Thrombin receptor antagonists

Abstract

Heterocyclic-substituted tricyclics of the formula or a pharmaceutically acceptable salt thereof, wherein: the dotted line represents an optional single bond; represents an optional double bond; n is 0-2; Q is cycloalkyl, optionally substituted by R 13 and R 14 ; R 13 and R 14 are independently selected from (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —OH, (C 1 -C 6 )alkoxy, R 27 -aryl(C 1 -C 6 )alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen and haloalkyl; or R 13 and R 14 together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms; Het is a mono- or bi-cyclic optionally substituted heteroaryl group; and B is a bond, alkylene, or optionally substituted alkenylene or alkynylene, wherein the remaining substituents are as defined in the specification, are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other cardiovascular agents is also claimed.

1 . A compound represented by the structural formula  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 the single dotted line represents an optional single bond;    
  represents an optional double bond;  
 n is 0-2;  
 Q is  
                     
 R 1  is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl-, difluoro(C 1 -C 6 )alkyl-, trifluoro-(C 1 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, hydroxy-(C 1 -C 6 )alkyl-, and amino(C 1 -C 6 )alkyl-;  
 R 2  is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl-, difluoro(C 1 -C 6 )alkyl-, trifluoro-(C 1 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, hydroxy-(C 1 -C 6 )alkyl-, and amino(C 1 -C 6 )alkyl-,  
 R 3  is H, hydroxy, (C 1 -C 6 )alkoxy, —SOR 16 , —SO 2 R 17 , —C(O)OR 17 , —C(O)NR 18 R 19 , —(C 1 -C 6 )alkyl-C(O)NR 18 R 19 , (C 1 -C 6 )alkyl, halogen, fluoro(C 1 -C 6 )alkyl-, difluoro(C 1 -C 6 )alkyl-, trifluoro(C 1 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )-cycloalkyl-(C 1 -C 6 )alkyl-, (C 2 -C 6 )alkenyl, aryl(C 1 -C 6 )alkyl-, aryl(C 2 -C 6 )alkenyl-, heteroaryl(C 1 -C 6 )alkyl-, heteroaryl(C 2 -C 6 )alkenyl-, hydroxy(C 1 -C 6 )-alkyl-, —NR 22 R 23 , NR 22 R 23 —(C 1 -C 6 )alkyl-, aryl, thio(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkyl-thio(C 1 -C 6 )alkyl-, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, NR 18 R 19 —C(O)—(C 1 -C 6 )alkyl- or (C 3 -C 6 )cycloalkyl-(C 1 -C 6 )alkyl-;  
 Het is a mono- or bi-cyclic heteroaryl group of 5 to 10 atoms comprised of 1 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein a ring nitrogen can form an N-oxide or a quaternary group with a (C 1 -C 4 )alkyl group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by W;  
 W is 1 to 4 substituents independently selected from the group consisting of H, (C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl-, difluoro(C 1 -C 6 )alkyl-, trifluoro(C 1 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, NR 25 R 26 (C 1 -C 6 )alkyl-, thio(C 1 -C 6 )alkyl-, —OH, (C 1 -C 6 )alkoxy, halogen, —NR 4 R 5 , —C(O)OR 17 , —COR 16 , (C 1 -C 6 )alkylthio-, R 21 -aryl, R 21 -aryl(C 1 -C 6 )alkyl-, aryl wherein adjacent carbons form a ring comprising a methylenedioxy group, and R 21 -heteroaryl;  
 R 4  and R 5  are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, phenyl, benzyl and (C 3 -C 6 )cycloalkyl, or R 4  and R 5  taken together are —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 NR 7 —(CH 2 ) 2 — and form a ring with the nitrogen to which they are attached;  
 R 6  is H, (C 1 -C 6 )alkyl or phenyl;  
 R 7  is H, (C 1 -C 6 )alkyl, —C(O)—R 16 , —C(O)OR 17  or —SO 2 R 17 ;  
 R 8 , R 10  and R 11  are independently selected from the group consisting of R 1  and —OR 1 , provided that when the optional double bond is present, R 10  is absent;  
 R 9  is H, OH or (C 1 -C 6 )alkoxy;  
 B is —(CH 2 ) n3 —, cis or trans —(CH 2 ) n4 CR 12 ═CR 12a (CH 2 ) n5 — or —(CH 2 ) n4 C≡C(CH 2 ) n5 —, wherein n 3  is 0-5, n 4  and n 5  are independently 0-2, and R 12  and R 12a  are independently selected from the group consisting of H, (C 1 -C 6 )alkyl and halogen;  
 X is —O— or —NR 6 — when the dotted line represents a single bond, or X is —OH or —NHR 20  when the bond is absent;  
 Y is ═O, ═S, (H, H), (H, OH) or (H, (C 1 -C 6 )alkoxy) when the dotted line represents a single bond, or when the bond is absent, Y is ═O, (H, H), (H, OH), (H, H) or (H, (C 1 -C 6 )alkoxy);  
 each R 13  is independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, —(CH 2 ) n6 NHC(O)OR 16b , —(CH 2 ) n6 NHC(O)R 16b , —(CH 2 ) n6 NHC(O)NR 4 R 5 , —(CH 2 ) n6 NHSO 2 R 16 , —(CH 2 ) n6 NHSO 2 NR 4 R 5 , and —(CH 2 ) n6 C(O)NR 28 R 29  where n 6  is 0-4, haloalkyl, and halogen;  
 each R 14  is independently selected from H, (C 1 -C 6 )alkyl, —OH, (C 1 -C 6 )alkoxy, R 27 -aryl(C 1 -C 6 )alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —(CH 2 ) n6 NHC(O)OR 16b , —(CH 2 ) n6 NHC(O)R 16b , —(CH 2 ) n6 NHC(O)NR 4 R 5 , —(CH 2 ) n6 NHSO 2 R 16 , —(CH 2 ) n6 NHSO 2 NR 4 R 5 , and —(CH 2 ) n6 C(O)NR 28 R 29  where n 6  is 0-4, halogen and haloalkyl; or  
 R 13  and R 14  taken together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms;  
 wherein at least one of R 13  or R 14  is selected from the group consisting of —(CH 2 ) n6 NHC(O)OR 16b , —(CH 2 ) n6 NHC(O)R 16b , —(CH 2 ) n6 NHC(O)NR 4 R 5 , —(CH 2 ) n6 NHSO 2 R 6 , —(CH 2 ) n6 NHSO 2 NR 4 R 5 , and —(CH 2 ) n6 C(O)NR 28 R 29  where n 6  is 0-4;  
 R 15  is absent when the dotted line represents a single bond and is H, (C 1 -C 6 )alkyl, —NR 18 R 19 , or —OR 17  when the bond is absent;  
 R 16  is independently selected from the group consisting of (C 1 -C 6 )alkyl, phenyl and benzyl;  
 R 16b  is H, alkoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl-, R 22 —O—C(O)—(C 1 -C 6 )alkyl-, (C 3 -C 6 )cycloalkyl, R 21 -aryl, R 21 aryl(C 1 -C 6 )alkyl, haloalkyl, alkenyl, halosubstituted alkenyl, alkynyl, halosubstituted alkynyl, R 21 -heteroaryl, R 21 -(C 1 -C 6 )alkyl heteroaryl, R 21 -(C 1 -C 6 )alkyl heterocycloalkyl, R 28 R 29 N—(C 1 -C 6 )alkyl, R 28 R 29 N—(CO)—(C 1 -C 6 )alkyl, R 28 R 29 N—(CO)O—(C 1 -C 6 )alkyl, R 28 O(CO)N(R 29 )—(C 1 -C 6 )alkyl, R 28 S(O) 2 N(R 29 )—(C 1 -C 6 )alkyl, R 28 R 29 N—(CO)—N(R 29 )—(C 1 -C 6 )alkyl, R 28 R 29 N—S(O)2N(R 29 )—(C 1 -C 6 )alkyl, R 28 —(CO)N(R 29 )—(C 1 -C 6 )alkyl, R 28 R 29 N—S(O) 2 —(C 1 -C 6 )alkyl, HOS(O) 2 —(C 1 -C 6 )alkyl, (OH) 2 P(O) 2 —(C 1 -C 6 )alkyl, R 28 —S—(C 1 -C 6 )alkyl, R 28 —S(O) 2 —(C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl);  
 R 17 , R 18  and R 19  are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, phenyl, and benzyl;  
 R 20  is H, (C 1 -C 6 )alkyl, phenyl, benzyl, —C(O)R 6  or —SO 2 R 6 ;  
 R 21  is 1 to 3 substituents independently selected from the group consisting of H, —CN, —CF 3 , —OCF 3 , halogen, —NO 2 , (C 1 -C 6 )alkyl, —OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkylamino-, di-((C 1 -C 6 )alkyl)amino-, NR 25 R 26 —(C 1 -C 6 )alkyl-, hydroxy-(C 1 -C 6 )alkyl-, —C(O)OR 17 , —C(O)R 17 , —NHCOR 16 , —NHSO 2 R 16 , —NHSO 2 CH 2 CF 3 , —C(O)NR 25 R 26 , —NR 25 —C(O)—NR 25 R 26 , —S(O)R 13 , —S(O)R 13  and —SR 13 ;  
 R 22  is H or (C 1 -C 6 )alkyl;  
 R 23  is H, (C 1 -C 6 )alkyl, —C(O)R 24 , —SO 2 R 24 , —C(O)NHR 24  or —SO 2 NHR 24 ;  
 R 24  is (C 1 -C 6 )alkyl, hydroxy (C 1 -C 6 )alkyl or NR 25 R 26 —((C 1 -C 6 )alkyl-;  
 R 25  and R 26  are independently selected from the group consisting of H and (C 1 -C 6 )alkyl;  
 R 27  is 1, 2 or 3 substituents selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkoxy, halogen and —OH; and  
 R 28  and R 29  are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, R 27 -aryl(C 1 -C 6 )alkyl, heteroaryl, heteroarylalkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, heterocyclyl, heterocyclylalkyl, and haloalkyl; or  
 R 28  and R 29  taken together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms.  
 
     
     
         2 . A compound of  claim 1  wherein n is 0.  
     
     
         3 . A compound of  claim 1  wherein the optional double bond is not present.  
     
     
         4 . A compound of  claim 1  wherein R 1  and R 2  are independently selected from the group consisting of H and (C 1 -C 6 )alkyl.  
     
     
         5 . A compound of  claim 4  wherein R 1  is (C 1 -C 6 )alkyl and R 2  is H.  
     
     
         6 . A compound of  claim 1  wherein R 3  is H, —OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, (C 3 -C 6 )cycloalkyl, —C(O)OR 17  or —NR 22 R 23 .  
     
     
         7 . A compound of  claim 6  wherein R 3  is H or (C 1 -C 6 )alkyl.  
     
     
         8 . A compound of  claim 1  wherein Het is pyridyl attached to B by a carbon ring member, and is substituted by 1 or 2 substituents selected from W.  
     
     
         9 . A compound of  claim 8  wherein W is R 21 -phenyl or R 21 -pyridyl.  
     
     
         10 . A compound of  claim 1  wherein R 8 , R 10  and R 11  are each independently selected from the group consisting of H and (C 1 -C 6 )alkyl and R 9  is H.  
     
     
         11 . A compound of  claim 1  wherein B is CH═CH—.  
     
     
         12 . A compound of  claim 1  wherein the optional single bond is present, X is —O—, Y is ═O, and R 15  is absent.  
     
     
         13 . A compound of  claim 1  wherein Q is  
       
         
           
           
               
               
           
         
       
       wherein at least one of R 13  and R 14  is R.  
     
     
         14 . A compound of  claim 13  wherein Q is  
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound of  claim 1  wherein R is —(CH 2 ) n6 NHC(O)OR 16b , —(CH 2 ) n6 NHCOR 16b , —(CH 2 ) n6 NHC(O)NR 4 R 5 , —(CH 2 ) n6 NHSO 2 R 16  or —(CH 2 ) n6 NHSO 2 NR 4 R 5 ; R 16b , R 16  and R 4  are (C 1 -C 6 )alkyl; and R 5  is H, where n 6  is 0-4.  
     
     
         16 . A compound of  claim 15  wherein R is —NHC(O)OR 16b , —NHC(O)R 16b  or —NHC(O)NR 4 R 5 , R 16b  and R 4  are (C 1 -C 6 )alkyl, and R 5  is H.  
     
     
         17 . A compound of  claim 16  wherein R is —NHC(O)OR 16b  wherein R 16b  is (C 1 -C 6 )alkyl.  
     
     
         18 . A compound of  claim 1  wherein n is 0, the optional single bond is present, X is —O—, Y is ═O and R 15  is absent.  
     
     
         19 . A compound of  claim 18  wherein R 2 , R 3 , R 8 , R 9 , R 10  and R 11  are each hydrogen, R 1  is —CH 3 , B is —CH═CH—, Het is W-pyridyl, W is R 21 -phenyl or R 21 -pyridyl, and R 21  is —CF 3  or F.  
     
     
         20 . A compound of  claim 19  wherein R is —NHC(O)OR 16b  and R 16b  is —CH 3  or —CH 2 CH 3 .  
     
     
         21 . A compound of  claim 1  selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 1  wherein said salt is a bisulfate.  
     
     
         23 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         24 . A method of inhibiting thrombin receptors comprising administering to a mammal in need of such treatment an effective amount of a compound of  claim 1 .  
     
     
         25 . A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular diseases, inflammatory disorders, cerebral ischemia or cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of  claim 1 .  
     
     
         26 . A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, inflammatory disorders, cerebral ischemia or cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of  claim 1  in combination with an additional cardiovascular agent.  
     
     
         27 . The method of  claim 26  wherein the additional cardiovascular agent is selected from the group consisting of thromboxane A2 biosynthesis inhibitors, GP IIb/IIIa antagonists, thromboxane antagonists, adenosine diphosphate inhibitors, cyclooxygenase inhibitors, angiotensin antagonists, endothelin antagonists, angiotensin converting enzyme inhibitors, neutral endopeptidase inhibitors, anticoagulants, diuretics, and platelet aggregation inhibitors.  
     
     
         28 . The method of  claim 27  wherein the additional cardiovascular agent is aspirin or clopidogrel bisulfate.