TRPV4 antagonists

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 to form morpholinyl,

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 ,

—C 1-5 alkylCF 3 ,

—CHF 2 ,

—CH 2 F,

—OC 1-5 alkyl,

—C(O)OC 1-5 alkyl, and

—C(O)OH; and

each R b4 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.

5. A compound selected from:

3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4S)-1-((2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4S)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4S)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4S)-1-((2-chloro-4-(trifluoromethoxy)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4S)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4R)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4R)-1-((2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4R)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4R)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4R)-1-((2-chloro-4-(trifluoromethoxy)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

4-(((3S,4R)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

5-chloro-2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

(3R,4S)-4-((4-chlorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzonitrile;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-methylbenzonitrile;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-fluorobenzonitrile;

4-(((3S,4R)-1-((2-bromo-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3S,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

4-(((3S,4R)-1-((4-chloro-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-3-(trifluoromethyl)benzonitrile;

4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((4-fluoro-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((4-bromo-2-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((4-methoxy-2-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-bromo-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-bromophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((4-bromo-2-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-methoxybenzonitrile;

4-(((3S,4R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

(3R,4S)-1-((2-chloro-4-(difluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

3-bromo-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-bromo-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

5-chloro-2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-chloro-4-(difluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

(3R,4S)-1-((2-chloro-4-(fluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

4-(((3S,4R)-1-((2-chloro-4-(fluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-ethylbenzonitrile;

2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-(difluoromethyl)benzonitrile;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-ethoxybenzonitrile;

4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-cyclopropoxybenzonitrile;

4-(((3S,4R)-1-((4-chloro-2-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((4-bromo-2-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-(difluoromethyl)-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-3-methoxybenzonitrile;

3-cyclopropoxy-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-chloro-4-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-bromo-4-chlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-bromo-4-methoxyphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

3-cyclopropoxy-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-chloro-4-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2,4-dichloro-5-fluorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

methyl 4-(((3S,4R)-1-((4-chloro-2-(difluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzimidate;

(3R,4S)-1-((4-chloro-2-(difluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

2-(5-chloro-2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)phenyl)acetonitrile;

(3R,4S)-4-((4-chlorophenyl)sulfonyl)-1-((2-(difluoromethoxy)pyridin-3-yl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(thiazol-2-ylsulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

2-fluoro-4-(((3S,4R)-1-((2-fluoro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((4-cyano-2-methylphenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

2-fluoro-4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

2-fluoro-4-(((3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-4-((5-chlorothiazol-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-4-((4-bromophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

4-(((3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

(3S,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

2-(((3S,4S)-4-((3,4-difluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;

(3S,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

4-(((3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,5-difluorobenzonitrile;

2-chloro-4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4S)-4-((5-bromopyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile;

5-chloro-2-(((3R,4S)-4-((4-cyanophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-difluorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-3-fluorobenzonitrile;

4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,6-difluorobenzonitrile;

(3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,6-difluorobenzonitrile;

5-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)picolinonitrile;

2-(((3R,4S)-4-((3,4-difluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;

2-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((3,4,5-trifluorophenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;

4-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2,5-difluorobenzonitrile;

(3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)-4-((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidin-3-ol;

(3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-((4-chlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

(3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

(3R,4S)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-((6-chloropyridin-3-yl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-methylbenzonitrile;

2-chloro-4-(((3S,4R)-1-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

2-chloro-5-(((3S,4R)-1-((2,4-dichlorophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-4-((4-ethylphenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-isopropylphenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((4-propylphenyl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-4-((4-chloro-3-fluorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)pyrrolidin-3-ol;

3-chloro-4-(((3S,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)picolinonitrile;

3-chloro-4-(((3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-((2-(trifluoromethyl)pyrimidin-5-yl)sulfonyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-4-((5-bromopyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

(3S,4S)-1-((2,4-dichlorophenyl)sulfonyl)-4-((3,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)pyrrolidin-3-ol;

(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)pyrrolidin-3-ol;

2-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)-5-(trifluoromethyl)benzonitrile;

(3R,4S)-1-((2,4-dichlorophenyl)sulfonyl)-3-(hydroxymethyl)-4-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl)pyrrolidin-3-ol;

3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((R)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-((S)-1-hydroxyethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3S,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

4-(((3R,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

4-(((3S,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

3-chloro-4-(((3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-((methylamino)methyl)pyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-3-(aminomethyl)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)-3-chlorobenzonitrile;

4-(((3S,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzonitrile;

4-(((3R,4S)-3-(aminomethyl)-4-((4-chlorophenyl)sulfonyl)-3-hydroxypyrrolidin-1-yl)sulfonyl)benzonitrile;

3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(((2,2,2-trifluoroethyl)amino)methyl)pyrrolidin-1-yl)sulfonyl)benzonitrile; and

3-chloro-4-(((4S,5R)-4-((5-chloropyridin-2-yl)sulfonyl)-6-oxa-2,9-diazaspiro[4.5]decan-2-yl)sulfonyl)benzonitrile;

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising 1) a compound of claim 5 or a pharmaceutically acceptable salt thereof and 2) a pharmaceutically acceptable excipient.

7. A method of treating a disease state selected from: atherosclerosis, vasogenic edema, postsurgical abdominal edema, ocular edema, cerebral edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, sinusitis/rhinitis, asthma, COPD, cough, acute cough, sub-acute cough, chronic cough, pulmonary hypertension, overactive bladder, cystitis, pain, motor neuron disorders, amyotrophic lateral sclerosis, multiple sclerosis, cardiovascular disease, acute, chronic and polycystic kidney disease, stroke, hydrocephalus, glaucoma, retinopathy, endometriosis, pre-term labor, dermatitis, pruritus, pruritus in liver disease, ascites and complications of portal hypertension and liver cirrhosis, diabetes, obesity, migraine, Alzheimer's disease, pancreatitis, osteoarthritis, Crohn's disease, colitis, diarrhea, fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence, in a human in need thereof, which comprises administering to such human a safe and effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof.

8. A method according to claim 7 wherein the compound or pharmaceutically acceptable salt thereof is administered orally.

9. A method according to claim 7 wherein the compound or pharmaceutically acceptable salt thereof is administered intravenously.

10. A method according to claim 7 wherein the compound or pharmaceutically acceptable salt thereof is administered by inhalation.

11. A method according to claim 7 wherein the disease state is acute lung injury.

12. A method according to claim 7 wherein the disease state is heart failure.

13. A method according to claim 7 wherein the disease state is acute respiratory distress syndrome.

14. A method according to claim 7 wherein the disease state is cough.

15. A method according to claim 7 wherein the disease state is acute cough.

16. A method according to claim 7 wherein the disease state is sub-acute cough.

17. A method according to claim 7 wherein the disease state is chronic cough.

18. The method of inhibiting TRPV4 activity in a human in need thereof, which comprises administering to such human a safe and effective amount of a compound claim 5 , or a pharmaceutically acceptable salt thereof.

19. A method of treating a disease state in a human in need thereof, which comprises administering to such human a safe and effective amount of

a) a compound of claim 5 or a pharmaceutically acceptable salt thereof; and

b) at least one agent selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blockers, aldosterone antagonists, inotropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, antihistamines, leukotriene antagonists, HMG-CoA reductase inhibitors, dual non-selective β-adrenoceptor and α1-adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.

20. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of claim 5 or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.

21. The compound of claim 4 , wherein said C 1-5 alkyl and said C 1-6 alkyl are independently methyl, ethyl, ethylene, ethynyl, n-propyl, or isopropyl.

22. The compound of claim 5 , wherein the compound is 3-chloro-4-(((3R,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile, illustrated by a chemical structure of:

23. The compound of claim 5 , wherein the compound is 3-chloro-4-(((3S,4S)-4-((5-chloropyridin-2-yl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile, illustrated by a chemical structure of:

24. The compound of claim 5 , wherein the compound is 3-chloro-4-(((3R,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile, illustrated by a chemical structure of:

25. The compound of claim 5 , wherein the compound is 3-chloro-4-(((3S,4S)-4-((4-chlorophenyl)sulfonyl)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)sulfonyl)benzonitrile, illustrated by a chemical structure of:

26. The compound of claim 5 , wherein the compound is 4-(((3S,4S)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile, illustrated by a chemical structure of:

27. The compound of claim 5 , wherein the compound is 4-(((3S,4R)-1-((2-chloro-4-cyanophenyl)sulfonyl)-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl)sulfonyl)-2-fluorobenzonitrile, illustrated by a chemical structure of:

28. A method according to claim 7 , wherein the disease state is ocular edema.