Pyrrolotriazine aniline prodrug compounds useful as kinase inhibitors

Abstract

Compounds having the Formula (I), including pharmaceutically acceptable salts thereof wherein at least one of X 1 , X 2 or X 3 is and any remaining X 1 , X 2 or X 3 is hydrogen, which are useful as kinase inhibitors, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A 1 , A 2 and m are as described herein.

1 . A compound of Formula I: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, wherein
 at least one of X 1 , X 2  or X 3  is 
 
     
       
         
         
             
             
         
       
     
     and any remaining X 1 , X 2  or X 3  is hydrogen;
 A 1  and A 2  are each independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted aryl, optionally-substituted aralkyl, optionally-substituted heterocyclo and optionally-substituted heteroaryl; 
 R 1 , R 3  and R 5  are each independently selected from hydrogen, optionally-substituted alkyl, —OR 14 , —C(═O)NR 14 R 14a , —NR 14 R 14a , —SO 2 NR 14 R 14a , —NR 14 SO 2 NR 14a R 14b , —NR 14a SO 2 R 14 , —NR 14 C(═O)R 14a , —NR 14 CO 2 R 14a , —NR 14 C(═O)NR 14a R 14b , halogen, cyano, optionally-substituted cycloalkyl, optionally-substituted aryl, optionally-substituted heterocyclo and optionally-substituted heteroaryl; 
 R 2  is independently selected from hydrogen and optionally-substituted alkyl; 
 R 4  is independently selected from: 
 
     
       
         
         
             
             
         
       
       R 6  is attached to any available carbon atom of the phenyl ring and at each occurrence is independently selected from optionally-substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, phenyl, benzyl, aryloxy and benzyloxy, wherein each R 6  group in turn may be further substituted by one to two R 18 ; 
       R 14 , R 14a  and R 14b  are independently selected from hydrogen, optionally-substituted alkyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclo, and optionally-substituted heteroaryl, except when R 14  is joined to a sulfonyl group, as in —S(═O)R 14 , —SO 2 R 14 , and —NR 14a SO 2 R 14 , then R 14  is not hydrogen; 
       R 18  is independently selected from C 1-6 alkyl, C 2-6 alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, hydroxy, hydroxyC 1-4 alkyl, alkoxy, C 1-4 alkylthio, aryl, heterocyclo, (aryl)alkyl, aryloxy, and (aryl)alkoxy; 
       R 27  and R 28  are independently selected from hydrogen, optionally-substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted aryl, optionally-substituted aralkyl, optionally-substituted heterocyclo and optionally-substituted heteroaryl; 
       one of D, E, G, J or L is ═N— and each remaining D, E, G, J or L is ═C—; 
       m is 0, 1, 2 or 3; 
       n is 0 or 1; and 
       k is 0, 1 or 2. 
     
   
   
       2 . The compound of  claim 1 , wherein k is 1 or 2. 
   
   
       3 . The compound of  claim 1 , wherein A 1  is selected from optionally-substituted C 1 -C 6  alkyl, optionally-substituted C 1 -C 6  cycloalkyl and optionally-substituted C 1 -C 6  heteroaryl. 
   
   
       4 . The compound of  claim 1 , wherein A 1  is ethyl. 
   
   
       5 . The compound of  claim 1 , wherein A 1  is propyl. 
   
   
       6 . The compound of  claim 1 , wherein A 1  is cyclopropyl. 
   
   
       7 . The compound of  claim 1 , wherein A 1  is iso-oxazole. 
   
   
       8 . The compound of  claim 1 , wherein A 2  is selected from optionally substituted C 1 -C 6  alkyl and optionally-substituted C 1 -C 6  cycloalkyl. 
   
   
       9 . The compound of  claim 1 , wherein A 2  is ethyl. 
   
   
       10 . The compound of  claim 1 , wherein A 2  is propyl. 
   
   
       11 . The compound of  claim 1 , wherein A 2  is cyclopropyl. 
   
   
       12 . The compound of  claim 1 , wherein R 1 , R 3  and R 5  are independently selected from hydrogen and optionally-substituted C 1 -C 4  alkyl. 
   
   
       13 . The compound of  claim 1 , wherein R 1  and R 5  are each hydrogen and R 3  is methyl. 
   
   
       14 . The compound of  claim 1 , wherein R 2  is selected from hydrogen and C 1 -C 4  alkyl. 
   
   
       15 . A pharmaceutical composition, which comprises a pharmaceutically effective amount of a compound of Formula I, including pharmaceutically acceptable salts thereof, as claimed in  claim 1 , and one or more pharmaceutically acceptable carriers, excipients or diluents. 
   
   
       16 . A method of treating an inflammatory disorder comprising administering to a patient in need of such treatment a pharmaceutical composition according to  claim 15 . 
   
   
       17 . The method of  claim 16 , wherein the inflammatory disorder is selected from asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, Alzheimer's disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, multiple myeloma, pain, myocardial ischemia and arthritis, including rheumatoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis. 
   
   
       18 . The compound of  claim 1 , wherein the salts are selected from sodium salts, potassium salts, calcium salts, magnesium salts, lithium salts, hydrogen chloride salts and methane sulfonic acid salts. 
   
   
       19 . The use of a carbamate substituted pyrrolotriazine compound of Formula I of  claim 1  as a prodrug for releasing a parent drug containing the substituted pyrrolotriazine compound after removal of the carbamate moiety in animals or humans. 
   
   
       20 . A compound having the Formula II: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, wherein
 R 7  is independently selected from: 
 
     
       
         
         
             
             
         
       
       R 8  and R 9  are independently selected from optionally-substituted alkyl, optionally-substituted cycloalkyl, optionally-substituted aryl, optionally-substituted aralkyl, optionally-substituted heterocyclo and optionally-substituted heteroaryl, or R 8  and R 9  can be taken together to be optionally substituted lactam; and 
       n is 0 or 1. 
     
   
   
       21 . The compound of  claim 20 , wherein R 7  is 
     
       
         
         
             
             
         
       
     
   
   
       22 . The compound of  claim 20 , wherein R 7  is 
     
       
         
         
             
             
         
       
     
   
   
       23 . The compound of  claim 20 , wherein R 7  is