Aziridine containing dna alkylating agents

Abstract

Provided herein are compounds of formula (I)-(VI), wherein the variables are defined herein, processes of making them, and methods of treating cancer comprising administering such compounds.

1 . A compound selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of each thereof, wherein
 R 1  is: hydrogen, —N 3 , CN, halo, NR 21 R 22 , —OR 23 , —SO 2 (C 1 -C 6  alkyl), C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether; 
 each R 21  and R 22  independently is hydrogen, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or —SO 2 (C 1 -C 6  alkyl); or R 21  and R 22  together with the nitrogen atom they are bonded to form a 4-15 membered heterocycle or a 5-15 membered heteroaryl; 
 R 23  is hydrogen, C 1 -C 6  alkyl, or C 6 -C 10  aryl; 
 R 2  and R 3  are independently hydrogen or halo; 
 R 4  is hydrogen, halo, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, or C 6 -C 10  aryl, 
 R 5 , R 7 , R 9 , R 12 , and R 15  independently are hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl; or R 4  and R 5  together with the intervening carbon atoms between them form a C 5 -C 6  cycloalkyl ring; 
 R 6  and R 10  independently are hydrogen or halo; 
 R 8  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or 5-15 membered heteroaryl; 
 each R 11  independently is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or C 6 -C 10  aryl; 
 R 13 , R 14 , R 16 , and R 17  are independently hydrogen, halo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkyny, or C 1 -C 6  alkoxy; 
 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy and ether groups are optionally substituted. 
 
     
     
         2 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2 , wherein R 1  is a non-hydrogen substituent, R 2  and R 3  are hydrogen, and R 4  is hydrogen or halo, or R 4  and R 5  together form a 5 membered cycloalkyl group. 
     
     
         4 . The compound of  claim 3 , wherein R 4  is hydrogen. 
     
     
         5 . The compound of  claim 3 , wherein R 4  is halo. 
     
     
         6 . The compound of  claim 3 , wherein R 4  is fluoro. 
     
     
         7 . The compound of  claim 3 , wherein R 1  is NR 21 R 22 , wherein each R 21  and R 22  independently is hydrogen, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 10  aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or —SO 2 (C 1 -C 6  alkyl); or R 21  and R 22  together with the nitrogen atom they are bonded to form a 4-15 membered heterocycle or a 5-15 membered heteroaryl. 
     
     
         8 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 8 , wherein R 8  is hydrogen. 
     
     
         14 . The compound of  claim 8 , wherein R 8  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     
     
         15 . The compound of  8 , wherein R 9  is optionally substituted C 1 -C 6  alkyl. 
     
     
         16 . The compound of  claim 9 , wherein R 7  is optionally substituted C 1 -C 6  alkyl. 
     
     
         17 . The compound of  claim 10 , wherein R 12  is optionally substituted C 1 -C 6  alkyl. 
     
     
         18 . The compound of  claim 11 , wherein R 15  is optionally substituted C 1 -C 6  alkyl. 
     
     
         19 . The compound of  claim 3 , wherein R 5  is a non-hydrogen substituent. 
     
     
         20 . The compound of  claim 3 , wherein R 1  is a non-hydrogen substituent; R 2  and R 3  are hydrogen, and R 4  is hydrogen or halo, and R 5  is optionally substituted C 1 -C 6  alkyl. 
     
     
         21 . A pharmaceutical composition comprising the compound of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         22 . A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of  claim 1 .