Compounds and compositions for inhibiting the activity of SHP2

Patent metadata

Field	Value
Publication number	US-10934285-B2
Application number	US-201716309076-A
Country	US
Kind code	B2
Filing date	Jun 12, 2017
Priority date	Jun 14, 2016
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

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

We claim:

1. A compound selected from formula I and 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 of formula I:

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, selected from:

4. N-(3-((3-Amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)-2-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of claim 1 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

• C07D491/107

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

• C07D401/12

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

• C07D221/20

  Spiro-condensed ring systems · CPC title

• C07D207/38

  2-Pyrrolones · CPC title