Heterocyclic spiro compounds as MAGL inhibitors
The present invention provides, in part, heterocyclic spiro compounds of Formula I: and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating MAGL-mediated diseases and disorders including, e.g., pain, an inflammatory disorder, depression, anxiety, Alzheimer's disease, a metabolic disorder, stroke, or cancer.
1. A compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
the moiety of Formula M-1 of Formula I
is a moiety of Formula M1-a:
wherein ring A 2 is 5- or 6-membered heterocycloalkyl; or
the moiety of Formula M-1 of Formula I
is a moiety of Formula M-1b, M-1c, M-1d, or M-1e:
R 1 is R 1B ;
R 1B is 2,5-dioxopyrrolidin-1-yl-;
R 4 is selected from the group consisting of R 6 , —N(R 5 )(C(═O)R 6 ), —N(R 5 )(S(═O) 2 R 6 ), —C(═O)—R 6 , —S(═O) 2 R 6 , —NR 5 R 6 , —SO 2 NR 5 R 6 , and —OR 6 ;
R 5 is selected from the group consisting of H, C 1-4 alkyl, C 3-4 cycloalkyl, and C 3-4 cycloalkyl-C 1-2 alkyl-;
R 6 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, (C 3-10 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the selections is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, oxo, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, C 1-4 alkoxy, C 1-4 haloalkoxy, —C(═O)C 1-4 alkyl, —C(═O)OH, —C(═O)O—C 1-4 alkyl, —C(═O)NHC 1-4 alkyl, —C(═O)N(C 1-4 alkyl) 2 , —OC(═O)—C 1-4 alkyl, —OC(═O)O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHC(═O)C 1-4 alkyl, —NHC(═O)OC 1-4 alkyl, and —NHC(═O)NHC 1-4 alkyl;
t1 is 0;
t2 is 0; and
t3 is 1.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety of Formula M-1 of Formula I
is a moiety of Formula M1-a:
wherein ring A 2 is 5- or 6-membered heterocycloalkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety of Formula M-1 of Formula I
is a moiety of Formula M-1b, M-1c, M-1d, or M-1e:
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the moiety of Formula M-1 of Formula I is a moiety of Formula M-1b; and R 4 is selected from the group consisting of R 6 , —N(R 5 )(C(═O)R 6 ), —N(R 5 )(S(═O) 2 R 6 ), and —OR 6 .
5. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the moiety of Formula M-1 of Formula I is a moiety of Formula M-1c; and R 4 is selected from the group consisting of R 6 , —C(═O)—R 6 , —S(═O) 2 R 6 , and —SO 2 NR 5 R 6 .
6. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the moiety of Formula M-1 of Formula I is a moiety of Formula M-1d; and R 4 is selected from the group consisting of R 6 , —N(R 5 )(C(═O)R 6 ), —N(R 5 )(S(═O) 2 R 6 ), —C(═O)—R 6 , —S(═O) 2 R 6 , —NR 5 R 6 , —SO 2 NR 5 R 6 , and —OR 6 .
7. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein the moiety of Formula M-1 of Formula I is a moiety of Formula M-1e; and R 4 is selected from the group consisting of R 6 , —C(═O)—R 6 , —S(═O) 2 R 6 , and —SO 2 NR 5 R 6 .
8. A compound of claim 1 selected from the group consisting of:
1-[({4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}carbonyl)oxy]pyrrolidine-2,5-dione;
N-[(3R)-8-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}-1-oxa-8-azaspiro[4.5]dec-3-yl]-N-methylbenzenesulfonamide;
1-cyclopropyl-N-[(3R)-8-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}-1-oxa-8-azaspiro[4.5]dec-3-yl]-N-methylmethanesulfonamide; and
1-{[(2-{[6-(difluoromethyl)pyridin-3-yl]oxy}-7-azaspiro[3.5]non-7-yl)carbonyl]oxy}pyrrolidine-2,5-dione,
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to claim 1 , and a pharmaceutically acceptable carrier.
10. A method for inhibiting MAGL comprising contacting the MAGL with a compound or pharmaceutically acceptable salt according to claim 1 .
11. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 4 is R 6 or —OR 6 ; and R 6 is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each of the selections is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, oxo, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, C 1-4 alkoxy, and C 1-4 haloalkoxy.
12. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of R 6 , —C(═O)—R 6 , —S(═O) 2 R 6 , and —SO 2 NR 5 R 6 .
13. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —C(═O)—R 6 .
14. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of R 6 , —N(R 5 )(C(═O)R 6 ), and —N(R 5 )(S(═O) 2 R 6 ).
15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H or C 1-4 alkyl; and R 6 is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, and (C 3-10 cycloalkyl)-C 1-4 alkyl-, wherein each of the selections is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, oxo, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, C 1-4 alkoxy, and C 1-4 haloalkoxy.
16. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of —N(R 5 )(C(═O)R 6 ) and —N(R 5 )(S(═O) 2 R 6 ); R 5 is H or C 1-4 alkyl; and R 6 is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, and (C 3-10 cycloalkyl)-C 1-4 alkyl-, wherein each of the selections is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, oxo, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, C 1-4 alkoxy, and C 1-4 haloalkoxy.
17. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —S(═O) 2 R 6 ; and R 6 is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, and (C 3-10 cycloalkyl)-C 1-4 alkyl-, wherein each of the selections is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, oxo, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 3-4 cycloalkyl, C 3-4 cycloalkyl-C 12 alkyl-, C 1-4 alkoxy, and C 1-4 haloalkoxy.