Substituted pyrrole-indoles

Abstract

The present invention relates generally to substituted pyrrole-indoles such as substituted pyrrole-indoles, and methods of using them.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or ester form thereof;  
     wherein: 
 X is O or NH;  
 R 2  is hydrogen, C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, C 7 -C 11  bicycloalkyl, arylalkyl, carboxyalkyl, C 6 -C 10  aryl, or heterocycle;  
 or X and R 2  together form an amino acid;  
 R 1  is hydrogen, C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, C 7 -C 11  bicycloalkyl, arylalkyl, carboxyalkyl, C 6 -C 10  aryl, or heterocycle;  
 R 3  is hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 3  perfluoroalkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkyl, or —C(═O)C 1 -C 3  alkyl;  
 R 4  and R 5  are, independently, hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 3  perfluoroalkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkyl, or —C(═O)C 1 -C 3  alkyl;  
 or R 4  and R 5 , together, form a phenyl ring; and  
 A is hydrogen, C 6 -C 10  aryl, or heterocycle;  
 wherein each of said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, phenyl and heterocycle groups or part of groups may be optionally substituted by one, two, three or more substituents.  
 
   
   
       2 . A compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, wherein A is phenyl optionally substituted by one or more substituents the same or different selected from C 1 -C 6  alkyl, halogen, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, aralkyl, C 6 -C 10  aryl, heterocyle, hydroxy, C 1 -C 6  alkoxy, aryl-oxy, oxo (═O), —CN, —C(═O)H, —CO 2 H, —OCO 2 C 1 -C 6  alkyl, —CO 2 C 1 -C 6  alkyl, —CO 2 -aryl, —CO 2 -alkyl-aryl, —OCO 2 -aryl, —C(═O)NH 2 , —C(═O)NHOH, amino, C 1 -C 6  alkylamino, dialkylamino of 1-6 carbons per alkyl moiety, —NHC(═O)NHC 1 -C 6  alkyl, —NHSO 2 C 1 -C 6  alkyl, —NHSO 2 -aryl, or —NHSO 2 -heterocycle.  
   
   
       3 . A compound of  claim 1  having the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 6  is C 1 -C 6  alkyl, halogen, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, aralkyl, C 6 -C 10  aryl, heterocyle, hydroxy, C 1 -C 6  alkoxy, aryl-oxy, —CN, —C(═O)H, —CO 2 H, —OCO 2 C 1 -C 6  alkyl, —CO 2 C 1 -C 6  alkyl, —CO 2 -aryl, —CO 2 -alkyl-aryl, —OCO 2 -aryl, —C(═O)NH 2 , —C(═O)NHOH, amino, C 1 -C 6  alkylamino, dialkylamino of 1-6 carbons per alkyl moiety, —NHC(═O)NHC 1 -C 6  alkyl, —NHSO 2 C 1 -C 6  alkyl, —NHSO 2 -aryl, or —NHSO 2 -heterocycle  
     or a pharmaceutically acceptable salt of ester form thereof.  
   
   
       4 . A compound of  claim 1  having the formula:  
     
       
         
         
             
             
         
       
     
     wherein R 6  is C 1 -C 6  alkyl, halogen, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, aralkyl, C 6 -C 10  aryl, heterocyle, hydroxy, C 1 -C 6  alkoxy, aryl-oxy, —CN, —C(═O)H, —CO 2 H, —OCO 2 C 1 -C 6  alkyl, —CO 2 C 1 -C 6  alkyl, —CO 2 -aryl, —CO 2 -alkyl-aryl, —OCO 2 -aryl, —C(═O)NH 2 , —C(═O)NHOH, amino, C 1 -C 6  alkylamino, dialkylamino of 1-6 carbons per alkyl moiety, —NHC(═O)NHC 1 -C 6  alkyl, —NHSO 2 C 1 -C 6  alkyl, —NHSO 2 -aryl, or —NHSO 2 -heterocycle  
     or a pharmaceutically acceptable salt or ester form thereof.  
   
   
       5 . A compound of  claim 1  having the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or ester form thereof, wherein Aa is an amino acid and R 6  is C 1 -C 6  alkyl, halogen, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, aralkyl, C 6 -C 10  aryl, heterocyle, hydroxy, C 1 -C 6  alkoxy, aryl-oxy, —CN, —C(═O)H, —CO 2 H, —OCO 2 C 1 -C 6  alkyl, —CO 2 C 1 -C 6  alkyl, —CO 2 -aryl, —CO 2 -alkyl-aryl, —OCO 2 -aryl, —C(═O)NH 2 , —C(═O)NHOH, amino, C 1 -C 6  alkylamino, dialkylamino of 1-6 carbons per alkyl moiety, —NHC(═O)NHC 1 -C 6  alkyl, —NHSO 2 C 1 -C 6  alkyl, —NHSO 2 -aryl, or —NHSO 2 -heterocycle.  
   
   
       6 . A compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, wherein A is unsubstituted phenyl or phenyl substituted with C 4  branched alkyl.  
   
   
       7 . A compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, wherein R 1  is hydrogen, C 1 -C 6  alkyl, or —(CH 2 ) n aryl optionally substituted with an aryl group, hydrogen, or C 1 -C 6  alkyl; wherein n is an integer from 1 to 6.  
   
   
       8 . A compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, wherein X is O and R 2  is H.  
   
   
       9 . A compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, wherein X is NH and R 2  is carboxyalkyl optionally substituted with aryl or C 1 -C 6  alkyl.  
   
   
       10 . A compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, wherein R 3  is hydrogen or C 1 -C 6  alkyl optionally substituted with halogen, cyano, or alkoxy.  
   
   
       11 . A compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, wherein R 4  and R 5  are independently hydrogen, C 1 -C 6  alkyl optionally substituted with halogen, cyano, or alkoxy, or R 4  and R 5  together form a phenyl ring.  
   
   
       12 . A compound of  claim 1  that is 1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-benzyl-5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; or 1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof.  
   
   
       13 . A compound of  claim 1  that is 1′-(1,1′-biphenyl-4-ylmethyl)-3′-phenyl-1′H-1,5′-biindole-2′-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; or 1-benzyl-3-(4-tert-butylphenyl)-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof.  
   
   
       14 . A compound of  claim 1  that is 1′-benzyl-3′-(4-tert-butylphenyl)-1′H-1,5′-biindole-2′-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; N-{[1-methyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}-L-phenylalanine or a pharmaceutically acceptable salt or ester form thereof or N-{[1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}-L-phenylalanine or a pharmaceutically acceptable salt or ester form thereof.  
   
   
       15 . A compound of  claim 1  that is N-{[1-benzyl-3-phenyl-5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}-L-leucine or a pharmaceutically acceptable salt or ester form thereof; N-{[1-benzyl-5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-phenyl-1H-indol-2-yl]carbonyl}-L-leucine or a pharmaceutically acceptable salt or ester form thereof or N-{[3-phenyl-5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}-L-phenylalanine or a pharmaceutically acceptable salt or ester form thereof.  
   
   
       16 . A method of inhibiting PAI-1 activity comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof.  
   
   
       17 . A method for treating a PAI-1 related disorder comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof.  
   
   
       18 . The method of  claim 17 , wherein the PAI-1 related disorder is impairment of the fibrinolytic system.  
   
   
       19 . The method of  claim 17 , wherein the PAI-1 related disorder is thrombosis, atrial fibrillation, pulmonary fibrosis, myocardial ischemia, stroke, thromboembolic complication of surgery, cardiovascular disease, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, diabetes, Alzheimer's disease, or cancer.  
   
   
       20 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, and a pharmaceutically acceptable excipient or carrier.