Aryl and heteroaryl compounds, compositions, and methods of use

Abstract

This invention provides aryl and heteroaryl compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention may be useful as antagonists, or partial antagonist of factor IX and/or factor XI and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds may be useful in a variety of applications including the management, treatment and/or control of diseases caused in part by the intrinsic clotting pathway utilizing factor IX and/or XI.

1 . A pharmaceutical composition comprising the compound of Formula (X)  
     
       
         
         
             
             
         
       
       wherein R 101  is selected from the group consisting of —H, or —CH 2 -thienyl wherein the thienyl group in —CH 2 -thienyl is optionally substituted with —Br or —CH 3 ;  
       R 102  is selected from the group consisting of —C(O)OH, —C(O)OCH 3 , —C(O)O-t-butyl, —C(O)NH—OCH 2 -phenyl, —C(O)NHOH, and —C(O)NHSO 2 CH 3 ;  
       R 103  is selected from the group consisting of —H, —CH 2 -thienyl, —CH 2 -phenyl, —CH 2 -furanyl, thienyl, and benzothienyl wherein each of the above possibilities for R 103  except —H are optionally substituted with one or more members selected from group consisting of  
       —H, —CH 3 , —CF 3 , —Cl, —Br, —F, —C(O)CH 3 , —CH 2 CH 3 , —CH═CH 2 , —CH 2 OH, —CH(CH 3 ) 2 , —CH 2 CH 2 CH 3 ,  
       
         
           
           
               
               
           
         
       
       R 104  is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       and Y is selected from the group consisting of H,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
     
   
   
       2 . The pharmaceutical composition according to  claim 1 , wherein R 104  is  
     
       
         
         
             
             
         
       
     
   
   
       3 . The pharmaceutical composition according to  claim 1 , wherein R 103  is optionally substituted —CH 2 -2-yl-thienyl or optionally substituted —CH 2 -phenyl.  
   
   
       4 . The pharmaceutical composition according to  claim 1 , wherein R 103  is optionally substituted —CH 2 -2-yl-thienyl.  
   
   
       5 . The pharmaceutical composition according to  claim 4 , wherein R 101  is H.  
   
   
       6 . The pharmaceutical composition according to  claim 1 , wherein Y is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       7 . The pharmaceutical composition according to  claim 1 , wherein Y is -methylene-cyclopentyl.  
   
   
       8 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is prepared in a dose in a range of from about 0.01 to 1,000 mg/kg of body weight per day.  
   
   
       9 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (X) is an antagonist of factor XI or factor IX/XI activity.  
   
   
       10 . The pharmaceutical composition of  claim 9 , wherein the compound of Formula (X) is a partial antagonist of both factor XI and factor XI/IX activity, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiological dose.  
   
   
       11 . The pharmaceutical composition of  claim 9 , comprising a therapeutically effective amount of the compound of Formula (X), wherein said therapeutically effective amount of Formula (X) preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade.  
   
   
       12 . The pharmaceutical composition of  claim 11 , wherein said therapeutically effective amount of Formula (X) comprises an amount sufficient to achieve and maintain a sustained blood level that at least partially antagonizes factor XI or factor IX/XI biological activity.  
   
   
       13 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (X) is an antagonist of factor IX activity.  
   
   
       14 . The pharmaceutical composition of  claim 13 , wherein the compound of Formula (X) is a partial antagonist of factor IX activity, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiological dose.  
   
   
       15 . The pharmaceutical composition of  claim 1 , comprising a therapeutically effective amount of the compound of Formula (X), wherein said therapeutically effective amount comprises a sufficient amount of the compound of Formula (X) to at least partially inhibit the biological activity of factor IX in a subject.  
   
   
       16 . The pharmaceutical composition of  claim 1 , comprising a therapeutically effective amount of the compound of Formula (X), wherein said therapeutically effective amount comprises a sufficient amount of the compound of Formula (X) to at least partially inhibit the biological activity of factor IX in a subject.  
   
   
       17 . The pharmaceutical composition of  claim 16 , wherein said therapeutically effective amount of Formula (X) preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade.  
   
   
       18 . The pharmaceutical composition of  claim 1 , wherein said therapeutically effective amount of Formula (X) comprises a sufficient amount of the compound of Formula (X) for at least partial amelioration of at least one factor IX-mediated disease.  
   
   
       19 . The pharmaceutical composition of  claim 1  in the form of an oral dosage or parenteral dosage unit.  
   
   
       20 . A method comprising administering to a subject a compound of Formula (X)  
     
       
         
         
             
             
         
       
       wherein R 101  is selected from the group consisting of —H, or —CH 2 -thienyl wherein the thienyl group in —CH 2 -thienyl is optionally substituted with —Br or —CH 3 ;  
       R 102  is selected from the group consisting of —C(O)OH, —C(O)OCH 3 , —C(O)O-t-butyl, —C(O)NH—OCH 2 -phenyl, —C(O)NHOH, and —C(O)NHSO 2 CH 3 ;  
       R 103  is selected from the group consisting of —H, —CH 2 -thienyl, —CH 2 -phenyl, —CH 2 -furanyl, thienyl, and benzothienyl wherein each of the above possibilities for R 103  except —H are optionally substituted with one or more members selected from group consisting of  
       
         
           
           
               
               
           
         
       
       R 104  is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       and Y is selected from the group consisting of H,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
     
   
   
       21 . The method according to  claim 20 , wherein the compound of Formula (X) is delivered as a part of a pharmaceutical composition comprising a therapeutically effective amount of said compound of Formula (X) and one or more pharmaceutically acceptable carriers, excipients, or diluents.  
   
   
       22 . The method according to  claim 20 , wherein R 104  is  
     
       
         
         
             
             
         
       
     
   
   
       23 . The method according to  claim 22 , wherein R 101  is —H.  
   
   
       24 . The method according to  claim 20 , wherein R 103  is optionally substituted —CH 2 -2-yl-thienyl or optionally substituted —CH 2 -phenyl.  
   
   
       25 . The method according to  claim 20 , wherein Y is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
   
   
       26 . The method according to  claim 20 , wherein Y is -methylene-cyclopentyl.  
   
   
       27 . The method according to  claim 20 , wherein the compound of Formula (X) is selected from the group consisting of 
 2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-phenyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid methyl ester,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopent-1-enyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid methyl ester,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-cyclopentyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-furan-3-yl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(4-isopropyl-phenyl)-thiophen-2-yl]-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-vinyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-p-tolyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(4-chloro-phenyl)-thiophen-2-yl]-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-ethyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-furan-2-yl-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(2-trifluoromethyl-phenyl)-propionic acid,    {(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid tert-butyl ester,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(3,5-difluorophenyl)-propionic acid,    [[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-(5-methyl-thiophen-2-ylmethyl)-amino]-acetic acid,    {(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid methyl ester,    {(4-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,    {(5-Bromo-thiophen-2-ylmethyl)-[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,    Benzo[b]thiophen-3-yl-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(4-fluoro-phenyl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-propenyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-propyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-[5-(3,3-dimethyl-but-1-enyl)-thiophen-2-yl]-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid methyl ester,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-hydroxymethyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-methyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropylthiophen-2-yl)-propionic acid,    3-(5-Bromo-thiophen-2-yl)-2(R)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,    2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-chloro-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-chloro-furan-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(2,5-dichloro-thiophen-3-yl)-propionic acid,    (5-Bromo-thiophen-2-yl)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-acetic acid,    3-(5-Bromo-furan-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,    3-(5-Bromo-thiophen-2-yl)-2(S)-{[7-(4-trans-tert-butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,    3-(5-Bromo-thiophen-2-yl)-2(S)-{[6-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,    2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropenyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-trans-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-furan-2-yl)-propionic acid,    2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-cyclohexyloxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(R)-{[7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[1-Cyclopentylmethyl-7-(4-trans-ethyl-cyclohexyloxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[1-Cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenoxy)-1-(tetrahydro-pyran-4-yl)-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[6-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-phenyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    2(S)-{[7-(4-tert-Butyl-benzoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid,    3-(5-Acetyl-thiophen-2-yl)-2(S)-{[7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}-propionic acid,    7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-(5-isopropyl-thiophen-2-ylmethyl)-2(R)-methanesulfonylamino-2-oxo-ethyl]-amide, and    7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-(5-isopropyl-thiophen-2-ylmethyl)-2(S)-methanesulfonylamino-2-oxo-ethyl]-amide,    7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-benzyloxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide, and    7-(4-tert-Butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid [1-hydroxycarbamoyl-2-(5-isopropyl-thiophen-2-yl)-ethyl]-amide.    
   
   
       28 . The method according to  claim 20 , wherein said compound of formula (X) inhibits up to 95% of factor IX activity.  
   
   
       29 . A method of treating stroke, myocardial infarction, an aneurysm, or thrombosis comprising the method of  claim 20 .  
   
   
       30 . The method of  claim 20 , wherein the compound of Formula (X) is an antagonist of factor IX activity.  
   
   
       31 . The method of  claim 20 , wherein said compound of Formula (X) is a partial antagonist of factor IX, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiological dose.  
   
   
       32 . The method of  claim 20 , wherein the compound of Formula (X) antagonizes blood clotting mediated by factor IX.  
   
   
       33 . The method of  claim 20 , wherein said compound of Formula (X) is administered in an amount sufficient to partially antagonize the biological activity of factor IX in said subject.  
   
   
       34 . The method of  claim 21 , wherein said therapeutically effective amount of the compound of Formula (X) comprises a sufficient amount of the compound of Formula (X) to at least partially inhibit the intrinsic clotting cascade in said subject.  
   
   
       35 . The method of  claim 21 , wherein said therapeutically effective amount of Formula (X) preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade.  
   
   
       36 . The method of  claim 21 , wherein said therapeutically effective amount of the compound of Formula (X) comprises a sufficient amount of the compound of Formula (X) for treatment or prevention of factor IX-mediated diseases.  
   
   
       37 . The method of  claim 20 , wherein said pharmaceutical composition is administered in the form of an oral dosage or parenteral dosage unit.  
   
   
       38 . The method of  claim 20 , wherein said compound of Formula (X) is administered as a dose in a range from about 0.01 to 1,000 mg/kg of body weight per day.  
   
   
       39 . The method of  claim 36 , wherein said factor IX-mediated disease comprises stroke.  
   
   
       40 . The method of  claim 36 , wherein said factor IX-mediated disease comprises deep vein thrombosis.  
   
   
       41 . The method of  claim 40 , wherein said thrombosis is associated with surgical procedures, long periods of confinement, acquired or inherited pro-coagulant states including anti-phospholipid antibody syndrome, protein C deficiency and protein S deficiency, or acute and chronic inflammation including recurrent miscarriage or Systemic Lupus Erythmatosis (SLE).  
   
   
       42 . The method of  claim 36 , wherein said factor IX-mediated disease comprises clotting associated with the treatment of kidney disease by hemodialysis and/or venous hemofiltration.  
   
   
       43 . The method of  claim 36 , wherein said factor IX-mediated disease comprises cardiovascular disease.  
   
   
       44 . The method of  claim 43 , wherein said cardiovascular disease comprises myocardial infarction, arrhythmia, or aneurysm.  
   
   
       45 . The method of  claim 20 , wherein said compound of Formula (X) is used to replace or supplement compounds that reduce clotting.  
   
   
       46 . The method of  claim 21 , wherein said pharmaceutical composition further comprises one or more therapeutic agents.  
   
   
       47 . A method for the inhibition of the normal biological function of factor XI or factor IX/XI comprising the method of  claim 20 .  
   
   
       48 . A method to inhibit blood clotting comprising the method of  claim 20.