Inhibitors of fatty acid amide hydrolase

Abstract

The present invention provides compounds, and pharmaceutically acceptable compositions thereof, encompassed by any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof. The present invention also provides methods for treating an FAAH mediated disease, disorder or condition by administering a therapeutically effective amount of a compound or composition comprising a compound of any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof, to a patient in need thereof. Additionally, the present invention provides methods for inhibiting FAAH by administering a therapeutically effective amount of a compound or composition comprising a compound of any of formulae (I), (II), (III), (IV), (V), or (VI), or subgenera thereof, to a patient in need thereof.

1 - 67 . (canceled) 
     
     
         68 . A compound of formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof; 
         wherein:
 (i) Z 1  is —OH or —OR 3  and Z 2  is —OH, —OR 4 , an optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted C 2-8  alkynyl, optionally substituted C 1-8  heteroalkyl, optionally substituted C 2-8  heteroalkenyl, optionally substituted C 2-8  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 (ii) Z 1  and Z 2  taken together with the boron atom to which they are bound, form a 5- to 8-membered ring having at least one O, S, N or NR 5  atom directly bonded to the boron atom; or 
 (iii) Z 1  is —OH or —OR 3 , and Z 2  and Ring A taken together form an optionally substituted 5- to 7-membered ring; 
 W 3  is C, CR 15 , or N; 
 X is a covalent bond, —O—, —N═N—, —C═N—, —NR 6 —, —C(NR 6 )—, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or optionally substituted C 1-6  alkylene, wherein one, two or three methylene units of the C 1-6  alkylene are optionally and independently replaced with one or more groups selected from —O—, —N═N—, —C═N—, —NR 6 —, —C(NR 6 )—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —; 
 each instance of R 1  is, independently, halogen, —OR 8 , —CF 3 , —CN, —NO 2 , —SO 2 R 8 , —SOR 8 , —C(O)R 8 , —CO 2 R 8 , —C(O)N(R) 2 , —CHO, —N 3 , —N 2 R 8 , —N(R 8 ) 2 , —B(OH 2 ), optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted C 2-8  alkynyl, optionally substituted C 1-8  heteroalkyl, optionally substituted C 2-8  heteroalkenyl, optionally substituted C 2-8  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 each instance of R 2  is, independently, halogen, —OR 9 , —CF 3 , —CN, —NO 2 , —SO 2 R 9 , —SOR 9 , —C(O)R 9 , —CO 2 R 9 , —C(O)N(R 9 ) 2 , —N 3 , —N 2 R 9 , —N(R 9 ) 2 , optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted C 2-8  alkynyl, optionally substituted C 1-8  heteroalkyl, optionally substituted C 2-8  heteroalkenyl, optionally substituted C 2-8  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 each instance of R 3  and R 4  is, independently, optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted C 2-8  alkynyl, optionally substituted C 1-8  heteroalkyl, optionally substituted C 2-8  heteroalkenyl, optionally substituted C 2-8  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 each instance of R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is, independently, hydrogen, —SO 2 R 11 , —SOR 11 , —C(O)R 11 , —CO 2 R 11 , —C(O)N(R 11 ) 2 , —C(O)NH(R 11 ), —C(O)NH 2 , optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted C 2-8  alkynyl, optionally substituted C 1-8  heteroalkyl, optionally substituted C 2-8  heteroalkenyl, optionally substituted C 2-8  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 
         each instance of R 11  is, independently, optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, optionally substituted C 2-8  alkynyl, optionally substituted C 2-8  heteroalkyl, optionally substituted C 2-8  heteroalkenyl, optionally substituted C 2-8  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
         R 15  is hydrogen, halogen, —CF 3 , optionally substituted C 1-8  alkyl, optionally substituted C 2-8  alkenyl, or optionally substituted C 2-8  alkynyl; 
         n is 0, 1, 2 or 3 and m is 0, 1, 2, 3, 4, or 5 
         with the proviso that the following compound is specifically excluded: 
       
       
         
           
           
               
               
           
         
       
     
     
         69 . (canceled) 
     
     
         70 . The compound of  claim 68 , wherein W 3  is C or CH. 
     
     
         71 . The compound of  claim 68 , wherein W 3  is N. 
     
     
         72 . The compound of  claim 68 , wherein X is a covalent bond. 
     
     
         73 . The compound of  claim 68 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         74 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof; 
         wherein:
 (i) Z 1  is —OH or —OR 3  and Z 2  is —OH, or —OR 4 , an optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; or 
 (ii) Z 1  is —OH or —OR 3 , and Z 2  and 
 
       
       
         
           
           
               
               
           
         
       
       taken together form an optionally substituted 5- to 7-membered ring, wherein the ring is comprised of carbon atoms and optionally one or more additional heteroatoms independently selected from the group consisting of N, S and O;
 W 3  is N;
 X is a covalent bond, —O—, —N═N—, —C═N—, —NR 6 —, —C(NR 6 )—, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or optionally substituted C 1-6  alkylene, wherein one, two or three methylene units of the C 1-6  alkylene are optionally and independently replaced with one or more groups selected from —O—, —N═N—, —C═N—, —NR 6 —, —C(NR 6 )—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —; each instance of R 1  is, independently, halogen, —OR 8 , —CF 3 , —CN, —NO 2 , —SO 2 R 8 , —SOR 8 , —C(O)R 8 , —CO 2 R 8 , —C(O)N(R 8 ) 2 , —CHO, —N 3 , —N 2 R 8 , —N(R 8 ) 2 , —B(OH) 2 , optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl; 
 each instance of R 2  is, independently, —OR 9 , —N(R) 2 , optionally substituted alkyl, optionally substituted C 2-6  alkenyl, or unsubstituted C 6-10  aryl; 
 each instance of R 3  and R 4  is, independently, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 each instance of R 6 , R 8  and R 9  is, independently, hydrogen, —SO 2 R 11 , —SOR 1 , —C(O)R 11 , —CO 2 R 11 , —C(O)N(R 11 ) 2 , —C(O)NH(R 11 ), —C(O)NH 2 , optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 each instance of R 11  is, independently, optionally substituted C 1-6 alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
 R 15  is hydrogen, halogen, —CF 3 , optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, or optionally substituted C 2-6  alkynyl; and 
 n is, 1, 2 or 3. 
 
 
     
     
         75 . The compound of  claim 74 , wherein X is a covalent bond, —O—, or —(CH 2 )—. 
     
     
         76 . The compound of  claim 74 , wherein Z 1  and Z 2  are both OH. 
     
     
         77 . The compound of  claim 74 , wherein n is 0. 
     
     
         78 . The compound of  claim 74 , wherein R 2  is optionally substituted C 1-6  alkyl. 
     
     
         79 . The compound of  claim 74 , wherein R 2  is unsubstituted C 6-10  aryl. 
     
     
         80 . The compound of  claim 74 , which is: 
       
         
           
           
               
               
           
         
       
     
     
         81 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof; 
         wherein:
 (i) Z 1  is —OH or —OR 3  and Z 2  is —OH, or —OR 4 , an optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; or 
 (ii) Z 1  is —OH or —OR 3 , and Z 2  and 
 
       
       
         
           
           
               
               
           
         
         
            taken together form an optionally substituted 5- to 7-membered ring, wherein the ring is comprised of carbon atoms and optionally one or more additional heteroatoms independently selected from the group consisting of N, S and O; 
           W 3  is CR 15 ; 
           X is a covalent bond, —O—, —N═N—, —C═N—, —NR 6 —, —C(NR 6 )—, —S—, —C(O)—, —S(O)—, —S(O) 2 —, or optionally substituted C 1-6  alkylene, wherein one, two or three methylene units of the C 1-6  alkylene are optionally and independently replaced with one or more groups selected from —O—, —N═N—, —C═N—, —NR 6 —, —C(NR 6 )—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —; each instance of R 1  is, independently, halogen, —OR 8 , —CF 3 , —CN, —NO 2 , —SO 2 R 8 , —SOR 8 , —C(O)R 8 , —CO 2 R 8 , —C(O)N(R 8 ) 2 , —CHO, —N 3 , —N 2 R 8 , —N(R 8 ) 2 , —B(OH) 2 , optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2 -6 alkynyl; 
           each instance of R 2  is, independently, optionally substituted 5-10 membered heteroaryl; 
           each instance of R 3  and R 4  is, independently, optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-6  alkynyl, optionally substituted C 1-6  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
           each instance of R 6  and R 8  is, independently, hydrogen, —SO 2 R 11 , —SOR 11 , —C(O)R 11 , —CO 2 R 11 , —C(O)N(R 11 ) 2 , —C(O)NH(R 11 ), —C(O)NH 2 , optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
           each instance of R 11  is, independently, optionally substituted C 1-6 alkyl, optionally substituted C 2-6  alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-6  heteroalkyl, optionally substituted C 2-6  heteroalkenyl, optionally substituted C 2-6  heteroalkynyl, optionally substituted C 3-10  carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-10 membered heteroaryl; 
           R 15  is hydrogen, halogen, —CF 3 , optionally substituted C 1-6  alkyl, optionally substituted C 2-6  alkenyl, or optionally substituted C 2-6  alkynyl; and 
           n is, 1, 2 or 3. 
         
       
     
     
         82 . The compound of  claim 81 , wherein X is a covalent bond, —O—, or —(CH 2 )—. 
     
     
         83 . The compound of  claim 81 , wherein Z 1  and Z 2  are both OH. 
     
     
         84 . The compound of  claim 81 , wherein n is 0. 
     
     
         85 . The compound of  claim 81 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         86 . A compound selected from: 
       
         
           
           
               
               
           
         
       
     
     
         87 . A method of treating a painful condition, disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 68 . 
     
     
         88 . A method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 68 . 
     
     
         89 . A method of treating a painful condition, disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 74 . 
     
     
         90 . A method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 74 . 
     
     
         91 . A method of treating a painful condition, disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 81 . 
     
     
         92 . A method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 81 . 
     
     
         93 . A method of treating a painful condition, disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 86 . 
     
     
         94 . A method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 86 .