Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases

1. A compound of formula (I)

or a stereoisomeric form thereof, wherein

R 1 is selected from the group consisting of a radical of formula (a-1), (a-2) and (a-3);

wherein

each R 6 , R 7 , R 8 independently is selected from the group consisting of fluoro; C 1-4 alkyl; C 1-4 alkyloxy; and C 1-4 alkyl substituted with 1, 2 or 3 fluoro atoms;

R 9 is hydrogen or C 1-4 alkyl;

each m 1 , m 2 , and m 3 is independently selected from 0, 1, 2, 3 and 4;

p 2 is selected from 1, 2, 3, and 4;

each p 1 and p 3 is independently selected from 1 and 2;

or R 1 is selected from the group consisting of unsubstituted pyridinyl; pyridinyl substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1-4 alkyl, trifluoromethyl and C 1-4 alkyloxy; and unsubstituted tetrahydropyranyl;

R 2 is selected from the group consisting of hydrogen; C 1-4 alkyl; trifluoromethyl; C 3-8 cycloalkyl; C 1-4 alkyloxy; and cyano;

R 3 is selected from the group consisting of hydrogen; C 1-4 alkyl; C 3-8 cycloalkyl; and C 1-4 alkyl substituted with 1, 2 or 3 fluoro atoms;

Het is a 5- or 6-membered heterocyclic ring, selected from the group consisting of pyridinyl; pyrimidinyl; pyridazinyl; pyrazinyl; pyrrolyl; oxazolyl; thiazolyl; imidazolyl; pyrazolyl; isothiazolyl; isoxazolyl; oxadiazolyl and triazolyl;

R 4 is selected from the group consisting of hydrogen; C 1-4 alkyl; C 1-4 alkyl substituted with 1, 2 or 3 fluoro atoms; (difluorocyclopropyl)methyl; (cyclopropyl)difluoromethyl; hydroxyC 1-4 alkyl; C 3-8 cycloalkyl; (C 3-8 cycloalkyl)-C 1-4 alkyl; C 1-4 alkyloxyC 1-6 alkyl; C 1-4 alkyloxy; C 1-4 alkyloxy substituted with 1, 2 or 3 fluoro atoms; (C 3-8 cycloalkyl)C 1-4 alkyloxy; (C 1-4 alkyloxyC 1-4 alkyl)oxy; (C 1-4 alkyl)-carbonyl; (C 1-4 alkyl)carbonylC 1-4 alkyl; (C 3-8 cycloalkyl)carbonyl; (C 3-8 cycloalkyl)-carbonylC 1-4 alkyl; unsubstituted phenyl; phenyl substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, cyano and C 1-4 alkyloxy; unsubstituted benzyl; benzyl substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, cyano and C 1-4 alkyloxy; unsubstituted tetrahydrofuranyl; tetrahydrofuranylmethyl; unsubstituted tetrahydropyranyl; tetrahydropyranylmethyl; pyridinylmethyl; quinolinylmethyl; (NR 10 R 11 )C 1-4 alkyl; and NR 10 R 11 ;

R 5 is hydrogen or fluoro;

R 10 and R 11 are independently selected from hydrogen and C 1-4 alkyl, or taken together with the ring nitrogen atom may form a radical of Formula (b-1), (b-2) or (b-3)

wherein each R 12 , R 13 and R 14 independently is C 1-4 alkyl or C 1-4 alkyloxy;

R 15 is hydrogen or C 1-4 alkyl;

each q1, q2 and q3 is independently selected from 0, 1, 2, 3 and 4;

s 1 is selected from 1, 2, 3 and 4;

each s 2 and s 3 is independently selected from 1 and 2;

or a pharmaceutically acceptable salt or a solvate thereof.

2. The compound according to claim 1 , or a stereoisomeric form thereof, wherein

R 1 is selected from the group consisting of a radical of formula (a-1), a radical of formula (a-2); a radical of formula (a-3); unsubstituted pyridinyl; pyridinyl substituted with halogen, C 1-4 alkyl, trifluoromethyl or C 1-4 alkyloxy; and unsubstituted tetrahydropyranyl;

wherein

each R 6 , R 7 and R 8 independently is selected from the group consisting of C 1-4 alkyl; and C 1-4 alkyloxy;

R 9 is selected from hydrogen and C 1-4 alkyl;

each m 1 , m 2 and m 3 is selected from 0, 1 and 2;

p 2 is selected from 2 and 3;

each p 1 and p 3 is 1;

R 2 is selected from the group consisting of hydrogen; methyl; ethyl; prop-2-yl; trifluoromethyl; cyano; methoxy and cyclopropyl;

R 3 is selected from the group consisting of hydrogen; methyl; trifluoromethyl; 3,3,3-trifluoropropyl; and cyclopropyl; and

Het is selected from the group consisting of pyridinyl; pyrimidinyl; 1H-pyrrolyl; oxazolyl; thiazolyl; 1H-imidazolyl; and 1H-pyrazolyl;

R 4 is selected from the group consisting of hydrogen; C 1-4 alkyl; C 1-4 alkyl substituted with 1, 2 or 3 fluoro atoms; (difluorocyclopropyl)methyl; (cyclopropyl)difluoromethyl; hydroxyC 1-4 alkyl; C 3-8 cycloalkyl; (C 3-8 cycloalkyl)-C 1-4 alkyl; C 1-4 alkyloxyC 1-6 alkyl; C 1-4 alkyloxy; C 1-4 alkyloxy substituted with 1, 2 or 3 fluoro atoms; (C 3-8 cycloalkyl)C 1-4 alkyloxy; (C 1-4 alkyloxyC 1-4 alkyl)oxy; (C 1-4 alkyl)-carbonylC 1-4 alkyl; (C 3-8 cycloalkyl)carbonylC 1-4 alkyl; unsubstituted phenyl; phenyl substituted with halogen, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, cyano or C 1-4 alkyloxy; unsubstituted benzyl; benzyl substituted with halogen, C 1-4 alkyl, trifluoromethyl, trifluoromethoxy, cyano or C 1-4 alkyloxy; unsubstituted tetrahydrofuranyl; tetrahydrofuranylmethyl; unsubstituted tetrahydropyranyl; tetrahydropyranylmethyl; pyridinylmethyl; quinolinylmethyl; (NR 10 R 11 )C 1-4 alkyl; and NR 10 R 11 ;

wherein R 10 and R 11 are independently selected from hydrogen and C 1-4 alkyl, or taken together with the ring nitrogen atom may form a radical of Formula (b-1), (b-2) or (b-3);

wherein

each R 12 , R 13 and R 14 is independently selected from C 1-4 alkyl and C 1-4 alkyloxy;

R 15 is selected from hydrogen and C 1-4 alkyl;

each q 1 , q 2 and q 3 is selected from 0, 1 and 2;

s 1 is selected from 2 and 3;

each s 2 and s 3 is 1;

and R 5 is as defined in claim 1 ;

or a pharmaceutically acceptable salt or a solvate thereof.

3. The compound according to claim 1 , or a stereoisomeric form thereof, wherein

R 1 is selected from the group consisting of a radical of formula (a-1); a radical of formula (a-2); unsubstituted pyridin-3-yl; and unsubstituted pyridin-4-yl;

wherein each m 1 , m 2 and m 3 is 0; p 2 is selected from 2 and 3; and each of p 1 and p 3 is 1;

R 4 is selected from the group consisting of hydrogen; C 1-4 alkyl; fluoroethyl; fluoropropyl; difluoroethyl; trifluoromethyl; trifluoroethyl; (difluorocyclopropyl)methyl; hydroxyC 1-4 alkyl; C 3-8 cycloalkyl; (C 3-8 cycloalkyl)-C 1-4 alkyl; C 1-4 alkyloxyC 1-6 alkyl; C 1-4 alkyloxy; trifluoromethyloxy; trifluoroethyloxy; (C 3-8 cycloalkyl)C 1-4 alkyloxy; (C 1-4 alkyloxyC 1-4 alkyl)oxy; (C 1-4 alkyl)carbonylC 1-4 alkyl; (C 3-8 cycloalkyl)carbonylC 1-4 alkyl; unsubstituted phenyl; phenyl substituted with halogen; unsubstituted benzyl; benzyl substituted with halogen; unsubstituted tetrahydrofuranyl; unsubstituted tetrahydropyranyl; tetrahydrofuranylmethyl; tetrahydropyranylmethyl; pyridinylmethyl; quinolinylmethyl; (NR 10 R 11 )C 1-4 alkyl; and NR 10 R 11 ;

wherein R 10 and R 11 are independently hydrogen or C 1-4 alkyl, or taken together with the nitrogen can be a radical of formula (b-1), (b-2) or (b-3), wherein

R 12 is C 1-4 alkyloxy;

s 1 is 2;

q 1 is selected from 0 and 1;

each q 2 and q 3 is 0;

each s 2 and s 3 is 1; and

R 15 is hydrogen;

and R 2 , R 3 , Het and R 5 are as defined in claim 1 ;

or a pharmaceutically acceptable salt or a solvate thereof.

4. The compound according to claim 1 , or a stereoisomeric form thereof, wherein

R 1 is selected from the group consisting of unsubstituted morpholin-4-yl; unsubstituted pyridin-3-yl; unsubstituted pyridin-4-yl and unsubstituted pyrrolidin-1-yl;

R 2 is selected from the group consisting of hydrogen; methyl; ethyl; prop-2-yl; trifluoromethyl; cyano; methoxy and cyclopropyl;

R 3 is selected from the group consisting of hydrogen; methyl; trifluoromethyl; 3,3,3-trifluoropropyl; and cyclopropyl; and

Het is selected from the group consisting of pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; pyrimidin-5-yl; 1H-pyrrol-3-yl; 1,3-oxazol-4-yl; 1,3-thiazol-5-yl; 1H-imidazol-5-yl; and 1H-pyrazol-5-yl;

R 4 is hydrogen; methyl; ethyl; prop-2-yl; 2-methylpropyl; 2-fluoroethyl; 3-fluoropropyl; 2,2-difluoroethyl; 2,2,2-trifluoroethyl; 2,2-difluorocyclopropylmethyl; 2-hydroxyethyl; cyclopropyl; cyclopropylmethyl; methyloxy; 1-methylethyloxy; ethyloxymethyl; 2-methyloxyethyl; 2-ethyloxyethyl; 3-methyloxypropyl; 1-methoxy-1-methylethyl; 1-ethoxy-1-methylethyl; 2-methoxy-2-methylpropyl; 2-(1-methylethoxy)-ethyl; 3-methoxypropyl; 2-methoxypropyl; 1-methoxyprop-2-yl; 1-methoxybut-2-yl; 2-methoxy-3-methylbutyl; 3-methoxy-3-methylbutyl; 3-methoxybutyl; 2,2,2-trifluoroethyloxy; cyclopropylmethyloxy; (2-methyloxyethyl)oxy; 2-methoxy-2-methylpropyloxy; 2-oxopropyl; 3-oxobutyl; 2-cyclopropyl-2-oxoethyl; 4-fluorophenyl; 2-chlorobenzyl; 4-chlorobenzyl; tetrahydrofuran-3-yl; tetrahydro-2H-pyran-4-yl; tetrahydrofuran-2-ylmethyl; tetrahydro-2H-pyran-2-ylmethyl; tetrahydro-2H-pyran-4-ylmethyl; pyridin-2-ylmethyl; pyridin-3-ylmethyl; pyridin-4-ylmethyl; quinolin-2-ylmethyl; (1-methylethyl)amino; pyrrolidin-1-yl; piperazin-1-yl; morpholin-4-yl; 3-methoxy-pyrrolidin-1-yl; 2-pyrrolidin-1-ylethyl; and 2-morpholin-4-ylethyl;

R 5 is hydrogen or fluoro;

or a pharmaceutically acceptable salt or a solvate thereof.

5. A compound of formula (I) according to claim 1 , selected from the group consisting of

3-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

3-[1-(2-methoxyethyl)-1H-pyrrol-3-yl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

2-methyl-3-[2-(2-methylpropyl)-5-thiazolyl]-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

3-[6-(2-methoxyethyl)-3-pyridinyl]-2-methyl-8-(4-pyridinyl)-imidazo[1,2-a]pyrazine;

3-[6-(2-methoxyethoxy)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

3-(6-cyclopropyl-3-pyridinyl)-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

2-methyl-8-(4-morpholinyl)-3-[6-(1-piperazinyl)-3-pyridinyl]-imidazo[1,2-a]pyrazine;

2-methyl-8-(4-morpholinyl)-3-[6-(tetrahydro-2H-pyran-4-yl)-3-pyridinyl]-imidazo[1,2-a]pyrazine;

3-[6-(1-methoxy-1-methylethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

3-[6-(ethoxymethyl)-3-pyridinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine; and

3-[2-(2-methoxyethyl)-5-pyrimidinyl]-2-methyl-8-(4-morpholinyl)-imidazo[1,2-a]pyrazine;

or a pharmaceutically acceptable salt or a solvate thereof.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

7. A method of treatment of a disease or disorder selected from the group consisting of schizophrenia, drug induced psychosis, obsessive-compulsive disorder, generalized anxiety disorder, Huntington's disease, dyskinesia, Parkinson's disease, depression, bipolar disorders, dementia, Alzheimer's disease dementia, attention-deficit/hyperactivity disorder, drug abuse, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, post traumatic pain, diabetes and obesity, comprising administering to a patient having said disease or disorder a therapeutically effective amount of a compound according to claim 1 .

8. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutical agent.

9. A process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier or excipient, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound.

10. A product comprising

(a) a compound as defined in claim 1 ; and

(b) a pharmaceutical agent,

as a combined preparation for simultaneous, separate or sequential administration.