CA2747365A1 - Derivatives of 6-cycloamino-2,3-di-pyridinyl-imidazo[1,2-b]-pyridazine, preparation and therapeutic application thereof - Google Patents

Abstract

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

Description

6-CYCLOAMINO-2,3-DI-PYRIDINYL-I MIDAZO [1,2-b] -PYRIDAZINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION.

The present invention relates to 6-cycloamino-2,3-di-derivatives.
pyridinyl imidazo [1,2-b] pyridazine, their preparation and their application in therapeutic, in the treatment or prevention of diseases involving casein kinase 1 epsilon and / or casein kinase 1 delta.

The subject of the present invention is compounds corresponding to the formula general (I) R7 YN, N

AN N
L, B

In which R2 represents a pyridinyl group optionally substituted with one or many substituents selected from halogen atoms and C 1-6 alkyl groups;

R3 represents a hydrogen atom or a C3-alkyl group.
- A represents a C, _, - alkylene group optionally substituted by one or two Ra groups;
- B represents a group C, _, - alkylene optionally substituted by a group Rb;
L represents either a nitrogen atom optionally substituted by an Rc group or Rd, either a carbon atom substituted by a group Re, and a group Rd or two Reg groups;

the carbon atoms of A and B being optionally substituted with one or several groups Rf identical or different from each other Ra, Rb and Rc are defined as:

2 two groups Ra may together form a C 1 -C 6 alkylene group;
Ra and Rb may together form a bond or a C1-C6 alkylene group;
Ra and Rf may together form a bond or a C6-alkylene group;
Rb and Rf may together form a bond or C6-alkylene group;
Rd represents a group selected from the hydrogen atom and C groups, alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-6 alkylthio-C 1-6 alkyl, C, .6-alkyloxy-C1-6alkyl, C6-6-fluoroalkyl, benzyl, C6-acyl, hydroxy-C6-alkyl;

Re, represents a group -NR4R5 or a cyclic monoamine comprising optionally an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents selected from atom fluorine and C 1-6 alkyl, C 1-6 alkyloxy or hydroxyl groups;

Two Regs form with the carbon atom that carries them a cyclic monoamine optionally comprising an oxygen atom, this cyclic monoamine being optionally substituted with one or more identical Rf groups or different from each other;

Rf is C, _6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C6;
alkyl, C, .6-alkyloxy-C1-6alkyl, hydroxy-C1-6alkyl, C1-6-fluoroalkyl or benzyl;

R4 and R5 represent, independently of one another, a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl;
- R7 and R8 represent, independently of one another, a hydrogen atom or one C 1 -C 6 alkyl group.

The compounds of formula (I) can comprise one or more atoms of carbon asymmetrical. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or salts of addition to acids. Such addition salts are part of the invention. These salts are

3 advantageously prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for purification or the isolation of compounds of formula (I) are also part of the invention.

The compounds of formula (I) may also exist in the form of hydrates or of solvates, namely in the form of associations or combinations with one or several molecules of water or with a solvent. Such hydrates and solvates make also part of the invention.

In the context of the invention, the following terms mean:
- Ct_Z where t and z can take values from 1 to 7, a carbon chain may have from t to z carbon atoms, for example C, _, a chain carbon which may have 1 to 7 carbon atoms;
alkyl, a saturated, linear or branched aliphatic group; for example a group C, _6-alkyl represents a carbon chain of 1 to 6 carbon atoms, linear or branched, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terbutyl, pentyl, hexyl;
alkylene, a saturated divalent alkyl group, linear or branched, for example a group C, _6-alkylene represents a divalent carbon chain of 1 to 6 carbon atoms, linear or branched, for example methylene, ethylene, 1-methylethylene, propylene;
cycloalkyl, a cyclic alkyl group, for example a C3 -7 group;
cycloalkyl represents a cyclic carbon group of 3 to 7 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl acyl, an alkyl-C (O) - group;
hydroxyl, an -OH group;
cyclic monoamine, a cyclic saturated carbon chain containing 1 nitrogen atom;
hydroxyalkyl, an alkyl group of which one hydrogen atom has been substituted by a hydroxyl group;
alkyloxy, a -O-alkyl group;
alkylthio, a -S-alkyl group;
fluoroalkyl, an alkyl group of which one or more hydrogen atoms summer substituted with a fluorine atom;

4 fluoroalkyloxy, an alkyloxy group including one or more hydrogen atoms have been substituted with a fluorine atom;
a halogen atom, a fluorine, chlorine, bromine or iodine atom;
aryl, a mono- or bicyclic aromatic group comprising between 6 and 10 carbon atoms. As an example of an aryl group, mention may be made of phenyl or naphthyl groups.

By way of non-limiting examples of cyclic amines or diamines formed by N, A, L and B, mention may in particular be made of aziridine, azetidine, pyrrolidine, piperidine azepine, morpholine, thiomorpholine, homopiperidine, decahydro-quinoline, decahydroisoquinoline, azabicycloheptane, azabicyclooctane, the azabicyclo nonane, aza-oxo-bicyclo-heptane, aza-thia-bicyclo-heptane, aza-oxo bicyclo-octane, aza-thia-bicyclooctane; piperazine, homopiperazine, diaza-cyclohexane octane, diaza-cyclo-nonane, diaza-cyclo-decane, diaza-cyclo-undecane, octahydro-pyrrolo-pyrazine, octahydro-pyrrolo-diazepine, octahydro-pyrrolo-pyrrole, octahydro-pyrrolo-pyridine, decahydro-naphthyridine, diaza-bicyclo heptane, the diaza-bicyclooctane, diaza-bicyclo-nonane, diaza-spiro-heptane, diaza-spiro octane, diaza-spiro-nonane, diaza-spiro-decane, diaza-spiro-undecane, the oxa-diaza-spiro-undecane.
Among the compounds of general formula (I) which are the subject of the invention, a first group of compound is constituted by compounds for which:
L represents either a nitrogen atom optionally substituted by an Rc group or Rd, either a carbon atom substituted with a Re group and a Rd group;
the other substituents being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a second group of compound is constituted by compounds for which:
R2 represents a pyridinyl group, optionally substituted with one or many substituents selected from fluorine and methyl group the other substituents being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a third group of compound is constituted by compounds for which:
- R3 represents a hydrogen atom or a methyl group;

the other substituents being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a fourth group of compound is constituted by compounds for which:

R7 and R8 represent a hydrogen atom or a methyl group;
the other substituents being as defined above.

Among the compounds that are the subject of the invention, a fifth group of compounds is consisting of compounds for which:
- A represents a C, _, - alkylene group optionally substituted by one or two Ra groups;
- B represents a group C, _, - alkylene optionally substituted by a group Rb;
L represents either a nitrogen atom optionally substituted by an Rc group or Rd the carbon atoms of A and B being optionally substituted with one or several groups Rf identical or different from each other Ra, Rb and Rc are defined as:
two groups Ra may together form a C 1 -C 6 alkylene group;
Ra and Rb may together form a bond or a C1-C6 alkylene group;
Ra and Rc may together form a bond or a C1-C6 alkylene group;
Rb and Rc may together form a bond or a C1-C6 alkylene group;

Rd represents a group selected from the hydrogen atom and C groups, alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-6 alkylthio-C 1-6 alkyl, C, .6-alkyloxy-C1-6alkyl, C6-6-fluoroalkyl, benzyl, C6-acyl, hydroxy-C6-alkyl;

Rf is C, _6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C6;
alkyl, C, .6-alkyloxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -fluoroalkyl or benzyl;

the other substituents are as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a sixth group of compound is constituted by compounds for which:

6 - A represents a C, _, - alkylene group optionally substituted by one or two Ra groups;
- B represents a group C, _, - alkylene optionally substituted by a group Rb;
L represents a carbon atom substituted by a Re group and a Rd group ;
the carbon atoms of A and B being optionally substituted with one or several groups Rf identical or different from each other Ra, Rb and Rc are defined as:
two groups Ra may together form a C 1 -C 6 alkylene group;
Ra and Rb may together form a bond or a C1-C6 alkylene group;
Ra and Rc may together form a bond or a C1-C6 alkylene group;
Rb and Rc may together form a bond or a C1-C6 alkylene group;

Rd represents a group selected from the hydrogen atom and C groups, alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-6 alkylthio-C 1-6 alkyl, C, .6-C 1 -C 6 alkyloxy, C 1 -C 6 -fluoroalkyl, benzyl, C 1 -C 6 acyl, C 1 -C 6 hydroxy;
alkyl;

Re1 represents a group -NR4R5 or a cyclic monoamine comprising optionally an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents selected from atom fluorine and C 1-6 alkyl, C 1-6 alkyloxy or hydroxyl groups;

Rf is C, _6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C6;
alkyl, C, .6-C 1 -C 6 alkyloxy, hydroxyC 1-6 alkyl, C 1-6 fluoroalkyl or benzyl;

R4 and R5 represent, independently of one another, a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-6 alkyl;
the other substituents are as defined above.
Among the compounds of general formula (I) which are the subject of the invention, a seventh group of compound is constituted by compounds for which:
the cyclic amine formed by -NALB- represents a piperazinyl group or hexahydropyrrolopyrrolyl, optionally substituted by one or more groups C, .6-alkyl;

7 the other substituents are as defined above.

Among the compounds of general formula (I) which are the subject of the invention, an eighth group of compounds is constituted by compounds for which:
the cyclic amine formed by -NALB- represents a pyrrol idinyl group;
piperidinyl;
R2, R3, R7, R8 being defined as above.

Among the compounds of general formula (I) which are the subject of the invention, a ninth group of compound is constituted by compounds for which:
the cyclic amine formed by -NALB- represents a (3S) -3-methyl-piperazin-1-yl, 3,3-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperazin-1-yl, (3R) -3-isopropyl-piperazin-1-yl, (cis) -5-methyl-hexahydro-pyrrol o [3,4-c] pyrrol 2 (1H) -yl;
the other substituents are as defined above.
Among the compounds of general formula (I) which are the subject of the invention, one tenth group of compound is constituted by compounds for which:
the cyclic amine formed by -NALB- represents a 4-pyrrolidin-1-yl-piperidin-1-yl;
the other substituents are as defined above.

Among the compounds of general formula (I) which are the subject of the invention, an eleventh group of compound is constituted by compounds for which:
the cyclic amine formed by -NALB- represents a (3S) -3-methyl-piperazin-1-yl, 3,3-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, piperazin-1-yl, (3R) -3-isopropyl-piperazin-1-yl, (cis) -5-methyl-hexahydro-pyrrol o [3,4-c] pyrrol 2 (1H) -yl, 4-pyrrolidin-1-yl-piperidin-1-yl;
R2 represents a pyridinyl group, optionally substituted with one or many substituents selected from fluorine and methyl;
- R3 represents a hydrogen atom or a methyl group;
R7 and R8 represent a hydrogen atom or a methyl group;
In the form of a base or an acid addition salt.

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

WO 2010/07023

8 PCT / FR2009 / 052594 6 - [(3S) -3-Methyl-piperazin-1-yl] -3- (pyridin-4-yl) -2- (pyridin-3-yl) -imidazo [1,2-b] pyridazine;
6 - [(3S) -3-Methyl-piperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2- (pyridin-3-yl) -imidazo [1,2-b] pyridazine;
6- (3,3-Dimethyl-piperazin-1-yl) -3- (pyridin-4-yl) -2- (pyridin-3-yl) -imidazo [1,2-b] pyridazine;
6- (4-Isopropyl-piperazin-1-yl) -3- (pyridin-4-yl) -2- (pyridin-3-yl) -imidazo [1,2-b] pyridazine;
6- (4-Isopropyl-piperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2- (pyridin-3-yl) -imidazo [1,2-b] pyridazine;
2- (5-Fluoro-pyridin-3-yl) -6 - [(3S) -3-methyl-piperazin-1-yl] -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
2- (5-Fluoro-pyridin-3-yl) -6 - [(3S) -3-methyl-piperazin-1-yl] -3- (2-methyl-pyridin 4-yl) -imidazo [1,2-b] pyridazine;
2- (5-Fluoro-pyridin-3-yl) -6- (4-isopropyl-piperazin-1-yl) -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
6- (4-Isopropyl-piperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2- (5-methyl-pyridin-3-yl) -imidazo [1,2-b] pyridazine;
6-piperazin-1-yl-2,3-di- (pyridin-4-yl) imidazo [1,2-b] pyridazine;
6 - [(3S) -3-Methyl-piperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
6- (3,3-Dimethyl-piperazin-1-yl) -2,3-di (pyridin-4-yl) -imidazo [1,2-b] pyridazine ;
6- (3,3-Dimethyl-piperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
6- (3,3-Dimethyl-piperazin-1-yl) -8-methyl-2,3-di (pyridin-4-yl) -imidazo [1,2-b] pyridazine 6 - [(3R) -3-Isopropyl-piperazin-1-yl] -2,3-di (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
6- (4-Isopropyl-piperazin-1-yl) -2,3-di (pyridin-4-yl) -imidazo [1,2-b] pyridazine ;
6- (4-Isopropyl-piperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
6 - [(cis) -5-Methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -2,3-di (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
2,3-Di (pyridin-4-yl) -6- (4-pyrrolidin-1-yl-piperidin-1-yl) -imidazo [1,2-b] pyridazine;
2- (2-Fluoro-pyridin-4-yl) -6 - [(3S) -3-methyl-piperazin-1-yl] -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
2- (2-Fluoro-pyridin-4-yl) -6 - [(3S) -3-methyl-piperazin-1-yl] -3- (2-methyl-pyridin 4-yl) -imidazo [1,2-b] pyridazine;

9 2- (2-Fluoro-pyridin-4-yl) -6- (4-isopropyl-piperazin-1-yl) -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazine;
2- (2-Fluoro-pyridin-4-yl) -6- (4-isopropyl-piperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -imidazo [1,2-b] pyridazine;
According to the invention, the compounds of general formula can be prepared (I) according to the general method described in Scheme 1 below.

RN
N / 2 X6 N1 ~

(III) (IV) M

NOT
R (IIIa) H s YEAR

AN N (IIa) (II) (I) In general and as illustrated in Figure 1, the derivatives of cycloamino-2,3-di-pyridinylimidazo [1,2-b] pyridazine of the general formula (I) in which R2, R3, A, L, B, R7 and R8 are as defined above may be be prepared from a 3- (pyridin-4-yl) imidazo [1,2-b] pyridazine derivative of the formula general (11), wherein R2, R3, R7 and R8 are as defined above and X6 represents a leaving group such as a halogen by treatment with an amine of formula general (IIa) in which A, L and B are as defined above.
This reaction can be carried out by heating the reagents in a solvent polar as pentanol or dimethylsulfoxide.

The imidazo [1,2-b] pyridazine derivatives of the general formula (II) can be prepared By metallocatalyzed coupling between a 3-haloimidazo derivative [1,2-b] pyridazine of general formula (III) in which R2, X6, R7, and R8 are such that defined above and X3 represents a halogen such as bromine or iodine and more especially iodine and a pyridine derivative of general formula (IIIa) in which R3 is such as defined above above and M represents a trialkylstannyl group, most frequently a

Tributylstannyl group, or a dihydroxyboryl group or dialkyloxyboryl, the most frequently a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group according to the conditions of Stille or Suzuki.
The couplings according to the Stille method are for example made by heating in presence of a catalyst such as tetrakis (triphenylphosphine) palladium, iodide copper, in a solvent such as N, N-dimethylacetamide.
The couplings according to the Suzuki method are for example made by heater in the presence of a catalyst such as 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium, a mineral base such as the cesium carbonate, in a solvent mixture such as dioxane and water.
3-Haloimidazo [1,2-b] pyridazine derivatives of general formula (III) are obtained by bromination or regioselective iodination of an imidazo derivative [1,2-b] pyridazine of general formula (IV), wherein R2, X6, R7 and R8 are such as defined above. 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.
The imidazo [1,2-b] pyridazine derivatives of general formula (IV) are known (Newspaper of Heterocyclic Chemistry (2002), 39 (4), 737-742) or can be prepared by analogy with methods known to those skilled in the art In a second alternative, according to scheme 2, the 6-cycloamino derivatives are 2,3-di-pyridinylimidazo [1,2-b] pyridazine of general formula (I) as defined above above, can be prepared in two stages from an imidazo derivative [1,2-b] pyridazine of general formula (V) in which R2, A, L, B, R7 and R8 are such that defined previously.

11 , NR2 AN N
II
LB (V) O
\ R3 CI O Alkyl (Goes) R $ R 8 R7 ~ NR
R 7 / ~ N

AN DN, ~ N 2 AN N

LB
(VII) R

lkyl M
O
R3 (VI) NOT
(Illa) R8 o / 0 ' this A -NN R2 0 Ci -NN C ' LB

(I) According to a first approach, the reaction of an imidazo derivative [1,2-b] pyridazine general formula (V) on the mixture of a pyridine derivative of formula General (Va) wherein R3 is defined as above, and chloroformate of alkyl in wherein the alkyl group represents a C 1 -C 6 alkyl, for example the chloroformate

12 of ethyl, leads to the derivative of general formula (VI) in which R2, A, L, B, R3, R7 and R8 are as defined above. The derivative of general formula (VI) is then oxidized with ortho-chloroanil in a solvent such as toluene for drive to 6-cycloamino-2,3-di-pyridinylimidazo [1,2-b] pyridazine derivatives of formula General (I).

According to a second approach, bromination or aromatic iodation regioselective derivative of imidazo [1,2-b] pyridazine derivatives of the general formula (V) pipe to 3-bromo or iodo-imidazo [1,2-b] pyridazine derivatives of the general formula (VII) wherein R2, A, L, B, R7 and R8 are as defined above and X3 represents a halogen such as bromine or iodine, more particularly iodine. This reaction can be carried out using N-bromo- or iodosuccinimide or monochloride diode in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or the chloroform.
The 6-cycloamino-2,3-di-pyridinylimidazo [1,2-b] pyridazine derivatives of formula (I), are then prepared by metallocatalytic coupling between these derivatives of 3-bromo- or iodoimidazo [1,2-b] pyridazine of the general formula (VII) and a derivative of pyridine of general formula (IIIa) as defined above according to the Stille conditions or Suzuki.
In a third alternative, according to scheme 3, the 6-cycloamino derivatives are 2,3-di-pyridinylimidazo [1,2-b] pyridazine of general formula (I) as defined above above, can be prepared in three stages from a derivative of 2-bromoimidazo [1,2-b] pyridazine of general formula (VIII) in which A, L, B, R7 and R8 are such as previously defined.
The regioselective aromatic iodination of imidazo [1,2-b] pyridazine derivatives formula (VIII) leads to 2-bromo-3-iodoimidazo [1,2-b] pyridazine derivatives of general formula (IX) in which A, L, B, R7 and R8 are as defined above.
above.
This reaction can be carried out using N-iodosuccinimide or monochloride iodine in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.

13 Rs Rs R7 / 5_N R7 / N
Br Br YEAR DNN
LB LB
(VIII) (IX) M

(IIIa) Rs Rs R R2M R / ~
'5_N Br N R2 (Xa) N
AN Y AN Y

LB

(I) (X) A first regioselective metallocatalytic coupling reaction between these derivatives 2-bromo-3-iodo-imidazo [1,2-b] pyridazine of the general formula (IX) and a derivative of pyridine of general formula (IIIa) as defined above according to the Stille conditions or Suzuki, leads to 2-bromo-imidazo [1,2-b] pyridazine of the general formula (X) wherein A, L, B, R3, R7 and R8 are defined as above.
Finally, a second metallocatalytic coupling reaction between a 2-bromo derivative iodo-imidazo [1,2-b] pyridazine of the general formula (X) and a pyridine derivative of general formula (Xa) wherein R2 is as defined above and M
represents a trialkylstannyl group, most frequently a tributylstannyl group, or one dihydroxyboryl or dialkyloxyboryl group, most frequently a group 4,4,5,5 tetramethyl-1,3,3,2-dioxaborolan-2-yl under the conditions of Stille or Suzuki, leads to 6-cycloamino-2,3-di-pyridinylimidazo [1,2-b] pyridazine of formula General (I) as defined above

14 The couplings according to the Stille method are for example made by heating in presence of a catalyst such as tetrakis (triphenylphosphine) palladium, iodide copper, in a solvent such as N, N-dimethylacetamide.

precursors 3-pyridin-4-ylimidazo [1,2-b] pyridazine derivatives of general formula (V) such as defined above can be prepared by condensation between a derivative of pyridazin 3-ylamine of general formula (XI) wherein A, L, B, R7 and R8 are such that defined above and a 2-bromo, chloro- or iodoethan-1-one derivative of the formula General (Xla) wherein R2 is as defined above and X represents an atom bromine, chlorine or iodine.
The reaction can be carried out by heating the reagents in a solvent polar than ethanol or butanol.
The pyridazin-3-ylamine derivatives of general formula (XI) are known (Journal of Medicinal Chemistry (2008), 51 (12), 3507-3525) or can be prepared by analogy with methods known to those skilled in the art.

3-pyridin-4-ylimidazo [1,2-b] pyridazine derivatives of general formula (V) such as defined above can also be prepared by coupling reaction metallocatalyzed between 2-bromo-imidazo [1,2-b] pyridazine derivatives of formula (VIII) as defined above and a pyridine derivative of formula (Xa) as defined above under the conditions of Stille or Suzuki.

The 2-bromo-imidazo [1,2-b] pyridazine derivatives of general formula (VIII) can be prepared from a 2-bromo-imidazo [1,2-b] pyridazine derivative of the formula General (XII), wherein R7 and R8 are as defined above and X6 represents a group starting such as a halogen more particularly the chlorine by treatment with way an amine of general formula (IIa) as defined above. This reaction can be carried out by heating the reagents in a polar solvent such as the pentanol or dimethylsulfoxide.
The 2-bromo-imidazo [1,2-b] pyridazine derivatives of general formula (XII) are obtained in two steps from a 5-halogenopyridazin-3-ylamine of formula (XIV) or X6 represents a leaving group such as a halogen plus particularly chlorine and R7 and R8 are as defined above.
Thus, 5-Halo-pyridazin-3-ylamine derivatives of general formula (XI) are alkylated medium of 2-bromo or 2-chloro-alkyl acetate, for example 2-bromoacetate of ethyl to yield a hydrobromide or a hydrochloride of 6-amino-3-halogeno-1- (alkyloxycarbonylmethyl) -pyridazin-1-ium of the general formula (XIII) for which X6 represents a leaving group such as a halogen plus especially the 5 chlorine while R7 and R8 are as previously defined. The hydrobromide or 6-amino-3-halo-1- (alkyloxycarbonylmethyl) -pyridazin-1-ium hydrochloride of general formula (XIII) are cyclized by means of phosphorus oxybromide for give the 2-bromo-3- (pyridin-4-yl) imidazo [1,2-b] pyridazine derivatives of formula General (XII).
O
Rs ~ R2 Rs AN Y AN Y
II (XIa) II
LB (XI) LB
(V) H (Xa) YEAR

Rs LB
(IIa) R7 ~ N
R7 N Br Br N
N Y N

LB
(XII) (VIII) Br Rs Rs R7 NI-12 OEt R7 NI-12 N Br N

O OEt (XIV) (XIII) In the foregoing, the term "leaving group" means a group that can be easily cleaved from a molecule by breaking a heterolytic bond, with starting of a pair electronic. This group can, for example, be easily replaced by a another group during a substitution reaction. Such starting groups are, by for example, halogens or an activated hydroxy group such as a mesyl, tosyl, triflate, acetyl, etc. Examples of starting groups as well as references for their preparations are given in Advances in Organic Chemistry, J. March, 3rd Edition, Wiley Interscience, p. 310-316.

Protective groups For the compounds of general formula (I) or (IIa) as defined above above and in the case where the NALB group comprises a primary amine function or secondary function, this function may possibly be protected during synthesis by a protecting group, for example benzyl or t-butyloxycarbonyl.

The following examples describe the preparation of certain compliant compounds at the invention. These examples are not limiting and are only illustrative the invention. The The numbers of the exemplified compounds refer to those given in Table 1, after, which illustrate the chemical structures and physical properties respectively of some compounds according to the invention.

Example 1 (Compound No. 13): 6- (3,3-Dimethylpiperazin-1-yl) -3- (2-methylpyridin) yl) -2- (pyridin-4-yl) -imidazof1,2-blpyridazine NOT
H C3C ~ ~ N / \ N
s \ NN
JST

LN

Step 1.1. 6-Chloro-2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine NC \ / NN
CI N

To a solution of 24.0 g (85.3 mmol) of 3-amino-6-chloro-pyridazine in 1.5 The of ethanol under reflux, 33.2 g (256 mmol) of hydrobromide 2-bromo-1- (pyridin-4-yl) -ethanone (CAS 5469-69-2) then 12.0 ml (85.4 mmol) of triethylamine drop by drop in 45 minutes. The mixture is refluxed while 3 hours. After cooling, the solvent is evaporated under reduced pressure and the reddish-brown residue is taken up with chloroform and 300 ml of a solution of 1N sodium hydroxide. After 15 minutes of stirring, the mixture is filtered, the residue solid washed with chloroform. The organic phase is separated, washed with water, dried on sodium sulphate to give 13 g of a brown solid after evaporation of solvent.
The residue is purified on a column of 500 g of silica gel, eluting with a mixed dichloromethane, methanol and ammonia (97/3 / 0.3) to give 10.1 g of 6-chloro-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine as a beige solid dark after trituration in diisopropyl ether, filtration and drying under pressure scaled down.

1H NMR (DMSOd6) δ: 9.15 (s, 1H); 8.70 (d, 2H); 8.30 (d, 1H); 8.0 (d, 2H);
7.45 (d, 1 H) ppm.

Step 1.2. 6-Chloro-3-iodo-2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine NC \ / NN
CI N

To a solution of 10.4 g (45.1 mmol) of 6-chloro-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine in 1 L of chloroform, added at room temperature, 21.9 g (135 mmol) of iodine chloride in 100 ml of methanol. After 24 hours of reaction, the mixture is then poured on a saturated solution of sodium bicarbonate and the mixture is decolorized by addition of an aqueous solution of 5% thiosulphate of sodium. The organic phase is separated, dried over sodium sulphate and concentrated under reduced pressure to give 14.4 g of 6-chloro-3-iodo-2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine as a beige solid, containing about 10% of chloro-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine after trituration in 200 ml acetonitrile, filtration and drying.
1 H NMR (DMSOd 6) δ: 8.75 (d, 2H); 8.30 (d, 1H); 8.15 (d, 2H); 7.50 (d, 1H) ppm.
Step 1.3. 6-Chloro-3- (2-methyl-pyridin-4-yl) -2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine NOT

NOT
CI N

NOT

To a mixture of 2.85 g (6.39 mmol) of 6-chloro-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine, 1.14 g (6.12 mmol) of (2-methyl-4-pyridinyl) boronic acid (CASE
579476-63-4) and 6.3 g (19 mmol) of cesium carbonate in 400 ml of a mixture of tetrahydrofuran and water (9/1) is added after degassing with argon 0.47 g (0.58 mmol) of 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) (CAS 72287-26-4). The mixed is stirred at reflux for 18 hours. The mixture is concentrated under pressure scaled down the residue is taken up with chloroform. The organic phase is washed with the water, dried over sodium sulphate and the solvent evaporated under reduced pressure. The residue is purified on a column of 110 g of silica gel, eluting with a mix of dichloromethane, methanol and ammonia (96/4 / 0.4) to give 1.35 g of chloro-3- (2-methyl-pyridin-4-yl) -2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine form of a white powder after trituration in acetonitrile, filtration and drying.
PF: 218-222 ° C
1H NMR (DMSOd6) δ: 8.60 (d, 1H); 8.55 (d, 2H); 7.95 (d, 1H); 7.50 (d, 2H) ; 7.35 (s, 1H); 7.25 (d, 1H); 7.15 (d, 1H); 2.60 (s, 3H) ppm.

Step 1.4. 6- (3,3-Dimethylpiperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2-(Pyridin-4-yl) -imidazo [1,2-b] pyridazine NOT

NN
JST

LN

A mixture of 0.500 g (1.55 mmol) of 6-chloro-3- (2-methyl-pyridin-4-yl) -2-(pyridin 4-yl) -imidazo [1,2-b] pyridazine and 0.52 g (4.7 mmol) of dimethylpiperazine in 5 ml of pentanol is refluxed for 24 hours at 150 ° C.
middle The reaction mixture is cooled and poured into an aqueous solution of hydrochloric aqueous 2N. The aqueous phase is washed with diethyl ether and then basified to 2N aqueous sodium hydroxide solution and the product is extracted with chloroform. The organic phase is dried over sodium sulphate and the solvent evaporated under reduced pressure. The solid obtained is purified on 35 g of gel of silica in eluent with a mixture of dichloromethane, methanol and ammonia (94/6 / 0.6) to give 0.17 g of 6- (3,3-dimethylpiperazin-1-yl) -3- (2-methyl-pyridin-4-yl) -2-(pyridin-4-yl) imidazo [1,2-b] pyridazine as a beige powder after dissolution in 10 ml of acetonitrile and crystallization by addition of diethyl ether, filtration and drying.
PF 185-187 ° C
1H NMR (CDCl3) δ: 8.60 (m, 3H); 7.80 (d, 1H); 7.60 (d, 2H); 7.50 (s, 1H);
7.40 (d, 2H); 6.95 (d, 1H); 3.45 (dd, 2H); 3.30 (s, 2H); 3.10 (dd, 2H); 2.65 (s, 3H); 1.2 (s, 6H) ppm.

Example 2 (Compound No. 14): 6- (3,3-Dimethyl-piperazin-1-yl) -8-methyl-2,3-di-(Pyridin-4-yl) -imidazo [1,2-blpyridazine NOT

JST

NOT

Step 2.1. 3-Amino-6-chloro-4-methyl-pyridazine and 3-amino-6-chloro-5-methyl-pyridazine H3C n, N11 NH2NH2 CI CI NN

In an autoclave, a suspension of 50.0 g (307 mmol) of 3,6-dichloro-4-methyl Pyridazine in 170 ml of 30% ammonia is heated at 120 ° C. for 18 hours.
hours. After cooling, the mixture is poured into 200 ml of water and the solid is recovered by filtration. After drying under reduced pressure the mixture of products is recrystallized from ethyl acetate to give 40 g of a mixture of 3-amino-6-Chloro-4-methyl-pyridazine and 3-amino-6-chloro-5-methyl-pyridazine (32/68).
1H NMR (CDCl3): 7.15 and 6.75 (s and s, 1H); 5.0 (wide signal, 2H); 2.35 and 2.25 (s and s, 3H).

Step 2.2. 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methylbromide pyridazin-1-ium and 6-amino-3-chloro-1-ethoxycarbonylmethyl-4-methyl-pyridazin-1-

15 ium H3C n, 11 NH2 NH2 CI N- It N
Br CI N Br H3C.1 ~ OO H3CO O

To a solution of 36.0 g (251 mmol) of the mixture of 3-amino-6-chloro-4-methyl-pyridazine and 3-amino-6-chloro-5-methyl-pyridazine (32/68) in 350 ml ethanol At reflux, 30.6 ml (275 mmol) of 2-bromoacetate are added per portion.
ethyl and the heating is continued for 24 hours. After cooling, middle The reaction mixture is partially concentrated under reduced pressure and is then diluted with 200 ml of acetone, the suspension is cooled to 0 ° C. and the precipitate is separated by filtration.
The filtrate is then partially concentrated under reduced pressure and is then diluted with 150 ml of acetone and the suspension is again cooled to 0 C. The precipitate is separated by filtration and joined to the first jet. After drying, we obtain in total 29.8 g of a mixture of 6-amino-3-chloro-1-ethoxycarbonylmethyl-4- bromide methyl-pyridazin-1-ium and 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methyl-pyridazin-1-ium (30/70).
1 H NMR (MeOD): 7.90 and 7.55 (s and s, 1H); 5.30 and 5.25 (s and s, 2H); 4.35 (q, 2H);
2.50 and 2.45 (s and s, 3H); 1.35 (t, 3H).

Step 2.3. 2-Bromo-6-chloro-bromo-7-methyl-imidazo [1,2-b] pyridazine and 2-bromo-6-chloro-bromo-8-methyl-imidazo [1,2-b] pyridazine H3C / YN N ~ N
\ / Br / NBr Br / CI N Br / CI N

A mixture of 27.8 g (89.5 mmol) of 6-amino-3-chloro-1-ethoxycarbonylmethyl-methyl-pyridazin-1-ium, 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methyl-pyridazin-1-ium (30/70) and 82 g (286 mmol) of phosphorus oxybromide in 100 ml of toluene is heated at 160 ° C. for 1 hour in a sealed tube.
After cooling, the solid deposited on the walls is unhooked and the mixture is paid in 500 ml of water at 0 C. The aqueous phase is then basified by addition of ammonia and after stirring for 1 hour, the product is solubilized by means of of chloroform. The organic phase is separated, dried over sodium sulphate and concentrated under reduced pressure to give 22 g of brown solid. The solid is then purified by chromatography on a column of 450 g of silica gel in eluent with dichloromethane to give 5.0 g of 2-bromo-6-chloro-8-methyl-imidazo [1,2-b] pyridazine containing 2,6-dibromo-8-methyl-imidazo [1,2-b] pyridazine under form of white powder (41/59).
1H NMR (CDCl3): 7.80 (s, 1H); 6.85 and 7.00 (s and s, 1H); 2.55 (s, 3H).

The continuation of the elution with a mixture of dichloromethane, methanol and of ammonia (90/10/1) gives 15.2 g of 2-bromo-6-chloro / bromo-7-methyl-imidazo [1,2-b] pyridazine containing 2,6-dibromo-7-methyl-imidazo [1,2-b] pyridazine in the form of a pink powder.
1H NMR (CDCl3): 7.95 (s, 1H); 7.75 (s, 1H); 2.55 (s, 3H).

Step 2.4. 2-Bromo-6- (3,3-dimethylpiperazin-1-yl) -8-methyl-imidazo [1,2-b] pyridazine H3C 211 - l / NBr H3C-Y ~ NN
JST

A mixture of 4.95 g (about 20 mmol) of 2-bromo-6-chloro-8-methyl-imidazo [1,2-b] pyridazine containing 2,6-dibromo-8-methylimidazo [1,2-b]
b] pyridazine, 2.5 g (22 mmol) of 2,2-dimethylpiperazine and 2.8 ml of triethylamine in 60 ml of pentanol is heated at 150 ° C. for 3 days in a sealed tube. After cooling, the reaction medium is poured into an aqueous solution acid 1N hydrochloric acid. The aqueous phase is washed with ethyl acetate then basified by means of an aqueous solution of ammonia and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and solvent is evaporated under reduced pressure. The beige solid obtained is purified on a column of 80 g of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (95/65 / 0.5) to give 4.6 g of 2-bromo-6- (3,3-dimethyl-piperazin 1-yl) -8-methyl-imidazo [1,2-b] pyridazine as a white powder.
PF 139-141 ° C
1H NMR (CDCl3) δ: 7.65 (s, 11-1); 7.65 (s, 1H); 3.5 (m, 2H); 3.30 (s, 2H);
3.10 (m, 2H) ; 2.60 (s, 3H); 1.25 (s, 6H) ppm.

Step 2.5. 6- (3,3-Dimethylpiperazin-1-yl) -8-methyl-2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine ~ N -NOT
H3C-Y ~ NN
JST
To a mixture of 2.64 g (14.3 mmol) of 2-bromo-6- (3,3-dimethylpiperazine-1) yl) -8-methyl-imidazo [1,2-b] pyridazine and 2.5 g (17 mmol) of acid (4-pyridinyl) boronic acid (CAS 1692-15-5) in 100 ml of a mixture of tetrahydrofuran and water (9/1), we after degassing with argon, 14 g (43 mmol) of cesium and 1.05 g (1.29 mmol) of complex of 1.1%
bis (diphenylphosphino) ferrocenedichloropalladium (11) and dichloromethane (PdC12 (dppf) .CH2CI2). After stirring for 8 hours at reflux, the medium reaction is poured into an aqueous solution of 1N hydrochloric acid. The aqueous phase is washed with ethyl acetate and then basified with an aqueous solution ammonia and the product is extracted with dichloromethane. The sentence organic is dried over sodium sulphate and the solvent is evaporated under pressure scaled down.
The black oil obtained is purified by chromatography on a column of 120 g of silica gel eluting with a mixture of dichloromethane, methanol and ammonia (95/65 / 0.5) to give 3.1 g of 6- (3,3-dimethylpiperazin-1-yl) -methyl-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine as an oil.
1H NMR (CDCl3) δ: 8.70 (d, 2H); 8.15 (s, 1H); 7.85 (d, 2H); 6.70 (s, 1H);
3.55 (m, 2H); 3.30 (s, 2H); 3.15 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm.
Step 2.6. 6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-8-methyl-2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine ~ N -NOT /
H3C-Y ~ NN
JST
To a solution of 3.13 g (9.71 mmol) of 6- (3,3-dimethyl-piperazin-1-yl) -8-methyl-2-(pyridin-4-yl) imidazo [1,2-b] pyridazine in 80 ml of dichloromethane on add to room temperature 19.4 ml (19.4 mmol) of a 1M solution of chloride diode in dichloromethane. After 2 hours of reaction, the solution is then paid on 150 ml of water and is basified by addition of sodium bicarbonate and the mixture is discolored by the addition, per portion, of sodium thiosulfate. The sentence organic is separated, dried over sodium sulfate and concentrated under reduced pressure to give a brown oil which is purified by chromatography on a column of 120 g of silica gel eluting with a mixture of dichloromethane, methanol and ammonia (90/10/1) to give 3.35 g of 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-8-methyl-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine as a beige solid.
PF 153-155 ° C

1 H NMR (CDCl3) δ: 8.75 (d, 2H); 8.15 (d, 2H); 6.75 (s, 1H); 3.70 (m, 2H) ; 3.40 (s, 2H); 3.20 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm.

Step 2.7. 6- (3,3-Dimethylpiperazin-1-yl) -8-methyl-2,3-di- (pyridin-4-yl) -imidazo [1,2-b] pyridazine NOT

JST

NOT
To a mixture of 0.40 g (0.89 mmol) of 6- (3,3-dimethyl-piperazin-1-yl) -3-iodo methyl-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine and 0.155 g (1.07 mmol) acid (4-pyridinyl) boronic (CAS 1692-15-5) in 15 ml of a mixture of tetrahydrofuran and water (9/1) is added after degassing with argon 0.87 g (2.7 mmol) of cesium carbonate and 0.057 g (0.08 mmol) complex of 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (11) and dichloromethane (PdCl2 (dppf) .CH2Cl2 - CAS 851232-71-8). After 18 hours of reaction, the medium The reaction mixture is poured into 150 ml of water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate and solvent is evaporated under reduced pressure. The black oil obtained is purified by chromatography on a column of 40 g of silica gel eluting with a mixed of dichloromethane, methanol and ammonia (95/65 / 0.5) to give 0.039 boy Wut 6- (3,3-dimethylpiperazin-1-yl) -8-methyl-2,3-di- (pyridin-4-yl) imidazo [1,2-b] pyridazine in beige powder form after recrystallization from acetonitrile, filtration and drying.
Mp 211-213 ° C
1 H NMR (CDCl3) δ: 8.70 (d, 2H); 8.60 (d, 2H); 7.60 (m, 4H); 6.75 (s, 1 H) ; 3.45 (m, 2H); 3.25 (s, 2H); 3.05 (m, 2H); 2.70 (s, 3H); 1.20 (s, 6H) ppm.

Example 3 (compound No. 12): 6- (3,3-Dimethylpiperazin-1-yl) -2,3-di- (pyridin-4-) yl) -imidazo 2-blpyridazine YN, N C3, N

JST

NOT
Step 3.1. 6-Chloro-2- (pyridin-4-yl) -imidazo [1,2-b] pyridazine NOT -N / N
CI N ~

A mixture of 3.80 g (28.1 mmol) of 3-amino-6-chloro-pyridazine and 5.00 g (17.8 mmol) of 2-bromo-1- (pyridin-4-yl) -ethanone hydrobromide in 50 mL
ethanol is heated in the microwave at 140 C for 50 minutes. After After cooling, the solvent is evaporated under reduced pressure and the residue is taken again with saturated aqueous sodium hydrogencarbonate solution. The solid is separated by filtration, washed with water and then chromatographed on a column of gel silica eluting with a mixture of dichloromethane and methanol (95/5) for yield 1.97 g of 6-chloro-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine under made of Yellow powder.
LC / MS: M + H + = 231 1 H NMR (CDCl3) δ: 8.71 (dd, 2H); 8.33 (d, 1H); 7.93 (dd, 1H); 7.82 (dd, 2H); 7.11 (d, 1H).

Step 3.2. 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyridin-4-yl) imidazo [1,2-b] pyridazine NC \ / H3C N ~ N
H3CN N ~
JST
A mixture of 1.95 g (8.45 mmol) of 6-chloro-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine and 2.4 g (21 mmol) of 2,2-dimethylpiperazine is heated at oven microwaves at 150 C for 13 hours. The medium is then cooled and the solvent evaporated under reduced pressure. The orange oil obtained is chromatographed sure silica gel column eluting with a mixture of dichloromethane and a 1 M solution of ammonia in methanol in (95/5) to give 1.63 g of 6-(3,3 dimethylpiperazin-1-yl) -2- (pyridin-4-yl) imidazo [1,2-b] pyridazine in the form of of yellow moss.
LC / MS: M + H + = 309 1 H NMR (DMSO-d 6): 8.67 (d, 1H); 8.57 (dd, 2H); 7.86 (m, 3H); 7.23 (d, 1 H); 3.41 (m, 2H); 3.25 (s, 2H); 3.17 (d, 1H); 2.84 (m, 2H); 1.95 (bs, 1H); 1.07 (s, 6H).

Step 3.3. 6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine ~ N -NN ~ ~
HNJ ~

To a solution of 1.37 g (4.45 mmol) of 6- (3,3-dimethylpiperazin-1-yl) -2-(Pyridin-4-yl) -imidazo [1,2-b] pyridazine in 20 ml of chloroform, a solution is added of 1.80 g (11.1 mmol) of iodine monochloride in 5 ml of methanol. The suspension obtained is stirred for 2 hours. A saturated aqueous solution Sodium hydrogencarbonate is added and then added in portions of sodium thiosulfate until the reaction medium remains yellow. The solid is filtered off and air-dried to give 1.95 g of 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine under made of yellow powder.
1 H NMR (DMSO-d6): 9.0 (bs, 2H); 8.70 (d, 2H); 8.10 (d, 2H); 8.00 (d, 1 H) ; 7.38 (d, 1H); 3.85 (m, 2H); 3.70 (m, 2H); 3.3 (m, 2H); 1.40 (s, 6H).

Step 3.4. 6- (3,3-Dimethylpiperazin-1-yl) -2,3-di- (pyridin-4-yl) imidazo [1,2-b] pyridazine YN, N C3 / N

JST

NOT
After degassing, a mixture of 0.28 g (0.55 mmol) of 6- (3,3-dimethylpiperazin) yl) -3-iodo-2- (pyridin-4-yl) imidazo [1,2-b] pyridazine, 0.095 g (0.77 mmol) acid (pyridin-4-yl) boronic acid, 0.89 (2.7 mmol) cesium carbonate and 45 mg (0.055 mmol) of complex 1,1'-bis (diphenylphosphinoferrocenedichlorobenzene) palladium (II) and dichloromethane (PdCl2 (dppf) .CH2Cl2 - CAS 851232-71-8) in 4 ml a mixture of 1,4-dioxane and water (75/2) is heated in the microwave at 105 C
during 30 minutes. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic phase is then dried sure magnesium sulfate, filtered and the solvent evaporated. The oil obtained is chromatographed on silica gel eluting with a mixture of a solution 1 M
of ammonia in a mixture of methanol and dichloromethane (3/97) to give 0.070 g of yellow powder.
LC / MS: M + H + = 386 1 H NMR (DMSO-d6): 8.70 (d, 2H); 8.54 (d, 2H); 7.96 (d, 1H); 7.60 (d, 2H) ; 7.51 (d, 2H); 7.34 (d, 1H); 3.45-3.10 (m, 4H); 2.83 (m, 2H); 1.05 (6H).

Example 4 (Compound No. 3): 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyridin-3-yl) -3-(pyridin-4-yl) imidazof 1,2-blpyridazine NOT

H3C \ NN
JST

NOT

Step 4.1. 6-Chloro-2- (pyridin-3-yl) imidazo [1,2-b] pyridazine ~ N -NOT \
CI NN

A suspension of 2.80 g (11.9 mmol) of 3-amino-6-chloro-pyridazine, of 3.69 boy Wut (13.2 mmol) of 2-bromo-1- (pyridin-3-yl) -ethanone hydrobromide and 3.7 ml (26 mmol) of triethylamine in 45 ml of ethanol is heated with microwaves at for 50 minutes. After cooling, the solvent is evaporated under pressure reduced and the residue is purified by column chromatography of 120 g of gel silica eluting with a mixture of dichloromethane and methanol (95/5) for lead to 0.77 g of product in the form of a beige powder after trituration in heptane, filtration and drying under reduced pressure.
LC / MS: M + H + = 231 1H NMR (DMSO-d6): 9.25 (s, 1H); 9.00 (s, 1H); 8.60 (d, 1H); 8.40 (dt, 1 H); 8.25 (d, 1H); 7.50 (dd, 1H); 7.40 (d, 1H).

Step 4.2. 6- (3,3-Dimethylpiperazin-1-yl) -2- (pyridin-3-yl) imidazo [1,2-b] pyridazine ~ __N -H3C \ N ~ \ N
H3CN N ~
JST
A mixture of 0.77 g (3.3 mmol) of 6-chloro-2- (pyridin-3-yl) imidazo [1,2-b] pyridazine and 1.1 g (9.6 mmol) of 2,2-dimethylpiperazine in 7 ml ethanol is heated in the microwave at 150 C for 13 hours. The middle is then cooled and the solvent evaporated under reduced pressure. The orange oil obtained is chromatographed on a column of silica gel eluting with a mixture of dichloromethane and a 1M solution of ammonia in methanol (97/3) for give 0.89 g of 6- (3,3-dimethylpiperazin-1-yl) -2- (pyridin-3-yl) imidazo [1,2-b] pyridazine as a yellow powder.
LC / MS: M + H + = 309 1H NMR (DMSO-d6): 9.14 (d, 1H); 8.56 (s, 1H); 8.48 (d, 1H); 8.23 (d, 1 H); 7.85 (d, 1H); 7.45 (dd, 1H); 7.20 (d, 1H); 3.41 (t, 2H); 2.86 (t, 2H); 1.95 (bs, 2H); 1.08 (s, 6H).

Step 4.3. 6- (3,3-Dimethylpiperazin-1-yl) -3-iodo-2- (pyridin-3-yl) imidazo [1,2-b] pyridazine ~ N -JST
To a solution of 0.870 g (2.82 mmol) of 6- (3,3-dimethylpiperazin-1-yl) -2-(pyridin 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 of methanol. The suspension orange is then stirred for 3 hours and then the solvent evaporated under pressure reduced to give a residue. A saturated aqueous solution hydrogencarbonate of sodium is then added and then added, in portions, thiosulphate of sodium until the reaction mixture remains yellow. The solid is separated by filtered and air-dried to give 0.90 g of 6- (3,3-dimethylpiperazin-1-yl) -3-iodo-2- (pyridin-3-yl) imidazo [1,2-b] pyridazine as a beige powder.
LC / MS: M + H + = 435 1H NMR (DMSO-d6): 9.26 (s, 1H); 8.57 (d, 1H); 8.39 (d, 1H); 7.92 (d, 1 H); 7.52 (dd, 1H); 7.31 (d, 1H); 3.75-3.10 (m, 6H); 1.25 (s, 6H).

Step 4.4. 6- (3,3-Dimethylpiperazin-1-yl) -2,3-di- (pyridin-3-yl) imidazo [1,2-b] pyridazine ~ N -H3C ~ NN
HN ~
NOT

After degassing, a mixture of 0.400 g (0.92 mmol) of 6- (3,3-dimethylpiperazin) yl) -3-iodo-2- (pyridin-3-yl) imidazo [1,2-b] pyridazine, 0.150 g (1.22 mmol) acid (pyridin-4-yl) boronic acid, of 0.89 (2.7 mmol) of cesium carbonate and 75 mg (0.092 mmol) of complex 1,1'-bis (diphenylphosphinoferrocenedichlorobenzene) palladium (II) and dichloromethane (PdCl2 (dppf) .CH2Cl2) in 6 ml of a mixture of 1,4-dioxane and water (3/1) is heated in the microwave oven at 105 C for 30 minutes.
After cooling, the mixture is diluted with dichloromethane and washed with the water. The organic phase is then dried over magnesium sulfate, filtered and the evaporated solvent to give a green oil. The oil obtained is chromatographed On a 25 g column of silica gel eluting with a mixture of 1M solution ammonia in methanol and dichloromethane (5/95) to give 0.170 g of 6-(3,3-dimethylpiperazin-1-yl) -2,3-di (pyridin-3-yl) -imidazo [1,2-b] pyridazine in the form of gray powder.
LC / MS: M + H + = 386 1H NMR (DMSO-d6): 8.70 (d, 1H); 8.67 (d, 2H); 8.52 (d, 1H); 7.96 (d, 1 H); 7.90 (d, 1H); 7.58 (d, 2H); 7.41 (dd, 1H); 7.33 (d, 1H); 3.40 (t, 2H); 3.25 (s, 2H); 2.84 (t, 2H); 1.06 (s, 6H).

Example 5 (Compound No. 22): 2- (2-Fluoro-pyridin-4-yl) -6- (4-isopropyl-piperazin) Yl) -3- (pyridin-4-yl) imidazo [1,2-blpyridazine]
F
NOT

N / \ / N
NN

I _ Step 5.1. 6-amino-3-chloro-1- (ethoxycarbonylmethyl) -pyridazin-1-bromide ium N Br CI N

20 O O.1_ ~ CH3 A mixture of 25.6 g (198 mmol) of 3-amino-6-chloro-pyridazine in 230 ml hot ethanol is treated with 34.0 g (206 mmol) of ethyl bromoacetate.
After refluxing for 24 hours, the mixture is cooled and the crystals are 25 separated by filtration. 36.6% of product is isolated after drying. We isolate 7.1 g by evaporation of the solvent under reduced pressure and recrystallization in ethanol.
1 H NMR (DMSO d 6) δ: 9.8 (broad signal, 1H); 9.4 (broad signal, 1H); 8.0 (d, 1H); 7.7 (d, 1H); 5.3 (s, 1H); 4.1 (d, 2H); 1.2 (t, 3H) ppm.
Step 5.2. 2-Bromo-6-chloro-imidazo [1,2-b] pyridazine and 2,6-dibromo imidazo [1,2-b] pyridazine Br Br ~ N ~
CI N Br / N

A mixture of 20 g (65 mmol) of 6-amino-3-chloro-1 bromide (ethoxycarbonylmethyl) -pyridazin-1-ium and 63 g of phosphorus oxybromide in 50 ml of toluene is heated at 160 ° C. for 3 hours. The mixture is then versed on ice (300 ml). After stirring, the solid is separated by filtration then purified by chromatography on a column of 120 g of silica gel eluting with a mixture of 0 to 10% methanol in dichloromethane. Is thus isolated 8.05 g of mixture of the two products used as such for the rest of the synthesis.
1H NMR (CDCl3) δ: 7.92 (s, 1H); 7.83 (d, 1H); 7.1 (d, 1H) Step 5.3. 2-Bromo-6- (4-isopropyl-piperazin-1-yl) -imidazo [1,2-b] pyridazine ~
\ N ~ Br rD N

I

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

I

A solution of 2.45 g (14.8 mmol) of iodine chloride in 2 ml of methanol is added dropwise to a solution of 2.45 g (7.56 mmol) of 2-bromo-6- (4-isopropyl-piperazin-1-yl) -imidazo [1,2-b] pyridazine in 20 ml of chloroform 0 C.
The mixture is stirred at ambient temperature for 4 hours. The mixture is so triturated with sodium thiosulfate. This mixture is concentrated under pressure scaled down in the presence of 15 g of silica gel. The residue is deposited on a column of 80 g of silica gel and is purified by chromatography eluting with a gradient of 0 to 10%
of methanol in dichloromethane to give 2.07 g of 2-bromo-3-iodo-6- (4-isopropylpiperazin-1-yl) imidazo [1,2-b] pyridazine as a solid orange.
1H NMR (CDCl3) δ: 7.5 (d, 1H); 6.9 (d, 1H); 3.55 (m, 4H); 3.19 (m, 4H), 3.17 (m, 1H) ; 1.32 (d, 6H) Step 5.5. 2-Bromo-6- (4-isopropyl-piperazin-1-yl) -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazine YN
N Br NN

I

To a mixture of 0.059 g (0.12 mmol) of 2-bromo-3-iodo-6- (4-isopropyl) piperazin 1-yl) -imidazo [1,2-b] pyridazine, 3 mg (0.004 mmol) of 1,1'-dichloride bis (diphenylphosphino) ferrocene palladium (CAS 72287-26-4), 18 mg (0.15 mg) mmol) of pyridin-4-yl-boronic acid (CAS 1692-15-5), 0.9 ml of a solution 2M aqueous cesium carbonate and 1.5 mL 1,4-dioxane in a tube sealed is heated at 110 C for 30 minutes in the microwave oven. 1 ml of a solution saturated with sodium chloride and 4 ml of ethyl acetate are added. After agitation the mixture is pierced through a sodium sulfate cartridge.
The solvent is evaporated to dryness in the presence of silica gel. The absorbed residue is deposited on a column of 4 g of silica gel and eluted with a gradient of 0 to 6% of methanol and 1% ammonia in dichloromethane to give 8.5 mg of bromo-6- (4-isopropyl-piperazin-1-yl) -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazine.
1 H NMR (CDCl3) δ: 8.74 (d, 2H); 7.94 (d, 2H); 7.7 (d, 1H); 6.93 (d, 1H);
3.5 (m, 4H);
2.75 (m, 1H); 2.65 (m, 4H); 1.10 (d, 6H).

Step 5.6. 2- (2-Fluoro-pyridin-4-yl) -6- (4-isopropyl-piperazin-1-yl) -3- (pyridin 4-yl) -imidazo [1,2-b] pyridazine F
NOT

N / \ / N
NN

I _ A mixture of 2.65 g (6.6 mmol) of 2-bromo-6- (4-isopropyl-piperazin-1-yl) -3-(pyridin-4-yl) imidazo [1,2-b] pyridazine, 0.46 g (0.65 mmol) of bis (diphenylphosphino) ferrocene palladium (CAS 72287-26-4), 1.12 g (9.10 mmol) of pyridine-4-boronic acid (CAS 169215-15-5) and 15 ml of solution 2M aqueous cesium carbonate in 25 ml of 1,4-dioxane in a tube sealed is heated at 120 C for 20 minutes. 0.237 g (2.7 mmol) of pyridine additional boronic is added and the reaction is heated to 110 ° C
during 30 minutes. The reaction medium is then diluted with water and the product extracted with ethyl acetate. The organic phase is washed with an aqueous solution saturated with sodium chloride and then dried over sodium sulfate. The solvent is chased under reduced pressure and the residue absorbed on silica gel. The product is purified by chromatography on a column of 80 g of silica gel eluting with a gradient 0 to 10% methanol in dichloromethane to give 1.85 g of 2- (2-fluoro pyridin-4-yl) -6- (4-isopropyl-piperazin-1-yl) -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazine after recrystallization from isopropanol.
Mp 196-198 ° C

1H NMR (CDCl3) δ: 8.74 (d, 2H); 8.15 (d, 1H); 7.80 (d, 1H); 7.56 (d, 2H);
7.39 (d, 1H); 7.25 (d, 1H); 6.98 (d, 1H); 3.50 (m, 4H); 2.76 (m, 1H); 2.62 (m, 4H); 1.08 (d, 6H).

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

In this table :
- the column "PF C" gives the melting points of the products in degrees Celsius.
"ND" means that the melting point is undetermined, - Column [a] D informs the result of the analysis of the rotatory power of the composed of array at the wavelength of 589 nM; the solvent indicated in parentheses corresponds to the solvent used to measure the rotational power in degrees and the letter c indicates the solvent concentration in g / 100 ml. N / A
means that the measurement of the rotatory power is not applicable, the "m / z" column gives the observed molecular ion (M + H +) by analysis of the products by mass spectrometry, or by LC-MS (liquid chromatography coupled to Mass Spectroscopy) performed on an Agilent LC-MSD Trap device in ESI mode positive, either by direct introduction by MS (Mass Spectroscopy) on a apparatus Autospec M (EBE) using the DCI-NH3 technique or using the technical electronic impact on a Waters GCT type device.
- CH3- means methyl, - CH3OH means methanol, - DMSO means dimethylsulfoxide, Table 1 D yN

I`'NN
L, B

PF miz [alo (0) N -NALB-R7 R8 R2 R3 C (M + H +) (solvent;
g / 100 ml) 1 (3S) -3-Methyl-HH pyridin-3-yl H 196- 372 +9.0 piperazin-1-yl 202 (CH3OH
0.535) 2 (3S) -3-Methyl-HH pyridin-3-yl CH 3 129-386 -2.2 piperazin-1-yl 130 (CH3OH
0.37) 3,3-Dimethyl-HH Pyridin-3-yl H 169-386 NA
piperazin-1-yl 171 4-Isopropyl-piperazin-HH pyridin-3-yl H 139-400 NA
1-yI 148 4-Isopropyl-piperazin-HH pyridin-3-yl CH3 63- 414 NA
1-yI 65 6 (3S) -3-Methyl-HH 5-Fluoro- H 172- 390 + 8.2 piperazin-1-yl pyridin-3-yl 173 (CH3OH
0.51) 7 (3S) -3-Methyl-HH 5-Fluoro- CH3 147-404 -3.5 piperazin-1-yl pyridin-3-yl 148 (CH3OH
0.54) 8 4-Isopropyl-piperazin-HH 5-Fluoro- H 171- 418 NA
1-pyridin-3-yl 182 4-Isopropyl-piperazin-HH 5-methyl-CH3 142-42 NA
1-pyridin-3-yl 147 Piperazin-1-yl HH Pyridin-4-yl H 183-358 NA

PF m / z [alo () N -NALB-R7 R8 R2 R3 C (M + H +) (solvent;
g / 100 ml) 11 (3S) -3-Methyl-HH-pyridin-4-yl CH3 55-386 No Piperazin-1-yl 58 determined 12 3,3-Dimethyl-HH Pyridin-4-yl H 149-386 NA
piperazin-1-yl 152 13,3-Dimethyl-HH pyridin-4-yl CH3 185-400 NA
piperazine-1-yl 187 14 3,3-Dimethyl-H CH3 Pyridin-4-yl H 211-400 NA
piperazin-1-yl 213 (3R) -3-Isopropyl-HH pyridin-4-yl H 189-400 +2.9 piperazin-1-yl 191 (DMSO;
0.847)

4-Isopropylpiperazine-HH Pyridin-4-yl H 66-400 NA
1-yl 68

4-Isopropyl-piperazin-HH pyridin-4-yl CH3 195 - 414 NA
1-yl 196

18 (cis) -5-methyl-HH pyridin-4-yl H 189-398 NA
hexahydro- 196 pyrrolo [3,4-c] pyrrol 2 (1H) -yl

19 4-Pyrrolidin-1-yl-HH Pyridin-4-yl H 187- 426 NA
pi perid in-1-yl 189

(3S) -3-Methyl-HH 2-Fluoro- H 150- 390 + 8.2 piperazin-1-yl pyridin-4-yl 152 (CH 3 OH
0.51)

21 (3S) -3-Methyl-HH 2-Fluoro- CH 3 128-404-0.9 piperazin-1-yl pyridin-4-yl 135 (CH 3 OH
0.53)

4-Isopropyl-piperazin-HH 2-Fluoro- H 196- 418 NA
1-pyridin-4-yl

4-Isopropyl-piperazin-HH 2-Fluoro- CH 3 129- 432 NA
1-pyridin-4-yl Biological examples The ability of the compounds of the invention to inhibit the phosphorylation of casein by the casein kinase 1 epsilon and delta can be evaluated according to the procedure described in US20050131012.

ATP-Filter-ATP Assay 33P for Screening CK1 Inhibitors epsilon The effect of compounds to inhibit casein phosphorylation is measured by the enzyme casein kinase 1 epsilon (CK1 epsilon) using a dosage of casein by filtration of ATP33P in vitro.
Casein Kinase 1 epsilon (0.58 mg / ml) is obtained by methods of fermentation and purification carried out according to well known methods of the man of the art or can also be obtained from Invitrogen CorporationTM
(human CK1 epsilon).
The compounds are tested at five different concentrations in order to generate IC50, ie the concentration at which a compound is capable to inhibit activity 50% enzyme, or the% inhibition at a concentration of 10%
micromolar.

U-shaped Falcon plates are prepared by placing 5 μl of compounds according to the invention at concentrations of 10, 1, 0.1, 0.01 or 0.001 pM
in different wells. The solutions of the compounds according to the invention with these different concentrations are prepared by dilution in a test buffer (50 mM Tris pH 7.5, 10 M MgCl 2, 2 mM DTT and 1 mM EGTA) of a stock solution in DMSO at room temperature.
concentration of 10 mM. Next, add 5 μl of dephosphorylated casein to the final concentration of 0.2 μg / μL, 20 μL of CK1 epsilon at concentration final of 3 ng / μL, and 20 μl of ATP33P at the final concentration of 0.02 μCi / μL mixed with Cold ATP (10 μM final - about 2X106 CPM per well). Total volume final test per well is equal to 50 pL.
The Falcon U-bottom test plate cited above is agitated at vortex and then incubated at room temperature for 2 hours. After 2 hours, the reaction is stopped by the addition of an ice-cold solution of 65 μl of cold ATP (2 mM) prepared in test buffer.

100 μl of the reaction mixture are then transferred from the Falcon plate thoroughly.
in U
in MAPH Millipore filter plates, previously impregnated with 25 pL
TCA 100% iced MAPH Millipore filter plates are shaken gently and leave it to rest at room temperature for at least 30 minutes to precipitate the proteins.
After 30 minutes, the filter plates are sequentially washed and filtered with 2X150 μl of 20% TCA, 2 × 150 μl of 10% TCA and 2 × 150 μl of 5% TCA (6%).
total wash per plate / 900 μL per well).
The plates are allowed to dry overnight at room temperature.
Then we add 40 μl of Packard Microscint-20 scintillation fluid per well and the plaques are tightly closed. The radiation emitted by each well for 2 minutes in a Topcount NXT Packard scintillation counter or the CPM / well values are measured.
The inhibition in% of the ability of the enzyme to phosphorylate the substratum (casein) for each concentration of test compound. These inhibition data expressed in% are used to calculate the value of C150 for each compound compared to controls.

Kinetic studies determined the value of KM for ATP as 21 pM
in this test system.

Table 2 below shows the IC50 inhibition of phosphorylation of the Casein Kinase 1 Epsilon for some compounds according to the invention.
Table 2 CK1 epsilon C150 (nM) Compound NOT

Under these conditions, the most active compounds of the invention exhibit (Concentration 50% inhibiting the enzymatic activity of Casein Kinase 1 Epsilon) between 1 nM and 2 μM.

The ability of the compounds of the invention to inhibit the phosphorylation of casein by casein kinases 1 epsilon and delta can be evaluated using a test of FRET fluorescence (energy transfer between fluorescent molecules, English Fluorescence Resonance Energy Transfer) from the Z'LyteTM kinase kit assay Kit (reference PV3670; Invitrogen CorporationTM) according to the instructions of the provider.

The Casein Kinases 1 used are obtained from Invitrogen Corporation (human CK1 epsilon PV3500 and human CK1 delta PV3665).

A substrate peptide, labeled at both ends by a fluorophore group giver (coumarin) and an acceptor fluorophore group (fluorescein) constituting a FRET system is phosphorylated in the presence of ATP by casein kinases 1 epsilon or delta in the presence of increasing concentrations of compounds of the invention.
The mixture is treated by means of a protease specific site cutting specifically the substrate peptide to form two fluorescent fragments exhibiting a big ratio fluorescence emission.
The observed fluorescence is therefore related to the capacity of the products of the invention to inhibit the phosphorylation of the substrate peptide by casein kinase 1 epsilon or from casein kinase 1 delta.
The compounds of the invention are dissolved in concentrations different to from a 10mM stock solution in DMSO diluted in buffer containing 50 mM HEPS, pH 7.5, 1 mMEGTA, 0.01% Brij-35, 10 mM MgCl for casein kinase 1 epsilon and supplemented with Trizma Base (50 mM), pH 8.0 and NaN3 (0.01% final) for casein kinase 1 delta.
The phosphorylation of the SER / THR 11 substrate peptide obtained from Invitrogen CorporationTM is performed at the final concentration of 2 μM. Concentration in ATP
is 4 times the KM, the latter being 2 μM for casein kinase 1 epsilon and 4 pM
for casein kinase 1 delta.

The measurement of the fluorescence emitted is carried out at wavelengths of 445 and nm (excitation at 400 nm).

Table 3 below shows the IC50 inhibition of phosphorylation of the Casein Kinase 1 Delta for some compounds according to the invention.

Table 3 CK1 delta C150 (nM) Compound NOT

13,107 22,287 Under these conditions, the most active compounds of the invention exhibit (Concentration 50% inhibiting the enzymatic activity of Casein Kinase 1 Delta) between 1 nM and 2 μM.

It therefore appears that the compounds according to the invention have an activity inhibitory on The enzyme Casein Kinase 1 epsilon or Casein Kinase 1 delta.

Experimental Protocols of Circadian Cell Dosage Mperl-luc Rat-1 (P2C4) fibroblast cultures were performed in dividing 20 cultures every 3-4 days (about 10-20% confluence) on flasks of culture degased polystyrene fabrics of 150 cm2 (Falcon # 35-5001) and maintained in growth medium [EMEM (Cellgro # 10-010-CV); 10% fetal bovine serum (FBS;
Gibco # 16000-044); and 50 IU / mL of penicillin-streptomycin (Cellgro # 30-001-CI)] to 37 C and under C02 5%.
Cells derived from Rat-1 fibroblast cultures at 30-50%
confluence as described above were co-transfected with vectors containing the marker selection for zeocin resistance for stable transfection and uncomfortable luciferase reporter driven by the mPer-1 promoter. After 24 to 48 hours, the cultures were divided on 96-well plates and maintained in medium of growth supplemented with 50-100 μg / mL Zeocin (Invitrogen # 45-0430) during 14 days. Zeocin-resistant stable transfectants were evaluated for the expression of the protractor by adding to the growth medium the luciferin 100 μM
(Promega # E1603) and by assaying the activity of luciferase on a counter at TopCount scintillation (Packard Model # C384V00). Rat-1 cell clones expressing Zeocin resistance as well as the activity of the luciferase run by mPerl were synchronized by serum shock with 50% horse serum [HS
(Gibco # 16050-122)] and circadian reporter activity was evaluated. The clone P2C4 Mperl-luc Rat-1 fibroblasts were selected for testing the compound.
Mperl-luc rat-1 fibroblasts (P2C4) at 40-50% confluence obtained according to the previously described protocol were plated on culture plates of tissue opaque 96 wells (Perkin Elmer # 6005680). The cultures are maintained in middle growth supplemented with 100 μg / mL Zeocin (Invitrogen # 45-0430) to this that they reached 100% confluence (48-72 h). The cultures then summer synchronized with 100 μL of synchronization medium [EMEM (Cellgro # 10-010-CV) ; 100 IU / mL penicillin-streptomycin (Cellgro # 30-001-C1); 50% HS
(Gibco # 16050-122)] for 2 hours at 37 ° C. and 5% CO 2. After synchronization, the cultures were rinsed with 100 μL of EMEM (Cellgro # 10-010-CV) for 10 minutes at room temperature. After rinsing, the medium was replaced by 300 pL of CO 2 independent medium [CO 2 I (Gibco # 18045-088); 2mM L-glutamine (Cellgro # 25-005-C1); 100 IU / mL penicillin-streptomycin (Cellgro # 30-001-C1);
luciferin 100 pM (Promega #E 1603)]. Compounds of the invention tested for effects circadian were added to CO 2 independent medium in 0.3% DMSO
(concentration final). The cultures were closed immediately in a sealed manner with movie TopSeal-A (Packard # 6005185) and transferred to measure the activity of luciferase.
After synchronization, the test plates were maintained at 37 C in a stove tissue culture (Forma Scientific Model # 3914). Luciferase activity In Vivo has been estimated by measuring the relative emission of light on a counter at scintillation TopCount (Packard Model # C384V00).
Period analysis was performed either by determining the interval between the minimum relative light emission over several days or by transformation of Fourier. Both methods produced a period estimate identical over a range of circadian periods. The power is reported in this Delta (t + 1 h), which is presented as the effective micromolar concentration who has induces an extension of the period of 1 hour. The data was analyzed by adjustment of a hyperbolic curve to the data expressed as a change of period (ordinate) as a function of the concentration of the test compound (abscissa) in the XLfitTM software and the Delta CE (t + 1 h) was interpolated from this curve.

Table 4 below shows the Delta CEs (t + 1 h) for some compounds according to the invention.

Table 4 CE Delta (t + 1 h) (nM) Compound NOT

Under these conditions, the most active compounds of the invention exhibit EC
Delta (t + 1 h) (effective micromolar concentration which induced a extension of the 1 hour period) between 1 nM and 2 μM.

By inhibiting the enzymes CKlepsilon and / or CK1 delta, the compounds object of the invention modulate circadian rhythmicity, and may be useful for treatment disorders related to the circadian rhythm.
The compounds according to the invention can in particular be used for preparation a medicine for preventing or treating sleep disorders; the unrest circadian rhythm, such as those due to jet lag, job posted.
Among the sleep disorders, one distinguishes notably the primary disorders of such as dyssomnia (eg primary insomnia), parasomnia, hypersomnia (eg excessive drowsiness), narcolepsy, disorders of the sleep related to sleep apnea, sleep disorders related to rhythm circadian and dyssomnias not specified otherwise, sleep disorders associated with of the medical / psychiatric disorders.

The compounds which are the subject of the invention also cause a displacement of the phase circadian and such a property can be useful as part of a monotherapy or a potential clinically effective combination therapy for mood.
Among the disorders of the mood, one distinguishes notably the depressive disorders (unipolar depression), bipolar disorders, mood disorders due to to one general medical condition as well as mood disorders induced by pharmacological substances.
Bipolar disorders include bipolar disorder I and bipolar disorder 11, including seasonal affective disorder.

The compounds of the invention that modulate circadian rhythmicity can to be useful in the treatment of anxiety and depressive disorders due to particular to a alteration on the secretion of CRF.
Depressive disorders include depressive disorders major, dysthymic disorders, depressive disorders not otherwise specified.

The compounds of the invention that modulate circadian rhythmicity can to be useful for the preparation of a medicament for treating diseases related to dependence on substances of abuse such as cocaine, morphine, nicotine, ethanol, cannabis.

By inhibiting casein kinase 1 epsilon and / or casein kinase 1 delta, the compounds according to the invention can be used for the preparation of medicaments, especially for the preparation of a medicament for the prevention or treatment of diseases related to the hyperphosphorylation of tau protein, including the disease Alzheimer.

These drugs also find their use in therapeutics, especially in the treatment or prevention of diseases caused or exacerbated by proliferation cells and in particular tumor cells.

As an inhibitor of the proliferation of tumor cells, these compounds are helpful in the prevention and treatment of liquid tumors such as leukemias, both primary and metastatic solid tumors, carcinomas and cancers, particular: breast cancer; lung cancer ; cancer of the small intestine, cancer of the colon and rectum; cancer of the respiratory tract, oropharynx and hypopharynx ; esophageal cancer; liver cancer, stomach cancer, cancer of the liver canals gallstones, gall bladder cancer, pancreatic cancer; cancers of urinary tract including kidney, urothelium and bladder; cancers of the female genital tract understood cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma;
cancers of the male genital tract including prostate cancer, vesicles seminal, testicles, germ cell tumors; cancers of glands endocrine including thyroid cancer, pituitary, glands adrenal skin cancers including hemangiomas, melanomas, sarcomas, including Kaposi's sarcoma; tumors of the brain, nerves, eyes, meninges, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, schwannomas, meningiomas; hematopoietic malignancies; leukemias, (Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Chronic lymphocytic leukemia (CLL)) chloromes, plasmocytomas, leukemias of T or B cells, non-Hodgkin's or Hodgkin's lymphoma, myeloma, various hematological malignancies.

The compounds according to the invention can also be used for the preparation of medicinal products, in particular for the preparation of a medicament for preventing or to to treat inflammatory diseases, such as diseases inflammatory central nervous system such as multiple sclerosis, encephalitis, myelitis and Encephalomyelitis and other inflammatory diseases such as pathologies vascular, atherosclerosis, inflammation of the joints, osteoarthritis, arthritis Rheumatoid.
The compounds according to the invention can therefore be used for the preparation of drugs, especially drugs inhibitors of casein kinase 1 epsilon and / or casein kinase 1 delta.
Thus, according to another of its aspects, the subject of the invention is medicaments who comprise a compound of formula (I), or an addition salt thereof to a acid a pharmaceutically acceptable salt or a hydrate or a compound of formula Mr.

According to another of its aspects, the present invention relates to compositions pharmaceutical compounds comprising, as an active ingredient, a compound according to the invention.
These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, a hydrate or Solvate of said compound, as well as at least one pharmaceutically acceptable excipient acceptable.
Said excipients are chosen according to the pharmaceutical form and the mode desired administration, among the usual excipients which are known to the man of career.
In the pharmaceutical compositions of the present invention for administration oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra tracheal, intranasal, transdermal or rectal, the active ingredient in formula (I) above, or its salt, solvate or hydrate, may be administered under form unit dose, mixed with pharmaceutical excipients classic, animals and humans for the prophylaxis or treatment of troubles or diseases above.

Appropriate unitary forms of administration include forms by way such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms of administration sublingual, intra-tracheal, intraocular, intranasal, inhalation, forms administered topically, transdermally, subcutaneously, intramuscularly or intravenous forms of rectal administration and implants. For application topically, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg Orally, the dose of active ingredient administered per day can reach 0.1 to 20 mg / kg, in one or more doses.
There may be special cases where higher or higher dosages weak are appropriate; such dosages are not outside the scope of the invention. According to convenient usual, the appropriate dosage for each patient is determined by the doctor according to mode of administration, weight and response of said patient.

The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which includes administration to a patient of an effective dose of a compound according to the invention, or of its pharmaceutically acceptable salts or hydrates or solvates.

Claims (14)

1. Compound of general formula (I) in which :
R2 represents a pyridinyl group optionally substituted with one or many substituents selected from halogen atoms and C1-6-alkyl groups;

- R3 represents a hydrogen atom or a C1-3-alkyl group;

- A represents a C1-7-alkylene group optionally substituted with one or two groups R a;
B represents a C1-7-alkylene group optionally substituted by a group R b;
L represents either a nitrogen atom optionally substituted by a group R
c or R d, either a carbon atom substituted with a group R e1 and a group R d or two groups R e2;

the carbon atoms of A and B being optionally substituted with one or several groups R f identical to or different from each other R a, R b and R c are defined such that:
two groups R a may together form a C1-6-alkylene group;
R a and R b may together form a bond or a C1-6-alkylene group;
R a and R c may together form a bond or a C1-6-alkylene group;
R b and R c may together form a bond or a C1-6-alkylene group;

R d represents a group selected from hydrogen and C1-6 groups;
alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-6 alkylthio-C 1-6 alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl, hydroxy-C1-6-alkyl;

R e1 represents a group -NR4R5 or a cyclic monoamine comprising optionally an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents selected from atom fluorine and C1-6-alkyl, C1-6-alkyloxy, hydroxyl groups;

Two R e2 form with the carbon atom which carries them a cyclic monoamine optionally comprising an oxygen atom, this cyclic monoamine being optionally substituted with one or more groups R f which are identical or different one of the other ;

R f is C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl;

R4 and R5 represent, independently of one another, a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl;

R7 and R8 represent, independently of one another, a hydrogen atom or a a C1-6-alkyl group;
In the form of a base or an acid addition salt. 2. Compound of general formula (I) according to claim 1, characterized in what:
L represents either a nitrogen atom optionally substituted by a group R
c or R d, either a carbon atom substituted with a group R e1 and a group R d. 3. Compound of general formula (I) according to any one of the claims preceding, characterized in that:
R2 represents a pyridinyl group, optionally substituted with one or many substituents selected from fluorine and methyl. 4. Compound of general formula (I) according to any one of the claims preceding, characterized in that:
R7 and R8 represent a hydrogen atom or a C1-6-alkyl group. 5. Compound of general formula (I) according to any one of the claims preceding, characterized in that:
- A represents a C1-7-alkylene group optionally substituted with one or two groups R a;
B represents a C1-7-alkylene group optionally substituted by a group R b;
L represents either a nitrogen atom optionally substituted by a group R
c or R d;
the carbon atoms of A and B being optionally substituted with one or several groups R f identical to or different from each other R a, R b and R c are defined such that:
two groups R a may together form a C1-6-alkylene group;
R a and R b may together form a bond or a C1-6-alkylene group;
R a and R c may together form a bond or a C1-6-alkylene group;
R b and R c may together form a bond or a C1-6-alkylene group;

R d represents a group selected from hydrogen and C1-6 groups;
alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-6 alkylthio-C 1-6 alkyl, C1- 6-alkyloxy-C1-6-alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl, hydroxy-C1-6-alkyl;

R f is C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl.

6. Compound of general formula (I) according to any one of the claims preceding, characterized in that:
- A represents a C1-7-alkylene group optionally substituted with one or two groups R a;
B represents a C1-7-alkylene group optionally substituted by a group R b;
L represents a carbon atom substituted by a group R e, and a group R
d;

the carbon atoms of A and B being optionally substituted with one or several groups R f identical to or different from each other R a, R b and R c are defined such that:
two groups R a may together form a C1-6-alkylene group;

R a and R b may together form a bond or a C1-6-alkylene group;
R a and R c may together form a bond or a C1-6-alkylene group;
R b and R c may together form a bond or a C1-6-alkylene group;

R d represents a group selected from hydrogen and C1-6 groups;
alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, C 1-6 alkylthio-C 1-6 alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-fluoroalkyl, benzyl, C1-6-acyl, hydroxy-C1-6-alkyl;

R a1 represents a NR4R5 group or a cyclic monoamine comprising optionally an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents selected from atom fluorine and C1-6-alkyl, C1-6-alkyloxy, hydroxyl groups;

R f is C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkyloxy-C1-6-alkyl, hydroxy-C1-6-alkyl, C1-6-fluoroalkyl or benzyl;

R4 and R5 represent, independently of one another, a hydrogen atom or a C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl. 7. Compound of general formula (I) according to any one of the claims preceding, characterized in that:
the cyclic amine formed by NALB represents a (3S) -3-methyl-piperazin 1-yl, 3,3-dimethylpiperazin-1-yl, 4-isopropyl-piperazin-1-yl, piperazin-1 yle, (3R) -3-isopropyl-piperazin-1-yl, (cis) -5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2 (1H) -yle, 4-pyrrolidin-1-yl-piperidin-1-yl;
R2 represents a pyridinyl group, optionally substituted with one or many substituents selected from fluorine and methyl;
- R3 represents a hydrogen atom or a methyl group;
R7 and R8 represent a hydrogen atom or a methyl group;
in the form of a base or an acid addition salt. 8. Process for the preparation of a compound of general formula (I) according to claim 1, characterized in that a compound of the general formula (II) is reacted wherein R2, R3, R7 and R8 are as defined in claim 1 and X6 represents a halogen, with an amine of general formula (III) wherein A, L and B are as defined in claim 1. 9. Process for preparing a compound of general formula (I) according to claim 1, characterized in that a compound of the general formula (V) is reacted in which A, L, B, R2, R7 and R8 are defined according to claim 1, on The mixture a pyridine derivative of general formula (Va) wherein R3 is defined according to claim 1 and chloroformate of alkyl, in wherein the alkyl group represents a C1-6-alkyl, to obtain a compound of general formula (VI) in which A, L, B, R2, R3, R7 and R8 are as defined in claim 1, said compound of general formula (VI) is then oxidized by means of ortho-chloranil. 10. Process for preparing a compound of general formula (I) according to Claim 1, characterized in that a compound of formula General (V) in which A, L, B, R2, R7 and R8 are as defined in claim 1, according to one bromination reaction or aromatic iodination, to obtain a compound of formula General (VII) wherein A, L, B, R2, R7 and R8 are defined according to claim 1 and X3 represents a bromine or iodine atom, then metallocatalytic coupling is effected between the formula obtained (VII) and a pyridine derivative of the general formula (IIIa) wherein R3 is as defined in claim 1 and M represents a group trialkylstannyl or a dihydroxyboryl or dialkyloxyboryl group. 11. Process for preparing a compound of general formula (I) according to claim 1, characterized in that:
a) a compound of the general formula (VIII) is reacted wherein A, L, B, R7 and R8 are as defined in claim 1, according to a reaction aromatic iodination to obtain a compound of general formula (IX) wherein A, L, B, R7 and R8 are as defined in claim 1;
b) the compound of general formula (IX) obtained in a) is reacted with a composed of general formula (IIIa) wherein R3 is defined according to claim 1 and M represents a group trialkylstannyl or a dihydroxyboryl or dialkyloxyboryl group, for obtain a compound of general formula (X) in which A, L, B, R3, R7 and R8 are as defined in claim 1 c) the compound of the general formula (X) obtained in b) is reacted with a composed of general formula (Xa) R2-M (Xa) wherein R2 is defined according to claim 1 and M represents a group trialkylstannyl or a dihydroxyboryl or dialkyloxyboryl group, in the presence a catalyst. 12. Medicinal product, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, in the basic state or salt of addition to a pharmaceutically acceptable acid. 13. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 7, in the basic form or salt addition to a pharmaceutically acceptable acid, as well as at least one excipient pharmaceutically acceptable. 14. Use of a compound of general formula (I) according to any one of the Claims 1 to 12 for the preparation of a medicinal product for prevention or treatment of sleep disorders, circadian rhythm disorders, mood disorders, anxiety and depressive disorders, illnesses related to the dependence on substances of abuse, diseases related to hyperphosphorylation tau protein, diseases caused or exacerbated by overgrowth cells or inflammatory diseases.