Substituted 4-aminoisoindoline-1,3-dione compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11358952-B2
Application number	US-201916390815-A
Country	US
Kind code	B2
Filing date	Apr 22, 2019
Priority date	Apr 23, 2018
Publication date	Jun 14, 2022
Grant date	Jun 14, 2022

Abstract

Provided herein are 4-aminoisoindoline-1,3-dione compounds having the following structure:wherein R, Ring A, and n are as defined herein, compositions comprising an effective amount of a 4-aminoisoindoline-1,3-dione compound, and methods for treating or preventing disorders.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein:
Ring A is a piperazinyl optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, OR 1 , CON(R 2 ) 2 , SO 2 (C 1-4 alkyl), N(R 2 )SO 2 (C 1-4 alkyl), —(C 0-3 alkyl)-(C 3-7 cycloalkyl), (non-aromatic heterocyclyl), aryl, heteroaryl, O-aryl, O-heteroaryl, and C(O)aryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with one or more substituents independently selected from halogen, alkyl optionally substituted with one or more of halogen, oxo, amido, and cyano; wherein R 1 is H, C 1-6 alkyl optionally substituted with one or more of halogen, or —(C 0-3 alkyl)-(C 3-7 cycloalkyl); and each R 2 is independently H, or C 1-6 alkyl;
each R is independently C 1-3 alkyl optionally substituted with one or more of halogen, or halogen; and
n is 0, 1, 2, 3 or 4.

2. The compound of claim 1 , wherein the compound is a compound of formula (II):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

3. The compound of claim 1 , wherein the compound is a compound of formula (III):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

4. The compound of claim 1 , wherein the compound is a compound of formula (IV):

or a pharmaceutically acceptable salt or tautomer thereof.

5. The compound of claim 4 , wherein the compound is a compound of formula (V):

or a pharmaceutically acceptable salt or tautomer thereof.

6. The compound of claim 4 , wherein the compound is a compound of formula (VI):

or a pharmaceutically acceptable salt or tautomer thereof.

7. The compound of claim 1 , wherein the compound is a compound of formula (VII):

or a pharmaceutically acceptable salt or tautomer thereof.

8. The compound of claim 7 , wherein the compound is a compound of formula (VIII):

or a pharmaceutically acceptable salt or tautomer thereof.

9. The compound of claim 7 , wherein the compound is a compound of formula (IX):

or a pharmaceutically acceptable salt or tautomer thereof.

10. The compound of claim 1 , wherein Ring A is

wherein R e is C 1-6 alkyl, SO 2 (C 1-4 alkyl), —(C 0-3 alkyl)-(C 3-7 cycloalkyl), aryl, heteroaryl or CO-aryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl are optionally substituted with one or more substituents independently selected from halogen, alkyl optionally substituted with one or more of halogen, oxo, amido, and cyano.

11. The compound of claim 1 , wherein Ring A is substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, OR 1 , CON(R 2 ) 2 , SO 2 (C 1-4 alkyl), N(R 2 )SO 2 (C 1-4 alkyl), —(C 0-3 alkyl)-(C 3-7 cycloalkyl), (non-aromatic heterocyclyl), aryl, heteroaryl, O-aryl, O-heteroaryl, and C(O)aryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with one or more substituents independently selected from halogen, alkyl optionally substituted with one or more of halogen, oxo, amido, and cyano; wherein R 1 is H, C 1-6 alkyl optionally substituted with one or more of halogen, or —(C 0-3 alkyl)-(C 3-7 cycloalkyl); and each R 2 is independently H, or C 1-6 alkyl.

12. The compound of claim 1 , wherein Ring A is substituted with one or more substituents independently selected from F, Cl, Br, CH 3 , CH 2 CH 3 , n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , CH(CH 3 )CF 3 , CH 2 CH 2 CF 3 , OH, OCH 3 , OCH 2 CH 3 , O-isopropyl, O-n-propyl, O-n-butyl, O-isobutyl, O-t-butyl, OCF 3 , O-cyclopropyl, O-cyclobutyl, OCH 2 -cyclopropyl, OCH 2 -cyclobutyl, CONH 2 , CONH(CH 3 ), CON(CH 3 ) 2 , SO 2 CH 3 , SO 2 CH 2 CH 3 , SO 2 -isopropyl, cyclopropyl, cyclobutyl, CH 2 -cyclopropyl, CH 2 -cyclobutyl; (non-aromatic heterocyclyl) selected from azetidyl, pyrrolidyl, pyrrolidonyl, isothiazolidyl, isothiazolidine 1,1-dioxidyl, piperidyl, piperazinyl, morpholinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from CH 3 , CH 2 CH 3 , or CF 3 ; phenyl, 0-phenyl or C(O)-phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH 3 , CN, or CONH 2 ; heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, or benzoisoxazolyl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from F, Cl, CF 3 , CN, CONH 2 , CONH(CH 3 ) or CON(CH 3 ) 2 ; O-pyridyl, and O-pyrimidyl.

13. The compound of claim 1 , wherein Ring A is substituted with one or more substituents independently selected from F, CH 3 , CH 2 CH 3 , isopropyl, t-butyl, CH 2 F, CF 3 , CH(CH 3 )CF 3 , OH, OCH 3 , OCH 2 CH 3 , O-isopropyl, O-n-propyl, O-isobutyl, O-t-butyl, OCF 3 , O-cyclobutyl, OCH 2 -cyclopropyl, CON(CH 3 ) 2 , SO 2 CH 2 CH 3 , SO 2 -isopropyl, cyclopropyl, cyclobutyl, CH 2 -cyclopropyl; (non-aromatic heterocyclyl) selected from pyrrolidyl, pyrrolidonyl, isothiazolidine 1,1-dioxidyl, morpholinyl, 3-oxa-8-azabicyclo[3.2.1]octyl, or 8-oxa-3-azabicyclo[3.2.1]octyl, wherein the heterocyclyl is optionally substituted with one or more CH 3 ; phenyl, O-phenyl or C(O)-phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH 3 , CN, or CONH 2 ; heteroaryl selected from pyrazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidyl or benzoisoxazolyl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from F, Cl, CF 3 , CN, CONH 2 , CON(CH 3 ) 2 ; O-pyridyl, and O-pyrimidyl.

14. The compound of claim 1 , wherein Ring A is piperazinyl, substituted with one or more substituents independently selected from C 1-6 alkyl, SO 2 (C 1-4 alkyl), —(C 0-3 alkyl)-(C 3-7 cycloalkyl), aryl, heteroaryl and CO-aryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl are optionally substituted with one or more substituents independently selected from halogen, alkyl optionally substituted with one or more of halogen, oxo, amido, and cyano.

15. The compound of claim 1 , wherein Ring A is piperazinyl, substituted with one or more substituents independently selected from CH 3 , C

Assignees

• Celgene Corp

Inventors

• Alexander Matthew D
• Carranclo Soraya
• Correa Matthew D
• Grant Virginia Heather Sharron
• Hansen Joshua
• Harris Roy L
• Huang Dehua
• Kercher Timothy S
• Lopez-Girona Antonia
• Nagy Mark A
• Plantevin-Krenitsky Veronique

Classifications

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/04 Primary

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