Nhe3-binding compounds and methods for inhibiting phosphate transport

Abstract

Provided are NHE3-binding and/or NHE3-modulating agents having activity as phosphate transport inhibitors, including inhibitors of phosphate transport in the gastrointestinal tract and the kidneys, and methods for their use as therapeutic or prophylactic agent.

1 - 18 . (canceled) 
     
     
         19 . A compound of Formula (I-H): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or a pharmaceutically acceptable salt thereof,
 wherein: 
 (a) n is an integer of 2 or more; 
 (b) Core is a Core moiety having two or more sites thereon for attachment to two or more NHE-binding small molecule moieties; 
 (c) L is a bond or linker connecting the Core moiety to the two or more NHE-binding small molecule moieties; and 
 (d) NHE is a NHE-binding small molecule moiety having the following structure of Formula (XI-H): 
 
       
         
           
           
               
               
           
         
         wherein: 
         B is selected from the group consisting of aryl and heterocyclyl; 
         each R is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 1-4 thioalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxyl, oxo, cyano, nitro, —NR 7 R 8 , —NR 7 C(═O)R 8 , —NR 7 C(═O)OR 8 , —NR 7 C(═O)NR 8 R 9 , —NR 7 SO 2 R 8 , —NR 7 S(O) 2 NR 8 R 9 , —C(═O)OR 7 , —C(═O)R 7 , —C(═O)NR 7 R 8 , —S(O) 1-2 R 7 , and —SO 2 NR 7 R 8 , wherein R 7 , R 8 , and R 9  are independently selected from the group consisting of hydrogen, C 1-4 alkyl, or a bond linking the NHE-binding small molecule moiety to L, provided at least one is a bond linking the NHE-binding small molecule moiety to L; 
         R 3  and R 4  are independently selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl and optionally substituted heteroaryl; or 
         R 3  and R 4  form together with the nitrogen to which they are bonded an optionally substituted 4-8 membered heterocyclyl; and 
         each R 1  is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl and optionally substituted C 1-6 alkoxy. 
       
     
     
         20 . The compound, stereoisomer, or pharmaceutically acceptable salt of  claim 19 , wherein NHE has Formula (XII-H): 
       
         
           
           
               
               
           
         
         wherein: 
         each R 3  and R 4  are independently selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl, or R 3  and R 4 , taken together with the nitrogen to which they are bonded, form an optionally substituted 4-8 membered heterocyclyl; 
         each R 1  is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; and 
         R 5  is selected from the group consisting of —SO 2 —NR 7 — and —NHC(═O)NH—, wherein R 7  is hydrogen or C 1-4 alkyl. 
       
     
     
         21 . The compound of  claim 19 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A pharmaceutical composition comprising a compound, stereoisomer, or pharmaceutically acceptable salt of  claim 19  and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         23 . A method for inhibiting phosphate uptake in the gastrointestinal tract of a patient in need of phosphate lowering, comprising enterally administering to the patient the compound, stereoisomer, or pharmaceutically acceptable salt as described in  claim 19 . 
     
     
         24 . A method for treating hyperphosphatemia in a subject in need thereof comprising administering to the subject an effective amount of the compound, stereoisomer, or pharmaceutically acceptable salt as described in  claim 19 . 
     
     
         25 . A compound of Formula (I-I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or a pharmaceutically acceptable salt thereof,
 wherein: 
 (a) NHE is a NHE-binding small molecule moiety having the following structure of Formula (A-I): 
 
       
         
           
           
               
               
           
         
         wherein: 
         each R 1 , R 2 , R 3 , R 5  and R 9  are independently selected from H, halogen, —NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R, —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7  and R 8  are independently selected from H, C 1-6 alkyl, —C 1-6 alkyl-OH or a bond linking the NHE-binding small molecule to L, provided at least one is a bond linking the NHE-binding small molecule to L; 
         R 4  is selected from H, C 1 -C 7  alkyl, or a bond linking the NHE-binding small molecule to L; 
         R 6  is absent or selected from H and C 1 -C 7  alkyl; and 
         Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring; 
         (b) Core is a Core moiety having the following structure of Formula (B-I): 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is selected from C(X 1 ), N and N(C 1-6 alkyl); 
         X 1  is selected from hydrogen, optionally substituted alkyl, —NX a X b , —NO 2 , —NX c —C(═O)—NX c —X a , —C(═O)NX c —X a , —NX c —C(═O)—X a , —NX c —SO 2 —X a , —C(═O)—X a  and —OX a , 
         each X a  and X b  are independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; 
         Y is C 1-6 alkylene; 
         Z is selected from —NZ a —C(═O)—NZ a —, —C(═O)NZ a —, —NZ a —C(═O)— and heteroaryl when X is CX 1 ; 
         Z is selected from —NZ a —C(═O)—NZ a —, —NZ a —C(═O)— and heteroaryl when X is N or N(C 1-6 alkyl); and 
         each X c  and Z a  is independently selected from hydrogen and C 1-6 alkyl; and 
         (c) L is a bond or linker connecting the Core moiety to the NHE-binding small molecule moieties. 
       
     
     
         26 . A pharmaceutical composition comprising a compound, stereoisomer, or pharmaceutically acceptable salt of  claim 25  and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         27 . A method for inhibiting phosphate uptake in the gastrointestinal tract of a patient in need of phosphate lowering, comprising enterally administering to the patient the compound, stereoisomer, or pharmaceutically acceptable salt as described in  claim 25 . 
     
     
         28 . A method for treating hyperphosphatemia in a subject in need thereof comprising administering to the subject an effective amount of the compound, stereoisomer, or pharmaceutically acceptable salt as described in  claim 25 . 
     
     
         29 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or a pharmaceutically acceptable salt thereof,
 wherein: 
 (a) NHE is a NHE-binding small molecule moiety having the structure of Formula (A-I): 
 
       
         
           
           
               
               
           
         
         wherein: 
         each R 1 , R 2 , R 3 , R 5  and R 9  are independently selected from H, halogen, —NR 7 (CO)R 8 , —(CO)NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 SO 2 R 8 , —NR 7 R 8 , —OR 7 , —SR 7 , —O(CO)NR 7 R 8 , —NR 7 (CO)OR 8 , and —NR 7 SO 2 NR 8 , where R 7  and R 8  are independently selected from H, C 1-6 alkyl, —C 1-6 alkyl-OH or a bond linking the NHE-binding small molecule to L, provided at least one is a bond linking the NHE-binding small molecule to L; 
         R 4  is selected from H, C 1 -C 7  alkyl, or a bond linking the NHE-binding small molecule to L; 
         R 6  is absent or selected from H and C 1 -C 7  alkyl; and 
         Ar1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring; 
         (b) Core is a Core moiety having the following structure of Formula (C-I): 
       
       
         
           
           
               
               
           
         
         wherein: 
         W is selected from alkylene, polyalkylene glycol —C(═O)—NH-(alkylene)-NH—C(═O)—, —C(═O)—NH-(polyalkylene glycol)-NH—C(═O)—, —C(═O)-(alkylene)-C(═O)—, —C(═O)-(polyalkylene glycol)-C(═O)— and cycloalkyl, 
         X is N; 
         Y is C 1-6 alkylene; 
         Z is selected from —NZ a —C(═O)—NZ a —, —C(═O)NZ a —, —NZ a —C(═O)— and heteroaryl; 
         each Z a  is independently selected from hydrogen and C 1-6 alkyl; and 
         (c) L is a bond or linker connecting the Core moiety to the NHE-binding small molecules. 
       
     
     
         30 . A pharmaceutical composition comprising a compound, stereoisomer, or pharmaceutically acceptable salt of  claim 29  and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         31 . A method for inhibiting phosphate uptake in the gastrointestinal tract of a patient in need of phosphate lowering, comprising enterally administering to the patient the compound, stereoisomer, or pharmaceutically acceptable salt as described in  claim 29 . 
     
     
         32 . A method for treating hyperphosphatemia in a subject in need thereof comprising administering to the subject an effective amount of the compound, stereoisomer, or pharmaceutically acceptable salt as described in  claim 29 . 
     
     
         33 . A method for inhibiting phosphate uptake in the gastrointestinal tract of a patient in need of phosphate lowering, comprising enterally administering to the patient a compound of Formula (X): 
       
         
           
           
               
               
           
         
       
       wherein
 NHE is 
 
       
         
           
           
               
               
           
         
         L is a polyalkylene glycol linker; 
         n is 2; and 
         Core has is selected from: