Fused dihydro-4H-pyrazolo[5,1-C][1,4]oxazinyl compounds and analogs for treating CNS disorders

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring B is a 6-membered aromatic ring, which ring is unsubstituted or substituted with 1 to 4 substituents independently selected from halo, —OH, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 and

—CF 3 ; or is a 5- or 6-membered heteroaromatic ring having 1 to 3 ring heteroatoms independently selected from O, N and S, which ring is unsubstituted or substituted with 1 to 3 substituents independently selected from halo, —OH, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 and —CF 3 ;

A 1 is —H or C 1-3 alkyl; and

A 2 is —C(R 7 )(R 8 )—(CH 2 ) p —N(R 9 )R 10 ;

or A 1 and A 2 , together with the carbon atom to which they are attached, form

m is 0, 1 or 2;

n1 is 1 or 2;

n2 is 0 or 1;

n3 is 0 or 1;

p is 0 or 1;

R is —H or C 1 -C 3 alkyl; or R is —CH 2 —(X), —CH 2 CH 2 —(X), —CH 2 —(Z) or —CH 2 CH 2 —(Z);

each instance of R 5 independently is halo, —CH 3 or ethyl;

each instance of R 6 independently is halo or —CH 3 ;

R 7 is —H or C 1 -C 3 alkyl;

R 8 is —H or C 1 -C 3 alkyl which is unsubstituted or substituted with C 3 -C 6 cycloalkyl;

R 9 is —H, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; and

R 10 is —H or C 1 -C 3 alkyl;

or R 9 and R 8 , together with the atoms to which they are attached, form

or R 9 and R 10 , together with the nitrogen atom to which they are attached, form

w is 0, 1 or 2;

X is CH or CH 2 ; and

Z is CH, CH 2 or O.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is —H.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein w is 0.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n1 is 1.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n1 is 2.

6. The compound of claim 1 of Formula (I-1):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 2 , R 3 and R 4 are independently —H, halo, —OH, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 or —CF 3 .

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are independently —H, —F or —Cl.

8. The compound of claim 1 of Formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein:

Y 1 is N or CR 1 ′;

Y 2 is N or CR 2 ′;

Y 3 is N or CR 3 ′; and

Y 4 is N or CR 4 ′;

wherein 1 to 3 of Y 1 , Y 2 , Y 3 and Y 4 are N; and

R 1 ′, R 2 ′, R 3 ′, and R 4 ′ are independently —H, halo, —OH, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 or —CF 3 .

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein Y 3 is N.

10. The compound of claim 1 of Formula (I-3):

or a pharmaceutically acceptable salt thereof, wherein:

Y 11 is CR 1 ″ or a heteroatom selected from O, S, N and NR 11 ;

Y 12 is CR 2 ″ or a heteroatom selected from O, S, N and NR 12 ; and

Y 13 is CR 3 ″ or a heteroatom selected from O, S, N and NR 13 ;

wherein at least one of Y 11 , Y 12 and Y 13 is a heteroatom;

R 1 ″, R 2 ″ and R 3 ″ are independently —H, halo, —OH, —NH 2 , —CH 3 , —CH 2 F, —CHF 2 or —CF 3 ; and

R 11 , R 12 and R 13 are independently —H or —CH 3 .

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Y 11 is S.

12. The compound of claim 6 , of formula (II-1):

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , of formula (II-1a):

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 , together with the nitrogen atom to which they are attached, form

15. The compound of claim 6 , of formula (III-1):

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 , of formula (III-1a):

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 6 , of formula (IV-1):

or a pharmaceutically acceptable salt thereof.

18. A composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

19. A method for treating a neurological or psychiatric disorder in a patient, comprising administering to said patient an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said neurological or psychiatric disorder is selected from depression, anxiety, psychosis, or attention-deficit hyperactivity disorder.

20. The method according to claim 19 , wherein the neurological or psychiatric disorder is depression.

21. The method according to claim 20 , wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder.

22. The compound of claim 1 selected from a compound shown below, or a pharmaceutically acceptable salt thereof:

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I-4

23. A composition comprising the compound of claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

24. A method for treating a neurological or psychiatric disorder in a patient, comprising administering to said patient an effective amount of the compound according to claim 22 , or a pharmaceutically acceptable salt thereof, wherein said neurological or psychiatric disorder is selected from depression, anxiety, psychosis, or attention-deficit hyperactivity disorder.

25. The method according to claim 24 , wherein the neurological or psychiatric disorder is depression.

26. The method according to claim 25 , wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder.

27. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, selected from:

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28. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, selected from:

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29. The compound of claim 27 , or a pharmaceutically acceptable salt thereof, selected from:

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68

30. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:

R 7 is —H;

R 8 is —H or —CH 3 ,

R 9 is —H, C 1 -C 3 alkyl, cyclopropyl or cyclobutyl; and

R 10 is —H or C 1 -C 2 alkyl.

31. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:

n1 is 1;

w is o;

A 1 is H;

R 1 and R 4 are each —H;

R 2 and R 3 are independently selected from —H, —Cl, or —F, wherein only one of R 2 and R 3 is not —H;

R 7 and R 8 are each —H;

R 9 is —H or C 1 -C 3 alkyl; and

R 10 is —H or —CH 3 .

32. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

33. The compound

or a pharmaceutically acceptable salt thereof.

34. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, selected from:

or a mixture thereof.

35. A composition comprising the compound of claim 33 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

36. A method for treating a neurological or psychiatric disorder in a patient, comprising administering to said patient an effective amount of the compound according to claim 33 , or a pharmaceutically acceptable salt thereof, wherein said neurological or psychiatric disorder is selected from depression, anxiety, psychosis, or attention-deficit hyperactivity disorder.

37. The method according to claim 36 , wherein the neurological or psychiatric disorder is depression.

38. The method according to claim 37 , wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder.

39. The compound

or a pharmaceutically acceptable salt thereof.

40. A composition comprising the compound of claim 39 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

41. A method for treating a neurological or psychiatric disorder in a patient, comprising administering to said patient an effective amount of the compound according to claim 39 , or a pharmaceutically acceptable salt thereof, wherein said neurological or psychiatric disorder is selected from depression, anxiety, psychosis, or attention-deficit hyperactivity disorder.

42. The method according to claim 41 , wherein the neurological or psychiatric disorder is depression.

43. The method according to claim 42 , wherein the depression is treatment-resistant depression (TRD), major depressive disorder (MDD), unipolar depression, bipolar depression or depression associated with another disease or disorder.

44. The method according to claim 41 , wherein the neurological or psychiatric disorder is anxiety.

45. The method according to claim 41 , wherein the neurological or psychiatric disorder is psychosis.

46. The method according to claim 41 , wherein the neurological or psychiatric disorder is attention-deficit hyperactivity disorder.

47. A composition according to claim 18 , wherein said composition is a pharmaceutically acceptable composition.

48. A composition according to claim 23 , wherein said composition is a pharmaceutically acceptable composition.

49. A composition according to claim 35 , wherein said composition is a pharmaceutically acceptable composition.

50. A composition according to claim 40 , wherein said composition is a pharmaceutically acceptable composition.

51. A method of treating a patient in need of an analgesic or a cognitive enhancer, comprising administering to said patient an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

52. A method of treating a patient in need of an analgesic or a cognitive enhancer, comprising administering to said patient an effective amount of the compound according to claim 22 , or a pharmaceutically acceptable salt thereof.

53. A method of treating a patient in need of an analgesic or a cognitive enhancer, comprising administering to said patient an effective amount of the compound according to claim 33 , or a pharmaceutically acceptable salt thereof.

54. A method of treating a patient in need of an analgesic or a cognitive enhancer, comprising administering to said patient an effective amount of the compound according to claim 39 , or a pharmaceutically acceptable salt thereof.