Azetidine and piperidine compounds useful as PDE10 inhibitors

Patent metadata

Field	Value
Publication number	US-9303028-B2
Application number	US-201414170146-A
Country	US
Kind code	B2
Filing date	Jan 31, 2014
Priority date	Jun 14, 2012
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

Azetidine and piperidine compounds of formula (I):

as defined in the specification, compositions containing them, and processes for preparing such compounds and intermediates thereof. Provided herein also are methods of treating cognitive disorders or diseases treatable by inhibition of PDE10, such as Huntington's Disease, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

First claim

What is claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is N or CR 4 ;
X 2 is N or CR 5 ;
wherein 0 to 1 of X 1 and X 2 are N;
each of p and q is independently; wherein the sum of p and q is 4; and
each R 1 , R 2 , R 3 , R 4 , and R 5 is independently hydrogen or halo.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is CH.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CH and X 2 is N.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CH and X 2 is CH.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is fluoro.

6. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is N or CR 4 ;
X 2 is N or CR 5 ;
wherein 0 to 1 of X 1 and X 2 are N;
each of p and q is independently 2; wherein the sum of p and q is 4; and
each R 1 , R 2 , R 3 , R 4 , and R 5 is independently hydrogen or halo;
wherein one of R 1 , R 2 , and R 3 is hydrogen.

7. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein two of R 1 , R 2 , and R 3 are hydrogens.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are hydrogen.

9. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is fluoro.

10. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is chloro.

11. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro or chloro.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen and R 2 is chloro or fluoro.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is chloro or fluoro and R 2 is hydrogen.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, which is:

Ex.
Structure

1

2

3

4

5

15. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. A method of treating a disorder that may be treated with PDE10 inhibitors comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said disorder is schizophrenia.

17. A method of treating a disorder that may be treated with PDE10 inhibitors according to claim 16 , and in combination with a suitable schizophrenia drug.

18. A method of preparing a compound Formula (I) according to claim 1 ; comprising the step of:
(a) reacting a compound of formula 3 with a compound of formula 5:

wherein X 1 , X 2 , R 1 , R 2 , R 3 , p and q are as defined in the compound of formula (I); and wherein LG 1 is a leaving group and M is a metal moiety; in the presence of a solvent and a catalyst;
or
(b) reacting a compound of formula 2 with a compound of formula 4:

wherein X 1 , X 2 , R 1 , R 2 , R 3 , p and q are as defined in the compound of formula (I), and LG 2 is a leaving group; in the presence of a solvent and a base;
to prepare the compound of formula (I).

Assignees

• Amgen Inc

Inventors

• Allen Jennifer R
• Chen Jian J
• Frohn Michael J
• Kaller Matthew R
• Liu Qingyian
• Nguyen Thomas T
• Pickrell Alexander J
• Qian Wenyuan
• Rzasa Robert M
• Zhong Wenge

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title