Substituted Indoles And Methods Of Their Use

Abstract

The present invention relates generally to substituted indoles and methods of using them.

1 . A compound having Formula 1: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof, wherein 
       R 1  is C 1-6  alkyl; 
       R 2  is NR 3 SO 2 R 4  or NHC(═O)NHR 5 ; 
       R 3  is hydrogen, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl; 
       R 4  is C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl; 
       with the proviso that either R 3  or R 4  is substituted by COOR 6 ; 
       R 5  is phenyl(CO 2 H) or —C 1-6  alkyl(CO 2 H) wherein the alkyl group is optionally substituted with phenyl or benzyl; 
       R 6  is hydrogen or C 1-6  alkyl; and 
       n is from 1 to 4. 
     
   
   
       2 . The compound of  claim 1 , wherein:
 R 5  is —C 1-6  alkyl(CO 2 H) wherein the alkyl group is substituted with phenyl or benzyl.   
   
   
       3 . The compound of  claim 1 , wherein:
 R 3  is hydrogen, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl unsubstituted or substituted with COOR 6 .   
   
   
       4 . The compound of  claim 1 , wherein:
 R 4  is C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl unsubstituted or substituted with COOR 6 .   
   
   
       5 . The compound of  claim 1 , wherein:
 n is 1.   
   
   
       6 . The compound of  claim 1  that is one of the following:
 3-[({[1-(4-tert-butylbenzyl)-1H-indol-5-yl]amino}carbonyl)amino]benzoic acid;   3-({[1-(4-tert-butylbenzyl)-1H-indol-5-yl]amino}sulfonyl)benzoic acid;   {benzenesulfonyl-[1-(4-tert-butyl-benzyl)-1H-indol-5-yl]-amino}-acetic acid;   4-{[[1-(4-tert-butylbenzyl)-1H-indol-5-yl](phenylsulfonyl)amino]methyl}benzoic acid;   4-({[1-(4-tert-butylbenzyl)-1H-indol-5-yl]amino}sulfonyl)benzoic acid;   N-({[1-(4-tert-butylbenzyl)-1H-indol-5-yl]amino}carbonyl)-L-phenylalanine; or   a pharmaceutically acceptable salt or ester form thereof.   
   
   
       7 . A compound having Formula 2 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof, wherein 
       R 7  is hydrogen, CO 2 H, or CONHNH 2 ; 
       p is from 0 to 4; 
       R 8  is hydrogen, —C 1-6 alkoxy(CO 2 H), C(═O)NR 10 R 11  or C(═O)amino acid; 
       R 10  and R 11  are joined together with the nitrogen to which they are attached to form a 3 to 9 membered saturated ring comprising 2 to 8 carbon ring atoms; 
       with the proviso that when R 8  is hydrogen, R 7  is CO 2 H or CONHNH 2 ; 
       N 9  is NR 12 SO 2 R 13 ; 
       N 12  is H, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl unsubstituted or substituted with OCF 3 , halogen, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl; and 
       R 13  is C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl unsubstituted or substituted with OCF 3 , halogen, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl. 
     
   
   
       8 . The compound of  claim 7 , wherein:
 said alkyl, perfluoroalkyl, benzyl, phenyl, and heterocyclyl groups are unsubstituted or substituted with OCF 3 , halogen, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl.   
   
   
       9 . The compound of  claim 7 , wherein:
 the amino acid is β-alanine, phenylalanine, or —NR 18 R 19  wherein R 18  and R 19  are joined together with the nitrogen to which they are attached to form a 3 to 9 membered saturated ring comprising 2 to 8 carbon ring atoms and substituted with CO 2 H or C(O)C 1-6  alkoxy.   
   
   
       10 . The compound of  claim 7  that is one of the following:
 [4-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1H-indol-1-yl}methyl)phenoxy]acetic acid;   {4-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H-indol-1-yl)methyl]phenoxy}acetic acid;   3-phenyl-2-[5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol-1-yl]propanoic acid;   1-{4-[(5-{[(3,4-dichlorophenyl)sulfonyl]amino}-1H-indol-1-yl)methyl]benzoyl}piperidine-4-carboxylic acid;   1-[4-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1H-indol-1-yl}methyl)benzoyl]piperidine-4-carboxylic acid;   1-{4-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H-indol-1-yl)methyl]benzoyl}piperidine-4-carboxylic acid;   N-(4-{[5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol-1-yl]methyl}benzoyl)-β-alanine;   N-[4-({5-[(1,1′-biphenyl)-4-ylsulfonyl)amino]-1H-indol-1-yl}methyl)benzoyl]-β-alanine;   N-{4-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H-indol-1-yl)methyl]benzoyl}-β-alanine;   N-[4-({5-[(phenylsulfonyl)amino]-1H-indol-1-yl}methyl)benzoyl]-L-phenylalanine;   N-(4-{[5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol-1-yl]methyl}benzoyl)-L-phenylalanine;   N-[4-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1H-indol-1-yl}methyl)benzoyl]-L-phenylalanine;   N-{4-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H-indol-1-yl)methyl]benzoyl}-L-phenylalanine;   N-[1-(1-benzyl-2-hydrazino-2-oxoethyl)-1H-indol-5-yl]-4-(trifluoromethoxy)benzenesulfonamide; or   a pharmaceutically acceptable salt or ester form thereof.   
   
   
       11 . A compound having Formula 3 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof, wherein 
       R 14  is —OH, C 1-6  alkoxy, or amino acid; 
       R 15  is NR 16 SO 2 R 17 ; 
       R 16  is H or a C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl unsubstituted or substituted with OCF 3 , halogen, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl; 
       R 17  is C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl unsubstituted or substituted with OCF 3 , halogen, C 1-6  alkyl, C 1-6  perfluoroalkyl, benzyl, phenyl, or heterocyclyl; and 
       s is from 1 to 4. 
     
   
   
       12 . The compound of  claim 11  with the proviso that when R 14  is —OH or C 1-6 alkoxy, R 16  or R 17  is substituted with OCF 3 , benzyl, phenyl, or heterocyclyl. 
   
   
       13 . The compound of  claim 11 , wherein:
 R 14  is alpha amino acid or NR 18 R 19  wherein R 18  and R 19  are joined together with the nitrogen to which they are attached to form a 3 to 9 membered saturated ring comprising 2 to 8 carbon ring atoms and substituted with CO 2 H or C(O)C 1-6  alkoxy.   
   
   
       14 . The compound of  claim 11  that is one of the following:
 {5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1H-indol-1-yl}acetic acid;   N-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1H-indol-1-yl}acetyl)-L-phenylalanine;   N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H-indol-1-yl)acetyl]-phenylalanine;   N-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1H-indol-1-yl}acetyl)-L-leucine;   N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H-indol-1-yl)acetyl]-L-leucine;   N-{[5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol-1-yl]acetyl}-L-phenylalanine;   N-({5-[(quinolin-8-ylsulfonyl)amino]-1H-indol-1-yl}acetyl)-L-phenylalanine;   N-{[5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol-1-yl]acetyl}-L-leucine;   1-{[5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol-1-yl]acetyl}piperidine-4-carboxylic acid;   1-({5-[(quinolin-8-ylsulfonyl)amino]-1H-indol-1-yl}acetyl)piperidine-4-carboxylic acid;   1-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1H-indol-1-yl}acetyl)piperidine-4-carboxylic acid;   1-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1H-indol-1-yl)acetyl]piperidine-4-carboxylic acid;   N-({5-[(quinolin-8-ylsulfonyl)amino]-1H-indol-1-yl}acetyl)-L-leucine;   or a pharmaceutically acceptable salt or ester form thereof.   
   
   
       15 . A method of inhibiting PAI-1 activity, comprising the step of:
 administering to a subject in need thereof a pharmaceutically effective amount of a compound of any one of  claim 1 ,  7 , or  11 .   
   
   
       16 . The method of  claim 15 ,
 wherein the pharmaceutically effective amount is from 25 mg/kg/day to 200 mg/kg/day.   
   
   
       17 . A method for treating a PAI-1 related disorder, comprising the step of:
 administering to a subject in need thereof a pharmaceutically effective amount of a compound of  claim 1 ,  7 , or  11 .   
   
   
       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 . The method of  claim 19 ,
 wherein the thrombosis is selected from the group consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein thrombosis.   
   
   
       21 . The method of  claim 17 ,
 wherein the PAI-1 related disorder is cardiovascular disease caused by noninsulin dependent diabetes mellitus in a subject.   
   
   
       22 . The method of  claim 17 ,
 wherein the pharmaceutically effective amount is from 25 mg/kg/day to 200 mg/kg/day.   
   
   
       23 . A method, comprising the step of:
 contacting a cell with a compound of  claim 1 ,  7 , or  11 .