Compounds and compositions for inhibiting the activity of SHP2

1. A compound of formula I:

in which:

Y 1 is selected from N and CR 7 ; wherein R 7 is selected from hydrogen, halo and amino;

Y 2 is selected from N and CR 8 ; wherein R 8 is selected from hydrogen, halo, C 1-4 alkyl, halo-substituted-C 1-2 alkyl, halo-substituted-C 1-2 alkoxy and amino;

Y 3 is selected from N, CR 9 and C(O); wherein R 9 is selected from hydrogen, amino, cyano, halo, C 1-2 alkoxy, halo-substituted-C 1-2 alkyl, halo-substituted-sulfanyl, C 1-3 alkyl, cyclopropyl, cyclopropyl-carbonyl-amino, C 1-2 alkyl-carbonyl-amino, morpholino-methyl and hydroxy;

wherein if Y 3 is C(O), Y 2 is selected from NH and —N—C 1-4 alkyl and the ring containing Y 1 , Y 2 and Y 3 has no more than 2 double bonds;

R 1 is selected from hydrogen, halo, halo-substituted-C 1-2 alkyl, halo-substituted-C 1-2 alkoxy, hydroxy-substituted-C 1-2 alkyl, C 1-4 alkyl, C 1-4 alkoxy, amino and cyano; or R 1 and R 9 together with the carbon atoms to which R 1 and R 9 are attached form cyclopentene or 1,3-dioxole, 2,3-dihydrofuran;

R 2 is selected from hydrogen, C 1-4 alkyl and fluoro;

R 4a and R 4b are each independently selected from hydrogen, hydroxy and fluoro; with proviso that R 4a and R 4b cannot both be OH; with the proviso that R 4a and R 4b cannot be OH and F simultaneously;

R 5a is selected from amino and amino-methyl;

R 5b is selected from OH, amino, fluoro, C 1-6 alkyl, methoxy-carbonyl, C 3-6 cycloalkyl-C 1-3 alkyl, hydroxy-substituted C 1-3 alkyl, C 1-2 alkoxy-substituted C 1-3 alkyl and a 5 to 6 member heteroaryl ring containing 1 to 4 heteroatoms selected from O, S and N; wherein said C 1-6 alkyl or C 1-2 alkoxy-substituted C 1-3 alkyl of R 5b is unsubstituted or substituted with 1-3 fluorines; with the proviso that if R 5a is amino, R 5b cannot be OH, amino or fluoro; or R 5a and R 5b , together with the carbon atom to which R 5a and R 5b are attached, form a group selected from:

wherein *C represents the carbon atom to which R 5a and R 5b are attached; R 10 is amino; R 11a is selected from hydrogen, hydroxy, fluoro, C 1-3 alkyl, halo-substituted-C 1-2 alkyl and hydroxy-methyl; R 11b is selected from fluoro, methyl and hydrogen; with the proviso that when R 11a is hydroxyl, R 11b is not fluoro; R 11c is selected from hydrogen, C 1-3 alkyl and hydroxy-methyl; R 12 is selected from hydrogen, halo, hydroxy, C 1-3 alkyl, halo-substituted-C 1-3 alkyl, halo-substituted-C 1-3 alkoxy and C 1-3 alkoxy; R 13 is selected from hydrogen, halo and C 1-2 alkyl; with the proviso that when R 12 is hydroxy, R 13 is not fluoro; R 14 is selected from hydrogen and fluoro; R 15 is selected from hydrogen and fluoro; and

R 6a and R 6b are each independently selected from hydrogen, hydroxy and fluoro; with proviso that R 6a and R 6b cannot both be OH and fluoro simultaneously; or the pharmaceutically acceptable salts thereof; with the proviso that compounds of formula I do not include a compound selected from: (R)-8-(5-((2-(tert-butyl)phenyl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine; (R)-8-(5-((2-(trifluoromethyl)phenyl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine; (R)-8-(5-((2-aminophenyl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine; (R)-8-(5-((2,3,5,6-tetrafluorophenyl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine; (R)-8-(5-(pyridin-3-ylthio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine; (R)-8-(5-((3-(trifluoromethoxy)phenyl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine; (S)-8-(5-((2-(tert-butyl)phenyl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine; and (S)-8-(5-((4-(tert-butyl)phenyl)thio)pyrazin-2-yl)-8-azaspiro[4.5]decan-1-amine.

2. The compound of claim 1 of formula Ia:

in which:

R 1 is selected from hydrogen, halo, halo-substituted-C 1-2 alkyl, halo-substituted-C 1-2 alkoxy, C 1-4 alkoxy, amino and cyano;

R 4 is selected from hydrogen, hydroxy and fluoro;

R 7 is selected from hydrogen, halo and amino;

R 9 is selected from hydrogen, methyl, methoxy, ethoxy, hydroxy, hydroxy-methyl, trifluoro-methyl, cyclopropyl, morpholino-methyl, cyano, methyl-carbonyl-amino, cyclopropyl-carbonyl-amino, pentafluoro-λ 6 -sulfanyl, amino and halo; or R 1 and R 9 together with the carbon atoms to which R 1 and R 9 are attached form cyclopentene;

R 10 is amino;

R 11a is selected from hydrogen, fluoro, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy and hydroxy-methyl;

R 11b is selected from fluoro and hydrogen; with the proviso that when R 11a is hydroxyl, R 11b is not fluoro;

R 12 is selected from hydrogen, halo, hydroxy, C 1-3 alkyl, halo-substituted-C 1-3 alkyl, halo-substituted-C 1-3 alkoxy and C 1-3 alkoxy;

R 13 is selected from hydrogen, fluoro and C 1-2 alkyl; with the proviso that when R 12 is hydroxy, R 13 is not fluoro;

R 14 is selected from hydrogen and fluoro;

R 15 is selected from hydrogen and fluoro; and

Y 2 is selected from N and CR 8 ; wherein R 8 is selected from hydrogen, halo, C 1-4 alkyl, halo-substituted-C 1-2 alkyl, halo-substituted-C 1-2 alkoxy and amino; or the pharmaceutically acceptable salts thereof.

3. The compound of claim 2 in which:

R 1 is selected from hydrogen, bromo, chloro, fluoro, methyl, isopropyl, t-butyl, fluoro-substituted methyl, methoxy, trifluoro-methyl, trifluoromethoxy, amino and cyano;

R 4 is selected from hydrogen and hydroxy;

R 7 is selected from hydrogen, fluoro, chloro and amino;

R 9 is selected from hydrogen, methyl, methoxy, ethoxy, hydroxy, hydroxy-methyl, cyclopropyl, amino, trifluoromethyl, morpholino-methyl, cyclopropyl-carbonyl-amino, methyl-carbonyl-amino, pentafluoro-λ 6 -sulfanyl, cyano, bromo, chloro and fluoro; or R 1 and R 9 together with the carbon atoms to which R 1 and R 9 are attached form cyclopentene;

R 10 is amino;

R 11a is selected from hydrogen, hydroxy, methyl and hydroxy-methyl;

R 11b is selected from fluoro and hydrogen; with the proviso that when R 11a is hydroxyl, R 11b is not fluoro;

R 12 is selected from hydrogen, fluoro, hydroxy, methyl and methoxy; and

R 13 is selected from hydrogen, fluoro and methyl; with the proviso that when R 12 is hydroxy, R 13 is not fluoro; and

Y 2 is selected from CR 8 and N; wherein R 8 is selected from hydrogen, chloro, fluoro, ethyl, trifluoromethyl, trifluoromethoxy and t-butyl; or the pharmaceutically acceptable salts thereof.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, selected from:

5. The compound of claim 1 of formula Ib:

in which:

R 1 is selected from hydrogen, halo, halo-substituted-C 1-2 alkyl, C 1-2 alkyl and cyano;

R 4 is selected from hydrogen, fluoro and hydroxy;

R 7 is selected from hydrogen, halo and amino;

R 9 is selected from hydrogen, methyl, methoxy, ethoxy, hydroxy, hydroxy-methyl, trifluoro-methyl, cyclopropyl, morpholino-methyl, cyano, methyl-carbonyl-amino, cyclopropyl-carbonyl-amino, pentafluoro-λ 6 -sulfanyl, amino and halo;

R 10 is amino;

R 11c is selected from hydrogen, ethyl, isopropyl, hydroxy-methyl and methyl;

Y 2 is selected from CR 8 and N; wherein R 8 is selected from hydrogen, chloro, fluoro, ethyl, trifluoromethyl, trifluoromethoxy and t-butyl; or the pharmaceutically acceptable salts thereof.

6. The compound of claim 5 in which:

R 1 is selected from hydrogen, chloro, fluoro, methyl, fluoro-substituted methyl and cyano;

R 4 is selected from hydrogen;

R 7 is selected from hydrogen, fluoro, chloro and amino;

R 9 is selected from hydrogen, amino, hydroxy, trifluoromethyl, methyl-carbonyl, hydroxy-methyl, chloro and fluoro;

R 10 is amino;

R 11c is selected from hydrogen, ethyl, isopropyl, hydroxy-methyl and methyl;

Y 2 is selected from CR 8 and N; wherein R 8 is selected from hydrogen, chloro, fluoro, ethyl, trifluoromethyl, trifluoromethoxy and t-butyl; or the pharmaceutically acceptable salts thereof.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, selected from:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:

9. The compound of claim 1 of formula Ic:

in which:

Y 2 is selected from N and CR 8 ; wherein R 8 is selected from hydrogen and amino;

Y 3 is selected from N and CR 9 ; wherein R 9 is selected from hydrogen, methyl, methoxy, ethoxy, hydroxy, hydroxy-methyl, trifluoro-methyl, cyclopropyl, morpholino-methyl, cyano, methyl-carbonyl-amino, cyclopropyl-carbonyl-amino, pentafluoro-λ 6 -sulfanyl, amino and halo;

R 1 is selected from halo, halo-substituted-C 1-2 alkyl, C 1-2 alkyl and cyano;

R 2 is hydrogen;

R 4 is selected from hydrogen, hydroxy and fluoro;

R 5a is selected from amino and amino-methyl;

R 5b is selected from OH, amino, fluoro, C 1-6 alkyl, methoxy-carbonyl, C 3-6 cycloalkyl-C 1-3 alkyl, hydroxy-substituted C 1-3 alkyl, C 1-2 alkoxy-substituted C 1-3 alkyl and a 5 to 6 member heteroaryl ring containing 1 to 4 heteroatoms selected from O, S and N; wherein said C 1-6 alkyl or C 1-2 alkoxy-substituted C 1-3 alkyl of R 5b is unsubstituted or substituted with 1-3 fluorines; with the proviso that if R 5a is amino, R 5b cannot simultaneously be OH, amino or fluoro;

R 7 is selected from hydrogen, halo and amino; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 in which:

Y 2 is selected from N and CR 8 ; wherein R 8 is selected from hydrogen and amino;

Y 3 is selected from N and CR 9 ; wherein R 9 is selected from hydrogen, amino, halo and hydroxy;

R 1 is selected from halo, halo-substituted-C 1-2 alkyl and cyano;

R 2 is selected from hydrogen and halo;

R 4 is selected from hydrogen and hydroxy;

R 5a is selected from amino and amino-methyl;

R 5b is selected from OH, methyl, ethyl, propyl, isopropyl, isobutyl, amino, amino-methyl, methoxy-carbonyl, pyridinyl and hydroxy-methyl; with the proviso that if R 5a is amino, R 5b cannot be OH, amino or fluoro;

R 7 is selected from hydrogen, halo and amino; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, selected from:

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

13. A method of therapeutic treatment comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a person in need of such treatment in an effective amount for the therapeutic treatment of a disease or disorder which is mediated by the activity of SHP2 selected from Noonan Syndrome and Leopard Syndrome.