Substituted heteroaryl benzofuran acids

Abstract

The present invention relates generally to substituted heteroaryl benzofuran acids and methods of using them.

1 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or ester form thereof 
     wherein:
 R, R 1 , R 2 , and R 3  are, independently, hydrogen, alkyl, cycloalkyl, alkanoyl, halo, hydroxy, aryl, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, or perfluoroalkoxy; 
 R 4  is hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, arylalkenyl, arylalkynyl, aryl, —C(═O)R 5 , —C(═S)R 5 , —CH 2 R 5 , or —CH(OH)R 5 ; 
 R 5  is hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, perfluoroalkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl; 
 R 6  is hydrogen, alkyl, aryl, or arylalkyl; 
 x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8  are, independently, carbon or nitrogen, wherein at least one of x 1 -x 8  is a nitrogen atom; 
 n is an integer from 0-6; and 
 A is COOH or an acid mimic or a pharmaceutically acceptable salt thereof. 
 
   
   
       2 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
     wherein:
 R, R 1 , R 2 , and R 3  are, independently, hydrogen, alkyl, cycloalkyl, alkanoyl, halo, hydroxy, aryl, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, or perfluoroalkoxy; 
 R 4  is hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, arylalkenyl, arylalkynyl, aryl, —C(═O)R 5 , —C(═S)R 5 , —CH 2 R 5 , or —CH(OH)R 5 ; 
 R 5  is hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, perfluoroalkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl; 
 R 6  is hydrogen, alkyl, aryl, or arylalkyl; 
 x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8  are, independently, carbon or nitrogen, wherein at least one of x 1 -x 8  is a nitrogen atom; and 
 A is an acid mimic or a pharmaceutically acceptable salt thereof. 
 
   
   
       3 . The compound of  claim 1  or  2 , wherein A is tetrazole, tetronic acid, acyl tetronic acid, or a group having the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 15  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkyl, —CH 2 —(C 3 -C 6  cycloalkyl), C 3 -C 6  cycloalkenyl, —CH 2 —(C 3 -C 6  cycloalkenyl), optionally substituted aryl or heteroaryl groups or optionally substituted aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       4 . The compound of  claims 1  or  2 , wherein A is tetrazole or a pharmaceutically acceptable salt thereof. 
   
   
       5 . The compound of  claims 1  or  2 , wherein R and R 1  are hydrogen or a pharmaceutically acceptable salt thereof. 
   
   
       6 . The compound of  claims 1  or  2 , wherein R 4  is hydrogen, alkyl, or aryl or a pharmaceutically acceptable salt thereof. 
   
   
       7 . The compound of  claims 1  or  2 , wherein R 2  and R 3  are, independently, hydrogen or perfluoroalkyl or a pharmaceutically acceptable salt thereof. 
   
   
       8 . The compound of  claims 1  or  2 , wherein R 4  is perfluoroalkyl, alkenyl, arylalkenyl, aryl, —C(—O)R 5 , —C(═S)R 5 , —CH 3 R 5 , or —CH 2 (OH)R 5 , or a pharmaceutically acceptable salt thereof. 
   
   
       9 . The compound of  claim 2  that is 6-(1-benzofuran-2-yl)-2-(trifluoromethyl)quinolin-4-yl 1H-tetraazol-5-ylmethyl ether or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       10 . The compound of  claim 2  that is 6-(3-Pentyl-1-benzofuran-2-yl)-4-(1H-tetraazol-5-ylmethoxy)-2-(trifluoromethyl)-quinoline or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       11 . The compound of  claim 2  that is 5-(1-Benzofuran-2-yl)-8-(1H-tetraazol-5-ylmethoxy)quinoline or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       12 . The compound of  claim 2  that is 5-(3-Phenyl-1-benzofuran-2-yl)-8-quinolinyl 1H-tetraazol-5-ylmethyl ether or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       13 . The compound of  claim 2  that is 5-(3-Pentyl-1-benzofuran-2-yl)-8-(1H-tetraazol-5-ylmethoxy)quinoline or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       14 . A method of inhibiting PAI-1 activity comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claims 1  or  2 . 
   
   
       15 . The method of  claim 14 , wherein the therapeutically effective amount is from 25 mg/kg/day to 200 mg/kg/day. 
   
   
       16 . A method for treating a PAI-1 related disorder in a subject, the method comprising identifying a subject having a PAI-1 related disorder and administering to a subject in need thereof a therapeutically effective amount of the compound of  claims 1  or  2 . 
   
   
       17 . The method of  claim 16 , wherein the therapeutically effective amount is from 25 mg/kg/day to 200 mg/kg/day. 
   
   
       18 . The method of  claim 16 , wherein the PAI-1 related disorder is impairment of the fibrinolytic system. 
   
   
       19 . The method of  claim 16 , wherein the PAI-1 related disorder is thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complication of surgery, cardiovascular disease, myocardial ischemia, stroke, 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 19 , wherein the PAI-1 related disorder is cardiovascular disease caused by noninsulin dependent diabetes mellitus in a mammal. 
   
   
       22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claims 1  or  2 , or a pharmaceutically acceptable salt or ester form thereof, and a pharmaceutically acceptable excipient or carrier. 
   
   
       23 . A method for treating thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complication of surgery, stroke, myocardial ischemia, atherosclerotic plaque formation, chronic obstructive pulmonary disease, or renal fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or ester form thereof 
     wherein:
 R, R 1 , R 2 , and R 3  are, independently, hydrogen, alkyl, cycloalkyl, alkanoyl, halo, hydroxy, aryl, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, or perfluoroalkoxy; 
 R 4  is hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, arylalkenyl, arylalkynyl, aryl, —C(═O)R 5 , —C(═S)R 5 , —CH 2 R 5 , or —CH(OH)R 5 . 
 R 5  is hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, perfluoroalkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl; 
 R 6  is hydrogen, alkyl, aryl, or arylalkyl; 
 x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8  are, independently, carbon or nitrogen, wherein at least one of x 1 -x 8  is a nitrogen atom; 
 n is an integer from 1-6; and 
 A is COOH or an acid mimic. 
 
   
   
       24 . A method for treating a PAI-1 related disorder in a subject, the method comprising identifying a subject having a PAI-1 related disorder and administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 2 . 
   
   
       25 . The method of  claim 24 , wherein the therapeutically effective amount is from 25 mg/kg/day to 200 mg/kg/day. 
   
   
       26 . The method of  claim 24 , wherein the PAI-1 related disorder is impairment of the fibrinolytic system. 
   
   
       27 . The method of  claim 24 , wherein the PAI-1 related disorder is thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complication of surgery, cardiovascular disease, myocardial ischemia, stroke, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, diabetes, Alzheimer's disease, or cancer. 
   
   
       28 . The method of  claim 27 , wherein the thrombosis is selected from the group consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein thrombosis. 
   
   
       29 . The method of  claim 24 , wherein the PAI-1 related disorder is cardiovascular disease caused by noninsulin dependent diabetes mellitus in a mammal. 
   
   
       30 . A method for treating thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complication of surgery, stroke, myocardial ischemia, atherosclerotic plaque formation, chronic obstructive pulmonary disease, or renal fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 2: 
     
       
         
         
             
             
         
       
     
     wherein:
 R, R 1 , R 2 , and R 3  are, independently, hydrogen, alkyl, cycloalkyl, alkanoyl, halo, hydroxy, aryl, perfluoroalkyl, alkoxy, amino, alkylamino, dialkylamino, or perfluoroalkoxy; 
 R 4  is hydrogen, alkyl, perfluoroalkyl, alkenyl, alkynyl, arylalkenyl, arylalkynyl, aryl, —C(═O)R 5 , —C(═S)R 5 , —CH 2 R 5 , or —CH(OH)R 5 . 
 R 5  is hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, perfluoroalkyl, aryl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl; 
 R 6  is hydrogen, alkyl, aryl, or arylalkyl; 
 x 1 , x 2 , x 3 , x 4 , x 5 , x 6 , x 7 , and x 8  are, independently, carbon or nitrogen, wherein at least one of x 1 -x 8  is a nitrogen atom; and 
 A is an acid mimic.