TRPV4 antagonists

Patent metadata

Field	Value
Publication number	US-10590077-B2
Application number	US-201716334410-A
Country	US
Kind code	B2
Filing date	Sep 20, 2017
Priority date	Sep 20, 2016
Publication date	Mar 17, 2020
Grant date	Mar 17, 2020

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 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 substitutents 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 1-6 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 1-6 alkyloxy, —OH, C 1-6 alkyl, phenyl, oxo, —COOH, —NO 2 , —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 1-6 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 1-6 alkyloxy, —OH, C 1-4 alkyl, phenyl, oxo, —COOH, —NO 2 , —NH 2 and —CN,
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:
aryl,
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:
aryl,
aryl 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 substitutents independently selected from:
fluoro,
chloro,
bromo,
—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 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 ,
—S(O) 2 NH 2 ,
—NHS(O) 2 H,
nitro, and
cyano;

each R a2 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 1-6 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 1-6 alkyl, phenyl, oxo, —COOH, —NO 2 , —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 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 1-6 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 1-6 alkyl, phenyl, oxo, —COOH, —NO 2 , —NH 2 and —CN,
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 ,
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,
pyridine substituted from 1 to 3 times by R b3 ,
pyrimidine,
pyrimidine substituted from 1 to 3 times by R b3 ,
pyridazine, and
pyridazine 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 ;
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 1-6 alkylCF 3 ,
—CHF 2 ,
—CH 2 F,
—OC 1-5 alkyl,
—OCF 3 ,
—O 1-4 alkylCF 3 ,
C 1-6 alkylCN,
—C(O)OC 1-3 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 1-6 alkylCF 3 ,
—CHF 2 ,
—CH 2 F,
—OC 1-3 alkyl,
—OCF 3 ,
—OC 1-6 alkylCF 3 ,
—C(O)CH 3 , and
—OCHF 2 ;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 represented by the following Formula (IV):

wherein:
R 41 is selected from:
phenyl, and
phenyl 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 2 NH 2 , and
—CH 2 NHR x40 ;
where each R x40 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 a4 is independently selected from:
fluoro,
chloro,
bromo,
—OH,
C 1-6 alkyl,
cyano,
—CF 3 ,
—CHF 2

Assignees

• Glaxosmithkline Ip No 2 Ltd
• Glaxosmithkline Ip Dev Ltd

Inventors

• Brnardic Edward J
• Brooks Carl A
• Budzik Brian W
• Lawhorn Brian Griffin
• Matthews Jay M
• Mcatee John Jeffrey
• Pero Joseph E
• Behm David J

Classifications

• A61P11/14

  Antitussive agents · CPC title

• C07D401/12

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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C07D207/48 Primary

  Sulfur atoms · CPC title