Pyrazole compounds and methods of making and using same

Abstract

Provided herein are pyrazole compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL and/or FAAH. Furthermore, the subject compounds and compositions are useful for the treatment of, for example, pain.

We claim: 
     
       1. A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, —CF 3 , C 1-6 alkyl, —CN, halogen, optionally substituted phenyl, —CO 2 R 11 , or —C(O)NR 12 R 13 ; 
         R 2  is H or optionally substituted phenyl; 
         R 3  is H, halogen, —OR 6 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted heterocycloalkyl, optionally substituted C 1-6 alkyl-heterocycloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl; 
         R 4  is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or phenyl; or 
         R 3  and R 4  are combined to form a heterocycloalkyl ring; 
         R 5  is H, halogen or C 1-6 alkyl; 
         R 6  is H, C 1-6 alkyl, optionally substituted phenyl, optionally substituted C 1-6 alkyl-phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or —C 1-6  alkylC(O)NR 9 R 10 ; 
         R 9  and R 10  are each independently H, or C 1-6 alkyl; or R 9  and R 10  together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; 
         R 11  is H or C 1-6 alkyl; and 
         R 12  and R 13  are each independently H, C 1-6 alkyl, or C 3-8 cycloalkyl; or R 12  and R 13  together with the nitrogen to which they are attached are combined to form a 4-, 5-, 6-, 7-, or 8-member heterocycloalkyl ring, optionally substituted with C 1-6 alkyl or C 3-8 cycloalkyl; 
         or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. 
       
     
     
       2. A compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, —CF 3 , C 1-6 alkyl, cyano, halogen, optionally substituted phenyl, —CO 2 R 11 , or —C(O)NR 12 R 13 ; 
         R 2  is H or optionally substituted phenyl; 
         R 3  is H, halogen, —OR 6 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted heterocycloalkyl, optionally substituted C 1-6 alkyl-heterocycloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl; 
         R 4  is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or phenyl; or 
         R 3  and R 4  are combined to form a heterocycloalkyl ring; 
         R 5  is H, halogen or C 1-6 alkyl; 
         R 6  is H, C 1-6 alkyl, optionally substituted phenyl, optionally substituted C 1-6 alkyl-phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or —C 1-6  alkylC(O)NR 9 R 10 ; 
         R 9  and R 10  are each independently H, or C 1-6 alkyl; or R 9  and R 10  together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; 
         R 1  is H or C 1-6 alkyl; 
         R 12  and R 13  are each independently H, C 1-6 alkyl, or C 3-8 cycloalkyl; or R 12  and R 13  together with the nitrogen to which they are attached are combined to form a 4-, 5-, 6-, 7-, or 8-member heterocycloalkyl ring, optionally substituted with C 1-6 alkyl or C 3-8 cycloalkyl, and optionally containing another heteroatom selected from N, S or O; 
         R 14  is H or C 1-6 alkyl; and 
         R 15  is H or C 1-6 alkyl; 
         or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof. 
       
     
     
       3. A compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, —CF 3 , C 1-6 alkyl, cyano, halogen, optionally substituted phenyl, —CO 2 R 11 , or —C(O)NR 12 R 13 ; 
         R 2  is H or optionally substituted phenyl; 
         R 3  is H, halogen, —OR 6 , C 1-6 alkyl, C 1-6 haloalkyl, optionally substituted heterocycloalkyl, optionally substituted C 1-6 alkyl-heterocycloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl; 
         R 4  is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or phenyl; or 
         R 3  and R 4  are combined to form a heterocycloalkyl ring; 
         R 5  is H, halogen or C 1-6 alkyl; 
         R 6  is H, C 1-6 alkyl, optionally substituted phenyl, optionally substituted C 1-6 alkyl-phenyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or —C 1-6  alkylC(O)NR 9 R 10 ; 
         R 9  and R 10  are each independently H, or C 1-6 alkyl; or R 9  and R 10  together with the nitrogen to which they are attached are combined to form a heterocycloalkyl ring; 
         R 11  is H or C 1-6 alkyl; 
         R 12  and R 13  are each independently H, C 1-6 alkyl, or C 3-8 cycloalkyl; or R 12  and R 13  together with the nitrogen to which they are attached are combined to form a 4-, 5-, 6-, 7-, or 8-member heterocycloalkyl ring, optionally substituted with C 1-6 alkyl or C 3-8 cycloalkyl, and optionally containing another heteroatom selected from N, S or O; and 
         R 16  is H, C 1-6 alkyl, or —C(O)C 1-6 alkyl; 
         or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof. 
       
     
     
       4. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 3  is optionally substituted heterocycloalkyl. 
     
     
       5. The compound of  claim 4 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 3  is optionally substituted heteroaryl and the heteroaryl is a 5-6 membered heteroaryl ring. 
     
     
       7. The compound of  claim 6 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
       8. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 3  is halogen. 
     
     
       9. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 3  is C 1-6 haloalkyl. 
     
     
       10. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 4  is halogen. 
     
     
       11. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 4  is C 1-6 haloalkyl. 
     
     
       12. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 5  is H and R 2  is H. 
     
     
       13. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 1  is halogen. 
     
     
       14. The compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 1  is —C(O)NR 12 R 13 . 
     
     
       15. The compound of  claim 14 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 12  and R 13  are each H. 
     
     
       16. The compound of  claim 14 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 12  and R 13  together with the nitrogen to which they are attached are combined to form a 5- or 6-member heterocycloalkyl ring, optionally substituted with C 1-6 alkyl or C 3-8 cycloalkyl. 
     
     
       17. The compound of  claim 16 , or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, wherein R 12  and R 13  together with the nitrogen to which they are attached are combined to form an unsubstituted pyrrolidine, unsubstituted piperidine, or unsubstituted morpholine ring. 
     
     
       18. A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. 
     
     
       19. A pharmaceutical composition comprising a compound of  claim 3 , or a solvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
       20. A method of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of  claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein the disease or disorder is selected from epilepsy/seizure disorder, neuromyelitis optica (NMO), Tourette syndrome, persistent motor tic disorder, persistent vocal tic disorder, abdominal pain associated with irritable bowel syndrome, multiple sclerosis, Alzheimer's disease, inflammatory bowel disease, neuropathic pain, and inflammatory pain.