Heterocyclic spiro compounds as magl inhibitors

Abstract

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.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 ring A 1  is C 4-7  cycloalkyl or 4- to 7-membered heterocycloalkyl; 
 R 1  is R 1A  or R 1B ; 
 R 1A  is 1,1,1,3,3,3-hexafluoropropan-2-yl-; 
 R 1B  is 2,5-dioxopyrrolidin-1-yl-, which is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of the group consisting of halogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-4  cycloalkyl, C 3-4  cycloalkyl-C 1-2  alkyl-, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
 each R 2  is independently selected from the group consisting of halogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-4  cycloalkyl, C 3-4  cycloalkyl-C 1-2  alkyl-, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
 each R 3  is independently selected from the group consisting of —OH, oxo, halogen, —CN, C 1-4  alkyl, C 1-4  haloalkyl, C 3-4  cycloalkyl, C 3-4  cycloalkyl-C 1-2  alkyl-, C 1-4  alkoxy, and C 1-4  haloalkoxy; 
 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, 1, or 2; 
 t2 is 0, 1, 2, 3, or 4; and 
 t3 is 0 or 1. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is R 1A . 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is R 1B . 
     
     
         4 . The compound of  claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 1  is 2,5-dioxopyrrolidin-1-yl-. 
     
     
         5 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A 1  is C 4-6  cycloalkyl or 4- to 6-membered heterocycloalkyl. 
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A 1  is C 4-6  cycloalkyl or 5- to 6-membered heterocycloalkyl. 
     
     
         7 . 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. 
     
     
         8 . 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: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is halogen, methyl, C 1  fluoroalkyl; t1 is 0 or 1; each R 3  is independently halogen, oxo, methyl, C 1  fluoroalkyl; and t2 is 0, 1, or 2. 
     
     
         10 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein t1 is 0. 
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein t2 is 0 or 1. 
     
     
         12 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein t2 is 0. 
     
     
         13 . The compound of  claim 8 , 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 . 
     
     
         14 . The compound of  claim 8 , 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 . 
     
     
         15 . The compound of  claim 8 , 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 . 
     
     
         16 . The compound of  claim 8 , 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 . 
     
     
         17 . A compound of  claim 1  selected from the group consisting of:
 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate; 
 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(tetrahydro-2H-pyran-3-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate; 
 1-[({4-[(4-fluorophenyl)sulfonyl]-1-oxa-4,9-diazaspiro[5.5]undec-9-yl}carbonyl)oxy]pyrrolidine-2,5-dione; 
 1,1,1,3,3,3-hexafluoropropan-2-yl (3R)-3-[methyl(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate; 
 N-[(3R)-8-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}-1-oxa-8-azaspiro[4.5]dec-3-yl]-N-methylbenzenesulfonamide; 
 1,1,1,3,3,3-hexafluoropropan-2-yl 3-(4-cyanophenyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate; 
 1,1,1,3,3,3-hexafluoropropan-2-yl 2-{[6-(difluoromethyl)pyridin-3-yl]oxy}-7-azaspiro[3.5]nonane-7-carboxylate; 
 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(pyrazin-2-ylsulfonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate; 
 1,1,1,3,3,3-hexafluoropropan-2-yl (3R)-3-[(phenylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate; 
 1-cyclopropyl-N-[(3R)-8-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}-1-oxa-8-azaspiro[4.5]dec-3-yl]-N-methylmethanesulfonamide; 
 1,1,1,3,3,3-hexafluoropropan-2-yl (3R)-3-{[(cyclopropylmethyl)sulfonyl](methyl)amino}-1-oxa-8-azaspiro[4.5]decane-8-carboxylate; 
 1,1,1,3,3,3-hexafluoropropan-2-yl 3-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate; 
 1,1,1,3,3,3-hexafluoropropan-2-yl 3-[3-(trifluoromethoxy)phenyl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate; 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. 
 
     
     
         18 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         20 . 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 or pharmaceutically acceptable salt according to  claim 1 , wherein the disorder is selected from the group consisting of a metabolic disorder; a kidney disease; vomiting or emesis; nausea; an eating disorder; neuropathy; burning feet syndrome; a neurodegenerative disorder; a cardiovascular disease; osteoporosis; osteoarthritis; schizophrenia; depression; bipolar disease; tremor; dyskinesia; dystonia; spasticity; Tourette's syndrome; sleep apnea; hearing loss; an eye disease; cachexia; insomnia; meningitis; sleeping sickness; progressive multifocal leukoencephalopathy; De Vivo disease; cerebral edema; cerebral palsy; withdrawal syndrome; traumatic brain injury; non-traumatic brain injury; spinal cord injury; seizures; excitotoxin exposure; ischemia; liver fibrosis, iron overload, cirrhosis of the liver; a lung disorder; a liver disorder, stroke; subarachnoid hemorrhage; intracerebral hemorrhage; vasospasm; AIDS wasting syndrome; renal ischemia; a disorder associated with abnormal cell growth or proliferation; an autoimmune disease; an inflammatory disorder; a disorder of the immune system; post-traumatic stress disorder (PTSD); acute stress disorder; panic disorder; substance-induced anxiety; obsessive-compulsive disorder (OCD); agoraphobia; specific phobia; social phobia; anxiety disorder; attention deficit disorder (ADD); attention deficit hyperactivity disorder (ADHD); Asperger's syndrome; pain; a demyelinating disease; and cognitive impairment. 
     
     
         21 . A method for inhibiting MAGL comprising contacting the MAGL with a compound or pharmaceutically acceptable salt according to  claim 1 .