Piperazine-piperidine antagonists and agonists of the 5-HT

1. A compound of Formula (I′):

and pharmaceutically acceptable salts and hydrates thereof,

wherein

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R a and R b are each independently —H or —CH 3 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; and

n is 0, 1 or 2.

2. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 .

3. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 9 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

4. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 10 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

5. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 12 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

6. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and R 9 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

7. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 9 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN; one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; R a and R b are each independently —H or —CH 3 ; and R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and the five remaining substituents of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each hydrogen.

8. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and one of R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

9. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 1 is —H, —CF 3 (C 1 -C 6 )-alkyl; R 4 and R 5 are each independently —H, halogen, —OR 25 , or —CF 3 ; R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently —H, halogen, -alkyl, —OR 25 , —CF 3 , or —NO 2 ; R 16 is —H or —CH 3 .

10. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein any one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any one of R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

11. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein any one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any two of R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

12. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein any one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any three of R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

13. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein R 25 is (C 1 -C 6 )-alkyl.

14. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein n is 1.

15. A compound of Formula (I″):

and pharmaceutically acceptable salts thereof,

wherein

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7′ , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 except for the R group through which the piperidine is connected;

R a and R b are each independently —H or —CH 3 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; and

where the piperidine group can be attached to the non-hetero atom containing ring of the quinoline through positions R 7 , R 7′ , R 8 , or R 9 .

16. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein any one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any one of R 7 , R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN, except for the R group through which the piperidine is connected.

17. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any one of R 7 , R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN, except for the R group through which the piperidine is connected.

18. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any two of R 7 , R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN, except for the R group through which the piperidine is connected.

19. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any three of R 7 , R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN, except for the R group through which the piperidine is connected.

20. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and R 7′ is —H, (C 1 -C 6 ) -alkyl, —OR 25 , halogen, —CF 3 , —NO 2 or —CN, and R 1 , R 2 , R 3 R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R a , and R b are each hydrogen except for the R group through which the piperidine is connected.

21. The compound or pharmaceutically acceptable salt of the compound of claim 20 , wherein the piperidine is connected through R 7 .

22. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein R 25 (C 1 -C 6 )-alkyl.

23. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein the piperidine is connected through R 7 .

24. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein the piperidine is connected through R 7 .

25. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein the piperidine is connected through R 8 .

26. The compound or pharmaceutically acceptable salt of the compound of claim 15 , wherein the piperidine is connected through R 9 .

27. A compound of Formula (I″a):

and pharmaceutically acceptable salts thereof,

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7′ , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R a and R b are each independently —H or —CH 3 ; and

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl.

28. The compound or pharmaceutically acceptable salt of the compound of claim 27 , wherein R 5 , is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 .

29. The compound or pharmaceutically acceptable salt of the compound of claim 27 , wherein any one R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and any one of R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN.

30. The compound or pharmaceutically acceptable salt of the compound of claim 27 , wherein R 4 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and any one of R 13 , R 14 , R 15 , and R 16 is —H, (C 1 -C 6 )-alkyl, —OR 25 , or halogen; and any two of R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN; and wherein the any two R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 can be either on the same ring of the quinoline or on different rings.

31. The compound or pharmaceutically acceptable salt of the compound of claim 27 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and any one of R 13 , R 14 , R 15 , and R 16 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen; and any two of R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN; and wherein the any two of R 7′ , R 8 , R 9 , R 10 , R 11 , and R 12 can be either on the same ring of the quinoline or on different rings.

32. The compound or pharmaceutically acceptable salt of the compound of claim 29 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and R 7′ is —H, (C 1 -C 6 ) -alkyl, —OR 25 , halogen, —CF 3 , —NO 2 , or —CN; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R a , and R b are each hydrogen.

33. The compound or pharmaceutically acceptable salt of the compound of claim 29 , wherein R 25 is (C 1 -C 6 )-alkyl.

34. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein

R 4 , R 5 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R a and R b are each independently —H or —CH 3 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 -alkynyl); and

R 4 and R 5 cannot both be hydrogen.

35. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 4 and R 5 are each independently —H, —OR 25 , halogen, or (C 1 -C 6 )-alkyl; R 15 and R 16 are each independently —H or —CH 3 ; and R 17 , R 18 , and R 19 are each independently —H, —OR 25 , halogen, (C 1 -C 6 )-alkyl, —CF 3 , —NO 2 , or —CN.

36. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 4 and R 5 are each independently —H, —OCH 3 , F, or —CH 3 ; R 15 and R 16 are each independently —H or —CH 3 ; and R 17 , R 18 , and R 19 are each independently —H, F, —CH 3 , —CF 3 , —NO 2 , —CN or Br.

37. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 4 and R 5 are each independently —H, or —OR 25 ; and R 17 , R 18 , and R 19 are each independently —H, —OR 25 , halogen, (C 1 -C 6 )-alkyl, or —CF 3 .

38. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 4 and R 5 are each independently —H, —OR 25 ; R 17 , R 18 , and R 19 are each independently —H, —OR 25 , halogen, (C 1 -C 6 )-alkyl, or —CF 3 ; and the remaining R groups are hydrogen.

39. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 19 is in the para position relative to the nitrogen of the piperidine.

40. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 17 and R 18 are located at positions 2 and 4 of the quinoline ring.

41. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 5 is (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and one of R 17 , R 18 , and R 19 is (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 .

42. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and two of R 17 , R 18 , and R 19 are each independently —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 .

43. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and R 17 , R 18 , and R 19 are each independently —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 .

44. The compound or pharmaceutically acceptable salt of the compound of claim 34 , wherein R 5 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 and one of R 17 , R 18 , and R 19 is —H, (C 1 -C 6 )-alkyl, —OR 25 , halogen, or —CF 3 ; and R 4 , R 15 , R 16 , R a , R b and the two remaining substituents from R 17 , R 18 , and R 19 are each hydrogen.

45. The compound or pharmaceutically acceptable salt of the compound of claim 1 wherein the compound is

6-methoxy-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

6-fluoro-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

5-fluoro-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

7-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline;

6-fluoro-8-{4-[1-(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-1-yl}quinoline;

3-trifluoromethyl-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline;

6-methoxy-8-(4-(1-(quinolin-8-ylmethyl)piperidin-4-yl)piperazin-1-yl)quinoline;

5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)-2-(trifluoromethyl)quinoline;

5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline;

8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

6-chloro-8-[4-(4-(6-chloro)-quinolin-8-yl-piperidin-1-yl)-piperazin-1-yl]-quinoline;

6-fluoro-8-[4-(4-(6-chloro)-quinolin-8-yl-piperidin-1-yl)-piperazin-1-yl]-quinoline;

5-chloro-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

2-methyl-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

6-chloro-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-5-trifluoromethyl-quinoline;

5-methoxy-8-[4-(1-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

5-fluoro-8-[4-(4-quinolin-8-yl-piperazin-1-yl)-piperidin-1-yl]-quinoline;

6-methoxy-8-[4-(2-methylquinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

6-fluoro-8-(4-(1-(2-methylquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-methoxy-8-[4-(3-methylquinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline;

6-methoxy-8-(4-(1-(4-methylquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-methoxy-8-(4-(1-(2,4-dimethylquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-methoxy-8-(4-(1-(2,4-dimethyl-5-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-methoxy-8-(4-(1-(2-(trifluoromethyl)quinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-fluoro-8-(4-(1-(5-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-methoxy-8-(4-(1-(6-bromoquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-methoxy-8-(4-(1-(6-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-fluoro-8-(4-(1-(7-fluoroquinolin-8-yl)piperidin-4-yl)piperazin-1-yl)quinoline;

6-methoxy-8-{4-[1-(8-fluoroquinolin-7-yl)piperidin-4-yl]piperazin-1-yl}quinoline;

6-methoxy-8-{4-[1-(2-trifluoromethyl-4-methoxyquinolin-7-yl)piperidin-4-yl]piperazin -1-yl}quinoline;

6-methoxy-8-(4-(1-(2-trifluoromethyl-4-methoxyquinolin-8-yl)piperidin-4-yl)piperazin -1-yl)quinoline;

5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl) -2-trifluoromethylquinoline;

5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl) -3-trifluoromethylquinoline;

5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl) -4-trifluoromethylquinoline;

2,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline;

3,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline; or

4,5-difluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline.

46. A pharmaceutical formulation comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier.

47. The pharmaceutical formulation of claim 46 , further comprising a second therapeutic agent.

48. The pharmaceutical formulation of claim 47 , wherein the second therapeutic agent is a selective serotonin reuptake inhibitor or a cholinesterase inhibitor.

49. A pharmaceutical formulation comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 15 and a pharmaceutically acceptable carrier.

50. The pharmaceutical formulation of claim 49 , further comprising a second therapeutic agent.

51. The pharmaceutical formulation of claim 50 , wherein the second therapeutic agent is a selective serotonin reuptake inhibitor or a cholinesterase inhibitor.

52. A pharmaceutical formulation comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 27 and a pharmaceutically acceptable carrier.

53. The pharmaceutical formulation of claim 52 , further comprising a second Therapeutic agent.

54. The pharmaceutical formulation of claim 53 , wherein the second therapeutic agent is a selective serotonin reuptake inhibitor or a cholinesterase inhibitor.

55. A pharmaceutical formulation comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 34 and a pharmaceutically acceptable carrier.

56. The pharmaceutical formulation of claim 55 , further comprising a second therapeutic agent.

57. The pharmaceutical formulation of claim 56 , wherein the second therapeutic agent is a selective serotonin reuptake inhibitor or a cholinesterase inhibitor.

58. A method of synthesizing a compound comprising:

a) reacting an optionally substituted aniline compound of Formula (VII):

wherein:

W is a leaving group;

R 4 , R 5 , and R 6 are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl;

under conditions effective to produce an optionally substituted quinoline of Formula (VIII):

wherein:

R 1 , R 2 , and R 3 are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 ) -alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

b) reacting the quinoline of Formula (VIII) with a protected piperazine derivative under conditions effective to provide a protected piperazino-quinoline of Formula (IX):

wherein:

R a and R b are each independently —H or —CH 3 and

X 1 is a protecting group

c) reacting the protected piperazino-quinoline of Formula (IX) under conditions effective to provide a substituted piperazino-quinoline compound of Formula (Xb):

d) reacting a second optionally substituted aniline compound of Formula (XI):

 wherein

R 7 , R 8 , and R 9 , are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 -alkynyl; and

W is a leaving group

under conditions effective to produce a second optionally substituted quinoline of Formula (XII):

wherein R 10 , R 11 , and R 12 , are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; and

W is a leaving group

e) reacting the quinoline of Formula (XII) with a protected piperidin-4-one derivative, under conditions effective to provide a compound of Formula (XIII):

wherein X 2 is a protecting group;

f) reacting the compound of Formula (XIII) under conditions effective to provide a piperidin-4-one compound of (XIVa):

g) reacting the substituted piperazine compound of Formula (Xb) with the substituted piperidin-4-one compound of Formula (XIVa) under conditions effective to provide a piperazine-piperidine compound having the Formula (XV):

59. A compound of Formula (XV):

wherein

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R a and R b are each independently —H or —CH 3 ; and

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl;

prepared by the method comprising:

a) reacting an optionally substituted aniline compound of Formula (VII):

wherein W is a leaving group;

under conditions effective to produce an optionally substituted quinoline of Formula (VIII):

b) reacting the leaving group of the quinoline of Formula (VIII) with a protected piperazine derivative under conditions effective to provide a protected piperazino-quinoline of Formula (XI):

wherein X 1 is a protecting group.

c) reacting the protected piperazino-quinoline of Formula (IX) under conditions effective to provide a substituted piperazine compound of Formula (Xb):

d) reacting a second optionally substituted aniline compound of Formula (XI):

wherein W is a leaving group;

under conditions effective to produce a second optionally substituted quinoline of Formula (XII):

e) reacting the leaving group of the second quinoline of Formula (XII) with a protected piperidin-4-one derivative under conditions effective to provide the compound (XIII):

wherein X 2 is a protecting group.

f) reacting the compound of Formula (XIII) under conditions effective to provide the compound of (XIVa):

g) reacting the substituted piperazine compound of Formula (X) with the substituted piperidin-4-one compound of Formula (XIV) under conditions effective to provide a piperazine-piperidine compound having the Formula (XV):

60. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein

R 99 is

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R a and R b are each independently —H or —CH 3 ; and

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl;

prepared by the method comprising:

reacting a substituted piperazine compound of Formula (X):

with a substituted piperidin-4-one compound of Formula (XIV):

under conditions effective to bring about reductive amination at the piperidine carbonyl, thereby providing an piperazine-piperidine compound having the Formula (I):

61. A compound of Formula (I′):

or a pharmaceutically acceptable salt thereof,

wherein

R 99 is

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 1 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 , are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 ;

R a and R b are each independently —H or —CH 3 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; and

n is 1 or 2;

prepared by the method comprising:

reacting a substituted piperazine compound of Formula (X):

with a substituted piperidin-4-one compound of Formula (XIVb):

under conditions effective to bring about reductive amination at the piperidine carbonyl, thereby providing a piperazine-piperidine compound having the Formula (I′):

62. A compound of Formula (I″):

or a pharmaceutically acceptable salt thereof,

wherein

R 99 is

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7′ , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently —H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, halogen, —CF 3 , —NO 2 , —CN, —OR 25 , —OSO 2 R 25 , —SR 25 , —SO 2 R 25 , —SO 2 N(R 25 ) 2 , —N(R 25 ) 2 , —COR 25 , —CO 2 R 25 , —NR 25 CO 2 R 25 , —NR 25 COR 25 , —NR 25 CON(R 25 ) 2 , or —CON(R 25 ) 2 except for the R group through which the piperidine is connected;

R a and R b are each independently —H or —CH 3 ;

R 25 is —H; or linear or branched (C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkyl, (C 2 -C 6 )-alkenyl, or (C 2 -C 6 )-alkynyl; and

where the piperidine group can be attached to the non-hetero atom containing ring of the piperidine through positions R 7 , R 7′ , R 8 , or R 9 ;

prepared by the method comprising:

reacting a substituted piperazine compound of Formula (X):

with a compound of formula (XIVc):

under conditions effective to bring about reductive amination at the piperidine carbonyl, thereby providing a piperazine-piperidine compound having the Formula (I″):

63. The pharmaceutical composition of claim 55 , wherein R 4 and R 5 are each independently —H, —OCH 3 , F, or —CH 3 ; R 15 and R 16 are each independently —H or —CH 3 ; and R 17 , R 18 , and R 19 are each independently —H, F, —CH 3 , —CF 3 , —NO 2 , —CN or Br.

64. The pharmaceutical composition of claim 55 , wherein R 4 and R 5 are each independently —H or —OR 25 ; R 17 , R 18 , and R 19 are each independently —H, —OR 25 , halogen, (C 1 -C 6 )-alkyl, or —CF 3 ; and R 15 , R 16 , R a , and R b are hydrogen.

65. The compound or pharmaceutically acceptable salt of the compound of claim 1 , wherein n is 0.

66. The compound or pharmaceutically acceptable salt of the compound of claim 1 wherein the compound is 5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl) piperazin-1-yl)piperidin-1-yl)quinoline.

67. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of a compound wherein the compound is 5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-1-yl)piperidin-1-yl)quinoline.