FR2945289A1 - 2-CYCLOAMINO-5- (PYRIDIN-4-YL) IMIDAZO-2,1-B1 DERIVATIVES 1,3,4! THIADIAZOLE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

The invention relates to 2-cycloamino-5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole derivatives of the general formula (I) wherein: R represents a hydrogen atom or a group C alkyl, NR R, or C alkyloxy; R represents an optionally substituted phenyl group; A represents a C-alkylene group optionally substituted with one or two R groups; B represents a C-alkylene group optionally substituted with an R group; L represents either a nitrogen atom optionally substituted by an R or R group, or a carbon atom substituted with an R group and an R group or two R groups; R and R represent, independently of one another, a hydrogen atom or a C alkyl group; Preparation process and therapeutic application

Description

2-CYCLOAMINO-5- (PYRIDIN-4-YL) IMIDAZO [2,1-b] [1,3,4] THIADIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE.

The present invention relates to 2-cycloamino-5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole derivatives, to their preparation and to their therapeutic application in the treatment or prevention of diseases involving casein kinase 1 epsilon and / or casein kinase 1 delta. The subject of the present invention is the compounds corresponding to the general formula (I) A \ \ L \, N B in which

R5 represents a hydrogen atom or a C1-3 alkyl, -NR, R6, or C1-3 alkyloxy group;

R 6 represents a phenyl group optionally substituted with one or more substituents chosen from halogen atoms and C 1-6 alkyl groups; C1-C6 alkyloxy;

- A represents a group C1 _, - alkylene optionally substituted with one or two groups Ra; - B represents a group C1 _, - alkylene optionally substituted by an Rb group; L represents either a nitrogen atom optionally substituted with a Rd or Rd group, or a carbon atom substituted with a Re1 group and a Rd group or two Re2 groups;

the carbon atoms of A and B being optionally substituted with one or more Rf groups which are the same or different from each other; Ra, Rb and Rd are defined such that: two groups Ra may together form a C1_6-alkylene group; Ra and Rb may together form a bond or a C 1-6 -alkylene group; Ra and R may together form a bond or a C1-6-alkylene group; Rb and Rd may together form a bond or a C1-6-alkylene group;

Rd represents a group selected from hydrogen, C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6-alkyl, C1-6-alkylthio-C-16-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-fluoroalkyl, hydroxy-C1-6-alkyl;

Re1 represents a group -NR3R4 or a cyclic monoamine optionally having an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents selected from fluorine atom and C1-6-alkyl, C1-6-alkyloxy, hydroxyl groups;

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

Rf is C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -fluoroalkyl;

R3 and R4 represent, independently of one another, a hydrogen atom or a C1-4 alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-6 alkyl group;

R7 and R8 represent, independently of one another, a hydrogen atom or a C1-3 alkyl group;

The compounds of formula (I) may have one or more asymmetric carbon atoms. They can therefore exist as 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 useful, for example, for the purification or isolation of the compounds of formula (I) are also part of the invention.

In the context of the invention, the following terms are understood: where Z and z can take the values from 1 to 6, a carbon chain that can have from t to z carbon atoms, for example C1_6 a carbon chain which can have from 1 to at 6 carbon atoms; alkyl, a saturated, linear or branched aliphatic group; for example a C1.6-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, a saturated divalent linear or branched alkyl group, for example a C1-C6 alkylene group, represents a divalent carbon chain of 1 to 6 carbon atoms, linear or branched, for example a methylene, ethylene, 1-methylethylene, propylene; - cycloalkyl, a cyclic alkyl group, for example a C3 .- cycloalkyl group represents a cyclic carbon group of 3 to 7 carbon atoms, for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; hydroxyl, -OH group; cyclic monoamine, a saturated cyclic carbon chain containing 1 nitrogen atom; hydroxyalkyl, an alkyl group of which one hydrogen atom has been substituted with a hydroxyl group; alkyloxy, an -O-alkyl group; alkylthio, a -S-alkyl group; 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. As an example of an aryl group, mention may be made of phenyl or naphthyl groups. By way of nonlimiting examples of cyclic amines or diamines formed by N, A, L and B, there may be mentioned aziridine, azetidine, pyrrolidine, piperidine, azepine, morpholine, thiomorpholine, homopiperidine, decahydroquinoline, decahydroisoquinoline, azabicycloheptane, azabicyclooctane, azabicyclononane, aza-oxo-bicycloheptane, aza-thia bicycloheptane, azaoxo-bicyclooctane, aza-thia-bicyclooctane; piperazine, homopiperazine, diaza-cyclooctane, diaza-cyclo-nonane, diaza-cyclo-decane, diaza-cycloundecane, octahydro-pyrrolo-pyrazine, octahydro-pyrrolo-diazepine, octahydropyrrolo-pyrrole, octahydro-pyrrolo-pyridine, decahydro-naphthyridine, diazabicyclo-heptane, diaza-bicyclooctane, diaza-bicyclo-nonane, diaza-spiroheptane, diaza-spiro-octane, diaza-spiro-nonane, diaza-spiro-decane, diaza-spiro-undecane, oxa-diaza-spiro-undecane.

Among the compounds of general formula (I) that are the subject of the invention, a first group of compounds consists of the compounds for which: R 5 represents a hydrogen atom or a methyl, methylamino or methoxy group; the other substituents being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a second group of compounds is constituted by compounds for which: R 6 represents a phenyl group optionally substituted with one or more substituents chosen from halogen atoms; the other substituents being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a third group of compounds is constituted by the compounds for which: R 6 represents a phenyl group optionally substituted with one or more substituents chosen from fluorine atoms; the other substituents being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a fourth group of compounds consists of the compounds for which: the cyclic amine formed by N-ALB represents a group chosen from piperazinyl and hexahydropyrrolo groups; pyrrolyl, optionally substituted by one or more groups selected from C1-6alkyl groups; The other substituents being as defined above. Among the compounds of general formula (I) that are the subject of the invention, a fifth group of compounds consists of the compounds for which: the cyclic amine formed by N-ALB represents a group chosen from the groups piperazinyl, (3R) -3-methyl-piperazinyl, 4-isopropyl-piperazinyl, (cis) -5-hexahydropyrrolo [3,4-c] pyrrol-2 (1H) yl; the other substituents being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a sixth group of compounds is constituted by the compounds for which: the cyclic amine formed by N-A-L-B- represents a diazaspiro-undecyl group; the other substituents being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, a seventh group of compounds consists of the compounds for which: the cyclic amine formed by N-ALB- represents a group chosen from groups 2,9- diaza-spiro [5.5] undec-9-yl, 3,9-diaza-spiro [5.5] undec-9-yl; the other substituents being as defined above.

Among the compounds of general formula (I) that are the subject of the invention, an eighth group of compounds is constituted by the compounds for which: the cyclic amine formed by N-A-L-B-represents a pyridinyl substituted piperidyl group; the other substituents being as defined above.

Among the compounds of general formula (I) which are the subject of the invention, a ninth group of compounds is constituted by the compounds for which: the cyclic amine formed by N-ALB- represents a 4-pyrrolidin-1-ylpiperidinyl group; ; the other substituents being as defined above. Among the compounds of general formula (I) that are the subject of the invention, a tenth group of compounds is constituted by the compounds for which: R5 represents a hydrogen atom or a C1_3-alkyl group, -NR, RB, C1_3 alkyloxy; R6 represents a phenyl group optionally substituted with one or more substituents selected from halogen atoms; The cyclic amine formed by N-A-L-B- is either a group selected from piperazinyl, hexahydropyrrolo-pyrrolyl, optionally substituted with one or more groups selected from C 1-6 alkyl groups; either a diazaspiro-undecyl group; or a piperidinyl group, optionally substituted by a pyrrolidinyl group; R 1 and R 8 represent, independently of one another, a hydrogen atom or a C 1-3 alkyl group; in the base state or acid addition salt.

Among the compounds of general formula (I) which are the subject of the invention, an eleventh group of compounds consists of the compounds for which: R 5 represents a hydrogen atom or a methyl, methylamino or methoxy group; R6 represents a phenyl group optionally substituted with one or more substituents selected from fluorine atoms; the cyclic amine formed by N-ALB- represents a group chosen from piperazinyl, (3R) -3-methyl-piperazinyl, 4-isopropyl-piperazinyl, (cis) -hexahydropyrrolo [3,4-c] pyrrol- 2 (1H) yl; 2,9-diaza-spiro [5.5] undec-9-yl, 3,9-diazaspiro [5.5] undec-9-yl; 4-pyrrolidin-1-yl-piperidinyl; at 1 base state or acid addition salt.

Among the compounds of general formula (I) which are subjects of the invention, mention may be made especially of the following compounds: 6- (4-Fluoro-phenyl) -2-piperazin-1-yl-5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole; 6- (4-Fluoro-phenyl) -2 - ((3R) -3-methyl-piperazin-1-yl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3]; 4] thiadiazole; 6- (4-Fluoro-phenyl) -2 - ((3R) -3-methyl-piperazin-1-yl) -5- (2-methyl-pyridin-4-yl) -imidazo [2,1-b] [1,3,4] thiadiazole; {4- [6- (4-Fluoro-phenyl) -2 - ((3R) -3-methyl-piperazin-1-yl) -imidazo [2,1-b] [1,3,4] thiadiazole-5 -yl] -pyridin-2-yl} -methyl-amine; 6- (4-Fluoro-phenyl) -5- (2-methoxy-pyridin-4-yl) -2 - ((R) -3-methyl-piperazin-1-yl) -imidazo [2,1-b] [1,3,4] thiadiazole; 6- (4-Fluoro-phenyl) -2- (4-isopropyl-piperazin-1-yl) -5- (pyridin-4-yl) imidazo [2,1- b] [1,3,4] thiadiazole; 6- (4-Fluoro-phenyl) -2- (4-isopropyl-piperazin-1-yl) -5- (2-methyl-pyridin-4-yl) -imidazo [2,1-b] - 1,3 , 4] thiadiazole; 7- {4- [6- (4-Fluoro-phenyl) -2- (4-isopropyl-piperazin-1-yl) -imidazo [2,1-b] [1,3,4] thiadiazol-5- yl] pyridin-2-yl) methylmethylamine; 6- (4-Fluoro-phenyl) -2- (4-isopropyl-piperazin-1-yl) -5- (2-methoxy-pyridin-4-yl) -imidazo [2,1-b] - 1,3 , 4] thiadiazole; 3- [6- (4-Fluoro-phenyl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] -3,9-diazaspiro [ 5.5] undecane and its hydrochloride; 9- [6- (4-Fluoro-phenyl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] -2,9-diazaspiro [ 5.5] undecane; 9- [6- (4-Fluoro-phenyl) -5- (2-methyl-pyridin-4-yl) -imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] -2 9-diaza-spiro [5.5] undecane; {4- [2- (2,9-Diaza-spiro [5.5] undec-9-yl) -6- (4-fluorophenyl) imidazo [2,1-b] [1,3,4] thiadiazole -5-yl] -pyridin-2-yl} methylmethylamine; 9- [6- (4-Fluoro-phenyl) -5- (2-methoxy-pyridin-4-yl) -imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] -2 9-diaza-spiro [5.5] undecane; 6- (4-Fluoro-phenyl) -2 - [(cis) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -5- (pyridin-4-yl) imidazo [2,1-b] ] [1,3,4] thiadiazole; 6- (4-Fluoro-phenyl) -2 - [(cis) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -5- (2-methyl-pyridin-4-yl) -imidazo [ 2,1-b] [1,3,4] thiadiazole; {4- [6- (4-Fluoro-phenyl) -2 - [(cis) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] imidazo [2,1- b] [1,3] 4-thiadiazol-5-yl] -pyridin-2-yl} -methyl-amine; 6- (4-Fluoro-phenyl) -2 - [(cis) -hexahydro-pyrrolo [3,4-c] pyrrol-2-yl] -5- (2-methoxypyridin-4-yl) -imidazo [2], 1-b] [1, 3,4] thiadiazole 6- (4-Fluoro-phenyl) -5- (pyridin-4-yl) -2- (4-pyrrolidin-1-yl-piperidin-1-yl) - imidazo [2,1-b] [1,3,4] thiadiazole; 6- (4-Fluoro-phenyl) -5- (2-methyl-pyridin-4-yl) -2- (4-pyrrolidin-1-yl-piperidin-1-yl) -imidazo [2,1-b] [1,3,4] thiadiazole; {4- [6- (4-Fluoro-phenyl) -2- (4-pyrrolidin-1-yl-piperidin-1-yl) imidazo [2,1-b] [1,3,4] thiadiazole- 5-yl] pyridin-2-yl) methylmethylamine; 6- (4-Fluoro-phenyl) -5- (2-methoxy-pyridin-4-yl) -2- (4-pyrrolidin-1-yl-piperidin-1-yl) -imidazo [2,1-b] [1,3,4] thiadiazole;

The subject of the invention is also a process for the preparation of the compounds of the invention of formula (I).

According to the invention, the compounds of general formula (I) can be prepared according to the general method described in scheme 1 below. ## STR2 ## wherein

Embedded image In general, and as illustrated in Scheme 1, the 2-cycloamino-5- (pyridin-4-yl) imidazo [2,1-b derivatives] ] [1,3,4] thiadiazole of general formula (I) wherein A, L, B, R5 and R6 are as defined above may be prepared by metallocatalyzed coupling between a 5-haloimidazo derivative [ 2,1-b] [1,3,4] thiadiazole of general formula (II), wherein A, L, B and R6 are as defined above and X5 represents a halogen such as bromine or iodine , especially iodine and a pyridine derivative of general formula (IIa) wherein R5 is as defined above and M represents a trialkylstannyl group, most frequently a tributylstannyl group or a dihydroxyboryl or dialkyloxyboryl group, most frequently 4,4,5,5-tetramethyl-1,3,3,2-dioxaborolan-2-yl under 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. The couplings according to the Suzuki method are for example made by heating in the presence of a catalyst such as 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium, a mineral base such as cesium carbonate, in a solvent mixture. such as dioxane or tetrahydrofuran and water.

The 5-haloimidazo [2,1-b] [1,3,4] thiadiazole derivatives of general formula (II) are obtained by bromination or regioselective iodization of an imidazo [2,1-b] derivative [1] , 3,4] thiadiazole of general formula (III), wherein A, L, B and R6 are as defined above. This reaction can be carried out using N-bromo or iodosuccinimide or iodine monochloride in a polar solvent such as acetonitrile, tetrahydrofuran, methanol or chloroform.

The imidazo [2,1-b] [1,3,4] thiadiazole derivatives of general formula (III) as defined above can be prepared by condensation between a [1,3,4] thiadiazole derivative. 2-ylamine of general formula (IV) wherein A, L and B are as defined above and a 2-haloethanone derivative of general formula (IVa) wherein R6 is as previously defined and X represents a leaving group such as bromine, chlorine or iodine. This reaction can be carried out by heating the reactants in a polar solvent such as ethanol.

Alternatively, the imidazo [2,1-b] [1,3,4] thiadiazole derivatives of general formula (III) in which A, L, B and R6 are as defined above can be prepared from a 2-haloimidazo [2,1-b] [1,3,4] thiadiazole derivative of general formula (V), in which R 6 is as defined above and X 2 represents a halogen, more particularly bromine, by treatment with a diamine of general formula (Va) in which A, L and B are as defined above. This reaction can be carried out according to the conditions of the Buchwald-Hartwig metallo-catalyzed coupling reaction. Couplings according to the Buchwald-Hartwig method are for example carried out by heating the reagents in the presence of a catalyst such as palladium acetate, a ligand such as 4,5-bis (diphenylphosphino) -9, 9-dimethylxanthene, a base such as cesium carbonate, in a solvent such as dioxane.

The imidazo [2,1-b] [1,3,4] thiadiazole derivatives of general formula (V) are known (Journal of Heterocyclic Chemistry (2008), 45 (1), 299-302; Chemistry of Heterocyclic Compounds (New York, NY, United States) (2007), 43 (4), 499-504), or may be prepared by analogy according to methods known to those skilled in the art

The imidazo [2,1-b] [1,3,4] thiadiazole derivatives of general formula (IV) are described in particular in documents WO2006 / 040569; Farmaco, Edizione Scientifica (1986), 41 (10), 737-46; Tetrahedron Letters (2008), 49 (36), 5241-5243; W01999 / 47507, or may be prepared by analogy with methods known to those skilled in the art.

In certain cases, the 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 usual methods known to those skilled in the art In the foregoing, by leaving group is meant a group which can be easily cleaved from a molecule by breaking a heterolytic bond, with departure of a pair electronic. 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 a mesyl, tosyl, triflate, acetyl, etc. group. Examples of leaving groups as well as references for their preparations are given in Advances in Organic Chemistry, J. March, 3rd Edition, Wiley Interscience, p. 310-316.

Protective groups For the compounds of general formula (I), (II), (II), (IV) and (Va) as defined above and comprising a primary or secondary amine function, this function can optionally be protected during synthesis by a protecting group, for example benzyl or t-butyloxycarbonyl.

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

Example 1 (Compound No. 1): 6- (4-Fluorophenyl) -2-piperazin-1-yl-5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole N 1.1. 4- (5-Amino-1,3,41-thiadiazol-2-yl) -piperazine-1-carboxylic acid tert-butyl ester (CAS 37566-39-5) SNH 2 H 3 H 3 C N H 3 C 1.00 g (5.55 mmol) of 5-bromo [1,3,4] thiadiazol-2-ylamine, 1.24 g (6.67 mmol) of 4- (tert-butyloxycarbonyl) piperazine (CAS 57260-71-6) and 1.45 g (8.33 mmol) of potassium hydrogencarbonate in 10 ml of dimethylformamide is heated at 140 ° C for 5 hours. After cooling, the mixture is poured into 100 ml of water and the product is extracted with ethyl acetate. The solution is then dried over sodium sulfate and the solvent is evaporated under reduced pressure. The brown oil obtained is then chromatographed on a column of 50 g of silica gel, eluting with a mixture of dichloromethane and methanol (95/5), to give 0.9 g of 4- (5-amino- [1 Tert-butyl 3,4-thiadiazol-2-yl) piperazine-1-carboxylate as a white powder after trituration in diisopropyl ether, filtration and drying.

1 H NMR (CDCl3) δ: 4.8 (broad signal); 3.50 (m, 4H); 3.30 (m, 4H); 1.45 (s, 9H) ppm. O 2945289 -12- 1.2. 4-f 6- (4-Fluorophenyl) imidazof 2,1-b1 [1,3,41thiadiazol-2-yl-piperazine-1-tert-butylcarboxylate O. / SN HC / N / N H The mixture of 5.59 g (19.6 mmol) of tert-butyl 4- (5-amino- [1,3,4] thiadiazol-2-yl) -piperazine-1-carboxylate and 5.53 g (25.5 mmol) of 2-bromo-1- (4-fluorophenyl) ethanone (CAS 403-29-2) in 75 ml of ethanol is refluxed for 2 hours. After cooling, the solvent is removed under reduced pressure and the product is partitioned between chloroform and aqueous saturated sodium hydrogencarbonate solution. The organic phase is separated, washed with water, dried and the solvent evaporated under reduced pressure to yield 9.5 g of 2-amino-5- (4-tert-butoxycarbonyl-piperazin-1-yl bromide. ) -3- [2- (4-Fluorophenyl) -2-oxo-ethyl] - [1,3,4] thiadiazol-3-ium crude that are dissolved in 200 ml of ethanol. The solution is heated at 120 ° C in a sealed tube for 4 hours and then cooled. The yellowish solid formed is separated by filtration and then purified by column chromatography of 50 g of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (98/2 / 0.2) to give 2.7 g. tert-butyl 4- [6- (4-fluorophenyl) imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] -piperazine-1-carboxylate as a white powder after trituration in diisopropyl ether, filtration and drying. 1 H NMR (DMSOd 6)?: 8.30 (s, 1H); 7.80 (dd, 2H); 7.20 (pseudo t, 1H); 3.5 (m, 8H); 1.40 (s, 9H) ppm. 1.3. 4H- (4-Fluorophenyl) -5-iodo-imidazof2,1,1-b1 [1,3,41-thiadiazol-2-yl-piperazin-1-tert-butylcarboxylate SH HdC / N <N H3C A suspension of 0.245 g (6.07 mmol) tert-butyl 4- [6- (4-fluorophenyl) imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] -piperazine-1-carboxylate in 100 ml of acetonitrile, 1.50 g (6.50 mmol) of N-iodosuccinimide (CAS 516-12-1) are added at room temperature. After 20 minutes of reaction at ambient temperature, the mixture is treated with an aqueous solution of sodium thiosulfate and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure to give 3.17 g of 4- [6- (4-fluorophenyl) -5-iodo-imidazo [2,1-b] [1, 3] 4-tert-butyl thiadiazol-2-yl] -piperazine-1-carboxylate as a white powder after trituration in diisopropyl ether, filtration and drying.

1H NMR (DMSOd6) δ: 7.90 (dd, 2H); 7.25 (pseudotax, 1H); 3.45 (m, 8H); 1.40 (s, 9H) ppm.

1.4. Tert-Butyl 4-f6- (4-fluorophenyl) -5- (pyridin-4-yl) imidazof2,1-blf 1,3,41thiadiazol-2-ylpiperazine-1-carboxylate O SN H HC / N 3 ~ O H3C N To the mixture of 0.700 g (1.32 mmol) of 4- [6- (4-fluorophenyl) -5-iodo-imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] tert-butyl piperazine-1-carboxylate, 0.230 g (1.59 mmol) of (4-pyridinyl) boronic acid (CAS 1692-15-5) and 0.280 g (2.64 mmol) of bicarbonate of sodium in 30 ml of N-methylpyrrolidinone under argon, 0.153 g (0.13 mmol) of tetrakis (triphenylphosphine) palladium (O) (CAS 14221-01-3) are added. The reaction is heated at 150 ° C for 5 minutes. After cooling, the solvent is evaporated under reduced pressure and the mixture is partitioned between ethyl acetate and water. The organic phase is then dried over sodium sulfate and the solvent evaporated under reduced pressure. After recrystallization of the solid from isopropyl alcohol, filtration and drying, 0.52 g of 4- [6- (4-fluorophenyl) -5- (pyridin-4-yl) imidazo [2,1-b]] are isolated. Tert-butyl 3,4-thiadiazol-2-yl] -piperazine-1-carboxylate as a yellow powder. 1H NMR (CDCl3) δ: 8.50 (d, 2H); 7.50 (m, 4H); 7.00 (pseudo t, 2H); 3.55 (m, 4H); 3.40 (m, 4H); 1.30 (s, 9H) ppm.

1.5. 6- (4-Fluorophenyl) -2- (piperazin-1-yl) -5- (pyridin-4-yl) imidazof2,1-30b] [1,3,4lthiadiazole-14-NA a solution of 0.650 g ( 1.35 mmol) 4- [6- (4-fluorophenyl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazol-2-yl] -piperazine 1-tert-butyl 1-carboxylate in 15 ml of dichloromethane is added dropwise at 0 ° C, 13.5 ml of trifluoroacetic acid. The mixture is poured into water and the whole is basified by the addition of ammonia. The product is then extracted with dichloromethane, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified on a column of 25 g of silica gel, eluting with a mixture of dichloromethane, methanol and ammonia (95/5 / 0.5) to give 0.225 g of 6- (4-fluorophenyl) - 2- (piperazin-1-yl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole as a white powder after trituration in diethyl ether; ethyl, filtration and drying. Mp: 233-235 ° C 1H NMR (CDCl3) δ: 8.60 (d, 2H); 7.55 (d, 1H); 7.05 (pseudotax, 2H); 3.55 (m, 4H); 3.05 (m, 4H) ppm. Example 2 (Compound No. 6): 6- (4-Fluorophenyl) -2- (4-isopropylpiperazin-1-yl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3 , 4] thiadiazole H3C \ / \ S ~ NNNI \ H3C / N- 2.1. 2-Bromo-6- (4-fluorophenyl) imidazo (2,1-bbl) 1,3,4-thiadiazole (CAS 1094275-22-Br) To a solution of 14.0 g (78 mmol) of 5-bromo-1,3 4-thiadiazol-2-amine (CAS 37566-39-5) in 300 ml of butanol is added in small portions 22.0 g (101 mmol) of 2-bromo-1- (4-fluorophenyl) -ethanone ( CAS 403-29-2) The mixture is heated at reflux for 18 hours After cooling, the butanol is evaporated and the residue is triturated in 100 ml of acetone and then isolated by filtration after cooling in an ice bath. The solid is taken up with saturated sodium carbonate solution and the product is extracted with chloroform.The organic phase is separated off, dried over sodium sulphate, filtered and the solvent is evaporated under reduced pressure to give 16.5 g of 2- bromo-6- (4-fluorophenyl) imidazo [2,1-b] [1,3,4] thiadiazole in powder form after rinsing with diethyl ether and drying 1H NMR (CDCl3): 8.01 ( 1H, s); 7.80 (2H, dd); 7.14 (2H, ps); (2.2) 6- (4-Fluorophenyl) -2- (4-isopropylpiperazin-1-yl) imidazof2,1-blf 1, 3,4-thiadiazole H3C / NNNH3 H3C A mixture 0.298 g (1.00 mmol) of 2-bromo-6- (4-fluorophenyl) imidazo [2,1-b] [1,3,4] thiadiazole, 0.652 g (2.00 mmol) of cesium, 0.011 g (0.05 mmol) of palladium acetate (CAS 3375-31-3) and 0.029 (0.05 mmol) of 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (CAS 161265-03-8) under argon, 0.21 ml (1.5 mmol) of 1-isopropylpiperazine (CAS 137186-14-2) and 3 ml of 1,4-dioxane are added. The mixture is heated at 100 ° C for 2 hours in a sealed tube. After cooling, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on an alumina column, eluting with dichloromethane, to give 0.278 g of 6- (4-fluorophenyl) -2- (4-isopropylpiperazin) yl) imidazo [2,1-b] [1,3,4] thiadiazole. Mp: 213 ° C 1H NMR (CDCl3): 7.74 (2H, dd); 7.70 (1H, s); 7.05 (2H, t); 3.50 (4H, pseudot); 2.80 (1H, m); 2.66 (4H, t); 1.09 (6H, d) ppm 2.3. 6- (4-Fluorophenyl) -5-iodo-2- (4-isopropylpiperazin-1-yl) imidazo [2,1-b] [1,3,4ththiadiazole H3C] SN H3CNN6. The mixture of 0.690 g ( 2.00 mmol) 6- (4-fluorophenyl) -2- (4-isopropylpiperazin-1-yl) imidazo [2,1-b] [1,3,4] thiadiazole and 1.125 g (5.02 mmol). N-iodosuccinimide in 14 ml of acetonitrile is stirred for 16 hours at room temperature. The solvent is evaporated under reduced pressure and the residue is then purified by chromatography on a column of alumina, eluting with 16-dichloromethane to give 0.548 g of 6- (4-fluorophenyl) -5-iodo-2- (4- isopropylpiperazin-1-yl) imidazo [2,1-b] [1,3,4] thiadiazole. 1H NMR (CDCl3): 7.96 (2H, dd); 7.13 (2H, pseudo t); 3.54 (4H, t); 2.80 (1H, m); 2.67 (4H, t); 1.09 (6H, d) ppm. 2.4. 6- (4-Fluorophenyl) -2- (4-isopropylpiperazin-1-yl) -5- (pyridin-4-yl) imidazo-2,1-b1f-1,3,41-thiadiazole H3C N / H3C / H3C / NN A mixture of 0.235 g (0.500 mmol) of 6- (4-fluorophenyl) -5-iodo-2- (4-isopropylpiperazin-1-yl) imidazo [2,1-b] [1,3,4] thiadiazole, 0.326 (1 mmol) cesium carbonate, 0.145 g (1.00 mmol) 4-pyridine boronic acid (10-15% water) (CAS 1692-15-5) and 0.041 g (0.05 mmol) of 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (CAS 124268-93-5) in a mixture of 2.7 ml of tetrahydrofuran and 0.3 ml of water is heated to 100 ° C for 24 hours in a sealed tube. After cooling, the contents of the tube are taken up with water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The product is then purified by chromatography on a silica column eluting with dichloromethane and then with a gradient of ethyl acetate to give 0.090 g of 6- (4-fluorophenyl) -2- (4-isopropylpiperazin-1) yl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole. PF: 216.1 ° C

1H NMR (CDCl3): 8.58 (2H, d); 7.55 (4H, m); 7.05 (2H, pseudot); 3.53 (4H, t); 2.80 (1H, m); 2.67 (4H, t); 1.08 (6H, d) ppm. Example 3 (Compound No. 7): 6- (4-Fluorophenyl) -2- (4-isopropylpiperazin-1-yl) -5- (2-methylpyridin-4-yl) imidazo [2,1-b] [1 , 3,4] thiadiazole

A mixture of 0.235 g (0.500 mmol) of 6- (4-fluorophenyl) -5-iodo-2- (4-isopropylpiperazin-1-yl) was added to the mixture. imidazo [2,1-b] [1,3,4] thiadiazole, 0.326 g (1 mmol) cesium carbonate, 0.137 g (1 mmol) 2-picolin-4-yl-boronic acid (CAS 579476-63-4) and 0.041 g (0.05 mmol) of 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (CAS 124268-93-5) in a mixture of 2.7 ml of tetrahydrofuran and 0 3 ml of water is heated at 100 ° C for 24 hours in a sealed tube. After cooling, the contents of the tube are taken up with water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure.

The product is then purified by chromatography on a silica column, eluting with dichloromethane and then with a gradient of ethyl acetate to give 0.055 g of 6- (4-fluorophenyl) -2- (4-isopropylpiperazin-1-yl) ) -5- (2-methylpyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole.

MP: 183.8 ° C 1H NMR (CDCl3): 8.46 (1H, d); 7.54 (2H, dd); 7.40 (1H, s); 7.34 (1H, d); 7.03 (2H, t); 3.51 (4H, t); 2.79 (1H, m, CH); 2.66 (4H, t); 2.53 (3H, s, CH3); 1.07 (6H, d) ppm.

Example 4 (Compound No. 8): 4- (6- (4-Fluorophenyl) -2- (4-isopropylpiperazin-1-yl) imidazo [2,1-b] [1,3,4] thiadiazol-5- yl) -N-methylpyridin-2-amine H3C> NN H3C 4.1. (4-Bromopyridin-2-yl) tert-butyl methylcarbamate (CAS 946000-13-1) CH3 To a suspension of 0.53 g (13 mmol) of sodium hydride (60% in oil) in 50 ml of anhydrous dimethylformamide at 0 ° C., 3.00 g (11.0 mmol) of tert-butyl (4-bromopyridin-2-yl) carbamate (CAS 207799-10-8) are added in portions. The mixture is stirred at 0.degree. To 10.degree. C. for 1 hour and then 1.79 g (12.6 mmol) of methyl iodide (CAS74-88-4) is added dropwise with cooling at 0.degree. ) diluted in 2-5 ml of dimethylformamide. The reaction is left stirring for 18 hours at room temperature then the mixture is poured into a saturated solution of sodium chloride and the product is extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure to give 3.1 g of yellow oil which is purified by chromatography on silica gel, eluting with a mixture of 20% of ethyl acetate. ethyl in cyclohexane to give 2.85 g of tert-butyl (4-bromopyridin-2-yl) methylcarbamate as a colorless oil.

1H NMR (DMSO) δ: 8.30 (d, 1H); 8.00 (s, 1H); 7.40 (d, 1H); 3.30 (s, 3H); 1.50 (s, 9H) ppm.

4.2. Tert-Butyl methyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-ylcarbamate H3C3H3 / CH3 H3C Where B H3C CH3 CH3 CH3 argon 2.70 g (9.75 mmol) tert-butyl (4-bromopyridin-2-yl) methylcarbamate, 4.95 g (19.5 mmol) bis (pinacolato) diboron (CAS 73183-34 3) and 3.16 g (32.2 mmol) of potassium acetate in 30 ml of dimethylformamide are added 0.64 g (0.78 mmol) of complex 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) and dichloromethane (PdCl2 (dppf) .CH2Cl2) (CAS 95464-05-4), the mixture is then heated at 85 ° C. for 2 hours, the mixture is then poured into water and the product The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure to give 6.5 g of brown oil, which is taken up in water. diisopropyl ether and treated with animal black at reflux of the solvent for 5 minutes give 5.7 g of oil after filtration on Buchner and evaporation of the solvent under reduced pressure. The residue is taken up and stirred for 5 minutes with a mixture of 30 ml of ethyl acetate and 70 ml of 1N aqueous sodium hydroxide. The aqueous phase is separated and then neutralized by adding an aqueous hydrochloric acid solution. The product is then extracted with dichloromethane, the organic phase is dried over sodium sulphate, filtered and the solvent is evaporated under reduced pressure to give 2.45 g of [4- (4,4,5,5-tetramethyl) -1 Tert-butyl 3,2-dioxaborolan-2-yl) pyridin-2-yl] methylcarbamate as an orange oil which crystallizes slowly.

Mp 108-112 ° C NMR H (DMSO) δ: 8.30 (d, 1H); 7.85 (s, 1H); 7.25 (d, 1H); 3.30 (s, 3H); 1.45 (s, 9H); 1.30 (s, 12H) ppm.

4.3. 4C- (4-fluorophenyl) -2- (4-isopropylpiperazin-1-yl) imidazof2,1-bif-1,3,4-thiadiazol-5-yl) -N-methylpyridin-2-amine H3C / NN H3C1 / HN CH3 A mixture of 0.235 g (0.500 mmol) of 6- (4-fluorophenyl) -5-iodo-2- (4-isopropylpiperazin-1-yl) imidazo [2,1-b] [1,3,4] thiadiazole, 0.326 (1 mmol) of cesium carbonate, 0.334 g of [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl] methylcarbamate -butyl (1.00 mmol) and 0.041 g (0.05 mmol) of 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (CAS 124268-93-5) in a mixture of 2.7 ml of tetrahydrofuran and 0.3 ml of water is heated at 100 ° C for 24 hours in a sealed tube. After cooling, the contents of the tube are taken up with water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The product is then purified by chromatography on a silica column, eluting with dichloromethane and then with a gradient of ethyl acetate. (4- {6- (4-Fluorophenyl) -2- [4- (propan-2-yl) piperazin-1-yl] imidazo [2,1-b] [1,3,4] thiadiazole-5- The tert-butyl yl} pyridin-2-yl) methylcarbamate thus obtained is treated with a solution of 2 ml of dichloromethane and 0.2 ml of trifluoroacetic acid for 26 hours. The mixture is then basified in a saturated aqueous solution of sodium carbonate and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure and the residue is then purified by chromatography on a column of silica gel, eluting with a gradient of ethyl acetate in dichloromethane to give give 0.075 g of 4- (6- (4-fluorophenyl) -2- (4-isopropylpiperazin-1-yl) imidazo [2,1-b] [1,3,4] thiadiazol-5-yl) -N- methylpyridin-2-amine. -20-

Mp: 205.0 ° C 1 H NMR (CDCl3): 8.08 (1H, d); 7.60 (2H, dd); 7.04 (2H, t); 6.82 (1H, d); 6.70 (1H, s); 4.72 (1H, d); 3.52 (4H, t); 2.87 (3H, d); 2.80 (1H, m); 2.66 (4H, t); 1.08 (6H, 5 d) ppm

Example 5 (Compound No. 2): 6- (4-Fluorophenyl) -2- (3 (R) -methylpiperazin-1-yl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole ## STR16 ## to a mixture of 0.298 g (1.00 mmol) of 2-bromo-6- (4-fluorophenyl) imidazo [2.1-b] ] [1,3,4] thiadiazole, 0.212 g (2.00 mmol) of sodium carbonate, 0.011 g (0.05 mmol) of palladium acetate (CAS 3375-31-3) and 0.029 g (0 , 05 mmol) of 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (CAS 161265-03-8) under argon, 0.300 g (1.5 mmol) of tert-butyl 2- (R) -methylpiperazinecarboxylate ( CAS 170033-47-3)) and 3 ml of 1,4-dioxane. The mixture is heated at 100 ° C for 16 hours in a sealed tube. After cooling, the solvent is evaporated under reduced pressure and the residue is purified by column chromatography on alumina, eluting with dichloromethane to give 0.407 g (R) -4- [6- (4-fluorophenyl) imidazo [2.1 tert-butyl [b] [1,3,4] thiadiazol-2-yl] -2-methylpiperazine-1-carboxylate. 1H NMR (CDCl3): 7.75 (2H, dd); 7.71 (1H, s); 7.10 (2H, t); 4.45 (1H, bs); 3.17-4.05 (6H, m); 1.52 (9H, s); 1.29 (3H, d) ppm

5.2. (R) -4- (6- (4-Fluorophenyl) -5-iodoimidazo [2,1-b1 [1,3,4lthiadiazol-2-yl] -2-30 methylpiperazine-1-carboxylic acid tert-butyl ester H3C N 5.1. (R) -4- [6- (4-Fluorophenyl) imidazo [2,1-b] [1,3,4lthiadiazol-2-yl] -2-methylpiperazine-1-carboxylic acid tert-butyl ester 10 - 21 - 0 H3C 7 N / N H3C) 0} H3C H3C The mixture of 4.04 g (9.68 mmol) of (R) -4- [6- (4-fluorophenyl) imidazo [2,1-b] [1,3, 4] tert-butyl thiadiazol-2-yl] -2-methylpiperazine-1-carboxylate and 4.36 g (19.4 mmol) of N-iodosuccinimide in 65 ml of acetonitrile is stirred for 30 hours at room temperature. The solvent is evaporated to dryness and the residue is then purified by chromatography on a column of alumina, eluting with dichloromethane to give 4.9 g of (R) -4- (6- (4-fluorophenyl) -5-iodoimidazo Tert-butyl [2,1-b] [1,3,4] thiadiazol-2-yl) -2-methylpiperazine-1-carboxylate.

1H NMR (CDCl3): 7.96 (2H, dd); 7.15 (2H, t); 4.47 (1H, bs); 3.89-4.07 (2H, m); 3.22-3.48 (4H, m); 1.53 (9H, s); 1.31 (3H, d) ppm

5.3. 6- (4-Fluorophenyl) -2- (3 (R) -metylpiperazin-1-yl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazole H 3 C N A mixture of 0.272 g (0.500 mmol) of (R) -4- (6- (4-fluorophenyl) -5-iodoimidazo [2,1-b] [1,3,4] thiadiazol-2-yl) -2 tert-butyl methylpiperazine-1-carboxylate, 0.326 (1.00 mmol) cesium carbonate, 0.205 g 4- (4,4,5,5-20 tetramethyl-1,3,2-dioxaborolan) 2-yl) pyridine (1.00 mmol) and 0.041 g (0.05 mmol) of 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (CAS 124268-93-5) in a 2.7 ml mixture Tetrahydrofuran and 0.3 ml of water are heated at 100 ° C for 24 hours in a sealed tube. After cooling, the contents of the tube are taken up with water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate, filtered and the solvent is evaporated under reduced pressure. The product is then purified by chromatography on a silica column, eluting with dichloromethane and then with a gradient of ethyl acetate. (R) -4- (6- (4-Fluorophenyl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3,4] thiadiazol-2-yl) -2-methylpiperazine The intermediate tert-butyl 1-carboxylate is treated with a solution of 3 ml of dichloromethane and 0.3 ml of trifluoroacetic acid for 4 hours. The mixture is basified in a saturated aqueous solution of sodium carbonate and the product is extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered and the solvent is evaporated off under reduced pressure and the residue is then purified by chromatography on a column of silica gel, eluting with a gradient of ethyl acetate in dichloromethane to give 0.097 g of 6- (4-fluorophenyl) -2- (3 (R) -methylpiperazin-1-yl) -5- (pyridin-4-yl) imidazo [2,1-b] [1,3], 4] thiadiazole.

Mp 208.2 ° C.1H NMR (CDCl3): 8.60 (2H, d); 7.57 (4H, m); 7.07 (2H, t); 3.75 (2H, t); 2.77-3.68 (5H, m); 1.86 (1H, s); 1.19 (3H, d) ppm.

Table 1 which follows illustrates the chemical structures and the physical properties of some compounds according to the invention. In this table: the column "PF ° C" gives the melting points of the products in degrees Celsius. "Dec." means decomposition of the product when measuring the melting point, - in the column "Salt" HCI represents a compound in hydrochloride form and the ratio in parentheses is the ratio (acid: base), HBr represents a compound in hydrobromide form and the parenthetical ratio is the ratio (acid: base), the sign - means that the compound is in base form, - column [a] d informs the result of analysis of the rotatory power of the compounds of the table to the length of d With a wave of 589 nM, the solvent indicated in parentheses corresponds to the solvent used to measure the rotary power in degrees and the letter c indicates the concentration of the solvent in g / 100 ml. NA means that the measurement of the rotatory power is not applicable, - the column "(M + H)" informs the mass of the molecular ion observed during the analysis of the products by LC-MS (liquid chromatography coupled to Mass Spectroscopy) performed on an Agilent LC-MSD Trap device in ESI positive mode or MS (Mass Spectroscopy) on an Autospec M (EBE) device using the DCI-NH3 technique, - F- means fluoro, - CH3- means methyl, CH3OH is methanol; CH3O- is methoxy; CH3NH- is methylamino; Ph- is phenyl; TABLE 1 N ° -NALB-R6 R5 PF (° C) salt Iald M + H 1 piperazin-1-yl 4-F-Ph-H-233-235 NA 381 + 21.3 2 (3R) 3-Methyl-piperazin-1-yl 4-F-Ph-H-208.2 (c = 1; 395 CH 3 OH) + 20.6 3 (3R) -3-methyl-piperazin-1-yl 4-F -Ph- CH3- - 184.1 (c 409 1.006; CH3OH) + 17.8 4 (3R) -3-Methyl-piperazin-1-yl 4-F-Ph-CH3-NH- - 220.8 (c) = 1.01; 424 CH3OH) N ° -NALB-R6 R5 PF (° C) salt [a] d Mi-H + 13.9 (3R) -3-methylpiperazin-1-yl 4-F- Ph-CH 3 -O- - 168.4 (c 425 0.998; CH 3 OH) 6 4-Isopropyl-piperazin-1-yl 4-F-Ph-H-216.1 NA 423 7 4-Isopropyl-piperazin-1 yl 4-F-Ph-CH 3 - 183.8 NA 437 8 4-Isopropyl-piperazin-1-yl 4-F-Ph-CH 3 -NH- - 205.0 NA 452 9 4-Isopropyl-piperazin-1 ## STR1 ## ) N ° -NALB-R6 R5 PF (° C) salt [a] d M + H 11 2.9-Diaza-spiro [5.5] undec-9-yl 4-F-Ph-H- - 238.3 NA 449 12 2,9-Diaza-spiro [5.5] undec-9-yl 4-F-Ph-CH3- - 217.5 NA 463 13 2.9-Diaza-spiro [5.5] undec 9-yl 4-F-Ph-CH 3 -NH- - 223.3 NA 478 14 2.9-Diaza-spiro [5.5] undec-9-yl 4-F-Ph-CH 3 -O- - 179.1 NA 479 (cis) -Hexahydro-pyrrolo [3,4-4-F-Ph-H-218,9 NA 407 c] pyrrol-2 (1H) -yl 16 (cis) -Hexahydro-pyrrolo [3, 4-4-F-Ph-CH3- - 159.3 NA 421 c] pyrrol-2 (1H) -yl N ° -NALB-R6 R5 PF (° C) salt [a] d M + H (cis) Hexahydro-pyrrolo [3,4-llll-15-yl] 4-F-Ph-CH 3 -NH- - NA 436 c] pyrrol-2 (1H) -yl dec. 18 (cis) -Hexahydro-pyrrolo [3,4-4-F-Ph-CH3-O- - 183-185 NA 437 c] pyrrol-2 (1H) -yl-4-pyrrolidin-1-yl-piperidin -1-yl 4-F-Ph-H- 214.9 NA 449 4-Pyrrolidin-1-yl-piperidin-1-yl 4-F-Ph-CH3- 197.4 NA 463 211-240 21 4-Pyrrolidin-1-yl-piperidin-1-yl 4-F-Ph-CH 3 -NH- NA 478 dec. 4-Pyrrolidin-1-yl-piperidin-1-yl 4-F-Ph-CH3-O- - 177.4 NA Biological Examples The ability of the compounds of the invention to inhibit casein phosphorylation by casein kinase 1 epsilon and delta can be evaluated according to the procedure described in document US20050131012.

Dosaqe on Plate-Filter-ATP-33P for Screening of CK1 Epsilon Inhibitors:

The effect of the compounds to inhibit casein phosphorylation by casein kinase 1 epsilon enzyme (CK1 epsilon) was measured using a casein assay by filtration of ATP-33P in vitro. Casein Kinase 1 epsilon (0.58 mg / ml) is obtained by fermentation and purification methods carried out according to methods that are well known to those skilled in the art or can also be obtained from Invitrogen CorporationTM (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 of 10 micromolar.

U-shaped Falcon plates are prepared by placing 5 μl of solutions of the compounds according to the invention at concentrations of 10, 1, 0.1, 0.01 or 0.001 μM in different 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. Then, 5 μl of dephosphorylated casein at the final concentration of 0.2 μg / μl, 20 μl of CK1 epsilon at the final concentration of 3 ng / μl, and 20 μl of ATP-33P at the final concentration of 0 μl were added. 0.2 μCi / μL mixed with cold ATP (10 μM final - approximately 2x106 CPM per well). The final total test volume per well is equal to 50 μL. The Falcon U-bottom test plate cited above is vortexed and incubated at room temperature for 2 hours. After 2 hours, the reaction is stopped by addition of an ice-cold solution of 65 μl of cold ATP (2 mM) prepared in test buffer. Then 100 μl of the U-bottom Falcon plate reaction mixture are transferred into Millipore MAPH filtration plates, previously impregnated with 25 μl of 100% ice-cold TCA. MAPH Millipore filter plates are gently shaken and allowed 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 μl of 20% TCA, 2x150 μl of 10% TCA and 2x150 μl of 5% TCA (6 total washes per plate / 900 μl per well). . The plates are allowed to dry overnight at room temperature. Next, 40 μl of Packard Microscint-20 scintillation fluid is added per well and the plates are sealed. 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 IC50 value for each compound compared to the controls.

Kinetic studies determined the value of KM for ATP to be 21 pM in this test system. Under these conditions, the most active compounds of the invention have IC50 (concentration 50% inhibiting the enzymatic activity of Casein Kinase 1 Epsilon or Casein Kinase 1 Delta) of between 1 nM and 500 nM. below shows the IC50 inhibition of the phosphorylation of Casein Kinase 1 Epsilon for some compounds according to the invention.

Table 2 Compound No. CK1 epsilon IC50 (nM) 1 40 4 126 12 128 17 134 19 155 The ability of the compounds of the invention to inhibit casein phosphorylation by casein kinases 1 epsilon and delta can be assessed using Fluorescence Resonance Energy Transfer (FRET) fluorescence test from the Z'LyteTM kinase assay kit (reference PV3670; Invitrogen CorporationTM) according to the supplier's instructions.

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 fluorescence observed is therefore 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 buffer containing 50 mM HEPS, pH 7.5, 1 mMEGTA, 0.01% Brij. -35, 10 mM MgCl for casein kinase 1 epsilon and supplemented with Trizma Base (50 mM), pH 8.0 and NaN3 (0.01% final) for casein kinase 1 delta. The phosphorylation of the SER / THR 11 substrate peptide obtained from Invitrogen CorporationTM is carried out at the final concentration of 2 μM. The concentration of ATP is 4 times KM, which is 2 μM for casein kinase 1 epsilon and 4 μM for casein kinase 1 delta. The measurement of the fluorescence emitted is measured at wavelengths of 445 and 520 nm (excitation at 400 nm). Under these conditions, the most active compounds of the invention have Cl 50 (concentration 50% inhibiting the enzymatic activity of Casein Kinase 1 Epsilon or Casein Kinase 1 Delta) of between 1 nM and 500 nM. Experimental Cell Circadian Assay Protocols Mperl-luc Rat-1 (P2C4) fibroblast cultures were performed by dividing the cultures every 3-4 days (approximately 10-20% confluence) on culture flasks. degased polystyrene fabrics 150 cm2 (Falcon # 35-5001) and maintained in growth medium [EMEM (Cellgro # 10-010-CV); 10% fetal bovine serum (FBS, Gibco # 16000-044); and 50 I.U./ml of penicillin-streptomycin (Cellgro # 30-001-C1) at 37 ° C and 5% CO 2. 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 medium supplemented with 50 to 100 μg / ml zeocin (Invitrogen # 45- 0430) for 10-14 days. Zeocin-resistant stable transfectants were evaluated for reporter expression by adding 100 μM luciferin (Promega # E1603) to the growth medium and assaying luciferase activity on a TopCount scintillation counter (Packard Model). # C384V00). Rat-1 cell clones expressing both zeocin resistance and mPerl-directed luciferase activity were synchronized by serum shock with 50% horse serum [HS (Gibco # 16050-122)] and circadian reporter activity was evaluated. Clone P2C4 from Mperl-luc Rat-1 fibroblasts was selected for testing the compound.

Mperl-luc Rat-1 (P2C4) fibroblasts at 40-50% confluence obtained according to the previously described protocol were plated on 96-well opaque tissue culture plates (Perkin Elmer # 6005680). The cultures are maintained in growth medium supplemented with 100 μg / ml zeocin (Invitrogen # 45-0430). until they have reached 100% confluence (48 to 72 h). The cultures were then synchronized with 100 μl of synchronization medium [EMEM (Cellgro # 10-010-CV); 100 I.U. / ml penicillin-streptomycin (Cellgro # 30-001-C1); 50% HS (Gibco # 16050-122)] for 2 hours at 37 ° C and under CO2 5%. After synchronization, the cultures were rinsed with 100 μl of EMEM (Cellgro # 10-010-CV) for 10 minutes at room temperature. After rinsing, the medium was replaced with 300 μl of CO2-independent medium [CO21 (Gibco # 18045-088); 2mM L-glutamine (Cellgro # 25-005-C1); 100 IU / ml penicillin-streptomycin (Cellgro # 30-001-C1); luciferin 100 μM (Promega #E 1603)]. Compounds of the invention tested for circadian effects were added to CO2 independent medium in 0.3% DMSO (final concentration). The cultures were sealed immediately with TopSeal-A film (Packard # 6005185) and transferred for luciferase activity measurement.

After synchronization, the test plates were maintained at 37 ° C in a tissue culture oven (Forma Scientific Model # 3914). In vivo luciferase activity was estimated by measuring the relative light emission on a TopCount scintillation counter (Packard Model # C384V00). The analysis of periods was carried out by determining the interval between the relative emission minimums of light over several days, or by Fourier transformation. 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 as the change of period (ordinate) versus the concentration of the test compound (abscissa) in the XLfitTM software and the Delta CE (t + lh) was interpolated from this curve.

Table 3 below shows the Delta ECs (t + 1 h) for some compounds according to the invention. TABLE 3 Compound No. EC Delta (t + 1H) (nM) 1,190-394 4,283 12,113 17 26 19 4 By inhibiting the CK1 epsilon and / or CK1 delta enzymes, the compounds of the invention modulate the 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; 30 circadian rhythm disorders, such as those due to jet lag, shift work. Among the sleep disorders, primary sleep disorders such as dyssomnia, for example primary insomnia, are particularly distinguished; parasomnia, hypersomnia, for example excessive drowsiness; narcolepsy; sleep disorders related to sleep apnea; sleep disorders related to circadian rhythm and dyssomnia 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, such as unipolar depression, bipolar disorder, 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 cocaine, morphine, nicotine, ethanol, cannabis.

By inhibiting casein kinase 1 epsilon and / or casein kinase 1 delta, the compounds according to the invention can be used for the preparation of medicaments, especially for the preparation of a medicament for preventing or treating diseases related to hyperphosphorylation of tau protein, especially Alzheimer's disease. These drugs also find use in therapy, particularly in the treatment or prevention of diseases caused or exacerbated by the proliferation of cells and in particular tumor cells.

As an inhibitor of tumor cell proliferation, these compounds are useful in the prevention and treatment of fluid tumors such as leukemias, both primary and metastatic solid tumors, carcinomas and cancers, particularly: breast cancer; lung cancer ; small bowel cancer, colon and rectal cancer; cancer of the respiratory tract, the oropharynx and the hypopharynx; cancer of the esophagus; 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 Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), Chronic lymphocytic leukemia (CLL)) Chloromas, Plasmacytomas, T or B cell leukemias, Non-Hodgkin's or Hodgkin's lymphomas, Myeloma , various hematological malignancies.

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.

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. 2945289 - 34 -

Thus, according to another of its aspects, the subject of the invention is medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid of the compound of formula (I). According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as an active ingredient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient. Said 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.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or its salt, 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 forms of administration. , intranasal, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions. By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg Orally, the dose of active substance administered per day may reach 0.1 to 20 mg / kg, in one or several takes. There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, 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, according to another of its aspects, also relates to a method of treatment of the above-indicated pathologies which comprises administering to a patient an effective dose of a compound according to the invention, or a of its pharmaceutically acceptable salts.

Claims (5)

Revendications1. A compound of the general formula (I) wherein - R5 is hydrogen, C1-3 alkyl, -NR, R6, or C1-3 alkyloxy; R 6 represents a phenyl group optionally substituted with one or more substituents chosen from halogen atoms and C 1-6 alkyl groups; C1_6 alkyloxy; A represents a C1-6 alkylene group optionally substituted with one or two Ra groups; B represents a C 17 -alkylene group optionally substituted by an Rb group; L represents either a nitrogen atom optionally substituted with a Rd or Rd group or a carbon atom substituted with a Re1 group and a Rd group or two Re2 groups; the carbon atoms of A and B being optionally substituted with one or more Rf groups which are identical to or different from each other; Ra, Rb and Rd are defined such that: two groups Ra may together form a C1_6-alkylene group; Ra and Rb may together form a bond or C1-6-alkylene group; Ra and Rd may together form a bond or a C 1-6 -alkylene group; Rb and R may together form a bond or a C1-6alkylene group; Rd represents a group selected from hydrogen and C1-6-alkyl, C3-, -cycloalkyl, C3-, -cycloalkyl-C1_6 groups; -alkyl, C1-6-alkylthio-C-1,6-alkyl, C1-6-alkyloxy-C1-6-alkyl, C1-6-fluoroalkyl, hydroxy-C1-6-alkyl; Re1 represents a group -NR3R4 or a cyclic monoamine optionally having an oxygen atom, the cyclic monoamine being optionally substituted by one or more substituents selected from fluorine atom and C1-6-alkyl, C1-6-alkyloxy, hydroxyl groups; Two Regs form with the carbon atom which carries them a cyclic monoamine optionally comprising an oxygen atom, this cyclic monoamine being optionally substituted with one or more Rf groups which are identical or different from each other; Rf is C1-6alkyl, C3-, cycloalkyl, C3-, cycloalkyl-C1-6alkyl, C1-6alkyloxy-C1-6alkyl, hydroxy-C1-6alkyl, C1-6-fluoroalkyl; R3 and R4 represent, independently of one another, a hydrogen atom or a C1-4alkyl, C3-, -cycloalkyl, C3-, -cycloalkyl-C1-6-alkyl group; R 1 and R 8 represent, independently of one another, a hydrogen atom or a C 1-3 alkyl group; in the base state or acid addition salt. 25 2. Compound according to claim 1, characterized in that: - R5 represents a hydrogen atom or a C1-3-alkyl group, -NR, R8, C1.3 alkyloxy; R 6 represents a phenyl group optionally substituted with one or more substituents chosen from halogen atoms; The cyclic amine formed by N-A-L-B- represents a group selected from piperazinyl, hexahydropyrrolo-pyrrolyl, optionally substituted with one or more groups selected from methyl, isopropyl; or N-A-L-B-represents a diazaspiro-undecyl group; or a piperidinyl group, optionally substituted with a pyrrolidinyl group; R 1 and R 8 represent, independently of one another, a hydrogen atom or a C 1-3 alkyl group; in the base state or acid addition salt. 2945289 - 38 - 3. Process for the preparation of a compound of general formula (I) according to claim 1, characterized in that a compound of general formula (II) ASL "N \ B / 5 X5 is reacted in which A, L , B and R6 are defined according to claim 1 and X5 represents a halogen selected from bromine or iodine, with a compound of general formula (IIa) MN 10 wherein R5 is defined according to claim 1 and M represents a trialkylstannyl group dihydroxyboryl or dialkyloxyboryl, wherein A, L, B and R6 are as defined in claim 1 and X5 is a halogen selected from bromine or iodine 5. A medicament, characterized in that it comprises a compound of the formula (I) according to any one of claims 1 or 2, in the form of a base or addition salt with a pharmaceutically acceptable acid, 6. Pharmaceutical composition, characterized in that it comprises a compound of formula ( I) according to any one of claims 1 or 2, in the form of a base or addition salt with a pharmaceutically acceptable acid, as well as at least one pharmaceutically acceptable excipient. 4. Compound of general formula (II) / A. The use of a compound of the general formula (I) according to claim 1 or 2 for the preparation of a medicament for the treatment or prevention of sleep disorders. , disorders of the circadian rhythm. 8. Use of a compound of general formula (I) according to any of claims 1 or 2 for the preparation of a medicament for the treatment or prevention of bipolar disorders. 9. Use of a compound of general formula (I) according to any one of claims 1 or 2 for the preparation of a medicament for the treatment or prevention of diseases related to substance dependence. abuse. 10. Use of a compound of general formula (I) according to any one of claims 1 or 2, for the preparation of a medicament for the treatment or prevention of diseases related to hyperphosphorylation of tau protein. . 11. Use of a compound of general formula (I) according to any one of claims 1 or 2, for the preparation of a medicament for the treatment or prevention of diseases caused or exacerbated by proliferation of cells. 12. Use of a compound of general formula (I) according to claim 11, characterized in that the cells are tumor cells. 13. Use of a compound of general formula (I) according to any one of claims 1 or 2 for the preparation of a medicament for the treatment or prevention of inflammatory diseases.