Soluble guanylate cyclase activators

1. A compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein

Z 1 is CH;

A is

D 1 is CH, CR 4 or N;

R 7 is selected from the group consisting of

1) hydrogen,

2) C 1-6 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms and unsubstituted or monosubstituted with OC 1-3 alkyl,

3) C 3-6 cycloalkyl wherein the cycloalkyl group may be unsubstituted or substituted with 1-3 fluorine atoms and unsubstituted or monosubstituted with OC 1-3 alkyl, and

4) phenyl, wherein the phenyl group is unsubstituted or substituted with C 1-4 alkyl, —OC 1-4 alkyl, halogen, CN, NO 2 , and S(O) 0-2 C 1-4 alkyl, wherein C 1-4 alkyl and —OC 1-4 alkyl are unsubstituted or substituted with 1-3 flourine atoms;

L 1 is selected from the group consisting of O, S, C(R 12 ) 2 and CF 2 ;

L 2 is selected from the group consisting of (CH 2 ) 2-4 , —C(R 12 ) 2 , —CF 2 —, O, and S, provided that when L 1 is O or S, L 2 is not O or S;

R 12 is independently selected from the group consisting of hydrogen and C 1-3 alkyl, wherein C 1-3 alkyl is unsubstituted or substituted with 1-3 flourine atoms;

E is a ring selected from the group consisting of

1) a 6-10 membered aryl ring,

2) a 5-10 membered heteroaryl ring having 1, 2 or 3 heteroatoms independently selected from the group consisting of 0, 1, 2, and 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms,

3) a C 3-8 cycloalkyl ring;

wherein aryl, heteroaryl, and C3-8 cycloalkyl are unsubstituted or monosubstituted with R5, and unsubstituted, monosubstituted or independently disubstituted with R8;

R4, in each instance in which it occurs, is independently selected from the group consisting of halogen,

C 1-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms,

—O—C 1-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms,

C 3-8 cycloalkyl, unsubstituted or substituted with 1-3 fluorine atoms,

—O—C 3-8 cycloalkyl, unsubstituted or substituted with 1-3 fluorine atoms,

CN, and

NO 2 ;

R 5 , in each instance in which it occurs, is independently selected from the group consisting of

1) R 6 ,

2) —OR 6 ,

3) C 1-6 alkyl which may be unsubstituted or substituted with 1-3 fluorine atoms, and unsubstituted or monosubstituted with a group independently selected from C 3-6 cycloalkyl, —O—C 1-4 alkyl, OH, ═O, S(O) 0-2 C 1-4 alkyl, —OR 6 and R 6 ,

4) C 1-6 alkenyl which may be unsubstituted or substituted with 1-3 fluorine atoms and unsubstituted or monosubstituted with a group independently selected from —O—C 1-4 alkyl, OH, ═O, S(O) 0-2 C 1-4 alkyl, —OR 6 and R 6 ,

5) O—C 1-6 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, and unsubstituted or monosubstituted with a group independently selected from C 3-6 cycloalkyl and R 6 ,

6) —S—C 1-6 alkyl,

7) a C 3-8 cycloalkyl ring which is unsubstituted or mono, di- or tri-substituted with groups independently selected from fluoro and C1-4 alkyl, and unsubstituted or monosubstituted with a group independently selected from (a) C 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, (b) —O—C 1-4 alkyl, (c) OH, (d) ═O, (e) S(O) 0-2 C 1-4 alkyl, (f) —OR 6 , (g) R 6 , and (h) NR 9 R 10 ,

8) a C 5-8 cycloalkenyl ring which is unsubstituted or mono, di- or tri-substituted with a group independently selected from fluoro and C 1-4 alkyl, and unsubstituted or monosubstituted with a group independently selected from (a) C 1-4 alkyl, wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, (b) —O—C 1-4 alkyl, (c) OH, (d) ═O, (e) S(O) 0-2 C 1-4 alkyl, and (f) R 6 , and

9) halogen;

R 6 is selected from the group consisting of

1) a phenyl ring which is unsubstituted, monosubstituted or disubstituted with a group independently selected from the group consisting of (a) halogen, (b) OH, (c) CN, (d) C 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, (e) OC 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, (f) NO 2 , (g) S(O) 0-2 C 1-4 alkyl, (h) C 2-4 alkenyl, (i) O—C 2-4 alkenyl, (j) NR 9 R 10 , and (k) COOH, and

2) a 5-6 membered heteroaryl ring containing 1-2 heteroatoms which are independently selected from N, O and S, wherein the heteroaryl ring is unsubstituted, monosubstituted or disubstituted with a group independently selected from: (a) halogen, (b) OH, (c) CN, (d) C 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, (e) OC 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, (f) NO 2 , (g) S(O) 0-2 C 1-6 alkyl, (h) S(O) 0-2 aryl, (i) C 2-6 alkenyl, (j) OC 2-6 alkenyl, (k) NR 9 R 10 , and (l) COOH;

R 8 is selected from the group consisting of

C 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms,

C 2-4 alkenyl,

halogen,

C 3-6 cycloalkyl, wherein the cycloalkyl group may be unsubstituted or substituted with 1-3 fluorine atoms,

OC 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms;

O—C 2-4 alkenyl,

NO 2 ,

S(O) 0-2 C 1-4 alkyl, and

CN;

R 9 and R 10 are independently selected from the group consisting of hydrogen and C 1-6 alkyl; and

R 11 is selected from the group consisting of hydrogen and C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of

wherein E 1 is CH or N.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of CH 3 , CF 3 and CF 2 H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from the group consisting of O and S.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from the group consisting of CH 2 , CH(CH 3 ), O, CH 2 CH 2 , CF 2 and CH 2 CH 2 CH 2 , provided that when L 2 is O, L 1 is not O.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from the group consisting of CH 2 and CF 2 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of Cl, F, Br, CH 3 , cyclopropyl, NO 2 , and CF 3 .

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of Cl and CH 3 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is a phenyl ring which is unsubstituted, or monosubstituted or disubstituted with a group independently selected from the group consisting of Cl, F, —CH 3 , —C(CH 3 ) 3 , CF 3 , —OCF 3 , —OCH 3 , —OCH(CH 3 ) 2 and COOH.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of

1) R 6 ,

2) a C 3-6 cycloalkyl ring which is unsubstituted or mono, di- or tri-substituted with a group independently selected from phenyl, F, CF 3 , CH 3 , OH, and ═O,

3) a pyridinyl ring, wherein the point of attachment to the pyridinyl ring is a carbon atom, and wherein the pyridinyl ring is unsubstituted or mono-substituted with CF 3 ,

4) —CH 2 -L 3 -R 6 , wherein L 3 is —CH 2 — or —O—,

5) —OR 6 ,

6) —OCH 2 R 6 ,

7)

8) —CF 3

9) Cl, F, or Br,

10) —CH 3 ,

11) OCH 3 ,

12) OCF 3 ,

13) —CH═CHR 6 , and

14) —SCH 2 CH 3 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of Cl, F, Br, —CH 3 , —C(CH 3 ) 3 , OCH 3 , OCF 3 , —SCH 2 CH 3 ,

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of —CH 3 ,

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from the group consisting of CH 3 , Cl, F, cyclopropyl, and CF 3 .

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is hydrogen.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of

1-[6-(2-{[4-(2-Phenylethyl)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-[6-(2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-(6-{2-[(4-{2-[4-(trifluoromethyl)phenyl]ethyl}benzyl)-oxy]phenyl}pyridin-2-yl)-1H-pyrazole-4-carboxylic acid,

1-{6-[2-({4-[(1S,2S)-2-Phenylcyclopropyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[2-({4-[(1R,2R)-2-Phenylcyclopropyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[6-(2-{[4-(4-Chlorophenoxy)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-{6-[2-({4-[4-(trifluoromethyl)phenoxy]benzyl}oxy)phenyl]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-(6-{2-[(4-{[4-(trifluoromethyl)phenoxy]methyl}benzyl)-oxy]phenyl}pyridin-2-yl)-1H-pyrazole-4-carboxylic acid,

1-{6-[5-Methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[5-Methyl-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[5-Chloro-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[5-Chloro-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[6-(2-{[4-(4-Oxocyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[6-(2-{[4-(4,4-Difluorocyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[6-(2-{[4-(trans-4-Methoxycyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[6-(2-{[4-(cis-4-Methoxycyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[6-(2-{[4-(trans)-4-Methoxycyclohexyl)-2-methylbenzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-{6-[2-({4-[6-(trifluoromethyl)pyridin-3-yl]benzyl}-oxy)phenyl]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid,

1-(6-{2-[(2,4-Dimethylbenzyl)oxy]-3-methylphenyl}pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{4-Methyl-6-[5-methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}-oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-[6-(2-{2-[4′-(trifluoromethyl)biphenyl-4-yl]ethyl}phenyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-(2′-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-2,3′-bipyridin-6-yl)-1H-pyrazole-4-carboxylic acid,

1-(5′-Methyl-2′-{[3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-2,3′-bipyridin-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-(5′-Chloro-2′-{[3-methyl-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-2,3′-bipyridin-6-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[2′-{[3-Methyl-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-5′-(trifluoromethyl)-2,3′-bipyridin-6-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-{6-[2-({[4′-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)phenyl]pyridin-2-yl}-1H-pyrazole-4-carboxylic acid,

5-(Trifluoromethyl)-1-(6-{2-[({5-[4-(trifluoromethyl)phenyl]pyridin-2-yl}oxy)methyl]phenyl}pyridin-2-yl)-1H-pyrazole-4-carboxylic acid,

1-{6-[5-Methyl-2-({[4′-(trifluoromethyl)biphenyl-4-yl]methyl}thio)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-[6-(2-{Difluoro[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[2-(Difluoro {4-[trans-4-(trifluoromethyl)cyclohexyl]phenyl}methoxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[2-(difluoro {4-[cis-4-(trifluoromethyl)cyclohexyl]phenyl}methoxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-(6-{2-[{2-Ethyl-4-[4 (trifluoromethyl)cyclohexyl]phenyl}(difluoro)methoxy]phenyl}pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, and

1-{6-[2-(Difluoro {[4′-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

R 11 is H, Z 1 is CH, R 7 is CF 3 or CF 2 H, D 1 is CH, L 1 is O, L 2 is CH 2 or CF 2 ,

ring A is

and

R 5 is

18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of

1-{6-[5-Methyl-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[5-Methyl-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid,

1-{6-[5-Chloro-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, and

1-{6-[5-Chloro-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid.

19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

20. The pharmaceutical composition of claim 19 further comprising a compound selected from the group consisting of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a neutral endopeptidase inhibitor, an aldosterone antagonist, a renin inhibitor, an endothelin receptors antagonist, a vasodilator, a calcium channel blocker, a potassium channel activator, a diuretic, a sympatholitic, a beta-adrenergic blocking drug, an alpha adrenergic blocking drug, a central alpha adrenergic agonist, a peripheral vasodilator, a lipid lowering agent, and a metabolic altering agent.

21. The compound 1-{6-[5-Chloro-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid having the structure

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound of claim 21 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

23. The pharmaceutical composition of claim 22 further comprising a compound selected from the group consisting of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, a neutral endopeptidase inhibitor, an aldosterone antagonist, a renin inhibitor, an endothelin receptors antagonist, a vasodilator, a calcium channel blocker, a potassium channel activator, a diuretic, a sympatholitic, a beta-adrenergic blocking drug, an alpha adrenergic blocking drug, a central alpha adrenergic agonist, a peripheral vasodilator, a lipid lowering agent, and a metabolic altering agent.