METHODS AND COMPOUNDS FOR RESTORING MUTANT p53 FUNCTION

Abstract

Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The present disclosure describes compounds and methods to recover wild-type function to p53 mutants. The compounds of the present disclosure can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA and activate downstream effectors involved in tumor suppression. The disclosed compounds can be used to reduce the progression of cancers that contain a p53 mutation.

1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 each   is independently a single bond or a double bond; 
 X 1  is CR 5 , CR 5 R 6 , N, NR 5 , O, S, C═O, C═S, or a carbon atom connected to Q 1 ; 
 X 2  is CR 7 , CR 7 R 8 , N, NR 7 , O, S, C═O, C═S, or a carbon atom connected to Q 1 ; 
 X 3  is CR 9 , CR 9 R 10 , N, NR 9 , O, S, C═O, C═S, or a carbon atom connected to Q 1 ; 
 X 4  is CR 11 , CR 11 R 12 , N, NR 11 , O, S, C═O, C═S, or a carbon atom connected to Q 1 ; 
 X 5  is CR 13 , N, or NR 13 ; 
 
       wherein at least one of X 1 , X 2 , X 3 , and X 4  is a carbon atom connected to Q 1 ;
 A is a substituted or unsubstituted ring; 
 Q 1  is C═O, C═S, C≡CR 14 R 15 , C≡NR 14 , alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted, or a bond; 
 m is 1, 2, 3, or 4; 
 Y is N, O, or absent; 
 R 1  is —C(O)R 16 , —C(O)OR 16 , —C(O)NR 16 R 17 , —OR 16 , —SR 16 , —NR 16 R 17 , —NR 16 C(O)R 16 , —OC(O)R 16 , —SiR 16 R 17 R 18 , alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, or halo, each of which is independently substituted or unsubstituted, or hydrogen; 
 each R 3  and R 4  is independently —C(O)R 19 , —C(O)OR 19 , —C(O)NR 19 R 20 , —SOR 19 , —SO 2 R 19 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, or R 3  and R 4  together with the nitrogen atom to which R 3  and R 4  are bound form a ring, wherein the ring is substituted or unsubstituted, or R 3  is absent; 
 each R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18  is independently —C(O)R 21 , —C(O)OR 21 , —C(O)NR 21 R 22 , —OR 21 , —SR 21 , —NR 21 R 22 , —NR 21 C(O)R 22 , —OC(O)R 21 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; 
 each R 19  and R 20  is independently —C(O)R 23 , —C(O)OR 23 , —C(O)NR 23 R 24 , —OR 23 , —SR 23 , —NR 23 R 24 , —NR 23 C(O)R 24 , —OC(O)R 23 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; 
 each R 21  and R 22  is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen; and 
 each R 23  and R 24  is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, or a pharmaceutically-acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1 , wherein A is substituted or unsubstituted aryl, heteroaryl, heterocyclyl, cycloalkylene. 
     
     
         3 . The compound of  claim 1 , wherein A is substituted aryl. 
     
     
         4 . The compound of  claim 3 , wherein A is substituted phenyl. 
     
     
         5 . The compound of  claim 4 , wherein A is phenyl substituted with alkyl, cycloalkyl, alkoxy, an amine group, a carboxyl group, a carboxylic acid group, a carbamide group, or an amide group, each of which is substituted or unsubstituted; cyano, halo-, or hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein A is substituted heteroaryl. 
     
     
         7 . The compound of  claim 1 , wherein A is an unsubstituted or substituted aromatic 5-membered, 6-membered, 7-membered, or 8-membered monocyclic ring system comprising 1, 2, or 3 heteroatoms as ring members, wherein each heteroatom is independently selected from O, N, or S. 
     
     
         8 . The compound of  claim 7 , wherein A is pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, pyrazolyl, thiophenyl, or oxadiazolyl, each of which is independently substituted or unsubstituted. 
     
     
         9 . The compound of  claim 8 , wherein A is 1,3,5-thiadiazol-2-yl. 
     
     
         10 . The compound of  claim 8 , wherein A is 1,3,4-oxadiazol-2-yl or 1,2,4-oxadiazol-2-yl. 
     
     
         11 . The compound of  claim 8 , wherein A is pyridinyl. 
     
     
         12 . The compound of  claim 8 , wherein A is an unsubstituted or substituted aromatic 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic ring system comprising 1, 2, 3, 4, 5, or 6 heteroatoms, wherein each heteroatom is independently selected from O, N, or S. 
     
     
         13 . The compound of  claim 1 , wherein m is 1. 
     
     
         14 . The compound of  claim 1 , wherein Q 1  is alkylene, alkenylene, or alkynylene, each of which is independently substituted or unsubstituted, or a bond. 
     
     
         15 . The compound of  claim 14 , wherein Q 1  is a bond. 
     
     
         16 . The compound of  claim 1 , wherein Y is N. 
     
     
         17 . The compound of  claim 1 , wherein R 2  is hydrogen. 
     
     
         18 . The compound of  claim 1 , wherein R 2  is substituted or unsubstituted alkyl. 
     
     
         19 . The compound of  claim 18 , wherein R 2  is trifluoroethyl. 
     
     
         20 . The compound of  claim 18 , wherein R 2  is cycloalkyl. 
     
     
         21 - 33 . (canceled)