1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors

1. A compound of Formula I-a or I-a1:

or a pharmaceutically acceptable salt thereof, wherein:

the moiety of “N(R 1 )(R 2 )” is a moiety of Formula a-13:

t1 is 0, 1, 2, or 3;

each of R 5 and R 6 is independently H or C 1-4 alkyl;

R 7 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or R 10 , wherein the C 1-6 alkyl of R 7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 3-6 cycloalkyl, and wherein the C 3-7 cycloalkyl of R 7 is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 8 is L 1 -R 11 , -L 2 -R 12 , -L 3 -R 13 , -L 4 -R 14 , —C(R 15 )(Cy 1 )(Cy 2 ), —C(R 15 )(Cy 1 )[—NR 23 —S(═O) 2 -Cy 2 ], or -L 5 -N(-L 6 -Cy 3 )(-L 7 -Cy 4 );

each R 9 is independently OH, oxo, halogen, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, or optionally substituted C 3-6 cycloalkyl;

R 10 is —P(═O)(OR 81 )(OR 82 ) or —S(═O) 2 OR 90 ;

each of L 1 , L 2 , L 3 , and L 4 is independently absent, —(CR 21 R 22 ) m —, —NR 23 —, —O—, —C(═O)—, —S(═O) 2 —, —S(═O) 2 —(CR 21 R 22 ) n —, —C(═O)—(CR 21 R 22 ) n —, —S(═O) 2 —NR 23 —, —C(═O)—NR 23 —, —(CR 21 R 22 ) f1 —NR 23 —(CR 21 R 22 ) f2 —, —(CR 21 R 22 ) f1 —O—(CR 21 R 22 ) f2 —, —C(═O)—NR 23 —(CR 21 R 22 ) p , or —S(═O) 2 —NR 23 —(CR 21 R 22 ) p —;

L 5 is absent or —(CR 21 R 22 )—;

L 6 is absent or —(CR 21 R 22 )—;

L 7 is absent, —(CR 21 R 22 )—, or —S(═O) 2 —;

R 11 is 5- to 10-membered heteroaryl optionally substituted with one or more independently selected R 31 ;

R 12 is 4- to 14-membered heterocycloalkyl optionally substituted with one or more independently selected R 32 ;

R 13 is C 6-10 aryl optionally substituted with one or more independently selected R 33 ;

R 14 is C 3-14 cycloalkyl optionally substituted with one or more independently selected R 34 ;

R 15 is H, OH, halogen, C 1-4 alkoxy, C 1-4 alkyl, or cyclopropyl;

each of R 21 and R 22 is independently H, OH, halogen, C 1-3 alkyl, or cyclopropyl, wherein the C 1-3 alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of OH, halogen, C 1-3 alkoxy, C 1-3 haloalkoxy, and cyclopropyl;

R 23 is H, C 1-4 alkyl, or cyclopropyl;

each of R 31 , R 32 , R 33 , and R 34 is independently selected from the group consisting of halogen, —N(R a )(R b ), —N(R c )(C(═O)R d ), —N(R c )(S(═O) 2 R d ), —C(═O)—N(R a )(R b ), —C(═O)—R d , —C(═O)—OR d , —OC(═O)—R d , —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , —S(═O) 2 R d , —OR d , —OR 35 , —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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 14 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 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- is optionally substituted with one or more independently selected R 36 ; and wherein each of the C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, (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- is further optionally substituted one or more oxo;

each R 35 is independently selected from the group consisting of H, 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 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- is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, —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 , oxo, —OH, —OC(═O)—C 1-4 alkyl, —OC(═O)O—C 1-4 alkyl, —NH2, —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —NHC(═O)C 1-4 alkyl, —NHC(═O)OC 1-4 alkyl, —NHC(═O)NHC 1-4 alkyl, and C 1-4 alkoxy;

each R 36 is independently selected from the group consisting of halogen, —OH, —NO 2 , —CN, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—N(R a )(R b ), —C(═O)—R d , —C(═O)—OR d , —OC(═O)—R d , —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , —S(═O) 2 R d , and —OR d , wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, —N(R a )(R b ), —N(R c )(C(═O)R d ), —C(═O)—OR d , —C(═O)H, —C(═O)R d , —C(═O)N(R a )(R b ), —N(R c )(S(═O) 2 R d ), —S(═O) 2 —N(R a )(R b ), —SR d , —S(═O) 2 R d , and —OR d ;

each of R 81 , R 82 , and R 90 is independently selected from the group consisting of H, C 1-6 alkyl, C 3-7 cycloalkyl, and (C 3-7 cycloalkyl)-C 1-4 alkyl-, wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, and (C 3-7 cycloalkyl)-C 1-4 alkyl- is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl;

or OR 81 and OR 82 , together with the P(═O) to which they are attached, form 4- to 10-membered heterocycloalkyl that is further optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CN, —OH, oxo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, and C 3-6 cycloalkyl;

each of Cy 1 , Cy 2 , Cy 3 , and Cy 4 is independently selected from the group consisting of R 11 , R 12 , R 13 , and R 14 ;

each R a is independently H, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, or (C 3-7 cycloalkyl)-C 1-4 alkyl-;

each R b is independently H or selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, (C 3-7 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 from the group is optionally substituted with one or more substituents each independently selected from the group consisting of —OH, —CN, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 hydroxylalkyl, —S—C 1-4 alkyl, —C(═O)H, —C(═O)—C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

or R a and R b , together with the N atom to which they are attached, form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, oxo, —C(═O)H, —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , —CN, C 1-4 alkyl, C 3-6 cycloalkyl, (C 3-6 cycloalkyl)-C 1-2 alkyl-, C 1-4 alkoxy, C 1-4 hydroxylalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

each R c is independently selected from the group consisting of H, C 1-4 alkyl, C 3-7 cycloalkyl, and (C 3-7 cycloalkyl)-C 1-4 alkyl-;

each R d is independently selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, (C 3-7 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 from the group is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, oxo, —S—C 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

each of f1 and f2 is independently 0, 1, or 2, provided that the sum of f1 and f2 is 1, 2, or 3;

m is 1, 2, or 3;

n is 1, 2, or 3; and

p is 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of I-a1.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 5 and R 6 is independently H or methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each of R 5 and R 6 is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H or R 10 ; and R 10 is —P(═O)(OR 81 )(OR 82 ).

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H.

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

R 8 is -L 1 -R 11 , -L 2 -R 12 , -L 3 -R 13 , or -L 4 -R 14 ;

each of L 1 , L 2 , L 3 , and L 4 is independently absent, —(CR 21 R 22 )—, —C(═O)—, —S(═O) 2 —, —S(═O) 2 —NR 23 —, —S(═O) 2 —(CR 21 R 22 )—, —S(═O) 2 —NR 23 —(CR 21 R 22 )—, or —S(═O) 2 —(CR 21 R 22 ) 2 —;

each of R 21 and R 22 is independently H, C 1-3 alkyl, or cyclopropyl;

R 11 is 5- to 6-membered heteroaryl optionally substituted with one or more independently selected R 31 ;

R 12 is 5- to 6-membered heterocycloalkyl optionally substituted with one or more independently selected R 31 ;

R 13 is phenyl optionally substituted with one or more independently selected R 33 ; and

R 14 is C 3-8 cycloalkyl optionally substituted with one or more independently selected R 34 .

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 8 is -L 1 -R 11 or -L 3 -R 13 .

9. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 8 is —R 11 or —R 13 .

10. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 8 is —R 11 .

11. A compound selected from the group consisting of:

(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-6-[1-(5-methoxypyridin-2-yl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate;

(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-6-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate;

rel-(2S,3R)-1,1,1,4,4,4-hexafluoro-3-hydroxybutan-2-yl (1α,5α,6α)-6-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate;

(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-641-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate;

1,1,1,3,3-pentafluoro-4-hydroxybutan-2-yl (1α,5α,6α)-6-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate;

(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-6-[1-(6-methoxypyridin-3-yl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate;

(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-6-[1-(4-ethynylphenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate; and

(2S)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-6-[1-(4-ethynylphenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate,

or a pharmaceutically acceptable salt thereof.

12. A compound of claim 1 that is (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-6-[1-(5-methoxypyridin-2-yl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate, or a pharmaceutically acceptable salt thereof.

13. A compound of claim 1 that is (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (1α,5α,6α)-6-[1-(4-fluorophenyl)-1H-pyrazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate, or a pharmaceutically acceptable salt thereof.

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

15. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

16. A method for treating a MAGL-mediated disease or disorder in a mammal, which method comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 or pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from the group consisting of nausea; neuropathy; a neurodegenerative disorder; multiple sclerosis; Parkinson's disease; tremor; dyskinesia; dystonia; spasticity; Tourette's syndrome; an inflammatory disorder; neuroinflammation; inflammation in the central nervous system; and pain.

17. A method for inhibiting MAGL comprising contacting the MAGL with a compound of claim 1 or pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of claim 11 or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.