TRPV4 antagonists

Patent metadata

Field	Value
Publication number	US-11229623-B2
Application number	US-202016796989-A
Country	US
Kind code	B2
Filing date	Feb 21, 2020
Priority date	Sep 20, 2016
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

The present invention relates to pyrrolidine sulfonamide analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.

First claim

What is claimed is:

1. A method of treating a disease selected from: ocular edema, glaucoma, and retinopathy, in a human subject which method comprises administering to a human subject in need thereof a therapeutically effective amount of a compound according to Formula (I)

wherein:
R 1 is selected from:
aryl,
aryl substituted from 1 to 4 times by R a ,
heteroaryl,
heteroaryl substituted from 1 to 4 times by R a ,
bicycloheteroaryl, and
bicycloheteroaryl substituted from 1 to 4 times by R a ;

R 2 is selected from:
aryl,
aryl substituted from 1 to 4 times by R b ,
heteroaryl,
heteroaryl substituted from 1 to 4 times by R b ,
bicycloheteroaryl, and
bicycloheteroaryl substituted from 1 to 4 times by R b , and

Y 1 is selected from:
C 1-6 alkyl, and
C 1-6 alkyl substituted with from: 1 to 9 substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
—OC 1-6 alkyl,
—OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , and CN,
mercapto,
—S(O)H,
—S(O) 2 H,
oxo,
hydroxy,
amino,
—NHR x11 ,
wherein R x11 is selected from C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , CN, —OC 1-5 alkyl,
—OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —NH 2 , —NR x12 R x13 ,
wherein R x12 and R x13 are each independently selected from C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , and —CN,

—C(O)NH 2 ,
aryl,
—Oaryl,
heteroaryl,
—Oheteroaryl,
—S(O) 2 NH 2 ,
—NHS(O) 2 H,
nitro, and
cyano, or

Y 1 is taken together with the adjacent —OH to form a heterocyclic ring selected from:
morpholinyl,
morpholinyl substituted by —CH 3 , and
oxazolidin-2-one;

each R a is independently selected from:
fluoro,
chloro,
bromo,
iodo,
—OH,
C 1-6 alkyl,
C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo,—NO2, —NH 2 and —CN,
cyano,
—OC 1-6 alkyl,
—OC 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo, —NO2, —NH 2 and —CN,
—Ophenyl,
—C(O)OC 1-6 alkyl,
—C(O)OC 1-6 alkyl substituted 1 to 5 times by fluoro, and
—Ocycloalkyl; and

each R b is independently selected from:
fluoro,
chloro,
bromo,
iodo,
—OH,
C 1-6 alkyl,
C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo, —NO2, —NH 2 and —CN,
cyano,
—OC 1-6 alkyl,
—OC 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo, —NO2, —NH 2 and —CN,
phenyl,
C 1-4 alkylphenyl,
—C≡C—Si(CH3) 3 , and
—C≡C-cycloalkyl;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein the compound is represented by the following Formula (II):

wherein:
R 21 is selected from:
aryl,
aryl substituted from 1 to 3 times by R a2 ,
heteroaryl,
heteroaryl substituted from 1 to 3 times by R a2 ,
bicycloheteroaryl, and
bicycloheteroaryl substituted from 1 to 3 times by R a2 ;

R 22 is selected from:
aryl,
aryl substituted from 1 to 3 times by R b2 ,
bicycloheteroaryl,
bicycloheteroaryl substituted from 1 to 3 times by R b2 ;
heteroaryl, and
heteroaryl substituted from 1 to 3 times by R b2 , and

Y 21 is selected from:
C 1-6 alkyl, and
C 1-6 alkyl substituted with from: 1 to 9 substituents independently selected from:
fluoro,
chloro,
bromo,
iodo,
—OC 1-6 alkyl,
—OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , and —CN,
mercapto,
—S(O)H,
—S(O) 2 H,
oxo,
hydroxy,
amino,
—NHR x21 ,
wherein R x21 is selected from C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , and —CN,

—NR x22 R x23 ,
wherein R x22 and R x23 are each independently selected from C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , and —CN,

—C(O)NH 2 ,
aryl,
—Oaryl,
heteroaryl,
—Oheteroaryl,
—S(O) 2 NH 2 ,
—NHS(O) 2 H,
nitro, and
cyano, or

Y 21 is taken together with the adjacent —OH to form a heterocyclic ring selected from:
morpholinyl,
morpholinyl substituted by —CH 3 , and
oxazolidin-2-one;

each R ae is independently selected from:
fluoro,
chloro,
bromo,
iodo,
—OH,
C 1-6 alkyl,
C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo, —NO2, —NH 2 and —CN,
cyano,
—OC 1-6 alkyl,
—OC 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo, —NO2, —NH 2 and —CN,
—Ophenyl,
—C(O)OC 1-5 alkyl,
—C(O)OC 1-5 alkyl substituted 1 to 5 times by fluoro, and
—Ocycloalkyl; and

each R b2 is independently selected from:
fluoro,
chloro,
bromo,
iodo,
—OH,
C 1-6 alkyl,
C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo, —NO2, —NH 2 and —CN,
cyano,
—OC 1-6 alkyl,
—OC 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, —OH, C 1-4 alkyl, phenyl, oxo, —NO2, —NH 2 and —CN,
phenyl,
C 1-4 alkylphenyl,
—C≡C—Si(CH3) 3 , and
—C≡C-cycloalkyl;

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein the compound is represented by the following Formula (III):

wherein:
R 31 is selected from:
phenyl,
phenyl substituted from 1 to 3 times by R a3 ,
benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]oxadiazolyl substituted from 1 to 3 times by R a3 ,
pyrimidinyl,
pyrimidinyl substituted from 1 to 3 times by R a3 ,
naphthalenyl,
naphthalenyl substituted from 1 to 3 times by R a3 ,
pyridinyl, and
pyridinyl substituted from 1 to 3 times by R a3 ;

R 32 is selected from:
phenyl,
phenyl substituted from 1 to 3 times by R b3 ,
pyridinyl,
pyridinyl substituted from 1 to 3 times by R b3 ,
benzo[c][1,2,5]oxadiazolyl,
benzo[c][1,2,5]oxadiazolyl substituted from 1 to 3 times by R b3 ,
thiophenyl,
thiophenyl substituted from 1 to 3 times by R b3 ,
thiazolyl,
thiazolyl substituted from 1 to 3 times by R b3 ,
pyrazolyl,
pyrazolyl substituted from 1 to 3 times by R b3 ,
imidazo [2,1-b]thiazolyl,
imidazo[2,1-b]thiazolyl substituted from 1 to 3 times by R b3 ,
pyrimidinyl,
pyrimidinyl substituted from 1 to 3 times by R b3 ,
pyridazinyl, and
pyridazinyl substituted from 1 to 3 times by R b3 ; and

Y 31 is selected from:
—CH 2 OH,
—CH(OH)CH 3 ,
—CH(OH)CH 2 CH 3 ,
—CH(OH)CH 2 CH 2 CH 3 ,
—CH(OH)CH 2 CH(CH 3 ) 2 ,
—C(OH)(CH 3 ) 2 ,
—CH 2 NH 2 ,
—CH 2 NHR x30 ,
—CH 2 NR x30 R x30 , and
—CH(NH 2 )CH 3 , or

Y 31 is taken together with the adjacent —OH to form a heterocyclic ring selected from:
morpholinyl,
morpholinyl substituted by —CH 3 , and
oxazolidin-2-one,
wherein each R x30 is independently

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Brnardic Edward J
• Brooks Carl A
• Lawhorn Brian Griffin
• Ye Guosen
• Barton Linda S
• Budzik Brian W
• Matthews Jay M
• Mcatee John Jeffrey
• Patterson Jaclyn R
• Pero Joseph E
• Sanchez Robert
• Sender Matthew Robert
• Terrell Lamont Roscoe
• Behm David J
• Thomas James V

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title

• A61P13/10

  of the bladder · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title