Pyrrole compositions useful as inhibitors of c-Met

Abstract

The present invention relates to compounds useful of inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds, processes for making the compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 Q is a C 1-6  alkylidene chain wherein one methylene unit of Q is replaced by —C(O)N(R)—, —C(O)—, —C(O)O—, —N(R)—, —O—, —S—, —SO 2 —, or —SO 2 N(R)—;  
 each R is independently hydrogen or an optionally substituted C 1-6  aliphatic group, wherein: 
 two R groups on the same nitrogen atom are optionally taken together with said nitrogen atom to form an optionally substituted 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;  
 
 R 1  is H, —N(R) 2 , or an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or suflur, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;  
 R 2  is an optionally substituted 6-membered aryl ring having 0-3 nitrogens;  
 each R 3  is independently R, CN, NO 2 , halogen, N(R) 2 , OR, or SR;  
 n is 0-2; and  
 Ring A is an optionally substituted ring selected from:  
                                       
 
     
     
         2 . The compound according to  claim 1 , wherein: 
 R 1  is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or suflur, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.    
     
     
         3 . The compound according to  claim 2 , wherein: 
 R 1  is an optionally substituted 4-6 membered saturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.    
     
     
         4 . The compound according to  claim 2 , wherein: 
 R 1  is an optionally substituted 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or suflur, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.    
     
     
         5 . The compound according to  claim 1 , wherein Q is —C(O)N(R)—.  
     
     
         6 . The compound according to  claim 1 , wherein Q is —C(O)—.  
     
     
         7 . The compound according to  claim 1 , wherein n is 0.  
     
     
         8 . The compound according to  claim 1 , wherein n is 1.  
     
     
         9 . The compound according to  claim 1 , wherein R 2  is an optionally substituted phenyl ring.  
     
     
         10 . The compound according to  claim 1 , wherein R 2  is an optionally subsituted pyridyl or pyrimidinyl ring.  
     
     
         11 . The compound according to  claim 1 , wherein Ring A is an optionally substituted ring selected from:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . A compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.  
     
     
         14 . The composition according to  claim 13 , wherein said compound is in an amount sufficient to detectably inhibit c-Met protein kinase activity.  
     
     
         15 . The composition according to  claim 14 , additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.  
     
     
         16 . A method of inhibiting c-Met kinase activity in: 
 (a) a patient; or    (b) a biological sample;    which method comprises administering to said patient, or contacting said biological sample with:    a) a composition according to  claim 13;  or    b) a compound according to  claim 1  or compound 1-47.    
     
     
         17 . A method of treating or lessening the severity of a cancer or a proliferative disorder in a patient in need thereof, comprising the step of administering to said patient: 
 a) a composition according to  claim 13;  or    b) a compound according to  claim 1 .    
     
     
         18 . The method according to  claim 17 , comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, wherein said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.  
     
     
         19 . A method of treating renal cancer in a patient in need thereof, comprising administering to said patient: 
 a) a composition according to  claim 13;  or    b) a compound according to  claim 1 .    
     
     
         20 . A method of inhibiting tumor metastisis in a patient, comprising administering to said patient: 
 a) a composition according to  claim 13;  or    b) a compound according to  claim 1.