# US 2021/0277020 A1 · Heterocyclic compounds as monoacylglycerol lipase inhibitors

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- Number: US 2021/0277020 A1
- Document ID: US20210277020A1
- Status: Published application
- Kind: A1
- Application number: 17/174,000
- Filed: 2021-02-11
- Published: 2021-09-09
- Earliest claimed: 2018-08-13
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Lilli ANSELM; Joerg BENZ; Uwe GRETHER; Katrin GROEBKE ZBINDEN; Dominik HEER; Benoit HORNSPERGER; Carsten KROLL; Bernd KUHN; Fionn O`HARA; Hans RICHTER
- Web page: https://patentgrep.com/patent/US20210277020A1

## CPC

- C07D 498/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides new heterocyclic compounds having the general formula (I) wherein A, L, X, m, n, R1 and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds, methods of using the compounds and methods of determining the monoacylglycerol lipase (MAGL) inhibitory activity of the compounds.

## Claims

### Claim at position 1

1-54. (canceled)

### Claim 55

A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is C—R3; m is 0 or 1; n is selected from 0, 1 and 2; and L is selected from —C≡C—, —CHR4—NR5—CH2—, —NR5—CH2—CHR4—, —NR5—CHR4—CH2—, —CH2—NR5—CHR4—, —(CR6R7)p—C(O)—NR8—, —C(O)—NR8—(CR6R7)p—, —(CR6R7)p—NR8—C(O)—, —NR8—C(O)—(CR6R7)p—, —(CH2)qNR9—, —NR9—(CH2)q—, —S—, —S(O)—, —SO2—, —SCH2—, —CH2S—, —S(O)CH2—, —CH2S(O)—, —SO2CH2—, and —CH2SO2—; or
X is N; m is 1; n is 1 or 2; and L is selected from —NR5—CH2—CHR4—, —NR5—CHR4—CH2—, and —NR8—C(O)—(CR6R7)p—;
p and q are each independently selected from 0, 1, and 2;
A is selected from:
(i) C6-C14-aryl substituted with R10, R11, and R12;
(ii) 5- to 14-membered heteroaryl substituted with R13, R14, and R15;
(iii) 3- to 14-membered heterocycloalkyl substituted with R16, R17, and R18; and
(iv) C3-C10-cycloalkyl substituted with R22;
R1 is hydrogen or C1-6-alkyl;
R2 is selected from hydrogen, C1-6-alkyl, and hydroxy-C1-6-alkyl;
R3 is selected from hydrogen, halogen, hydroxy, C1-6-alkoxy, C1-6-alkyl, and halo-C1-6-alkyl;
R4 is selected from hydrogen, C1-6-alkyl, and halo-C1-6-alkyl;
R5 is selected from hydrogen, C1-6-alkyl, and halo-C1-6-alkyl-CH2—;
each of R6 and R7 is independently hydrogen or C1-6-alkyl; or
R6 and R7, taken together with the carbon atom to which they are attached, form a 3- to 14-membered heterocycloalkyl or a C3-10-cycloalkyl;
R8 is selected from hydrogen, C1-6-alkyl, and hydroxy-C1-6-alkyl;
R9 is selected from hydrogen, C1-6-alkyl, halo-C1-6-alkyl-CH2—, (C1-6-alkyl)(halo-C1-6-alkyl)CH—, and hydroxy-C1-6-alkyl-CH2—;
each of R10, R11, R12, R13, R14, R15, R16, R17 and R18 is independently selected from hydrogen, halogen, cyano, hydroxy, C1-6-alkyl, halo-C1-6-alkyl, hydroxy-C1-6-alkyl, halo-C1-6-alkyl-CH(OH)—, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, halo-C1-6-alkoxy, SF5, C1-6-alkylsulfonyl, C3-10-cycloalkyl, C3-10-cycloalkyl substituted with R19, 3-to 14-membered heterocycloalkyl, 3- to 14-membered heterocycloalkyl substituted with R20, 5- to 14-membered heteroaryl, C6-C14-aryl, and halo-C6-C14-aryl;
each of R19 and R20 is independently selected from C1-6-alkyl, cyano, and hydroxy; and
R22 is hydrogen or hydroxy.

### Claim 56 (depends on 55)

The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein:
X is C—R3;
m, n, and p are each independently 0 or 1;
L is selected from —C≡C—, —CHR4—NR5—CH2—, —CH2—NR5—CHR4—, —(CR6R7)p—C(O)—NR8—, —(CR6R7)p—NR8—C(O)—, —(CH2)qNR9—, —S—, —S(O)—, —SO2—, —SCH2—, —CH2S—, —S(O)CH2—, —CH2S(O)—, —SO2CH2—, and —CH2SO2—;
q is 0;
R2 is hydrogen;
R3 is selected from hydrogen, hydroxy, and C1-6-alkyl;
R4 is halo-C1-6-alkyl;
R6 and R7 are both hydrogen; or
R6 and R7, together with the carbon atom to which they are attached, form a C3-10-cycloalkyl; and
R9 is C1-6-alkyl.

### Claim 57 (depends on 56)

The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein:
m and n are both 0; or
m and n are both 1;
L is selected from —C≡C—, —CHR4—NR5—CH2—, —(CH2)qNR9—, —SCH2—, and —CH2S—; and
R3 and R5 are both hydrogen.

### Claim 58 (depends on 57)

The compound claim 57, or a pharmaceutically acceptable salt thereof, wherein R4 is CF3 and R9 is methyl.

### Claim 59 (depends on 55)

The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
(i) C6-C14-aryl substituted with R10, R11, and R12;
(ii) 5- to 14-membered heteroaryl substituted with R13, R14, and R15; and
(iii) C3-C10-cycloalkyl substituted with R22;
R10 is selected from hydrogen, halogen, cyano, C1-6-alkyl, halo-C1-6-alkyl, C1-6-alkylsulfonyl, C1-6-alkoxy, halo-C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C3-10-cycloalkyl, and C3-10-cycloalkyl substituted with R19;
R11 is selected from hydrogen, C1-6-alkyl, and halogen;
R12 is hydrogen or halogen;
R13 is halogen;
R14 and R15 are both hydrogen; and
R19 is hydroxy or cyano.

### Claim 60 (depends on 55)

The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein:
A is C6-C14-aryl substituted with R10, R11, and R12;
R10 is selected from halogen, C1-6-alkyl, halo-C1-6-alkyl, halo-C1-6-alkoxy, and C3-10-cycloalkyl;
R11 is selected from hydrogen, halogen, and C1-6-alkyl; and
R12 is hydrogen or halogen.

### Claim 61 (depends on 55)

The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein:
A is phenyl substituted with R10, R11, and R12;
R10 is methyl, difluoromethyl, —CF3, —OCF3, cyclopropyl, fluoro, or chloro;
R11 is hydrogen, methyl, chloro, or fluoro; and
R12 is hydrogen or fluoro.

### Claim 62 (depends on 55)

The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

### Claim 63

A compound, wherein the compound is:
(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (mixture of sulfoxide isomers);
(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenyl)sulfonyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (mixture of sulfoxide isomers);
(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (sulfoxide isomer A);
(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (sulfoxide isomer B);
(4aR,8aS)-6-(3-(((2-Chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Fluoro-6-(trifluoromethyl)benzyl)sulfonyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[[2-Fluoro-6-(trifluoromethyl)phenyl]methylsulfinyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (sulfoxide isomer A);
(4aR,8aS)-6-[3-[[2-Fluoro-6-(trifluoromethyl)phenyl]methylsulfinyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (sulfoxide isomer B);
(4aR,8aS)-6-(3-(((2-Chloro-4-(trifluoromethyl)phenyl)sulfonyl)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-(((2-Chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (mixture of sulfoxide isomers);
(4aR,8aS)-6-(3-(((2-Chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (sulfoxide isomer A);
(4aR,8aS)-6-(3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (sulfoxide isomer B);
(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)benzyl)thio)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2,6-Dichlorophenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-[2-Fluoro-4-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-(3-((2,6-Difluorophenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((3-Chloro-4-(trifluoromethyl)phenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Chloro-6-fluorophenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Chloro-4-cyclopropylphenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Methoxyphenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-[4-Chloro-2-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(3-Chlorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[4-Trifluoromethoxy)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[4-(Trifluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(3-Fluoro-2-methylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2,6-Dimethylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-(Trifluoromethoxy)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Bromophenyl)ethynyl]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-fluorophenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-(o-Tolylethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-(4-Chloro-2-fluorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-(Difluoromethoxy)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
2-[2-[1-[(4aR,8aS)-3-Oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]ethynyl]-3-chlorobenzonitrile;
(4aR,8aS)-6-[3-[2-[4-(Difluoromethoxy)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
1-[4-[2-[1-[(4aR,8aS)-3-Oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]ethynyl]phenyl]cyclopropane-1-carbonitrile;
(4aR,8aS)-6-[3-[2-(4-Cyclopropylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[4-(1-Hydroxycyclopropyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(3-Methoxyphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-(Difluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(3-Methoxy-2-methylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Chloro-6-methylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Chloro-5-fluorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(4-Methylsulfonylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(5-Chlorothiophen-2-yl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(5-Chlorothiophen-3-yl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-Chloro-6-fluoro-4-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Chlorophenyl)ethynyl]-3-hydroxyazetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-(Methoxymethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-(4-((2-(Trifluoromethyl)phenyl)ethynyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(4-((2-Methoxyphenyl)ethynyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(4-(o-Tolylethynyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(4-((2,6-Dimethylphenyl)ethynyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(4-((2,4-Dichlorophenyl)ethynyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(4-((2-Chloro-4-fluorophenyl)ethynyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-(1-Hydroxycyclopentyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(Cyclopenten-1-yl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Fluoro-6-(trifluoromethyl)benzyl)thio)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-(4aR,8aS)-6-[3-[[[2,2,2-Trifluoro-1-[4-(trifluoromethyl)phenyl]ethyl]amino]methyl]azetidine-1-carbonyl]hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-N-Benzyl-N-(2-hydroxyethyl)-1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidine-4-carboxamide;
(+)- or (−)-N-Benzyl-1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidine-4-carboxamide;
(+)- or (−)-(4aR,8aS)-6-(3-(((2,2,2-Trifluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-(4aR,8aS)-6-(3-(((1-(2,4-Dichlorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-(4aR,8aS)-6-(3-(((1-(2-Chlorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-(4aR,8aS)-6-(3-(((2,2,2-Trifluoro-1-phenylethyl)amino)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-2-Chloro-4-fluoro-N-(1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)azetidin-3-yl)benzamide;
(+)- or (−)-(4aR,8aS)-6-(3-((Methyl(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
N-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]piperidin-4-yl]-N-methyl-1-[3-(trifluoromethyl)phenyl]cyclopropane-1-carboxamide;
N-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]piperidin-4-yl]-2-[2-chloro-3-(trifluoromethyl)phenyl]-N-methylacetamide;
N-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]piperidin-4-yl]-2-[2-chloro-5-(trifluoromethyl)phenyl]-N-methylacetamide;
N-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]piperidin-4-yl]-N-methyl-4-(trifluoromethyl)benzamide;
N-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]piperidin-4-yl]-N-methyl-2-[3-(trifluoromethyl)phenyl]acetamide;
(4aR,8aS)-6-[3-[[[2,2,2-Trifluoro-1-(4-fluorophenyl)ethyl]amino]methyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[4-[2,2,2-Trifluoro-1-[[3-(trifluoromethyl)phenyl]methylamino]ethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[4-[2-(2-Chlorophenyl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[4-[2-(4-Chloropyridin-3-yl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(+)- or (−)-(4aR,8aS)-6-[4-[2-(3-Chloropyridin-2-yl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(+)- or (−)-(4aR,8aS)-6-[4-[2-(2-Chloro-4-fluorophenyl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(+)- or (−)-(4aR,8aS)-6-(4-((3-Chiorophenyl)ethynyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-(4aR,8aS)-6-(4-((4-Chlorophenyl)ethynyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-(4aR,8aS)-6-(4-((2,4-Dichlorophenyl)ethynyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(+)- or (−)-(4aR,8aS)-6-[4-[2-(2-Chlorophenyl)ethynyl]-4-hydroxypiperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Chlorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-(3-((2,4-Dichlorophenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-(2-Chloro-4-fluorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[4-[N-methyl-4-(trifluoromethyl)anilino]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; or
(4aR,8aS)-6-[3-[N-methyl-4-(trifluoromethyl)anilino]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one,
or a pharmaceutically acceptable salt thereof.

### Claim 64

A compound, wherein the compound is:
(+)- or (−)-(4aR,8aS)-6-[3-[[[2,2,2-Trifluoro-1-[4-(trifluoromethyl)phenyl]ethyl]amino]methyl]azetidine-1-carbonyl]hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[4-[2-(2-Chlorophenyl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(+)- or (−)-(4aR,8aS)-6-[4-[2-(2-Chloro-4-fluorophenyl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Chlorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Chloro-4-fluorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[4-[N-methyl-4-(trifluoromethyl)anilino]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-(3-(((2-Chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Fluoro-4-(trifluoromethyl)benzyl)thio)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2,6-Dichlorophenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-[2-Fluoro-4-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-(3-((2-Chloro-6-fluorophenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-(3-((2-Chloro-4-cyclopropylphenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-[4-Trifluoromethoxy)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2,6-Dimethylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-(Trifluoromethoxy)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-(3-(o-Tolylethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
(4aR,8aS)-6-[3-[2-(4-Chloro-2-fluorophenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-(Difluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-(2-Chloro-6-methylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;
(4aR,8aS)-6-[3-[2-[2-Chloro-6-fluoro-4-(trifluoromethyl)phenyl]ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; or
(4aR,8aS)-6-(3-((2-Chloro-4-(trifluoromethyl)phenyl)ethynyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;
or a pharmaceutically acceptable salt thereof.

### Claim 65 (depends on 55)

A pharmaceutical composition comprising a compound of claim 55, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

### Claim 66 (depends on 63)

A pharmaceutical composition comprising a compound of claim 63, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

### Claim 67 (depends on 64)

A pharmaceutical composition comprising a compound of claim 64, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

### Claim 68 (depends on 55)

A process of manufacturing a compound of claim 55, or a pharmaceutically acceptable salt thereof, comprising:
reacting a first amine of formula 1, wherein R1 is as described in claim 55:
with a second amine 2, wherein A, L, m, n, X and R2 are as described in claim 55:
in the presence of a base and a urea forming reagent to form said compound of claim 55, or a pharmaceutically acceptable salt thereof.

### Claim 69 (depends on 55)

A method, comprising administering to a mammal an effective amount of a compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein the method is for the treatment or prophylaxis of neuroinflammation, neurodegenerative disease, pain, cancer, or mental disorder in the mammal.

### Claim 70 (depends on 55)

A method comprising administering to a mammal an effective amount of a compound of claim 55, or a pharmaceutically acceptable salt thereof, 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.

### Claim 71 (depends on 63)

A method comprising administering to a mammal an effective amount of a compound of claim 63, or a pharmaceutically acceptable salt thereof, wherein the method is for the treatment or prophylaxis of neuroinflammation, neurodegenerative disease, pain, cancer, or mental disorder in the mammal.

### Claim 72 (depends on 63)

A method comprising administering to a mammal an effective amount of a compound of claim 63, or a pharmaceutically acceptable salt thereof, 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.

### Claim 73 (depends on 64)

A method comprising administering to a mammal an effective amount of a compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein the method is for the treatment or prophylaxis of neuroinflammation, neurodegenerative disease, pain, cancer, or mental disorder in the mammal.

### Claim 74 (depends on 64)

A method comprising administering to a mammal an effective amount of a compound of claim 64, or a pharmaceutically acceptable salt thereof, 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.