Small-molecule ut-a-selective urea transport inihibitors

Abstract

Provided herein are compounds that are urea transporter-A inhibitors that are useful for producing a strong diuretic response and may be used for treating refractory edema associated with cardiovascular, renal, and metabolic diseases, disorders, and conditions.

1 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein, 
         m is 0, 1, 2 or 3; 
         R c  is hydrogen, halo, or alkyl; or 
         R c  and R d , together with the C and N atoms to which they are attached respectively, form a 5-member or 6-member heterocyclyl ring; 
         R e  is alkyl; or 
         R e  and R d , together with the S and N atoms to which they are attached respectively, form a 5-member or 6-member heterocyclyl ring; 
         R f  is hydrogen or alkoxy; and 
         R g  is independently, at each occurrence, alkyl, alkoxy, or halo, 
         a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
       
     
     
         2 . The pharmaceutical composition of  claim 1 , comprising a pharmaceutically acceptable excipient and a compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein, 
         m is 0, 1, 2 or 3; 
         R c  is hydrogen, halo, or C 1-3 alkyl; or 
         R c  and R d , together with the C and N atoms to which they are attached respectively, form a 5-member or 6-member heterocyclyl ring; 
         R e  is C 1-3 alkyl; or 
         R e  and R d , together with the S and N atoms to which they are attached respectively, form a 5-member or 6-member heterocyclyl ring; 
         R f  is hydrogen or C 1-3 alkoxy; and 
         R g  is independently, at each occurrence, C 1-3 alkyl, C 1-3 alkoxy, or halo, 
         a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
       
     
     
         3 . The pharmaceutical composition of  claim 1 , comprising a pharmaceutically acceptable excipient and a compound of Formula (IIa): 
       
         
           
           
               
               
           
         
         wherein, 
         m is 0, 1, 2 or 3; 
         R c  is hydrogen, halo or C 1-3 alkyl; 
         R f  is hydrogen or C 1-3 alkoxy; and 
         R g  is independently, at each occurrence, C 1-3 alkyl, C 1-3 alkoxy, or halo, 
         a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
       
     
     
         4 . The pharmaceutical composition of  claim 3  wherein,
 m is 2 or 3; 
 R c  is hydrogen or chloro; 
 R f  is methoxy; and 
 R g  is independently, at each occurrence, methyl, methoxy, fluoro or chloro. 
 
     
     
         5 . The pharmaceutical composition of  claim 1 , comprising a pharmaceutically acceptable excipient and a compound of Formula (IIb): 
       
         
           
           
               
               
           
         
         wherein, 
         m is 0, 1, 2 or 3; 
         R e  is C 1-3 alkyl; 
         R f  is hydrogen or C 1-3 alkoxy; and 
         R g  is independently, at each occurrence, C 1-3 alkyl, C 1-3 alkoxy, or halo, 
         a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
       
     
     
         6 . The pharmaceutical composition of  claim 5  wherein
 m is 0; 
 R e  is C 1-3 alkyl; and 
 R f  is hydrogen. 
 
     
     
         7 . A method for treating a disease or disorder treatable by inhibiting transport of urea in a subject, said method comprising administering to the subject the pharmaceutical composition according to  claim 1 . 
     
     
         8 . The method of  claim 7  wherein the disease or disorder is selected from (a) refractory edema associated with cirrhosis, nephritic syndrome, acute renal failure, chronic renal insufficiency, or congestive heart failure; (b) syndrome of inappropriate antidiuretic hormone secretion (SIADH); (c) azotemia; (e) fluid retention; (f) hypertension, and (g) abnormal uresis. 
     
     
         9 . A method for treating a disease or disorder treatable by inhibiting transport of urea in a subject, said method comprising administering to the subject pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein, R a  is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and 
         R b  is alkyl, 
         a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
       
     
     
         10 . The method of  claim 9 , said method comprising administering to the subject pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein, R a  is aryl, heteroaryl, cycloalkyl, or heterocyclyl; and 
         R b  is methyl or ethyl, 
         a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
       
     
     
         11 . The method of  claim 9  wherein R a  is phenyl or indolyl. 
     
     
         12 . The method of  claim 9 , wherein R b  is methyl. 
     
     
         13 . The method of  claim 9  wherein the disease or disorder is selected from (a) refractory edema associated with cirrhosis, nephritic syndrome, acute renal failure, chronic renal insufficiency, or congestive heart failure; (b) syndrome of inappropriate antidiuretic hormone secretion (SIADH); (c) azotemia; (e) fluid retention; (f) hypertension, and (g) abnormal uresis. 
     
     
         14 .- 19 . (canceled)