Aryl and heteroaryl compounds and methods to modulate coagulation

Abstract

This invention provides certain compounds, methods of their preparation, pharmaceutical compositions comprising the compounds, and their use in treating human or animal disorders. The compounds of the invention are useful as antagonists, or more preferably, partial antagonist of factor IX and thus, may be used to inhibit the intrinsic pathway of blood coagulation. The compounds are 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. Such diseases or disease states include stroke, myocardial infarction, aneurysm surgery, and deep vein thrombosis associated with surgical procedures, long periods of confinement, and acquired or inherited pro-coagulant states.

1 . A method for the inhibition of the normal biological function of factor IX comprising administering to a subject in need thereof a compound of Formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 c is equal to 0, 1, or 2; wherein the values of 0, 1, and 2 represent a direct bond, —CH 2 —, and —CH 2 —CH 2 —, respectively, and —CH 2 — and —CH 2 —CH 2 — are optionally substituted 1 to 4 times with a substituent group independently selected from the group consisting of: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl, —O-aryl, and -hydroxyl;  
 G is: -hydrogen, —CO 2 R 1 , —CH 2 OR 1 , —C(O)—R 1 , —C(R 1 )═N—O—R 2 , or an acid isostere; wherein R 1  and R 2  are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;  
 V is: —(CH 2 ) b —O—(CH 2 ) a —, —(CH 2 ) b —N(R 7 )—(CH 2 ) a —, —(CH 2 ) b —O—, —(CH 2 ) b —N(R 7 ), —(CH 2 ) a —, or a direct bond; in which a is equal to 0, 1, or 2, b is equal to 1 or 2, and R 7  is: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, or -alkylene-arylene-alkyl; 
 wherein 
 the alkylene groups of V are optionally substituted 1 to 4 times with a substituent group independently selected from the group consisting of: -alkyl, -aryl, -alkylene-aryl, -arylene-alkyl, -alkylene-arylene-alkyl, —O-alkyl, —O-aryl, and -hydroxyl;  
 
 
 X is: —N(R 8 )—, —CON(R 8 )—, —N(R 8 )CO—, —N(R 8 )CON(R 9 )—, —OC(O)N(R 8 )—, —SO 2 N(R 8 )—, or —N(R 8 )SO 2 N(R 9 )—; 
 wherein 
 R 8  and R 9  are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-cycloalkylene-c(O)-alkylene-aryl, -alkylene-heterocyclylene-C(O)-alkylene-aryl, -alkylene-C(H)(R 10 )(R 11 ), and -alkylene-N-(R 10 )(R 11 ),  
 wherein 
 R 10  is H, alkyl, alkylene-aryl, alkylene-heteroaryl, aryl, or heteroaryl, and R 11  is H, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, -aryl, -heteroaryl, —C(O)—O-alkyl, —C(O)—O-alkylene-aryl, —C(O)—O-alkylene-heteroaryl, —C(O)-alkyl, —C(O)-alkylene-aryl, —C(O)-alkylene-heteroaryl, —S(O) 2 -alkyl, —S(O) 2 -aryl, —S(O) 2 -heteroaryl, —S(O) 2 -alkylene-aryl, —S(O) 2 -alkylene-heteroaryl, —S(O) 2 —NH-alkyl, —S(O) 2 —NH-alkylene-aryl, —S(O) 2 —NH-alkylene-heteroaryl, —S(O) 2 —NH-aryl, or —S(O) 2 —NH-heteroaryl; or  
 R 10  and R 11 , may be taken together to form a ring having the formula—(CH 2 ) m —Z—(CH 2 ) n -bonded to the nitrogen or carbon atom to which R 10  and R 11  are attached, wherein m and n are, independently, 1, 2, 3, or 4; Z is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O) 2 —, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO) 2 —, —S(O 2 )N(H)—, —(O)CO—, —NHS(O) 2 NH—, —OC(O)—, —N(R 12 )—, —N(C(O)R 12 )—, —N(C(O)NHR 12 )—, —N(S(O) 2 NHR 12 )—, —N(SO 2 R 12 )—, or —N(C(O)OR, 12 )—; wherein R 12  is hydrogen, aryl, alkyl, or alkylene-aryl; or  
 R 10  and R 11 , may be taken together, with the nitrogen or carbon atom to which they are attached, to form a heterocyclyl or heteroaryl ring;  
 
 
 
 Ar 1  is an aryl, heteroaryl, fused cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl, or fused heterocyclylheteroaryl group optionally substituted 1 to 7 times, wherein the substituents are independently selected from the group-consisting of: 
 a) -fluoro;  
 b) -chloro;  
 c) -bromo;  
 d) -iodo;  
 e) -cyano;  
 f) -nitro;  
 g) -perfluoroalkyl;  
 h) -D 1 -R 13 ;  
 i) -alkyl;  
 j) -aryl;  
 k) -heteroaryl;  
 l) -heterocyclyl;  
 m) -cycloalkyl;  
 n) -alkylene-aryl;  
 o) -alkylene-heteroaryl;  
 p) -alkylene-arylene-D 1 -R 13 ;  
 q) -alkylene-heteroarylene-D 1 -R 13 ;  
 r) -alkylene-arylene-aryl;  
 S) -alkylene-heteroarylene-aryl;  
 t) -alkylene-arylene-heteroaryl  
 u) -alkylene-arylene-arylene-D 1 -R 13 ;  
 v) -alkylene-arylene-alkyl;  
 w) -alkylene-heteroarylene-alkyl;  
 x) -arylene-alkyl;  
 y) -arylene-cycloalkyl;  
 z) -heteroarylene-alkyl;  
 aa) -arylene-arylene-alkyl;  
 bb) -D 1 -alkyl;  
 cc) -D 1 -aryl;  
 dd) -D 1 -heteroaryl;  
 ee) -D 1 -arylene-D 2 -R 14 ;  
 ff) -D 1 -heteroarylene-D 2 -R 14 ;  
 gg) -D 1 -alkylene-heteroaryl;  
 hh) -D 1 -alkylene-aryl;  
 ii) -D 1 -alkylene-arylene-D 2 -R 14    
 jj) -D 1 -alkylene-heteroarylene-D 2 -R 14    
 kk) -D 1 -arylene-alkyl;  
 ll) -D 1 -heteroarylene-alkyl;  
 mm) -D 1 -alkylene-arylene-aryl;  
 nn) -D 1 -alkylene-heteroarylene-aryl;  
 oo) -D 1 -arylene-arylene-aryl;  
 pp) -D 1 -alkylene-arylene-alkyl;  
 qq) -D 1 -alkylene-heteroarylene-alky  
 ss) -alkylene-D 1 -alkylene-aryl;  
 tt) -alkylene-D 1 -alkylene-arylene-D 2 -R 14    
 uu) -arylene-D 1 -alkyl;  
 vv) -arylene-D 1 -cycloalkyl;  
 ww) -arylene-D 1 -heterocyclyl;  
 xx) -alkylene-D 1 -aryl;  
 yy) -alkylene-D 1 -heteroaryl;  
 zz) -alkylene-D 1 -arylene-D 2 -R 14    
 aaa) -alkylene-D 1 -heteroarylene-D 2 -R 14    
 bbb) -alkylene-D 1 -heteroaryl;  
 ccc) -alkylene-D 1 -cycloalkyl;  
 ddd) -alkylene-D 1 -heterocyclyl;  
 eee) -alkylene-D 1 -arylene-alkyl;  
 fff) -alkylene-D 1 -heteroarylene-alkyl;  
 ggg) -alkylene-D 1 -alkylene-arylene-alkyl;  
 hh) -alkylene-D 1 -alkylene-heteroarylene-alkyl;  
 iii) -alkylene-D 1 -alkyl;  
 jjj) -alkylene-D 1 -R 13 ;  
 kkk) -arylene-D 1 -R 13 ;  
 lll) -heteroarylene-D 1 -R 13 ; and  
 mmm) -hydrogen;  
 wherein 
 D 1  is —CH 2 —, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O) 2 —, —S(O) 2 -alkylene, —O—, —N(R 15 )—, —C(O)—, —CON(R 15 )—, —N(R 15 )C(O)—, —N(R 15 )CON(R 16 )—, —N(R 15 )C(O)O—, —OC(O)N(R 15 )—, —N(R 15 )SO 2 —, —SO 2 N(R 15 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, —N(R 15 )SO 2 N(R 16 )—,  
                     
 and 
 wherein R 13 , R 15 , R 16 , and R 17  are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, and -alkylene-heteroarylene-alkyl;  
 
 D 2  is —CH 2 —, -alkylene-, -alkenylene-, -alkylene-S—, —S-alkylene-, -alkylene-O—, —O-alkylene-, -alkylene-S(O) 2 —, —S(O) 2 -alkylene, —O—, —N(R 25 )—, —C(O)—, —CON(R 25 )—, —N(R 18 )C(O)—, —N(R 18 )CON(R 19 )—, —N(R 18 )C(O)O—, —OC(O)N(R 18 )—, —N(R 18 )SO 2 ˜, ˜SO 2 N(R 18 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, or —N(R 18 )SO 2 N(R 19 )—, 
 wherein R 18  and R 19  are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl; and  
 
 R 14  is -hydrogen, -alkyl, -aryl, -heteroaryl, -arylene-alkyl, -heteroarylene-alkyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-arylene-alkyl, or -alkylene-heteroarylene-alkyl;  
 
 
 Ar 2  is an aryl or heteroaryl group optionally substituted 1 to 7 times, wherein the substituents are independently selected from the group consisting of: 
 a) -fluoro;  
 b) -chloro;  
 c) -bromo;  
 d) -iodo;  
 e) -cyano;  
 f) -nitro;  
 g) -perfluoroalkyl;  
 h) -T 1 -R 20 ;  
 i) -alkyl;  
 j) -aryl;  
 k) -heteroaryl;  
 l) -heterocyclyl;  
 m) -cycloalkyl;  
 n) -alkylene-aryl;  
 o) -alkylene-arylene-aryl;  
 p) -alkylene-arylene-alkyl;  
 q) -arylene-alkyl;  
 r) -arylene-aryl;  
 s) -arylene-heteroaryl;  
 t) -heteroarylene-aryl;  
 u) -heteroarylene-heteroaryl;  
 v) -heteroarylene-heterocyclyl;  
 w) -arylene-heterocyclyl;  
 x) -arylene-arylene-alkyl;  
 y) -T 1 -alkyl;  
 z) -T 1 -aryl;  
 aa) -T 1 -alkylene-aryl;  
 bb) -T 1 -alkenylene-aryl;  
 cc) -T 1 -alkylene-heteroaryl;  
 dd) -T 1 -alkenylene-heteroaryl;  
 ee) -T 1 -cycloalkylene-aryl;  
 ff) -T 1 -cycloalkylene-heteroaryl;  
 gg) -T 1 -heterocyclylene-aryl;  
 hh) -T 1 -heterocyclylene-heteroaryl;  
 ii) -T 1 -arylene-alkyl;  
 jj) -T 1 -arylene-alkenyl;  
 kk) -T 1 -alkylene-arylene-aryl;  
 ll) -T 1 -arylene-T 2 -aryl;  
 mm) -T 1 -arylene-arylene-aryl;  
 nn) -T 1 -alkylene-arylene-alkyl;  
 oo) -alkylene-T 1 -alkylene-aryl;  
 pp) -arylene-T 1 -alkyl;  
 qq) -arylene-T 1 -alkylene-aryl;  
 rr) -T 1 -alkylene-T 2 -aryl;  
 ss) -T 1 -alkylene-aryl;  
 tt) -alkylene-T 1 -heteroaryl;  
 uu) -alkylene-T 1 -cycloalkyl;  
 vv) -alkylene-T 1 -heterocyclyl;  
 ww) -alkylene-T-arylene-alkyl;  
 xx) -alkylene-T 1 -alkylene-arylene-alkyl;  
 yy) -alkylene-T 1 -alkyl;  
 zz) -alkylene-T 1 -R 20 ;  
 aaa) -arylene-T 1 -R 20 ; and  
 bbb) -hydrogen;  
 wherein 
 T 1  is —CH 2 —, —O—, —N(R 21 )—, —C(O)—, —CON(R 21 )—, —N(R 21 )C(O)—, —N(R 21 )CON(R 22 )—, —N(R 21 )C(O)O—, —OC(O)N(R 21 )—, —N(R 21 )SO 2 —, —SO 2 N(R 21 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O 2 )—, —N(R 21 )SO 2 N(R 22 )—,  
                     
 and 
 wherein R 20 , R 21 , R 22  and R 23 , are independently selected from the group consisting of: -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, -alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, -alkylene-arylene-alkyl, -alkylene-arylene-aryl, -alkylene-arylene-alkylene-aryl, -alkylene-arylene-O-arylene, and alkylene-arylene-O—alkylene-aryl; and  
 
 T 2  is a direct bond, —CH 2 —, —O—, —N(R 24 )—, —C(O)—, —CON(R 24 )—, —N(R 24 )C(O)—, —N(R 24 )CON(R 25 )—, —N(R 24 )C(O)O—, —OC(O)N(R 24 )—, —N(R 24 )SO 2 —, —SO 2 N(R 24 )—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O) 2 —, or —N(R 24 )SO 2 N(R 25 )—, 
 wherein R 24  and R 25  are independently selected from the group consisting of: -hydrogen, -alkyl, -alkenyl, -alkylene-cycloalkyl, alkynene-heterocyclyl, -aryl, -heteroaryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl;  
 and wherein  
 
 
 
 the alkyl, aryl, heteroaryl, alkylene, and arylene groups in Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , and R 23  may be optionally substituted 1 to 4 times with a substituent group independently selected from the group consisting of: 
 a) -hydrogen;  
 b) -fluoro;  
 c) -chloro;  
 d) -bromo;  
 e) -iodo;  
 f) -cyano;  
 g) -nitro;  
 h) -perfluoroalkyl;  
 i) -Q-perfluoroalkyl  
 j) -Q-R 24 ;  
 k) -Q-alkyl;  
 l) -Q-aryl;  
 m) -Q-alkylene-aryl;  
 n) -Q-alkylene-NR 25 R 26 ; and  
 o) -Q-alkyl-W-R 27 ;  
 wherein 
 Q and W are independently selected from the group consisting of: —CH 2 —, —O—, —N(R 28 )—, —C(O)—, —CON(R 28 )—, —N(R 28 )C(O)—, —N(R 28 )CON(R 29 )—,—N(R 28 )C(O)O—, —OC(O)N(R 28 )—,—N(R 28 )SO 2 —, SO 2 N(R 28 )—, —C(O)—O—, —O—C(O)—, and —N(R 28 )SO 2 N(R 29 )—,  
 wherein 
 R 24 , R 25 , R 26 , R 27 , R 28 , and R 29  are independently selected from the group consisting of: -hydrogen, -alkyl, -aryl, -arylene-alkyl, -alkylene-aryl, and -alkylene-arylene-alkyl,  
 or a pharmaceutically acceptable salt thereof.  
 
 
 
 
   
   
       2 . The method of  claim 1 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to said subject as a pharmaceutical composition comprising a therapeutically effective amount of said compound and a pharmaceutically acceptable carrier, excipient, or diluent.  
   
   
       3 . The method of  claim 1 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof is an antagonist of factor IX activity.  
   
   
       4 . The method of  claim 1 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof is a partial antagonist of factor IX, wherein a partial antagonist comprises a compound that inhibits less than complete activity at a physiologically tolerable dose.  
   
   
       5 . The method of  claim 4 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof inhibits up to 95% of factor IX activity.  
   
   
       6 . The method of  claim 4 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof inhibits up to 80% of factor IX activity.  
   
   
       7 . The method of  claim 4 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof inhibits up to 50% of factor IX activity.  
   
   
       8 . The method of  claim 1 , wherein the compound of Formula (I) or a pharmaceutically acceptable salt thereof antagonizes blood clotting mediated by factor IX.  
   
   
       9 . The method of  claim 1 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount sufficient to partially antagonize the biological activity of factor IX in said subject.  
   
   
       10 . The method of  claim 2 , wherein said therapeutically effective amount at least partially inhibits the intrinsic clotting cascade in said subject.  
   
   
       11 . The method of  claim 2 , wherein said therapeutically effective amount preferentially inhibits the intrinsic clotting cascade as compared to the extrinsic clotting cascade in said subject.  
   
   
       12 . The method of  claim 2 , wherein said therapeutically effective amount inhibits the intrinsic clotting cascade in said subject by greater than 80% and inhibits the extrinsic clotting cascade by less than 50%.  
   
   
       13 . The method of  claim 2 , wherein said therapeutically effective amount comprises a sufficient amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof for treatment or prevention of factor IX-mediated diseases.  
   
   
       14 . The method of  claim 1 , wherein said pharmaceutical composition is administered in the form of an oral dosage or parenteral dosage unit.  
   
   
       15 . The method of  claim 1 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a dose in a range from about 0.01 to 1,000 mg/kg of body weight per day.  
   
   
       16 . The method of  claim 1 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a dose in a range from about 0.1 to 100 mg/kg of body weight per day.  
   
   
       17 . The method of  claim 1 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered as a dose in a range from about 0.5 to 10 mg/kg of body weight per day.  
   
   
       18 . The method of  claim 13 , wherein said factor IX-mediated disease is a stroke.  
   
   
       19 . The method of  claim 13 , wherein said factor IX-mediated disease is deep vein thrombosis.  
   
   
       20 . The method of  claim 19 , 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).  
   
   
       21 . The method of  claim 13 , wherein said factor IX-mediated disease is clotting associated with the treatment of kidney disease by hemodialysis and/or venous hemofiltration.  
   
   
       22 . The method of  claim 13 , wherein said factor IX-mediated disease is cardiovascular disease.  
   
   
       23 . The method of  claim 22 , wherein said cardiovascular disease is myocardial infarction, arrhythmia, or aneurysm.  
   
   
       24 . The method of  claim 1 , wherein said compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to replace or supplement compounds that reduce clotting.  
   
   
       25 . The method of  claim 2 , wherein said pharmaceutical composition further comprises one or more therapeutic agents.