D2 receptor modulators and methods of use thereof in the treatment of diseases and disorders

Patent metadata

Field	Value
Publication number	US-9951088-B2
Application number	US-201314399334-A
Country	US
Kind code	B2
Filing date	May 9, 2013
Priority date	May 9, 2012
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

Provided herein are heteroaryl compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. In one embodiment, the compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and neurological disorders, including, but not limited to, e.g., psychosis, schizophrenia, depression, movement disorders, and Parkinson's disease.

First claim

What is claimed:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
n is 2, 3, or 4;
W is O, NR 5 , or CH2;
X is N
Y is N or CH;
each R 10 and each R 11 are independently H, F, OH, or (C 1 -C 4 )alkyl;
(i) R 1 is amido, sulfonamido, optionally substituted imidazolyl, or optionally substituted pyrazolyl; and R 2 is H, halogen, CN, (C 1 -C 4 )alkyl, or (C 1 -C 3 )alkoxyl; or (ii) R 1 and R 2 together with the carbon atoms to which they are attached form a 5-, 6-, or 7-membered aryl, heteroaryl, cycloalkyl, or heterocyclyl ring, each of which is optionally substituted with one to three R 6 ,wherein the only ring heteroatoms in said heteroaryl or heterocyclyl ring is one or more nitrogen atoms;
R 3 and R 4 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl Q;
Q is

R 5 is H or (C 1 -C 3 )alkyl;
each R 6 is independently OH, keto, halogen, CN or (C 3 -C 3 )alkoxyl;
R 7 is 5- to 10-membered aryl or heteroaryl, each optionally substituted with one to three substituents selected from the group consisting of halogen, alkoxy, —CF 3 and —CN; and
Ring Ar is a benzo, pyrazolo, pyrido, thieno, pyrimido, pyrazino, furarano, pyridazino, thiazolo, or imidazolo ring, each optionally substituted with one to three substituents.

2. The compound of claim 1 , wherein n is 4.

3. The compound of claim 1 , wherein W is O.

4. The compound of claim 1 , wherein each of R 10 and R 11 is H.

5. The compound of claim 1 , wherein R 1 is

wherein R 8 is (C 1 -C 5 )alkyl or optionally substituted phenyl.

6. The compound of claim 1 , wherein

7. The compound of claim 5 , wherein R 1 is

8. The compound of claim 1 , wherein Ring Ar is a benzo, pyrazolo, thieno, pyrimido, pyrazino, thiazolo, imidazolo, furans, gar pyridazino ring, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylamino, dialkylamino. (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro, optionally substituted phenyl, and optionally substituted pyridyl.

9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient, diluent, or carrier.

10. The compound of claim 1 , wherein:
W is O;
n is 4; and
each of R 10 and R 11 is H.

11. The compound of claim 10 , wherein Q is

and
Ring Ar is a benzo, mazolo, pyrido, thieno, pyrimido, pyrazino, furano, pyridazino, thiazolo, or imidazolo ring, each of which is optionally substituted with one to three substituents, independently selected from halo, cyano, alkylanxino, dialkylamino, (C 1 - 3 )alkyl optionally substituted with one or more fluoro, (C 1 -C 3 )alkoxyl optionally substituted with one or more fluoro, optionally substituted phenyl, and optionally substituted pyridyl.

12. A compound, selected from:

and pharmaceutically accept le salts thereof.

13. A compound of formula (II-b):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
n is 2, 3, or 4;
W is O, NR 5 , or CH 2;

 is

X is N or CH;
Y is N or CH;
each R 10 and each R 11 are independently H, F, OH, or (C 1 -C 4 )alkyl;
R 5 is H (C 1 -C 3 )alkyl; and
Ring Ar is a benzo, pyrazolo, pyrido, thieno, pyrimido, pyrazino, furano, pyridazmo, thiazolo, or imidazolo ring, each optionally substituted with one to three substituents;
provided that:
when Ar is an optionally substituted benzo ring, then

 is not

14. The compound of claim 13 , wherein X is CH.

15. The compound of claim 14 which is selected from;

and pharmaceutically acceptable salts thereof.

16. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein
n is 2. 3, or 4;
W is O, NR 5 , or CH 2 ;

X is N or CH;
Y is N or CH;
each R 10 and each R 11 are independently H, F, OH, or (C 1 -C 4 )alkyl;
R 3 and R 4 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl Q;
Q is

R 5 is H or (C 1 -C 3 )alkyl;
each R 6 is independently OH, keto, halogen, CN, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxyl;
R 7 is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or naphthyl, each of which is optionally substituted with one substituent selected from halo, cyano, alkylamino, dialkylamino, (C 1 -C 3 )alkyl optionally substituted with one or more fluoro, and (C 1 -C 3 )alkoxyl substituted with one or more fluoro; and
Ring Ar is a benzo, pyrazole, pyrido, thieno, pyrirnido, pyrazino, furano, pyridazino, thiazolo, or imidazolo ring, each optionally substituted with one to three substituents;
provided that:
when Ar is an optionally substituted benzo ring then,

 is not

Assignees

• Sunovion Pharmaceuticals Inc

Inventors

• Jones Philip G
• Lew Robert
• Spear Kerry L
• Xie Linghong

Classifications

• 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

• A61P25/24

  Antidepressants · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title