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 - 63 . (canceled) 
     
     
         64 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 2C  is —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, or optionally substituted C 1-12  hydrocarbyl or 2-12-membered heterocarbyl, which optional substitution is with one or more with one or more amino, cyano, halo, hydroxyl, or R 2D ; and 
 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, or hydroxyl. 
 
     
     
         65 . The compound of  claim 64 , wherein R 2C  is —C(O)OR 2D . 
     
     
         66 . The compound of  claim 65 , wherein R 2D  is C 1-12  hydrocarbyl. 
     
     
         67 . The compound of  claim 65 , wherein R 2D  is 2-12-membered heterocarbyl. 
     
     
         68 . A compound, which compound is isopropyl 4-(3-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         69 . A compound, which compound is 2-methoxyethyl 4-(3-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         70 . A compound, which compound is 3-methyloxetan-3-yl 4-(3-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         71 . A pharmaceutical composition comprising a compound of  claim 64  and a pharmaceutically acceptable excipient or diluent. 
     
     
         72 . A method of inhibiting AAK1 activity, which comprises contacting AAK1 with a compound of  claim 64 . 
     
     
         73 . A method of treating or managing a disease or disorder mediated by AAK1 activity, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 64 . 
     
     
         74 . The method of  claim 73 , wherein the disease or disorder is Alzheimer's disease, bipolar disorder, pain, Parkinson's disease, or schizophrenia. 
     
     
         75 . The method of  claim 74 , wherein the pain is neuropathic pain. 
     
     
         76 . The method of  claim 75 , wherein the neuropathic pain is fibromyalgia or peripheral neuropathy. 
     
     
         77 . The method of  claim 76 , wherein the peripheral neuropathy is diabetic neuropathy.