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Definitions

• the present invention relates to 6-cycloamino-2-thienyl-3- (pyridin-4-yl) imidazo [1,2-b] pyridazine and 6-cycloamino-2-furanyl-3- (pyridine) derivatives.
• the subject of the present invention is the compounds corresponding to the general formula (I)
• R 2 represents a thienyl group or a furanyl group optionally substituted by one or more substituents selected from halogen atoms and the groups Ci -6 - alkyl;
• R 3 represents a hydrogen atom or a Ci -3 alkyl group, -NR 4 R 5, or Ci -4 - alkyloxy;
• A represents a C 1-7 -alkylene group optionally substituted with one or two R 3 groups;
• B represents a C 1-7 -alkylene group optionally substituted with a group R b ;
• L represents either a nitrogen atom optionally substituted with an R c or R d group or a carbon atom substituted by a group R e i and an R d group or two groups
• R a, R b and R c are defined such that: two groups R 3 may together form a Ci -6 alkylene group;
• R 3 and R b may together form a bond or a Ci -6 alkylene group
• R 3 and R c may together form a bond or a Ci -6 alkylene group
• R b and R c may together form a bond or a C6-alkylene group
• R d represents a group selected from hydrogen and Ci -6 alkyl groups, C 3-7 cycloalkyl, C 3- 7 cycloalkyl-C6-alkyl, Ci -6 alkylthio-Ci - 6 alkyl, Ci -6 -alkyloxy- d-6-alkyl, Ci -6 fluoroalkyl, benzyl, hydroxy-Ci -6 alkyl;
• R i represents an -NR 4 R 5 or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted by one or more substituents selected from fluoro and Ci -6 alkyl groups, Ci -6 alkyloxy, hydroxy;
• R ⁇ 2 form with the carbon atom carrying 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 to or different from each other;
• R f represents a Ci -6 alkyl group, C 3-7 cycloalkyl, C 3- 7 cycloalkyl-C6-alkyl, Ci -6 - alkyloxy-d-6-alkyl, hydroxy-Ci -6 alkyl , Ci -6 fluoroalkyl or phenyl;
• R 4 and R 5 represent, independently of one another, a hydrogen atom or a Ci -4 alkyl group, C 3-7 cycloalkyl, C 3- 7 cycloalkyl-Ci -6 alkyl;
• R 7 and R 8 represent, independently of one another, a hydrogen atom or a group Ci -6 alkyl group.
• the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
• the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
• the compounds of formula (I) may also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
• t and z may take the values from 1 to 7, a carbon chain which can have from t to z carbon atoms, for example Ci -7 a carbon chain which can have from 1 to 7 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example, a d-6-alkyl group 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 group, a saturated divalent alkyl, linear or branched, for example a Ci -6 alkylene group 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
• fluoroalkyl an alkyl group in which one or more hydrogen atoms have been substituted by a fluorine atom
• fluoroalkyloxy an alkyloxy group in which one or more hydrogen atoms have been substituted by 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.
• aryl group mention may be made of phenyl or naphthyl groups.
• cyclic amines or diamines formed by N, A, L and B there may be mentioned aziridine, azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, and the like.
• homopiperidine decahydroquinoline, decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclonnonane, aza-oxo-bicycloheptane, aza-thia-bicyclo heptane, aza-oxo-bicyclooctane, aza-thia-bicyclooctane; piperazine, homopiperazine, diaza-cyclooctane, diaza-cyclo-nonane, diaza-cyclo-decane, diaza-cyclo-undecane, octahydro-pyrrolopyrazine, octahydro-pyrrolo-diazepine hexahydro-pyrrolo-pyrrole, octahydro-pyrrolopyridine, decahydro-naphthyridine, diaza-bicyclo-heptan
• a first group of compounds consists of the compounds for which: R 2 represents a thienyl group optionally substituted by one or more substituents selected from halogen atoms and the groups Ci -6 - alkyl; the other substituents being as defined above.
• a second group of compounds consists of the compounds for which:
• R 2 represents a thienyl group, optionally substituted by one or more substituents identical or different from each other selected from the chlorine atom and the methyl group; the other substituents being as defined above.
• a third group of compounds consists of the compounds for which:
• R 2 is furanyl optionally substituted by one or more identical or different substituents from one another, chosen from halogen atoms and the groups Ci -6 alkyl; the other substituents being as defined above.
• a fourth group of compounds consists of the compounds for which: R 2 is furanyl optionally substituted by one or more Ci -6 alkyl groups, more particularly methyl; the other substituents being as defined above.
• a fifth group of compounds consists of the compounds for which:
• R 2 is thien-2-yl, 5-methyl-thien-2-yl, 5-chloro-thien-2-yl, thien-3-yl, 2,5-dimethyl-thien-3-yl, 2 5-dichloro-thien-3-yl, furan-2-yl; 5-methyl-furan-2-yl; furan-3-yl; the other substituents being as defined above.
• a sixth group of compounds is constituted by the compounds for which:
• R 3 represents a hydrogen atom or a C 1-3 -alkyl group, -NR 4 R 5 ;
• R 4 and R 5 represent, independently of one another, a hydrogen atom or a C 1-4 -alkyl group; the other substituents being as defined above.
• a seventh group of compounds is constituted by the compounds for which: R 3 represents a hydrogen atom, a methyl group or an -NH 2 group; the other substituents being as defined above.
• an eighth group of compounds is constituted by the compounds for which: R 7 and R 8 represent a hydrogen atom; the other substituents being as defined above.
• a ninth group of compounds is constituted by the compounds for which: A represents a C 1-7 -alkylene group optionally substituted with one or two R 3 groups;
• B represents a C 1-7 -alkylene group optionally substituted with a group R b ;
• L represents either a nitrogen atom optionally substituted with an R c or Rd group, or a carbon atom substituted with a group R e i and a group R d or two groups R e2 ; the carbon atoms of A and B being optionally substituted with one or more groups R f which are identical or different from one another;
• R 3, R b and R c are defined such that: two groups R 3 may together form a Ci -6 alkylene group; R 3 and R b may together form a bond or a Ci -6 alkylene group;
• R 3 and R c may together form a bond or a Ci -6 alkylene group;
• R b and R c may together form a bond or a Ci -6 alkylene group;
• R d represents a group selected from hydrogen and Ci -6 alkyl groups, hydroxy-d-6-alkyl; - R e i represents a cyclic monoamine;
• R ⁇ 2 form with the carbon atom which carries them a monoamine, this cyclic monoamine being optionally substituted by one or more groups R f identical or different from each other;
• R f represents a Ci -6 alkyl group; the other substituents being as defined above.
• a tenth group of compounds consists of the compounds for which: the cyclic amine formed by -NALB- represents a piperazinyl, hexahydro-pyrrolopyrrolyl, octahydropyrrolopyridinyl, diaza-spiro-undecyl, pyrrolidinyl- piperidinyl, optionally substituted by one or more groups selected independently of one another from Ci -6 alkyl group, hydroxy-Ci -6 alkyl; the other substituents being as defined above.
• an eleventh group of compounds is constituted by the compounds for which: the cyclic amine formed by -NALB- represents a piperazin-1-yl, 3-methylpiperazin-1-yl group, 4-methyl-piperazin-1-yl, 3,3-dimethyl-piperazin-1-yl, (c / s) -3,5-dimethylpiperazin-1-yl, 4- (2-hydroxyethyl) piperazine -1-yl, 4- (2-hydroxy-2-methyl-propyl) piperazin-1 -yl, (c / s /) -hexahydro-pyrrolo [3,4-c] pyrrol-2 (1 H) -y (1S) -5-methylhexahydro-pyrrolo [3,4-c] pyrrol-2 (1H) -yl, octahydro-6H-pyrrolo [3,4-b] pyridin 6-yl, 2,9-diaza-s
• a twelfth group of compounds consists of the compounds for which:
• R 2 is thien-2-yl, 5-methyl-thien-2-yl, 5-chloro-thien-2-yl, thien-3-yl, 2,5-dimethyl-thien-3-yl, 2 5-dichloro-thien-3-yl, furan-2-yl; 5-methyl-furan-2-yl; furan-3-yl;
• R 3 represents a hydrogen atom, a methyl group or an -NH 2 group
• R 7 and R 8 represent a hydrogen atom;
• the cyclic amine formed by -NALB- is piperazin-1-yl, 3-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, fc / s) -3,5-dimethyl-piperazin-1-yl, 4- (2-hydroxy-ethyl) piperazin-1-yl, 4- (2-hydroxy-2-methyl-propyl) piperazin-1-yl (c / s / ) -hexahydro-pyrrolo [3,4-c] pyrrol-2 (1H) -yl, (c / s) -5-methylhexahydro-pyrrolo [3,4-c] pyrrol -2 (1H) -yl, octahydro-6H-pyrrolo [3,4-b] pyridin-6-yl, 2,9-diaza-spiro [5.5] undec-9
• the compounds of general formula (I) can be prepared according to the general method described in scheme 1 below.
• the 6-cycloamino-3- (pyridin-4-yl) imidazo [1,2-b] pyridazine derivatives of general formula (I) in which R 2 , R 3, A, L, B, R 7 and R 8 are as defined above may be prepared from a 3- (pyridin-4-yl) imidazo [1,2-bb] pyridazine derivative of the general formula ( II), 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 (IIa) wherein A, L and B are as previously defined.
• This reaction can be carried out by heating the reactants in a polar solvent such as pentanol or dimethylsulfoxide.
• the 3- (pyridin-4-yl) imidazo [1,2-b] pyridazine derivatives of general formula (II), in which R 2 , R 3, X ⁇ , R 7 and R 8 are as defined above may be prepared by metallocatalyzed coupling of a 3-halo-imidazo [1,2-b] pyridazine derivative of general formula (III) in which R 2 , X ⁇ , R 7 and R 8 are as defined above and X 3 represents a halogen chosen from bromine and iodine, more particularly iodine, with a pyridine derivative of general formula (NIa) in which R 3 is as defined above and M represents a trialkylstannyl group, the most frequently one tributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, most frequently a 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl group, according to the conditions of Stille or Suzuki
• Couplings according to the Stille method are for example carried out by heating in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium, copper iodide, in a solvent such as N, N-dimethylacetamide.
• a catalyst such as tetrakis (triphenylphosphine) palladium, copper iodide, in a solvent such as N, N-dimethylacetamide.
• the couplings according to the Suzuki method are for example carried out by heating in the presence of a catalyst such as 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium, of a mineral base such as cesium carbonate, in a solvent mixture. such as dioxane and water.
• a catalyst such as 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium
• a mineral base such as cesium carbonate
• a solvent mixture such as dioxane and water.
• the 3-halogenoimidazo [1,2-b] pyridazine derivatives of general formula (III) are obtained by bromination or regioselective iodination of an imidazo [1,2-t)] pyridazine derivative of general formula (IV ), wherein R 2 , X ⁇ , R 7 and R 8 are as defined above.
• This reaction can be carried out by means of ⁇ -bromo or iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.
• a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.
• imidazo [1,2-t)] pyridazine derivatives of general formula (IV) are known to those skilled in the art (Journal of Heterocyclic Chemistry (2002), 39 (4), 737-742) or can be prepared by analogy with methods known to those skilled in the art.
• the 6-cycloamino-3-pyridin-4-ylimidazo [1,2- ⁇ b] pyridazine derivatives of general formula (I) wherein R 2 , R 3, A, L, B , R 7 and R 8 are as defined above may be prepared by metallocatalyzed coupling between a 3-haloimidazo [1,2-b] pyridazine derivative of general formula (V) wherein R 2 , A, L , B, R 7 and R 8 are as defined above and X 3 represents a halogen selected from bromine and iodine, more particularly iodine, and a pyridine derivative of general formula (NIa) as defined previously under the conditions of Stille or Suzuki.
• the 3-halogenoimidazo [1,2-t]] pyridazine derivatives of general formula (V) are obtained by the bromination or regioselective iodination of an imidazo [1,2-b] pyridazine derivative of general formula (VI ), wherein R 2 , A, L, B, R 7 and R 8 are as defined above.
• This reaction can be carried out by means of ⁇ -bromo or iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.
• the 3-pyridin-4-yl-imidazo [1,2-b] pyridazine derivatives of general formula (VI) in which R 2 , A, L, B, R 7 and R 8 are as defined above are prepared by condensation between a pyridazin-3-ylamine derivative of general formula (VII) in which A, L, B, R 7 and R 8 are as defined above and a derivative of 2-bromo, chloro- or iodoethan -1-one of general formula (VIIa) wherein R 2 is as defined above and X represents a bromine, chlorine or iodine atom.
• the reaction can be carried out by heating the reactants in a polar solvent such as ethanol or butanol.
• pyridazin-3-ylamine derivatives of general formula (VII) are known to those skilled in the art (Journal of Medicinal Chemistry (2008), 51 (12), 3507-3525) or may be prepared by analogy with known methods of the skilled person.
• the 6-cycloamino-3-pyridin-4-ylimidazo [1,2-bb] pyridazine derivatives of general formula (I) wherein R 2 , A, L, B, R 7 and R 8 are as defined above and wherein R 3 represents a hydrogen atom or a Ci -3 alkyl group, can be prepared in two steps from a imidazo [1, 2-b] pyridazine of general formula (VI) as defined above.
• the 6-cycloamino-3-pyridin-4-ylimidazo [1,2-b] pyridazine derivatives of general formula (I) in which R 2 , R 3, A, L, B, R 7 and R 8 are as defined above may be prepared by metallocatalyzed coupling according to the conditions of Stille or Suzuki as defined above between a derivative of 2-bromo-3-pyridin-imidazo [1,2-ib] pyridazine of general formula (X) in which R 3 , A, L, B, R 7 and R 8 are as defined above and a thienyl or furanyl derivative of general formula (Xa) wherein R 2 and M are as defined above.
• the 2-bromo-3-pyridinimidazo [1,2-b] pyridazine derivatives of general formula (X) are obtained by metallocatalytic coupling regioselective according to the conditions of Stille or Suzuki as defined above between a derivative of 2- bromo-3-iodoimidazo [1,2-bb] pyridazine of the general formula (Xl) in which A, L, B, R 7 and R 8 are as defined above and a pyridine derivative of the general formula ( NIa) as defined previously.
• the 2-bromo-3-iodo-imidazo [1,2-bb] pyridazine derivatives of general formula (Xl) are obtained by iodination of a 2-bromo-imidazo [1,2-b] pyridazine derivative of formula general (XII), wherein A, L, B, R 7 and R 8 are as defined above.
• This reaction may be carried out using N-iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.
• the 2-bromo-imidazo [1,2-t]] pyridazine derivatives of general formula (XII) are obtained from a 2-bromoimidazo [1,2-b] pyridazine derivative of general formula (XIII) wherein R 7 and R 8 are as defined above and X 6 represents a leaving group such as halogen, by treatment with an amine of the general formula (IIa) in which A, L and B are as defined previously.
• This reaction can be carried out by heating the reactants in a polar solvent such as pentanol or dimethylsulfoxide.
• the 6-cycloamino-3- (pyridin-4-yl) imidazo [1,2-t]] pyridazine derivatives of general formula (I) for which the amine formed by N, L, A and B comprises a second secondary or tertiary amine can be prepared respectively from the corresponding primary or secondary amine by alkylation or amino-reduction according to methods customary for those skilled in the art.
• a leaving group is understood to mean a group which can be easily cleaved from a molecule by breaking a heterolytic link, starting from an electronic pair. This group can, for example, be easily replaced by another group during a substitution reaction.
• Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups as well as references for their preparations are given in Advances in Organic Chemistry, J. March, 3 rd Edition, Wiley Interscience, p. 310-316.
• this function may optionally be protected during synthesis by a protecting group, for example benzyl or t-butyloxycarbonyl.
• Example No. 1 (compound No. 1): 6- (piperazin-1-yl) -3- (pyridin-4-yl) -2- (thien-2-yl) -imidazof 1,2-folpyridazine
• Step 1.2 4- (6-Amino-pyridazin-3-yl) -piperazine-1-carboxylic acid tert-butyl ester
• Step 1.3 4- (2- (Thien-2-yl) imidazo [1,2- ⁇ 1 -pyridazin-6-yl] -piperazine-1-carboxylic acid tert-butyl ester
• reaction is allowed to warm to room temperature and the reaction is left for 18 hours.
• the mixture is diluted with dichloromethane and poured into water.
• the organic phase is separated, dried over sodium sulfate and the solvent is removed by evaporation under reduced pressure.
• the brown solid obtained (1.4 g) is recrystallized from about 30 ml of acetonitrile to give 1.10 g of 4- [3- (1-ethoxycarbonyl-1,4-dihydro-pyridin-4-yl) A tert -butyl 2- (thien-2-yl) imidazo [1,2-b] pyridazin-6-yl] piperazine-1-carboxylate in the form of a solid after filtration, rinsing with diethyl ether. -ethyl and drying.
• Step 1.6 6- (Piperazin-1-yl) -3- (pyridin-4-yl) -2- (thien-2-yl) -imidazo [1,2- ⁇ -pyridazine]
• the solid obtained is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (92/8 / 0.8) to give 0.47 g of pale yellow solid.
• 0.36 g of 6- (piperazin-1-yl) -3- (pyridin-4-yl) -2- (thien-2-yl) -imidazo [1,2-bb] pyridazine is isolated after crystallization from 20 ml. ml of acetonitrile containing a few ml of butanol, followed by drying.
• Example No. 2 (Compound No. 9): 3- (Pyridin-4-yl) -6- (4-pyrrolidin-1-ylpiperidin-1-yl) -2- (thien-2-yl) imidazof1,2 -b1pyridazine
• the solid is triturated in a mixture of 75 ml of isopropanol and diisopropyl ether (1/1) to give 2.69 g of 6-chloro-2- (thien-2-yl) imidazo [1, 2- b] pyridazine as a dark beige solid after filtration and drying under reduced pressure.
• Step 2.4 3- (pyridin-4-yl) -6- (4-pyrrolidin-1-pyridin-1-yl) -2- (th ⁇ en-2-yl) Vimidazol, 2- blpvridazine
• reaction medium is then cooled and the mixture is poured into a 1N aqueous hydrochloric acid solution and the aqueous phase is washed with ethyl acetate.
• the aqueous phase is then basified with ammonia and the product is extracted with dichloromethane.
• the organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure.
• Example No. 4 (Compound No. 7): 6- (Octahydro-6H-pyrrolor-3,4-fo-pyridin-6-yl) -3- (pyridin-4-yl) -2- (thien-2-yl) -imidazori , 2-fo1pyridazine
• reaction medium is cooled and 5 ml of 3N aqueous hydrochloric acid (15 mmol) are added.
• the mixture is stirred for one hour and then diluted with water.
• the aqueous phase is washed with ethyl acetate and then basified with ammonia and the product is extracted with dichloromethane.
• the organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure.
• Example No. 5 (Compound No. 14): 2- ⁇ 4- [2- (5-Chloro-thien-2-yl) -3- (pyridin-4-yl) -imidazo] -2-folpyridazin-6-yl] (piperazin-1-yl)) - ethanol
• Step 5.2 6-Chloro-3-iodo-2- (5-chlorothien-2-yl) imidazo [1,2- ⁇ ] pyridazine and 6-chloro-3-chloro-2- (5-chlorothien-2-yl) imidazo [ 1, 2- ⁇ 1pyridazine
• aqueous phase is washed with diethyl ether and then basified with 2N sodium hydroxide and the product is extracted with dichloromethane.
• the organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure.
• the residue is purified by column chromatography of 50 g of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (93/7 / 0.7) to give 0.17 g of [2- (5-Chloro-thien-2-yl) -3- (pyridin-4-yl) -imidazo [1,2-b] pyridazin-6-yl] - (piperazin-1-yl) ⁇ ethanol in the form of a beige solid after crystallization from 20 ml of acetonitrile, filtration and drying. Mp 216-218 ° C
• the mixture is stirred for one hour and then diluted with water.
• the aqueous phase is washed with ethyl acetate and then basified with ammonia and the product is extracted with dichloromethane.
• the organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure.
• the brown oil obtained is purified by column chromatography on 35 g of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (90/10/1) to give 0.235 g of 6- (hexahydro-pyrrolo [3,4-c] pyrrol-2 (1H-yl) -3- (pyridin-4-yl) -2-thien-3-yl-imidazo [1,2-b] pyridazine in the form of a beige solid after crystallization in 15 ml of acetonitrile, filtration and drying.
• Example No. 7 (Compound No. 32) 2- (Furan-2-yl) -6-r (cs) -5-methylhexahydropyrrolor-3,4-pyrryp-2 (1H) -n-3-pyridin -4-yl) -imidazori, 2-b1pyridazine
• Step 7.2 6-Chloro-3- (pyridin-4-yl) -2- (furan-2-yl) -imidazo ⁇ , 2- ⁇ lpyridazine
• the mixture is poured into 60 ml of a 1N aqueous hydrochloric acid solution and the aqueous phase is washed with ethyl acetate.
• the aqueous phase is then basified with ammonia and the product is extracted with chloroform.
• the organic phase is dried over sodium sulphate and the solvent evaporated under reduced pressure.
• Step 8.1 4- [2- (2,5-Dimethyl-thien-3-yl) -imidazo [1,2- ⁇ ] -pyridazin-6-yl] -piperazine-1-carbaldehyde
• Step 8.2. 4- (2- (2,5-Dimethyl-thien-3-yl) -3-iodo-imidazo) -2- ⁇ -pyridazin-6-yl-piperazine-1-carbaldehyde
• Step 8.3. 4- [2- (2,5-Dimethylthien-3-yl) -3- (2-methyl-pyridin-4-yl) -imidazo] -2-yl] pyridazin-6-yl] piperazine-1-carbaldehyde
• the mixture is then partitioned between 5 ml of a saturated aqueous solution of sodium chloride and 40 ml of ethyl acetate.
• the organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure with 1.5 g of silica gel.
• the product is then purified by column chromatography of 10 g of silica gel, eluting with a gradient of 0 to 10% of methanol in dichloromethane, to give 0.295 g of 4- [2- (2,5-dimethylthienate) 3-yl) -3- (2-methyl-pyridin-4-yl) -imidazo [1,2-b] pyridazin-6-yl] piperazine-1-carbaldehyde.
• Example 9 (Compound No. 33): 2- (5-Methyl-furan-2-yl) -6-r (c / s) -5-methyl-hexahydropyrrolo [3,4-c] pyrrol-2 (1H) -vn -3- (pyridin-4-yl) -imidazori, 2-b1pyridazine
• the mixture is poured into 20 ml of a 1N aqueous hydrochloric acid solution and the aqueous phase is washed with ethyl acetate.
• the aqueous phase is then basified with 2M sodium hydroxide and the product is extracted with dichloromethane.
• the organic phase is dried over sodium sulphate and the solvent evaporated under reduced pressure.
• the residue is purified by column chromatography of 80 g of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (93/7 / 0.7) to give 2.6 g of 2-bromo-6.
• the reaction is stirred at reflux for 24 hours.
• the mixture is poured into a 1N aqueous hydrochloric acid solution and the aqueous phase is washed with ethyl acetate.
• the aqueous phase is then basified with ammonia and the product is extracted with dichloromethane.
• the organic phase is dried over sodium sulphate and the solvent is evaporated off under reduced pressure.
• the brown solid residue is purified by column chromatography on 150 g of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (98/2 / 0.2) to give 1.26 g of 2-bromo -6 - [(c / s) -5-methylhexahydropyrrolo [3,4-c] pyrrol-2 (1H) -yl] -3- (pyridin-4-yl) -imidazo [1,2] pyridazine in the form of a beige powder after crystallization from diisopropyl ether, filtration and drying. M.p .: 195-197 ° C
• Table 1 which follows illustrates the chemical structures and the physical properties of some compounds according to the invention.
• Casein Kinase 1 epsilon (0.58 mg / ml) is obtained by fermentation and purification methods carried out according to methods well known to those skilled in the art or can also be obtained from Invitrogen Corporation TM (human CK1 epsilon ).
• the compounds are tested at five different concentrations so as to generate Cl 50 , that is to say the concentration at which a compound is capable of inhibiting the enzymatic activity by 50%, or the inhibition in% at a concentration. 10 micromolar.
• "Falcon" U-shaped plates are prepared by placing 5 ⁇ l of solutions of the compounds according to the invention at concentrations of 10, 1, 0.1, 0.01 or 0.001 ⁇ M in various wells.
• the solutions of the compounds according to the invention at 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 the solution. DMSO at the concentration of 10 mM.
• the Falcon ® "U” bottom test plate mentioned above is vortexed and incubated at room temperature for 2 hours. After 2 hours, the reaction is stopped by adding an ice-cold solution of 65 ⁇ l of cold ATP (2 mM) prepared in test buffer.
• Millipore MAPH filtration plates 100 ⁇ L of the Falcon ® U-bottom plate reaction mixture is then transferred to Millipore ® MAPH filtration plates, previously impregnated with 25 ⁇ L of 100% ice-cold TCA. Millipore MAPH filtration plates are shaken gently and left to dry. stand at room temperature for at least 30 minutes to precipitate the proteins.
• the filter plates are sequentially washed and filtered with 2x150 ⁇ L of 20% TCA, 2x150 ⁇ L of 10% TCA and 2x150 ⁇ L of 5% TCA (6 total washes per plate / 900 ⁇ L per well). .
• the plates are allowed to dry overnight at room temperature.
• the radiation emitted by each well is then measured for 2 minutes in a Topcount NXT Packard ® scintillation counter where the CPM / well values are measured.
• The% inhibition of the ability of the enzyme to phosphorylate the substrate (casein) for each concentration of test compound is determined. These inhibition data expressed in% are used to calculate the Cl 50 value for each compound compared to the controls.
• Kinetic studies determined the value of K M for ATP to be 21 ⁇ M in this test system.
• Table 2 below shows the IC 50 inhibition of the phosphorylation of Casein Kinase 1 Epsilon for some compounds according to the invention.
• the most active compounds of the invention have Cl 5 0 (a 50% inhibiting concentration of the enzymatic activity of Casein Kinase 1 Epsilon) of between 1 nM and 2 ⁇ M.
• 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 donor fluorophore group (coumarin) and an acceptor fluorophore group (fluorescein) constituting a FRET system is phosphorylated in the presence of ATP by casein kinase 1 epsilon or delta in the presence of concentrations increasing amounts of compounds of the invention.
• the mixture is treated with a specific site protease that specifically cleaves the substrate peptide to form two fluorescent moieties with a large fluorescence emission ratio.
• the observed fluorescence is thus related to the ability of the products of the invention to inhibit the phosphorylation of the substrate peptide by casein kinase 1 epsilon or casein kinase 1 delta.
• the compounds of the invention are dissolved at different concentrations from a 10 mM stock solution in DMSO diluted in a 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 Corporation TM is carried out at the final concentration of 2 ⁇ M.
• the concentration of ATP is 4 times the K M , which is 2 ⁇ M for casein kinase 1 epsilon and 4 ⁇ M for casein kinase 1 delta.
• the measurement of the fluorescence emitted is carried out at wavelengths of 445 and 520 nm (excitation at 400 nm).
• Table 3 below shows the IC 50 inhibition of the phosphorylation of Casein Kinase 1 Delta for some compounds according to the invention.
• the most active compounds of the invention have Cl 50 (50% concentration inhibiting the enzymatic activity of Casein Kinase 1 Delta) between 1 nM and 2 ⁇ M.
• Mper1-luc Rat-1 (P2C4) fibroblast cultures were performed by dividing the cultures every 3-4 days (approximately 10-20% confluency) on 150-cm 2 degassed polystyrene tissue culture flasks ( 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 penicillin-streptomycin (Cellgro # 30-001-Cl) at 37 ° C and 5% CO 2 .
• EMEM Cellgro # 10-010-CV
• FBS fetal bovine serum
• penicillin-streptomycin Cellgro # 30-001-Cl
• Cells from rat-1 fibroblast cultures at 30-50% confluency as described above were co-transfected with vectors containing the selection marker for zeocin resistance for stable transfection and a reporter gene of luciferase directed by the mPer-1 promoter. After 24 to 48 hours, the cultures were split on 96-well plates and maintained in growth media supplemented with 50-100 ug / mL Zeocin (I nvitrogen ® # 45-0430) for 10- 14 days.
• Stable transfectants resistant to Zeocin were evaluated for expression of the reporter by adding to the growth medium of the 100 microM luciferin (Promega # E1603 ® ®) and assaying luciferase activity on a TopCount scintillation counter ® (Packard Model # C384V00). Rat-1 cell clones expressing both zeocin resistance and mPeri-directed luciferase activity were synchronized by serum shock with 50% horse serum [HS (Gibco ® # 16050-122) ] and circadian reporter activity was evaluated. Clone P2C4 of Mper1-luc Rat-1 fibroblasts was selected for the test of the compound.
• Fibroblast Mpeii-luc Rat-1 (P2C4) at 40-50% confluence obtained according to the protocol described above were plated on culture plates with opaque 96-well tissue (Perkin Elmer ® # 6005680). The cultures are maintained in growth medium supplemented with 100 ⁇ g / ml Zeocin (Invitrogen # 45-0430) until they have reached 100% confluency (48-72 h). The cultures were then synchronized with 100 ⁇ l of synchronization medium [EMEM (Cellgro # 10-010-CV); 100 LU. / ml penicillin-streptomycin (Cellgro # 30-001 -C1); 50% HS (Gibco # 16050-122)] for 2 hours at 37 ° C and 5% CO 2 .
• EMEM Cellgro # 10-010-CV
• 100 LU. / ml penicillin-streptomycin (Cellgro # 30-001 -C1); 50% HS (Gibco # 16050-122)] for 2 hours at 37
• the cultures were rinsed with 100 ⁇ l of EMEM (Cellgro # 10-010-CV) for 10 minutes at room temperature. After rinsing, the medium was replaced with 300 ⁇ L of medium independent of CO 2 [CO 2 I (Gibco # 18045-088); 2 mM L-glutamine (Cellgro # 25-005-C1); 100 IU / mL penicillin-streptomycin (Cellgro # 30-001 -C1); luciferin 100 ⁇ M (Promega #E 1603)].
• CO 2 I Gibco # 18045-088
• 2 mM L-glutamine Cellgro # 25-005-C1
• penicillin-streptomycin Cellgro # 30-001 -C1
• luciferin 100 ⁇ M Promega #E 1603
• Period analysis was performed either by determining the interval between the relative light emission minima over several days or by Fourier transform. Both methods produced a substantially identical period estimate over a range of circadian periods.
• the power is reported in CE Delta (t + 1 h), which is presented as the effective micromolar concentration which induced an extension of the period of 1 hour.
• the data were analyzed by fitting a hyperbolic curve to the data expressed in period change (ordinate) as a function of the test compound concentration (abscissa) in the XLfit TM software and the Delta CE (t + 1 h) a interpolated from this curve.
• Table 4 shows the Delta EC (t + 1 h) for some compounds according to the invention.
• the most active compounds of the invention have EC Delta (t + 1 h) (effective micromolar concentration which induced an extension of the period of 1 hour) of between 1 nM and 2 ⁇ M.
• the object compounds of the invention modulate circadian rhythmicity, and may be useful for the treatment of circadian rhythm disorders.
• 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, such as those due to jet lag, shift work.
• sleep disorders include dyssomnia (eg primary insomnia), parasomnia, hypersomnia (eg excessive sleepiness), narcolepsy, sleep disorders related to sleep apnea, sleep disorders related to circadian rhythm and dyssomnias not otherwise specified, sleep disorders associated with medical / psychiatric disorders.
• dyssomnia eg primary insomnia
• parasomnia eg excessive sleepiness
• hypersomnia eg excessive sleepiness
• narcolepsy e.g., sleep disorders related to sleep apnea
• sleep disorders related to circadian rhythm and dyssomnias not otherwise specified sleep disorders associated with medical / psychiatric disorders.
• the subject compounds of the invention also cause circadian phase shift and such a property may be useful in the context of monotherapy or a potential combination therapy clinically effective for mood disorders.
• Mood disorders include depressive disorders (unipolar depression), bipolar disorders, mood disorders due to a general medical condition and mood disorders induced by pharmacological substances.
• Bipolar disorders include bipolar I disorder and bipolar II disorder, including seasonal affective disorder.
• the compounds of the invention modulating circadian rhythmicity may be useful in the treatment of anxiety and depressive disorders due in particular to an alteration on the secretion of CRF.
• Depressive disorders include major depressive disorders, dysthymic disorders, depressive disorders not otherwise specified.
• the subject compounds of the invention modulating circadian rhythmicity may be useful for the preparation of a medicament for treating diseases related to dependence on abusive substances such as ***e, morphine, nicotine, ethanol, cannabis.
• the compounds according to the invention can be used for the preparation of medicaments, especially for the preparation of a medicament for preventing or treating diseases related to hyperphosphorylation of tau protein, especially Alzheimer's disease.
• These drugs also find use in therapy, especially in the treatment or prevention of diseases caused or exacerbated by the proliferation of cells and in particular tumor cells.
• these compounds are useful in the prevention and treatment of fluid tumors such as leukemias, both primary and metastatic solid tumors, carcinomas and cancers, in particular: breast cancer; lung cancer ; small bowel cancer, colon and rectal cancer; cancer of the respiratory tract, oropharynx and hypopharynx
• esophageal cancer liver cancer, stomach cancer, bile duct cancer, gall bladder cancer, pancreatic cancer; urinary tract cancers including kidney, urothelium and bladder; cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma; cancers of the male genital tract including prostate cancer, seminal vesicles, testes, germ cell tumors; cancers of the endocrine glands including thyroid, pituitary, adrenal gland cancer; 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; leukemia, (Acute
• the compounds according to the invention can also be used for the preparation of medicaments, in particular for the preparation of a medicament intended to prevent or treat inflammatory diseases, such as in particular inflammatory diseases of the central nervous system such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis and other inflammatory diseases such as vascular diseases, atherosclerosis, inflammation of the joints, osteoarthritis, rheumatoid arthritis.
• inflammatory diseases such as in particular inflammatory diseases of the central nervous system such as multiple sclerosis, encephalitis, myelitis and encephalomyelitis and other inflammatory diseases such as vascular diseases, atherosclerosis, inflammation of the joints, osteoarthritis, rheumatoid arthritis.
• the compounds according to the invention can therefore be used for the preparation of medicaments, in particular drugs which inhibit casein kinase 1 epsilon and / or casein kinase 1 delta.
• the invention relates to medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or a hydrate or a solvate of the compound of formula (I).
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt, a hydrate or solvate of said compound, as well as at least one pharmaceutically acceptable excipient.
• excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
• the active ingredient of formula (I) above, or its salt, solvate or hydrate may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• a unitary form of administration of a compound according to the invention in tablet form may comprise the following components:
• 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 lower dosages are appropriate; such dosages are not outside the scope of the invention.
• the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.

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