Substituted isoindolinones
Substituted isoindolinones of Formula (I), methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to treat or ameliorate diseases, disorders, or conditions associated with protein malfunction, such as cancer, are provided.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH 2 or C═O;
R 1 is C 3 -C 8 cycloalkyl, optionally substituted with one or more R A ;
each of R 2 , R 5 , and R 6 is independently hydrogen, deuterium, halogen, hydroxy, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted N-sulfonamido, optionally substituted S-sulfoamido, C 1 -C 6 alkylamino, (amino)C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 4 -C 8 cycloalkenyl;
R 3 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl;
R 4 and R 7 are each independently hydrogen or C 1 -C 6 alkyl;
R 8 is H, deuterium, C 1 -C 6 alkyl,
each R A is independently deuterium, hydroxy, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, C 1 -C 6 alkylamino, (amino)C 1 -C 6 alkyl, —(C═O)NR 12a R 12b , —NR 12a (C═O)(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 4 -C 8 cycloalkenyl, or optionally substituted 3 to 7 membered heterocyclyl; or two geminal R A form oxo;
R 9a and R 9b are each independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
R 10a and R 10b are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 3 -C 8 carbocyclyl;
R 11a and R 11b are each independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 7 -C 14 aralkyl, or optionally substituted C 3 -C 8 carbocyclyl;
each R 12a and R 12b is independently H or C 1 -C 6 alkyl, or R 12a and R 12b together with the nitrogen atom to which they are attached form an optionally substituted 5 or 6 membered heterocyclyl optionally substituted with one or more R 13 ; and
each R 13 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted amino, halogen, or cyano; or two geminal R 13 form oxo.
2. The compound of claim 1 , wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl, each optionally substituted with one or more R A .
3. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH 2 or C═O;
R 1 is C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or two R A ; or C 1 -C 6 alkyl substituted with one or two R A ;
R 2 is halogen, hydroxy, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted N-sulfonamido, optionally substituted S-sulfoamido, C 1 -C 6 alkylamino, (amino)C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 4 -C 8 cycloalkenyl;
R 5 and R 6 are each independently hydrogen, deuterium, halogen, hydroxy, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted N-sulfonamido, optionally substituted S-sulfoamido, C 1 -C 6 alkylamino, (amino)C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 4 -C 8 cycloalkenyl;
R 3 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl;
R 4 and R 7 are each independently hydrogen or C 1 -C 6 alkyl;
R 8 is H, deuterium, C 1 -C 6 alkyl,
each R A is independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 7 cycloalkyl optionally substituted with one or more halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy;
R 9a and R 9b are each independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 7 -C 14 aralkyl, optionally substituted 3 to 10 membered heterocyclyl, or optionally substituted C 3 -C 8 carbocyclyl;
R 10a and R 10b are each independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 3 -C 8 carbocyclyl; and
R 11a and R 11b are each independently H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 7 -C 14 aralkyl, or optionally substituted C 3 -C 8 carbocyclyl.
4. The compound of claim 3 , wherein R 1 is
5. The compound of claim 3 , wherein R 1 is —CH 2 F, —CHF 2 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH(CH 3 )CF 3 , or —CH(CH 2 CH 3 )CF 3 .
6. The compound of claim 1 , wherein R 2 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 3 haloalkyl.
7. The compound of claim 6 , wherein R 2 is hydrogen, fluoro, chloro, methyl, trifluoromethyl, or methoxy.
8. The compound of claim 1 , wherein R 3 is hydrogen, deuterium, fluoro, methyl, or ethyl.
9. The compound of claim 1 , wherein R 4 is hydrogen or methyl.
10. The compound of claim 1 , wherein R 5 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 3 haloalkyl.
11. The compound of claim 1 , wherein R 6 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 3 haloalkyl.
12. The compound of claim 11 , wherein R 6 is hydrogen, fluoro, chloro, methyl, trifluoromethyl, or methoxy.
13. The compound of claim 1 , wherein R 7 is hydrogen.
14. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is CH 2 or C═O;
R 1 is C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, or 3 to 10 membered heterocyclyl, each optionally substituted with one or more R A ; or C 1 -C 6 alkyl substituted with one or more R A ;
each of R 2 , R 5 , and R 6 is independently hydrogen, deuterium, halogen, hydroxy, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted N-sulfonamido, optionally substituted S-sulfoamido, C 1 -C 6 alkylamino, (amino)C 1 -C 6 alkyl, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 4 -C 8 cycloalkenyl;
R 3 is hydrogen, deuterium, halogen, or C 1 -C 6 alkyl;
R 4 and R 7 are each independently hydrogen or C 1 -C 6 alkyl;
R 8 is
each R A is independently deuterium, hydroxy, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, optionally substituted amino, C 1 -C 6 alkylamino, (amino)C 1 -C 6 alkyl, —(C═O)NR 12a R 12b , —NR 12a (C═O)(C 1 -C 6 alkyl), (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 4 -C 8 cycloalkenyl, or optionally substituted 3 to 7 membered heterocyclyl; or two geminal R A form oxo;
R 9a and R 9b are each independently H or C 1 -C 6 alkyl;
R 10a , R 10b , R 11a , and R 11b are each independently hydrogen or C 1 -C 6 alkyl;
each R 12a and R 12b is independently H or C 1 -C 6 alkyl, or R 12a and R 12b together with the nitrogen atom to which they are attached form an optionally substituted 5 or 6 membered heterocyclyl optionally substituted with one or more R 13 ; and
each R 13 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, —O—(C 1 -C 6 alkoxy)C 1 -C 6 alkyl, optionally substituted amino, halogen, or cyano; or two geminal R 13 form oxo.
15. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.
17. The compound of claim 3 , wherein R 1 is C 3 -C 8 cycloalkyl or C 4 -C 8 cycloalkenyl, each optionally substituted with one or two R A .
18. The compound of claim 17 , wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl, each optionally substituted with one or two R A .
19. The compound of claim 17 , wherein R 1 is cyclopentenyl, cyclohexenyl, or cycloheptenyl, each optionally substituted with one or two R A .
20. The compound of claim 3 , wherein R 2 is halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 3 haloalkyl.
21. The compound of claim 20 , wherein R 2 is fluoro, chloro, methyl, trifluoromethyl, or methoxy.
22. The compound of claim 3 , wherein R 3 is hydrogen, deuterium, fluoro, methyl, or ethyl.
23. The compound of claim 3 , wherein R 4 is hydrogen or methyl.
24. The compound of claim 3 , wherein R 5 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 3 haloalkyl.
25. The compound of claim 3 , wherein R 6 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 3 haloalkyl.
26. The compound of claim 25 , wherein R 6 is hydrogen, fluoro, chloro, methyl, trifluoromethyl, or methoxy.
27. The compound of claim 3 , wherein R 7 is hydrogen.
28. The compound of claim 14 , wherein R 1 is C 3 -C 8 cycloalkyl, each optionally substituted with one or more R A .
29. The compound of claim 28 , wherein R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl, each optionally substituted with one or more R A .
30. The compound of claim 1 , wherein X is CH 2 .
31. The compound of claim 3 , wherein R 2 is fluoro.
32. The compound of claim 3 , wherein R 1 is C 1 -C 6 alkyl substituted with one or two R A .
33. The compound of claim 3 , wherein R 1 is C 2 -C 4 alkyl substituted with methyl.
34. The compound of claim 3 , having the structure of Formula (Ic):
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 34 , wherein R 1 is C 2 -C 4 alkyl substituted with methyl.
36. The compound of claim 3 , wherein the compound is
or a pharmaceutically acceptable salt thereof.