Imidazo[5,1-f][1,2,4]triazines for the treatment of neurological disorders

1. A compound of the Formula I

or a pharmaceutically acceptable salt thereof, wherein:

“-A-R 5 ” is:

R 1 is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 15 )cycloalkyl, —(C 1 -C 6 )alkyl-OH, —(C 1 -C 6 )alkyl-CN, —SF 5 , —CF 3 , —CHF 2 , or —CH 2 F;

R 2 is —(C 1 -C 6 )alkyl-R 9 , —NHR 3 , —N(R 3 ) 2 , —O—(C 1 -C 6 )alkyl-R 9 , —OR 8 , (C 3 -C 15 )cycloalkyl, (C 6 -C 10 )aryl, (3- to 14-membered)heterocyclic, and (5- to 14-membered)heteroaryl; wherein said (C 3 -C 15 )cycloalkyl and (3- to 14- membered)heterocyclic may optionally contain one double or triple bond and one to two oxo (O═) groups; and wherein said —(C 1 -C 6 )alkyl-R 9 , —NHR 3 , —N(R 3 ) 2 , —O—(C 1 -C 6 )alkyl-R 9 , —OR 8 , (C 3 -C 15 )cycloalkyl, (C 6 -C 10 )aryl, (3- to 14-membered)heterocyclic, or (5- to 14- membered)heteroaryl moieties may be optionally substituted with one to three substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, and —CF 3 ;

Each R 3 is independently selected from the group consisting of —(C 1 -C 6 )alkyl-R 9 , —(C2-C6)alkenyl-R 9 , —(C 2 -C 6 )alkynyl-R 9 , and —(C 3 -C 15 )cycloalkyl-R 9 , or when R 2 is —N(R 3 ) 2 both of said R 3 may be taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclic ring optionally containing one or two oxo groups (O═) and optionally substituted with one to three substituents independently selected from the group consisting of hydrogen, fluoro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —OH, —O—(C 1 -C 6 )alkyl, NH 2 , —NH—(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 , —O—(C═O)—R 8 , —OR 8 , —O—(C═O)—OR 8 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 N(R 8 ) 2 , —NH—(C═O)—R 8 , —NH—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NH—(C═O)—N(R 8 ) 2 , —N[(C 1 -C 6 )alkyl](C═O)—R 8 , —N[(C 1 -C 6 )alkyl](C═O)—OR 8 , —N[(C 1 -C 6 )alkyl](C═O)—N(R 8 ) 2 , (C 3 -C 15 )cycloalkyl, (C 6 -C 10 )aryl, (3- to 14-membered)heterocyclic and (5- to 14-membered)heteroaryl; wherein said (C 3 -C 15 )cycloalkyl and (3- to 14- membered)heterocyclic moieties may optionally contain one double or triple bond and one to two oxo (O═) groups,

Each R 4 is independently selected from the group consisting of hydrogen, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —CF 3 , —CHF 2 , —CH 2 F, and (C 3 -C 15 )cycloalkyl;

Each R 4a is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, —CF 3 , —CHF 2 , —CH 2 F, and (C 3 -C 15 )cycloalkyl;

R 5 is:

where n is 0, 1, 2, 3, or 4;

Each R 6 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, —CF 3 , —CHF 2 , —CH 2 F, —CF 2 —(C 1 -C 6 )alkyl, —SF 5 , —CN, —(C 1 -C 6 )alkyl-CN, —NO 2 , —(C═O)—R 8 , —(C═O)—OR 8 , —OR 8 , —O—(C═O)—N(R 8 ) 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , —NH—(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —NH—(C═O)—R 8 , —NH—(C═O)—OR 8 , —N[(C 1 -C 6 )alkyl](C═O)—R 8 , —N[(C 1 -C 6 )alkyl](C═O)—OR 8 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 15 )cycloalkyl, (3- to 14-membered)heterocyclic, (C 6 -C 10 )aryl, and (5- to 14- membered)heteroaryl; wherein said (C 3 -C 15 )cycloalkyl and (3- to 14- membered)heterocyclic moieties may optionally contain one double or triple bond and one to two oxo (O═) groups;

Each R 7 is independently selected from the group consisting of hydrogen, halo, (C 1 -C 6 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 6 )alkynyl, —CN, —CF 3 , —CHF 2 , —CH 2 F, —O—(C 1 -C 6 )alkyl and (C 3 -C 15 )cycloalkyl;

Each R 8 wherever it occurs is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 15 )cycloalkyl, —CF 3 , and —CHF 2 ; and

Each R 9 is independently selected from the group consisting of hydrogen, halo, —CF 3 , —CHF 2 , —CH 2 F, —CF 2 —(C 1 -C 6 )alkyl, —CN, —(C 1 -C 6 )alkyl-CN, —NO 2 , —(C═O)—R 8 , —(C═O)—OR 8 , —OR 8 , —O—(C═O)—N(R 8 ) 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , —NH—(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —NH—(C═O)—R 8 , —NH—(C═O)—OR 8 , —N[(C 1 -C 6 )alkyl](C═O)—R 8 , —N[(C 1 -C 6 )alkyl](C═O)—OR 8 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 15 )cycloalkyl, (3- to 14-membered)heterocyclic, (C 6 -C 10 )aryl, and (5- to 14-membered)heteroaryl, wherein said (C 3 -C 15 )cycloalkyl and (3- to 14-membered)heterocyclic moieties may optionally contain one double or triple bond and one to two oxo (O═) groups; and wherein each of said (C 3 -C 15 )cycloalkyl, (3- to 14-membered)heterocyclic, (C 6 -C 10 )aryl, and (5- to 14-membered)heteroaryl moieties may be optionally substituted with one to three substituents independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo, and —CF 3 .

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

“-A-R 5 ” is:

R 1 is —(C 1 -C 6 )alkyl;

R 2 is —NHR 3 , or —N(R 3 ) 2 ;

Each R 3 is independently selected from the group consisting of —(C 1 -C 6 )alkyl-R 9 , —(C 2 -C 6 )alkenyl-R 9 , —(C 2 -C 6 )alkynyl-R 9 , and —(C 3 -C 15 )cycloalkyl-R 9 ; or when R 2 is —N(R 3 ) 2 both of said R 3 may be taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclic ring optionally containing one or two oxo groups (O═); and optionally may be substituted with one to three substituents independently selected from the group consisting of hydrogen, fluoro, —CN, —CF 3 , —CHF 2 , —CH 2 F, —OH, —O—(C 1 -C 6 )alkyl, NH 2 , —NH—(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —(C═O)—R 8 , —(C═O)—OR 8 , —(C═O)—N(R 8 ) 2 —O—(C═O)—R 8 , —OR 8 , —O—(C═O)—OR 8 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —S(O) 2 N(R 8 ) 2 , —NH—(C═O)—R 8 , —NH—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —NH—(C═O)—N(R 8 ) 2 , —N[(C 1 -C 6 )alkyl](C═O)—R 8 , —N[(C 1 -C 6 )alkyl](C═O)—OR 8 , —N[(C 1 -C 6 )alkyl](C═O)—N(R 8 ) 2 , (C 3 -C 15 )cycloalkyl, (C 6 -C 10 )aryl, (3- to 14-membered)heterocyclic, and (5- to 14-membered)heteroaryl; wherein said (C 3 -C 15 )cycloalkyl and (3- to 14-membered)heterocyclic moieties may optionally contain one double or triple bond and one to two oxo (O═) groups;

R 4 is hydrogen;

R 4a is (C 1 -C 6 )alkyl;

R 5 is:

where n is 0, 1, 2, 3, or 4.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having the formula

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having the formula

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, having the formula

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is:

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —(C 1 -C 6 )alkyl-R 9 , —NHR 3 , —N(R 3 ) 2 , —O—(C 1 -C 6 )alkyl-R 9 , or —OR 8 .

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —N(R 3 ) 2 , or —NHR 3 .

15. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is (C 3 -C 15 )cycloalkyl, (C 6 -C 10 )aryl, (3- to 14-membered)heterocyclic, or (5- to 14-membered)heteroaryl; wherein said (C 3 -C 15 )cycloalkyl and (3- to 14-membered)heterocyclic moieties may optionally contain one or two double or triple bonds and one to three oxo (O═) groups.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of hydrogen, halo, —CF 3 , —CHF 2 , and —CH 2 F.

17. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of—(C═O)—R 8 , —(C═O)—OR 8 , —OR 8 , —O—(C═O)—N(R 8 ) 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , NH 2 , —NH—(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , —NH—(C═O)—R 8 , —NH—(C═O)—OR 8 , —O—(C═O)—N(R 8 ) 2 , —N((C 1 -C 6 )alkyl)-(C═O)—R 8 , and —N((C 1 -C 6 )alkyl)-(C═O)—OR 8 .

18. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is (C 1 -C 6 )alkyl or (C 3 -C 15 )cycloalkyl.

19. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of (C2-C6)alkenyl, (C 2 -C 6 )alkynyl, (3- to 14-membered)heterocyclic, (C 6 -C 10 )aryl, and (5- to 14-membered)heteroaryl.

20. The compound according to claim 1 wherein said compound is:

4-(azetidin-1-yl)-7-methyl-5-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine;

4-(azetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine;

4-(azetidin-1-yl)-7-methyl-5-{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine;

4-(azetidin-1-yl)-5-[5-(4-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine;

4-(azetidin-1-yl)-5-[5-(5-chloropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine;

5-{5-[4-(difluoromethyl)phenyl]-1-methyl-1H-pyrazol-4-yl}-N,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-amine;

7-methyl-N-(d 3 )methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine;

N,7-dimethyl-5-{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine;

4-(azetidin-1-yl)-5-{5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1-methyl-1H-pyrazol-4-yl}-7-methylimidazo[5,1-f][1,2,4]triazine;

N, 7-dimethyl-5-{1-methyl-5-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine;

4-(azetidin-1-yl)-5-{5-[4-(difluoromethyl)phenyl]-1-methyl-1H-pyrazol-4-yl}-7-methylimidazo[5,1-f][1,2,4]triazine;

4-(3-fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine;

4-(azetidin-1-yl)-5-[5-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine;

4-(azetidin-1-yl)-5-{5-[4-(difluoromethoxy)phenyl]-1-methyl-1H-pyrazol-4-yl}-7-methylimidazo[5,1-f][1,2,4]triazine;

4-azetidin-1-yl-7-methyl-5-{1-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-][1,2,4]triazine;

4-azetidin-1-yl-5-[5-(5-bromopyridin-2-yl)-1-methyl-1H-pyrazol-4-yl]-7-methylimidazo[5,1-f][1,2,4]triazine; or

N,7-dimethyl-5-{1-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine; or a pharmaceutically acceptable salt thereof.

21. A method for alleviating one or more symptoms of cognitive impairment associated with schizophrenia in a human, comprising administering to said human a therapeutically effective amount of the compound of Formula I according to claim 1 , or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

23. 4-(azetidin-1-yl)-7-methyl-5-{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazol[5,1-f][1,2,4]triazine, or a pharmaceutically acceptable salt thereof.

24. 4-(azetidin-1-yl)-7-methyl-5-{1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}imidazol[5,1-f][1,2,4]triazine.

25. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 23 together with a pharmaceutically acceptable carrier.

26. A method of alleviating one or more symptoms of migraine comprising:

administering to a patient in need thereof a therapeutically effective amount of the compound of Formula I according to claim 1 , or a pharmaceutically acceptable salt thereof.