HK1159088A

HK1159088A - 6-cycloamino-3-(1h-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine derivatives, preparation thereof and therapeutic use thereof

Info

Publication number: HK1159088A
Application number: HK11113362.0A
Authority: HK
Inventors: Christophe Pacaud; Frédéric Puech
Original assignee: 赛诺菲
Priority date: 2008-12-01
Filing date: 2009-11-30
Publication date: 2012-07-27

Description

6-cycloamino-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine derivatives, preparation thereof and therapeutic use thereof

Technical Field

The present invention relates to 6-cyclic amino-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine derivatives, to their preparation and to their therapeutic use in the treatment or prevention of diseases in which casein kinase 1 epsilon and/or casein kinase 1 delta is involved.

Disclosure of Invention

One subject of the present invention is a compound corresponding to general formula (I):

wherein:

-R₂represents an optionally substituted radical selected from halogen atoms and C_1-6Alkyl radical, C_1-6-alkyloxy, C_1-6-alkylthio radical, C_1-6-fluoroalkyl radical, C_1-6Aryl or R as one or more substituents of-fluoroalkoxy and-CN groups₂Is represented by C_1-6Alkyl radical, C_1-6-fluoroalkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group;

-A represents optionally substituted with one or two R_aC of a radical_1-7-an alkylene group;

-B represents optionally substituted with R_bC of a radical_1-7-an alkylene group;

-L represents optionally substituted with R_cOr R_dNitrogen atom of the radical, or substituted by R_e1Group and R_dA radical or two R_e2Carbon atoms of the group;

the carbon atoms of A and B being optionally substituted by one or more R_fGroups, which may be the same or different from each other;

-R_a、R_band R_cAs defined below:

two R_aThe radicals may together form C_1-6-an alkylene group;

R_aand R_bMay together form a chemical bond or C_1-6-an alkylene group;

R_aand R_cMay together form a chemical bond or C_1-6-an alkylene group;

R_band R_cMay together form a chemical bond or C_1-6-an alkylene group;

-R_drepresents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-alkyloxy-C_1-6Alkyl radical, C_1-6-alkylthio-C_1-6Alkyl radical, C_1-6-fluoroalkyl or benzyl radicals；

-R_e1represents-NR₄R₅A radical or a cyclic monoamine optionally containing an oxygen atom, optionally substituted with a group chosen from fluorine atoms, C_1-6Alkyl radical, C_1-6-one or more substituents of alkyloxy and hydroxy;

two R_e2The radicals forming, with the carbon atom bearing them, a cyclic monoamine optionally containing an oxygen atom, optionally substituted with one or more R_fGroups, which may be the same or different from each other;

-R_fis represented by C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_1-6-alkyloxy-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-fluoroalkyl, phenyl or benzyl;

-R₄and R₅Independently of one another, represents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group; and is

-R₇And R₈Independently of one another, represents a hydrogen atom or C_1-6-an alkyl group.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may thus exist in enantiomeric or diastereomeric forms. These enantiomers, diastereomers and mixtures thereof (including racemic mixtures) form part of the present invention.

The compounds of formula (I) may be present in the form of a base or an addition salt with an acid. Such addition salts form part of the present invention. These salts are advantageously prepared using pharmaceutically acceptable acids, but salts of other useful acids, such as those used for purification and isolation of the compounds of formula (I), also form part of the invention.

The compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. in combination or association with one or more water molecules or with a solvent. Such hydrates and solvates also form part of the present invention.

In the context of the present invention, the following definitions apply:

-C_t-zwhere t and z may take values of 1-7: a carbon chain which may have t-z carbon atoms; e.g. C_1-7Is a carbon chain which may contain 1 to 7 carbon atoms;

-an alkyl group: a linear or branched saturated aliphatic group; e.g. C_1-7Alkyl represents a linear or branched carbon chain having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl or heptyl;

-alkylene groups: a linear or branched saturated divalent alkyl group; e.g. C_1-6Alkylene represents a linear or branched divalent carbon chain of 1 to 6 carbon atoms, such as methylene, ethylene, 1-methylethylene, propylene or butylene;

-a cycloalkyl group: a cyclic alkyl group; e.g. C_3-7Cycloalkyl represents a cyclic carbon group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

-a hydroxyl group: -an OH group;

- -CN: a cyano group;

-cyclic monoamines: a saturated cyclic or polycyclic carbon chain containing 1 nitrogen atom, optionally a bridged or fused ring;

as examples of cyclic monoamines formed from N, A, L and B, optionally containing oxygen atoms, mention may be made in particular of aziridines, azetidines, pyrrolidines, piperidines, azanesMorpholine, homopiperidine, decahydroquinoline, decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclononeAlkanes, azabicycloheptanes and azabicyclooctanes;

-hydroxyalkyl: alkyl whose hydrogen atom has been substituted with hydroxyl;

-an alkyloxy group: -O-alkyl;

-alkylthio groups: -S-alkyl;

-a fluoroalkyl group: alkyl in which one or more hydrogen atoms have been substituted by fluorine atoms;

-fluoroalkyloxy group: an alkyloxy group in which one or more hydrogen atoms have been substituted with fluorine atoms;

-a halogen atom: a fluorine, chlorine, bromine or iodine atom;

-aryl: monocyclic or bicyclic aryl containing 6 to 10 carbon atoms. Examples of aryl groups include phenyl or naphthyl.

In the compounds of the general formula (I) subject of the invention, the first group of compounds consists of those for which R is₂Represents phenyl optionally substituted with one or more of the following groups: halogen atoms or C_1-6-alkyl or C_1-6-a fluoroalkyl group;

A、L、B、R₇and R₈As defined above.

Among the compounds of general formula (I) which are the subject of the present invention, the compounds of the second group are constituted by those for which R is₂Represents phenyl optionally substituted with one or more fluorine atoms;

A、L、B、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the third group of compounds consists of the compounds for which R is₂Represents a 3-fluorophenyl group or a 4-fluorophenyl group;

A、L、B、R₇and R₈As defined above.

Among the compounds of general formula (I) which are the subject of the present invention, the fourth group of compounds consists of those for which R is₂Is represented by C_1-6Alkyl radical, C_1-6-fluoroalkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group;

A、L、B、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the fifth group of compounds consists of the compounds for which R is₂Represents a methyl group;

A、L、B、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the sixth group of compounds consists of the compounds for which R is₇And R₈Independently of one another, represents a hydrogen atom or a methyl group;

A. l, B and R₂As defined above.

Among the compounds of general formula (I) subject of the present invention, the seventh group of compounds consists of the compounds for which:

-L represents optionally substituted with R_cOr R_dNitrogen atom of the group;

two R_aThe radicals may together form C_1-6-an alkylene group;

-R_aand R_bMay form a chemical bond togetherOr C_1-6-an alkylene group;

-R_aand R_cMay together form a chemical bond or C_1-6-an alkylene group;

-R_band R_cMay together form a chemical bond or C_1-6-an alkylene group;

-R_drepresents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-alkyloxy-C_1-6Alkyl radical, C_1-6-alkylthio-C_1-6Alkyl radical, C_1-6-a fluoroalkyl or benzyl group; and is

-R_fIs represented by C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_1-6-alkyloxy-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-fluoroalkyl or phenyl;

-R_a、R_b、R_c、R₂、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the eighth group of compounds consists of the compounds for which:

-the cyclic amine formed by-N-A-L-B-represents A piperazinyl, diazabicycloheptyl, hexahydropyrrolopyrrolyl or octahydropyrrolopyridinyl group, said groups being optionally substituted with one or more of the following groups: methyl, isopropyl, butylene, phenyl, benzyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl, or hydroxymethylbutyl;

-R₂、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the ninth group of compounds consists of the compounds for which:

the cyclic amine formed by-N-A-L-B-represents (R) -3-methylpiperazin-1-yl, 3-dimethylpiperazin-1-yl, (cis) -3, 5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 6, 9-diazaspiro [4.5] decan-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 (1H) -yl, (cis) -5- (2-hydroxyethyl) hexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl, methyl-1H-yl, methyl-4-methyl-1H-yl, (4aR, 7aR) -1-methyloctahydro-6H-pyrrolo [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-diazabicyclo [2.2.1] hept-2-yl;

-R₂、R₇and R₈As defined above.

In the compounds of general formula (I) subject of the present invention, a tenth group of compounds consists of the compounds for which:

-L represents optionally substituted with two R_e2Carbon atoms of the group;

two R_e2The radicals forming, with the carbon atom bearing them, a cyclic monoamine optionally containing an oxygen atom, optionally substituted with one or more R_fGroups, which may be identical to one another or notThe same is true; and is

-R_fIs represented by C_1-6-an alkyl group;

-R_a、R_b、R₂、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the eleventh group of compounds consists of the compounds for which:

the cyclic amine formed by-N-A-L-B-represents diazaspiro undecyl;

R₂、R₇and R₈As defined above.

In the compounds of general formula (I) subject of the present invention, a twelfth group of compounds consists of the compounds for which:

the cyclic amine formed by-N-A-L-B-represents 2, 9-diazaspiro [5.5] undecan-9-yl;

R₂、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the thirteenth group of compounds consists of the compounds for which:

-A represents C_1-7-an alkylene group;

-B represents C_1-7-an alkylene group;

-L represents a substitution with R_e1Group and R_dCarbon atoms of the group;

-R_drepresents a hydrogen atom;

-R_e1represents-NR₄R₅A radical or a cyclic monoamine optionally containing an oxygen atom, optionally substituted with one or more R_fGroups, which may be the same or different from each other; and is

-R_fIs represented by C_1-6-an alkyl group,C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group;

-R₂、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the fourteenth group of compounds consists of the compounds for which:

-A represents-C₂H₄-a group;

-B represents-C₂H₄-a group;

-L represents a substitution with R_e1Group and R_dCarbon atoms of the group;

-R_drepresents a hydrogen atom; and is

-R_e1Represents a pyrrolidinyl group;

-R₂、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the fifteenth group of compounds consists of compounds for which:

-the cyclic amine formed by-N-A-L-B-represents 4- (pyrrolidin-1-yl) piperidin-1-yl;

-R₂、R₇and R₈As defined above.

Among the compounds of general formula (I) subject of the present invention, the sixteenth group of compounds consists of compounds for which:

-R₂represents a methyl group;

-the cyclic amine formed by-N-A-L-B-represents (3R) -3-methylpiperazin-1-yl, 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; and is

-R₇And R₈Represents a hydrogen atom.

Among the compounds of general formula (I) subject of the present invention, the seventeenth group of compounds consists of compounds for which:

-R₂represents a 3-fluorophenyl group or a 4-fluorophenyl group;

the cyclic amine formed by-N-A-L-B-represents (R) -3-methylpiperazin-1-yl, 3-dimethylpiperazin-1-yl, (cis) -3, 5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 6, 9-diazaspiro [4.5] decan-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 (1H) -yl, (cis) -5- (2-hydroxyethyl) hexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl, methyl-1H-yl, methyl-4-methyl-1H-yl, (4aR, 7aR) -1-methyloctahydro-6H-pyrrolo [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-diazabicyclo [2.2.1] hept-2-yl; and is

-R₇And R₈Independently of one another, represents a hydrogen atom or a methyl group.

Among the compounds of general formula (I) subject of the present invention, the eighteenth group of compounds consists of the compounds for which:

-R₂represents a 4-fluorophenyl group;

-the cyclic amine formed by-N-A-L-B-represents 2, 9-diazaspiro [5.5] undecan-9-yl; and is

-R₇And R₈Represents a hydrogen atom.

Among the compounds of general formula (I) subject of the present invention, the nineteenth group of compounds consists of compounds for which:

-R₂represents a 4-fluorophenyl group;

-the cyclic amine formed from-N-A-L-B-represents 4- (pyrrolidin-1-yl) -piperidin-1-yl;

-R₇and R₈Represents a hydrogen atom.

Among the compounds of general formula (I) which are the subject of the present invention, mention may in particular be made of the following compounds:

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 its trihydrochloride salts;

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 its trihydrochloride salts;

6- (4-isopropylpiperazin-1-yl) -2-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine and its trihydrochloride salts;

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 its trihydrochloride salts;

2- (4-fluorophenyl) -6- [ (R) -3-methylpiperazin-1-yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

{4- [2- (4-fluorophenyl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazin-6-yl ] piperazin-2-yl } methanol;

6- (3, 3-dimethylpiperazin-1-yl) -2- (4-fluorophenyl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -imidazo [1,2-b ] pyridazine;

6- (3, 3-dimethylpiperazin-1-yl) -2- (3-fluorophenyl) -8-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

6- (3, 3-dimethylpiperazin-1-yl) -2- (4-fluorophenyl) -8-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

6- [ (cis) -3, 5-dimethylpiperazin-1-yl ] -2- (4-fluorophenyl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

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;

2- (4-fluorophenyl) -6- (4-isopropylpiperazin-1-yl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

2- (4-fluorophenyl) -6- (4-isopropylpiperazin-1-yl) -8-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

(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;

(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;

6- (6, 9-diazaspiro [4.5] decan-9-yl) -2- (4-fluorophenyl) -8-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

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- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazin-6-yl ] piperazin-1-yl } -2-methylpropan-2-ol;

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 } -2-methylpropan-2-ol;

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;

(R) -2- (4-fluorophenyl) -6- [ 3-phenylpiperazin-1-yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine and its trihydrochloride salts;

(S) -2- (4-fluorophenyl) -6- [ 3-phenylpiperazin-1-yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine and its trihydrochloride salts;

2- (4-fluorophenyl) -8-methyl-6- [ 3-phenylpiperazin-1-yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

6- (4-benzylpiperazin-1-yl) -2- (4-fluorophenyl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

(cis) -2- (4-fluorophenyl) -6- (5-methylhexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

(cis) -2- (4-fluorophenyl) -8-methyl-6- (5-methylhexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine;

(cis) -2- {5- [2- (4-fluorophenyl) -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;

(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;

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;

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-b ] 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-yl) piperidin-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 the preparation of the compounds of formula (I) according to the invention.

According to the present invention, the compounds of general formula (I) can be prepared according to the general method described in scheme 1 below.

Generally, and as illustrated in scheme 1, 6-cyclic amino-3- (1H-pyrrolo [2, 3-b) of formula (I)]Pyridin-4-yl) imidazo [1,2-b]Pyridazine derivatives (wherein R₂、A、L、B、R₇And R₈As defined above) may be represented by the general formula (II) (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) imidazo [1,2-b]Pyridazine derivatives (wherein R₂、R₇And R₈As defined above and X₆Representing a leaving group such as halogen) is prepared by treatment with an amine of formula (III) wherein A, L and B are as previously defined. The reaction can be carried out by heating the reactants in a polar solvent such as pentanol or dimethyl sulfoxide.

Of the general formula (II) as defined above(1H-pyrrolo [2,3-b ]]Pyridin-4-yl) imidazo [1,2-b]The pyridazine derivative may be derived from a derivative of the general formula (IV) (wherein R is₂、X₆、R₇And R₈As defined above and PG denotes a protecting group for protecting amine functions such as sulfonates, for example tosylate groups or any other group commonly used for protecting imidazoles, pyrroles or indoles ("Protective groups in organic chemistry", t.w.greene and P.G m.wuts, 2^ndEdition, Wiley Interscience, p.385-397)). Then, when PG represents a phenylsulfonyl group or a tosyl group, the conversion of the derivative of the general formula (IV) is carried out by deprotection reaction, for example, by treatment with a base such as sodium hydroxide.

Scheme 1

Alternatively, 6-cyclic amino-3- (1H-pyrrolo [2, 3-b) of formula (I)]Pyridin-4-yl) imidazo [1,2-b]Pyridazine derivatives can also be prepared by reacting (1H-pyrrolo [2,3-b ] of the formula (V)]Pyridin-4-yl) imidazo [1,2-b]Pyridazine derivatives (wherein R₂、A、L、B、R₇、R₈And PG as defined above) are deprotected. Then, when PG represents a phenylsulfonyl group or a tosyl group, the conversion of the derivative of the general formula (V) is carried out by deprotection reaction, for example, by treatment with a base such as sodium hydroxide.

The derivatives of formula (V) may be prepared from the derivatives of formula (IV) as defined above by treatment with an amine of formula (III) wherein A, L and B are as previously defined. The reaction can be carried out by heating the reactants in a polar solvent such as pentanol or dimethyl sulfoxide.

(1H-pyrrolo [2, 3-b) of the general formula (IV)]Pyridin-4-yl) imidazo [1,2-b]Pyridazine derivatives (wherein R₂、X₆、R₇、R₈And PG as defined above) can be prepared according to Suzuki conditions by reaction of compounds of the general formula (VI)3-halogenoimidazo [1,2-b ] s]Pyridazine derivatives (wherein R₂、X₆、R₇And R₈As defined above, and X₃Represents a bromine or iodine atom) and 1H-pyrrolo [2,3-b ] of the formula (VII)]Pyridine derivatives (wherein PG is as defined above and M represents a dihydroxyboronyl or dialkyloxyboronyl group, most commonly 4, 4, 5, 5-tetramethyl-1, 3, 3, 2-dioxaborolan-2-yl) are prepared by metal-catalyzed coupling between them.

For example, coupling according to the Suzuki method is carried out by heating in a solvent mixture (such as dioxane and water) in the presence of a catalyst (such as [ 11' -bis (diphenylphosphino) ferrocene ] palladium dichloride) and an inorganic base (such as cesium carbonate).

The 3-halo- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine derivatives of formula (VI) and 1H-pyrrolo [2,3-b ] pyridine derivatives of formula (VII) as defined above are known or can be prepared according to methods known to the person skilled in the art.

In some cases, 6-cyclic amino-3- (1H-pyrrolo [2,3-B ] pyridin-4-yl) imidazo [1,2-B ] pyridazine derivatives of formulA (I), wherein the amine formed from-N-A-L-B-comprises A second secondary or tertiary amine, may be prepared from the corresponding primary or secondary amine, respectively, by alkylation or reductive amination according to methods commonly used by those skilled in the art.

Protecting group

For derivatives of general formulA (I) or (V) as defined above, in case the group N-A-L-B comprises A primary or secondary amine function, it may be protected during the synthesis at the primary or secondary amine function with A protecting group (e.g. benzyl or tert-butyloxycarbonyl).

The product of general structure (I) as defined above is then obtained according to said method, after a supplementary step of deprotection of the protecting group according to conventional conditions known to the person skilled in the art.

Leaving group

In the above, the term "leaving group" is considered to mean a group which can readily cleave and carry away a pair of electron pairs from a molecule by breaking a heterolytic bond. Such a group can thus be easily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, halogens or activated hydroxyl groups such as methanesulfonyl, toluenesulfonyl, trifluoromethanesulfonyl, acetyl and the like. Examples of leaving groups and references for their preparation are given in "Advances in Organic Chemistry", J^rdEdition, Wiley Interscience, p.310-316.

The following examples describe the preparation of various compounds of the invention. These examples are not limiting and merely illustrate the invention. The numbers of the exemplified compounds are referenced to the numbers given in table 1 below, which respectively illustrate the chemical structures and physical properties of the various compounds of the present invention.

Detailed Description

Example 1 (compound 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 1.16-chloro-4-methylpyridazin-3-ylamine and 6-chloro-5-methylpyridazin-3-ylamine

A mixture of 50.0g (307mmol) of 3, 6-dichloro-4-methylpyridazine in 170ml of aqueous ammonia (30%) is heated in a steel reactor at an internal pressure of 10 bar for 16 hours at 120 ℃.

The reactor was cooled and the reaction mixture was poured into 200ml of water. The resulting solid was isolated by filtration and dried under vacuum to give 38.7g of a mixture containing about 45% of 6-chloro-4-methylpyridazin-3-ylamine (CAS64068-00-4) and 55% of 6-chloro-5-methylpyridazin-3-ylamine (CAS 66346-87-0).

¹H NMR(CDCl₃) δ: 7.20 and 6.75(2s, 1H); (d, 0.55H); 4.9(sl, 2H); 2.40 and 2.25(2s, 3H) ppm.

Step 1.26-chloro-2- (4-fluorophenyl) -8-methylimidazo [1,2-b ] pyridazine and 6-chloro-2- (4-fluorophenyl) -7-methylimidazo [1,2-b ] pyridazine

A mixture of 76g (350mmol) of 2-bromo-1- (4-fluorophenyl) ethanone (CAS 403-29-2) and 38.7g (269mmol) of the mixture of 6-chloro-4-methylpyridazin-3-ylamine and 6-chloro-5-methylpyridazin-3-ylamine obtained in step 1.1 in 500ml of n-butanol is heated at 120 ℃ for 18 hours.

The solvent was removed by evaporation under reduced pressure and the solid was triturated in acetone. After cooling, the solid was isolated by filtration. The filtrate was concentrated under reduced pressure and the residue was triturated in ether. After cooling, the solvent is separated again by filtration. The two batches of solid (75g) were combined and dissolved in 1L of water. The solution was basified by adding aqueous ammonia and the product was extracted with chloroform. The organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give a reddish brown solid. The separation of the two isomers was carried out by chromatography on a silica gel column (2x800g) (eluting with dichloromethane). After trituration in isopropyl ether, cooling, filtration and drying 21.9g of 6-chloro-2- (4-fluorophenyl) -8-methylimidazo [1,2-b ] pyridazine was obtained in the form of a beige solid.

MP：210-212℃

¹H NMR(CDCl₃)δ：8.20(s，1H)；8.00(dd，2H)；7.25(pt，2H)；6.95(s，1H)；2.75(s，3H)ppm。

Elution with a mixture of 2% methanol in dichloromethane was continued to give, after trituration in isopropyl ether, cooling, filtration and drying, 22.0g of 6-chloro-2- (4-fluorophenyl) -7-methylimidazo [1,2-b ] pyridazine in the form of a beige solid.

MP：196-198℃

¹H NMR(CDCl₃)δ：8.15(s，1H)；8.00(dd，2H)；7.80(s，1H)；7.20(pt，2H)；2.55(s，3H)ppm。

Step 1.36-chloro-2- (4-fluorophenyl) -3-iodo-8-methylimidazo [1,2-b ] pyridazine

To a suspension of 21.9g (83.7mmol) 6-chloro-2- (4-fluorophenyl) -8-methyl-imidazo [1,2-b ] pyridazine in 500ml chloroform is added a solution of 20.4g (126mmol) iodine monochloride in 40 to 50ml methanol. After stirring for 2 hours at ambient temperature, a solution of 5.0g (31mmol) of iodine monochloride in about 10ml of methanol is added again.

After stirring again for 2 hours, the solution was poured into 500ml of aqueous sodium bicarbonate solution and the mixture was treated with sodium thiosulfate while stirring vigorously, which was added in portions until the mixture was decolorized (red became yellow).

The organic phase is separated, dried over sodium sulfate and the solvent is removed by evaporation under reduced pressure. The resulting solid was then triturated in acetonitrile, the suspension cooled and the solid isolated by filtration to give 30.7g of 6-chloro-2- (4-fluorophenyl) -3-iodo-8-methylimidazo [1,2-b ] pyridazine in the form of a beige powder.

MP：190-192℃

¹H NMR(CDCl₃)δ：8.05(dd，2H)；7.10(pt，2H)；6.90(s，1H)；2.65(s，3H)ppm。

Step 1.46-chloro-2- (4-fluorophenyl) -8-methyl-3- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine

To a mixture of 5.00g (12.9mmol) of 6-chloro-2- (4-fluorophenyl) -3-iodo-8-methylimidazo [1,2-b ] pyridazine, 5.95g (15.5mmol) of 1- (phenylsulfonyl) -4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine (CAS 942919-24-6) and 12.6g (38.7mmol) of cesium carbonate in 50ml of a mixture of tetrahydrofuran and water (9/1), which had been previously degassed, were added 0.95g (1.2mmol) of a complex of [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) and dichloromethane under argon.

The mixture was heated at reflux for 18 hours and then poured into 300ml of water. The product was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The chestnut brown solid obtained is then purified by chromatography on a column of silica (200g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (97/3/0.3), triturating in isopropyl ether, cooling, filtering and drying, yielding 5.99g of 6-chloro-2- (4-fluorophenyl) -8-methyl-3- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine in the form of a yellow powder.

MP：226-228℃

¹H NMR(CDCl₃)δ：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 1.56-chloro-2- (4-fluorophenyl) -8-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine

To a suspension of 0.50g (0.97mmol) 6-chloro-2- (4-fluorophenyl) -8-methyl-3- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine in a mixture of 10ml methanol and a few ml tetrahydrofuran is added 0.32ml (1.9mmol)6N aqueous sodium hydroxide solution. The mixture gradually became homogeneous and the reaction mixture was stirred for 30 minutes. The reaction medium is diluted with 100ml of water and the product is extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The orange solid obtained is then purified by chromatography on a column of silica (35g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5), triturating in isopropyl ether, cooling, filtering and drying, yielding 0.293g 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.

MP：226-228℃

¹H NMR(CDCl₃)δ：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-methylhexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine

A mixture of 0.29g (0.77mmol) 6-chloro-2- (4-fluorophenyl) -8-methyl-3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine, 0.12g (0.92mmol) of (cis) -octahydro-6H-2-methylpyrrolo [3, 4-c ] pyrrole (CAS 172739-03-6) and 0.11ml (0.77mmol) triethylamine in 4ml pentanol is heated at 150 ℃ for 26H in a sealed tube.

After cooling, the reaction mixture was poured into 60ml of 1N aqueous hydrochloric acid solution and the solution was 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 was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting chestnut-brown oil is then purified by chromatography on a column of silica gel (35g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1), triturated in ether, cooled, filtered and dried to yield 0.101g of 2- (4-fluorophenyl) -8-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 in the form of a beige powder.

MP: 255 ℃ (decomposition)

¹H NMR(DMSO-d₆)δ：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 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

To a solution of 7.00g (41.8mmol) of 6-chloro-2-methylimidazo [1,2-b ] pyridazine (CAS 14793-00-1) in 300ml of chloroform cooled to 0 ℃ was added a solution of 10.2g (62.7mmol) of iodine monochloride in 20ml of methanol. The reaction mixture was then left at ambient temperature for 16 hours and then a mixture of 5% sodium thiosulfate solution and sodium bicarbonate was poured in. The product was extracted with dichloromethane, the organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure.

The solid residue was triturated with acetonitrile, then isolated by filtration and dried to give 8.5g of 6-chloro-3-iodo-2-methylimidazo [1,2-b ] pyridazine in the form of a yellow solid.

¹H NMR(CDCl₃)δ：7.80(d，1H)；7.10(d，1H)；2.55(s，3H)ppm。

Step 2.2.6-chloro-2-methyl-3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine

To 0.470g (1.60mmol) of 6-chloro-3-iodo-2-methylimidazo [1, 2-b), which had been previously degassed]Pyridazine, 0.765g (1.92mmol) of 1- [ (4-methylphenyl) sulfonyl]-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b]Mixture of pyridine (CAS 916176-50-6) and 1.56g (4.80mmol) of cesium carbonate in 10ml of a mixture of tetrahydrofuran and water (9/1) under argon was added 0.12g (0.14mmol) of [1, 1' -bis (diphenylphosphino) ferrocene]A complex of palladium (II) dichloride and dichloromethane. The mixture was heated at reflux for 18 hours and then poured into 100ml of water. The product was extracted with dichloromethane. The organic phase is separated and dried over sodium sulfateAnd the solvent was removed by evaporation under reduced pressure. The resulting chestnut brown solid was then applied to an aminopropyl-grafted (aminopropyl-grafted) silica gel column (SiNH)₂(ii) a 30g) Chromatography (eluting with a mixture of methylene chloride and petroleum ether (70/30)) afforded 0.42g of 6-chloro-2-methyl-3- {1- [ (4-methylphenyl) sulfonyl]-1H-pyrrolo [2,3-b]Pyridin-4-yl } imidazo [1,2-b]Pyridazine in the form of a white powder.

MP：138-140℃

¹H NMR(CDCl₃)δ：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) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine

A mixture of 0.325g (0.97mmol) 6-chloro-2-methyl-3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine, 0.15g (1.5mmol) of (2R) -2-methylpiperazine and 0.10ml (0.74mmol) triethylamine in 5ml pentanol is heated at 150 ℃ under reflux for 3 days. The reaction medium is diluted with 100ml of 1N aqueous 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 was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting chestnut-brown oil was then purified by chromatography on a column of silica gel (35g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1), to give, after drying, 0.293g of 2-methyl-6- [ (3R) -3-methylpiperazin-1-yl ] -3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine in the form of a yellow oil.

¹H NMR(CDCl₃)δ：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(sl，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

To a solution of 0.300g (0.60mmol) of 2-methyl-6- [ (3R) -3-methylpiperazin-1-yl ] -3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine in 5ml of methanol was added 0.20ml (1.6mmol) of 6N aqueous sodium hydroxide solution.

The mixture was heated at 60 ℃ for 1 hour and then poured into 100ml of water. The product was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The residue obtained is then purified by chromatography on a column of silica (15g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1), trituration in diisopropyl ether, cooling, filtration and drying to yield 0.195g of 2-methyl-6- [ (3R) -3-methylpiperazin-1-yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine.

MP：202-204℃

[α]_D＝+29.0°(CH₃OH，c＝0.683g/100ml)

¹H NMR(CDCl₃)δ：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(sl，1H)；0.95(d，3H)ppm。

Example 3 (compound 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 6.61g (40.9mmol) of iodine monochloride in 40ml of chloroform was added in a rapid dropwise addition to a solution of 5.20g (21.0mmol) of 6-chloro-2- (4-fluorophenyl) imidazo [1,2-b ] pyridazine (CAS number: 244081-70-7) in 130ml of chloroform cooled to 0 ℃. After returning to ambient temperature and stirring for 4 hours, the mixture was treated with 5% aqueous sodium thiosulfate. The product was extracted with dichloromethane and the organic phase was filtered dry on a hydrophobic cartridge and concentrated under reduced pressure. The residue is triturated in acetonitrile, filtered and the solid is isolated after washing with diisopropyl ether. After drying under vacuum, 5.7g of a beige powder are isolated.

MP：215℃

¹H NMR(DMSO-d₆)δ：8.20(m；3H)，7.40(m，3H)ppm。

Step 3.2.6-chloro-2- (4-fluorophenyl) -3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine

To 0.782g (2.09mmol) of 6-chloro-2- (4-fluorophenyl) -3-iodoimidazo [1, 2-b), which had been previously degassed]Pyridazine, 1.00g (2.51mmol) of 1- [ (4-methylphenyl) sulfonyl group]-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolePentane-2-yl) -1H-pyrrolo [2,3-b]Mixture of pyridine (CAS 916176-50-6) and 2.05g (6.28mmol) of cesium carbonate in 15ml of a mixture of tetrahydrofuran and water (9/1) under argon was added 0.15g (0.19mmol) of [1, 1' -bis (diphenylphosphino) ferrocene]A complex of palladium (II) dichloride and dichloromethane. The mixture was heated at reflux for 18 hours and then poured into 100ml of water. The product was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. Then the obtained chestnut brown solid is put on aminopropyl-grafted silica gel column (SiNH)₂(ii) a 30g) Purification by chromatography (eluting with a mixture of methylene chloride and petroleum ether (70/30)) afforded 0.62g of 6-chloro-2- (4-fluorophenyl) -3- {1- [ (4-methylphenyl) sulfonyl]-1H-pyrrolo [2,3-b]Pyridin-4-yl } imidazo [1,2-b]Pyridazine in the form of a white powder.

MP：244-246℃

¹H NMR(CDCl₃)δ：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) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine

A mixture of 0.330g (0.58mmol) 6-chloro-2- (4-fluorophenyl) -3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine, 0.116g (1.16mmol) of (2R) -2-methylpiperazine and 0.08ml (0.6mmol) triethylamine in 5ml pentanol is heated at reflux for 24 hours. The reaction medium is diluted with 100ml of aqueous 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 was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The chestnut brown solid obtained is then purified by chromatography on a column of silica gel (35g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5), and after drying 0.232g of 2- (4-fluorophenyl) -6- [ (3R) -3-methylpiperazin-1-yl ] -3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine is obtained in the form of a yellow powder.

MP：253-256℃

¹H NMR(CDCl₃)δ：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(sl)；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 [1,2-b ] pyridazine

To a solution of 0.230g (0.40mmol) of 2- (4-fluorophenyl) -6- [ (3R) -3-methylpiperazin-1-yl ] -3- {1- [ (4-methylphenyl) sulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazine obtained in step 3.3 in 5ml of methanol was added 0.13ml (0.76mmol) of a 6N aqueous solution of sodium hydroxide. The mixture was heated at 60 ℃ for 30 minutes and then poured into 100ml of water. The product was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The resulting residue was recrystallized from acetonitrile and dried to give 0.156g of 2- (4-fluorophenyl) -6- [ (3R) -3-methylpiperazin-1-yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine.

MP：285-287℃

[α]_DNot ═ 4.8 ° (dichloromethane, c not 0.998g/100ml)

¹H NMR(CDCl₃)δ：9.3(sl，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 13):2- {4- [2- (4-fluorophenyl) -8-methyl-3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) imidazo [1,2-b]Pyridazin-6-yl radicals]Piperazin-1-yl } ethanol

Step 4.1.2- {4- [2- (4-fluorophenyl) -8-methyl-3- {1- [ phenylsulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazin-6-yl ] piperazin-1-yl } ethanol

A mixture of 0.530g (1.02mmol) of 6-chloro-2- (4-fluorophenyl) -8-methyl-3- [1- (phenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine, prepared according to the process described in example 1 step 1.4, 0.266g (2.05mmol) of 1- (2-hydroxyethyl) piperazine (CAS 103-76-4) and 0.14ml (1.0mmol) of triethylamine in 5ml of pentanol is stirred at 150 ℃ for 2 days. The reaction medium is diluted with 20ml of aqueous 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 was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The brown oil obtained is then purified by chromatography on a column of silica (40g) eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) to give 0.220g of 2- {4- [2- (4-fluorophenyl) -8-methyl-3- {1- [ phenylsulfonyl ] -1H-pyrrolo [2,3-b ] 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(CDCl₃)δ：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- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazin-6-yl ] piperazin-1-yl } ethanol

To a solution of 0.22g (0.36mmol) of 2- {4- [2- (4-fluorophenyl) -8-methyl-3- {1- [ phenylsulfonyl ] -1H-pyrrolo [2,3-b ] pyridin-4-yl } imidazo [1,2-b ] pyridazin-6-yl ] piperazin-1-yl } ethanol in 5ml of a mixture of tetrahydrofuran and methanol (1/1) was added 0.12ml (0.72mmol) of 6N aqueous sodium hydroxide solution. The mixture was heated at 50 ℃ for 1 hour and then poured into 20ml of water. The product was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The yellow residue obtained is then purified by chromatography on a column of silica (40g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5), crystallized in 10ml of acetonitrile, filtered and dried to yield 0.110g of 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.

MP：239-242℃

¹H NMR(CDCl₃)δ：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 35):9- [2- (4-fluorophenyl) -3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) imidazo [1,2-b]Pyridazin-6-yl radicals]-2, 9-diazaspiro [5.5]Undecane

Step 5.1.9- {2- (4-fluorophenyl) -3- [1- (4-methylphenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazin-6-yl } -2, 9-diazaspiro [5.5] undecane-2-carboxylic acid tert-butyl ester

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

Step 5.2.9- [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-carboxylic acid tert-butyl ester

The tert-butyl 9- {2- (4-fluorophenyl) -3- [1- (4-methylphenylsulfonyl) -1H-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 3ml of a mixture of methanol and tetrahydrofuran (2/1) and treated with 0.09ml (0.54mmol) of 6N aqueous sodium hydroxide solution at 60 ℃ for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was taken up in 3ml of water. The product was extracted twice with 3ml dichloromethane. The organic phase was dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The residue obtained is then purified by chromatography on a column of silica gel (4g), eluting with a gradient of dichloromethane, methanol and aqueous ammonia (95/5/05 to 90/10/1), crystallized in 10ml of acetonitrile, filtered and dried to yield 0.06g 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.

MP：192-193℃

M+H＝582

¹H NMR(DMSO-d₆)δ：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(sl)；3.40-3.10(m)；1.2-15(m)ppm。

Step 5.3.9- [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

0.20mg (0.34mmol) 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 are treated with 5ml of 3N aqueous hydrochloric acid at ambient temperature for 18 hours. The reaction medium is poured into 20ml of water and neutralized by adding concentrated sodium hydroxide. The product was then extracted with dichloromethane, the organic phase was then dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure.

The residue obtained is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1), to give 0.07g of 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.

MP：279-280℃

¹H NMR(DMSO-d₆)δ：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 36):2- (4-fluorophenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -3- (1H-pyrrolo [2, 3-b)]Pyridin-4-yl) imidazo [1,2-b]Pyridazine

Step 6.1.2- (4-fluorophenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -3- [1- (4-methylphenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine

A mixture of 0.15g (0.29mmol) of 6-chloro-2- (4-fluorophenyl) -3- [1- (4-methylphenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine, prepared according to the method described in example 3 step 3.2, and 0.179g (1.16mmol) of 4- (pyrrolidin-1-yl) piperidine is heated at reflux at 140 ℃ for 40 hours. The reaction medium is cooled. The crystalline solid formed on cooling was triturated in 1ml diisopropyl ether and separated by centrifugation and the supernatant removed to give 0.144g of 2- (4-fluorophenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -3- [1- (4-methylphenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine, which was used without further purification in the remainder of the synthesis.

M+H＝636

Step 6.2.2- (4-fluorophenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine

2- (4-fluorophenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -3- [1- (4-methylphenylsulfonyl) -1H-pyrrolo [2,3-b ] pyridin-4-yl ] imidazo [1,2-b ] pyridazine obtained in step 6.1 is dissolved in 3ml of a mixture of methanol and tetrahydrofuran (2/1) and then treated with 0.09ml (0.54mmol) of a 6N aqueous solution of sodium hydroxide at 60 ℃ for 1.5 hours. The solvent was evaporated and the residue was taken up in 3ml of water. The product was extracted twice with 3ml dichloromethane. The organic phase was dried over sodium sulfate and the solvent was removed by evaporation under reduced pressure. The residue obtained is then purified by chromatography on a column of silica (4g) with a gradient of dichloromethane, methanol and aqueous ammonia (95/5/05 to 90/10/1) and, after crystallization in 10ml of acetonitrile, filtration and drying, 0.064g of 2- (4-fluorophenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine is obtained.

MP：261-264℃

M+H＝582

¹H NMR(DMSO-d₆)δ：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 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 radicals]Piperazin-1-yl } propan-2-ol

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

A mixture of 10.3g (87.2mmol) of (R) -ethyl lactate (CAS 7699-00-5) and 15.3g of benzylpiperazine (CAS 2759-28-6) was heated in a microwave oven at 150 ℃ for 2 hours. The reaction medium is cooled and purified by chromatography on a column of silica gel (elution with a mixture of ethyl acetate and methanol (99/1 then 98/2)) to give 10g of (R) -1- (4-benzylpiperazin-1-yl) -2-hydroxypropan-1-one in the form of a brown oil.

[α]_D2.4 ° (methanol, c 1g/100ml)

¹H NMR(DMSO-d₆)δ：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

To a suspension of 3.9g (103mmol) of lithium aluminium hydride in 200ml of tetrahydrofuran at 20 ℃ is added dropwise, with stirring, over the course of 20 minutes, a solution of 12.8g (51.7mmol) of (R) -1- (4-benzylpiperazin-1-yl) -2-hydroxypropan-1-one in 100ml of tetrahydrofuran. It was observed that the temperature of the reaction medium rose to 35 ℃ and the temperature of the reaction mixture was reduced back to ambient temperature. After 30 minutes, the excess hydride is hydrolyzed by addition of hydrated sodium sulfate, then the mixture is filtered and the solid residue is washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to give 11g of a yellow oil, which was purified by chromatography on a silica gel column (eluting with a mixture of ethyl acetate, methanol and aqueous ammonia (95/5/0.5)) to give 6.4g of (R) -1- (4-benzylpiperazin-1-yl) propan-2-ol in the form of a yellow oil.

[α]_DNot-20.5 ° (methanol, c not 0.1g/100ml)

¹H NMR(CDCl₃) δ: 7.25(m, 5H); 4.20(d, 1H); 3.70(m, 1H); 3.45(s, 2H); 2.4 and 2.2(m, 10H); 1.0(d, 3H) ppm.

Step 7.3.(R) -1- (piperazin-1-yl) propan-2-ol dihydrochloride

A solution of 6.2g (26.5mmol) of (R) -1- (4-benzylpiperazin-1-yl) propan-2-ol in 60ml of methanol was hydrogenated at 60psi of hydrogen in the presence of 2.95g of palladium hydroxide on charcoal (CAS 12135-22-7) at ambient temperature for 2 hours. The mixture was then filtered through a buchner funnel and the filtrate was concentrated under reduced pressure to give 3.8g of a yellow oil. The oil was diluted in about 60ml of isopropanol and the solution was acidified by adding a solution of 5-6N hydrochloric acid in isopropanol. The precipitate was stirred for 15 minutes and separated by filtration and dried to give 4.97g of (R) -1- (piperazin-1-yl) propan-2-ol dihydrochloride in the form of a white powder.

MP：222-224℃

[α]_DNot-29.2 ° (methanol, c not 1g/100ml)

¹H NMR(CDCl₃) δ: 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- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -imidazo [1,2-b ] pyridazin-6-yl ] piperazin-1-yl } propan-2-ol

A solution of 0.450g (1.19mmol) 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 example 1, step 1.5, 0.517g (2.38mmol) of (R) -1- (piperazin-1-yl) propan-2-ol dihydrochloride and 0.98ml of diisopropylethylamine in 5ml of dimethyl sulfoxide is heated at 85 ℃ for 7 days. After cooling, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic phase is then dried over sodium sulfate and then concentrated under reduced pressure. The brown residue obtained is then purified by chromatography on a column of silica gel (elution with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5)), recrystallised from 40ml of acetonitrile, filtered and dried to yield 0.04g 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.

MP：＞350℃

[α]_D12.6 ° (methanol, c 0.09g/100ml)

¹H NMR(DMSO-d₆) δ: 11.7 (broad singlet, 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+H₂O)；2.60(s，3H)；2.40(m，4H+DMSOd₅)；2.25(m，2H)；1.05(d，3H)。

example 8 (compound 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 radicals]Piperazin-1-yl } propan-2-ol

Step 8.1.(S) -1- (4-benzylpiperazin-1-yl) -2-hydroxypropan-1-one

A mixture of 6.00g (50.8mmol) of (S) -ethyl lactate (CAS 687-47-8) and 9.85g (50.8mmol) of benzylpiperazine (CAS 2759-28-6) was heated in a microwave oven (300W) at 140 ℃ for 1 hour. The reaction medium is cooled and then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5), to give 7g of a yellow oil. The oil was diluted in acetone and (S) -1- (4-benzylpiperazin-1-yl) -2-hydroxypropan-1-one hydrochloride was formed by adding a solution of hydrochloric acid in isopropanol. The white precipitate formed was separated by filtration, then taken up in water and treated with ammonia. The product was then extracted with dichloromethane, the solution was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give 3.7g of (S) -1- (4-benzyl-piperazin-1-yl) -2-hydroxypropan-1-one as a colorless oil.

[α]_D2.2 ° (methanol, c 1.56g/100ml)

¹H NMR(CDCl₃)δ：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

To a suspension of 1.13g (29.8mmo1) of lithium aluminium hydride in 20ml of tetrahydrofuran at 20 ℃ a solution of 3.70g (14.9mmol) of (S) -1- (4-benzyl-piperazin-1-yl) -2-hydroxypropan-1-one in 100ml of tetrahydrofuran is added dropwise with stirring. The temperature of the reaction mixture was allowed to drop back to ambient temperature. After 2 hours, the excess hydride was hydrolyzed by addition of hydrated sodium sulfate, then the mixture was filtered and the filtrate was concentrated under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel (elution with a mixture of methanol and aqueous ammonia in dichloromethane (100/0/0 to 95/5/0.5)) to give 1.2g of(s) -1- (4-benzyl-piperazin-1-yl) propan-2-ol in the form of a yellow oil.

[α]_D23.2 ° (methanol, c 1g/100ml)

¹H NMR(CDCl₃)δ：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 1.2g (5.1mmol) of (S) -1- (4-benzylpiperazin-1-yl) propan-2-ol in 50ml of methanol was hydrogenated under 50psi of hydrogen at ambient temperature in the presence of 0.6g of palladium hydroxide for 2 hours. The mixture was then filtered through a buchner funnel and the filtrate was concentrated under reduced pressure to give 0.5g of a yellow oil.

[α]_DNot ═ 30.5 ° (methanol, c not 1g/100ml)

¹H NMR(CDCl₃)δ：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- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -imidazo [1,2-b ] pyridazin-6-yl ] piperazin-1-yl } propan-2-ol

A solution of 0.300g (0.79mmol) 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 example 1, step 1.5, 0.345g (1.59mmol) of (S) -1- (piperazin-1-yl) propan-2-ol and 0.45ml (3.18mmol) of diisopropylethylamine in 5ml of pentanol is heated at 150 ℃ for 8 days. After cooling, the reaction mixture was poured into 1N aqueous hydrochloric acid and the aqueous phase was washed with ethyl acetate. The aqueous phase is then basified with aqueous ammonia solution and the product is extracted with dichloromethane. The organic phase is then dried over sodium sulfate and then concentrated under reduced pressure. The brown residue obtained is then purified by chromatography on a column of silica gel (elution with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5)), recrystallised from acetonitrile, filtered and dried, yielding 0.05g 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.

MP：＞350℃

[α]_D13.9 ° (methanol, c 0.2g/100ml)

¹H NMR(DMSO-d₆) δ: 11.7 (broad singlet, 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 below illustrates the chemical structures and physical properties of some of the compounds of the present invention.

In this table:

in the column "salts", the "-" indicates the compound in free base form and "HCl" the compound in hydrochloride salt form, with the ratio between the brackets being acid: base ratio;

the column "MP ℃ reports the melting point of the product in degrees Celsius. "n.d" indicates melting point is not determined;

-[α]_Dcolumn one reports the results of an analysis of the optical rotation at a wavelength of 589nm of the compounds in the table; the solvents indicated in parentheses correspond to the solvents used for the measurement of optical rotation (in degrees), and the letter "c" indicates the solvent concentration in g/100 ml. "n.a." means not applicable to optical rotation measurement;

the column entitled "M/z" reports the molecular ion (M + H) observed by analyzing the product by the following method⁺) Or (M)⁺): mass spectrometry; LC-MS (liquid chromatography-Mass Spectrometry) in positive ESI mode on an Agilent LC-MSD Trap instrument; using DCI-NH₃The technique was either introduced directly onto an Autospec M (EBE) instrument via MS (mass spectrometry) using electron bombardment technique on a Waters GCT instrument. The values with asterisks ". correspond to ions (M)⁺) Detecting;

-″CH₃- "represents a methyl group;

-″CH₃OH "represents methanol;

-″CH₂Cl₂"denotes methylene chloride; and is

- "DMSO" means dimethyl sulfoxide.

TABLE 1

Biological examples

The ability of the compounds of the invention to inhibit casein phosphorylation by casein kinases 1 epsilon and delta can be assessed according to the procedure described in US 2005/0131012.

ATP-containing protein for screening CK1 epsilon inhibitor ³³ Filter-plate assay of P:

use by ATP in vitro-³³P-filtered casein assay to measure the inhibitory effect of the compounds on casein phosphorylation by casein kinase 1 epsilon (CK1 epsilon).

Casein kinase 1. epsilon. (0.58mg/ml) was obtained by fermentation and purification procedures carried out by methods well known to those skilled in the art, or may also be obtained from Invitrogen Corporation^TM(human CK 1. epsilon.).

The compound was present at 5 different concentrationsTesting to produce ICs₅₀The value, i.e., the concentration at which the compound is capable of inhibiting 50% of the enzyme activity, or the percent inhibition at 10 micromolar.

Falcon plates with "U" shaped bottoms were prepared by placing 5 μ L of a solution of a compound of the invention at a concentration of 10, 1, 0.1, 0.01 or 0.001 μ M in different wells. Solutions of these various concentrations of the compounds of the invention were prepared by running 10mM stock solutions in DMSO in assay buffer (50mM Tris, pH7.5, 10M MgCl)₂2mM DTT and 1mM EGTA). Then, 5. mu.L of dephosphorylated casein was added to a final concentration of 0.2. mu.g/. mu.L, 20. mu.L of CK 1. epsilon. to a final concentration of 3 ng/. mu.L and 20. mu.L of ATP + mixed with cold ATP³³P to final concentration of 0.02. mu. Ci/. mu.L (final 10. mu.M-about 2X 10)⁶CPM/pore). The final total test volume per well was equal to 50 μ L.

So that said bottom has a "U" shapeThe test plates were vortexed and then incubated at ambient temperature for 2 hours. After 2 hours, the reaction was stopped by adding 65 μ L of cold ATP (2mM) ice cold solution prepared in test buffer.

Then 100. mu.L of the reaction mixture was removed from the flask with a "U" shaped bottomThe plate is transferred toMAPH filter plates were pre-impregnated with 25. mu.L of ice-cold 100% TCA.

The Millipore MAPH filter plates were gently stirred and allowed to stand at ambient temperature for at least 30 minutes to precipitate the proteins.

After 30 minutes, the filter plates were washed with 2 × 150 μ L of 20% TCA, 2 × 150 μ L of 10% TCA, and 2 × 150 μ L of 5% TCA, followed by filtration (6 washes per plate per well 900 μ L total).

The plates were allowed to dry overnight at ambient temperature. Then, 40. mu.L of Microscint-20 was added to each wellScintillating the liquid and hermetically sealing the plate. And then using a value in which CPM/pore is measuredThe TopCount NXT scintillation counter measures the radiation emitted by each well for 2 minutes.

The percent inhibition of the ability of the enzyme to phosphorylate a substrate (casein) is determined for each concentration of test compound. These inhibition data, expressed as a percentage, were used to calculate the IC of each compound (compared to the control compound)₅₀The value is obtained.

Dynamics study determines K_MThe value (for ATP) was 21. mu.M as in the assay system.

Table 2 below shows the IC for inhibition of phosphorylation of casein kinase 1 epsilon for various compounds of the invention₅₀The value is obtained.

TABLE 2

Compound (I)	CK1εIC₅₀(nM)
		3	303
6	1-2
		35	6
36	5-8

Under these conditions, the most active compounds of the invention have an IC of 1nM to 2. mu.M₅₀Value (concentration inhibiting 50% of the enzymatic activity of casein kinase 1 epsilon).

The ability of the compounds of the present invention to inhibit casein phosphorylation by casein kinases 1 epsilon and delta can be determined by using the enzyme "Z' Lyte^TMKinase assay kit "(reference PV 3670; Invitrogen corporation)^TM) The FRET (fluorescence resonance energy transfer) fluorescence test of (2) was evaluated according to the manufacturer's instructions.

Casein kinase 1 used was obtained from Invitrogen Corporation (human CK1 epsilon PV3500 and human CK1 delta PV 3665).

In the presence of increasing concentrations of the compounds of the invention, the peptide substrates constituting the FRET system, labelled at both ends with a fluorophore-providing group (coumarin) and a fluorophore-receiving group (fluorescein), are phosphorylated by casein kinase 1 epsilon or delta in the presence of ATP.

The mixture is treated with a site-specific protease that specifically cleaves the substrate peptide to form two fluorescent fragments with a large fluorescence emission ratio.

The observed fluorescence is thus related to the ability of the product of the invention to inhibit phosphorylation of a peptide substrate by casein kinase 1 epsilon or casein kinase 1 delta.

The compounds of the invention are dissolved at various concentrations to be in a slow stateStarting from a 10mM stock solution in DMSO diluted in a wash, for casein kinase 1 ε, the buffer contained 50mM HEPS, pH7.5, 1mM EGTA, 0.01% Brij-35, 10mM MgCl₂For casein kinase 1 delta, the buffer was supplemented with Trizma Base (50mM), pH8.0 and NaN₃(0.01% final).

From Invitrogen Corporation^TMPhosphorylation of the obtained peptide substrate SER/THR 11 was achieved at a final concentration of 2. mu.M. ATP concentration 4 times K_MIt was 2. mu.M for casein kinase 1. epsilon. and 4. mu.M for casein kinase 1. delta.

Measurement of emitted fluorescence the measurement was performed at wavelengths of 445 and 520nm (excitation at 400 nm).

The IC for inhibition of casein kinase 1. delta. phosphorylation by various compounds of the present invention is given in Table 3 below₅₀The value is obtained.

TABLE 3

Compound numbering	CK1δIC₅₀(nM)
		20	30-42
29	5
		36	19

Under these conditions, the most active compounds of the invention have IC₅₀The value (concentration at which 50% of the enzymatic activity of casein kinase 1. delta. is inhibited) is 1nM to 2. mu.M.

It is thus seen that the compounds of the present invention have inhibitory activity against the enzyme casein kinase 1 epsilon or casein kinase 1 delta.

Protocol for determination of cell circadian rhythm (circadian)

At 37 ℃ and at 5% CO₂Next, Mper1-luc Rat-1(P2C4) fibroblast cultures were cultured at 150cm by every 3-4 days (about 10-20% confluency)²Degassed polystyrene tissue culture flasks (#35-5001) was prepared separately and maintained in growth medium [ EMEM (Cellgro # 10-010-CV); 10% fetal bovine serum (FBS; Gibco # 16000-044); and 50I.U./ml penicillin-streptomycin (Cellgro #30-001-Cl)]In (1).

30-50% confluent cells obtained from Rat-1 fibroblast cultures as described above were co-transfected with a vector containing a selectable marker for zeocin resistance for stable transfection and a luciferase reporter gene controlled by the promoter mPer-1. After 24-48 hours, cultures were split on 96-well plates and supplemented with 50-100. mu.g/ml zeocin (R) ((R))#45-0430) was maintained in growth medium for 10-14 days. By adding 100. mu.M fluorescein to the growth medium: (#) And by being inLuciferase activity was measured on a scintillation counter (Packard Model # C384V00) to evaluate reporter gene expression against stable transfectants against zeocin. Rat-1 cell clones simultaneously expressing zeocin resistance and luciferase activity controlled by mPer1 were cloned by using 50% horse serum [ HS ] (II)#16050-122)]Serous shock synchronization (serum-shock synchronization) was performed and circadian reporter activity was evaluated. The P2C4 clone of fibroblast cells Mper1-luc Rat-1 was selected for the assay of this compound.

40-50% confluent Mper1-luc Rat-1(P2C4) fibroblasts obtained according to the protocol described above were seeded on 96-well opaque tissue culture plates (# 6005680). The cultures were maintained in growth medium supplemented with 100. mu.g/ml zeocin (Invitrogen #45-0430) until they reached 100% confluence (48-72 hours). At 37 ℃ and at 5% CO₂Next, the culture was then incubated with 100. mu.L of synchronization medium [ EMEM (Cellgro # 10-010-CV); 100i.u./ml penicillin-streptomycin (Cellgro # 30-001-C1); 50% HS (Gibco #16050-]Synchronization was performed for 2 hours. After synchronization, cultures were rinsed with 100 μ L EMEM (Cellgro #10-010-CV) for 10 minutes at ambient temperature. After flushing, the medium was used in 300. mu.L CO-independent₂Culture medium of [ CO ]₂I (Gibco # 18045-088); 2mM L-glutamine (Cellgro # 25-005-C1); 100U.I./ml penicillin-streptomycin (Cellgro # 30-001-C1); 100 μ M fluorescein (Promega # E1603)]And (6) replacing. The compounds of the invention tested for circadian effect were added to 0.3% (final concentration) of CO-independent in DMSO₂In the medium of (1). The culture is immediately usedThe membrane (Packard #6005185) was hermetically sealed and transferred for luciferase activity measurements.

After synchronization, the test plate was maintained at 37 ℃ in a tissue culture incubator (Forma Scientific Model # 3914). Luciferase activity in vivo was assessed by measuring relative light emission on a TopCount scintillation counter (Packard Model # C384V 00).

The periodic analysis is performed by determining the interval between minima of relative light emission over a period of several days or by fourier transformation. Both methods produce almost the same cycle assessment for the circadian cycle range. The power (power) is given as CE Δ (t +1h) and is expressed as the effective micromolar concentration that causes a period extension of 1 hour. By using a catalyst in XLfit^TMThe hyperbola is adjusted in the software, the data expressed as periodic changes (Y-axis) are analyzed as a function of the concentration of the test compound (X-axis), and CE Δ (t +1h) is interpolated from the curve.

Table 4 below gives the CE Δ (t +1h) for various compounds of the invention.

TABLE 4

Compound numbering	CEΔ(t+1h)(nM)
		6	2-3
35	305
		36	1-7

Under these conditions, the most active compounds of the invention had CE Δ (t +1h) values (effective micromolar concentration for induction of an extension of the 1 hour period) of between 1nM and 2. mu.M.

By inhibiting enzymes CK1 epsilon and/or CK1 delta, the subject compounds modulate circadian periodicity and may be used to treat circadian rhythm disorders.

The compounds of the invention can be used, inter alia, for the preparation of medicaments for the prophylaxis or treatment of sleep disorders: circadian rhythm disturbances, such as those caused by jet lag (jetlag) or shift work, among others.

Among the sleep disorders, primary sleep disorders are particularly proposed, such as dyssomnias (dyssomnia) (e.g. primary insomnia), parasomnia, hypersomnia (e.g. excessive sleepiness), narcolepsy, sleep disorders related to sleep apnea, sleep disorders related to circadian rhythms and other unspecified sleep disorders, sleep disorders related to medical/psychiatric diseases.

The subject compounds also cause circadian phase shift (phase shift), a property that may be used in the context of potential monotherapy or combination therapy that is clinically effective for mood disorders.

Among the mood disorders, particular emphasis is given to depression (unipolar depression), bipolar disorders, mood disorders caused by general medical diseases and mood disorders caused by pharmacological substances.

Of the bipolar disorders, particularly prominent are bipolar I disorders and bipolar II disorders, including especially seasonal affective disorders.

The subject compounds that modulate circadian periodicity are useful for treating anxiety and depression, particularly caused by impairment of CRF secretion.

Among the depressive disorders, particularly prominent are major depressive disorders, dysthymic disorders and other unspecified depressive disorders.

The subject compounds that modulate the circadian periodicity may be used in the manufacture of medicaments for the treatment of diseases associated with dependence on abusive psychoactive substances (abuse substances), such as cocaine, morphine, nicotine, alcohol and cannabis.

By inhibiting casein kinase 1 epsilon and/or casein kinase 1 delta, the compounds of the invention may be used for the preparation of medicaments, in particular for the preparation of medicaments for the prevention or treatment of diseases associated with hyperphosphorylation of tau protein, in particular alzheimer's disease.

These medicaments can also be used in therapy, in particular in the treatment or prevention of diseases which are caused or aggravated by cell (in particular tumour cell) proliferation.

As inhibitors of tumor cell proliferation, these compounds are useful for the prevention and treatment of liquid tumors (liquid tumors), such as leukemias, primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer; lung cancer; small bowel and colorectal cancers; cancers of the respiratory tract, oropharynx and hypopharynx; esophageal cancer; liver cancer, gastric cancer, bile duct cancer, gallbladder cancer, pancreatic cancer; cancers of the urinary tract (including kidney, urothelium, and bladder); cancers of the female reproductive tract, including uterine cancer, cervical cancer, ovarian cancer, choriocarcinoma, and chorioepithelioma; male reproductive tract cancers, including prostate cancer, seminal vesicle cancer, testicular cancer, and germ cell tumors; endocrine gland cancers, including thyroid cancer, pituitary cancer, and adrenal cancer; skin cancers, including hemangiomas, melanomas, and sarcomas, including kaposi's sarcoma; brain, nerve, eye or meningeal tumors, including astrocytoma, glioma, glioblastoma, retinoblastoma, neuroblastoma, schwannoma, and meningioma; malignant hematological tumors; leukemias (acute lymphocytic leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL)), green leukemia, plasmacytoma, T or B cell leukemia, hodgkin or non-hodgkin lymphoma, myeloma, and various hematological malignancies.

The compounds of the invention can also be used for the preparation of medicaments, in particular for the preparation of medicaments for the treatment or prophylaxis of inflammatory diseases such as, in particular, inflammatory diseases of the central nervous system, for example, multiple sclerosis, encephalitis, myelitis and encephalomyelitis, and also other inflammatory diseases, for example, vascular pathologies, atherosclerosis, arthritis, arthrosis and rheumatoid arthritis.

The compounds of the invention can therefore be used for the preparation of medicaments, in particular medicaments for the inhibition of casein kinase 1 epsilon and/or casein kinase 1 delta.

Thus, according to a further aspect of the invention, there is provided a medicament comprising a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid, or a hydrate or solvate of a compound of formula (I).

According to another aspect of the invention, the invention relates to a pharmaceutical composition comprising a compound of the invention as an active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, or a hydrate or solvate of said compound, and at least one pharmaceutically acceptable excipient.

The excipients are selected from the usual excipients known to the person skilled in the art, according to the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical (topical), topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or a possible salt, solvate or hydrate thereof, may be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prevention or treatment of the above-mentioned disorders or diseases.

Suitable unit administration forms include oral route forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, administration forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical administration, the compounds of the invention may be used in the form of creams, gels, ointments or lotions.

For example, a unit dosage form (in the form of a tablet) of a compound of the invention may comprise the following components:

by oral route, the dose of active ingredient administered per day may be from 0.1 to 20mg/kg, taken in one or more portions.

There may be special cases where higher or lower doses are appropriate; such dosages do not depart from the scope of the present invention. According to common practice, the dosage suitable for each patient is determined by a physician according to the mode of administration and the weight and response of said patient.

According to another aspect of the present invention, the present invention also relates to a method of treating the above-indicated conditions, which comprises administering to a patient an effective dose of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

Claims

1. A compound of formula (I) in base form or in addition salt form with an acid:

wherein:

-R_a、R_band R_cAs defined below:

two R_aThe radicals may together form C_1-6-an alkylene group;

R_aand R_bMay together form a chemical bond or C_1-6-an alkylene group;

R_aand R_cMay together form a chemical bond or C_1-6-an alkylene group;

R_band R_cMay together form a chemical bond or C_1-6-an alkylene group;

-R_drepresents a hydrogen atom or C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-alkyloxy-C_1-6Alkyl radical, C_1-6-alkylthio-C_1-6Alkyl radical, C_1-6-a fluoroalkyl or benzyl group;

-R_e1represents-NR₄R₅A radical or a cyclic monoamine optionally containing an oxygen atom, optionally substituted with a group chosen from fluorine atoms and C_1-6Alkyl radical, C_1-6-one or more substituents of alkyloxy and hydroxy;

2. Compounds of general formula (I) according to claim 1, characterized in that:

-R₂represents phenyl optionally substituted with one or more of the following groups: halogen atoms or C_1-6-alkyl or C_1-6-a fluoroalkyl group.

3. Compounds of general formula (I) according to claim 1, characterized in that:

-R₂represents a group selected from C_1-6Alkyl radical, C_1-6-fluoroalkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-a radical of an alkyl group.

4. A compound of general formula (I) according to any one of claims 1 to 3, characterized in that:

5. A compound of general formula (I) according to any one of claims 1 to 4, characterized in that:

-L represents optionally substituted with R_cOr R_dNitrogen atom of the group;

two R_aThe radicals may together form C_1-6-an alkylene group;

-R_aand R_bMay together form a chemical bond or C_1-6-an alkylene group;

-R_aand R_cMay together form a chemical bond or C_1-6-an alkylene group;

-R_band R_cMay together form a chemical bond or C_1-6-an alkylene group;

-R_fIs represented by C_1-6Alkyl radical, C_3-7-cycloalkyl, C_3-7-cycloalkyl-C_1-6Alkyl radical, C_1-6-alkyloxy-C_1-6-alkyl, hydroxy-C_1-6Alkyl radical, C_1-6-fluoroalkyl or phenyl.

6. A compound of general formula (I) according to any one of claims 1 to 4, characterized in that:

-L represents optionally substituted with two R_e2Carbon atoms of the group;

two R_e2The radicals forming, with the carbon atom bearing them, a cyclic monoamine optionally containing an oxygen atom, optionally substituted with one or more R_fGroups, which may be the same or different from each other; and is

-R_fIs represented by C_1-6-an alkyl group.

7. A compound of general formula (I) according to any one of claims 1 to 4, characterized in that:

-A represents C_1-7-an alkylene group;

-B represents C_1-7-an alkylene group;

-L represents a substitution with R_e1Group and R_dCarbon atoms of the group;

-R_drepresents a hydrogen atom;

-R_fIs represented by C_1-6Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-an alkyl group.

8. A compound of general formula (I) according to any one of claims 1, 3, 4 and 5, characterized in that:

-R₂represents a methyl group;

-the cyclic amine formed by-N-A-L-B-represents (R) -3-methylpiperazin-1-yl, 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; and is

-R₇And R₈Represents hydrogenAn atom.

9. A compound of general formula (I) according to any one of claims 1,2, 4 and 5, characterized in that:

-R₂represents a 3-fluorophenyl group or a 4-fluorophenyl group;

10. Compounds of general formula (I) according to any one of claims 1,2, 4 and 6, characterized in that:

-R₂represents a 4-fluorophenyl group;

-R₇And R₈Represents a hydrogen atom.

11. A compound of general formula (I) according to any one of claims 1,2, 4 and 7, characterized in that:

-R₂represents a 4-fluorophenyl group;

-R₇and R₈Represents a hydrogen atom.

12. The compound of claim 1 selected from:

2- (4-fluorophenyl) -6- [ (3R) -3-methylpiperazin-1-yl ] -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) -imidazo [1,2-b ] pyridazine;

2- (4-fluorophenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) -3- (1H-pyrrolo [2,3-b ] pyridin-4-yl) imidazo [1,2-b ] pyridazine.

13. A process for the preparation of the compounds of the general formula (I) according to claim 1, characterized in that a reaction of a compound of the general formula (II) with an amine of the general formula (III),

a compound of the general formula (II):

wherein R is₂、R₇And R₈As defined in claim 1 and X₆Represents a leaving group, and represents a leaving group,

an amine of the general formula (III):

wherein A, L and B are defined according to claim 1.

14. A process for the preparation of a compound of the general formula (I) according to claim 1, characterized in that a compound of the general formula (V) is deprotected using a base,

a compound of the general formula (V):

wherein R is₂、A、L、B、R₇And R₈As defined in claim 1 and PG represents a phenylsulfonyl or tosyl group.

15. Pharmaceutical, 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.

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 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 for the treatment or prophylaxis of sleep disorders, circadian rhythm disorders, mood disorders, anxiety and depression, diseases associated with abuse substance dependence, diseases associated with hyperphosphorylation of tau protein, diseases caused or exacerbated by cell proliferation or inflammatory diseases.