Triazolopyridine jak inhibitor compounds and methods

Abstract

A compound of Formula I, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 are defined herein, are useful as JAK kinase inhibitors. A pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of JAK kinase activity in a patient are disclosed.

What is claimed is: 
     
         1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof, wherein: 
         R 1  is H, C(O)OR a , phenyl, C 1 -C 9  heterocyclyl or C 1 -C 9  heteroaryl, wherein said phenyl and heteroaryl are optionally substituted by 1 to 5 R 6 ; 
         R 2  is phenyl, C 1 -C 9  heteroaryl or C 1 -C 9  heterocyclyl, wherein the phenyl, heteroaryl and heterocyclyl are optionally substituted by 1 to 5 R 7 ; 
         R 3 , R 4  and R 5  are independently H, CH 3 , CH 2 CH 3 , OCH 3 , CF 3 , F or Cl; 
         R 6  is independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 0 -C 6  alkyl)OR a , (C 0 -C 6  alkyl)NR a R b , halo, CN, CF 3 , S(O) 1-2 NR a R b , C(O)R a , NR a C(O)OR b , NR a S(O) 1-2 NR b , (C 0 -C 6  alkyl)C 1 -C 5  heteroaryl, (C 0 -C 6  alkyl)C 1 -C 5  heterocyclyl, (C 0 -C 6  alkyl)C 3 -C 6  cycloalkyl, (C 0 -C 6  alkyl)C 6 -C 9  aryl, (C 0 -C 6  alkyl)C(O)OR a , C(O)(C 0 -C 5  alkyl)NR a R b , C(O)(C 0 -C 5  alkyl)(C 1 -C 5  heterocyclyl), C(O)NR a (C 0 -C 5  alkyl)(C 1 -C 5  heterocyclyl), C(O)NR a (C 0 -C 5  alkyl)(C 3 -C 6 cycloalkyl), C(O)NR a (C 0 -C 5  alkyl)(C 1 -C 5  heteroaryl), C(O)NR a (C 1 -C 5  alkyl)NR a R b  or C(O)NR a (C 1 -C 5  alkyl)(C 6  aryl), wherein said alkyl, alkenyl and alkynyl are optionally substituted by 1 to 5 substituents independently selected from OR a , NR c R d , oxo and halo, and said aryl, heterocyclyl, heteroaryl and cycloalkyl are optionally substituted by 1 to 5 substituents independently selected from OR a , oxo, halo, CF 3 , NR c R d , C 1 -C 4  alkyl, (C 0 -C 6  alkyl)C 1 -C 5  heterocyclyl and C(O)(C 1 -C 4  alkyl); 
         R 7  is independently H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 0 -C 6  alkyl)OR a , (C 0 -C 6  alkyl)NR a R b , (C 0 -C 6  alkyl)(C 6 -C 9  aryl), halo, C(O)NR a R b , NR a C(O)R b , SO 2 (C 1 -C 6  alkyl), SO 2 NR a R b , CN, CF 3 , CH 2 CF 3 , nitro, S(O)(C 1 -C 6  alkyl), S(O)NR a R b , NR a S(O) 1-2 R b , C(O)R a , C(O)OR a , (C 0 -C 6  alkyl)C 1 -C 5  heteroaryl, (C 0 -C 6  alkyl)C 1 -C 5  heterocyclyl or (C 0 -C 6  alkyl)C 3 -C 6  cycloalkyl, wherein said alkyl, alkenyl and alkynyl are optionally substituted by 1 to 5 substituents independently selected from oxo, NR a R b , OR a , and halo, and said aryl, heteroaryl, heterocyclyl and cycloalkyl are optionally substituted by 1 to 5 substituents independently selected from OR a , halo, CF 3 , NR c R d  and C 1 -C 4  alkyl; 
         R a  and R b  are independently H, OR c , C(O)O(C 1 -C 6  alkyl), C 1 -C 6  alkyl, C 6  aryl or C 3 -C 6  cycloalkyl, wherein said alkyl, aryl and cycloalkyl are optionally substituted by 1 to 5 substituents independently selected from C 1 -C 4  alkyl, (C 0 -C 3  alkyl)OR c , oxo, halo, NR c R d  and C 4 -C 5  heterocyclyl; or 
         R a  and R b  together with the atom to which they are attached form a C 1 -C 5  heterocyclyl; and 
         R c  and R d  are independently H, C 1 -C 3  alkyl, C 3 -C 6  cycloalkyl or phenyl, wherein said alkyl, cycloalkyl and phenyl are optionally substituted by 1 to 5 substituents independently selected from halo, CH 3 OH or NH 2 , C(O)O(C 1 -C 6  alkyl) and C(O)NH(C 1 -C 6  alkyl). 
       
     
     
         2 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         3 . A pharmaceutical composition comprising a compound of  claim 1  in an amount to detectably inhibit JAK2 kinase activity and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         4 . A method of treating or lessening the severity of a disease or condition responsive to the inhibition of JAK2 kinase activity in a patient, comprising administering to said patient a therapeutically effective amount of a compound of  claim 1 . 
     
     
         5 . A kit for treating a disease or disorder responsive to the inhibition of a JAK kinase, comprising:
 (a) a first pharmaceutical composition comprising a compound of  claim 1 ; and   (b) instructions for use.   
     
     
         6 . A compound of  claim 1 , selected from a compound of Examples 1-312.