Triazole glycolate oxidase inhibitors

Abstract

The present invention provides triazole carboxylic acids and related compounds, as well as pharmaceutically acceptable salts thereof, which are useful as glycolate oxidase inhibitors. Pharmaceutical compositions and methods for treating primary hyperoxaluria, type I (PH) and kidney stones are also described.

1 . A compound according to Formula Ia: 
       
         
           
           
               
               
           
         
       
       
         or a pharmaceutically acceptable salt thereof, wherein: 
         L is ; 
         the dashed line connected to Z 1  is a single bond, Z 1  is NR 5 , the dashed line connected to Z 2  is a double bond, and Z 2  is N, or 
         the dashed line connected to Z 1  is a double bond, Z 1  is N, the dashed line connected to Z 2  is a single bond, and Z 2  is NR 5 ; 
         R 1  is selected from H, unsubstituted C 1-6  alkyl, substituted C 1-6  alkyl, —(C 1—6  alkylene)—OC(O)—(C 1—6  alkyl), and —(C 1—6  alkylene)—OC(O)—(C 1—6  alkoxy); 
         R 2  is selected from the group consisting of H and halogen; 
         R 3  is selected from the group consisting of H, halogen, C 1-12  alkyl, and C 1-12  alkoxy ; 
         R 4  is selected from the group consisting of C 6-12  aryl and 5- to 12-membered heteroaryl; 
         R 4  is substituted with one or more R 4a ; 
         each R 4a  is independently C 3-8  halocycloalkyl ; and 
         R 5  is selected from the group consisting of H, unsubstituted C 1-6  alkyl, substituted C 1-6  alkyl, C 2-7  acyl, —(C 1—6  alkylene)—OC(O)—(C 1—6  alkyl), and —(C 1—6  alkylene)—OC(O)—(C 1—6  alkoxy); . 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula Ib: 
       
         
           
           
               
               
           
         
       
       . 
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula Ic: 
       
         
           
           
               
               
           
         
       
       . 
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is H. 
     
     
         5 - 15 . (canceled) 
     
     
         16 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  and R 3  are H. 
     
     
         17 . (canceled) 
     
     
         18 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is selected from the group consisting of phenyl and biphenyl, each of which is substituted with C 3-8  halocycloalkyl. 
     
     
         19 - 29 . (canceled) 
     
     
         30 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is H. 
     
     
         31 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of unsubstituted C 1-6  alkyl and substituted C 1-6  alkyl. 
     
     
         32 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of —(C 1—6  alkylene)—OC(O)—(C 1—6  alkyl) and —(C 1—6  alkylene)—OC(O)—(C 1—6  alkoxy). 
     
     
         33 . (canceled) 
     
     
         34 . The compound of  claim 1 , represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         36 - 43 . (canceled) 
     
     
         44 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is phenyl, substituted with C 3-8  halocycloalkyl. 
     
     
         45 . The compound of  claim 1 , represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A compound, represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof. 
     
     
         47 . A pharmaceutical composition comprising the compound of  claim 46 , or a tautomer thereof, and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
         48 . A process for preparing a compound represented by formula (36): 
       
         
           
           
               
               
           
         
       
       
         or a tautomer thereof, and/or a salt thereof, comprising:
 a) combining a compound of formula (9a) or (9b): 
                     
                     
  or a salt thereof, with a compound of formula (33): 
                     
  Pd(dppf)Cl 2  or Pd(dppf)Cl 2 -CH 2 Cl 2 , and potassium carbonate in a mixture of 1,4-dioxane and water to form a compound of formula (34) or (34b): 
                     
                     
  or a salt thereof; 
 b) treating the compound of formula (34) or (34b), or the salt thereof, with trifluoroacetic acid and anisole in dichloromethane to provide a compound of formula (35) or (35b): 
                     
                     
  a tautomer thereof, or a salt thereof; 
 c) saponifying the compound of formula (35) or (35b), the tautomer thereof, or the salt thereof with an aqueous solution of sodium hydroxide in tetrahydrofuran; and 
 d) acidifying with an aqueous solution of HCl to provide the compound of formula (36), the tautomer thereof, or the salt thereof. 
 
       
     
     
         49 . The process of  claim 48 , wherein:
 a) combining a compound of formula (9a):                          or a salt thereof, with a compound of formula (33):                          Pd(dppf)Cl 2 -CH 2 Cl 2 , and potassium carbonate in a mixture of 1,4-dioxane and water to form a compound of formula (34):                          or a salt thereof;   b) treating the compound of formula (34) or the salt thereof, with trifluoroacetic acid and anisole in dichloromethane to provide a compound of formula (35):                          a tautomer thereof, or a salt thereof;   c) saponifying the compound of formula (35), the tautomer thereof, or the salt thereof with an aqueous solution of sodium hydroxide in tetrahydrofuran; and   d) acidifying with an aqueous solution of HCl to provide the compound of formula (36):                          the tautomer thereof, or the salt thereof.   
     
     
         50 . The process of  claim 49 , wherein step a) is conducted at a temperature of about 85° C.; step b) is conducted at a temperature of about 50° C.; and step c) is conducted at a temperature of about 50° C.; and step d) is conducted at room temperature.