Multisubstituted aromatic compounds as inhibitors of thrombin

Abstract

There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.

What is claimed is: 
     
         1 . A method for treating and/or preventing a disease or disorder in a subject, comprising administering a compound to a subject in need thereof in an amount effective to treat or prevent said disease or disorder, wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof; 
         wherein
 ring A is substituted or unsubstituted pyrazolyl, or substituted or unsubstituted triazolyl; 
 L 1 , L 2  and L 3  are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 5 —; 
 L 4  is absent, a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 5 —; 
 R 1 , R 2  and R 3  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is absent, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, provided that when L 4  is absent, then R 4  is absent; and 
 R 5  is independently hydrogen, or substituted or unsubstituted alkyl. 
 
       
     
     
         2 . The method according to  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
         wherein
 L 1  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —NHSO 2 —, or —NR 5 —; 
 L 2  is a bond; 
 L 3  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 5 —; 
 L 4  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO 2 —, —O—, —NHSO 2 —, or —NR 5 —; 
 R 1  is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl having at least one heteroatom selected from the group consisting of N, P, Si, and S, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein the substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl has a substituent group selected from the group consisting of —OH, —NH 2 , —SH, —CN, —CF 3 , —NO 2 , oxo, halogen, —COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl, wherein the substituted cycloalkyl, substituted cycloalkenyl, substituted heterocycloalkyl, substituted heterocycloalkenyl, substituted fused ring aryl, or substituted heteroaryl has a substituent group selected from the group consisting of oxo, —OH, —NH 2 , —SH, —CN, —CF 3 , —NO 2 , halogen, —COOH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; 
 R 3  is substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted aryl, or substituted or unsubstituted heteroaryl, and 
 R 5  is independently hydrogen, or substituted or unsubstituted alkyl. 
 
       
     
     
         3 . The method according to  claim 1 , wherein said disease or disorder is a thrombotic disorder and/or involves a blood clot thrombus or the potential formation of a blood clot thrombus. 
     
     
         4 . The method according to  claim 3 , wherein said thrombotic disorder comprises acute coronary syndrome, thromboembolism, and/or thrombosis. 
     
     
         5 . The method according to  claim 4 , wherein the thromboembolism comprises venous thromboembolism, arterial thromboembolism, and/or cardiogenic thromboembolism. 
     
     
         6 . The method according to  claim 5 , wherein the venous thromboembolism comprises deep vein thrombosis and/or pulmonary embolism. 
     
     
         7 . The method according to  claim 6 , wherein the deep vein thrombosis and/or pulmonary embolism occurs following a medical procedure. 
     
     
         8 . The method according to  claim 3 , wherein said thrombotic disorder involves dysfunctional coagulation or disseminated intravascular coagulation. 
     
     
         9 . The method according to  claim 8 , wherein the subject is undergoing percutaneous coronary intervention (PCI). 
     
     
         10 . The method according to  claim 3 , wherein said thrombotic disease or disorder involves a blood clot thrombus or the potential formation of a blood clot thrombus and further involves stroke and/or one or more transient ischemic attacks (TIA). 
     
     
         11 . The method according to  claim 10 , wherein said thrombotic disease or disorder involving a blood clot thrombus or the potential formation of a blood clot thrombus further involves stroke and wherein the subject has non-valvular atrial fibrillation. 
     
     
         12 . The method according to  claim 3 , wherein said thrombotic disease or disorder involves a blood clot thrombus or the potential formation of a blood clot thrombus and further involves pulmonary hypertension. 
     
     
         13 . The method according to  claim 12 , wherein the pulmonary hypertension is caused by one or more left heart disorder and/or chronic thromboembolic disease. 
     
     
         14 . The method according to  claim 12 , wherein the pulmonary hypertension is associated with one or more lung disease, including pulmonary fibrosis (idiopathic or otherwise), and/or hypoxia. 
     
     
         15 . The method according to  claim 1 , wherein said disease or disorder comprises fibrosis, Alzheimer's Disease, multiple sclerosis, pain, cancer, inflammation, and/or Type I diabetes mellitus. 
     
     
         16 . The method according to  claim 1 , wherein the disease or disorder involves recurrent cardiac events after myocardial infarction. 
     
     
         17 . The method according to  claim 5 , wherein the venous thromboembolism is associated with formation of a thrombus within a vein associated with one or more acquired or inherited risk factors and/or embolism of peripheral veins caused by a detached thrombus. 
     
     
         18 . The method according to  claim 17 , wherein the one or more risk factors comprise a previous venous thromboembolism. 
     
     
         19 . The method according to  claim 5 , wherein the cardiogenic thromboembolism is due to formation of a thrombus in the heart associated with cardiac arrhythmia, heart valve defect, prosthetic heart valves or heart disease, and/or embolism of peripheral arteries caused by a detached thrombus. 
     
     
         20 . The method according to  claim 19 , wherein the detached thrombus is in the brain (ischemic stroke). 
     
     
         21 . The method according to  claim 20 , wherein the detached thrombus causes a transient ischemic attack (TIA). 
     
     
         22 . The method according to  claim 19 , wherein the cardiogenic thromboembolism is due to non-valvular atrial fibrillation. 
     
     
         23 . The method according to  claim 4 , wherein the thrombosis is arterial thrombosis. 
     
     
         24 . The method according to  claim 23 , wherein the arterial thrombosis is due to one or more underlying atherosclerotic processes in the arteries. 
     
     
         25 . The method according to  claim 24 , wherein the one or more underlying atherosclerotic processes in the arteries obstruct or occlude an artery, cause myocardial ischemia (angina pectoris, acute coronary syndrome), cause myocardial infarction, obstruct or occlude a peripheral artery (ischemic peripheral artery disease), and/or obstruct or occlude the artery after a procedure on a blood vessel (reocclusion or restenosis after transluminal coronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty of peripheral arteries). 
     
     
         26 . The method according to  claim 1 , wherein the treatment or prevention comprises an adjunct therapy. 
     
     
         27 . The method according to  claim 26 , wherein the subject has myocardial infarction, and the adjunct therapy is in conjunction with thrombolytic therapy. 
     
     
         28 . The method according to  claim 26 , wherein the subject has unstable angina pectoris, thrombosis, and/or heparin-induced thrombocytopenia, and the adjunct therapy is in combination with antiplatelet therapy. 
     
     
         29 . The method according to  claim 26 , wherein the subject has non-valvular atrial fibrillation, and the adjunct therapy is in conjunction with other therapies.