IP Library › Granted Patent US 12,662,490
Granted Patent B2
US 12,662,490 · App. 17/569,749 · Granted Jun 23, 2026

Heterocyclic compounds

Inventors: Carsten Kroll (Basel, CH); Flore Reggiani (Ranspach le Haut, FR); Miroslav Kosar (Urdorf, CH); Maurice Biedermann (Zurich, CH); Bernd Kuhn (Reinach, CH); Benoit Hornsperger (Altkirch, FR); Uwe Grether (Efringen-Kirchen, DE); Fionn O'Hara (Basel, CH); Hans Richter (Grenzach-Wyhlen, DE)
Assignee: Hoffmann-La Roche Inc.
C07D498/04C07D513/04C07D519/00
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Quick Facts
Patent No.
US 12,662,490
App. No.
17/569,749
Filed
Jan 6, 2022
Granted
Jun 23, 2026
Kind
B2
Art Unit
1623
USPC
514/234.2
Abstract

The invention provides new heterocyclic compounds having the general formula (I) wherein R 1 , R 2 , X, and Y are as defined herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

Claims (247)

1 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is —CH 2 CR 3 R 4 — or —CH═CR 3 —;

Y is —O— or —S;

R 1 is

(a) 5- to 10-membered heteroaryl substituted with 1 substituent selected from halogen; or

(b) a group

R 2 is hydrogen or C 1 -C 6 -alkyl;

R 3 is a group

R 4 is hydrogen, halogen or hydroxy;

R 5 is hydrogen, halogen, hydroxy, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, cyano or oxo;

R 6 is hydrogen, halogen, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, halo-C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, oxo, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 14 -cycloalkyl or cyano; wherein said 5- to 10-membered heteroaryl or C 6 -C 10 -aryl is optionally substituted with 1-2 substituents selected from halogen, cyano, -amino, hydroxy, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy;

R 7 is hydrogen or C 1 -C 6 -alkoxy;

R 8 is hydrogen or C 1 -C 6 -alkoxy;

R 9 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy or a group

R 10 is hydrogen, halogen, or cyano;

A and B are each independently 5- to 10-membered heteroaryl, C 6 -C 10 -aryl or 3- to 14-membered heterocyclyl; and

n and p are each independently 1, 2, 3, 4 or 5.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 CR 3 R 4 —.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is —O—.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted with 2-3 substituents independently selected from chloro, fluoro, methoxy, and a group

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or hydroxy.

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, halogen, cyano, hydroxy or oxo.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, fluoro, cyano, hydroxy or oxo.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, halogen, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, halo-C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, oxo, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 14 -cycloalkyl or cyano, wherein said 5- to 10-membered heteroaryl or C 6 -C 10 -aryl is optionally substituted with a substituent selected from halogen, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy.

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen, oxo, halo-C 1 -C 6 -alkyl or halo-C 1 -C 6 -alkoxy.

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is chloro, fluoro, oxo, trifluoromethyl or difluoromethoxy.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1, 2 or 3.

14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is 5- to 10-membered heteroaryl, phenyl or 3- to 14-membered heterocyclyl.

16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is 5- to 10-membered heteroaryl or 3- to 14-membered heterocyclyl.

17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is imidazolyl, pyrazolyl, pyrrolyl, or 1,2-dihydropyridinyl.

18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is phenyl, 5- to 10-membered heteroaryl or 3- to 14-membered heterocyclyl.

19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is phenyl, 1,2-dihydropyridinyl or pyridyl.

20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is —CH 2 CR 3 R 4 —;

Y is —O—;

R 1 is phenyl substituted with 2-3 substituents independently selected from chloro, fluoro, methoxy, and a group

R 2 is hydrogen;

R 4 is hydrogen or hydroxy;

R 5 is hydrogen, halogen, hydroxy, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkyl, cyano or oxo;

R 6 is hydrogen, halogen, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, halo-C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, oxo, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 14 -cycloalkyl or cyano, wherein said 5- to 10-membered heteroaryl or C 6 -C 10 -aryl is optionally substituted with a substituent selected from halogen, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy;

n is 1 or 2;

p is 1, 2 or 3;

A is 5- to 10-membered heteroaryl or 3- to 14-membered heterocyclyl; and

B is phenyl, 5- to 10-membered heteroaryl or 3- to 14-membered heterocyclyl.

21 . A compound selected from the group consisting of:

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

(2-bromo-3-methoxy-phenyl)-[rac-(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(4-chlorothieno[2,3-b]pyridin-5-yl)-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(3-bromo-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-fluoro-3-methoxy-phenyl)methanone;

(2-chloro-3-methoxy-phenyl)-[(3R,9aS)-3-[4-fluoro-3-[rac-(E)-prop-1-enyl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(4-fluoro-3-phenyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3S,9aS)-3-(4-fluoro-3-phenyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(4-fluoro-3-prop-1-ynyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3,9aS)-3-(3-cyano-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-3-quinolyl)methanone;

[(3S,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,5-dimethoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,5-dimethoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,4-dimethoxy-phenyl)methanone;

2-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-6-methyl-benzonitrile;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-(trifluoromethoxy)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-phenyl-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-methoxyphenyl)phenyl]methanone;

[(3R,9aS)-3-(3-cyclopropyl-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(difluoromethoxy)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(5-methyl-1H-pyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(4-methyl-3-pyridyl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methyl-4-pyridyl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-pyridazin-4-yl-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-pyridyl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-pyridazin-3-yl-phenyl)methanone;

(2-chloro-3-methoxy-phenyl)-[(rel-3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-9a-methyl-1,3,4,6,7,9-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[(rel-3S,9aR)-3-(3-chloro-4-fluoro-phenyl)-9a-methyl-1,3,4,6,7,9-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(4-methylpyridazin-3-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(5-methylpyrimidin-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-imidazol-5-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methyl-2-pyridyl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1,5-dimethylpyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methylisoxazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-3-methyl-1H-indazol-5-yl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-morpholino-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-triazol-5-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3S,9aR)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[3-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

(2-chloro-3-methoxy-phenyl)-[3-[4-(difluoromethyl)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3S,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

(2-chloro-3-methoxy-phenyl)-[rel-(3S,9aS)-3-(2,4-dimethylthiazol-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rel-(3R,9aR)-3-(2,4-dimethylthiazol-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rac-(3R,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rac-(3S,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rac-(3S,9aS)-3-(5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rac-(3R,9aS)-3-(5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rel-(3S,9aS)-3-(1H-benzimidazol-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rel-(3R,9aR)-3-(1H-benzimidazol-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rel-(3S,9aS)-3-[6-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)pyridin-3-yl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

(2-chloro-3-methoxy-phenyl)-[rel-(3R,9aR)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[rel-(3S,9aS)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(9aS)-3-[6-(trifluoromethyl)-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[(3R,9aS)-3-[4-(difluoromethoxy)phenyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[(9aS)-3-(6-bromo-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3S,9aS)-3-hydroxy-3-(1-methylbenzimidazol-2-yl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

5-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-2-fluoro-benzonitrile;

(2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl)((9aS)-3-(4-(difluoromethoxy)phenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone;

3-[(3 S,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one;

3-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-oxazol-5-yl-phenyl)methanone;

3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one;

[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

4-[3-[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrazole-3-carbonitrile;

[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazol-4-yl)phenyl]methanone;

(2-chloro-3-methoxyphenyl)((3S,9aS)-3-(5-chloro-4-methylpyridin-2-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone;

(2-chloro-3-methoxyphenyl)((3R,9aS)-3-(5-chloro-4-methylpyridin-2-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone;

[(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-oxazol-4-yl-phenyl)methanone;

[3-(1,3-benzothiazol-2-yl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[(3 S,9aS)-3-fluoro-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[6-(trifluoromethyl)pyridazin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3S,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(9aS)-3-[5-(trifluoromethyl)-2-pyridyl]-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3S,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3S,9aS)-3-[6-(trifluoromethyl)pyridazin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

(2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[5-chloro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

(2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[4-(trifluoromethoxy)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridin-2-one;

(2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[5-fluoro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-[5-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[3-[5-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]methanone;

(2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[4-(difluoromethyl)-5-fluoro-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyridin-2-one;

5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyridin-2-one;

(2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[5-chloro-4-bromo-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-hydroxyazetidin-1-yl)phenyl]methanone;

4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrrole-2-carbonitrile;

[(3R,9aS)-3-(4-bromo-3-chloro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-6-fluoro-3-methoxy-phenyl)methanone;

4-[3-[(3R,9aS)-3-[2-oxo-6-(trifluoromethyl)-1H-pyridin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile;

4-[3-[(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrrole-2-carbonitrile;

4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyridin-2-one;

4-[3-[(3R,9aS)-3-(5-chloro-2-oxo-1H-pyridin-3-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-6-fluoro-3-methoxy-phenyl)methanone;

4-[3-[(3R,9aS)-3-(5-chloro-2-oxo-1H-pyridin-3-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrrole-2-carbonitrile;

5-[3-[(3R,9aS)-3-(3,4-dichlorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-oxazol-2-one;

[(3R,9aS)-3-hydroxy-3-[4-(trifluoromethyl)phenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(4-chloro-3-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-oxazol-2-one;

5-[3-[(3R,9aS)-3-(3,4-dichlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-oxazol-2-one;

4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-6-methyl-1H-pyridin-2-one;

5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-6-methyl-1H-pyridin-2-one;

[(3R,9aS)-3-(3-bromo-5-chloro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]piperazin-2-one;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-isothiazol-4-yl-phenyl)methanone;

[(3R,9aS)-3-(2,4,5-trifluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(2,4-dichlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-hydroxy-3-(2,3,4-trifluorophenyl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3S,9aS)-3-(4-bromo-5-methoxy-2-thienyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

4-[3-[(3R,9aS)-3-[4-oxo-6-(trifluoromethyl)-1H-pyridin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile;

3-[(3R,9aS)-8-[2-chloro-5-fluoro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one;

5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-1,3,4-oxadiazol-2-one;

5-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-3-chloro-2-fluoro-benzonitrile;

3-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridin-2-one;

[(3R,9aS)-3-(3-chloro-4-oxazol-5-yl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

3-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrazole-5-carbonitrile;

[(3S,9aS)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

3-[(3R,9aS)-8-[2-chloro-3-(4-fluoro-1H-pyrazol-3-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one;

[(3R,9aS)-3-hydroxy-3-[3-(trifluoromethyl)phenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(2,3-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3S,9aS)-3-hydroxy-3-(3-phenylisoxazol-5-yl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-hydroxy-3-(2,4,5-trifluorophenyl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(9aS)-3-(4-fluoro-3-oxazol-5-yl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3S,9aS)-3-(1,3-benzothiazol-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

3-[(3R,9aS)-8-(2-chloro-6-fluoro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one;

[(3S,9aS)-3-[5-chloro-6-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(2,3-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(2-chlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

4-[3-[(3S,9aS)-3-[4-oxo-6-(trifluoromethyl)-1H-pyridin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile;

5-[3-[(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-imidazole-2-carbonitrile;

[(3R,9aS)-3-hydroxy-3-[2-methyl-6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-5-oxazol-5-yl-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

3-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridin-2-one;

[(9aS)-3-[4-fluoro-3-(1-methylpyrrol-3-yl)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3S,9aS)-3-(3-bromoisoxazol-5-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyridazin-4-one;

[(3S,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-6-fluoro-3-methoxy-phenyl)methanone;

[(3S,9aS)-3-hydroxy-3-[2-(6-methoxy-3-pyridyl)thiazol-4-yl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; and

[(9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

or a pharmaceutically acceptable salt thereof.

22 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

23 . A pharmaceutical composition comprising a compound of claim 21 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

24 . A process of manufacturing a compound of claim 1 , comprising:

(a) reacting a diol 5, wherein R 1 and R 3 are as defined in claim 1 ,

with an etherification reagent to yield the compound of claim 1 , wherein X is —CH 2 CHR 3 —, Y is —O—, R 1 and R 3 are as defined in claim 1 , and R 2 is hydrogen; or

(b) reacting an amine 8a, wherein Y, R 2 and R 3 are as defined in claim 1 ,

with a carboxylic acid 1, wherein R 1 is as defined in claim 1 ,

in the presence of a base and a coupling reagent to yield said compound of claim 1 , wherein X is —CH 2 CHR 3 —, Y, R 1 and R 3 are as defined in claim 1 , and R 2 is hydrogen; or

(c) submitting a compound of formula (I), wherein Y is as defined in claim 1 , X is —CH 2 CR 3 R 4 —, R 1 to R 3 are as defined in claim 1 , and R 4 is hydroxy, to dehydrating conditions to yield: a compound of formula (I) wherein Y is as defined in claim 1 , X is —CH 2 CR 3 — and R 1 to R 3 are as defined in claim 1 , or to yield a compound of formula (I) wherein Y is as defined in claim 1 , X is —CH═CR 3 — and R 1 to R 3 are as defined in claim 1 ; or

(d) reacting a compound of claim 1 wherein Y is as defined in claim 1 , X is —CH 2 CR 3 R 4 —, R 1 to R 3 are as defined in claim 1 , and R 4 is hydroxy, with a nucleophilic fluorinating agent to yield a compound of claim 1 wherein X is —CH 2 CFR 3 — and R 1 to R 3 are as defined in claim 1 ; or

(e) submitting a compound of formula (I),

wherein R 1 , R 2 , R 4 , and B are as defined in claim 1 , and R 6 is bromo, to a transition metal catalyzed cross-coupling reaction to afford compound of formula (I)

wherein R 1 , R 2 , R 4 , and B are as defined in claim 1 , and R 6 is selected from aryl, alkenyl, alkynyl, alkyl, cyano, cycloalkyl, and heteroaryl; or

(f) submitting a compound 12, wherein R 1 is aryl or heteroaryl optionally substituted with 1-4 substituents independently selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, and cyano; and R 2 to R 4 are as defined in claim 1 ,

to a Suzuki-Miyaura cross coupling reaction with a compound 13, wherein A, R 5 , and n are as defined in claim 1

in the presence of a transition metal catalyst and an organic or inorganic base; to afford said compound of formula (I), wherein R 1 is aryl or heteroaryl optionally substituted with 1-4 substituents independently selected from C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, and cyano; and R 2 to R 5 and n are as defined in claim 1

 or

(g) reacting a compound of formula (I), wherein Y is sulfur and R 1 , R 2 , and R 3 are as defined in claim 1 ,

with an oxidizing agent, to afford a compound of formula (I), wherein Y is a sulfoxide or a sulfone and R 1 , R 2 , and R 3 are as defined in claim 1 :

25 . A method, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a mammal, wherein the method is for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy induced neuropathy, acute pain, chronic pain, or spasticity associated with pain in the mammal.

26 . The compound of claim 1 , wherein the compound is:

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(5-methyl-1H-pyrazol-4-yl)phenyl]methanone;

or is a pharmaceutically acceptable salt thereof.

27 . The compound of claim 1 , selected from the group consisting of:

4-(2-chloro-3-((3R,9aS)-3-(5-chloro-2-oxo-1,2-dihydropyridin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile;

4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile;

4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)-5-fluorophenyl)pyridin-2(1H)-one;

4-(2-chloro-3-((3R,9aS)-3-(5-chloro-2-oxo-1,2-dihydropyridin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)-5-fluorophenyl)-1H-pyrrole-2-carbonitrile;

4-(2-chloro-5-fluoro-3-((3R,9aS)-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridin-3-yl)octahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile;

((3R,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-6-fluoro-3-methoxyphenyl)methanone;

[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[rac-(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-imidazol-5-yl)phenyl]methanone;

[(3R,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3S,9aS)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyridin-2-one;

[(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-hydroxyazetidin-1-yl)phenyl]methanone;

[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone;

[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[rac-(9aS)-3-[6-(trifluoromethyl)-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone;

[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; and

[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[rac-(9aS)-3-[4-(difluoromethoxy)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone,

or is a pharmaceutically acceptable salt thereof.

28 . A pharmaceutical composition comprising a compound of claim 27 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 10, 2023
From: KROLL, CARSTEN; REGGIANI, FLORE; KOSAR, MIROSLAV; BIEDERMANN, MAURICE; KUHN, BERND; HORNSPERGER, BENOIT; GRETHER, UWE; O`HARA, FIONN; RICHTER, HANS
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 062322/0480 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 10, 2023
From: F. HOFFMANN-LA ROCHE AG
To: HOFFMANN-LA ROCHE INC.
Reel/Frame 062322/0767 →
Priority Claims (1)
EP 19185088 · Jul 9, 2019 · regional
Continuity (2)
Continuation PCTEP2020069074 · Jul 7, 2020
Related Publication 20220242876A1 · Aug 4, 2022
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