Inhibitors of Factor XA and Other Serine Proteases Involved in the Coagulation Cascade

Abstract

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

1 . A compound of formula II: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof wherein 
          is a bond; 
       X II  is N; 
       R 11  is absent and R 10  is 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, (C 1 -C 6 )alkylaryl, —CH═O, —CH 2 OR 2 , —COR 2 , —CO 2 R 2 , or —CONR 3 R 4 ; 
       A is an optionally substituted aryl or optionally substituted monocyclic heteroaryl; 
       B is 
     
     
       
         
         
             
             
         
       
        (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 4 -C 7 )heterocycloalkenyl, aryl, or heteroaryl, any of which may be optionally substituted by oxo, formyl, —OH, halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —O—(C 1 -C 6 ), —CN, —CO 2 R 2 , —S(C 1 -C 6 )alkyl, —COR 2 , —(C 1 -C 6 )alkyl-NR 3 R 4 , —NR 3 R 4 , —NR 2 COR 2′ , SOR 2 , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; 
       C is phenyl or heteroaryl optionally substituted with one or more substituents selected from halo, oxo, hydroxy, —CO 2 R 2 , —COR 2 , —CONR 2 R 2′ , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —CN, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-NR 3 R 4 , —NR 3 R 4 , —NR 2 COR 2′ , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; 
       G is H, halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, —CH 2 O—(C 1 -C 6 )alkyl, —CH 2 —CO 2 (C 1 -C 6 )alkyl, —CH 2 —NR 2 R 2′ , or —CH 2 —CONH(C 1 -C 6 )alkyl; 
       R 1  is (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 4 -C 7 )heterocycloalkenyl, aryl, monocyclic heteroaryl, or —NR 3 R 4 ; 
       R 2  and R 2′  are each independently H or (C 1 -C 6 )alkyl; and 
       R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, aralkyl, aryl, monocyclic heteroaryl, —CO 2 (C 1 -C 6 )alkyl, —CO 2 aryl, —SO 2 (C 1 -C 6 )alkyl, or are taken together to form an optionally substituted saturated or unsaturated 5 to 7 membered ring and 
       R 8  and R 9  are as defined for R 3  and R 4 . 
     
   
   
       2 . The compound of  claim 1 , wherein G is H, F, or methyl. 
   
   
       3 . The compound of  claim 1 , wherein A is an optionally substituted phenyl or optionally substituted pyridyl. 
   
   
       4 . The compound of  claim 1 , wherein A is 
     
       
         
         
             
             
         
       
     
     wherein   indicate points of attachment. 
   
   
       5 . The compound of  claim 1 , wherein B is phenyl which is substituted at the ortho position with formyl, —SO 2 NH 2 , —SO 2 (C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —S(C 1 -C 6 )alkyl, —CO 2 (C 1 -C 6 )alkyl, —CN, —CH 2 NH 2 , —(C 1 -C 6 )alkoxy, or —OH. 
   
   
       6 . The compound of  claim 1 , wherein B is 
     
       
         
         
             
             
         
       
     
     an optionally substituted 4, 5, 6 or 7-membered ring and   indicates the point of attachment, and wherein R x  and R y  are H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or —CO(C 1 -C 6 )alkyl, or are taken together to form O═;
 X III  is CH 2 , CH—OH, CH—CO 2 (C 1 -C 6 )alkyl, O, S, NH, or N(C 1 -C 6 )alkyl, provided that when R x  and R y  taken together are O═, X III  is CH 2 . 
 
   
   
       7 . The compound of  claim 1 , wherein B is optionally substituted imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl. 
   
   
       8 . The compound of  claim 7 , wherein B is 
     
       
         
         
             
             
         
       
     
     wherein   indicates the point of attachment;
 X a , Y a , and Z a  are each independently CR c  or N, wherein R c  is H or (C 1 -C 6 )alkyl; and 
 R 18  is H, (C 1 -C 6 )alkyl, hydroxymethyl, CH 2 O—(C 1 -C 6 )alkyl, or NR 3 R 4 . 
 
   
   
       9 . The compound of  claim 1 , wherein 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, hydroxy, NH 2 , NR 23 R 24 , NO 2 , SH, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —CO(C 1 -C 6 )alkyl, —CO 2 (C 1 -C 6 )alkyl, 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 (C 1 -C 6 )alkyl, —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 , respectively, is absent at that position. 
   
   
       10 . The compound of  claim 9 , wherein B is 
     
       
         
         
             
             
         
       
     
     wherein   indicates the point of attachment; and
 R 19 , R 20 , and R 21 , R 22  are each independently H, halo, —OH, —NR 23 R 24 , NO 2 , SH, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —CO(C 1 -C 6 )alkyl, —CO 2 (C 1 -C 6 )alkyl, 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 (C 1 -C 6 )alkyl, —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. 
 
   
   
       11 . A compound of formula III: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof wherein   is a bond; 
       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; 
       X II  is N; 
       R 11  is absent and R 10  is 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═O, —CH 2 OR 2 , —COR 2 , —CO 2 R 2 , or —CONR 3 R 4 ; 
       A is optionally substituted aryl or optionally substituted monocyclic heteroaryl; 
       B is 
     
     
       
         
         
             
             
         
       
        (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocyclo, (C 4 -C 7 )cycloalkenyl, (C 4 -C 7 )heterocycloalkenyl, aryl, or heteroaryl, any of which may be optionally substituted by halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, —O—(C 1 -C 6 ), —CN, (C 1 -C 6 )alkyl NR 3 R 4 , —NR 3 R 4 , —NR 2 COR 2′ , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; or —NR 2 SO 2 R 2 ; 
       G is H, halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, —CH 2 O—(C 1 -C 6 )alkyl, —CH 2 —CO 2 (C 1 -C 6 )alkyl, —CH 2 —CONH 2 , or —CH 2 —CONH(C 1 -C 6 )alkyl; 
       R 1  is (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 4 -C 7 )heterocycloalkenyl, aryl, monocyclic heteroaryl, or —NR 3 R 4 ; 
       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 (C 1 -C 6 )alkyl, —CO 2 aryl, —SO 2 R 2 , or are taken together to form an optionally substituted saturated or unsaturated 5 to 7 membered ring; and 
       R 12  and R 13  are each independently H, halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy; and 
       R 8  and R 9  are as defined for R 3  and R 4 . 
     
   
   
       12 . The compound of  claim 11 , wherein G is H, F, or methyl. 
   
   
       13 . The compound of  claim 11 , wherein A is an optionally substituted phenyl or pyridyl. 
   
   
       14 . The compound of  claim 11 , wherein B is 
     
       
         
         
             
             
         
       
     
     wherein   indicates the point of attachment and which is an optionally substituted 4, 5, 6 or 7-membered ring;
 R x  and R y  are each independently H, halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )carboxyalkyl, or taken together are O═; 
 X III  is CH 2 , CH—OH, CH—CO 2 (C 1 -C 6 )alkyl, O, S, NH, or N(C 1 -C 6 )alkyl, provided that when R x  and R y  taken together are O═, X III  is CH 2 . 
 
   
   
       15 . The compound of  claim 11 , wherein B is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, any of which may be optionally substituted. 
   
   
       16 . The compound of  claim 11 , wherein B is 
     
       
         
         
             
             
         
       
     
     wherein   indicates the point of attachment; and
 R 19 , R 20 , and R 21 , R 22  are each independently H, halo, hydroxy, NH 2 , NR 23 R 24 , NO 2 , SH, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, 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, —COR 2 , —CO 2 R 2 , —SO 2 (C 1 -C 6 )alkyl, 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 seven membered saturated or unsaturated cycloalkyl or heterocycloalkyl ring, or an aryl or heteroaryl ring. 
 
   
   
       17 . A process for preparing a compound of Formula I: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable salt thereof wherein: 
       A is an optionally substituted aryl or an optionally substituted monocyclic heteroaryl; 
       W 1  is —N═CR 5 —CH 2 —, wherein W 1  connects the nitrogen atom at position 1 to the carbon atom at position 2 to form a five membered ring; 
       R 5  is 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, (C 1 -C 6 )alkylaryl, —CH═O, —CH 2 OR 2 , —COR 2 , —CO 2 R 2 , or —CONR 3 R 4 ; 
       B is 
     
     
       
         
         
             
             
         
       
        (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 4 -C 7 )heterocycloalkenyl, aryl, or heteroaryl, any of which may be optionally substituted by oxo, formyl, —OH, halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, —CN, —CO 2 R 2 , —S(C 1 -C 6 )alkyl, —COR 2 , (C 1 -C 6 )alkyl-NR 3 R 4 , —NR 3 R 4 , —NR 2 COR 2′ , SOR 2 , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; 
       C is phenyl or heteroaryl either or which may be optionally substituted with one or more substituents selected from halo, oxo, hydroxy, —CO 2 R 2 , —COR 2 , —CONR 2 R 2′ , (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, —CN, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylNR 3 R 4 , —NR 3 R 4 , —NR 2 COR 2′ , —SO 2 NR 2 R 2′  or —SO 2 R 2 ; 
       G is H, halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, —CH 2 O—(C 1 -C 6 )alkyl, —CH 2 —CO 2 (C 1 -C 6 )alkyl, —CH 2 —NR 2 R 2 , or —CH 2 —CONH(C 1 -C 6 )alkyl; 
       R 1  is (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )heterocycloalkyl, (C 4 -C 7 )cycloalkenyl, (C 4 -C 7 )heterocycloalkenyl, aryl, monocyclic heteroaryl, or —NR 3 R 4 ; 
       R 2  and R 2′  are each independently H or (C 1 -C 6 )alkyl; and 
       R 3  and R 4  are each independently H, (C 1 -C 6 )alkyl, aralkyl, aryl, monocyclic heteroaryl, —CO 2 (C 1 -C 6 )alkyl, —CO 2 aryl, —SO 2 (C 1 -C 6 )alkyl, or are taken together to form an optionally substituted saturated or unsaturated 5 to 7 membered ring and 
       R 8  and R 9  are as defined for R 3  and R 4 ; 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 to form a compound of Formula I, wherein C is as defined above. 
     
   
   
       18 . The process of  claim 17  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 17 . 
   
   
       19 . The process of  claim 18  wherein said compound of Formula Y-A-B is