N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2

Patent metadata

Field	Value
Publication number	US-12209098-B2
Application number	US-202117182744-A
Country	US
Kind code	B2
Filing date	Feb 23, 2021
Priority date	Jan 17, 2014
Publication date	Jan 28, 2025
Grant date	Jan 28, 2025

Abstract

The present invention relates to compounds of formula I:

in which p, q, Y 1 , Y 2 , R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 7 and R 8 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 method of treating a patient having a disease or disorder associated with receptor tyrosine kinase (RTK) alterations wherein SHP2 acts as a positive regulator, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula I:

wherein:
p is selected from 0 and 1;
q is selected from 0 and 1;
Y 1 is N;
Y 2 is CR 6 ;
R 1 is —XR 1a ; wherein R 1a is selected from C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl and a 5-9 member heteroaryl group containing from 1 to 4 heteroatoms or groups independently selected from N, C(O), O and S; wherein said aryl or heteroaryl of R 1a is substituted with 1 to 5 R 9 groups each independently selected from halo, amino, hydroxy, N 3 , C 1-4 alkoxy, C 1-4 alkyl, dimethyl-amino, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkyl, amino-substituted-C 1-4 alkyl, —C(O)OR 10 , —C(O)NH 2 , and —NHC(O)R 10 ; wherein R 10 is selected from hydrogen, phenyl, and naphthyl; wherein said phenyl of R 10 is unsubstituted or substituted with methoxy; and X is selected from a bond, S(O) m , O, C(O), CR 10a R 10b , NR 11 ; wherein m is selected from 0, 1 and 2; each R 10a and R 10b is independently selected from halo and C 1-4 alkyl; and R 11 is selected from hydrogen and C 1-4 alkyl;
R 2a and R 2b are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino;
R 3a and R 3b are independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino;
R 4a and R 4b are independently selected from hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino;
R 5a and R 5b are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino;
R 6 is selected from hydrogen, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkoxy, hydroxy-substituted C 1-4 alkyl, amino-substituted C 1-4 alkyl, —S(O) 1-2 R 6a , —C(S)R 6a , —C(O)NR 6a R 6b , —C(NH)NR 6a R 6b and —NR 6a C(O)R 6b ; wherein R 6a and R 6b are independently selected from hydrogen and C 1-4 alkyl;
R 7 and R 8 together with the carbon atom to which they are both attached form a 3 to 7 member saturated or partially unsaturated ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from N, C(O), O and S(O) m ; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7 and R 8 can be unsubstituted or substituted with 1 to 3 groups independently selected from amino, hydroxy, methoxy, halo, methyl, amino-methyl, methyl-amino and isobutyryloxy; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the compound has a structure according to Formula Ia:

wherein:
n is selected from 1, 2, and 3;
p is selected from 0 and 1;
q is selected from 0 and 1;
Y 1 is N;
Y 2 is CR 6 ;
Y 4 is independently selected from N and CR 9 ;
R 6 is selected from hydrogen, halo, and methyl;
R 7 and R 8 together with the carbon atom to which they are both attached form a 3 to 7 member saturated or partially unsaturated ring that can optionally contain a heteroatom or group selected from N, C(O), O and S(O) m ; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7 and R 8 can be unsubstituted or substituted with 1 to 3 groups independently selected from amino, halo, hydroxy, methyl, methoxy, amino-methyl, methyl-amino, and isobutyryloxy;
R 9 is selected from halo, amino, hydroxy, N 3 , dimethyl-amino, C 1-4 alkyl, halo-substituted-C 1-4 alkyl, C 1-4 alkoxy, —C(O)OR 10 , —C(O)NH 2 , and —NHC(O)R 10 ;
R 10 is selected from hydrogen, phenyl and naphthyl; wherein said phenyl of R 10 is unsubstituted or substituted with methoxy; or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein R 7 and R 8 together with the carbon atom to which they are both attached form a 5 member saturated or partially unsaturated ring that can optionally contain 1 to 2 heteroatoms or groups independently selected from N, O, C(O) and S(O) m ; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7 and R 8 is substituted with 1 to 3 groups independently selected from amino, hydroxy, methoxy, halo, methyl, methyl-amino and isobutyryloxy.

4. The method of claim 3 , wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from:

5. The method of claim 2 , wherein R 7 and R 8 together with the carbon atom to which they are both attached form a 6 member saturated or partially unsaturated ring that can optionally contain a heteroatom or group selected from N, O and S(O) m ; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7 and R 8 is substituted with amino.

6. The method of claim 5 , wherein the compound, or the pharmaceutically acceptable salt thereof, is:

7. The method of claim 2 , wherein R 7 and R 8 together with the carbon atom to which they are both attached form a 4 member saturated or partially unsaturated ring that can optionally contain a heteroatom or group selected from N, O and S(O) m ; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7 and R 8 is substituted with a group selected from amino, amino-methyl and methyl-amino.

8. The method of claim 7 , wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from:

9.

Assignees

• Novartis Ag

Inventors

• Chen Christine Hiu-Tung
• Chen Zhuoliang
• Dore Michael
• Fortanet Jorge Garcia
• Giraldes John William
• Karki Rajesh
• Kato Mitsunori
• Lamarche Matthew J
• Perez Lawrence Blas
• Sendzik Martin
• Smith Troy Douglas
• Toure Bakary-Barry
• Williams Sarah

Classifications

• C07D495/10

  Spiro-condensed systems · CPC title

• C07D491/107

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

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D403/04

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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title