Organic compounds

Abstract

The present invention provides novel organic compounds of Formula (I): methods of use, and pharmaceutical compositions thereof.

1 - 30 . (canceled) 
     
     
         31 . 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1a  is hydrogen; 
 R 2a  is hydrogen, halogen, or hydroxy; 
 R 3a  is hydrogen, halogen, cyano, or alkoxy; 
 R 4a  is hydrogen or halogen; 
 R 5a  is hydrogen or alkyl; 
 R 6a  and R 7a  are hydrogen; 
 R 8a  is: 
 
       
         
           
           
               
               
           
         
         L is alkyl, carbonyl, sulfonyl, or —(CH 2 ) 2 —O—; and 
         R 11a , R 12a , R 13a , R 14a , and R 15a  are each independently hydrogen, alkyl, cyano, halogen, alkoxy, alkoxycarbonyl, carboxylate, heteroaryl, or sulfonyl; with the proviso that at least one of R 1a -R 7a  is other than hydrogen; or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 . A compound according to  claim 31  wherein the compound is selected from:
 1-Benzyl-3-methyl-2-pyridin-3-yl-1H-indole; 
 4-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid methyl ester; 
 4-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid methyl ester; 
 4-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid methyl ester; 
 3-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile; 
 3-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride; 
 3-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride; 
 4-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile; 
 4-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride; 
 4-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile; 
 3-Fluoro-4-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile; 
 3-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile; 
 4-(3-Methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile; 
 1-(2-Fluoro-4-methoxy-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride; 
 4-(5-chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid; 
 4-(5-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid; 
 4-(6-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid; 
 4-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid; 
 4-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid; 
 4-(5-Cyano-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzoic acid; 
 3-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid; 
 2,6-Dimethyl-4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzoic acid; 
 5-Chloro-3-methyl-2-pyridin-3-yl-1-[4-(2H-tetrazol-5-yl)-benzyl]-1H-indole; 
 3-(3-Methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile; 
 4-(3-Methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile; 
 (3-Methyl-2-pyridin-3-yl-indol-1-yl)-phenyl-methanone; 
 3-(5-Cyano-3-methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile; 
 1-(3-Cyano-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 4-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid methyl ester; 
 4-(5-cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid; 
 1-(4-cyano-3-methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 3-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid tert-butyl ester; 
 1-(3-Methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 1-(3,4-Dimethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 1-(4-Methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile 
 1-(3-Methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 1-(3,4-Dimethoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 1-(3-Ethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 1-(3,5-Dimethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 5-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acid; 
 3-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid; 
 1-(3-Cyano-benzenesulfonyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 3-Methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 1-(2-Phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile; 
 3-Methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole; 
 3-[2-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester; 
 4-[2-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester 
 4-[2-(5-Cyano-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid; and 
 4-[2-(5-Chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A method of treating an aldosterone synthase associated state in a subject, comprising administering to said subject a therapeutically effective amount of a compound according to  claim 31 ; or a pharmaceutically acceptable salt thereof; such that said aldosterone synthase associated state in said subject is treated. 
     
     
         34 . The method of  claim 33 , wherein said aldosterone synthase associated state is a cardiovascular disease selected from heart failure, congestive heart failure, arrhythmia, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filling, systolic dysfunction, ischemia, hypertropic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, decreased ejection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, and fibrinoid necrosis of coronary arteries. 
     
     
         35 . The method of  claim 33 , wherein said aldosterone synthase associated state is selected from renal dysfunction, liver diseases, cerebrovascular diseases, vascular diseases, retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction, migraine headaches, and hypertension. 
     
     
         36 . A method of treating an aldosterone synthase associated state in a subject, comprising administering to said subject a therapeutically effective amount of a compound of according to  claim 32 ; or a pharmaceutically acceptable salt thereof; such that said aldosterone synthase associated state in said subject is treated. 
     
     
         37 . The method of  claim 36 , wherein said aldosterone synthase associated state is a cardiovascular disease selected from heart failure, congestive heart failure, arrhythmia, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filling, systolic dysfunction, ischemia, hypertropic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, impaired arterial compliance, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, decreased ejection fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, and fibrinoid necrosis of coronary arteries. 
     
     
         38 . The method of  claim 37 , wherein said aldosterone synthase associated state is selected from renal dysfunction, liver diseases, cerebrovascular diseases, vascular diseases, retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction, migraine headaches, and hypertension. 
     
     
         39 . A pharmaceutical composition, comprising
 an effective amount of a compound according to  claim 31 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.   
     
     
         40 . The pharmaceutical composition of  claim 39 , further comprising a second agent. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein said second agent is an HMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist, angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB), a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, or a CETP inhibitor. 
     
     
         42 . A pharmaceutical composition, comprising
 an effective amount of a compound according to  claim 32 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.   
     
     
         43 . The pharmaceutical composition of  claim 42 , further comprising a second agent. 
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein said second agent is an HMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist, angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB), a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, or a CETP inhibitor.