Modulators of pharmacokinetic properties of therapeutics

Abstract

The present application provides for a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods and include the administration of such compounds with at least one additional therapeutic agent.

1 - 20 . (canceled) 
     
     
         21 . An in vivo metabolic product of a compound Formula IB: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 L 2  is a covalent bond, —C(R 6 ) 2 , or —C(O)—; 
 Z 1  is —O— or —N(R 7 )—; 
 R 6  is selected from H, alkyl, substituted alkyl, and heteroalkyl; 
 R 7  is selected from H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; and 
 R 8  and R 9  are each independently selected from H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN. 
 
     
     
         22 . The metabolic product of  claim 21  which is substantially isolated. 
     
     
         23 . A method of preparing the in vivo metabolic product of  claim 21  comprising contacting the compound of Formula IB with a mammal for a period of time sufficient to yield the in vivo metabolic product. 
     
     
         24 . The method of  claim 23  wherein the mammal is a rat, mouse, guinea pig, monkey, or human. 
     
     
         25 . The method of  claim 23  wherein the compound of Formula B is orally administered to the mammal. 
     
     
         26 . The method of  claim 23  wherein the compound of Formula IB is radiolabeled. 
     
     
         27 . The method of  claim 26  wherein the radiolabel comprises C 14  or H 3 . 
     
     
         28 . A method of determining the optimal therapeutic dose of a compound of Formula B in a mammal comprising measuring the quantity of the in vivo metabolic product of  claim 21  produced upon contacting the mammal with a radiolabeled compound of Formula IB and correlating the measured quantity of the in vivo metabolic product with therapeutic effectiveness of the compound of Formula IB. 
     
     
         29 . A prodrug of a compound Formula TB: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 L 2  is a covalent bond, —C(R 6 ) 2 , or —C(O)—; 
 Z 1  is —O— or —N(R 7 )—; 
 R 6  is selected from H, alkyl, substituted alkyl, and heteroalkyl; 
 R 7  is selected from H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; and 
 R 8  and R 9  are each independently selected from H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN. 
 
     
     
         30 . The prodrug of  claim 29  which is an ester of a compound of Formula IB. 
     
     
         31 . A pharmaceutical composition comprising the prodrug of  claim 29 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         32 . A method of improving the pharmacokinetics of a drug, comprising administering to a patient treated with said drug, a therapeutically effective amount of a prodrug of  claim 29 , or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A solvate of a compound of Formula TB: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 L 2  is a covalent bond, —C(R 6 ) 2 , or —C(O)—; 
 Z 1  is —O— or —N(R 7 )—; 
 R 6  is selected from H, alkyl, substituted alkyl, and heteroalkyl; 
 R 7  is selected from H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; and 
 R 8  and R 9  are each independently selected from H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN. 
 
     
     
         34 . A pharmaceutical composition comprising the solvate of  claim 33 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. 
     
     
         35 . A method of improving the pharmacokinetics of a drug, comprising administering to a patient treated with said drug, a therapeutically effective amount of a solvate of  claim 33 , or a pharmaceutically acceptable salt thereof.