Heterocyclic compounds as monoacylglycerol lipase inhibitors

Abstract

wherein A, L, X, m, n, R1 and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

1 - 56 . (canceled) 
     
     
         57 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         (i) X is C—R 3 ; m is 0 or 1; n is selected from 0, 1 and 2; and L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —CH 2 OCH 2 —, —CF 2 CH 2 —, —CH 2 ═CH 2 —, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 CF 2 —; or 
         (ii) X is N; m is 1; n is 1 or 2; and L is —(CH 2 ) p — or —CF 2 CH 2 —; 
         p is selected from 1, 2, and 3; 
         q is 0 or 1; 
         A is selected from:
 (i) C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; 
 (ii) 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; and 
 (iii) 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; 
 
         R 1  is hydrogen or C 1-6 -alkyl; 
         R 2  is selected from hydrogen, C 1-6 -alkyl, and hydroxy-C 1-6 -alkyl; 
         R 3  is selected from hydrogen, halogen, hydroxy, C 1-6 -alkoxy, C 1-6 -alkyl, and halo-C 1-6 -alkyl; 
         each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  is independently selected from hydrogen, halogen, cyano, hydroxy, C 1-6-alkyl , halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -alkanoyl, halo-C 1-5 -alkyl-CH(OH)—, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, SF 5 , CH 3 SO 2 , C 3-10 -cycloalkyl, C 3-10 -cycloalkyl substituted with R 13 , 3- to 14-membered heterocycloalkyl, 3- to 14-membered heterocycloalkyl substituted with R 14  and R 15 , 5- to 14-membered heteroaryl, C 6 -C 14 -aryl, C 6 -C 14 -aryloxy, halo-C 6 -C 14 -aryl, and halo-C 6 -C 14 -aryloxy; 
         each of R 13 , R 14 , and R 15  is independently selected from C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkoxy, halogen, and hydroxy; and 
         R 16  and R 17 , taken together with the carbon atom to which they are attached, form a C 3-10 -cycloalkyl. 
       
     
     
         58 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
         wherein A, L, X, m, n, R 1 , and R 2  are as defined in  claim 57 . 
       
     
     
         59 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib): 
       
         
           
           
               
               
           
         
         wherein A, L, X, m, n, R 1 , and R 2  are as defined in  claim 57 . 
       
     
     
         60 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein:
 (i) X is C—R 3 ; m is 0 or 1; n is selected from 0, 1, and 2; and L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —CF 2 CH 2 —, —CH 2 ═CH 2 —, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 OCH 2 —; or   (ii) X is N; m and n are both 1; and L is —(CH 2 ) p —.   
     
     
         61 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein:
 X is C—R 3 ;   m and n are both 0; or   m and n are both 1; and   L is selected from —(CH 2 ) p —, —O—, —OCH 2 — and —CH 2 O—.   
     
     
         62 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2. 
     
     
         63 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein p is 2. 
     
     
         64 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1. 
     
     
         65 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein q is 0. 
     
     
         66 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein A is selected from:
 (i) C 6 -C 14 -aryl substituted with R 4 , R 5  and R 6 ; and   (ii) 5- to 14-membered heteroaryl substituted with R 7 , R 8  and R 9 .   
     
     
         67 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein A is selected from:
 (i) phenyl substituted with R 4 , R 5 , and R 6 ;   (ii) oxazolyl substituted with R 7 , R 8 , and R 9 ; and   (iii) pyridyl substituted with R 7 , R 8 , and R 9 .   
     
     
         68 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen. 
     
     
         69 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen or C 1-6 -alkyl. 
     
     
         70 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen or methyl. 
     
     
         71 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from hydrogen, halogen, C 1-6 -alkyl, and halo-C 1-6 -alkyl. 
     
     
         72 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from hydrogen, halogen, and C 1-6 -alkyl. 
     
     
         73 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from hydrogen, fluoro, and methyl. 
     
     
         74 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 4  is selected from hydrogen, halogen, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkanoyl, SF 5 , C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, 3- to 14-membered heterocyclyl, 3- to 14-membered heterocycloalkyl substituted with R 14  and R 15 , 5- to 14-membered heteroaryl, C 6 -C 14 -aryloxy, and halo-C 6 -C 14 -aryl. 
     
     
         75 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 4  is selected from halogen, SF 5 , C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, and 3- to 14-membered heterocycloalkyl. 
     
     
         76 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 4  is selected from chloro, SF 5 , methyl, methoxy, OCF 3 , CF 3 , cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl. 
     
     
         77 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 5  is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C 6 -C 14 -aryl. 
     
     
         78 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 5  is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, and halo-C 6 -C 14 -aryl. 
     
     
         79 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 5  is selected from hydrogen, cyano, fluoro, chloro, methyl, CF 3 , pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl. 
     
     
         80 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 6  is hydrogen or halogen. 
     
     
         81 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 6  is hydrogen. 
     
     
         82 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 7  is selected from hydrogen, C 1-6 -alkyl, C 6 -C 14 -aryl, halo-C 6 -C 14 -aryl, halo-C 6 -C 14 -aryloxy, and halo-C 1-6 -alkyl. 
     
     
         83 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 7  is C 1-6 -alkyl or halo-C 1-6 -alkyl. 
     
     
         84 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 7  is tert-butyl or CF 3 . 
     
     
         85 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 8  is selected from hydrogen, halogen, C 1-6 -alkyl, and halo-C 1-6 -alkyl. 
     
     
         86 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 8  is hydrogen or halo-C 1-6 -alkyl. 
     
     
         87 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 8  is hydrogen or CF 3 . 
     
     
         88 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 9  is hydrogen. 
     
     
         89 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 10  is halogen. 
     
     
         90 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 11  is halogen. 
     
     
         91 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 12  is hydrogen. 
     
     
         92 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 14  is selected from C 1-6 -alkyl, C 1-6 -alkoxy, and halogen. 
     
     
         93 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein R 15  is hydrogen or halogen. 
     
     
         94 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein:
 (i) X is C—R 3 ; m is 0 or 1; n is selected from 0, 1, and 2; and L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —(CR 16 R 17 ) q —CH 2 O—, —CH 2 OCH 2 —, —CF 2 CH 2 —, and —CH 2 ═CH 2 —; or   (ii) X is N; m and n are both 1; and L is —(CH 2 ) p —;   p is 1 or 2;   q is 0 or 1;   A is selected from:
 (i) C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; 
 (ii) 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; and 
 (iii) 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; 
   R 1  is hydrogen or C 1-6 -alkyl;   R 2  is hydrogen or C 1-6 -alkyl;   R 3  is selected from hydrogen, halogen, C 1-6 -alkyl, and halo-C 1-6 -alkyl;   R 4  is selected from hydrogen, halogen, cyano, SF 5 , C 1-6 -alkyl, C 1-6 -alkanoyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, 3- to 14-membered heterocycloalkyl, 3- to 14-membered heterocycloalkyl substituted with R 14  and R 15 , 5- to 14-membered heteroaryl, halo-C 6 -C 14 -aryl, and C 6 -C 14 -aryloxy;   R 5  is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, 3- to 14-membered heterocycloalkyl, C 1-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C 6 -C 14 -aryl;   R 6  is hydrogen or halogen;   R 7  is selected from hydrogen, C 1-6 -alkyl, C 6 -C 14 -aryl, halo-C 6 -C 14 -aryl, halo-C 6 -C 14 -aryloxy, and halo-C 1-6 -alkyl;   R 8  is selected from hydrogen, halogen, C 1-6 -alkyl, and halo-C 1-6 -alkyl;   R 9  is hydrogen;   R 10  is halogen;   R 11  is halogen;   R 12  is hydrogen;   R 14  is selected from halogen, C 1-6 -alkyl, and C 1-6 -alkoxy;   R 15  is hydrogen or halogen; and   R 16  and R 17 , taken together with the carbon atom to which they are attached, form a C 3-10 -cycloalkyl.   
     
     
         95 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein:
 X is C—R 3 ;   m and n are both 0; or   m and n are both 1;   L is selected from —(CH 2 ) p —, —O—, —OCH 2 — and —CH 2 O—;   p is 1 or 2;   A is selected from:
 (i) C 6 -C 14 -aryl substituted with R 4 , R 5  and R 6 ; and
 (ii) 5- to 14-membered heteroaryl substituted with R 7 , R 8  and R 9 ; 
 
   R 1  is hydrogen;   R 2  is hydrogen or C 1-6 -alkyl;   R 3  is selected from hydrogen, halogen and C 1-6 -alkyl;   R 4  is selected from halogen, SF 5 , C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, and 3- to 14-membered heterocycloalkyl;   R 5  is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl and halo-C 6 -C 14 -aryl;   R 6  is hydrogen;   R 7  is C 1-6 -alkyl or halo-C 1-6 -alkyl;   R 8  is hydrogen or halo-C 1-6 -alkyl; and   R 9  is hydrogen.   
     
     
         96 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein:
 X is C—R 3 ;   m and n are both 0; or   m and n are both 1;   L is selected from —(CH 2 ) p —, —O—, —OCH 2 — and —CH 2 O—;   p is 1 or 2;   A is selected from:
 (i) phenyl substituted with R 4 , R 5 , and R 6 ; 
 (ii) oxazolyl substituted with R 7 , R 8 , and R 9 ; and 
 (iii) pyridyl substituted with R 7 , R 8 , and R 9 ; 
   R 1  is hydrogen;   R 2  is hydrogen or methyl;   R 3  is selected from hydrogen, fluoro and methyl;   R 4  is selected from chloro, SF 5 , methyl, methoxy, OCF 3 , CF 3 , cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl;   R 5  is selected from hydrogen, cyano, fluoro, chloro, methyl, CF 3 , pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl;   R 6  is hydrogen;   R 7  is selected from tert-butyl, methyl, and CF 3 ;   R 8  is hydrogen or CF 3 ; and   R 9  is hydrogen.   
     
     
         97 . A compound of  claim 57 , or a pharmaceutically acceptable salt thereof, selected from the compounds disclosed in Table 1. 
     
     
         98 . A compound of  claim 57 , wherein the compound is:
 (+)-(4aR,8aS)-6-(4-((4-(tert-Butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)-(4aR,8aS)-6-[4-[[4-(Trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (+)-(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   rac-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-(4-(Trifluoromethoxy)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-(4-Chloro-3-fluorobenzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-(3-(Trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-[4-[[2-Chloro-4-(trifluoromethoxy)phenoxy]methyl]piperidine-1-carbonyl]-4,4a 5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (+)- or (−)-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-((4-Chloro-2-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-((4-Fluoro-2-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-((2-Fluoro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-(2-(Pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-4-((2-Chloro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-[4-[[2-Cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (+)- or (−)-3-Chloro-4-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl)methoxy)benzonitrile;   (+)- or (−)-(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-((4′,6-Dichloro-[1,1′-biphenyl]-3-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(cis-4-((2-Chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (+)- or (−)-(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenoxy)methyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-[3-[(2,4-Dichlorophenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[4-[[2-Fluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[4-[[2-Cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[[3-Chloro-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[[2-Fluoro-5-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[2-[2-Fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   6-(3-((2,4-bis(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-[4-[3-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-(3-methyl-4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-(3-((3,4-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-(3-((2,5-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   rac-(4aR,8aS)-6(2-methyl-3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-(3-(((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   rac-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-methyl azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-(3-((2-fluoro-4-(pentafluoro-16-sulfaneyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-(3-((4-methyl-2-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-[4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[2-[4-methoxy-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   (4aR,8aS)-6-(3-((2-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;   rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-4-(trifluoromethoxy)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-3-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carbonyl]-4,4# a!,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[4-[2-chloro-3-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-(2-chloro-3-cyclopropyl-phenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-2-chloro-phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[2-chloro-3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-[3-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;   (4aR,8aS)-6-(3-((E)-2-fluoro-6-(trifluoromethyl)styryl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; or   (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one,   or a pharmaceutically acceptable salt thereof.   
     
     
         99 . A process of manufacturing a compound of  claim 57 , or a pharmaceutically acceptable salt thereof, the process comprising:
 reacting a first amine of formula 1, wherein R 1  is as described in  claim 57 :   
       
         
           
           
               
               
           
         
         with a second amine 2, wherein A, L, m, n, X and R 2  are as described in  claim 57 : 
       
       
         
           
           
               
               
           
         
         in the presence of a base and a urea forming reagent, 
         to form said compound of  claim 57 , or a pharmaceutically acceptable salt thereof. 
       
     
     
         100 . A compound of  claim 57 , or a pharmaceutically acceptable salt thereof, when manufactured by a process comprising:
 reacting a first amine of formula 1, wherein R 1  is as described in  claim 57 :   
       
         
           
           
               
               
           
         
         with a second amine 2, wherein A, L, m, n, X and R 2  are as described in  claim 57 : 
       
       
         
           
           
               
               
           
         
         in the presence of a base and a urea forming reagent, 
         to form said compound of  claim 57 , or a pharmaceutically acceptable salt thereof. 
       
     
     
         101 . The compound of  claim 57 , or a pharmaceutically acceptable salt thereof, wherein said compound has an IC 50  for monoacylglycerol lipase below 10 μM. 
     
     
         102 . A pharmaceutical composition, comprising a compound of  claim 57 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. 
     
     
         103 . A pharmaceutical composition, comprising a compound of  claim 98 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. 
     
     
         104 . A method for the treatment or prophylaxis of a condition in a mammal, wherein the condition is neuroinflammation, a neurodegenerative disease, pain, cancer, or a mental disorder, the method comprising administering an effective amount of a compound of  claim 57 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         105 . A method for the treatment or prophylaxis of a condition in a mammal, wherein the condition is neuroinflammation, a neurodegenerative disease, pain, cancer, or a mental disorder, the method comprising administering an effective amount of a compound of  claim 98 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         106 . A method for the treatment or prophylaxis of a condition in a mammal, wherein the condition is 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, the method comprising administering an effective amount of a compound of  claim 57 , or a pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         107 . A method for the treatment or prophylaxis of a condition in a mammal, wherein the condition is 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, the method comprising administering an effective amount of a compound of  claim 98 , or a pharmaceutically acceptable salt thereof, to the mammal.