Mineralocorticoid receptor antagonists

1. A compound selected from

IUPAC Name

N-(1-(2-(4-chlorophenyl)-1-hydroxybutan-2-yl)-1H-indazol-4-

yl)methanesulfonamide;

N-(1-(1-hydroxy-2-(4-(trifluoromethyl)phenyl)butan-2-yl)-1H-indazol-

y4-l)methanesulfonamide;

N-(1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-1H-indazol-

4-yl)methanesulfonamide;

N-(1-(2-hydroxy-2-methyl-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-

1H-indazol-4-yl)methanesulfonamide;

N-(1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-1H-indazol-

4-yl)methanesulfonamide;

N-{1-[3-(4-chlorophenyl)-2-hydroxypentan-3-yl]-1H-indazol-

4-ylmethanesulfonamide;

N-{1-[3-(4-chlorophenyl)-2-hydroxypentan-3-yl]-1H-indazol-

4-ylmethanesulfonamide

N-(6-fluoro-1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-

3-yl)-1H-indazol-4-yl)methanesulfonamide;

N-(1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-

4-yl)methanesulfonamide

N-(3-(3-(4-chlorophenyl)-2-hydroxypentan-3-yl)-1H-indazol-7-

yl)methanesulfonamide;

N-(1-(2-(4-chlorophenyl)-1-cyanobutan-2-yl)-1H-indazol-4-

yl)methanesulfonamide;

N-(1-(3-(4-chlorophenyl)-1-cyanopentan-3-yl)-1H-indazol-4-

yl)methanesulfonamide;

N-(1-(1-cyano-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-

4-yl)methanesulfonamide

N-(1-(1-cyano-3-phenylpentan-3-yl)-6-fluoro-1H-indazol-4-

yl)methanesulfonamide;

N-(1-(3-(4-chlorophenyl)-1-cyanopentan-3-yl)-6-fluoro-1H-indazol-

4-yl)methanesulfonamide;

N-(l-(3-(4-Chlorophenyl)-1-cyano-2-oxopentan-3-yl)-1H-indol-4-

yl)methanesulfonamide;

N-(1-(3-(4-chlorophenyl)-1,1,1-trifluoropentan-3-yl)-1H-indazol-

4-yl)methanesulfonamide;

methyl 4-(4-chlorophenyl)-4-(4-(methylsulfonamido)-

1H-indazol-1-yl)hexanoate;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 which is

N-(1-(2-(4-chlorophenyl)-1-hydroxybutan-2-yl)-1H-indazol-4-yl)methanesulfonamide;

N-{1-[3-(4-chlorophenyl)-2-hydroxypentan-3-yl]-1H-indazol-4-ylmethanesulfonamide;

N-(1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;

N-(1-(2-hydroxy-2-methyl-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;

N-(1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;

N-(1-(3-(4-chlorophenyl)-1-cyanopentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;

N-(1-(1-cyano-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide;

N-(1-(1-cyano-3-phenylpentan-3-yl)-6-fluoro-1H-indazol-4-yl)methanesulfonamide;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 which is:

N-(1-(2-(4-chlorophenyl)-1-hydroxybutan-2-yl)-1H-indazol-4-yl)methanesulfonamide;

N-{1-[3-(4-chlorophenyl)-2-hydroxypentan-3-yl]-1H-indazol-4-ylmethanesulfonamide;

1-(1-(3-(4-chlorophenyl)-2-hydroxy-2-methylpentan-3-yl)-1H-indazol-4-yl)-3-methyl-sulfonylurea;

or a pharmaceutically acceptable salt thereof.

4. A compound of Formula I:

or pharmaceutically acceptable salts thereof, wherein

Y is N;

Ry is independently H or C 1 -C 6 alkyl, said alkyl is optionally substituted with halo or OH;

Each R x is independently H, halo, OR, C 1 -C 6 alkyl, (CR 2 ) 0-1 CN, C 3 -C 10 cycloalkyl, or NH 2 , said alkyl is optionally substituted with 1 to 3 substituents selected from halo, OR and C 1 -C 6 alkyl;

Each R is independently H, C 1 -C 6 alkyl or aryl, said alkyl and aryl are optionally substituted with 1 to 3 substituents selected from halo, aryl and C 1 -C 6 alkyl;

R 1 is:

1) C 1 -C 6 alkyl, said alkyl is optionally substituted with one to three C 1 -C 6 alkyl, OR, NR 2 , CF 3 , SR, OS(O) 2 R 8 , CN or halo substituents, or

2) —(CR a 2 ) n C(O)NRR 7 ;

R 2 is C 1 -C 6 alkyl, which is optionally substituted with one to three groups selected from R 12 ;

R 3 is phenyl, wherein said phenyl is optionally substituted with one to three R 9 ;

R 4 is —N(R 6 )S(O) 2 R 8 ;

R 6 is H or (C 1 -C 6 )alkyl;

Each R 7 is independently H or (C 1 -C 6 )alkyl;

Each R 8 is independently C 1 -C 6 alkyl, which is optionally substituted with one to three halo, CN, OR or NH 2 substituent, or —NRR 7 ;

Each R 9 is independently halo, CN, C 1 -C 6 alkyl, OR, or NH 2 , said alkyl is optionally substituted with one to three halo, CN, OR, C 1 -C 6 alkyl, NH 2 substituents

Each R 11 is independently H, C 1 -C 6 alkyl, or aryl;

Each R 12 is independently halo, CN, C(O)OR 11 , C 1 -C 6 alkyl, OR, or NH 2 , where said alkyl is optionally substituted with one to three halo, CN, OR, C 1 -C 6 alkyl or NH 2 substituents;

Each R a is independently H or C 1 -C 6 alkyl, said alkyl is optionally substituted with one to three halo substituents;

n is 0, 1, 2, 3 or 4; and

x is 0, 1, 2 or 3.

5. A pharmaceutical composition comprised of an effective amount the compound of claim 4 and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition of claim 5 which further comprises an effective amount one or more additional pharmaceutically active agents.

7. A method for treating aldosterone-mediated disorders in a human patient in need thereof, comprising administering a therapeutically effective amount of a compound of claim 4 , or a pharmaceutically acceptable salt thereof.

8. A method of treating cardiovascular disease, heart failure, hypertension, atherosclerosis, primary hyperaldosteronism or a related condition in a human patient in need thereof, comprising administering a therapeutically effective amount of a compound of claim 4 , or a pharmaceutically acceptable salt thereof.

9. A method of treating metabolic syndrome in a mammal in need of such treatment, comprising administering a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

10. A method of treating a physiological or pathologic disease, selected from including 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, Butter's Syndrome, and disorders associated with excess catecholamine levels in a human patient in need of, comprising administering to the patient a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

11. A method of treating renal failure in a human patient in need of such treatment comprising administering a therapeutically effective amount of a compound of claim 4 or a pharmaceutically acceptable salt thereof.

12. The A compound of claim 4 or a pharmaceutically acceptable salt thereof, which has the formula

13. The compound of claim 12 , which is:

N-(1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide, diastereoisomer A;

N-(1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide, diastereoisomer C; or

N-(1-(2-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-3-yl)-1H-indazol-4-yl)methanesulfonamide, diastereoisomer D.

14. The compound of claim 4 wherein R y is H.

15. the compound of claim 4 , as illustrated by Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R 2 is C 1 -C 6 alkyl, said alkyl is optionally substituted with one to three OR, CN or halo substituents;

R 3 is phenyl, wherein said phenyl is optionally substituted with one to three R 9 ;

R 4 is —NR 6 S(O) 2 R 8 ;

Each R 9 is independently halo or OR.

16. The compound of claim 4 , as illustrated by Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

Y is N;

Each R x is independently H, halo, OR, or C 1 -C 6 alkyl, said alkyl is optionally substituted with 1 to 3 substituents selected from halo, OR and C 1 -C 6 alkyl;

Each R is independently H, C 1 -C 6 alkyl or aryl, said alkyl and aryl are optionally substituted with 1 to 3 substituents selected from halo, aryl and C 1 -C 6 alkyl;

R 1 is C 1 -C 6 alkyl, said alkyl is optionally substituted with one to three C 1 -C 6 alkyl, OR, NR 2 , CF 3 , SR, OS(O) 2 R 8 , CN or halo substituents,

R 2 is C 1 -C 6 alkyl, which is optionally substituted with one to three groups selected from R 12 ;

R 3 is phenyl, wherein said phenyl is optionally substituted with one to three R 9 ;

Each R 9 is independently halo, CN, C 1 -C 6 alkyl, OR, or NH 2 , where said alkyl may be optionally substituted with one to three halo, CN, OR, C 1 -C 6 alkyl or NH 2 substituents;

Each R 11 is independently H or C 1 -C 6 alkyl;

Each R 12 is independently halo, CN, C(O)OR 11 , C 1 -C 6 alkyl, OR, NH 2 , where said alkyl may be optionally substituted with one to three halo, CN, OR, C 1 -C 6 alkyl or NH 2 substituents; and

x is 0 or 1.

17. A compound of claim 4 which is:

or a pharmaceutically acceptable salt thereof.