TRPV4 antagonists

Patent metadata

Field	Value
Publication number	US-11260049-B2
Application number	US-201716334400-A
Country	US
Kind code	B2
Filing date	Sep 20, 2017
Priority date	Sep 20, 2016
Publication date	Mar 1, 2022
Grant date	Mar 1, 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 TRPV4 antagonist compound according to Formula I:

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

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

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, —COOH, —NH 2 , and —CN,
mercapto,
—S(O)H,
—S(O) 2 H,
oxo,
hydroxy,
amino,
NHR x11 ,
 where 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, —COOH, —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 ,
 where 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, —COOH, —NH 2 , and —CN,
—C(O)OH,
—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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —NH 2 and —CN,
—Ophenyl,
—C(O)O 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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —NH 2 and —CN,
—Ocycloalkyl
phenyl,
—C≡C—Si(CH 3 ) 3 , and
—C≡C-cycloalkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 represented by the following Formula (II):

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

R 22 is selected from:
monocyclic aryl,
monocyclic aryl substituted from 1 to 4 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,
—OC 1-6 alkyl,
—OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,
oxo,
hydroxy,
amino,
—NHR x21 ,
where R x21 is selected from C 1-5 alkyl,
and C 1-5 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

—C(O)OH,
—C(O)NH 2 ,
nitro, and
cyano, or

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

each R a2 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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —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,
—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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —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 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —NH 2 and —CN,
—Ocycloalkyl, and
phenyl;

or a pharmaceutically acceptable salt thereof.

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

wherein:
R 31 is selected from:
phenyl,
phenyl substituted from 1 to 3 times by R a3 ,
thiazole,
thiazole substituted from 1 to 3 times by R a3 ,
pyrimidine,
pyrimidine substituted from 1 to 3 times by R a3 ,
pyridine, and
pyridine 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 ,
pyridine, and
pyridine 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 ,
—C(OH)(CH 3 ) 2 ,
—CH 2 NH 2 ,
—CH 2 NHR x30 , and
—CH(NH 2 )CH 3 , or

Y 31 is taken together with the adjacent —OH to form morpholinyl,
where each R x30 is 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, —COOH, —NH 2 , and —CN;

each R a3 is independently selected from:
fluoro,
chloro,
bromo,
—OH,
C 1-6 alkyl,
cyano,
—CF 3 ,
—C 1-5 alkylCF 3 ,
—CHF 2 ,
—CH 2 F,
—OC 1-5 alkyl,
—OCF 3 ,
—OC 1-5 alkylCF 3 ,
C 1-5 alkylCN,
—C(O)OC 1-5 alkyl,
—C(O)OH, and
—Ocycloalkyl; and

each R b3 is independently selected from:
fluoro,
chloro,
bromo,
—OH,
C 1-6 alkyl,
cyano,
—CF 3 ,
—C 1-5 alkylCF 3 ,
—CHF 2 ,
—CH 2 F,
—OC 1-5 alkyl,
—OCF 3 ,
—OC 1-5 alkylCF 3 ,
—C(O)CH 3 ,
—OCHF 2 , and
—Ocyclopropyl;

or a pharmaceutically acceptable salt thereof.

4. A TRPV4 antagonist compound represented by the following Formula (IV):

wherein:
R 41 is selected from:
phenyl,
phenyl substituted from 1 to 3 times by R a4 ,
thiazole,
thiazole substituted from 1 to 3 times by R a4 ,
pyrimidine,
pyrimidine substituted from 1 to 3 times by R a4 ;
pyridine, and
pyridine substituted from 1 to 3 times by R a4 ;

R 42 is selected from:
phenyl,
phenyl substituted from 1 to 3 times by R b4 ,
pyridine, and
pyridine substituted from 1 to 3 times by R b4 ; and

Y 41 is selected from:
—CH 2 OH,
—CH(OH)CH 3 ,
—CH 2 NH 2 , and
—CH 2 NHR x40 , or

Y 41 is taken together with the adjacent —OH

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Brnardic Edward J
• Brooks Carl A
• Lawhorn Brian Griffin
• Li Peng
• Matthews Jay M
• Mcatee John Jeffrey
• Pero Joseph E
• Sender Matthew Robert
• Terrell Lamont Roscoe
• Behm David J

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P11/14

  Antitussive agents · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title