Octahydropyrido[1,2-alpha]pyrazines as MAGL inhibitors

Patent metadata

Field	Value
Publication number	US-11608347-B2
Application number	US-202016922427-A
Country	US
Kind code	B2
Filing date	Jul 7, 2020
Priority date	Jan 8, 2018
Publication date	Mar 21, 2023
Grant date	Mar 21, 2023

Abstract

The invention provides new heterocyclic compounds having the general formula (Ie)wherein R1, R1a and R7 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

First claim

The invention claimed is:

1. A compound of formula (Ie):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 a is selected from the group consisting of
(i) C 1-6 -alkyl;
(ii) C 1-6 -alkoxy; and
(iii) aryl substituted with R 2 , R 3 , R 4 , R 5 , and R 6 , or a combination thereof;

R 1 is selected from the group consisting of
(i) aryl substituted with R 8 , R 9 , and R 10 ; and
(ii) heteroaryl substituted with R 11 and R 12 ;

each of R 2 , R 3 , R 4 , R 5 , and R 6 is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkoxy, hydroxy, amino, —NH-alkyl, —N(alkyl) 2 , and cyano;
R 7 is selected from the group consisting of hydrogen, halogen, alkoxy, cycloalkyloxy, and hydroxy;
each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl, haloalkyl, alkylsulfanyl, amino, —NH-alkyl, —N(alkyl) 2 , —NH-aryl, —NH-heteroaryl, and a group

R 13 is selected from the group consisting of hydrogen, halogen, alkyl, oxo, carbamoyl, substituted carbamoyl, and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;
R 14 is hydrogen or halogen;
L is selected from the group consisting of a covalent bond, —CH═CH—, —O—, —CH 2 —, —OCH 2 —, —CH 2 — and —CH 2 CH 2 —; and
A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl;
wherein the compound of formula (Ie) is not (4-fluorophenyl)-[7-(4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone.

2. The compound of claim 1 , wherein said compound is a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of:
(i) aryl substituted with R 8 , R 9 , and R 10 ; and
(ii) heteroaryl substituted with R 11 and R 12 ,

each of R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkoxy, hydroxy, amino, —NH-alkyl, —N(alkyl) 2 , and cyano;
R 7 is selected from the group consisting of hydrogen, halogen, alkoxy, cycloalkyloxy, and hydroxy;
each of R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from the group consisting of hydrogen, hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl, haloalkyl, alkylsulfanyl, amino, —NH-alkyl, —N(alkyl) 2 , —NH-aryl, —NH-heteroaryl, and a group

R 13 is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl, and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;
R 14 is hydrogen or halogen;
L is selected from the group consisting of a covalent bond, —CH═CH—, —O—, —CH 2 O—, —OCH 2 —, —CH 2 —, and —CH 2 CH 2 —; and
A is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl.

3. The compound of claim 1 , wherein said compound is a compound of formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1 .

4. The compound of claim 1 , wherein said compound is a compound of formula (Ib)

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1 .

5. The compound of claim 1 , wherein said compound is a compound of formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1 .

6. The compound of claim 1 , wherein said compound is a compound of formula (Id):

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in claim 1 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of
(i) aryl substituted with R 8 , R 9 and R 10 ; and
(ii) heteroaryl substituted with R 11 and R 12 ;

R 8 is selected from the group consisting of hydroxy, alkoxy, cyano, alkoxyalkyl, haloalkoxy, halogen, alkyl, haloalkyl, and a group

R 9 is hydrogen or halogen;
R 10 is hydrogen or halogen;
R 11 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, and alkylsulfanyl;
R 12 is selected from the group consisting of hydrogen, halogen, and alkyl;
R 13 is selected from the group consisting of hydrogen, halogen, alkyl, carbamoyl, substituted carbamoyl, and alkoxycarbonyl, wherein said substituted carbamoyl is substituted at the nitrogen atom with one to two alkyl substituents;
R 14 is hydrogen or halogen;
L is selected from the group consisting of a covalent bond, —CH═CH—, —O—, and —CH 2 O—; and
A is selected from the group consisting of aryl, heteroaryl, cycloalkyl and heterocyclyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of
(i) aryl substituted with R 8 , R 9 and R 10 ; and

(ii) heteroaryl substituted with R 11 and R 12 ;
R 8 is selected from the group consisting of alkoxy, haloalkoxy, alkyl and a group

R 9 is halogen;
R 10 is hydrogen or halogen;
R 11 is selected from the group consisting of hydrogen, alkyl and alkylsulfanyl;
R 12 is selected from the group consisting of hydrogen, halogen and alkyl;
R 13 is hydrogen;
R 14 is hydrogen;
L is a covalent bond or —CH 2 O—; and
A is heteroaryl or heterocyclyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of:
(i) phenyl substituted with R 8 , R 9 , and R 10 ; and
(ii) heteroaryl substituted with R 11 and R 12 , wherein said heteroaryl is selected from the group consisting of indolyl, pyrrolo[2,3-b]pyridyl, 1,3-benzothiazolyl, thiazolo[5,4-b]pyridyl, 1H-indazol-5-yl, thieno[2,3-b]pyridin-5-yl, and pyrazolo[3,4-b]pyridyl;

R 8 is selected from the group consisting of methoxy, 2,2,2-trifluoroethoxy, methyl, and a group

R 9 is Cl or Br;
R 10 is hydrogen or F;
R 11 is selected from the group consisting of hydrogen, methyl, and methylsulfanyl;
R 12 is selected from the group consisting of hydrogen, Cl, and methyl;
R 13 is hydrogen;
R 14 is h

Assignees

• Hoffmann La Roche

Inventors

• Petersen Ann
• Benz Joerg
• Grether Uwe
• Hornsperger Benoit
• Kocer Buelent
• Kuhn Bernd
• Richter Hans
• Tsuchiya Satoshi
• Qiu Yangcheng
• Chen Rui

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title