 3, characterized in
that:
- R7 and R8 represent, independently of each other, a hydrogen atom or a methyl group.
5. Compound of general formula (I) according to any one of Claims 1 to 4, characterized in
that:
- A represents a Ci.7-alkylene group optionally substituted with one or two Ra groups;
- B represents a C1-6-alkylene group optionally substituted with an Rb group;
- L represents a nitrogen atom optionally substituted with an Rc or Rd group;
the carbon atoms of A and of B being optionally substituted with one or more Rf groups,
which may be identical to or different from each other;
- two Ra groups may together form a C1-6-alkylene group;
- Ra and Rb may together form a bond or a C1-6-alkylene group;
- Ra and Rc may together form a bond or a C1-6-alkylene group;
- Rb and Rc may together form a bond or a C1-6-alkylene group;
- Rd represents a group chosen from a hydrogen atom and C1-6-alkyl, C3_7-cycloalkyl, C3-7-
cycloalkyl-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-alkylthio-C1-6-alkyl,
C1-6-fluoroalkyl or benzyl groups; and
- Rf represents a C1-6-alkyl, C1-6-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl,
hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or phenyl group.
6. Compound of general formula (I) according to any one of Claims 1 to 4, characterized in
that:
- A represents a C1-6-alkylene group optionally substituted with one or two Ra groups;
- B represents a C-1-7-alkylene group optionally substituted with an Rb group;
- L represents a carbon atom optionally substituted with two Re2 groups;
the carbon atoms of A and of B being optionally substituted with one or more Rf groups,
which may be identical to or different from each other;
- two Re2 groups 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 Rf groups, which may be identical to or different from one another; and
- Rf represents a C1-6-alkyl group.
7. Compound of general formula (I) according to any one of Claims 1 to 4, characterized in
that:
- A represents a C1-6-alkylene group;
- B represents a C1-6-alkylene group;
- L represents a carbon atom substituted with an Re1 group and an Rd group;
- Rd represents a hydrogen atom;
- Re1 represents an -NR4R5 group or a cyclic monoamine optionally comprising an oxygen
atom, the cyclic monoamine being optionally substituted with one or more Rf groups, which
may be identical to or different from one another; and
- Rf represents a C1-6-alkyl, C1-6-cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl group.
8. Compound of general formula (I) according to any one of Claims 1, 3, 4 and 5,
characterized in that:
- R2 represents a methyl group;
- the cyclic amine formed by -N-A-L-B- represents an (R)-3-methylpiperazin-1-yl, 3,3-
dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl or (cis)-5-
methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl group; and
- R7 and R8 represent a hydrogen atom.
9. Compound of general formula (I) according to any one of Claims 1, 2, 4 and 5,
characterized in that:
- R2 represents a 3-fluorophenyl or a 4-fluorophenyl group;
- the cyclic amine formed by -N-A-L-B- represents an (R)-3-methylpiperazin-1-yl, 3,3-
dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 6,9-
diazaspiro[4.5]dec-9-yl, 3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 3-
hydroxymethylpiperazin-1 -yl, 4-(2-hydroxyethyl)piperazin-1 -yl, (R)-4-(2-hydroxypropyl)-
piperazin-1-yl, (S)-4-(2-hydroxypropyl)piperazin-1-yl, 4-(1-hydroxy-2-methylpropan-2-yl)-
piperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, 4-(3-hydroxy-3-methylbutyl)-
piperazin-1-yl, (R)-3-phenylpiperazin-1-yl, (S)-3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-
yl, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl, (cis)-5-(2-hydroxyethyl)hexahydro-
pyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR, 7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl,
{4aS, 7aS) -methyloctahydro-6H-pyrrolo[3,4-6]pyridin-6-yl, or (1S,4S)-5-methyl-2,5-diaza-
bicyclo[2.2.1]hept-2-yl group; and
- R7 and R8 represent, independently of each other, a hydrogen atom or a methyl group.
10. Compound of general formula (I) according to any one of Claims 1, 2, 4 and 6,
characterized in that:
- R2 represents a 4-fluorophenyl group;
- the cyclic amine formed by -N-A-L-B- represents a 2,9-diazaspiro[5.5]undec-9-yl group;
and
- R7 and R8 represent a hydrogen atom.
11. Compound of general formula (I) according to any one of Claims 1, 2, 4 and 7,
characterized in that:
- R2 represents a 4-fluorophenyl group;
- the cyclic amine formed by -N-A-L-B- represents a 4-(pyrrolidin-1-yl)-piperidin-1-yl group;
- R7 and R8 represent a hydrogen atom..
12. Compound according to Claim 1, chosen from:
1. 2-Methyl-6-[(R)-3-methylpiperazin-1 -yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine;
2. 6-(3,3-Dimethylpiperazin-1 -yl)-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine and the trihydrochloride thereof;
3. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine and the trihydrochloride thereof;
4. 6-(4-lsopropylpiperazin-1 -yl)-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazine and the trihydrochloride thereof;
5. 2-Methyl-6-[(cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(1H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;
6. 2-(4-Fluorophenyl)-6-[(3R )-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine;
7. {4-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-
piperazin-2-yl}methanol;
8. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(4-fiuorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine;
9. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(3-fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
10. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(4-fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
11. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine;
12. 2-{4-[2-(3-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}ethanol;
13. 2-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1 -yl}ethanol;
14. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1 -yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine;
15. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-8-methyl-3-(1H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
16. (R)-1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;
17. (S)-1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;
18.6-(6,9-Diazaspiro[4.5]dec-9-yl)-2-(4-fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-
b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
19. 2-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-
yl]piperazin-1-yl}-2-methylpropan-1-ol;
20.1-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-
yl]piperazin-1-yl}-2-methylpropan-2-ol;
21. 1 -{4-[2-(3-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;
22. 1 -{4-[2-(4-Fluorophenyl)-8-methyl-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;
23.4-{4-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-
yl]piperazin-1-yl}-2-methylbutan-2-ol;
24. (R)-2-(4-Fluorophenyl)-6-[3-phenylpiperazin-1 -yl]-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine and the trihydrochioride thereof;
25. (S)-2-(4-Fluorophenyi)-6-[3-phenylpiperazin-1 -yl]-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-b]pyridazine and the trihydrochioride thereof;
26. 2-(4-Fluorophenyl)-8-methyl-6-[3-phenylpiperazin-1 -yl]-3-(1-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine;
27.6-(4-Benzyipiperazin-1 -yl)-2-(4-fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-
imidazo[1,2-o]pyridazine;
28. (cis)-2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3>4-c]pyrrol-2(1 H)-yl)-3-(1 H-
pyrrolo[2,3-fa]pyridin-4-yl)imidazo[1,2-b]pyridazine;
29. (cis)-2-(4-Fluorophenyl)-8-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-
yl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
30. (cis)-2-{5-[2-(4-Fluorophenyl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;
31. (cis)-2-{5-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-
b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;
32.2-(4-Fluorophenyl)-8-methyl-6-((4aR, 7aR)-1 -methyloctahydro-6H-pyrrolo[3,4-
b]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
33.2-(4-Fluorophenyl)-8-methyl-6-((4aS, 7aS)-1 -methyloctahydro-6H-pyrrolo[3,4-
b]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-]pyridazine;
34.2-(4-Fluorophenyl)-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(1H-
pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;
35. 9-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-
2,9-diazaspiro[5.5]undecane;
36. 2-(4-Fluorophenyl)-6-(4-pyrrolidin-1 -ylpiperidin-1 -yl)-3-(1 H-pyrrolo[2,3-b]pyridin-4-
yl)imidazo[1,2-b]pyridazine.
13. 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, R7 and R8 are as defined according to Claim 1 and X6 represents a leaving
group, is reacted with an amine of general formula (III):
H
ak ¦
in which A, L and B are as defined according to Claim 1.
14. Process for preparing a compound of general formula (I) according to Claim 1,
characterized in that a compound of general formula (V):
>
I
in which R2, A, L, B, R7 and R8 are as defined according to Claim 1 and PG represents a
benzene or toluenesulphonyl group, is deprotected using a base.
15. Medicament, characterized in that it comprises a compound of formula (I) according to
any one of Claims 1 to 12, in the form of a base or an addition salt with a pharmaceutically
acceptable acid.
16. Pharmaceutical composition, characterized in that it comprises a compound of formula
(I) according to any one of Claims 1 to 12, in the form of a base or of an addition salt with a
pharmaceutically acceptable acid, and also at least one pharmaceutically acceptable
excipient.
17. Use of a compound of general formula (I) according to any one of Claims 1 to 12, for
the preparation of a medicament intended for preventing or treating sleep disorders,
circadian rhythm disorders, mood disorders, anxiety and depressives disorders, diseases
associated with a 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 6-cycloamino-3-(1H-pyrrolo[2,3-b]pyridin-yl)imidazo[1,2-b]pyridazine derivatives
corresponding to the general formula (I) in which R2 represents an aryl group optionally substituted with one or more halogen
atoms or C1-6-alkyl, C1-6-alkyloxy, C1-6-alkylthio, C1-6-fluoroalkyl, C1-6-fluoroalkyloxy and -CN groups or R2 represents a group
chosen from C1-6-alkyl, C1-6-fluoroalkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkyl groups; A represents a C1-7-alkylen group; B
represents a C1-7-alkylene group; L represents either a nitrogen atom optionally substituted with an Rc or Rd group, or a carbon
atom substituted with an Rc1 group and an Rd group or two Rc2 groups; the carbon atoms of A and of B being optionally
substituted with one or more Rf groups, which may be identical to or different from one another. Preparation process and
therapeutic use.