Compounds and compositions for inhibiting the activity of SHP2

Patent metadata

Field	Value
Publication number	US-11905283-B2
Application number	US-202017130374-A
Country	US
Kind code	B2
Filing date	Dec 22, 2020
Priority date	Jun 14, 2016
Publication date	Feb 20, 2024
Grant date	Feb 20, 2024

Abstract

The present invention relates to compounds of formula I:

in which Y 1 , Y 2 , R 1 , R 2 and R 3 are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.

First claim

The invention claimed is:

1. A compound of formula II:

in which:
R 1 is selected from:

R 2 and R 3 together with the nitrogen to which both R 2 and R 3 are attached form a ring selected from piperidinyl, piperazinyl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 8-azaspiro[4.5]decan-8-yl and pyrrolidinyl; wherein said pyrrolidinyl, piperazinyl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 8-azaspiro[4.5]decan-8-yl or piperidinyl is unsubstituted or substituted with 1 to 3 groups independently selected from amino, methyl, ethyl, amino-methyl, methyl-amino, hydroxyl, cyano, fluoro-methyl, fluoro and ((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)methyl;
R 4 is selected from hydroxyl, C 1-3 alkoxy and OC(O)C 1-3 alkyl;
R 5 is selected from H and methyl;
R 6 is selected from hydrogen, methyl and phenyl;
R 7 is selected from hydrogen, methyl, ethyl, phenyl and benzyl;
R 8 is selected from hydrogen and methyl;
Y 1 is selected from N and CH;
Y 2 is selected from N and CH;
Y 3 is selected from NH and CH 2 ;
Y 4 is selected from N and CH;
Y 5 is selected from N and CH; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 in which:
R 1 is selected from:

R 2 and R 3 together with the nitrogen to which both R 2 and R 3 are attached form a ring selected from piperidinyl, piperazinyl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 8-azaspiro[4.5]decan-8-yl and pyrrolidinyl; wherein said pyrrolidinyl, piperazinyl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 8-azaspiro[4.5]decan-8-yl or piperidinyl is unsubstituted or substituted with 1 to 3 groups independently selected from amino, methyl, ethyl, amino-methyl, methyl-amino, hydroxyl, cyano, fluoro-methyl, fluoro and ((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)methyl;
R 4 is selected from hydroxyl;
R 5 is selected from H and methyl;
R 6 is selected from hydrogen, methyl and phenyl;
R 7 is selected from hydrogen, methyl, ethyl, phenyl and benzyl;
R 8 is selected from hydrogen and methyl;
Y 1 is selected from N and CH;
Y 2 is selected from N and CH;
Y 3 is selected from NH and CH 2 ;
Y 4 is selected from N and CH;
Y 5 is selected from N and CH; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or the pharmaceutically acceptable salt thereof, in which:
R 1 is selected from:

R 4 is selected from hydroxyl;
R 5 is selected from H and methyl;
R 6 is selected from hydrogen, methyl and phenyl;
R 7 is selected from hydrogen, methyl, ethyl, phenyl and benzyl;
R 8 is selected from hydrogen and methyl;
Y 4 is selected from N and CH; and
Y 5 is selected from N and CH.

4. The compound of claim 3 , or the pharmaceutically acceptable salt thereof, wherein R 1 is

5. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, wherein R 2 and R 3 together with the nitrogen to which both R 2 and R 3 are attached form a piperidinyl ring, wherein said piperidinyl is unsubstituted or substituted with 1 to 3 groups independently selected from amino, methyl, ethyl, amino-methyl, methyl-amino, hydroxyl, cyano, fluoro-methyl, fluoro and ((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)methyl.

6. The compound of claim 3 , or the pharmaceutically acceptable salt thereof, selected from:

7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising a compound of claim 6 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Assignees

• Novartis Ag

Inventors

• Chen Zhuoliang
• Fortanet Jorge Garcia
• Karki Rajesh
• Lamarche Matthew J
• Majumdar Dyuti
• Perez Lawrence Blas
• Sendzik Martin
• Smith Troy Douglas
• Yang Fan
• Yu Bing

Classifications

• A61K31/4545 Primary

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D455/02

  containing not further condensed quinolizine ring systems · CPC title