US2021330674A1PendingUtilityA1

Deuterated derivatives of ruxolitinib

74
Assignee: CONCERT PHARMACEUTICALS INCPriority: Jun 15, 2012Filed: Dec 10, 2020Published: Oct 28, 2021
Est. expiryJun 15, 2032(~5.9 yrs left)· nominal 20-yr term from priority
A61P 37/02C07D 487/04C07B 2200/05A61K 45/06A61K 31/7068A61K 31/5685A61K 31/454A61K 31/4045A61K 31/519A61P 35/02A61P 35/00
74
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Claims

Abstract

The present invention in one embodiment provides a compound of Formula A: or a pharmaceutically acceptable salt thereof; pharmaceutical compositions comprising the compound; and methods of treating the indications disclosed herein.

Claims

exact text as granted — not AI-modified
1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y 6 , Y 7  and Y 8  are each hydrogen, and the compound is selected from any one of the compounds set forth in the table below: 
       
       
         
           
                 
                 
                 
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Cmpd 
                   Y 1   
                   Each Y 2   
                   Each Y 3   
                   Y 4   
                   each Y 5   
                 
                     
                     
                 
                     
                   100 
                   H 
                   H 
                   H 
                   D 
                   H 
                 
                     
                   101 
                   H 
                   H 
                   H 
                   H 
                   D 
                 
                     
                   102 
                   H 
                   H 
                   H 
                   D 
                   D 
                 
                     
                   103 
                   H 
                   H 
                   D 
                   H 
                   H 
                 
                     
                   104 
                   H 
                   H 
                   D 
                   D 
                   H 
                 
                     
                   105 
                   H 
                   H 
                   D 
                   H 
                   D 
                 
                     
                   106 
                   H 
                   H 
                   D 
                   D 
                   D 
                 
                     
                   107 
                   H 
                   D 
                   H 
                   H 
                   H 
                 
                     
                   108 
                   H 
                   D 
                   H 
                   D 
                   H 
                 
                     
                   109 
                   H 
                   D 
                   H 
                   H 
                   D 
                 
                     
                   110 
                   H 
                   D 
                   H 
                   D 
                   D 
                 
                     
                   111 
                   H 
                   D 
                   D 
                   H 
                   H 
                 
                     
                   112 
                   H 
                   D 
                   D 
                   D 
                   H 
                 
                     
                   113 
                   H 
                   D 
                   D 
                   H 
                   D 
                 
                     
                   114 
                   H 
                   D 
                   D 
                   D 
                   D 
                 
                     
                   115 
                   D 
                   H 
                   H 
                   H 
                   H 
                 
                     
                   116 
                   D 
                   H 
                   H 
                   D 
                   H 
                 
                     
                   117 
                   D 
                   H 
                   H 
                   H 
                   D 
                 
                     
                   118 
                   D 
                   H 
                   H 
                   D 
                   D 
                 
                     
                   119 
                   D 
                   H 
                   D 
                   H 
                   H 
                 
                     
                   120 
                   D 
                   H 
                   D 
                   D 
                   H 
                 
                     
                   121 
                   D 
                   H 
                   D 
                   H 
                   D 
                 
                     
                   122 
                   D 
                   H 
                   D 
                   D 
                   D 
                 
                     
                   123 
                   D 
                   D 
                   H 
                   H 
                   H 
                 
                     
                   124 
                   D 
                   D 
                   H 
                   D 
                   H 
                 
                     
                   125 
                   D 
                   D 
                   H 
                   H 
                   D 
                 
                     
                   126 
                   D 
                   D 
                   H 
                   D 
                   D 
                 
                     
                   128 
                   D 
                   D 
                   D 
                   D 
                   H 
                 
                     
                   129 
                   D 
                   D 
                   D 
                   H 
                   D 
                 
                     
                   130 
                   D 
                   D 
                   D 
                   D 
                   D 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein any atom not designated as deuterium is present at its natural isotopic abundance. 
     
     
         2 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y 6 , Y 7  and Y 8  are each deuterium, and the compound is selected from any one of the compounds set forth in the table below: 
       
       
         
           
                 
                 
                 
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Cmpd 
                   Y 1   
                   Each Y 2   
                   Each Y 3   
                   Y 4   
                   each Y 5   
                 
                     
                     
                 
                     
                   200 
                   H 
                   H 
                   H 
                   D 
                   H 
                 
                     
                   201 
                   H 
                   H 
                   H 
                   H 
                   D 
                 
                     
                   202 
                   H 
                   H 
                   H 
                   D 
                   D 
                 
                     
                   203 
                   H 
                   H 
                   D 
                   H 
                   H 
                 
                     
                   204 
                   H 
                   H 
                   D 
                   D 
                   H 
                 
                     
                   205 
                   H 
                   H 
                   D 
                   H 
                   D 
                 
                     
                   206 
                   H 
                   H 
                   D 
                   D 
                   D 
                 
                     
                   207 
                   H 
                   D 
                   H 
                   H 
                   H 
                 
                     
                   208 
                   H 
                   D 
                   H 
                   D 
                   H 
                 
                     
                   209 
                   H 
                   D 
                   H 
                   H 
                   D 
                 
                     
                   210 
                   H 
                   D 
                   H 
                   D 
                   D 
                 
                     
                   211 
                   H 
                   D 
                   D 
                   H 
                   H 
                 
                     
                   212 
                   H 
                   D 
                   D 
                   D 
                   H 
                 
                     
                   213 
                   H 
                   D 
                   D 
                   H 
                   D 
                 
                     
                   214 
                   H 
                   D 
                   D 
                   D 
                   D 
                 
                     
                   215 
                   D 
                   H 
                   H 
                   H 
                   H 
                 
                     
                   216 
                   D 
                   H 
                   H 
                   D 
                   H 
                 
                     
                   217 
                   D 
                   H 
                   H 
                   H 
                   D 
                 
                     
                   218 
                   D 
                   H 
                   H 
                   D 
                   D 
                 
                     
                   219 
                   D 
                   H 
                   D 
                   H 
                   H 
                 
                     
                   220 
                   D 
                   H 
                   D 
                   D 
                   H 
                 
                     
                   221 
                   D 
                   H 
                   D 
                   H 
                   D 
                 
                     
                   222 
                   D 
                   H 
                   D 
                   D 
                   D 
                 
                     
                   223 
                   D 
                   D 
                   H 
                   H 
                   H 
                 
                     
                   224 
                   D 
                   D 
                   H 
                   D 
                   H 
                 
                     
                   225 
                   D 
                   D 
                   H 
                   H 
                   D 
                 
                     
                   226 
                   D 
                   D 
                   H 
                   D 
                   D 
                 
                     
                   227 
                   D 
                   D 
                   D 
                   H 
                   H 
                 
                     
                   228 
                   D 
                   D 
                   D 
                   D 
                   H 
                 
                     
                   229 
                   D 
                   D 
                   D 
                   H 
                   D 
                 
                     
                   230 
                   D 
                   D 
                   D 
                   D 
                   D 
                 
                     
                   231 
                   H 
                   H 
                   H 
                   H 
                   H 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein any atom not designated as deuterium is present at its natural isotopic abundance. 
     
     
         3 . A pharmaceutical composition comprising the compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         4 . A pharmaceutical composition comprising the compound of  claim 2 , and a pharmaceutically acceptable carrier. 
     
     
         5 . The composition of  claim 3  further comprising a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof 
     
     
         6 . A method of inhibiting the activity of one or more of JAK1 or JAK2, in a cell, comprising contacting such a cell with a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         7 . A method of treating myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin's lymphoma, multiple myeloma, psoriasis, or a combination thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of  claim 3 . 
     
     
         8 . The method of  claim 7 , wherein the myelofibrosis is primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, essential thrombocythemia or a combination thereof. 
     
     
         9 . The method of  claim 7 , further comprising administering to the subject in need thereof, a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof. 
     
     
         10 . The composition of  claim 4  further comprising a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof. 
     
     
         11 . A method of inhibiting the activity of one or more of JAK1 or JAK2, in a cell, comprising contacting such a cell with a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method of treating myelofibrosis, pancreatic cancer, prostate cancer, breast cancer, leukemia, non-Hodgkin's lymphoma, multiple myeloma, psoriasis, or a combination thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of  claim 4 . 
     
     
         13 . The method of  claim 12 , wherein the myelofibrosis is primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, essential thrombocythemia or a combination thereof. 
     
     
         14 . The method of  claim 12 , further comprising administering to the subject in need thereof, a therapeutic agent selected from lenalidomide, panobinostat, capecitabine, exemestane and combinations thereof.

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