Small molecule mdm2 protein degraders

Abstract

The present disclosure provides compounds represented by Formula I: wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4 , A, L, X, Y, and Z are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat cancer or any other disease, condition, or disorder that is responsive to degradation of MDM2 protein.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1a  and R 1b  are independently selected from the group consisting of hydrogen, fluoro, and chloro; 
         R 2a  and R 2b  are independently selected from the group consisting of hydrogen, fluoro, and chloro; 
         R 3a  and R 3b  taken together with the carbon atom to which they are attached form a cyclobutyl, cyclopentyl, or cyclohexyl group that is unsubstituted or substituted with one or two methyl groups; 
         R 4  is selected from the group consisting of hydrogen, methyl, and ethyl; 
         X is 
       
       
         
           
           
               
               
           
         
         wherein the bond projecting to the right is attached to —C(═O)—Y-L-Z-A; 
         each R 5  is independently selected from the group consisting of hydrogen and methyl; 
         R 6  is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and methoxy; 
         Y is —N(H)—; 
         wherein the bond projecting to the right is attached to -L-Z-A; 
         L is selected from the group consisting of —(CH 2 ) m  and —(CH 2 CH 2 O) n — 
         m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 
         n is 2, 3, 4, 5, or 6; 
         Z is absent; 
         A is 
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt or solvate thereof. 
         
       
     
     
         2 . The compound of  claim 1  selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein the pharmaceutically acceptable salt is the ethane-1,2-disulfonic acid salt or the naphthalene-1,5-disulfonic acid salt. 
     
     
         4 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. 
     
     
         5 . A method of treating a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein the subject has cancer. 
     
     
         6 . The method of  claim 5 , wherein the cancer is any one or more of the cancers of Table 2. 
     
     
         7 . The method of  claim 5 , wherein the cancer is a hematological cancer. 
     
     
         8 . The method of  claim 7 , wherein the hematological cancer is any one or more of the cancers of Table 3. 
     
     
         9 . A kit comprising the compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject having cancer. 
     
     
         10 . A method of treating a subject having cancer comprising:
 (a) determining whether an overexpression of MDM2 is present or absent in a biological sample taken from the subject; and   (b) administering a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to the subject if an overexpression of MDM2 is present in the biological sample.   
     
     
         11 . A method, comprising administering a therapeutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to a subject in need thereof, wherein:
 (a) the subject has cancer; and   (b) the cancer is characterized as having an overexpression of MDM2.   
     
     
         12 . The method of  claim 7 , wherein the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia, or acute myeloid leukemia.