Pyrazolyl-substituted pyridone compounds as serine protease inhibitors

Abstract

There are provided inter alia pyrazolyl-substituted pyridone compounds, which exhibit biological activity, e.g., inhibitory action, against serine proteases, including thrombin and various kallikreins. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing certain diseases or disorders, which disease or disorder is amenable to treatment or prevention by the inhibition of serine proteases, including thrombin and various kallikreins.

1 . A compound comprising a substituted or unsubstituted pyridone ring attached to a substituted or unsubstituted pyrazole ring with structure of Formula (I): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof; 
         wherein 
         L 1  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —O—, or —NR 6 —; 
         L 2  and L 4  are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, or —SO 2 —; 
         L 3  and L 5  are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or —O—; 
         R 1  is hydrogen, halogen, substituted or unsubstituted 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, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl; 
         R 2  and R 4  are independently hydrogen, substituted or unsubstituted 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, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl; 
         R 3  and R 5  are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
         R 6  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         provided that if the compound has a structure according to Formula (IIa), as follows, either L 3  is not a bond or R 3  is not hydrogen: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound according to  claim 1 , with structure of Formula (IIa), Formula (IIIa), Formula (IVa), or Formula (Va): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 2 , wherein L 2  is a bond, and R 2  is hydrogen. 
     
     
         4 . The compound according to any of Formula (IIIa), Formula (IVa), or Formula (Va) as set forth in  claim 2 , wherein L 3  is a bond, and R 3  is hydrogen. 
     
     
         5 . The compound according to  claim 2 , wherein L 4  is a bond and R 4  is hydrogen. 
     
     
         6 . The compound according to  claim 2 , wherein L 5  is a bond, and R 5  is hydrogen. 
     
     
         7 . The compound according to  claim 2 , wherein L 2  is —C(O)—, and R 2  is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The compound according to  claim 2 , wherein L 1  is bond, —S—, —O—, —NR 6 —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, and R 1  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl. 
     
     
         13 . (canceled) 
     
     
         14 . The compound according to  claim 2 , wherein L 4  is a bond or substituted or unsubstituted alkylene, and R 4  is substituted or unsubstituted aryl, substituted or unsubstituted fused ring aryl, or substituted or unsubstituted heteroaryl. 
     
     
         15 . (canceled) 
     
     
         16 . The compound according to  claim 2 , wherein L 4  is substituted or unsubstituted alkylene, and R 4  is substituted or unsubstituted heterocycloalkyl, or wherein L 4  is a bond, and R 4  is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The compound according to  claim 2 , wherein L 3  is bond, and R 3  is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The compound according to  claim 1 , wherein L 5  is bond, and R 5  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         23 . The compound according to  claim 1 , as set forth in Table A. 
     
     
         24 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         25 . A method for treating a disease or disorder in a subject, comprising administering a compound according to  claim 1 , or a pharmaceutical composition comprising a compound according to  claim 1 , to a subject in need thereof in an amount effective to treat or prevent said disease or disorder. 
     
     
         26 . The method according to  claim 25 , wherein said disease or disorder is a thrombotic disorder, a kallikrein-related disorder, fibrosis, Alzheimer's Disease, multiple sclerosis, pain, or cancer. 
     
     
         27 . The method according to  claim 26 , wherein said thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism, cardiogenic thromboembolism, disseminated intravascular coagulation, or a blood clot thrombus, or wherein said kallikrein-related disorder is a thrombotic disease, a fibrinolytic disease, a type of cancer, an inflammatory condition, a dermatological condition, or an ophthalmic disease. 
     
     
         28 . The method according to  claim 26 , wherein said compound acts by inhibiting thrombin, or wherein said compound acts by inhibiting plasma kallikrein. 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled)