Substituted isoindole allosteric EGFR inhibitors

Patent metadata

Field	Value
Publication number	US-11117890-B2
Application number	US-201916700900-A
Country	US
Kind code	B2
Filing date	Dec 2, 2019
Priority date	Jun 2, 2017
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

The present invention provides substituted isoindole compounds which are selective allosteric EGFR inhibitors, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances, generally of Formula:or a pharmaceutically acceptable salt thereof.

First claim

We claim:

1. A compound of formula I,

wherein
A is aryl or heteroaryl,
B is aryl or heteroaryl,
C is heteroaryl,
R 1 is each independently selected from the group consisting of
i) amino,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) cyano,
v) halogen,
vi) halogen-C 1-6 -alkyl,
vii) halogen-C 1-6 -alkoxy, and
viii) hydroxy;

R 2 is each independently selected from the group consisting of
i) —(CH 2 ) k —N(R 4 )(R 5 ),
ii) —(C═O)—N(R 4 )(R 5 ),
iii) halogen,
iv) —NH—(C═O)—C 1-6 -alkyl, and
v) C 1-6 -alkyl;

R 3 is each independently selected from the group consisting of
i) amino,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) cyano,
v) halogen,
vi) halogen-C 1-6 -alkyl,
vii) halogen-C 1-6 -alkoxy, and
viii) hydroxy;

R 4 is each independently selected from the group consisting of
i) H, and
ii) C 1-6 -alkyl;

R 5 is each independently selected from the group consisting of
i) H,
ii) C 1-6 -alkyl, and
iii) —(C═O)—C 1-6 -alkyl;

or R 4 and R 5 form together with the N they are attached to a heterocyclyl, which heterocyclyl is optionally substituted with R 6 ;
R 6 is each independently selected from the group consisting of
i) —OH,
ii) C 1-6 -alkyl, and
iii) —(C═O)—C 1-6 -alkyl;

k is 0, 1 or 2,
n is 0, 1, 2 or 3;
m is 0, 1 or 2; and
p is 0 or 1;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:
A is aryl or heteroaryl,
B is aryl or heteroaryl,
C is heteroaryl,
R 1 is each independently selected from the group consisting of
i) amino,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) cyano,
v) halogen,
vi) halogen-C 1-6 -alkyl,
vii) halogen-C 1-6 -alkoxy, and
viii) hydroxy;

R 2 is each independently selected from the group consisting of
i) —(CH 2 ) k —N(R 4 )(R 5 ),
ii) —(C═O)—N(R 4 )(R 5 ),
iii) —NH—(C═O)—C 1-6 -alkyl, and
iv) C 1-6 -alkyl;

R 3 is each independently selected from the group consisting of
i) amino,
ii) C 1-6 -alkyl,
iii) C 1-6 -alkoxy,
iv) cyano,
v) halogen,
vi) halogen-C 1-6 -alkyl,
vii) halogen-C 1-6 -alkoxy, and
viii) hydroxy;

R 4 is each independently selected from the group consisting of
i) H, and
ii) C 1-6 -alkyl;

R 5 is each independently selected from the group consisting of
i) H,
ii) C 1-6 -alkyl, and
iii) —(C═O)—C 1-6 -alkyl;

or R 4 and R 5 form together with the N they are attached to a heterocyclyl;
k is 0, 1 or 2;
n is 0, 1, 2 or 3;
m is 0, 1 or 2; and
p is 0 or 1.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is aryl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is aryl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is phenyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is heteroaryl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is pyridinyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein C is thiazolyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 2.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is: —(C═O)-morpholinyl, —(C═O)N(H)(CH 3 ), —CH 2 -(4-methylpiperazinyl), —CH 2 -(4-acetylpiperazinyl), —CH 2 -(4-ethylpiperazinyl), —CH 2 -(4-hydroxy-piperidyl), —CH 2 -(morpholinyl), —CH 2 NH 2 , —CH 2 -piperazinyl, Cl, —N(H)(C═OCH 3 ), or —NH 2 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(2RS)-2-(5-Fluoro-2-hydroxy-phenyl)-2-[1-oxo-6-(2-phenylethynyl)isoindolin-2-yl]-N-thiazol-2-yl-acetamide,
(2RS)-2-(5-Fluoro-2-hydroxy-phenyl)-2-[1-oxo-6-[2-(3-pyridyl)ethynyl]isoindolin-2-yl]-N-thiazol-2-yl-acetamide,
(2RS)-2-(5-Fluoro-2-hydroxy-phenyl)-2-[1-oxo-6-[2-[4-(piperazin-1-ylmethyl)phenyl]ethynyl]isoindolin-2-yl]-N-thiazol-2-yl-acetamide,
(2RS)-2-(5-Fluoro-2-hydroxy-phenyl)-2-[6-[2-[4-(morpholinomethyl)phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide,
(2RS)-2-(5-Fluoro-2-hydroxy-phenyl)-2-[6-[2-[4-[(4-hydroxy-1-piperidyl)methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide,
(2RS)-2-(5-Fluoro-2-hydroxy-phenyl)-2-[6-[2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-N-thiazol-2-yl-acetamide,
(2RS)-2-(5-Fluoro-2-hydroxy-phenyl)-2-[7-fluoro-1-oxo-6-[2-(3-pyridyl)ethynyl]isoindolin-2-yl]-N-thiazol-2-yl-acetamide,
(2RS)-2-[1-Oxo-6-(2-phenylethynyl)isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[1-oxo-6-[2-(3-pyridyl)ethynyl]isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[1-Oxo-6-[2-[4-(piperazin-1-ylmethyl)phenyl]ethynyl]isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(2-Aminopyrimidin-5-yl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(5-fluoro-2-hydroxy-phenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(2-Chloro-4-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(5-fluoro-2-hydroxy-phenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Acetamido-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(3-fluorophenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(2,5-difluorophenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(5-fluoro-2-hydroxy-phenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(5-fluoro-2-hydroxy-phenyl)-N-(2-pyridyl)acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(5-chloro-2-hydroxy-phenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(2-hydroxyphenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-1-oxo-isoindolin-2-yl]-2-(3-hydroxy-2-pyridyl)-N-thiazol-2-yl-acetamide trifluoroacetate,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-7-methyl-1-oxo-isoindolin-2-yl]-2-(5-fluoro-2-hydroxy-phenyl)-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-(6-Amino-3-pyridyl)ethynyl]-7-methyl-1-oxo-isoindolin-2-yl]-2-(5-fluoro-2-hydroxy-phenyl)-N-(2-pyridyl)acetamide,
(2RS)-2-[6-[2-[4-(Aminomethyl)phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-[4-(Morpholinomethyl)phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-[4-[(4-acetylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-[4-[(4-Ethylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-yl]-2-phenyl-N-thiazol-2-yl-acetamide,
(2RS)-2-[6-[2-[4-[(4-Ethylpiperazin-1-yl)methyl]phenyl]ethynyl]-1-oxo-isoindolin-2-y

Assignees

• Hoffmann La Roche

Inventors

• Jaeschke Georg
• Ricci Antonio
• Rueher Daniel
• Steiner Sandra
• Duplessis Martin
• Nagel Yvonne Alice
• Kuhn Bernd

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title