Macrocyclic factor viia inhibitors useful as anticoagulants

Abstract

The present invention relates generally to novel macrocycles of Formula (I): or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the variables A, B, L, M, W, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined herein. These compounds are selective inhibitors of the serine protease coagulation factor VIIa which can be used as medicaments.

1 . A compound of Formula (I): 
     
       
         
         
             
             
         
       
     
     or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 ring A is phenyl or a pyridyl isomer defined by replacing one of CR 1 , CR 2 , CR 3 , or CR 4  in ring A of formula (I) with N; 
 ring B is phenyl or a pyridyl isomer defined by replacing one of CR 8 , CR 9 , CR 10 , or CR 11  in ring B of formula (I) with N; 
 for the definitions of M and L, as they are written from left to right, the atom connectivity is in the order (ring A)-L-M-(ring B); 
 M is —CONH—, —SO 2 NH—, —NHCO—, or —NHSO 2 —; 
 when M is —CONH—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )—, —C(R 12 R 13 )Y—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )Y—, —XC(R 12 R 13 )Y—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )XC(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )Y—, —XC(R 12 R 13 )C(R 12 R 13 )Y—, —XC(R 12 R 13 )XC(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )Y—; 
 when M is —SO 2 NH—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 ) y —, —C(R 12 R 13 )C(R 12 R 13 )XC(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )Y—, —XC(R 12 R 13 )C(R 12 R 13 )Y—, —XC(R 12 R 13 )XC(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )Y—; 
 when M is —NHCO—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—; 
 when M is —NHSO 2 —, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—; 
 W is substituted with 0-2 R 14  and is selected from: 
 
     
       
         
         
             
             
         
       
       X is O, S(O) p , or NR 16 ; 
       Y is O or NR 16a ; 
       Z is NH, O or S; 
       R 1  is H, F, Cl, Br, I, C 1-4  alkyl substituted with 0-10H, C 1-4  fluoroalkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxy, C 1-4  alkylthio, or C 3-6  cycloalkyl; 
       R 2  is H, F, Cl, Br, I, —(CH 2 ) s OR a , —(CH 2 ) s SR b , —(CH 2 ) s CF 3 , —(CH 2 ) s OCF 3 , —(CH 2 ) s OCHF 2 , —(CH 2 ) s OCH 2 F, —(CH 2 ) s CN, —(CH 2 ) s NO 2 , —(CH 2 ) s NR c R d , —(CH 2 ) s C(O)R a , —(CH 2 ) s CO 2 R a , —(CH 2 ) s NR c C(O)R a , —(CH 2 ) s C(O)NR c R d , —(CH 2 ) s NR c C(O)OR b , —(CH 2 ) s OC(O)OR b , —(CH 2 ) s NR c C(O)NR c R d , —(CH 2 ) s OC(O)NR c R d , —(CH 2 ) s SO 2 NR c R d , —(CH 2 ) s NR c SO 2 NR c R d , —(CH 2 ) s NR c SO 2 R b , —(CH 2 ) s NR c SO 2 CF 3 , —(CH 2 ) s SO 2 CF 3 , —(CH 2 ) s S(O) 2 R b , C 1-6  alkyl substituted with 0-2 R e , C 1-4  fluoroalkyl, C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —(CH 2 ) s C 3-6  carbocycle substituted with 0-2 R f , —(CH 2 ) s -(5- to 6-membered heterocycle), —(CH 2 ) s —NR c -(5- to 6-membered heterocycle), or —(CH 2 ) s —O-(5- to 6-membered heterocycle); wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g ; 
       R 3  is H, F, Cl, Br, I, —(CH 2 ) s OR a , —(CH 2 ) s SR b , —(CH 2 ) s CF 3 , —(CH 2 ) s OCF 3 , —(CH 2 ) s OCHF 2 , —(CH 2 ) s OCH 2 F, —(CH 2 ) s CN, —(CH 2 ) s NO 2 , —(CH 2 ) s NR c R d , —(CH 2 ) s C(O)R a , —(CH 2 ) s CO 2 R a , —(CH 2 ) s NR c C(O)R a , —(CH 2 ) s C(O)NR c R d , —(CH 2 ) s NR c C(O)OR b , —(CH 2 ) s OC(O)OR b , —(CH 2 ) s NR c C(O)NR c R d , —(CH 2 ) s OC(O)NR c R d , —(CH 2 ) s SO 2 NR c R d , —(CH 2 ) s NR c SO 2 NR c R d , —(CH 2 ) s NR c SO 2 R b , —(CH 2 ) s NR c SO 2 CF 3 , —(CH 2 ) s SO 2 CF 3 , —(CH 2 ) s S(O) 2 R b , —O(CH 2 ) n CO 2 R a , —(CH 2 ) s SO 2 NHCOR b , —(CH 2 ) s CONHSO 2 R b , C 1-6  alkyl substituted with 0-2 R e , C 1-4  fluoroalkyl, C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —O(benzyl substituted with CO 2 R a ), —(CH 2 ) s tetrazolyl, —(CH 2 ) s —C 3-6  carbocycle substituted with 0-2 R f1 , —(CH 2 ) s -(5- to 6-membered heterocycle), —(CH 2 ) s —NR c -(5- to 6-membered heterocycle), or —(CH 2 ) s —O-(5- to 6-membered heterocycle); wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g1 ; 
       alternatively, R 2  and R 3  may combine to form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-2 heteroatoms selected from N, NR c , O, and S(O) p ; wherein said carbocycle and heterocycle are substituted with 0-3 R g1 ; 
       R 4  is H, F, Cl, Br, I, or C 1-4  alkyl; 
       R 5  is H, —(CH 2 ) q OR a , —(CH 2 ) q SR b , —(CH 2 ) r CF 3 , —(CH 2 ) q OCF 3 , —(CH 2 ) q OCHF 2 , —(CH 2 ) q OCH 2 F, —(CH 2 ) q CN, —(CH 2 ) q NO 2 , —(CH 2 ) q NR c R d , —(CH 2 ) s C(O)R a , —(CH 2 ) s CO 2 R a , —(CH 2 ) q NR c C(O)R a , —(CH 2 ) s C(O)NR c R d , —(CH 2 ) q NR c C(O)OR b , —(CH 2 ) q OC(O)OR b , —(CH 2 ) q NR c C(O)NR c R d , —(CH 2 ) q OC(O)NR c R d , —(CH 2 ) q SO 2 NR c R d , —(CH 2 ) q NR c SO 2 NR c R d , —(CH 2 ) q NR c SO 2 R b , —(CH 2 ) q NR c SO 2 CF 3 , —(CH 2 ) q SO 2 CF 3 , —(CH 2 ) q S(O) 2 R b , —(CH 2 ) q SO 2 NHCOR b , —(CH 2 ) s CONHSO 2 R b , —O(benzyl substituted with CO 2 R a ), —(CH 2 ) s tetrazolyl, C 1-6  alkyl substituted with 0-2 R e , C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —(CH 2 ) s —C 3-6  carbocycle substituted with 0-2 R f1 , or —(CH 2 ) s -5- to 6-membered heterocycle; wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g1 ; 
       R 6  is H, —(CH 2 ) r OR a , —(CH 2 ) r SR b , —(CH 2 ) s CF 3 , —(CH 2 ) r OCF 3 , —(CH 2 ) r OCHF 2 , —(CH 2 ) r OCH 2 F, —(CH 2 ) s CN, —(CH 2 ) s NO 2 , —(CH 2 ) r NR c R d , —(CH 2 ) s C(O)R a , —(CH 2 ) s CO 2 R a , —(CH 2 ) r NR c C(O)R a , —(CH 2 ) s C(O)NR c R d , —(CH 2 ) r NR c C(O)OR b , —(CH 2 ) r OC(O)OR b , —(CH 2 ) r NR c C(O)NR c R d , —(CH 2 ) r OC(O)NR c R d , —(CH 2 ) r SO 2 NR c R d , —(CH 2 ) r NR c SO 2 NR c R d , —(CH 2 ) r NR c SO 2 R b , —(CH 2 ) r NR c SO 2 CF 3 , —(CH 2 ) r SO 2 CF 3 , —(CH 2 ) r S(O) 2 R b , —(CH 2 ) r SO 2 NHCOR b , —(CH 2 ) s CONHSO 2 R b , C 1-6  alkyl substituted with 0-2 R e , C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —(CH 2 ) s —C 3-6  carbocycle substituted with 0-2 R f1 , or —(CH 2 ) s -5- to 6-membered heterocycle; wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g1 ; 
       alternatively, R 5  and R 6  can be joined to form a 2 to 5-membered alkylene chain, which may be substituted with 0-1 R f1 ; 
       R 7  is H or C 1-6  alkyl; 
       alternatively, R 6  and R 7  can be joined to form a 3-7 membered carbocycle or heterocycle; wherein said carbocycle may be substituted with 0-2 R f1 ; and said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g1 ; 
       R 8  is H, F, Cl, Br, CN, CH 2 F, CHF 2 , —(CH 2 ) s CF 3 , —(CH 2 ) s OCF 3 , —(CH 2 ) s SCF 3 , —(CH 2 ) s OCHF 2 , —(CH 2 ) s OCH 2 F, —(CH 2 ) s CN, —(CH 2 ) s NO 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, —(CH 2 ) n —OR a , —(CH 2 ) n —SR b , —(CH 2 ) n —NR c R d , —(CH 2 ) s C(O)R a , —(CH 2 ) s CO 2 R a , —(CH 2 ) s NR c C(O)R a , —(CH 2 ) s CONR c R d , —(CH 2 ) s SO 2 R b , —(CH 2 ) s SO 2 NR c R d , —(CH 2 ) s NR c C(O)OR b , —(CH 2 ) s OC(O)OR b , —(CH 2 ) s NR c C(O)NR c R d , —(CH 2 ) s OC(O)NR c R d , —(CH 2 ) s NR c SO 2 NR c R d , —(CH 2 ) s NR c SO 2 R b , —(CH 2 ) s NR c SO 2 CF 3 , —(CH 2 ) s SO 2 CF 3 , —O(CH 2 ) n CO 2 R a , —(CH 2 ) s SO 2 NHCOR b , —(CH 2 ) s CONHSO 2 R b , —O(benzyl substituted with CO 2 R a ), —(CH 2 ) s tetrazolyl, C 1-6  alkyl substituted with 0-2 R e , C 1-4  fluoroalkyl, C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —(CH 2 ) s —C 3-6  carbocycle substituted with 0-2 μl, or —(CH 2 ) n -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR c , O, and S(O) p , wherein said phenyl and heterocycle are substituted with 0-3 R g1 ; 
       R 9 , R 10 , and R 11  are, independently at each occurrence, H, F, Cl, Br, I, C 1-4  alkyl, or C 1-4  alkoxy; 
       R 12  and R 13  are, independently at each occurrence, H, F, Cl, OR a , SR b , CF 3 , OCF 3 , OCHF 2 , OCH 2 F, CN, NO 2 , —NR c R d , —C(O)R a , —CO 2 R a , —NR c C(O)R a , —C(O)NR c R d , —NR c C(O)OR b , —NR c C(O)NR c R d , —OC(O)NR c R d , —OC(O)OR a , —SO 2 NR c R d , —NR c SO 2 NR c R d , —NR c SO 2 R b , —NR c SO 2 CF 3 , —SO 2 CF 3 , —S(O) 2 R b , C 1-6  alkyl substituted with 0-2 R e , C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —(CH 2 ) s —C 3-6  carbocycle substituted with 0-2 μl, —(CH 2 ) s -(5- to 6-membered heterocycle), —NR c -(5- to 6-membered heterocycle), or —O-(5- to 6-membered heterocycle); wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g1 ; 
       alternatively, any two R 12  or R 13  attached to either the same carbon or to two adjacent carbons may combine to form a 3- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-3 heteroatoms selected from N, NR c , O, and S(O) p , wherein said carbocycle or heterocycle is substituted with 0-3 R g1 ; 
       alternately, two R 12  or R 13  on the same carbon atom can be replaced with oxo; 
       optionally, two R 12  or R 13  on adjacent carbon atoms in L may be replaced with a double or triple bond between the two carbon atoms; 
       R 14  is, independently at each occurrence, CN, F, Cl, Br, I, OH, N(R 17 R 17 ), C 1-3  alkyl, or C 1-3  alkoxy; 
       R 15  is, independently at each occurrence, H, —C(═NH)NH 2 , N(R 17 R 17 ), —C(R 17 R 17 )N(R 17 R 17 ), —CON(R 17 R 17 ), CN, F, Cl, Br, I, OH, C 1-3  alkyl, or C 1-3  alkoxy; 
       R 16  is, independently at each occurrence, H, C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, benzyl, —C(O)R a , —C(O)NR c R d , —C(O)OR b , —SO 2 NR c R d , —SO 2 CF 3 , —S(O) 2 R b , or —(CH 2 ) s -(5- to 6-membered heterocycle); wherein said alkyl or cycloalkyl are optionally substituted with 0-2 R e , said phenyl and benzyl are optionally substituted with 0-2 R f  and said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g ; 
       R 16a  is, independently at each occurrence, H, C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, benzyl, —C(O)R a , —C(O)NR c R d , —C(O)OR b , —SO 2 NR c R d , —SO 2 CF 3 , —S(O) 2 R b , or 5- to 6-membered heterocycle; wherein said alkyl or cycloalkyl are optionally substituted with 0-2 R e , said phenyl and benzyl are optionally substituted with 0-2 R f , and said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g ; 
       R 17  is, independently at each occurrence, H or Me; 
       R a  is, independently at each occurrence, H, C 1-4  alkyl, C 3-6  cycloalkyl, phenyl, or benzyl; wherein said alkyl and cycloalkyl are optionally substituted with 0-2 R e , and said phenyl and benzyl are optionally substituted with 0-2 R f ; 
       R b  is, independently at each occurrence, C 1-4  alkyl, C 3-6  cycloalkyl, phenyl, or benzyl; wherein said alkyl and cycloalkyl are optionally substituted with 0-2 R e , and said phenyl and benzyl are optionally substituted with 0-2 R f ; 
       R c C and R d  are, independently at each occurrence, H, C 1-4  alkyl, C 3-6  cycloalkyl, phenyl, or benzyl; 
       alternatively, R c C and R d , when attached to the same nitrogen atom, combine to form a 4- to 7-membered heterocycle comprising: carbon atoms and 0-2 additional heteroatoms selected from N, O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R g ; 
       R e  is, independently at each occurrence, F, CF 3 , OH, or C 1-3  alkoxy; 
       R f  is, independently at each occurrence, F, Cl, Br, CF 3 , OH, C 1-3  alkyl, or C 1-3  alkoxy; 
       R f1  is, independently at each occurrence, R f , —CO 2 R a , —C(O)NR c R d , —CONHSO 2 R b , or —CH 2 CONHSO 2 R b ; 
       R g  is, independently at each occurrence, ═O, F, Cl, Br, CF 3 , OH, C 1-3  alkyl, or C 1-3  alkoxy; 
       R g1  is, independently at each occurrence, R g , —CO 2 R a , —C(O)NR c R d , —CONHSO 2 R b , or —CH 2 CONHSO 2 R b ; 
       n, at each occurrence, is selected from 0, 1, 2, 3, and 4; 
       p, at each occurrence, is selected from 0, 1, and 2; 
       q, at each occurrence is selected from 2 or 3; 
       r, at each occurrence is selected from 1, 2, or 3; and 
       s, at each occurrence, is selected from 0, 1, and 2. 
     
   
   
       2 . A compound according to  claim 1 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 M is —CONH—, —SO 2 NH—, —NHCO—, or —NHSO 2 —;   when M is —CONH—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )—, —C(R 12 R 13 )Y—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )Y—, —XC(R 12 R 13 )Y—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )XC(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )Y—, and —XC(R 12 R 13 )C(R 12 R 13 )Y—;   when M is —SO 2 NH—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—;   when M is —NHCO—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—;   when M is —NHSO 2 —, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—;   X is O, S, or NR 16 ;   Z is NH or O;   R 2  is H, F, Cl, Br, I, OR a , SR b , CF 3 , OCF 3 , OCHF 2 , OCH 2 F, CN, NO 2 , —NR c R d , —C(O)R a , —CO 2 R a , —NR c C(O)R a , —C(O)NR c R d , —NR c C(O)OR b , —NR c C(O)NR c R d , —OC(O)NR c R d , —SO 2 NR c R d , —NR c SO 2 NR c R d , —NR c SO 2 R b , —NR c SO 2 CF 3 , —SO 2 CF 3 , —S(O) 2 R b , C 1-6  alkyl substituted with 0-2 R e , C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , C 3-6  carbocycle substituted with 0-2 R f , —(CH 2 ) s -(5- to 6-membered heterocycle), —NR c -(5- to 6-membered heterocycle), or —O-(5- to 6-membered heterocycle); wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g ;   R 3  is H, F, Cl, Br, I, OR a , SR b , CF 3 , OCF 3 , OCHF 2 , OCH 2 F, CN, NO 2 , —NR c R d , —C(O)R a , —CO 2 R a , —NR c C(O)R a , —C(O)NR c R d , —NR c C(O)OR b , —NR c C(O)NR c R d , —OC(O)NR c R d , —SO 2 NR c R d , —NR c SO 2 NR c R d , —NR c SO 2 R b , —NR c SO 2 CF 3 , —SO 2 CF 3 , —S(O) 2 R b , —O(CH 2 ) n CO 2 R a , —SO 2 NHCOR b , —CONHSO 2 R b , C 1-6  alkyl substituted with 0-2 R e , C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —O(benzyl substituted with CO 2 R a ), or tetrazolyl;   alternatively, R 2  and R 3  may combine to form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-2 heteroatoms selected from N, NR c , O, and S(O) p ; wherein said carbocycle and heterocycle are substituted with 0-3 R g ;   R 5  is H, —CH 2 CO 2 R a , —CH 2 C(O)NR c R d , —CH 2 CH 2 CO 2 R a , —CH 2 CH 2 C(O)NR c R d , —CH 2 CH 2 OR a , —CH 2 CH 2 CH 2 OR a , —CH 2 CONHSO 2 R b , —CH 2 CH 2 CONHSO 2 R b , C 1-6  alkyl substituted with 0-2 R e , —(CH 2 ) s —C 3-6  carbocycle substituted with 0-2 R f , or —(CH 2 ) s -5- to 6-membered heterocycle; wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g ;   R 6  is H, —CH 2 OR a , —CH 2 CH 2 OR a , CN, —CO 2 R a , —C(O)NR c R d , —CH 2 CO 2 R a , —CH 2 C(O)NR c R d , —CONHSO 2 R b , —CH 2 CONHSO 2 R b , C 1-6  alkyl substituted with 0-2 R e , —(CH 2 ) s —C 3-6  carbocycle substituted with 0-2 R f , or —(CH 2 ) s -5- to 6-membered heterocycle; wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g ;   alternatively, R 5  and R 6  can be joined to form a 2 to 5-membered alkylene chain, which may be substituted with 0-1 R f1 ;   R 7  is H or C 1-6  alkyl;   alternatively, R 6  and R 7  can be joined to form a 3-7 membered carbocycle or heterocycle; wherein said carbocycle may be substituted with 0-2 R f1 ; and said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R g1 ;   R 8  is, H, F, Cl, Br, CN, CH 2 F, CHF 2 , CF 3 , OCF 3 , SCF 3 , NO 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, —(CH 2 ) n —OR a , —(CH 2 ) n —SR b , —(CH 2 ) n —NR c R d , —CONR c R d , —SO 2 R b , —SO 2 NR c R d , —(CH 2 ) n -phenyl, or —(CH 2 ) n -5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , wherein said phenyl and heterocycle are substituted with 0-3 R g ;   R 9  is H, F, Cl, Br, J, C 1-4  alkyl, or C 1-4  alkoxy; and   R 10  and R 11  are, independently at each occurrence, H, F, Cl, Br, I, or C 1-4  alkyl.   
   
   
       3 . A compound according to  claim 1 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 ring A is phenyl or a pyridyl isomer defined by replacing one of CR 1 , CR 2 , CR 3 , or CR 4  in ring A of formula (I) with N;   ring B is phenyl or a pyridyl isomer defined by replacing one of CR 8 , CR 9 , CR 10 , or CR 11  in ring B of formula (I) with N;   with the proviso that when ring A is pyridyl, then ring B is not pyridyl;   M is —CONH—, —SO 2 NH—, —NHCO—, or —NHSO 2 —;   when M is —CONH—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )—, —C(R 12 R 13 )Y—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )—, XC(R 12 R 13 )Y—, and —C(R 12 R 13 )C(R 12 R 13 ) y —;   when M is —SO 2 NH—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—;   when M is —NHCO—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—;   when M is —NHSO 2 —, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —C(R 12 R 13 )XC(R 12 R 13 )C(R 12 R 13 )—;   Z is NH or O;   R 4  is H or F;   R 10  and R 11  are H; and   R 15  is, independently at each occurrence, —C(═NH)NH 2 , N(R 17 R 17 ), —C(R 17 R 17 )N(R 17 R 17 ), —CON(R 17 R 17 ), or OH.   
   
   
       4 . A compound according to  claim 1 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 ring A is phenyl;   ring B is phenyl;   M is —CONH— or —NHSO 2 —;   when M is —CONH—, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )—, —C(R 12 R 13 )Y—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )—, and —C(R 12 R 13 )C(R 12 R 13 )Y—;   when M is —NHSO 2 —, L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, and —XC(R 12 R 13 )C(R 12 R 13 )—;   W is substituted with 0-2 R 14  and is selected from:   
     
       
         
         
             
             
         
       
       Z is NH; 
       R 1  is H, Cl, Br, methyl, ethyl, 1-hydroxyethyl, propyl, isopropyl, vinyl, allyl, 2-propenyl, ethynyl, 1-propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, or cyclopentyl; 
       R 4  is H; 
       R 5  is H, C 1-4  alkyl, —CH 2 CO 2 R a , —CH 2 C(O)NR c R d , —CH 2 CH 2 CO 2 R a , —CH 2 CH 2 C(O)NR c R d , —CH 2 CH 2 OR a , or —CH 2 CH 2 CH 2 OR a ; 
       R 6  is H, —CH 2 OR a , —CH 2 CH 2 OR a , CN, C 1-4  alkyl, —CO 2 R a , —C(O)NR c R d , —CH 2 CO 2 R a , or —CH 2 C(O)NR c R d ; 
       R 7  is H; 
       R 10  and R 11  are H; and 
       R 15  is, independently at each occurrence, —C(═NH)NH 2 , N(R 17 R 17 ), —C(R 17 R 17 )N(R 17 R 17 ), or —CONH 2 . 
     
   
   
       5 . A compound according to  claim 1 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 ring A is phenyl;   ring B is phenyl;   M is —CONH—;   L is selected from —C(R 12 R 13 )C(R 12 R 13 )—, —XC(R 12 R 13 )—, —C(R 12 R 13 )Y—, —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )XC(R 12 R 13 )—, and —C(R 12 R 13 )C(R 12 R 13 )Y—;   W is substituted with 0-2 R 14  and is selected from:   
     
       
         
         
             
             
         
       
       Z is NH; 
       R 1  is H, Cl, Br, methyl, ethyl, vinyl, 2-propenyl, allyl, ethynyl, 1-propynyl, methoxy, ethoxy, or cyclopropyl; 
       R 4  is H; 
       R 5  is H, C 1-4  alkyl, —CH 2 CO 2 R a , —CH 2 C(O)NR c R d , —CH 2 CH 2 CO 2 R a , —CH 2 CH 2 C(O)NR c R d , —CH 2 CH 2 OR a , or —CH 2 CH 2 CH 2 OR a ; 
       R 6  is H, —CH 2 OR a , —CH 2 CH 2 OR a , CN, C 1-4  alkyl, —CO 2 R a , —C(O)NR c R d , —CH 2 CO 2 R a , or —CH 2 C(O)NR c R d ; 
       R 7  is H; 
       R 8  is H, C 1-6  alkyl, OR a , —CONR c R d , —SO 2 R b , —SO 2 NR c R d , phenyl, or 5- to 6-membered heterocycle comprising: carbon atoms and 1-3 heteroatoms selected from N, O, and S(O) p , wherein said phenyl and heterocycle are substituted with 0-3 R g ; 
       R 9 , R 10 , and R 11  are H; and 
       R 14  is, independently at each occurrence, F, Cl, methyl, ethyl, hydroxyl, or methoxy. 
     
   
   
       6 . A compound according to  claim 1 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 ring A is phenyl;   ring B is phenyl;   M is —CONH—;   L is selected from —C(R 12 R 13 )C(R 12 R 13 )C(R 12 R 13 )—, —C(R 12 R 13 )NR 16 C(R 12 R 13 )—, —C(R 12 R 13 )C(R 12 R 13 )Y—, C(R 12 R 13 )C(R 12 R 13 )—, —OC(R 12 R 13 )—, or —C(R 12 R 13 )Y—;   W is selected from:   
     
       
         
         
             
             
         
       
       Y is O Or NMe, 
       Z is NH; 
       R 1  is H, Cl, Br, methyl, ethyl, vinyl, 2-propenyl, ethynyl, methoxy, or ethoxy; 
       R 2  is H, F, Cl, Br, —OR a , —SR b , —CF 3 , —OCF 3 , —OCHF 2 , —OCH 2 F, CN, NO 2 , —NR c R d , —C(O)R a , —CO 2 R a , —NR c C(O)R a , —C(O)NR c R d , —NR c C(O)OR b , —OC(O)OR b —NR c C(O)NR c R d , —OC(O)NR c R d , —SO 2 NR c R d , —NR c SO 2 NR c R d , —NR c SO 2 R b , —S(O) 2 R b , C 1-6  alkyl substituted with 0-2 R e , C 1-4  fluoroalkyl, C 2-4  alkenyl substituted with 0-2 R e , C 2-4  alkynyl substituted with 0-2 R e , —C 3-6  carbocycle substituted with 0-2 R f -(5- to 6-membered heterocycle), —NR c -(5- to 6-membered heterocycle), or —O-(5- to 6-membered heterocycle); wherein said heterocycle comprises carbon atoms and 1-3 heteroatoms selected from N, NR c , O, and S(O) p  and is substituted with 0-2 R 9 ; 
       R 3  is H, F, Cl, Me, OCH 2 CO 2 H; 
       R 4  is H; 
       R 5  is H, C 1-4  alkyl, —CH 2 CO 2 R a , or —CH 2 C(O)NR c R d ; 
       R 6  is H, C 1-4  alkyl, —CO 2 R a , —C(O)NR c R d , —CH 2 CO 2 R a , or —CH 2 C(O)NR c R d ; 
       R 7  is H; 
       R 8  is —CONR c R d , —SO 2 R b , —SO 2 NR c R d , or 4-morpholino; 
       R 9 , R 10 , and R 11  are H; 
       R 12  and R 13  are, independently at each occurrence, H, methyl, ethyl, propyl, isopropyl, cyclopropyl, t-butyl, methoxy, ethoxy, propoxy, isopropoxy, or cyclopropoxy, with the proviso that no more than two of R 12  and R 13  in L are other than H; and 
       R 16  is H, C 1-4  alkyl, —C(O)R a , —C(O)NR c R d , —C(O)OR b , or —S(O) 2 R b . 
     
   
   
       7 . A compound according to  claim 6 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 M is —CONH—;   L is selected from —C(R 12 R 13 )C(R 12 R 13 )CH 2 —, —C(R 12 R 13 )C(R 12 R 13 )O—, —C(R 12 R 13 )C(R 12 R 13 )NMe-, —C(R 12 R 13 )N(C═OCH 3 )CH 2 —, —C(R 12 R 13 )NHCH 2 —, —C(R 12 R 13 )CH 2 —, and —OCH 2 —;   W is selected from:   
     
       
         
         
             
             
         
       
       R 1  is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy; 
       R 2  is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy; 
       R 3  is H; 
       R 4  is H; 
       R 5  is H, methyl, ethyl, or —CH 2 CO 2 H; 
       R 6  is H, methyl, ethyl, —CO 2 H or —CH 2 CO 2 H; 
       R 7  is H; and 
       R 8  is —CONR c R d  or —SO 2 R b . 
     
   
   
       8 . A compound according to  claim 1 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 when M is —CONH—; L is selected from —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —O(CH 2 )—, —O(CH 2 ) 2 —, —O(CH 2 ) 3 —, —(CH 2 ) 2 O—, —CH(Me)CH 2 O—, —C(Me) 2 CH 2 O—, —CH 2 CH(Me)O—, —CH(Et)CH 2 O—, —CH 2 CH(Et)O—, —CH 2 OCH 2 —, —(CH 2 ) 2 NMe-, —(CH 2 ) 3 NMe-, —CH 2 NHCH 2 —, and —CH 2 N(Ac)CH 2 —;   when M is —NHSO 2 —, L is selected from —(CH 2 ) 2 — and —(CH 2 ) 3 —;   W is selected from:   
     
       
         
         
             
             
         
       
       Z is NH; 
       R 1  is H, Cl, Br, C 1-4  alkyl, or C 1-4  alkoxy; 
       R 2  is H, Cl, Br, C 1-4  alkyl, or C 1-4  alkoxy; 
       R 3  is H; 
       R 4  is H; 
       R 5  is H, C 1-4  alkyl, —CH 2 CO 2 H, or —CH 2 CO 2 Et; 
       R 6  is H, C 1-4  alkyl, —CO 2 H, —CH 2 CO 2 H, or —CH 2 CO 2 Et; 
       R 7  is H; 
       R 8  is H, —SO 2 (C 1-4  alkyl), or —S(C 1-4  alkyl); 
       R 9  is H; and 
       R 10  is H. 
     
   
   
       9 . A compound according to  claim 8 , wherein the compound is of Formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, wherein:
 W is selected from:   
     
       
         
         
             
             
         
       
       R 1  is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy; 
       R 2  is H, Cl, Br, methyl, ethyl, methoxy, or ethoxy; 
       R 5  is H, methyl, ethyl, or —CH 2 CO 2 H; 
       R 6  is H, methyl, ethyl, —CO 2 H, —CH 2 CO 2 H, or —CH 2 CO 2 Et; and 
       R 8  is H, —SO 2 Et, —SO 2 (i-Pr), —SO 2 (t-Bu), or —S(i-Pr). 
     
   
   
       10 . A compound according to  claim 1 , wherein the compound is selected from the exemplified examples or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. 
   
   
       11 . A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of  claim 1 , or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. 
   
   
       12 . A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 , or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. 
   
   
       13 . A method according to  claim 12 , wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or in the peripheral circulation. 
   
   
       14 . A method according to  claim 12 , wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.