Mineralocorticoid receptor antagonists

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X is NH or O;

Each R 1 is independently halo, CF 3 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

Each R is independently H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or CF 3 wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OH, C 1 -C 6 alkoxy, CF 3 , or CN;

Each R a is independently H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or CF 3 wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

Each R b is independently H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, CF 3 , or aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

R 2 is triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or oxazolyl, where triazolyl, oxadiazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl or oxazolyl is optionally substituted with one to two groups from R 5 ;

R 4 is H, C 1 -C 6 alkyl, aryl, or C 3 -C 10 cycloalkyl, where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from halo or OR;

Each R 5 is independently OR, (CR c 2 ) 0-3 —CF 3 , C 1 -C 6 alkyl, (CR c 2 ) 0-3 —C 3 -C 10 cycloalkyl, (CR c 2 ) 0-3 -aryl, (CR c 2 ) 0-3 -heteroaryl, or (CR c 2 ) 0-3 -halo, where said alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to three groups selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, OR, halo, CF 3 or NH 2 ; and wherein said optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl are optionally substituted one to four times by halo, CF 3 , NH 2 or OR;

Each R c is independently H, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

m is 0, 1, 2 or 3; and

p is 0, 1, 2 or 3.

2. The compound of Formula I, according to claim 1 , wherein

Each R a is independently H or C 1 -C 6 alkyl wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

R 2 is triazolyl, oxadiazolyl, imidazolyl or oxazolyl, where triazolyl, oxadiazolyl, imidazolyl or oxazolyl is optionally substituted with one to two groups from R 5 ;

R 4 is aryl or C 3 -C 10 cycloalkyl, where said aryl or cycloalkyl is optionally substituted with one to four groups selected from halo or OR;

Each R 5 is independently OR, C 1 -C 6 alkyl, (CR c 2 ) 0-3 —C 3 -C 10 cycloalkyl, (CR c 2 ) 0-3 -aryl, (CR c 2 ) 0-3 -heteroaryl, or (CR c 2 ) 0-3 -halo, where said alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to three groups selected from aryl, heteroaryl, or heterocyclyl;

m is 0 or 1; and

p is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

3. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein

Each R 1 is independently halo, CF 3 , C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or OR, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

Each R is independently H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, or CF 3 wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

Each R b is independently H or C 1 -C 6 alkyl, wherein said alkyl is optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

Each R c is independently H, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl, wherein said alkyl and cycloalkyl are optionally substituted with one to three groups selected from halo, OR, CF 3 , or CN;

R 2 is triazolyl, oxadiazolyl, imidazolyl or oxazolyl, where triazolyl, oxadiazolyl, imidazolyl or oxazolyl is optionally substituted with one to two groups from R 5 ;

R 4 is C 1 -C 6 alkyl, aryl, or C 3 -C 10 cycloalkyl, where said alkyl, aryl, or cycloalkyl is optionally substituted with one to four groups selected from halo or OR;

Each R 5 is independently (CR c 2 ) 0-3 —CF 3 , C 1 -C 6 alkyl, (CR c 2 ) 0-3 —C 3 -C 1 cycloalkyl, (CR c 2 ) 0-3 aryl, (CR c 2 ) 0-3 -heteroaryl, or (CR c 2 ) 0-3 -halo, where said alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted with one to three groups selected from aryl, heteroaryl, heterocyclyl, OR, halo, CF 3 or NH 2 ;

m is 0 or 1; and

p is 1 or 2.

4. The compound of claim 3 , having the structural Formula II, wherein

Each R b is independently H or C 1 -C 6 alkyl;

R 4 is aryl, or C 3 -C 10 cycloalkyl, where said aryl, or cycloalkyl is optionally substituted with one to four groups selected from halo or OR;

Each R 5 is independently (CR c 2 ) 0-3 —C 3 -C 10 cycloalkyl, (CR c 2 ) 0-3 -aryl, or (CR c 2 ) 0-3 -heteroaryl, where said cycloalkyl, aryl or heteroaryl is optionally substituted with one to three groups selected from aryl, heteroaryl, heterocyclyl, OR, halo, CF 3 or NH 2 ; and

p is 1;

or a pharmaceutically acceptable salt thereof.

5. A compound which is

Compound

Number

IUPAC Name

1

5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-

[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione

2

(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

3

(5R)-5-Benzyl-5-(5-benzyl-1,3,4-oxadiazol-2-yl)-3-

[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

4

(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

5

(5R)-5-Benzyl-5-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

6

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-1,2,4-

oxadiazol-5-yl)-1,3-oxazolidine-2,4-dione

7

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-pyridin-4-

yl-1,3,4-oxadiazol-2-yl)-1,3-oxazolidine-2,4-dione

8

(5R)-5-Benzyl-5-[5-(4,6-dimethoxypyrimidin-2-yl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

9

(5R)-5-Benzyl-5-{5-[1-(3,5-difluorophenyl)cyclopropyl]-1,3,4-oxadiazol-

2-yl}-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

10

(5R)-5-[5-(3-Amino-5-methoxyphenyl)-1,3,4-oxadiazol-2-yl]-

5-benzyl-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

11

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(2,2,2-trifluoroethyl)-

1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione

12

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-{5-[1-(trifluoromethyl)

cyclopropyl]-1,3,4-oxadiazol-2-yl}-1,3-oxazolidine-2,4-dione

13

(5R)-5-Benzyl-5-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

14

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-[5-(1-pyridin-4-ylcyclopropyl)-

1,3,4-oxadiazol-2-yl]-1,3-oxazolidine-2,4-dione

15

(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

16

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-

1H-imidazol-2-yl)-1,3-oxazolidine-2,4-dione

17

(5R)-5-Benzyl-5-(5-benzyl-1H-imidazol-2-yl)-3-

[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

18

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(4-phenyl-

1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione

19

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(5-phenyl-

1,3-oxazol-2-yl)-1,3-oxazolidine-2,4-dione

20

(5R)-5-Benzyl-5-(5-benzyl-1,3-oxazol-2-yl)-3-

[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

21

(5R)-5-Benzyl-3-[(1R)-1-phenylethyl]-5-(3-phenyl-

1H-1,2,4-triazol-5-yl)-1,3-oxazolidine-2,4-dione

22

(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , which is

Compound

Number

IUPAC Name

1

5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]-3-

[(1R)-1-(4-fluorophenyl)ethyl]-1,3-oxazolidine-2,4-dione

2

(5R)-5-Benzyl-5-[5-(3,5-dimethoxybenzyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

3

(5R)-5-Benzyl-5-(5-benzyl-1,3,4-oxadiazol-2-yl)-3-

[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

4

(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

5

(5R)-5-Benzyl-5-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

8

(5R)-5-Benzyl-5-[5-(4,6-dimethoxypyrimidin-2-yl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

13

(5R)-5-Benzyl-5-[5-(cyclopropylmethyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

15

(5R)-5-Benzyl-5-[4-(3,5-dimethoxyphenyl)-1H-imidazol-

2-yl]-3-[(1R)-1-phenylethyl]-1,3-oxazolidine-2,4-dione

22

(5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-

2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprised of the compound of Formula I of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 comprising one or more pharmaceutically active agents in addition to the compound of Formula I or a pharmaceutically acceptable salt thereof.

9. A method of treating heart failure, hypertension, atherosclerosis or primary hyperaldosteronism in a human patient in need of, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. A method of treating metabolic syndrome in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. A method of treating a physiological or pathologic disease, selected from Conn's Syndrome, primary and secondary hyperaldosteronism, increased sodium retention, increased magnesium and potassium excretion (diuresis), increased water retention, hypertension (isolated systolic and combined systolic/diastolic), arrhythmias, myocardial fibrosis, myocardial infarction, and Bartter's Syndrome in a human patient in need of, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. A method of treating renal failure in a human patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. A method for antagonizing aldosterone receptor (MR) and increasing aldosterone levels in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.