Octahydropyrido[1,2-alpha]pyrazines as MAGL inhibitors
The invention provides new heterocyclic compounds having the general formula (Ie) wherein R 1 , R 1a and R 7 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.
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 hydrogen;
L is a covalent bond or —CH 2 O—; and
A is thiazolyl, pyrazolyl, or 2-oxa-6-azaspiro[3.3]heptan-6-yl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
11. The compound claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen and halogen.
12. The compound of claim 1 , wherein R 3 is selected from the group consisting of hydrogen and Cl.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of hydrogen and halogen.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of hydrogen, F and Cl.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of hydrogen, F, methoxy, and hydroxy.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 is hydrogen;
R 3 is selected from the group consisting of hydrogen and halogen;
R 4 is selected from the group consisting of hydrogen and halogen;
R 5 is hydrogen;
R 6 is hydrogen; and
R 7 is selected from the group consisting of hydrogen, F, methoxy, and hydroxy.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1a is selected from the group consisting of
(i) C 1-6 -alkyl;
(i) C 1-6 -alkoxy; and
(ii) aryl substituted with R 2 , R 3 , R 4 , R 5 and R 6 , or a possible 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 ;
R 2 , R 5 , and R 6 are hydrogen;
R 3 and R 4 are independently selected from the group consisting of hydrogen and halogen;
R 7 is selected from the group consisting of hydrogen, halogen, alkoxy, and hydroxy;
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.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1a is aryl substituted with R 2 , R 3 , R 4 , R 5 , and R 6 , or a possible 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 ;
R 2 , R 5 , and R 6 are hydrogen;
R 3 and R 4 are independently selected from the group consisting of hydrogen and halogen;
R 7 is selected from the group consisting of hydrogen, halogen, alkoxy, and hydroxy;
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.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1a is phenyl substituted with R 2 , R 3 , R 4 , R 5 , and R 6 , or a possible combination thereof;
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 2 , R 5 , and R 6 are hydrogen;
R 3 is selected from the group consisting of hydrogen and Cl;
R 4 is selected from the group consisting of hydrogen, F and Cl;
R 7 is selected from the group consisting of hydrogen, F, methoxy, and hydroxy;
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 hydrogen;
L is a covalent bond or —CH 2 O—; and
A is thiazolyl, pyrazolyl, or 2-oxa-6-azaspiro[3.3]heptan-6-yl.
22. The compound of claim 1 , selected from the group consisting of:
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-phenoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;hydrochloride;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[3-(3,5-difluorophenoxy)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-mrethoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-(trifluoromethoxy)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2,3-dihydro-1-benzofuran-7-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-indol-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-6-fluorophenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chlorophenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-fluoro-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-pyrrolo[2,3-b]pyridin-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(trifluoromethyl)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-4-fluoro-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-chloro-2-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-6-methylpyridin-3-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2,4-dimethyl-1,3-benzothiazol-5-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(7-chloro-2-methylsulfanyl-[1,3]thiazolo[5,4-b]pyridin-6-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-benzothiophen-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-(trifluoromethyl)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-phenoxyphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone;hydrochloride;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-5-fluoro-3-methylphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-bromo-3-(methoxymethyl)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-indol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-methylindol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-hydroxyphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-methylthieno[3,2-c]pyridin-7-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-methyl-2,3-dihydroindol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-propan-2-ylindol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-propan-2-yloxyphenyl)methanone;hydrochloride;
3-[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-2-chlorobenzonitrile;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-[(1-methylpyrazol-4-yl)methoxy]phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-propan-2-ylpyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7S,9aS)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-benzofuran-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-chloro-2-methoxypyridin-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(1,3-thiazol-4-ylmethoxy)phenyl]methanone;
4-[[3-[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-2-chlorophenoxy]methyl]-N-methylbenzamide;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrazolo[3,4-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-(3,4-dichlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7S,9aS)-7-(3,4-dichlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(6-methoxypyridin-2-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-imidazo[1,2-a]pyridin-5-ylmethanone;
tert-butyl 4-[[3-[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-2-chlorophenoxy]methyl]pyrazole-1-carboxylate;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(1H-pyrazol-4-ylmethoxy)phenyl]methanone;hydrochloride;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(pyridazin-3-ylmethoxy)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(pyridin-4-ylmethoxy)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(pyridin-3-ylmethoxy)phenyl]methanone;
3-[(E)-2-[4-[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]phenyl]vinyl]-2-bromo-N-methyl-benzamide;
3-[(E)-2-[4-[(7S,9aS)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]phenyl]vinyl]-2-bromo-N-methyl-benzamide;
3-[(E)-2-[4-[(7S,9aS)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-3-bromo-phenyl]vinyl]-N-methyl-benzamide;
3-[(E)-2-[4-[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-3-bromo-phenyl]vinyl]-N-methyl-benzamide;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-[(E)-2-cyclopropylethenyl]phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-5-methoxypyridin-3-yl)methanone;
(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone;
[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone;
(3-methyl-1H-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-methyl-1H-indazol-5-yl)methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-methyl-1H-indazol-5-yl)methanone;
(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(3-chloroimidazo[1,2-a]pyridin-6-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(4-chlorothieno[2,3-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chlorothieno[2,3-b]pyridin-5-yl)methanone;
[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chlorothieno[2,3-b]pyridin-5-yl)methanone;
(4-chloro-3-methyl-[1,2]oxazolo[5,4-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a] pyrazin-2-yl]methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-3-methyl-[1,2]oxazolo[5,4-b]pyridin-5-yl)methanone;
[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-3-methyl-[1,2]oxazolo[5,4-b]pyridin-5-yl)methanone;
(4-chloro-1H-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
[(7S,9aS)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(difluoromethoxy)phenyl]methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(difluoromethoxy)phenyl]methanone;
(4-chloro-3-methyl-1H-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(4-chloro-[1,2]thiazolo[5,4-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluoro phenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(6-amino-4-chloropyridin-3-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(4-chloro-3-methyl-1H-indazol-5-yl)-[rac-(7R,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
(4-chloro-3-methyl-1H-indazol-5-yl)-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(4-chloro-3-methyl-1H-indazol-5-yl)methanone;
[(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(4-chloro-3-methyl-1H-indazol-5-yl)methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[(7S,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-[rac-(7R,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chlorophenyl)-7-fluoro-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-fluoro-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chlorophenyl)-7-methoxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-methoxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-methyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-methyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(2-methylpropoxy)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone; and
(1,3-dimethylthieno[2,3-c]pyrazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 1 , selected from the group consisting of:
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-phenoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;hydrochloride;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[3-(3,5-difluorophenoxy)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-(trifluoromethoxy)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2,3-dihydro-1-benzofuran-7-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-indol-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-6-fluorophenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chlorophenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-fluoro-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-pyrrolo[2,3-b]pyridin-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(trifluoromethyl)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-4-fluoro-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-chloro-2-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-6-methylpyridin-3-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2,4-dimethyl-1,3-benzothiazol-5-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(7-chloro-2-methylsulfanyl-[1,3]thiazolo[5,4-b]pyridin-6-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-benzothiophen-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-(trifluoromethyl)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-phenoxyphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone;hydrochloride;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-5-fluoro-3-methylphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-bromo-3-(methoxymethyl)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-indol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-methylindol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-hydroxyphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-methylthieno[3,2-c]pyridin-7-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-methyl-2,3-dihydroindol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-propan-2-ylindol-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-propan-2-yloxyphenyl)methanone;hydrochloride;
3-[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-2-chlorobenzonitrile;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-[(1-methylpyrazol-4-yl)methoxy]phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-propan-2-ylpyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7S,9aS)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1-benzofuran-4-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-chloro-2-methoxypyridin-4-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrrolo[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(1,3-thiazol-4-ylmethoxy)phenyl]methanone;
4-[[3-[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-2-chlorophenoxy]methyl]-N-methylbenzamide;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrazolo[3,4-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-(3,4-dichlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7S,9aS)-7-(3,4-dichlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(6-methoxypyridin-2-yl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-imidazo[1,2-a]pyridin-5-ylmethanone;
tert-butyl 4-[[3-[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazine-2-carbonyl]-2-chlorophenoxy]methyl]pyrazole-1-carboxylate;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(1H-pyrazol-4-ylmethoxy)phenyl]methanone;hydrochloride;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(pyridazin-3-ylmethoxy)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(pyridin-4-ylmethoxy)phenyl]methanone;
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(pyridin-3-ylmethoxy)phenyl]methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone;
(3-methyl-1H-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(3-methyl-1H-indazol-5-yl)methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chlorothieno[2,3-b]pyridin-5-yl)methanone;
[(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(difluoromethoxy)phenyl]methanone;
(4-chloro-3-methyl-1H-indazol-5-yl)-[rac-(7R,9aR)-7-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methanone;
(4-chloro-3-methyl-1H-indazol-5-yl)-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(4-chloro-3-methyl-1H-indazol-5-yl)methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[(7S,9aR)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[2-chloro-3-(difluoromethoxy)phenyl]-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-hydroxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-fluoro-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone; and
(2-chloro-3-methoxyphenyl)-[rac-(7R,9aS)-7-(4-chlorophenyl)-7-methoxy-3,4,6,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl]methanone;
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 1 , selected from the group consisting of:
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methoxyphenyl)methanone;
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-indol-4-yl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(1H-pyrrolo[2,3-b]pyridin-4-yl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-4-fluoro-3-methylphenyl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2,4-dimethyl-1,3-benzothiazol-5-yl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(7-chloro-2-methylsulfanyl-[1,3]thiazolo[5,4-b]pyridin-6-yl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methylphenyl)methanone
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-chloro-3-methylphenyl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrrolo[2,3-b]pyridin-5-yl)methanone
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(1,3-thiazol-4-ylmethoxy)phenyl]methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(4-chloro-1-methylpyrazolo[3,4-b]pyridin-5-yl)methanone
[(7R,9aR)-7-(3,4-dichlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone
[(7S,9aS)-7-(3,4-dichlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-(2-bromo-3-methoxyphenyl)methanone
[(7R,9aR)-7-(4-chlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(2,2,2-trifluoroethoxy)phenyl]methanone; and
[(7R,9aR)-7-phenyl-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]-[2-chloro-3-(1H-pyrazol-4-ylmethoxy)phenyl]methanone;hydrochloride;
or a pharmaceutically acceptable salt thereof.
25. A process of manufacturing a compound of claim 1 , or a pharmaceutically acceptable salt thereof, comprising the steps of:
a) reacting an amine 13, wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as described in claim 1 ,
with an acid 14, wherein R 1 is as described in claim 1 ,
or
b) reacting an amine 13, wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as described in claim 1 ,
with an acid chloride 15, wherein R 1 is as described in claim 1 ,
to form said compound, or a pharmaceutically acceptable salt thereof.
26. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, when manufactured according to the process comprising the steps of:
b) reacting an amine 13, wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as described in claim 1 ,
with an acid 14, wherein R 1 is as described in claim 1 ,
or
b) reacting an amine 13, wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as described in claim 1 ,
with an acid chloride 15, wherein R 1 is as described in claim 1 ,
to form said compound, or a pharmaceutically acceptable salt thereof.
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound or pharmaceutically acceptable salt thereof has an IC 50 for monoacylglycerol lipase below 10 μM.
28. A pharmaceutical composition comprising:
(i) a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and
(ii) a therapeutically inert carrier.
29. A method for treating a disorder or condition in a mammal in need thereof, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal, wherein the disorder or condition is a neurodegenerative disease, wherein the neurodegenerative disease is multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, or epilepsy.
30. The method of claim 29 , wherein the mammal is a human.