Triazole derivatives and their use as PDE4 activators

Abstract

Compounds of Formula (I), which are activators of long form cyclic nucleotide phosphodiesterase-4 (PDE4) enzymes, are provided. Methods and uses of these compounds for the treatment or prevention of disorders requiring a reduction of second messenger responses mediated by cyclic 3′,5′-adenosine monophosphate (cAMP) are also described.

The invention claimed is: 
     
       1. A compound of Formula 1: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from H, (C1-4)alkyl and (C1-4)alkyloxy, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros; 
         R 2  and R 6  are independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros; 
         R 3 , R 4  and R 5  are independently selected from H, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkylsulfonyl, C(O)—NR 16 R 17 , C(O)—OR 16 , S(O) 2 —NR 16 R 17 , CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros; 
         R 7 , R 8 , R 10  and R 11  are independently selected from H and F; 
         R 9  is selected from H, (C1-4)alkyl, (C1-4)alkyloxy, (C1-4)alkylsulfonyl, C(O)—NR 16 R 17 , C(O)—OR 16 , S(O) 2 —NR 16 R 17 , CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros; 
         R 12 , R 13 , R 14  and R 15  are independently selected from H and (C1-4)alkyl; 
         each R 16  and R 17 , when present, is independently selected from H and (C1-4)alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 7  and R 11  are H and/or wherein R 11 , R 12 , R 13 , R 14  and R 15  are H. 
     
     
       3. The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 9  is selected from (C1-4)alkyl, (C1-4)alkyloxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros. 
     
     
       4. The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 7 , R 11 , R 12 , R 13 , R 14  and R 15  are H, and R 9  is selected from (C1-4)alkyl, (C1-4)alkyloxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros. 
     
     
       5. The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 1  is selected from H, methyl, and methoxy. 
     
     
       6. The compound or pharmaceutically acceptable salt of  claim 1  wherein R 2  and R 6  are each independently selected from H and halogen. 
     
     
       7. The compound or pharmaceutically acceptable salt of  claim 1  wherein R 3 , R 4  and R 5  are each independently selected from H, halogen, CN, (C1-4)alkyl and (C1-4)alkyloxy, the (C1-4)alkyl and (C1-4)alkyloxy groups being optionally substituted with 1 to 3 fluoros. 
     
     
       8. The compound or pharmaceutically acceptable salt of  claim 1  wherein R 4  is selected from H, fluoro and methoxy. 
     
     
       9. The compound or pharmaceutically acceptable salt of  claim 1  wherein R 9  is selected from methyl, chloro and trifluoromethoxy. 
     
     
       10. The compound or pharmaceutically acceptable salt of  claim 1  wherein:
 a. one of R 8  and R 10  is H and the other is fluoro; 
 b. R 8  and R 10  are both H; or 
 c. R 9  is chloro, one of R 8  and R 10  is H and the other of R 8  and R 10  is fluoro. 
 
     
     
       11. The compound of  claim 1  selected from
 N-(3-Fluorobenzyl)-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-Benzyl-2-[3-(4-chlorophenyl)-5-methoxymethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-Benzyl-2-[3-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-(3-Fluorobenzyl)-2-{3-[4-(trifluoromethoxy)-phenyl]-5-methoxymethyl-1H-1,2,4-triazol-1-yl}acetamide; 
 N-(3-Chlorobenzyl)-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-(3-Cyanobenzyl)-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-[3-(Trifluoromethyl)benzyl]-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-(3-Methoxybenzyl)-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-[3-(Trifluoromethoxy)benzyl]-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-(2-Fluorobenzyl)-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-(4-Fluorobenzyl)-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 N-(3,4-Dimethoxybenzyl)-2-[3-(4-chloro-3-fluorophenyl)-5-ethyl-1H-1,2,4-triazol-1-yl]acetamide; 
 and pharmaceutically acceptable salts thereof. 
 
     
     
       12. A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
       13. A method of preparing a compound of Formula 1 as defined in  claim 1  or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of Formula 1A 
       
         
           
           
               
               
           
         
         with a compound of Formula 1B 
       
       
         
           
           
               
               
           
         
         wherein R 1 -R 15  are defined in  claim 1 . 
       
     
     
       14. A method of preparing a compound of Formula 1 as defined in  claim 1  or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of Formula 1C 
       
         
           
           
               
               
           
         
         with a compound of Formula 1D 
       
       
         
           
           
               
               
           
         
         wherein R 1 -R 15  are defined in  claim 1 .