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

1. A compound of formula I:

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;

or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

11. The compound of claim 1 of formula II:

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 X is a bond and 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 selected from N, 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, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkyl, amino-substituted-C 1-4 alkyl, —C(O)OR 10 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;

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 and amino-substituted 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 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 can be unsubstituted or substituted with 1 to 3 groups independently selected from amino, halo, hydroxy, amino-methyl and methyl-amino;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 of Formula IIa:

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 selected from N;

Y 2 is selected from CR 6 ;

Y 4 is 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 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 a group selected from amino, amino-methyl and methyl-amino;

R 9 is selected from halo, amino, hydroxy, N 3 , C 1-4 alkyl, halo-substituted-C 1-4 alkyl, —C(O)OR 10 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.

13. The compound of claim 12 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 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.

14. The compound of claim 13 , or the pharmaceutically acceptable salt thereof, selected from:

15. The compound of claim 12 in which R 7 and R 8 together with the carbon atom to which they are both attached form a 6 member saturated 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.

16. The compound of claim 15 , or the pharmaceutically acceptable salt thereof, wherein the compound is

17. The compound of claim 12 in which R 7 and R 8 together with the carbon atom to which they are both attached form a 4 member saturated 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.

18. The compound of claim 17 , or the pharmaceutically acceptable salt thereof, selected from:

19. The compound of claim 12 in which p and q are both 0; or the pharmaceutically acceptable salt thereof.

20. The compound of claim 19 , or the pharmaceutically acceptable salt thereof, wherein the compound is

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

22. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, selected from: