Isoxazolines as inhibitors of fatty acid amide hydrolase

Abstract

The present invention provides isoxazoline FAAH inhibitors of the formula (I): or pharmaceutically acceptable forms thereof, wherein each of G, R a , R b , R c , and R d are as defined herein. The present invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. The present invention also provides methods for treating an FAAH-mediated condition comprising administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable form thereof, to a subject in need thereof.

1 - 13 . (canceled) 
     
     
         14 . A compound having formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable form thereof; 
         wherein 
         R 18  is selected from —OH, —OR 16 , —N(R 17 ) 2 , —CN, —C(═O)R 16 , —C(═O)N(R 17 ) 2 , —CO 2 R 16 , —SO 2 R 16 , —C(═NR 17 )OR 16 , —C(═NR 17 )N(R 17 ) 2 , —SO 2 N(R 17 ) 2 , —SO 2 R 17 , —SO 2 OR 17 , —SOR 16 , —C(═S)N(R 7 ) 2 , —C(═O)SR 17 , —C(═S)SR 17 , —P(═O) 2 R 16 , —P(═O)(R 16 ) 2 , —P(═O) 2 N(R 17 ) 2 , —P(═O)(NR 17 ) 2 , C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, or two R 17  groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 19  groups; 
         each instance of R 16  is, independently, selected from C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 19  groups; 
         each instance of R 17  is, independently, selected from hydrogen, C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, or two R 17  groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 19  groups; 
         each instance of R 19  is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR 20 , —ON(R 21 ) 2 , —N(R 21 ) 2 , —N(R 21 ) 3 X − , —N(OR 20 )R 21 , —SH, —SR 20 , —SSR 20 , —C(═O)R 20 , —CO 2 H, —CO 2 R 20 , —OC(═O)R 20 , —OC 2 R 20 , —C(═O)N(R 21 ) 2 , —OC(═O)N(R 21 ) 2 , —NR 21 C(═O)R 20 , —NR 21 CO 2 R 20 , —NR 21 C(═O)N(R 21 ) 2 , —C(═NR 21 )OR 20 , —OC(═NR 21 )R 20 , —OC(═NR 21 )OR 20 , —C(═NR 21 )N(R 21 ) 2 , —OC(═NR 21 )N(R 21 ) 2 , —NR 21 C(═NR 21 )N(R 21 ) 2 , —NR 21 SO 2 R 20 , —SO 2 N(R 21 ) 2 , —SO 2 R 20 , —SO 2 OR 20 , —OSO 2 R 20 , —S(═O)R 20 , —Si(R 20 ) 3 , —OSi(R 20 ) 3 , —C(═S)N(R 21 ) 2 , —C(═O)SR 20 , —C(═S)SR 20 , —SC(═S)SR 20 , —P(═O) 2 R 20 , —P(═O)(R 20 ) 2 , —OP(═O)(R 20 ) 2 , —OP(═O)(OR 20 ) 2 , C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  carbocyclyl, 3-10 membered heterocyclyl, C 6-10  aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 22  groups, or two geminal R 19  substituents can be joined to form ═O or ═S; 
         each instance of R 20  is, independently, selected from C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-10  carbocyclyl, C 6-10  aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 22  groups; 
         each instance of R 21  is, independently, selected from hydrogen, C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  carbocyclyl, 3-10 membered heterocyclyl, C 6-10  aryl and 5-10 membered heteroaryl, or two R 21  groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 22  groups; and 
         each instance of R 22  is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6  alkyl, —ON(C 1-6  alkyl) 2 , —N(C 1-6  alkyl) 2 , —N(C 1-6  alkyl) 3 X, —NH(C 1-6  alkyl) 2 X, —NH 2 (C 1-6  alkyl)X, —NH 3 X, —N(OC 1-6  alkyl)(C 1-6  alkyl), —N(OH)(C 1-6  alkyl), —NH(OH), —SH, —SC 1-6  alkyl, —SS(C 1-6  alkyl), —C(═O)(C 1-6  alkyl), —CO 2 H, —CO 2 (C 1-6  alkyl), —OC(O)(C 1-6  alkyl), —OCO 2 (C 1-6  alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6  alkyl) 2 , —OC(═O)NH(C 1-6  alkyl), —NHC(═OX)(C 1-6  alkyl), —N(C 1-6  alkyl)C(═O)(C 1-6  alkyl), —NHCO 2 (C 1-6  alkyl), —NHC(═O)N(C 1-6  alkyl) 2 , —NHC(═O)NH(C 1-6  alkyl), —NHC(═O)NH 2 , —C(═NH)O(C 1-6  alkyl), —OC(═NH)(C 1-6  alkyl), —OC(═NH)OC 1-6  alkyl, —C(═NH)N(C 1-6  alkyl) 2 , —C(═NH)NH(C 1-6  alkyl), —C(═NH)NH 2 , —OC(═NH)N(C 1-6  alkyl) 2 , —OC(NH)NH(C 1-6  alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6  alkyl) 2 , —NHC(═NH)NH 2 , —NHSO 2 (C 1-6  alkyl), —SO 2 N(C 1-6  alkyl) 2 , —SO 2 NH(C 1-6  alkyl), —SO 2 NH 2 , —SO 2 C 1-6  alkyl, —SO 2 OC 1-6  alkyl, —OSO 2 C 1-6  alkyl, —SOC 1-6  alkyl, —Si(C 1-6  alkyl) 3 , —OSi(C 1-6  alkyl) 3  —C(═S)N(C 1-6  alkyl) 2 , C(═S)NH(C 1-6  alkyl), C(═S)NH 2 , —C(═O)S(C 1-6  alkyl), —C(═S)SC 1-6  alkyl, —SC(═S)SC 1-6  alkyl, —P(═O) 2 (C 1-6  alkyl), —P(═O)(C 1-6  alkyl) 2 , —OP(═O)(C 1-6  alkyl) 2 , —OP(═O)(OC 1-6  alkyl) 2 , C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  carbocyclyl, C 6-10  aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R 22  substituents can be joined to form ═O or ═S; 
         wherein X −  is a counterion 
         G is selected from —CN, —NO 2 , —S(═O)R e , —SO 2 R e , —SO 2 NR f R e , —PO 2 R e , —PO 2 OR e , —PO 2 NR f R e , —(C═O)R e , —(C═O)OR e , —(C═O)NR f R e , —Br, —I, —F, —Cl, —OR e , —ONR f R e , —ONR f (C═O)R e , —ONR f SO 2 R e , —ONR f PO 2 R e , —ONR f PO 2 OR e , —SR e , —OSO 2 R e , —NR f SO 2 R e , —OPO 2 R e , —OPO 2 OR e , —NR f PO 2 R e , —NR f PO 2 OR e , —OPO 2 NR f R e , —O(C═O)R e , —O(C═O)OR e , —NR f R e , —NR f (C═O)R e , —NR f (C═O)R e , —O(C═O)NR f R e , —NR f (C═NR f )NR f R e , —O(C═NR f )NR f R e , —NR f (C═NR f )R e , —[N(R f ) 2 R e ] 30  X − ; and 
         each R e  is selected from C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  carbocycyl, C 6-14  aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl: each R f  attached to a nitrogen atom is, independently, selected from —H, C 1-10  alkyl, or an amino protecting group: or R e  and R f  are joined to form an 3-14 membered heterocyclyl ring or an 5-14 membered heteroaryl ring. 
       
     
     
         15 - 19 . (canceled) 
     
     
         20 . The compound according to  claim 14 , wherein G is selected from —Cl, —Br, —I, —OR e , —ONR f R e , —ONR f (C═O)R e , —ONR f SO 2 R e , —ONR f PO 2 R e , —ONR f PO 2 OR e , —SR e , —OSO 2 R e , —NR f SO 2 R e , —OPO 2 R e , —OPO 2 OR e , —NR f PO 2 R e , —NR f PO 2 OR e , —OPO 2 NR f R e , —O(C═O)R e , —O(C═O)OR e , —NR f R e , —NR f (C═O)R e , —NR f (C═O)OR e , —O(C═O)NR f R e , —NR f (C═NR f )NR f R e , —O(C═NR f )NR f R e , —NR f (C═NR f )OR e , and —[N(R ff ) 2 R e ] + X −  wherein X −  is a counterion. 
     
     
         21 . The compound according to  claim 20 , wherein G is —OR e . 
     
     
         22 . The compound according to  claim 21 , wherein R e  is C 6-14  aryl. 
     
     
         23 . The compound according to  claim 22 , wherein R e  is phenyl. 
     
     
         24 . (canceled) 
     
     
         25 . The compound according to  claim 23 , wherein R e  is a phenyl group of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         x is 0, 1, 2, 3, 4 or 5, and 
         each R h  is, independently, selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR i , —ON(R k ) 2 , —N(R k ) 2 , —N(R k ) 3   + X − , —N(OR j )R k , —SH, —SR i , —SSR j , —C(═O)R i , —CO 2 H, —CHO, —CO 2 R i , —OC(═O)R i , —OCO 2 R i , —C(═O)N(R k ) 2 , —OC(═O)N(R k ) 2 , —NR k  C(═O)R i , —NR k  CO 2 R i , —NR k  C(═O)N(R k ) 2 , —C(═NR k ) R i , —C(═NR k )OR i , —OC(═NR k )R i , —OC(═NR k )OR i , —C(═NR k )N(R k ) 2 , —OC(═NR k )N(R k ) 2 , —NR k  C(═NR k )N(R k ) 2 , —C(═O)NR k  SO 2 R i , —NR k  SO 2 R i , —SO 2 N(R k ) 2 , —SO 2 R i , —SO 2 OR i , —OSO 2 R i , —S(═O)R i , —OS(═O)R i , —Si(R i ) 3 , —OSi(R i ) 3  —C(═S)N(R k ) 2 , —C(═O)SR i , —C(═S)SR i , —SC(S)SR i , —P(═O) 2 R i , —OP(═O) 2 R i , —P(═O)(R i ) 2 , —OP(═O)(R i ) 2 , —OP(═O)(OR j ) 2 , —P(═O) 2 N(R k ) 2 , —OP(═O) 2 N(R k ) 2 , —P(═O)(NR k ) 2 , —OP(═O)(NR k ) 2 , —NR k  P(═OX)(OR j ) 2 , —NR k  P(═O)(NR k ) 2 , —P(R j ) 2 , —P(R j ) 3 , —OP(R j ) 2 , —OP(R j ) 3 , —B(OR j ) 2 , —BR i (OR j ), C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-14  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R m  groups; 
         each instance of R i  is, independently, selected from C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R m  groups; 
         each instance of R k  is, independently, selected from hydrogen, —OH, —OR i , —N(R j ) 2 , —CN, —C(═O)R i , —C(═O)N(R j ) 2 , —CO 2 R i , —SO 2 R i , —C(═NR j )OR i , —C(═NR j )N(R j ) 2 , —SO 2 N(R j ) 2 , —SO 2 R j , —SO 2 OR j , —SOR i , —C(═S)N(R j ) 2 , —C(═O)SR j , —C(═S)SR j , —P(═O) 2 R i , —P(═O)(R i ) 2 , —P(═O) 2 N(R j ) 2 , —P(═O)(NR j ) 2 , C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, or two Rj groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R m  groups; 
         each instance of R j  is, independently, selected from hydrogen, C 1-10  alkyl, C 1-10  perhaloalkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, and 5-14 membered heteroaryl, or two Rj groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R m  groups; 
         each instance of R m  is, independently, selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR o , —ON(R n ) 2 , —N(R no ) 2 , —N(R n ) 3  X − , —N(OR o )R n , —SH, —SR o , —SSR o , —C(═O)R o , —CO 2 H, —CO 2 R o , —OC(═O)R o , —OCO 2 R o , —C(═O)N(R n ) 2 , —OC(═O)N(R o ) 2 , —NR c  (═O)R o , —NR n CO 2 R o , —NR c  (═O)N(R n ) 2 , —C(═NR n )OR o , —OC(═NR n )R o , —OC(═NR n )OR o , —C(═NR n )N(R n ) 2 , —OC(═NR n )N(R n ) 2 , —NR n C(═NR n )N(R n ) 2 , —NR n SO 2 R o , —SO 2 N(R n ) 2 , —SO 2 R o , —SO 2 OR o , —OSO 2 R o , —S(═O)R o , —Si(R o ) 3 , —OSi(R o ) 3 , —C(═S)N(R n ) 2 , —C(═O)SR o , —C(═S)SR o , —SC(═S)SR o , —P(═O) 2 R o , —P(═O)(R o ) 2 , —OP(═O)(R o ) 2 , —OP(═O)(OR o ) 2 , C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  carbocyclyl, 3-14 membered heterocyclyl, C 6-14  aryl, 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R p  groups, or two geminal R m  substituents can be joined to form ═O or ═S; 
         each instance of R o  is, independently, selected from C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-10  carbocyclyl, C 6-10  aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R p  groups; 
         each instance of R n  is, independently, selected from hydrogen, C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-10  carbocyclyl, 3-10 membered heterocyclyl, C 6-10  aryl and 5-10 membered heteroaryl, or two R n  groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R p  groups; and 
         each instance of R p  is, independently, fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6  alkyl, —ON(C 1-6  alkyl) 2 , —N(C 1-6  alkyl) 2 , —N(C 1-6  alkyl) 3 X, —NH(C 1-6  alkyl) 2 X, —NH 2 (C 1-6  alkyl)X, —NH 3 X, —N(OC 1-6  alkyl)(C 1-6  alkyl), —N(OH)(C 1-6  alkyl), —NH(OH), —SH, —SC 1-6  alkyl, —SS(C 1-6  alkyl), —C(═O)(C 1-6  alkyl), —CO 2 H, —CO 2 (C 1-6  alkyl), —OC(═O)(C 1-6  alkyl), —OCO 2 (C 1-6  alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6  alkyl) 2 , —OC(═O)NH(C 1-6  alkyl), —NHC(═O)(C 1-6  alkyl), —N(C 1-6  alkyl)C(═O)(C 1-6  alkyl), —NHCO 2 (C 1-6  alkyl), —NHC(═O)N(C 1-6  alkyl) 2 , —NHC(═O)NH(C 1-6  alkyl), —NHC(═O)NH 2 , —C(═NH)O(C 1-6  alkyl), —OC(═NH)(C 1-6  alkyl), —OC(═NH)OC 1-6  alkyl, —C(═NH)N(C 1-6  alkyl) 2 , —C(═NH)NH(C 1-6  alkyl), —C(═NH)NH 2 , —OC(═NH)N(C 1-6  alkyl) 2 , —OC(NH)NH(C 1-6  alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6  alkyl) 2 , —NHC(═NH)NH 2 , —NHSO 2 (C 1-6  alkyl), —SO 2 N(C 1-6  alkyl) 2 , —SO 2 NH(C 1-6  alkyl), —SO 2 NH 2 , —SO 2 Cl alkyl, —SO 2 OC 1-6  alkyl, —OSO 2 C 1-6  alkyl, —SOC 1-6  alkyl, —Si(C 1-6  alkyl) 3 , —OSi(C 1-6  alkyl) 3  —C(═S)N(C 1-6  alkyl) 2 , C(═S)NH(C 1-6  alkyl), C(═S)NH 2 , —C(═O)S(C 1-6  alkyl), —C(═S)SC 1-6  alkyl, —SC(═S)SC 1-6  alkyl, —P(═O) 2 (C 1-6  alkyl), —P(═O)(C 1-6  alkyl) 2 , —OP(═O)(C 1-6  alkyl) 2 , —OP(═O)(OC 1-6  alkyl) 2 , C 1-6  alkyl, C 1-6  perhaloalkyl, C 2-6  alkenyl, C 2  alkynyl, C 3-10  carbocyclyl, C 6-14  aryl, 3-14 membered heterocyclyl, 5-14 membered heteroaryl; or two geminal R p  substituents can be joined to form ═O or ═S; 
         wherein X −  is a counterion. 
       
     
     
         26 - 32 . (canceled) 
     
     
         33 . The compound according to  claim 25 , wherein R e  is a 6-membered heteroaryl. 
     
     
         34 . The compound according to  claim 33 , wherein R e  is a pyrindinyl group. 
     
     
         35 - 42 . (canceled) 
     
     
         43 . The compound according to  claim 14 , wherein the compound is substantially enantiomerically pure. 
     
     
         44 . A pharmaceutical composition comprising a compound of  claim 14 , or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. 
     
     
         45 . A method of treating an FAAH-mediated condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 14  or a pharmaceutically acceptable form thereof. 
     
     
         46 . The method according to  claim 45 , wherein the FAAH-mediated condition is selected from a painful condition, an inflammatory condition, an immune disorder, a disorder of the central nervous system, a metabolic disorder, a cardiac disorder and glaucoma. 
     
     
         47 . The method according to  claim 46 , wherein the FAAH-mediated condition is a painful condition selected from neuropathic pain, central pain, deafferentiation pain, chronic pain, post-operative pain, pre-operative pain, nociceptive pain, acute pain, non-inflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder, pain associated with premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with drawal symptoms from drug addiction, joint pain, arthritic pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache dental/maxillofacial pain and visceral pain. 
     
     
         48 . The method according to  claim 46 , wherein the FAAH-mediated condition is an inflammatory condition or an immune disorder. 
     
     
         49 . The method according to  claim 48 , wherein the inflammatory condition or immune disorder is a gastrointestinal disorder. 
     
     
         50 . The method according to  claim 48 , wherein the inflammatory condition or immune disorder is a skin condition. 
     
     
         51 . The method according to  claim 46 , wherein the FAAH-mediated condition is a disorder of the central nervous system selected from neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord injury, epilepsy, a mental disorder, a sleep condition, a movement disorder, nausea and/or emesis, amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction. 
     
     
         52 . The method according to  claim 46 , wherein the FAAH-mediated condition is a metabolic disorder selected from a wasting condition or an obesity-related condition or complication thereof. 
     
     
         53 . The method according to  claim 46 , wherein the FAAH-mediated condition is a cardiac disorder selected from hypertension, circulatory shock, myocardial reperfusion injury and atherosclerosis. 
     
     
         54 . The method according to  claim 46 , wherein the FAAH-mediated condition is glaucoma. 
     
     
         55 . The compound according to  claim 14 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         56 . A compound selected from: