Methods of treatment comprising the administration of haloaryl substituted aminopurines or compositions thereof

Abstract

Provided herein are Aminopurine Compounds having the following structure: wherein R 1 , R 2 and and R 3 are as defined herein, compositions comprising an effective amount of an Aminopurine Compound and methods for treating or preventing cancer, a cardiovascular disease, a renal disease, an autoimmune condition, an inflammatory condition, macular degeneration, ischemia-reperfusion injury, pain and related syndromes, disease-related wasting, an asbestos-related condition, pulmonary hypertension or a condition treatable or preventable by inhibition of the JNK pathway comprising administering an effective amount of an Aminopurine Compound to a patient in need thereof.

1 . A method for treating a disease or disorder responsive to the inhibition of JNK, comprising administering to a patient having a disease or disorder responsive to the inhibition of JNK an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2 is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       2 . The method of  claim 1 , wherein the disease or disorder is an inflammatory disease, a metabolic disease, cancer, a cardiovascular disease, a renal disease, an autoimmune disease, macular degeneration, ischemia-reperfusion injury, pain or a pain-related syndrome, disease-related wasting, an asbestos-related condition or pulmonary hypertension. 
   
   
       3 . A method for treating an inflammatory disease, comprising administering to a patient having an inflammatory disease an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       4 . The method of  claim 3 , wherein the inflammatory disease is asthma, allergic rhinitis, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, mucous colitis, ulcerative colitis or obesity. 
   
   
       5 . A method for treating a metabolic disease, comprising administering to a patient having a metabolic disease an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       6 . The method of  claim 5 , wherein the metabolic disease is obesity or diabetes. 
   
   
       7 . A method for treating cancer, comprising administering to a patient having cancer an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       8 . The method of  claim 7 , wherein the cancer is of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system. 
   
   
       9 . A method for treating a cardiovascular disease, comprising administering to a patient having a cardiovascular disease an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       10 . The method of  claim 9 , wherein the cardiovascular disease is stroke, myocardial infarction or ischemic damage to the heart, lung, gut, kidney, liver, pancreas, spleen or brain. 
   
   
       11 . A method for treating a renal disease, comprising administering to a patient having a renal disease an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       12 . The method of  claim 11 , wherein the renal disease is atherosclerosis or restenosis after vascular intervention. 
   
   
       13 . A method for treating an autoimmune disease, comprising administering to a patient having an autoimmune disease an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       14 . The method of  claim 13 , wherein the autoimmune disease is rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, multiple sclerosis, lupus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, Grave's disease or diabetes. 
   
   
       15 . A method for treating macular degeneration, comprising administering to a patient having macular degeneration an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       16 . The method of  claim 15 , wherein the macular degeneration is Best's disease, vitelliform, Stargardt's disease, juvenile macular dystrophy, fundus flavimaculatus, Behr's disease, Sorsby's disease, Doyne's disease, honeycomb dystrophy or age-related macular degeneration. 
   
   
       17 . A method for treating ischemia-reperfusion injury, comprising administering to a patient having ischemia-reperfusion injury an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       18 . A method for treating an asbestos-related condition, comprising administering to a patient having an asbestos-related condition an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       19 . The method of  claim 18 , wherein the asbestos-related condition is malignant mesothelioma, asbestosis, malignant pleural effusion, benign pleural effusion, pleural plaque, pleural calcification, diffuse pleural thickening, round atelectasis or bronchogenic carcinoma. 
   
   
       20 . A method for treating pulmonary hypertension, comprising administering to a patient having pulmonary hypertension an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       21 . A method for treating a central nervous system injury or damage, comprising administering to a patient having a central nervous system injury or damage an effective amount of a compound having the formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein: 
       R 1  is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; 
       R 2  is H, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycle or substituted or unsubstituted C 3-10 heteroaryl; and 
       R 3  is aryl substituted with one or more halogens or C 3-10 heteroaryl substituted with one or more halogens, wherein the aryl or C 3-10 heteroaryl group is optionally further substituted with one or more C 1-6 alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, carboxy, aminocarbonyl, cyano, acylamino, alkanesulfonylamino, tetrazolyl, triazolyl or imidazolyl groups. 
     
   
   
       22 . The method of  claim 21 , wherein the central nervous system injury or damage is primary brain injury, secondary brain injury, traumatic brain injury, focal brain injury, diffuse axonal injury, head injury, concussion, post-concussion syndrome, cerebral contusion and laceration, subdural hematoma, epidermal hematoma, post-traumatic epilepsy, chronic vegetative state, complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI, central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome, conus medullaris syndrome, cauda equina syndrome, neurogenic shock, spinal shock, altered level of consciousness, headache, nausea, emesis, memory loss, dizziness, diplopia, blurred vision, emotional lability, sleep disturbances, irritability, inability to concentrate, nervousness, behavioral impairment, cognitive deficit or seizure.