Triazole-derived kinase inhibitors and uses thereof

Abstract

Described herein are compounds that are useful as protein kinase inhibitors having the formula: where Ht, R 2 , T, and m are as described in the specification. The compounds are useful for treating diseases in mammals that are alleviated by a protein kinase inhibitor, particularly diseases such as cancer, inflammatory disorders, restenosis, and cardiovascular disease.

1 . A compound of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or derivative thereof, wherein: 
 Ht is tetrazol-5-yl;  
 T is selected from —C(R 7 ) 2 —, —C(O)—, —C(O)C(O)—, —C(O)NR 7 —, —C(O)NR 7 NR 7 —, —CO 2 —, —OC(O)—, —NR 7 CO 2 —, —O—, —NR 7 C(O)NR 7 —, —OC(O)NR 7 —, —NR 7 NR 7 —, —NR 7 C(O)—, —S—, —SO—, —SO 2 —, —NR 7 —, —SO 2 NR 7 —, or —NR 7 SO 2 —, —NR 7 SO 2 NR 7 —;  
 m is selected from zero or one;  
 R 2  is selected from hydrogen, CN, halogen, R, N(R 7 ) 2 , OR, or OH;  
 each R is independently selected from an optionally substituted group selected from C 1-6  aliphatic, C 6-10  aryl, heteroaryl having 5-10 ring atoms, and heterocyclyl having 3-10 ring atoms;  
 each R 7  is independently selected from hydrogen or an optionally substituted C 1-6  aliphatic group, or two R 7  on the same nitrogen are taken together with the nitrogen to form a 5-8 membered ring heterocyclyl or heteroaryl ring;  
 provided that: 
 when m is 0, R 2  is other than H or an unsubstituted phenyl.  
 
 
   
   
       2 - 3 . (canceled)  
   
   
       4 . The compound according to  claim 1 , wherein T m R 2  is N(R 7 ) 2 , OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring.  
   
   
       5 . The compound according to  claim 4 , wherein T m R 2  is N(R 7 ) 2 , OH, 3-6 membered carbocyclyl, or an optionally substituted group selected from C 1-6  aliphatic or a 5-6 membered aryl or heteroaryl ring.  
   
   
       6 . The compound according to  claim 5 , wherein T m R 2  is selected from optionally substituted phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, CH 2 OCH 3 , CH 2 OH, OH, NH 2 , NHCH 3 , NHAc, NHC(O)NHCH 3 , or CH 2 NHCH 3 .  
   
   
       7 - 19 . (canceled)  
   
   
       20 . The compound according to  claim 1  wherein said compound is selected from any one of the following compounds:  
     
       
         
               
               
             
                   
               
                   
               
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                 II-E 1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
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                 II-E 5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 II-E 6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                   
               
           
              
              
              
              
             
             
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
     
   
   
       21 . (canceled)  
   
   
       22 . A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant, or vehicle.  
   
   
       23 . The composition according to  claim 22 , additionally comprising an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, 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.  
   
   
       24 . A method of inhibiting ERK kinase activity in a biological sample comprising the step of contacting said biological sample with: 
 a) a compound according to  claim 1;  or    b) a composition according to  claim 22 .    
   
   
       25 . A method of treating or lessening the severity of an ERK-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to  claim 22 .  
   
   
       26 . A method of treating or lessening the severity of an cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, or CNS disorders, comprising the step of administering to said patient a composition according to  claim 22 .  
   
   
       27 . The method according to  claim 26 , wherein said method is used to treat or prevent cancer.  
   
   
       28 . The method according to  claim 27 , wherein said method is used to treat or prevent a cancer selected from breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon, adenoma; pancreas, adenocarcinoma; thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidney carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine; colon-rectum, large intestine, rectum; brain and central nervous system; or leukemia.  
   
   
       29 . The method according to  claim 26 , wherein said method is used to treat or prevent cardiovascular disease.  
   
   
       30 . The method according to  claim 29 , wherein said method is used to treat or prevent a cardiovascular disease selected from restenosis, cardiomegaly, artherosclerosis, myocardial infarction, or congestive heart failure.  
   
   
       31 . The method according to  claim 26 , wherein said method is used to treat or prevent neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.  
   
   
       32 . The method according to  claim 26 , comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, 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, wherein: 
 said additional therapeutic agent is appropriate for the disease being treated; and    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.    
   
   
       33 . A composition for coating an implantable device comprising a compound according to  claim 1  and a carrier suitable for coating said implantable device.  
   
   
       34 . An implantable device coated with a composition according to  claim 33.