1,1,1-trifluoro-3-hydroxypropan-2-yl carbamate derivatives and 1,1,1-trifluoro-4-hydroxybutan-2-yl carbamate derivatives as MAGL inhibitors
The present invention provides, in part, 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, traumatic brain injury, depression, anxiety, Alzheimer's disease, a metabolic disorder, stroke, or cancer.
1. A compound selected from the group consisting of:
(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate;
(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 4-(phenylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate;
(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl (3R)-3-[methyl(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate;
(2R)-3,3,3-trifluoro-2-[({(3R)-3-[methyl(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]dec-8-yl}carbonyl)oxy]propyl dihydrogen phosphate;
(2R)-3,3,3-trifluoro-2-[({4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}carbonyl)oxy]propyl dihydrogen phosphate;
(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, DIAST-1;
(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, DIAST-2; and
(2R)-3,3,3-trifluoro-2-({[(3R)-3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]dec-8-yl]carbonyl}oxy)propyl dihydrogen phosphate,
or a pharmaceutically acceptable salt thereof,
or a pharmaceutically acceptable salt selected from the group consisting of:
(2R)-3,3,3-trifluoro-2-[({(3R)-3-[methyl(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]dec-8-yl}carbonyl)oxy]propyl phosphate, disodium salt;
(2R)-3,3,3-trifluoro-2-[({4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}carbonyl)oxy]propyl phosphate, disodium salt;
(2R)-3,3,3-trifluoro-2-[({4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}carbonyl)oxy]propyl phosphate, (bis)-L-lysine salt;
(2R)-3,3,3-trifluoro-2-({[4-(phenylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl]carbonyl}oxy)propyl phosphate, disodium salt;
(2R)-3,3,3-trifluoro-2-[({(3R)-3-[methyl(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]dec-8-yl}carbonyl)oxy]propyl phosphate, (bis)-L-lysine salt;
(2R)-3,3,3-trifluoro-2-({[4-(phenylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undec-9-yl]carbonyl}oxy)propyl phosphate, (bis)-L-lysine salt, and
(2R)-3,3,3-trifluoro-2-({[(3R)-3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]dec-8-yl]carbonyl}oxy)propyl phosphate, (bis)-L-lysine salt.
2. A compound of claim 1 that is (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate, or a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 that is (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 4-(phenylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate, or a pharmaceutically acceptable salt thereof.
4. A compound of claim 1 that is (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl(3R)-3-[methyl(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, or a pharmaceutically acceptable salt thereof.
5. A compound of claim 1 that is (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, DIAST-1; or (2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl 3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]decane-8-carboxylate, DIAST-2; or a pharmaceutically acceptable salt thereof.
6. A compound of claim 1 that is (2R)-3,3,3-trifluoro-2-[({(3R)-3-[methyl(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]dec-8-yl}carbonyl)oxy]propyl dihydrogen phosphate, or a pharmaceutically acceptable salt thereof.
7. A compound of claim 1 that is (2R)-3,3,3-trifluoro-2-[({4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}carbonyl)oxy]propyl dihydrogen phosphate, or a pharmaceutically acceptable salt thereof.
8. A compound of claim 1 that is (2R)-3,3,3-trifluoro-2-({[(3R)-3-{[(4-fluorophenyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]dec-8-yl]carbonyl}oxy)propyl dihydrogen phosphate, or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.