Pyrazole derivatives and use thereof as orexin receptor antagonists

1. A compound of the general formula (I)

wherein:

Ar represents phenyl group or a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms, where any of these rings may optionally be mono- or polysubstituted with halogen atom, C 1-4 alkyl group, C 1-4 alkoxy group, hydroxyl group, cyano group, trihalogenomethyl group, amino group or an amino group substituted with one or two C 1-4 alkyl groups;

Y stands —CH 2 - group;

X stands for sulphur atom, oxygen atom, —NH-group, —N(C 1-4 alkyl)group, —CH 2 -group, —(S═O)— or —SO 2 -group; or X and Y together represent a —CH═CH— group with cis or trans geometry;

A represents a moiety with a five- or six-membered aromatic ring which contains in ortho-, meta- or para-position two free valencies, and is optionally mono- or polysubstituted with halogen atom, C 1-4 alkyl group or C 1-4 alkoxy group; or with a partially or fully saturated five- or six-membered cycloalkyl ring optionally mono- or polysubstituted with halogen atom, C 1-4 alkyl group or C 1-4 alkoxy group; or with a heteroaromatic or partially or fully saturated heterocyclic ring which contains 1-3 heteroatoms and which is optionally mono- or polysubstituted with halogen atom, C 1-4 alkyl group or C 1-4 alkoxy group;

R 1 represents benzyl group, C 1-4 -alkyl-, C 1-4 -hydroxyalkyl-, C 3-8 -alkoxycarbonylalkyl-, C 2-7 -alkylcarbonyl-, C 2-7 -carboxyalkyl-, aminocarbonyl-(C 1-4 )-alkyl, C 1-3 -alkylaminocarbonyl-(C 1-4 )-alkyl, amino-(C 1-4 )-alkyl, C 1-3 -alkylamino-(C 1-4 )-alkyl-, morpholino-(C 1-4 )-alkyl-, or morpholinocarbonyl-(C 1-4 )-alkyl group or a phenyl group, optionally substituted with one or more halogen atoms;

R 2 represents one of the following groups which is optionally substituted with one or more halogen atom, hydroxyl group, C 1-4 alkyl group, trihalogenomethyl-group, thio-C 1-4 -alkyl group, amino group, —(C═O)—NH—C 1-4 -alkyl or cycloalkyl group: phenyl group, phenylethyl group, naphthyl group, indanyl- or indenyl group, five- or six-membered heteroaromatic or partially or fully saturated cyclic group containing 1-3 identical or different heteroatoms, a group containing a bicyclic heteroaromatic moiety or a partially or fully saturated bicyclic heteroring with 1 or 2 or 3 identical or different heteroatoms;

R 3 stands for hydrogen atom or C 1-4 alkyl group;

or R 3 and R 3 together with the nitrogen atom to which they are attached may represent a partly or fully saturated six-membered ring optionally substituted with a substituted phenyl or benzyl group; and

R 5 stands for halogen atom, hydrogen atom, C 1-4 alkyl group, C 1-4 thioalkyl group, or C 1-4 alkoxy group;

or a salt thereof.

2. A compound of the general formula (I)

wherein:

Ar represents phenyl group or a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms, where any of these rings may optionally be mono- or polysubstituted with halogen atom, C 1-4 alkyl group, C 1-4 alkoxy group, hydroxyl group, cyano group, trihalogenomethyl group, amino group or an amino group substituted with one or two C 1-4 alkyl group;

Y stands for —CH 2 -group;

X stands for sulphur atom, oxygen atom, —NH-group, —N(C 1-4 alkyl) group, —CH 2 -group, —(S═O)— or —SO 2 -group; or X and Y together represent a —CH═CH— group with cis or trans geometry;

A represents a moiety with a live- or six-membered aromatic ring which contains in ortho-, meta- or para-position two free valencies, and is optionally mono- or polysubstituted with halogen atom, C 1-4 alkyl group or C 1-4 alkoxy group; or with a partially or fully saturated five- or six-membered cycloalkyl ring optionally mono- or polysubstituted with halogen atom, C 1-4 alkyl group or C 1-4 alkoxy group; or with a heteroaromatic or partially or fully saturated heterocyclic ring which contains 1-3 heteroatoms, and is optionally mono- or polysubstituted with halogen atom, C 1-4 alkyl group or C 1-4 alkoxy group;

R 1 represents benzyl group, C 1-4 -alkyl-, C 1-4 -hydroxyalkyl-, C 3-8 -alkoxycarbonylalkyl-, C 2-7 -alkylcarbonyl-, C 2-7 -carboxyalkyl-, aminocarbonyl-(C 1-4 )-alkyl, C 1-3 -alkylaminocarbonyl (C 1-4 )-alkyl, amino-(C 1-4 )-alkyl, C 1-3 -alkylamino-(C 1-4 )-alkyl-, morpholino-(C 1-4 )-alkyl-, or morpholinocarbonyl-(C 1-4 )-alkyl group or a phenyl group, optionally substituted with one or more halogen atoms;

R 2 represents one of the following groups, optionally substituted with one or more halogen atom, C 1-4 alkyl group, trihalogenomethyl-group, thio-C 1-4 -alkyl group, amino group, —(C═O)—NH—C 1-4 -alkyl or cycloalkyl group: phenyl group, phenylethyl group, naphthyl group, indanyl- or indenyl group, five- or six-membered heteroaromatic or partially or fully saturated cyclic group containing 1-3 identical or different heteroatoms, a group containing a bicyclic heteroaromatic moiety or a partially or fully saturated bicyclic heteroring with 1 or 2 or 3 identical or different heteroatoms;

R 3 stands for hydrogen atom or C 1-4 alkyl group;

R 2 and R 3 together with the nitrogen atom to which they are attached may represent a partly or fully saturated six-membered ring optionally substituted with a substituted phenyl or benzyl group,

R 5 stands for halogen atom, hydrogen atom, C 1-4 alkyl group, C 1-4 thioalkyl group, C 1-4 alkoxy group or a salt thereof.

3. A compound of the general formula (I) according claim 1 , wherein:

Ar stands for phenyl group or a 6-membered heteroaromatic ring with 1 or 2 nitrogen atoms, where the aromatic rings may optionally be mono- or polysubstituted with halogen atom or C 1-4 alkoxy group;

Y stands for methylene group;

X stands for sulphur atom, oxygen atom, methylene group, —N(methyl)group;

A represents ortho-phenylene group or a heteroaromatic moiety containing in ortho- position two free valencies;

R 1 represents C 1-4 -alkyl-, C 1-5 -hydroxyalkyl-, C 3-8 -alkoxycarbonylmethyl, C 2-6 -carboxyalkyl-or methylaminocarbonyl group, or an alkylaminocarbonyl group substituted with one or two C 1-4 -alkyl group;

R 2 represents aromatic or partially saturated bicyclic group containing 0, 1, 2 or 3 heteroatoms, optionally substituted with one or more C 1-4 -alkyl group, halogen atom or amino group;

R 3 represents hydrogen atom; and

R 5 represents halogen atom, C 1-4 -alkyl-, or C 1-4 -alkylthio group; or a salt thereof.

4. A compound of the general formula (I) according claim 1 , wherein:

Ar represents a phenyl group, optionally substituted with halogen atom; or a 6-membered heteroaromatic ring with 1 or 2 nitrogen atoms, optionally substituted with halogen atom;

Y stands for methylene group;

X represents methylene group, sulphur atom, oxygen atom, or a nitrogen atom carrying a C 1-4 -alkyl group;

A represents ortho-phenylene group or a heteroaromatic moiety containing in ortho-position two free valencies;

R 1 represents a straight or branched C 1-4 -alkyl group, C 1-3 -hydroxyalkyl group or C 3-6 -alkoxycarbonylmethyl group;

R 2 represents an aromatic or partially saturated bicyclic moiety optionally substituted with C 1-4 alkyl group or halogen atom; or an aromatic or partially saturated bicyclic moiety containing 1-3 heteroatoms;

R 3 represents hydrogen atom; and

R 5 represents chloro atom, methyl group or thiomethyl group; or a salt thereof.

5. A compound according claim 1 ,

wherein said compound is:

2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulplhanyl)-N-naphthalin-2-ylbenzamide;

2-(3-Phenyl-5-chloro-1-methyl-1-H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-6-ylbenzamide hydrochloride;

2-(3-Phenyl-5-chloro-1-methyl-1-H-pyrazol-4-ylmethylsulphanyl)-N-indan-5-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-2-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-naphthalin-2-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-2-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-6-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

N-(1-Bromisoquinolin-3-yl)-2-(5-chloro-1-methyl-3-pyridin-3yl-1H-pyrazol-4-ylmethylsulphanyl)benzamide;

2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-iquinolin-6-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-naphthalin-2-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-6-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyrazin-2-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-methylisoquinolin-3-yl)benzamide;

2-(1-Ethyl-3-phenyl-5-chloro-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

2-(3-Phenyl-5-chloro-1-propyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

2-(1-Butyl-3-phenyl-5-chloro-4H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

Ethyl-{3-phenyl-5-chloro-4-[2-(quinolin-3-ylcarbamoyl)-phenylsulphanylmethyl]-1H-pyrazol-1-yl}-acetate;

2-[3-Phenyl-1-(2-hydroxyethyl)-5-chloro-1H-pyrazol-4-ylmethylsulphanyl]-N-quinolin-3-ylbenzamide;

2-(3-Phenyl-1,5-dimethyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

2-(3-Phenyl-1-methyl-5-methylsulphanyl-1H-pyrazol-4-ylmethylsulphanyl)-N-quinolin-3-ylbenzamide;

3-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethylsulphanyl)-thiophen-2-carboxylic acid naphthalin-2-ylamide;

2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;

2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy)-N-naphthalin-2-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-2-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide;

2-[3-(4-Fluorophenyl)-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy]-N-quinolin-3-ylbenzamide;

2-[2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-yl)ethyl]-N-quinolin-3-ylbenzamide;

2-[3-(4-Fluorophenyl)-5-chloro-1-methyl-1H-pyrazol-4-ylmethoxy]-N-quinolin-3-ylbenzamide;

2-[2-(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-yl)ethyl]-N-quinolin-3-ylbenzamide;

2-[2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-yl)ethyl]-N-quinolin-3-ylbenzamide;

2-[(3-Phenyl-5-chloro-1-methyl-1H-pyrazol-4-ylmethyl)methylamino]-N-quinolin-3-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-4-yl-1H-pyrazol-4-ylmethylsulphanyl)-N-(3,4-dichlorophenyl)benzamide;

2-[5-Chloro-1-methyl-3-(2-thienyl)-1H-pyrazol-4-ylmethoxy]-N-quinolin-3-ylbenzamide;

2-[(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethyl)methylamino]-N-quinolin-3-ylbenzamide;

2-(5-Chloro-1-methyl-3-pyridin-3-yl-1H-pyrazol-4-ylmethoxy)-N-(6,7-difluoroquinolin-3-yl)benzamide;

2-(5-Chloro-1-methyl-3-pyridazin-3-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide; or

2-(5-Chloro-1-methyl-3-pyridazin-4-yl-1H-pyrazol-4-ylmethoxy)-N-quinolin-3-ylbenzamide; or a salt thereof.

6. A pharmaceutical composition, character in that it contains a compound of the general formula (I) according to claim 1 or salt thereof.

7. A pharmaceutical composition characterized in that it contains a compound of the general formula (I) according to claim 5 or a salt thereof.

8. A pharmaceutical composition, characterized in that it contains a compound of the general formula (I) according to claim 1 or a salt thereof, and at least one pharmaceutically acceptable excipient.

9. A compound according to claim 1 , wherein each of said heteroatoms in each of said aromatic heterocycles and non-aromatic heterocycles is selected from the group consisting of nitrogen, oxygen, and sulphur;

or a salt thereof.

10. A compound according to claim 2 , wherein each of said heteroatoms in each of said aromatic heterocycles and non-aromatic heterocycles is selected from the group consisting of nitrogen, oxygen, and sulphur;

or a salt thereof.

11. A compound according to claim 4 , wherein each of said heteroatoms in each of said aromatic heterocycles and non-aromatic heterocycles is selected from the group consisting of nitrogen, oxygen, and sulphur;

or a salt thereof.