Organic compounds

Abstract

The present invention provides a compound of formula I; a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt thereof, wherein:
 X is O, S or —NR 1 ; 
 each R 1  are independently C 1-7 alkyl or C 3-8 cycloalkyl; 
 each of R 2  and R 6  are independently hydrogen, halogen, cyano, C 1-7 alkyl, hydroxy-C 1-7 alkyl, —OR 7 , C 3-8 cycloalkyl, halo-C 1-7 alkyl or —CH 2 —NR 8 —SO 2 —R 10 ; 
 R 3  and R 4  are independently hydrogen, halogen or cyano; 
 R 5  is hydrogen, C 1-7 alkyl, halogen, cyano, hydroxy, hydroxy-C 1-7 alkyl, hydroxy-C 3-8 cycloalkylalkyl, C 1-7 alkoxy-C 3-8 alkyl, —OR 7 , C 6-10 aryl, heteroaryl, heterocyclyl, C 3-8 cycloalkyl, halo-C 1-7 alkyl, —NR 8 R 9 , —CH 2 —NR 8 —C(O)NR 8 R 9 , —CH 2 NR 8 —SO 2 —R 10 , —C(O)—R 10 , —SO 2 R 10 , —C(O)—NR 8 R 9 , —SO 2 —NR 8 R 9 , —NR 8 C(O)—R 10 , —CH 2 CN, or —NR 8 —SO 2 R 10 ; 
 R 7  is C 1-7 alkyl, C 3-8 cycloalkyl-C 1-7 alkyl, heterocyclyl-C 1-7 alkyl, C 6-10 aryl-C 1-7 alkyl, heteroaryl-C 1-7 alkyl or —C(O)—R 10 ; in which C 6-10 aryl, heteroaryl, C 1-7 alkyl, heterocyclyl and C 3-8 cycloalkyl are optionally substituted with C 1-7 alkoxy, halo, halo-C 3-8 alkoxy, C 1-7 alkyl, OH or halo-C 1-7 alkyl; 
 each of R 8 , R 9  are independently hydrogen, C 1-7 alkyl, halo-C 1-7 alkyl, C 6-10 aryl-C 1-7 alkyl or heterocyclyl; or R 8  and R 9  can form together with the nitrogen atom to which they are attached a 5- or 6-membered ring heterocyclyl, wherein said heterocyclyl optionally contain an additional heteroatom selected from N, O or S and is optionally substituted with C 1-7 alkyl; and 
 R 10  is hydrogen, C 1-7 alkyl, halo-C 1-7 alkyl, C 6-10 aryl-C 1-7  alyl, —NR 8 R 9 , or heterocyclyl; 
 wherein each heteroaryl is a mono- or bicyclic aromatic moiety comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and 
 each heterocyclyl is a mono- or bicyclic saturated or partialy saturated but non-aromatic moiety comprising 4-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms; and each heteroatoms being O, N or S; and with the proviso that when R 5  is halogen or hydrogen than R 2  is other than H; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . (canceled) 
     
     
         3 . The compound according to  claim 1 , wherein:
 R 5  is C 1-7 alkyl, cyano, hydroxy, hydroxy-C 1-7 alkyl, hydroxy-C 3-8 cycloalkylalkyl, C 1-7 alkoxy-C 3-8 alkyl, —OR 7 , C 6-10 aryl, heteroaryl, heterocyclyl, C 3-8 cycloalkyl, halo-C 1-7 alkyl, —NR 8 R 9 , —CH 2 —NR 8 —C(O)NR 8 R 9 , —CH 2 —NR 8 —SO 2 —R 10 , —C(O)—R 10 , —SO 2 R 10 , —C(O)—NR 8 R 9 , —SO 2 —NR 8 R 9 , —NR 8 C(O)—R 10 , —CH 2 CN, or —NR 8 —SO 2 R 10 , or pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 1 , wherein:
 R 1  is methyl;   R 2  is hydrogen, halogen, —OR 7  or C 1-7 alkyl;   R 3  and R 4  are hydrogen;   R 5  is hydrogen, C 1-7 alkyl, halogen, halo-C 1-7 alkyl, hydroxy, hydroxy-C 1-7 alkyl, C 1-7 alkoxy, benzyloxy, C 6-10 aryl, heteroaryl, C 3-8 cycloalkyl, —CH 2 NR 8 SO 2 R 10 , —SO 2 NR 8 R 10  or —NR 8 R 9 ;   R 6  is hydrogen or C 1-7 alkyl;   R 7  is C 1-7 alkyl, or C 6-10 aryl-C 1-7 alkyl; and   each of R 8 , R 9  and R 10  are independently C 1-7 alkyl or H, or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The compound according to  claim 1 , wherein:
 R 1  is methyl; and   R 2  is hydrogen, chloro, methyl, methoxy or —O-benzyl, or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The compound according to  claim 1 , wherein R 2  is chloro, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according to  claim 1 , wherein R 2  is —OR 7 , wherein R 7  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound according to  claim 1 , wherein R 5  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of the compound according to  claim 1  and one or more pharmaceutically acceptable carriers. 
     
     
         10 . A combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents selected from 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, and a CETP inhibitor. 
     
     
         11 . A method of inhibiting aldosterone synthase activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to  claim 1 , or a pharmaceutically acceptable salt. 
     
     
         12 . A method of treating a disorder or a disease in a subject mediated by aldosterone synthase, comprising:
 administering to the subject a therapeutically effective amount of the compound according to  claim 1 , or a pharmaceutically acceptable salt thereof.   
     
     
         13 . A method according to  claim 12 , wherein the disorder or the disease is selected from hypokalemia, hypertension, Conn's disease, renal failure, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, increased formation of collagen, fibrosis and remodeling following hypertension and endothelial dysfunction, cardiovascular diseases, renal dysfunction, liver diseases, cerebrovascular diseases, vascular diseases, retinopathy, neuropathy, insulinopathy, edema, endothelial dysfunction, baroreceptor dysfunction, migraine headaches, heart failure such as congestive heart failure, arrhythmia, diastolic dysfunction, left ventricular diastolic dysfunction, diastolic heart failure, impaired diastolic filing, systolic dysfunction, ischemia, hypertrophic 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. 
     
     
         14 - 17 . (canceled)