Soluble guanylate cyclase activators

Abstract

A compound having the structure useful for treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes, or cirrhosis of the liver in a human or animal patient.

1 . A compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 Z 1  is selected from the group consisting of CH and N; 
 A is a ring selected from the group consisting of 
 
       
         
           
           
               
               
           
         
         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 C 3-8  cycloalkyl are unsubstituted or monosubstituted with R 5 , and unsubstituted, monosubstituted or independently disubstituted with R 8 ; 
 
 
         R 4 , 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 C 1-4  alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, —O—C 1-4  alkyl, OH, ═O, S(O) 0-2 C 1-4  alkyl, —OR 6 , R 6 , and 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 C 1-4  alkyl, wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, —O—C 1-4  alkyl, OH, ═O, S(O) 0-2 C 1-4  alkyl, and R 6 , 
 9) a 5- to 6 membered heterocyclyl ring having 1 or 2 heteroatoms selected from the group consisting of N, O and S, and which is unsubstituted or monosubstituted with a group independently selected from C 1-4  alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, —OC 1-4  alkyl, and ═O, and 
 10) 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 halogen, OH, CN, C 1-4  alkyl wherein the alkyl 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, NO 2 , S(O) 0-2 C 1-4  alkyl, C 2-4  alkenyl, O—C 2-4  alkenyl, NR 9 R 10 , and 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: halogen, OH, CN, C 1-4  alkyl wherein the alkyl 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, NO 2 , S(O) 0-2 C 1-6  alkyl, S(O) 0-2  aryl, C 2-6  alkenyl, OC 2-6  alkenyl, NR 9 R 10 , and 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 . A 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 . A compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1  is CH. 
     
     
         5 . A 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. 
     
     
         6 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L 1  is selected from a group consisting of O and S. 
     
     
         7 . A 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. 
     
     
         8 . A compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein L 2  is selected from the group consisting of CH 2  and CF 2 . 
     
     
         9 . A 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 . 
     
     
         10 . A compound of  claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 4  is selected from the group consisting of Cl and CH 3 . 
     
     
         11 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6  is a phenyl ring which is unsubstituted or mono, di- or tri-substituted 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. 
     
     
         12 . A 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 . 
       
     
     
         13 . A compound of  claim 12 , 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 , 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A compound of  claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 5  is selected from the group consisting of —CH 3 , - 
       
         
           
           
               
               
           
         
       
     
     
         15 . A 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 . 
     
     
         16 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a ring selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11  is hydrogen. 
     
     
         18 . A 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, 
 Ethyl 1-{6-[5-chloro-2-({4-[trans-4-(trifluoromethyl)cyclohexyl]benzyl}-oxy)phenyl]pyrazin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 
 Ethyl 1-{6-[5-chloro-2-({4-[cis-4-(trifluoromethyl)cyclohexyl]benzyl}-oxy)phenyl]pyrazin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate, 
 5-(Trifluoromethyl)-1-[4-(2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)-1,3-thiazol-2-yl]-1H-pyrazole-4-carboxylic acid, 
 1-[2-(2-{[4-(2-Phenylethyl)benzyl]oxy}phenyl)pyrimidin-4-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, 
 1-{6-[2-(Difluoro {[4′-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, and 
 5-(Trifluoromethyl)-1-[6-(2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyridin-2-yl]-1H-1,2,3-triazole-4-carboxylic acid. 
 
     
     
         19 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  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 
       
         
           
           
               
               
           
         
         R 5  is 
       
       
         
           
           
               
               
           
         
       
     
     
         20 . A compound of  claim 18 , 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.   
     
     
         21 . A composition useful for the treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes or cirrhosis of the liver, said composition comprising an amount efficacious for said treatment or prevention of a compound of formula I as claimed in  claim 1 , a stereoisomeric form thereof, or a physiologically acceptable salt thereof, or a mixture of two or more of any of the foregoing, and one or more pharmaceutically acceptable carriers. 
     
     
         22 . A method for activating soluble guanylate cyclase, said method comprising the step of administering an amount efficacious therefore of a compound of formula I as claimed in  claim 1 , a stereoisomeric form thereof, a physiologically acceptable salt thereof, or a mixture of any two or more of the foregoing. 
     
     
         23 . A composition comprising a compound of  claim 1  and 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 activators, 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 agents. 
     
     
         24 . A method for treatment or prevention of cardiovascular diseases, endothelial dysfunction, diastolic dysfunction, atherosclerosis, hypertension, angina pectoris, thromboses, restenoses, myocardial infarction, strokes, cardiac insufficiency, pulmonary hypertonia, erectile dysfunction, asthma bronchiale, chronic kidney insufficiency, diabetes, or cirrhosis of the liver in a human or animal patient, said method comprising the step of administering to the patient an amount efficacious for said treatment or prevention of a compound of formula I as claimed in  claim 1 , a stereoisomeric form thereof, a physiologically acceptable salt thereof, or a mixture of any two or more of the foregoing.