N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2

Patent metadata

Field	Value
Publication number	US-2018201623-A1
Application number	US-201815899821-A
Country	US
Kind code	A1
Filing date	Feb 20, 2018
Priority date	Jan 17, 2014
Publication date	Jul 19, 2018
Grant date	—

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 treatment comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, to a person in need of such treatment in an effective amount for the prophylactic or therapeutic treatment of a disease or disorder which is mediated by the activity of SHP2:

in which:
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 independently selected from halo, amino, hydroxy, N 3 , C 1-4 alkyl, C 1-4 alkoxy, 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, amino-carbonyl, 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;

and wherein the disease or disorder mediated by the activity of SHP2 is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous-cell carcinoma of the head and neck, gastric carcinoma, anaplastic large-cell lymphoma and glioblastoma.

2 . The method of claim 1 wherein the compound is a compound of Formula Ia:

in which:
n is selected from 1, 2, 3 and 4;
p is selected from 0 and 1;
q is selected from 0 and 1;
Y 1 is N;
Y 2 is CR 6 ;
each Y 4 is independently selected from N and CR 9 ;
R 6 is selected from hydrogen, halo, methyl and amino-carbonyl;
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 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 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 2 in which 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; or a pharmaceutically acceptable salt thereof.

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

5 . The method of claim 2 in which 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 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; or a pharmaceutically acceptable salt thereof.

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

7 . The method of claim 2 in which 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 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; or a pharmaceutically acceptable salt thereof.

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

9 . The method of claim 2 in which p and q are both 0; or the pharmaceutically acceptable salt thereof.

10 . The method of claim 9 , wherein the compound, or the pharmaceutically acceptable salt thereof, selected from:

11 . The method of claim 1 , wherein the compound is a compound of formula II:

in which:
p is selected from 0 and 1;

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D495/10

  Spiro-condensed systems · CPC title