PTPN11 inhibitors

1. A compound represented by Formula I

or a salt thereof, wherein:

subscript a is 0 or 1;

subscript b is 0 or 1;

Y 1 is a direct bond or CR 17 R 18 ;

Y 2 is selected from the group consisting of C 1-4 alkyl, amino, C 1-4 alkylC(O)O—, C 1-4 alkylamino and C 1-4 aminoalkyl;

R 1 is selected from the group consisting of C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, and a 5-10 membered heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 1 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 , and S(O) 2 R 14 ;

R 2 , R 3 , R 10 , and R 11 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 3-8 cycloalkyl;

R 4 , R 5 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl, halo, and C 1-4 alkylamino;

R 6 is selected from the group consisting of amino, C 1-4 aminoalkyl, and C 1-4 alkylamino;

R 7 is selected from the group consisting of hydrogen, amido, cyano, halo, and hydroxy, or is selected from the group consisting of C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which is optionally substituted with one to five groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino, and C 1-4 aminoalkyl;

or R 6 and R 7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring, having 0 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O) m ;

subscript m is 0, 1, or 2;

said saturated or unsaturated ring formed by R 6 and R 7 is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl;

any two groups of R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 and R 11 can form a 5 to 6 membered ring, having 0 to 2 heteroatoms as ring vertices elected from N, O and S;

any two groups of R 2 , R 4 , R 6 , R 8 and R 10 can form a direct bond, or a 1 or 2 atom carbon bridge;

R 13 is selected from the group consisting of hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl, —NH—NHR 19 , —OR 19 , —NHC(O)R 19 , —NHC(O)NHR 19 , —NHS(O) 2 NHR 19 , —NHS(O) 2 R 19 , —C(O)OR 19 , —C(O)NR 19 R 20 , —C(O)NH(CH 2 ) q OH, —C(O)NH(CH 2 )R 21 , —C(O)R 21 , —NH 2 , —OH, —S(O) 2 NR 19 R 20 , C 3-8 cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms as ring vertices selected from N, O, S and P, heteroaryl having 1-5 heteroatoms as ring vertices selected from N, O, S and P; wherein the subscript q is an integer of from 0 to 6; and wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from the group consisting of C 1-4 alkyl, —OH, —NH 2 , —OR 21 , halo, cyano, and oxo;

R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted by one or more groups independently selected from the group consisting of amido, amino, halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl;

R 17 and R 18 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, and CF 3 ;

R 19 and R 20 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; and

each R 21 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl.

2. The compound of claim 1 , wherein:

subscript a is 0 or 1;

subscript b is 0 or 1;

Y 1 is a direct bond or CR 17 R 18 ;

Y 2 is selected from the group consisting of C 1-4 alkyl, amino, C 1-4 alkylC(O)O—, C 1-4 alkylamino and C 1-4 aminoalkyl;

R 1 is selected from the group consisting of C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, and a 5-10 membered heteroaryl group having 1 to 4 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S; said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, cyano, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 14 , NR 15 C(O)OR 14 , NR 14 C(O)NR 15 R 16 , NR 15 S(O)R 14 , NR 15 S(O) 2 R 14 , C(O)NR 15 C R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 14 , C(O)OR 14 , OR 14 , SR 14 , S(O)R 14 , and S(O) 2 R 14 ,

R 2 , R 3 , R 10 , and R 11 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 3-8 cycloalkyl;

R 4 , R 5 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, cyano, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl, halo, and C 1-4 alkylamino;

R 6 is selected from the group consisting of amino, C 1-4 aminoalkyl, and C 1-4 alkylamino;

R 7 is selected from the group consisting of hydrogen, halo, and hydroxy, or is selected from the group consisting of amido, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which is optionally substituted with one to five groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, and C 1-4 aminoalkyl;

or R 6 and R 7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring, having 0 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O) m ;

subscript m is 0, 1, or 2;

said saturated ring formed by R 6 and R 7 is unsubstituted or substituted with 1 to 3 groups independently selected from the group consisting of amino, halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl;

any two groups of R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 and R 11 can form a 5 to 6 membered ring, having 0 to 2 heteroatoms as ring vertices selected from N, O and S;

any two groups of R 2 , R 4 , R 6 , R 8 and R 10 can form a direct bond, or a 1 or 2 atom carbon bridge;

R 13 is selected from the group consisting of hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 dihydroxyalkyl, —NH—NHR 19 , —NHR 19 , —OR 19 , —NHC(O)R 19 , —NHC(O)NHR 19 , —NHS(O) 2 NHR 19 , —NHS(O) 2 R 19 , —C(O)OR 19 , —C(O)NR 19 R 20 , —C(O)NH(CH 2 ) q OH, —C(O)NH(CH 2 ) q R 21 , —C(O)R 21 , —NH 2 , —OH, —S(O) 2 NR 19 R 20 , C 3-8 cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms as ring vertices selected from N, O, S and P, heteroaryl having 1-5 heteroatoms as ring vertices selected from N, O, S and P; wherein the subscript q is an integer of from 0 to 6; and wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from the group consisting of C 1-4 alkyl, —OH, —NH 2 , —OR 21 , halo, cyano, and oxo;

R 14 , R 15 and R 16 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, and C 1-4 alkyl;

R 17 and R 18 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, and CF 3 ;

R 19 and R 20 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl; and

each R 21 is independently selected from the group consisting of hydrogen, —OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl.

3. The compound of claim 1 , wherein subscripts a and b are each 1.

4. The compound of claim 1 , wherein Y 1 is a direct bond.

5. The compound of claim 1 , wherein Y 2 is C 1-4 alkyl.

6. The compound of claim 5 , wherein Y 2 is methyl.

7. The compound of claim 1 , wherein R 13 is selected from the group consisting of hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl.

8. The compound of claim 7 , wherein R 13 is hydrogen, Cl, Br, methyl, or CF 3 .

9. The compound of claim 1 , wherein

R 1 is phenyl or a 5- to 6-member heteroaryl group having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S; and is optionally substituted with 1, 2 or 3 R 12 groups independently selected from the group consisting of halo, hydroxy, amino, C 1-4 amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl, and OR 14 .

10. The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are hydrogen.

11. The compound of claim 1 , wherein:

R 6 is selected from the group consisting of amino, C 1-4 aminoalkyl, and C 1-4 alkylamino; and

R 7 is selected from the group consisting of hydrogen, amido, cyano, halo, and hydroxy, or is selected from the group consisting of C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which is optionally substituted with one or two groups selected from the group consisting of amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy.

12. The compound of claim 11 , wherein

R 6 is amino or aminomethyl; and

R 7 is selected from the group consisting of hydroxy, C 1-4 alkyl, and C 1-4 hydroxyalkyl.

13. The compound of claim 1 , wherein

R 6 and R 7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring having 1 to 3 heteroatoms or groups as ring vertices independently selected from N, C(O), O, and S(O) m , and that is optionally substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C 1-4 alkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

14. The compound of claim 13 , wherein

R 6 and R 7 together with the carbon atom to which they are both attached form a 4- to 6-membered saturated ring having 1 to 3 heteroatoms as ring vertices independently selected from N and O, and that is optionally substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C 1-4 alkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

15. The compound of claim 1 , wherein

R 6 and R 7 together with the carbon atom to which they are both attached form a 3- to 7-membered cycloalkyl ring that is optionally substituted with one or two groups independently selected from the group consisting of amino, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

16. The compound of claim 1 , wherein R 1 is phenyl or pyridyl, each of which is substituted with 1 to 3 R 12 independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl, and OR 14 .

17. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

each R 12 is independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 aminoalkyl, and OR 14 .

18. The compound of claim 17 , wherein R 1 is selected from the group consisting of:

19. The compound of claim 1 , wherein R 14 is selected from the group consisting of C 6-10 aryl and a 5-10 membered heteroaryl, each of which is optionally substituted by one or more groups independently selected from the group consisting of C 1-4 alkylamido, amino, halo, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylamino and C 1-4 aminoalkyl.

20. The compound of claim 1 , wherein R 1 is

each R 12 is independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl; and

R 14 is phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms as ring vertices independently selected from N, O, and S, each of which is optionally substituted by one or two groups independently selected from the group consisting of C 1-4 alkylamido, halo, hydroxy, cyano, and C 1-4 alkyl.

21. The compound of claim 1 , wherein each R 12 is independently selected from the group consisting of F, Cl, Br, CH 3 , OCH 3 , CF 3 ,

22. The compound of claim 1 , having a structure selected from the group consisting of:

23. A pharmaceutical composition comprising a compound of claim 1 , together with a pharmaceutically acceptable carrier.

24. A method of treatment of a PTPN11-mediated disease comprising the administration of a therapeutically effective amount of a compound of claim 1 , to a patient in need thereof, wherein the PTPN11-mediated disease is a Noonan Syndrome, LEOPARD Syndrome, or cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, esophageal cancer, gastric cancer, leukemia, and melanoma.