Tricyclic degraders of ikaros and aiolos

Abstract

Tricyclic cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway for therapeutic applications are described.

We claim: 
     
         1 . A method of treating a human with multiple myeloma comprising administering an effective amount of a compound of Formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or composition thereof to the human in need thereof; 
       wherein:
 R 2  is independently selected at each occurrence from the group consisting of hydrogen, alkyl, and haloalkyl; 
 R 3  is hydrogen, halogen, alkyl, haloalkyl, —OR 8 , or NR 8 R 8′ ; 
 R 3′  is hydrogen; 
 R 7  is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxyl, cyano, nitro, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, —OR 8 , —NR 8 R 8′ , —C(O)R 8 , —C(O)OR 8 , —C(O)—NR 8 R 8′ , —OC(O)R 8 , —NR 2 —C(O)R 8 , —S(O)R 8 , —SO 2 R 8 , —SO 2 —OR 8 , and —SO 2 —NR 8 R 8′ ; 
 R 8  and R 8′  are independently selected at each occurrence from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl; and 
 each R 9  is independently selected from the group consisting of hydrogen and alkyl. 
 
     
     
         2 . The method of  claim 1 , wherein one R 7  is hydrogen. 
     
     
         3 . The method of  claim 1 , wherein two R 7 s are hydrogen. 
     
     
         4 . The method of  claim 3 , wherein the remaining R 7 s are independently selected at each occurrence from the group consisting of alkyl, halogen, and haloalkyl. 
     
     
         5 . The method of  claim 1 , wherein three R 7 s are hydrogen. 
     
     
         6 . The method of  claim 1 , wherein R 7  is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkene, alkyne, heterocycle, aryl, and heteroaryl. 
     
     
         7 . The method of  claim 1 , wherein R 7  is independently selected at each occurrence from the group consisting of hydrogen, alkyl, halogen, and haloalkyl. 
     
     
         8 . The method of  claim 1 , wherein R 7  is independently selected at each occurrence from the group consisting of hydrogen and halogen. 
     
     
         9 . The method of  claim 1 , wherein all R 7 s are hydrogen. 
     
     
         10 . The method of  claim 1 , wherein R 3  is hydrogen. 
     
     
         11 . The method of  claim 10 , wherein both R 9 s are hydrogen. 
     
     
         12 . The method of  claim 10 , wherein all R 7 s are hydrogen. 
     
     
         13 . The method of  claim 1 , wherein both R 9 s are hydrogen. 
     
     
         14 . The method of  claim 13 , wherein all R 7 s are hydrogen. 
     
     
         15 . The method of  claim 13 , wherein R 7  is independently selected at each occurrence from the group consisting of hydrogen, halogen, hydroxyl, alkyl, haloalkyl, alkene, alkyne, heterocycle, aryl, and heteroaryl. 
     
     
         16 . The method of  claim 13 , wherein R 7  is independently selected at each occurrence from the group consisting of hydrogen, alkyl, halogen, and haloalkyl. 
     
     
         17 . The method of  claim 13 , wherein R 7  is independently selected at each occurrence from the group consisting of hydrogen and halogen. 
     
     
         18 . The method of  claim 13 , wherein three R 7 s are hydrogen. 
     
     
         19 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 20 , wherein the compound is administered systematically. 
     
     
         22 . The method of  claim 20 , wherein the compound is administered orally. 
     
     
         23 . The method of  claim 20 , wherein the compound is administered parenterally. 
     
     
         24 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method of  claim 1 , wherein the compound is administered systematically. 
     
     
         26 . The method of  claim 1 , wherein the compound is administered orally. 
     
     
         27 . The method of  claim 1 , wherein the compound is administered parenterally.