Compounds, compositions and methods of using same for modulating uric acid levels

Abstract

Described herein are compounds useful in the modulation of blood uric acid levels, formulations containing them and methods of making and using them. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders related to aberrant levels of uric acid.

1 .- 10 . (canceled) 
     
     
         48 .- 51 . (canceled) 
     
     
         52 . A compound of formula (II), or a pharmaceutically acceptable salt, ester or tautomer thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         W is O, S, S(O), S(O) 2 , NH, N(optionally substituted alkyl), CH 2 , CH 2 O, CH 2 S or CH 2 NH; 
         R 1  is F, Cl, Br or I; 
         a is 0, 1 or 2; 
         R a  is H or optionally substituted C 1-3  alkyl; 
         R a′  is H or optionally substituted C 1-3  alkyl; or 
         R a  and R a′  together with the carbon atom to which they are attached form an optionally substituted, 3-, 4-, 5- or 6-membered ring, optionally comprising 1 or 2 heteroatoms selected from O, N and S; 
         R d  is H; 
         R b , R c , R e  and R f  are each independently H, F, Cl, Br, I, CF 3 , CN, alkyl, cycloalkyl, cyclopropylmethyl, NH 2 , NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO 2 H, COOR′, CONH 2 , CONHR′, CONR′R″, SO 3 H, S(O) 2 R′, S(O) 2 NH 2 , S(O) 2 NHR′, S(O) 2 NR′R″, aryl, heterocyclyl or heteroaryl; wherein
 R′ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; 
 R″ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl or phenyl; or 
 R′ and R″ together with the nitrogen atom to which they are attached form an optionally substituted, saturated or unsaturated 4-, 5- or 6-membered heterocyclic ring; or 
 
         R b  and R c  or R e  and R f  together with the two carbon atoms to which they are attached, form an optionally substituted, aromatic or non-aromatic, 5-, 6- or 7-membered ring, optionally comprising 1 or 2 heteroatoms selected from O, N and S, and wherein said ring may be optionally fused to 1 or 2 additional optionally substituted, aromatic or non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms selected from O, N and S; and wherein the optional substituents are each independently F, Cl, Br, I, CF 3 , CN, alkyl, cycloalkyl, cyclopropylmethyl, NH 2 , NHR′, NR′R″, OH, OR′, SH, SR′, C(O)R′, CO 2 H, COOR′, CONH 2 , CONHR′, CONR′R″, SO 3 H, S(O) 2 R′, S(O) 2 NH 2 , S(O) 2 NHR′, S(O) 2 NR′R″, aryl, heterocyclyl or heteroaryl; 
         x is 0 or 1; 
         y is 0 or 1; 
         z is 0 or 1; 
         R x , R x′ , R y , R y′ , R z  and R z′  are each independently H, F, Cl, Br, or optionally substituted C 1-3  alkyl; or 
         R x  and R x′ , or R y  and R y′ , or R z  and R z′ , or R x  and R y , or R y  and R z , or R x  and R z  together with the carbon atoms to which they are attached, form an optionally substituted, aromatic or non-aromatic, 3-7 membered ring, optionally comprising 1 or 2 heteroatoms selected from O, N and S, and wherein said ring may be optionally fused to 1 or 2 additional optionally substituted, aromatic or non-aromatic, 5-, 6- or 7-membered rings, optionally comprising 1 or 2 heteroatoms selected from O, N and S; 
         A is C(O)O—B 1  or C(O)NH—B 2 ; wherein 
         B 1  is H, optionally substituted C 1-6  alkyl or a pharmaceutically acceptable cation; 
         B 2  is H or optionally substituted C 1-6  alkyl; and wherein 
         all alkyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl moieties may be optionally further substituted. 
       
     
     
         53 . The compound of  claim 52 , wherein W is S. 
     
     
         54 . The compound of  claim 52 , wherein R 1  is Br. 
     
     
         55 . The compound of  claim 52 , wherein
 W is S; and   R 1  is Br.   
     
     
         56 . The compound of  claim 52 , wherein
 a is 1;   R a  is H; and   R a′  is H.   
     
     
         57 . The compound of  claim 52 , wherein A is C(O)O—B 1 . 
     
     
         58 . The compound of  claim 52 , wherein
 A is C(O)O—B 1 ;   x is 1; and   R x  and R x′  are not H.   
     
     
         59 . The compound of  claim 52 , wherein R x  and R x′  together with the carbon atoms to which they are attached, form an optionally substituted, non-aromatic 3 membered ring. 
     
     
         60 . The compound of  claim 52 , wherein R b , R c , R e  and R f  are all H. 
     
     
         61 . The compound of  claim 52 , wherein R b  and R c  together with the two carbon atoms to which they are attached, form an aromatic, 6-membered ring. 
     
     
         62 . A method of treating gout in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound of  claim 52 . 
     
     
         63 . A method of treating hyperuricemia in an individual or reducing serum uric acid in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound of  claim 52 . 
     
     
         64 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 52 , and a pharmaceutically acceptable excipient. 
     
     
         65 . The compound of  claim 52 , which is 2-((5-bromo-4-(naphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid: