PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE

Abstract

Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R 1 , R 2 and R 3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.

1 - 24 . (canceled) 
     
     
         25 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is cyclic C 1-12  hydrocarbyl or 4-7-membered heterocycle; 
 D is cyclic C 1-12  hydrocarbyl or 4-7-membered heterocycle bound to C5 by one of its carbon atoms; 
 each R 1A  is independently —OR 1C , —N(R 1C ) 2 , —C(O)R 1C , —C(O)OR 1C , —C(O)N(R 1C ) 2 , —N(R 1C )C(O)OR 1C , cyano, halo, or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more R 1B ; 
 each R 1B  is independently —OR 1C , —N(R 1C ) 2 , —C(O)R 1C , —C(O)OR 1C , —C(O)N(R 1C ) 2 , —N(R 1C )C(O)OR 1C , cyano or halo; 
 each R 1C  is independently hydrogen or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more of cyano, halo or hydroxyl; 
 each R 2C  is independently —OR 2D , —N(R 2D ) 2 , —C(O)R 2D , —C(O)OR 2D , —C(O)N(R 2D ) 2 , —N(R 2D )C(O)OR 2D , cyano, halo, oxo, or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more amino, cyano, halo, hydroxyl, or R 2D ; 
 each R 2D  is independently hydrogen or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more of amino, cyano, halo, hydroxyl; 
 n is 1-3; and 
 m is 0-3. 
 
     
     
         26 . (canceled) 
     
     
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         29 . (canceled) 
     
     
         30 . The compound of  claim 25 , which is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein X is CH or N. 
     
     
         31 . The compound of  claim 30 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 30 , which is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 2C  is —C(O)R 2D , —C(O)OR 2D , or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more amino, cyano, halo, hydroxyl, or R 2D . 
     
     
         33 . The compound of  claim 30 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 30 , which is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 2C  is —C(O)R 2D , —C(O)OR 2D , or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more amino, cyano, halo, hydroxyl, or R 2D . 
     
     
         35 . The compound of  claim 25 , wherein X is N and m is 1 or 2 
     
     
         36 . The compound of  claim 34 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 36 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 37 , which is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 25 , wherein at least one R 1A  is halo. 
     
     
         40 . The compound of  claim 25 , wherein at least one R 1A  is —OR 1C . 
     
     
         41 . The compound of  claim 40 , wherein R 1C  is optionally substituted C 1-12  hydrocarbyl. 
     
     
         42 . The compound of  claim 25 , wherein R 2C  is optionally substituted C 1-6  hydrocarbyl. 
     
     
         43 . The compound of  claim 25 , wherein each R 2D  is independently hydrogen or C 1-12  hydrocarbyl. 
     
     
         44 . The compound of  claim 25 , wherein at least one R 2D  is optionally substituted C 1-12  hydrocarbyl, which optional substitution is with one or more of amino, cyano, halo, hydroxyl. 
     
     
         45 . The compound of  claim 25 , wherein R 2D  is 2-12-membered heterocarbyl comprising at least one nitrogen atom. 
     
     
         46 - 51 . (canceled)