Alvocidib prodrugs having increased bioavailability

Abstract

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein one of R1, R2 or R3 is —P(═O)(OH)2, and the other two of R1, R2 and R3 are each H, are provided. Pharmaceutical compositions comprising the compounds, and methods for use of the compounds for treating diseases associated with overexpression of a cyclin-dependent kinase (CDK) are also provided.

1 - 23 . (canceled) 
     
     
         24 . A method for treating a solid tumor in a mammal in need thereof, the method comprising administering a therapeutically effective amount of a compound having the following structure: 
       
         
           
           
               
               
           
         
         or a tautomer or pharmaceutically acceptable salt thereof, to the mammal. 
       
     
     
         25 . The method of  claim 24 , comprising orally administering the compound, or a tautomer or pharmaceutically acceptable salt thereof, to the mammal. 
     
     
         26 . The method of  claim 24 , further comprising administering one or more additional therapeutic agents to the mammal. 
     
     
         27 . The method of  claim 24 , comprising administering to the mammal a therapeutically effective amount of the compound having the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method of  claim 24 , wherein the solid tumor is an adenocarcinoma of the breast, prostate or colon. 
     
     
         29 . The method of  claim 28 , wherein the adenocarcinoma is an adenocarcinoma of the breast. 
     
     
         30 . The method of  claim 28 , wherein the adenocarcinoma is an adenocarcinoma of the prostate. 
     
     
         31 . The method of  claim 28 , wherein the adenocarcinoma is an adenocarcinoma of the colon. 
     
     
         32 . The method of  claim 24 , wherein the solid tumor is cholangioma. 
     
     
         33 . A pharmaceutical dosage formulation comprising:
 a first pharmaceutical dosage formulation comprising a compound having the following structure:   
       
         
           
           
               
               
           
         
         or a tautomer or pharmaceutically acceptable salt thereof; and 
         a second pharmaceutical dosage formulation comprising another therapeutic agent. 
       
     
     
         34 . The pharmaceutical dosage formulation of  claim 33 , wherein the first pharmaceutical dosage formulation is formulated for oral delivery. 
     
     
         35 . The pharmaceutical dosage formulation of  claim 33 , wherein the first pharmaceutical dosage formulation comprises the compound having the following structure: