Substituted heterocyclic compounds

Abstract

Disclosed are novel heterocyclic compounds having the structure which are useful for the treatment of various disease states, in particular cardiovascular diseases such as atrial and ventricular arrhythmias, intermittent claudication, Prinzmetal's (variant) angina, stable and unstable angina, exercise induced angina, congestive heart disease, and myocardial infarction. The compounds are also useful in the treatment of diabetes.

1 . A compound of Formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are hydrogen, lower alkyl, or —C(O)R; in which R is —OR 9  or —NR 12 R 13 , where R 12  and R 13  are hydrogen or lower alkyl; or  
 R 1  and R 2 , R 3  and R 4 , R 5  and R 6 , R 7  and R 8 , when taken together with the carbon to which they are attached, represent carbonyl; or  
 R 1  and R 5 , or R 1  and R 7 , or R 3  and R 5 , or R 3  and R 7 , when taken together form a bridging group —(CR 14 R 15 ) n —, in which n is 1, 2 or 3, and R 14  and R 15  are independently hydrogen or lower alkyl;  
 with the proviso that 
 (i) the maximum number of carbonyl groups is 2; and  
 (ii) the maximum number of bridging groups is 1;  
 
 R 9  and R 11  are independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;  
 R 10  is hydrogen or lower alkyl;  
 T is oxygen, sulfur, or ═NR 16 , in which R 16  is hydrogen, lower alkyl, cyano, lower alkoxy, or C(O)OR 17 , in which R 17  is lower alkyl;  
 X is —N< or —NH—CH<;  
 Y is optionally substituted alkylene of 1-3 carbon atoms; and  
 Z is —O—, —S—, —N(R 18 )— where R 18  is hydrogen or lower alkyl, or a covalent bond.  
 
   
   
       2 . The compound of  claim 1 , wherein R 1 , R 2 ,R 3 ,R 4 ,R 5 , R 6 , R 7 , and R 8  are independently chosen from hydrogen and methyl.  
   
   
       3 . The compound of  claim 2 , wherein R 10  is hydrogen.  
   
   
       4 . The compound of  claim 3 , wherein R 11  is optionally substituted aryl or optionally substituted heteroaryl.  
   
   
       5 . The compound of  claim 4 , wherein X is —N<.  
   
   
       6 . The compound of  claim 5 , wherein T is oxygen.  
   
   
       7 . The compound of  claim 6 , wherein R 9  is optionally substituted alkyl.  
   
   
       8 . The compound of  claim 7 , wherein R 9  is optionally substituted benzyl.  
   
   
       9 . The compound of  claim 8 , wherein R 11  is optionally substituted heteroaryl.  
   
   
       10 . The compound of  claim 9 , selected from the group consisting of: 
 {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(2-fluorophenyl)methyl]carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(2,4-dichlorophenyl)methyl]carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(3,4-dichlorophenyl)methyl]carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(4-fluorophenyl)methyl]carboxamide; and    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(2-chlorophenyl)methyl]carboxamide.    
   
   
       11 . The compound of  claim 6 , wherein R 9  is optionally substituted aryl.  
   
   
       12 . The compound of  claim 11 , wherein R 9  is optionally substituted phenyl.  
   
   
       13 . The compound of  claim 12 , wherein R 11  is optionally substituted heteroaryl.  
   
   
       14 . The compound of  claim 13 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are hydrogen.  
   
   
       15 . The compound of  claim 14 , selected from the group consisting of: 
 {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-phenoxyphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(9-oxofluoren-3-yl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2-fluorophenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2-chlorophenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[4-(trifluoromethyl)phenyl]carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-phenylphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-fluoren-2-ylcarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-methoxyphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[4-(trifluoromethoxy)phenyl]carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-ethoxyphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[2-(trifluoromethoxy)phenyl]carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2-phenylphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-chlorophenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(3-phenylphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-morpholin-4-ylphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-cyclohexylphenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(4-chlorophenyl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[4-(4-chlorophenoxy)phenyl]carboxamide; and    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(3-phenoxyphenyl)carboxamide.    
   
   
       16 . The compound of  claim 13 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  is methyl and the others are hydrogen.  
   
   
       17 . The compound of  claim 16 , selected from the group consisting of: 
 {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-fluoren-2-ylcarboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(4-phenylphenyl)carboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(9-oxofluoren-3-yl)carboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(4-chlorophenyl)carboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(4-cyanophenyl)carboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-[4-(4-chlorophenoxy)phenyl]carboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(4-phenoxyphenyl)carboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(4-morpholin-4-ylphenyl)carboxamide;    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(4-cyclohexylphenyl)carboxamide; and    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(3-phenylphenyl)carboxamide.    
   
   
       18 . The compound of  claim 6 , wherein R 9  is optionally substituted heteroaryl.  
   
   
       19 . The compound of  claim 18 , wherein R 11  is optionally substituted heteroaryl.  
   
   
       20 . The compound of  claim 19 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are hydrogen.  
   
   
       21 . The compound of  claim 20 , selected from the group consisting of: 
 {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(3-methyl-5-phenylisoxazol-4-yl)carboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(9-ethylcarbazol-3-yl)carboxamide; and    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-benzo[d]benzo[3 ,4-b]furan-3-ylcarboxamide.    
   
   
       22 . The compound of  claim 13 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  is methyl and the others are hydrogen.  
   
   
       23 . The compound of  claim 22 , selected from the group consisting of: 
 {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-(9-ethylcarbazol-3-yl)carboxamide; and    {(3S)-4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpiperazinyl}-N-benzo[d]benzo[3,4-b]furan-3-ylcarboxamide.    
   
   
       24 . The compound of  claim 5 , wherein T is sulfur.  
   
   
       25 . The compound of  claim 24 , wherein R 9  is optionally substituted alkyl.  
   
   
       26 . The compound of  claim 25 , wherein R 9  is optionally substituted benzyl.  
   
   
       27 . The compound of  claim 26 , wherein R 11  is optionally substituted heteroaryl.  
   
   
       28 . The compound of  claim 27 , selected from the group consisting of: 
 {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(4-chlorophenyl)methyl]thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(3,4-dichlorophenyl)methyl]thiocarboxamide; and    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(4-fluorophenyl)methyl]thiocarboxamide.    
   
   
       29 . The compound of  claim 24 , wherein R 9  is optionally substituted aryl.  
   
   
       30 . The compound of  claim 29 , wherein R 9  is optionally substituted phenyl.  
   
   
       31 . The compound of  claim 30 , wherein R 11  is optionally substituted aryl.  
   
   
       32 . The compound of  claim 31 , namely {4-[(2R)-2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazinyl}-N-(6-chloro-2-methylphenyl)thiocarboxamide.  
   
   
       33 . The compound of  claim 20 , wherein R 11  is optionally substituted heteroaryl.  
   
   
       34 . The compound of  claim 33 , selected from the group consisting of: 
 {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[4-(trifluoromethyl)phenyl]thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2-fluorophenyl)thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[2-chlorophenyl]thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[4-fluorophenyl]thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[2-methylphenyl]thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[naphth-1-yl]thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[(4-phenylmethoxyphenyl)]thiocarboxamide;    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-(2-phenylphenyl)thiocarboxamide; and    {4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-N-[4-ethoxyphenyl]thiocarboxamide.    
   
   
       35 . The compound of  claim 5 , wherein T is nitrogen.  
   
   
       36 . The compound of  claim 35 , wherein R 9  is optionally substituted aryl.  
   
   
       37 . The compound of  claim 36 , wherein R 9  is optionally substituted phenyl.  
   
   
       38 . The compound of  claim 37 , wherein R 11  is optionally substituted heteroaryl.  
   
   
       39 . The compound of  claim 38 , namely 3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}(2Z)-2-aza-3-[(3 ,4-dichlorophenyl)amino]prop-2-enenitrile.  
   
   
       40 . The compound of  claim 4 , wherein X is —NH—CH<.  
   
   
       41 . The compound of  claim 40 , wherein T is oxygen, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  are hydrogen, and R 9  and R 11  are both optionally substituted aryl.  
   
   
       42 . The compound of  claim 41 , namely N-(2,6-dimethylphenyl)({1-[2-hydroxy-3-(2-methoxyphenoxy)propyl](4-piperidyl)}amino)carboxyamide.  
   
   
       43 . A method of treating a disease state chosen from diabetes, damage to skeletal muscles resulting from trauma or shock and a cardiovascular disease in a mammal by administration of a therapeutically effective dose of a compound of  claim 1 .  
   
   
       44 . The method of  claim 43 , wherein the cardiovascular disease is atrial arrhythmia, intermittent claudication, ventricular arrhythmia, Prinzmetal's (variant) angina, stable angina, unstable angina, congestive heart disease, or myocardial infarction.  
   
   
       45 . The method of  claim 44 , wherein the disease state is diabetes.  
   
   
       46 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1.