Mnk inhibitors and methods related thereto

Abstract

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R4b, R5, R6, R7, R8, W1, W2, Y and n are as defined herein. Also described are pharmaceutically acceptable compositions of Formula I compounds as well as methods for utilizing the compounds of Formula I and the pharmaceutically acceptable compositions of Formula I compounds as inhibitors of Mnk as well as therapeutics for the treatment of diseases such as cancer.

1 - 19 . (canceled) 
     
     
         20 . A method for treating a MnK dependent condition in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. 
       
     
     
         21 . The method of  claim 20  wherein the pharmaceutically acceptable salt is an organic or inorganic acid salt selected from the group consisting of acetate, mesylate, sulfate, citrate, oxalate, hydrochloride, dihydrochloride, isothionate, lactate, and laurate. 
     
     
         22 . The method of  claim 21  wherein the pharmaceutically acceptable salt is hydrochloride. 
     
     
         23 . The method of  claim 20  wherein the mammal is a human. 
     
     
         24 . A process for preparing a compound 5a 
       
         
           
           
               
               
           
         
         comprising: 
         (a) contacting a compound 1a 
       
       
         
           
           
               
               
           
         
         with an alcohol in the presence of an acid to obtain a compound 2a 
       
       
         
           
           
               
               
           
         
         (b) oxidizing a compound 2a to obtain a nitrone compound 3a 
       
       
         
           
           
               
               
           
         
         (c) contacting a compound 3a with trifluoroacetic anhydride to obtain a compound 4a 
       
       
         
           
           
               
               
           
         
         (d) subjecting a compound 4a to conditions suitable to amidate an ester to obtain a compound 5a 
       
       
         
           
           
               
               
           
         
         wherein: 
         X is halogen, -OTf, —B(OH) 2 , or —B(OR′) 2 ; 
         R 4a  is —H, halogen, —OH, —SH, hydroxyalkylene, —CN, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocycle; and 
         R′ and Y are each independently alkyl, cycloalkyl, aryl, heterocycle, or heteroaryl. 
       
     
     
         25 . The process according to  claim 24 , wherein R 4a  is alkyl. 
     
     
         26 . The process according to  claim 24 , wherein X is halogen. 
     
     
         27 . The process according to  claim 26 , wherein the halogen is bromine. 
     
     
         28 . The process according to  claim 24 , wherein Y is alkyl. 
     
     
         29 . The process according to  claim 24 , wherein in step (a) the acid is hydrochloric, sulfuric, or p-toluenesulfonic. 
     
     
         30 . The process according to  claim 24 , wherein in step (d) the conditions suitable to amidate an ester comprise contact with ammonia. 
     
     
         31 . A process for preparing a compound 9a 
       
         
           
           
               
               
           
         
         comprising: 
         (a) subjecting a compound 6a 
       
       
         
           
           
               
               
           
         
         to conditions suitable to add protecting groups to an amine to produce a compound 7a 
       
       
         
           
           
               
               
           
         
         (b) coupling a compound 7a with a compound R′ONH 2  in the presence of a metal catalyst, an inorganic base, and a phosphine ligand in a non-polar aprotic solvent to obtain a compound 8a 
       
       
         
           
           
               
               
           
         
         (c) subjecting a compound 8a to conditions suitable to remove the protecting groups from the amine to produce a compound 9a 
       
       
         
           
           
               
               
           
         
         
           wherein: 
         
         X is halogen, -OTf, —B(OH) 2 , or —B(OR′) 2 ; 
         R′ is alkyl, cycloalkyl, aryl, heterocycle, or heteroaryl; and 
         R″ is Fmoc, Boc, Cbz, Ac, TFA, Bn, Ts, or pthalamide. 
       
     
     
         32 . The process according to  claim 31 , wherein in step (b) the metal catalyst is a palladium catalyst, the inorganic base is Cs 2 CO 3 , and the phosphine ligand is xantphos. 
     
     
         33 . The process according to  claim 32 , wherein the palladium catalyst is Pd 2 (dba) 3  or Pd(OAc) 2 . 
     
     
         34 . The process according to  claim 32 , wherein the non-polar aprotic solvent is 1,4-dioxane. 
     
     
         35 . The process according to  claim 32 , wherein the reaction temperature is between 90° C. and 105° C. 
     
     
         36 . The process according to  claim 31 , wherein X is halogen. 
     
     
         37 . The process according to  claim 36 , wherein the halogen is chlorine. 
     
     
         38 . The process according to  claim 31 , wherein R′ is cycloalkyl. 
     
     
         39 . The process according to  claim 38 , where the cycloalkyl is cyclopropyl.