Fused dihydro-4h-pyrazolo[5,1-c][1,4]oxazinyl compounds and analogs for treating cns disorders

Patent metadata

Field	Value
Publication number	US-2016264597-A1
Application number	US-201615041827-A
Country	US
Kind code	A1
Filing date	Feb 11, 2016
Priority date	Feb 11, 2015
Publication date	Sep 15, 2016
Grant date	—

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 . (canceled)

3 . The compound of claim 1 , wherein A 1 is —H.

4 . (canceled)

5 . The compound of claim 1 , wherein w is 0.

6 . The compound of claim 1 , wherein n1 is 1.

7 . The compound of claim 1 , wherein n1 is 2.

8 . 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 .

9 - 11 . (canceled)

12 . The compound of claim 8 , wherein R 1 , R 2 , R 3 and R 4 are independently —H, —F or —Cl.

13 . 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′, 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 .

14 - 19 . (canceled)

20 . The compound of claim 13 , wherein Y 3 is N.

21 . 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 .

22 - 27 . (canceled)

28 . The compound of claim 21 , wherein Y 11 is S.

29 . The compound of claim 8 , of formula (II-1):

or a pharmaceutically acceptable salt thereof.

30 . The compound of claim 29 , of formula (II-1a):

or a pharmaceutically acceptable salt thereof.

31 - 37 . (canceled)

38 . The compound of claim 29 , wherein R 9 and R 10 , together with the nitrogen atom to which they are attached, form

39 . (canceled)

40 . The compound of claim 8 , of formula (III-1):

or a pharmaceutically acceptable salt thereof.

41 . The compound of claim 40 , of formula (III-1a):

or a pharmaceutically acceptable salt thereof.

42 - 46 . (canceled)

47 . The compound of claim 8 , of formula (IV-1):

or a pharmaceutically acceptable salt thereof.

48 - 50 . (canceled)

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

52 . 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 .

53 - 55 . (canceled)

Assignees

• Sunovion Pharmaceuticals Inc
• Pgi Drug Discovery Llc

Inventors

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

Classifications

• A61P29/00

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

• A61P25/22

  Anxiolytics · CPC title

• A61P25/04

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

• A61P25/30

  for treating abuse or dependence · 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