TRICYCLIC DEGRADERS OF IKAROS AND AIOLOS
Tricyclic cereblon binders for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway for therapeutic applications are described.
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.