Fused azaheterocyclic compounds and their use as AMPA receptor modulators

1. A compound of Formula (I):

wherein

X is N or CH;

Y is selected from the group consisting of: N, CH, CF, and CCl;

R 1 is H or CH 3 ;

R 2 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 OCH 3 , C 3-8 cycloalkyl and phenyl;

R 3 is selected from the group consisting of: H, halo, CH 3 , and CF 3 ;

R 4 is selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, C 3-8 cycloalkyl, azetidinyl, azetidinyl substituted with F, and phenyl substituted with F; and

 is selected from the group consisting of: —CH═N—; —CF═N—; —CH 2 —C(═O)—; and —S—C(═O)—; and

pharmaceutically acceptable salts, N-oxides, or solvates thereof.

2. The compound of claim 1 , wherein X is N.

3. The compound of claim 1 , wherein X is CH.

4. The compound of claim 1 , wherein Y is N.

5. The compound of claim 1 , wherein Y is CH, CF, or CCl.

6. The compound of claim 1 , wherein Y is CH.

7. The compound of claim 1 , wherein R 1 is H.

8. The compound of claim 1 , wherein R 1 is CH 3 .

9. The compound of claim 1 , wherein R 2 is C 1-6 alkyl, C 1-6 haloalkyl, CH 2 OCH 3 , cyclopropyl, cyclobutyl, cyclopentyl, or phenyl.

10. The compound of claim 1 , wherein R 2 is CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CF 2 H, CF 3 .

11. The compound of claim 1 , wherein R 2 is CF 3 .

12. The compound of claim 1 , wherein R 3 is H, F, Cl, or CH 3 .

13. The compound of claim 1 , wherein R 4 is C 1-6 alkyl, C 1-6 haloalkyl, Cl, CN, OCH 3 , phenyl substituted with F, cyclopropyl, cyclopentyl, azetidinyl, or azetidinyl substituted with F.

14. The compound of claim 1 , wherein R 4 is CF 3 .

15. The compound of claim 1 , wherein

is —CH═N—.

16. The compound of claim 1 , wherein

is CH 2 —C(═O)—.

17. The compound of claim 1 , and pharmaceutically acceptable salts, solvates, or N-oxides thereof, having the structure of Formula (1A):

wherein

R 1 is H;

R 2 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 OCH 3 , and C 3-8 cycloalkyl;

R 4 is selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, C 3-8 cycloalkyl, azetidinyl, azetidinyl substituted with F, and phenyl substituted with F; and

R 5 is selected from the group consisting of:

18. The compound of claim 1 , and pharmaceutically acceptable salts, solvates, or N—oxides thereof, having the structure of Formula (1B):

wherein

R 1 is H;

R 2 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 OCH 3 , C 3-8 cycloalkyl and phenyl;

R 4 is selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, C 3-8 cycloalkyl, azetidinyl, azetidinyl substituted with F, and phenyl substituted with F; and

R 5 is selected from the group consisting of:

19. The compound of claim 1 , and pharmaceutically acceptable salts, solvates, or N—oxides thereof, having the structure of Formula (1C):

wherein

Y is selected from the group consisting of: CH, CF, and CCl;

R 1 is H or CH 3 ;

R 2 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 OCH 3 , C 3-8 cycloalkyl and phenyl;

R 4 is selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, C 3-8 cycloalkyl, azetidinyl, azetidinyl substituted with F, and phenyl substituted with F; and

R 5 is selected from the group consisting of:

20. A compound selected from the group consisting of:

8-(7-Chloro-1H-indazol-5-yl)-2-(difluoromethyl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-Chloro-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

6-(2,7-Bis(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzo[d]thiazol-2(3H)-one;

2-Cyclobutyl-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine;

6-(7-(4-Fluorophenyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)benzo[d]thiazol-2(3H)-one;

7-Cyclopentyl-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-(Azetidin-1-yl)-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-(3-Fluoroazetidin-1-yl)-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

2-Cyclopentyl-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(7-Methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile;

7-Methyl-5-[7-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolin-2-one;

5-(7-(4-Fluorophenyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-1H-indazole;

8-(7-Chloro-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-2-(difluoromethyl)-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

2-(Difluoromethyl)-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Methyl-1H-indazol-5-yl)-2-(difluoromethyl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-Chloro-5-(2-(difluoromethyl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)indolin-2-one;

7-Methyl-5-(2-(difluoromethyl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)indolin-2-one;

8-(7-Chloro-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(7-Methyl-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

5-(2,7-Bis(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-7-chloroindolin-2-one;

5-(2,7-Bis(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-7-methylindolin-2-one;

8-(7-Chloro-1H-indazol-5-yl)-7-(difluoromethyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(7-Methyl-1H-indazol-5-yl)-7-(difluoromethyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-Chloro-5-(7-(difluoromethyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)indolin-2-one;

7-Methyl-5-(7-(difluoromethyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)indolin-2-one;

7-Methyl-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-Ethyl-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-Methoxy-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(7-Chloro-1H-indazol-5-yl)-2-cyclopropyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

2-Cyclopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(7-Choro-1H-indazol-5-yl)-2-methyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

2-Methyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(7-Chloro-1H-indazol-5-yl)-2-ethyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

2-Ethyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

5-[2-Ethyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-7-methyl-indolin-2-one;

8-(7-Chloro-1H-indazol-5-yl)-2-isopropyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

2-Isopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

5-[2-Isopropyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-7-methyl-indolin-2-one;

2-Isopropyl-7-methyl-8-(7-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine;

7-Chloro-8-(7-chloro-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-(4-Fluorophenyl)-8-(7-fluoro-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

7-(4-Fluorophenyl)-8-(7-chloro-1H-indazol-5-yl)-2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine;

7-(4-Fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(3-Fluoro-1H-indazol-5-yl)-7-(4-fluorophenyl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

2-(Difluoromethyl)-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine;

7-(4-Fluorophenyl)-2-(methoxymethyl)-8-(7-methyl-1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine;

2-Cyclopropyl-7-(4-fluorophenyl)-8-(7-methyl- 1H-indazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridine;

7-Isopropyl-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine;

8-(1H-Indazol-5-yl)-7-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridine;

7-Fluoro-5-[7-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolin-2-one;

7-Methyl-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine;

2-tert-Butyl-7-methyl-8-(7-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyridine;

5-(2-tert-Butyl-7-methyl-imidazo[1,2-a]pyridin-8-yl)-7-methyl-indolin-2-one;

7-Methyl-5-(7-methyl-2-phenyl-imidazo[1,2-a]pyridin-8-yl)indolin-2-one;

7-Methyl-8-(7-methyl- 1H-indazol-5-yl)-2-phenyl-imidazo[1,2-a]pyridine;

2-Cyclopropyl-7-methyl-8-(7-methyl- 1H-indazol-5-yl)imidazo[1,2-a]pyridine;

5-[7-Methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]-7-methyl-indolin-2-one;

7-Methoxy-8-(7-methyl- 1H-indazol-5-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine;

7-Chloro-8-(7-methyl- 1H-indazol-5-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine;

5-(2,7-Bis(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-1H-indazole;

5-(2,7-Bis(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-7-methyl-1H-indazole;

8-(7-Methyl-1H-indazol-5-yl)-2,7-bis(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro- 1H-indazol-5-yl)-2-ethyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

2-Ethyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-2-isopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-2-cyclopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

2-Cyclopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

7-Chloro-5-[2-cyclopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-8-yl]indolin-2-one;

5-[2-Cyclopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-8-yl]-7-fluoro-indolin-2-one;

8-(7-Chloro-1H-indazol-5-yl)-7-isopropyl-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-2-(difluoromethyl)-7-isopropyl-imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-7-ethyl-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

7-Ethyl-8-(7-methyl-1H-indazol-5-yl)-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-2-(difluoromethyl)-7-ethyl-imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-7-methyl-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-7-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-7-cyclopropyl-2-(difluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-7-cyclopropyl-5-methyl-2-trifluoromethyl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-7-cyclopropyl-2-(difluoromethyl)-5-methyl-imidazo[1,2-c]pyrimidine;

3-Chloro-8-(7-chloro-1H-indazol-5-yl)-2-cyclopropyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine; and

8-(7-Chloro-1H-indazol-5-yl)-2-cyclopropyl-3-fluoro-7-(trifluoromethyl)imidazo[1,2-c]pyrimidine;

5-(2,7-Bis(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-7-chloroindolin-2-one;

5-(2,7-Bis(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-7-methylindolin-2-one;

5-(2,7-Bis(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-7-chloro-1H-indazole;

8-(7-Chloro-1H-indazol-5-yl)-2-isopropyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine;

2-Isopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine;

2-Cyclopropyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine;

2-Ethyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine;

2-(Difluoromethyl)-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine; and

2-Methyl-8-(7-methyl-1H-indazol-5-yl)-7-(trifluoromethyl)imidazo[1,2-a]pyridine; and pharmaceutically acceptable salts, N-oxides or solvates thereof.

21. A compound selected from the group consisting of:

7-Cyclopropyl-2-(difluoromethyl)-5-methyl-8-(7-(trifluoromethyl)-1H-indazol-5-yl)imidazo[1,2-c]pyrimidine;

8-(7-Chloro-1H-indazol-5-yl)-7-(difluoromethyl)-2-ethyl-[1,2,4]triazolo[1,5-a]pyridine; and

8-(7-chloro-1H-indazol-5-yl)-2-cyclopropyl-7-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine; and pharmaceutically acceptable salts, N-oxides or solvates thereof.

22. A pharmaceutical composition comprising:

(A) an effective amount of at least one compound of Formula (I):

wherein

X is N or CH;

Y is selected from the group consisting of: N, CH, CF, or CCl;

R 1 is H or CH 3 ;

R 2 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 OCH 3 , C 3-8 cycloalkyl and phenyl;

R 3 is selected from the group consisting of: H, halo, CH 3 , and CF 3 ;

R 4 is selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, C 3-8 cycloalkyl, azetidinyl, azetidinyl substituted with F, and phenyl substituted with F; and

 is selected from the group consisting of: —CH═N—; —CF═N—; —CH 2 —C(═O)—; and —S—C(═O)—; and

pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I); and

(B) at least one pharmaceutically acceptable excipient.

23. A pharmaceutical composition comprising an effective amount of at least one compound of claim 21 and at least one pharmaceutically acceptable excipient.

24. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by AMPA receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I):

wherein

X is N or CH;

Y is selected from the group consisting of: N, CH, CF, and CCl;

R 1 is H or CH 3 ;

R 2 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 OCH 3 , C 3-8 cycloalkyl and phenyl;

R 3 is selected from the group consisting of: H, halo, CH 3 , and CF 3 ;

R 4 is selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, C 3-8 cycloalkyl, azetidinyl, azetidinyl substituted with F, and phenyl substituted with F; and

 is selected from the group consisting of: —CH═N—; —CF═N—; —CH 2 —C(═O)—; and —S—C(═O)—; and

pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I).

25. The method of claim 24 , wherein the AMPA receptor mediated disease, disorder, or medical condition is selected from cerebral ischemia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's chorea, AIDS nervous disturbance, epilepsy, mental disorder, mobility disturbance, pain, spasticity, nervous disturbance by toxin in food, neurodegenerative diseases, chronic pain, migraine, cancer pain, diabetic neuropathy, encephalitis, acute disseminated encephalomyelitis, acute demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, Marchifava-Bignami disease, central pontine myelinolysis, Devic syndrome, Balo disease, HIV- or HTLV-myelopathy, progressive multifocal leucoencephalopathy, a secondary demyelinating disorder, schizophrenia, prodromal schizophrenia, cognitive disorder, depression, anxiety disorders, anxious depression, and bipolar disorder.

26. The method of claim 24 , wherein the AMPA receptor mediated disease, disorder or condition is depression, post traumatic stress disorder, epilepsy, schizophrenia, prodromal schizophrenia, or a cognitive disorder.