Inhibitors of factor xa and other serine proteases involved in the coagulation cascade

Abstract

Compounds useful as intermediates for synthesis of compounds of Formula (1): wherein A, B, C, G, and W 1 have any of the values defined in the specification.

1 . A method of treating a thrombotic disorder in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula V: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof wherein:
 A is aryl or substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl; 
 B is optionally substituted heteroaryl, 
 
     
       
         
         
             
             
         
       
     
     wherein   is a bond and Y 1  is selected from CHR a , CHR a —CHR b , CHR a —CHR b —CHR c , CR a ═CR b , NR c , wherein R a -R c  are each independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )hydroxyalkyl; 
     
       
         
         
             
             
         
       
     
     wherein Y 1  is selected from CHR a , CHR a —CHR b , CHR a  CHR b —CHR c , CR a ═CR b , NR c , wherein R a -R c  are each independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )hydroxyalkyl; 
     
       
         
         
             
             
         
       
     
     wherein each   is a bond and Y 1 , Y 2 , and Y 3  are each independently selected from N or CR a ; 
     
       
         
         
             
             
         
       
     
     wherein   is a bond, Y 2 , is selected from NH or CHR a , and Y 1  and Y 3  are each independently selected from N or CR a ; 
     
       
         
         
             
             
         
       
     
     wherein   is a bond, Y 2 , is selected from N or CR a , and Y 1  and Y 3  are each independently selected from NH or CHR a ; 
     
       
         
         
             
             
         
       
     
     wherein Y 1 , Y 2 , and Y 3  are each independently selected from NH or CHR a ;
 C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, —OH, —CO 2 R 2 , —COR 2 , (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, —CONR 3 R 4 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —CN, halo(C 1 -C 6 )alkyl, —NR 3 R 4 , —NR 2 COR 2′ , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; 
 R 2  and R 2′  are each independently H, (C 1 -C 6 )alkyl, or optionally substituted (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, aryl, or monocyclic heteroaryl; and 
 R 3  and R 4  are each independently selected from H, (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, aryl, monocyclic heteroaryl aralkyl, aryl, —CO 2 R 2 , —CO 2 aryl, —SO 2 R 2 , or are taken together to form an optionally substituted, saturated or unsaturated 3 to 7 membered ring. 
 
   
   
       2 . The method of  claim 1  wherein the compound of Formula I is (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide or a pharmaceutically acceptable salt thereof. 
   
   
       3 . The method of  claim 1 , wherein the thrombotic disorder is arterial thrombosis, thrombophlebitis, pulmonary embolism, kidney embolism, cerebral embolism, myocardial infarction, cerebral infarction, arterial embolism, atherosclerosis, angina, atrial fibrillation, stroke, or venous thrombosis including primary and secondary deep vein thrombosis. 
   
   
       4 . A method for treating a thrombotic disorder in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof wherein:
 A is aryl or substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl; 
 B is 
 
     
       
         
         
             
             
         
       
     
     wherein   indicates the point of attachment;
 J 1 , J 2 , J 3 , and J 4  are each C, or one of J 1 , J 2 , J 3 , and J 4  is N; and R 19 , R 20 , R 21 , and R 22  are each independently H, halo, —OH, NH 2 , NR 23 R 24 , NO 2 , SH, —SO 2 R 2 , (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —COR 2 , —CO 2 R 2 , or (C 1 -C 6 )alkoxy, wherein R 23  and R 24  are each independently H, (C 1 -C 6 )alkyl, aralkyl, aryl, monocyclic heteroaryl, —CO 2 R 2 , —CO 2 aryl, —SO 2 R 2 , or are taken together to form an optionally substituted saturated or unsaturated 3 to 7 membered ring; or R 19  and R 20 , R 20  and R 21 , or R 21 , and R 22 , together with the carbons to which they are attached, form an optionally substituted 5, 6, or 7 membered saturated or unsaturated cycloalkyl or heterocycloalkyl ring, or an optionally substituted aryl or heteroaryl ring, provided that when any of J 1 , J 2 , J 3 , or J 4  is N, then R 19 , R 20 , R 21  or R 22 , respectively, is absent at that position; 
 C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, aryl, heteroaryl, —OH, —CO 2 R 2 , —COR 2 , (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, —CONR 3 R 4 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —CN, halo(C 1 -C 6 )alkyl, —NR 3 R 4 , —NR 2 COR 2 , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; 
 G is halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl; 
 W 1  is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CR 5 R 6 —, —CH 2 —CR 5 R 6 —CH 2 —, —CH 2 —CH 2 —CR 7 —R 8 —, —CH 2 —CR 7 R 8 —CH 2 —, —CH 2 —C═R 9 —CH 2 —, or —CH 2 —CH 2 —C═R 9 —, wherein W 1  connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a five membered ring; 
 R 2  and R 2′  are each independently H or (C 1 -C 6 )alkyl; 
 R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, aralkyl, aryl, monocyclic heteroaryl, —CO 2 R 2 , —CO 2 aryl, —SO 2 R 2 , or are taken together to form a saturated or unsaturated 3 to 7 membered ring and; 
 R 5  is —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, —NR 3 R 4 , —OR 2 , halo, —CN, —CH 2 OR 2 , —CH 2 —NR 3 R 4 , aryl, monocyclic heteroaryl, alkylaryl, —CONR 3 R 4 , —COR 2 , or —CO 2 R 2 ; 
 R 6  is H, (C 1 -C 6 )alkyl, aralkyl, aryl, or monocyclic heteroaryl; 
 R 7  and R 8  are each independently halo; and 
 R 9  is ═O. 
 
   
   
       5 . The method of  claim 4 , wherein the thrombotic disorder is arterial thrombosis, thrombophlebitis, pulmonary embolism, kidney embolism, cerebral embolism, myocardial infarction, cerebral infarction, arterial embolism, atherosclerosis, angina, atrial fibrillation, stroke, or venous thrombosis including primary and secondary deep vein thrombosis. 
   
   
       6 . A method for treating a thrombotic disorder in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula X: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof wherein
    is absent; 
 Z is C—H, C-halo, C—(C 1 -C 6 )alkyl, C-halo(C 1 -C 6 )alkyl, C—(C 1 -C 6 )alkoxy, or N; 
 G is halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or hydroxy(C 1 -C 6 )alkyl; 
 X II  is CH 2 ; 
 R 10  and R 11  are each independently H, —OH, halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —NR 8 R 9 , —OR 2 , —CN, —CH 2 OH, —CH 2 —NR 3 R 4 , aryl, monocyclic heteroaryl, alkylaryl, —CH 2 OR 2 , —COR 2 , —CO 2 R 2 , or —CONR 3 R 4  or are taken together to form ═O; 
 R 2  and R 2′  are each independently H or (C 1 -C 6 )alkyl; 
 R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, aralkyl, aryl, monocyclic heteroaryl, —CO 2 R 2 , —CO 2 aryl, —SO 2 R 2 , or are taken together to form an optionally substituted saturated or unsaturated 3 to 7 membered ring; 
 R 12  and R 13  are each independently H, halo, (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy; 
 R 14  and R 15  are each independently H, halo, (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl, or NR 8 R 9  wherein R 8  and R 9  are as defined for R 3  and R 4 ; 
 X and Y are each independently C or N, provided that when one of X or Y is N, R 14  or R 15  is absent at that position; 
 J 1 , J 2 , J 3 , and J 4  are C or one of J 1 , J 2 , J 3 , and J 4  is N; 
 R 19 , R 20 , R 21 , and R 22  are each independently H, halo, —OH, NH 2 , NR 23 R 24 , NO 2 , SH, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —COR 2 , —CO 2 R 2 , or (C 1 -C 6 )alkoxy, wherein R 23  and R 24  are each independently H, (C 1 -C 6 )alkyl, aralkyl, aryl, monocyclic heteroaryl, —CO 2 R 2 , —CO 2 aryl, —SO 2 R 2 , or are taken together to form an optionally substituted saturated or unsaturated 3 to 7 membered ring; or R 19  and R 20 , R 20  and R 21 , or R 21  and R 22 , together with the carbons to which they are attached, form an optionally substituted 5, 6, or 7 membered saturated or unsaturated cycloalkyl or heterocycloalkyl ring, or an aryl or heteroaryl ring; provided that when any of J 1 , J 2 , J 3 , or J 4  is N, R 19 , R 20 , R 21 , or R 22  is absent at that position. 
 
   
   
       7 . The method of  claim 6 , wherein the thrombotic disorder is arterial thrombosis, thrombophlebitis, pulmonary embolism, kidney embolism, cerebral embolism, myocardial infarction, cerebral infarction, arterial embolism, atherosclerosis, angina, atrial fibrillation, stroke, or venous thrombosis including primary and secondary deep vein thrombosis. 
   
   
       8 . A process for preparing a compound of Formula I: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt thereof wherein: 
       A is aryl or substituted aryl or monocyclic heteroaryl or substituted monocyclic heteroaryl; 
       W 1  is —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CR 5 R 6 —, —CH 2 —CR 5 R 6 —CH 2 —, —CH 2 —CH 2 —CR 7 R 8 —, —CH 2 —CR 7 R 8 —CH 2 —, —CH 2 —CR 9 —CH 2 —, or —CH 2 —CH 2 —CR 9 —, wherein W 1  connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a five membered ring; 
       R 2  and R 2′  are each independently hydrogen or alkyl; 
       R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, aralkyl, aryl, monocyclic heteroaryl, —CO 2 R 2 , —CO 2 aryl, —SO 2 alkyl, or are taken together to form an optionally substituted saturated or unsaturated 3 to 7 membered ring; 
       R 5  is —OH, alkyl, halo(C 1 -C 6 )alkyl, —NR 3 R 4 , —OR 2 , halo, —CN, —CH 2 OR 2 , —CH 2 —NR 3 R 4 , aryl, monocyclic heteroaryl, alkylaryl, —CONR 3 R 4 , —COR 2 , or —CO 2 R 2 ; 
       R 6  is H, alkyl, aralkyl, aryl, or monocyclic heteroaryl; 
       R 7  and R 8  are each independently halo; 
       R 9  is ═O; 
       C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionally substituted with one or more substituents selected from halogen, aryl, heteroaryl, —OH, —CO 2 R 2 , —COR 2 , (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, —CONR 3 R 4 , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —CN, halo(C 1 -C 6 )alkyl, —NR 3 R 4 , —NR 2 COR 2 , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; 
       and B is optionally substituted heteroaryl, 
     
     
       
         
         
             
             
         
       
     
     wherein Y 1  is selected from CHR a , CHR a —CHR b , CHR a —CHR b —CHR c , CR═CR b , NR c , wherein R a -R c  are each independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )hydroxyalkyl, and  is a bond; or B is 
     
       
         
         
             
             
         
       
     
     wherein Y 1  is selected from CHR a , CHR a —CHR b , CHR a ═CHR b —CHR c , CR a ═CR b , NR c , wherein R a -R c  are each independently H, (C 1 -C 6 )alkyl, or (C 1 -C 6 )hydroxyalkyl; or B is 
     
       
         
         
             
             
         
       
     
     or B is 
     
       
         
         
             
             
         
       
     
     wherein each   is a bond and Y 1 , Y 2 , and Y 3  are each independently selected from N or CR a ; or B is 
     
       
         
         
             
             
         
       
     
     wherein   is a bond, Y 2 , is selected from NH or CHR a , and Y 1  and Y 3  are each independently selected from N or CR a ; or B is 
     
       
         
         
             
             
         
       
     
     wherein   is a bond, Y 2 , is selected from N or CR a , and Y 1  and Y 3  are each independently selected from NH or CHR a ; or B is 
     
       
         
         
             
             
         
       
     
     wherein Y 1 , Y 2 , and Y 3  are each independently selected from NH or CHR a ; said process comprising:
 (a) deprotecting a compound of formula ID 
 
     
       
         
         
             
             
         
       
       wherein P 1  is a protecting group and W 1 , G, A and B are as defined above; and 
       (b) reacting the resulting deprotected compound with a C-isocyanate, wherein C is as defined above, to form a compound of Formula I. 
     
   
   
       9 . The process of  claim 8  wherein said compound of Formula ID is prepared by: reacting a compound of formula IB 
     
       
         
         
             
             
         
       
     
     with a compound of formula Y-A-B, wherein P 1  is a protecting group, Y is NH 2 , and W 1 , G, A and B are as defined in  claim 8 . 
   
   
       10 . The process of  claim 9  wherein said compound of Formula Y-A-B is 
     
       
         
         
             
             
         
       
     
   
   
       11 . The process of  claim 8  wherein the compound of Formula I is (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}, or a pharmaceutically acceptable salt thereof. 
   
   
       12 . The process of  claim 8  wherein the compound of Formula I is 2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}, or a pharmaceutically acceptable salt thereof.