KR20110095964A - Derivatives of 6-cycloamino-2,3-di-pyridinyl-imidazo[1,2-b]-pyridazine, preparation and therapeutic application thereof - Google Patents

Abstract

The present invention relates to 6-cycloamino-3- (1H-pyrrolo [2,3-b] pyridin-4-yl) imidazo [1,2b] pyridazine derivatives of formula (I). The present invention also relates to a method for its preparation and its therapeutic use in the treatment or prevention of diseases associated with casein kinase 1 epsilon and / or casein kinase 1 delta.
<Formula I>

Description

Derivatives of 6-cycloamino-2,3-di-pyridinyl-imidazo [1,2-VII] -pyridazine, preparation and therapeutic use thereof {DERIVATIVES OF 6-CYCLOAMINO-2,3-DI-PYRIDINYL-IMIDAZO [1,2-B] -PYRIDAZINE, PREPARATION AND THERAPEUTIC APPLICATION THEREOF}

The present invention relates to a 6-cycloamino-2,3-dihydropyridylimidazo [1,2-b] pyridazine derivative, to a process for the preparation thereof, and to a disease associated with casein kinase 1 epsilon and / or casein kinase 1 delta. To a therapeutic use thereof in treatment or prophylaxis.

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

<Formula I>

Where

- R ₂ is a halogen atom and a C _{1 -6} - represents an optionally substituted pyridyl with one or more substituents selected from alkyl groups,

- represents an alkyl group, - R ₃ represents a hydrogen atom or a C _{1 -3}

- A is one or two R _a groups optionally substituted with C _{1 -7} - represents an alkylene group,

- B is a group R _b, optionally substituted C _{1 -7} - represents an alkylene group,

L represents a nitrogen atom optionally substituted with a R _c or R _d group, or a carbon atom substituted with a R _e1 group and an R _d group or two R _e2 groups,

The carbon atoms of A and B are optionally substituted with one or more R _f groups, which may be the same or different from each other,

R _a , R _b and R _c are defined as follows:

Two R _a groups with C _{1 -6} - may form an alkylene group,

R _a and R _b is a bond or C _{1 -6} together - may form an alkylene group,

R _a and R _c is a bond or C _{1 -6} together - may form an alkylene group,

R _b and R _c is a bond or C _{1 -6} together - may form an alkylene group,

R _d is a hydrogen atom and a C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkylthio -C _{1 -6} - alkyl , C _{1 -6} - alkyloxy -C _{1 -6} - alkyl, C _{1 -6} - fluoroalkyl, benzyl, C _{1 -6} - acyl and hydroxy -C _{1 -6} - represents a group selected from alkyl group,

R _e1 is a -NR ₄ R ₅ represents a group, or represents a cyclic monoamine containing an oxygen atom, optionally, the cyclic monoamines are a fluorine atom and a C _{1 -6} - alkyl, C _{1 -6} - alkyloxy, and hydroxy Optionally substituted with one or more substituents selected from hydroxyl groups,

Two R _e2 groups together with the carbon atoms bearing them form a cyclic monoamine optionally containing an oxygen atom, said cyclic monoamine is optionally substituted with one or more R _f groups which may be the same or different from each other,

R _f is C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkyloxy-C _1-6 -alkyl, hydroxy A -C _1-6 -alkyl, C _1-6 -fluoroalkyl or benzyl group,

R ₄ and R ₅ are independently a hydrogen atom or a C _{1 -6} each other represent an alkyl, -alkyl, C _{3 -7-cycloalkyl,} or C _3-7 - cycloalkyl, -C _{1 -6}

- R ₇ and R ₈ are independently a hydrogen atom or a C _{1 -6} each other represent an alkyl.

The compound of formula (I) may comprise one or more asymmetric carbon atoms. Thus, they may exist in enantiomeric or diastereomeric forms. These enantiomers and diastereomers, and also mixtures thereof, such as racemic mixtures, form part of the present invention.

The compounds of formula (I) may exist in base form or in acid addition salt form. Such addition salts form part of the present invention. These salts are advantageously prepared using pharmaceutically acceptable acids, but salts of other acids useful for example for the purification or isolation of the compounds of formula (I) also form part of the present invention.

The compounds of formula (I) may also be in the form of hydrates or solvates, ie in association with or combined with one or more water molecules or solvents. Such hydrates and solvates also form part of the invention.

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

C _{t -z} where t and z can have a value of 1 to 7: a carbon-based chain possibly containing t to z carbon atoms. For example, C _{1 -7} carbon which may contain 1 to 7 carbon atoms swaeim of the substrate.

Alkyl: linear or branched saturated aliphatic groups. For example, C _{1 -6-alkyl} group is 1 to 6 linear or branched carbon of the carbon atoms of the base chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl , Pentyl or hexyl.

Alkylene: linear or branched saturated divalent alkyl groups. For example, C _{1 -6-alkylene} group from 1 to 6 linear or branched carbon atoms, a divalent carbon-containing chain of, for example, the substrate represents a methylene, ethylene, 1-methylethylene or propylene.

Cycloalkyl: a cyclic alkyl group. For example, C _{3 -7-cycloalkyl} group from 3 to 7 cyclic carbon atoms of the carbon-containing the group, examples of the base cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or represents a cycloheptyl.

Acyl: alkyl-C (O) — groups.

Hydroxyl: —OH group.

Cyclic monoamines: a saturated cyclic carbon-based chain comprising one nitrogen atom.

Hydroxyalkyl: an alkyl group in which hydrogen atoms have been replaced by hydroxyl groups.

Alkyloxy: —O-alkyl groups.

Alkylthio: an -S-alkyl group.

Fluoroalkyl: alkyl group in which at least one hydrogen atom is replaced by a fluorine atom.

Fluoroalkyloxy: alkyloxy groups in which at least one hydrogen atom is replaced by a fluorine atom.

Halogen atoms: fluorine, chlorine, bromine or iodine atoms.

Aryl: monocyclic or bicyclic aromatic groups containing 6 to 10 carbon atoms. Examples of aryl groups that may be mentioned include phenyl and naphthyl groups.

Non-limiting examples of cyclic amines or diamines formed by N, A, L and B include in particular aziridine, azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, homopiperi Dean, decahydroquinoline, decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclononane, azaoxobicycloheptane, azathiabicycloheptane, azaoxobicyclooctane, azathiabicyclooctane; Piperazine, Homopiperazine, Diazacyclooctane, Diazacyclononane, Diazacyclodecane, Diazacycloundecane, Octahydropyrrolopyrazine, Octahydropyrrolodiazepine, Octahydropyrrolopyrrole, Octahydropy Rolopyridine, decahydronaphthyridine, diazabicycloheptane, diazabicyclooctane, diazabicyclononane, diazaspiroheptane, diazaspirooctane, diazaspironan, diazaspirodecane, diazaspirodecane and oxa Diazaspirondecan may be mentioned.

Among the compounds of formula (I) which are the subject of the invention, the compounds of the first group are

L represents a nitrogen atom optionally substituted with a R _c or R _d group or a carbon atom substituted with a R _e1 group and a R _d group,

Other substituents consist of compounds as defined above.

Among the compounds of formula (I) which are the subject of the invention, the compounds of the second group are

R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and a methyl group,

Other substituents consist of compounds as defined above.

Among the compounds of the formula (I) which are the subject of the invention, the third group of compounds

R ₃ represents a hydrogen atom or a methyl group,

Other substituents consist of compounds as defined above.

Among the compounds of the formula (I) which are the subject of the invention, the compounds of the fourth group are

R ₇ and R ₈ represent a hydrogen atom or a methyl group,

Other substituents consist of compounds as defined above.

Among the compounds that are the subject of the present invention, the compound of the fifth group is

- it represents an alkylene group, - A is one or two R _a groups optionally substituted with C _{1 -7}

- B is a group R _b, optionally substituted C _{1 -7} - represents an alkylene group,

L represents a nitrogen atom optionally substituted by R _c or R _d groups,

The carbon atoms of A and B are optionally substituted with one or more R _f groups which may be the same or different from each other,

R _a , R _b and R _c are defined as follows:

Two R _a groups with C _{1 -6} - may form an alkylene group,

R _a and R _b is a bond or C _{1 -6} together - may form an alkylene group,

R _a and R _c is a bond or C _{1 -6} together - may form an alkylene group,

R _b and R _c is a bond or C _{1 -6} together - may form an alkylene group,

R _d is a hydrogen atom and a C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkylthio -C _{1 -6} - alkyl , C _{1 -6-alkyl-oxy} -C _{1 -6-alkyl,} C _{1 -6} - represents a group selected from alkyl group, - fluoro-alkyl, benzyl, C _{1 -6-acyl} or hydroxy -C _1-6

R _f is C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkyloxy -C _{1 -6} - alkyl, hydroxy -C _{1 -6} - alkyl, C _{1 -6} - represents an alkyl or benzyl fluoro,

Other substituents consist of compounds as defined above.

Among the compounds of the formula (I) which are the subject of the invention, the compounds of the sixth group

- it represents an alkylene group, - A is one or two R _a groups optionally substituted with C _{1 -7}

- B is a group R _b, optionally substituted C _{1 -7} - represents an alkylene group,

L represents a carbon atom substituted with an R _e1 group and an R _d group,

The carbon atoms of A and B are optionally substituted with one or more R _f groups which may be the same or different from each other,

R _a , R _b and R _c are defined as follows:

Two R _a groups with C _{1 -6} - may form an alkylene group,

R _a and R _b is a bond or C _{1 -6} together - may form an alkylene group,

R _a and R _c is a bond or C _{1 -6} together - may form an alkylene group,

R _b and R _c is a bond or C _{1 -6} together - may form an alkylene group,

R _d is a hydrogen atom and a C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkylthio -C _{1 -6} - alkyl , C _{1 -6} - alkyloxy -C _{1 -6} - alkyl, C _{1 -6} - fluoroalkyl, benzyl, C _{1 -6} - acyl or hydroxy -C _{1 -6} - represents a group selected from alkyl group,

R _e1 is -NR ₄ R ₅ represents a group, or represents a cyclic monoamine containing an oxygen atom, optionally, the cyclic monoamines are a fluorine atom and a C _{1 -6} - alkyl, C _{1 -6} - alkyloxy or hydroxy Optionally substituted with one or more substituents selected from hydroxyl groups,

R _f is C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkyloxy -C _{1 -6} - alkyl, hydroxy -C _{1 -6} - alkyl, C _{1 -6} - represents an alkyl or benzyl fluoro,

R ₄ and R ₅ are independently a hydrogen atom or a C _{1 -6} each other represent an alkyl, -alkyl, C _{3 -7-cycloalkyl,} or C _3-7 - cycloalkyl, -C _{1 -6}

Other substituents consist of compounds as defined above.

Among the compounds of the formula (I) which are the subject of the invention, the compounds of group 7 are

- when -NALB- formed by cyclic amines with more than ₁ C 1 _-6 - represents a piperazinyl or hexahydro-pyrrolo pyrrolyl optionally substituted with alkyl,

Other substituents consist of compounds as defined above.

Among the compounds of formula (I) which are the subject of the invention, the compounds of group 8 are

The cyclic amine formed by -N-A-L-B- represents a pyrrolidinylpiperidyl group,

R ₂ , R ₃ , R ₇ and R ₈ consist of compounds as defined above.

Among the compounds of formula (I) which are the subject of the invention, the compounds of group 9 are

Cyclic amines formed by -NALB- are (3S) -3-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperazine -1-yl, (3R) -3-isopropylpiperazin-1-yl or (cis) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl group,

Other substituents consist of compounds as defined above.

Among the compounds of formula (I) which are the subject of the invention, the compounds of group 10

The cyclic amine formed by -N-A-L-B- represents a 4-pyrrolidin-1-ylpiperidin-1-yl group,

Other substituents consist of compounds as defined above.

Among the compounds of formula (I) which are the subject of the invention, the compounds of group 11 are

Cyclic amines formed by -NALB- are (3S) -3-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperazine -1-yl, (3R) -3-isopropylpiperazin-1-yl, (cis) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl or 4-pi Represents a Ralidin-1-ylpiperidin-1-yl group,

R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and a methyl group,

R ₃ represents a hydrogen atom or a methyl group,

R ₇ and R ₈ represent a hydrogen atom or a methyl group,

It consists of a compound in base form or in acid addition salt form.

Among the compounds which are the subject of the invention, mention may be made in particular of:

6-[(3S) -3-methylpiperazin-1-yl] -3- (pyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine ,

6-[(3S) -3-methylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b ] Pyridazine,

6- (3,3-dimethylpiperazin-1-yl) -3- (pyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine,

6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine,

6- (4-isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine ,

2- (5-fluoropyrid-3--3-)-6-[(3S) -3-methylpiperazin-1-yl] -3- (pyrid-4-yl) imidazo [1,2- b] pyridazine,

2- (5-fluoropyrid-3-yl) -6-[(3S) -3-methylpiperazin-1-yl] -3- (2-methylpyrid-4-yl) imidazo [1 , 2-b] pyridazine,

2- (5-fluoropyrid-3--3-)-6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyri chop,

6- (4-isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (5-methylpyrid-3-yl) imidazo [1,2-b ] Pyridazine,

6-piperazin-1-yl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,

6-[(3S) -3-methylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b ] Pyridazine,

6- (3,3-dimethylpiperazin-1-yl) -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,

6- (3,3-dimethylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyrid chop,

6- (3,3-dimethylpiperazin-1-yl) -8-methyl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,

6-[(3R) -3-isopropylpiperazin-1-yl] -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,

6- (4-isopropylpiperazin-1-yl) -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine,

6- (4-isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine ,

6-[(cis) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2-yl] -2,3-bis (pyrid-4-yl) imidazo [1,2-b] Pyridazine,

2,3-bis (pyrid-4-yl) -6- (4-pyrrolidin-1-ylpiperidin-1-yl) imidazo [1,2-b] pyridazine,

2- (2-fluoropyrid-4-yl) -6-[(3S) -3-methylpiperazin-1-yl] -3- (pyrid-4-yl) imidazo [1,2- b] pyridazine,

2- (2-fluoropyrid-4-yl) -6-[(3S) -3-methylpiperazin-1-yl] -3- (2-methylpyrid-4-yl) imidazo [1 , 2-b] pyridazine,

2- (2-fluoropyrid-4-yl) -6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyri chop,

2- (2-fluoropyrid-4--4-)-6- (4-isopropylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) imidazo [1,2- b] pyridazine.

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

<Scheme 1>

In general and as illustrated in Scheme 1, the 6-cycloamino-2,3-di-pyridylimidazo [1,2-b] pyridazine derivatives of Formula I, wherein R ₂ , R ₃ , A , L, B, R ₇ and R ₈ are as defined above, the 3- (pyrid-4-yl) imidazo [1,2-b] pyridazine derivative of Formula II wherein R ₂ , R ₃ , R ₇ and R ₈ are as defined above and X ₆ represents a leaving group such as halogen to be prepared by treatment with an amine of formula IIa, wherein A, L and B are as defined above. Can be. This reaction can be carried out by heating the reagent in a polar solvent such as pentanol or dimethyl sulfoxide.

The imidazo [1,2-b] pyridazine derivatives of formula (II) are the 3-haloimidazo [1,2-b] pyridazine derivatives of formula (III) under Still or Suzuki conditions, wherein R ₂ , X ₆ , R ₇ and R ₈ are as defined above, X ₃ represents a halogen such as bromine or iodine, more particularly iodine and a pyridine derivative of formula IIIa wherein R ₃ is as defined above, M is a trialkylstannyl group, typically a tributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, usually 4,4,5,5-tetramethyl-1,3,3,2- Metal-catalyzed coupling between dioxaborolan-2-yl group).

Coupling according to the Steel method is carried out by heating in a solvent such as N, N-dimethylacetamide, for example in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium or copper iodide.

Coupling according to the Suzuki method is for example a furnace in a solvent mixture such as dioxane and water in the presence of a catalyst such as 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium and an inorganic base such as cesium carbonate. Is performed.

3-haloimidazo [1,2-b] pyridazine derivatives of Formula III are imidazo [1,2-b] pyridazine derivatives of Formula IV, wherein R ₂ , X ₆ , R ₇ and R ₈ are As defined) regioselective bromination or iodide. This reaction can be carried out using N-bromo- or iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.

Imidazo [1,2-b] pyridazine derivatives of Formula IV are known (Journal of Heterocyclic Chemistry (2002), 39 (4), 737-742) or prepared analogously to methods known to those skilled in the art. Can be.

In a second alternative according to Scheme 2, the 6-cycloamino-2,3-dipyridylimidazo [1,2-b] pyridazine derivatives of Formula I as defined above are imidazo [1] , 2-b] pyridazine derivatives wherein R ₂ , A, L, B, R ₇ and R ₈ are as defined above in two steps.

<Scheme 2>

According to a first approach, imidazo [1,2-b] pyridazine derivatives of formula V and pyridine derivatives of formula Va, wherein R ₃ is as defined above, and alkyl chloroformate, wherein the alkyl group is C _1-6-alkyl, such as ethyl chloro formate represents a) derivatives of the formula VI by the reaction of a mixture of (wherein, R _2, a, L, B, R _3, R ₇ and R ₈ are as defined above Is generated). The derivative of formula VI is then oxidized using ortho-chloranil in a solvent such as toluene to give the 6-cycloamino-2,3-bis-pyridylimidazo [1,2-b] pyridazine derivative of formula I To obtain.

According to a second approach, the regioselective aromatic bromination or iodide of the imidazo [1,2-b] pyridazine derivative of the formula (V) to the 3-bromo- or iodoimidazo [1,2-b] pyrid of the formula (VII) Minced derivatives are produced wherein R ₂ , A, L, B, R ₇ and R ₈ are as defined above and X ₃ represents a halogen such as bromine or iodine, more particularly iodine. This reaction can be carried out by using N-bromo- or iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.

Thereafter, the 6-cycloamino-2,3-di-pyridylimidazo [1,2-b] pyridazine derivative of formula (I) is subjected to such 3-bromo- or iodoimi of formula (VII) under still or Suzuki conditions. Prepared by metal-catalyzed coupling between a polyzo [1,2-b] pyridazine derivative and a pyridine derivative of formula IIIa as defined above.

In a third alternative according to Scheme 3, the 6-cycloamino-2,3-di-pyridylimidazo [1,2-b] pyridazine derivatives of formula (I) as defined above are substituted with 2-bromine of formula (VIII) It can be prepared in three steps from the momiidazo [1,2-b] pyridazine derivatives, wherein A, L, B, R ₇ and R ₈ are as defined above.

Regioselective aromatic iodide of the imidazo [1,2-b] pyridazine derivatives of Formula VIII is a 2-bromo-3-iodoimidazo [1,2-b] pyridazine derivative of Formula IX wherein A, L, B, R ₇ and R ₈ are as defined above). This reaction can be carried out using N-iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.

<Scheme 3>

A first regioselective metal-catalyzed between this 2-bromo-3-iodoimidazo [1,2-b] pyridazine of formula (IX) and a pyridine derivative of formula (IIIa) as defined above under steel or Suzuki conditions Coupling reactions yield 2-bromoimidazo [1,2-b] pyridazine derivatives of Formula X, wherein A, L, B, R ₃ , R ₇ and R ₈ are as defined above .

Finally, 2-bromo-3-iodoimidazo [1,2-b] pyridazine derivatives of formula X and pyridine derivatives of formula Xa under Still or Suzuki conditions, wherein R ₂ is as defined above, M is a trialkylstannyl group, typically a tributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, usually 4,4,5,5-tetramethyl-1,3,3,2- 6-cycloamino-2,3-di-pyridylimidazo of formula I as defined above in a second metal-catalyzed coupling reaction between the dioxaborolan-2-yl group). 2-b] pyridazine derivatives are produced.

Coupling according to the Steel method is carried out by heating in a solvent such as N, N-dimethylacetamide, for example in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium or copper iodide.

Precursor

3-Pyrid-4-ylimidazo [1,2-b] pyridazine derivatives of Formula (V) as defined above are pyridazin-3-ylamine derivatives of Formula (XI) wherein A, L, B, R ₇ and R ₈ are as defined above and a 2-bromo, chloro- or iodoethan-1-one derivative of formula (XIa) wherein R ₂ is as defined above and X is bromine, chlorine or Condensation between iodine atoms).

The reaction can be carried out by heating the reagent in a polar solvent such as ethanol or butanol.

Pyridazin-3-ylamine derivatives of formula (XI) are known (Journal of Medicinal Chemistry (2008), 51 (12), 3507-3525) or can be prepared analogously to methods known to those skilled in the art.

3-Pyrid-4-ylimidazo [1,2-b] pyridazine derivatives of Formula (V) as defined above may also be 2-bromoimidazo of Formula (VIII) as previously defined under Still or Suzuki conditions. It can be prepared by a metal-catalyzed coupling reaction between a [1,2-b] pyridazine derivative and a pyridine derivative of formula (Xa) as defined above.

2-bromoimidazo [1,2-b] pyridazine derivatives of formula (VIII) are 2-bromoimidazo [1,2-b] pyridazine derivatives of formula (XII), wherein R ₇ and R ₈ are defined above X ₆ can be prepared by treatment of an amine of formula (IIa) as defined above from a leaving group such as halogen, more particularly chlorine). This reaction can be carried out by heating the reagent in a polar solvent such as pentanol or dimethyl sulfoxide.

2-bromoimidazo [1,2-b] pyridazine derivatives of formula XII are 5-halopyridazin-3-ylamines of formula XIV wherein X ₆ represents a leaving group such as halogen, more particularly chlorine , R ₇ and R ₈ are as defined above in two steps. Thus, the 5-halopyridazin-3-ylamine derivatives of formula XI are alkylated with alkyl 2-bromo- or 2-chloroacetates, for example ethyl 2-bromoacetate, to yield 6-amino-3- of formula XIII. Halo-1- (alkyloxycarbonylmethyl) pyridazine-1-ium hydrobromide or hydrochloride, wherein X ₆ represents a leaving group such as halogen, more particularly chlorine and R ₇ and R ₈ are as defined above Equals) 6-amino-3-halo-1- (alkyloxycarbonylmethyl) pyridazine-1-ium hydrobromide or hydrochloride of formula XIII is cyclized using phosphorus oxybromide to form 2-bromo-3 of formula XII To form-(pyrid-4-yl) imidazo [1,2-b] pyridazine derivatives.

In this context herein, the term “leaving group” means a group that can be easily cleaved from the molecule while losing the electron pair by the breakdown of heterolytic bonds. Thus, such groups can be easily replaced with other groups, for example, during the substitution reaction. For example, such leaving groups are halogen, or activated hydroxyl groups such as mesyl, tosyl, triflate, acetyl and the like. Examples of leaving groups and their preparation are described in reference to [ "Advances in Organic Chemistry", J. March, 3 rd Edition, Wiley Interscience, pp. 310-316.

Saver

If the NALB group in the compound of formula (I) or (IIa) as defined above comprises a primary or secondary amine functional group, such functional group may be optionally protected during the synthesis with a protecting group such as benzyl or t-butyloxycarbonyl have.

The following examples describe the preparation of certain compounds according to the invention. Such embodiments do not limit the invention, but merely serve to illustrate. The numbers of the compounds exemplified refer to the numbers set forth in Table 1 below, each describing the chemical structure and physical properties of the numerous compounds according to the invention.

Example  1 (Compound 13): 6- (3,3-dimethylpiperazin-1-yl) -3- (2- Methylpyrid -4-yl) -2- ( Period -4- days) Imidazo [1,2-b] Pyridazine

Step 1.1: 6-Chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

To a solution of 24.0 g (85.3 mmol) of 3-amino-6-chloropyridazine in 1.5 L of reflux ethanol 2-bromo-1- (pyrid-4-yl) ethanone hydrobromide (CAS 5469-69-2) After 33.2 g (256 mmol) was added in portions, 12.0 mL (85.4 mmol) of triethylamine was added dropwise over 45 minutes. The mixture was refluxed for 3 hours. After cooling, the solvent was evaporated under reduced pressure and the reddish brown residue was taken up in chloroform and 300 mL of 1 N sodium hydroxide solution. After stirring for 15 minutes the mixture was filtered and the solid residue was washed with chloroform. The organic phase was separated and washed with water, dried over sodium sulphate and after evaporation of the solvent 13 g of a brown solid was obtained. The residue was purified by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (97/3 / 0.3) on a 500 g silica gel column, trituration in diisopropyl ether, filtration and drying under reduced pressure. Then 10.1 g of 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine was obtained in the form of a dark beige solid.

Step 1.2: 6-Chloro-3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

To a solution of 10.4 g (45.1 mmol) of 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 1 L of chloroform, 21.9 g (135) of iodine chloride in 100 mL of methanol at room temperature mmol) was added. After reacting for 24 hours, the mixture was poured into saturated sodium bicarbonate solution and the resulting mixture was decolorized by addition of aqueous 5% sodium thiosulfate solution. The organic phase was separated, dried over sodium sulphate and concentrated under reduced pressure and after about 10% 6-chloro-2- (pyrid-4-yl) imidazo [1] after softening, filtration and drying in acetonitrile 200 mL [1] 14.4 g of 6-chloro-3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine containing, 2-b] pyridazine in the form of a beige colored solid Obtained.

Step 1.3: 6-Chloro-3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

2.85 g (6.39 mmol) of 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 400 mL of a mixture of tetrahydrofuran and water (9/1), (2- 1,1'-bis (diphenylphosphino) after argon degassing in a mixture of 1.14 g (6.12 mmol) of methyl-4-pyridyl) boronic acid (CAS 579476-63-4) and 6.3 g (19 mmol) of cesium carbonate 0.47 g (0.58 mmol) of ferrocenedichloropalladium (II) (CAS 72287-26-4) was added. The mixture was stirred at reflux for 18 hours. The mixture was concentrated under reduced pressure and the residue was taken up in chloroform. The organic phase was washed with water, dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (96/4 / 0.4) in a 110 g silica gel column, and after 6-chloro-3- (softening in acetonitrile, filtration and drying. 1.35 g of 2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine were obtained in the form of a white powder.

Step 1.4: 6- (3,3-Dimethylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2- b] pyridazine

0.500 g (1.55 mmol) 6-chloro-3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 5 mL of pentanol And a mixture of 0.52 g (4.7 mmol) of 2,2-dimethylpiperazine was refluxed at 150 ° C. for 24 hours. The reaction medium was cooled and poured into an aqueous 2 N hydrochloric acid solution. The aqueous phase was washed with diethyl ether and then basified with aqueous 2N sodium hydroxide solution and the product was extracted with chloroform. The organic phase was dried over sodium sulphate and the solvent was evaporated under reduced pressure. The solid obtained was eluted with a mixture of dichloromethane, methanol and aqueous ammonia (94/6 / 0.6) in 35 g of silica gel, dissolved in 10 mL of acetonitrile and crystallized by addition of diethyl ether, filtered and dried. 6- (3,3-dimethylpiperazin-1-yl) -3- (2-methylpyrid-4-yl) -2- (pyrid-4-yl) imidazo [1,2-b] 0.17 g of pyridazine was obtained in the form of a powder of beige color.

Example  2 (Compound 14): 6- (3,3-dimethylpiperazin-1-yl) -8- methyl -2,3-bis ( Period -4- days) Imidazo [1,2-b] Pyridazine

Step 2.1: 3-amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methylpyridazine

In the autoclave, a suspension of 50.0 g (307 mmol) of 3,6-dichloro-4-methylpyridazine in 170 mL of 30% aqueous ammonia was heated at 120 ° C. for 18 hours. After cooling, the mixture was poured into 200 mL of water and the solids were recovered by filtration. After drying under reduced pressure, the mixture of products was recrystallized from ethyl acetate to give a mixture of 3-amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methylpyridazine (32/68) 40 g were obtained.

Step 2.2: 6-Amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridazine-1-ium bromide and 6-amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyri Chopped-1-ium bromide

Ethyl 2 in a solution of 36.0 g (251 mmol) of a mixture of 3-amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methylpyridazine (32/68) in 350 mL of reflux ethanol Bromoacetate 30.6 mL (275 mmol) was added in portions and heating continued for 24 hours. After cooling, the reaction medium was partially concentrated under reduced pressure and then diluted with 200 mL of acetone, the suspension was cooled to 0 ° C. and the precipitate was separated by filtration. The filtrate was then partially concentrated under reduced pressure, diluted with 150 mL of acetone, and the suspension was cooled back to 0 ° C. The precipitate was separated by filtration and combined with the first yield. After drying, 6-amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyridazine-1-ium bromide and 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methyl A total of 29.8 g of a mixture of pyridazine-1-ium bromide (30/70) was obtained.

Step 2.3: 2-Bromo-6-chloro / bromo-7-methylimidazo [1,2-b] pyridazine and 2-bromo-6-chloro / bromo-8-methylimidazo [ 1,2-b] pyridazine

6-amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyridazine-1-ium and 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridine in 100 mL toluene 27.8 g (89.5 mmol) and 82 g (286 mmol) of a mixture of Dajin-1-Ium (30/70) were heated in a closed tube at 160 ° C. for 1 hour. After cooling, the solid deposited on the wall was removed and the mixture was poured into 500 mL of water at 0 ° C. The aqueous phase was then basified with aqueous ammonia addition and stirred for 1 hour before dissolving the product in chloroform. The organic phase was separated, dried over sodium sulphate and concentrated under reduced pressure to give 22 g of a brown solid. The solid was then purified by chromatography on a 450 g silica gel column, eluting with dichloromethane to give 2,6-dibromo-8-methylimidazo [1,2-b] pyridazine. 5.0 g (41/59) of bromo-6-chloro-8-methylimidazo [1,2-b] pyridazine were obtained in the form of a white powder.

2-bromo containing 2,6-dibromo-7-methylimidazo [1,2-b] pyridazine, continuing to elute with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1) 15.2 g of -6-chloro / bromo-7-methylimidazo [1,2-b] pyridazine were obtained in the form of a pink powder.

Step 2.4: 2-bromo-6- (3,3-dimethylpiperazin-1-yl) -8-methylimidazo [1,2-b] pyridazine

2-bromo-6-chloro-8-methylimidazo [1,2 containing 2,6-dibromo-8-methylimidazo [1,2-b] pyridazine in 60 mL of pentanol -b] A mixture of 4.95 g (about 20 mmol) pyridazine, 2.5 g (22 mmol) 2,2-dimethylpiperazine and 2.8 mL triethylamine was heated at 150 ° C. in a closed tube for 3 days. After cooling, the reaction medium was poured into aqueous 1 N hydrochloric acid solution. The aqueous phase was washed with ethyl acetate and then basified with aqueous ammonia solution and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent was evaporated under reduced pressure. The beige colored solid obtained was purified by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/65 / 0.5) in 80 g of silica gel column to give 2-bromo-6- (3,3-dimethylpipepe. 4.6 g of razin-1-yl) -8-methylimidazo [1,2-b] pyridazine were obtained in the form of a white powder.

Step 2.5: 6- (3,3-Dimethylpiperazin-1-yl) -8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

2-bromo-6- (3,3-dimethylpiperazin-1-yl) -8-methylimidazo [1,2-b] pyridine in 100 mL of a mixture of tetrahydrofuran and water (9/1) To a mixture of chopped 4.64 g (14.3 mmol) and 2.5 g (17 mmol) of (4-pyridyl) boronic acid (CAS 1692-15-5) followed by argon degassing 14 g (43 mmol) and 1,1'- 1.05 g (1.29 mmol) of a complex of bis (diphenylphosphino) ferrocenedichloropalladium (II) and dichloromethane (PdCl ₂ (dppf) .CH ₂ Cl ₂ ) were added. After stirring under reflux for 8 hours, the reaction medium was poured into aqueous 1 N hydrochloric acid solution. The aqueous phase was washed with ethyl acetate and then basified with aqueous ammonia solution and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent was evaporated under reduced pressure. The black oil obtained was purified by chromatography on a 120 g silica gel column, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/65 / 0.5) to give 6- (3,3-dimethylpiperazin-1- Il) -8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine was obtained in the form of an oil.

Step 2.6: 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

3.13 g (9.71) of 6- (3,3-dimethylpiperazin-1-yl) -8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 80 mL of dichloromethane mmol) was added 19.4 mL (19.4 mmol) of a 1 M iodine chloride solution in dichloromethane at room temperature. After reacting for 2 hours, the solution was poured into 150 mL of water and basified by addition of sodium bicarbonate, and the resulting mixture was decolorized with little addition of sodium thiosulfate. The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure to give a brown oil which was eluted with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1) by chromatography on a 120 g silica gel column. 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-8-methyl-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine 3.35 g was obtained as a beige solid.

Step 2.7: 6- (3,3-dimethylpiperazin-1-yl) -8-methyl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine

6- (3,3-dimethylpiperazin-1-yl) -3-iodo-8-methyl-2- (pyrid-4-yl) in 15 mL of a mixture of tetrahydrofuran and water (9/1) 0.87 g of cesium carbonate after argon degassing in a mixture of 0.40 g (0.89 mmol) of imidazo [1,2-b] pyridazine and 0.155 g (1.07 mmol) of (4-pyridyl) boronic acid (CAS 1692-15-5) (2.7 mmol) and a complex of 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) and dichloromethane (PdCl ₂ (dppf) .CH ₂ Cl ₂ -CAS 851232-71-8) 0.057 g ( 0.08 mmol) was added. After reacting for 18 hours, the reaction medium was poured into 150 mL of water and the product extracted with dichloromethane. The organic phase was dried over sodium sulphate and the solvent was evaporated under reduced pressure. The black oil obtained was purified by chromatography on a 40 g silica gel column, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/65 / 0.5), and recrystallized from acetonitrile, filtered and dried. 0.039 g of-(3,3-dimethylpiperazin-1-yl) -8-methyl-2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine is beige Obtained in powder form.

Example  3 (Compound 12): 6- (3,3-dimethylpiperazin-1-yl) -2,3-bis ( Period -4- day) imidazo 1,2-b] pyridazine

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

A microwave mixture of 3.80 g (28.1 mmol) of 3-amino-6-chloropyridazine and 5.00 g (17.8 mmol) of 2-bromo-1- (pyrid-4-yl) ethanone hydrobromide in 50 mL of ethanol Heated at 140 ° C. for 50 minutes. After cooling, the solvent was evaporated under reduced pressure and the residue was taken up in saturated aqueous sodium hydrogen carbonate solution. The solid was separated by filtration, washed with water, eluted with a mixture of dichloromethane and methanol (95/5) on a silica gel column, and chromatographed to give 6-chloro-2- (pyrid-4-yl) imidazo [ 1,2-b] pyridazine was obtained in the form of a yellow powder.

Step 3.2: 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

A microwave oven was mixed with 1.95 g (8.45 mmol) of 6-chloro-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine and 2.4 g (21 mmol) of 2,2-dimethylpiperazine. Heated at 150 ° C. for 13 h. The medium is then cooled and the solvent is evaporated under reduced pressure. The resulting orange oil was eluted with a mixture of 1 M ammonia solution in dichloromethane and methanol (95/5) in a silica gel column and chromatographed to give 6- (3,3-dimethylpiperazin-1-yl) -2. 1.63 g of-(pyrid-4-yl) imidazo [1,2-b] pyridazine were obtained in the form of a yellow foam.

Step 3.3: 6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] pyridazine

To a solution of 1.37 g (4.45 mmol) of 6- (3,3-dimethylpiperazin-1-yl) -2- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 20 mL of chloroform. A solution of 1.80 g (11.1 mmol) of iodine monochloride in 5 mL methanol was added. The resulting suspension was stirred for 2 hours. After addition of saturated aqueous sodium hydrogen carbonate solution, sodium thiosulfate was added in portions until the reaction medium remained yellow. The solid was separated by filtration and air dried to give the product 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-4-yl) imidazo [1,2-b] 1.95 g of pyridazine were obtained in the form of a yellow powder.

Step 3.4: 6- (3,3-Dimethylpiperazin-1-yl) -2,3-bis (pyrid-4-yl) imidazo [1,2-b] pyridazine

After degassing, 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-4- in 4 mL of a mixture of 1,4-dioxane and water (75/2) Il) imidazo [1,2-b] pyridazine 0.28 g (0.55 mmol), (pyrid-4-yl) boronic acid 0.095 g (0.77 mmol), cesium carbonate 0.89 g (2.7 mmol) and 1,1 ' A mixture of 45 mg (0.055 mmol) of bis (diphenylphosphinoferrocene) dichloropalladium (II) and dichloromethane (PdCl ₂ (dppf) .CH ₂ Cl ₂ -CAS 851232-71-8) in a microwave oven Heated at 105 ° C. for 30 minutes. After cooling, the mixture was diluted with dichloromethane and washed with water. The organic phase was then dried over magnesium sulfate, filtered and the solvent was evaporated. The resulting oil was chromatographed on silica gel, eluting with a mixture of a 1 M ammonia solution in a mixture of methanol and dichloromethane (3/97) to afford 0.070 g of a yellow powder.

Example  4 (Compound 3): 6- (3,3-dimethylpiperazin-1-yl) -2- ( Period -3- days) -3- ( Period -4- days) Imidazo [1,2-b] Pyridazine

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

2.80 g (11.9 mmol) of 3-amino-6-chloropyridazine, 3.69 g (13.2 mmol) of 2-bromo-1- (pyrid-3-yl) ethanone hydrobromide and 3.7 triethylamine in 45 mL of ethanol A mL (26 mmol) suspension was heated to microwave at 140 ° C. for 50 minutes. After cooling the solvent is evaporated under reduced pressure, the residue is purified by chromatography on a 120 g silica gel column, eluting with a mixture of dichloromethane and methanol (95/5), softening in heptane, filtration and reduced pressure. 0.77 g of product was obtained in the form of a powder of beige color after drying under.

Step 4.2: 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine

0.77 g (3.3 mmol) of 6-chloro-2- (pyrid-3-yl) imidazo [1,2-b] pyridazine and 7 g (9.6 mmol) of 2,2-dimethylpiperazine in 7 mL of ethanol. The mixture was heated in a microwave oven at 150 ° C. for 13 hours. The medium is then cooled and the solvent is evaporated under reduced pressure. The resulting orange oil was eluted with a mixture of dichloromethane and 1 M ammonia solution in methanol (97/3) on a silica gel column and chromatographed to give 6- (3,3-dimethylpiperazin-1-yl) -2. 0.89 g of-(pyrid-3-yl) imidazo [1,2-b] pyridazine were obtained in the form of a yellow powder.

Step 4.3: 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-3-yl) imidazo [1,2-b] pyridazine

To a solution of 0.870 g (2.82 mmol) of 6- (3,3-dimethylpiperazin-1-yl) -2- (pyrid-3-yl) imidazo [1,2-b] pyridazine in 10 mL of chloroform A solution of 0.600 g (3.70 mmol) of iodine monochloride in 4 mL methanol was added. The orange colored suspension is then stirred for 3 hours and the solvent is evaporated under reduced pressure to give a residue. Subsequently, saturated aqueous sodium hydrogen carbonate solution was added and then sodium thiosulfate was added in portions until the reaction mixture remained yellow. The solid was isolated by filtration and air dried to afford the product 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-3-yl) imidazo [1,2-b ] 0.90 g of pyridazine was obtained in the form of a powder of beige color.

Step 4.4: 6- (3,3-Dimethylpiperazin-1-yl) -2,3-bis (pyrid-3-yl) imidazo [1,2-b] pyridazine

After degassing, 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyrid-3- in 6 mL of a mixture of 1,4-dioxane and water (3/1) I) imidazo [1,2-b] pyridazine 0.400 g (0.92 mmol), (pyrid-4-yl) boronic acid 0.150 g (1.22 mmol), cesium carbonate 0.89 g (2.7 mmol) and 1,1 ' A mixture of 75 mg (0.092 mmol) of -bis (diphenylphosphinoferrocenedichloropalladium (II) and dichloromethane (PdCl ₂ (dppf) .CH ₂ Cl ₂ )) was heated in a microwave oven at 105 ° C. for 30 minutes. After cooling, the mixture was diluted with dichloromethane and washed with water, then the organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated to give a green oil. Chromatography eluted with a mixture of 1 M ammonia solution in methanol and dichloromethane (5/95) to give 6- (3,3-dimethylpiperazin-1-yl) -2,3-bis (pyrid-3). Imida-jo 0.170 g of [1,2-b] pyridazine was obtained in the form of a gray powder.

Example  5 (Compound 22): 2- (2- Fluoropyrides -4-yl) -6- (4- Isopropylpiperazine -1-yl) -3- ( Period -4- days) Imidazo [1,2-b] Pyridazine

Step 5.1: 6-Amino-3-chloro-1- (ethoxycarbonylmethyl) pyridazine-1-ium bromide

A mixture of 25.6 g (198 mmol) of 3-amino-6-chloropyridazine in 230 mL of hot ethanol was treated with 34.0 g (206 mmol) of ethyl bromoacetate. After refluxing for 24 hours the mixture was cooled and the crystals were separated by filtration. After drying 36.6 g of product was isolated. The solvent was evaporated under reduced pressure and 7.1 g further isolated after recrystallization from ethanol.

Step 5.2: 2-bromo-6-chloroimidazo [1,2-b] pyridazine and 2,6-dibromoimidazo [1,2-b] pyridazine

A mixture of 20 g (65 mmol) of 6-amino-3-chloro-1- (ethoxycarbonylmethyl) pyridazine-1-ium bromide and 63 g of phosphorus oxybromide in 50 mL of toluene was heated at 160 ° C. for 3 hours. It was. The mixture was then poured on ice (300 mL). After stirring, the solid was separated by filtration and purified by chromatography on a 120 g silica gel column, eluting with a mixture of 0% to 10% methanol in dichloromethane. This gave 8.05 g of a mixture of the two products, which was used without further purification for the remainder of the synthesis.

Step 5.3: 2-bromo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine

3.98 g of 2-bromo-6-chloroimidazo [1,2-b] pyridazine and 2,6-dibromoimidazo [1,2-b] pyridazine obtained in the previous step in 15 mL of ethanol ( 14.4 mmol) and 3.7 g (28.5 mmol) of 1-isopropylpiperazine were heated in a microwave reactor in a closed tube at 160 ° C. for 8 hours. The mixture was diluted with ethanol and then filtered to yield 2.49 g of 2-bromo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine.

Step 5.4: 2-bromo-3-iodo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine

A solution of 2.45 g (14.8 mmol) of iodine chloride in 2 mL of methanol was added to 2-bromo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine in 20 mL of chloroform. g (7.56 mmol) was added dropwise at 0 ° C. The mixture was stirred at rt for 4 h. The mixture was then triturated with sodium thiosulfate. This mixture was concentrated under reduced pressure in the presence of 15 g of silica gel. The residue was deposited on 80 g of silica gel column, purified by chromatography eluting with a gradient of 0% to 10% methanol in dichloromethane to 2-bromo-3-iodo-6- (4-isopropylpiperazine 2.07 g of -1-yl) imidazo [1,2-b] pyridazine were obtained as an orange solid.

Step 5.5: 2-Bromo-6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine

2-bromo-3-iodo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine 0.059 g (0.12 mmol), 1,1'-bis (di Phenylphosphino) ferrocenepalladium dichloride (CAS 72287-26-4) 3 mg (0.004 mmol), pyrid-4-ylboronic acid (CAS 1692-15-5) 18 mg (0.15 mmol), aqueous 2 M cesium carbonate A mixture of 0.9 mL of solution and 1.5 mL of 1,4-dioxane was heated in a microwave oven at 110 ° C. for 30 minutes in a closed tube. 1 mL saturated sodium chloride solution and 4 mL ethyl acetate were added. After stirring the mixture was allowed to soak through a sodium sulfate cartridge.

The solvent was evaporated to dryness in the presence of silica gel. The absorbed residue was deposited on 4 g of silica gel column and diluted with gradient 0% to 6% methanol and 1% aqueous ammonia (in dichloromethane) to 2-bromo-6- (4-isopropylpiperazine- 8.5 mg of 1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine were obtained.

Step 5.6: 2- (2-Fluoropyrid-4-yl) -6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2- b] pyridazine

2-bromo-6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine in 25 mL of 1,4-dioxane 2.65 g (6.6 mmol), 1,1'-bis (diphenylphosphino) ferrocene palladium (CAS 72287-26-4) 0.46 g (0.65 mmol), pyridine-4-boronic acid (CAS 169215-15-5) A mixture of 1.12 g (9.10 mmol) and 15 mL of an aqueous 2 M cesium carbonate solution was heated in a sealed tube at 120 ° C. for 20 minutes. Further 0.237 g (2.7 mmol) of pyridine-4-boronic acid were added and the reaction mixture was heated at 110 ° C. for 30 minutes. The reaction medium was then diluted with water and the product extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was stripped under reduced pressure and the residue was adsorbed onto silica gel. The product was purified by chromatography on 80 g silica gel column, eluting with a 0% to 10% methanol gradient in dichloromethane, and after recrystallization from isopropanol 2- (2-fluoropyrid-4-yl)- 1.85 g of 6- (4-isopropylpiperazin-1-yl) -3- (pyrid-4-yl) imidazo [1,2-b] pyridazine were obtained.

Table 1 below illustrates the chemical structures and physical properties of the numerous compounds according to the invention.

In this table:

Column "m.p. (° C)" indicates the melting point of the product in degrees Celsius, "N.D" means that no melting point was measured,

Column “[α] _D ” shows the results of optical rotation analysis of the compound of the table at wavelength 589 nm, the solvent in parentheses corresponds to the solvent used for the optical rotation (°) measurement, and the letter “c” indicates the concentration of the solvent. expressed in g / 100 mL, “NA” means that no optical rotation measurements were applicable,

Column “m / z” is performed by LC-MS (liquid chromatography coupled with mass spectrometry) performed on an Agilent LC-MSD Trap type machine in a positive ESI mode, or Mass spectrometry, performed by direct introduction by MS (mass spectroscopy) on an Autospec M (EBE) machine using DCI-NH3 technology or electron impact technology on Waters GCT type machines Represents the molecular ions (M + H ⁺ ) observed in the analysis of the product by,

-"CH _3- " means methyl,

"CH ₃ OH" means methanol,

"DMSO" means dimethyl sulfoxide.

Biological Example

The ability of the compounds of the present invention to inhibit the phosphorylation of casein by casein kinase 1 epsilon and delta can be assessed according to the procedure described in document US 2005/0 131 012.

Filter-plate Assay of ATP - ³³ P for Screening of CK1 Epsilon Inhibitor :

The effect of the compound on the inhibition of phosphorylation of casein by the enzyme casein kinase 1 epsilon (CK1 epsilon) was determined by a casein assay through filtration of ATP- ³³ P in vitro.

Casein kinase 1 epsilon (0.58 mg / mL) can be obtained through fermentation and purification processes performed according to methods known to those skilled in the art, or can also be obtained from Invitrogen Corporation ^™ (human CK1 epsilon). .

Compounds may be tested at five different concentrations to obtain IC ₅₀ values, ie, concentrations at which the compounds can inhibit 50% enzymatic activity, or alternatively, percent inhibition at 10 micromolar concentrations. It was.

A “U” bottom Falcon plate was prepared by placing 5 μl of a solution of the compound according to the invention at a concentration of 10, 1, 0.1, 0.01 or 0.001 μM in different wells.

Solutions of the compounds according to the present invention at various concentrations were prepared by diluting a stock solution of 10 mM concentration in DMSO in test buffer (Tris 50 mM, pH 7.5), MgCl ₂ 10 M, DTT 2 mM and EGTA 1 mM. Then 5 μl of dephosphorylated casein was added to a final concentration of 0.2 μg / μl, 20 μl of CK1 epsilon was added to a final concentration of 3 ng / μl, and 20 μl of ATP- ³³ P was mixed with normal ATP (cold ATP) To a final concentration of 0.02 μCi / μl (final 10 μM-approximately 2 × 10 ⁶ CPM per well). The final total test volume per well was 50 μl.

The above mentioned “U” bottom Falcon ^® test plates were vortexed and then incubated for 2 hours at room temperature. After 2 hours, the reaction was stopped by addition of 65 μl of normal ATP (2 mM) ice cold solution prepared in test buffer.

Then, the reaction "U" the chair 100 ㎕ mixture was transferred from the bottom plate Falcon ^® by Millipore (Millipore) ^® MAPH filter plate was pre-impregnated with ice-cold 100% TCA 25 ㎕.

The Millipore MAPH filter plate was gently stirred and left at room temperature for at least 30 minutes to precipitate the protein.

After 30 minutes, the filter plate was washed sequentially with 2 × 150 μl of 20% TCA, 2 × 150 μl of 10% TCA and 2 × 150 μl of 5% TCA and filtered (6 washes / well per plate in total) 900 μl).

The plate was dried overnight at room temperature. It was then added to the micro-Sint -20 (Microscint-20) Packard (Packard) scintillation liquid ^® 40 ㎕ each well and sealed in a manner that is leak-proof the plates. Then, the value of CPM per well was measured by the radiation emitted by each well Top Count (TopCount) NXT measured in a Packard ^® scintillation counter for 2 minutes.

Percent inhibition of the ability of the enzyme to phosphorylate the substrate (casein) was measured for each concentration of test compound. This inhibition data, expressed as a percentage, was used to calculate IC ₅₀ values for each compound compared to the control.

Epidemiological studies have determined that the K _M value for ATP in this test system is 21 μM.

Table 2 below provides IC ₅₀ values related to the phosphorylation inhibition of casein kinase 1 epsilon for compound numbers according to the invention.

Under these conditions, the most active compound of the present invention had an IC ₅₀ value (a concentration that inhibits the enzymatic activity of casein kinase 1 epsilon by 50%) between 1 nM and 2 μM.

The ability of the compounds of the present invention to inhibit the phosphorylation of casein by casein kinase 1 epsilon and delta was determined according to the manufacturer's instructions with the help of the "Z'Lyte ™ Kinase Assay Kit" (PV3670, Invitrogen Corporation ™). Can be evaluated using the FRET (fluorescence resonance energy transfer) fluorescence test.

Casein kinase 1 used was obtained from Invitrogen Corporation (human CK1 epsilon PV3500 and human CK1 delta PV3665).

Peptide substrates labeled both ends with a fluorophore-donating group (coumarin) and a fluorophore-receptor group (fluorescein) constituting the FRET system are present in increasing concentrations in the presence of ATP and casein kinase 1 epsilon or delta. Dephosphorized in the presence of a compound of.

The mixture was treated with site specific proteases that specifically cleaved the substrate peptide to form two fluorescent fragments with high fluorescence emission rates.

Thus, the fluorescence observed was related to the ability of the product of the present invention to inhibit phosphorylation of substrate peptides by casein kinase 1 epsilon or casein kinase 1 delta.

Compounds of the invention are diluted in a buffer containing 50 mM HEPS (pH 7.5), 1 mM EGTA, 0.01% Brij-35, 10 mM MgCl ₂ for casein kinase 1 epsilon and tree for casein kinase 1 delta Trizma base (50 mM) (pH 8.0), and NaN ₃ (final 0.01%) were dissolved in various concentrations starting with 10 mM stock in DMSO diluted in buffer supplemented.

Phosphorylation of the substrate peptide SER / THR 11 obtained from Invitrogen Corporation ™ was performed at a final concentration of 2 μΜ. The ATP concentration was four times that of K _M , which was 2 μM for casein kinase 1 epsilon and 4 μM for casein kinase 1 delta.

The emitted fluorescence was measured at wavelengths of 445 nm and 520 nm (excitation at 400 nm).

Table 3 below provides IC ₅₀ values related to the inhibition of phosphorylation of casein kinase 1 delta for compound numbers according to the invention.

Under these conditions, the most active compound of the present invention had an IC ₅₀ value (concentration that inhibits the enzymatic activity of casein kinase 1 delta by 50%) between 1 nM and 2 μM.

Thus, the compounds according to the present invention have been shown to have inhibitory activity against the enzyme casein kinase 1 epsilon or casein kinase 1 delta.

Experimental protocol for circadian cell assay

Mper1-luc Rat -1 (Rat-1) (P2C4 ) fibroblast cultures, the culture each in a 150 cm ² tissue culture polystyrene flasks (Falcon ^® # 35-5001) degassed three to four days ( About 10% to 20% total growth) divided and prepared in growth medium (EMEM (Cellgro # 10-010-CV) under 5% CO ₂ at 37 ° C .; 10% fetal bovine serum (FBS; Gibco # 16000-044); And 50 IU / mL penicillin-streptomycin (Selgro # 30-001-Cl)].

Cells obtained from rat-1 fibroblast cultures at 30% to 50% contiguous growth as described above contain a luciferase reporter gene dictated by the zeocin resistance selection marker for stable transfection and the promoter mPer-1. Co-transfection with the vector. After 24 hours to 48 hours, and was maintained for dividing the culture in a 96-well plate, 50 to 100 ㎍ / mL Zeocin (Invitrogen ^® # 45-0430) 10 to 14 days from the supplemented growth medium. The reporter was tested for stable transfectants resistant to zeocin by adding 100 μM luciferin (Promega ^® # E1603 ^® ) to growth medium and assaying luciferase activity on a TopCount ^® scintillation counter (Packard Model # C384V00). The expression of was evaluated. Zeocin resistance and the rat -1-cell clones expressing luciferase activity both indicated by mPer1 serum with 50% horse serum [HS (Gibco ^® # 16050-122)] - shock-synchronization, active periodicity of reporter Was evaluated. Compounds were tested by selecting P2C4 clones of fibroblast Mper1-luc rat-1.

It was plated on a Mper1-luc Rat -1 (P2C4) of the fibroblast opaque 96 well tissue culture plates at the time of the resultant 40% to 50% over growth (Perkin Elmer (Perkin Elmer) ^® # 6005680) according to the protocol. The cultures were maintained in growth medium supplemented with 100 μg / mL Zeosin (Invitrogen # 45-0430) until they reached 100% confluence (48-72 hours). The culture was then subjected to synchronization medium [EMEM (Selgro # 10-010-CV); 100 IU / mL penicillin-streptomycin (Selgro # 30-001-C1); 50% HS (Gibco # 16050-122)] was synchronized to 100 μl for 2 hours at 37 ° C. under 5% CO ₂ . After synchronization, the cultures were rinsed with 100 μl of EMEM (Selgro # 10-010-CV) for 10 minutes at room temperature. After rinsing, the CO ₂ medium--independent media [CO ₂ I (Gibco # 18045-088); 2 mM L-glutamine (Celgro # 25-005-C1); 100 UI / mL penicillin-streptomycin (Selgro # 30-001-C1); 100 μM Luciferin (Promega #E 1603)] was replaced with 300 μl. Compounds of the invention tested for circadian effect were added at 0.3% (final concentration) to CO ₂ -independent media in DMSO. Immediately sealed in a manner that is tight to the culture using a tapsil (TopSeal) -A ^® film (Packard # 6005185) and transferred for luciferase activity measurement.

After synchronization, test plates were maintained at 37 ° C. in a tissue culture oven (Forma Scientific Model # 3914). In vivo luciferase activity was estimated by measuring relative light emission on a top count scintillation counter (Packard Model # C384V00).

Periodic analysis was performed by measuring the interval between relative light emission minimums over several days or by Fourier transform. The two methods produced virtually identical period estimates over a range of one period periods. Ability was reported in EC delta (t + 1h), which is presented as a micromolar concentration effective to extend the cycle 1-hour. The data were analyzed by adjusting the hyperbolic curves in the data expressed as the cyclic change (y-axis) as a function of test compound concentration (x-axis) in the XLfit ™ software, and interpolated the EC delta (t + 1h) from this curve. .

Table 4 below provides the EC delta (t + 1h) for compound numbers according to the invention.

Under these conditions, the most active compounds of the present invention had EC delta (t + 1h) values (micromolar concentrations effective for extending the cycle 1-hour) between 1 nM and 2 μM.

By inhibiting the enzymes CK1 epsilon and / or CK1 delta, compounds of the present invention may be useful for modulating circadian periodicity and treating circadian rhythm disorders.

The compounds according to the invention are particularly useful for sleeping disorders; It may be used in the manufacture of a medicament for preventing or treating circadian rhythm disorders, in particular disorders caused by, for example, parallax or shift work.

Particularly distinguished sleep disorders include primary sleep disorders such as abnormal sleep (e.g. primary insomnia), event sleep, excessive sleep (e.g. excessive drowsiness), narcolepsy, sleep disorders associated with sleep apnea, circadian rhythm And sleep disorders associated with medical and psychological disorders.

Compounds of the present invention also cause circadian phase shifts, and these properties may be useful in connection with potential monotherapy or combination therapy that is clinically effective in the case of mood disorders.

Among the distinguished mood disorders are depressive disorders (unipolar depression), bipolar disorders, mood disorders caused by general medical complaints, and also mood disorders caused by pharmacological substances.

Among the distinguishing bipolar disorders are bipolar I disorders and bipolar II disorders, in particular seasonal affective disorders, for example.

Compounds of the invention that modulate circadian periodicity may be particularly useful in the treatment of anxiety and depressive disorders caused by CRF secretion damage.

Among the distinguishing depressive disorders are major depressive disorders, dysthymic disorders and other atypical depressive disorders.

Compounds of the present invention that modulate circadian periodicity may be useful in the manufacture of a medicament for treating diseases associated with dependence on abuse substances such as cocaine, morphine, nicotine, ethanol and cannabis.

By inhibiting casein kinase 1 epsilon and / or casein kinase 1 delta, the compounds according to the invention can be used in the manufacture of a medicament, in particular in the manufacture of a medicament for preventing or treating diseases associated with hyperphosphorylation of tau protein, in particular Alzheimer's disease. have.

Such medicaments are also used in therapy, in particular for the treatment or prevention of diseases caused or exacerbated by cell proliferation, in particular tumor cell proliferation.

As tumor cell proliferation inhibitors, these compounds are flowable tumors such as leukemia, solid tumors of both primary and metastatic, carcinoma and cancer, in particular: breast cancer; Lung cancer; Small bowel cancer and colorectal cancer; Cancer, oropharyngeal and hypopharyngeal cancers of the respiratory path; Esophageal cancer; Liver cancer, stomach cancer, bile duct cancer, gallbladder cancer, pancreatic cancer; Urinary tract cancers such as kidney cancer, urinary tract cancer and bladder cancer; Female genital cancers such as uterine cancer, cervical cancer, ovarian cancer, chorionic carcinoma and trophoblastic tumors; Male germline cancers such as prostate cancer, seminal vesicle cancer, testicular cancer and germ cell tumors; Endocrine gland cancers such as thyroid cancer, pituitary cancer and adrenal cancer; Skin cancers such as hemangiomas, melanoma and sarcomas such as Kaposi's sarcoma; Brain tumors, nerve tumors, eye tumors, or meningococcal tumors such as astrocytoma, glioma, glioblastoma, retinoblastoma, schwannoma, neuroblastoma, schwannomas and meningiomas; Malignant hematopoietic tumors; Leukemia (acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL)) melanoma, plasmacytoma, T or B cell leukemia, Hodgkin's or non-homologous It is useful for the prevention and treatment of Keukin's lymphoma, myeloma and various malignant hemopathies.

The compounds according to the invention are also useful in the manufacture of medicaments, in particular inflammatory diseases, in particular inflammatory diseases of the central nervous system such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis, and other inflammatory diseases such as vascular pathology, atherosclerosis, It can be used in the manufacture of a medicament for preventing or treating joint inflammation, arthrosis and rheumatoid arthritis.

The compounds according to the invention can therefore be used in the manufacture of a medicament, in particular a medicament for inhibiting casein kinase 1 epsilon and / or casein kinase 1 delta.

Accordingly, according to another aspect of the invention, a subject of the invention is a medicament comprising a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid, or alternatively a hydrate or solvate of a compound of formula (I) to be.

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

Such excipients are selected from conventional excipients which are known to those skilled in the art depending on the pharmaceutical form and the mode of administration desired.

In pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I), or a possible salt, solvate or hydrate thereof, It may be administered in unit dosage form to humans and animals as a mixture with standard pharmaceutical excipients for the prevention or treatment of this disorder or disease.

Suitable unit dosage 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 dosage forms, inhalation forms, Topical, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms and implants. For topical administration, the compounds according to the invention can be used as creams, gels, ointments or lotions.

By way of example, unit dosage forms of the tablet forms of the compounds according to the invention may comprise the following ingredients:

50.0 mg of the compound according to the invention

Mannitol 223.75 mg

Croscarmellose Sodium 6.0 mg

Corn starch 15.0 mg

Hydroxypropylmethylcellulose 2.25 mg

Magnesium stearate 3.0 mg

The dose of active ingredient administered per day via the oral route may range from 0.1 to 20 mg / kg with one or more dose intakes.

There may be special cases where higher or lower dosages are appropriate, and such dosages do not depart from the context of the present invention. According to conventional practice, the dosage appropriate for each patient is determined by the physician depending on the mode of administration and the weight and response of the patient.

According to another aspect, the invention also relates to a method of treating the above-mentioned pathologies comprising administering to a patient an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt or hydrate or solvate thereof. will be.

Claims (14)

A compound of formula I in base form or in acid addition salt form:
<Formula I>

Where
R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from halogen atoms and C _1-6 -alkyl groups,
- represents an alkyl group, - R ₃ represents a hydrogen atom or a C _{1 -3}
- A is one or two R _a groups optionally substituted with C _{1 -7} - represents an alkylene group,
B represents a C _1-7 -alkylene group optionally substituted with a R _b group,
L represents a nitrogen atom optionally substituted with a R _c or R _d group, or a carbon atom substituted with a R _e1 group and an R _d group or two R _e2 groups,
The carbon atoms of A and B are optionally substituted with one or more R _f groups, which may be the same or different from each other,
R _a , R _b and R _c are defined as follows:
Two R _a groups together may form a C _1-6 -alkylene group,
R _a and R _b together may form a bond or a C _1-6 -alkylene group,
R _a and R _c together may form a bond or a C _1-6 -alkylene group,
R _b and R _c together may form a bond or a C _1-6 -alkylene group,
R _d is a hydrogen atom and a C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkylthio -C _{1 -6} - alkyl , C _{1 -6-alkyl-oxy} -C _{1 -6-alkyl,} C _{1 -6} - represents a group selected from alkyl group, - fluoro-alkyl, benzyl, C _{1 -6-acyl} or hydroxy -C _1-6
R _e1 is a -NR ₄ R ₅ represents a group, or represents a cyclic monoamine containing an oxygen atom, optionally, the cyclic monoamines are a fluorine atom and a C _{1 -6} - alkyl, C _{1 -6} - alkyloxy or hydroxy Optionally substituted with one or more substituents selected from hydroxyl groups,
Two R _e2 together with the carbon atoms bearing them form a cyclic monoamine optionally containing an oxygen atom, said cyclic monoamine is optionally substituted with one or more R _f groups which may be the same or different from each other,
R _f is a C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkyloxy -C _{1 -6} - alkyl, hydroxy -C _{1 -6} - alkyl, C _{1 -6} - represents an alkyl or benzyl fluoro,
R ₄ and R ₅ are independently a hydrogen atom or a C _{1 -6} each other represent an alkyl, -alkyl, C _{3 -7-cycloalkyl,} or C _3-7 - cycloalkyl, -C _{1 -6}
- R ₇ and R ₈ are independently a hydrogen atom or a C _{1 -6} each other represent an alkyl. The method of claim 1,
L represents a nitrogen atom optionally substituted with a R _c or R _d group or a carbon atom substituted with a R _e1 group and a R _d group
A compound of formula I, characterized in that The method according to claim 1 or 2,
R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and a methyl group
A compound of formula I, characterized in that 4. The method according to any one of claims 1 to 3,
- R ₇ and R ₈ is a hydrogen atom or a C _{1 -6} - represents an alkyl
A compound of formula I, characterized in that The method according to any one of claims 1 to 4,
- it represents an alkylene group, - A is one or two R _a groups optionally substituted with C _{1 -7}
B represents a C _1-7 -alkylene group optionally substituted with a R _b group,
L represents a nitrogen atom optionally substituted by R _c or R _d groups,
The carbon atoms of A and B are optionally substituted with one or more R _f groups which may be the same or different from each other,
R _a , R _b and R _c are defined as follows:
Two R _a groups together may form a C _1-6 -alkylene group,
R _a and R _b together may form a bond or a C _1-6 -alkylene group,
R _a and R _c together may form a bond or a C _1-6 -alkylene group,
R _b and R _c together may form a bond or a C _1-6 -alkylene group,
R _d is a hydrogen atom and C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkylthio-C _1-6 -alkyl , C _1-6 - alkyloxycarbonyl -C _1-6 - alkyl, C _1-6 - represents a group selected from alkyl group, - fluoro-alkyl, benzyl, C _1-6 - acyl or hydroxy -C _{1 -6}
R _f is C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - _-6 alkyloxy -C ₁ - alkyl, hydroxy -C _{1 -6} - alkyl, C _{1 -6} - represents an alkyl or fluoro-benzyl
A compound of formula I, characterized in that The method according to any one of claims 1 to 5,
- it represents an alkylene group, - A is one or two R _a groups optionally substituted with C _{1 -7}
- B is a group R _b, optionally substituted C _{1 -7} - represents an alkylene group,
L represents a carbon atom substituted with an R _e1 group and an R _d group,
The carbon atoms of A and B are optionally substituted with one or more R _f groups which may be the same or different from each other,
R _a , R _b and R _c are defined as follows:
Two R _a groups together may form a C _1-6 -alkylene group,
R _a and R _b together may form a bond or a C _1-6 -alkylene group,
R _a and R _c together may form a bond or a C _1-6 -alkylene group,
R _b and R _c together may form a bond or a C _1-6 -alkylene group,
R _d is a hydrogen atom and C _1-6 -alkyl, C _3-7 -cycloalkyl, C _3-7 -cycloalkyl-C _1-6 -alkyl, C _1-6 -alkylthio-C _1-6 -alkyl , C _1-6 - alkyloxycarbonyl -C _1-6 - alkyl, C _1-6 - represents a group selected from alkyl group, - fluoro-alkyl, benzyl, C _1-6 - acyl or hydroxy -C _1-6
R _e1 is -NR ₄ R ₅ represents a group, or represents a cyclic monoamine containing an oxygen atom, optionally, the cyclic monoamines are a fluorine atom and a C _{1 -6} - alkyl, C _{1 -6} - alkyloxy or hydroxy Optionally substituted with one or more substituents selected from hydroxyl groups,
R _f is C _{1 -6} - alkyl, C _{3 -7} - cycloalkyl, C _{3 -7} - cycloalkyl, -C _{1 -6} - alkyl, C _{1 -6} - alkyloxy -C _{1 -6} - alkyl, hydroxy -C _{1 -6} - alkyl, C _{1 -6} - represents an alkyl or benzyl fluoro,
R ₄ and R ₅ are independently from each other hydrogen or C _{1 -6} -alkyl, C _{3 -7-cycloalkyl,} or C _3-7 - cycloalkyl, -C _{1 -6} - represents an alkyl
A compound of formula I, characterized in that The method according to any one of claims 1 to 6,
Cyclic amines formed by -NALB- are (3S) -3-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperazine -1-yl, (3R) -3-isopropylpiperazin-1-yl, (cis) -5-methylhexahydropyrrolo [3,4-c] pyrrole-2 (1H) -yl or 4-pi Represents a Ralidin-1-ylpiperidin-1-yl group,
R ₂ represents a pyridyl group optionally substituted with one or more substituents selected from fluorine and a methyl group,
R ₃ represents a hydrogen atom or a methyl group,
R ₇ and R ₈ represent a hydrogen atom or a methyl group
A compound of formula I, characterized in that in base form or in acid addition salt form. A process for preparing a compound of formula (I) according to claim 1 characterized by reacting a compound of formula (II) with an amine of formula (IIa):
<Formula II>

Wherein R ₂ , R ₃ , R ₇ and R ₈ are as defined in claim 1 and X ₆ represents halogen.
<Formula IIa>

Wherein A, L and B are as defined in claim 1. A compound of formula (V) comprising a pyridine derivative and an alkyl chloroformate

To the mixture by the reaction of - (wherein the alkyl group is C _{1 -6} represents an alkyl) and then obtain a compound of formula VI, the compound of formula (VI) in o -, comprising a step of oxidation with chloranil, claim 1, wherein Process for the preparation of compounds of formula (I) according to
<Formula V>

Wherein A, L, B, R ₂ , R ₇ and R ₈ are defined in accordance with claim 1
<Formula Va>

Wherein R ₃ is defined in accordance with claim 1
&Lt; Formula (VI)

Wherein A, L, B, R ₂ , R ₃ , R ₇ and R ₈ are defined according to claim 1. By reacting a compound of formula (V) according to an aromatic bromination or iodide reaction to give a compound of formula (VII), and performing a metal-catalyzed coupling between the obtained compound of formula (VII) and a pyridine derivative of formula (IIIa) A process for preparing a compound of formula I according to claim 1
<Formula V>

Wherein A, L, B, R ₂ , R ₇ and R ₈ are defined in accordance with claim 1
(VII)

Wherein A, L, B, R ₂ , R ₇ and R ₈ are defined according to claim 1 and X ₃ represents a bromine or iodine atom
<Formula IIIa>

Wherein R ₃ is as defined in claim 1 and M represents a trialkylstannyl group or a dihydroxyboryl or dialkyloxyboryl group. a) reacting a compound of formula VIII according to an aromatic iodide reaction to obtain a compound of formula IX
b) reacting a compound of formula IX obtained in a) with a compound of formula IIIa to give a compound of formula
c) reacting the compound of formula X obtained in b) with a compound of formula Xa in the presence of a catalyst
A process for preparing a compound of formula (I) according to claim 1, characterized in that
<Formula VIII>

Wherein A, L, B, R ₇ and R ₈ are defined in accordance with claim 1
<Formula IX>

Wherein A, L, B, R ₇ and R ₈ are defined in accordance with claim 1
<Formula IIIa>

Wherein R ₃ is defined according to claim 1 and M represents a trialkylstannyl group or a dihydroxyboryl or dialkyloxyboryl group
<Formula X>

Wherein A, L, B, R ₃ , R ₇ and R ₈ are defined in accordance with claim 1
<Formula Xa>

Wherein R ₂ is defined according to claim 1 and M represents a trialkylstannyl group or a dihydroxyboryl or dialkyloxyboryl group. A medicament comprising the compound of formula (I) according to any one of claims 1 to 7 in base form or in pharmaceutically acceptable acid addition salt form. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 in base form or in pharmaceutically acceptable acid addition salt form and also at least one pharmaceutically acceptable excipient. Preventing or treating sleep or circadian rhythm disorders, mood disorders, anxiety and depressive disorders, diseases associated with dependence on abuse substances, diseases associated with hyperphosphorylation of tau protein, diseases caused or exacerbated by cell proliferation, or inflammatory diseases Use of a compound of formula (I) according to any one of claims 1 to 12 in the manufacture of a medicament for