Granted Patent B2

US 12,281,124 · App. 18/475,065 · Granted Apr 22, 2025

Inventors: Charles Bell (Cheshire, GB); Joerg Benz (Rheinfelden, DE); Luca Gobbi (Buus, CH); Uwe Grether (Efringen-Kirchen, DE); Katrin Groebke Zbinden (Liestal, CH); Benoit Hornsperger (Altkirch, FR); Buelent Kocer (Maulburg, DE); Carsten Kroll (Basel, CH); Bernd Kuhn (Reinach, CH); Marius Daniel Rinaldo Lutz (Zurich, CH); Fionn O'Hara (Basel, CH); Hans Richter (Grenzach-Wyhlen, DE); Martin Ritter (Mumpf, CH); Didier Rombach (Mulhouse, FR); Martin Kuratli (Birsfelden, CH)

Assignee: Hoffmann-La Roche Inc.

C07D498/04C07D519/00

Abstract

Claims (187)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

(i) X is C—R 3 ; m is 0; n is selected from 0, 1 and 2; L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —CH 2 OCH 2 —, —CF 2 CH 2 —, —CH═CH—, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 CF 2 —; and A is C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; or A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; or

(ii) X is C—R 3 ; m is 1; n is selected from 0, 1 and 2; L is selected from —O—, —OCH 2 —, —CH 2 OCH 2 —, —CF 2 CH 2 —, —CH═CH—, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 CF 2 —; and A is C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; or A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; or

(iii) X is C—R 3 ; m is 1; n is selected from 0, 1 and 2; L is —(CH 2 ) p —; and A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ; or

(iv) X is N; m is 1; n is 1 or 2; L is —(CH 2 ) p — or —CF 2 CH 2 —; and A is C 6 -C 14 -aryl substituted with R 4 , R 5 , and R 6 ; or A is 5- to 14-membered heteroaryl substituted with R 7 , R 8 , and R 9 ; or A is 3- to 14-membered heterocycloalkyl substituted with R 10 , R 11 , and R 12 ;

p is selected from 1, 2, and 3;

q is 0 or 1;

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.

2. The compound of claim 1 , 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 1 .

3. The compound of claim 1 , 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 1 .

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

X is C—R 3 ; m is 0; n is selected from 0, 1, and 2; and L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —CF 2 CH 2 —, —CH═CH—, —(CR 16 R 17 ) q —CH 2 O—, and —CH 2 OCH 2 —; or

X is N; m and n are both 1; and L is —(CH 2 ) p —; and

p is 1 or 2;

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

R 3 is selected from hydrogen, halogen, C 1-6 -alkyl and halo-C 1-6 -alkyl.

5. The compound of claim 1 , 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 2;

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

R 3 is selected from hydrogen, halogen and C 1-6 -alkyl.

6. The compound of claim 1 , 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 heterocycloalkyl, 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;

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;

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 C 1-6 -alkyl, C 1-6 -alkoxy, and halogen; and

R 15 is hydrogen or halogen.

7. The compound of claim 1 , 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 ;

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.

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein:

X is C—R 3 ;

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; and

R 1 is hydrogen.

9. The compound of claim 1 , 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 ;

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 tert-butyl or —CF 3 ;

R 8 is hydrogen or —CF 3 ; and

R 9 is hydrogen.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:

X is C—R 3 ;

m and n are both 1;

L is selected from —O—, —OCH 2 — and —CH 2 O—;

R 1 is hydrogen;

A is phenyl substituted with R 4 , R 5 , and R 6 ;

R 4 is selected from chloro, SF 5 , methyl, methoxy, —OCF 3 , and —CF 3 ;

R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, —CF 3 ; and

R 6 is hydrogen.

11. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:

X is C—R 3 ;

m and n are both 0;

L is selected from —(CH 2 ) p —, —O—, —OCH 2 — and —CH 2 O—;

A is phenyl substituted with R 4 , R 5 , and R 6 ;

p is 1 or 2;

R 1 is hydrogen;

R 4 is selected from chloro, SF 5 , methyl, methoxy, —OCF 3 , and —CF 3 ;

R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, —CF 3 ; and

R 6 is hydrogen.

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

X is C—R 3 ;

m and n are both 0;

L is selected from —(CH 2 ) p —, —O—, —OCH 2 —, —CH═CH—, and —(CR 16 R 17 ) q —CH 2 O—;

A is phenyl substituted with R 4 , R 5 , and R 6 ;

p is 1 or 2;

q is 0;

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 hydrogen

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; and

R 6 is hydrogen.

13. The compound of claim 1 , 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-((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;

(+)-(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(−)-(4aR,8aS)-6-(3-((2-Chloro-4-fluorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(+)-(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;

(−)-(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;

(+)-(4aR,8aS)-6-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(−)-(4aR,8aS)-6-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(+)-(4aR,8aS)-6-(4-(3-(Trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(−)-(4aR,8aS)-6-(4-(3-(Trifluoromethyl)phenoxy)piperidine-i-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-(4aR,8aS)-6-(4-((4-Chloro-2-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(−)-(4aR,8aS)-6-(4-((4-Chloro-2-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-3-Chloro-4-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl)methoxy)benzonitrile;

(−)-3-Chloro-4-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl)methoxy)benzonitrile;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-(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;

(−)-(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;

(+)-(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-(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-[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-methylazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one;

(4aR,8aS)-6-(3-((2-fluoro-4-(pentafluoro-16-sulfanyl)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]-4,4,5,7,8,8a-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.

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

15. A pharmaceutical composition, comprising a compound of claim 13 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

16. A process of manufacturing a compound of claim 1 , or a pharmaceutically acceptable salt thereof, the process comprising:

reacting a first amine of formula 1, wherein R 1 is as described in claim 1 :

with a second amine 2, wherein A, L, m, n, X and R 2 are as described in claim 1 :

in the presence of a base and a urea forming reagent,

to form said compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. A method for the treatment of a condition in a human, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the human, wherein the condition is a neurodegenerative disease.

18. The method of claim 17 , wherein the condition is multiple sclerosis, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis.

19. A method for the treatment of a condition in a human, comprising administering an effective amount of a compound of claim 13 , or a pharmaceutically acceptable salt thereof, to the human, wherein the condition is a neurodegenerative disease.

20. The method of claim 19 , wherein the condition is multiple sclerosis, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis.

Priority Claims (1)

Continuity (4)

References Cited (188)