AU2009329427A1 - 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 derivatives of 6-cycloamino-3-(1 -pyrrolo[2,3-]pyridin-4-yl)imidazo[1,2]pyridazine with general formula (I). The invention also relates to a method for the preparation and therapeutic application thereof, in the treatment or prevention of illnesses involving casein kinase 1 epsilon and/or casein kinase 1 delta.

Description

WO 20101070238 PCT/FR20091052594 DERIVATIVES OF 6-CYCLOAMINO-2,3-DIPYRIDINYLIMIDAZO[1,2-b]-PYRIDAZINE PREPARATION AND THERAPEUTIC APPLICATION THEREOF 5 The present invention relates to 6-cycloamino-2,3-dihydropyridylimidazo[1,2 b]pyridazine derivatives, to a process for preparing them and to their therapeutic use, in the treatment or prevention of diseases involving casein kinase I epsilon and/or casein kinase 1 delta. 0 One subject of the present invention is compounds corresponding to the general formula (1) R N R R2 L -B N in which 5 - R 2 represents a pyridyl group optionally substituted with one or more substituents chosen from halogen atoms and groups C 1

.

6 -alkyl; - R 3 represents a hydrogen atom or a group C1- 3 -alkyl; 0 - A represents a group Ci.r-alkylene optionally substituted with one or two groups R.; - B represents a group C1.7-alkylene optionally substituted with a group Rb: - L represents either a nitrogen atom optionally substituted with a group Ro or Rd, or a carbon atom substituted with a group Rei and a group Rd or two groups Re 2 ; 5 the carbon atoms of A and B being optionally substituted with one or more groups Rf, which may be identical to or different from each other; wu Zuluiuuc23 PCT/FR2009/052594 -2 Ra, Rb and R, are defined such that: two groups Ra may together form a group C-alkylene; Ra and Rb may together form a bond or a group C1.e-alkylene; 5 Ra and R. may together form a bond or a group C 1 .- alkylene; Rb and R, may together form a bond or a group C 1

.

6 -alkylene; Rd represents a group chosen from a hydrogen atom and the groups C1.e-alkyl, C3-7 cycloalkyl, C3-.rcycloalkyl-C 1

.

6 -alkyl, C1.

6 -alkylthio-C-1.

6 -alkyl, C 1

.

6 -alkyloxy-C 1 -6 0 alkyl, C1.

6 -fluoroalkyl, benzyl, C1.

6 -acyl and hydroxy-C-alkyl; Ra 1 represents a group -NR 4

R

5 or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents chosen from a fluorine atom and the groups C-alkyl, C.-6 5 alkyloxy and hydroxyl; two groups Re 2 form, with the carbon atom that bears them, a cyclic monoamine optionally comprising an oxygen atom, this cyclic monoamine being optionally substituted with one or more groups Rf, which may be identical to or different 0 from each other; Rf represents a group Cw 4 alkyl, C3.7-cycloalkyl, C3-7-cycloalkyl-C1.

6 -alkyl, C 1 -6 alkyloxy-C.-alkyl, hydroxy-C.

6 -alkyl, C1.,-fluoroalkyl or benzyl; 5 R 4 and R 5 represent, independently of each other, a hydrogen atom or a group C1.6 alkyl, C3.7-cycloalkyl or C 3 .7-cycloalkyl-C.,-alkyl; - R- and R8 represent, independently of each other, a hydrogen atom or a group C1.6 alkyl. 0 The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

WIO 20101070238 PCT/FR20091052594 -3 The compounds of formula (1) may exist in the form of bases or of acid-addition salts. Such addition salts form part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are 5 useful, for example, for purifying or isolating the compounds of formula (1) also form part of the invention. The compounds of formula (1) may also exist in the form of hydrates or solvates, i.e. in the form of associations or combinations with one or more water molecules or with 0 a solvent. Such hydrates and solvates also form part of the invention. In the context of the invention, the following definitions apply: - Ct-z in which t and z may take values from 1 to 7: a carbon-based chain possibly containing from t to z carbon atoms, for example C1-7 is a carbon 5 based chain that may contain from 1 to 7 carbon atoms; - alkyl: a linear or branched, saturated aliphatic group; for example a group C 1 6 alkyl represents a linear or branched carbon-based chain of 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl; 0 - alkylene: a linear or branched, saturated divalent alkyl group, for example a group C 1 .- alkylene represents a linear or branched divalent carbon-based chain of 1 to 6 carbon atoms, for example a methylene, ethylene, 1 methylethylene or propylene; - cycloalkyl: a cyclic alkyl group, for example a group C3-rcycloalky represents 5 a cyclic carbon-based group of 3 to 7 carbon atoms, for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; - acyl: a group alkyl-C(O)-; - hydroxyl: a group -OH; - cyclic monoamine: a saturated cyclic carbon-based chain comprising 1 0 nitrogen atom; - hydroxyalkyl: an alkyl group in which a hydrogen atom has been replaced with a hydroxyl group; - alkyloxy: a group -0-alkyl; - alkylthio: a group -S-alkyl; WO 2010/070238 PCT/FR20091052594 -4 - fluoroalkyl: an alkyl group in which one or more hydrogen atoms have been replaced with a fluorine atom; - fluoroalkyloxy: an alkyloxy group in which one or more hydrogen atoms have been replaced with a fluorine atom; 5 - a halogen atom: a fluorine, chlorine, bromine or iodine atom; - aryl: a monocyclic or bicyclic aromatic group containing between 6 and 10 carbon atoms. Examples of aryl groups that may be mentioned include phenyl and naphthyl groups. O As non-limiting examples of cyclic amines or diamines formed by N, A, L and B, mention may be made especially of aziridine, azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, homopiperidine, decahydroquinoline, decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclononane, azaoxobicycloheptane, azathiabicycloheptane, azaoxobicyclooctane, 5 azathiabicyclooctane; piperazine, homopiperazine, diazacyclooctane, diazacyclononane, diazacyclodecane, diazacycloundecane, octahydropyrrolopyrazine, octahydropyrrolodiazepine, octahydropyrrolopyrrole, octahydropyrrolopyridine, decahydronaphthyridine, diazabicycloheptane, diazabicyclooctane, diazabicyclononane, diazaspiroheptane, diazaspirooctane, 0 diazaspirononane, diazaspirodecane, diazaspiroundecane and oxadiazaspiroundecane. Among the compounds of general formula (1) that are subjects of the invention, a first group of compounds is constituted by compounds for which: 5 - L represents either a nitrogen atom optionally substituted with a group R, or Rd, or a carbon atom substituted with a group R.

1 and a group Rd; the other substituents being as defined above. Among the compounds of general formula (1) that are subjects of the invention, a O second group of compounds is constituted by compounds for which: - R 2 represents a pyridyl group, optionally substituted with one or more substituents chosen from fluorine and a methyl group; the other substituents being as defined above.

WO 20101070238 PCT/FR2009/052594 Among the compounds of general formula (1) that are subjects of the invention, a third group of compounds is constituted by compounds for which: - R 3 represents a hydrogen atom or a methyl group; the other substituents being as defined above. 5 Among the compounds of general formula (1) that are subjects of the invention, a fourth group of compounds is constituted by compounds for which:

R

7 and R 8 represent a hydrogen atom or a methyl group; the other substituents being as defined above. 0 Among the compounds that are subjects of the invention, a fifth group of compounds is constituted by compounds for which: - A represents a group Ciralkylene optionally substituted with one or two groups Ra; - B represents a group Ciralkylene optionally substituted with a group Rb; 5 - L represents a nitrogen atom optionally substituted with a group R, or Rd; the carbon atoms of A and B being optionally substituted with one or more groups Rf, which may be identical to or different from each other; 0 Ra, Rb and R, are defined such that: two groups Ra may together form a group C1- 6 -alkylene; Ra and Rb may together form a bond or a group C 6 -alkylene; Ra and Re may together form a bond or a group C 1

.

6 -alkylene; Rb and Rc may together form a bond or a group C 1

.

6 -alkylene; 5 Rd represents a group chosen from a hydrogen atom and groups C 16 -alkyl, C3-7 cycloalkyl, C3-7-cycloalkyl-C 1

.

6 -alkyl, C1- 6 -alkyithio-CI- 6 -alkyl, C1-,-alkyloxy-Cl-6 alkyl, C 1 .. e-fluoroalkyl, benzyl, C1.-acyl or hydroxy-C 1

.

6 -alkyl; 0 Rf represents a group C 14 -alkyl, C 3 7 -cycloalkyl, C3.7-cycloalkyl-CI,-alkyl,

C

1 6 alkyloxy-C1- 6 -alkyl, hydroxy-C 1

.

6 -alkyl, Ci 6 -fluoroalkyl or benzyl; the other substituents being as defined above.

WO 2010/070238 PCT/FR2009/052594 -6 Among the compounds of general formula (1) that are subjects of the invention, a sixth group of compounds is constituted by compounds for which: - A represents a group C 7 -alkylene optionally substituted with one or two groups Ra; - B represents a group Ci..ralkylene optionally substituted with a group Rb; 5 - L represents a carbon atom substituted with a group Rei and a group Rd; the carbon atoms of A and B being optionally substituted with one or more groups Rf, which may be identical to or different from each other; o R 2 , Rb and R, are defined such that: two groups Ra may together form a group C1-iralkylene; Ra and Rb may together form a bond or a group CIwalkylene; Ra and Re may together form a bond or a group Cw- 6 -alkylene; Rb and Re may together form a bond or a group C1.e-alkylene; 5 Rd represents a group chosen from a hydrogen atom and groups C 6 -alkyl, C3-7 cycloalkyl, C 3 -7-cycloalkyl-C-alkyl, C1.-alkylthio-C 1

.

6 -alkyl, Cw.

6 -alkyloxy-C alkyl, C-fluoroalkyl, benzyl, C6-acyl or hydroxy-C 6 -alkyl; o Rei represents a group -NR 4

R

5 or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents chosen from a fluorine atom and groups C 1 -alkyl, C1_ alkyloxy or hydroxyl; 5 Rf represents a group C.

6 -alkyl, C3.7-cycloalkyl, C3-7-cycloalkyl-C 16 -- alkyl, C 1 alkyloxy-C1.

6 -alkyl, hydroxy-C.

6 -alkyl, C1.

6 -fluoroalkyl or benzyl; R4 and R 5 represent, independently of each other, a hydrogen atom or a group C1.

alkyl, C3-rcycloalkyl or C 37 -cycloalkyl-C 1

.

6 -akyl; 0 the other substituents being as defined above. Among the compounds of general formula (1) that are subjects of the invention, a seventh group of compounds is constituted by compounds for which: WO 20101070238 PCT/FR2009/052594 -7 - the cyclic amine formed by -N-A-L-B- represents a piperazinyl or hexahydropyrrolopyrrolyl group, optionally substituted with one or more groups C 6 alkyl; the other substituents being as defined above. 5 Among the compounds of general formula (I) that are subjects of the invention, an eighth group of compounds is constituted by compounds for which: the cyclic amine formed by -N-A-L-B- represents a pyrrolidinylpiperidyl group; - R 2 , R 3 , R 7 and Rs being as defined above. 0 Among the compounds of general formula (1) that are subjects of the invention, a ninth group of compounds is constituted by compounds for which: - the cyclic amine formed by -N-A-L-B- represents a (3S)-3-methylpiperazin-1 -yl, 3,3 dimethylpiperazin-1 -y, 4-isopropylpiperazin-1 -yl, piperazin-1 -yl, (3R)-3 5 isopropylpiperazin-1 -yl or (cis)-5-methylhexahydropyrrolo[3,4-cpyrrol-2(1 H)-yl group; the other substituents being as defined above. Among the compounds of general formula (i) that are subjects of the invention, a tenth group of compounds is constituted by compounds for which: 0 - the cyclic amine formed by -N-A-L-B- represents a 4-pyrrolidin-1-ylpiperidin-1-yl group; the other substituents being as defined above. Among the compounds of general formula (1) that are subjects of the invention, an !5 eleventh group of compounds is constituted by compounds for which: - the cyclic amine formed by -N-A-L-B- represents a (3S)-3-methylpiperazin-1-yl, 3,3 dimethylpiperazin-1 -yl, 4-isopropylpiperazin-1 -yl, piperazin-1 -yl, (3R)-3 isopropylpiperazin-1-yi, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl or 4 pyrrolidin-1-ylpiperidin-1-yl group; 0 - R 2 represents a pyridyl group, optionally substituted with one or more substituents chosen 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; in the form of the base or of an acid-addition salt.

WO 2010/070238 PCT/FR2009/052594 -8 Among the compounds that are subjects of the invention, mention may be made especially of: 6-{(3S)-3-Methylpiperazin-1 -yl]-3-(pyrid-4-yl)-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine; 5 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 -y)-3-(2-methylpyrid-4-yl)-2-(pyrid-3-yl)imidazo[I,2 0 b]pyridazine; 2-(5-Fl uormpyrid-3-yl)-6-[(3S)-3-methylpiperazin-1 -yl]-3-(pyrid-4-yl)imid azo[1,2 b]pyridazine; 2-(5-Fl uo ro pyrid -3-yl)-6-[(3S)-3-m ethyl p iperazin- 1 -yl]-3-(2-methylpyrid-4 yl)imidazo[1,2-b]pyridazine; 5 2-(5-Fluoropyrid-3-yl)-6-(4-isopropylpiperazin-1 -yl)-3-(pyrid-4-yl)im idazo[1,2 b]pyridazine; 6-(4-Isopropylpiperazin-1 -yI)-3-(2-methylpyrid-4-yl)-2-(5-methylpyrid-3-yl)imidazo[1,2 b]pyridazine; 6-Piperazin-i -yl-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine; 0 6-[(3S)-3-Methylpiperazin-1 -yl)-3-(2-methylpyrid-4-y)-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-Di methyl pi perazin-1 -yl)-3-(2-methyl pyrid-4-yl)-2-(pyrid-4-yl)i midazo[1,2 b]pyridazine; 5 6-(3,3-Dimethylpiperazin-1 -yl)-8-methyl-2,3-bis(pyrid-4-yl)imidazo[1,2-bjpyridazine; 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-I -yl)-3-(2-methylpyrid-4-yl)-2-(pyrid-4-yl)imidazo[1,2 b]pyridazine; o 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-Fl uo ro pyrid-4-y)-6- [(3S)-3-methyl pi perazin- 1 -yl]-3-(pyrid-4-yl)imidazo[1,2 b]pyridazine; WO 2010/070238 PCT/FR20091052594 -9 2-(2-Fluoropyrid-4-yl)-6-[(3S)-3-methylpiperazin-I -yl]-3-(2-methylpyrid-4 yl)imidazo[1,2-b]pyridazine; 2-(2-Fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1 -yl)-3-(pyrid-4-yl)imidazo[1,2 b]pyridazine; 5 2-(2-F I uoropyrid-4-yl)-6-(4-isopropyl p iperazi n-1 -yl)-3-(2-methylpyrid-4-yl)imidazo[1,2 b]pyridazine. In accordance with the invention, the compounds of general formula (1) may be prepared according to the general process described in Scheme 1 below. 0 SCHEME 1 R 7 ~ N 7

R

2 R2 N (IV) M R 3 N R (IIa) H R8 Q A-N

-

7 N RR3

F?

7 N N

-

R2 F 2 N A-N N I I (Ila) L-B R3 ~ ~~N (I In general and as illustrated in Scheme 1, the 6-cycloamino-2,3-di-pyridylimidazo[1,2 5 b]pyridazine derivatives of general formula (1) in which R 2 , R 3 , A, L, B, R 7 and R 8 are as defined above may be prepared from a 3-(pyrid-4-yl)imidazo[1,2-b]pyridazine derivative of general formula (li), in which R 2 , R 3 , R 7 and R 8 are as defined above and

X

6 represents a leaving group such as a halogen, by treatment with an amine of general formula (Ila) in which A, L and B are as defined previously. This reaction may WO 2010/070238 PCT/FR2009/052594 -10 be performed by heating the reagents in a polar solvent such as pentanol or dimethyl sulfoxide. The imidazo[1,2-b]pyridazine derivatives of general formula (11) may be prepared by 5 metal-catalysed coupling between a 3-haloimidazo[l,2-b]pyridazine derivative of general formula (Il1), in which R 2 , X 6 , R 7 , and R 8 are as defined above and X 3 represents a halogen such as bromine or iodine and more particularly iodine, and a pyridine derivative of general formula (Ilia) in which R 3 is as defined above and M represents a trialkylstannyl group, usually a tributylstannyl group or a dihydroxyboryl 0 or dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-y group, under the Stille or Suzuki conditions. The couplings according to the Stille method are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium or copper iodide, in a solvent such as N,N-dimethylacetamide. 5 The couplings according to the Suzuki method are performed, for example, by heating in the presence of a catalyst such as 1,1' bis(diphenylphosphino)ferrocenedichloropalladium and a mineral base such as caesium carbonate, in a solvent mixture such as dioxane and water. 0 The 3-haloimidazo[1,2-b]pyridazine derivatives of general formula (111) are obtained by regioselective bromination or iodination of an imidazo[1,2-b]pyridazine derivative of general formula (IV), in which R 2 , X 6 , R 7 and R 8 are as defined above. This reaction may be performed using N-bromo- or iodosuccinimide or iodine 5 monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform. The imidazo[1,2-b]pyridazine derivatives of general formula (IV) are known (Journal of Heterocyclic Chemistry (2002), 39(4), 737-742) or may be prepared by analogy 0 with methods known to those skilled in the art. In a second alternative, according to Scheme 2, the 6-cycloamino-2,3 dipyridylimidazo[1,2-b]pyridazine derivatives of general formula (1) as defined above WO 20101070238 PCT/FR2009/052594 - 11 may be prepared in two steps from an imidazo[1,2-b]pyridazine derivative of general formula (V) in which R 2 , A, L, B, R 7 and R 8 are as defined previously.

WO 20101070238 PCTIFR2009/052594 - 12 SCHEME 2 R8 R 7 N / R 2 A-N N I I L-B (V)

R

3 CKI oAlkyl (Va) (1a RR c R7 7 R~ ~ ? R R2 / R A-N N A-N L-B I31 L-B (VII)R3 M N ,Alkyl 0 (VI) N

/R

2 0 * CI A-N N c1 L-Bs N 5 According to a first approach, the reaction of an imidazo[1,2-b]pyridazine derivative of general formula (V) with the mixture of a pyridine derivative of general formula (Va) in which R 3 is as defined previously, and of an alkyl chloroformate in which the alkyl group represents a C 1 ..-alkyl, for example ethyl chloroformate, leads to the derivative of general formula (VI) in which R 2 , A, L, B, R 3 , R 7 and R 8 are as defined above. The 0 derivative of general formula (VI) is then oxidized using ortho-chloranil in a solvent WO 20101070238 PCT/FR20091052594 -13 such as toluene, to give the 6-cycloamino-2,3-bis-pyridylimidazo[1,2-b]pyridazine derivatives of general formula (1). According to a second approach, a regioselective aromatic bromination or iodination 5 of imidazo[1,2-blpyridazine derivatives of general formula (V) gives the 3-bromo- or iodoimidazo[1,2-b]pyridazine derivatives of general formula (VII) in which 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 may be performed using N-bromo- or iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, o tetrahydrofuran, methanol or chloroform. The 6-cycloamino-2,3-di-pyridylimidazo[1,2-b]pyridazine derivatives of general formula (1) are then prepared by metal-catalysed coupling between these 3-bromo- or iodoimidazo[1,2-b]pyridazine derivatives of general formula (VII) and a pyridine 5 derivative of general formula (ilila) as defined above, under the Stille or Suzuki conditions. In a third alternative, according to Scheme 3, the 6-cycloamino-2,3-di pyridylimidazo[1,2-b]pyridazine derivatives of general formula (1) as defined above 0 may be prepared in three steps from a 2-bromoimidazo[1,2-b]pyridazine derivative of general formula (Vill) in which A, L, B, R 7 and R 8 are as defined previously. Regioselective aromatic iodination of imidazo[1,2-b]pyridazine derivatives of general formula (Vill) gives the 2-bromo-3-iodoimidazo[1,2-b]pyridazine derivatives of general 5 formula (IX) in which A, L, B, R 7 and R 8 are as defined above. This reaction may be performed using N-iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.

WO 2010/070238 PCTIFR2009/052594 -14 SCHEME 3 R8 R8 R7 55. _N R 7 R B r ' R/ Br A-N N A-N N I I I II L-B L-B I (VilI) (IX) M 3 (Ilila) N R- Ra A.R/ R 2 (Xa) A Br A-N NN L-B L-B N 3 N R N 5 A first regioselective metal-catalysed coupling reaction between these 2-bromo-3-iodo imidazo[1,2-b]pyridazine of general formula (IX) and a pyridine derivative of general formula (Iia) as defined above, under the Stille or Suzuki conditions, leads to the 2 bromoimidazo[1,2-b]pyridazine derivatives of general formula (X) in which A, L, B, R 3 , R 7 and R are as defined above. 0 Finally, a second metal-catalysed coupling reaction between a 2-bromo-3 iodoimidazo[1,2-blpyridazine derivative of general formula (X) and a pyridine derivative of general formula (Xa) in which R 2 is as defined above and M represents a trialkylstannyl group, usually a tributyistannyl group or a dihydroxyboryl or 5 dialkyloxyboryl group, usually a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group, under the Stille or Suzuki conditions, leads to the 6-cycloamino-2,3-di pyridylimidazo[1,2-b]pyridazine derivatives of general formula (1) as defined above.

WO 2010/070238 PCT/FR2009/052594 - 15 The couplings according to the Stille methods are performed, for example, by heating in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium or copper iodide, in a solvent such as N,N-dimethylacetamide. 5 Precursors The 3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of general formula (V) as defined above may be prepared by condensation between a pyridazin-3-ylamine derivative of general formula (XI) in which A, L, B, R 7 and R8 are as defined above and a 2-bromo, chloro- or iodoethan-1-one derivative of general formula (Xla) in which R 2 is as 0 defined above and X represents a bromine, chlorine or iodine atom. The reaction may be performed by heating the reagents in a polar solvent such as ethanol or butanol. 5 The pyridazin-3-ylamine derivatives of general formula (XI) are known (Journal of Medicinal Chemistry (2008), 51(12), 3507-3525) or may be prepared by analogy with methods known to those skilled in the art. The 3-pyrid-4-ylimidazo[1,2-b]pyridazine derivatives of general formula (V) as defined !0 above may also be prepared via a metal-catalysed coupling reaction between the 2 bromoimidazo[1,2-b]pyridazine derivatives of general formula (Vill) as defined previously and a pyridine derivative of general formula (Xa) as defined above, under the Stille or Suzuki conditions. .5 The 2-bromoimidazo[1,2-b]pyridazine derivatives of general formula (VillI) may be prepared from a 2-bromoimidazo[1,2-b]pyridazine derivative of general formula (XII), in which R 7 and R 8 are as defined above and X represents a leaving group such as a halogen, more particularly chlorine, by treatment with an amine of general formula (Ila) as defined previously. This reaction may be performed by heating the reagents 0 in a polar solvent such as pentanol or dimethyl sulfoxide. The 2-bromoimidazo[1,2-b]pyridazine derivatives of general formula (XII) are obtained in two steps from a 5-halopyridazin-3-ylamine of general formula (XIV) in which X& represents a leaving group such as a halogen, more particularly chlorine, WU ZUuluJUJ23 PCT/FR20091052594 -16 and R 7 and R 8 are as defined previously. Thus, the 5-halopyridazin-3-ylamine derivatives of general formula (XI) are alkylated using an alkyl 2-bomo-or 2 chloroacetate, for example ethyl 2-bromoacetate, to give a 6-amino-3-halo-1 (alkyloxycarbonylmethyl)pyridazin-1-ium hydrobromide or hydrochloride of general 5 formula (XIII) for which X6 represents a leaving group such as a halogen, more particularly chlorine, while R 7 and R 8 are as defined previously. The 6-amino-3-halo 1-(alkyloxycarbonylmethyl)pyridazin-1-lum hydrobromides or hydrochlorides of general formula (XIIl) are cyclized using phosphorus oxybromide to give the 2-bromo 3-(pyrid-4-yl)imidazo[1,2-bjpyridazine derivatives of general formula (XII). 0 R

NH

2 X RA R7 R A-N N A-N N'I I I(Ma) I I L-B (XI) L-B

R

2 M H (Xa) RI I_ R8 Br (I*A)ANB -L-B XII (Ha) (I / Br goNY Br NN A-N N N I I L-B Br R O. NH Et O Et R, NH X N-5 Br X 6 N I (XIV) 0 (XM) In the text hereinabove, the term "leaving group" means a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with loss of an electron pair.

VVU 20101070238 PCT/FR20091052594 -17 This group may thus be readily replaced with another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxyl group such as a mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups and references for preparing them are given in "Advances in Organic Chemistry", 5 J. March, 3r Edition, Wiley Interscience, pp. 310-316. Protecting groups For the compounds of general formula (1) or (Ila) as defined above and in the case where the group N-A-L-B comprises a primary or secondary amine function, this 0 function may be optionally protected during the synthesis with a protecting group, for example a benzyl or a t-butyloxycarbonyl. The examples that follow describe the preparation of certain compounds in accordance with the invention. These examples are not limiting, but serve merely to 5 illustrate the invention. The numbers of the illustrated compounds refer to those given in Table 1 hereinbelow, which illustrate the chemical structures and physical properties, respectively, of a number of compounds according to the invention. Example I (compound 13): 6-(3.3-Di methyl pipe razi n-1 -yl)-3-(2-m ethyl pyrid-4-yI) 0 2-(pyrid-4-yl)imidazo[1,2-blpyridazine H3C N

H

3 C N N HN N CH 3 Step 1.1. 6-Chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine NN/ \N Cl N 5 To a solution of 24.0 g (85.3 mmol) of 3-amino-6-chloropyridazine in 1.5 L of refluxing ethanol are added portionwise 33.2 g (256 mmol) of 2-bromo-1-(pyrid-4-yl)ethanone WO 2010/070238 PCT/FR2009/052594 -18 hydrobromide (CAS 5469-69-2) and then 12.0 ml (85.4 mmol) of triethylamine, dropwise over 45 minutes. The mixture is refluxed for 3 hours. After cooling, the solvent is evaporated off under reduced pressure and the red-brown residue is taken up in chloroform and 300 ml of 1N sodium hydroxide solution. After stirring for 15 5 minutes, the mixture is filtered and the solid residue is washed with chloroform. The organic phase is separated out, washed with water and dried over sodium sulfate to give 13 g of a brown solid, after evaporating off the solvent. The residue is purified on a column of 500 g of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (97/3/0.3) to give 10.1 g of 6-chloro-2-(pyrid-4-yl)imidazo[1,2 0 b]pyridazine in the form of a dark beige solid, after triturating in diisopropyl ether, filtering off and drying under reduced pressure. m.p. 203-205*C 'H NMR (DMSO-d 6 ) 5: 9.15 (s, 1H); 8.70 (d, 2H); 8.30 (d, 1H); 8.0 (d, 2H); 7.45 (d, 1H) ppm. 5 Step 1.2. 6-Chloro-3-iodo-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine Cl N To a solution of 10.4 g (45.1 mmol) of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine in I L of chloroform are added, at room temperature, 21.9 g (135 mmol) of iodine 0 chloride in 100 ml of methanol. After reaction for 24 hours, the mixture is poured into saturated sodium bicarbonate solution and the resulting mixture is decolorized by adding aqueous 5% sodium thiosulfate solution. The organic phase is separated out, dried over sodium sulfate and concentrated under reduced pressure to give 14.4 g of 6-chloro-3-iodo-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine in the form of a beige-coloured 5 solid, containing about 10% of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine, after triturating in 200 ml of acetonitrile, filtering off and drying. H NMR (DMSO-d 8 ) 6: 8.75 (d, 2H); 8.30 (d, 1H); 8.15 (d, 2H); 7.50 (d, IH) ppm.

WO 2010/070238 PCT/FR2009/052594 -19 Step 1.3. 6-Chlo ro-3-(2-methylpyrd-4-yl)-2-(pyrid-4-yl)i midazo[ 1,2-b]pyridazi ne ~N CI N. N CHs To a mixture of 2.85 g (6.39 mmol) of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine, 1.14 g (6.12 mmol) of (2-methyl-4-pyridyl)boronic acid (CAS 579476-63-4) and 6.3 g 5 (19 mmol) of caesium carbonate in 400 ml of a mixture of tetrahydrofuran and water (9/1) is added, after degassing with argon, 0.47 g (0.58 mmol) of 1,1' bis(diphenylphosphino)ferrocenedichloropalladium (II) (CAS 72287-26-4). The mixture is stirred at reflux for 18 hours. The mixture is concentrated under reduced pressure and the residue is taken up in chloroform. The organic phase is washed with 0 water and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure. The residue is purified on a column of 110 g of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (96/4/0.4) to give 1.35 g of 6-chloro-3-(2-methylpyrid-4-y)-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine in the form of a white powder, after triturating in acetonitrile, filtering off and drying. 5 m.p.: 218-222*C 'H NMR (DMSO-d 6 ) 8: 8.60 (d, 1H); 8.55 (d, 2H); 7.95 (d, 1H); 7.50 (d, 2H); 7.35 (s, 1 H); 7.25 (d, 1 H); 7.15 (d, 1 H); 2.60 (s, 3H) ppm. Step 1.4. 6-(3,3-Dimethylpiperazin-1 -yI)-3-(2-methylpyrid-4-yl)-2-(pyrid-4 0 yl)imidazo[1,2-b]pyridazine HC N

H

3 C N N HN NCH ~N 3 A mixture of 0.500 g (1.55 mmol) of 6-chloro-3-(2-methylpyrid-4-y)-2-(pyrid-4 yl)imidazo[1,2-b]pyridazine and 0.52 g (4.7 mmol) of 2,2-dimethylpiperazine in 5 ml of pentanol is refluxed for 24 hours at 150 0 C. The reaction medium is cooled and 5 poured into aqueous 2N hydrochloric acid solution. The aqueous phase is washed WO 2010/070238 PCT/FR2009/052594 -20 with diethyl ether and then basified with aqueous 2N sodium hydroxide solution, and the product is extracted with chloroform. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The solid obtained is purified on 35 g of silica gel, eluting with a mixture of dichloromethane, methanol 5 and aqueous ammonia (94/6/0.6) to give 0.17 g of 6-(3,3-dimethylpiperazin-1 -yl)-3-(2 methylpyrid-4-yl)-2-(pyrid-4-y)i m idazo[1,2-b]pyridazine in the form of a beige coloured powder, after dissolving in 10 ml of acetonitrile and crystallizing by addition of diethyl ether, filtering off and drying. m.p.: 185-187*C 0 'H NMR (CDCl3) 5: 8.60 (m, 3H); 7.80 (d, 1 H); 7.60 (d, 2H); 7.50 (s, 1 H); 7.40 (d, 2H); 6.95 (d, 1H); 3.45 (dd, 2H); 3.30 (s, 2H); 3.10 (dd, 2H); 2.65 (s, 3H); 1.2 (s, 6H) ppm. Example 2 (compound 14): 6-(3,3-Di methyl pipe razi n-1 -yl)-8-methyl-2,3 bis(pyrid-4-yl)imidazo[1,2-bi pyridazine

CH

3 N 13C N NN HN 5 N Step 2.1. 3-Amino-6-chloro-4-methylpyridazine and 3-amino-6-chloro-5-methyl pyridazine

CH

3

H

3 C

NH

2

NH

2 Cl N CI N In an autoclave, a suspension of 50.0 g (307 mmol) of 3,6-dichloro-4 0 methylpyridazine in 170 ml 30% aqueous ammonia is heated at 120"C for 18 hours. After cooling, the mixture is poured into 200 ml of water and the solid is recovered by filtration. After drying under reduced pressure, the mixture of products is recrystallized from ethyl acetate to give 40 g of a mixture of 3-amino-6-chloro-4 methylpyridazine and 3-amino-6-chioro-5-methylpyridazine (32/68).

WO 2010/070238 PCT/FR2009/052594 -21 'H NMR (CDC1 3 ): 7.15 and 6.75 (s and s, 1H); 5.0 (broad signal, 2H); 2.35 and 2.25 (s and s, 3H). Step 2.2. 6-Amino-3-chloro-1 -ethoxycarbonylmethyl-5-methylpyridazin-I-ium 5 bromide and 6-amino-3-chloro-1 -ethoxycarbonylmethyl-4-methypyridazin-1 -ium bromide CH3

H

3 C

NH

2 NH 2 N Cl NN Br C I N NBr

H

3 C 0 0

H

3 C ' 0 0 To a solution of 36.0 g (251 mmol) of a mixture of 3-amino-6-chloro-4 0 methylpyridazine and 3-amino-6-chloro-5-methylpyridazine (32/68) in 350 ml of refluxing ethanol are added portionwise 30.6 ml (275 mmol) of ethyl 2-bromoacetate and heating is continued for 24 hours. After cooling, the reaction medium is partially concentrated under reduced pressure and then diluted with 200 ml of acetone, the suspension is cooled to 0"C and the precipitate is separated out by filtration. The 5 filtrate is then partially concentrated under reduced pressure and diluted with 150 ml of acetone, and the suspension is again cooled to 0*C. The precipitate is separated out by filtration and combined with the first crop. After drying, 29.8 g of a mixture of 6 amino-3-chloro-1-ethoxycarbonylmethyl-4-methylpyridazin-1-ium bromide and 6 amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridazin-1-ium bromide (30/70) are 0 obtained in total. 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-methylimidazo[1,2-b]pyridazine and 2 5 bromo-6-chloro/bromo-8-methyli midazo[11,2-b]pyridazine

CH

3 CBr NBr Br/Cl N Br/CI N vvu zulululuz3u PCT/FR20091052594 -22 A mixture of 27.8 g (89.5 mmol) of 6-amino-3-chloro-1-ethoxycarbonylmethyl-4 methylpyridazin-1-ium, 6-amino-3-chloro-1-ethoxycarbonylmethyl-5-methylpyridazin I -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 5 walls is detached and the mixture is poured into 500 ml of water at 00C. The aqueous phase is then basified by addition of aqueous ammonia and, after stirring for 1 hour, the product is dissolved in chloroform. The organic phase is separated out, dried over sodium sulfate and concentrated under reduced pressure to give 22 g of a brown solid. The solid is then purified by chromatography on a column of 450 g of silica gel, 0 eluting with dichloromethane, to give 5.0 g of 2-bromo-6-chloro-8-methylimidazo[1,2 b]pyridazine containing 2,6-dibromo-8-methylimidazo[1,2-b]pyridazine in the form of a white powder (41/59). 1 H NMR (CDC13): 7.80 (s, 1 H); 6.85 and 7.00 (s and s, 1 H); 2.55 (s, 3H). 5 Continuing the elution with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1) gives 15.2 g of 2-bromo-6-chloro/bromo-7-methylimidazo[1,2 b]pyridazine containing 2,6-dibromo-7-methylimidazo[1,2-b]pyridazine, in the form of a pink powder. 'H NMR (CDC 3 ): 7.95 (s, 1 H); 7.75 (s, 1 H); 2.55 (s, 3H). 0 Step 2.4. 2-Bromo-6-(3,3-dimethylpiperazin-1 -yl)-8-methylimidazo[1,2

CH

3 ~N

H

3 C -NBr 3 N

H

3 C N N H-N b]pyridazine A mixture of 4.95 g (about 20 mmol) of 2-bromo-6-chloro-8-methylimidazo[1,2 b]pyridazine ontaining 2,6-dibromo-8-methylimidazo[1,2-b~pyridazine, 2.5 g (22 5 mmol) of 2,2-dimethylpiperazine and 2.8 ml of triethylamine in 60 ml of pentanol is heated at 1500C for 3 days in a sealed tube. After cooling, the reaction medium is poured into aqueous 1N hydrochloric acid solution. The aqueous phase is washed with ethyl acetate and then basified with aqueous ammonia solution and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate WO 2010/070238 PCT/FR20091052594 - 23 and the solvent is evaporated off under reduced pressure. The beige-coloured solid obtained is purified on a column of 80 g of silica gel, eluting with a mixture of dichioromethane, methanol and aqueous ammonia (95/65/0.5) to give 4.6 g of 2 bromo-6-(3,3-d i methyl pi perazin-1 -yl )-8-methyli mid azo[1,2-b] pyridazine in the form of 5 a white powder. m.p.: 139-141*C 'H NMR (CDC 3 ) 6: 7.65 (s, 1H); 7.65 (s, 1H); 3.5 (m, 2H); 3.30 (s, 2H); 3.10 (m, 2H); 2.60 (s, 3H); 1.25 (s, 6H) ppm. 0 Step 2.5. 6-(3,3-Dimethylpiperazin-1 -yl)-8-methyl-2-(pyrid-4-yl)imidazo[1,2 b]pyridazine

CH

3 s- N

H

3 C N NN HN To a mixture of 4.64 g (14.3 mmol) of 2-bromo-6-(3,3-dimethylpiperazin-1-y)-8 methylimidazo[1,2-b]pyridazine and 2.5 g (17 mmol) of (4-pyridyl)boronic acid (CAS 5 1692-15-5) in 100 ml of a mixture of tetrahydrofuran and water (9/1), are added, after degassing with argon, 14 g (43 mmol) of caesium carbonate and 1.05 g (1.29 mmol) of a complex of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (11) and dichloromethane (PdC 2 (dppf).CH 2 Cl 2 ). After stirring for 8 hours at reflux, the reaction medium is poured into aqueous 1 N hydrochloric acid solution. The aqueous phase is .0 washed with ethyl acetate and then basified with aqueous ammonia solution and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The black oil obtained is purified by chromatography on a column of 120 g of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/65/0.5) to give 5 3.1 g of 6-(3,3-dimethylpiperazin-1-yl)-8-methyl-2-(pyrid-4-yl)imidazo{1,2-b]pyridazine in the form of an oil. 1 H NMR (CDCl 3 ) 6: 8.70 (d, 2H); 8.15 (s, 1H); 7.85 (d, 2H); 6.70 (s, IH); 3.55 (m, 2H); 3.30 (s, 2H); 3.15 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm.

WO 2010/070238 PCT/FR20091052594 -24 Step 2.6. 6-(3,3-Dimethylpiperazin-1 -yI)-3-iodo-8-methyl-2-(pyrid-4-yl)imidazo[1,2 b]pyridazine

CH

3 H 3 C rN \C 1 N H C N N HN To a solution of 3.13 g (9.71 mmol) of 6-(3,3-dimethylpiperazin-1-yI)-8-methyl-2 5 (pyrid-4-yl)imidazo[1,2-b]pyridazine in 80 ml of dichloromethane are added at room temperature 19.4 ml (19.4 mmol) of a 1M solution of iodine chloride in dichloromethane. After reaction for 2 hours, the solution is poured into 150 ml of water and basified by addition of sodium bicarbonate, and the resulting mixture is decolorized by portionwise addition of sodium thiosulfate. The organic phase is 0 separated out, dried over sodium sulfate and concentrated under reduced pressure to give a brown oil, which is purified by chromatography on a column of 120 g of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1), to give 3.35 g of 6-(3,3-dimethylpiperazin-1 -yl)-3-iodo-8-methyl-2-(pyrid-4 yl)imidazo[1,2-b]pyridazine in the form of a beige-coloured solid. 5 m.p.: 153-155"C 'H NMR (CDCl 3 ) 5: 8.75 (d, 2H); 8.15 (d, 2H); 6.75 (s, 1H); 3.70 (m, 2H); 3.40 (s, 2H); 3.20 (m, 2H); 2.70 (s, 3H); 1.30 (s, 6H) ppm. Step 2.7. 6-(3,3-Dimethylpiperazin-1 -yl)-8-methyl-2,3-bis(pyrid-4-yl)imidazo[1,2 0 b]pyridazine

CH

3 N H 3 C N N N HN N To a mixture of 0.40 g (0.89 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-3-iodo-8-methyl 2-(pyrid-4-yl)imidazo[1,2-b]pyridazine and 0.155 g (1.07 mmol) of (4-pyridyl)boronic acid (CAS 1692-15-5) in 15 ml of a mixture of tetrahydrofuran and water (9/1) are WU 20101070235 PCTIFR2009/052594 - 25 added, after degassing with argon, 0.87 g (2.7 mmol) of caesium carbonate and 0.057 g (0.08 mmol) of a complex of 1,1' bis(diphenylphosphino)ferrocenedichloropalladium (11) and dichloromethane (PdCl 2 (dppf).CH 2

CI

2 - CAS 851232-71-8). After reaction for 18 hours, the reaction 5 medium is poured into 150 ml of water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The black oil obtained is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/65/0.5) to give 0.039 g of 6 0 (3,3-dimethylpiperazin-1 -yl)-8-methyl-2,3-bis(pyrid-4-yl)imidazo[1,2-b]pyridazine in the form of a beige-coloured powder after recrystallizing from acetonitrile, filtering off and drying. m.p. = 211-213*C 1 H NMR (CDC1 3 ) 8: 8.70 (d, 2H); 8.60 (d, 2H); 7.60 (m, 4H); 6.75 (s, 1H); 3.45 (m, 5 2H); 3.25 (s, 2H); 3.05 (m, 2H); 2.70 (s, 3H); 1.20 (s, 6H) ppm. Example 3 (compound 12): 6-(3,3-Dimethylpiperazin-1 -2,3-bis(pyrid-4 yl)imidazo[1,2-blpyridazine

N

H3C H 3C N N/ HN N 0 Step 3.1. 6-Chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine ~ ~N N Cl N A mixture of 3.80 g (28.1 mmol) of 3-amino-6-chloropyridazine any 5.00 g (17.8 mmol) of 2-bromo-1-(pyrid-4-yl)ethanone hydrobromide in 50 ml of ethanol is heated by microwave 140"C for 50 minutes. After cooling, the solvent is evaporated off under 5 reduced pressure and the residue is taken up in saturated aqueous sodium hydrogen carbonate solution. The solid is separated out by filtration, washed with water and then chromatographed on a column of silica gel, eluting with a mixture of WU 2U010U70235 PCT/FR2009/052594 -26 dichloromethane and methanol (95/5), to give 1.97 g of 6-chloro-2-(pyrid-4 yl)imidazo[1,2-b]pyridazine in the form of a yellow powder. LC/MS: M+H* = 231 1 H NMR (CDCI 3 ) 6: 8.71 (dd, 2H); 8.33 (d, 1H); 7.93 (dd, 1H); 7.82 (dd, 2H); 7.11 (d, 5 1H). Step 3.2. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(pyrid-4-yl)imidazo[11,2-b]pyridazine

H

3 0 NN/ \/

H

3 C N NN HN A mixture of 1.95 g (8.45 mmol) of 6-chloro-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine and 0 2.4 g (21 mmol) of 2,2-dimethylpiperazine is heated in a microwave oven at 150"C for 13 hours. The medium is then cooled and the solvent is evaporated off under reduced pressure. The orange oil obtained is chromatographed on a column of silica gel, eluting with a mixture of dichloromethane and a 1 M solution of ammonia in methanol (95/5), to give 1.63 g of 6-(3,3-dimethylpiperazin-1-yl)-2-(pyrid-4 5 yl)imidazo[1,2-b]pyridazine in the form of a yellow foam. LC/MS: M+H* = 309 1 H NMR (DMSO-d 6 ): 8.67 (d, IH); 8.57 (dd, 2H); 7.86 (m, 3H); 7.23 (d, 1H); 3.41 (m, 2H); 3.25 (s, 2H); 3.17 (d, 1 H); 2.84 (m, 2H); 1.95 (bs, 1 H); 1.07 (s, 6H). 0 Step 3.3. 6-(3,3-Dimethylpiperazin-1 -yl)-3-iodo-2-(pyrid-4-yl)imidazo[1,2 b]pyridazine H3C -CN H N N HN To a solution of 1.37 g (4.45 nmol) of 6-(3,3-dimethylpiperazin-1-yl)-2-(pyrid-4 yl)imidazo[1,2-b]pyridazine in 20 ml of chloroform is added a solution of 1.80 g (11.1 5 mmol) of iodine monochloride in 5 ml of methanol. The suspension obtained is stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution is added, followed by portionwise addition of sodium thiosulfate until the reaction medium WO 20 101070238 PCT/FR20091052594 -27 remains yellow. The solid is separated out by filtration and air-dried to give 1.95 g of the product 6-(3,3-dimethylpiperazin-I -yl)-3-iodo-2-(pyrid-4-yl)imidazo[1,2 bipyridazine in the form of a yellow powder. 1 H NMR (DMSO-d 6 ): 9.0 (bs, 2H); 8.70 (d, 2H); 8.10 (d, 2H); 8.00 (d, 1H); 7.38 (d, 5 1 H); 3.85 (m, 2H); 3.70 (m, 2H); 3.3 (m, 2H); 1.40 (s, 6H). Step 3.4. 6-(3,3-Dimethylpiperazin-I -yl)-2,3-bis(pyrid-4-yl)imidazo[1,2 N -

H

3 C N 'N / HN b]pyridazine_ N 0 After degassing, a mixture of 0.28 g (0.55 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-3 iodo-2-(pyrid-4-yl)imidazo[1,2-b]pyridazine, 0.095 g (0.77 mmol) of (pyrid-4-yl)boronic acid, 0.89 g (2.7 mmol) of caesium carbonate and 45 mg (0.055 mmol) of a complex of 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (II) and dichloromethane (PdCl 2 (dppf).CH 2 Cl 2 - CAS 851232-71-8) in 4 ml of a mixture of 1,4-dioxane and 5 water (75/2) is heated in a microwave oven at 105 0 C for 30 minutes. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic phase is then dried over magnesium sulfate and filtered, and the solvent is evaporated off. The oil obtained is chromatographed on silica gel, eluting with a mixture of a 1M solution of ammonia in a mixture of methanol and dichloromethane 0 (3/97), to give 0.070 g of a yellow powder. LC/MS: M+H* = 386 1 H NMR (DMSO-d 6 ): 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). 5 Example 4 (compound 3): 6-(3,3-Dimethylpiperazin-1-yI)-2-(pyrid-3-yl)-3-(pyrid 4-yl)imidazo[11,2-blpyridazine WO 2010/070238 PCT/FR2009/052594 -28 N H 3 N N N HN N Step 4.1. 6-Chloro-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine Cl N N A suspension of 2.80 g (11.9 mmol) of 3-amino-6-chlompyridazine, 3.69 g (13.2 5 mmol) of 2-bromo-1 -(pyrid-3-yl)ethanone hydrobromide and 3.7 ml (26 mmol) of triethylamine in 45 ml of ethanol is heated by microwave at 140*C for 50 minutes. After cooling, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of 120 g of silica gel, eluting with a mixture of dichloromethane and methanol (95/5) to give 0.77 g of product in the form of a 0 beige-coloured powder, after triturating in heptane, filtering off and drying under reduced pressure. LC/MS: M+H 4 = 231 'H NMR (DMSO-d 6 ): 9.25 (s, 1H); 9.00 (s, 1H); 8.60 (d, 1H); 8.40 (dt, 1H); 8.25 (d, 1H); 7.50 (dd, IH); 7.40 (d, 1H). 5 Step 4.2. 6-(3,3-Dimethylpiperazin-1 -yl)-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine H3 N

H

3 C N N N HN A mixture of 0.77 g (3.3 mmol) of 6-chloro-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine and 1.1 g (9.6 mmol) of 2,2-dimethylpiperazine in 7 ml of ethanol is heated in a 0 microwave oven at 1500C for 13 hours. The medium is then cooled and the solvent is evaporated off under reduced pressure. The orange oil obtained is chromatographed on a column of silica gel, eluting with a mixture of dichloromethane and a 1 M solution of ammonia in methanol (97/3), to give 0.89 g of 6-(3,3-dimethylpiperazin-1-yl)-2 (pyrid-3-yl)imidazo[1,2-b]pyridazine in the form of a yellow powder.

WO 20101070238 PCT/FR2009/052594 -29 LC/MS: M+H* = 309 'H NMR (DMSO-d 6 ): 9.14 (d, 1H); 8.56 (s, 1H); 8.48 (d, 1H); 8.23 (d, IH); 7.85 (d, 1 H); 7.45 (dd, 1 H); 7.20 (d, 1 H); 3.41 (t, 2H); 2.86 (t, 2H); 1.95 (bs, 2H); 1.08 (s, 6H). 5 Step 4.3. 6-(3,3-Dimethylpiperazin-1 -yl)-3-iodo-2-(pyrid-3-yl)imidazo[1,2 bipyridazine 13C

H

3 C N N N HN I To a solution of 0.870 g (2.82 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-2-(pyrid-3 yl)imidazo[1,2-b]pyridazine in 10 ml of chloroform is added a solution of 0.600 g (3.70 0 mmol) of iodine monochloride in 4 ml of methanol. The orange-coloured suspension is then stirred for 3 hours and the solvent is evaporated off under reduced pressure to give a residue. Saturated aqueous sodium hydrogen carbonate solution is then added, followed by portionwise addition of sodium thiosulfate until the reaction mixture remains yellow. The solid is separated out by filtration and air-dried to give 5 0.90 g of product 6-(3,3-dimethylpiperazin-1-yl)-3-iodo-2-(pyrid-3-yl)imidazo[1,2 b]pyridazine in the form of a beige-coloured powder. LC/MS: M+H* = 435 'H NMR (DMSO-de): 9.26 (s, IH); 8.57 (d, IH); 8.39 (d, 1H); 7.92 (d, 1H); 7.52 (dd, 1 H); 7.31 (d, 1H); 3.75-3.10 (m, 6H); 1.25 (s, 6H). .0 Step 4.4. 6-(3,3-Dimethylpiperazin-1 -yl)-2,3-bis(pyrid-3-yl)imidazo[1,2 b]pyridazine 1- 3 CNN\/ Ha0 N N N HN N 5 VVV ZuluIUuzU PCT/FR2009/052594 - 30 After degassing, a mixture of 0.400 g (0.92 mmol) of 6-(3,3-dimethylpiperazin-1-yl)-3 iodo-2-(pyrid-3-yl)imidazo[1,2-b]pyridazine, 0.150 g (1.22 mmol) of (pyrid-4-yl)boronic acid, 0.89 g (2.7 mmol) of caesium carbonate and 75 mg (0.092 mmol) of a complex of 1,1'-bis(diphenylphosphinoferrocenedichloropalladium (11) and dichloromethane 5 (PdC 2 (dppf).CH 2 Cl 2 ) in 6 ml of a mixture of 1,4-dioxane and water (3/1) is heated in a microwave oven at 105*C for 30 minutes. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic phase is then dried over magnesium sulfate and filtered, and the solvent is evaporated off to give a green oil. The oil obtained is chromatographed on a column of 25 g of silica gel, eluting with a 0 mixture of a 1 M solution of ammonia in methanol and dichloromethane (5/95) to give 0.170 g of 6-(3,3-dimethylpiperazin-1 -yl)-2,3-bis(pyrid-3-yl)imidazo[1,2-b]pyridazine in the form of a grey powder. LC/MS: M+H* = 386 1 H NMR (DMSO-d 6 ): 8.70 (d, 1H); 8.67 (d, 2H); 8.52 (d, 1H); 7.96 (d, 1H); 7.90 (d, 5 1H); 7.58 (d, 2H); 7.41 (dd, 1H); 7.33 (d, 1H); 3.40 (t, 2H); 3.25 (s, 2H); 2.84 (t, 2H); 1.06 (s, 6H). Example 5 (compound 22): 2-(2-Fluoropyrid-4-yI)-6-(4-isopropylpiperazin-1-vi) 3-(pvrid-4-yI)imidazoi 1 ,2-blpyridazine F

N

N N 113C N 0

CH

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

NH

2 Nj Br C N 0 0

CH

3 5 WO 20101070238 PCT/FR2009/052594 -31 A mixture of 25.6 g (198 mmol) of 3-amino-6-chloropyridazine in 230 ml of hot ethanol is treated with 34.0 g (206 mmol) of ethyl bromoacetate. After refluxing for 24 hours, the mixture is cooled and the crystals are separated out by filtration. 36.6 g of product are isolated after drying. A further 7.1 g are isolated by evaporating off the 5 solvent under reduced pressure and recrystallizing from ethanol. 'H NMR (DMSO-d 6 ) 5: 9.8 (broad signal, 1H); 9.4 (broad signal, 1H); 8.0 (d, 1H); 7.7 (d, 1H); 5.3 (s, 1H); 4.1 (d, 2H); 1.2 (t, 3H) ppm. Step 5.2. 2-Bromo-6-chloroimidazo[1,2-b]pyridazine and 2,6-dibromoimidazo[1,2 0 b]pyridazine Cl Br Br Br A mixture of 20 g (65 mmol) of 6-amino-3-chloro-1-(ethoxycarbonylmethyl)pyridazin 1-ium bromide and 63 g of phosphorus oxybromide in 50 ml of toluene is heated at 1600C for 3 hours. The mixture is then poured onto ice (300 ml). After stirring, the 5 solid is separated out by filtration and then purified by chromatography on a column of 120 g of silica gel, eluting with a mixture of 0 to 10% of methanol in dichloromethane. 8.05 g of a mixture of the two products are thus obtained, and are used without further purification for the rest of the synthesis. 1 H NMR (CDC13) 5: 7.92 (s, 1H); 7.83 (d, 1H); 7.1 (d, 1H) .0 Step 5.3. 2 -Bromo-6-(4-isopropylpiperazin-1 -yl)imidazo[1,2-b]pyridazine Br N N H3C N

CH

3 5 The mixture of 3.98 g (14.4 mmol) of 2-bromo-6-chloroimidazo[1,2-b]pyridazine and 2,6-dibromoimidazo[1,2-b]pyridazine obtained in the preceding step and 3.7 g (28.5 mmol) of 1-isoproylpiperazine in 15 ml of ethanol is heated at 1600C for 8 hours in a sealed tube in a microwave reactor. The mixture is diluted with ethanol and then WO 2010/070238 PCT/FR2009/052594 -32 filtered to give 2.49 g of 2-bromo-6-(4-isopropylpiperazin-1-yl)imidazo[1,2 b]pyridazine. 1H NMR (CDC13) 8: 7.62 (s, 1H); 7.60 (d, 1H); 6.9 (d, IH); 3.5 (m, 4H); 2.73 (m, 1H); 2.64 (m, 4H); 1.1 (d, 6H) 5 Step 5.4. 2 -Bromo-3-iodo-6-(4-isopropylpiperazin-1 -yl)imidazo[1,2-b]pyridazine NN / Br N NB H3C N I

CH

3 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-broimo-6-(4-isopropylpiperazin-1 0 yl)imidazo[1,2-b]pyridazine in 20 ml of chloroform at 0*C. The mixture is stirred at room temperature for 4 hours. The mixture is then triturated with sodium thiosulfate. This mixture is concentrated under reduced pressure in the presence of 15 g of silica gel. The residue is deposited on a column of 80 g of silica gel and is purified by chromatography, eluting with a gradient of from 0 to 10% methanol in 5 dichloromethane, to give 2.07 g of 2-bromo-3-iodo-6-(4-isopropylpiperazin-1 yl)imidazo[1,2-b]pyridazine in the form of an orange-coloured solid. 1H NMR (CDC1 3 ) : 7.5 (d, 1H); 6.9 (d, 1H); 3.55 (m, 4H); 3.19 (m, 4H), 3.17 (m, 1H); 1.32 (d, 6H) 0 Step 5.5. 2-Bomo-6-(4-isopropylpiperazin-1 -yl)-3-(pyrid-4-yl)imidazo[1,2 b]pyridazine :IN N A /Br N N Br

H

3 C N

CH

3 N A mixture of 0.059 g (0.12 mmol) of 2-bromo-3-iodo-6-(4-isopropylpiperazin-I yl)imidazo[1,2-b]pyridazine, 3 mg (0.004 mmol) of 1,1' 5 bis(diphenylphosphino)ferrocenepalladium dichloride (CAS 72287-26-4), 18 mg (0.15 WO 20101070238 PCT/FR2009/052594 -33 mmol) of pyrid-4-ylboronic acid (CAS 1692-15-5), 0.9 ml of aqueous 2M caesium carbonate solution and 1.5 ml of 1,4-dioxane in a sealed tube is heated at 1100C for 30 minutes in a microwave oven. 1 ml of saturated sodium chloride solution and 4 ml of ethyl acetate are added. After stirring, the mixture is percolated through a sodium 5 sulfate cartridge. The solvent is evaporated off to dryness in the presence of silica gel. The absorbed residue is deposited on a column of 4 g of silica gel and diluted with a gradient of from 0 to 6% methanol and 1% aqueous ammonia in dichloromethane, to give 8.5 mg 0 of 2-bromo-6-(4-isopropylpiperazin-1-yl)-3-(pyrid-4-yl)imidazo[1,2-b]pyridazine. 'H NMR (CDC13) 8: 8.74 (d, 2H); 7.94 (d, 2H); 7.7 (d.1H); 6.93 (d, 1H); 3.5 (m, 4H); 2.75 (m, 1H); 2.65 (m, 4H); 1.10 (d, 6H). Step 5.6. 2-(2-Fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1 -yl)-3-(pyrid-4 5 yl)imidazo[1,2-b]pyridazine F N N N

H

3 C N

CH

3 N A mixture of 2.65 g (6.6 mmol) of 2-bromo-6-(4-isopropypiperazin-1-yl)-3-(pyrid-4 yl)imidazo[1,2-b]pyridazine, 0.46 9 (0.65 mmol) of 1,1' bis(diphenylphosphino)ferrocene palladium (CAS 72287-26-4), 1.12 g (9.10 mmol) of 0 pyridine-4-boronic acid (CAS 169215-15-5) and 15 ml of aqueous 2M caesium carbonate solution in 25 ml of 1,4-dioxane in a sealed tube is heated at 120CC for 20 minutes. A further 0.237 g (2.7 mmol) of pyridine-4-boronic acid is added and the reaction mixture is heated at 1100C for 30 minutes. The reaction medium is then diluted with water and the product is extracted with ethyl acetate. The organic phase 5 is washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent is stripped off under reduced pressure and the residue is adsorbed on silica gel. The product is purified by chromatography on a column of 80 g of silica gel, eluting with a gradient of from 0 to 10% methanol in dichloromethane VU zuUutUz3S PCT/FR2009/052594 -34 to give 1.85 g of 2-(2-fluoropyrid-4-yl)-6-(4-isopropylpiperazin-1-yl)-3-(pyrid-4 yl)imidazo[1,2-b]pyridazine, after recrystallizing from isopropanol. m.p. = 196-198*C 1 H NMR (CDCl 3 ) 8: 8.74 (d, 2H); 8.15 (d, 1H); 7.80 (d, 1H); 7.56 (d, 2H); 7.39 (d, 1H); 5 7.25 (d, 1 H); 6.98 (d, 1 H); 3.50 (m, 4H); 2.76 (m, 1 H); 2.62 (m, 4H); 1.08 (d, 6H). Table 1 below illustrates the chemical structures and the physical properties of a number of compounds according to the invention. 0 In this table: - the column "m.p. "C" indicates the melting points of the products in degrees Celsius. "N.D" means that the melting point is not determined, - the column "[a]D" indicates the result of analysis of the optical rotation of the compounds of the table at a wavelength of 589 nm; the solvent indicated in 5 parentheses corresponds to the solvent used for measuring the optical rotation, in degrees, and the letter "c" indicates the concentration of the solvent in g/100 ml. "N.A." means that the optical rotation measurement is not applicable, - the column "m/z" indicates the molecular ion (M+H*) observed by analysis of the products by mass spectrometry, either by LC-MS (liquid chromatography coupled to 0 Mass Spectroscopy) performed on a machine of Agilent LC-MSD Trap type in positive ESI mode, or by direct introduction by MS (Mass Spectroscopy) on- an Autospec M (EBE) machine using the DCI-NH3 technique or using the electron impact technique on a machine of Waters GCT type. - "CH 3 -" means methyl, 5 - "CH 3 0H" means methanol, - "DMSO" means dimethyl sulfoxide, WO 2010/070238 PCTIFR2009/052594 - 35 TABLE 1 R 7N A N N 5 LB N mz [ao () No R m.p (solvent -N-A-L-B- R(M+H* 7 . c; in g/100 m) 1 (3S)-3-Methylpiperazin-1 -yl H H Pyrid- H 196 372 +9.0 3 -yl - (CH 3 0H; 202 0.535) 2 (3S)-3-Methylpiperazin-1-yI H H Pyrid- CH 129 386 -2.2 3-yl 3 - (CH30H; 130 0.37) 3 3,3-Dimethylpiperazin-1-yI H H Pyrid- H 169 386 N.A. 3 -yI 171 4 4-Isopropylpiperazin-1-yI H H Pyrid- H 139 400 N.A. 3 -yl 148 5 4-Isopropylpiperazin-1-yl H H Pyrid- CH 63- 414 N.A. 3-yI 3 65 6 (3S)-3-Methylpiperazin-i-y H H 5- H 172 390 +8.2 Fluoro - (CH 3 0H; pyrid- 173 0.51) 3 -yl VVu Zu-luIuuzSU PCT/FR2009/052594 -36 mlz [a]D

(

0 ) NoR mp(solvent -N-A-L-B- RR R2 R3 (M+H* 7 .*C c; in g/1 00 m) 7 (3S)-3-Methylpiperazin-1-y H H 5- CH 147 404 -3.5 Fluoro 3 -

(CH

3 0H; pyrid- 148 0.54) 3-yl 8 4-Isopropylpiperazin-1-y H H 5- H 171 418 N.A. Fluoro pyrid- 182 3 -yl 9 4 -Isopropylpiperazin-1-yl H H 5- CH 142 428 N.A. Methyl 3 pyrid- 147 3-yl 10 Piperazin-1-yl H H Pyrid- H 183 358 N.A. 4 -yi 189 11 (3S)-3-Methylpiperazin-1-yI H H Pyrid- CH 55- 386 Not 4-yl 3 58 determine d 12 3,3-Dimethylpiperazin-1-y H H Pyrid- H 149 386 N.A. 4 -yl 152 13 3,3-Dimethylpiperazin-1-yl H H Pyrid- CH 185 400 N.A. 4-yl 3 187 14 3,3-Dimethylpiperazin-1-yi H CH Pyrid- H 211 400 N.A. 3 4-yl 213 15 (3R)-3-Isopropylpiperazin- H H Pyrid- H 189 400 +2.9 1-yl 4-yI - (DMSO; 191 0.847) VVu ZUUIUOZ3u PCT/FR2009/052594 - 37 m/z [aID (0) No -N-A-L-B- Re(MH (solvent . C c; in g/100 m) 16 4 -isopropyipiperazin-1-yl H H Pyrid- H 66- 400 N.A. 4-yl 68 17 4-Isopropylpiperazin-1-y H H Pyrid- CH 195 414 N.A. 4-yI 3 196 18 (cis)-5- H H Pyrid- H 189 398 N.A. Methylhexahydropyrrolo[3, 4-yl 196 4-c]pyrrol-2(1 H)-yI 19 4-Pyrrolidin-1-ylpiperidin-1- H H Pyrid- H 187 426 N.A. yl 4-yl 189 20 (3S)-3-Methylpiperazin-1-yl H H 2- H 150 390 +8.2 Fluoro - (CH 3 0H; pyrid- 152 0.51) 4-yl 21 (3S)-3-Methylpiperazin-1-yl H H 2- CH 128 404 -0.9 Fluoro 3 - (CH 3 0H; pyrid- 135 0.53) 4-yl 22 4 -Isopropylpiperazin-1-yl H H 2- H 196 418 N.A. Fluoro pyrid- 198 4-yl 23 4-Isopropylpiperazin-1 -yl H H 2- CH 129 432 N.A. Fluoro 3 pyrid- 130 4-yl vvu Iluuruuzju PCT/FR2009/052594 -38 Biological examples The capacity of the compounds of the invention to inhibit the phosphorylation of 5 casein by casein kinases 1 epsilon and delta may be evaluated according to the procedure described in document US 2005/0 131 012. Filter-plate assay of ATP- 33 P for the screening of CK1 epsilon inhibitors: 0 The effect of the compounds on inhibition of the phosphorylation of casein by the enzyme casein kinase 1 epsilon (CK1 epsilon) is measured, using a casein assay via filtration of ATP- 33 P in vitro. Casein kinase 1 epsilon (0.58 mg/ml) is obtained via fermentation and purification 5 processes performed according to methods that are well known to those skilled in the art, or may also be obtained from Invitrogen CorporationTM (human CKi epsilon). The compounds are tested at five different concentrations so as to generate IC 50 values, i.e. the concentration at which a compound is capable of inhibiting the ?0 enzymatic activity by 50%, or alternatively the percentage of inhibition at a concentration of 10 micromolar. "U"-bottomed Falcon plates are prepared by placing 5 pL of solutions of the compounds according to the invention at concentrations of 10, 1, 0.1, 0.01 or 0.001 5 pM in different wells. The solutions of the compounds according to the invention at these various concentrations are prepared by diluting in a test buffer (Tris 50 mM pH 7.5, MgCl 2 10 M, DTT 2 mM and EGTA 1 mM) a stock solution in DMSO at a concentration of 10 mM. Next, 5 pL of dephosphorylated casein are added to a final concentration of 0.2 0 pg/pL, 20 pL of CK1 epsilon to a final concentration of 3 ng/pL, and 20 pL of ATP- 33 p to a final concentration of 0.02 pCi/pL mixed with cold ATP (10 pM final approximately 2x106 CPM per well). The final total test volume per well is equal to 50 pL.

WVU 201W070238 PCT/FR2009/052594 - 39 The "U"-bottomed Falcon@ test plate mentioned above is vortexed, and then incubated at room temperature for 2 hours. After 2 hours the reaction is stopped by adding an ice-cold solution of 65 pL of cold ATP (2 mM) prepared in test buffer. 5 100 pL of the reaction mixture are then transferred from the "U"-bottomed Falcon® plate into Millipore@ MAPH filter plates, preimpregnated with 25 pL of ice-cold 100% TCA. 10 The Millipore MAPH filter plates are agitated gently and are left to stand at room temperature for at least 30 minutes to precipitate the proteins. After 30 minutes, the filter plates are sequentially washed and filtered with 2x150 pL of 20% TCA, 2x1 50 pL of 10% TCA and 2x150 pL of 5% TCA (6 washes in total per I5 plate/900 pL per well). The plates are left to dry overnight at room temperature. Next, 40 pL of Microscint-20 Packard@ scintillation liquid are added per well and the plates are closed in a leaktight manner. The radiation emitted by each well is then measured for 2 minutes ?0 in a TopCount NXT Packard® scintillation counter, in which the values of CPM/well are measured. The percentage inhibition of the capacity of the enzyme to phosphorylate the substrate (casein) is determined for each concentration of test compound. These 5 inhibition data expressed as percentages are used to calculate the IC0 value for each compound compared with the controls. The kinetic studies determined the KM value for ATP as being 21 pM in this test system. 0 Table 2 below gives the IC50 values for the inhibition of phosphorylation of casein kinase 1 epsilon for a number of compounds according to the invention. Table 2 WO 2010/070238 PCT/FR2009/052594 - 40 Compound CK1 epsilon IC50 (nM) No. 3 106-193 12 55-267 13 89-472 Under these conditions, the compounds of the invention that are the most active have ICo values (concentrations that inhibit 50% of the enzymatic activity of casein kinase 1 epsilon) of between 1 nM and 2 pM. 5 The capacity of the compounds of the invention to inhibit the phosphorylation of casein by the casein kinases 1 epsilon and delta may be evaluated using an FRET (Fluorescence Resonance Energy Transfer) fluorescence test with the aid of the "Z'LyteTM kinase assay kit" (reference PV3670; Invitrogen CorporationTM) according 0 to the manufacturer's instructions. The casein kinases 1 used are obtained from Invitrogen Corporation (human CK1 epsilon PV3500 and human CK1 delta PV3665). 5 A peptide substrate labelled at both ends with a fluorophore-donating group (coumarin) and a fluorophore-accepting group (fluorescein) constituting an FRET system is dephosphorylated in the presence of ATP by casein kinase 1 epsilon or delta in the presence of increasing concentrations of compounds of the invention. 0 The mixture is treated with a site-specific protease that specifically cleaves the substrate peptide to form two fluorescent fragments having a large fluorescence emission ratio. The fluorescence observed is thus related to the capacity of the products of the 5 invention to inhibit the phosphorylation of the substrate peptide by casein kinase I epsilon or casein kinase 1 delta.

WU 2010/070238 PCT/FR2009/052594 - 41 The compounds of the invention are dissolved at different concentrations starting with a 10 mM stock solution in DMSO diluted in a buffer containing 50 mM HEPS, pH 7.5, 1 mM EGTA, 0.01% Brij-35, 10 mM MgCl 2 for casein kinase I epsilon and supplemented with Trizma Base (50 mM), pH 8.0 and NaN 3 (0.01% final) for casein 5 kinase 1 delta. The phosphorylation of the substrate peptide SER/THR 11 obtained from Invitrogen CorporationTM is performed at a final concentration of 2 pM. The ATP concentration is 4 times the Km, this value being 2 pM for casein kinase 1 epsilon and 4 pM for 0 casein kinase 1 delta. The emitted fluorescence is measured at wavelengths of 445 and 520 nm (excitation at 400 nm). 5 Table 3 below gives the IC5o values for the inhibition of phosphorylation of casein kinase 1 delta for a number of compounds according to the invention. Table 3 Compound CK1 delta IC50 (nM) No. 12 358-382 13 107 22 287 Under these conditions, the compounds of the invention that are the most active 0 have IC5o values (concentration that inhibits 50% of the enzymatic activity of casein kinase 1 delta) of between I nM and 2 pM. It is thus seen that the compounds according to the invention have inhibitory activity on the enzyme casein kinase 1 epsilon or casein kinase 1 delta. 5 Experimental protocols for circadian cell assay VVU U01/070238 PCT/FR2009/052594 -42 Mperl-luc Rat-1 (P2C4) fibroblast cultures were prepared by dividing the cultures every 3-4 days (about 10-20% of confluence) on 150 cm 2 degassed polystyrene tissue culture flasks (Falcon@ # 35-5001) and maintained in growth medium [EMEM 5 (Cellgro #10-010-CV); 10% foetal bovine serum (FBS; Gibco #16000-044); and 50 I.U./mL of penicillin-streptomycin (Cellgro #30-001-Cl)] at 37*C and under 5% CO 2 . Cells obtained from Rat-1 fibroblast cultures at 30-50% of confluence as described above were co-transfected with vectors containing the selection marker for resistance 10 to zeocin for a stable transfection and a luciferase reporter gene directed by the promoter mPer-1. After 24 to 48 hours, the cultures were divided on 96-well plates and maintained in growth medium supplemented with 50-100 pg/mL of zeocin (Invitrogen@ #45-0430) for 10-14 days. The zeocin-resistant stable transfectants were evaluated for expression of the reporter by adding to the growth medium 5 luciferin 100 pM (Promega® #E1603®) and by assaying the luciferase activity on a TopCount@ scintillation counter (Packard model #C384V00). The Rat-I cell clones expressing both zeocin resistance and luciferase activity directed by mPerl were serum-shock-synchronized with 50% horse serum [HS (Gibco® #16050-122)] and the activity of the circadian reporter was evaluated. The P2C4 clone of fibroblasts ?0 Mperi-luc Rat-1 was selected to test the compound. The Mperl-luc Rat-1 (P2C4) fibroblasts at 40-50% of confluence obtained according to the protocol described above were plated out onto 96-well opaque tissue culture plates (Perkin Elmer@ #6005680). The cultures are maintained in growth medium 5 supplemented with 100 pg/mL of zeocin (Invitrogen #45-0430) until they reached 100% of confluence (48-72 hours). The cultures were then synchronized with 100 pL of synchronization medium [EMEM (Celigro #10-010-CV); 100 L.U./mL of penicillin streptomycin (Cellgro #30-001-Cl); 50% HS (Gibco #116050-122)] for 2 hours at 37*C and under 5% CO 2 . After synchronization, the cultures were rinsed with 100 pL of 0 EMEM (Cellgro #10-010-CV) for 10 minutes at room temperature. After rinsing, the medium is replaced with 300 pL of C0 2 -independent medium [CO21 (Gibco #18045 088); L-glutamine 2 mM (Cellgro #25-005-Cl); 100 U.l./mL of penicillin-streptomycin (Cellgro #30-001-C1); luciferin 100 pM (Promega #E 1603)]. The compounds of the WO 20101070238 PCT/FR2009/052594 -43 invention tested for the circadian effects were added to C02-independent medium in DMSO at 0.3% (final concentration). The cultures were immediately closed in a leaktight manner with TopSeal-A® film (Packard #6005185) and transferred for the luciferase activity measurement. 5 After synchronization, the test plates were maintained at 370C in a tissue culture oven (Forma Scientific Model #3914). The in vivo luciferase activity was estimated by measuring the relative light emission on a TopCount scintillation counter (Packard model #C384V00). I0 The period analysis was performed either by determining the interval between the relative light emission minima over several days or by Fourier transform. The two methods produced a virtually identical period estimation on a range of circadian periods. The power is given in EC Delta (t+1 h), which is presented as the effective 5 micromolar concentration that induce a 1-hour prolongation of the period. The data were analysed by adjusting a hyperbolic curve to the data expressed as change of period (y-axis) as a function of the concentration of the test compound (x-axis) in the XLfitTm software and the EC Delta (t+1 h) was interpolated from this curve. .0 Table 4 below gives the EC Delta (t+1 h) for a number of compounds according to the invention. Table 4 Compound EC Delta (t+1 h) (nM) No. 10 658 20 17-398 22 6-273 Under these conditions, the compounds of the invention that are the most active 5 have EC Delta (t+1h) values (effective micromolar concentration that induced a 1 hour prolongation of the period) of between 1 nM and 2 pM.

WO 20101070238 PCT/FR20091052594 -44 By inhibiting the enzymes CK1 epsilon and/or CKI delta, the compounds that are the subject of the invention modulate the circadian periodicity, and may be useful for treating circadian rhythm disorders. 5 The compounds according to the invention may especially be used for the preparation of a medicament for preventing or treating sleep disorders; circadian rhythm disorders, especially such as those caused by jetlag or shift work. Among the sleep disorders that are especially distinguished are primary sleep 0 disorders such as dyssomnia (for example primary insomnia), parasomnia, hypersomnia (for example excessive somnolence), narcolepsy, sleep disorders related to sleep apnoeia, sleep disorders related to the circadian rhythm and other unspecified dyssomnias, sleep disorders associated with medical/psychiatric disorders. 5 The compounds that are the subject of the invention also cause a circadian phase shift and such a property may be useful in the context of a potential monotherapy or combined therapy that is clinically effective in the case of mood disorders. .0 Among the mood disorders that are especially distinguished are depressive disorders (unipolar depression), bipolar disorders, mood disorders caused by a general medical complaint and also mood disorders induced by pharmacological substances. Among the bipolar disorders that are especially distinguished are bipolar I disorders 5 and bipolar 11 disorders, especially including seasonal affective disorders. The compounds that are the subject of the invention, which modulate the circadian periodicity, may be useful in the treatment of anxiety and depressive disorders caused in particular by an impairment in the secretion of CRF. 0 Among the depressive disorders that are especially distinguished are major depressive disorders, dysthymic disorders and other unspecified depressive disorders.

WO 2010/070238 PCT/FR20091052594 -45 The compounds that are the subject of the invention, which modulate the circadian periodicity, may be useful for preparing a medicament for treating diseases related to dependency on abuse substances such as cocaine, morphine, nicotine, ethanol and cannabis. 5 By inhibiting casein kinase 1 epsilon and/or casein kinase 1 delta, the compounds according to the invention may be used for preparing medicaments, especially for preparing a medicament for preventing or treating diseases related to hyperphosphorylation of the tau protein, especially Alzheimer's disease. 10 These medicaments also find their use in therapy, especially in the treatment or prevention of diseases caused or exacerbated by the proliferation of cells and in particular of tumour cells. 15 As tumour cell proliferation inhibitors, these compounds are useful in the prevention and treatment of liquid tumours such as leukaemias, solid tumours that are both primary and metastatic, carcinomas and cancers, in particular: breast cancer; lung cancer; small intestine cancer and colorectal cancer; cancer of the respiratory pathways, of the oropharynx and of the hypopharynx; cancer of the oesophagus; liver 20 cancer, stomach cancer, cancer of the bile ducts, cancer of the bile vesicle, pancreatic cancer; cancers of the urinary pathways including the kidney, urothelium and bladder; cancers of the female genital tract, including cancer of the uterus, of the cervix, of the ovaries, choriocarcinoma and trophoblastoma; cancers of the male genital tract, including cancer of the prostate, of the seminal vesicles, of the testicles ?5 and germinal cell tumours; cancers of the endocrine glands, including cancer of the thyroid, of the pituitary and of the adrenal glands; skin cancers including haemiangiomas, melanomas and sarcomas, including Kaposi's sarcoma; brain, nerve, eye or meningeal tumours, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neurinomas, neuroblastomas, schwannomas and meningiomas; MO malignant haematopoietic tumours; leukaemias (Acute Lymphocytic Leukaemia (ALL), Acute Myeloid Leukaemia (AML), Chronic Myeloid Leukaemia (CML), Chronic lymphocytic leukaemia (CLL)) chloromas, plasmocytomas, T or B cell leukaemias, Hodgkin or non-Hodgkin lymphomas, myelomas and various malignant haemopathies.

VVU ZU101070238 PCTIFR2009/052594 -46 The compounds according to the invention may also be used for the preparation of medicaments, especially for the preparation of a medicament for preventing or treating inflammatory diseases especially such as inflammatory diseases of the 5 central nervous system, for instance multiple sclerosis, encephalitis, myelitis and encephalomyelitis, and other inflammatory, diseases, for instance vascular pathologies, atherosclerosis, joint inflammations, arthrosis and rheumatoid arthritis. The compounds according to the invention may thus be used for the preparation of 0 medicaments, in particular of medicaments for inhibiting casein kinase 1 epsilon and/or casein kinase 1 delta. Thus, according to another of its aspects, a subject of the invention is medicaments comprising a compound of formula (1), or an addition salt thereof with a 5 pharmaceutically acceptable acid, or alternatively a hydrate or solvate of the compounds of formula (1). According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. 0 These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, a hydrate or solvate of the said compound, and also at least one pharmaceutically acceptable excipient. 5 The said excipients are chosen, according to the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art. In the pharmaceutical compositions of the present invention for oral, sublingual, 0 subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or the possible salt, solvate or hydrate thereof, may be administered in unit administration form, as a mixture with standard pharmaceutical excipients, to man and animals for the prophylaxis or treatment of the above disorders or diseases.

VV ZU 1UJ7O238 PCTIFR2009/052594 -47 The appropriate unit administration forms include oral-route forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, 5 inhalation forms, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical administration, the compounds according to the invention may be used in creams, gels, ointments or lotions. 10 By way of example, a unit administration form 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 5 Croscarmellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg 0 Via the oral route, the dose of active principle administered per day may range from 0.1 to 20 mg/kg, in one or more dosage intakes. There may be particular cases in which higher or lower dosages are appropriate; such dosages are not outside the context of the invention. According to the usual practice, the dosage that is appropriate to each patient is determined by the 5 practitioner according to the mode of administration and the weight and response of the said patient. According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration to a 0 patient of an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt or hydrate or solvate thereof.

Claims (14)

1. Compound of general formula (1) R 8 R7 - N R-N A- NN/ 2 N N LB N in which: 5 - R 2 represents a pyridyl group optionally substituted with one or more substituents chosen from halogen atoms and groups C 1 . 6 -alkyl; - R 3 represents a hydrogen atom or a group C1- 3 -alkyl; 0 - A represents a group C1.ralkylene optionally substituted with one or two groups Ra; - B represents a group C1-ralkylene optionally substituted with a group Rb; - L represents either a nitrogen atom optionally substituted with a group R. or Rd, or a carbon atom substituted with a group R, 1 and a group Rd or two groups Re2; 5 the carbon atoms of A and B being optionally substituted with one or more groups Rf, which may be identical to or different from each other; Ra, Rb and R 0 are defined such that: two groups Ra may together form a group C 1 .- alkylene; 0 R, and Rb may together form a bond or a group C 1 . 6 -alkylene; Ra and Rc may together form a bond or a group C1. 6 -alkylene; Rb and R, may together form a bond or a group C 1 . 6 -alkylene; | Rd represents a group chosen from a hydrogen atom and groups C 1 .e-alkyl, C3.7 5 cycloalkyl, C3-7-cycloalkyl-C 1 .-- alkyl, C 1 . 6 -alkylthio-C 1 . 6 -alkyl, C 1 . 6 -alkyloxy-C 1 . alkyl, C1.e-fluoroalkyl, benzyl, C 1 . 6 -acyl or hydroxy-C 1 . 6 -alkyl; Rei represents a group -NR4R 5 or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or WO 2010/070238 PCT/FR2009/052594 -49 more substituents chosen from a fluorine atom and groups C 1 -- alkyl, C1.6 alkyloxy or hydroxyl; two Re2 form, with the carbon atom that bears them, a cyclic monoamine optionally 5 comprising an oxygen atom, this cyclic monoamine being optionally substituted with one or more groups Rf, which may be identical to or different from each other; Rf represents a group C 1 . 6 -alkyl, C3.-rcycloalkyl, C3-rcycloalkyl-C 1 . 6 -alkyl, C1_ 10 alkyloxy-C 1 . 6 -alkyl, hydroxy-C 1 . 6 -alky, C1.6-fluoroalkyl or benzyl; R4 and R 5 represent, independently of each other, a hydrogen atom or a group C 1 e alkyl, C3-7-cycloalkyl or C3-rcycloalkyl-C 1 . 4 -alkyl; 15 R 7 and R 8 represent, independently of each other, a hydrogen atom or a group C1.e alkyl; in the form of the base or of an acid-addition salt,

2. Compound of general formula (I) according to Claim 1, characterized in that: ?0 - L represents either a nitrogen atom optionally substituted with a group Rc or Rd, or a carbon atom substituted with a group Re1 and a group Rd.

3. Compound of general. formula (1) according to any one of the preceding claims, characterized in that: ?5 - R 2 represents a pyridyl group, optionally substituted with one or more substituents chosen from fluorine and a methyl group.

4. Compound of general formula (I) according to any one of the preceding claims, characterized in that: 0 R 7 and R 8 represent a hydrogen atom or a group C1-6-alkyl.

5. Compound of general formula (1) according to any one of the preceding claims, characterized in that: - A represents a group Ci-7ralkylene optionally substituted with one or two groups Ra; 5 - B represents a group C1.7-alkylene optionally substituted with a group Rb; vvU zulIU(fUzaj PCT/FR2009/052594 -50 - L represents a nitrogen atom optionally substituted with a gmup Rb or Rd; the carbon atoms of A and B being optionally substituted with one or more groups Rf, which may be identical to or different from each other; 5 Ra, Rb and Re are defined such that: two groups Ra may together form a group C 1 . 6 -alkylene; Ra and Rb may together form a bond or a group Ci. 6 -alkylene; Ra and R 0 may together form a bond or a group Ce-alkylene; 10 Rb and Re may together form a bond or a group C1. 6 -alkylene; Rd represents a group chosen from a hydrogen atom and groups C--alkyl, C3-r cycloalkyl, C3-rcycloalkyl-C- 6 -alkyl, C.e-alkylthio-Ce 6 -alkyl, C - 6 -alkyloxy-C -6 alkyl, CI. 6 -fluoroalkyl, benzyl, C 1 . 4 -acyl or hydroxy-C, 6 -alkyl; 15 Rf represents a group C1- 6 -alkyl, C3-7rcycloalkyl, C3.-rcycloalkyl-C 1 . 6 -alkyl, C1.-6 alkyloxy-C1. 6 -alkyl, hydroxy-Cl6s-alkyl, C1-e-fluo malkyl or benzyl.

6. Compound of general formula (1) according to any one of the preceding claims, ?0 characterized in that: - A represents a group C1.7-alkylene optionally substituted with one or two groups R.; - B represents a group COj-ralkylene optionally substituted with a group Rb; - L represents a carbon atom substituted with a group R., and a group Rd; 25 the carbon atoms of A and B being optionally substituted with one or more groups Rf, which may be identical to or different from each other; Ra, Rb and Rc are defined such that: two groups R 8 may together iorm a group C.e-alkylene; W0 Ra and Rb may together form a bond or a group C1.-alkylene; Ra and R 0 may together form a bond or a group Ci..-alkylene; Rb and RO may together form a bond or a group C1.-alkylene; vvu ZUE uUfUAsU PCT/FR2009/052594 -51 Rd represents a group chosen from a hydrogen atom and groups C1. 6 -alkyl, C 3 - 7 cycloalkyl, C3-rcycloalkyl-C 1 . 6 -alkyl, C 1 .e-alkylthio-C 1 . 6 -alkyl, C 1 .e-alkyloxy-C1.e alkyl, C1-e-fluoroalkyl, benzyl, C. .- acyl or hydroxy-C 1 . 6 -alkyl; 5 Re1 represents a group -NR 4 R 5 or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents chosen from a fluorine atom and groups C1-6-alkyl, C1.e alkyloxy or hydroxyl; 10 Rf represents a group C1-6-alkyl, C.3-r-cycloalkyl, C3.7-cycloalkyl-C1. 6 -alkyl, C1.e alkyloxy-C1- 6 -alkyl, hydroxy-C. 6 -alkyl, C. 6 -fluoroalkyl or benzyl; R 4 and R 5 represent, independently of each other, a hydrogen atom or a group C1.6 alkyl, C3.7-cycloalkyl or C3-7-cycloalkyl-C. 6 -alkyl. 5

7. Compound of general formula (1) according to any one of the preceding claims, characterized in that: - the cyclic amine formed by -N-A-L-B- represents a (3S)-3-methylpiperazin-1 -yl, 3,3 dimethylpiperazin-1 -y, 4-isopropylpiperazin-i -yl, piperazin-1-yl, (3R)-3 .0 isopropylpiperazin-1-yl, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl or 4 pyrrolidin-1-ylpiperidin-1-yl group; - R 2 represents a pyridyl group, optionally substituted with one or more substituents chosen from fluorine and a methyl group; - R 3 represents a hydrogen atom or a methyl group; 5 - R 7 and R 8 represent a hydrogen atom or a methyl group; in the form of the base or of an acid-addition salt.

8. Process for preparing a compound of general formula (I) according to Claim 1, characterized in that a compound of general formula (11 VVU ZUUIUUZ3 PCT/FR2009/052594 -52 RsR R16 N ~- R3 N (11) N R in which R 2 , R 3 , R 7 and Rs are as defined in Claim 1 and X 6 represents a halogen, is reacted with an amine of general formula (111) H A-N 11 I(Ila) L-B 5 in which A, L and B are as defined in Claim 1.

9. Process for preparing a compound of general formula (1) according to Claim 1, characterized in that a compound of general formula (V) R - N R2 (V) A-N N I I L-B 10 in which A, L, B, R 2 , R 7 and R8 are defined according to Claim 1, is reacted with a mixture of a pyridine derivative of general formula (Va) 0 CI 0'Alkyl (Va) in which R 3 is defined according to Claim I and an alkyl chloroformate, in which the alkyl group represents a C1. 6 -alkyl, to obtain a compound of general formula (VI) Re R7 ;wN NN /R 2 A-N N L-B N O,Alkyl 5 (VI) VVU ZU010/07238 PCT/FR2009/052594 - 53 in which A, L, B, R 2 , R 3 , R 7 and R 8 are defined according to Claim 1, the said compound of general formula (VI) is then oxidized using ortho-chloranil.

10. Process for preparing a compound of general formula (1) according to Claim 1, 5 characterized in that a compound of general formula (V) R8 R7 5'N NN / R 2 (V) A-N N I I L-B in which A, L, B, R 2 , R 7 and R 8 are defined according to Claim 1, is reacted according to an aromatic bromination or iodination reaction, to obtain a compound of general formula (VII) . R7 NN / R 2 (VII) A-N N I I 10 L-B 3 in which 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, and in that a metal-catalysed coupling is carried out between the compound of [5 general formula (VII) obtained and a pyridine derivative of general formula (IlIla) M R (Illa) N in which R 3 is as defined in Claim I and M represents a trialkylstannyl group or a dihydroxybonyl or dialkyloxyboryl group 0

11. Process for preparing a compound of general formula (1) according to Claim 1, characterized in that: a) a compound of general formula (VIII) vit zul Uluujts PCT/FR2009/052594 - 54 -54 R8 A-N N in which A, L, B, R 7 and R 8 are defined according to Claim 1, is reacted is- reacted according to an aromatic iodination reaction to obtain a compound of general formula (IX) Ra AN / Br (IX) A-N N 5 L-B in which A, L, B, R 7 and R 8 are defined according to Claim 1; b) the compound of general formula (IX) obtained in a) is reacted with a compound of general formula (ilila) M R3 (lila) ~N R? 3 10 in which R 3 is defined according to Claim I and M represents a trialkylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, to obtain a compound of general formula (X) R8 R -N AN / Br A-N N- MX I I L-B / N in which A, L, B, R 3 , R 7 and R 8 are defined according to Claim 1; 5 c) the compound of general formula (X) obtained in b) is reacted with a compound of general formula (Xa) R 2 -M (Xa) in which R 2 is defined according to Claim 1 and M represents a trialkylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, in the presence of a catalyst. vu zuiUoa23s PCT/FR2009/052594 -55

12. Medicament, characterized in that it comprises a compound of formula (1) according to any one of Claims I to 7, in the form of the base or of a pharmaceutically acceptable acid-addition salt. 5

13. Pharmaceutical composition, characterized in that it comprises a compound of formula (1) according to any one of Claims I to 7, in the form of the base or of a pharmaceutically acceptable acid-addition salt, and also at least one pharmaceutically acceptable exciplent. 10

14. Use of a compound of general formula (1) according to any one of Claims 1 to 12, for the preparation of a medicament for preventing or treating sleep disorders or circadian rhythm disorders, mood disordes, anxiety and depressive disorders, diseases associated with dependence on abuse substances, diseases related to 5 hyperphosphorylation of the tau protein, diseases caused or exacerbated by cell proliferation or inflammatory diseases.