Slc26a3 inhibitors and use thereof

Patent metadata

Field	Value
Publication number	US-2025073242-A1
Application number	US-202218292329-A
Country	US
Kind code	A1
Filing date	Jul 29, 2022
Priority date	Jul 30, 2021
Publication date	Mar 6, 2025
Grant date	—

Abstract

Provided herein are inhibitors of SLC26A3, which is an anion (Cl−, HCO3−, oxalate) exchanger expressed in intestinal epithelial cells. SLC26A3 inhibitors have potential utility for treatment of constipation including chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), constipation-predominant irritable bowel syndrome (IBS-C), cystic fibrosis-associated constipation, meconium ileus, distal intestinal obstruction syndrome, calcium oxalate kidney stone disease, enteric hyperoxaluria and primary hyperoxalurias.

First claim

1 .- 7 . (canceled)

8 . A method for preventing or treating a condition, disease, or disorder associated with SLC26A3-mediated anion exchange in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or (V):
wherein,
formula (I) is represented by the following structure:

wherein,
R 1e is (i) phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halo, —NO 2 , phenyl, and C 1-6 alkoxy; (ii) C 3-6 alkyl, or (iii) heterocyclylC 1-4 alkyl; and
R 2e is carboxy-substituted phenyl, optionally further substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halo, hydroxyl and C 1-6 alkoxy;

formula (II) is represented by the following structure:

wherein,
R 1f is hydrogen or C 1-3 alkyl;
R 2f is phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halo, and C 1-6 alkoxy; or
R 1f and R 2f together with the nitrogen to which they are connected form a heteroaryl optionally substituted with C 1-3 alkyl; and
R 3f is
(i) phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halo, —NO 2 , and C 1-6 alkoxy;
(ii) C 5-6 cycloalkyl or C 5-6 heteroaryl;
(iii)

wherein n is 0, 1 or 2, R 4f is C 1-6 alkyl, halo, or C 1-6 alkoxy.
formula (III) is represented by the following structure:

wherein,
R 1 g is

wherein, n is 0, 1, 2, or 3;
L is —(CH 2 ) m —X—(CH 2 ) p —, wherein m and p are independently 0 or 1, X is —O—, —S—, —N(R 5g )—, or —OC(O)—;
R 2g is phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-4 alkyl and C 1-4 alkoxy;
R 3g is hydrogen or C 1-4 alkyl;
R 4g is C 1-4 alkyl, halo, or C 1-4 alkoxy; or two adjacent R 4g and the carbons to which they are attached form a 5-member or 6-member heteroaryl; and
R 5g is hydrogen or C 1-3 alkyl;

formula (IV) is represented by the following structure:

wherein,
R 1h is C 1-3 alkyl or phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, halo, and C 1-4 alkoxy;
R 2h is —COOR 5h ;
R 3h is

wherein, n is 0, 1, or 2;
L is —X—(CH 2 ) m —Y—(CH 2 ) p —, wherein m and p are independently 0 or 1, X is —O— or —S—, Y is a direct bond or —C(O)O—;
R 4h is C 1-4 alkyl or halo; and
R 5h is hydrogen or C 1-4 alkyl; and

formula (V) is represented by the following structure:

wherein,
R 1i is
(i) phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, halo, —NO 2 , C 1-4 alkoxy and —NHC(O)—R 5i ; or
(ii)

R 2i is hydrogen or C 1-3 alkyl;
R 3i and R 4i are hydrogen; and
R 5i is
(i) C 1-4 alkyl;
(ii) -L-phenyl, wherein phenyl is optionally substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, halo, C 1-4 alkoxy and C(O)O—C 1-4 alkyl; L is a direct bond or —(CH 2 ) m —X—, and X is O or S;

R 6i is C 1-4 alkyl or phenyl optionally substituted with C 1-4 alkyl.

9 . The method of claim 8 , wherein the compound of Formula (I) is represented by Formula (Ia):

wherein,
m is 0, 1 or 2;
n is 1, 2 or 3;
R 3e is C 1-6 alkyl, halo, —NO 2 , phenyl, and C 1-6 alkoxy;
R 4e is C 1-6 alkyl, halo, hydroxyl or C 1-6 alkoxy.

10 . The method of claim 8 , wherein the compound of Formula (I) has one of the following structures:

11 . The method of claim 8 , wherein the compound of Formula (II) has one of the following structures:

12 . The method of claim 8 , wherein the compound of Formula (III) has one of the following structures:

13 . The method of claim 8 , wherein the compound has one of the following structures:

14 . The method of claim 8 , wherein the condition, disease, or disorder associated with SLC26A3-mediated anion exchange is constipation or hyperoxaluria.

15 . The method of claim 8 , wherein the condition, disease, or disorder associated with SLC26A3-mediated anion exchange is constipation or hyperoxaluria.

16 . The method of claim 8 , wherein the condition, disease, or disorder associated with SLC26A3-mediated anion exchange is constipation or hyperoxaluria.

17 . The method of claim 8 , wherein the condition, disease, or disorder associated with SLC26A3-mediated anion exchange is chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), constipation-predominant irritable bowel syndrome (IBS-C), CF-associated constipation, meconium ileus, distal intestinal obstruction syndrome, calcium oxalate kidney stone disease, enteric hyperoxaluria, or primary hyperoxaluria.

Assignees

• Univ California

Inventors

• Verkman Alan S
• Cil Onur
• Haggie Peter M

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/433

  Thidiazoles · CPC title

• A61K31/4035

  Isoindoles, e.g. phthalimide · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title