COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS

摘要

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.

主权项

1. A compound having the structure of Formula (I):or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,
wherein: (a) NHE is a NHE-inhibiting small molecule moiety having the following structure of Formula (A): wherein:
each R1, R2, R3, R5 and R9 are independently selected from H, halogen, —NR7(CO)R8, —(CO)NR7R8, —SO2—NR7R8, —NR7SO2R8, —NR7R8, —OR7, —SR7, —O(CO)NR7R8, —NR7(CO)OR8, and —NR7SO2NR8, where R7 and R8 are independently selected from H, C1-6alkyl, —C1-6alkyl-OH or a bond linking the NHE-inhibiting small molecule to L, provided at least one is a bond linking the NHE-inhibiting small molecule to L;R4 is selected from H, C1-C7 alkyl, or a bond linking the NHE-inhibiting small molecule to L;R6 is absent or selected from H and C1-C7 alkyl; andAr1 and Ar2 independently represent an aromatic ring or a heteroaromatic ring;(b) Core is a Core moiety having the following structure of Formula (B): wherein:
X is selected from C(X1), N and N(C1-6alkyl);X1 is selected from hydrogen, optionally substituted alkyl, —NXaNb, —NO2, —NXc—C(═O)—NXc—Xa, —C(═O)NXc—Xa, —NXc—C(═O)—Xa, —NXc—SO2—Xa, —C(═O)—Xa and —OXa,each Xa and Xb 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 C1-6alkylene;Z is selected from —NZa—C(═O)—NZa—, —C(═O)NZa—, —NZa—C(═O)— and heteroaryl when X is CX1;Z is selected from —NZa—C(═O)—NZa—, —NZa—C(═O)— and heteroaryl when X is N or N(C1-6alkyl); andeach X, and Za is independently selected from hydrogen and C1-6alkyl; and(c) L is a bond or linker connecting the Core moiety to the NHE-inhibiting small molecule moieties.