Substituted 7-aza-quinazoline compounds useful as p38 kinase inhibitors

Abstract

Compounds having the formula (I) or (II), are useful as p38 kinase inhibitors, wherein R is an optionally substituted alkyl, cycloalkyl, or aryl; R 6 is hydrogen or lower alkyl; R 7 is hydrogen or a non-interfering substituent, and Q is a non-aromatic moiety as defined in the specification.

1 - 17 . (canceled)  
   
   
       18 . A method for treating a p38-mediated disorder in a patient comprising administering to the patient in need of such treatment, an effective amount of a compound of formula I or II:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt thereof, wherein: 
 R is selected from: 
 (a) alkyl optionally-substituted with one to three of R 17;    
 (b) cycloalkyl optionally substituted with one, two or three groups selected from R 18 ; and  
 (c) optionally-substituted aryl;  
 
 Q is selected from alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, and alkyl substituted with one, two or three of halogen, cyano, —OR 8 , —SR 8 , —C(═O)R 8 , —C(O) 2 R 8 , —C(═O)NR 8 R 9 , —S(O) p R 10 , —C(O) p  NR 8 R 9 , —S(O) 2 NR 8 R 9 , —NR 8 R 9 , cycloalkyl, substituted cycloalkyl, heterocyclyl, and/or substituted heterocyclyl;  
 R 6  is hydrogen or lower alkyl;  
 R 7  is selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, and optionally-substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl:  
 R 8  and R 9  are (i) independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl; or (ii) when R 8  and R 9  are attached to the same nitrogen atom (as in —C(O) 2 NR 8 R 9 , —S(O) 2 NR 8 R 9 , and —NR 8 R 9 ), R 8  and R 9  may be taken together to form an optionally-substituted heterocyclyl tins;  
 R 10  is alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl;  
 R 17  is at each occurrence independently selected from halogen, haloalkoxy, haloalkyl, alkoxy, or optionally-substituted phenyl, benzyl, phenyloxy, benzyloxy, or cycloalkyl:  
 R 18  is at each occurrence independently selected from alkyl, substituted alkyl, halogen, haloalkyl, haloalkoxy, cyano, alkoxy, acyl, alkoxycarbonyl, alkylsulfonyl, or optionally-substituted phenyl, phenyloxy, benzyloxy, cycloalkyl, heterocyclyl, or heteroaryl: and  
 p is 1 or2  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       19 . The method of  claim 18 , wherein the p38-mediated disorder is selected from the group consisting of arthritis, Crohn's disease, Alzheimer's disease, adult respiratory distress syndrome, chronic obstructive pulmonary disease, asthma, stroke, sepsis, myocardial infarction, and spondylitis.  
   
   
       20 . A method for inhibiting p38 kinase in a mammal comprising administering to said mammal a compound of formula I or II:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt thereof, wherein: 
 R is selected from: 
 (d) alkyl optionally-substituted with one to three of R 17 ;  
 (e) cycloalkyl optionally substituted with one, two or three groups selected from R 18 l and  
 (f) optionally-substituted aryl;  
 
 Q is selected from alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, and alkyl substituted with one, two or three of halogen, cyano, —OR 8 , —SR 8 , —C(═O)R 8 , —C(O)R 8 , —C(═O)NR 8 R 9 , —S(O) p R 10 , —C(O)NR 8 R 9 , —S(O) 2 NR 8 R 9 , —NR 8 R 9 , cycloalkyl, substituted cycloalkyl. heterocyclyl, and/or substituted heterocyclyl;  
 R 6 is hydrogen or lower alkyl:  
 R 7  is selected from hydrogen, alkyl, substituted alkyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, amino, alkylamino, and optionally-substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl;  
 R 8  and R 9  are (i) independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl: or (ii) when R 8  and R 9  are attached to the same nitrogen atom (as in —C(O) 2 NR 8 R 9 , —S(O) 2 NR 8 R 9 , and —NR 8 R 9 ), R 8  and R 9  may be taken together to form an optionally-substituted heterocyclyl ring;  
 R 10  is alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, or substituted heterocyclyl;  
 R 17  is at each occurrence independently selected from halogen, haloalkoxy, haloalkyl, alkoxy, or optionally-substituted phenyl, benzyl, phenyloxy, benzyloxy, or cycloalkyl;  
 R 18  is at each occurrence independently selected from alkyl, substituted alkyl, halogen, haloalkyl, haloalkoxy, cyano, alkoxy, acyl, alkoxycarbonyl, alkylsulfonyl, or optionally-substituted phenyl, phenyloxy, benzyloxy, cycloalkyl, heterocyclyl, or heteroaryl; and  
 p is 1 or 2.  
 
   
   
       21 - 22 . (canceled)  
   
   
       23 . The method of  claim 20 , wherein: 
 Q is selected from an alkyl or substituted alkyl having the formula —C(R 1 R 2 R 3 );    R 1 , R 2  and R 3  are selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, —(C 1-4 alkylene)-S(O) p R 10 , -(C 1-4 alkylene)-C(O) 2 R 8 , cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocycloalkyl, wherein said cycloalkyl and heterocyclyl groups are, in turn, optionally substituted with up to one of R 12  and up to one of R 14 ; and    R 12 and R 14  are independently selected where valence allows from C 1-4 alkyl, hydroxy, oxo (═O),    —O(C 1-4 alkyl), —C(═O)H, —C(═O)(C 1-4 alkyl), —C(O) 2 H, —C(O) 2 (C 1-4 alkyl), and —S(O) 2 (C 1-4 alkyl),    or a pharmaceutically acceptable salt thereof.    
   
   
       24 . The method of  claim 20 , wherein said compound has the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       25 . The method of  claim 24 , wherein said compound has the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 X is —O—, —C(═O)—, —N(R 12a )—, or —CH(R 12b )—;  
 R 12a  is selected from hydrogen, C 1-4 alkyl, —C(═O)R 15 , —C(O) 2 R 15 , and —S(O) 2 (C 1-4 alkyl);  
 R 12b  is selected from hydrogen, C 1-4 alkyl, —OR 15 , —C(═O)R 15 , —C(O) 2 R 15 , and —S(O) 2 (C 1-4 alkyl);  
 R 14  is selected from C 1-4 alkyl, oxo (═O), —OR 15 , —C(═O)R 15 , —C(O) 2 R 15 , and —S(O) 2 (C 1-4 alkyl);  
 R 15  is selected from hydrogen and C 14 alkyl;  
 q is 0 or 1; and  
 r is 0, 1 or 2,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       26 . The method of  claim 25 , wherein R 4  and R 5  are both fluoro.  
   
   
       27 . The method of  claim 19 , wherein said disorder comprises rheumatoid arthritis.  
   
   
       28 . The method of  claim 19 , wherein said disorder comprises Crohn's disease.  
   
   
       29 . The method of  claim 19 , wherein said disorder comprises Alzheimer's disease.  
   
   
       30 . The method of  claim 19 , wherein said disorder comprises adult respiratory distress syndrome.  
   
   
       31 . The method of  claim 19 , wherein said disorder comprises chronic obstructive pulmonary disease.  
   
   
       32 . The method of  claim 19 , wherein said disorder comprises asthma.  
   
   
       33 . The method of  claim 19 , wherein said disorder comprises stroke.  
   
   
       34 . The method of  claim 19 , wherein said disorder comprises sepsis.  
   
   
       35 . The method of  claim 19 , wherein said disorder comprises myocardial infarction.  
   
   
       36 . The method of  claim 19 , wherein said disorder comprises spondylitis.