Compounds useful for treating gastrointestinal tract disorders

Patent metadata

Field	Value
Publication number	US-11242337-B2
Application number	US-201816476836-A
Country	US
Kind code	B2
Filing date	Jan 9, 2018
Priority date	Jan 9, 2017
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

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.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
Linker is —R 13 —(CHR 13 ) p —[Y—(CH 2 ) r ] s —Z—R 13 —(CH 2 ) t —Z—;
X is a bond, H, N, O, CR 11 R 12 , CR 11 , C, —NHC(O)NH—, —(CHR 13 ) p - or C 3 -C 6 cyclolakyl;
W is independently, at each occurrence, S(O) 2 , C(O), or —(CH 2 ) m —;
Z is independently, at each occurrence, a bond, C(O), or —C(O)NH—;
Y is independently, at each occurrence, O, S, NH, N(C 1 -C 3 alkyl), or —C(O)NH—;
Q is a bond, NH, —C(O)NH—, —NHC(O)NH—, —NHC(O)N(CH 3 )—, or —NHC(O)NH—(CHR 3 );
m is an integer from 1 to 2;
n is an integer from 1 to 4;
r and p are independently, at each occurrence, integers from 0 to 8;
s is an integer from 0 to 4;
t is an integer from 0 to 4;
u is an integer from 0 to 2;
R 1 and R 2 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more halogen, OH, CN, —NO 2 , oxo, —SR 9 , —OR 9 , —NHR 9 , —NR 9 R 10 , —S(O) 2 N(R 9 ) 2 —, —S(O) 2 R 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 9 R 10 , —NR 9 S(O) 2 R 10 , —S(O)R 9 , —S(O)NR 9 R 10 , —NR 8 S(O)R 9 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl; or
R 1 and R 2 together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl group is optionally substituted with one or more halogen, OH, CN, —NO 2 , oxo, —SR 9 , —OR 9 , —NHR 9 , —NR 9 R 10 , —S(O) 2 N(R 9 ) 2 —, —S(O) 2 R 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 9 R 10 , —NR 9 S(O) 2 R 10 , —S(O)R 9 , —S(O)NR 9 R 10 , —NRS(O)R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl;
R 3 is CN and R 4 is halogen, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or —C(O)NR 9 R 10 ;
R 5 , R 6 , R 7 , and Re are independently H, halogen, OH. CN, —NO 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, —SR 9 , —OR 9 , —NHR 9 , —NR 9 R 10 , —S(O) 2 N(R 9 ) 2 —, —S(O) 2 R 9 , —C(O)R 9 , —C(O)OR 9 , —NR 9 S(O) 2 R 10 , —S(O)R 9 , —S(O)NR 9 R 10 , —NR 8 S(O)R 9 ;
R 9 and R 10 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O
R 11 and R 12 are independently H, C 1 -C 6 alkyl, OH, NH 2 , CN, or NO 2 ;
R 13 is independently, at each occurrence, a bond, H, C 1 -C 6 alkyl, C 4 -C 8 cycloalkenyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 19 ;
R 14 is independently, at each occurrence, H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or
R 6 and R 14 together with the atoms to which they are attached may combine to form, independently, at each occurrence, 5- to-6 membered heterocyclyl, wherein each C 3 -C 8 cycloalkyl, or heterocyclyl is optionally substituted with one or more R 19 ; or
R 3 and R 14 together with the atoms to which they are attached may combine to form independently, at each occurrence, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein each heterocyclyl or heteroaryl is optionally substituted with one or more R 19 ;
R 15 , R 16 , R 17 , and R 18 are independently, at each occurrence, H, OH, NH 2 , or C 1 -C 3 alkyl, wherein the alkyl is optionally substituted with one or more R 19 ;
R 19 are independently, at each occurrence, H, OH, NH 2 , oxo, C 1 -C 6 alkyl, C 1 -C 6 Hhaloalkyl, C 1 -C 6 alkoxy; and
provided that:
(1) when X is H, n is 1;
(2) when X is a bond, O, or CR 11 R 12 , n is 2;
(3) when n is 3, X is CR 11 or N;
(4) when n is 4 X is C; and
(5) only one of Q or X is —NHC(O)NH— at the time.

2. The compound of claim 1 , wherein Linker is selected the group consisting of:

3. The compound of claim 1 , wherein Linker is selected from the group consisting of:

4. The compound of claim 1 , wherein R 1 and R 2 are methyl.

5. The compound of claim 1 , wherein R 1 and R 2 together with the nitrogen to which they are attached can form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more oxo.

6. The compound of claim 1 having the formula Ia:

wherein the ring Het represents R 1 and R 2 together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl group is optionally substituted with one or more halogen, OH, CN, —NO 2 , oxo, —SR 9 , —OR 9 , —NHR 9 , —NR 9 R 10 , —S(O) 2 N(R 9 ) 2 —, —S(O) 2 R 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 9 R 10 , —NR 9 S(O) 2 R 10 , —S(O)R 9 , —S(O)NR 9 R 10 , —NR 9 S(O)R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl.

7. The compound of claim 1 having the formula Ib:

wherein the ring Het represents R 1 and R 2 together with the nitrogen to which they are attached can form a heterocyclyl or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl group is optionally substituted with one or more halogen, OH, CN, —NO 2 , oxo, —SR 9 , —OR 9 , —NHR 9 , —NR 9 R 10 , —S(O) 2 N(R 9 ) 2 —, —S(O) 2 R 9 , —C(O)R 9 , —C(O)OR 9 , —C(O)NR 9 R 10 , —NR 9 S(O) 2 R 10 , —S(O)R 9 , —S(O)NR 9 R 10 , —NR 9 S(O)R 10 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 4 -C 8 cycloalkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl.

8. The compound of claim 1 having the formula Ic:

wherein Het B represents a C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, wherein each heterocyclyl or heteroaryl is optionally substituted with one or more R 19 .

9. The compound of claim 1 having the formula Id:

Assignees

• Ardelyx Inc

Inventors

• Dragoli Dean
• DOTSENKO Irina
• Lewis Jason

Classifications

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P1/10

  Laxatives · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title