Substituted azetidinones

Abstract

Compounds are provided which have the structure Wherein A, B, C, D, m, Y, Ra, Rc, Rd, and Rd′ are as described herein, and which are useful as inhibitors of tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, Factor XIa, and urokinase-type plasminogen activator and may be employed in preventing and/or treating asthma, chronic asthma, allergic rhinitis, and thrombotic disorders.

1 . A compound according to the following structure or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 A, B, C, D and m are defined such that 
 
     
       
         
         
             
             
         
       
     
     comprises a structure selected from: 
     
       
         
         
             
             
         
       
       wherein
 R z1  is a member independently selected from H and CH 3    
 R z2  is a member selected from H and C 1 -C 4  alkyl 
 R z3  is a member selected from H and NH 2    
 X 1  is a member selected from C and N 
 k 1  is an integer selected from 0 and 1; 
 
       X is a member selected from S and O; 
       Y is a member selected from a bond, C═O, and SO 2 ; 
       R a  is a member selected from NR 7 R 8 , substituted or unsubstituted heteroaryl, and 
     
     
       
         
         
             
             
         
       
       wherein
 R 7  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 R 8  is a member selected from substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and 
 k2 is an integer selected from 1, 2 and 3; 
 
       R c  is a member selected from H and substituted or unsubstituted C 1 -C 5  alkyl; 
       R d  is a member selected from R 16  and CH 2 R 16    
       wherein 
       R 16  is a member selected from C(O)R 18 , 
     
     
       
         
         
             
             
         
       
       wherein 
       R 18  is a member selected from OR 21 , NR 19 N 20 , and NR 19 SO 2 R 20  
 R z4  is a member selected from C 1 -C 5  alkyl, C 3 -C 6  cycloalkyl, and substituted or unsubstituted phenyl 
 R z5  is a member selected from H, C 1 -C 5  alkyl, C 3 -C 6  cycloalkyl, and substituted or unsubstituted phenyl 
 R z6  is a member selected from C 1 -C 5  alkyl and C 3 -C 6  cycloalkyl 
 wherein
 R 21  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted aryl; 
 R 19  is a member selected from H and substituted or unsubstituted C 1 -C 5  alkyl; and 
 R 20  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and 
 R 19  and R 20  can be optionally joined, together with the atoms to which they are attached, to form a 5 or 6 membered ring; and 
 
 
       R d ′ is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, and substituted or unsubstituted C 3 -C 6  cycloalkyl. 
     
   
   
       2 . A pharmaceutical composition comprising an effective amount of the compound of  claim 1  including an inner salt or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       3 . A method for enhancing thrombolysis or inhibiting or preventing thrombosis in a mammalian species comprising administering a therapeutically effective amount of the compound of  claim 1 . 
   
   
       4 . A method of inhibiting tryptase or Factor XIa in a mammal by administration of the compound of  claim 1 . 
   
   
       5 . A method of treating a member selected from the group consisting of venous thrombosis, arterial thrombosis, atrial fibrillation, and stroke, comprising administering a therapeutically effective amount of the compound of  claim 1 . 
   
   
       6 . A compound according to the following structure or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 A is a member selected from CH 2 , O and S 
 B is a member independently selected from unsubstituted alkyl, —S—, and —O—; 
 m is an integer selected from 0, 1 and 2; 
 C is a member selected from a bond and —O—; 
 D is a member selected from 
 
     
       
         
         
             
             
         
       
       X is a member selected from S and O; 
       Y is a member selected from a bond and C═O; 
       R a  is 
     
     
       
         
         
             
             
         
       
       wherein k2 is an integer selected from 1, 2 and 3; 
       R c  is a member selected from H and substituted or unsubstituted C 1 -C 5  alkyl; 
       R d  is a member selected from R 16  and CH 2 R 16    
       wherein
 R 16  is a member selected from C(O)R 18 , 
 
     
     
       
         
         
             
             
         
       
       
         wherein 
       
       R 18  is a member selected from OR 21 , NR 19 N 20 , and NR 19 SO 2 R 20  
 R z4  is a member selected from C 1 -C 5  alkyl, C 3 -C 6  cycloalkyl, and substituted or unsubstituted phenyl 
 R z5  is a member selected from H, C 1 -C 5  alkyl, C 3 -C 6  cycloalkyl, and substituted or unsubstituted phenyl 
 R z6  is a member selected from C 1 -C 5  alkyl and C 3 -C 6  cycloalkyl 
 wherein
 R 21  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted aryl; 
 R 19  is a member selected from H and substituted or unsubstituted C 1 -C 5  alkyl; and 
 R 20  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and 
 R 19  and R 20  can be optionally joined, together with the atoms to which they are attached, to form a 5 or 6 membered ring; and 
 
 
       R d ′ is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, and substituted or unsubstituted C 3 -C 6  cycloalkyl. 
     
   
   
       7 . A pharmaceutical composition comprising an effective amount of the compound of  claim 6  including an inner salt or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       8 . A method for enhancing thrombolysis or inhibiting or preventing thrombosis in a mammalian species comprising administering an effective amount of the compound of  claim 6 . 
   
   
       9 . A method of inhibiting tryptase or Factor XIa in a mammal by administration of the compound of  claim 6 . 
   
   
       10 . A method of treating a member selected from the group consisting of venous thrombosis, arterial thrombosis, atrial fibrillation, and stroke, comprising administering a therapeutically effective amount of the compound of  claim 6 . 
   
   
       11 . A compound according to the following structure or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 A is a member selected from CH 2 , O and S B is a member independently selected from unsubstituted alkyl, —S—, and —O—; 
 m is an integer selected from 0, 1 and 2; 
 C is a member selected from a bond and —O—; 
 D is a member selected from 
 
     
       
         
         
             
             
         
       
       X is a member selected from S and O; 
       Y is a member selected from a bond, C═O, and SO 2 ; 
       R a  is a member selected from NR 7 R 8  and substituted or unsubstituted heteroaryl 
       wherein
 R 7  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and 
 R 8  is a member selected from substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 
       R c  is a member selected from H and substituted or unsubstituted C 1 -C 5  alkyl; 
       R d  is a member selected from R 16  and CH 2 R 16    
     
     wherein
 R 16  is a member selected from C(O)R 18 , 
 
     
       
         
         
             
             
         
       
       wherein
 R 18  is NR 19 R 20    
 R z4  is a member selected from C 1 -C 5  alkyl, C 3 -C 6  cycloalkyl, and substituted or unsubstituted phenyl 
 R z5  is a member selected from H, C 1 -C 5  alkyl, C 3 -C 6  cycloalkyl, and substituted or unsubstituted phenyl 
 R z6  is a member selected from C 1 -C 5  alkyl and C 3 -C 6  cycloalkyl 
 wherein
 R 19  is a member selected from substituted or unsubstituted C 1 -C 5  alkyl; and 
 R 20  is a member selected from substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and 
 R 19  and R 20  are joined, together with the atoms to which they are attached, to form a 5 membered ring; and 
 
 
       R d ′ is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, and substituted or unsubstituted C 3 -C 6  cycloalkyl. 
     
   
   
       12 . A pharmaceutical composition comprising an effective amount of the compound of  claim 11  including an inner salt or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       13 . A method for enhancing thrombolysis or inhibiting or preventing thrombosis in a mammalian species comprising administering an effective amount of the compound of  claim 11 . 
   
   
       14 . A method of inhibiting tryptase or Factor XIa in a mammal by administration of the compound of  claim 11 . 
   
   
       15 . A method of treating a member selected from the group consisting of venous thrombosis, arterial thrombosis, atrial fibrillation, and stroke, comprising administering a therapeutically effective amount of the compound of  claim 11 . 
   
   
       16 . A compound according to the following structure or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 A is a member selected from CH 2 , O and S 
 B is a member independently selected from unsubstituted alkyl, —S—, and —O—; 
 m is an integer selected from 0, 1 and 2; 
 C is a member selected from a bond and —O—; 
 D is a member selected from 
 
     
       
         
         
             
             
         
       
       X is a member selected from S and O; 
       Y is a member selected from a bond, C═O, and SO 2 ; 
       R a  is a member selected from NR 7 R 8  and substituted or unsubstituted heteroaryl 
       wherein
 R 7  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and 
 R 8  is a member selected from substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; 
 
       R c  is a member selected from H and substituted or unsubstituted C 1 -C 5  alkyl; 
       R d  is a member selected from R 16  and CH 2 R 16    
       wherein
 R 16  is a member selected from C(O)R 18 , 
 
     
     
       
         
         
             
             
         
       
       
         wherein
 R 18  is a member selected from OR 21 , NR 19 R 20 , and NR 19 SO 2 R 20    
 wherein
 R 21  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, and substituted or unsubstituted aryl; 
 R 19  is a member selected from H and substituted or unsubstituted C 1 -C 5  alkyl; and 
 R 20  is a member selected from H, substituted or unsubstituted C 1 -C 5  alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted C 3 -C 6  cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and 
 R 19  and R 20  can be optionally joined, together with the atoms to which they are attached, to form a 6 membered ring; and 
 
 
       
       R d ′ is a member selected from substituted or unsubstituted C 1 -C 5  alkyl and substituted or unsubstituted C 3 -C 6  cycloalkyl. 
     
   
   
       17 . A pharmaceutical composition comprising an effective amount of the compound of  claim 16  including an inner salt or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 
   
   
       18 . A method for enhancing thrombolysis or inhibiting or preventing thrombosis in a mammalian species comprising administering an effective amount of the compound of  claim 16 . 
   
   
       19 . A method of inhibiting tryptase or Factor XIa in a mammal by administration of the compound of  claim 16 . 
   
   
       20 . A method of treating a member selected from the group consisting of venous thrombosis, arterial thrombosis, atrial fibrillation, and stroke, comprising administering a therapeutically effective amount of the compound of  claim 16 .