Imidazotetrazine compounds

Abstract

New synthetic methods to provide access to previously unexplored functionality at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 hours), a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent was derived. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a salt thereof; 
         wherein
 X is O or S; 
 R 1  is halo, —CN, —NO 2 , —(C 1 -C 6 )alkyl, —C(═O)R a , phenyl, or a 5- or 6-membered heterocycle, wherein R a  is H, halo, —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, OR b , SR b , or —NR b R c ; wherein
 R b  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 R c  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; or 
 when R a  is —NR b R c , Rb and R c  taken together optionally forms a heterocycle; 
 
 R 2  is —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, propargyl, phenyl, or a 5- or 6-membered heterocycle; and 
 R 3  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 
         wherein each —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, propargyl, phenyl, and 5- or 6-membered heterocycle are optionally substituted with one or more substituents, and each —(C 1 -C 6 )alkyl is unbranched or optionally branched. 
       
     
     
         2 . The compound of  claim 1  wherein R 1  is halo, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl. 
     
     
         3 . The compound of  claim 1  wherein R 1  is —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—NH(C 1 -C 6 )alkyl, or —C(═O)—N[(C 1 -C 6 )alkyl] 2 . 
     
     
         4 . The compound of  claim 1  wherein R 1  is a moiety of Formula IB: 
       
         
           
           
               
               
           
         
       
       wherein
 W is O, S, or NR d ; wherein R d  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 V is N or CR, wherein R X  is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; 
 Y is N or CR Y , wherein R is H, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl; and Z is N or CH. 
 
     
     
         5 . The compound of  claim 4  wherein R 1  is i, ii, or iii: 
       
         
           
           
               
               
           
         
         wherein (i), (ii) and (iii) are optionally substituted at position 4 or 5. 
       
     
     
         6 . The compound of  claim 1  wherein R 1  is a para-substituted phenyl. 
     
     
         7 . The compound of  claim 6  wherein the para-substituent is halo, —CN, —CF 3 , —CF 2 CF 3 , or —(C 1 -C 6 )alkyl. 
     
     
         8 . The compound of  claim 1  wherein X is O, R 3  is H and R 1  is —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—NH(C 1 -C 6 )alkyl, or —C(═O)—N[(C 1 -C 6 )alkyl] 2 . 
     
     
         9 . The compound of  claim 1  wherein X is O and R is —C(═O)—(C 1 -C 6 )alkyl. 
     
     
         10 . The compound of  claim 1  wherein X is O, R 2  is —(C 1 -C 6 )alkyl, and R 3  is H. 
     
     
         11 . The compound of  claim 1  wherein R 2  is —(C 1 -C 6 )alkyl and R 3  is H. 
     
     
         12 . The compound of  claim 1  wherein R 2  is propargyl or a substituted phenyl. 
     
     
         13 . The compound of  claim 12  wherein the substituted phenyl is substituted with halo, alkyl, alkoxy, phenoxy, dialkylamine, or combination thereof. 
     
     
         14 . The compound of  claim 1  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1  wherein the compound of Formula I is a compound of Formula IC: 
       
         
           
           
               
               
           
         
         wherein G 1  is OCH 3 , OCH 2 CH 3 , OPh, or N(CH 3 ) 2 . 
       
     
     
         16 . The compound of  claim 1  wherein the compound of Formula I is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 16  wherein R 2  is —(C 1 -C 6 )alkyl and R 3  is H. 
     
     
         18 . The compound of  claim 16  wherein R a  is CH 3 , CH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , N(CH 2 CH 2 CH 3 ) 2 , N(CH 2 CH 2 CH 2 CH 3 ) 2 , N(CH 2 CH 2 ) 2 , N[(CH 2 CH 2 ) 2 ], OCH 3 , OCH 2 CH 3 , SCH 3 , or SCH 2 CH 3 . 
     
     
         19 . The compound of  claim 18  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 16  wherein the compound is K-TMZ: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 1  wherein the compound of Formula I is a compound of Formula IIIA or IIIB: 
       
         
           
           
               
               
           
         
         wherein R Z  is H, halo, —(C 1 -C 6 )alkyl, or —(C 3 -C 6 )cycloalkyl. 
       
     
     
         22 . The compound of  claim 21  wherein R is CH 3  or CH 2 CH 3 . 
     
     
         23 . The compound of  claim 21  wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         24 . A method of treating a cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , wherein the cancer is thereby treated. 
     
     
         25 . The method of  claim 20  wherein the cancer is glioblastoma (GBM).