Substituted Dihydroquinazolines as Platelet ADP Receptor Inhibitors

Abstract

Compounds of formula I are provided: wherein Ar 1 and Ar 2 are substituted aromatic rings and L 1 and L 2 are independent divalent linking groups. The compounds are useful as platelet ADP receptor inhibitors, for treating thrombosis and for reducing the likelihood and/or severity of a secondary ischemic event in a patient.

1 .- 68 . (canceled) 
     
     
         69 . A method for preventing or treating thrombosis and thrombosis related conditions in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound having the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 Y 1  is NH; 
 Y 2  is CO, 
 each R 1 , R 2  and R 3  is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6  alkenyl, C 2-6  alkynyl, —N(R 7 ) 2 , C 1-6 alkoxy, halogen, C 1-6 haloalkyl, hydroxyC 1-6 alkyl, cyano, —C(O)R 6  , C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, aryl and arylC 1-6 alkyl, wherein each of said C 1-6 alkyl, C 2-6  alkenyl, C 2-6  alkynyl and aryl portions is optionally substituted with from 1 to 3 substituents, each independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, amino, C 1-6 alkoxy, halogen, hydroxyl, cyano, oxo, thio, C 3-6 cycloalkyl, aryl and heteroaryl; 
 R 4  is H or —(CH 2 ) m CO 2 H; 
 R 6  is selected from the group consisting of hydroxy, C 1-6 alkyl, C 1-6 alkoxy, heterocyclylC 1-6 alkoxy and —N(R 7 ) 2 ; 
 each R 7  is independently selected from the group consisting of H, C 1-6 alkyl and arylC 1-6 alkyl or optionally, two R 7  groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring; wherein each of said C 1-6  alkyl and arylC 1-6  alkyl is optionally substituted with from 1 to 3 substituents, each independently selected from the group consisting of halogen, amino, hydroxyl, C 1-6  alkoxy, cyano, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, and heteroaryl; 
 Ar 1  is an aromatic ring selected from the group consisting of benzene and thiophene, each of which is optionally substituted with from 1-2 R 8  substituents, 
 Ar 2  is an aromatic ring selected from the group consisting of benzene, tetrazole and thiophene, each of which is optionally substituted with from 1-2 R 8  substituents, 
 each R 8  is independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 3-5 cycloalkyl-C 1-6 alkoxy, —NR 7 , —C(═NR 8a )—N(R 8b ) 2 , —C(O)R 8a , —O(CH 2 ) m OR 8b , —(CH 2 ) m OR 8b , —O(CH 2 ) m N(R 8b ) 2  and —(CH 2 ) m N(R 8b ) 2 , 
 each R 8a  is a member independently selected from the group consisting of H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and —NR 7 ; 
 each R 8b  is a member independently selected from the group consisting of H, C 1-4  alkyl and C 1-4 alkanoyl, and optionally, two R 8b  groups attached to nitrogen are combined with the nitrogen atom to form an azetidine, pyrrolidine, piperidine or morpholine ring; wherein each of said C 1-4  alkyl and C 1-4  alkanoyl is optionally substituted with from 1 to 3 substituents, each independently selected from the group consisting of halogen, amino, hydroxyl, C 1-6  alkoxy, cyano, C 1-6  alkyl, C 3-6  cycloalkyl, aryl, and heteroaryl; 
 L 1  is a linking group selected from the group consisting of —CO— and —CH 2 —, 
 L 2  is a linking group selected from the group consisting of a —C(R 9 ) 2 —, —C(R 9 ) 2 CH 2 — and —CO—; 
 each R 9  is independently selected from the group consisting of H, C 1-6 alkyl, —(CH 2 ) m C(O)R 6 , —C(O)R 6  and heterocyclyl substituted with from 0 to 2 substituents selected from the group halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkyl, oxo and thio; 
 each subscript m is independently 1, 2 or 3, 
 or pharmaceutically acceptable salts thereof. 
 
     
     
         70 . A method in accordance with  claim 69 , wherein said mammal is human. 
     
     
         71 . A method in accordance with  claim 69 , wherein said compound is administered in combination with a second therapeutic agent. 
     
     
         72 . A method in accordance with  claim 71 , wherein said second therapeutic agent is useful for treating a condition or disorder selected from the group consisting of acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic complications following invasive procedures resulting from angioplasty, carotid endarterectorny, post CABG (coronary artery bypass graft) surgery, vascular gram surgery, stent placements and insertion of endovascular devices and prostheses. 
     
     
         73 . A method in accordance with  claim 71 , wherein said second therapeutic agent. selected from the group consisting of antiplatelet compounds, anticoagulants, fibrinolytics, anti-inflammatory compounds, cholesterol-lowering agents, blood pressure-lowering agents and serotonin blockers. 
     
     
         74 . A method in accordance with  claim 71 , wherein said second therapeutic agent is an antiplatelet compound selected from the group consisting of GPIIB-IIIa antagonists, aspirin, phosphodiesterase III inhibitors and thromboxane A2 receptor antagonists. 
     
     
         75 . A method in accordance with  claim 71 , wherein said second therapeutic agent is an anticoagulant selected from the group consisting of thrombin inhibitors, Coumadin and heparin. 
     
     
         76 . A method in accordance with  claim 71 , wherein said second therapeutic agent is an anti-inflammatory compound selected from the group consisting of non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors and rheumatoid arthritis agents. 
     
     
         77 . A method in accordance with  claim 71 , wherein said compound is administered orally, parenterally or topically. 
     
     
         78 .- 83 . (canceled) 
     
     
         84 . A method in accordance with  claim 71 , wherein Ar 1  is benzene, which is optionally substituted with from 1-2 R 8  substituents. 
     
     
         85 . A method in accordance with  claim 71 , wherein Ar 1  is thiophene, which is optionally substituted with from 1-2 R 8  substituents. 
     
     
         86 . A method in accordance with  claim 71 , wherein Ar 2  is tetrazole, which is optionally substituted with from 1-2 R 8  substituents. 
     
     
         87 . A method in accordance with  claim 71 , wherein Ar 2  is benzene, which is optionally substituted with from 1-2 R 8  substituents. 
     
     
         88 . A method in accordance with  claim 71 , wherein Ar 2  is thiophene, which is optionally substituted with from 1-2 R 8  substituents. 
     
     
         89 . A method in accordance with  claim 71 , wherein at least one R 9  is —C(O)R 6 . 
     
     
         90 . A method in accordance with  claim 71 , wherein at least one R 9  is —(CH 2 ) m C(O)R 6 . 
     
     
         91 . A method in accordance with  claim 71 , wherein at least one R 9  is heterocyclyl. 
     
     
         92 . A method in accordance with  claim 71 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein the subscript n is an integer of from 0 to 2. 
       
     
     
         93 . A method in accordance with  claim 71 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein the subscript n is an integer of from 0 to 2. 
       
     
     
         94 . A method in accordance with  claim 71 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         wherein the subscript n is an integer of from 0 to 2. 
       
     
     
         95 . A method in accordance with  claim 71 , wherein said compound is selected from the group consisting of:
 2-(5-chlorothiophen-2-yl)-2-(5-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)thiophene-2-carboxamido)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(5-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)thiophene-3-carboxamido)acetic acid;   2-(4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-3-(thiophen-2-yl)propanoic acid;   2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-3-(thiophen-2-yl)propanoic acid;   N-((1H-tetrazol-5-yl)methyl)-4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((3-chlorophenyl)(1H-tetrazol-5-ypmethyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((4-chlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(4-chlorophenyl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   2-(3-chlorophenyl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   N-((1H-tetrazol-5-yl)(m-tolyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-((3-methoxyphenyl)(1H-tetrazol-5-yl)methyl)benzamide;   4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-N-((3-fluorophenyl)(1H-tetrazol-5-yl)methyl)benzamide;   N-((2-chlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((3,4-dichlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((3,5-dichlorophenyl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((1H-tetrazol-5-yl)(3-(trifluoromethoxy)phenyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((1H-tetrazol-5-yl)(3-(trifluoromethyl)phenyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(5-chloro-N-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzyl)thiophene-2-carboxamido)acetic acid;   3-(5-chlorothiophen-2-yl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzylamino)propanoic acid;   N-((5-chlorothiophen-2-yl)methyl)-4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(4-(7-(4-fluorobenzylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-2-(thiophen-2-yl)acetic acid;   N-((5-chlorothiophen-2-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   2-(N-((5-chlorothiophen-2-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   N-((5-chlorothiophen-2-yl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-2-(thiophen-2-yl)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)benzamido)-2-(5-methylthiophen-2-yl)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(4-(7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   ethyl 2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetate;   3-(5-chlorothiophen-2-yl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)propanoic acid;   N-((5-chlorothiophen-2-yl)(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(5-chlorothiophen-2-yl)-2-(4-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   N-((1H-tetrazol-5-yl)(3-(trifluoromethyl)phenyl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-morpholinoethyl 2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetate;   N-(1-(5-chlorothiophen-2-yl)-2-hydroxyethyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(5-chlorothiophen-2-yl)-2-(4-(6-iodo-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(4-(6-isopropoxy-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(4-(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   3-(N-((5-chlorothiophen-2-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)propanoic acid;   2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylbenzamido)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methoxybenzamido)acetic acid;   2-(2-chloro-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)-2-(5-chlorothiophen-2-yl)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(2-fluoro-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   N-(2-amino-1-(5-chlorothiophen-2-yl)-2-oxoethyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(5-chlorothiophen-2-yl)-2-(4-(7-fluoro-6-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   N-((5-chlorothiophen-2-yl)(1H-tetrazol-5-yl)methyl)-4-(7-fluoro-6-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(7-fluoro-6-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide;   2-(5-chlorothiophen-2-yl)-2-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-methoxybenzamido)acetic acid;   N-((5-chlorothiophen-2-yl)(1H-tetrazol-5-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-methoxybenzamide;   N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-3-methoxybenzamide;   2-(1-((5-chlorothiophen-2-yl)methyl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-1H-1,2,4-triazol-5-ylthio)acetic acid;   2-(5-chlorothiophen-2-yl)-2-(3-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamido)acetic acid;   N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide,   (S)—N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide and   (R)—N-((5-chlorothiophen-2-yl)(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzamide.