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.

What is claimed is: 
     
       1. A compound of structural Formula VI 
       
         
           
           
               
               
           
         
         or a salt, ester, or prodrug thereof, wherein: 
         R 1  is —(CH 2 ) s G 1 G 2 G 3 ; 
         R 2  is lower alkyl; 
         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 heterocycloalkyl; 
         G 3  is selected from the group consisting of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid, phosphonate, phosphoamide, and null; and 
         R 20  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. 
       
     
     
       2. The compound of  claim 1  wherein G 1  is null. 
     
     
       3. The compound of  claim 1  wherein G 3  is null. 
     
     
       4. The compound of  claim 1  wherein each of G 1  and G 3  is null. 
     
     
       5. The compound of  claim 1  wherein R 2  is methyl. 
     
     
       6. The compound of  claim 1  wherein s is 1-6. 
     
     
       7. The compound of  claim 1  wherein each of R 20  and R 24  is halogen. 
     
     
       8. The compound of  claim 1  wherein G 2  is selected from the group consisting of aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, and thiomorpholinyl. 
     
     
       9. The compound of  claim 1  wherein G 2  is morpholinyl. 
     
     
       10. The compound of  claim 1  wherein s is 6. 
     
     
       11. The compound of  claim 4  wherein:
 R 2  is methyl. 
 
     
     
       12. The compound of  claim 11  wherein s is 1-6. 
     
     
       13. The compound of  claim 12  wherein G 2  is selected from the group consisting of aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, and thiomorpholinyl. 
     
     
       14. The compound of  claim 13  wherein G 2  is morpholinyl. 
     
     
       15. The compound of  claim 14  wherein each of R 20  and R 24  is halogen. 
     
     
       16. The compound of  claim 15  wherein each of R 20  and R 24  is chlorine. 
     
     
       17. The compound of  claim 16  wherein s is 6.