Carbamate compounds and methods of making and using same

Abstract

This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition.

What is claimed is: 
     
         1 . A compound represented by: 
       
         
           
           
               
               
           
         
         wherein T is CX 3  or 
       
       
         
           
           
               
               
           
         
         X is selected independently, for each occurrence, from H, F, Cl or Br; wherein at least three occurrences of X are F; 
         V is O or NR a ; 
         R V  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3-6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl, or when R a  and R v  occur together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N; wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, heterocyclic ring and heterocyclyl are optionally substituted by one, two, or three moieties independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, cyano, phenyl; and 
         wherein 
         a) 
         R 1  and R 2  taken together with the nitrogen to which they are attached form a moiety selected from: 
         a 4-7 membered heterocyclic ring B having an additional nitrogen; or 
         a 4-7 membered heterocyclic ring A;
 wherein one carbon of ring A has a substituent represented by: 
 
       
       
         
           
           
               
               
           
         
         
           L 2  is C 1 -C 6 alkylene or C 1 -C 6 alkylene-NR a —; 
           R 3  and R 5  are each independently selected from phenyl, naphthyl, a mono or bicyclic heteroaryl and a mono or bicyclic heterocycle, wherein the heterocycle or heteroaryl has 1, 2 or 3 heteroatoms independently selected from O, S, or N; and wherein R 3  and R 5  may be independently and optionally substituted by one, two, three or four moieties each independently selected from R g ; 
           R 4  is selected from the group consisting of H, halogen, hydroxyl, cyano, or C 1 -C 5 alkoxy; 
           A is optionally substituted on another carbon by one, two, three or four substituents each independently selected from R d ; 
         
         the additional nitrogen of ring B has a substituent represented by: 
       
       
         
           
           
               
               
           
         
         
           L 3  is selected from the group consisting of: a bond, C 1 -C 6 alkylene, —C(O)—, C 1 -C 6 alkylene-C(O)—, C(O)—C 1 -C 6 alkylene-, NR a —C(O)—C 1 -C 6 alkylene-, C 1 -C 6 alkylene-O—C(O)—, —S(O) w —, and C 1 -C 6 alkylene-S(O) w —, wherein w is 0, 1, or 2, and wherein C 1 -C 6 alkylene is optionally substituted by one or two substituents selected from the group consisting of: halogen, hydroxyl, cyano, and an additional R 7 , wherein when L 3  is —S(O) w —, then R 7  is not H; 
           R 7  is selected from the group consisting of: H, phenyl, naphthyl, mono or bicyclic heteroaryl, and mono or bicyclic heterocyclyl, wherein the heteroaryl or the heterocyclyl has 1, 2 or 3 heteroatoms independently selected from O, S, or N; wherein R 7  is optionally substituted by one, two, three or four moieties independently selected from R h ; 
           B is optionally substituted on one or more carbons by one, two, three or four moieties each independently selected from R d ; 
         
         or 
         b)
 R 1  is -L 1 -R 6 ; 
 R 2  is H or C 1 -C 6 alkyl; 
 L 1  is C 1 -C 6 alkylene or a bond; 
 R 6  is selected from the group consisting of phenyl, naphthyl, a mono or bicyclic heteroaryl, and a mono or bicyclic heterocycle, wherein the heteroaryl or heterocycle has 1, 2 or 3 heteroatoms independently selected from O, S, or N; and R 6  is optionally substituted by one, two, three or four moieties independently selected from the group consisting of: halogen, phenyl (optionally substituted by one, two or three moieties independently selected from R c ), phenyloxy (optionally substituted by one, two or three moieties independently selected from R c ), anilinyl (optionally substituted on a carbon by one, two or three moieties independently selected from R c ), hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 1-6 alkoxy (optionally substituted by one, two or three halogens, cyano, or hydroxyl), R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, R a —S(O) w —, R a —S(O) w —NR b — (wherein w is 0, 1 or 2), heteroaryl (optionally substituted by one, two or three moieties independently selected from R c ), or heteroaryloxy;
 R a  and R b  may be independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl, heterocycle, and phenyl; 
 or R a  and R b , when they occur together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring or a 9-10 membered bicyclic heterocycle or spirocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-6 membered heterocyclic ring or 9-10 membered bicyclic heterocycle or spirocycle may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), hydroxyl, —C(O)—C 1-6 alkyl, —NH 2 , and —NH—C(O)—C 1-6 alkyl; 
 R c  is selected from the group consisting of halogen, cyano, hydroxyl, nitro, C 1-6 alkyl (optionally substituted by one, two, or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two, or three halogens), C 2-6 alkynyl (optionally substituted by one, two, or three halogens), C 3-6 cycloalkyl, C 1-6 alkoxy (optionally substituted by one, two, or three halogens), R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, R a —C(O)—NR a —, R a —C(O)—, R a —S(O) w —NR b — (wherein w is 0, 1 or 2), or R a —S(O) w — (wherein w is 0, 1 or 2); 
 R d  is selected from the group consisting of: H, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl) or R a R b N—C(O)—; 
 R g  is selected from the group consisting of: halogen, phenyl, phenyloxy, anilinyl, hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 3-6 cycloalkyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 2-6 alkynyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl) C 1-6 alkoxy (optionally substituted by one, two or three halogens, cyano, or hydroxyl), R a —C(O)NR a —, R a R b N—, R a R b N—SO 2 —, R a —S(O) w — (wherein w is 0, 1 or 2), R a —SO 2 —NR b —, R a R b N—C(O)—, heterocycle (optionally substituted by one, two or three moieties each independently selected from R c , and connected to R 3  or R 5  through a carbon or heteroatom) or heteroaryl (optionally substituted by one, two or three moieties each independently selected from R c , and connected to R 3  or R 5  through a carbon or heteroatom), or two adjacent R g  groups along with the carbons to which they are attached can be taken together to form a 5- or 6-member heterocyclic or heteroaryl ring optionally substituted with 0, 1 or 2 halogens selected from F or Cl and which may have one or two additional heteroatoms selected from O, S, or N; 
 R h  is selected from the group consisting of: halogen, phenyl (optionally substituted by one, two, or three moieties each independently selected from R c ), phenyloxy (optionally substituted by one, two, or three moieties each independently selected from R c ), hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 2-6 alkynyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 1-6 alkoxy (optionally substituted by one, two or three halogens, cyano, or hydroxyl), R a R b N—, R a —C(O)NR a —, R a R b N—SO 2 —, R a R b N—C(O)—, R a —S(O) w — (wherein w is 0, 1 or 2), R a —SO 2 —NR b —, heteroaryl (optionally substituted by one, two or three moieties each independently selected from R c , and connected to R 7  through a carbon or heteroatom), heterocycle (optionally substituted by one, two or three moieties each independently selected from R c , and connected to R 7  through a carbon or heteroatom) or heteroaryloxy (optionally substituted by one, two, or three moieties each independently selected from R c ), or two adjacent R h  groups along with the carbons to which they are attached can be taken together to form a 5- or 6-member heterocyclic or heteroaryl ring optionally substituted with 0, 1 or 2 halogens selected from F or Cl and which may have one or two additional heteroatoms selected from O, S, or N; 
 
 
         and pharmaceutically acceptable salts or stereoisomers thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein T is CX 3 . 
     
     
         3 . The compound of  claim 1 , wherein R V  is selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, benzyl and phenyl. 
     
     
         4 . The compound of anyone of  claims 1 - 3 , wherein at least four occurrences of X is halogen. 
     
     
         5 . The compound of any one of  claims 1 - 4 , wherein six occurrences of X is halogen. 
     
     
         6 . The compound of any one of  claims 1 - 5 , represented by: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of any one of  claims 1 - 6 , wherein R 1  and R 2  taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring B having an additional nitrogen. 
     
     
         8 . The compound of any one of  claims 1 - 7 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
         wherein p is 0, 1, or 2; and 
         R d  is selected from the group consisting of: H, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl) or R a R b N—C(O)—, wherein L 3  and R 7  are described above 
       
     
     
         9 . The compound of  claim 8 , wherein:
 L 3  is selected from the group consisting of a bond, C 1 -C 2 alkylene, —C(O)—, —CH—C(O)—NH, —S(O) w —, and C 1 -C 2 alkylene-S(O) w —, wherein w is 0, 1, or 2, and wherein C 1 -C 2 alkylene is optionally substituted by a substituent selected from the group consisting of: phenyl, biphenyl, phenyloxyphenyl (each optionally substituted by halogen, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl)), mono or bicyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from O, S, or N and mono or bicyclic heterocycle having 1, 2 or 3 heteroatoms independently selected from O, S, or N; and   R 7  is selected from the group consisting of phenyl, biphenyl, phenyloxyphenyl, and mono or bicyclic heteroaryl or mono or bicyclic heterocycle, wherein the heteroaryl or heterocycle has 1, 2 or 3 heteroatoms independently selected from O, S, or N, and R 7  is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, cyano, phenyl (optionally substituted by one, two, or three substituents selected from the group consisting of: halogen, methyl, ethyl, propyl, t-butyl, cyano or CF 3 ), phenyloxy, hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl), C 1-6 alkoxy (optionally substituted by one, two or three halogens), R a R b N—, R a R b N—SO 2 —, R a —S(O) w —NR b — (wherein w is 0, 1 or 2), R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, heteroaryl (optionally substituted by one or two substituents each selected from C 1-6 alkyl or halogen), or heteroaryloxy (optionally substituted by one or two substituents each selected from C 1-6 alkyl or halogen).   
     
     
         10 . The compound of  claim 8  or  9 , wherein L 3  is selected from the group consisting of a bond, —CH 2 —, —S(O) 2 —, or —C(O)—. 
     
     
         11 . The compound of  claim 8  or  9 , wherein R 7  is selected from the group consisting of phenyl, naphthyl, indanyl, benzodioxole, benzoxazole, benzoisoxazole, benzimidazole, benzotriazole, oxadiazole, indazole, isooxazole, quinoline, isoquinoline, pyridine, pyrazine, pyrimidine, thienyl, thiazole, benzothiopene, indole, benzothiadiazole, pyrazole, or 3,4-dihydro-2H-benzo[b][1,4]oxazine, and R 7  is optionally substituted by one, two, three or four substituents selected from the group consisting of halogen, phenyl (optionally substituted by one, two, or three substituents selected from the group consisting of: halogen, methyl, ethyl, propyl, t-butyl, cyano or CF 3 ), phenyloxy, hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl), C 1-6 alkoxy(optionally substituted by one, two or three halogens), R a R b N—, R a R b N—SO 2 —, R a —S(O) w —NR b — (wherein w is 0, 1 or 2), R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, heteroaryl (optionally substituted by one or two substituents each selected from C 1-6 alkyl or halogen), or heteroaryloxy. 
     
     
         12 . The compound of any one of  claims 1 - 11 , wherein R 7  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein
 R c  is selected from the group consisting of H, phenyl (optionally substituted by one, two or three substituents each independently selected from halogen, C 1-6 alkyl (optionally substituted by one, two or three halogens), and C 1-6 alkoxy (optionally substituted by one, two or three halogens)), and C 1-6 alkyl (optionally substituted by one, two or three halogens); and 
 R i  and R j  may be independently selected from the group consisting of: H, CH 3 , C 2-6 alkyl (optionally substituted by one, two or three moieties independently selected from R c )), phenyl (optionally substituted by one, two or three moieties independently selected from R c ), and C 3-6 cycloalkyl (optionally substituted by one, two or three moieties independently selected from R c ) where R c  is described above. 
 
       
     
     
         13 . The compound of any one of  claims 1 - 12 , represented by a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein R f  is independently selected for each occurrence from H, R a R b N—, R a R b N—C(O)—, phenyoxy, halogen, C 1-6 alkyl (optionally substituted by one, two or three halogens) and C 1-6 alkoxy (optionally substituted by one, two or three halogens) wherein R a  and R b  together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring or a 9-10 membered bicyclic heterocyclic ring or spirocycle, which may have an additional heteroatom selected from O, S, or N; wherein the 4-6 membered heterocyclic ring or 9-10 membered bicyclic heterocyclic ring or spirocycle may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, C 1-6 alkyl, hydroxyl, —NH 2 , —S(O) w —C 1-6 alkyl (wherein w is 0, 1 or 2) and NH—C(O)—C 1-6 alkyl. 
       
     
     
         14 . The compound of  claim 13 , wherein one R f  is a heterocyclic ring selected from piperidinyl, pyrrolidinyl, morpholinyl, and pyrazole. 
     
     
         15 . The compound of any one of  claims 1 - 7 , wherein L 3  is —CH—R 10 , wherein R 10  selected from the group consisting of phenyl, naphthyl, indanyl, benzodioxole, benzoxazole, benzoisoxazole, benzimidazole, benzotriazole, oxadiazole, indazole, isooxazole, quinoline, isoquinoline, pyridine, pyrazine, pyrimidine, thienyl, thiazole, benzothiopene, indole, benzothiadiazole, pyrazole, or 3,4-dihydro-2H-benzo[b][1,4]oxazine, wherein R 10  may be optionally substituted by one, two or three moieties each independently selected from the group consisting of halogen, phenyl (optionally substituted by halogen, cyano, methyl or CF 3 ), phenyloxy (optionally substituted by halogen, cyano, methyl or CF 3 ), hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl), C 1-6 alkoxy (optionally substituted by one, two or three halogens, cyano or hydroxyl), R a R b N—, R a R b N—SO 2 —, R a —S(O) w —NR b — (wherein w is 0, 1 or 2), R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, heteroaryl (optionally substituted by C 1-6 alkyl), or heteroaryloxy. 
     
     
         16 . The compound of  claim 15 , wherein R 10  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein
 R c  is selected from the group consisting of H, phenyl (optionally substituted by one, two or three substituents each independently selected from halogen, C 1-6 alkyl (optionally substituted by one, two or three halogens), and C 1-6 alkoxy (optionally substituted by one, two or three halogens)), and C 1-6 alkyl (optionally substituted by one, two or three halogens); 
 
       
     
     
         17 . The compound of  claim 15 , wherein R 7  is selected from the group consisting of phenyl, naphthyl, indanyl, benzodioxole, benzoxazole, benzoisoxazole, benzimidazole, benzotriazole, oxadiazole, indazole, isooxazole, quinoline, isoquinoline, pyridine, pyrazine, pyrimidine, thienyl, thiazole, benzothiopene, indole, benzothiadiazole, pyrazole, or 3,4-dihydro-2H-benzo[b][1,4]oxazine, and R 7  is optionally substituted by one, two or three substituents selected from the group consisting of halogen, phenyl (optionally substituted by one, two, or three substituents selected from the group consisting of: halogen, methyl, ethyl, propyl, t-butyl, cyano or CF 3 ), phenyloxy, hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl), C 1-6 alkoxy, R a R b N—, R a R b N—SO 2 —, R a —S(O) w —NR b — (wherein w is 0, 1 or 2), R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, heteroaryl (optionally substituted by one or two substituents each selected from C 1-6 alkyl or halogen), or heteroaryloxy. 
     
     
         18 . The compound of any one of  claims 1 - 6 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 2  is H or C 1 -C 3 alkyl; 
 L 1  is —CH 2 — or —CH 2 —CH 2 —; and 
 R 6  is selected from the group consisting of phenyl, naphthyl, indanyl, benzodioxole, benzoxazole, benzoisoxazole, benzimidazole, benzotriazole, oxadiazole, indazole, isooxazole, quinoline, isoquinoline, pyridine, pyrazine, pyrimidine, thienyl, thiazole, benzothiopene, indole, benzothiadiazole, pyrazole, or 3,4-dihydro-2H-benzo[b][1,4]oxazine, wherein R 6  may be optionally substituted by one, two, three or four moieties each independently selected from the group consisting of halogen, phenyl (optionally substituted by halogen, cyano, methyl or CF 3 ), phenyloxy, hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl), C 1-6 alkoxy (optionally substituted by one, two or three halogens, or hydroxyl), R a R b N—, R a R b N—SO 2 —, R a —S(O) w — (wherein w is 0, 1 or 2), R a —S(O) w —NR b — (wherein w is 0, 1 or 2), R a R b N—C(O)—, C 1-6 alkyl-C(O)NR a —, heteroaryl (optionally substituted by C 1-6 alkyl), or heteroaryloxy. 
 
     
     
         19 . The compound of  claim 18 , wherein R 6  is phenyl, optionally substituted by halogen, cyano, hydroxyl, methoxy, pyridine (optionally substituted by methyl), phenyl, or phenyloxy. 
     
     
         20 . The compound of  claim 18  or  19 , wherein R 2  is methyl. 
     
     
         21 . The compound of any one of  claims 18 - 20 , wherein L 1  is —CH 2 —. 
     
     
         22 . The compound of any one of  claims 18 - 20 , wherein R 6  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of any one of  claims 1 - 6 , wherein R 1  and R 2  taken together with the nitrogen to which they are attached form a 4-7 membered heterocyclic ring A wherein one carbon of ring A has a substituent represented by: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 23 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
         wherein p is 0, 1, or 2; and 
         R d  is selected from the group consisting of: H, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl) or R a R b N—C(O)—. 
       
     
     
         25 . The compound of  claim 23  or  24 , wherein R 3  and R 5  are each independently selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of any one of  claims 23 - 25 , wherein R 4  is selected from the group consisting of H, hydroxyl and methoxy. 
     
     
         27 . A compound represented by: 
       
         
           
           
               
               
           
         
         wherein:
 p is 0, 1, or 2; 
 R d  is selected from the group consisting of: H, C 1-6 alkyl (optionally substituted by one, two or three halogens, or hydroxyl) or R a R b N—C(O)—. 
 L 3  is selected from the group consisting of: a bond, C 1 -C 6 alkylene, —C(O)—, C 1 -C 6 alkylene-C(O)—, C 1 -C 6 alkylene-O—C(O)—, NR a —C(O)—C 1 -C 6 alkylene-, —S(O) w —, and C 1 -C 6 alkylene-S(O) w —, wherein w is 0, 1, or 2, and wherein C 1 -C 6 alkylene is optionally substituted by one or two substituents selected from the group consisting of: halogen, hydroxyl, cyano, and an additional R 7 ; 
 R 7  is selected from the group consisting of: H, phenyl, naphthyl, mono or bicyclic heteroaryl or mono or bicyclic heterocycle, wherein the heteroaryl or heterocycle has 1, 2 or 3 heteroatoms independently selected from O, S, or N; wherein R 7  is optionally substituted by one, two, three or four moieties independently selected from the group consisting of halogen, phenyl (optionally substituted by one, two, or three moieties each independently selected from R c ), phenyloxy (optionally substituted by one, two, or three moieties each independently selected from R c ), hydroxyl, cyano, C 1-6 alkyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two or three halogens, cyano, or hydroxyl), C 1-6 alkoxy (optionally substituted by one, two or three halogens, cyano, or hydroxyl), R a R b N—, R a —C(O)NR a —, R a R b N—SO w — (wherein w is 0, 1 or 2); R a R b N—C(O)—, R a —S(O) w — (wherein w is 0, 1 or 2), R a —S(O) w —NR b — (wherein w is 0, 1 or 2), heteroaryl (optionally substituted by one, two or three moieties each independently selected from R c ) or heteroaryloxy (optionally substituted by one, two, or three moieties each independently selected from R c );
 R a  and R b  may be independently selected, for each occurrence, from the group consisting of hydrogen and C 1-3 alkyl; wherein C 1-3 alkyl may optionally be substituted by one or more substituents selected from halogen, cyano, oxo, hydroxyl, heterocycle, and phenyl; 
 
 or R a  and R b , when they occur together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring or a 9-10 membered bicyclic heterocycle or spirocyclic ring, which may have an additional heteroatom selected from O, S, or N; wherein the 4-6 membered heterocyclic ring or 9-10 membered bicyclic heterocycle or spirocycle may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo, C 1-6 alkyl, —S(O) w —C 1-6 alkyl (where w is 0, 1 or 2), hydroxyl, —NH 2 , and NH—C(O)—C 1-6 alkyl; 
 R c  is selected from the group consisting of halogen, cyano, hydroxyl, nitro, C 1-6 alkyl (optionally substituted by one, two, or three halogens, cyano, or hydroxyl), C 2-6 alkenyl (optionally substituted by one, two, or three halogens), C 3-6 cycloalkyl, C 1-6 alkoxy (optionally substituted by one, two, or three halogens), R a R b N—, R a R b N—SO 2 —, R a R b N—C(O)—, R a —C(O) w —NR a —, R a —C(O)—, R a —S(O) w —NR b — (wherein w is 0, 1 or 2), or R a —S(O) w — (wherein w is 0, 1 or 2); 
 
       
       
         
           
           
               
               
           
         
         
           T is CX 3  or 
           X is independently for each occurrence halogen or H; 
           V is O or NR a ; 
           R V  is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3-6 cycloalkyl, phenyl, heteroaryl, and heterocyclyl, or when R a  and R v  occur together with the nitrogen to which they are attached, form a 4-6 membered heterocyclic ring which may have an additional heteroatom selected from O, S, or N; wherein C 1 -C 6 alkyl, C 2 -C 6 alkenyl, phenyl, heterocyclic ring and heterocyclyl are optionally substituted by one, two, or three moieties independently selected from the group consisting of halogen, hydroxyl, C 1 -C 6 alkyl, cyano, phenyl; 
         
         or pharmaceutically acceptably salts or stereoisomers thereof. 
       
     
     
         28 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and stereoisomers thereof, or pharmaceutically acceptable salts thereof. 
     
     
         29 . A compound selected from the group consisting of:
 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[bis(4-chlorophenyl)methyl]-3-methylpiperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(oxazol-4-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(4-chloro-2-methylphenyl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(1-methyl-1H-indazol-5-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(di(pyridin-3-yl)methyl)piperazine-1-carboxylate   1,1,1-trifluoro-3-methoxy-3-oxopropan-2-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate   2-((4-(bis(4-chlorophenyl)methyl)piperazine-1-carbonyl)oxy)-3,3,3-trifluoropropanoic acid   1,1,1-trifluoro-3-(methylamino)-3-oxopropan-2-yl 4-(bis(4-chlorophenyl)methyl)piperazine-1-carboxylate   Methyl 3,3,3-trifluoro-2-((methyl(phenethyl)carbamoyl)oxy)propanoate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-fluoro-4-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-bromo-2-phenoxybenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-(morpholin-4-yl)-3-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-fluoro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-chloro-4-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-chloro-4-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl (2 S)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl (2S)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl (2R)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl (2R)-2-methyl-4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chlorobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-methyl-4-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-bromo-2-(piperidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-bromo-2-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-methoxy-4-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-methyl-4-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-methoxybenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-methylbenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-bromo-2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-fluoro-4-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-chloro-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-chloro-6-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(1H-pyrazol-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-acetamidopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-morpholinobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(4-chloro-1H-pyrazol-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(morpholin-4-yl)-2-(trifluoromethoxy)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl (2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl (2R)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate   (S)-1,1,1,3,3,3-hexafluoropropan-2-yl 2-methyl-4-(4-morpholino-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate   (R)-1,1,1,3,3,3-hexafluoropropan-2-yl2-methyl-4-(4-morpholino-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-(pyrrolidin-1-yl)-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-chloro-2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-fluoro-2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((3-isopropyl-[1,1′-biphenyl]-4-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-isopropyl-4-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(4-acetylpiperazin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(azetidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-fluoro-4-(1H-pyrazol-1-yl)benzyl)piperazine-1-carboxylate   (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-acetamidopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate   (S)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-acetamidopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(morpholin-4-yl)-2-(propan-2-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-chloro-4-(pyrrolidine-1-carbonyl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-(azetidine-1-carbonyl)-2-chlorobenzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-chloro-2-(morpholine-4-carbonyl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(3-chloro-2-(pyrrolidine-1-carbonyl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(5H-pyrrolo [3,4-b]pyridin-6(7H)-yl)benzyl)piperazine-1-carboxylate   (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(hexahydropyrrolo[1,2-c]pyrazin-2(1H)-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-chloro-2-(4-(methylsulfonyl)piperazin-1-yl)benzyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((5-(4-methoxyphenyl)isoxazol-3-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((5-phenylisoxazol-3-yl)methyl)piperazine-1-carboxylate,   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl)piperazine-1-carboxylate,   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((1-methyl-3-phenyl-1H-pyrazol-5-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((1-methyl-3-phenyl-1H-pyrazol-4-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((4-bromo-1-methyl-1H-pyrazol-5-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-(2-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-phenyl-1-(propan-2-yl)-1H-pyrazol-4-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[3-(2-chlorophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 3-methyl-4-[[4-phenylphenyl)methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[6-(2-fluorophenyl)-2-methylpyridin-3-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-6-(3-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[6-(3-fluorophenyl)-2-methylpyridin-3-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-((3-morpholino-[1,1′-biphenyl]-4-yl)methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[(2-methoxy-4-phenylphenyl)methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(pyridin-3-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(3-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(3-fluorophenyl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[(2-fluoro-4-phenylphenyl)methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[(2-methyl-4-phenylphenyl)methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(2-methylpyridin-3-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(2-methylpyridin-3-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-(3-fluorophenyl)-6-methylpyridin-2-yl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-(dimethylcarbamoyl)-4-phenylphenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-([4-phenyl-2-[(pyrrolidin-1-yl)carbonyl]phenyl]methyl)piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(3-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(6-methylpyridin-2-yl)phenyl]methyl]piperazine-1-carboxylate   1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[6-methyl-5-(3-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate   And pharmaceutically acceptable salt or stereoisomers thereof.   
     
     
         30 . A pharmaceutically acceptable composition comprising a compound of anyone of  claims 1 - 29 , and a pharmaceutically acceptable excipient. 
     
     
         31 . A method of treating pain, comprising administering to a patient in need thereof an effective amount of a compound of any one of  claims 1 - 29 . 
     
     
         32 . A method of treating a solid tumor cancer in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of any one of  claims 1 - 29 . 
     
     
         33 . A method of treating obesity or reducing adipose tissue in patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of any one of  claims 1 - 29 . 
     
     
         34 . A method of treating or ameliorating Downs syndrome or Alzheimer's disease, comprising administering to a patient in need thereof an effective amount of a compound of any one of  claims 1 - 29 .