Piperazine azaspiro derivatives

Patent metadata

Field	Value
Publication number	US-11524954-B2
Application number	US-201917040479-A
Country	US
Kind code	B2
Filing date	Mar 25, 2019
Priority date	Mar 23, 2018
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

Abstract

The present invention provides, in part, compounds of Formula I: or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein: X1, X2, R1, R2, m and n are as described herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, N-oxides, or salts, and their uses for treating M4-mediated (or M4-associated) disorders including, e.g., Alzheimer's Disease, Parkinson's Disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and a sleep disorder.

First claim

What is claimed is:

1. A compound of Formula I:

or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein:
X 1 and X 2 are each independently CH or nitrogen, provided that X 1 and X 2 cannot both be CH;
R 1 is selected from the group consisting of halogen, cyano, hydroxy, —SF S , nitro, —N(R 6 )(R 7 ), (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, —O-(4- to 6-membered)heterocycloalkyl, (C 6 -C 10 )aryl, (5- to 10-membered)heteroaryl and (4- to 8-membered)heterocycloalkyl, wherein said (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, —O-(4- to 6-membered)heterocycloalkyl, (C 6 -C 10 )aryl, (5- to 10-membered)heteroaryl and (4- to 8-membered)heterocycloalkyl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, —N(R 6 )(R 7 ), (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (5- to 6-membered)heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy;
R 2 is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, —SF 5 , nitro, —N(R 6 )(R 7 ), (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with 1 to 3 halogen;
R 6 and R 7 are each independently selected from hydrogen, (C 1 -C 6 )alkyl or C(O)—CH 3 ;
m is 1 or 2; and
n is 1 or 2.

2. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein X 1 is nitrogen and X 2 is CH.

3. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein X 1 is nitrogen and X 2 is nitrogen.

4. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein X 1 is CH and X 2 is nitrogen.

5. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein R 1 is selected from the group consisting of halogen, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (C 3 -C 6 )cycloalkyl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (5- to 6-membered)heteroaryl are each optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy.

6. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein R 1 is a (5- to 10-membered)heteroaryl selected from the group consisting of pyrazolyl, pyrimidinyl, pyridazinyl, thiazolyl, pyrazinyl, oxazolyl, thiadiazolyl, pyridinyl, imidazopyridinyl, triazolopyridinyl, and oxadiazolyl, wherein said (5- to 10-membered)heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, -(CH 2 ) 2 —O-CH 2 CH 3 , and (5- to 6-membered)heteroaryl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and said (5- to 6-membered)heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy.

7. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein R 1 is a (4- to 8-membered)heterocycloalkyl selected from the group consisting of oxetanyl, morpholino, 2-oxa-6-azaspiro[3.3]hept-6-yl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperidinyl, wherein said heterocycloalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and said (5- to 6-membered)heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy.

8. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein R 2 is hydrogen.

9. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein m is 2 and n is 1.

10. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein m is 1 and n is 2.

11. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein m is 1 and n is 1.

12. The compound according to claim 1 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein the compound is of Formula I A :

wherein:
X 1 and X 2 are each independently CH or nitrogen, provided that X 1 and X 2 cannot both be CH;
R 1 is selected from the group consisting of halogen, cyano, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, —O-(4- to 6-membered)heterocycloalkyl, (C 6 -C 10 )aryl, (5- to 10-membered)heteroaryl and (4- to 8-membered)heterocycloalkyl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, —O-(4- to 6-membered)heterocycloalkyl, (C 6 -C 10 )aryl, (5- to 10-membered)heteroaryl and (4- to 8-membered)heterocycloalkyl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl, and (5- to 6-membered)heteroaryl, wherein said (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and (5- to 6-membered)heteroaryl are optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxy, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy; and
R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl, and (C 1 -C 6 )alkoxy, wherein said (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy are optionally substituted with 1 to 3 halogen.

13. The compound according to claim 12 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein X 1 is nitrogen and X 2 is CH.

14. The compound according to claim 12 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein X 1 is nitrogen and X 2 is nitrogen.

15. The compound according to claim 12 , or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein X 1 is CH and X 2 is nitrogen.

16. The compound according to claim 12 , or an N-

Assignees

• Pfizer

Inventors

• Zhang Lei
• Lachapelle Erik Alphie
• Butler Christopher Ryan
• Kablaoui Natasha Mariam
• Brodney Michael Aaron
• Mcallister Laura Ann
• Yang Qingyi
• Helal Christopher John
• Webb Damien

Classifications

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title