Bicyclic Heterocyclic p-38 Kinase Inhibitors

Abstract

Provided are bicyclic heterocycle-based p38 kinase, including p38α and p38β kinase, inhibitors. Pharmaceutical compositions containing the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amelioration of one or more symptoms of p38 kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

1 . A compound that has formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative thereof, wherein:
 R 1  is alkyl, 
 R 2  at each occurrence is independently selected from alkyl, or cycloalkyl, 
 n is 0, 1 or 2; 
 R 3  is cycloalkyl; 
 Y is —C(═O)NH—, or —SO 2 NH—, 
 X 1  is a single bond, or alkylene; 
 A is imidazolopyrimidine or imidazolopyrimidinone and is optionally substituted with up to two R 13 ; 
 X 2  is a single bond, alkylene, —NH—, —N(C 1-4 alkyl)-, —NH—C 1-4 alkylene-, —N(C 1-4 alkyl)-C 1-4  alkylene; 
 D is a monocyclic or bicyclic aromatic or non-aromatic ring system optionally containing up to four heteroatoms selected from N, O, and S, or D is C 1-6 alkyl, and wherein D is optionally substituted by one to four (CR 9 R 10 ) w E groups; 
 CR 9 R 10 ) w E is alkyl, alkoxy, halo, —CH 2 -heterocyclyl, —CONH-cycloalkyl, alkylsulfonyl, alkylthio, alkylsulfonylamino, haloalkyl, aminocarbonyl, alkylcarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, heterocyclylalkyl, alkylcarbonyl-N(alkyl)-, cycloalkylaminocarbonyl, alkylaminocarbonyl, heteroaryl, dialkylaminoalkyl, pseudohalo or heterocyclyl, or two (CR 9 R 10 ) w E groups, which substitute adjacent atoms on D, together form alkylenedioxy; 
 R 13  is hydrogen, alkyl hydroxy or NH 2 . 
 
   
   
       2 - 14 . (canceled) 
   
   
       15 . The compound of  claim 1 , wherein R 3  is cyclopropyl. 
   
   
       16 . (canceled) 
   
   
       17 . The compound of  claim 1 , wherein Y is —C(═O)NH—. 
   
   
       18 . (canceled) 
   
   
       19 . The compound of  claim 1 , wherein X 1  is a single bond or —CH 2 —. 
   
   
       20 . The compound of  claim 1 , wherein X 1  is a single bond. 
   
   
       21 - 24 . (canceled) 
   
   
       25 . The compound of  claim 1 , wherein A is a imidazolopyrimidine. 
   
   
       26 . The compound of  claim 1 , wherein X 2  is a single bond, alkylene or —NH—. 
   
   
       27 . (canceled) 
   
   
       28 . The compound of  claim 1 , wherein X 2  is a single bond. 
   
   
       29 . The compound of  claim 1 , wherein D is heterocyclyl, cycloalkyl, heteroaryl or aryl, and is optionally substituted by one or two, (CR 9 R 10 ) w E groups. 
   
   
       30 . The compound of  claim 1 , wherein D is cyclohexyl, cyclopentyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or phenyl, and is optionally substituted by one or two, (CR 9 R 10 ) w E groups. 
   
   
       31 . The compound of  claim 1 , wherein D is phenyl and is optionally substituted by one or two, (CR 9 R 10 ) w E groups. 
   
   
       32 - 43 . (canceled) 
   
   
       44 . The compound of  claim 1 , wherein the compound has formula X: 
     
       
         
         
             
             
         
       
     
     wherein k is an integer from 0 to 4. 
   
   
       45 . The compound of  claim 1 , wherein the compound has formula XI: 
     
       
         
         
             
             
         
       
     
     wherein k is an integer from 0 to 4. 
   
   
       46 - 50 . (canceled) 
   
   
       51 . A pharmaceutical composition, comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       52 - 104 . (canceled) 
   
   
       105 . A method of treatment or amelioration of one or more symptoms of a disease or disorder that is modulated or otherwise affected by cytokine activity or in which cytokine activity is implicated, comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
   
   
       106 . The method of  claim 105 , wherein the disease or disorder is selected from inflammatory disease, autoimmune disease, destructive bone disorder, proliferative disorder, angiogenic disorder, infectious disease, neurodegenerative disease and viral disease. 
   
   
       107 . The method of  claim 105 , wherein the disease or disorder is modulated or otherwise affected by the activity of cytokine IL-1, TNF, IL- or IL-8. 
   
   
       108 . The method of  claim 107 , wherein the cytokine TNFα modulated disease or disorder is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, AIDS, malignancy, keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis or pyresis. 
   
   
       109 . A method of treating or ameliorating one or more symptoms of cancer, comprising administering a compound of  claim 1 . 
   
   
       110 . The method of  claim 109 , wherein the cancer is breast cancer, stomach cancer, cancer of the ovaries, cancer of the colon, lung cancer, brain cancer, cancer of the larynx, cancer of the lymphatic system, cancer of the genito-urinary tract including the bladder and the prostate, bone cancer and cancer of the pancreas.