Bicyclic heteroaryl inhibitors of PDE4

Abstract

The present invention relates to compounds and methods which may be useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.

1. A compound of structural Formula V 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 1  and R 2  are independently selected from the group consisting of —(CH 2 ) s G 1 G 2 G 3 , acyl, acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl, heteroaralkyl, and hydroxyalkyl, any of which may be optionally substituted; 
 s is 1-8; 
 G 1  is selected from the group consisting of alkoxy, amino, amido, carbonyl, hydroxy, ether, an amino acid, and null; 
 G 2  is selected from the group consisting of alkyl, alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino, guanidine, an amino acid, and null, any of which may be optionally substituted; 
 G 3  is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide, and null, any of which may be optionally substituted; 
 R 5  is selected from the group consisting of —(CR 8 R 9 ) m W(CR 10 R 11 ) n — and —(CR 12 R 13 ) p —; 
 W is selected from the group consisting of O, N(R 7 ), C(O)N(R 7 ), and SO q ; 
 m, n, and q are independently 0, 1 or 2; 
 p is 1 or 2; 
 R 6  is selected from the group consisting of carboxyl, alkylcarboxy, amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkyl, heteroalkyl, acyl, and hydroxamic acid, any of which may be optionally substituted; 
 R 7  and R 14  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl, haloalkyl, and aminoalkyl; 
 R 8 , R 9 , R 10 , R 11 , R 12  and R 13  are independently selected from the group consisting of hydrogen and optionally substituted lower alkyl; 
 and R 19  is selected from the group consisting of hydrogen, halogen, lower alkyl and haloalkyl. 
 
       
     
     
       2. The compound as recited in  claim 1 , wherein R 7  and R 14  are independently selected from the group consisting of hydrogen, halogen and optionally substituted lower alkyl. 
     
     
       3. The compound as recited in  claim 1 , wherein R 6  is selected from the group consisting of aryl and heteroaryl, either of which may be optionally substituted. 
     
     
       4. The compound as recited in  claim 1 , wherein R 19  is hydrogen. 
     
     
       5. The compound as recited in  claim 1 , wherein R 6  is selected from the group consisting of phenyl, pyridine, pyrimidine, pyridazine, and pyrazine, any of which may be optionally substituted. 
     
     
       6. The compound as recited in  claim 1 , wherein R 14  is hydrogen. 
     
     
       7. The compound as recited in  claim 1 , wherein:
 R 5  is —(CR 8 R 9 ) m W(CR 10 R 11 ) n —; 
 m and n are both 0; 
 W is N(R 7 ); and 
 R 7  is hydrogen. 
 
     
     
       8. The compound as recited in  claim 1 , wherein R 2  is lower alkyl. 
     
     
       9. The compound as recited in  claim 1 , wherein:
 R 1  is selected from the group consisting of —(CH 2 ) s G 1 G 2 G 3 , lower alkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may be optionally substituted; 
 s is 1-6; 
 G 1  is selected from the group consisting of amino, amido, and null; 
 G 2  is selected from the group consisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any of which may be optionally substituted; and 
 G 3  is selected from the group consisting of alkyl, carboxyl, and null, any of which may be optionally substituted. 
 
     
     
       10. The compound as recited in  claim 1 , wherein R 2  is methyl. 
     
     
       11. The compound as recited in  claim 1 , wherein R 6  has a formula selected from the group consisting of 
       
         
           
           
               
               
           
         
         R 20 , R 21 , R 22 , R 23  and R 24  are independently selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, amino, and carboxyl. 
       
     
     
       12. A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       13. A pharmaceutical composition comprising a compound as recited in  claim 1 , together with a pharmaceutically acceptable carrier.