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

Patent metadata

Field	Value
Publication number	US-9758529-B2
Application number	US-201615041827-A
Country	US
Kind code	B2
Filing date	Feb 11, 2016
Priority date	Feb 11, 2015
Publication date	Sep 12, 2017
Grant date	Sep 12, 2017

Abstract

Disclosed are compounds of Formula (I):

and pharmaceutically acceptable salts thereof, wherein Ring B, A 1 , A 2 , R 6 , w and n1 are defined and described herein; compositions thereof; and methods of use thereof. These compounds are useful for treating a variety of neurological and psychiatric disorders, such as those described herein.

First claim

What is claimed is:

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:

1

2

Assignees

• Sunovion Pharmaceuticals Inc
• Pgi Drug Discovery Llc

Inventors

• Chytil Milan
• Engel Sharon
• Hanania Taleen G
• Alexandrov Vadim
• Leahy Emer

Classifications

• A61P25/22

  Anxiolytics · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title