Substituted isoindolinones

Patent metadata

Field	Value
Publication number	US-10844039-B2
Application number	US-201916681180-A
Country	US
Kind code	B2
Filing date	Nov 12, 2019
Priority date	Nov 13, 2018
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

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.

First claim

What is claimed is:

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, ea

Assignees

• Biotheryx Inc

Inventors

• Chan Kyle W H
• Chourasia Aparajita Hoskote
• Erdman Paul E
• Fung Leah
• Lam Imelda
• Mercurio Frank
• Sullivan Robert
• Torres Eduardo

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title